Two new HLA-DQB1*03:02:01 variants with substitutions in intron 2: HLA-DQB1*03:02:01:19 and -DQB1*03:02:01:21.

Two different single nucleotide substitutions in intron 2 give rise to novel HLA-DQB1*03:02:01 alleles.

Control Compounds for Preclinical Drug-Induced Liver Injury Assessment: Consensus-driven systematic review by the ProEuroDILI Network.

BACKGROUND & AIMS: Idiosyncratic drug-induced liver injury (DILI) is a complex and unpredictable event caused by drugs, herbal or dietary supplements. Early identification of human hepatotoxicity at preclinical stages remains a major challenge, in which the selection of validated in vitro systems and test drugs has a significant impact. This systematic review analyzed the compounds used in hepatotoxicity assays and established a list of DILI positive and negative control drugs for validation of in vitro models of DILI, supported by literature and clinical evidence and endorsed by an expert committee from COST Action ProEuroDILI Network (CA17112). METHODS: Following 2020 PRISMA guidelines, original research articles focusing on DILI which used in vitro human models and performed at least one hepatotoxicity assay with positive and negative control compounds, were included. Bias of the studies was assessed by a modified 'Toxicological Data Reliability Assessment Tool'. RESULTS: 51 studies (out of 2,936) met the inclusion criteria, with 30 categorized as reliable without restrictions. Although there was a broad consensus on positive compounds, the selection of negative compounds lacked clarity. 2D monoculture, short exposure times and cytotoxicity endpoints were the most tested, although there was no consensus on the drug concentrations. CONCLUSIONS: The extensive analysis highlighted the lack of agreement on control compounds for in vitro DILI assessment. Following comprehensive in vitro and clinical data analysis together with input from the expert committee, an evidence-based consensus-driven list of 10 positive and negative drugs is proposed for validating in vitro models for improving preclinical drug safety testing regimes. IMPACT AND IMPLICATIONS: Prediction of human toxicity early in the drug development process remains a major challenge. For this, human in vitro models are becoming increasingly important, however, the development of more physiologically relevant liver models and careful selection of control DILI+ and DILI- drugs are requisites to better predict DILI liability of new drug candidates. Thus, this systematic study holds critical implications for standardizing validation of new in vitro models for studying drug-induced liver injury (DILI). By establishing a consensus-driven list of positive and negative control drugs, the study provides a scientifically justified framework for enhancing the consistency of preclinical testing, thereby addressing a significant challenge in early hepatotoxicity identification. The results are of paramount importance to all the actors involved in the drug development process, offering a standardized approach to assess hepatotoxic risks. Practically, these findings can guide researchers in evaluating safety profiles of new drugs, refining in vitro models, and informing regulatory agencies on potential improvements to regulatory guidelines, ensuring a more systematic and efficient approach to drug safety assessment.

Reconstruction Using Perforator Propeller Flaps After Malignant Melanoma Resection of the Lower Extremity.

Introduction: Surgical excision with margin of 2 cm is the treatment of choice in malignant cutaneous melanoma when Breslow index is >1 mm. When located on the lower limb, these resections can lead to large defects that require complex reconstruction in order to salvage the limb. The use of propeller-perforator flaps has multiple advantages such as the preservation of adjacent muscles, decrease in morbidity in the donor site, and good aesthetic and functional results. Our objective is to expose our experience and results with the use of propeller-perforator flaps for coverage of this kind of defects. Materials and Methods: Patients with malignant cutaneous melanoma of the lower limb who required reconstruction with a propeller-perforator flap between the years 2015 and 2021 in our plastic surgery department were included in this retrospective research. Demographic, reconstructive, oncologic, and functional data were collected and analyzed. Results: The cohort of 22 patients showed 100% of successful reconstructive outcomes. Only 2 patients experienced distal necrosis of the flap that was resolved with local dressings. Fast recovery and early capacity to walk were achieved in the majority of the patients with an average of 10.1 days until weight-baring walking. The 2-year overall and progression-free survival rates were 86.37% and 81.82%, respectively. Conclusion: The use of propeller perforator flaps for oncological defects coverage in the lower limb location has to be considered as a reliable choice as it takes less surgical time and a faster recovery. It allows limb salvage with an adequate length and functionality, with minimal donor site morbidity and a lower index of complications, contributing to improve patient's quality of life and not delaying other oncological treatments.

