A Systematic Review and Meta-Analysis on the Prevalence of Mild Cognitive Impairment and Dementia in Mexico.

INTRODUCTION: Age remains one of the major risk factors for the onset of mild cognitive impairment (MCI) and dementia. Studies on the prevalence of these conditions in Mexico used different methods, tools, and populations with different health statuses. All these heterogeneous results may be a problem in identifying the true prevalence of MCI and dementia in Mexico. To our knowledge, there is not a systematic review available that presents essential figures on the prevalence of these conditions in Mexico. Therefore, we intend to access the maximum number of reports published on the topic and determine the prevalence of MCI and dementia in older Mexican adults. METHODS: A systematic review using PubMed, Cochrane, Research Gate, Lilacs, and Scielo databases was performed. Meta-analysis of the prevalence of MCI and dementia was performed using a random-effects model and presented in a forest plot among cross-sectional, epidemiological, and pooled studies. RESULTS: Sixteen articles were included. The overall prevalence of MCI of 18% (95% CI 0.10-0.27) was estimated from pooled information from 12 selected studies, in women 21% (95% CI 0.08-0.38) and in men 18% (95% CI 0.06-0.33). The overall prevalence of dementia of 10% (95% CI 0.06-0.14) was estimated from pooled information from 9 selected studies, in women 14% (95% CI 0.05-0.25) and in men 10% (95% CI 0.04-0.17). CONCLUSION: Mexican older individuals have a similar prevalence of dementia and MCI as reported by international data; nevertheless, the prevalence is higher than in some Latin American countries. Mexico has particular issues that must be resolved, such as a lack of research in the southern regions of the country and the high incidence of comorbidities.

Echocardiographic Findings in Critically Ill COVID-19 Patients Treated With and Without Extracorporeal Membrane Oxygenation.

OBJECTIVES: To describe echocardiographic findings among mechanically ventilated patients with COVID-19 acute respiratory distress syndrome, comparing those with and without venovenous extracorporeal membrane oxygenation (VV ECMO) support. DESIGN: Single-center, retrospective cohort study. SETTING: Intensive care unit (ICU) of a quaternary academic center. PARTICIPANTS: Patients with COVID-19 admitted between March 2020 and June 2021 receiving mechanical ventilation, with an echocardiogram within 72 hours of admission. INTERVENTIONS: Admission and follow-up echocardiograms during ICU stay. MEASUREMENTS: Patient characteristics and echocardiographic findings were analyzed. Mortality odds ratio (OR) for right ventricular (RV) systolic dysfunction and acute cor pulmonale (ACP) was calculated. MAIN RESULTS: Among 242 patients, 145 (60%) received VV ECMO. Median (IQR) PaO2/FiO2 was 76 (65-95) and 98 (85-140) in ECMO and non-ECMO patients, respectively (p ≤ 0.001). Initial echocardiograms showed no significant differences in left ventricular systolic dysfunction (10% v 15 %, p = 0.31) and RV systolic dysfunction (38% v. 27%, p = 0.27) between ECMO and non-ECMO patients. ACP was more frequent in the ECMO group at baseline (41% v. 26 %, p = 0.02). During the ICU stay, patients on ECMO exhibited a higher prevalence of RV systolic dysfunction (55% v 34%, p = 0.001) and ACP (51% v 26%, p = 0.002). RV systolic dysfunction (OR 1.99; 95% CI 1.09-3.63) and ACP (OR 2.95; 95% CI 1.55-5.62) on the follow-up echocardiograms were associated with higher odds of ICU mortality. CONCLUSIONS: The prevalence of echocardiographic abnormalities, in particular RV dysfunction, was frequent among patients with COVID-19 receiving VV ECMO support and was associated with worse clinical outcomes.

Monitoring during extracorporeal membrane oxygenation.

