Cognitive phenotypes in patients with relapsing-remitting multiple sclerosis with different disease duration, applying the international classification of cognitive disorders in MS (IC-CoDiMS).

Objective: Cognitive impairment is experienced by 40-70% of multiple sclerosis patients, with information processing speed and memory most affected. Until now, cognitive results classified patients as impaired and not impaired. With this dichotomous approach, it is difficult to identify, in a heterogeneous group of patients with cognitive impairment, which cognitive domain(s) are most altered. This study aims to identify cognitive phenotypes in a clinical cohort of adult patients with Relapsing-Remitting Multiple Sclerosis (RRMS) using the International Classification of Cognitive Disorders in MS (IC-CoDiMS) and to characterize their clinical features. Methods: Three hundred patients with RRMS underwent neuropsychological assessment with the Brief Repeatable Battery of Neuropsychological Tests (BRBN-T) and the Brief International Cognitive Multiple Sclerosis (BICAMS). Results: In our cohort, the mean age was 41.38 [11.48 SD] years, and 205 [68.3%] were women. At the -1 SD threshold, 49% were cognitively intact, 25% had uni-domain impairment, 17% had bi-domain impairment, and 9% had multi-domain impairment. Processing speed was the most frequent single-domain impairment, followed by memory and verbal fluency. At the -1.5 SD threshold, 74.7% were cognitively intact, 17% had uni-domain impairment, 6% had bi-domain impairment, had bi-domain impairment, and 3.0% had multi-domain impairment. Memory was the most frequent single-domain impairment, followed by processing speed and verbal fluency. Conclusions: This study corroborates the importance of determining cognitive phenotypes through taxonomy (IC-CoDiMS). In addition, it contributes to improving the classification of cognitive phenotypes in patients with RRMS to enhance the development of more effective treatments and cognitive interventions.

Coexisting presentation of two rare genetic variants of autosomal dominant polycystic kidney disease and Alport syndrome.

Alport syndrome and autosomal dominant polycystic kidney disease are monogenic causes of chronic kidney disease and end-stage kidney failure. We present a case of a man in his 60s with progressive chronic kidney disease, bilateral sensorineural hearing loss and multiple renal cysts. Genetic analysis revealed a heterozygous variant in COL4A3 (linked to Alport syndrome) and in the GANAB gene (associated with a milder form of autosomal dominant polycystic kidney disease). Although each variant confers a mild risk of developing end-stage kidney disease, the patient presented a pronounced and accelerated progression of chronic kidney disease, which goes beyond what would be predicted by adding up their individual effects. This suggests a potential synergic effect of both variants, which warrants further investigation.

Endoscopic Retrograde Cholangiopancreatography on Pediatric Patients: Experience of a Portuguese Adult Gastroenterology Department.

Introduction: Experience with endoscopic retrograde cholangiopancreatography (ERCP) in the pediatric population is limited. Few medical centers have experts specifically trained in pediatric therapeutic endoscopy. As a result, patients are generally referred to adult endoscopists with high experience in the procedure. The aim of this study was to characterize the experience of an adult endoscopy unit with ERCP on pediatric patients, with a special focus on very young patients. Methods: We retrospectively analyzed indications, technical success rate, final clinical diagnosis, and complications of ERCPs in children <18 years at our tertiary referral hospital center between January 1994 and June 2022. Results: Sixty-five ERCPs were performed on 57 children with a median age of 13 years (range 1-17 years). Eleven ERCPs were performed on 9 patients up to 5 years old. Indications for ERCP were as follows: biliary obstruction (n = 40), mainly due to choledocholithiasis, lithiasic acute pancreatitis (n = 19), recurrent pancreatitis (n = 3), stent extraction (n = 2), and post-operative biliary fistula (n = 1). The cannulation success rate was 95.1%. Therapeutic interventions were performed in 79% of ERCP. All patients were followed up as inpatients. Complications were recorded in two procedures (3.1%), and no procedure-related mortality occurred. Conclusion: In our experience, ERCP in children can be safely performed with high success rates by advanced adult-trained expert endoscopists at a high-volume center.

