Category: 8. Health

  • Scientists grow a mini human brain that connects, glows, and thinks like the real thing

    Scientists grow a mini human brain that connects, glows, and thinks like the real thing

    Image: © Alexander Sikov | iStock

    Johns Hopkins researchers have grown a multi-region human brain organoid with rudimentary blood vessels and connected neural circuits that mimic fetal brain development

    In a significant leap for neuroscience, researchers at Johns Hopkins have grown a miniature human brain in the lab that mimics key features of real brain development. This multi-region organoid not only forms functional neural connections but also glows as it transmits signals, offering a powerful new model for studying conditions like autism, schizophrenia, and Alzheimer’s disease.

    “We’ve made the next generation of brain organoids,” said lead author Annie Kathuria, an assistant professor in JHU’s Department of Biomedical Engineering who studies brain development and neuropsychiatric disorders. “Most brain organoids that you see in papers are one brain region, like the cortex, the hindbrain or the midbrain. We’ve grown a rudimentary whole-brain organoid; we call it the multi-region brain organoid (MRBO).”

    The findings are detailed in Advanced Science.

    A world-first for scientists

    The research marks one of the first times scientists have generated an organoid with tissues from each region of the brain connected and acting in concert.

    To create a whole-brain organoid, Kathuria and her team first grew neural cells from the separate regions of the brain and rudimentary forms of blood vessels in separate lab dishes. The researchers then stuck the individual parts together with sticky proteins that act as a biological superglue and allowed the tissues to form connections. As the tissues began to grow together, they started producing electrical activity and responding as a network.

    The multi-region mini brain organoid retained a broad range of types of neuronal cells, with characteristics resembling a brain in a 40-day-old human fetus. Some 80% of the range of the kinds of cells commonly seen at the early stages of human brain development was equally expressed in the laboratory-crafted miniaturised brains. Much smaller compared to a real brain, weighing in at 6 million to 7 million neurons compared with tens of billions in adult brains, these organoids provide a unique platform on which to study whole-brain development.

    The researchers saw the creation of an early blood-brain barrier formation, which is the layer of cells surrounding the brain that controls which molecules can pass through.

    “We need to study models with human cells if you want to understand neurodevelopmental disorders or neuropsychiatric disorders, but I can’t ask a person to let me take a peek at their brain just to study autism,” Kathuria said. “Whole-brain organoids let us watch disorders develop in real time, see if treatments work, and even tailor therapies to individual patients.”

    New targets for drug screening

    Whole-brain organoids could be a beacon of hope in drug development, potentially improving the success rate of clinical trials and saving money. This is vital as around 85% to 90% of drugs fail during Phase 1 clinical trials. For neuropsychiatric drugs, the failure rate is closer to 96%. The failure rate is high as scientists mostly use animal models during the early stages of drug development, which, unlike whole-brain organoids, do not closely resemble the natural development of the human brain.

    “Diseases such as schizophrenia, autism, and Alzheimer’s affect the whole brain, not just one part of the brain. If you can understand what goes wrong early in development, we may be able to find new targets for drug screening,” Kathuria said. “We can test new drugs or treatments on the organoids and determine whether they’re having an impact on the organoids.”

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  • Flu Treatment in Children: Study Confirms Safety of Tamiflu

    Flu Treatment in Children: Study Confirms Safety of Tamiflu


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    For decades, medical professionals debated whether a common antiviral medication used to treat flu in children caused neuropsychiatric events or if the infection itself was the culprit.

    Now researchers at Monroe Carell Jr. Children’s Hospital at Vanderbilt have debunked a long-standing theory about oseltamivir, known as Tamiflu.

    According to the study, published in JAMA Neurology, oseltamivir treatment during flu episodes was associated with a reduced risk of serious neuropsychiatric events, such as seizures, altered mental status and hallucination.

    “Our findings demonstrated what many pediatricians have long suspected, that the flu, not the flu treatment, is associated with neuropsychiatric events,” said principal investigator James Antoon, MD, PhD, MPH, assistant professor of Pediatrics in the Division of Pediatric Hospital Medicine at Monroe Carell. “In fact, oseltamivir treatment seems to prevent neuropsychiatric events rather than cause them.”

    Key points:

    • Influenza itself was associated with an increase in neuropsychiatric events compared to children with no influenza, regardless of oseltamivir use.
    • Among children with influenza, those treated with oseltamivir had about 50% reduction in neuropsychiatric events.
    • Among children without influenza, those who were treated with oseltamivir prophylactically had the same rate of events as the baseline group with no influenza.

    “Taken together, these three findings do not support the theory that oseltamivir increases the risk of neuropsychiatric events,” said Antoon. “It’s the influenza.”

    The team reviewed the de-identified data from a cohort of children and adolescents ages 5-17 who were enrolled in Tennessee Medicaid between July 1, 2016, and June 30, 2020.

    During the four-year period, 692,295 children, with a median age of 11 years, were included in the study cohort. During follow-up, study children experienced 1,230 serious neuropsychiatric events (898 neurologic and 332 psychiatric).

    The clinical outcomes definition included both neurologic (seizures, encephalitis, altered mental status, ataxia/movement disorders, vision changes, dizziness, headache, sleeping disorders) and psychiatric (suicidal or self-harm behaviors, mood disorders, psychosis/hallucination) events.

    “The 2024-2025 influenza season highlighted the severity of influenza-associated neurologic complications, with many centers reporting increased frequency and severity of neurologic events during the most recent season,” said Antoon. “It is important for patients and families to know the true risk-benefit profile of flu treatments, such as oseltamivir, that are recommended by the American Academy of Pediatrics.”

    “These flu treatments are safe and effective, especially when used early in the course of clinical disease,” added senior author Carlos Grijalva, MD, MPH, professor of Health Policy and Biomedical Informatics at Vanderbilt University Medical Center.

    Investigators hope the findings will provide reassurance to both caregivers and medical professionals about the safety of oseltamivir and its role in preventing flu-associated complications.

    Reference: Antoon JW, Williams DJ, Bruce J, Sekmen M, Zhu Y, Grijalva CG. Influenza with and without oseltamivir treatment and neuropsychiatric events among children and adolescents. JAMA Neurol. 2025. doi: 10.1001/jamaneurol.2025.1995

    This article has been republished from the following materials. Note: material may have been edited for length and content. For further information, please contact the cited source. Our press release publishing policy can be accessed here.