PURPOSE OF REVIEW: Extracorporeal membrane oxygenation (ECMO) offers advanced mechanical support to patients with severe acute respiratory and/or cardiac failure. Ensuring an adequate therapeutic approach as well as prevention of ECMO-associated complications, by means of timely liberation, forms an essential part of standard ECMO care and is only achievable through continuous monitoring and evaluation. This review focus on the cardiorespiratory monitoring tools that can be used to assess and titrate adequacy of ECMO therapy; as well as methods to assess readiness to wean and/or discontinue ECMO support. RECENT FINDINGS: Surrogates of tissue perfusion and near infrared spectroscopy are not standards of care but may provide useful information in select patients. Echocardiography allows to determine cannulas position, evaluate cardiac structures, and function, and diagnose complications. Respiratory monitoring is mandatory to achieve lung protective ventilation and identify early lung recovery, surrogate measurements of respiratory effort and ECMO derived parameters are invaluable in optimally managing ECMO patients. SUMMARY: Novel applications of existing monitoring modalities alongside evolving technological advances enable the advanced monitoring required for safe delivery of ECMO. Liberation trials are necessary to minimize time sensitive ECMO related complications; however, these have yet to be standardized.

A CADM3 variant causes Charcot-Marie-Tooth disease with marked upper limb involvement.

The CADM family of proteins consists of four neuronal specific adhesion molecules (CADM1, CADM2, CADM3 and CADM4) that mediate the direct contact and interaction between axons and glia. In the peripheral nerve, axon-Schwann cell interaction is essential for the structural organization of myelinated fibres and is primarily mediated by the binding of CADM3, expressed in axons, to CADM4, expressed by myelinating Schwann cells. We have identified-by whole exome sequencing-three unrelated families, including one de novo patient, with axonal Charcot-Marie-Tooth disease (CMT2) sharing the same private variant in CADM3, Tyr172Cys. This variant is absent in 230 000 control chromosomes from gnomAD and predicted to be pathogenic. Most CADM3 patients share a similar phenotype consisting of autosomal dominant CMT2 with marked upper limb involvement. High resolution mass spectrometry analysis detected a newly created disulphide bond in the mutant CADM3 potentially modifying the native protein conformation. Our data support a retention of the mutant protein in the endoplasmic reticulum and reduced cell surface expression in vitro. Stochastic optical reconstruction microscopy imaging revealed decreased co-localization of the mutant with CADM4 at intercellular contact sites. Mice carrying the corresponding human mutation (Cadm3Y170C) showed reduced expression of the mutant protein in axons. Cadm3Y170C mice showed normal nerve conduction and myelin morphology, but exhibited abnormal axonal organization, including abnormal distribution of Kv1.2 channels and Caspr along myelinated axons. Our findings indicate the involvement of abnormal axon-glia interaction as a disease-causing mechanism in CMT patients with CADM3 mutations.

Transesophageal Echocardiography-Guided Extracorporeal Membrane Oxygenation Cannulation in COVID-19 Patients.

OBJECTIVES: A paucity of data supports the use of transesophageal echocardiography (TEE) for bedside extracorporeal membrane oxygenation (ECMO) cannulation. Concerns have been raised about performing TEEs in patients with COVID-19. The authors describe the use and safety of TEE guidance for ECMO cannulation for COVID-19. DESIGN: Single-center retrospective cohort study. SETTING: The study took place in the intensive care unit of an academic tertiary center. PARTICIPANTS: The authors included 107 patients with confirmed SARS-CoV-2 infection who underwent bedside venovenous ECMO (VV ECMO) cannulation under TEE guidance between May 2020 and June 2021. INTERVENTIONS: TEE-guided bedside VV ECMO cannulation. MEASUREMENTS: Patient characteristics, physiologic and ventilatory parameters, and echocardiographic findings were analyzed. The primary outcome was the number of successful TEE-guided bedside cannulations without complications. The secondary outcomes were cannulation complications, frequency of cannula repositioning, and TEE-related complications. MAIN RESULTS: TEE-guided cannulation was successful in 99% of the patients. Initial cannula position was adequate in all but 1 patient. Fourteen patients (13%) required cannula repositioning during ECMO support. Forty-five patients (42%) had right ventricular systolic dysfunction, and 9 (8%) had left ventricular systolic dysfunction. Twelve patients (11%) had intracardiac thrombi. One superficial arterial injury and 1 pneumothorax occurred. No pericardial tamponade, hemothorax or intraabdominal bleeding occurred in the authors' cohort. No TEE-related complications or COVID-19 infection of healthcare providers were reported during this study. CONCLUSIONS: Bedside TEE guidance for VV ECMO cannulation is safe in patients with severe respiratory failure due to COVID-19. No tamponade or hemothorax, nor TEE-related complications were observed in the authors' cohort.

