The pathogenesis of Parkinson's disease (PD) has been linked to environmental factors, toxins, genetics, and peripheral inflammation. Importantly, intestinal inflammation like that seen in Crohn's disease (CD) or food allergies has been implicated in risk for neurodegeneration and late-onset PD. Further, CD and PD share genetic risk factors including gain-of-function leucine-rich repeat kinase 2 (LRRK2) mutations. Here, we aim to better understand how intestinal inflammation synergizes with Lrrk2 levels or kinase activation to promote neurodegeneration in young and old mice. We utilized bacterial artificial chromosome (BAC) mice overexpressing wildtype mouse Lrrk2 or mutant G2019S mouse Lrrk2 and compared them with C57B6J mice at baseline and under conditions of intestinal inflammation using dextran sodium sulfate (DSS) colitis models. While our data revealed regulation of the brain inflammatory state by Lrrk2, we did not observe age-dependent selective vulnerability or protection in Lrrk2 mouse lines in colitis protocols. Instead, DSS phenotypes were associated with increased nigrostriatal dysregulation in all genotypes independent of age. While Lrrk2 mutations appear to influence the genesis of peripheral inflammation, our data suggest that Lrrk2 activation due to a gain-of-function mutation does not exacerbate the effects of inflammation on nigrostriatal degeneration in this model.
Inflammatory activation is a major cause to nasal diseases, such as chronic rhinosinusitis and allergic rhinitis. However, in vitro research model to mimic the process of olfactory inflammation and to screen new therapeutic target is still lacking. We established three inflammatory models based on olfactory epithelium (OE) organoids, using lipopolysaccharide (LPS), TNFα treatment and doxycycline induction. The efficacy of these models was evaluated by immunostaining, RNA sequencing, qPCR, and functional assays. These inflammatory organoid models mimicked impairment in cell proliferation and neuronal genesis, and showed upregulation of inflammation-related signaling pathway and downregulation of cell cycle-related pathway. We identified that DNA damage inducible transcript 3 (Ddit3) was upregulated in all inflammatory organoid models. Ddit3 downregulation counteracted apoptosis, alleviated cell proliferation and neuronal differentiation, and recovered the functional response to odor stimulation in all three inflammatory organoid models. Ddit3 deficiency counteracted effect of LPS instillation by promoting cell proliferation, recovering neurogenesis, attenuating inflammation, and improving electrophysiological response to odor mixes in the OE. Single-cell RNA sequencing analysis showed that Ddit3 upregulation in mature olfactory sensory neurons of inducible inflammation model and patients with aging-related olfactory dysfunction correlated with endoplasmic reticulum stress and neuron apoptotic process. We established olfactory inflammation organoid models, and made use of these models to identify Ddit3 as a potential therapeutic target against inflammation-related olfactory neuronal loss and functional deficit.
The human vascular network is a highly dynamic, complex and organ-specific microenvironment essential for organ homeostasis. Traditional 2D cell cultures fail to capture its complex intercellular interactions, tissue-specific architectures, and mechanobiological cues. Blood vessel organoids (BVOs) generated from human induced pluripotent stem cells (hiPSCs) replicate the structure and function of blood vessels. Because hiPSCs preserve the donor's telomere length and epigenetic memory, BVOs may preserve the genesis memory, opening up a completely new avenue for the study of vascular disorders. In this review, we systematically outline the methods for in vitro blood vessel generation and explore how vascularizing parenchymal organoids actively drives tissue maturation while overcoming hypoxic limitations. We assess the vital transition from biochemical induction to biomechanical integration, highlighting how microfluidic organ-on-a-chip (OoC) platforms resolve the lineage-specific media dilemma and impose the physiological shear stress necessary for definitive vascular maturation. Furthermore, we comprehensively summarize the applications of BVOs as personalized preclinical avatars across diverse pathologies, including diabetic vasculopathy, cerebrovascular and cardiovascular diseases, tumor immune evasion, hereditary anomalies, and infectious vasculotropism. Finally, we address critical current bioengineering constraints-notably incomplete vessel maturation, the absence of functional lymphatic systems, and the lack of immunocompetent microenvironments-providing strategic future perspectives to accelerate the translation of BVOs in precision and regenerative medicine.