Introdução: Existe pouca experiência na realização de colangiopancreatografia retrógrada endoscópica (CPRE) na população pediátrica. A maioria dos centros carece de especialistas especificamente treinados em endoscopia terapêutica pediátrica, sendo os doentes geralmente referenciados para Gastroenterologistas de adultos com elevada experiência na técnica. O objectivo deste estudo foi caracterizar a experiência de um departamento de Gastrenterologia de adultos em CPRE pediátrica, com destaque particular nos doentes muito novos. Métodos: Foram analisadas retrospectivamente as indicações, sucesso técnico, diagnósticos e complicações das colangiopancreatografias retrógradas endoscópicas (CPREs) realizadas no nosso hospital terciário em crianças <18 anos, entre Janeiro de 1994 e Junho de 2022. Resultados: Foram realizadas 65 CPREs em 57 crianças com idade mediana 13 anos (1­17 anos). Doze procedimentos foram realizados em 9 crianças com idade até 5 anos. As indicações para CPRE foram: obstrução biliar (n = 40), sobretudo devido a coledocolitíase, pancreatite aguda litiásica (n = 19), pancreatite recorrente (n = 3), extracção de prótese (n = 2) e fístula biliar pós cirurgia (n = 1). A taxa de sucesso de canulação foi 95.4%. Foram realizados procedimentos terapêuticos em 80.0% das CPREs. Todos os doentes foram vigiados em regime de internamento, tendo-se registado complicações em dois exames (3.1%). Não existiram mortes relacionadas com a técnica. Discussão/ Conclusão: A CPRE pode ser realizada na população pediátrica com segurança e elevada taxa de sucesso por Gastrenterologistas de adultos com experiência na técnica, num centro com elevado volume de exames.

The Kidney Transplant Lottery: A Highly Sensitized Patient, Without Mismatches and Vein Thrombosis of the Graft; A Case Report.

A kidney transplant is the best option for patients with end-stage renal disease. The waiting list period can be long, especially for highly sensitized patients. We describe a 60-year-old woman who received a second transplant and was highly sensitized to vascular access exhaustion, anuric, and performing peritoneal dialysis. At 27 days post-transplant, the patient developed thrombosis of the allograft vein, oliguria, and elevated serum creatinine. Fibrinolysis was attempted, but the patient remained oliguric and with acute graft dysfunction. She had a suction thrombectomy using the Penumbra System, allowing the removal of all thrombi and repermeabilization of the vein graft, resolving the acute graft dysfunction.

Reactivity of the triple task on writing processes and product in adults with dyslexia.

Introduction: The triple task (TT) is a method for assessing the dynamics of writing processes. It involves three tasks in one: writing a text, responding to a sound, and reporting the process. Previous research has mostly shown that the TT does not affect the writing process or the product. However, individuals with dyslexia often show difficulties in tasks that require organization, automation, integration of multiple processes, inhibition, and shifting/cognitive flexibility. The aim of this study was therefore to investigate whether TT affects the writing process and written product differently in adults with dyslexia compared to a control group of adults with typical reading skills. Methods: Two groups of adult native Croatian speakers were included in this study: 20 adults with developmental dyslexia and 20 adults with typical reading skills; evenly distributed by: age (18-38 years), gender (13 males, 7 females per group), educational level, and nonverbal cognitive abilities. All participants wrote one text with a TT and another without. The writing of the text was tracked with a keystroke logging program - Inputlog. The two texts were compared at process and product level. Results and discussion: The results showed that measures of writing processes and text quality in the groups of adults with dyslexia and adults with typical reading skills were unlikely to be differentially affected by TT. However, in the condition without TT, the total number of characters per minute was higher, more keys were typed per minute and more words were deleted. As expected, adults with dyslexia produced shorter texts of lower quality and with more errors; they also produced fewer characters per minute, used fewer keystrokes and typed fewer. Conclusion: The study suggests that TT is unlikely to have a different impact on the writing process or written product in adults with dyslexia compared to adults with typical reading skills.

A Solution to Prevent and Minimize the Consequences of Accidents with Farm Tractors in the Context of Mountainous Regions with Low Population Density.

