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Stroke survivors often face tough choices about managing menopause symptoms.

A new study from Copenhagen University Hospital–Herlev and Gentofte found that vaginal estrogen tablets were not linked to an increased risk of recurrent ischemic stroke in postmenopausal women.

The results suggest these drugs may be a safe option for symptom relief in women with a prior stroke.

Estrogen therapy and its stroke risks

Stroke is a serious concern for postmenopausal women. Many of these women turn to hormone therapy to relieve menopause symptoms that affect daily life, such as hot flashes, vaginal dryness or pain during sex. For some, these drugs can make the difference between ongoing discomfort and a return to normal activities.

Systemic hormone therapy, such as oral estrogen pills or patches, is linked to a higher risk of ischemic stroke. Large trials such as the Women’s Health Initiative found that estrogen (with or without progestin) raises stroke risk by ~30–40% in generally healthy postmenopausal women. Because of that, these systemic hormone drugs are usually off-limits for women with a history of stroke.

Vaginal estrogen tablets may offer an alternative. They are prescribed to ease vaginal dryness, uncomfortable sex or urinary symptoms. These tablets act locally and cause only a small amount of estrogen to enter the bloodstream.

“While other studies have not detected an increased risk of stroke associated with the use of vaginal estrogen in healthy postmenopausal women, there is no data on whether vaginal estrogen tablets pose an increased risk for women who have already had a stroke,” said lead author Dr. Kimia Ghias Haddadan, from the Department of Cardiology at Copenhagen University Hospital-Herlev and Gentofte.

This is the first large study to test the safety of vaginal estrogen in women with a history of stroke.

Vaginal estrogen and recurrent stroke in postmenopausal women

Haddadan and colleagues identified 56,642 women who had a first ischemic stroke between 2008 and 2017 using nationwide health records from Denmark. Women under 45, those who had used vaginal estrogen before their stroke and those who had taken systemic hormone therapy were excluded – leaving 34,276 women in the final analysis.

The team then identified 3,353 women who went on to have another stroke. Each of these cases was matched by birth year with a control who had not had a second stroke.

There was no link between vaginal estrogen use and recurrent ischemic stroke. The risk of another stroke was the same whether women had recently used vaginal estrogen, had used it months or years earlier or had taken higher doses. No pattern suggested that the drug raised stroke risk.

Use of vaginal estrogen was slightly less common in women who had another stroke than in those who did not.

“It is important to note that these findings suggest that vaginal estrogen is likely safe for this high-risk group of women who have already had a stroke; however, they do not imply that vaginal estrogen prevents strokes,” said Haddadan.

Postmenopausal women and future research

The results offer reassurance to doctors and patients: the drug can help ease menopausal symptoms without adding to stroke risk. It also extends earlier safety findings from healthy women to a higher-risk group.

“As an epidemiologist, I see this study as a valuable contribution because it focuses on a population often excluded from hormone therapy research, midlife women with a prior stroke, and examines an increasingly used route of administration: vaginal tablets,” said Dr. Samar R. El Khoudary, a professor in the department of epidemiology at the University of Pittsburgh School of Public Health who was not involved in the study.

“While the study did not find a statistically significant association with stroke recurrence, the findings should be interpreted with caution. Real-world data can’t account for all clinical and behavioral factors, and prescription fill records don’t confirm whether the medication was actually used,” she added.

Future research should test different vaginal estrogen formulations and include more clinical data to refine risk estimates.

“We hope our findings reassure health professionals caring for postmenopausal women with a history of stroke. For these women, especially those with troubling menopause symptoms, the study shows that this type of therapy may be a safe choice. It could improve their quality of life without raising the risk of another stroke,” said Haddadan.

Reference: Haddadan KG, Eckert-Lind C, Meaidi A, et al. Recurrent ischemic stroke and vaginal estradiol in women with prior ischemic stroke: a nationwide nested case-control study. Stroke. 2025. doi: 10.1161/STROKEAHA.125.050986

This article is a rework of a press release issued by the American Heart Association. Material has been edited for length and content. 