Air pollution is responsible for millions of global deaths annually. The most dangerous pollutants for health are particulate matter (PM), nitrogen oxides (NOx), sulfur dioxide (SO2), and carbon monoxide (CO). Recent studies have demonstrated an increased probability of cardiac arrhythmias, such as atrial fibrillation (AF). AF is the most common type of sustained cardiac arrhythmia, characterized by a process of atrial remodeling, where fibrosis is a hallmark of arrhythmogenic structural remodeling, which alters tissue composition and function. In addition to AF, both the genesis and aggravation of fibrosis have been reported as an effect of exposure to air pollutants. However, since most studies are epidemiological, the pathophysiological mechanisms by which pollutants aggravate AF in humans remain unclear. In this study, the effects of major atmospheric pollutants on the aggravation of AF were evaluated. Mathematical formulations describing pollutant-induced alterations in ionic currents were incorporated into a Courtemanche human atrial myocyte model previously remodeled for AF, which was then coupled to a three-dimensional atrial model. Structural remodeling was represented using the MacCannell fibroblast model. Electrogram recordings from virtual basket catheters were analyzed, and approximate entropy was computed. Results showed that pollutant exposure produced a marked loss of the action potential plateau and, at high concentrations, reduced action potential duration by approximately 35% in both atria. Likewise, pollutants favor the aggravation of AF, characterized by a greater number of reentries, in a concentration-dependent manner. The left atrial electrograms exhibited significantly increased approximate entropy; the effect was larger as the concentrations of the pollutants increased. These findings provide mechanistic insights into the effect of pollutants on the aggravation of atrial arrhythmias and may support public policies aimed at mitigating air pollution.
Oncogenic tyrosine kinase activity of BCR::ABL1 is causally associated with chronic phase (CP) of chronic myeloid leukemia (CML) and its inhibition by tyrosine kinase inhibitors (TKIs) induces remission in majority of patients. However, in the terminal blast crisis (BC) phase, 80% patients are resistant to TKIs. Forty percent among them are resistant despite inhibition of BCR::ABL1 activity by TKIs and in earlier study, we observed similar antithesis in K562 cells resistant to TKI-imatinib. We demonstrated active BCR::ABL1 signaling downstream of inactivated BCR::ABL1 and its causal association with resistance. This study explores the involvement of ITGB1, integrin with significant role in genesis of CML and differentially expressed in resistant K562 cells, in mediation of atypical activation of BCR::ABL1 pathway and thus resistance. Imatinib-sensitive and resistant K562 cells as well as sensitive cells with ITGB1 knockdown (KD) to mimic resistant cells, were analyzed for proteome and phosphoproteome by mass spectrometry and kinome was profiled by quantification of kinase activities in an array-based assay. The commonality between differentially expressed proteins (DEPs) identified in resistant cells and ITGB1-KD cells together with ITGB1 interactors, identified from ITGB1-immunoprecipitate by mass spectrometry, provided a comprehensive sketch of ITGB1-mediated signaling in resistant cells. The proteins identified as key players in ITGB1-mediated activation of BCR::ABL1 signaling were validated in K562 and KU812 cells, CD34+ cells from patient samples and their functional significance was assessed by inhibition studies in K562 cells. It was observed that the reduced levels of ITGB1 in resistant cells activated BCR::ABL1 downstream signaling kinases- p38MAPK and ERK. Though not influenced by ITGB1, LYN was active in resistant cells. Inhibition studies revealed that p38MAPK, ERK and LYN regulate the activity of each other, thereby explaining ITGB1-independent activation of LYN. The three kinases in turn activate members of CDK, MAPK, AKT and PKC families while ERK alone modulates EPH activity. Thus, reduction in level of ITGB1 in resistant cells leads to activation of ERK and p38MAPK belonging to BCR::ABL1 pathway, despite inactivation of BCR::ABL1, which in turn leads to activation of LYN. Together, these kinases activate members of vital pro-survival pathways, thereby imparting imatinib resistance in CML-BC cells.