Farm tractors have become a key part of daily routine agriculture, converting complex and time-consuming tasks into tasks that are easier to perform and less dependent on human labor, contributing directly to increasing the economic value generated by this activity sector, either by increasing the productivity or by making certain agricultural crops viable, which otherwise would not be sustainable. However, despite all the advantages, accidents with this type of equipment are common, often with critical and sometimes fatal consequences. The evolution of safety requirements of these machines has occurred at a good level; however, a significant part of the agricultural tractors in use are older models that do not have such solutions. Even in the new models, which contain such solutions, these are not always correctly used, and it is even common that they are turned off or simply not used at all. It is therefore natural that accidents continue to occur, a situation that is aggravated by other factors. Lack of situational awareness of the operators, which can result from advanced age, inadequate training, reduced sensitivity/respect for safety rules, or working on irregular terrain like mountainous areas, contribute to high-risk contexts that end in the loss of human life. The consequences of such accidents are clearly aggravated by the time it takes to assist the victims-either because accidents are simply not identified/reported immediately, or by the time it takes to locate and provide help to the victims. This is a scenario that is more common in mountainous regions and regions with low population density. The current paper, using NB-IoT, a set of sensors, and a web application, presents a conceptual toolset conceived to prevent accidents and minimize consequences (human and material) that can be applied to old and new farm tractors. The development was carried out taking the characterization of the farmers and the land in the region in which the authors' research institution is located into account, which has the highest rate of fatal accidents with agricultural tractors in the country; it is a region of mountainous with a very low population density.

Massive blood loss from urethrorrhage in a 16-year-old boy: Case report and review of two rare causes.

Urethral varices and hemangiomas are rare, underreported conditions that can be asymptomatic or present with intermittent urethrorrhage that can start or worsen with erection, sexual intercourse and ejaculation. Diagnosis can be made with urethroscopy and there are a wide variety of possible treatments that can suit both conditions. We present a case of a pediatric patient with severe blood loss from urethral varices that was treated with electrofulguration after laser treatment with Holmium failed.

Helicopter Air Transport of a Patient Using High Flow Nasal Cannula: A Case Report.

The classic out-of-hospital approach to a patient with severe acute respiratory failure involves both orotracheal intubation and invasive mechanical ventilation. The use of non-invasive methods for respiratory support has been shown to be beneficial in managing both acute and chronic respiratory failure. However, its use had not been previously considered for air medical transport due to concerns related to airway safety during flight, limited oxygen availability, and limited experience in this setting. We describe the successful inter-hospital helicopter transport of a patient with end-stage lung disease to a transplantation unit while utilizing a high-flow oxygen cannula, which was performed without significant complications. Our successful case report raises the possibility that high-flow nasal cannulas may be safely employed in the management of respiratory failure in specific patient populations during air medical transport.

Dual Kidney Transplantation: Single-Center Experience.

BACKGROUND: Dual and en bloc kidney transplantation are strategies used to mitigate the disparity between a reduced organ pool and an ever-increasing need for organ procurement. En bloc refers to the implantation of 2 kidneys from a pediatric donor, compensating for small renal mass, whereas dual expanded criteria donor (DECD) transplantation refers to older donors with grafts otherwise rejected for single transplant, including expanded. This study describes one center's experience with dual and en bloc transplantation. METHODS: A retrospective cohort study of dual kidney transplants (en bloc and DECD) from 1990 through 2021. The analysis included demographic, clinical, and survival analysis. RESULTS: Of 46 patients who underwent dual kidney transplantation, 17 (37 %) received en-bloc transplantation. The overall mean recipient age was 49.4 ± 13.9 years old, younger in the en-bloc subgroup (39.2 vs 59.8 years old, P < .01). The mean time on dialysis was 37 ± 25 months. Delayed graft function was present in 17.4 % and primary nonfunction in 6.4 %, all from the DECD group. The estimated glomerular filtration rates at 1 and 5 years were 76.7 ± 28.7 and 80.4 ± 24.8 mL/min/1.73 m2, lower in the DECD group (65.9 vs 88.7 mL/min/1.73 m2, P = 0.02). Eleven recipients lost their graft during the study period: 63.6% from death with a functioning graft, 27.3% due to chronic graft dysfunction (a mean of 76.3 months after transplantation), and 9.1% due to vascular complications. Subgroup comparison found no differences regarding cold ischemia time or length of hospitalization. Kaplan-Meier estimates, censored for death with a functioning graft, resulted in a mean graft survival of 21.3 ± 1.3 years, with survival rates of 93.5, 90.5, and 84.1% at 1, 5, and 10 years, respectively, without significant differences between subgroups. CONCLUSIONS: Both DECD and en bloc strategies provide safe and effective options to further expand the use of otherwise rejected kidneys. Neither of the 2 techniques was superior to the other.

