Identification and characterization of a new pathologic mutation in a large Leber hereditary optic neuropathy pedigree.

BACKGROUND: Most patients suffering from Leber hereditary optic neuropathy carry one of the three classic pathologic mutations, but not all individuals with these genetic alterations develop the disease. There are different risk factors that modify the penetrance of these mutations. The remaining patients carry one of a set of very rare genetic variants and, it appears that, some of the risk factors that modify the penetrance of the classical pathologic mutations may also affect the phenotype of these other rare mutations. RESULTS: We describe a large family including 95 maternally related individuals, showing 30 patients with Leber hereditary optic neuropathy. The mutation responsible for the phenotype is a novel transition, m.3734A > G, in the mitochondrial gene encoding the ND1 subunit of respiratory complex I. Molecular-genetic, biochemical and cellular studies corroborate the pathogenicity of this genetic change. CONCLUSIONS: With the study of this family, we confirm that, also for this very rare mutation, sex and age are important factors modifying penetrance. Moreover, this pedigree offers an excellent opportunity to search for other genetic or environmental factors that additionally contribute to modify penetrance.

Expanding the Phenotypic Spectrum of TRAF7-Related Cardiac, Facial, and Digital Anomalies With Developmental Delay: Report of 11 New Cases and Literature Review.

BACKGROUND: TRAF7-related cardiac, facial, and digital anomalies with developmental delay (CAFDADD), a multisystemic neurodevelopmental disorder caused by germline missense variants in the TRAF7 gene, exhibits heterogeneous clinical presentations. METHODS: We present a detailed description of 11 new TRAF7-related CAFDADD cases, featuring eight distinct variants, including a novel one. RESULTS: Phenotypic analysis and a comprehensive review of the 58 previously reported cases outline consistent clinical presentations, emphasizing dysmorphic features, developmental delay, endocrine manifestations, and cardiac defects. In this enlarged collection, novelties include a wider range of cognitive dysfunction, with some individuals exhibiting normal development despite early psychomotor delay. Communication challenges, particularly in expressive language, are prevalent, necessitating alternative communication methods. Autistic traits, notably rigidity, are observed in the cohort. Also, worth highlighting are hearing loss, sleep disturbances, and endocrine anomalies, including growth deficiency. Cardiac defects, frequently severe, pose early-life complications. Facial features, including arched eyebrows, contribute to the distinct gestalt. A novel missense variant, p.(Arg653Leu), further underscores the complex relationship between germline TRAF7 variants and somatic changes linked to meningiomas. CONCLUSIONS: Our comprehensive analysis expands the phenotypic spectrum, emphasizing the need for oncological evaluations and proposing an evidence-based schedule for clinical management. This study contributes to a better understanding of TRAF7-related CAFDADD, offering insights for improved diagnosis, intervention, and patient care.

Preventing alpelisib-related hyperglycaemia in HR+/HER2-/PIK3CA-mutated advanced breast cancer using metformin (METALLICA): a multicentre, open-label, single-arm, phase 2 trial.