Fatigue is one of the most prevalent and debilitating symptoms in individuals with multiple sclerosis (MS). We recorded somatosensory high-frequency oscillatory (HFO) thalamocortical activity in a group of MS patients without history of optic neuritis (ON). Furthermore, we examined if, like what was previously observed in response to visual stimuli, patients exhibit diminished amplitude habituation, and whether this may further exacerbate fatigue in individuals with MS. Twenty patients diagnosed with relapsing-remitting MS were prospectively enrolled. The MS cohorts were compared with a cohort of 20 healthy volunteers (HV). Fatigue Severity Scale (FSS) was employed to evaluate the trait levels of reported fatigue. We assessed the N20 somatosensory evoked potentials (SSEPs) parameters and N20-P25 amplitude habituation, and, following the application of a band-pass filter (450-750 Hz), we evaluated electrophysiological parameters of pre- and post-synaptic HFOs. The latency and amplitude of the N20 SSEP and its habituation do not exhibit significant differences between MS patients and HVs. MS patients exhibited delayed latency of negative oscillatory maximum and reduced maximum peak-to-peak amplitude of the pre-synaptic HFOs (all p < 0.01). In patients, post-synaptic HFOs showed a significant delayed latency and a trend towards a reduction in the maximal peak-to-peak amplitude. The pre-synaptic HFO latency of the negative oscillatory maximum, reflecting thalamocortical activity, shows a correlation with the FSS in MS patients (r = 0.522, p = 0.018). No significant ophthalmological anomalies were identified. Our data revealed a significant reduction and slowing of somatosensory thalamocortical network activity in MS patients without history of ON. Furthermore, our findings showed that fatigue levels may be affected by slowed thalamocortical activity, but not by habituation of cortical responses. Our findings suggest a potential role of the thalamo-cortical network on the genesis of MS-related fatigue.
Heterozygous missense mutations of TAU cause frontotemporal dementia with parkinsonism linked to chromosome 17 with tau pathology (FTDP-17T). FTDP-17T neurodegeneration of hippocampal and substantia nigra dopaminergic cells causes dementia and parkinsonism motor deficits. FTDP-17T cellular model of mutant TAU-expressing differentiated dopaminergic or hippocampal neurons was utilized to test hypothesis that FTDP-17T (R5H), (N279K), (K298E), (P301S), (K317M) and (G389R) TAUs located in different domains of TAU cause neurodegeneration with the same pathomechanism. (R5H), (N279K), (K298E), (P301S), (K317M) and (G389R) TAUs caused degeneration of dopaminergic or hippocampal neurons via mutation-induced gain-of-neurotoxicity. (R5H), (N279K), (K298E), (P301S), (K317M) and (G389R) mutations promoted Ser202/Ser396/Ser404 phosphorylations of TAU and formation of phospho-FTDP-17T TAUSer202/Ser396/Ser404 oligomers in dopaminergic or hippocampal neurons. GSK-3β inhibitor AR-A014418 completely blocked (R5H), (N279K), (K298E), (P301S), (K317M) and (G389R) TAUs-induced neurotoxicity by preventing (R5H), (N279K), (K298E), (P301S), (K317M) and (G389R) mutations-augmented Ser202/Ser396/Ser404 phosphorylations and genesis of phospho-FTDP-17T TAUSer202/Ser396/Ser404 oligomers. Phospho-(R5H), phospho-(N279K), phospho-(K298E), phospho-(P301S), phospho-(K317M) or phospho-(G389R) TAUSer202/Ser396/Ser404 oligomers were found in ER of dopaminergic or hippocampal neurons and activated ER stress, UPR and ER stress apoptotic signaling. Overexpression of mitochondrial phospho-FTDP-17T TAUSer202/Ser396/Ser404 oligomers caused mitochondrial malfunction via depolarizing mitochondrial membrane potential and oxidative damage by increasing ROS. Phospho-FTDP-17T TAUSer202/Ser396/Ser404 oligomers-evoked upregulation of Noxa, Bim or Puma and mitochondrial defect and oxidative stress excited mitochondrial pro-apoptotic pathway. Our results suggest that shared pathomechanism underlying FTDP-17T (R5H), (N279K), (K298E), (P301S), (K317M) and (G389R) TAUs-induced neurotoxicity is mutation-augmented GSK-3β-mediated Ser202/Ser396/Ser404 phosphorylations and generation of phospho-FTDP-17T TAUSer202/Ser396/Ser404 oligomers, which cause neurodegeneration by stimulating ER stress and mitochondrial pro-apoptotic cascades.
