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PURPOSE: To assess the learning curve of MSICS in three different groups of trainees with varying prior MSICS experience. To evaluate the effectiveness of ICO OSCAR for objective assessment of surgical skill transfer. METHODS: Ninety-five MSICS trainees were divided into three groups as 1st year resident, fellow and external trainee. Each group were evaluated for their surgical skill acquisition during one month MSICS training program using ICO-OSCAR. Each trainee performed an average of 19 surgeries. The progress in the learning curve of the three groups of trainees was analyzed by evaluating the mean scores in sets of five consecutive cases. Complications during the training period were also noted. RESULTS: The study evaluated a total of 1842 cases. The fellows and external trainees, with prior MSICS experience, had an initial mean score of 57.57 ± 16.16 and 56.86 ± 17.82 respectively, whereas the 1st year resident group had a relatively low initial mean score of 45.91(p = 0.009). The difference in mean scores between the 1st year resident group and other groups significantly reduced towards the end of training. The most common complications made by 1st year residents were in sclero-corneal tunnel construction. The external trainee group had statistically significant higher rates of zonular dialysis in the study. CONCLUSIONS: ICO-OSCAR is an effective tool for assessing MSICS training program. Structured short term MSICS surgical training program is effective in surgical skill transfer, especially in novice surgeons.
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Extracción de Catarata , Competencia Clínica , Educación de Postgrado en Medicina , Evaluación Educacional , Internado y Residencia , Oftalmología , Humanos , Oftalmología/educación , Internado y Residencia/métodos , Extracción de Catarata/educación , Educación de Postgrado en Medicina/métodos , Evaluación Educacional/métodos , Femenino , Masculino , Curva de Aprendizaje , Adulto , Microcirugia/educaciónRESUMEN
Anastomosis of catheterising channels (Mitrofanoff and ACE) to the skin can be a challenge. The Kelly VV plasty is a straightforward solution but has been described only as a point of technique. We used the previously described method with minor modification. The technique has been used in 14 patients, including 9 children and 5 adults for Mitrofanoff,ACE and Monti channels. At a median follow-up of 25 months all patients continue to catheterise; none have required revision surgery. The Kelly VV plasty is a potentially robust solution to the problem of skin anastomosis; technique merits wider adoption and evaluation.
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The multifaceted nature of multiple sclerosis requires quantitative biomarkers that can provide insights related to diverse physiological pathways. To this end, proteomic analysis of deeply-phenotyped serum samples, biological pathway modeling, and network analysis were performed to elucidate inflammatory and neurodegenerative processes, identifying sensitive biomarkers of multiple sclerosis disease activity. Here, we evaluated the concentrations of > 1400 serum proteins in 630 samples from three multiple sclerosis cohorts for association with clinical and radiographic new disease activity. Twenty proteins were associated with increased clinical and radiographic multiple sclerosis disease activity for inclusion in a custom assay panel. Serum neurofilament light chain showed the strongest univariate correlation with gadolinium lesion activity, clinical relapse status, and annualized relapse rate. Multivariate modeling outperformed univariate for all endpoints. A comprehensive biomarker panel including the twenty proteins identified in this study could serve to characterize disease activity for a patient with multiple sclerosis.
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Biomarcadores , Esclerosis Múltiple , Proteómica , Humanos , Biomarcadores/sangre , Esclerosis Múltiple/sangre , Esclerosis Múltiple/diagnóstico por imagen , Femenino , Masculino , Adulto , Proteómica/métodos , Persona de Mediana Edad , Proteínas de Neurofilamentos/sangre , Proteínas Sanguíneas/análisis , Imagen por Resonancia Magnética/métodos , Inflamación/sangre , Estudios de CohortesRESUMEN
Although immune tolerance evolved to reduce reactivity with self, it creates a gap in the adaptive immune response against microbes that decorate themselves in self-like antigens. This is particularly apparent with carbohydrate-based blood group antigens, wherein microbes can envelope themselves in blood group structures similar to human cells. In this study, we demonstrate that the innate immune lectin, galectin-4 (Gal-4), exhibits strain-specific binding and killing behavior towards microbes that display blood group-like antigens. Examination of binding preferences using a combination of microarrays populated with ABO(H) glycans and a variety of microbial strains, including those that express blood group-like antigens, demonstrated that Gal-4 binds mammalian and microbial antigens that have features of blood group and mammalian-like structures. Although Gal-4 was thought to exist as a monomer that achieves functional bivalency through its two linked carbohydrate recognition domains, our data demonstrate that Gal-4 forms dimers and that differences in the intrinsic ability of each domain to dimerize likely influences binding affinity. While each Gal-4 domain exhibited blood group-binding activity, the C-terminal domain (Gal-4C) exhibited dimeric properties, while the N-terminal domain (Gal-4N) failed to similarly display dimeric activity. Gal-4C not only exhibited the ability to dimerize but also possessed higher affinity toward ABO(H) blood group antigens and microbes expressing glycans with blood group-like features. Furthermore, when compared to Gal-4N, Gal-4C exhibited more potent antimicrobial activity. Even in the context of the full-length protein, where Gal-4N is functionally bivalent by virtue of Gal-4C dimerization, Gal-4C continued to display higher antimicrobial activity. These results demonstrate that Gal-4 exists as a dimer and exhibits its antimicrobial activity primarily through its C-terminal domain. In doing so, these data provide important insight into key features of Gal-4 responsible for its innate immune activity against molecular mimicry.