Background: Hyperglycaemia is an early and frequent adverse event during alpelisib treatment. METALLICA aimed to evaluate prophylactic metformin to prevent or reduce hyperglycaemia occurrence in patients with HR+/HER2-/PIK3CA-mutated advanced breast cancer (ABC). Methods: Between August 13th, 2020 and March 23rd, 2022, this 2-cohort, phase 2, multicentre, single-arm trial (NCT04300790) enrolled patients with HR+/HER2-/PIK3CA-mutated ABC: cohort A, normal glycaemia (fasting plasma glucose <100 mg/dL [<5.6 mmol/L] and HbA1c <5.7%), and cohort B, prediabetes (fasting plasma glucose 100-140 mg/dL [5.6-7.8 mmol/L] and/or haemoglobin A1C [HbA1c] 5.7-6.4%). Participants were at least 18 years old, with Eastern Cooperative Oncology Group performance status of 0-1, and up to two prior lines of endocrine therapy (ET) for ABC. Alpelisib plus ET were administered in 28-day cycles after initiation of prophylactic metformin plus ET. Primary endpoint was the incidence of grade 3-4 hyperglycaemia over the first 8 weeks. Secondary endpoints included safety, progression-free survival (PFS), objective response rate (ORR), and clinical benefit rate (CBR). The primary objective for cohort A and B is met with ≤7 (14.6%) and ≤4 (20%) patients with grade 3-4 hyperglycaemia over the first 8 weeks, respectively. Findings: 233 patients were screened, and 68 (20.2%) patients were enrolled in cohorts A (n = 48) and B (n = 20). Median follow-up was 7.8 months (IQR 1.4-19.6). Over the first 8 weeks, one (2.1%) of 48 patients in cohort A (95% CI: 0.5-11.1; P < 0.0001), and three (15.0%) of 20 patients in cohort B (95% CI: 5.6-37.8; P = 0.016) had grade 3-4 hyperglycaemia. Serious treatment-related adverse events occurred in seven patients (10.3%). The most common were rash (two [2.9%]), vomiting (two [2.9%]), and diarrhoea (two [2.9%]). Discontinuation of alpelisib caused by AEs was reported in nine patients (13.2%), none caused by hyperglycaemia. At data cutoff (15 June, 2022), no treatment-related deaths were observed. In the full analysis set, median PFS was 7.3 months (95% CI: 5.9-not reached), ORR was 20.6% (95% CI: 11.7-32.1%), and CBR was 52.9% (95% CI: 40.4-65.2). Interpretation: In HR+/HER2-/PIK3CA-mutated ABC, prophylactic metformin before alpelisib plus endocrine treatment has low incidence and severity of alpelicib-induced hyperglycaemia. Funding: Novartis Pharmaceuticals.

Antifungal and Antivirulence Activity of Vanillin and Tannic Acid Against Aspergillus fumigatus and Fusarium solani.

Aspergillus fumigatus and Fusarium solani infections have become severe health threat; both pathogens are considered a priority due to the increasing emergence of antifungal-resistant strains and high mortality rates. Therefore, the discovery of new therapeutic strategies has become crucial. In this study, we evaluated the antifungal and antivirulence effects of vanillin and tannic acid against Aspergillus fumigatus and Fusarium solani. The minimum inhibitory concentrations of the compounds were determined by the microdilution method in RPMI broth in 96-well microplates according to CLSI. Conidial germination, protease production, biofilm formation, and in vivo therapeutic efficacy assays were performed. The results demonstrated that vanillin and tannic acid had antifungal activity against Aspergillus fumigatus, while tannic acid only exhibited antifungal activity against Fusarium solani. We found that vanillin and tannic acid inhibited conidial germination and secreted protease production and biofilm formation of the fungal pathogens using sub-inhibitory concentrations. Besides, vanillin and tannic acid altered the fungal membrane permeability, and both compounds showed therapeutic effect against aspergillosis and fusariosis in an infection model in Galleria mellonella larvae. Our results highlight the antivirulence effect of vanillin and tannic acid against priority pathogenic fungi as a possible therapeutic alternative for human fungal infections.

A systematic review and meta-analysis of the validation of serological methods for detecting anti-Toxoplasma gondii antibodies in humans and animals.

Toxoplasma gondii is a paradigmatic zoonotic parasite from the One Health perspective, since it is broadly distributed and virtually infects all warm-blooded species. A wide variety of serological techniques have been developed to detect T. gondii infection in humans and animals. Our aim was to describe and compare the main characteristics of these serological tests and validation processes and to critically analyze whether these tests meet the standards required to ensure an accurate serological diagnosis. The current systematic review and meta-analysis included 134 studies that were published from 2013 to 2023. QUADAS 2 tool was used to evaluate the quality of the included studies. A total of 52 variables related to the characteristics of the techniques and analytical and diagnostic validation parameters were studied. A wider panel of tests was developed for humans, including techniques exclusively developed for humans that involve costly equipment and the measurement of different Ig isotypes that are considered biomarkers of congenital toxoplasmosis. Studies conducted in humans frequently employed commercial techniques as reference tests, measured different immunoglobulin isotypes with a predominance for IgG (>50%) and discriminated between acute and chronic infections. In animals, the most commonly used reference techniques were in-house tests, which almost exclusively detected IgG. Common limitations identified in a large number of studies were some misunderstandings of the terms "gold standard" and "reference test" and the absence of information about the negative and positive control sera used or the exact cutoff employed, which were independent of the quality of the study. There is a lack of analytical validation, with few evaluations of cross-reactivity with other pathogens. Diagnostic odds ratio values showed that indirect ELISA based on native or chimeric antigens performed better than other tests. The reproducibility of serological test results in both humans and animals is not guaranteed due to a lack of relevant information and analytical validation. Thus, several key issues should be considered in the future, including interlaboratory ring trials.