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  • Fecal transplant may cut infections in long-term care patients

    Fecal transplant may cut infections in long-term care patients

    Doctors tested fecal transplants from donor gut bacteria in frail hospital patients. Could this be the next tool to fight deadly drug-resistant infections?

    Study: Microbiota Transplantation Among Patients Receiving Long-Term Care. Image credit: 3dMediSphere/Shutterstock.com

    A non-randomized clinical trial examining the safety and acceptability of fecal microbiota transplantation in long-term acute care hospital patients revealed that the intervention is safe and well-tolerated. A detailed trial report is published in JAMA Network Open. This could potentially reduce some infection-related outcomes, although in this pilot study, all recipients remained colonized with at least one multidrug-resistant organism (MDRO) at follow-up.

    Background

    Multidrug-resistant microbial colonization in the intestine is associated with an increased risk of systemic infection and transmission, particularly in patients receiving long-term care in hospitals while recovering from critical illnesses. However, the U.S. Food and Drug Administration (FDA) has not approved effective interventions to manage these conditions.

    Emerging evidence indicates that microbiome interventions, such as fecal microbiota transplantation, are being investigated for their potential to reduce infection risk, antibiotic treatment duration, and hospital stay in patients with intestinal multidrug-resistant microbial colonization. However, results have been mixed across different settings and patient populations, and some prior evidence comes from indirect findings or from groups not exclusively colonized with MDROs.

    In this single-center nonrandomized clinical trial, researchers investigated the safety and acceptability of fecal microbiota transplantation in long-term acute care hospital patients.

    Trial design

    The trial enrolled 42 patients with intestinal multidrug-resistant microbial colonization from a long-term acute care hospital in Atlanta, Georgia.

    Of enrolled patients, 10 received fecal microbiota from healthy donors via gastrostomy tube or enema without antibiotic or bowel preparation conditioning. The remaining 32 patients were the control group and did not receive fecal microbiota transplantation.  

    The frequency and severity of adverse events related to fecal microbiota transplantation were assessed and compared with those of the control group. The proportion of patients with positive MDRO stool culture results after six months of transplantation was also evaluated.

    Trial findings

    The safety assessment at the six-month follow-up revealed that fecal microbiota transplantation is not associated with any severe adverse events. Adverse events reported after the transplantation were generally mild.

    The most noticeable non-severe adversity in one patient was vomiting after administration of the fecal microbiota via gastrostomy tube. Two patients died after the transplantation; however, the deaths were not related to the transplantation, but instead were associated with the medical complexities of the patients.  

    The assessment of intestinal microbial colonization revealed that patients with fecal microbiota transplantation have fewer episodes of systemic bacterial infection, decreased pathogen intestinal dominance, and fewer days of antibiotic therapy than control patients. Still, these findings were exploratory, based on post hoc analyses, and not statistically significant.

    Compared to 19% of control patients, none of the fecal microbiota transplantation recipients had positive blood cultures six months after the treatment, though this difference did not reach statistical significance.

    Despite these trends, all fecal microbiota transplantation recipients remained positive for at least one MDRO in perirectal cultures at follow-up, and 60% acquired a new MDRO category during the study.

    Significance

    The trial findings indicate that healthy donor-derived fecal microbiota administered via gastrostomy or enema instillation is well tolerated and safe for long-term acute care hospital patients with intestinal multidrug-resistant microbial colonization.

    The trial also suggests that fecal microbiota transplantation can potentially reduce systemic bacterial infection, intestinal pathogen domination, and antibiotic use in this high-risk population. However, the small sample size and study design limit definitive conclusions about efficacy.

    MDRO intestinal colonization increases the risk of systemic and urinary tract infection. Existing evidence highlights the significance of fecal microbiota transplantation in reducing mortality, systemic infection, and health care utilization, even among patients with persistent multidrug-resistant microorganism-positive culture results. This study also observed increased gut microbial diversity among fecal microbiota transplantation recipients, suggesting a possible microbiome shift despite persistent colonization.

    The current trial highlights the acceptability, safety, and potential efficacy of a single fecal microbiota transplantation. These pilot findings highlight the need for further large-scale clinical trials to explore whether increased doses, more frequent dosing, or conditioning regimens with antibiotics or laxatives can more effectively prevent microbial colonization in the intestine.

    Given the current unavailability of FDA-approved therapies, optimizing microbiota conditioning and dosing strategies would be particularly beneficial for long-term acute care hospitals and other health care facilities that treat patients with a high prevalence of intestinal multidrug-resistant microbial colonization.

    Patients were not randomly assigned to the intervention and control groups in this trial, and the treatment was not concealed. Future trials should consider these factors for a more conclusive interpretation.

    The trial measured treatment-related outcomes using qualitative culture methods, with positive or negative results. Therefore, it could not provide information on potential quantitative reductions in pathogen density following fecal microbiota transplantation.

    Long-term acute care hospital patients are at a higher risk of mortality from various medical complications and require frequent empirical antibiotic treatments. Moreover, the burden of colonized patients, particularly with multidrug-resistant bacteria, in a hospital unit further increases the risk of acquisition of new microbial colonization after fecal microbiota transplantation. These competing risks may bias clinical outcomes associated with the intervention.

    The progression from colonization to infection is relatively rare in many populations, making this a challenging endpoint. Studying interventions in patients with a higher colonization prevalence and colonization to infection progression increases the efficiency of measuring these critical endpoints, but also potentially increases the frequency of competing risks with many safety and efficacy outcomes.

    As the researchers stated, these limitations are offset by the demonstration of the feasibility of screening for microbiome interventions with facility-wide prevalence sampling followed by targeted treatment.

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  • Triple Serosal Involvement in End-Stage Renal Disease (ESRD): A Case of Atypical Uremic Polyserositis With Elevated Serum-Ascites Albumin Gradient and Alkaline Phosphatase

    Triple Serosal Involvement in End-Stage Renal Disease (ESRD): A Case of Atypical Uremic Polyserositis With Elevated Serum-Ascites Albumin Gradient and Alkaline Phosphatase


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  • WHO SEARO Hosts High-Level Webinar Amid Rising H5 Threats.

    WHO SEARO Hosts High-Level Webinar Amid Rising H5 Threats.

    New Delhi, 25th July 2025 – In response to the increasing detection of avian influenza A(H5) cases in humans globally and across the South-East Asia Region, WHO Regional Office for South -East Asia (SEARO)  convened a regional webinar to review preparedness mechanisms, strengthen Surveillance pathways, and promote timely reporting of unusual respiratory events.

