Exposure to space radiation represents a critical issue for astronauts' health, since it can lead to different types of effects including cancer, cataract, skin damage, damage to blood forming organs, cardiovascular diseases, CNS damage etc. Space radiation exposure is characterized by relatively low dose rates over long periods due to Galactic Cosmic Rays, plus short, higher-dose exposures in case of intense Solar Particle Events (SPE). In this framework the BIANCA biophysical model, which until now has been applied to predict cell death and chromosomal aberrations following acute exposure, was extended by integrating the Lea-Catcheside approach, which takes into account the effects of dose fractionation and dose rate; the good agreement between model predictions and proton cell survival data on fractionated irradiation (either obtained in this work, or taken from the literature) allowed validating the model for the considered scenarios. Afterwards, exploiting an interface with the FLUKA radiation transport code, BIANCA was applied to analyze the impact of dose rate for the August 1972 SPE, by calculating RBE-weighted organ doses in a human voxel phantom under different shielding conditions and for different irradiation durations. The results showed differences up to 50 % in the RBE-weighted dose between acute and protracted irradiation; such difference tends to decrease with increasing shielding. Following this work, BIANCA can now predict RBE values for cell survival taking into account not only the RBE dependence on particle type, energy and dose, but also the dependence on dose-rate. This allowed improving the accuracy in the prediction of astronauts' Gy-equivalent doses in case of a SPE exposure.
In malaria-endemic regions, repeated episodes of uncomplicated malaria during infancy are common; however, their associations with neurodevelopment remain unclear. We examined relationships between malaria frequency in infancy and neurodevelopmental outcomes in early and middle childhood, using data from the APEC birth cohort nested within the MiPPAD birth cohort study of Benin. Children were enrolled between January 2010 and June 2011 and followed from birth to 24 months of age. Malaria was assessed at scheduled visits at 6, 9 and 12 months using both PCR and microscopy, and at unscheduled visits for symptomatic episodes using only microscopy; haemoglobin was measured concurrently. Neurodevelopment was assessed at age 1 and 6 years. Analyses included 311 children at 1-year and 248 at 6-year assessments. Malaria exposure was defined as the number of episodes from birth to 1-year neurodevelopmental assessment for three measures: (i) total malaria (PCR- or microscopy-positive), (ii) symptomatic malaria (positive with fever) and (iii) malaria with anaemia (positive with haemoglobin < 11.0 g/dL). Associations with neurodevelopment and haemoglobin's mediating role were assessed using adjusted generalized linear models and mediation analysis. We found that a higher number of symptomatic malaria episodes during infancy was associated with lower motor scores at age one (β: -2.81, [-4.73, -0.89]) and age six (β: -1.43, [-2.65, -0.22]), partially and potentially mediated by haemoglobin concentration. Malaria with anaemia was associated with lower motor scores at age one (β: -1.57, [-3.04, -0.10]) and age six (β: -0.96, [-1.86, -0.05]). No consistent associations were observed with cognitive outcomes. These findings indicate that uncomplicated malaria in infancy is an important risk factor for impaired child development and should not be overlooked. Integrating anaemia screening and management into malaria control and routine child health services may help mitigate long-term developmental impacts in malaria-endemic settings.
This work presents a numerical investigation of interacting chiral oscillators (COs), characterized by an intrinsic rotational handedness. The coupling of positional and orientational degrees of freedom drives a mutual influence between synchronization and spatial dynamics. The control parameter, Δ (anisotropy or detuning), represents the frequency difference between two COs (for the two-body case) or between two families of COs (for the many-body case) with opposite handedness. For two COs with opposite handedness, interaction forces generate a helical excitable dipole (HED), where excitability is a spatiotemporal act characterized by a helical trajectory. For many COs moving in two dimensions, the model displays a locking-to-unlocking transition of the Kuramoto kind driven by Δ, leading the system from ordered states to irregular spatiotemporal dynamics. Within the locking region, many "superexcitable" states emerge, sustained by a global saddle-node bifurcation, detected by the collective period behavior versus Δ. These coherent, topological states are characterized by dissipationless phase-momentum locking, which I quantified using appropriate global metrics, including the Kuramoto order parameter and parameter S, capable of detecting the phase-momentum locking. These states exhibit a wide variety of topologically protected vortex complexes, whose complexity increases with system size. The model provides a unified framework for diverse biophysical applications-from molecular ratchets to cardiac looping-identifying the symmetry breaking of motile excitable units as a fundamental process for large-scale, robust collective transport.