Characterisation and beneficial effects of a Lupinus angustifolius protein hydrolysate obtained by immobilisation of the enzyme alcalase®.

Bioactive peptides have been considered potential components for the future functional foods and nutraceuticals generation. The enzymatic method of hydrolysis has several advantages compared to those of chemical hydrolysis and fermentation. Despite this fact, the high cost of natural and commercial proteases limits the commercialization of hydrolysates in the food and pharmacological industries. For this reason, more efficient and economically interesting techniques, such as the immobilisation of the enzyme, are gaining attention. In the present study, a new protein hydrolysate from Lupinus angustifolius was generated by enzymatic hydrolysis through the immobilisation of the enzyme alcalase® (imLPH). After the chemical and nutritional characterization of the imLPH, an in vivo study was carried out in order to evaluate the effect of 12 weeks treatment with imLPH on the plasmatic lipid profile and antioxidant status in western-diet-fed apolipoprotein E knockout mice. The immobilisation of alcalase® generated an imLPH with a degree of hydrolysis of 29.71 ± 2.11%. The imLPH was mainly composed of protein (82.50 ± 0.88%) with a high content of glycine/glutamine, arginine, and aspartic acid/asparagine. The imLPH-treatment reduced the amount of abdominal white adipose tissue, total plasma cholesterol, LDL-C, and triglycerides, as well as the cardiovascular risk indexes (CRI) -I, CRI-II, and atherogenic index of plasma. The imLPH-treated mice also showed an increase in the plasma antioxidant capacity. For the first time, this study demonstrates the beneficial in vivo effect of a lupin protein hydrolysate obtained with the alcalase® immobilised and points out this approach as a possible cost-effective solution at the expensive generation of the hydrolysate through the traditional batch conditions with soluble enzymes.

C-H, N-H, and O-H Bond Activations to Prepare Phosphorescent Hydride-Iridium(III)-Phosphine Emitters with Photocatalytic Achievement in C-C Coupling Reactions.

Complex IrH5(PiPr3)2 (1) activates two different σ-bonds of 3-phenoxy-1-phenylisoquinoline, 2-(1H-benzimidazol-2-yl)-6-phenylpyridine, 2-(1H-indol-2-yl)-6-phenylpyridine, 2-(2-hydroxyphenyl)-6-phenylpyridine, N-(2-hydroxyphenyl)-N'-phenylimidazolylidene, and 1,3-di(2-pyridyl)-4,6-dimethylbenzene to give IrH{κ3-C,N,C-[C6H4-isoqui-O-C6H4]}(PiPr3)2 (2), IrH{κ3-N,N,C-[NBzim-py-C6H4]}(PiPr3)2 (3), IrH{κ3-N,N,C-[Ind-py-C6H4]}(PiPr3)2 (4), IrH{κ3-C,N,O-[C6H4-py-C6H4O]}(PiPr3)2 (5), IrH{κ3-C,C,O-[C6H4-Im-C6H4O]}(PiPr3)2 (6), and IrH{κ3-N,C,C-[py-C6HMe2-C5H3N]}(PiPr3)2 (7), respectively. The activations are sequential, with the second generally being the slowest. Accordingly, dihydride intermediates IrH2{κ2-C,N-[C6H4-isoqui-O-C6H5]}(PiPr3)2 (2d), IrH2{κ2-N,N-[NBzim-py-C6H5]}(PiPr3)2 (3d), IrH2{κ2-N,N-[Ind-py-C6H5]}(PiPr3)2 (4d), and IrH2{κ2-N,C-[py-C6HMe2-py]}(PiPr3)2 (7d) were characterized spectroscopically. Complexes 3 and 5 are green phosphorescent emitters upon photoexcitation, exhibiting good absorption over a wide range of wavelengths, emission quantum yields about 0.70 in solution, long enough lifetimes (10-17 µs), and reversible electrochemical behavior. In agreement with these features, complex 3 promotes the photocatalytic α-amino C(sp3)-H arylation of N,N-dimethylaniline and N-phenylpiperidine with 1,4-dicyanobenzene and 4-cyanopyridine under blue LED light irradiation. The C-C coupling products are isolated in high yields with only 2 mol % of photocatalyst after 24 h.

