Intrathecal magnesium delivery for Mg++-insensitive NMDA receptor activity due to GRIN1 mutation.

BACKGROUND: Mutations in the NMDA receptor are known to disrupt glutamatergic signaling crucial for early neurodevelopment, often leading to severe global developmental delay/intellectual disability, epileptic encephalopathy, and cerebral palsy phenotypes. Both seizures and movement disorders can be highly treatment-refractory. RESULTS: We describe a targeted ABA n-of-1 treatment trial with intrathecal MgSO4, rationally designed based on the electrophysiologic properties of this gain of function mutation in the GRIN1 NMDA subunit. CONCLUSION: Although the invasive nature of the trial necessitated a short-term, non-randomized, unblinded intervention, quantitative longitudinal neurophysiologic monitoring indicated benefit, providing class II evidence in support of intrathecal MgSO4 for select forms of GRIN disorders.

Comentario acerca del caso Belcebú / Commentary on the Beelzebub case / Commentaire sur le cas clinique de Belzébuth / Comentário sobre o caso Belzebu

A partir de la presentación del caso clínico de un niño de 10 años llamado Belcebú, atendido durante la pandemia de forma virtual a lo largo de un año y cuatro meses, se realiza un comentario teórico-clínico puntualizando los aspectos vinculados a:los enunciados identificatorios; el niño en la estructura familiar y, como aspecto más relevante, el lugar del juego producido en las sesiones, el que sostenido por la mirada posibilitadora de la analista, le permitió alniño elaborar y rescribir marcas identitarias,en pos de una subjetivación menos tanática AU

Based on the presentation of the clinical case of a 10-year-old boy named Belcebú, treated virtually during the pandemic for a yearand four months, a theoretical-clinical comment is made, pointing out the aspects related to: the identifying statements; the child in the family structure and, as a most relevant aspect, the place of the play produced in the sessions, which, supported by the analyst's enabling gaze, allowed the child to elaborate and rewrite identity marks, in pursuit of a less thanatic subjectivation AU

Sur la base de la présentation du cas clinique d'un garçon de 10 ans nommé Belcebú, traité virtuellement pendant la pandémie durant un an et quatre mois, un commentaire théorico-clinique est fait, soulignant les aspects liés:aux énoncés identifiants; l'enfant dans la structure familiale et, comme aspect le plus pertinent, la place du jeu produit dans les séances, qui, soutenu par le regard habilitant de l'analyste, a permis à l'enfant d'élaborer et de réécrire des marques identitaires, à la poursuite d'une subjectivation moins thanatique AU

A partir da apresentação do caso clínico de um menino de 10 anos chamado Belcebú, tratado virtualmente durante a pandemia por um ano e quatro meses, é feito um comentário teórico-clínico, apontando os aspectos relacionados: a os depoimentos identificadores; a criança na estrutura familiar e, como aspecto mais relevante, o lugar da brincadeira produzida nas sessões, que, amparada pelo olhar capacitador do analista, permitiu à criança elaborar e reescrever marcas identitárias, em busca de uma subjetivação menos tanática AU

Individualized Studies of Triggers of Paroxysmal Atrial Fibrillation: The I-STOP-AFib Randomized Clinical Trial.