    The virtual webinar brought together more than 50 participants from Ministries of Health, National Influenza Centres (NICs),National  Focal Points(NFP)  of  International Health Regulation (IHR)  in WHO South-East Asia Region (SEAR) , WHO Headquarters, WHO  Country Offices in SEAR , and WHO Collaborating Centres (CCs) for influenza.

    *  Dr Nilesh Buddha delivers the opening remarks, highlighting regional risks and the importance of preparedness. (Picture -IHM/WHE/SEARO)

    The webinar was inaugurated  by Dr Nilesh Buddha, the Regional Emergency Director (RED). Dr Pushpa Ranjan Wijesinghe, Programme Area Manager for Infectious Hazard Management at WHO SEARO, outlined the core objectives of the webinar. These included reviewing recent human detections of avian influenza A(H5) in SEAR and assessing their public health implications. He emphasized the need for timely reporting  non -seasonal influenza events  under the International Health Regulations , the strategic importance of virus sharing—especially for un-subtyped and non-seasonal strains—and enhanced coordination between NICs, IHR focal points, and WHO Collaborating Centres.

    Global and Technical Perspectives

    Dr Aspen Hammond(WHO-HQ) delivered a presentation providing the  global overview of recent non-seasonal influenza virus activity, with particular focus on the implications of zoonotic spillovers such as H5N1. She underscored the increasing frequency of detections across multiple WHO regions and highlighted the  value of  interconnectedness of surveillance systems worldwide. Dr Aspen emphasized the critical role of timely event notification through IHR mechanisms, not just as a legal obligation but as a cornerstone of effective global risk assessment and coordinated response. She explained how early reporting of unusual influenza events allows WHO to rapidly conduct risk evaluations, alert global stakeholders, and guide countries on appropriate preparedness actions.

    Professor Ian Barr from the WHO Collaborating Centre for Reference and Research on Influenza at the Victorian Infectious Diseases Reference Laboratory (VIDRL) in Melbourne , Australia  presented a detailed analysis of the recent A(H5) virus detections. He described genetic patterns observed in these viruses, including features suggestive of reassortment between different clades; a process that can influence virus evolution and adaptation. While there was no current evidence of mutations associated with increased transmissibility or antiviral resistance, Professor Barr emphasized the importance of continued genetic monitoring to detect any early signs of change.
    He also underlined the critical role of timely virus sharing for full characterization with  WHO Collaborating Centres, which support both regional preparedness and global risk assessments. The value of depositing sequences on platforms such as  the  Global initiative on sharing all influenza data (GISAID) was also highlighted as a means to facilitate transparency and scientific collaboration.

    GISAID presentation

    ** Professor Ian Barr (WHO CC Melbourne) discusses recent H5 detections and underscores the value of timely virus characterization and sequence sharing. (Picture -IHM/WHE/SEARO)

    Dr Magdi Samman (WHO- HQ) followed by presenting the logistics, training programmes and funding mechanisms available to support virus sharing. He clarified that the Global Shipping Fund (SF) is designed to facilitate urgent shipments, while the PIP Partnership Contributions (PC), can be used to support additional shipments based on surveillance needs. Together, these mechanisms help ensure that countries can share viruses promptly, supporting the global response.

    Dr Masaya Kato, Programme Area Manager for Health Information Management at WHO SEARO delivered a presentation on the critical role of Public Health Intelligence (PHI) in detecting early warning signs of diseases such as avian influenza A(H5). He outlined how WHO systematically monitors signals through event-based surveillance and works with Member States to verify and assess potential risks.

    He emphasized the importance of timely IHR event notification which allows countries and WHO to act faster and more effectively.  He introduced the use Multi-Source Collaborative Surveillance (MSCS); a system that combines data from different sources to get a fuller detailed picture and for public health decision making.

    Dr Masaya underscored that collaborative intelligence efforts such as  PHI and MSCS are key to triggering rapid, evidence-informed public health action.

    Dr Masaya highlights PHI and MSCS

    Dr Masaya highlights how PHI and MSCS contribute to early detection and coordinated response to threats like avian influenza A(H5).(Picture -IHM/WHE/SEARO)

    Country Experience: Bangladesh

    Dr Shirin Tahmina, the Director General from the Institute of Epidemiology, Disease Control and Research (IEDCR), Bangladesh delivered a comprehensive presentation showcasing the country’s influenza surveillance system and its coordinated national network. The presentation outlined the structure of the sentinel-based Severe Acute  Respiratory Infections (SARI) and Influenza Like Illness (ILI) surveillance system, highlighting integration with national networks, public health institutions, and other key stakeholders. The speaker emphasized the importance of sustained capacity-building, cross-sector collaboration, and the value of timely detection and reporting, especially in light of recent H5 virus detections. The experience also shed light on practical challenges such as specimen logistics, resource constraints and reaffirmed the need for sustained support to further strengthen national and regional  influenza surveillance capacities.

    The webinar was  concluded with heartfelt thanks to all speakers, panellists, and participants for their valuable contributions and active engagement. Appreciation was extended to country representatives, WHO Collaborating Centres, and WHO technical teams for sharing their experiences, insights, and support in advancing influenza preparedness across the WHO South East Asia Region.

    As a next step, countries are  encouraged to continue strengthening influenza  surveillance systems, prioritize timely IHR reporting, and share viruses with WHO Global Influenza Surveillance and Response System (GISRS)  —particularly in advance of the September 2025 Vaccine Composition Meeting (VCM). The WHO Regional Office reaffirmed its commitment to supporting Member States through technical collaboration, capacity-building, and coordinated response efforts.

     

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  • Mental Health Drugs: New Insight Into 5-HT1A Receptor

    Mental Health Drugs: New Insight Into 5-HT1A Receptor


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    In a discovery that could guide the development of next-generation antidepressants and antipsychotic medications, researchers at the Icahn School of Medicine at Mount Sinai have developed new insights into how a critical brain receptor works at the molecular level and why that matters for mental health treatments.

    The study, published in the August 1 online issue of Science Advances [10.1126/sciadv.adu9851], focuses on the 5-HT1A serotonin receptor, a major player in regulating mood and a common target of both traditional antidepressants and newer therapies such as psychedelics. Despite its clinical importance, this receptor has remained poorly understood, with many of its molecular and pharmacological properties largely understudied—until now.