Pediatric immunological and allergic conditions represent a broad spectrum, ranging from highly prevalent polygenic disorders (e.g., food allergy, atopic dermatitis, asthma, and allergic rhinitis) to rarer monogenic primary atopic disorders. The management of these conditions has undergone a paradigm shift in recent years. Moving away from a "one-size-fits-all" approach, precision medicine aims to deliver the right treatment to the right patient at the right time. By integrating clinical phenotypes with molecular endotypes and using specific biomarkers and "Omics" techniques, scientists and clinicians can now employ targeted biological therapies that significantly improve patient outcomes. By identifying early therapeutic windows and specific biomarkers, pediatric specialists can implement personalized interventions that halt the atopic march and mitigate the global burden of chronic allergic diseases. By shifting the focus from symptom management to the neutralization of specific molecular pathways, it is now possible to achieve better disease control, reduce side effects associated with broad-spectrum treatments such as systemic corticosteroids, and improve the quality of life for patients with refractory allergic diseases. This review, generated during a seminar funded by the Clemens von Pirquet Foundation, aims to delineate the "rare to common" pipeline, illustrating how precision medicine tools, including multi-omics, biomarkers, and artificial intelligence methods, can connect mechanistic pathways across the immunological spectrum.
In moderately advanced (T2-T3) glottic cancer, eligibility for organ-preserving surgery is limited by tumor extension into certain high-risk areas within the larynx that can be identified on preoperative imaging and serve as predictive factors for poorer outcomes. Their relevance in conservative treatment modalities, including (chemo)radiotherapy ([C]RT), remains unclear. The objective was to evaluate the impact of these predefined surgical high-risk zones in patients treated with (C)RT. This retrospective study included patients with T2-3, N0-3, M0 glottic carcinoma treated with primary (C)RT and with available diagnostic imaging from three academic medical centers between 2014 and 2018. Imaging was scored for tumor involvement of high-risk areas. The 5-year rates of locoregional control (LRC) and disease-specific survival (DSS) were compared using the log-rank test and Cox proportional hazards model. Imaging from 180 patients (mean age, 68 ± 11 years, 154 men) was assessed, with 173 entering the risk factor analysis after excluding unreliable scans. Significant findings were observed in the anterior larynx: vertical anterior commissure involvement negatively affected LRC and DSS, while horizontal anterior commissure and anterior paraglottic space reduced LRC. Deep vocal muscle infiltration showed negative trends. In multivariable analysis, vertical anterior commissure infiltration retained a trend toward lower DSS. Involvement of the anterior commissure, particularly vertical extension, which is a known predictive factor from surgical studies, likely predicts poorer outcomes after (C)RT for T2-T3 glottic carcinoma. Involvement of the anterior paraglottic space and depth of tumor infiltration carry potential predictive value. Question Can radiological risk factors proven in surgically treated patients with T2-T3 glottic carcinoma also predict treatment failure in patients treated with (chemo)radiotherapy? Findings On multivariable analysis, vertical anterior commissure involvement showed a trend toward poorer disease-specific survival. Clinical relevance Our findings contribute to the search for harmonized prognostic factors across treatment modalities for glottic carcinoma and provide a basis for integrating these risk factors into staging and treatment counseling.
