An Individual Participant Data Network Meta-analysis

[Posted 17/Jul/2026]

AUDIENCE: Emergency Medicine, Psychiatry

KEY FINDINGS: This IPD network meta-analysis suggests that antipsychotic–benzodiazepine combinations may provide the most effective pharmacologic option for rapid tranquilisation in emergency settings, particularly compared with haloperidol monotherapy. While other antipsychotics and benzodiazepines also demonstrated favorable efficacy, haloperidol alone appeared less effective and was associated with extrapyramidal adverse effects. Given the very low certainty of evidence and the heterogeneity across studies, treatment selection should be individualized, and additional large pragmatic randomized trials are needed to strengthen the evidence base.

BACKGROUND: Psychomotor agitation is a frequent medical emergency requiring rapid pharmacologic intervention when nonpharmacologic de-escalation is insufficient. Although multiple parenteral agents are available, including antipsychotics, benzodiazepines, and combination regimens, treatment recommendations vary across clinical guidelines and practice settings. This systematic review and individual participant data (IPD) network meta-analysis evaluated the comparative effectiveness and safety of pharmacologic agents used for rapid tranquilisation in psychiatric and general emergency settings.

DETAILS: This systematic review included randomized controlled trials comparing intramuscular or intravenous pharmacologic treatments for rapid tranquilisation in patients with psychomotor agitation. Literature searches were conducted from database inception through November 14, 2025. A total of 18 trials involving 3,411 participants across eight regions met the inclusion criteria, with 13 trials (2,705 participants) providing individual participant data for the primary analysis. Participants had a mean age of 36.0 years (SD 11.7), 58.3% were men, and 68.2% presented with severe agitation at baseline. The primary outcome was achievement of sedation within 15-30 minutes after treatment. Bayesian one-stage random-effects IPD network meta-regression was used to compare treatment classes while accounting for agitation severity and other prognostic factors. Safety outcomes were assessed using aggregate data. Baseline agitation severity significantly influenced treatment response. In patients with moderate agitation, the likelihood of achieving sedation within 15-30 minutes, compared with haloperidol monotherapy, was greatest with antipsychotic-benzodiazepine combinations (OR 12.93, 95% CrI 3.00-50.91; RR 1.58), followed by benzodiazepines (OR 5.52, 95% CrI 1.37-21.02; RR 1.49) and other antipsychotics (OR 4.54, 95% CrI 1.35-14.45; RR 1.45). Among patients with severe agitation, antipsychotic-benzodiazepine combinations remained more effective than haloperidol monotherapy (OR 4.86, 95% CrI 1.28-17.54; RR 1.73), whereas the comparative effectiveness of benzodiazepines (OR 2.09, 95% CrI 0.58-6.99; RR 1.38) and other antipsychotics (OR 1.70, 95% CrI 0.62-4.59; RR 1.28) was less certain. Most participants (>90%) achieved sedation within 45-240 minutes irrespective of treatment. Antipsychotic-benzodiazepine combinations demonstrated the greatest advantage during the first 10 minutes after administration, although early time-point data were limited. Haloperidol monotherapy was associated with extrapyramidal adverse effects, whereas benzodiazepines were linked to cardiorespiratory depression. Sensitivity analyses suggested ketamine ranked as the most effective treatment; however, this finding was derived from a single study without individual participant data. Overall confidence in the evidence for the primary outcome was rated as very low.

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Source: Siafis, S., Philipona, F., Nomura, N., et al. Comparative Effectiveness and Safety of Pharmacological Treatments for Rapid Tranquilisation in Emergency Settings: A Systematic Review and Individual Participant Data Network Meta-Analysis. The Lancet Psychiatry. 2026; 13(7): 567-580. Published: July, 2026. DOI: 10.1016/S2215-0366(26)00097-0.

[Posted 15/Sep/2026]

AUDIENCE: Cardiology, Oncology, Hematology

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.

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.

[Posted 8/Sep/2026]

AUDIENCE: Endocrinology, Internal Medicine, Ob/Gyn

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.

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.

[Posted 7/Sep/2026]

AUDIENCE: Nephrology, Internal Medicine, Pediatric

KEY FINDINGS: In this experimental mouse study, irregularly shaped microplastic particles demonstrated a different biological distribution and renal effect profile from spherical particles. Despite >99% of administered particles being excreted in feces, irregular fragments persisted in the circulation, accumulated in the kidneys, and were detected in urine. Renal exposure was associated with vascular and tubular lesions, capillary flow disturbances, and changes suggesting disruption of the glomerular filtration barrier. The findings indicate that microplastic morphology may be an important determinant of biological effects, although the clinical relevance to human kidney health remains to be established.

BACKGROUND: Human exposure to microplastics is widespread, but the biological effects of particle shape remain incompletely understood. Most experimental studies have used spherical particles, despite environmental microplastics commonly occurring as irregular fragments. This study compared spherical and irregularly shaped microplastic particles to determine whether particle morphology influences their distribution in the body and their effects on renal function.

