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1.
Genome Med ; 16(1): 72, 2024 05 30.
Article in English | MEDLINE | ID: mdl-38811945

ABSTRACT

BACKGROUND: We previously described the KINSSHIP syndrome, an autosomal dominant disorder associated with intellectual disability (ID), mesomelic dysplasia and horseshoe kidney, caused by de novo variants in the degron of AFF3. Mouse knock-ins and overexpression in zebrafish provided evidence for a dominant-negative mode of action, wherein an increased level of AFF3 resulted in pathological effects. METHODS: Evolutionary constraints suggest that other modes-of-inheritance could be at play. We challenged this hypothesis by screening ID cohorts for individuals with predicted-to-be damaging variants in AFF3. We used both animal and cellular models to assess the deleteriousness of the identified variants. RESULTS: We identified an individual with a KINSSHIP-like phenotype carrying a de novo partial duplication of AFF3 further strengthening the hypothesis that an increased level of AFF3 is pathological. We also detected seventeen individuals displaying a milder syndrome with either heterozygous Loss-of-Function (LoF) or biallelic missense variants in AFF3. Consistent with semi-dominance, we discovered three patients with homozygous LoF and one compound heterozygote for a LoF and a missense variant, who presented more severe phenotypes than their heterozygous parents. Matching zebrafish knockdowns exhibit neurological defects that could be rescued by expressing human AFF3 mRNA, confirming their association with the ablation of aff3. Conversely, some of the human AFF3 mRNAs carrying missense variants identified in affected individuals did not rescue these phenotypes. Overexpression of mutated AFF3 mRNAs in zebrafish embryos produced a significant increase of abnormal larvae compared to wild-type overexpression further demonstrating deleteriousness. To further assess the effect of AFF3 variation, we profiled the transcriptome of fibroblasts from affected individuals and engineered isogenic cells harboring + / + , KINSSHIP/KINSSHIP, LoF/ + , LoF/LoF or KINSSHIP/LoF AFF3 genotypes. The expression of more than a third of the AFF3 bound loci is modified in either the KINSSHIP/KINSSHIP or the LoF/LoF lines. While the same pathways are affected, only about one third of the differentially expressed genes are common to the homozygote datasets, indicating that AFF3 LoF and KINSSHIP variants largely modulate transcriptomes differently, e.g. the DNA repair pathway displayed opposite modulation. CONCLUSIONS: Our results and the high pleiotropy shown by variation at this locus suggest that minute changes in AFF3 function are deleterious.


Subject(s)
Intellectual Disability , Transcriptome , Zebrafish , Animals , Female , Humans , Male , Intellectual Disability/genetics , Loss of Function Mutation , Mutation, Missense , Phenotype , Zebrafish/genetics
2.
medRxiv ; 2024 Jan 17.
Article in English | MEDLINE | ID: mdl-38293053

ABSTRACT

Background: We previously described the KINSSHIP syndrome, an autosomal dominant disorder associated with intellectual disability (ID), mesomelic dysplasia and horseshoe kidney,caused by de novo variants in the degron of AFF3. Mouse knock-ins and overexpression in zebrafish provided evidence for a dominant-negative (DN) mode-of-action, wherein an increased level of AFF3 resulted in pathological effects. Methods: Evolutionary constraints suggest that other mode-of-inheritance could be at play. We challenged this hypothesis by screening ID cohorts for individuals with predicted-to-be deleterious variants in AFF3. We used both animal and cellular models to assess the deleteriousness of the identified variants. Results: We identified an individual with a KINSSHIP-like phenotype carrying a de novo partial duplication of AFF3 further strengthening the hypothesis that an increased level of AFF3 is pathological. We also detected seventeen individuals displaying a milder syndrome with either heterozygous LoF or biallelic missense variants in AFF3. Consistent with semi-dominance, we discovered three patients with homozygous LoF and one compound heterozygote for a LoF and a missense variant, who presented more severe phenotypes than their heterozygous parents. Matching zebrafish knockdowns exhibit neurological defects that could be rescued by expressing human AFF3 mRNA, confirming their association with the ablation of aff3. Conversely, some of the human AFF3 mRNAs carrying missense variants identified in affected individuals did not complement. Overexpression of mutated AFF3 mRNAs in zebrafish embryos produced a significant increase of abnormal larvae compared to wild-type overexpression further demonstrating deleteriousness. To further assess the effect of AFF3 variation, we profiled the transcriptome of fibroblasts from affected individuals and engineered isogenic cells harboring +/+, DN/DN, LoF/+, LoF/LoF or DN/LoF AFF3 genotypes. The expression of more than a third of the AFF3 bound loci is modified in either the DN/DN or the LoF/LoF lines. While the same pathways are affected, only about one-third of the differentially expressed genes are common to these homozygote datasets, indicating that AFF3 LoF and DN variants largely modulate transcriptomes differently, e.g. the DNA repair pathway displayed opposite modulation. Conclusions: Our results and the high pleiotropy shown by variation at this locus suggest that minute changes in AFF3 function are deleterious.