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Galectina 4 , Humanos , Galectina 4/metabolismo , Dominios Proteicos , Unión Proteica , Multimerización de Proteína , Antígenos de Grupos Sanguíneos/metabolismo , Escherichia coli/metabolismo , Antiinfecciosos/farmacología , Sistema del Grupo Sanguíneo ABO/metabolismo , Sistema del Grupo Sanguíneo ABO/inmunologíaRESUMEN
Objectives: Patient Health Questionnaire-9 (PHQ-9) in Indian settings is yet not very often used in palliative care with the Hindi-speaking population. The Hindi version of PHQ-9 is available but its cultural adaptation to the Hindi-speaking population in North India receiving palliative care services is required to be tested. PHQ-9 as a depression screening questionnaire may help to identify depression symptoms among patients with cancer. This study aimed to examine the cultural equivalence of PHQ-9 Hindi for use with patients with cancer receiving palliative care services in North India. Material and Methods: Based on the standard methodology of translation and adaptation of the scale, the following process was used: (i) Two focused group discussions with 17 experts working in a cancer palliative care setting, (ii) qualitative interviewing with 11 patients, and (iii) research team review. All interviews were audio recorded, transcribed, and item-wise content analysis was conducted. Results: A few difficult phrases in the original PHQ-9 were 'dilchaspi', 'avasadgrast', 'kam urja', 'nakaam', parivar ko neecha dhikhana and 'ashthir' which were changed to Kam Mann Lagna, Mann Dukhi hona, kamjori, saksham nahi hain' 'asafal', Parivar ko nirash karna' and 'bechain,' respectively. Two items, namely no. 6 and 8 were changed to shorten the length for appropriately conveying the meaning. Conclusion: Hindi language involves various dialects which change from region to region bringing variations in understanding the meaning of the words. It is recommended that culturally equivalent scales are used in practice and research. PHQ-9 is now culturally adapted for the Hindi-speaking population in North India. PHQ-9 will help identidy depressive symptoms at an early stage. Psychometric testing of PHQ-9 is underway.