DETAILS: Investigators administered labeled spherical and irregular microplastic particles to mice by oral gavage, either as a single dose or daily for 7 days. Microplastic distribution was evaluated in multiple organs, while renal effects were assessed using histochemistry and intravital multiphoton microscopy. Additional functional experiments were performed using isolated perfused mouse kidneys. Overall intestinal absorption was limited, with >99% of administered microplastic particles being eliminated in feces. However, irregular fragments remained detectable in the circulation for several days and accumulated in multiple organs following oral exposure.

Irregular microplastic particles were detected in the urine as well as within renal blood vessels, glomeruli, and tubules. Their presence in the urine suggested that these particles could cross the glomerular filtration barrier. Within the kidney, irregular particles were associated with phagocytic cells. Functional studies demonstrated that irregular microplastics caused disturbances in capillary flow and produced lesions involving renal blood vessels and the tubular system. They also resulted in glomerular albumin hyperfiltration and increased proximal tubular albumin uptake, findings consistent with impairment of the glomerular filtration barrier. These effects were not observed following ingestion of spherical microplastic particles.

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Source: Triebel, H., De Luca, F., Baumann, S. J., et al. Irregularly Shaped Microplastic Particles Compromise the Integrity of the Glomerular Filtration Barrier of the Kidney. Kidney360. 2026; 7(8): 1750-1762. Published: May 12, 2026. DOI: 10.34067/KID.0000001215.

[Posted 4/Sep/2026]

AUDIENCE: Ob/Gyn, Family Medicine

KEY FINDINGS: In 203 nulliparous women assessed at 35+0 to 36+6 weeks, higher sFlt-1/PlGF ratios were associated with higher OA-PSV ratios, lower OA-PI, and higher MAP. An OA-PSV ratio 0.61 identified women with an sFlt-1/PlGF ratio <38 with 90.5% accuracy at a 15% false-positive rate. The findings suggest that OA Doppler, particularly the PSV ratio, may provide a noninvasive and accessible surrogate for angiogenic imbalance near term. Further validation is needed before OA Doppler can replace biochemical assessment in clinical practice.

BACKGROUND: Angiogenic imbalance, reflected by an elevated soluble fms-like tyrosine kinase-1 to placental growth factor (sFlt-1/PlGF) ratio, is associated with the pathophysiology of pre-eclampsia. Although the sFlt-1/PlGF ratio can help identify angiogenic imbalance, its use may be limited by cost and availability. This study evaluated whether ophthalmic artery (OA) Doppler parameters are associated with the sFlt-1/PlGF ratio and whether OA Doppler could help identify or exclude angiogenic imbalance in near-term pregnancy.

DETAILS: This cross-sectional cohort study was nested within the PE37 randomized controlled trial and included nulliparous women recruited between January 2023 and January 2025. Women underwent sFlt-1/PlGF measurement between 35+0 and 36+6 weeks' gestation. A subsample underwent OA Doppler assessment, including the OA peak systolic velocity (PSV) ratio and pulsatility index (PI), together with measurement of mean arterial pressure (MAP) and mean uterine artery PI. The Doppler operator was blinded to the sFlt-1/PlGF results. The analysis included 203 women, distributed across the lowest, middle, and highest sFlt-1/PlGF ratio tertiles as 62, 71, and 70 women, respectively.

Increasing sFlt-1/PlGF ratio was associated with progressive changes in OA Doppler measurements. The median OA-PSV ratio increased from 0.45 (IQR, 0.39–0.53) in the lowest tertile to 0.48 (IQR, 0.41–0.58) in the middle tertile and 0.59 (IQR, 0.50–0.66) in the highest tertile (adjusted P<0.001). Conversely, median OA-PI decreased from 2.20 (IQR, 1.92–2.61) to 2.13 (IQR, 1.86–2.37) and 1.86 (IQR, 1.60–2.26), respectively (adjusted P=0.031).

MAP also increased across the sFlt-1/PlGF tertiles, from 87.0 (IQR, 82.7–92.0) mmHg to 88.7 (IQR, 83.7–93.7) mmHg and 94.7 (IQR, 89.3–100.0) mmHg (adjusted P<0.001). In contrast, mean uterine artery PI did not demonstrate a significant trend across the sFlt-1/PlGF tertiles.

For identifying an sFlt-1/PlGF ratio <38, an OA-PSV ratio <0.61 correctly identified 90.5% of women at a 15% false-positive rate. The authors therefore identified OA Doppler, particularly the PSV ratio, as a potentially useful surrogate measure for angiogenic imbalance and a promising approach for ruling out abnormal angiogenic status.