Introduction

Legionella spp., aerobic Gram-negative bacilli, emerged as significant human pathogens following the 1976 Philadelphia outbreak where 182 American Legion convention attendees developed mysterious pneumonia, resulting in 29 fatalities (16% mortality).¹ This seminal event prompted the Centers for Disease Control and Prevention to deploy its largest investigative team to date, culminating in Joseph McDade’s isolation of Legionella pneumophila – marking the genus’ first scientific documentation.² Subsequent taxonomic advances have identified over 65 species, with L. pneumophila responsible for 90% of human infections, predominantly causing pneumonia.³ Non-pneumophila species (eg, L. longbeachae, L. bozemanii, L. micdadei) account for 2–7% of cases, typically manifesting as opportunistic infections in immunocompromised hosts.⁴

The pathogenic success of Legionella relies fundamentally on its Dot/Icm (Defect in organelle trafficking/Intracellular multiplication) type IV secretion system,^5–7 through which Legionella delivers effector proteins to the host cell, holds the vesicle transport between the endoplasmic reticulum and the Golgi apparatus and interferes with the signaling pathways of the host cell to provide an optimal environment for its own growth.⁸ Such sophisticated host-pathogen interplay enables intracellular proliferation while evading lysosomal degradation–a survival strategy particularly effective in alveolar macrophages.^9–12

We present the first documented pediatric case of Legionella maceachernii soft tissue infection in a 4-month-old male with X-linked severe combined immunodeficiency (X-SCID). The infant presented with fever and multifocal masses (occipital, anterior thoracic, wrist) were diagnosed through metagenomic next-generation sequencing (mNGS) of tissue biopsies with histopathological correlation. Comprehensive genomic sequencing revealed a hemizygous IL2RG mutation confirming X-SCID. This dual discovery of a novel Legionella manifestation and underlying immunodeficiency provides critical insights into pediatric host-pathogen dynamics. Our findings emphasize three key imperatives: 1) expanding differential diagnoses for pediatric soft tissue infections, 2) underlying immunodeficiency must be systematically evaluated in pediatric patients with atypical Legionella infections, 3) implementing advanced molecular diagnostics for fastidious pathogens, such as mNGS.

Case Report

A 42-day-old male infant was admitted to the Children’s Hospital Affiliated to Shandong University on December 18, 2024, presenting with a 15-day history of occipital mass and 4-day recurrent fever (peak temperature 39.8°C). Initial laboratory evaluation at an external facility revealed leukocytosis (WBC 18.25 × 10⁹/L) and elevated C-reactive protein (CRP 76.43 mg/L). On admission, physical examination identified three distinct lesions: a 4 × 6 cm firm, ill-defined occipital mass; a 1 × 1 cm dark red wrist nodule; and a 5-mm chest wall nodule (Figure 1A–C). Color ultrasound Doppler of surface masses showed that hyperechoic nodules were detected in the subcutaneous part of the occipital region, the subcutaneous part of the left wrist, and the subcutaneous part of the right chest wall (Figure 1F–H). Cardiac color ultrasound Doppler showed that a cystic solid mass echo was detected in the pericardium of the posterior wall of the left ventricle. The border was unclear (Figure 1I); an irregular solid hypoechoic mass was detected posterior to the posterior mediastinal mass, with unclear border, heterogeneous internal echogenicity, and localized compression of lung tissue (Figure 1J). Cranial MRI showed a mass-like iso-slightly shorter T1, slightly longer/iso T2 signal shadow under the soft tissue of the scalp in the posterior occipital region (Figure 1K and L).

Laboratory findings included leukocytosis (WBC 19.57 × 10⁹/L), elevated C-reactive protein (CRP 148.40 mg/L), hypogammaglobulinemia (IgA < 0.058 g/L, IgM 0.141 g/L), and profound lymphopenia: total T cells 60/ µL, CD4⁺T cells 4/µL, CD8⁺T cells 1/µL, NK cells 17/µL, and elevated B cells (1025/µL). The infant was heavily infected and was empirically given vancomycin (0.075 g IV pumped q8h 12.18–12.21) in combination with cefotaxime (0.25 g IV pumped bid 12.18–12.21) for anti-infective and immunoglobulin supportive therapy. Cerebrospinal fluid examination: colorless, slightly turbid, Cl⁻ 115 mmol/L, glucose 0.73 mmol/L, protein quantification 1102 mg/L, white blood cell counts 1.165 × 10⁹/L, percentage of single nucleated cells 48.6%, and percentage of lobulated nucleated cells 51.4%, suggesting intracranial infection, and immunoglobulin was added on top of the original antibiotic to strengthen immune support. Dexamethasone was added to the original antibiotic for anti-inflammation, while the cerebrospinal fluid was sent for mNGS detection. Cerebrospinal fluid mNGS sequencing results returned L. maceachernii (Figure 1M).

