The choice of first-line therapy is exceptionally challenging when multiple myeloma is associated with advanced renal failure. In this issue of Med, Xiao and colleagues report on results from a randomized phase 2 study¹ indicating that the pomalidomide, bortezomib, and dexamethasone triplet leads to better myeloma disease control, thereby increasing renal function after four cycles.

Cigarette smoke contains numerous toxic compounds that can induce oxidative stress and DNA damage. While smoking is a well-established driver of lung cancer initiation, the biological consequences of continued exposure after tumor establishment remain poorly understood. This study investigated the genomic and phenotypic effects of chronic cigarette smoke exposure in established lung cancer cells.

Human lung adenocarcinoma A549 cells were chronically exposed to cigarette smoke extract to model sustained exposure. Cellular proliferation and migration assays were performed to evaluate phenotypic changes. Transcriptomic profiling was used to examine alterations in gene expression related to cell cycle regulation and DNA repair pathways. Whole-genome sequencing was conducted to identify mutational signatures associated with genomic instability. Tumor growth and histological features were further evaluated using xenograft models.

Chronic cigarette smoke extract exposure increased the clonogenic capacity and migratory behavior of A549 cells and induced phenotypic features consistent with partial epithelial-mesenchymal transition. Transcriptomic analysis revealed disruption of cell cycle regulation and reduced expression of homologous recombination DNA repair genes, including RAD51. Whole-genome sequencing identified mutational signatures associated with oxidative damage, mismatch repair deficiency, and homologous recombination defects. These alterations were accompanied by increased tumor growth and cellular atypia in xenograft models.

Chronic cigarette smoke exposure may enhance genomic instability and promote aggressive phenotypes in established lung cancer cells, suggesting that continued smoking after cancer development may contribute to tumor progression.

We compared two surrogate markers of insulin sensitivity - the single-point insulin sensitivity estimator (SPISE) and HOMA-IR - and evaluated their associations with OSA severity in children with genetically confirmed PWS and a symptomatic non-syndromic referral group (NSR) with available polysomnography (PSG) and fasting biochemical data. In this single-centre retrospective cross-sectional study, OSA severity was indexed by the obstructive apnoea-hypopnoea index (oAHI), central AHI (cAHI) and oxygen desaturation index (ODI), and caregiver-reported symptoms by the PSQ-SRBD scale. Multivariable models were fitted within the PWS group. Of 458 PSG studies screened, 31 children with PWS and 47 NSR met the inclusion criteria. cAHI was higher in PWS (p < 0.001), and PSQ-SRBD scores were slightly lower, despite a similar oAHI distribution. Within the PWS group, oAHI correlated inversely with SPISE (ρ =  - 0.378, p = 0.036). In multivariable models adjusted for age, sex, BMI-SDS, and growth hormone therapy, higher oAHI was associated with lower SPISE (B =  - 0.154, p = 0.015), whereas the association with ln(HOMA-IR) was borderline (B = 0.081, p = 0.0497). ODI correlated with SPISE (ρ =  - 0.427, p = 0.017) but not with HOMA-IR (ρ = 0.319, p = 0.081). Phase-stratified analyses showed oAHI-SPISE correlations in phases 2 and 3 and an oAHI-HOMA-IR correlation in phase 3.

In children with PWS, OSA severity was associated with markers of impaired insulin sensitivity. The associations of SPISE with oAHI and ODI support its further investigation as a candidate metabolic correlate of OSA severity. These findings are hypothesis-generating and require validation in larger independent cohorts.

• OSA is highly prevalent in PWS. OSA severity is associated with insulin resistance in adults and in non-syndromic children with obesity, but this relationship and the insulin-independent SPISE index have not been evaluated in PWS.

• OSA severity was associated with impaired insulin sensitivity markers in children with PWS. • SPISE, derived from lipids and BMI without fasting insulin, was associated with oAHI and ODI in PWS; it merits further investigation as a candidate metabolic correlate of OSA severity.

The lungs, once considered sterile, are now known to contain diverse, dynamic microbial communities that are metabolically active and immunologically consequential even in health. In respiratory disease, these communities undergo quantitative and compositional changes that predict clinical trajectories and may contribute to pathogenesis. The past decade of research has advanced our understanding of the complex bidirectional relationship between the respiratory tract and the microbial communities it encounters. In health, the lungs are nutrient poor and defended by robust host defences, limiting local microbial growth and keeping bacterial populations sparse and transient. Yet, in respiratory disease, the ecological conditions of the lungs permit and promote the outgrowth of select microorganisms. Recent in vivo and ex vivo discoveries explain how this respiratory dysbiosis is both a cause and a consequence of airway and alveolar injury. To leverage the respiratory microbiome for therapeutic benefit, we must interrogate both how disease-altered microbial communities shape immune responses, treatment efficacy and outcomes, and how host and environmental factors, in turn, shape the respiratory microbiome. In this Review, we synthesize current insights into how the respiratory microbiome contributes to chronic and acute lung diseases and explore its clinical implications for diagnosis, prognosis and therapy.

