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Integrating Functional Consequence Annotation With PAH Allelic Phenotype Values Refines Prediction of Tetrahydrobiopterin Responsiveness.

Himmelreich N et al. · Jul 1, 2026

Tetrahydrobiopterin (BH4; sapropterin) responsiveness in phenylalanine hydroxylase (PAH) deficiency is genotype dependent, yet many patients remain untested. Allelic phenotype values (APV) summarize allele severity, but responsiveness can be heterogeneous within APV strata. We assessed whether integrating functional consequence annotation from Ensembl variant effect predictor (VEP) improves genotype-based prediction of BH4 response. We analyzed 23 640 individuals with biallelic PAH genotypes and BH4 status (RESP, S-RESP, N-RESP, or not tested). Tested individuals were used for model development (responders defined as RESP+S-RESP; nonresponders as N-RESP). APV values were assigned from published APV resources and merged at the variant level. Functional consequence predictors were derived from VEP output and included strict predicted loss-of-function (pLoF) flags, splice-impact scores (SpliceAI maximum delta score), and missense pathogenicity predictions (SIFT and PolyPhen). Genotype predictors were constructed using a milder-versus-severer allele framework, with the milder allele defined as the allele with the higher APV. Models were evaluated using genotype-held-out cross-validation (GroupKFold by genotype). Among 4640 tested individuals, 2044 (44.1%) were BH4 responders. Responder rates were enriched in milder phenotypes and increased monotonically across milder-allele APV bins. In genotype-held-out evaluation, integrating functional consequence predictors with APV improved discrimination modestly overall and more clearly in intermediate APV genotypes. Genotype predicts BH4 responsiveness with high performance under stringent genotype-held-out validation, and VEP-derived functional consequence annotation provides modest complementary value beyond APV, particularly for intermediate-severity genotypes.

Biochemistry, Genetics and Molecular Biology

Integrating Individual Placement Support in Early Psychosis Programs: A Necessary Step to Foster Return to Employment in First Episode Psychosis Patients.

Renda M et al. · Jul 1, 2026

Introduction Return to studies or employment, a major element of recovery after a first episode of psychosis (FEP), is out of reach of a significant proportion of patients. Specific programs such as Individual Placement Support (IPS) have been proposed to overcome this hurdle. While some early intervention programs include IPS, others must rely on IPS programs that are open to a wider range of patients. The aim of this paper was to explore the accessibility of IPS for FEP patients treated in such a context. Methods One hundred and eighty nine patients of an ongoing FEP cohort study who were treated at our program in the period where the IPS program was available and for whom sufficient data was available were included in the study. We assessed reasons for non-referral to RESSORT and compared baseline and outcome characteristics of patients who did or did not enter the program. Results A small minority of patients had access to RESSORT. Patients who entered RESSORT had better premorbid functioning and a higher degree of insight at baseline than the ones who did not enter the program. Patients who entered RESSORT had a significantly higher rate of return to premorbid PAS score, without significant difference on other dimensions of functioning. Conclusions When IPS programs are not embedded in early intervention programs, FEP patients have limited chances to access them. Integrating supported employment skills within the role of case managers may be a solution in programs where resources are lacking to develop an IPS program specifically dedicated to FEP patients.

Medicine

Preschoolers' Early Sentence Comprehension: Comparing Bilingual and Monolingual Children and the Role of Executive Function and Vocabulary Development.