    “This receptor is like a control panel that helps manage how brain cells respond to serotonin, a key chemical involved in mood, emotion, and cognition,” says senior author Daniel Wacker, PhD, Assistant Professor of Pharmacological Sciences, and Neuroscience, at the Icahn School of Medicine at Mount Sinai. “Our findings shed light on how that control panel operates—what switches it flips, how it fine-tunes signals, and where its limits lie. This deeper understanding could help us design better therapies for mental health conditions like depression, anxiety, and schizophrenia.”

    Using innovative lab techniques, the research team discovered that the 5-HT1A receptor is inherently wired to favor certain cellular signaling pathways over others—regardless of the drug used to target it. However, drugs can still influence the strength with which those pathways are activated. For example, the antipsychotic asenapine (brand name Saphris) was found to selectively engage a specific signaling route due to its relatively weak activity at the receptor.

    To explore these mechanisms in greater detail, the researchers combined experiments in lab-grown cells with high-resolution cryo-electron microscopy—a cutting-edge imaging technology that reveals molecular structures at near-atomic resolution. Their work focused on how various drugs activate the 5-HT1A receptor and how the receptor interacts with internal signaling proteins known as G proteins.

    Different signaling pathways controlled by the 5-HT1A receptor are linked to different aspects of mood, perception, and even pain. As scientists better understand which pathways are activated, and how, they can more precisely design drugs that treat specific symptoms or conditions without unwanted side effects.

    “Our work provides a molecular map of how different drugs ‘push buttons’ on this receptor—activating or silencing specific pathways that influence brain function,” says study first author Audrey L. Warren, PhD, a former student in Dr. Wacker’s lab who is now a postdoctoral researcher at Columbia University. “By understanding exactly how these drugs interact with the receptor, we can start to predict which approaches might lead to more effective or targeted treatments and which ones are unlikely to work. It’s a step toward designing next-generation therapies with greater precision and fewer side effects.”

    In a particularly surprising finding, the researchers discovered that a phospholipid—a type of fat molecule found in cell membranes—plays a major role in steering the receptor’s activity, almost like a hidden co-pilot. This is the first time such a role has been observed among the more than 700 known receptors of this type in the human body.

    While current antidepressants often take weeks to work, scientists hope this new understanding of 5-HT1A signaling could help explain those delays and lead to faster-acting alternatives.

    “This receptor may help explain why standard antidepressants take long to work,” says Dr. Wacker. “By understanding how it functions at a molecular level, we have a clearer path to designing faster, more effective treatments, not just for depression, but also for conditions like psychosis and chronic pain. It’s a key piece of the puzzle.”

    Next, the research team plans to dig deeper into the role of the phospholipid “co-factor” and to test how their lab-based findings hold up in more complex experiments. They’re also working on turning these discoveries into real-world compounds that could become future psychiatric medications, building on their earlier success with drug candidates derived from psychedelics.

    Reference: Warren AL, Zilberg G, Abbassi A, Abraham A, Yang S, Wacker D. Structural determinants of G protein subtype selectivity at the serotonin receptor 5-HT1A. Sci Adv. 11(31):eadu9851. doi: 10.1126/sciadv.adu9851

    This article has been republished from the following materials. Note: material may have been edited for length and content. For further information, please contact the cited source. Our press release publishing policy can be accessed here.

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  • Inflammation Control in Lupus Nephritis Research

    Inflammation Control in Lupus Nephritis Research

    At the time when patients with lupus, or systemic lupus erythematosus (SLE), are diagnosed, approximately 15% to 30% will already have the inflammation-caused kidney disease lupus nephritis, which compromises kidney function and can lead to kidney failure. Between 30% and 50% of SLE patients will ultimately go on to develop lupus nephritis, and half of them will eventually develop end-stage renal disease.

    An MUSC research team led by Jim Oates, M.D., director of the Division of Rheumatology and Immunology and vice chair for Research in the Department of Medicine, is developing a new approach to preventing lupus nephritis – improving the health and function of the cells that line the kidney blood vessels, or renal endothelial cells, to prevent immune cells from leaking into kidney tissue and damaging it.

    The team reports in Lupus Science & Medicine that the exposure of renal endothelial cells to serum from patients with lupus nephritis who are experiencing a flare caused the cells to malfunction, leading to inflammation. In contrast, when those same cells were exposed simultaneously to flare lupus nephritis serum and the investigational drug L-sepiapterin, inflammation was reduced, and genes associated with the production of nitric oxide, known to be protective against inflammation, were enhanced. Serum was obtained from a biobank with specimens from patients with lupus, and the South Carolina Clinical & Translational Research Institute assisted with the processing and banking of samples.

    In patients with SLE, an autoimmune disease, the body musters its immune defenses not against an invading germ but against the body itself, causing inflammation, tissue damage and sometimes organ failure. In lupus nephritis, it is the kidney that is targeted by the immune system.

    “I liken this targeting by the immune system to what happens after a transplant,” said Oates. “So patients who have had a transplanted kidney require drugs that suppress the immune system to prevent rejection. In the case of those with lupus nephritis, they’re rejecting their own kidney.”

    Immune suppression has also been the go-to therapy for patients with lupus nephritis, but it carries a cost – patients become much more vulnerable to infection.

    The treatment approach being developed by the Oates Lab does not suppress natural body functions, such as immunity, but uses pharmaceuticals to dial back inflammation and establish a more protective environment for endothelial cells, enabling proper functioning.

    “When the endothelial cells that line your blood vessels are impaired, it puts people at risk for things like heart attacks and strokes but also inflammatory or scarring events in the kidney. It puts people at risk for organ damage,” said Oates. “That’s a major focus of my laboratory – to restore the protective effects of properly functioning endothelial cells.”

    Oates Laboratory manager Dayvia Russell, first author of the recent publication, sums up the new approach.

    “The vasculature is the gateway to your organs,” she said. “The concept of our research is to try to protect the kidneys in patients with lupus nephritis by preventing vascular damage.”

    The key to maintenance of healthy endothelial cells is the production of the molecule nitric oxide, which can protect against inflammation and oxidative stress as well as help to maintain healthy blood flow and prevent leakage of immune cells into the tissue. However, oxidative stress, such as that produced by risk factors for chronic disease, such as obesity, smoking and diabetes, can cause endothelial cells to malfunction, making inflammation more likely.