L. maceachernii is an intracellular bacterium, after discussion, it was decided to give the infant levofloxacin and rifampicin anti-infective treatment (0.049 g intravenous pump q12h, 12.21–12.30). As the nature of the mass was unknown, it was considered to be an infectious or neoplastic mass, and ultrasound-guided biopsy was performed to clarify the nature of the mass, and Gram-negative rod-shaped bacilli were found in both Gram and HE stains of the puncture tissue (Figure 1D and E), and at the same time, the puncture tissue was sent to mNGS sequencing, which showed that it was L. maceachernii. Tissue and CFS used BCYE medium, but the cultures were all negative.

During the treatment, the infant’s soft tissue mass was reduced, but the infant still had recurrent fever. Taking into account the infant’s clinical manifestations and various examinations, considering that extrapulmonary infections of Legionella spp. often occur in immunocompromised populations, we hypothesized that the infant might have a defect in the immune system, and we performed genetic tests on the infant and his parents to clarify the diagnosis. Whole exome and Sanger sequencing of the infant and his parents revealed a hemizygous mutation in the IL2RG gene: the change in nucleotide 718 from thymine T to cytosine C (c.718T > C) resulted in a change in amino acid 240 from tryptophan to arginine (p. Trp240Arg), no mutation in this locus in the father and a heterozygous mutation in this locus in the mother (Figure 2). Based on the above results, the infant was diagnosed with X-SCID. Due to the infant’s severe infection and poor immune function, hematopoietic stem cell transplantation is the first choice for the treatment of X-SCID, and he has now gone to a higher-level hospital.

Figure 2 Chromatograms showing a mutation in the X-SCID gene. (A): deletion of “T” at position 718 in the patient (indicated by red arrows). (B): wild-type c. 718T sequence in the patient’s healthy father (indicated by red arrows). (C): heterozygous c. 718delT deletion in patient’s mother (indicated by red arrows).

Discussion

Legionella usually causes pulmonary infections, but soft tissue infections are rare, and this case report is the first soft tissue L. maceachernii infection found in infant. We searched PubMed with the keywords “Legionella and soft tissue” and compiled previous case reports of a total of 10 patients (excluding our patient),^13–22 no immunocompromised or related underlying disease (n=1),¹³ received organ or stem cell transplantation (n=4),^14–17 taking cortisol hormones or immunosuppressive drugs (n=7),^{15,16,18–22} required surgical debridement or incision and drainage after soft tissue infection (n=4).^16,17,20,22 There were 6 patients received treatment and recovered,^13,16–20 1 patients developed new lesions,²² and 3 patients died,^14,15,21 the mortality rate reported in 10 cases was as high as 30%. As a result, soft tissue infections caused by Legionella warrant clinical attention (Table 1).

Table 1 Reported Cases of Soft Tissue Infection with Legionella

Legionella is an opportunistic pathogen in aquatic environments, commonly found in freshwater environments (eg lakes, hot springs, artificial water supply systems), and can parasitize protozoa, such as amoebae, or invade mammalian alveolar epithelial cells and monocyte macrophages and reproduce therein, ultimately leading to death of the host cells.²³Legionella has a low risk of infection in healthy people, but immunocompromised individuals (organ transplant, HIV patients) may become infected by inhaling aerosols containing the bacteria (atomized droplets from contaminated water sources such as showerheads, air-conditioning cooling towers, humidifiers, etc.), which can lead to pneumonia or other respiratory infections, with symptoms that include fever, coughing, and respiratory distress, and can lead to multiple organ failure in severe cases. Currently, Legionella infections are identified by isolation culture, pathologic examination, serologic testing, mass spectrometry, PCR, DFA and mNGS.³ Legionella spp. is susceptible to macrolides (erythromycin, azithromycin and clarithromycin), fluoroquinolones and rifampicin.^24,25 L. maceachernii was detected in the cerebrospinal fluid and puncture tissue mNGS of the infant in this case, and we also found gram-negative rod-shaped bacilli in the histopathological sections of the child, but unfortunately, the child’s blood, puncture tissue, and CSF were negative after 14 days of culture due to the extremely low number of bacilli and the difficulty of culturing clinical specimens of non-pneumophila Legionella infections in vitro. It has been reported in the literature that among Legionella-infected patients, those with immunosuppression are more susceptible to non-pneumophila Legionella infections than immunocompetent patients,³ combined with the child’s laboratory tests and pathogenetic testing, we further hypothesized that the child may have an immune system defect, and further genetic sequencing was performed on the infant and his parents, and the results confirmed our conjecture.