Importance: Atrial fibrillation (AF) is the most common arrhythmia. Although patients have reported that various exposures determine when and if an AF event will occur, a prospective evaluation of patient-selected triggers has not been conducted, and the utility of characterizing presumed AF-related triggers for individual patients remains unknown. Objective: To test the hypothesis that n-of-1 trials of self-selected AF triggers would enhance AF-related quality of life. Design, Setting, and Participants: A randomized clinical trial lasting a minimum of 10 weeks tested a smartphone mobile application used by symptomatic patients with paroxysmal AF who owned a smartphone and were interested in testing a presumed AF trigger. Participants were screened between December 22, 2018, and March 29, 2020. Interventions: n-of-1 Participants received instructions to expose or avoid self-selected triggers in random 1-week blocks for 6 weeks, and the probability their trigger influenced AF risk was then communicated. Controls monitored their AF over the same time period. Main Outcomes and Measures: AF was assessed daily by self-report and using a smartphone-based electrocardiogram recording device. The primary outcome comparing n-of-1 and control groups was the Atrial Fibrillation Effect on Quality-of-Life (AFEQT) score at 10 weeks. All participants could subsequently opt for additional trigger testing. Results: Of 446 participants who initiated (mean [SD] age, 58 [14] years; 289 men [58%]; 461 White [92%]), 320 (72%) completed all study activities. Self-selected triggers included caffeine (n = 53), alcohol (n = 43), reduced sleep (n = 31), exercise (n = 30), lying on left side (n = 17), dehydration (n = 10), large meals (n = 7), cold food or drink (n = 5), specific diets (n = 6), and other customized triggers (n = 4). No significant differences in AFEQT scores were observed between the n-of-1 vs AF monitoring-only groups. In the 4-week postintervention follow-up period, significantly fewer daily AF episodes were reported after trigger testing compared with controls over the same time period (adjusted relative risk, 0.60; 95% CI, 0.43- 0.83; P < .001). In a meta-analysis of the individualized trials, only exposure to alcohol was associated with significantly heightened risks of AF events. Conclusions and Relevance: n-of-1 Testing of AF triggers did not improve AF-associated quality of life but was associated with a reduction in AF events. Acute exposure to alcohol increased AF risk, with no evidence that other exposures, including caffeine, more commonly triggered AF. Trial Registration: ClinicalTrials.gov Identifier: NCT03323099.

Adaptive single case design (ASCD): a model for education, training, and assessment / Estudo de caso único adaptado (ASCD): um modelo para educação, treinamento e avaliação

Aims: single case designs (SCDs) can help us understand change in learning-related variables, such as knowledge and skill, at the level of an individual learner, at the level of a team or group of learners, or at the level of a situation or system. Adaptive single case design (ASCD) is a new model that integrates (i.) elements of methods of education, training, and assessment that, through research methods other than SCDs, have received solid empirical evidence in the research literature and (ii.) principles of SCDs that can facilitate the integration of research in everyday practice. The rationale behind ASCD is to allow rapid evidence-based decision making in the practice of education, training, and assessment, at the unit of analysis ­ individual, group, team, situation, or system ­ that is considered appropriate in the context at hand. Method: an ASCD algorithm is introduced and discussed in the context of change at the level of the individual, change in a group or team, and change in a situation or system. Results: ASCD can be used to understand change at each of the previously mentioned units of analysis at any number of units including a single unit (one individual, one team, or one situation or system), and this change can be used for research purposes as well. Conclusion: ASCD enables both evidence-based practical decision making and research without stringent demands on the number of learners, groups, teams, situations, or systems.

Objetivos: estudos de caso único podem nos ajudar a entender a mudança nas variáveis relacionadas ao aprendizado, como conhecimento e habilidade, no nível de um aluno individual, no nível de uma equipe ou grupo de alunos, ou no nível de uma situação ou sistema. O Estudo adaptativo de caso único (ASCD) é um novo modelo que integra (i.) elementos de métodos de educação, treinamento e avaliação que, por meio de métodos de pesquisa que não sejam estudos de caso único, receberam evidências empíricas sólidas na literatura de pesquisa e (ii.) princípios de estudos de caso único, que podem facilitar a integração da pesquisa na prática cotidiana. A lógica por trás do ASCD é permitir a rápida tomada de decisão baseada em evidências na prática da educação, treinamento e avaliação, na unidade de análise ­ individual, grupo, equipe, situação ou sistema ­ que é considerada apropriada no contexto em questão. Método: um algoritmo ASCD é introduzido e discutido no contexto de mudança no nível do indivíduo, mudança em um grupo ou equipe e mudança em uma situação ou sistema. Resultados: o ASCD pode ser usado para entender a mudança em cada uma das unidades de análise mencionadas anteriormente em qualquer número de unidades, incluindo uma única unidade (um indivíduo, uma equipe ou uma situação ou sistema), e para fins de pesquisa. Conclusão: o ASCD permite a a pesquisa e a tomada de decisão prática baseada em evidências, sem demandas rigorosas sobre o número de alunos, grupos, equipes, situações ou sistemas.