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INTRODUCTION: Foreskin reconstruction (FR) at the time of primary hypospadias repair is a truly anatomically complete reconstruction of the hypospadic penis. We prospectively collected penile and preputial measurement of children undergoing single-stage hypospadias repair and FR with the aim to identify possible relations between penile and preputial anatomy and the likelihood to develop complications. MATERIALS AND METHODS: We prospectively studied children who underwent single stage hypospadias repair associated with FR from 2016 to 2019. We recorded intra-operative foreskin and penile measurements and post-operative outcomes. Logistic Regression analysis was performed to explore independent factors affecting urethroplasty and skin complications. Chi square test was used to compare outcomes in different groups based on ventral foreskin defect (VFD) width, Glans size, age at surgery and meatal location. RESULTS: From a total of 181 consecutive patients, 86 boys who underwent a single stage hypospadias repair combined with FR were included in the study. Patients were excluded because they were either lost at follow up (n = 10), required a 2-stage repair (n = 2), were circumcised at birth (n = 3) or parents requested a circumcision (n = 78); in 2 patients, a decision to perform circumcision was made intraoperatively due to aesthetic reasons (monk-hood deformity of the prepuce). Median age at surgery was 17 months. Mean glans width was 14.4 mm. Mean unstretched and stretched foreskin circumference were 29.5 mm and 40.9 mm, respectively. Mean VFD (the distance between the proximal insertion of the foreskin hood on either side of the midline at the level of the coronal sulcus) was 7.2 mm (Fig. 1). At median follow-up of 8 months (6-23), 9 complications were recorded (10.4%): foreskin dehiscence occurred in 1% (1/86), a foreskin fistula was noted in 4.6% (4/86), tight, non-retractile, foreskin in 1% (1/86); urethrocutaneous fistula in 2.3% (2/86) and complete dehiscence of the glans and foreskin in 1 (1.2%). Multiple logistic regression analysis demonstrated that none of the measurements obtained was an independent risk factor for developing urethroplasty or skin complications. There was no significant difference in complications between wide VFD (>7 mm) vs. narrow VFD (≤7 mm), large glans (>14 mm) vs. small glans (≤14 mm), age at surgery ≤24 months vs. > 24 month and meatal location distal (glanular, coronal, subcoronal and distal penile) vs. proximal (midpenile, proximal penile and penoscrotal). CONCLUSION: To the best of our knowledge, this is the first study reporting a prospective and objective assessment of the foreskin in the context of single stage hypospadias repair. Individual anatomical differences in preputial and penile anatomy do not seem to affect the likelihood of skin and urethroplasty complications. FR can, therefore, be offered to all boys undergoing primary single stage hypospadias repair . Further studies on larger numbers and external validation of these measurements is necessary.
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Hipospadias , Masculino , Niño , Recién Nacido , Humanos , Lactante , Preescolar , Hipospadias/cirugía , Hipospadias/etiología , Prepucio/cirugía , Estudios Prospectivos , Resultado del Tratamiento , Procedimientos Quirúrgicos Urológicos Masculinos/efectos adversos , Uretra/cirugía , Estudios RetrospectivosRESUMEN
Background/Objectives: Serum proteomic analysis of deeply-phenotyped samples, biological pathway modeling and network analysis were performed to elucidate the inflammatory and neurodegenerative processes of multiple sclerosis (MS) and identify sensitive biomarkers of MS disease activity (DA). Methods: Over 1100 serum proteins were evaluated in >600 samples from three MS cohorts to identify biomarkers of clinical and radiographic (gadolinium-enhancing lesions) new MS DA. Protein levels were analyzed and associated with presence of gadolinium-enhancing lesions, clinical relapse status (CRS), and annualized relapse rate (ARR) to create a custom assay panel. Results: Twenty proteins were associated with increased clinical and radiographic MS DA. Serum neurofilament light chain (NfL) showed the strongest univariate correlation with radiographic and clinical DA measures. Multivariate modeling significantly outperformed univariate NfL to predict gadolinium lesion activity, CRS and ARR. Discussion: These findings provide insight regarding correlations between inflammatory and neurodegenerative biomarkers and clinical and radiographic MS DA. Funding: Octave Bioscience, Inc (Menlo Park, CA).
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An 18-protein multiple sclerosis (MS) disease activity (DA) test was validated based on associations between algorithm scores and clinical/radiographic assessments (N = 614 serum samples; Train [n = 426; algorithm development] and Test [n = 188; evaluation] subsets). The multi-protein model was trained based on presence/absence of gadolinium-positive (Gd+) lesions and was also strongly associated with new/enlarging T2 lesions, and active versus stable disease (composite of radiographic and clinical evidence of DA) with improved performance (p < 0.05) compared to the neurofilament light single protein model. The odds of having ≥1 Gd+ lesions with a moderate/high DA score were 4.49 times that of a low DA score, and the odds of having ≥2 Gd+ lesions with a high DA score were 20.99 times that of a low/moderate DA score. The MSDA Test was clinically validated with improved performance compared to the top-performing single-protein model and can serve as a quantitative tool to enhance the care of MS patients.