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Source: Tinajero, M. F., Faraci, C., Cuenca, M., et al. Ophthalmic artery Doppler as potential surrogate marker of angiogenic imbalance in near-term pregnancy. Ultrasound in Obstetrics & Gynecology. 2026; 68(2):211–219. Published: August, 2026. DOI: 10.1002/uog.70270.

[Posted 31/Aug/2026]

AUDIENCE: Endocrinology, Ob/Gyn, Internal Medicine

KEY FINDINGS: Approximately one in four women with recent GDM developed hypertension by 5 months postpartum. Higher maternal weight and blood pressure early in pregnancy, as well as Black or mixed ethnicity, were associated with increased risk, while gestational hypertension or pre-eclampsia was also associated with postpartum hypertension. Women with postpartum hypertension had greater adiposity and more frequent dyslipidemia, highlighting the broader cardiometabolic abnormalities present after GDM. Because early-pregnancy characteristics provided only modest prediction, the findings support structured postpartum assessment that includes blood pressure and broader cardiometabolic risk evaluation rather than focusing solely on dysglycemia.

BACKGROUND: Gestational diabetes mellitus (GDM) is associated with an increased risk of later cardiometabolic disease, including hypertension. However, the occurrence and determinants of hypertension soon after pregnancy complicated by GDM have not been well defined. This prospective study evaluated the incidence and predictors of hypertension at 5 months postpartum and examined its relationship with other cardiometabolic abnormalities in women with recent GDM.

DETAILS: This single-center observational prospective cohort study was conducted at King's College Hospital, London, between September 2023 and January 2025. Women with GDM who received routine prenatal care at 12 weeks' gestation were invited for a postpartum assessment at approximately 5 months after delivery; women with chronic hypertension were excluded. The assessment included blood pressure, BMI, waist circumference, glucose status, lipid profile, and renal function. Hypertension was defined as systolic BP ≥ 130 mmHg, diastolic BP ≥ 80 mmHg, or receipt of antihypertensive treatment. Of 912 women with GDM invited for postpartum review, 696 (76.3%) attended. After excluding 18 women with chronic hypertension, 678 women constituted the study cohort. Follow-up occurred at a median of 5.1 (IQR, 4.4-6.7) months after birth.

Among the 678 women with previous GDM, 179 (26.4%) developed hypertension at a median of 5.1 (IQR, 4.4-6.7) months postpartum. Women who subsequently developed hypertension had higher early-pregnancy weight and blood pressure. At 12 weeks' gestation, median weight was 79.3 kg versus 69.3 kg among women who remained normotensive, while median systolic BP was 121.8 versus 115.5 mmHg and median diastolic BP was 74.5 versus 70.3 mmHg, respectively. Obesity at this stage was also more frequent among women who later developed hypertension (50.3% vs 28.5%). Pregnancy hypertensive disorders were more common among women who developed postpartum hypertension. Gestational hypertension occurred in 8.4% versus 3.8%, and pre-eclampsia in 9.5% versus 1.8%, among women who developed postpartum hypertension compared with those who remained normotensive.

Multivariable analysis identified higher maternal age, Black or mixed ethnicity, higher weight, and higher systolic and diastolic BP at 12 weeks as predictors of postpartum hypertension. Black ethnicity was associated with an adjusted OR of 1.88 (95% CI, 1.19-3.00), mixed ethnicity with an adjusted OR of 2.75 (95% CI, 1.21-6.24), and weight ≥ 73 kg with an adjusted OR of 1.57 (95% CI, 1.04-2.38). Each 1-mmHg increase in systolic BP was associated with an adjusted OR of 1.04 (95% CI, 1.02-1.07), and each 1-mmHg increase in diastolic BP with an adjusted OR of 1.04 (95% CI, 1.00-1.07). Development of gestational hypertension or pre-eclampsia was associated with an adjusted OR of 3.00 (95% CI, 1.69-5.34).

At the postpartum assessment, women with hypertension had a median BMI of 30.1 (IQR, 26.7-36.8) kg/m² compared with 27.0 (IQR, 23.5-30.6) kg/m² among normotensive women. A waist-to-height ratio > 0.5 was present in 87.7% versus 69.1%, and dyslipidemia in 35.8% versus 24.4%, respectively. Dysglycemia and renal dysfunction did not differ significantly between the groups.

The prenatal prediction model had only modest discriminatory ability. The AUC was 0.723 (95% CI, 0.680-0.766) using characteristics available at 12 weeks and 0.739 (95% CI, 0.697-0.782) after adding gestational hypertension or pre-eclampsia. At a 20% false-positive rate, detection rates were 49.5% and 53.7%, respectively.

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Source: Gomez Fernández, C., Charakida, M., Moser, M., et al. Hypertension at 5 months postpartum in women with gestational diabetes. Ultrasound in Obstetrics & Gynecology. 2026; 68(2): 202-210. Published: July 17, 2026. DOI: 10.1002/uog.70291.