Apolipoprotein A-IV Concentrations and Clinical Outcomes In A Large CKD Cohort
ApoA-IV appears to be an independent risk marker for reduced all-cause mortality, cardiovascular events and heart failure in a large cohort of patients with CKD.
KEY FINDINGS: The data support a link between elevated apoA-IV concentrations and reduced inflammation in moderate CKD. ApoA-IV appears to be an independent risk marker for reduced all-cause mortality, cardiovascular events and heart failure in a large cohort of patients with CKD.
BACKGROUND: Chronic kidney disease (CKD) represents a chronic proinflammatory state and is associated with very high cardiovascular risk. Apolipoprotein A-IV (apoA-IV) has antiatherogenic, antioxidative, anti-inflammatory and antithrombotic properties and levels increase significantly during the course of CKD. Study aimed to investigate the association between apoA-IV and all-cause mortality and cardiovascular outcomes in the German Chronic Kidney Disease study.
DETAILS: This was a prospective cohort study including 5141 Caucasian patients with available apoA-IV measurements and CKD. The majority of the patients had an estimated glomerular filtration rate (eGFR) of 30-60 ml/min/1.73m2 or an eGFR >60 ml/min/1.73m2 in the presence of overt proteinuria. Median follow-up was 6.5 years. The association of apoA-IV with comorbidities at baseline and endpoints during follow-up was modelled adjusting for major confounders. Mean apoA-IV concentrations of the entire cohort were 28.9 ± 9.8 mg/dl. Patients in the highest apoA-IV quartile had the lowest high-sensitivity C-reactive protein values despite the highest prevalence of diabetes, albuminuria and the lowest eGFR. Each 10 mg/dl higher apoA-IV translated into lower odds of prevalent cardiovascular disease (1289 cases, odds ratio = 0.80, 95% confidence interval [CI] 0.72-0.86, p = 0.0000003). During follow-up, each 10 mg/dl higher apoA-IV was significantly associated with a lower risk for all-cause mortality (600 cases, hazard ratio [HR] = 0.81, 95% CI 0.73-0.89, p = 0.00004), incident major adverse cardiovascular events (506 cases, HR = 0.88, 95% CI 0.79-0.99, p = 0.03) and death or hospitalizations due to heart failure (346 cases, HR = 0.84, 95% CI 0.73-0.96, p = 0.01).
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Source: Schwaiger, J. P., Kollerits, B., Steinbrenner, I., et al. (2022). Apolipoprotein A-IV Concentrations And Clinical Outcomes In A Large Chronic Kidney Disease Cohort: Results from the GCKD Study. Journal of Internal Medicine. 2022; 291(5): 622-636. Published: May, 2022. DOI: 10.1111/joim.13437.
Ophthalmic Artery Doppler May Serve as a Noninvasive Marker of Angiogenic Imbalance in Near-Term Pregnancy
The findings demonstrate a significant relationship between the sFlt-1/PlGF ratio and ophthalmic artery Doppler measurements in near-term pregnancy. In particular, the OA peak systolic velocity ratio appears to reflect underlying angiogenic imbalance. Because OA Doppler is noninvasive, relatively accessible, and inexpensive, it may represent a useful surrogate approach for excluding angiogenic imbalance.
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.
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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.
Next-Generation Phenotyping May Strengthen Variant Interpretation in Mowat-Wilson Syndrome
In a proof-of-concept study, GestaltMatcher ranked Mowat-Wilson syndrome as the leading diagnosis in a 4-year-old child with a de novo ZEB2 variant. Three of 4 facial images met the PP4 moderate threshold and 1 met the supporting threshold. Integration of facial, HPO, and molecular data through PEDIA ranked ZEB2 as the most likely disease-causing gene. The findings suggest that AI-assisted phenotyping may provide quantitative support for variant interpretation while complementing expert clinical genetics assessment.
KEY FINDINGS: Computational facial phenotyping using GestaltMatcher identified MWS as the leading diagnosis in a child with a suspected de novo ZEB2 variant and provided quantitative evidence that supported variant interpretation. Three of 4 facial images reached the PP4 moderate threshold, while 1 reached the supporting threshold. Integration of facial phenotype, HPO information, and molecular data through PEDIA ranked ZEB2 first and contributed to classification of the variant as likely pathogenic. The findings provide a proof of concept for incorporating NGP into rare-disease diagnostic and variant-interpretation workflows, although larger, multicenter studies are needed to establish reproducibility and generalizability.