Benefits of 1-Yr Home Training With Functional Electrical Stimulation Cycling in Paraplegia During COVID-19 Crisis.

ABSTRACT: The purpose of this observational study was to report the experience of a 1-yr home training with functional electrical stimulation cycling of a person with T4 American Impairment Scale A paraplegia for 9 yrs, homebound due to the COVID-19 health crisis. The 40-yr-old participant had a three-phase training: V1, isometric stimulation; V2, functional electrical stimulation cycling for 3 sessions/wk; and V3, functional electrical stimulation cycling for 2-4 sessions/wk. Data on general and physical tolerance, health impact, and performance were collected. Borg Scale score relating to fatigue was 10.1 before training and 11.8 after training. The average score for satisfaction at the end of sessions was 8.7. Lean leg mass increased more than 29%, although total bone mineral density dropped by 1.6%. The ventilatory thresholds increased from 19.5 to 29% and the maximum ventilatory peak increased by 9.5%. Rosenberg's Self-esteem Scale score returned to its highest level by the end of training. For the only track event on a competition bike, the pilot covered a distance of 1607.8 m in 17 mins 49 secs. When functional electrical stimulation cycling training is based on a clear and structured protocol, it offers the person with paraplegia the opportunity to practice this activity recreationally and athletically. In times of crisis, this training has proven to be very relevant.

Does amantadine maintain function in long-established brain injury? A single case experimental design.

OBJECTIVE: The role of dopamine agonist (DA) in restoring consciousness and cognition in recovery phase following acquired brain injury (ABI) is established (1-5). The role in later recovery is less well defined. We report a single case experimental design (SCED) trial of amantadine demonstrating improvement in function, six years following ABI. METHOD: A scoring system based on established abilities in personal care and interaction was used to identify tasks with component actions, 34 actions in total, each ranked in terms of quality of response to a request or prompt. Actions were scored on maintenance dose amantadine; on withdrawal; and after reintroduction. Daytime sleep duration was also recorded. RESULTS: At 3rd and 5th weeks post withdrawal, deterioration was noted in 27 of 34 graded activities. At 3rd and 5th weeks following reintroduction, all but 3 grades returned to baseline or better. Afternoon sleep duration increased from 35 to 80 minutes during withdrawal period returning towards baseline on amantadine resumption. CONCLUSION: We believe this provides evidence for benefit of amantadine in sustaining function following ABI. The SCED model used provides a template for others to use to identify comparable change in similar trials.

Establishment of Three Types of Immortalized Human Skin Stem Cell Lines Derived from the Single Donor.

Currently, human-skin derived cell culture is a basic technique essential for dermatological research, cellular engineering research, drug development, and cosmetic development. But the number of donors is limited, and primary cell function reduces through cell passage. In particular, since adult stem cells are present in a small amount in living tissues, it has been difficult to obtain a large amount of stem cells and to stably culture them. In this study, skin derived cells were isolated from the epidermis, dermis, and adipose tissue collected from single donor, and immortalization was induced through gene transfer. Subsequently, cell lines that could be used as stem cell models were selected using the differentiation potential and the expression of stem cell markers as indices, and it was confirmed that these could be stably cultured. The immortalized cell lines established in this study have the potential to be applied not only to basic dermatological research but also to a wide range of fields such as drug screening and cell engineering.

Prostate permanent implant brachytherapy with BARC I-125 Ocu-Prosta seeds.