Mild Cognitive Impairment (MCI) is a heterogeneous clinical condition characterized by a wide spectrum of cognitive and behavioural manifestations. Despite numerous studies, the link between neuropsychological performance and pathophysiological signatures of the disease-including Aβ and tau accumulation along with altered excitation/inhibition (E/I) balance and brain rhythms-remains elusive. Here Aβ/tau biomarkers were used to distinguish positive (MCI+- prodromal Alzheimer's disease) and negative (MCI-) subjects in a cohort of 30 MCI patients (18 MCI+ and 12 MCI-). Virtual brain models based on high-field magnetic resonance imaging data were then developed to determine the inter-node coupling and E/I profile in resting-state networks, while node spectral information was obtained from source analysis of high-density electroencephalography (HD-EEG). Finally, virtual brains and HD-EEG parameters, creating brain digital twins of individual subjects, were correlated with cognitive performance. While virtual brain simulations did not reveal E/I differences between MCI+ and MCI-, a positive correlation emerged between synaptic parameters of the limbic network and verbal episodic memory for both groups. EEG power spectral density revealed a lower high-frequency/low-frequency ratio in MCI+ largely due to a reduced alpha band in the default mode, limbic, attention, frontoparietal, visual and somatomotor networks. A strong correlation emerged between multimodal parameters and memory functions, supporting that brain digital twin simulations can effectively explain the variability of neuropsychological performance in MCI patients beyond the sensitivity of individual techniques alone. In particular, the combination of HD-EEG and virtual brain parameters explained more than 90% of variance for episodic memory patients' scores, confirming the compound origin of memory performance involving network specific E/I levels and electroencephalographic activity acting in concert. This multimodal and multiparametric analysis combining virtual brain modelling with HD-EEG and molecular data enhances the stratification of MCI patients and could be used to develop digital biomarkers of progression to dementia, opening new perspectives for personalized prognosis and treatment.
As the European Society of Clinical Microbiology and Infectious Diseases (ESCMID) continues to expand its guidelines programme, further methodological standardisation is needed. This project aimed to develop a framework for standardising consensus methods in ESCMID guideline panels. Two scoping reviews were conducted to inform the framework: (i) a PubMed review to identify and map formal consensus methods used in guideline development, and (ii) a review of methodological guidance documents from national and international guideline-developing organisations to examine how consensus is operationalised in practice. Findings were synthesised using descriptive analyses and narrative synthesis and were integrated with ESCMID's methodological approach and feasibility considerations. The draft framework underwent stakeholder review and was revised accordingly before final approval by ESCMID governance bodies. ESCMID developed a standardised framework for reaching consensus in guideline panels, centred on mandatory anonymous voting when issuing recommendations, with consensus defined as ≥80% agreement among voting members. The framework defines voting rights and participation requirements, standardises voting options and outcome reporting, and establishes procedures to manage non-responsiveness and address lack of consensus through iterative rewording and repeat voting rounds. Oversight and documentation requirements are specified to support transparency and consistency. This framework represents an advancement in guideline development for ESCMID. It is designed to enhance quality, transparency, and consistency of ESCMID guidelines, while reducing sources of bias. Aligned with ESCMID's methodological rigour and commitment to evidence-based practice, it strengthens trustworthiness of ESCMID clinical guidelines.
The performance of the SAMElife™ rapid hair screening kit was evaluated for the detection of drugs of abuse in 31 anonymized hair samples, encompassing 217 analyses for morphine, cocaine, amphetamines, buprenorphine, oxycodone, fentanyl, and methadone. Screening results were compared with confirmatory gas chromatography-mass spectrometry (GC-MS) and liquid chromatography-tandem mass spectrometry (LC-MS/MS) analyses. The kit demonstrated high specificity (100%) and good sensitivity (81.8%) for basic drugs, with four false negatives observed for cocaine, while no false positives were recorded. Detection of Δ9-tetrahydrocannabinol (THC) was unreliable, yielding uniformly positive results regardless of confirmatory analysis. The automated workflow, requiring only hair cutting and no prior decontamination, provides a rapid and practical approach for preliminary screening in routine toxicology laboratories. Despite limitations in THC detection and the small number of positive samples for some analytes, the SAMElife™ kit offers a reliable tool to reduce the number of samples requiring confirmatory analysis. Further evaluation on larger populations and optimization of the THC assay are recommended.