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Esclerosis Múltiple , Humanos , Imagen por Resonancia Magnética , Proteínas Sanguíneas , Gadolinio , AlgoritmosRESUMEN
Among the risk factors for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), ABO(H) blood group antigens are among the most recognized predictors of infection. However, the mechanisms by which ABO(H) antigens influence susceptibility to COVID-19 remain incompletely understood. The receptor-binding domain (RBD) of SARS-CoV-2, which facilitates host cell engagement, bears significant similarity to galectins, an ancient family of carbohydrate-binding proteins. Because ABO(H) blood group antigens are carbohydrates, we compared the glycan-binding specificity of SARS-CoV-2 RBD with that of galectins. Similar to the binding profile of several galectins, the RBDs of SARS-CoV-2, including Delta and Omicron variants, exhibited specificity for blood group A. Not only did each RBD recognize blood group A in a glycan array format, but each SARS-CoV-2 virus also displayed a preferential ability to infect blood group A-expressing cells. Preincubation of blood group A cells with a blood group-binding galectin specifically inhibited the blood group A enhancement of SARS-CoV-2 infection, whereas similar incubation with a galectin that does not recognize blood group antigens failed to impact SARS-CoV-2 infection. These results demonstrated that SARS-CoV-2 can engage blood group A, providing a direct link between ABO(H) blood group expression and SARS-CoV-2 infection.
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COVID-19 , Humanos , SARS-CoV-2 , Sistema del Grupo Sanguíneo ABO , GalectinasRESUMEN
The purpose of this study was to examine whether myeloid dendritic cells (mDCs) from patients with multiple sclerosis (MS) and healthy controls (HCs) become similarly tolerogenic when exposed to IL-27 as this may represent a potential mechanism of autoimmune dysregulation. Our study focused on natural mDCs that were isolated from HCs and MS patient peripheral blood mononuclear cells (PBMCs). After a 24-h treatment with IL-27 ± lipopolysaccharide (LPS), the mDCs were either harvested to identify IL-27-regulated gene expression or co-cultured with naive T-cells to measure how the treated DC affected T-cell proliferation and cytokine secretion. mDCs isolated from HCs but not untreated MS patients became functionally tolerogenic after IL-27 treatment. Although IL-27 induced both HC and untreated MS mDCs to produce similar amounts of IL-10, the tolerogenic HC mDCs expressed PD-L2, IDO1, and SOCS1, while the non-tolerogenic untreated MS mDCs expressed IDO1 and IL-6R. Cytokine and RNA analyses identified two signature blocks: the first identified genes associated with mDC tolerizing responses to IL-27, while the second was associated with the presence of MS. In contrast to mDCs from untreated MS patients, mDCs from HCs and IFNb-treated MS patients became tolerogenic in response to IL-27. The genes differentially expressed in the different donor IL-27-treated mDCs may contain targets that regulate mDC tolerogenic responses.
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Interleucina-27 , Esclerosis Múltiple , Humanos , Células Cultivadas , Citocinas/metabolismo , Células Dendríticas , Interleucina-27/metabolismo , Leucocitos Mononucleares/metabolismo , Esclerosis Múltiple/genética , Esclerosis Múltiple/metabolismo , Linfocitos T/metabolismoRESUMEN
BACKGROUND: Multiple sclerosis (MS) is a disabling autoimmune demyelinating disorder affecting young people and causing significant disability. In the last decade, different microRNA (miRNA) expression patterns have been associated to several treatment response therapies such as interferon and glatiramer acetate. Nowadays, there is increasing interest in the potential role of miRNA as treatment response biomarkers to the most recent oral and intravenous treatments. In this study, we aimed to evaluate serum miRNAs as biomarkers of No Evidence of Disease Activity (NEDA-3) at 2 years in patients with relapsing remitting MS (RRMS) treated with fingolimod. MAIN BODY: A Discovery cohort of 31 RRMS patients treated with fingolimod were identified from the CLIMB study and classified as No Evidence of Disease Activity (NEDA-3) or Evidence of Disease Activity (EDA-3) after 2 years on treatment. Levels of miRNA expression were measured at 6 months using human serum miRNA panels and compared in EDA-3 and NEDA-3 groups using the Wilcoxon rank sum test. A set of differentially expressed miRNA was further validated in an independent cohort of 22 fingolimod-treated patients. We found that 548a-3p serum levels were higher levels in fingolimod-treated patients classified as NEDA-3, compared to the EDA-3 group in both the Discovery (n = 31; p = 0.04) and Validation (n = 22; p = 0.03) cohorts 6 months after treatment initiation; miR-548a-3p provided an AUC of 0.882 discriminating patients with NEDA-3 at 2 years in the Validation cohort. CONCLUSION: Our results show differences in miR-548a-3p expression at 6 months after fingolimod start in patients with MS with NEDA-3 at 2 years. These results provide class III evidence of the use of miR-548a-3p as biomarker of NEDA-3 in patients with fingolimod.