The prevalence of skin tears and associated factors in hospitalised patients with cancer.

OBJECTIVE: Oncology patients are vulnerable to skin breakdown. The primary purpose of this study was to estimate the prevalence of skin tears (STs) in hospitalised patients with cancer and to explore related sociodemographic and clinical factors. METHOD: This was an observational, epidemiological, cross-sectional study conducted in an oncology hospital in the city of São Paulo. All STs were classified using the STAR Classification adapted and validated for Brazil. RESULTS: Of the 341 patients evaluated, 22 had STs, equating to a prevalence of 6.5%. A higher number of STs were noted on the lower limbs (26.9%) than on other body areas. The main factors associated with STs were the use of anticoagulants, the presence of ecchymosis and the use of incontinence briefs. CONCLUSION: This study contributed to a better understanding of the epidemiology of STs in hospitalised patients with cancer, as well as its associated factors. Results may inform nursing professionals with regard to the need to develop prevention strategies and early interventions.

The prevalence of skin lesions and associated factors in hospitalised adult patients with cancer.

OBJECTIVE: To assess the prevalence of skin lesions and evaluate the clinical and sociodemographic factors associated with their presence in hospitalised patients. METHOD: This descriptive, cross-sectional, correlational study was performed in inpatient units and intensive care units of a cancer hospital in São Paulo, Brazil, after approval by the Institutional Research Ethics Committee. Data from hospitalised adult patients with cancer were collected during physical examinations and from medical records. A Chi-squared test, univariate analysis, a logistic regression model with results expressed as odds ratio (OR) and 95% confidence intervals (CI), and Classification and Regression Tree (CART) analysis were used to evaluate the data. RESULTS: Of 341 patients, 80 had skin lesions, equating to an overall prevalence of 23.5%. The skin lesions included pressure injuries (10%), incontinence-associated dermatitis (6.7%), skin tears (6.5%), malignant wounds (3.8%) and complicated surgical wounds (3.2%). The factors associated with skin lesions in cancer patients were the use of disposable nappies (OR: 4.436) and age (59.1±15.1 years), according to the CART analysis, and the wearing of nappies (OR: 4.466, p<0.001), presence of ecchymosis (OR: 2.532, p<0.001) and infection (OR: 6.449, p=0.040), according to multiple regression analysis. CONCLUSION: This study contributed to knowledge about prevalence and associated factors of skin lesions in hospitalised patients with cancer, allowing the implementation of preventive measures.

Safety and efficacy of nusinersen in spinal muscular atrophy: The EMBRACE study.