AIM: The aim of this study is implementation and establishment of standard operating procedure for permanent prostate implant brachytherapy technique using BARC I-125 Ocu-Prosta seeds. MATERIALS AND METHODS: The transrectal ultrasound (US)-guided procedure was used for permanent implant procedure. The Best® Sonalis™ US Imaging System and Best NOMOS™ Treatment Planning system was used for volume study and implant procedure. The BARC provided I-125 Ocu-Pro radioactive seeds were implanted into the patient with help of Mick@ Applicator. The implant was performed based on pre-implant dosimetry and intraoperative planning performed during implant procedure. RESULTS: The necessary quality assurance tests were performed for US system before clinical use. The boost dose of 110 Gy was prescribed to the prostate volume of 34.71 cc. About 48 seeds with activity of 0.35 mCi (each) implanted into the prostate volume with reference to intraoperative planning. At the end of procedure, the patient underwent abdomen fluoroscopic examination, to ensure the seed counts in the prostate volume. The day after the implant, the patient was discharged. One month later a planning computed tomography and treatment planning was performed for seed position and dose verification. CONCLUSIONS: Low dose rate permanent implant brachytherapy has the advantage of being a one-time procedure and the existing long term follow-up supports its excellent outcome and low morbidity. BARC-BRIT is supplying the loose 125I seeds. These seeds can be easily implanted into the patient using Mick applicator. However, the pre-implant seed preparation and implant procedure may result some radiation exposure to staff involved. The radiation dose can be minimized with good practice. This report is one patient pilot study and intended to test the implant systems and standard operative procedure henceforth for permanent implant brachytherapy procedure.

A preliminary investigation of a novel method to manipulate penis length to measure female sexual satisfaction: a single-case experimental design.

OBJECTIVES: To investigate a novel methodology and explore whether artificially reducing the depth of penetration during intercourse matters to women. STUDY DESIGN AND METHODS: A study with a single-case experimental design ('n of 1'), in which a heterosexual couple act as their own control and the study is then replicated in subsequent couples, was conducted. Thirty-five couples were assessed for eligibility to participate. Twenty-nine couples without any sexual problems were randomized and 12 submitted sufficient data to analyse. As a proxy for reducing penis length, we artificially reduced the depth of penetration by using different sizes of silicone rings around the base of the man's erect penis. The main outcome measures were provided by the female partner on a scale of 0-100 and comprised: degree of (i) overall sexual pleasure; (ii) sexual pleasure from intercourse alone; and (iii) emotional connection to the male partner. The female partner was also asked before the experiment began to rate the degree of positive or negative change that would be personally meaningful for her. RESULTS: On average, reducing the depth of penetration led to a statistically significant 18% reduction of overall sexual pleasure with an average 15% reduction in length of the penis. The longer the erect penis, the less likely the rings were to have an impact on sexual pleasure. There was a range of individual responses, however, with a minority of women reporting that reducing the depth of penetration was more pleasurable on some occasions. CONCLUSIONS: Size may matter in women in a healthy stable relationship when there is penile shortening. Because of the small number of couples and the inclusion of men with an apparently long penis, our results are preliminary, and we welcome replication in a larger sample with a more diverse range of penile lengths. Our results should not be misinterpreted as meaning that increasing penile length will increase sexual pleasure in women.

Intense Pulsed Light: A Methodical Approach to Understanding Clinical Endpoints.