Diabetes Mellitus (DM) has been recognized as a potential risk factor and disease-modifier in Parkinson's Disease (PD), being associated with worse motor and cognitive outcomes, and altered susceptibility of neural pathways. This study investigated the impact of DM on nigrostriatal dopaminergic vulnerability independently of disease severity in drug-naïve PD patients. This study analyzed two independent cohorts of PD patients (multi-center PPMI n = 174, single-center UniBS n = 95). Patients with and without DM were first compared and then matched for age, sex, and clinical severity. All patients underwent baseline 123I-FP-CIT imaging to quantify dopamine transporter binding. Dopaminergic binding, neural reserve index and molecular connectivity patterns were compared between severity-matched groups. Patients with DM were older, predominantly male, and exhibited worse non-motor and cognitive symptoms. After severity matching, PD-DM exhibited more preserved nigrostriatal dopamine uptake compared to PD-n. PD-DM also showed fewer nigrostriatal dopaminergic connectivity alterations (10% vs. 21%) and reduced neural reserve index in the left putamen and - only in the single-center cohort- whole striatum. In drug-naïve PD patients, comorbid diabetes is associated with comparable clinical severity despite milder dopaminergic loss. This suggests an increased dopamine system vulnerability linked to DM, reducing the efficiency and compensatory mechanisms of nigrostriatal dopaminergic networks in PD.
Randomized trials support early initiation of direct oral anticoagulants (DOACs) after atrial fibrillation (AF)-related ischemic stroke, but patients with breakthrough ischemic stroke occurring despite ongoing anticoagulation have been largely under-represented. We evaluated the effectiveness and safety of early versus delayed DOAC initiation after breakthrough ischemic stroke. We performed a target trial emulation comparing early versus delayed DOAC initiation in patients with breakthrough ischemic stroke. Treatment strategies were prespecified using severity-adapted timing thresholds based on baseline National Institutes of Health Stroke Scale (NIHSS) scores. The study population was drawn from the retrospective arm of the international, multicentre ASPERA study and included patients with AF who experienced an ischemic stroke while receiving continuous anticoagulation. To emulate random assignment and avoid immortal time bias, a cloning-censoring-weighting approach with inverse probability weighting was applied. Primary outcomes were 90-day new ischemic events and moderate-to-severe bleeding. Risk ratios (RRs), absolute risk differences (RDs), and hazard ratios (HRs) were estimated using weighted regression and Cox models. Among 833 patients (median age 81 years), 336 were assigned to early and 497 to delayed DOAC initiation. At 90 days, early initiation was associated with a lower risk of new ischemic events (RR 0.44, 95% CI 0.21-0.90; RD -3.64%, 95% CI -6.40 to -0.87; HR 0.43, 95% CI 0.21-0.91). Moderate-to-severe bleeding occurred less frequently with early initiation (RR 0.10, 95% CI 0.01-0.76). Early initiation was also associated with lower 90-day all-cause and vascular mortality. A Net Early Benefit Score integrating ischemic and bleeding risks was positive across all NIHSS strata. In patients with breakthrough ischemic stroke, early severity-adapted DOAC initiation was associated with lower risks of recurrent ischemic events and mortality at 90 days without an increase in major bleeding. These findings support early anticoagulation initiation in this high-risk population.