Rodenhurst N et al. · Jul 1, 2026

Previous research into children's comprehension of syntactic structures has investigated early awareness of transitive and intransitive structures amongst monolingual children but research into bilingual children's understanding of the same sentence structures is lacking. This study compared 46 3-5-year-old bilingual children who spoke English and an additional language with 64 monolingual, English-speaking children, in their ability to associate transitive sentences with a causal scene, and intransitive sentences with a non-causal scene. In contrast to previous studies, the current study used still images instead of videos to create eight trials per structure, increasing the number of trials and testing structure as a within-participants manipulation. Children's vocabulary and executive function skills were also tested to observe interactions with the sentence comprehension task. Both groups showed the same overall pattern of effects, though the monolingual children were reliably more likely to match the causal scene to a transitive than bilingual children: Older children associated the transitive trials with causal scenes more than the intransitive trials, whereas 3-year-olds tended to associate both the transitive and intransitive sentences with causal scenes. Executive function performance did not differ between bilingual and monolingual children and was not related to sentence interpretation, but monolingual children had higher English vocabulary scores and children with greater vocabularies were better able to distinguish causal scenes as a match for transitive sentences. The results suggest that differences in comprehension of syntactic structures are more likely to be related to age and language ability, rather than differences in the number of languages spoken. SUMMARY: Bilingual and monolingual children showed similar patterns in their ability to comprehend transitive and intransitive sentences, though monolinguals more reliably associated transitives with causal scenes. 4- and 5-year-olds were better at associating transitives with causal scenes and intransitives with either causal or non-causal, whereas 3-year-olds associated both sentences with causal scenes. Age was a better predictor of differences in interpreting transitivity than the number of languages children speak. No executive function differences between bilinguals and monolinguals were found, monolinguals had larger English verb vocabularies; vocabulary was related positively to causal scene/transitive associations.

Psychology

Effects of a 4-Week Multi-Exercise Isometric Resistance Training Programme on Resting and Ambulatory Blood Pressure in Normotensive Adults.

Wright BH et al. · Jul 1, 2026

Isometric resistance training (IRT) can reduce resting and ambulatory blood pressure (AmBP) yet established exercise methods lack versatility and may present with participation barriers. An isometric training band (ITB) has been identified as an alternative modality; however, its long-term effects on resting and ambulatory blood pressure (BP) remains unknown. This study assessed the effects of the ITB on resting BP and AmBP following 4 weeks of IRT. Forty-two normotensive adults (22 male, 20 female; mean ± SD, age 31 ± 14 years, systolic [sBP], 120 ± 5 mmHg, diastolic [dBP], 72 ± 7 mmHg), were randomised to a control (CON), isometric handgrip (IHG) or ITB group. Resting (systolic, diastolic, mean arterial BP and heart rate [HR]) and AmBP (24-h, daytime and night-time) were measured pre- and post-4 weeks of supervised IRT (4 x 2-min contractions at 30% MVC [IHG] or 4 x 2-min contractions at CR-10 values equivalent to 30% MVC [ITB]). Resting sBP was reduced for IHG (-4.6 mmHg, p 0.05 across all measures). These findings suggest 4 weeks of IRT using the ITB can elicit reductions in resting BP and night-time AmBP in normotensives comparable to IHG, indicating the ITB may offer a practical and cost-effective alternative to established interventions.

Medicine

FuelGuard AI:An AI-Driven Unified Framework for Intelligent Fuel and LPG Allocation During Emergencies and Supply Shortages

Akshay N, Akshay Guptha L, Akshatha H M, Aishwarya S · Aug 15, 2026

Abstract. Fuel and LPG are essential resources for transportation, households, healthcare, agriculture, and other critical services. During emergencies, supply shortages, and sudden demand fluctuations, conventional distribution systems may face challenges in forecasting demand, managing limited resources, and ensuring fair and secure access. This paper presents FuelGuard AI, an intelligent digital framework developed to support fuel and LPG allocation through centralized monitoring, quota management, priority-based allocation, demand analysis, and secure transaction verification. The implemented prototype integrates citizen and station-operator interfaces with a secure QR-based authentication mechanism using short-lived cryptographic tokens, enabling authorized operators to verify allocation requests before dispensing fuel. The system also maintains transaction records and supports server-side quota deduction to improve traceability and prevent unauthorized or duplicate allocations. In addition, the framework provides a foundation for AI-assisted demand forecasting, shortage detection, and adaptive allocation during critical situations. The proposed system aims to improve transparency, security, resource utilization, and fairness while complementing existing fuel and LPG distribution infrastructure.

Energy ManagementCybersecurityResource AllocationArtificial IntelligenceFuel Management

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