X-SCID is a rare inherited immune system disorder that is the most common type of severe combined immunodeficiency disease (SCID), accounting for about 50% of SCID cases. The disease is inherited in an X-linked recessive pattern and is caused by mutations in the IL2RG gene located on the X chromosome (Xq13.1) and mainly affects males (because males have only one X chromosome), and female carriers are usually asymptomatic but may pass the mutated gene to their offspring. The IL2RG gene encodes a common γ chain, a protein that is a core component of various interleukin receptors (eg, IL-2, IL-4, IL-7, IL-9, IL-15, IL-21).²⁶ Within a few months after birth, the infant has recurrent and severe bacterial, viral, fungal infections (such as pneumonia, chronic diarrhea, thrush, BCG vaccination, etc.), and other symptoms are growth retardation, intractable rash, etc. and most untreated infant die of severe infection within 1 year of age. The treatment of choice is hematopoietic stem cell transplantation (HSCT), the earlier the transplantation the higher the survival rate of the patient, and the preferred donor is matched sibling or umbilical cord blood.²⁷ In this case, the mother had a hemizygous mutation in the IL2RG gene: from thymine T to cytosine C (c. 718T > C), resulting in the change of amino acid 240 from tryptophan to arginine (p. Trp240Arg), for missense mutations, we used the SWISS-MODEL database (https://swissmodel.expasy.org) to query the 3D model data of wild-type and mutant proteins of IL2RG gene, visualized with PyMOL (https://pymol.org), and the predictive model obtained is shown in Figure 3.

Figure 3 Wild-type and mutant-type crystal structure of the X-SCID gene. (A): wild-type amino acid number 240 consists of tryptophan in the patient’s healthy father. (B): mutant-type amino acid number 240 changes from tryptophan to arginine in the patient and patient’s mother.

Limitations

This case report has several limitations. Firstly, the definitive diagnosis of L. maceachernii infection relied primarily on metagenomic next-generation sequencing (mNGS) of cerebrospinal fluid and lesional tissue. Despite supportive histopathological findings (Gram-negative bacilli), all attempts at conventional culture (blood, tissue, CSF) using BCYE medium were unsuccessful, precluding isolation and antimicrobial susceptibility testing of the pathogen. This highlights the inherent challenges in culturing non-pneumophila Legionella species and underscores the diagnostic reliance on molecular methods in such scenarios. Secondly, after 9 days of treatment with levofloxacin in combination with rifampicin, the infant’s soft-tissue infection improved, but the mass did not disappear until discharge from the hospital; therefore, we were unable to determine the optimal length of treatment for L. maceachernii infection of the soft tissues of immunocompromised children. Thirdly, the nature of the pericardial and mediastinal masses detected on imaging remained undetermined, although they were hypothesized to be related to the underlying immunodeficiency. Soft tissue infections with Legionella, particularly L. maceachernii, are uncommon, and in the differential diagnosis, attention needs to be paid to the patient’s underlying disease, medication use, and, in infant, the presence of immune deficiencies due to congenital disorders needs to be consider.

Conclusion

This case report provides the first case of soft tissue L. maceachernii infection in an infant worldwide and reviews the relevant literature. In the soft tissue of infant’s infections with Legionella, the presence of comorbid immunodeficiency disorders needs to be considered. Our results illuminate the critical intersections between host immunity and atypical pathogen behavior. Our findings extend the clinical spectrum of legionellosis while reinforcing three paradigm-shifting concepts in pediatric infectious disease management, including 1) L. maceachernii should be included in the differential diagnosis of pediatric soft tissue infections refractory to standard therapy, 2) underlying immunodeficiency must be systematically evaluated in pediatric patients with atypical Legionella infections, and 3) the diagnostic utility of mNGS in identifying fastidious pathogens and underscore the importance of genomic investigations in elucidating immunological comorbidities.