    Specifically, oxidative stress interrupts nitric oxide production by disabling the enzyme endothelial nitric oxide synthase (eNOS), causing superoxide, a powerful free radical, to be produced instead. Superoxide has an unpaired electron, making it highly reactive with and damaging to other molecules.

    “eNOS is a yin and yang molecule,” said Oates. “When it’s functioning properly, it can produce nitric oxide, which is protective against inflammation, but when it’s not, it can have the opposite effect, making superoxide that causes oxidative stress.”

    In their study, the MUSC researchers showed for the first time the impact of lupus nephritis on the genetic profile of renal endothelial cells and the ways in which L-sepiapterin, which enhances eNOS function, alters those genetic profiles. The team showed that the exposure of renal endothelial cells to serum from patients with a flare-up of lupus nephritis led to higher expression of genes associated with inflammation. In contrast, simultaneous exposure of renal endothelial cells to both flare lupus nephritis serum and L-sepiapterin resulted in decreased expression of genes associated with oxidative stress and increased expression of genes associated with nitric oxide production, suggesting a protective effect.

    This line of research is novel in that it seeks to control the inflammatory environment that can cause tissue and organ damage, not by suppressing the immune system, which can leave people susceptible to infection, but by using pharmaceuticals to adjust the natural cell processes to restore endothelial cell function and thereby protect against inflammation.

    If these findings are borne out in animal studies of lupus-prone mice, the team would next like to perform a small-scale proof-of-concept study in humans once it obtains the necessary funding.

    The findings could also have implications for L-sepiapterin use in diseases other than lupus nephritis, said Russell. One of the genes increased with L-sepiapterin is known to be reduced in the kidney in Type 2 diabetes.

    “This suggests that L-sepiapterin has potential not only in the treatment of lupus nephritis but also other vascular diseases and maybe even Type 2 diabetes,” she said.

    Reference: Russell DA, Beusecum JPV, Markiewicz M, Sanchez SM, Barth JL, Oates JC. Lupus nephritis serum induces changes in gene expression in human glomerular endothelial cells, which is modulated by L-sepiapterin: implications for redox-mediated endothelial dysfunction. Lupus Sci Med. 2025;12(1). doi: 10.1136/lupus-2025-001568

    This article has been republished from the following materials. Note: material may have been edited for length and content. For further information, please contact the cited source. Our press release publishing policy can be accessed here.

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  • Can an at-home test replace a Pap smear for cervical cancer screening?

    Can an at-home test replace a Pap smear for cervical cancer screening?

    Maybe you have avoided doing a Pap smear (Pap test) for cervical cancer screening for years even though you know it saves lives. Many women do, for a variety of reasons. Some may feel uncomfortable with pelvic exams or face barriers related to past trauma. And for many, having access to and getting time to see a healthcare professional is difficult.

    You might be surprised to learn that several new options make it simpler. It’s now even possible to collect a sample yourself for screening.

    There are two Food and Drug Administration (FDA)-approved self-collection tests for HPV — the virus that causes nearly all cervical cancers — that you can do in a healthcare setting like a healthcare clinic, lab, pharmacy or doctor’s office, without needing to have a pelvic exam. There is also a recently approved home device to collect a vaginal sample for testing.

    You may hear this new test referred to as an “at-home Pap smear,” although that’s not really accurate. During a Pap test, a healthcare professional inserts a speculum and scrapes cells directly from the cervix. The cervix is attached to the lower part of the uterus and opens into the vagina. The collected cells are tested for cancer and precancer, and often also for HPV. The new test is different — it is an at-home test to check for the presence of HPV.

    How do HPV self-swab tests work?

    With the HPV self-collection tests, you use a swab to collect your own vaginal sample, says Kathy L. MacLaughlin, M.D., a family medicine specialist at Mayo Clinic in Minnesota. The sample is then sent to a lab that tests the vaginal cells for high-risk types of HPV, the types that are most likely to cause cancer.

    The two tests that you can use on your own in a healthcare clinic or doctor’s office are:

    • Roche cobas HPV test (with Copan swab or Evalyn brush).
    • BD Onclarity HPV Assay (with Copan swab).

     “They are not yet approved for at-home use,” Dr. MacLaughlin says.

    At-home Pap smear alternative

    The first FDA-approved HPV self-collection test you can use at home is from the Teal Health company. This test uses a device called the Teal Wand to collect a vaginal sample.

    Like the clinic-based self-collection tests, the Teal Health test examines cells from the vagina — not directly from the cervix, as happens with a Pap smear. After collecting the sample, the user mails it back and receives results, follow-up recommendations and referrals if needed through a phone app or teleheath visit.

    Who can benefit from HPV self-collection tests?

    HPV self-collection tests are intended for people at average risk of cervical cancer who don’t have any symptoms. Some women may be told by their healthcare team that they are at higher risk and need a Pap test or more-frequent screening. Among the factors that increase risk are having a history of cervical changes detected by a previous Pap test, irregular bleeding, HIV or a suppressed immune system, for example.

    You also should avoid the self-collection test if you’re currently menstruating or you have used any vaginal products — such as moisturizers, lubricants or spermicides — in the past couple of days.

    But for many, self-collection offers a flexible and convenient option. “We have a lot of folks who come in for other reasons — diabetes, ear pain — and we notice they’ve never had (cervical cancer screening) or they’re long overdue,” Dr. MacLaughlin says. “They can collect the self-test while they are in the office.”

    Pros and cons of at-home HPV testing

    At-home testing offers privacy and convenience, so people can screen without visiting a doctor’s office. According to Teal Health’s website, tests using the Teal Wand have been shown to detect cervical precancer 96% of the time, which is on par with samples collected by a healthcare professional.

    However, Dr. MacLaughlin has some reservations about the at-home test, especially when it comes to follow-up care. If you do a self-collection test in a healthcare clinic or other healthcare setting, your healthcare professional knows you did it and to expect the results. But with an at-home test, you need to make sure your healthcare professional knows you did it (and when). And the results of the at-home test are not integrated automatically into your medical records, which can affect follow-up care.

    “HPV screening is not quite like taking a home COVID test,” Dr. MacLaughlin says. “We need to coordinate and provide access to next steps in the cancer prevention continuum such as a follow-up Pap, colposcopy or precancer treatment.”

    If you do opt for at-home testing, Dr. MacLaughlin strongly recommends keeping your gynecologist, primary care or another healthcare professional in the loop. “Take this to your primary care to review results. Make sure your record is updated,” she says.