Cancer risks of individuals heterozygous for an ATM pathogenic or predicted pathogenic variant (PV/PPV) remain imprecise to guide optimal clinical management. Therefore, we aimed to estimate these risks in different family settings. Data were collected on 141 ataxia-telangiectasia families, 398 Hereditary Breast and Ovarian Cancer families and 96 families with a history of pancreatic cancer enrolled in French nation-wide epidemiological studies CoF-AT2, TUMOSPEC or GENESIS. Hazard ratios (HR) and cumulative risks were estimated using a modified segregation analysis method. An increased risk of breast and pancreatic cancers was observed for PV/PPV heterozygotes, and HRs were similar in the three family sets. When combined, HR were 4.0 (95%CI:2.9-5.6) for female breast cancer, 6.6 (95%CI:3.6-12.1) for female pancreatic cancer, and 2.8 (95%CI:1.4-5.5) for male pancreatic cancer. In birth cohort 1960-1969, female heterozygotes had a cumulative risk of breast cancer of 9.9% (95%CI:7.1%-13%) by age 50, and of 40% (95%CI:31%-51%) by age 80. Their risk of pancreatic cancer by age 80 was 8.1% (95%CI:4.3%-14%). The risk of male pancreatic cancer by age 80 was 5.1% (95%CI:2.4%-9.3%). No increased risk of ovarian and prostate cancers was observed. Our findings will help in the clinical management of families where an ATM PV/PPV segregates.
Congenital heart disease is among the most common fetal abnormalities and birth defects. Despite identifying numerous risk factors influencing its onset, a comprehensive understanding of its genesis and management across diverse populations remains limited. Recent advancements in machine learning have demonstrated the potential for leveraging patient data to enable early congenital heart disease detection. Over the past seven years, researchers have proposed various data-driven and algorithmic solutions to address this challenge. This paper presents a systematic review of congenital heart disease recognition using machine learning, conducting a meta-analysis of 432 references from leading journals published between 2018 and 2025. A detailed investigation of 74 scholarly works highlights key factors, including databases, algorithms, applications, and solutions. Additionally, the survey outlines reported datasets used by machine learning experts for congenital heart disease recognition. Using a systematic literature review methodology, this study identifies critical challenges and opportunities in applying machine learning to congenital heart disease.
As employee turnover intensifies and the talent shortage grows, boomerang employment-the phenomenon of former employees returning to their previous organizations-has become increasingly common. However, theoretical understanding of how this behavior occurs remains limited. This study aims to explore the formation mechanisms of workplace boomerang behavior and construct a theoretical model to explain this process. Employing a grounded theory approach, we collected data from two sources: online secondary materials and semi-structured interviews with former employees who had returned to their previous companies. The data were systematically analyzed through open coding, axial coding, and selective coding to identify core categories and their interrelationships. Anchoring factors (rational, emotional, matching, normative) and driving factors (career, contextual, cognitive) shape boomerang intention (cognitive commitment and behavioral enactment), ultimately leading to boomerang behavior. Organizational opportunities (talent gaps, value assessments, industry ecology) are critical for enabling boomerang behavior. Our work makes the following theoretical advancements. First, by systematically examining how boomerang behavior emerges, this study shifts the analytical focus from "outcome analysis" to "process genesis." Second, by investigating the critical role of the former organization in the formation of boomerang behavior, this study builds a "bilateral interaction" decision model. Third, by framing boomerang behavior as a distinct form of situated job choice, this study addresses the explanatory shortcomings of traditional job-choice theories in this context.
GABAA and protein hypotheses aside, the lipid theory remains the most influential account of anaesthetic effects in modern pharmacology. An apparent aspect of the lipoidal model's continued dominance is its long historical pedigree, frequently aligned with a process of steady refinement from Bibra and Harless to Hermann, Pohl, and finally Meyer/Overton. This paper problematizes this continuum by placing the genesis of a short-lived experimental entity-protagon-at the centre of the transition from the fat-solvation theory to the modern lipoidal theory of anaesthesia, which broadly identifies fat as a central mediating substance. A 'historical ontology' of protagon and an outline of the 19th century history of brain composition in relation to the early history of anaesthetic pharmacology, it treats the initial appearance of fat-oriented theories of anaesthesia as emergent of the focus on cerebral fat endemic to early 19th century organic principle analysis.