Identifying Factors Associated With Disparities in Access to Integrative Oncology Program.

CONTEXT AND OBJECTIVES: Cancer centers are increasingly providing complementary medicine as part of an emerging discipline termed 'integrative oncology' (IO). The present study explored factors associated with disparities in referral and adherence to a freely-provided IO program. METHODS: The databases of three oncology centers in northern Israel were searched retrospectively for chemotherapy-treated oncology patients eligible for referral by their oncology healthcare professionals to an integrative physician (IP) consultation. Demographic and cancer-related variables associated with the referral, and attendance by patients at the consultation were identified, as was adherence to the 6-week IO treatment program (high adherence, attending ≥4 IO treatment sessions; low adherence, 0-3 sessions). RESULTS: Of 4988 eligible patients, 1694 (34%) were referred to the IP consultation, with 1331 (78.6%) attending the consultation of which 766 (57.6%) were adherent to IO treatments. Multivariate analysis revealed lower referral rates among patients speaking primarily Arabic and Russian vs. Hebrew (OR = 3.0, 95% CI = 2.0-4.6, P < 0.0001); males vs. females (OR = 1.94, CI = 1.3-2.9, P = 0.001); those not reporting emotional distress (OR = 1.5, CI = 1.02-2.16, P = 0.037); and older age (OR = 1.04, CI = 1.03-1.06, P < 0.0001). Arabic and Russian-speaking patients were less likely to adhere to IO treatments (OR = 0.52, 95% CI = 0.32-0.83, P = 0.006). CONCLUSION: Patients' ethno-national origin and immigration status (primary language, Arabic and Russian), male gender and older age were associated with lower rates of referral to and attendance of the IP consultation, with reduced adherence to weekly IO treatments. These findings require further study to identify barriers toward diversity, equity and inclusion in IO care, increasing awareness among healthcare professionals regarding the benefits of these services for improving patient wellbeing.

Loss of WIPI4 in neurodegeneration causes autophagy-independent ferroptosis.

ß-Propeller protein-associated neurodegeneration (BPAN) is a rare X-linked dominant disease, one of several conditions that manifest with neurodegeneration and brain iron accumulation. Mutations in the WD repeat domain 45 (WDR45) gene encoding WIPI4 lead to loss of function in BPAN but the cellular mechanisms of how these trigger pathology are unclear. The prevailing view in the literature is that BPAN is simply the consequence of autophagy deficiency given that WIPI4 functions in this degradation pathway. However, our data indicate that WIPI4 depletion causes ferroptosis-a type of cell death induced by lipid peroxidation-via an autophagy-independent mechanism, as demonstrated both in cell culture and in zebrafish. WIPI4 depletion increases ATG2A localization at endoplasmic reticulum-mitochondrial contact sites, which enhances phosphatidylserine import into mitochondria. This results in increased mitochondrial synthesis of phosphatidylethanolamine, a major lipid prone to peroxidation, thus enabling ferroptosis. This mechanism has minimal overlap with classical ferroptosis stimuli but provides insights into the causes of neurodegeneration in BPAN and may provide clues for therapeutic strategies.

Health Insurance Navigation Tools Intervention: A Pilot Trial Within the Childhood Cancer Survivor Study.

PURPOSE: Childhood cancer survivors are at increased risk for underinsurance and health insurance-related financial burden. Interventions targeting health insurance literacy (HIL) to improve the ability to understand and use health insurance are needed. METHODS: We codeveloped a four-session health insurance navigation tools (HINT) intervention, delivered synchronously by a patient navigator, and a corresponding booklet. We conducted a randomized pilot trial with survivors from the Childhood Cancer Survivor Study comparing HINT with enhanced usual care (EUC; booklet). We assessed feasibility, acceptability, and preliminary efficacy (HIL, primary outcome; knowledge and confidence with health insurance terms and activity) on a 5-month survey and exit interviews. RESULTS: Among 231 invited, 82 (32.5%) survivors enrolled (53.7% female; median age 39 years, 75.6% had employer-sponsored insurance). Baseline HIL scores were low (mean = 28.5; 16-64; lower scores better); many lacked knowledge of Affordable Care Act (ACA) provisions. 80.5% completed four HINT sessions, and 93.9% completed the follow-up survey. Participants rated HINT's helpfulness a mean of 8.9 (0-10). Exit interviews confirmed HINT's acceptability, specifically its virtual and personalized delivery and helpfulness in building confidence in understanding one's coverage. Compared with EUC, HINT significantly improved HIL (effect size = 0.94. P < .001), ACA provisions knowledge (effect size = 0.73, P = .003), psychological financial hardship (effect size = 0.64, P < .006), and health insurance satisfaction (effect size = 0.55, P = .03). CONCLUSION: Results support the feasibility and acceptability of a virtual health insurance navigation program targeted for childhood survivors to improve HIL. Randomized trials to assess the efficacy and sustainability of health insurance navigation on HIL and financial burden are needed.