Introduction: Une excision chirurgicale aux marges de 2 cm est le traitement de première intention des mélanomes cutanés malins lorsque l'indice de Breslow est supérieur à 1 mm. Situées sur un membre inférieur, ces résections peuvent provoquer de grosses anomalies qui exigent une reconstruction complète pour sauver le membre. Le recours aux lambeaux perforants en hélice comporte de multiples avantages, tels que la préservation des muscles adjacents, la diminution des problèmes médicaux au foyer du donneur ainsi que des résultats esthétiques et fonctionnels satisfaisants. Les auteurs visent à présenter leur expérience et leurs résultats lorsqu'ils recouvrent ce type d'anomalie à l'aide de lambeaux perforants en hélice. Matériel et méthodologie: Les patients atteints d'un mélanome cutané malin d'un membre inférieur qui nécessitaient une reconstruction à l'aide d'un lambeau perforant en hélice entre 2015 et 2021 au département de chirurgie plastique des auteurs ont été inclus dans la présente recherche rétrospective. Les auteurs ont recueilli et analysé les caractéristiques démographiques ainsi que les données reconstructives, oncologiques et fonctionnelles des patients. Résultats: Les résultats reconstructifs ont été satisfaisants dans toute la cohorte de 22 patients. Seuls deux d'entre eux ont vécu une nécrose distale du lambeau, qui a été corrigée par des pansements locaux. La majorité des patients se sont remis rapidement et ont pu recommencer à marcher tôt, soit en moyenne au bout de 10,1 jours avec mise en charge. Le taux de survie global et le taux d'absence de détérioration au bout de deux ans s'élevaient à 86,37 % et à 81,82 %, respectivement. Conclusion: Le recours à des lambeaux perforants en hélice pour couvrir des anomalies oncologiques du membre inférieur doit être considéré comme un choix fiable, car l'intervention chirurgicale et la convalescence sont plus courtes. Cette intervention permet de sauver le membre, dont la longueur et la fonction demeurent appropriées, elle est associée à des problèmes médicaux minimes au foyer du donneur et à un faible indice de complications, elle contribue à améliorer la qualité de vie du patient et elle ne retarde pas les autres traitements oncologiques.

Vulnerable at rest? A resting-state EEG study and psychosocial factors of young adult offspring of alcohol-dependent parents.

BACKGROUND: Offspring of parents with alcohol use disorder (AUD) are more susceptible to developing AUD, with an estimated heritability of around 50%. Vulnerability to AUD in first-degree relatives is influenced by biological factors, such as spontaneous brain activity, and high-risk psychosocial characteristics. However, existing resting-state EEG studies in AUD offspring have shown inconsistent findings regarding theta, alpha, and beta band frequencies. Additionally, research consistently demonstrates an increased risk of internalizing and externalizing disorders, self-regulation difficulties, and interpersonal issues among AUD offspring. METHODS: This study aimed to investigate the absolute power of theta, alpha, and beta frequencies in young adult offspring with a family history of AUD compared to individuals without family history. The psychosocial profiles of the offspring were also examined in relation to individuals without a family history of AUD. Furthermore, the study sought to explore the potential association between differences in frequency bands and psychosocial variables. Resting-state EEG recordings were obtained from 31 young adult healthy offspring of alcohol-dependent individuals and 43 participants with no family history of AUD (age range: 16-25 years). Participants also completed self-report questionnaires assessing anxiety and depressive symptoms, impulsivity, emotion regulation, and social involvement. RESULTS: The results revealed no significant differences in spontaneous brain activity between the offspring and participants without a family history of AUD. However, in terms of psychosocial factors, the offspring exhibited significantly lower social involvement than the control group. CONCLUSIONS: This study does not provide evidence suggesting vulnerability in offspring based on differences in spontaneous brain activity. Moreover, this investigation highlights the importance of interventions aimed at enhancing social connections in offspring. Such interventions can not only reduce the risk of developing AUD, given its strong association with increased feelings of loneliness but also improve the overall well-being of the offspring.

Detection of two HLA-B*35 variants: HLA-B*35:01:01:39 and -B*35:03:01:32.

Two nucleotide substitutions in intronic regions give rise to the novel alleles: HLA-B*35:01:01:39 and -B*35:03:01:32.

Modeling the Therapeutic Process of Patients with Cocaine Use Disorders: A Guide for Predicting Readmission.