Date Sharing Statement

All data generated or analyzed during this study are included in this published article. It is clarified that the data presented in this study were contributed by Shifu Wang, one of the corresponding authors.

Ethical Approval and Consent Statements

This study underwent rigorous review and was approved by the Ethical Review Committee of Children’s Hospital Affiliated to Shandong University (approval no. SDFE-IRB/P-2022017). All procedures were conducted in strict compliance with the Ethical Review of Biomedical Research Involving Human Subjects (2016), the Declaration of Helsinki, and the International Ethical Guidelines for Biomedical Research Involving Human Subjects.

This study has been reviewed and approved by the Research Ethics Committee of the Children’s Hospital Affiliated to Shandong University (Approval No. SDFE-IRB/P-2022017), and the legal guardian of the patient has provided written informed consent for publication of the case details and clinical images.

Author Contributions

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

Funding

This work was supported by Guangzhou National Laboratory Special Project “Cross-Species Risk Research on Respiratory Viruses Potentially Threatening Humans” (grant number: GZNL2024A01019), the Shandong Children’s Health and Disease Clinical Medical Research Center Project (grant number: RC006), the special fund for high-level talents in the medical and health industry of Jinan City (Shifu Wang), and the Science and Technology Development Program of Jinan Municipal Health Commission (2022-1-45).

Disclosure

All authors disclosed no competing interests for this work.

References

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2. McDade JE, Shepard CC, Fraser DW, et al. Legionnaires’ disease: isolation of a bacterium and demonstration of its role in other respiratory disease. N Engl J Med. 1977;297(22):1197–1203. doi:10.1056/NEJM197712012972202

3. Cunha BA, Burillo A, Bouza E. Legionnaires’ disease. Lancet. 2016;387(10016):376–385. doi:10.1016/S0140-6736(15)60078-2

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6. Zhan XY, Yang JL, Zhou X, et al. Virulence effector SidJ evolution in Legionella pneumophila is driven by positive selection and intragenic recombination. PeerJ. 2021;9:e12000. doi:10.7717/peerj.12000

7. Fu J, Zhou M, Gritsenko MA, et al. Legionella pneumophila modulates host energy metabolism by ADP-ribosylation of ADP/ATP translocases. Elife. 2022;11. doi:10.7554/eLife.73611

8. Bitar DM, Molmeret M, Abu Kwaik Y. Molecular and cell biology of Legionella pneumophila. Int J Med Microbiol. 2004;293(7–8):519–527. doi:10.1078/1438-4221-00286

9. Newton HJ, Ang DK, van Driel IR, et al. Molecular pathogenesis of infections caused by legionella pneumophila. Clin Microbiol Rev. 2010;23(2):274–298. doi:10.1128/CMR.00052-09

10. Torres-Escobar A, Wilkins A, Juarez-Rodriguez MD, et al. Iron-depleting nutritional immunity controls extracellular bacterial replication in Legionella pneumophila infections. Nat Commun. 2024;15(1):7848. doi:10.1038/s41467-024-52184-x

11. Graham CI, MacMartin TL, de Kievit TR, et al. Molecular regulation of virulence in Legionella pneumophila. Mol Microbiol. 2024;121(2):167–195. doi:10.1111/mmi.15172

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13. Gubler JG, Schorr M, Gaia V, et al. Recurrent soft tissue abscesses caused by legionella cincinnatiensis. J Clin Microbiol. 2001;39(12):4568–4570. doi:10.1128/JCM.39.12.4568-4570.2001

14. Padrnos LJ, Blair JE, Kusne S, et al. Cutaneous legionellosis: case report and review of the medical literature. Transplant Infect Dis. 2014;16(2):307–314. doi:10.1111/tid.12201

15. Bond AR, Bainbridge E, Doernberg SB, et al. Disseminated Legionella micdadei infection in a liver transplant patient presenting as pulmonary nodules and a laryngeal lesion. Transpl Infect Dis. 2021;23(3):e13563. doi:10.1111/tid.13563

16. Kilborn JA, Manz LA, O’Brien M, et al. Necrotizing cellulitis caused by Legionella micdadei. Am J Med. 1992;92(1):104–106. doi:10.1016/0002-9343(92)90024-6