X-linked ichthyosis is caused by pathogenic variants or deletions involving STS at Xp22.31. Because some deletions include contiguous genes and cardiac rhythm abnormalities have been reported, we characterized the cardiac phenotype of children with genetically confirmed steroid sulfatase-related syndromic epidermal differentiation disorder (STS-sEDD). This prospective, observational, single-centre study included 14 boys aged 2-16 years. Assessment comprised clinical history and examination, 12-lead electrocardiography, echocardiography, exercise testing when age-appropriate, and 5-day ambulatory electrocardiographic monitoring. Genetic findings were reviewed, and 11 obligate-carrier mothers also underwent cardiological assessment. Nine patients (64%) were asymptomatic and five (36%) reported mild, nonspecific symptoms. Minor electrocardiographic findings in 11 patients were considered age-appropriate variants. All hearts were structurally normal except for one previously known, haemodynamically compensated partial anomalous pulmonary venous return. Exercise testing in 12 patients identified one isolated premature ventricular contraction; 5-day monitoring in 13 detected no clinically significant arrhythmia. Twelve patients had contiguous-gene deletions and two had pathogenic STS sequence variants, with no apparent association between deletion extent and cardiac findings. Maternal echocardiograms were normal; one mother had isolated atrial and ventricular ectopy during exercise without clinically significant arrhythmia.

Clinically relevant cardiac involvement appeared uncommon in this small pediatric cohort. The sample size and cross-sectional assessment preclude definitive risk estimates; cardiological evaluation should be individualized according to symptoms, cardiovascular findings, and family history.

• X-linked ichthyosis is caused by STS variants or deletions that may involve contiguous genes. • Cardiac arrhythmias have been reported with Xp22.31 deletions, but pediatric data are scarce.

• No clinically significant arrhythmia was found in 14 boys undergoing multimodal assessment. • Deletion extent did not predict cardiac findings; follow-up should reflect symptoms and family history.

Movement disorders comprise a heterogeneous spectrum of neurological conditions characterized by impaired motor control. Limited epidemiological data exist for Latin American populations, particularly for Mexican Mestizos.

To characterize the epidemiological profile and clinical features of movement disorders in a large cohort of Mexican Mestizo patients evaluated at a public tertiary referral center in western Mexico.

We conducted a 10-year retrospective cohort study (2012-2022) analyzing medical records from the Movement Disorders and Neurodegenerative Diseases Unit at the Hospital Civil de Guadalajara, a public tertiary university hospital from the western region of Mexico. Inclusion criteria were confirmed movement disorder diagnosis and a minimum of two clinical evaluations. Binary logistic regression was used to calculate odds ratios (OR) and 95% confidence intervals (CIs).

Among 1,830 records (mean age 58.5 ± 17.0 years, 53.9% female, all self-identified as Mexican Mestizo), hypokinetic disorders comprised 63.9% (n = 1,170) and hyperkinetic disorders 36.1% (n = 660). Parkinsonism (63.6%, n = 1,163) and tremor (11.3%, n = 206) were the most frequent subtypes. Hypokinetic disorders were associated with older age (64.2 ± 12.8 vs. 48.5 ± 18.9 years, p < 0.001), hypertension (OR = 2.29; 1.78-2.95; p = 0.001), and smoking (OR = 1.51; 1.13-2.03; p = 0.005). Hyperkinetic disorders were associated with male sex (OR = 1.47; 1.19-1.82; p < 0.001), family history (OR = 1.92; 1.49-2.47; p < 0.001), and functional presentations (OR = 11.0; 5.53-22.14; p < 0.001).

This is the largest reported Mexican Mestizo cohort with movement disorders evaluated in a single public tertiary center. Findings reveal distinct demographic and clinical patterns and may inform integrated cardiovascular-neurological care models, screening protocols, and resource allocation within the Mexican public health system.