BACKGROUND: Intense Pulsed Light (IPL) is a non-coherent polychromatic broadband filtered flashlamp that emits light in the spectrum of approximately 400–1200 nm. Its effects on photorejuvenation are well documented. The goal of this study is to help practitioners better conceptualize and fine tune IPL device settings in order to produce the most effective and safest clinical outcome. MATERIALS/METHODS: This was a prospective study testing several filters (515 nm; 560 nm; 590 nm and 530–650; 900–1200 nm vascular filter), fluences, pulse durations, and pulse numbers (ie, multiple sequence pulsing or MSP) with a new IPL system. RESULTS: Post-procedure erythema response was more pronounced with increasing fluence, decreasing wavelength, fewer pulses and shorter pulse duration. The exception was the 515 nm filter with regard to pulse duration, which was observed to have a more pronounced response with longer pulse durations. The overall clinical outcome at the 4-week follow-up visit demonstrated greatest improvement in erythema and pigmentation using the 515 nm filter on a Fitzpatrick Skin Type III individual. CONCLUSION: Greatest clinical endpoint response at 4-week follow-up was observed with more robust initial responses. This was most apparent at higher fluence levels and fewer pulse counts. However, when the IPL is pushed to aggressive parameters, there is risk of hypopigmentation and hair loss as seen in this case study. Skin type is an important consideration when using IPL and MSP adds to its safety profile. J Drugs Dermatol. 2021;20(2):203-207. doi:10.36849/JDD.5638.

N of 1 Data Sharing: The Impact of Data Sharing within the Hematology-Oncology Drug Products Division of the US FDA.

Despite both enthusiasm and concern regarding data sharing from clinical trials, few studies have documented the outputs of data sharing. The FDA has a considerable collection of raw data from drugs for their marketing authorization. An examination of data sharing with the FDA provides a snapshot into studies that this may facilitate.

Bayesian Analysis for Multiple-baseline Studies Where the Variance Differs across Cases in OpenBUGS.

Objective: There is a growing interest in the potential benefits of applying Bayesian estimation for multilevel models of SCED data. Methodological studies have shown that Bayesian estimation resolves convergence issues, can be adequate for the small sample, and can improve the accuracy of the variance components. Despite the potential benefits, the lack of accessibility to software codes makes it difficult for applied researchers to implement Bayesian estimation in their studies. The purpose of this article is to illustrate a feasible way to implement Bayesian estimation using OpenBUGS software to analyze a complex SCED model where within-participants variability and autocorrelation may differ across cases. Method: By using extracted data from a published study, step-by-step guidance in analyzing the data using OpenBUGS software is provided, including (1) model specification, (2) prior distributions, (3) data entering, (4) model estimation, (5) convergence criteria, and (6) posterior inferences and interpretations. Result: Full codes for the analysis are provided.

From Tissue-Agnostic to N-of-One Therapies: (R)Evolution of the Precision Paradigm.

Precision medicine has exploited next-generation sequencing (NGS) and gene/immune-targeted drug deployment to transform the outlook for several lethal cancers. For instance, there are now several FDA-approved medications that target the sequelae of aberrant genes in a tissue-agnostic approach: pembrolizumab [microsatellite instability and tumor mutational burden (TMB) ≥10 mutations/megabase (mut/Mb)] and larotrectinib/entrectinib (NTRK fusions). Molecular interrogation further reveals the disruptive reality that metastatic cancers are tremendously complex and individually distinct. Therefore, optimized treatment often requires drug combinations (rather than monotherapy) and N-of-one customization. Early studies of this approach suggest feasibility, safety, and efficacy. Real-world data/master registry trials may also provide massive, clinically relevant datasets that further fuel the (r)evolution in oncology.

Gaussian Surface Curvature Mapping Indicating High Risk Type B Thoracic Aortic Dissections.