BACKGROUND: Mowat-Wilson syndrome (MWS) is a rare neurodevelopmental disorder caused by pathogenic variants in the ZEB2 gene and characterized by developmental impairment, epilepsy, congenital anomalies, and distinctive craniofacial features. Although next-generation phenotyping (NGP) tools such as GestaltMatcher can assist in recognizing rare genetic disorders, their use as quantitative evidence for variant interpretation within the American College of Medical Genetics and Genomics (ACMG) framework remains less established. This study evaluated whether computational facial phenotyping and multimodal clinical data could support variant prioritization and the ACMG PP4 phenotype-specificity criterion in MWS.
DETAILS: The investigators applied GestaltMatcher to a 4-year-old child with an undiagnosed neurodevelopmental disorder, suspected MWS, and a de novo ZEB2 variant. Facial photographs were analyzed alongside Human Phenotype Ontology (HPO) terms and simulated exome data using the PEDIA framework. Bayesian likelihood modeling was used to establish Gestalt score thresholds corresponding to supporting, moderate, strong, and very strong PP4 evidence. Brain MRI was also analyzed for structural abnormalities associated with MWS. The GestaltMatcher model had been trained using 9,671 images from 7,294 patients representing 275 disorders. For the MWS analysis, the dataset included 11 individuals with MWS and 14 age-matched controls.
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GestaltMatcher ranked MWS as the leading diagnosis, while integration through PEDIA also ranked ZEB2 as the most likely disease-causing gene. Across the 4 facial images from the proband, 3 achieved the PP4 moderate threshold and 1 achieved the PP4 supporting threshold. The established Gestalt score thresholds were 0.5111 for supporting, 0.5672 for moderate, 0.6609 for strong, and 0.7632 for very strong evidence.
Using the NGP-derived PP4 moderate evidence together with the original ACMG evidence, the ZEB2 variant was classified as likely pathogenic. Brain MRI demonstrated subtle thinning of the corpus callosum, a finding consistent with previously reported MWS-associated neuroimaging abnormalities. MRI-derived features also differentiated individuals with MWS from age-matched controls in exploratory analysis.
An additional exploratory case involving an infant with molecularly confirmed MWS showed that GestaltMatcher could prioritize MWS based solely on infant facial characteristics. The authors emphasize that NGP is intended to complement, rather than replace, expert clinical genetic assessment.
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Source: Hsieh, T. C., Todd, D., Warner, T., et al. Leveraging Next-Generation Phenotyping in Dysmorphology to Support Variant Interpretation in Mowat-Wilson Syndrome. Neurology Genetics. 2026; 12(4): e200384. Published: July 1, 2026. DOI: 10.1212/NXG.0000000000200384
Long-Term Outcomes of Azacitidine, Venetoclax, and Gilteritinib in Newly Diagnosed FLT3-Mutated Acute Myeloid Leukemia
In a phase II study of 30 patients with newly diagnosed FLT3-mutated AML, azacitidine, venetoclax, and gilteritinib produced a 96% CR/CRi rate. At a median follow-up of 41.5 months, median RFS and OS were 23.4 and 29.7 months, with 3-year rates of 43% and 46%, respectively. Baseline RAS pathway mutations were associated with poorer outcomes, while 67% of evaluable relapses lacked detectable FLT3 mutations. The triplet produced durable remissions but frequently required treatment dose or duration reductions because of myelosuppression.
KEY FINDINGS: In this phase II study, azacitidine, venetoclax, and gilteritinib produced high remission rates and encouraging long-term survival in patients with newly diagnosed FLT3-mutated AML who were unfit for intensive chemotherapy. The 3-year RFS and OS rates were 43% and 46%, respectively, although outcomes were less favorable in patients with FLT3-ITD mutations and baseline RAS pathway mutations. Most evaluable relapses were FLT3-negative, suggesting that resistance may involve mechanisms beyond persistent FLT3-mutated disease. Dose or duration reductions were frequently required during consolidation, primarily reflecting the challenge of managing myelosuppression. Randomized studies are needed to establish the role of this triplet regimen relative to current standard approaches.