Transcriptomics of Besnoitia besnoiti-Infected Fibroblasts Reveals Hallmarks of Early Fibrosis and Cancer Progression.

Endothelial injury, inflammatory infiltrate and fibrosis are the predominant lesions in the testis of bulls with besnoitiosis that may result in sterility. Moreover, fibroblasts, which are key players in fibrosis, are parasite target cells in a Besnoitia besnoiti chronic infection. This study aimed to decipher the molecular basis that underlies a drift toward fibrosis during the disease progression. Transcriptomic analysis was developed at two times post-infection (p.i.), representative of invasion (12 h p.i.) and intracellular proliferation (32 h p.i.), in primary bovine aorta fibroblasts infected with B. besnoiti tachyzoites. Once the enriched host pathways were identified, we studied the expression of selected differentially expressed genes (DEGs) in the scrotal skin of sterile infected bulls. Functional enrichment analyses of DEGs revealed shared hallmarks of cancer and early fibrosis. Biomarkers of inflammation, angiogenesis, cancer, and MAPK signaling stood out at 12 h p.i. At 32 h p.i., again MAPK and cancer pathways were enriched together with the PI3K-AKT pathway related to cell proliferation. Some DEGs were also regulated in the skin samples of naturally infected bulls (PLAUR, TGFß1, FOSB). We have identified potential biomarkers and host pathways regulated during fibrosis that may hold prognostic significance and could emerge as potential therapeutic targets.

Syringes for intraocular administration: Systematic review. / Jeringas para administración intraocular: revisión sistemática.

OBJECTIVE: The off-label use in clinical practice of non-approved syringes for intravitreal drug administration has resulted in the detection of silicone oil drops in the vitreous of some patients. This situation derives from the lack of approved syringes for intraocular use in the Spanish market. The aim of this work is to review the use of syringes for intraocular administration, as well as to search for alternatives that meet the legal requirements for these unmet needs. METHOD: A systematic review was performed following the PRISMA 2020 Guidelines by searching PubMed with the descriptors: "silicone" AND "syringes" AND ("intraocular" OR "intravitreal") and filtering all existing publications from January 2006 to December 2023, including all those articles dealing with silicone oil release in intravitreal injections and analysing the possible consequences. RESULTS: Sixty-eight results were found, 23 of which were excluded because they did not deal with the subject under study, leaving a total of 45 articles for the systematic review. These were classified according to the conclusions obtained in 4 groups: the adverse reactions produced by silicone, the administration technique, the physicochemical aspects of silicone release, and the characteristics of the medical device. After reviewing the current manufacturers and technical data sheets of commercialized syringes, the existing syringes for this use have been collected, finding two that will probably be commercialized in Spain at the beginning of 2024: Zero Residual™ 0.2 ml SiO-free and VitreJect® Ophthalmic. CONCLUSIONS: From the results obtained, it can be interpreted that the use of syringes and needles with silicone for intravitreal use is a concern for health professionals due to the implications and consequences that may arise in patients, the most important being adverse reactions, so it is necessary to have silicone-free syringes on the market that are specific for intraocular use. Safety and legality in the use of intraocular syringes and needles is essential to guarantee ocular integrity and patient health.

[Delphi Consensus of Argentine Pulmonologists on the Management of Patients with COPD in Real Life]. / Consenso Delphi de neumólogos argentinos sobre el manejo de los pacientes con EPOC en la vida real.