Reliable tools to quantify nutrition knowledge are crucial for planning education and prevention. We developed the Questionario delle Conoscenze Alimentari Italiano (QCAI) for Italian adults and assessed its reliability. A convenience sample of 165 participants (18-89 years; 70.9% women) completed a self-administered, 69-item questionnaire organized into four content sections (experts' recommendations; nutrient content of foods; healthy choices; meal frequency and labels) plus demographics. Participants completed the questionnaire at baseline (T0) and again after seven days (T1) under identical conditions. Internal consistency was evaluated with Cronbach's alpha (and KR-20 for dichotomous items). Temporal stability was assessed with intraclass correlation coefficients (ICC<inf>(2,1)</inf>) for section and total scores, Cohen's kappa (κ) for items, and Bland-Altman analysis. Total-scale internal consistency was acceptable (Cronbach's α=0.757 for available items), but domain-level α values were heterogeneous and in some sections low (α: 0.307-0.638), indicating limited coherence of some subscales. Test-retest stability for the total score was moderate (ICC<inf>(2,1)</inf>=0.62), and 64.29% of items showed at least moderate agreement (κ≥0.40). Age-stratified analyses showed no linear trend in the total score across groups (18-39, 40-59, ≥60; P<inf>trend</inf>=0.26). QCAI is a low-cost instrument that shows moderate temporal stability and acceptable reliability for the total score in Italian adults. However, the low internal consistency observed in some domains limits the interpretability of section scores and highlights the need for item refinement and formal validation (content, construct, and criterion validity) against established measures before routine clinical or public-health use.
Five-membered oxygenated heterocycles, such as substituted tetrahydrofurans (THFs), are important structural motifs in bioactive compounds and can be efficiently accessed through palladium-catalyzed asymmetric allylic alkylation (AAA). In this context, the desymmetrization of mesodiols represents a powerful strategy for the stereocontrolled construction of chiral THF frameworks. Herein, we present a combined experimental and computational study aimed at elucidating the origin of an unusual diastereoselectivity inversion observed in this reaction. While ligands of the Trost family are generally considered interchangeable when sharing the same chiral information, experimental results show that switching between (S,S)-DACH-Ph (L1) and (R,R)-ANDEN-Ph (L2) leads to a reversal of the major diastereomer formed without significant loss of enantioselectivity. Density functional theory (DFT) calculations reveal that this behavior cannot be rationalized by the only classical Trost-Toste steric quadrant model. Instead, the selectivity is governed by a network of ligand-controlled noncovalent interactions, including hydrogen bonding between the ligand amide N-H, the acetate counteranion, and the substrate hydroxyl groups, which dictate the relative stability of the competing transition states. These findings provide a mechanistic framework that explains the observed disaster conversion and highlights the critical role of interaction patterns beyond steric effects, offering new predictive insights for the design of asymmetric AAA processes.
Mild cognitive impairment (MCI) represents a transitional stage between normal aging and dementia, yet sensitive behavioral and neural markers of early cognitive decline remain to be fully characterized. Increasing evidence suggests that instability of proactive control mechanisms, rather than generalized slowing, may play a critical role in early cognitive impairment. The present study investigated whether behavioral variability and preparatory neural activity constitute neurobehavioral markers of global cognitive functioning in older adults. Ninety‑two older adults (65-89 years) completed a discriminative response task while electroencephalography was recorded. Behavioral performance was quantified using mean response time, error rate, and the intra‑individual coefficient of variation of response time (ICV). Preparatory neural activity was indexed by the Bereitschaftspotential (BP) and prefrontal negativity (pN) measured in the pre‑stimulus interval. Global cognition was assessed using the Montreal Cognitive Assessment (MoCA), analyzed both categorically (MCI‑range vs. cognitively normal) and continuously. Group comparisons, correlational analyses, regression models, and mediation analyses were conducted. Compared with cognitively normal participants, individuals in the MCI range exhibited significantly greater behavioral variability (higher ICV) and reduced preparatory neural activity (attenuated BP and pN amplitudes), while mean response time did not differ between groups. Across the entire sample, higher ICV was associated with lower MoCA scores, whereas larger BP and pN amplitudes were associated with better global cognition. Behavioral instability and preparatory neural activity independently predicted MoCA scores in continuous models. Mediation analyses indicated that ICV and preparatory ERP measures partially mediated the relationship between age and cognitive performance. The present findings demonstrate that behavioral instability and reduced preparatory neural engagement are closely linked to global cognitive performance and MCI-range in older adults. By integrating behavioral and pre‑stimulus electrophysiological measures, this study supports a neurobehavioral framework in which proactive control instability is associated with early cognitive decline. Preparatory processes emerge as sensitive and informative markers linked with variability in cognitive functioning in aging, with potential relevance for understanding early neurobehavioral changes.