3.
Neurol Clin Pract ; 14(1): e200233, 2024 Feb.
Article in English | MEDLINE | ID: mdl-38156118

ABSTRACT

Purpose of Review: Access to pediatric neurology care is limited, and outpatient waits can exceed 6 months. The referral process is often complex and burdensome. Our objective was to trial a program for scheduling access to pediatric neurology, to be controlled and accessed directly by outside providers. Recent Findings: We developed a web-based automated system, "Rapid Access Scheduler" (RASr), for direct scheduling by outside providers. RASr is built around a calendar view that allows the provider to see and reserve an available slot at the time of care. Once a slot is reserved, the scheduling team contacts the family to finalize scheduling. Summary: The RASr system is a novel approach for facilitating pediatric neurology patient access through direct scheduling by outside providers using a web-based portal. Advantages of this include control and responsibility by outside providers, easy visibility of availability, and opportunity to inform patients and families at their point-of-care.

4.
Health Educ Behav ; 50(2): 268-280, 2023 04.
Article in English | MEDLINE | ID: mdl-35306908

ABSTRACT

As persistent inequities in health gained increased attention nationally due to COVID-19 and racial justice protests in 2020, it has become increasingly important to evaluate both the process and outcomes associated with coalition-based efforts to address health inequities. The Two Georgias Initiative supports coalitions in 11 rural counties to (1) achieve greater health equity, (2) improve health and health care, (3) build healthier rural communities and improve social conditions that impact the health of rural populations, and (4) build community, organizational, and individual leadership capacity for health equity. Rural communities suffer significant health disparities relative to urban areas, and also experience internal inequities by race and poverty level. The evaluation framework for The Two Georgias Initiative provides a comprehensive mixed methods approach to evaluating both processes and outcomes. Early results related to community readiness and capacity to address health inequities, measured through a coalition member survey (n = 236) conducted at the end of the planning phase, suggest coalitions were in the preparation stage, with higher levels of readiness among coalition members and organizations/groups similar to the coalition members' own, lower levels among public officials and other leaders, and the lowest levels among county residents. In addition, coalition members reported more experience with downstream drivers (e.g., access to care) of health than upstream drivers (e.g., affordable housing, environmental or racial justice). By providing a logic model, evaluation questions and associated indicators, as well as a range of data collection methods, this evaluation approach may prove practical to others aiming to evaluate their efforts to address health equity.


Subject(s)
Health Equity , Humans , Georgia , Rural Population
5.
JAMA Neurol ; 79(12): 1267-1276, 2022 12 01.
Article in English | MEDLINE | ID: mdl-36315135

ABSTRACT

Importance: It is currently unknown how often and in which ways a genetic diagnosis given to a patient with epilepsy is associated with clinical management and outcomes. Objective: To evaluate how genetic diagnoses in patients with epilepsy are associated with clinical management and outcomes. Design, Setting, and Participants: This was a retrospective cross-sectional study of patients referred for multigene panel testing between March 18, 2016, and August 3, 2020, with outcomes reported between May and November 2020. The study setting included a commercial genetic testing laboratory and multicenter clinical practices. Patients with epilepsy, regardless of sociodemographic features, who received a pathogenic/likely pathogenic (P/LP) variant were included in the study. Case report forms were completed by all health care professionals. Exposures: Genetic test results. Main Outcomes and Measures: Clinical management changes after a genetic diagnosis (ie, 1 P/LP variant in autosomal dominant and X-linked diseases; 2 P/LP variants in autosomal recessive diseases) and subsequent patient outcomes as reported by health care professionals on case report forms. Results: Among 418 patients, median (IQR) age at the time of testing was 4 (1-10) years, with an age range of 0 to 52 years, and 53.8% (n = 225) were female individuals. The mean (SD) time from a genetic test order to case report form completion was 595 (368) days (range, 27-1673 days). A genetic diagnosis was associated with changes in clinical management for 208 patients (49.8%) and usually (81.7% of the time) within 3 months of receiving the result. The most common clinical management changes were the addition of a new medication (78 [21.7%]), the initiation of medication (51 [14.2%]), the referral of a patient to a specialist (48 [13.4%]), vigilance for subclinical or extraneurological disease features (46 [12.8%]), and the cessation of a medication (42 [11.7%]). Among 167 patients with follow-up clinical information available (mean [SD] time, 584 [365] days), 125 (74.9%) reported positive outcomes, 108 (64.7%) reported reduction or elimination of seizures, 37 (22.2%) had decreases in the severity of other clinical signs, and 11 (6.6%) had reduced medication adverse effects. A few patients reported worsening of outcomes, including a decline in their condition (20 [12.0%]), increased seizure frequency (6 [3.6%]), and adverse medication effects (3 [1.8%]). No clinical management changes were reported for 178 patients (42.6%). Conclusions and Relevance: Results of this cross-sectional study suggest that genetic testing of individuals with epilepsy may be materially associated with clinical decision-making and improved patient outcomes.