BACKGROUND: Relapse after frontline azacitidine and venetoclax remains a major challenge in patients with FLT3-mutated acute myeloid leukemia (AML), with relapse often associated with expansion of FLT3-mutated clones. This phase II study evaluated the long-term efficacy and safety of adding the FLT3 inhibitor gilteritinib to azacitidine and venetoclax in adults with newly diagnosed FLT3-mutated AML who were considered unfit for intensive chemotherapy.
DETAILS: Thirty patients with newly diagnosed FLT3-mutated AML were treated with the azacitidine, venetoclax, and gilteritinib triplet regimen. The median age was 71 years, and 22 (73%) patients had FLT3-ITD mutations. Fourteen patients (47%) proceeded to allogeneic hematopoietic stem cell transplantation in first remission. The median follow-up was 41.5 months.
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The complete remission or complete remission with incomplete hematologic recovery rate was 96%. Eleven patients (37%) subsequently relapsed, and among evaluable relapses, the FLT3 mutation was no longer detectable in 67%, indicating that relapse mechanisms were not necessarily driven by persistent FLT3-mutated disease.
The median relapse-free survival (RFS) was 23.4 months and median overall survival (OS) was 29.7 months. At 3 years, RFS was 43% and OS was 46%. Among patients with FLT3-ITD-mutated AML, median RFS and OS were 17.0 months and 21.8 months, respectively, with 3-year RFS and OS rates of 32% and 36%. Baseline RAS pathway mutations were associated with poorer outcomes.
Survival outcomes were similar regardless of whether patients underwent allogeneic hematopoietic stem cell transplantation in first remission. Among patients receiving at least one consolidation cycle, 68% required a reduction in the dose or duration of at least one study drug, highlighting the need to manage treatment-related myelosuppression during prolonged therapy.
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Source: Short, N. J., Kantarjian, H. M., Daver, N., et al. Long-Term Outcomes of Azacitidine, Venetoclax and Gilteritinib in Newly Diagnosed FLT3-Mutated AML. Blood Advances.. 2026; 10(17): 5743–5750. Published: May 27, 2026. DOI: 10.1182/bloodadvances.2026019841.
[Posted 2/Sep/2026]
AUDIENCE: Hematology, Oncology
KEY FINDINGS: In this phase II study, azacitidine, venetoclax, and gilteritinib produced high remission rates and encouraging long-term survival in patients with newly diagnosed FLT3-mutated AML who were unfit for intensive chemotherapy. The 3-year RFS and OS rates were 43% and 46%, respectively, although outcomes were less favorable in patients with FLT3-ITD mutations and baseline RAS pathway mutations. Most evaluable relapses were FLT3-negative, suggesting that resistance may involve mechanisms beyond persistent FLT3-mutated disease. Dose or duration reductions were frequently required during consolidation, primarily reflecting the challenge of managing myelosuppression. Randomized studies are needed to establish the role of this triplet regimen relative to current standard approaches.
BACKGROUND: Relapse after frontline azacitidine and venetoclax remains a major challenge in patients with FLT3-mutated acute myeloid leukemia (AML), with relapse often associated with expansion of FLT3-mutated clones. This phase II study evaluated the long-term efficacy and safety of adding the FLT3 inhibitor gilteritinib to azacitidine and venetoclax in adults with newly diagnosed FLT3-mutated AML who were considered unfit for intensive chemotherapy.
DETAILS: Thirty patients with newly diagnosed FLT3-mutated AML were treated with the azacitidine, venetoclax, and gilteritinib triplet regimen. The median age was 71 years, and 22 (73%) patients had FLT3-ITD mutations. Fourteen patients (47%) proceeded to allogeneic hematopoietic stem cell transplantation in first remission. The median follow-up was 41.5 months.
The complete remission or complete remission with incomplete hematologic recovery rate was 96%. Eleven patients (37%) subsequently relapsed, and among evaluable relapses, the FLT3 mutation was no longer detectable in 67%, indicating that relapse mechanisms were not necessarily driven by persistent FLT3-mutated disease.
