A Pilot Randomized Control Trial of Holding During Hypothermia and Effects on Maternal and Infant Salivary Cortisol Levels
Authors demonstrate positive effects of holding during TH as evidenced by lower salivary cortisol for both mother and infant and decreased heart rate, respiratory rate, and blood pressure for the infant on day-2. Further research is needed to replicate these results, to understand the lack of infant response on day-3 and to assess correlation with cumulative morphine exposure.
KEY FINDINGS: Authors demonstrate positive effects of holding during TH as evidenced by lower salivary cortisol for both mother and infant and decreased heart rate, respiratory rate, and blood pressure for the infant on day-2. Further research is needed to replicate these results, to understand the lack of infant response on day-3 and to assess correlation with cumulative morphine exposure.
BACKGROUND: The lack of physical contact during therapeutic hypothermia (TH) is challenging for parents of newborns with hypoxic ischemic encephalopathy. Holding is often avoided due to concerns for effects on infant temperature and for dislodging equipment. Authors assessed the effect of holding during TH on maternal and infant salivary cortisol levels and on infant vital signs.
DETAILS: Prospective crossover study with infants randomized to a 30-minute session of holding on day-2 versus day-3 of TH. "No-holding" occurred on the alternate day at the same time. Pre- and post-holding salivary cortisol levels were compared between holding and no-holding conditions. Vital signs were collected at 2-minute intervals. Data was analyzed using mixed-effects models. Thirty-four mothers and infants were recruited. The median gestational age was 39 weeks, 16 (94%) had moderate encephalopathy and all were on morphine during TH. Salivary cortisol levels decreased after holding for infants on day-2 (P = .02) and mothers on day-2 and day-3 (P = .01). Infants held on day-2, but not on day-3, had lower heart rates, respiratory rates, and mean arterial pressures. Temperature and oxygen saturations were stable on both days.
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Source: Fox, L., Cutler, A., Kaneko-Tarui, T., et al. (20245). A Pilot Randomized Control Trial of Holding During Hypothermia and Effects on Maternal and Infant Salivary Cortisol Levels. Advances in Neonatal Care. 2025; 25(2): 173-180. Published: April, 2025. DOI: 10.1097/ANC.0000000000001239.
Palliative Extracorporeal Membrane Oxygenation Decannulation: An Ethical, Evidence-Based Approach
A structured approach to ECMO de-escalation and decannulation can reduce practice variability while incorporating patient and family preferences. Proactive symptom management may improve the patient and family experience, supporting a more comfortable and dignified end-of-life journey.
KEY FINDINGS: A structured, interprofessional approach to palliative ECMO de-escalation can reduce variability in end-of-life practice and support more consistent symptom management and communication. Incorporating patient and family preferences into the process, together with proactive symptom management and staff debriefing, was associated with a more comfortable and dignified end-of-life experience in this quality-improvement setting.
BACKGROUND: Extracorporeal membrane oxygenation (ECMO) is an invasive, potentially lifesaving therapy associated with complications involving multiple organ systems. When ECMO is no longer considered beneficial, de-escalation or decannulation may be required as part of a transition to comfort-focused care and natural death. At a tertiary care facility with 64 beds using ECMO, variability was identified in ECMO initiation, communication with patients and families, determination of nonbeneficial therapy, and symptom management during de-escalation.
DETAILS: This quality-improvement project integrated palliative care, reviewed existing literature on best practices, and established an interprofessional task force focused on ECMO de-escalation. New clinical guidelines were developed to provide a consistent, evidence-based framework for communication, decision-making, symptom management, and de-escalation/decannulation. The initiative was designed to reduce practice variability while improving the experience of patients, families, and clinicians during transition to comfort-directed care.
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Implementation of the guidelines decreased practice variability and reduced patient and family stress and discomfort during ECMO de-escalation and decannulation. Team members reported decreases in symptoms of secondary trauma and moral distress associated with these situations. They also reported improved delivery of end-of-life care, including family education and support, patient advocacy, and symptom management. Family members valued greater attention to both patient and family well-being, while structured staff debriefings supported reflection and identification of opportunities for improvement.
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Source: Arbour, R., Abate, M., Garcia, O., et al. Palliative Extracorporeal Membrane Oxygenation Decannulation: An Ethical, Evidence-Based Approach. Critical Care Nurse. 2026; 46(4): 17-28. Published: August 1, 2026. DOI: 10.4037/ccn2026166.
