[Posted 30/Sep/2025]

AUDIENCE: Internal Medicine, Nursing

KEY FINDINGS:

• DPP-4 inhibitors offer a safer alternative to meglitinides in T2D patients with Stage 5 CKD with lower severe renal outcomes and hypoglycemia risk.
• Hypoglycemia risk is lower with DPP-4i due to glucose-dependent insulinotropic action.
• DPP-4i are weight neutral, helpful in normal or lower BMI patients.
• Renoprotection mechanisms of DPP-4i may involve GLP-1 dependent pathways and antifibrotic effects but need further study.
• Observational data with residual confounding; randomized trials needed for conclusive evidence.
• Cost and access issues may influence DPP-4i use in some settings.

BACKGROUND: Managing hyperglycemia in type 2 diabetes (T2D) patients with advanced chronic kidney disease (CKD) is complex due to altered drug metabolism and risk of adverse events. Conventional treatments like metformin pose risks due to renal excretion; sulphonylureas and pioglitazone involve metabolites renally cleared raising hypoglycemia and fluid retention risks. Meglitinide repaglinide is preferred in this setting due to hepatic metabolism and flexible dosing. DPP-4 inhibitors (DPP-4i) offer a safer profile with low hypoglycemia risk and weight neutrality, but data on their safety and efficacy in Stage 5 CKD remain scarce.

DETAILS: Hung et al. conducted a nationwide Taiwanese cohort study (2012-2020) comparing renal outcomes in Stage 5 CKD patients with T2D starting either DPP-4i (n=5028) or meglitinides (n=2243). Stage 5 CKD was defined using erythropoiesis-stimulating agent (ESA) use as a surrogate for eGFR <15 mL/min/1.73 m². Propensity score matching adjusted for confounders. The primary composite outcome included renal replacement therapy (RRT), renal death, and kidney-related hospitalization. DPP-4i use was associated with a 14% lower risk of the primary composite renal outcome vs. meglitinides (HR 0.86; 95% CI 0.81-0.92), mainly through reduced need for RRT. Severe hypoglycemia risk was 41% lower in the DPP-4i group. The findings support the renal safety and possible benefits of DPP-4i over meglitinides in severe CKD. Limitations include observational design, ESA use as CKD surrogate, lack of clinical measurements, and limited generalizability due to homogeneous Taiwanese cohort.

Copyright © John Wiley & Sons, Inc. All rights reserved

Source: Ryden, M. (2025). Choosing Oral Antihyperglycaemic Drugs in People Living With Type 2 Diabetes and Severe Chronic Kidney Disease. Journal of Internal Medicine. 2025; 298(3): 149-151. Published: September, 2025. DOI: 10.1111/joim.70002.

[Posted 3/Sep/2026]

AUDIENCE: Neurology, Pediatric, Radiology

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.

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

[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.

[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.

Copyright © Skyscape. All rights reserved.

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 1/Sep/2026]

AUDIENCE: Internal Medicine, Neurology, Cardiology

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.

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.

[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.

[Posted 28/Aug/2026]

AUDIENCE: Dermatology, Family Medicine

KEY FINDINGS: Clinicians should consider Pso-Ec when an adult patient has persistent lesions showing simultaneous psoriasiform and eczematous clinical and histopathologic characteristics, particularly when there is no clear dominant inflammatory pathway. In this study, the phenotype was associated with dual Th2/Tc2 and Th17/Tc17 activity and involvement of JAK1-STAT2/6 signaling. Prior Pso- or AD-directed biologics were often inadequate, whereas JAK1 inhibitors achieved minimal disease activity with BSA ≤2 and NRS ≤1 during a median 17-month follow-up. The findings support recognition of Pso-Ec as a distinct phenotype and suggest JAK1 inhibition as a mechanism-based therapeutic approach. The study's interpretation is limited by its small sample size and the fact that immunologic analyses were performed in a representative subset of patients.

BACKGROUND: Psoriasis (Pso) and atopic dermatitis (AD) are generally characterized by different dominant inflammatory pathways. However, some patients present with lesions containing both psoriasiform and eczematous features, creating diagnostic and therapeutic challenges. This prospective study characterized a distinct psoriasis–atopic dermatitis overlapping phenotype, termed Pso-Ec, with particular attention to its clinical, histopathologic, immunologic, and treatment characteristics.

DETAILS: The two-center prospective study enrolled 30 patients with Pso-Ec between January 2021 and December 2025. Reference cohorts consisted of 150 patients with typical Pso and 150 with AD. The Pso-Ec group included patients aged 13-72 years, with a mean age of 49.7 ± 17.7 years and a male-to-female ratio of 19:11. None had a previous history of Pso or AD. Notably, 63.3% had associated atopic diseases, compared with 2.7% of patients with typical Pso and 47.3% of those with AD (P < .001). Pso-Ec lesions were characterized clinically by ill-defined erythematous plaques, thin scales, excoriation, and prominent pruritus. Histopathologic examination demonstrated concurrent psoriatic and eczematous features within the same lesions. Immunologic assessment of lesional skin and peripheral blood identified simultaneous type 2 and type 3 inflammatory activity, represented by Th2/Tc2 and Th17/Tc17 populations. JAK1-STAT2/6 signaling was also implicated in the inflammatory profile.

Treatment histories indicated that conventional pathway-directed biologic therapy was frequently inadequate in this phenotype. Among the Pso-Ec patients, 18 had previously received Pso-targeted biologics and 15 had received AD-targeted biologics, with responses described as often inadequate. In contrast, treatment with JAK1 inhibitors was associated with achievement of minimal disease activity, defined as body surface area (BSA) ≤2 and numerical rating scale (NRS) ≤1. This response was maintained during a median follow-up of 17 months. During follow-up, none of the patients progressed to a classic Pso or AD phenotype.

The investigators concluded that Pso-Ec represents a distinct, predominantly adult-onset inflammatory phenotype rather than simply a transitional presentation between psoriasis and atopic dermatitis. Its defining immunologic characteristic is the concurrent presence of type 2 and type 3 inflammation, which may explain the limited effectiveness of therapies directed primarily against either pathway. JAK1 inhibition emerged as an effective treatment option in this cohort.

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Source: Chen, M., Shen, C., Chen, C. B., et al. A Distinct Psoriasis–Atopic Dermatitis Overlapping Phenotype in Adults With Dual Type 2 and Type 3 Immune Features and Favorable Response to Janus Kinase 1 Inhibition. Journal of the American Academy of Dermatology. 2026; Published: September 22, 2026. DOI: 10.1016/j.jaad.2026.05.042.