While the advent of Clustered Regularly Interspaced Short Palindromic Repeats (CRISPR)-based technologies has democratized the genesis of precise mutations, there is a need for more sophisticated tools to enable large-scale DNA manipulations, advancing genome editing across medicine, biotechnology, and agriculture. The success of Cas9 and Cas12 has hinged on the generation of precise DNA nicks and double-stranded breaks (DSBs), enabling local sequence mutagenesis, albeit of a limited size range. Emerging effectors combining Cas with other enzymatic functions, such as CRISPR-associated transposons and site-specific recombinases, enable larger integrations. Sophisticated combinations such as programmable addition via site-specific targeting element (PASTE), prime-editing-assisted site-specific integrase gene editing (PASSIGE), and prime-editing-mediated recombination of opportune target (PrimeRoot) expand payload options and DSB-free editing modalities, with translational potential for next-generation crop breeding in sustainable agriculture and the development of gene and cell therapies in personalized medicine.
General intelligence enables flexible problem solving across diverse contexts by minimizing uncertainty. Symbolic systems such as language extend this capacity, allowing humans to build social groups and construct world models beyond typical biological constraints. Previous research on linguistic communication within active inference has emphasized deep hierarchical models that ensure shared semantics between communicators. We argue that these models, while powerful, require extension to account for symbolic genesis, specifically using morality not only as uncertainty minimization across cultural niches, but also as the mechanism that created the virtual space enabling symbolic cognition. Our ancestors transcended dyadic modeling by implementing cultural layers through novel model selection, enabling in-group signaling and hierarchical social organization through psychological typing. This rendered the generative process endogenous (self-referential). Our emotional and impulsive tendency toward morality, we argue, enabled the deeper level of abstraction and the stable third-party triangulated perspective necessary for symbolic thought. This framework can be evaluated through simulations similar to recent active inference literature and provides a foundation for building generally intelligent systems aligned with human cultural values.
After February 1948, the new communist regime began to subordinate areas of life in Czechoslovakia to advocated political and ideological demands. Consequently, the unification of physical education and sports into Sokol was declared. In addition to institutional and legislative changes, the system of training for specialists was reorganized. The genesis of the Institute of Physical Education and Sport is reconstructed to illustrate organization and management of Czechoslovak physical education. The process of adopting the Soviet model of direct state control is described in the context of the geographic, historical, economic, and social specifics of a given territory. This research was based on the study of archival documents from the provenance of the State Committee and the State Office for Physical Education and Sport. This paper examines the intentions of the competent authorities, the circumstances of the foundation, mission, application of graduates and the content of studies at the Institute.
Natural polymers can be engineered into nanoscale "molecular traps", the bioMIPs, by the technique of molecular imprinting, which is a template-directed synthesis to generate selective binding sites in a crosslinked matrix. To date, bioMIPs are synthesized in solution by nano-aggregation of the polymeric units around a template, yielding to selective meta-biomaterials. Yet, the in-solution process limits the uniformity and scale-up of the bioMIPs. Here we report the first solid-phase synthesis (SPS) of interleukin-6 (IL-6) selective bioMIPs made of Gelatin methacryloyl (GelMA) and establish design rules for producing monomodal bioMIPs from protein building blocks. SPS synthesis is based on the oriented immobilization of the template to a solid support. SPS nucleation was studied on a plasmonic surface permitting real-time monitoring of bioMIP genesis. Subsequently, it was translated into a prototype reactor for scaling up the production. Guided by Flory-Huggins-De Gennes theory, we mapped the synthetic space by varying GelMA concentration, density and architecture of the surface-immobilized templates, and nucleation-time. The formed SPS bioMIPs were structurally and functionally characterized. Compared with analogous bioMIPs prepared by in-solution imprinting, SPS bioMIPs displayed a low picomolar dissociation constant, surpassing the in-solution ones by 3 orders of magnitude; showed ∼1 ng/μg IL-6 uptake in human serum, i.e., ∼45-fold increase with respect to in-solution ones, underscoring robust selective recognition under physiologically relevant conditions. Overall, the SPS strategy enables template-free isolation of high-quality bioMIPs and provides a practical route toward manufacturing cytokine-targeting nanotraps for inflammation-modulating biomedical applications.