Introduction: COPD is the third cause of death globally and in Argentina COPD has a prevalence of 14.5%, but the management of patients in real life is unknown. The objectives of this work were: a) To know the opinions of pulmonologists in Argentina who manage patients with COPD in different aspects of daily practice. b) Compare our findings with specialists from Spain and c) Consider our results to plan future directives in the management of COPD in our country. Material and methods: 89 pulmonologists from Argentina, experts in COPD, participated in a Delphi consensus, who responded to a survey with five domains. a) Adherence to treatment, b) Control of COPD, c) Treatable features, d) Inhalation devices and e) Accessibility to therapeutic resources. Results: After two rounds of questions, total consensus was achieved in 77.6% of the statements and discriminating by domain: Treatment adherence: 5/9 (55.5%). COPD control: 10/14 (71.4%). Treatable traits: 6/6 (100%). Inhalation devices: 10/14 (71.4%) and Accessibility to treatment: 6/6 (100%). In most of the affirmations, the results were similar to those obtained by Spanish pulmonologists. Conclusions: Pulmonologists from Argentina manage COPD patients in a similar way and with minimal differences with our Spanish colleagues. It became evident that, in daily practice, there are factors that negatively impact access to the indicated treatments. Our work could serve as a starting point to improve this situation.

Virtual Surgical Planning for Temporomandibular Joint Reconstruction with Stock TMJ Prostheses: Pilot Study.

The temporomandibular joint (TMJ) is one of the most complex joints in the human anatomy. In advanced degenerative stages, conservative or minimally invasive surgical therapies have failed to restore joint function, and joint replacement with prostheses has been required. Stock prostheses, compared to custom-made prostheses, are much less expensive and require less pre-operative preparation time. Four patients followed for years for temporomandibular dysfunction and previously operated on by arthroscopy or open joint surgery that have been reconstructed with stock TMJ prostheses (STMJP) through virtual surgical planning (VSP) and an STL model with surgical and positioning guides were included. The median follow-up was 15 months; the median number of previous TMJ surgeries was 2. The mean preoperative MIO was 24.6 mm and at longest follow-up was 36.4 mm. The median preoperative TMJ pain score was 8, and the median postoperative TMJ pain was 3. All patients have improved their mandibular function with a clear improvement of their initial situation. In conclusion, we believe that stock TMJ prostheses with virtual surgical planning and surgical guides are a good alternative for TMJ reconstruction at the present time. Nonetheless, prospective and randomized trials are required with long-term follow up to assess their performance and safety.

A lupin protein hydrolysate protects the central nervous system from oxidative stress in WD-fed ApoE-/- mice.

Oxidative stress plays a crucial role in neurodegenerative diseases like Parkinson's and Alzheimer's. Studies indicate the relationship between oxidative stress and the brain damage caused by a high-fat diet. It is previously found that a lupin protein hydrolysate (LPH) has antioxidant effects on human leukocytes, as well as on the plasma and liver of Western diet (WD)-fed ApoE-/- mice. Additionally, LPH shows anxiolytic effects in these mice. Given the connection between oxidative stress and anxiety, this study aimed to investigate the antioxidant effects of LPH on the brain of WD-fed ApoE-/- mice. LPH (100 mg kg-1) or a vehicle is administered daily for 12 weeks. Peptide analysis of LPH identified 101 amino acid sequences (36.33%) with antioxidant motifs. Treatment with LPH palliated the decrease in total antioxidant activity caused by WD ingestion and regulated the nitric oxide synthesis pathway in the brain of the animals. Furthermore, LPH increased cerebral glutathione levels and the activity of catalase and glutathione reductase antioxidant enzymes and reduced the 8-hydroxy-2'-deoxyguanosine levels, a DNA damage marker. These findings, for the first time, highlight the antioxidant activity of LPH in the brain. This hydrolysate could potentially be used in future nutraceutical therapies for neurodegenerative diseases.

Expanding the genetic and phenotypic spectrum of congenital myasthenic syndrome: new homozygous VAMP1 splicing variants in 2 novel individuals.