Real-World Study Finds No Significant Difference in Heart Failure Risk Between Biosimilar and Reference Trastuzumab
In real-world practice, trastuzumab biosimilars were not associated with a statistically significant increase in heart failure compared with reference trastuzumab, supporting their cardiac safety. However, older age, anthracycline use, and greater comorbidity burden remain important risk factors, and larger studies are needed to assess cardiac safety differences among individual biosimilars.
KEY FINDINGS: In this large real-world cohort of patients with early-stage HER2-positive breast cancer, biosimilar trastuzumab use increased markedly between 2018 and 2024 without a statistically significant difference in heart failure risk compared with reference trastuzumab. Overall heart failure occurred in 5.9% of the study population. Comorbidity burden and older age were associated with higher heart failure risk, emphasizing the importance of cardiovascular risk assessment during HER2-directed therapy. Because this was a retrospective claims-based study, longer follow-up and additional real-world studies are needed to further evaluate long-term cardiac outcomes.
BACKGROUND: Trastuzumab is an important treatment for HER2-positive breast cancer, but cardiac dysfunction, including heart failure, remains a recognized safety concern. Biosimilar trastuzumab products have expanded treatment access and may reduce costs, although real-world data comparing their cardiac safety with the reference product remain limited. This study evaluated the uptake of biosimilar trastuzumab and compared heart failure risk between patients receiving biosimilar and reference trastuzumab in routine clinical practice.
DETAILS: The investigators analyzed patients aged ≥18 years with breast cancer who received trastuzumab between 2018 and 2024 using the IQVIA PharMetrics Plus Closed Health Plan Claims database. Patients who underwent breast cancer surgery within the first year after diagnosis were considered to have early-stage disease. Individuals with a heart failure diagnosis before breast cancer surgery were excluded. Trastuzumab products were identified using Healthcare Common Procedure Coding System Level II codes, while heart failure was identified using International Classification of Diseases codes. The analysis used multivariable cause-specific Cox proportional hazards regression to evaluate the association between trastuzumab type and subsequent heart failure risk. The study included 5,135 patients, of whom 43.9% received reference trastuzumab.
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Use of biosimilar trastuzumab increased substantially during the study period, from 0% in 2018 to 71.3% in 2024 (P<0.001). Overall, heart failure occurred in 5.9% of patients, including 5.5% of those receiving reference trastuzumab and 6.3% of those receiving biosimilar trastuzumab (P=0.26). After adjustment for relevant factors, there was no statistically significant difference in heart failure risk between biosimilar and reference trastuzumab (adjusted HR, 1.16; 95% CI, 0.92-1.46). In contrast, patients with a Charlson Comorbidity Index score ≥2 had a higher heart failure risk than those with a score of 0 (adjusted HR, 1.52; 95% CI, 1.11-2.08). Older age was also associated with greater risk: compared with patients aged 18-54 years, the adjusted HR was 1.61 (95% CI, 1.19-2.19) for those aged 65-74 years and 1.95 (95% CI, 1.29-2.96) for those aged ≥75 years.
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Source: Jackson, I., Zhang, N., Sullivan, M., et al. Real-World Cardiotoxicity of Biosimilar versus Reference Trastuzumab in Early HER2-Positive Breast Cancer. JACC: CardioOncology. Published: September 10, 2026. DOI: 10.1016/j.jaccao.2026.07.009.
Formononetin May Protect Against Anthracycline Cardiotoxicity Through Cardiac Metabolic Improvement
A preclinical study identified ERRa as an early metabolic regulator of anthracycline-induced cardiotoxicity, with its reduction occurring before overt cardiac dysfunction. Formononetin, an ERRa activator, improved cardiac metabolism and function in mouse and pig models while also enhancing doxorubicin's anticancer activity in breast cancer organoids. The findings suggest a potential dual-action strategy for protecting the heart during anthracycline therapy, but clinical studies are still needed.
KEY FINDINGS: The findings identify ERRα downregulation as an early and potentially causal component of anthracycline-induced cardiac injury. Formononetin improved cardiac energy metabolism and function in experimental models while retaining, and potentially enhancing, doxorubicin's anticancer activity in breast cancer organoids. The study therefore suggests that pharmacologic activation of ERRα could represent a future strategy for simultaneously addressing anthracycline cardiotoxicity and cancer treatment. However, the evidence remains preclinical, and clinical studies are required to determine whether these findings translate into cardioprotection in patients receiving anthracycline chemotherapy.
BACKGROUND: Anthracyclines such as doxorubicin are effective anticancer agents, but their use can be limited by anthracycline-induced cardiotoxicity (AIC). Early metabolic disturbances in cardiac muscle may contribute to the development of cardiac dysfunction. This study investigated the role of estrogen-related receptor α (ERRα), a regulator of cardiac energy metabolism, in AIC and evaluated whether pharmacologic activation of ERRα with formononetin could provide cardiac protection while maintaining anticancer activity.