INTRODUCTION: The EMBRACE study (Clinical Trials No. NCT02462759) evaluated nusinersen in infants/children with infantile- or later-onset spinal muscular atrophy (SMA) who were ineligible for the ENDEAR and CHERISH studies. METHODS: Participants were randomized to intrathecal nusinersen (12-mg scaled equivalent dose; n = 14) or sham procedure (n = 7) in part 1 (~14 months) and subsequently received open-label nusinersen for ~24 months in part 2 of the study. RESULTS: Part 1 was stopped early after the demonstration of motor function benefit with nusinersen in ENDEAR. There were no nusinersen-related adverse events (AEs) and no study discontinuations due to nusinersen-related AEs. The most common AEs included pyrexia, cough, pneumonia, and upper respiratory tract infections. Motor milestone responder rates were higher in those receiving nusinersen at last available assessment (93%) than in those receiving sham procedure in part 1 (29%) or transitioned from sham to nusinersen in part 2 (83%). This functional improvement was observed despite the small sample size and shortened part 1 trial duration that undermined the power of the study to demonstrate such treatment effects at a significant level. DISCUSSION: Nusinersen demonstrated a favorable long-term benefit-risk profile in this broad population of individuals with infantile- or later-onset SMA.

Recurrent TTN metatranscript-only c.39974-11T>G splice variant associated with autosomal recessive arthrogryposis multiplex congenita and myopathy.

We present eight families with arthrogryposis multiplex congenita and myopathy bearing a TTN intron 213 extended splice-site variant (NM_001267550.1:c.39974-11T>G), inherited in trans with a second pathogenic TTN variant. Muscle-derived RNA studies of three individuals confirmed mis-splicing induced by the c.39974-11T>G variant; in-frame exon 214 skipping or use of a cryptic 3' splice-site effecting a frameshift. Confounding interpretation of pathogenicity is the absence of exons 213-217 within the described skeletal muscle TTN N2A isoform. However, RNA-sequencing from 365 adult human gastrocnemius samples revealed that 56% specimens predominantly include exons 213-217 in TTN transcripts (inclusion rate ≥66%). Further, RNA-sequencing of five fetal muscle samples confirmed that 4/5 specimens predominantly include exons 213-217 (fifth sample inclusion rate 57%). Contractures improved significantly with age for four individuals, which may be linked to decreased expression of pathogenic fetal transcripts. Our study extends emerging evidence supporting a vital developmental role for TTN isoforms containing metatranscript-only exons.

Efficacy and safety of vamorolone in Duchenne muscular dystrophy: An 18-month interim analysis of a non-randomized open-label extension study.