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18. Neiderud C-J, Lagerqvist Vidh A, Salaneck E. Soft tissue infection caused by Legionella bozemanii in a patient with ongoing immunosuppressive treatment. Infect Ecol Epidemiol. 2013;3(1):20739. doi:10.3402/iee.v3i0.20739

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24. Baltch AL, Smith RP, Ritz W. Inhibitory and bactericidal activities of levofloxacin, ofloxacin, erythromycin, and rifampin used singly and in combination against Legionella pneumophila. Antimicrob Agents Chemother. 1995;39(8):1661–1666. doi:10.1128/AAC.39.8.1661

25. Torres A, Cilloniz C. Are macrolides as effective as fluoroquinolones in legionella pneumonia? yes, but. Clin Infect Dis. 2021;72(11):1990–1991. doi:10.1093/cid/ciaa442

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New research has revealed how a common inherited mutation in the DDX41 gene – one of the most common genetic risk factors for bone marrow cancers – can disrupt red blood cell development and activate inflammatory responses that may drive progression to leukemia.

The research is published in Nature Communications.

Red blood cell precursors are highly sensitive to DDX41 loss

The research set out to shed light on a long-standing mystery: how DDX41 normally functions in healthy cells and why its loss can be so damaging.

“We noticed that many patients with faulty DDX41 often develop anemia,” explained senior author Peng Ji, MD, PhD, the Marie A. Fleming research professor of  pathology in Northwestern University’s Feinberg School of Medicine. “That led us to suspect that red blood cell development might be especially vulnerable to the loss of this gene.”

In the study, researchers deleted DDX41 in mouse models and cell cultures to examine its role in blood cell development. Loss of the gene during early red blood cell formation was found to be fatal in mice, while deletion in other blood cell types or later stages of development had limited effects. This suggests that DDX41 is particularly critical during the early stages of red blood cell formation.

DNA damage initiates inflammatory cell death

To validate their findings in human tissue, the team created bone marrow organoids from patient-derived stem cells that either contained no mutations or DDX41 mutations. Organoids with DDX41 mutations showed disrupted red blood cell development and elevated levels of DNA damage.

From this, the researchers concluded that DDX41 acts as type of “DNA detangler”, playing a critical role in maintaining the integrity of DNA in red blood precursor cells. Specifically, it helps resolve complex DNA structures known as G-quadruplexes – knot-like formations that can interfere with DNA replication and gene expression if left unresolved.

“Red blood cell genes are rich in these DNA knots,” said Ji, who is also a member of the Robert H. Lurie Comprehensive Cancer Center of Northwestern University. “We found that DDX41 binds to and unwinds them. When it’s mutated, these knots accumulate, causing DNA damage and triggering a cellular alarm system.”

When DDX41 is mutated or absent, unresolved G-quadruplexes build up, leading to DNA damage. This damage triggers the cGAS-STING pathway, a key immune surveillance mechanism that responds to the presence of cytosolic DNA by initiating inflammation. Persistent activation of this pathway in red blood cell precursors results in their destruction, ultimately leading to anemia.

“Collectively, the study positions DDX41 as a guardian of red blood cell precursors and traces how its failure sparks cGAS-STING–driven inflammation that progresses from anemia to blood cancer,” Ji explained.

Implications for treatment

Researchers are now testing whether blocking the cGAS-STING pathway in animal models could prevent red blood cell loss in individuals with DDX41 mutations. They also aim to investigate whether G-quadruplex accumulation contributes to other hematological diseases.

“We’re elevating G-quadruplexes from biochemical curiosities to real drug targets,” Ji said. “DDX41 is the cell’s DNA detangler for building red blood cells. When it’s absent, knots accumulate, trigger an inflammatory kill-switch, and lead to anemia — a chain reaction we believe can be halted by drugs that either block the switch or help untangle the knots.”

Reference: Bi H, Ren K, Wang P, et al. DDX41 resolves G-quadruplexes to maintain erythroid genome integrity and prevent cGAS-mediated cell death. Nat Commun. 2025;16(1):7195. doi: 10.1038/s41467-025-62307-7

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.

We all know exercising can improve our lives, but many of us don’t do it nearly enough. Work, stress and lack of time all get in the way of getting to the gym.

Only 24% of Americans meet the recommended physical activity guidelines set by the federal government. According to the Centers for Disease Control and Prevention, American adults should be getting 150 minutes of moderate-intensity aerobic activity each week and 2 days of muscle-strengthening activities each week.