DETAILS: The investigators used a porcine model of anthracycline cardiotoxicity to examine changes in ERRα over time and cardiomyocyte-specific gain- and loss-of-function mouse models to assess its functional role. Mechanistic experiments, including ChIP-qPCR, reporter assays, and microscale thermophoresis, were used to investigate how formononetin interacts with the ERRα pathway. Cardiac tissue from patients who had received chemotherapy was also examined, while human breast cancer patient-derived organoids were used to evaluate potential effects on tumor activity. ERRα expression was reduced in hearts from the porcine AIC model and in cardiac tissue from patients treated with chemotherapy. In pigs, the reduction occurred at the 6-week subclinical stage, before overt cardiac dysfunction developed. Increasing ERRα expression specifically in cardiomyocytes enhanced mitochondrial metabolic programs and fatty-acid oxidation and preserved systolic function after doxorubicin exposure, whereas ERRα reduction worsened metabolic dysfunction and cardiac impairment.
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Drug screening identified formononetin as a selective ERRα activator. In mouse and pig models, formononetin increased ERRα activity, improved cardiac mitochondrial metabolism, and reduced anthracycline-associated cardiac injury. Mechanistic experiments indicated that formononetin interacts with the ERRα/PGC-1α complex and promotes its stability, supporting activation of downstream metabolic pathways.
Importantly, formononetin also demonstrated anticancer activity in human breast cancer patient-derived organoids. Treatment with formononetin alone reduced organoid viability and proliferation, while combining formononetin with doxorubicin produced greater antitumor effects.
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Source: Wang, X., Ling, G., Wei, Y., et al. Natural ERRα Activator Formononetin Ameliorates Anthracycline Cardiotoxicity via Metabolic Improvement. Circulation Research. 2026; 139(7): e329042. Published: September 11, 2026. DOI: 10.1161/CIRCRESAHA.126.329042.
Self-Sampling HPV Testing Increases Cervical Cancer Screening Uptake in Primary Care
A Singapore randomized trial found that offering HPV self-sampling increased cervical cancer screening uptake from 42.8% to 56.6%. More than half of screened women chose self-sampling, suggesting that flexible screening options may help reach women who otherwise remain unscreened.
KEY FINDINGS: Offering HPV self-sampling as an additional screening option substantially increased cervical cancer screening participation and high-risk HPV detection compared with clinician sampling alone in this Singapore primary care population. The benefit was particularly relevant to women who had never previously undergone screening, suggesting that providing greater choice and convenience may help reach populations that are otherwise difficult to engage. More than half of screened women in the intervention group selected self-sampling, indicating substantial acceptance of this approach. However, lower uptake among women with less educational attainment highlights the need for targeted education and engagement strategies when implementing self-sampling programs.
BACKGROUND: Cervical cancer screening remains suboptimal in Singapore, where clinician-collected HPV testing has been the standard approach. Concerns related to discomfort, privacy, embarrassment, or the clinical setting may discourage some women from participating in screening. This pragmatic randomized controlled trial evaluated whether offering self-sampling for HPV DNA testing alongside clinician sampling could increase cervical cancer screening uptake and detection of high-risk human papillomavirus (HPV) compared with clinician sampling alone.
DETAILS: The open-label, 2-arm randomized controlled trial used a Zelen design and was conducted across National Healthcare Group Polyclinics in Singapore. Women aged 30-69 years who were due for cervical cancer screening were randomly assigned 1:1 to an intervention group or usual care. Women in the intervention group were offered clinician sampling followed by self-sampling if they did not choose clinician sampling, whereas women receiving usual care were offered clinician sampling alone. The primary outcome was detection of high-risk HPV DNA, with screening uptake as the secondary outcome.
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Between August 2024 and February 2025, 650 women were randomized, with 640 participants included in the final analysis, 320 in each group. Subgroup analyses evaluated outcomes according to previous screening history, while multivariable analyses examined factors associated with screening choices.
High-risk HPV detection was significantly greater when self-sampling was offered alongside clinician sampling than with clinician sampling alone: 3.1% versus 0.3%, respectively, representing an absolute difference of 2.8% (95% CI, 0.8-4.8; P<.001). The higher detection rate was driven by greater screening participation, with screening uptake reaching 56.6% in the intervention group compared with 42.8% with usual care, an absolute difference of 13.8% (95% CI, 6.0-21.4; P<.001).