Vitiligo is a chronic autoimmune disease characterized by loss of pigment in the skin, hair, or both, which can impact quality of life. To describe the demographic and clinical characteristics of patients with vitiligo and to characterize vitiligo treatment patterns, by vitiligo extent and age. This retrospective cohort study analyzed deidentified data from the linked Komodo Healthcare Map and OMNY Health Foundation databases. The linked databases capture health care and pharmacy claims and electronic health record data for patients with vitiligo receiving care in US dermatology practices and across all other settings. The index date was the date of first observed diagnosis of vitiligo during the index identification period (January 1, 2018, to August 31, 2023), allowing for 3 months or more of follow-up. Eligible patients were those with diagnosed vitiligo and 365 days or more of continuous health care plan enrollment (or eligibility proxy for patients with open claims) before index date. Patients missing age data or without any follow-up were excluded. Patients were stratified into cohorts by age and vitiligo percentage of body surface area (BSA) involvement (≤10%, >10%, and no BSA assessment) at index. The data analysis was conducted between April 2024 and August 2024. Baseline demographics, baseline clinical characteristics, and vitiligo treatment patterns following index date were described. Of the 24 949 included patients, 1329 (5.3%) had a BSA assessment at index (963 had ≤10% BSA involvement; 366 had >10%). Most patients (n = 21 996 [88.2%]) were 18 years and older and female (n = 14 057 [56.3%]). The face was the most frequently affected area at index, impacting 5482 of 16 674 patients (32.9%) with reported location of vitiligo. Across BSA groups, 27% (6308 of 23 620 without BSA assessment) to 32% (310 of 963 with ≤10% BSA involvement) of patients did not receive treatment for vitiligo during follow-up. The most common treatments following index were topical and oral corticosteroids and topical calcineurin inhibitors/phosphodiesterase-4 inhibitors, with no substantial differences across BSA groups during follow-up. Topical treatments were prescribed more frequently to children and adolescents vs adults, while systemic treatments were prescribed more to adults. High variability across treatment sequences was observed. Median therapy duration ranged from 1.8 (95% CI, 1.6-2.1) months to 4.1 (95% CI, 3.7-4.4) months, for first and second lines of treatment depending on treatment type. This cohort study reported treatment patterns in patients with vitiligo. A high proportion of patients with vitiligo did not receive treatment during follow-up, and therapy duration was relatively short.
Background/Objectives: Primary acquired lacrimal drainage obstruction (PALDO) is a common cause of epiphora. Although dacryoendoscopic recanalization (DER) is widely performed, its long-term success is limited by restenosis related to fibro-inflammatory processes. This study aimed to evaluate the efficacy of a novel Q-needle for targeted intraductal delivery of antifibrotic and anti-inflammatory agents during DER. Methods: A retrospective review was performed on 190 eyes treated with DER, silicone tube intubation (SI), and retrograde intraductal injection via the inferior meatus using a Q-needle. A mixture of dexamethasone (1 mL), 5-fluorouracil (1 mL), and triamcinolone acetonide (1 mL) was administered directly into the obstruction site under endoscopic visualization. Obstruction type was classified intraoperatively as secretory or structural based on dacryoendoscopic findings. Results: The overall surgical success rate was 92.1%, with significantly greater success in secretory-type PALDO compared to the structural type (96.8% vs. 87.4%, p = 0.031). These outcomes contrast with previous reports in which secretory-type PALDO was associated with poorer prognosis after DER. Conclusions: The improved outcomes in the secretory group suggest a potential role of combined antiproliferative and multi-phase anti-inflammatory therapy in effectively addressing the key mechanisms of restenosis. Q-needle-assisted intraductal injection during DER may represent a simple and safe adjunctive approach to improve surgical consistency and long-term patency in patients with PALDO.
Genome sequencing (GS) has proven effective in reducing morbidity in critically ill infants, however, equitable access to testing remains a challenge in some populations. This study evaluates the use of GS in critically ill infants in Brazil, focusing on diagnostic yield and clinical utility. A national prospective study was conducted through a public-private partnership. GS was performed on infants under one year of age admitted to intensive care units. Clinical utility was evaluated based on physician perception, impact on clinical management, relevance for infants or family members/caregivers, and implications for genetic counseling. GS was performed on 100 infants, yielding a confirmed molecular diagnosis in 32% of cases. An additional 7% were classified as likely diagnostic, resulting in a potential diagnostic yield of 39%. The median turnaround time was 13 days (7-25 days). Physicians recognized clinical utility for 81.1% of participants. Diagnostic and negative test results impacted clinical management, genetic counseling and/or demonstrated relevance for infants and families in 100% and 86.9% of reports, respectively. This study represents the largest South American cohort of critically ill infants evaluated by GS and provides a model for national implementation. Assessing clinical utility provided a comprehensive view of GS's impact. This article shows that genome sequencing (GS) in critically ill infants has clinical utility beyond diagnostic yield and management changes. Our study provides additional genomic data from a population typically underrepresented in international genomic research. This study represents the largest cohort of critically ill infants evaluated by GS in South America, providing a model for national-level implementation of GS in a resource-constrained setting.