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Enfermedades Autoinmunes , MicroARNs , Esclerosis Múltiple Recurrente-Remitente , Esclerosis Múltiple , Humanos , Adolescente , Clorhidrato de Fingolimod/uso terapéutico , Esclerosis Múltiple Recurrente-Remitente/tratamiento farmacológico , BiomarcadoresRESUMEN
Background: There is limited knowledge about T cell responses in patients with multiple sclerosis (MS) after 3 doses of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) mRNA vaccine. Objectives: Assess the SARS-CoV-2 spike antibody and T cell responses in MS patients and healthy controls (HCs) after 2 doses (2-vax) and 3 doses (3-vax) of SARS-CoV-2 mRNA vaccination. Methods: We studied seroconversion rates and T cell responses by flow cytometry in HC and MS patients on fingolimod or ocrelizumab. Results: After 2-vax, 8/33 (24.2%) patients in ocrelizumab group, 5/7 (71.4%) in fingolimod group, and 29/29 (100%) in HC group (P = 5.7 × 10-11) seroconverted. After 3-vax, 9/22 (40.9%) patients in ocrelizumab group, 19/21 (90.5%) in fingolimod group, and 7/7 (100%) in HC group seroconverted (P = 0.0003). The percentage of SARS-CoV-2 peptide reactive total CD4+ T cells increased in HC and ocrelizumab group but not in fingolimod group after 2-vax and 3-vax (P < 0.0001). The percentage of IFNγ and TNFα producing total CD4+ and CD8+ T cells increased in fingolimod group as compared to HC and ocrelizumab group after 2-vax and 3-vax (P < 0.0001). Conclusions: MS patients on ocrelizumab and fingolimod had attenuated humoral responses, but preserved cytokine producing T cell responses compared to HCs after SARS-CoV-2 mRNA vaccination. Clinical Trials Registration: NCT05060354.
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BACKGROUND: Early risk-stratification in multiple sclerosis (MS) may impact treatment decisions. Current predictive models have identified that clinical and imaging characteristics of aggressive disease are associated with worse long-term outcomes. Serum biomarkers, neurofilament (sNfL) and glial fibrillary acidic protein (sGFAP), reflect subclinical disease activity through separate pathological processes and may contribute to predictive models of clinical and MRI outcomes. METHODS: We conducted a retrospective analysis of the Comprehensive Longitudinal Investigation of Multiple Sclerosis at the Brigham and Women's Hospital (CLIMB study), where patients with multiple sclerosis are seen every 6 months and undergo Expanded Disability Status Scale (EDSS) assessment, have annual brain MRI scans where volumetric analysis is conducted to calculate T2-lesion volume (T2LV) and brain parenchymal fraction (BPF), and donate a yearly blood sample for subsequent analysis. We included patients with newly diagnosed relapsing-remitting MS and serum samples obtained at baseline visit and 1-year follow-up (both within 3 years of onset), and were assessed at 10-year follow-up. We measured sNfL and sGFAP by single molecule array at baseline visit and at 1-year follow-up. A predictive clinical model was developed using age, sex, Expanded Disability Status Scale (EDSS), pyramidal signs, relapse rate, and spinal cord lesions at first visit. The main outcome was odds of developing of secondary progressive (SP)MS at year 10. Secondary outcomes included 10-year EDSS, brain T2LV and BPF. We compared the goodness-of-fit of the predictive clinical model with and without sNfL and sGFAP at baseline and 1-year follow-up, for each outcome by area under the receiver operating characteristic curve (AUC) or R-squared. RESULTS: A total 144 patients with median MS onset at age 37.4 years (interquartile range: 29.4-45.4), 64% female, were included. SPMS developed in 25 (17.4%) patients. The AUC for the predictive clinical model without biomarker data was 0.73, which improved to 0.77 when both sNfL and sGFAP were included in the model (P = 0.021). In this model, higher baseline sGFAP associated with developing SPMS (OR=3.3 [95%CI:1.1,10.6], P = 0.04). Adding 1-year follow-up biomarker levels further improved the model fit (AUC = 0.79) but this change was not statistically significant (P = 0.15). Adding baseline biomarker data also improved the R-squared of clinical models for 10-year EDSS from 0.24 to 0.28 (P = 0.032), while additional 1-year follow-up levels did not. Baseline sGFAP was associated with 10-year EDSS (ß=0.58 [95%CI:0.00,1.16], P = 0.05). For MRI outcomes, baseline biomarker levels improved R-squared for T2LV from 0.12 to 0.27 (P<0.001), and BPF from 0.15 to 0.20 (P = 0.042). Adding 1-year follow-up biomarker data further improved T2LV to 0.33 (P = 0.0065) and BPF to 0.23 (P = 0.048). Baseline sNfL was associated with T2LV (ß=0.34 [95%CI:0.21,0.48], P<0.001) and 1-year follow-up sNfL with BPF (ß=-2.53% [95%CI:-4.18,-0.89], P = 0.003). CONCLUSIONS: Early biomarker levels modestly improve predictive models containing clinical and MRI variables. Worse clinical outcomes, SPMS and EDSS, are associated with higher sGFAP levels and worse MRI outcomes, T2LV and BPF, are associated with higher sNfL levels. Prospective study implementing these predictive models into clinical practice are needed to determine if early biomarker levels meaningfully impact clinical practice.