INTRODUCTION: Patients with cocaine use disorders have very high readmission rates. Our aim was to model the relationships between attributes of patients with cocaine use disorder at the beginning of treatment, therapeutic process indicators of time in treatment or proportion of appointments attended, and treatment outcomes, including outcomes at discharge and non-readmissions posttreatment as indicators of therapeutic success. METHOD: A retrospective observational design was used with 10,298 cocaine use disorder patients. Electronic health records were used for statistical analysis of the data. Randomized subsample 1 (n = 5,150) was used for exploratory analysis and subsample 2 (n = 5,148) for modeling relationships between the variables. RESULTS: Patients attributes at intake (e.g., legal services as the source of referral) were of limited significance in explaining time in treatment, proportion of appointments attended, and treatment outcomes. Time in treatment and proportion of appointments attended emerged as significant factors in explaining outcomes at discharge. However, readmissions were primarily explained by time in treatment and outcomes at discharge, although referrals to addiction centers by health services also appeared to be relevant for explaining readmission. DISCUSSION/CONCLUSION: Our study has shown that maintaining a sufficient appointment attendance rate and remaining in treatment for a longer duration are critical therapeutic process indicators for explaining outcomes at the point of discharge and therapeutic success, as indicated by a reduced likelihood of readmissions. Patients who remained in treatment for an extended period were found to have a reduced risk of future readmissions. In addition, our study highlights the importance of maintaining a satisfactory appointment attendance rate to attain successful short- and medium-term therapeutic discharge outcomes. These guidelines could help to increase the efficiency of patient treatment and alleviate the suffering of both patients and their families.

Effects of transcutaneous radiofrequency diathermy versus ultrasound on latent myofascial trigger points in the upper trapezius: A randomized crossover trial.

BACKGROUND: Currently, the use of radiofrequency diathermy for the treatment of neck pain is booming. OBJECTIVE: This study aimed to evaluate the clinical efficacy of Digital Capacitive Diathermy (DCD®) on stiffness, pain, cervical range of motion, and cervical disability and to compare it with ultrasound (US) in patients with latent myofascial trigger point (MTrP) in the upper trapezius. METHODS: Nineteen participants with latent MTrPs in the upper trapezius were included in the assessor-masked, randomized, clinical crossover trial. Subjects were exposed to both interventions: US and DCD® and treatment effectiveness was measured by myotonometric variables, pressure pain threshold (PPT), visual analog scale (VAS), cervical side-bending flexion ranges, and the neck disability index scale (NDI). RESULTS: There were no significant differences between US and DCD® interventions regarding changes in outcome measures. The US group achieved a statistically significant difference of 2.16 to 1.13 points (p= 0.005; r= 0.646) for the VAS. The DCD® intervention showed a statistically significant improvement of 1.11 points for the NDI at 1-week following intervention (95% CI 0.14-2.07; p= 0.27; d= 0.217). CONCLUSION: Our findings suggest that DCD® and US can both be considered effective modalities for the treatment of latent MTrPs, having a longer duration of action with DCD® therapy.

Lettre to editor: Case report of an ictal asystole as debut in new onset epilepsy.

The case report describes a 65-year-old man with arterial hypertension and a metallic aortic valve who presented to the emergency room for a loss of consciousness event and memory impairment. The electroencephalographic recording showed right temporal epileptiform activity followed by a 9 s asystole with quick consciousness recovery. The patient was diagnosed with right temporal epilepsy with asystole and was prescribed levetiracetam to prevent new events. A pacemaker was indicated in the follow-up for the long duration of the asystole, preventing major morbidity. Ictal asystole (IA) is a rare phenomenon of epilepsy that leads to syncope. It is observed in focal epilepsy, especially in left temporal epilepsy. Underlying cardiac pathology may facilitate IA, especially when the onset of the epilepsy is new. Knowledge of focal temporal semiology is key, concerning our case report, the memory impairment points to temporal pathology, and ictal vomiting in the non-dominant hemisphere. Anti-seizures drugs must be initiated in all patients, and there is a recommendation to avoid those with negative inotropic and arrhythmogenic effects (such as phenytoin, carbamazepine, and lacosamide). There is a discussion about pacemaker indication, however, it is highly recommended in non-controlled epilepsy and in ictal asystoles that last for more than 6 s to reduce morbidity.

Examining Profiles and Treatment Outcomes in Dual Diagnosis: Comparison of Coordinated Treatment With Mental Health Services Versus Addiction Center Alone: A Real-World Data Analysis.