Cisplatin-associated deterioration in sensorineural hearing thresholds is an important survivorship concern in HPV-positive oropharyngeal squamous cell carcinoma (OPSCC). Weekly low-dose cisplatin may reduce ototoxicity compared with high-dose schedules, but randomized audiometric data are limited. This secondary analysis of TROG 12.01 compared hearing outcomes between weekly cisplatin + radiotherapy (RT) and cetuximab + RT. Audiometric data were available for 101 TROG 12.01 trial participants. Patients received 70 Gy in 35 fractions with either weekly cisplatin (40 mg/m2, n = 55) or cetuximab (400 mg/m2 loading, then 250 mg/m2 weekly, n = 46). Pure-tone audiometry (500-8000 Hz) was obtained at baseline and 12-months. Linear mixed-effects models assessed absolute change in air-conduction thresholds. Logistic regression identified predictors of clinically significant deterioration in sensorineural hearing thresholds. To evaluate radiation-specific effects, receiver-operating characteristic (ROC) analyses of cochlea dose were performed in the cetuximab + RT cohort. Across 101 patients, 41% developed clinically significant deterioration in sensorineural hearing thresholds at 12-months: 45.5% with cisplatin + RT and 34.8% with cetuximab + RT. At 8000 Hz, cisplatin + RT was associated with greater deterioration (mean shift 6.83 dB; p = 0.01), remaining significant after multivariable adjustment (estimate 5.58 dB; p = 0.04). In the cetuximab + RT cohort, ROC analysis identified cochlea mean dose > 5.09 Gy (AUC 0.69) and maximum dose > 7.16 Gy (AUC 0.70) as cut-points associated with deterioration in sensorineural hearing thresholds. Weekly low-dose cisplatin is associated with clinically significant deterioration in high-frequency hearing. Cochlea RT doses contributed independently to ototoxicity however dose-estimation thresholds require further validation. Findings highlight the value of audiologic monitoring and the relevance of cochlear dose in HPV-positive OPSCC treated with low-dose cisplatin, with implications for future prospective trials.
Focal segmental glomerulosclerosis (FSGS) is a progressive glomerular disease characterized by podocyte injury, proteinuria, and risk of kidney failure. Until recently, no medicines had been approved by the FDA or European Medicines Agency, with management focused on supportive care and proteinuria reduction. This supplement explores the burden of FSGS from a clinical, humanistic, and economic perspective, informed by the results of 3 systematic literature reviews. FSGS is associated with poorer quality of life and high health care costs, and these outcomes are correlated with disease severity. Kidney Disease: Improving Global Outcomes guidelines recommend monitoring estimated glomerular filtration rate (eGFR) for kidney function; however, it is acknowledged that given the variable decline in FSGS, eGFR is not an ideal trial end point. Consequently, proteinuria reduction has become the preferred surrogate efficacy end point, as supported by the International Society of Glomerular Disease's global Proteinuria and Other Biomarkers as Endpoints for Clinical Trials in Kidney Disease initiative and subsequent FDA endorsement. Available treatments, such as glucocorticoids or calcineurin inhibitors, are limited in efficacy and safety. Among emerging medicines, sparsentan, a dual endothelin and angiotensin receptor antagonist (DEARA), has demonstrated consistent and significant reductions in proteinuria among patients with primary and genetic FSGS resulting in its approval by the FDA to reduce proteinuria in adult and pediatric patients aged 8 years and older with FSGS without nephrotic syndrome. In the phase 2 DUET clinical trial (NCT01613118), those treated with sparsentan showed a urine protein-creatinine ratio reduction of -35.6% (95% CI, -46.3% to -24.6%) vs baseline at 240 weeks. Sparsentan also showed greater reductions in proteinuria vs irbesartan, a standard renin-angiotensin system agent, along with a comparable safety profile in the phase 3 DUPLEX trial (NCT03493685). In model-based projections among real-world registry cohorts, sustained reductions in proteinuria are associated with lower long-term risk of kidney failure. These findings align with the PARASOL-FSGS initiative, supporting the role of proteinuria reduction as a key end point, facilitating pragmatic trial designs to address the persistent treatment gap in FSGS.