Many of us aren’t meeting those benchmarks, but working out can help you fight disease, get more fit and even improve your mental health.

So how can you develop a consistent fitness routine — and stick with it?

Before you begin, it’s important to realize why you want to exercise more, says Aubre Winters, a fitness instructor based in Chicago and creator of the Sweat Sessions studio and workout program.

“I think that is the driving force. It’s kind of like the spark that starts your routine, whatever it is,” she said. “When you can really identify the way that you want to feel, and you can stick to that feeling, I think that is the real motivation for continuing to show up.”

4 tips with Aubre Winters

Figure out your motivation to exercise

“I think saying to someone, ‘How do you want to feel when you wake up in the morning? How do you want to feel when you rest your head on your pillow at night?’ And I always think, what are the little tools that we can do to just help bridge that gap between where we are and how we really want to feel. And sometimes I think that we get overwhelmed with thinking it needs to be a 60-minute workout or it needs to be an hour and a half of meditation.

“I think that starting really small and just noticing the shift even when you do 15 minutes of movement, even when you step outside to get fresh air for five minutes. It’s those little micro moments and the intentional choice that we make to just do something to make ourselves feel even 10% better. Then that’s where we can help get a little more inspired to show up to the 30-minute workout or to go to the group fitness class, to go on the 5-mile run when we thought we couldn’t. So I think that it’s just noticing those micro moments where we really feel just a little internal shift. That’s kind of the driver, I think, to staying consistent and to really feeling better.”

Find a workout you enjoy doing 

“I think you have to find something that you really enjoy doing, and I think that people [have] these big unattainable goals or these like, ‘Oh, I want to lose all of this weight,’ or ‘I’m going to buy the unlimited membership and go every day.’ It’s like we just set ourselves up for failure. So I think that doing something that … feels natural. It’s something you enjoy. That’s where we can stick with that consistency and continue to show up even when life gets really crazy.

“I work with a trainer as well, and he went out of town for a few weeks, and he was like, ‘Alright, here’s your workout plan. You’re going to go to the gym and do this plan.’ And for the first week, I was feeling so guilty while he was gone because I didn’t go to the gym once, because really, truth be told, A: I need the accountability to lift the way that I’m lifting outside of my dance and barre workouts that I do at my studio. And B: I don’t enjoy going to the gym floor and working out solo. I really like being in a group fitness setting when I’m choosing to work out for myself. So when you do something that you like, you’re more willing to go show up and create the time.”

Hold yourself accountable 

“If you even just tell a friend, ‘Hey, I’m signing up for the 6 a.m. tomorrow and check in on me afterwards and see that I went,’ or you put it in your calendar and you hold yourself accountable to it. That’s why I think I love group fitness, because I think that you kind of are starting to see the same people, and then it’s like you’re all in this together, and you kind of show up for each other. Even inviting a friend to go to a workout with you or to go on the walk with you — even if you both are listening to your own music and your own podcasts — at least you’re getting up and you have that accountability piece. I think the accountability piece is very, very important, and everyone finds that in different ways.”

Start slow and easy 

“I want you to ask yourself, ‘How do I want to feel?’ And I think that awareness and that feeling is going to help create the next step. So if it’s like, ‘I want to feel more clear.’ I’m going to then tell myself, ‘Alright, tomorrow morning I’m waking up and I’m going on that 30-minute walk before I have to go get ready for work. And it’s almost like if you don’t do it, you’re like … at the end of the day, the only one who’s really letting me down right now is myself. And I know that sounds a little harsh, but it does come down to a choice that you’re making between you and you.

“And I think with the workout piece, it’s very similar. I want to feel strong. I want to feel like I can lift my 2-year-old and walk around the house with them without being in pain. I want to be able to have longevity and be able to go grocery shopping and go play tennis and do all these things as I age. And so what can I do to bridge that gap right here, right now? Maybe it’s that 30-minute workout or asking a friend to go show up to the gym with you or just anything that you can schedule and go do. But part one, ask yourself how you want to feel, and part two is making the plan, signing up for the workout, going on the walk.”

This interview was edited for clarity.

Samantha Raphelson produced and edited this interview for broadcast with Catherine Welch. Raphelson also produced it for the web.

This segment aired on August 21, 2025.