Changing biosynthesis of terpenoid percursors in rice through synthetic biology.

Many highly valued chemicals in the pharmaceutical, biotechnological, cosmetic, and biomedical industries belong to the terpenoid family. Biosynthesis of these chemicals relies on polymerization of Isopentenyl di-phosphate (IPP) and/or dimethylallyl diphosphate (DMAPP) monomers, which plants synthesize using two alternative pathways: a cytosolic mevalonic acid (MVA) pathway and a plastidic methyleritritol-4-phosphate (MEP) pathway. As such, developing plants for use as a platform to use IPP/DMAPP and produce high value terpenoids is an important biotechnological goal. Still, IPP/DMAPP are the precursors to many plant developmental hormones. This creates severe challenges in redirecting IPP/DMAPP towards production of non-cognate plant metabolites. A potential solution to this problem is increasing the IPP/DMAPP production flux in planta. Here, we aimed at discovering, understanding, and predicting the effects of increasing IPP/DMAPP production in plants through modelling. We used synthetic biology to create rice lines containing an additional ectopic MVA biosynthetic pathway for producing IPP/DMAPP. The rice lines express three alternative versions of the additional MVA pathway in the plastid, in addition to the normal endogenous pathways. We collected data for changes in macroscopic and molecular phenotypes, gene expression, isoprenoid content, and hormone abundance in those lines. To integrate the molecular and macroscopic data and develop a more in depth understanding of the effects of engineering the exogenous pathway in the mutant rice lines, we developed and analyzed data-centric, line-specific, multilevel mathematical models. These models connect the effects of variations in hormones and gene expression to changes in macroscopic plant phenotype and metabolite concentrations within the MVA and MEP pathways of WT and mutant rice lines. Our models allow us to predict how an exogenous IPP/DMAPP biosynthetic pathway affects the flux of terpenoid precursors. We also quantify the long-term effect of plant hormones on the dynamic behavior of IPP/DMAPP biosynthetic pathways in seeds, and predict plant characteristics, such as plant height, leaf size, and chlorophyll content from molecular data. In addition, our models are a tool that can be used in the future to help in prioritizing re-engineering strategies for the exogenous pathway in order to achieve specific metabolic goals.

Factors Influencing Short-Term Patient Survival in Elderly Kidney Transplant Recipients.

BACKGROUND: For the average patient with end-stage renal disease, kidney transplantation improves quality of life and prolongs survival compared with patients on the transplant waiting list who remain on dialysis. Patients ≥65 years of age represent an increasing proportion of adults with end-stage renal disease, and kidney transplantation outcomes remain controversial in this population. The aim of this study was to evaluate factors that may increase 1-year mortality after renal transplantation in older recipients. METHODS: A retrospective study that included 147 patients (75.5% men) ≥65 years old (mean age 67.5 ± 2 years) who were transplanted between January 2011 and December 2020. The mean follow-up was 52.6 ± 27.2 months. RESULTS: Rehospitalization (<1 year) occurred in 39.5% of patients. Infectious complications were present in 18.4% of patients. The overall mortality rate was 23.1%, and 1-year mortality was 6.8%. As 1-year mortality predictors, we found a positive correlation with factors related to kidney transplant, such as cold ischemia time (P = .003), increasing donor age (P = .001); and factors related to the receptor such as pretransplantation dialysis modality as peritoneal dialysis (P = .04), cardiovascular disease (P = .004), delayed graft function (P = .002), early cardiovascular complications after kidney transplant (P < .001), and early rehospitalizations (P < .001). No correlation was found between 1-year mortality and age, sex, race, body mass index, and type of kidney transplant. CONCLUSION: A more rigorous pretransplant evaluation, focusing on cardiovascular disease and strict exclusion criteria, is recommended for patients ≥65 years old.