BACKGROUND: Treatment with corticosteroids is recommended for Duchenne muscular dystrophy (DMD) patients to slow the progression of weakness. However, chronic corticosteroid treatment causes significant morbidities. Vamorolone is a first-in-class anti-inflammatory investigational drug that has shown evidence of efficacy in DMD after 24 weeks of treatment at 2.0 or 6.0 mg/kg/day. Here, open-label efficacy and safety experience of vamorolone was evaluated over a period of 18 months in trial participants with DMD. METHODS AND FINDINGS: A multicenter, open-label, 24-week trial (VBP15-003) with a 24-month long-term extension (VBP15-LTE) was conducted by the Cooperative International Neuromuscular Research Group (CINRG) and evaluated drug-related effects of vamorolone on motor outcomes and corticosteroid-associated safety concerns. The study was carried out in Canada, US, UK, Australia, Sweden, and Israel, from 2016 to 2019. This report covers the initial 24-week trial and the first 12 months of the VBP15-LTE trial (total treatment period 18 months). DMD trial participants (males, 4 to <7 years at entry) treated with 2.0 or 6.0 mg/kg/day vamorolone for the full 18-month period (n = 23) showed clinical improvement of all motor outcomes from baseline to month 18 (time to stand velocity, p = 0.012 [95% CI 0.010, 0.068 event/second]; run/walk 10 meters velocity, p < 0.001 [95% CI 0.220, 0.491 meters/second]; climb 4 stairs velocity, p = 0.001 [95% CI 0.034, 0.105 event/second]; 6-minute walk test, p = 0.001 [95% CI 31.14, 93.38 meters]; North Star Ambulatory Assessment, p < 0.001 [95% CI 2.702, 6.662 points]). Outcomes in vamorolone-treated DMD patients (n = 46) were compared to group-matched participants in the CINRG Duchenne Natural History Study (corticosteroid-naïve, n = 19; corticosteroid-treated, n = 68) over a similar 18-month period. Time to stand was not significantly different between vamorolone-treated and corticosteroid-naïve participants (p = 0.088; least squares [LS] mean 0.042 [95% CI -0.007, 0.091]), but vamorolone-treated participants showed significant improvement compared to group-matched corticosteroid-naïve participants for run/walk 10 meters velocity (p = 0.003; LS mean 0.286 [95% CI 0.104, 0.469]) and climb 4 stairs velocity (p = 0.027; LS mean 0.059 [95% CI 0.007, 0.111]). The vamorolone-related improvements were similar in magnitude to corticosteroid-related improvements. Corticosteroid-treated participants showed stunting of growth, whereas vamorolone-treated trial participants did not (p < 0.001; LS mean 15.86 [95% CI 8.51, 23.22]). Physician-reported incidences of adverse events (AEs) for Cushingoid appearance, hirsutism, weight gain, and behavior change were less for vamorolone than published incidences for prednisone and deflazacort. Key limitations to the study were the open-label design, and use of external comparators. CONCLUSIONS: We observed that vamorolone treatment was associated with improvements in some motor outcomes as compared with corticosteroid-naïve individuals over an 18-month treatment period. We found that fewer physician-reported AEs occurred with vamorolone than have been reported for treatment with prednisone and deflazacort, and that vamorolone treatment did not cause the stunting of growth seen with these corticosteroids. This Phase IIa study provides Class III evidence to support benefit of motor function in young boys with DMD treated with vamorolone 2.0 to 6.0 mg/kg/day, with a favorable safety profile. A Phase III RCT is underway to further investigate safety and efficacy. TRIAL REGISTRATION: Clinical trials were registered at www.clinicaltrials.gov, and the links to each trial are as follows (as provided in manuscript text): VBP15-002 [NCT02760264] VBP15-003 [NCT02760277] VBP15-LTE [NCT03038399].

Response to treatment in pediatric ocular myasthenia gravis.

INTRODUCTION: Juvenile myasthenia gravis (JMG), a pediatric autoimmune neuromuscular junction disorder, includes generalized (GMG), and ocular (OMG) variants. We sought to determine whether differences existed between OMG and GMG children regarding demographics or treatment response. METHODS: We performed retrospective analysis of 60 children with JMG seen between 1990 and 2018. Osserman scores were used to define OMG and GMG. The myasthenia scale of Millichap and Dodge was used to assess treatment responses. RESULTS: There were no differences between GMG and OMG regarding time interval from disease onset to prednisone initiation (P = .42), or treatment response according to Millichap and Dodge (P = .12). Compared with GMG, OMG children showed younger age of disease onset and better outcomes after treatment. No OMG patients progressed to generalized disease during the follow-up period. DISCUSSION: Compared with GMG, OMG patients had earlier disease onset and improved outcomes after treatment.

Spinal muscular atrophy care in the COVID-19 pandemic era.

The coronavirus disease 2019 (COVID-19) pandemic has resulted in reorganization of healthcare settings affecting the delivery of clinical care to patients with spinal muscular atrophy (SMA). There is a concern that patients with SMA may be at increased risk of manifesting severe symptoms of COVID-19. Currently approved therapies for SMA improve survival and motor function; however, their delivery requires an increased exposure to the health system and a dedicated healthcare team. In this study, we discuss consensus recommendations pertaining to care of SMA patients during the pandemic. We highlight that SMA treatments should not be perceived as elective. Decisions regarding the delay of treatments should be made with consideration of the potential risks of COVID-19 exposure and the risk of that delay. We emphasize the importance of collaborative treatment decisions between the patient, family, and healthcare provider, considering any geographic- or institution-specific policies and precautions for COVID-19.

Malignant Wounds in Hospitalized Oncology Patients: Prevalence, Characteristics, and Associated Factors.