Pets are subject to latent toxicological hazard from microplastics (MPs) contamination in dry pet food (DPF). Very little is understood about the commercial and regional variables leading to the MP exposure by DPF intake. The goal of this study was to compare MP contamination in dog and cat DPF commercially available in Spain and Ecuador. The analysis relied on stereomicroscopy, scanning electron microscopy, and μFTIR spectrophotometry, which indicated a significant difference in MP abundance and composition. Ecuadorian items, especially those sold in bulk (loose), achieved concentrations of 12.33 ± 1.53 MPs/5g, whereas Spanish samples maintained lower baselines (3.33-11.33 MPs/5g). In unsealed Ecuadorian samples, Fourier transform infrared spectroscopy spectroscopy (μFTIR) revealed a broad polymeric profile that included polyethylene terephthalate (PET), polyethylene (PE), and polypropylene (PP) in combination with industrial indicators such as polytetrafluoroethylene (PTFE) and polydimethylsiloxane (PDMS) and the dangerous plasticiser benzyl butyl phthalate (BBP). According to morphological analysis, fibres represented 70-80% of the particles, and as many as 44% of them were classified in the potential translocatable 1-20 μm range. According to daily intake estimates, dogs in Ecuador had the greatest cumulative MP burden, consuming roughly 461 MPs/day as compared to 395 MPs/day in Spain. These results suggested that bulk commercialisation was a significant secondary vector for hazardous exposure, whereas industrial processing and raw materials (marine and agricultural) were the main contaminant sources. In conclusion, enhanced regulatory control of storage and packing processes shall be crucial to reduce chronic MP intake and potential endocrine disruption in pets.
Metastasis-directed stereotactic body radiotherapy (SBRT), in combination with systemic therapy, is increasingly used in patients with oligometastatic disease (OMD), supported by international guidelines. However, real-world data on health-related quality of life (HRQoL) following SBRT remain limited. This study aimed to describe baseline HRQoL, evaluate changes over time, and identify clinical factors associated with HRQoL and its evolution. OligoCare is a pragmatic, prospective cohort study within the E2-RADIatE registry, including patients with oligometastatic breast, colorectal, non-small cell lung cancer (NSCLC), and prostate cancer treated with SBRT. An optional HRQoL sub-study assesses patient-reported outcomes at baseline and within 6 months post-SBRT. Analyses included descriptive assessment of baseline HRQoL, multivariable regression to identify factors associated with baseline global health status (GHS), and longitudinal evaluation of HRQoL changes. Clinically meaningful changes were defined using a minimal clinically important difference (MCID) of ≥ 10 points. Of 2,041 patients, 1,033 (50.6%) completed baseline HRQoL questionnaires and 450 (22%) had follow-up data. The median time to follow-up HRQoL assessment was 2.7 months (range 0.5-6.1). Median baseline GHS was 75. Higher baseline GHS was associated with prostate cancer and good performance status (p < 0.0001). At follow-up, mean GHS remained stable (71, SD 19). Among patients with follow-up data, 23% reported worsened HRQoL, 15% improved. No significant associations were found between HRQoL changes and clinical variables. Early findings support that SBRT for OMD maintains overall HRQoL in most patients, reinforcing its role in multimodal treatment without compromising patient-reported outcomes.