    Is HPV self-collection right for you?

    While not many healthcare clinics or doctors’ offices offer it yet, Dr. MacLaughlin believes growing awareness and acceptance of HPV self-collection will make cervical cancer screening more accessible, especially for those who face obstacles such as discomfort, a trauma history, embarrassment or scheduling limitations.

    She also believes home-based tests will eventually integrate more smoothly with clinic-based lab systems, which could ensure better follow-up. “I hope that in the near future we see home-based approval for the systems that already have clinic-based approval, as they are integrated into the health monitoring and the lab ordering process,” she says.

    In the meantime, if you’re interested in self-collection, ask your healthcare professional if it’s available and right for you. If you choose a home test, make sure you understand what steps you may need to take if the result is positive, and let your healthcare team know the results.

    Overall, Dr. MacLaughlin is excited by what self-collection could mean for many people. “It’s not replacing current options — it’s expanding the menu of screening options,” she says. “And really empowering those who have barriers.”

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    Growth in the cancer vaccine market is supported by the growing investments in R&D, particularly in mRNA vaccine platforms and neoantigen-based vaccines, are fuelling innovation across the cancer vaccine market. Companies are leveraging AI and genome sequencing to design individualized vaccines targeting tumor-specific mutations. The FDA approvals of vaccines such as Sipuleucel-T and BCG for prostate and bladder cancer, respectively, have further validated the clinical potential of cancer vaccines.

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  • Non-Immune Hydrops Fetalis in a Pregnant Woman with Chronic Alcohol Us

    Non-Immune Hydrops Fetalis in a Pregnant Woman with Chronic Alcohol Us

    Aisyah Shofiatun Nisa, Hadi Susiarno, Gatot Nyarumenteng Adipurnawan Winarno, Putri Nadhira Adinda Adriansyah

    Department of Obstetrics and Gynecology, Faculty of Medicine, Universitas Padjadjaran – Dr. Hasan Sadikin General Hospital, Bandung, Indonesia

    Correspondence: Aisyah Shofiatun Nisa, Department of Obstetrics and Gynecology, Faculty of Medicine, Universitas Padjadjaran – Dr. Hasan Sadikin Hospital, Jl. Pasteur 38, Bandung, West Java, 40161, Indonesia, Email [email protected]

    Introduction: Hydrops fetalis is a condition characterized by excessive fluid accumulation within the fetal extravascular compartments and body cavities. It is classified into two categories: immune hydrops fetalis (IHF) and non-immune hydrops fetalis (NIHF). The primary cause of NIHF is fetal cardiovascular abnormalities, often stemming from congenital heart disease. One of the significant contributors to congenital heart defects is prenatal alcohol exposure (PAE).
    Case Illustration: A woman in her early 30s presented to the emergency department with the chief complaint of not feeling fetal movements for one day prior to admission. This was her fourth pregnancy, with no history of miscarriage or abortion. The patient reported a history of regular smoking (two packs per day) and frequent alcohol consumption. Her vital signs were unremarkable upon admission. The baby was delivered weighing 1755 grams and measuring 44 cm, with grade 2 maceration and no signs of life. Physical findings, including fluid accumulation in the chest and body, led to a pediatric diagnosis of hydrops fetalis.
    Conclusion: The risk factor for hydrops fetalis in this case is likely associated with prenatal alcohol exposure, which may have disrupted fetal teratogenesis. Comprehensive prenatal examinations are essential for monitoring fetal health, identifying complications and congenital abnormalities, and assessing risk factors.

    Keywords: hydrops fetalis, non-immune hydrops fetalis, prenatal alcohol exposure, congenital heart disease

    Introduction

    Hydrops Fetalis refers to a condition in which the fetus has excessive fluid accumulation within the fetal extra vascular compartments and body cavities; this is typically characterized by skin thickness greater than 5 mm (skin edema), placental enlargement, pericardial or pleural effusion, and ascites.1,2 Hydrops Fetalis is divided into 2 categories: immune hydrops fetalis (IHF) and non-immune hydrops fetalis (NIHF).3 NIHF specifically refers to cases not associated with maternal antibody reactions against fetal red blood cell antigens. The incidence of NIHF occurs in 1 out of 1700–3000 pregnancies, with live birth rates of 1 in 4000 pregnancies.1,4 The majority of NIHF cases are related to intrauterine fetal death. The main causes of NIHF are fetal cardiovascular problems, idiopathic, and lymphatic dysplasia.2

    The etiologies of NIHF are diverse, with the most common causes including fetal cardiovascular anomalies, idiopathic origins, and lymphatic dysplasia.5 Among fetal cardiovascular conditions, congenital heart disease (CHD) is a leading contributor. CHD is the most frequently occurring congenital anomaly globally, affecting approximately 4 to 12 out of every 1000 live births.6–8 CHD is a major contributor to infant mortality. One of the risk factors linked to CHD is maternal alcohol consumption prior to pregnancy. More than 40% of adults worldwide consume alcohol, and over 50% of women of childbearing age consume alcohol at varying levels.9,10 Interestingly, 51% of pregnancies are unplanned, and pregnancy often becomes known only around weeks 5–6. Prenatal alcohol exposure (PAE) is believed to be a key factor influencing the teratogenic process in heart development, ultimately affecting the heart’s septum, valves, chambers, arteries, and heart pathways.11,12 This case report aims to present a rare case of non-immune hydrops fetalis in a fetus from a mother with a history of heavy alcohol consumption, without any underlying hematologic disorders. This case emphasizes the need for improved prenatal counseling and awareness of modifiable risk factors that may contribute to fetal morbidity and mortality.

    Case Illustration

    A woman in her early 30s presented to the emergency department with the chief complaint of not feeling fetal movements for one day prior to admission. She estimated her pregnancy to be at six months but was unable to recall the date of her last menstrual period. This was her fourth pregnancy, with no history of miscarriage or abortion. The patient reported a history of smoking two packs of cigarettes daily and regular alcohol consumption. She reported consuming approximately 620–1860 mL of alcohol daily (around 2–3 bottles per day) with an alcohol concentration of approximately 14.7%, beginning at least three months prior to conception and continuing throughout the pregnancy. Based on the duration and volume of intake, this pattern meets the clinical criteria for chronic alcohol use. She denied any family history of blood disorders, infections, chromosomal abnormalities, or congenital anomalies, and she had no personal history of similar conditions. Her vital signs were within normal limits.