The increase in screening uptake was particularly evident among women who had no previous screening and those with a regular screening history. Among women who underwent screening in the intervention group, 56.4% selected self-sampling. Lower educational attainment was associated with lower odds of choosing self-sampling rather than declining screening altogether.
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Source: Ng, X. R., Quek, I. P., Pereira, M. J., et al. Effect of Self-Sampling HPV DNA Testing on Cervical Cancer Screening in Singapore's Primary Care: Pragmatic Randomized Controlled Trial Annals of Family Medicine.. 2026; 24(4): 291-300. Published: July, 2026. DOI: 10.1370/afm.250683.
Biochemical Effects of Oral Contraceptives in Young Women With Classic Congenital Adrenal Hyperplasia
A prospective study found that ethinylestradiol/levonorgestrel reduced key adrenal androgens while increasing cortisol levels. Nearly half of participants had a reduction in hydrocortisone dose following biochemical changes. Larger randomized studies are needed to confirm these findings.
KEY FINDINGS: In adolescent and young women with classic 21OHD, combined OC containing 0.03 mg ethinylestradiol and 0.15 mg levonorgestrel was associated with broad reductions in circulating and urinary androgen-related steroids and an increase in cortisol levels. Nearly half of the participants who completed the study required a reduction in hydrocortisone dosage during the six-OC-cycle observation period. These findings suggest that combined OCs may provide an adjunctive approach for managing persistent androgen excess in females with classic CAH when conventional glucocorticoid treatment does not provide satisfactory biochemical control. However, the study was small and observational, so the findings do not establish a causal relationship, and randomized studies are needed to determine the longer-term clinical and metabolic effects of OC therapy in this population.
BACKGROUND: Androgen excess remains a therapeutic challenge in adolescent and young women with classic 21-hydroxylase deficiency (21OHD), the most common form of congenital adrenal hyperplasia (CAH). Combined oral contraceptives (OCs) containing ethinylestradiol and a progestin can influence ovarian and adrenal steroidogenesis, but their effects on the broader steroid profile in women with classic 21OHD have not been systematically characterized. This prospective observational study evaluated changes in circulating and urinary steroid metabolites following initiation of a combined OC in adolescent and young women with classic 21OHD.
DETAILS: The multicenter study enrolled 20 young women with genetically confirmed classic 21OHD between March 2021 and March 2024. Participants were 13-25 years old at baseline sampling, although the recruited cohort had a median age of 16 years and a range of 11-24 years. The participants initiated a combined OC containing 0.03 mg ethinylestradiol and 0.15 mg levonorgestrel. The study included three assessments: before OC initiation, during the third OC cycle, and during the sixth OC cycle. Blood samples and 24-hour urine collections were obtained at each visit, with plasma steroids measured using liquid chromatography-mass spectrometry and urinary metabolites assessed using gas chromatography-mass spectrometry. Seventeen of the 20 participants completed the study, with a median age of 16.8 years (range, 11-24). The reasons for OC initiation included irregular menses, contraception, amenorrhea, dysmenorrhea, and hyperandrogenemia. Most participants were receiving hydrocortisone and fludrocortisone for CAH management. The prospective design and combined assessment of plasma and urinary steroid profiles allowed detailed characterization of biochemical changes during OC treatment.
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Combined OC therapy was associated with significant reductions in several circulating androgens and androgen precursors. Compared with baseline, plasma concentrations of 17α-hydroxyprogesterone, androstenedione, dehydroepiandrosterone, and testosterone decreased significantly, with all P values <0.005. Plasma cortisol concentrations increased significantly (P<0.001), while urinary 24-hour excretion of androgen metabolites, including the 11-oxygenated androgen metabolite 11-oxo-etiocholanolone, also declined.
The broader steroid analysis showed reductions in multiple androgen-related metabolites, including androsterone, etiocholanolone, DHEA, testosterone, dihydrotestosterone, 11-oxo-etiocholanolone, and 11β-hydroxyandrosterone. Cortisol concentrations and urinary cortisol excretion increased during OC treatment. These biochemical changes had implications for glucocorticoid management: 8 of 17 participants (47%) who completed the study had at least one reduction in hydrocortisone dose during follow-up in response to laboratory changes.
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Source: Kouri, C., Sommer, G., Cavalieri Costa, F., et al. Biochemical Control in Young Women With Congenital Adrenal Hyperplasia Taking Oral Contraceptives: A Prospective Observational Study. v. 2026; 195(3): 385-395. Published: September, 2026. DOI: 10.1093/ejendo/lvag160.
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