Pediculosis capitis is a common parasitic infestation in school settings and can disrupt wellbeing and school attendance. Despite its public-health relevance, epidemiological data describing Pediculosis capitis prevalence and associated factors in Mexico remain limited at the city level. This study aimed to estimate the prevalence of Pediculosis capitis and identify associated factors among schoolchildren from Monterrey and Mérida, Mexico. Aggregated data from a school-based cross-sectional survey were analyzed. Infestation status was determined through standardized individual scalp inspection performed by the research team. Prevalence and unadjusted odds ratio were calculated for sociodemographic, household, and hygiene-related variables. A total of 6372 schoolchildren were examined (3743 in Monterrey; 2629 in Mérida) with 590 positive cases overall. Prevalence was 16.40% in Monterrey and 6.57% in Mérida, with marked variation among schools. The strongest and most consistent associations were observed for sex and hair length, with higher infestation rates among girls and children with long hair. Associations with household and hygiene factors such as sharing of personal items, bathing frequency, room density, parental education, and employment were heterogeneous across cities and did not follow a uniform pattern. These findings highlight the need for school-home collaboration and continuous surveillance, promoting early detection, hygiene education, and preventive practices adapted to local school environments.
To compare serial prenatal MRI findings in valacyclovir-treated vs untreated fetuses with confirmed congenital cytomegalovirus (cCMV) infection, focusing on the occurrence and timing of minor brain lesions. In this retrospective single-center cohort study, fetuses with confirmed cCMV infection and at least two prenatal brain MRI examinations were included. Fetuses with major brain malformations at baseline were excluded. Treated fetuses received oral valacyclovir (8 g/day) from diagnosis to delivery. Two senior neuroradiologists assessed MRI examinations in consensus, focusing on minor lesions (temporal pole T2 hyperintensity, focal temporal horn dilation, small cysts). Lesion timing was categorized as absent, late-onset, or early-onset. Statistical analyses included Fisher's exact test, χ²-test, and odds ratios. Seventy-seven fetuses were included (62 untreated, 15 treated). Persistently negative MRI findings were observed in 73.3% of treated fetuses vs 37.1% of untreated fetuses (p = 0.018; OR 4.67, 95% CI: 1.29-16.9). Early-onset minor lesions were observed only in untreated fetuses (11.3%). A significant difference between groups was confirmed when analysis was restricted to temporal pole lesions (p = 0.02). Maternal valacyclovir therapy was associated with a significantly higher likelihood of persistently normal prenatal MRI findings and absence of early minor brain lesions, suggesting a protective effect on fetal brain involvement in cCMV. Question Minor temporal pole lesions are common early MRI findings in cCMV. Findings Valacyclovir-treated fetuses showed fewer and later-onset minor lesions. Clinical relevance Serial fetal MRI may serve as an imaging surrogate marker of treatment response.
Artificial intelligence-enhanced electrocardiogram (AI-ECG) has shown promise as an inexpensive, ubiquitous, and non-invasive screening tool to detect left ventricular systolic dysfunction in pediatric congenital heart disease. However, current approaches rely heavily on large-scale labeled datasets, which poses a major obstacle to the democratization of AI in hospitals where only limited pediatric ECG data are available. In this work, we propose a robust training framework to improve AI-ECG performance under low-resource conditions. Specifically, we introduce an on-manifold adversarial perturbation strategy for pediatric ECGs to generate synthetic samples that better reflect real-world signal variations. Building on this, we develop an uncertainty-aware adversarial training algorithm that is architecture-agnostic and enhances model robustness. Internal and external evaluation on real-world pediatric (n=178,495) and adult (n=100,000) datasets demonstrates that our method enables low-cost and reliable detection of left ventricular systolic dysfunction, highlighting its potential for deployment in resource-limited clinical settings.