Renal Transplantation in Antineutrophil Cytoplasmic Antibody-Associated Vasculitis: A Single-Center 10-Year Experience.

BACKGROUND: Antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV) is a common cause of rapidly progressive glomerulonephritis resulting in end-stage renal disease. The optimal timing of kidney transplantation for end-stage renal disease due to AAV and the risk of relapse after kidney are poorly defined. Our study aimed to evaluate the clinical outcomes of AAV after kidney transplantation, namely the risk of relapse, rejection, and oncologic disease. METHODS: This retrospective study included all patients with AAV submitted to a kidney transplant between January 2011 and December 2020. RESULTS: Twenty-seven patients (20 males/7 females; mean age 47 years) received a kidney transplant for end-stage renal disease secondary to microscopic polyangiitis (n = 25) or granulomatosis with polyangiitis (n = 2). All patients were in clinical remission at the time of the kidney transplant, but 11 patients were ANCA-positive. A vasculitis relapse after kidney transplantation occurred in only 1 patient (3.7%). Rejection episodes, proven by allograft biopsy, were present in 3 patients (11.1%), with graft losses in 2 (66.7%). The median time until the graft was lost after the initial rejection diagnosis was 27 ± 8 months. Oncologic complications were present in 9 patients (33.3%). Five patients died (18.5%), and the main cause of death was cardiovascular disease (n = 3, 60.0%), followed by oncologic disease (n = 2, 40.0%). CONCLUSIONS: Kidney transplantation is a safe and effective option for treating end-stage renal disease secondary to AAV. Current immunosuppression regimens make relapses and rejection infrequent but place oncologic complications at a higher incidence.

Gastric epithelial response to milk fat using the semi-dynamic INFOGEST digestion model coupled with NCI-N87 cells.

The stomach is a relevant spot of lipolysis for milk fat, but research on the effect of digested milk fat in the gastric epithelium is scarce and difficult to evaluate. In the present study, we implemented the semi-dynamic in vitro digestion model of INFOGEST, combined with gastric NCI-N87 cells, to study the effect of fat-free, whole conventional, and whole pasture-based milk on gastric epithelium. Cellular messenger ribonucleic acid (mRNA) expression of membrane fatty acids receptors (GPR41, GPR84), antioxidant enzymes (CAT, SOD, GPX), and inflammatory molecules (NF-κB p65, IL-1ß, IL-6, IL-8 and TNF-α) was assessed. No significant differences were observed in mRNA expression of GPR41, GPR84, SOD, GPX, IL-6, IL-8, and TNF-α, after exposure of the NCI-N87 cells to milk digesta samples (p > 0.05). An increase of CAT mRNA expression was observed (p < 0.05), at a similar level, for all milk types. Whole milk digested samples induced higher mRNA expression of NF-κB p65 and IL-1ß than fat-free milk (p < 0.05); while no differences were observed between whole conventional and whole pasture-based milk (p > 0.05). Moreover, the effect of milk digesta on gastric mRNA expression was studied in a scenario of subsequent stimulation of NCI-N87 monolayer with the pro-inflammatory cytokine IFN-γ. In these conditions, milk digesta samples increased CAT mRNA expression (p < 0.05), but had no effect in the expression of NF-κB p65 and IL-1ß (p > 0.05). The increase of CAT mRNA expression suggests that milk fatty acids are used for energy production by gastric epithelial cells. Cellular antioxidant response to higher milk fatty acids availability could be associated to gastric epithelial inflammation, but did not contribute to increased inflammation in case of an external contact with IFN-γ. Besides, a conventional or a pasture-based origin did not affect the impact of whole milk in the NCI-N87 monolayer. The combined model responded to differences in milk fat content, which indicates its usefulness to study effects of foods at the gastric level.

Treatment of Recurrent Antineutrophil Cytoplasmic Antibody-Associated Vasculitis After Kidney Transplant With Rituximab: A Successful Case Report.