Objective: The aim of this work was to examine the profile and treatment outcomes of patients with dual pathology depending on whether the patients were attending addiction centers or are being treated in a coordinated model by mental health services. Methods: Data from 7225 dual diagnosis patients were used, of whom 2417 (33.5%) received treatment in the mental health coordinated modality. Clinical information was taken from the patients' electronic health record. Results: Differences were found in patients' sociodemographic and comorbidity profiles according to treatment modality. In general, coordinated care yielded favorable outcomes (higher attendance and lower dropout rates but no differences in retention). The logistic regression analysis identified predictors of patient profiles in coordinated care, emphasizing having a severe mental health disorder (OR = 3.878, 95% CI [3.443, 4.368]; p = .000), being referred by social/health services, or having retired status. Main differences were observed according to the comorbid diagnosis presented, particularly in cases in which the patient had impulse control, hyperkinetic, or cluster C personality disorder. Conclusions: While therapeutic outcomes are influenced by associated comorbidities, the disorders prognosis can be favorable with appropriate treatment. Furthermore, analysis of differences according to treatment modality allows for predicting the type of patient who will receive a particular service, which enables the development of tailored treatments.

Utility of non-invasive monitoring of exhaled carbon dioxide and perfusion index in adult patients in the emergency department.

BACKGROUND: Several noninvasive solutions are available for the assessment of patients at risk of deterioration. Capnography, in the form of end-tidal exhaled CO2 (ETCO2) and perfusion index (PI), could provide relevant information about patient prognosis. The aim of the present project was to determine the association of ETCO2 and PI with mortality of patients admitted to the emergency department (ED). METHODS: Multicenter, prospective, cohort study of adult patients with acute disease who needed continuous monitoring in the ED. The study included two tertiary hospitals in Spain between October 2022 and June 2023. The primary outcome of the study was in-hospital mortality (all-cause). Demographics, vital signs, ETCO2 and PI were collected. RESULTS: A total of 687 patients were included in the study. The in-hospital mortality rate was 6.8%. The median age was 79 years (IQR: 69-86), and 63.3% were males. The median ETCO2 value was 30 mmHg (26-35) in survivors and 23 mmHg (16-30) in nonsurvivors (p = 0.001). For the PI, the medians were 4.7% (2.8-8.1) for survivors and 2.5% (0.98-4-4) for nonsurvivors (p < 0.001). The model that presented the best AUC was age (odds ratio (OR): 1.02 (1.00-1.05)), the respiratory rate (OR: 1.06 (1.02-1.11)), and the PI (OR: 0.83 (0.75-0.91)), with a result of 0.840 (95% CI: 0.795-0.886); the model with the respiratory rate (OR: 1.05 (1.01-1.10)), the PI (OR: 0.84 (0.76-0.93)), and the ETCO2 (no statistically significant OR), with an AUC of 0.838 (95% CI: 0.787-0.889). CONCLUSIONS: The present study showed that the PI and respiratory rate are independently associated with in-hospital mortality. Both the PI and ETCO2 are predictive parameters with improved prognostic performance compared with that of standard vital signs.

HLA-DPA1*02:01:25, a novel allele with a synonymous transition in exon 2 identified by next-generation sequencing.

HLA-DPA1*02:01:25 differs from DPA1*02:01:01:02 by a synonymous transition in exon 2.

Characterization of seven novel HLA-DPA1*01:03:01 non-coding variants by next-generation sequencing.

Seven different single nucleotide substitutions in non-coding regions gave rise to novel HLA-DPA1*01:03:01 variants.

Next-generation sequencing identifies four novel HLA class I alleles with nucleotide substitutions in the 3' UTR.

Characterization by next-generation sequencing of four novel HLA alleles: C*17:03:01:07, C*16:01:01:39, B*15:17:01:07, and B*44:03:01:57.

Multimodal characterization of the collagen hydrogel structure and properties in response to physiologically relevant pH fluctuations.