We report the cases of two Spanish pediatric patients with hypotonia, muscle weakness and feeding difficulties at birth. Whole-exome sequencing (WES) uncovered two new homozygous VAMP1 (Vesicle Associated Membrane Protein 1) splicing variants, NM_014231.5:c.129+5 G > A in the boy patient (P1) and c.341-24_341-16delinsAGAAAA in the girl patient (P2). This gene encodes the vesicle-associated membrane protein 1 (VAMP1) that is a component of a protein complex involved in the fusion of synaptic vesicles with the presynaptic membrane. VAMP1 has a highly variable C-terminus generated by alternative splicing that gives rise to three main isoforms (A, B and D), being VAMP1A the only isoform expressed in the nervous system. In order to assess the pathogenicity of these variants, expression experiments of RNA for VAMP1 were carried out. The c.129+5 G > A and c.341-24_341-16delinsAGAAAA variants induced aberrant splicing events resulting in the deletion of exon 2 (r.5_131del; p.Ser2TrpfsTer7) in the three isoforms in the first case, and the retention of the last 14 nucleotides of the 3' of intron 4 (r.340_341ins341-14_341-1; p.Ile114AsnfsTer77) in the VAMP1A isoform in the second case. Pathogenic VAMP1 variants have been associated with autosomal dominant spastic ataxia 1 (SPAX1) and with autosomal recessive presynaptic congenital myasthenic syndrome (CMS). Our patients share the clinical manifestations of CMS patients with two important differences: they do not show the typical electrophysiological pattern that suggests pathology of pre-synaptic neuromuscular junction, and their muscular biopsies present hypertrophic fibers type 1. In conclusion, our data expand both genetic and phenotypic spectrum associated with VAMP1 variants.

Incorporación del dietista-nutricionista en un hospital universitario: declaración de postura de la Comisión de Nutrición del Hospital Universitario La Paz / Dietitian-nutritionist incorporation in a university hospital: position statement of the Commission on Nutrition, Hospital Universitario La Paz

El presente documento tiene como objetivo plantear y justificar la incorporación del dietista-nutricionista en los equipos multidisciplinares deatención integrada en la educación, el tratamiento y el seguimiento de aquellos pacientes con patologías que cursen con alteraciones del estadonutricional, tanto en su defecto como en su exceso, en el área sanitaria de la Comunidad Autónoma de Madrid.El estado nutricional de los pacientes hospitalizados se beneficiará de la incorporación del dietista-nutricionista al equipo multidisciplinar que,actualmente, se ocupa de la atención de estos. El manejo de la terapia nutricional por dietistas-nutricionistas ha demostrado ser costo-efectiva,habida cuenta de la repercusión sanitaria que tiene el estado nutricional en la evolución clínica y prevención de enfermedades como la diabetes,los trastornos de la conducta alimentaria, la obesidad, el cáncer, la insuficiencia cardiaca, la osteoporosis, la enfermedad celiaca y la enfermedadrenal crónica, entre otras.(AU)

The present document has the objective of justifying the incorporation of a dietician/nutritionist to the multidisciplinary teams of specialized carethat provide education, food anamnesis, nutritional recommendations, treatment and follow up of those patients in risk of malnutrition in Madrid.The appropriate nutritional status of hospitalized patients bears a close relationship with the existence of dieticians at hospitals. Dieticians usenutrition therapy as a cost-effective means to achieve significant health benefits by preventing or altering the course of diabetes, obesity, hyper-tension, lipid metabolism disorders, heart failure, osteoporosis, celiac disease, and chronic kidney disease, among other diseases.(AU)

Establishing an Integrative Oncology Service: Essential Aspects of Program Development.

PURPOSE OF REVIEW: Over the last 2 decades, integrative oncology (IO) has seen exponential growth within cancer care. It aims to combine evidence-based complementary therapies with conventional treatments to improve the well-being and quality of life for individuals dealing with cancer. The proliferation of integrative medicine programs in major cancer centers globally reflects varying approaches shaped by cultural, demographic, and resource-based factors. RECENT FINDINGS: Drawing upon the expertise of leaders in IO from the Society for Integrative Oncology (SIO) Clinical Practice Committee, this manuscript serves as a practical guide for establishing an IO practice. Collating insights from diverse professionals, including oncologists, integrative oncologists, supportive care physicians, researchers, and clinicians, the paper aims to provide a comprehensive roadmap for initiating and advancing IO services. The primary objective is to bridge the gap between conventional cancer care and complementary therapies, fostering a patient-centric approach to address the multifaceted challenges encountered by individuals with cancer. This paper delineates several key sections elucidating different aspects of IO practice. It delves into the core components necessary for an IO service's foundation, outlines the initial medical consultation process, and presents crucial tools essential for successful consultations. By consolidating insights and expertise, this manuscript seeks to facilitate the integration of IO into mainstream cancer care, ultimately enhancing patient outcomes and experiences.