The median relapse-free survival (RFS) was 23.4 months and median overall survival (OS) was 29.7 months. At 3 years, RFS was 43% and OS was 46%. Among patients with FLT3-ITD-mutated AML, median RFS and OS were 17.0 months and 21.8 months, respectively, with 3-year RFS and OS rates of 32% and 36%. Baseline RAS pathway mutations were associated with poorer outcomes.
Survival outcomes were similar regardless of whether patients underwent allogeneic hematopoietic stem cell transplantation in first remission. Among patients receiving at least one consolidation cycle, 68% required a reduction in the dose or duration of at least one study drug, highlighting the need to manage treatment-related myelosuppression during prolonged therapy.
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Source: Short, N. J., Kantarjian, H. M., Daver, N., et al. Long-Term Outcomes of Azacitidine, Venetoclax and Gilteritinib in Newly Diagnosed FLT3-Mutated AML. Blood Advances.. 2026; 10(17): 5743–5750. Published: May 27, 2026. DOI: 10.1182/bloodadvances.2026019841.
Somatic Diseases May Affect the Brain Primarily Through Vascular Injury and Neuronal Loss
A narrative review found that common age-related somatic diseases were consistently associated with brain atrophy, neuronal loss, and cerebrovascular lesions. Evidence linking these diseases to amyloid and tau pathology was limited and inconsistent. The findings suggest that systemic diseases may contribute to dementia primarily through non-Alzheimer's mechanisms, particularly vascular injury and neuronal loss. The review underscores the importance of recognizing mixed dementia and considering systemic health in the assessment of cognitive decline.
KEY FINDINGS: Common age-related somatic diseases appear to be more consistently associated with cerebrovascular injury, brain atrophy, and neuronal loss than with amyloid or tau pathology. These findings suggest that the relationship between systemic disease and dementia may involve multiple non-AD pathways rather than a direct effect on classical AD pathology. The review highlights the importance of recognizing mixed dementia and considering systemic health when evaluating brain aging and cognitive decline.
BACKGROUND: Several common age-related somatic diseases are associated with an increased risk of dementia, but the neuropathological pathways underlying these associations remain incompletely understood. This narrative review examined evidence linking heart disease, type 2 diabetes, kidney disease, liver disease, lung disease, and anemia with brain pathology, including Alzheimer's disease (AD)-related amyloid and tau pathology and non-AD changes such as neuronal loss, brain atrophy, cerebrovascular lesions, neuroinflammation, and non-AD proteinopathies.
DETAILS: The authors conducted a PubMed search for human studies investigating associations between somatic diseases and brain pathology using postmortem examinations, brain imaging, or cerebrospinal fluid biomarkers. The available evidence was qualitatively synthesized and graded according to its strength. The review specifically evaluated whether common systemic diseases were associated with AD-related pathology or with other forms of brain injury that may contribute to cognitive impairment and dementia.
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Across the conditions examined, the strongest and most consistent associations were between somatic diseases and global neuronal loss or brain atrophy, as well as cerebrovascular lesions. In contrast, associations between somatic diseases and amyloid or tau deposition were limited and inconsistent. The review found no systematic studies examining neuroinflammation or non-AD proteinopathies in relation to somatic diseases.
Overall, the available evidence suggests that systemic diseases may contribute to brain damage predominantly through non-AD mechanisms, particularly cerebrovascular injury and diffuse neuronal loss, rather than by directly driving the characteristic amyloid and tau pathology of AD. The authors emphasize that these processes may contribute to the complex combination of pathologies frequently underlying dementia in older adults.
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Source: Grande, G., Valletta, M., Gasparini, F., et al. Brain pathology in relation to somatic diseases: Exploring the body–brain crosstalk. Journal of Internal Medicine. 2026; 300(3): 223–237. Published: June 2, 2026. DOI: 10.1111/joim.70119.
Hypertension at 5 Months Postpartum in Women With Gestational Diabetes
Among 678 women with recent gestational diabetes mellitus, 26.4% developed hypertension by 5 months postpartum. Higher early-pregnancy weight and blood pressure, Black or mixed ethnicity, and gestational hypertension or pre-eclampsia were associated with increased risk. Postpartum hypertension was also associated with greater adiposity and dyslipidemia. The findings support structured postpartum screening for blood pressure and broader cardiometabolic risk after GDM.
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.
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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.
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