    Physical examination revealed the absence of a fetal heart rate and uterine contractions. Laboratory results showed an elevated fibrinogen level (> 400 mg/dL), while other parameters were within normal ranges. Ultrasonography (USG) indicated a single intrauterine fetus with no signs of life, corresponding to a gestational age of 27 weeks (Figure 1). The estimated fetal weight is 1148 grams (35th percentile), with a negative fetal heart pulsation. Mild scalp edema is present, measuring 0.62×0.63×0.70 cm. Subcutaneous edema is present, measuring 0.61×0.60×0.62 cm. Based on these findings, fetal hydrops was suspected and pregnancy termination was initiated using misoprostol.

    Figure 1 Ultrasound examination results upon the patient’s arrival at the Emergency Department (ED), indicating fetal hydrops with fluid accumulation in the brain and abdomen. (A) Ultrasound image of the fetal head shown scalp edema (red arrow). (B) Ultrasound image of the fetal abdomen shown excess fluid within the abdomen. Red arrow shown the subcutaneous edema within the abdomen.

    The baby was delivered four hours after the first dose of misoprostol. The newborn weighed 1755 grams and measured 44 cm in length, with grade 2 maceration and no signs of life. Examination revealed fluid accumulation in the chest and body, consistent with a diagnosis of fetal hydrops (Figure 2). The patient had not undergone an ultrasound examination earlier in the pregnancy, as her antenatal care was limited to visits with a midwife. The placenta was delivered intact and weighed 500 grams, which is larger than normal (Figure 3). The findings of placentomegaly and abnormalities in the placenta’s structure are significant in the context of Non-Immune Hydrops Fetalis (NIHF). These observations support the pathological process of fluid accumulation and placental dysfunction, which are hallmark features of NIHF. The enlarged placenta reflects underlying fetal cardiovascular compromise and systemic congestion, often associated with prenatal alcohol exposure and other contributing factors in this case.

    Figure 2 Clinical presentation of a neonate diagnosed with Hydrops Fetalis.

    Figure 3 (A) Maternal surface of the placenta, showing a coarse and vascularized appearance. (B) Fetal surface of the placenta, highlighting the translucent membrane and visible vasculature. (C) Close-up view of the umbilical cord, showing the blood vessels. (D) Measurement of the placenta’s weight, approximately 500 grams, indicating placentomegaly.

    Discussion

    Prenatal alcohol exposure (PAE) has been associated with various adverse fetal outcomes, including congenital heart defects (CHD), which may contribute to the development of non-immune hydrops fetalis (NIHF).13 NIHF has an incidence of 1 in 1700–3000 pregnancies.4 This condition can affect maternal health by causing polyhydramnios, malpresentation, and premature birth. Meta-analyses conducted by Bellini et al categorized the causes of NIHF into 14 categories, with the highest contributor being cardiovascular system abnormalities.2 Cardiovascular disorders leading to NIHF are divided into 4 categories: structural heart disease, cardiomyopathies, fetal arrhythmias, and vascular disorders.3 The presence of congenital heart disease can lead to both structural and vascular disturbances, hence congenital heart disease is often associated with NIHF occurrences.3 PAE is considered a key factor causing CHD.14 Alcohol consumption has been widespread globally and has increased in usage across the world. According to the WHO, around 47.2 billion liters of pure alcohol were consumed in 2015.15

    In this case, the patient presented with Intrauterine Fetal Demise (IUFD) without any prior ultrasound examination. Upon further questioning, the patient denied any history of blood disorders, multiple pregnancies, or other significant illnesses. However, she disclosed a history of alcohol consumption, typically consuming 2–3 bottles daily. The exact concentration and type of alcohol could not be determined, as the patient frequently changed brands. Most commonly, she consumed alcohol with an approximate concentration of 14.7%, in quantities ranging from 620 mL to 1860 mL per day. At delivery, the baby was born lifeless, exhibiting signs of skin edema, as shown in Figure 2. The Department of Pediatrics subsequently diagnosed the fetus with hydrops fetalis.

    In normal non-pregnant women, the fibrinogen level ranges between 200–400 mg/dL. However, during pregnancy, fibrinogen levels can increase by up to 50%, and in the late trimester of pregnancy, fibrinogen levels can range between 300–600 mg/dL. The increase in fibrinogen levels in this case is not a basis for the occurrence of hydrops fetalis.16,17

    While PAE is a plausible contributing factor in this case, other potential etiologies such as intrauterine infection, chromosomal or genetic abnormalities, and fetal anemia must also be considered. The lack of a fetal autopsy and advanced genetic testing limits our ability to exclude these possibilities.18 This highlights the need for comprehensive diagnostic evaluation in future similar cases.

    In certain instances of hydrops fetalis, placentomegaly and polyhydramnios may be observed, although they are not included in the diagnostic criteria.19 The placenta at full term pregnancy has a disc-like shape and is of a dark red color, weighing between 500 to 600 grams. The growth and development of the fetus during pregnancy heavily depend on the vascular supply from the uteroplacental. In cases of hydrops fetalis, the placenta’s size tends to be larger than the normal size called placentomegaly.20 The birth weight to placental weight ratio is often used as an indicator of placental efficiency. In several cohort studies, birth weight has been found to be 5–7 times greater than placental weight during pregnancy.21–23 In this case, the birth weight is 1700 grams while the placental weight is 500 grams. This demonstrates a larger placental size compared to its normal size.

    The patient does not have any risk factors that could lead to hydrops fetalis during pregnancy. The patient denies having a history of similar pregnancies, blood disorders, or infections. However, we cannot diagnose a CHD in the fetus either, as the patient did not undergo the necessary antenatal examinations as she should have. The only potential risk factor that could contribute to hydrops fetalis in this case is alcohol consumption prior to and during pregnancy. The mechanism of PEA lead to NIHF was described in Figure 4.

    Figure 4 Mechanism by which Prenatal Alcohol Exposure (PAE) contributes to Non-Immune Hydrops Fetalis (NIHF).

    Abbreviations: NIHF, Non-immune hydrops Fetalis; HATs, Histone Acetyltransferases; ERK 1/2, Extracellular signal-Regulated Kinases 1 and 2; BMP, Bone Morphogenetic Protein; Klf-2a, Krüppel-like factor 2a.