Epidemiological and descriptive research on malignant wounds (MWs) is scarce. The objective of this study was to identify the prevalence of MWs and analyze the characteristics and associated factors of MWs in hospitalized patients at an oncological institution. An epidemiological, cross-sectional, and descriptive study, which was derived from a larger study that collected data on the prevalence of different types of wounds in 341 adults hospitalized in a large oncological hospital, was conducted. The present study comprehensively analyzed data related to MWs. Information was obtained through participant interviews, physical examination, and medical record review. The study was approved by the ethics committee of the institution where the study was conducted. Fourteen MWs were identified in 13 patients, who were primarily married (58%) and men (75%), with a mean age of 60.5 ± 15.1 years. Malignant wounds were predominantly located in the head and neck region (43%) and classified as 1N (50%) according to the Staging of Malignant Cutaneous Wounds instrument. Malignant wounds were characterized as painful (83.3%), with significant pain present during dressing changes (93%). The presence of MWs was associated with the use of antidepressants (odds ratio [OR] = 4.95; p = .012), upper-limb edema (OR = 8.39; p = .003), and infection (OR = 12.16; p = .051). The prevalence of MWs in hospitalized patients was 3.8%. Associated clinical variables were related to the degree of disease progression. This information provides evidence of the need for research identifying and investigating nursing interventions for patients with MW to assist with pain control during dressing changes.

Complicated Surgical Wounds and Associated Factors in Oncology Patients.

The objective of this study was to identify the occurrence of complicated surgical wounds (CSWs) and to analyze the associated factors in hospitalized patients at an oncology institution. This was an epidemiological, observational, cross-sectional, descriptive, and correlational study conducted in the intensive care and hospitalization units forming part of a large cancer hospital. Sociodemographic and clinical data were collected from medical records and physical examinations of the skin. Associations between the dependent variable (presence of CSWs) and the independent variables were obtained by chi-square tests and odds ratio (OR) calculations with a 95% confidence interval. Logistic regression (LASSO) was used to verify the possible predictors of the outcome. The sample consisted of 341 patients, specifically individuals who are White (46.9%), married (53.4%), and men (58.1%) with an average age of 59.2 years. Complicated surgical wounds were present in 3.2% of patients, and the most frequent types of complications were dehiscence (40%), infection (26.7%), and fistula (20%) present in the abdominal (40%), cephalic (26.7%), and cervical (13.3%) regions. Senile purpura, diaper use, and infection were the clinical variables associated with the occurrence of CSWs (p = .044, p = .001, and p < .001, respectively). Based on the logistic regression, the presence of infection (p < .001; OR = 90.8; 95% CI [18.42, 538.79]) persisted as a predictor of the occurrence of CSWs. From these observations, recommendations regarding best practices for the prevention of CSWs are made, specifically for patients with cancer.

Clinical and genetic characteristics of childhood-onset myotonic dystrophy.

INTRODUCTION: Myotonic dystrophy type 1 (DM1) is caused by a CTG (cytosine-thymine-guanine) trinucleotide repeat expansion. Congenital DM (CDM) presents in the first month of life, whereas individuals with infantile and juvenile DM1 have later onset of symptoms. METHODS: We performed a retrospective chart review of patients with childhood-onset DM1 seen at one of three locations in Dallas, Texas between 1990 and 2018. Symptoms, disease course, cognitive features, and family history were reviewed. RESULTS: Seventy-four patients were included; CDM was diagnosed in 52 patients. There was maternal inheritance in 74% of patients. CTG repeat number ranged from 143 to 2300. Neuropsychiatric and cognitive deficits were common. Over half of the patients had GI disturbances, and orthopedic complications were common. DISCUSSION: Myotonic dystrophy type 1 in children requires a multidisciplinary approach to management. Presenting symptoms vary, and repeat expansion size does not necessarily directly relate to severity of symptoms. A consensus for outcome measures is required.

Analysis of single nucleotide polymorphisms (SNPs) associated with antibiotic resistance genes in Chilean Piscirickettsia salmonis strains.