BACKGROUND: Identifying fragile aortas that are more likely to lead to adverse clinical outcomes would provide surgeons with a better sense of how to balance the risks of surgical versus medical management in patients with type B dissections. We examine the progression of a type B dissection into a type A dissection in a patient and analyze changes in the Gaussian surface curvature distribution, as well as the response of the stress distribution at the lesser curve in response to pressurization. We hypothesize that examining the Gaussian curvature will provide us with a link between aortic surface geometry and the stress distribution, which is crucial to understanding the process driving aortic dissection. METHODS: Computed tomography scans of a patient before and after the type A dissection are obtained. These are segmented in Simpleware ScanIP. Centerline curvatures are calculated on segmented models in ScanIP. Models are then pressurized in the finite element analysis software Abaqus. The Gaussian curvature is calculated by exporting segmentations into the computational program Matlab and applying a modified previously published algorithm. RESULTS: The centerlines generated in ScanIP fail to capture the change in the acuity of the lesser curve before and after the type A dissection. Instead, Gaussian curvature analysis shows that the curvature distribution before the type A dissection is much wider compared with the distribution after the type A dissection. In addition, analyzing the stress distribution in response to pressurization reveals that before the type A dissection there is a large divergence in the principal stress vectors at the lesser curve but this transitions to a more uniform hoop stress after the type A dissection. CONCLUSIONS: Our analysis demonstrates that Gaussian surface curvature analysis captures changes in aortic geometry that are otherwise silent in centerline curvature analysis. Here, we show that as the aorta develops a type A dissection it is able to more smoothly handle the hoop stress at the lesser curve compared with the stress focusing seen in the before type A geometry. We propose that the geometric focusing before type A creates a higher energy stress state, which is relaxed on retrograde dissection. Thus, Gaussian curvature analysis may provide a window to capture underlying geometric instability in type B dissections.

Infarto esplénico asociado a infección por citomegalovirus, primer reporte de caso en Colombia / Splenic infarction associated with cytomegalovirus infection, first Colombian Case report

Resumen Introducción: El infarto esplénico ocurre cuando la arteria esplénica o alguna de sus ramas quedan ocluidas, ya sea por émbolos distantes o por trombosis in situ. Dentro de la literatura mundial hay muy pocos casos documentados de infarto esplénico asociado a infección por Citomegalovirus, por lo que este podría considerarse el primero en Colombia. Presentación del Caso: Se trata de una paciente femenina de 53 años quien fue atendida en una institución de tercer nivel de la Ciudad de Bogotá, Colombia, por cuadro de dolor abdominal, a quien se le realizó una tomografía abdominal contrastada que demostró en el bazo una lesión hipodensa en cuña correspondiente con infarto esplénico por lo cual se realizaron estudios complementarios evidenciando como único dato positivo la positividad de la IgM para Citomegalovirus, descartándose eventos de h ipercoagulabilidad. Discusión: El infarto esplénico es una condición infrecuente que normalmente se presenta con síntomas variables e inespecíficos, dentro de las enfermedades infecciosas que corresponden con aproximadamente el 30% de los diagnósticos de Infarto esplénico, la infección por Citomegalovirus únicamente ha sido reportada en muy pocos casos. Se presenta el caso de una mujer joven con infarto esplénico como diagnóstico final de dolor abdominal en quien se descartaron causas de hipercoagulabilidad y se confirma la infección aguda por Citomegalovirus, lo cual se ha descrito muy poco en la literatura y puede considerarse el primer caso reportado en Colombia.

Abstract Introduction: Splenic infarction occurs when the splenic artery or any of its branches are occluded, either by distant emboli or by thrombosis in situ. Within the world literature, there are very few documented cases of splenic infarction associated with Cytomegalovirus infection, so this could be considered the first in Colombia. Case Presentation: This is a 53-year-old female patient who was treated at a third-level institution in the City of Bogotá, Colombia, for symptoms of abdominal pain, who underwent a contrasted abdominal tomography that she demonstrated in the spleen. a hypodense wedge lesion corresponding to splenic infarction, for which reason complementary studies were carried out, showing the positivity of IgM for Cytomegalovirus as the only positive data, ruling out events of hypercoagulability. Discussion: Splenic infarction is an infrequent condition that normally presents with variable and nonspecific symptoms. Among infectious diseases that correspond to approximately 30% of the diagnoses of splenic infarction, Cytomegalovirus infection has only been reported in very few cases. The case of a young woman with splenic infarction is presented as the final diagnosis of abdominal pain in whom causes of hypercoagulability were ruled out and acute infection by Cytomegalovirus was confirmed, which has been described very little in the literature and can be considered the first reported case In colombia.