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Esclerosis Múltiple Crónica Progresiva , Esclerosis Múltiple , Humanos , Femenino , Adulto , Masculino , Esclerosis Múltiple/diagnóstico , Estudios Retrospectivos , Estudios Prospectivos , Proteína Ácida Fibrilar de la Glía , Filamentos Intermedios/metabolismo , Filamentos Intermedios/patología , Esclerosis Múltiple Crónica Progresiva/metabolismo , BiomarcadoresRESUMEN
T cells are present in early stages of the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection and play a major role in disease outcome and long-lasting immunity. Nasal administration of a fully human anti-CD3 monoclonal antibody (Foralumab) reduced lung inflammation as well as serum IL-6 and C-reactive protein in moderate cases of COVID-19. Using serum proteomics and RNA-sequencing, we investigated the immune changes in patients treated with nasal Foralumab. In a randomized trial, mild to moderate COVID-19 outpatients received nasal Foralumab (100 µg/d) given for 10 consecutive days and were compared to patients that did not receive Foralumab. We found that naïve-like T cells were increased in Foralumab-treated subjects and NGK7+ effector T cells were reduced. CCL5, IL32, CST7, GZMH, GZMB, GZMA, PRF1, and CCL4 gene expression were downregulated in T cells and CASP1 was downregulated in T cells, monocytes, and B cells in subjects treated with Foralumab. In addition to the downregulation of effector features, an increase in TGFB1 gene expression in cell types with known effector function was observed in Foralumab-treated subjects. We also found increased expression of GTP-binding gene GIMAP7 in subjects treated with Foralumab. Rho/ROCK1, a downstream pathway of GTPases signaling was downregulated in Foralumab-treated individuals. TGFB1, GIMAP7, and NKG7 transcriptomic changes observed in Foralumab-treated COVID-19 subjects were also observed in healthy volunteers, MS subjects, and mice treated with nasal anti-CD3. Our findings demonstrate that nasal Foralumab modulates the inflammatory response in COVID-19 and provides a novel avenue to treat the disease.
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Anticuerpos Monoclonales , COVID-19 , Animales , Humanos , Ratones , Administración Intranasal , Anticuerpos Monoclonales/uso terapéutico , Proteínas de Unión al GTP , Proteínas de la Membrana , Quinasas Asociadas a rho , SARS-CoV-2 , Linfocitos T , Factor de Crecimiento Transformador beta1/genéticaRESUMEN
INTRODUCTION: Previously in our unit, urodynamics were delayed after insertion of suprapubic (SP) lines. We postulated that performing urodynamics on the same day as SP line insertion would not result in increased morbidity. We retrospectively compared complications in those having urodynamics on the same day against those who had delayed urodynamics. PATIENTS AND METHODS: Notes were reviewed for patients undergoing urodynamics via SP lines from May 2009 until December 2018. In 2014 we modified our practice to allow urodynamics on the same day as SP line insertion in some patients. Patients undergoing videourodynamics would have two 5 Fr (mini Paed) SP lines inserted under general anaesthesia. Patients were divided into two groups: those that had urodynamics on the same day as SP line insertion and those that had urodynamics after an interval of more than one day. The outcome measure was the number of problems affecting those in each group. The two groups were compared using Mann-Whitney U tests and Fisher's Exact tests. RESULTS: There were a total of 211 patients with a median age of 6.5 years (range three months to 15.9 years). Urodynamics were performed on the same day in 86. Delayed Urodynamics were performed at an interval of more than one day in 125. Adverse events included pain or difficulty with voiding, increased urinary frequency, urinary incontinence, leak from catheter site, extravasation, extension of in-patient stay, visible haematuria, urethral catheterisation, and urinary tract infection. Problems affected 43 (20.4%) children. In the same day group, 11 (13.3%) patients had problems, in the delayed group 32 (25.6%) had problems; this was statistically significant (p = 0.03). The difference in combined incidence of important problems (requiring urethral catheterisation, extended admission or abandonment of urodynamics) was not statistically significant between the two groups. CONCLUSION: When using suprapubic catheters for urodynamics there is no additional morbidity when catheters are inserted on the same day as the urodynamics study compared to when urodynamic are delayed.