Antineutrophil cytoplasm antibody-associated systemic vasculitis is a rare disease that frequently leads to end-stage renal disease. Kidney transplant should be delayed until patients are in complete clinical remission for at least 6 months, but the persistence of antineutrophil cytoplasmic antibody titers should not delay transplant. Recurrence of disease after kidney transplant is rare, with only a few cases described in the literature with heterogenous clinical manifestations, therapeutic approaches, and prognosis. We describe the case of a young male patient with recurrent antineutrophil cytoplasmic antibody vasculitis, 5 years after kidney transplant, successfully treated with methylprednisolone pulses plus rituximab. Rituximab presents a new valid option for the treatment of antineutrophil cytoplasmic antibody vasculitis relapse in kidney grafts.

Modeling the effects of strigolactone levels on maize root system architecture.

Maize is the most in-demand staple crop globally. Its production relies strongly on the use of fertilizers for the supply of nitrogen, phosphorus, and potassium, which the plant absorbs through its roots, together with water. The architecture of maize roots is determinant in modulating how the plant interacts with the microbiome and extracts nutrients and water from the soil. As such, attempts to use synthetic biology and modulate that architecture to make the plant more resilient to drought and parasitic plants are underway. These attempts often try to modulate the biosynthesis of hormones that determine root architecture and growth. Experiments are laborious and time-consuming, creating the need for simulation platforms that can integrate metabolic models and 3D root growth models and predict the effects of synthetic biology interventions on both, hormone levels and root system architectures. Here, we present an example of such a platform that is built using Mathematica. First, we develop a root model, and use it to simulate the growth of many unique 3D maize root system architectures (RSAs). Then, we couple this model to a metabolic model that simulates the biosynthesis of strigolactones, hormones that modulate root growth and development. The coupling allows us to simulate the effect of changing strigolactone levels on the architecture of the roots. We then integrate the two models in a simulation platform, where we also add the functionality to analyze the effect of strigolactone levels on root phenotype. Finally, using in silico experiments, we show that our models can reproduce both the phenotype of wild type maize, and the effect that varying strigolactone levels have on changing the architecture of maize roots.

Evolution of an Iron-Detoxifying Protein: Eukaryotic and Rickettsia Frataxins Contain a Conserved Site Which Is Not Present in Their Bacterial Homologues.

Friedreich's ataxia is a neurodegenerative disease caused by mutations in the frataxin gene. Frataxin homologues, including bacterial CyaY proteins, can be found in most species and play a fundamental role in mitochondrial iron homeostasis, either promoting iron assembly into metaloproteins or contributing to iron detoxification. While several lines of evidence suggest that eukaryotic frataxins are more effective than bacterial ones in iron detoxification, the residues involved in this gain of function are unknown. In this work, we analyze conservation of amino acid sequence and protein structure among frataxins and CyaY proteins to identify four highly conserved residue clusters and group them into potential functional clusters. Clusters 1, 2, and 4 are present in eukaryotic frataxins and bacterial CyaY proteins. Cluster 3, containing two serines, a tyrosine, and a glutamate, is only present in eukaryotic frataxins and on CyaY proteins from the Rickettsia genus. Residues from cluster 3 are blocking a small cavity of about 40 Å present in E. coli's CyaY. The function of this cluster is unknown, but we hypothesize that its tyrosine may contribute to prevent formation of reactive oxygen species during iron detoxification. This cluster provides an example of gain of function during evolution in a protein involved in iron homeostasis, as our results suggests that Cluster 3 was present in the endosymbiont ancestor of mitochondria and was conserved in eukaryotic frataxins.

Strategies to Overcome HLA Sensitization and Improve Access to Retransplantation after Kidney Graft Loss.

An increasing number of patients waitlisted for kidney transplantation have a previously failed graft. Retransplantation provides a significant improvement in morbidity, mortality, and quality of life when compared to dialysis. However, HLA sensitization is a major barrier to kidney retransplantation and the majority of the highly sensitized patients are waiting for a subsequent kidney transplant. A multidisciplinary team that includes immunogeneticists, transplant nephrologists and surgeons, and adequate allocation policies is fundamental to increase access to a kidney retransplant. A review of Pubmed, ScienceDirect, and the Cochrane Library was performed on the challenges of kidney retransplantation after graft loss, focusing on the HLA barrier and new strategies to overcome sensitization. Conclusion: Technical advances in immunogenetics, new desensitization protocols, and complex allocation programs have emerged in recent years to provide a new hope to kidney recipients with a previously failed graft.