Healing success for fifth metatarsal fracture nonunions is challenging and hindered by risk factors for nonunion. Pulsed electromagnetic field stimulation (PEMF) promotes bone healing and can help overcome biological deficiencies in patients at risk. The current study assessed the impact of PEMF treatment to promote successful bone healing in metatarsal nonunion. A multi-center, retrospective study was conducted to evaluate PEMF treatment for fifth metatarsal fracture nonunion. Subjects undergoing treatment and eligible for treatment with PEMF (PhysioStim™ device) were enrolled. Subjects were followed for up to 12 months to determine bone healing status determined by radiographic assessment. Subjects were assessed for healing status and impact of risk factors for nonunion. Fifty-six (n=56) subjects were included in the analysis. Subjects were 89.3% female with a mean age of 59.7 years. Of the risk factors studied, 75.0% of subjects had at least 1 risk factor associated with compromised bone healing. PEMF treatment started shortly after the nonunion diagnosis, and the average time from nonunion diagnosis until successful healing was 154.7 days. Approximately 62.5% of subjects showed successful healing of their 5th metatarsal fracture by 4 months; 75.0% of subjects healed by 6 months; 91.1% of subjects healed by 12-months. The number of risk factors (up to 5 total per subject) was associated with longer heal times (p<0.02). Of the risk factors studied, only nicotine use was associated with longer healing times (p<0.03). Metatarsal nonunion subjects treated with PEMF achieved favorable time to healing despite having risk factors for compromised healing.
This study aimed to identify problems and highlight opportunities for pharmaceutical sciences research in the Philippine pharmaceutical industry's regulatory and clinical research sectors that might have been previously overlooked or underrepresented. It identified current issues that can be addressed by research covering four areas of pharmaceutical sciences: drug design and discovery, pharmacokinetic/pharmacodynamic studies, formulation design and pharmaceutical technology, and regulatory science. A descriptive qualitative approach was used in this study. Data collection was facilitated by key informant interviews (KII) using a standardized interview guide with open-ended questions to identify the pharmaceutical science research needs of the specific sectors. A purposive sampling method was employed, with five key informants (KIs), including the company vice president, director, and top-level managers from different local and multinational pharmaceutical companies. ATLAS.ti software was utilized to facilitate thematic synthesis for qualitative data analysis. Thirteen common themes were identified from the KIs, such as (1) incomplete development of therapeutic compounds, (2) sustainability of raw materials supply, (3) regulation of herbal medicines versus food supplements, (4) mapping disease priorities through the Philippine pharmaceutical roadmap, (5) government incentives and policies to support research, (6) technical personnel, (7) suboptimal regulatory process, approvals, and implementation, (8) gap in utilization of acquired knowledge on regulations, (9) regulatory governance, (10) passive regulatory action on counterfeit drugs, (11) PIC/S GMP version 14 adaption, (12) formulation optimization, and (13) active pharmaceutical ingredient (API) sourcing and regulation. Based on insights from the International Pharmaceutical Federation regarding anticipated hurdles in pharmaceutical sciences over the next 5-10 years, priority research needs were identified through KIs' input. Relevant action plans were developed, including the creation of research proposals to isolate, purify, and determine chemical structures of natural products, as well as analyzing recent Philippine Health Statistics to help assess the appropriateness of new drug releases for patient needs. Other action plans include forecasting future disease burdens in the country, performing toxicology studies (Health-Based Evaluation Levels/No Observed Adverse Effect Level or HBEL/NOAEL) for common generic drugs, and ensuring that research efforts are directed toward addressing the Philippine pharmaceutical regulatory and clinical research sector's most pressing needs practically and feasibly. This study offers valuable insights into pharmaceutical sciences research and development initiatives within the regulatory and clinical research sectors in the Philippine pharmaceutical industry. These findings have the potential to catalyze transformative advancements in healthcare delivery and outcomes, positioning the Philippines for global excellence and competitiveness.