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Incontinencia Urinaria , Infecciones Urinarias , Humanos , Niño , Lactante , Estudios Retrospectivos , Incontinencia Urinaria/complicaciones , Infecciones Urinarias/etiología , Micción , Morbilidad , UrodinámicaRESUMEN
BACKGROUND: Cognitive decline is inadequately captured by the standard neurological examination. Serum neurofilament light chain (sNfL) and glial fibrillary acidic protein (sGFAP) are biomarkers of neuronal damage and astrocytic reactivity that may offer an accessible measure of the multiple sclerosis (MS) pathology linked to cognitive decline. OBJECTIVE: To investigate the association of sNfL and sGFAP with cognitive decline in MS patients at high risk for progressive pathology. METHODS: We included 94 MS patients with sustained Expanded Disability Status Score (EDSS) ⩾ 3, available serum samples and cognitive assessment performed by symbol digit modalities test (SDMT) over a median of 3.1 years. The visit for sGFAP/sNfL quantification was at confirmed EDSS ⩾ 3. Linear regression analysis on log-transformed sGFAP/sNfL assessed the association with current and future SDMT. Analyses were adjusted for age, sex, EDSS, treatment group, and recent relapse. RESULTS: sNfL was significantly associated with concurrent SDMT (adjusted change in mean SDMT = -4.5; 95% confidence interval (CI): -8.7, -0.2; p = 0.039) and predicted decline in SDMT (adjusted change in slope: -1.14; 95% CI: -1.83, -0.44; p = 0.001), particularly in active patients. sGFAP was not associated with concurrent or future SDMT. CONCLUSIONS: Higher levels of sNfL were associated with cognitive impairment and predicted cognitive decline in MS patients at high risk for having an underlying progressive pathology.
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Disfunción Cognitiva , Esclerosis Múltiple Crónica Progresiva , Esclerosis Múltiple , Humanos , Esclerosis Múltiple/patología , Proteína Ácida Fibrilar de la Glía , Esclerosis Múltiple Crónica Progresiva/complicaciones , Neuronas/patología , Disfunción Cognitiva/etiología , Disfunción Cognitiva/complicaciones , Proteínas de Neurofilamentos , BiomarcadoresRESUMEN
BACKGROUND AND OBJECTIVES: Neurodegeneration and astrocytic activation are pathologic hallmarks of progressive multiple sclerosis (MS) and can be quantified by serum neurofilament light chain (sNfL) and glial fibrillary acidic protein (sGFAP). We investigated sNfL and sGFAP as tools for stratifying patients with progressive MS based on progression and disease activity status. METHODS: We leveraged our Comprehensive Longitudinal Investigation of MS at the Brigham and Women's Hospital (CLIMB) natural history study, which includes clinical, MRI data and serum samples collected over more than 20 years. We included patients with MS with a confirmed Expanded Disability Status Scale (EDSS) score ≥3 that corresponds with our classifier for patients at high risk of underlying progressive pathology. We analyzed sNfL and sGFAP within 6 months from the confirmed EDSS score ≥3 corresponding with our baseline visit. Patients who further developed 6-month confirmed disability progression (6mCDP) were classified as progressors. We further stratified our patients into active/nonactive based on new brain/spinal cord lesions or relapses in the 2 years before baseline or during follow-up. Statistical analysis on log-transformed sGFAP/sNfL assessed the baseline association with demographic, clinical, and MRI features and associations with future disability. RESULTS: We included 257 patients with MS who had an average EDSS score of 4.0 and a median follow-up after baseline of 7.6 years. sNfL was higher in patients with disease activity in the 2 years before baseline (adjusted ß = 1.21; 95% CI 1.04-1.42; p = 0.016), during the first 2 years of follow-up (adjusted ß = 1.17; 95% CI = 1.01-1.36; p = 0.042). sGFAP was not increased in the presence of disease activity. Higher sGFAP levels, but not sNfL levels, were associated with higher risk of 6mCDP (adjusted hazard ratio [HR] = 1.71; 95% CI = 1.19-2.45; p = 0.004). The association was stronger in patients with low sNfL (adjusted HR = 2.44; 95% CI 1.32-4.52; p = 0.005) and patients who were nonactive in the 2 years prior or after the sample. DISCUSSION: Higher levels of sGFAP correlated with subsequent progression, particularly in nonactive patients, whereas sNfL reflected acute disease activity in patients with MS at high risk of underlying progressive pathology. Thus, sGFAP and sNfL levels may be used to stratify patients with progressive MS for clinical research studies and clinical trials and may inform clinical care.