Sphingolipids constitute essential membrane lipids that also function as signaling molecules mediating fundamental cellular processes. Disruption of constitutive sphingolipid metabolism contributes to a range of metabolic diseases. Sphingolipid biosynthesis is initiated by serine palmitoyltransferase (SPT), a heteromeric enzyme composed of Sptlc1 and either Sptlc2 or the less-characterized subunit Sptlc3. While the canonical Sptlc1/Sptlc2 complex generates most sphingolipids, Sptlc1/Sptlc3 produces non-canonical sphingolipids that remain poorly understood. Sptlc3 expression increases in liver disease in both mouse models and humans, yet its biological role remains unclear. To address this, we generated a liver-specific SPTLC3 knockout (SPT3-hKO) mouse model. Loss of SPTLC3 resulted in severe mitochondrial dysfunction in hepatocytes, characterized by reduced oxygen consumption, decreased ATP production, and elevated NADH/NAD⁺ ratios with a concomitant increase in glycolytic activity. Mechanistically, we found a defect in the electron transport chain (ETC) which stemmed not from intrinsic impairment of the ETC complexes but rather from hindered electron flow between complex I and complex III likely due to reduced availability of Coenzyme Q. While atypical ceramides constituted (∼4% of total ceramides) when measured in liver homogenates, there measurements in mitochondria-enriched fractions revealed enrichment in this cell compartment. Together, our findings identify SPTLC3 as a critical modulator of mitochondrial ceramide composition and ETC function, revealing a specialized role for non-canonical sphingolipids in hepatocyte energy metabolism.

Hereditary angioedema is a bradykinin-mediated genetic disorder increasingly controlled with effective long-term prophylaxis. In a phase 3 trial, a single dose of lonvoguran ziclumeran, an in vivo CRISPR-Cas9 therapy targeting KLKB1, significantly reduced attack rates. This approach represents a highly promising therapeutic strategy for HAE. However, it also raises important questions that require further investigation.

Cardiac fibrosis is a central feature of many cardiovascular diseases, contributing to myocardial stiffening, electrical dysfunction, and progression to heart failure. Despite its clinical importance, no therapy directly targeting myocardial fibrosis is currently established in practice. Advances in the understanding of cardiac fibroblast biology and profibrotic signaling pathways, including transforming growth factor-β and neurohormonal activation, have driven the development of multiple antifibrotic strategies in preclinical models, ranging from small molecules to gene- and cell-based approaches. However, translation into clinical benefit has remained limited, with existing evidence largely derived from early-phase studies that rely on indirect imaging or biomarker-based assessments. This review examines the mechanisms underpinning cardiac fibrosis and evaluates current antifibrotic strategies across key cardiovascular conditions from a translational perspective. We argue that translational failure arises not simply from ineffective therapies, but from a mismatch between the biological complexity of human fibrotic remodeling and the simplified paradigms underpinning current therapeutic development. We highlight key barriers to translation, including limitations of experimental models, fibroblast heterogeneity, temporal dependence of therapeutic efficacy, challenges in fibrosis assessment, and constraints in trial design. We further outline emerging strategies to bridge the translational gap.

Obesity affects over 1.5 billion adults worldwide, necessitating early cardiovascular detection. We identified subclinical biventricular dysfunction in young overweight/obese individuals.

In this prospective study (2023-2024), 60 participants were enrolled: 30 overweight/obese individuals (BMI ≥ 25 kg/m²) and 30 age-sex-matched controls. Conventional echocardiography, tissue Doppler imaging, and 2D speckle tracking strain analysis were performed. Stepwise multiple linear regression identified independent predictors of RWT, LV GLS, e' medial, RV S' and RV_FWLS, entering BMI, age, sex, blood pressure, heart rate, SPAP (RV_FWLS) and metabolic variables (obese group). Variables required p < 0.10 in univariate analysis.

Obese individuals showed LV remodeling: greater posterior (9.1 ± 1.2 vs. 8.1 ± 1.2 mm, p < 0.01) and septal wall thickness (10.1 ± 1.4 vs. 8.5 ± 1.3 mm, p < 0.001), LV mass index (76.6 ± 18.2 vs. 67.9 ± 14.6 g/m², p < 0.05), and RWT (0.39 ± 0.04 vs. 0.37 ± 0.06, p < 0.005). BMI independently predicted RWT (β = 0.42, p < 0.005). Despite preserved EF, LV GLS was impaired (-22.7 ± 6.1% vs. -23.4 ± 4.2%, p < 0.01). Reduced e' medial velocity (14.0 ± 2.7 vs. 15.3 ± 2.6 cm/s, p < 0.01) was predicted solely by BMI (β = -0.62, p < 0.0001). S' decreased (13.1 ± 1.7 vs. 14.2 ± 1.6 cm/s, p < 0.01). RV free wall strain (-20.9 ± 5.2% vs. -27.6 ± 4.1%, p < 0.001) and pulmonary systolic pressure (26.6 ± 5.8 vs. 22.7 ± 4.8 mm Hg, p < 0.01) were abnormal versus controls.

Young overweight/obese individuals show early biventricular dysfunction, detectable particularly by speckle tracking, which may be more sensitive than conventional parameters and enable earlier prevention. Modest strain differences indicate long-term rather than immediate clinical relevance.