    Figure 4 shown the diagram of causes in case of Prenatal Alcohol Exposure (PAE) contributes to the development of Non-Immune Hydrops Fetalis (NIHF) through a multifactorial mechanism that impacts fetal cardiovascular health and fluid balance. PAE induces hyperactivity of histone acetyltransferases (HATs), leading to epigenetic changes that disrupt normal gene expression. Additionally, PAE enhances ERK 1/2 phosphorylation and causes vitamin A deficiency, which are crucial for proper fetal development. It also reduces Wnt transcription activity mediated by internal calcium, impairs bone morphogenetic protein (BMP) signaling in cardiac chamber cells, and decreases the activity of Notch signaling pathways. These disruptions collectively interfere with the transcription of klf-2a, a critical factor in cardiac development.24–26

    HATs play a crucial role in activation, transcription, cell cycle, and epigenetic regulation of mesenchymal stem cells into cardiomyocytes. Disruption in the balance of HATs can interfere with heart development by inducing H3K9 hyperacetylation.24–26 Additionally, alcohol exposure increases the phosphorylation of extracellular signal-regulated kinase (ERK)1/2, inducing the overexpression of Gata4 and Mef2c in alcohol-cultured h9c2 cells to participate in CHD development.27–29 Genetic variations in Gata4 can lead to CHDs such as ASD, VSD, and TOF.29 Ethanol exposure can also induce Vitamin A deficiency, which can impact embryonic gene expression.30

    The relationship between PEA and CHD can be illustrated through seven main theories: hyperactivity of histone acetyltransferases (HATs), increased extracellular signal-regulated kinase (ERK)1/2 phosphorylation, induction of Vitamin A deficiency, spatial-temporal control of Wnt signaling, hyperactivity of BMP in chamber cells, reduction of active Notch cells, and transcription of the Klf-2a factor.12 As a result, these abnormalities contribute to the development of congenital heart disease, including both structural heart defects and vascular disorders. Such cardiovascular abnormalities lead to cardiac failure, which increases central venous pressure and promotes the accumulation of interstitial fluid.31 The excessive buildup of fluid in the fetal body ultimately manifests as NIHF. This cascade underscores the complex interplay between prenatal environmental factors, such as alcohol exposure, and their detrimental impact on fetal health, emphasizing the importance of preventive care and early monitoring during pregnancy.

    According to research by Parnell et al, structural brain abnormalities caused by ethanol exposure were found to vary depending on the stage of gestation. Exposure to ethanol during gestational days (GD) 7–11 led to a notable decrease in cerebellar volume and an increase in septal volume. In contrast, ethanol exposure during GD 12–16 was associated with a reduction in right hippocampal volume and enlarged pituitary glands. Furthermore, ethanol exposure during GD 12–16 was linked to a high occurrence of edema or fetal hydrops.32

    Apoptosis and disturbances in CNCC function are common causes of CHDs.33 Several studies have revealed that alcohol can affect the Wntβ-catenin signaling pathway, which functions in normal gene activation and cardiogenesis.34 BMP signaling is necessary for heart specification, endocardial differentiation, chamber morphogenesis, heart looping, and OFT septation. Meanwhile, PEA can influence BMP activity from cardiomyocytes.35 Notch signaling is crucial in endocardium differentiation, epicardial cell interactions, cardiac looping, and OFT development during embryogenesis. Alcohol exposure, on the other hand, can reduce Notch cell activity.36 Klf2a plays an important role in valvulogenesis and heart chamber development, while PEA can affect Klf2a expression, potentially leading to CHDs, which often involve valve disturbances.37 CHD can cause impaired blood flow or blood flow obstruction, leading to increased pressure within capillaries and veins. This increased pressure can disrupt the balance between intravascular blood flow and interstitial fluid, ultimately contributing to the accumulation of fluid within fetal body cavities.

    Ultimately, this case underscores the complex interplay between prenatal environmental factors, such as alcohol exposure, and fetal cardiovascular compromise. It highlights the importance of early prenatal screening, comprehensive maternal counseling, and thorough diagnostic workup to assess for possible infections, genetic anomalies, and hematologic conditions in cases of NIHF.

    This case report has several strengths. It presents a rare and clinically relevant instance of non-immune hydrops fetalis (NIHF) potentially associated with prenatal alcohol exposure, contributing valuable insight into a less frequently reported etiology. The detailed maternal history, including lifestyle factors such as smoking and alcohol consumption, combined with clinical, ultrasonographic, and placental findings, provides a comprehensive view of the case. Furthermore, the discussion integrates current evidence on the molecular and epigenetic mechanisms through which alcohol may contribute to congenital heart disease and NIHF, adding scientific depth and relevance. However, the case also has notable limitations. The absence of early antenatal care and ultrasound examination limits the ability to confirm gestational age accurately and detect fetal anomalies earlier in the pregnancy. The patient’s inability to recall her last menstrual period further complicates pregnancy dating and assessment of fetal growth. Additionally, no fetal autopsy or genetic testing was performed, restricting definitive conclusions regarding the underlying cause of hydrops fetalis and the exclusion of chromosomal or structural abnormalities. Lastly, the history of alcohol consumption was based solely on patient self-reporting, without objective confirmation, which may affect the accuracy of exposure assessment.

    Conclusion

    The development of hydrops fetalis in this case is suspected to be associated with maternal alcohol consumption prior to conception, which may have disrupted fetal development through teratogenic mechanisms. This case highlights the significant impact of maternal lifestyle choices, particularly alcohol and tobacco use, on fetal health. These factors may contribute to intrauterine growth restriction, placental insufficiency, and fetal hypoxia. Hydrops fetalis, characterized by fluid accumulation in multiple fetal compartments, can result from various underlying conditions such as fetal anemia, congenital infections, or chromosomal abnormalities. Comprehensive and routine prenatal assessments are essential for early detection of fetal abnormalities, monitoring growth parameters, and identifying risk factors that may affect pregnancy outcomes. The delayed maternal recognition of absent fetal movement emphasizes the importance of antenatal education to increase awareness of fetal well-being. In addition, further diagnostic evaluations including fetal autopsy and genetic analysis are recommended to determine the underlying cause of hydrops fetalis and to guide management and counseling in future pregnancies.

    Informed Consent Patient Statement

    No formal ethical clearance was required for the publication of this case. The authors confirm that written informed consent for publication of this case report and any accompanying images was obtained from the patient and her spouse. The patient was informed in detail about the case content and agreed to its publication. All personal identifiers have been removed to ensure patient anonymity.

    Disclosure

    The authors report no conflicts of interest in this work.

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