The aetiological agent of Piscirickettsiosis is Piscirickettsia salmonis, a Gram-negative intracellular pathogen, and high doses of antibiotics have regularly been employed to treat this infection. Seven florfenicol and/or oxytetracycline resistance genes (tet pump, tetE, Tclor/flor, Tbcr, TfloR, ompF and mdtN) were identified in strains by in silico genome analyses. Later, the number of single nucleotide polymorphisms (SNPs) and its relationship with the resistance to these antibiotics were identified and analysed, using the original LF-89 strain as reference. Trials to determine and compare the minimum inhibitory concentration (MIC) of oxytetracycline and florfenicol in each strain, as well as to quantify the gPCR transcripts levels in the selected genes, were performed. Therefore, variations in the resistance to both antibiotics were observed, where the strain with fewer SNPs showed the highest susceptibility. Consistently, the in silico 3D analyses of proteins encoded by the selected genes revealed structural changes, evident in the sequences with the highest number of SNPs. These results showed that the bacterial resistance to oxytetracycline was mainly linked to the presence of SNPs in relevant sites, antibiotic resistance genes and an OmpF porin, leading to important changes in the protein structure.

Clinical and molecular spectrum of thymidine kinase 2-related mtDNA maintenance defect.

Mitochondrial DNA maintenance (mtDNA) defects have a wide range of causes, each with a set of phenotypes that overlap with many other neurological or muscular diseases. Clinicians face the challenge of narrowing down a long list of differential diagnosis when encountered with non-specific neuromuscular symptoms. Biallelic pathogenic variants in the Thymidine Kinase 2 (TK2) gene cause a myopathic form of mitochondrial DNA maintenance defect. Since the first description in 2001, there have been 71 patients reported with 42 unique pathogenic variants. Here we are reporting 11 new cases with 5 novel pathogenic variants. We describe and analyze a total of 82 cases with 47 unique TK2 pathogenic variants in effort to formulate a comprehensive molecular and clinical spectrum of TK2-related mtDNA maintenance disorders.

Natural history of infantile-onset spinal muscular atrophy.

OBJECTIVE: Infantile-onset spinal muscular atrophy (SMA) is the most common genetic cause of infant mortality, typically resulting in death preceding age 2. Clinical trials in this population require an understanding of disease progression and identification of meaningful biomarkers to hasten therapeutic development and predict outcomes. METHODS: A longitudinal, multicenter, prospective natural history study enrolled 26 SMA infants and 27 control infants aged <6 months. Recruitment occurred at 14 centers over 21 months within the NINDS-sponsored NeuroNEXT (National Network for Excellence in Neuroscience Clinical Trials) Network. Infant motor function scales (Test of Infant Motor Performance Screening Items [TIMPSI], The Children's Hospital of Philadelphia Infant Test for Neuromuscular Disorders, and Alberta Infant Motor Score) and putative physiological and molecular biomarkers were assessed preceding age 6 months and at 6, 9, 12, 18, and 24 months with progression, correlations between motor function and biomarkers, and hazard ratios analyzed. RESULTS: Motor function scores (MFS) and compound muscle action potential (CMAP) decreased rapidly in SMA infants, whereas MFS in all healthy infants rapidly increased. Correlations were identified between TIMPSI and CMAP in SMA infants. TIMPSI at first study visit was associated with risk of combined endpoint of death or permanent invasive ventilation in SMA infants. Post-hoc analysis of survival to combined endpoint in SMA infants with 2 copies of SMN2 indicated a median age of 8 months at death (95% confidence interval, 6, 17). INTERPRETATION: These data of SMA and control outcome measures delineates meaningful change in clinical trials in infantile-onset SMA. The power and utility of NeuroNEXT to provide "real-world," prospective natural history data sets to accelerate public and private drug development programs for rare disease is demonstrated. Ann Neurol 2017;82:883-891.