pH fluctuations within the extracellular matrix (ECM) and its principal constituent collagen, particularly in solid tumors and chronic wounds, may influence its structure and function. Whereas previous research examined the impact of pH on collagen fibrillogenesis, this study focuses on determining how pH fluctuations affect collagen hydrogels that mimic the physiological ECM. Utilizing a type I collagen hydrogel, we examined the influence of pH fluctuations on its structure, properties, and function while keeping the collagen hydrated. We show that collagen's secondary structure remains unaltered during pathologically relevant microenvironmental pH changes. By employing cryo scanning electron microscopy and artificial intelligence-assisted image analysis, we show that at physiological pH, collagen hydrogel presents densely packed, aligned, and elongated fibrils, which upon a decrease to pH 6.5, are transformed into shorter, sparser, and disoriented fibrils. The collagen possesses a higher storage modulus yet a lower permeability at pH 7 and 7.8 compared with pH 6.5 and 7.4. Exposing acidified collagen to a basic buffer reinstates its native structure and viscoelastic properties. Our study offers an innovative approach to analyze and characterize perturbations in hydrated collagen-based systems with potential implications for better understanding and combating disease progression. STATEMENT OF SIGNIFICANCE: As the main component of the extracellular matrix, collagen undergoes conformational changes associated with pH changes during disease. We analyze the impact of pH on pre-formed collagen fibers mimicking healthy tissues subjected to disease, and do not focus on the more studied fibrillogenesis process. Using cryogenic SEM, which allowed imaging close to the native state, we show that even minor fluctuations in the pH affect the collagen thickness, length, fiber alignment, and rheological properties. Following exposure to acidic pH, the collagen had short fibers, lacked orientation, and had low mechanical strength. This acidic collagen restored its original properties after returning to a neutral pH. These findings can help determine how pH changes can be modulated to restore healthy collagen properties.

Discovery of three HLA-DQB1*03:01:01 variants: HLA-DQB1*03:01:01:54, -DQB1*03:01:01:56 and -DQB1*03:01:01:58.

Three nucleotide substitutions in intronic regions give rise to the novel alleles: HLA-DQB1*03:01:01:54, -DQB1*03:01:01:56, -DQB1*03:01:01:58.

Validation of the Collett-Lester fear of death scale in occupational therapy students: psychometric testing and implications for palliative care education.

BACKGROUND: The fear of death is a common experience among healthcare students and professionals that may impact the quality of care provided to patients, particularly those receiving palliative care. The Collett-Lester Fear of Death Scale is a widely used instrument to assess this fear, although its psychometric properties have not been extensively studied in Occupational Therapy students. The present study aimed to validate the Collett-Lester Fear of Death Scale (CL-FODS) in a sample of Occupational Therapy students and to explore its implications for palliative care education. METHOD: A cross-sectional study was conducted to perform psychometric testing of the CL-FODS in Occupational Therapy undergraduate students. Structural validity, internal consistency, and test-retest reliability were analysed. A total of 195 Occupational Therapy students were included in this study. Additionally, the participants completed a brief survey on their experiences and attitudes towards palliative care. RESULTS: The internal consistency was satisfactory (α = 0.888). The exploratory factor analysis to evaluate the internal structure yielded four factors. The model fit indices were: comparative fit index = 0.89, and root mean square error of approximation = 0.06). The test-retest reliability was satisfactory and demonstrated an intraclass correlation coefficient of 0.939. CONCLUSION: The Spanish version of the CL-FODS showed satisfactory psychometric properties; therefore, assessing fear of death in Occupational Therapy students is helpful. This study highlights the importance of addressing fear of death and palliative care education in Occupational Therapy undergraduates to improve future professional attitudes and, consequently, the quality of patient care at the end of life.

A Smartphone App for Real-Time Assessment of Malaria Prophylaxis Adverse Events.

Background: Growth of international travel to malarial areas over the last decades has contributed to more travelers taking malaria prophylaxis. Travel-related symptoms may be wrongly attributed to malaria prophylaxis and hinder compliance. Here, we aimed to assess the frequency of real-time reporting of symptoms by travelers following malaria prophylaxis using a smartphone app. Method: Adult international travelers included in this single-center study (Barcelona, Spain) used the smartphone Trip Doctor® app developed by our group for real-time tracking of symptoms and adherence to prophylaxis. Results: Six hundred four (n = 604) international travelers were included in the study; 74.3% (449) used the app daily, and for one-quarter of travelers, malaria prophylaxis was prescribed. Participants from the prophylaxis group traveled more to Africa (86.7% vs. 4.3%; p < 0.01) and to high travel medical risk countries (60.8% vs. 18%; p < 0.01) and reported more immunosuppression (30.8% vs. 23.1% p < 0.01). Regarding symptoms, no significant intergroup differences were observed, and no relationship was found between the total number of malarial pills taken and reported symptoms. Conclusions: In our cohort, the number of symptoms due to malaria prophylaxis was not significantly higher than in participants for whom prophylaxis was not prescribed, and the overall proportion of symptoms is higher compared with other studies.