Asunto(s)
Proteína Ácida Fibrilar de la Glía , Esclerosis Múltiple Crónica Progresiva , Proteínas de Neurofilamentos , Humanos , Biomarcadores/sangre , Proteína Ácida Fibrilar de la Glía/sangre , Imagen por Resonancia Magnética , Esclerosis Múltiple Crónica Progresiva/diagnóstico por imagen , Progresión de la Enfermedad , Proteínas de Neurofilamentos/sangreRESUMEN
BACKGROUND: Patients with multiple sclerosis (MS) on some disease modifying therapies (DMTs), particularly anti-CD20 and sphingosine-1-phosphate (S1P) modulators, are at increased risk of severe Coronavirus Disease 19 (COVID-19) and death. COVID-19 vaccinations are effective in preventing infection and severe disease, but humoral response to vaccination and outcomes of COVID-19 infection after vaccination in MS patients on DMTs remain less understood. METHODS: In this retrospective single-center study, patients enrolled in the CLIMB (Comprehensive Longitudinal Investigation of Multiple Sclerosis at Brigham and Women's Hospital) study and biorepository who had been vaccinated against COVID-19 and had SARS-CoV-2 spike antibody (anti-SARS-CoV-2 S Roche-Elecsys) testing were identified and compared to healthy controls. Demographic data, serum immune profiles including lymphocyte count, B-cell count, and immunoglobulins, and clinical outcome of COVID-19 infection were collected. RESULTS: 254 patients (73.2% female, mean (SD) age 52.9 (11.2) years) were identified. When controlling for age, time since vaccination, and vaccine type, patients on fingolimod, ocrelizumab, rituximab, mycophenolate mofetil, natalizumab and teriflunomide had significantly lower levels of spike antibodies compared to healthy controls (n = 34). Longer duration of treatment was associated with lower spike antibody levels in patients on anti-CD20 therapy (p = 0.016) and S1P modulators (p = 0.016) compared to healthy controls. In patients on anti-CD20 therapy, higher spike antibody levels were associated with higher CD20 cell count (p<0.001), and longer time since last anti-CD20 therapy infusion (p<0.001). 92.8% (13/14) vaccine responders (spike antibody titer >100 ug/dL) on anti-CD20 therapy demonstrated B-cell reconstitution (mean CD20 3.6%). Only 1 out of 86 patients with CD20 of 0% had a measurable spike antibody response to vaccination. During follow-up (mean 270 days), five patients were diagnosed with COVID-19 after vaccination (incidence 1.9%), all of whom had spike antibody < 20 ug/dL. No patients required ICU care or died. CONCLUSIONS: Patients on some DMTs demonstrate reduced humoral immunity after Sars-CoV-2 vaccination. Longer duration of anti-CD20 therapy and reduced CD20 cell count is associated with blunted humoral response to vaccination. CD20 reconstitution >0.1% appears necessary, but not always sufficient, for humoral response to vaccination. Breakthrough COVID-19 infection in our cohort of MS patients on DMT was higher than in population studies. We propose that adjustment of B-cell therapy administration to allow for B-cell reconstitution prior to vaccination should be considered.