Subject(s)
Epilepsy , Genetic Testing , Humans , Female , Infant, Newborn , Infant , Child, Preschool , Child , Adolescent , Young Adult , Adult , Middle Aged , Male , Retrospective Studies , Cross-Sectional Studies , Genetic Testing/methods , Epilepsy/drug therapy , Epilepsy/genetics , Seizures/genetics
6.
J Child Neurol ; 37(4): 303-313, 2022 03.
Article in English | MEDLINE | ID: mdl-34927485

ABSTRACT

Autoimmune encephalitis is an increasingly recognized entity in children. When treated promptly, favorable outcomes are seen in a majority of pediatric patients. However, recognition of autoimmune encephalitis in young patients is challenging. Once autoimmune encephalitis is suspected, additional difficulties exist regarding timing of treatment initiation and duration of treatment, as evidence to guide management of these patients is emerging. Here, we review available literature regarding pediatric autoimmune encephalitis and present our institution's comprehensive approach to the evaluation and management of the disease. These guidelines were developed through an iterative process involving both pediatric neurologists and rheumatologists.


Subject(s)
Encephalitis , Hashimoto Disease , Child , Cognition , Encephalitis/diagnosis , Encephalitis/therapy , Hashimoto Disease/diagnosis , Hashimoto Disease/therapy , Humans , Neurologists
8.
Bioorg Med Chem Lett ; 30(20): 127428, 2020 10 15.
Article in English | MEDLINE | ID: mdl-32799032

ABSTRACT

Delafloxacin, a fourth-generation anionic fluoroquinolone (FQ) was approved in 2019 for community acquired bacterial pneumonia (CARP). It has broad spectrum activity and an improved class-related toxicity profile. However, it has recently failed a Phase 3 clinical trial for treatment of N. gonorrhoeae infections due to the lack of sufficient efficacy at the dose administered. Inspired by the microbiological and safety profile of delafloxacin, we have developed and profiled the first reported delafloxacin carbon analogue whereby a Nitrogen-for-Carbon swap has been successfully carried out at the C7 position. Not only have we shown that compounds with this modification maintain activity against N. gonorrhoeae (plus other gram-positive and gram-negative bacteria) but they also demonstrate a differentiated physicochemical profile. A zwitterionic derivative of delafloxacin was also profiled and demonstrated a superior microbiological profile against gram-negative strains, whilst maintaining favorable selected ADMET properties.


Subject(s)
Anti-Bacterial Agents/pharmacology , Bacterial Infections/drug therapy , Bacterial Infections/microbiology , Carbon/pharmacology , Fluoroquinolones/pharmacology , Neisseria gonorrhoeae/drug effects , Anti-Bacterial Agents/chemical synthesis , Anti-Bacterial Agents/chemistry , Carbon/chemistry , Dose-Response Relationship, Drug , Fluoroquinolones/chemical synthesis , Fluoroquinolones/chemistry , Humans , Microbial Sensitivity Tests , Molecular Structure , Structure-Activity Relationship
9.
PLoS One ; 15(2): e0228671, 2020.
Article in English | MEDLINE | ID: mdl-32053652

ABSTRACT

BACKGROUND: Acute flaccid myelitis (AFM) is a severe illness similar to paralytic poliomyelitis. It is unclear how frequently AFM occurred in U.S. children after poliovirus elimination. In 2014, an AFM cluster was identified in Colorado, prompting passive US surveillance that yielded 120 AFM cases of unconfirmed etiology. Subsequently, increased reports were received in 2016 and 2018. To help inform investigations on causality of the recent AFM outbreaks, our objective was to determine how frequently AFM had occurred before 2014, and if 2014 cases had different characteristics. METHODS: We conducted a retrospective study covering 2005-2014 at 5 pediatric centers in 3 U.S. regions. Possible AFM cases aged ≤18 years were identified by searching discharge ICD-9 codes and spinal cord MRI reports (>37,000). Neuroradiologists assessed MR images, and medical charts were reviewed; possible cases were classified as AFM, not AFM, or indeterminate. RESULTS: At 5 sites combined, 26 AFM cases were identified from 2005-2013 (average annual number, 3 [2.4 cases/100,000 pediatric hospitalizations]) and 18 from 2014 (12.6 cases/100,000 hospitalizations; Poisson exact p<0.0001). A cluster of 13 cases was identified in September-October 2014 (temporal scan p = 0.0001). No other temporal or seasonal trend was observed. Compared with cases from January 2005-July 2014 (n = 29), cases from August-December 2014 (n = 15) were younger (p = 0.002), more frequently had a preceding respiratory/febrile illness (p = 0.03), had only upper extremities involved (p = 0.008), and had upper extremity monoplegia (p = 0.03). The cases had higher WBC counts in cerebrospinal fluid (p = 0.013). CONCLUSION: Our data support emergence of AFM in 2014 in the United States, and those cases demonstrated distinctive features compared with preceding sporadic cases.


Subject(s)
Central Nervous System Viral Diseases/diagnosis , Central Nervous System Viral Diseases/epidemiology , Disease Outbreaks , Myelitis/diagnosis , Myelitis/epidemiology , Neuromuscular Diseases/diagnosis , Neuromuscular Diseases/epidemiology , Adolescent , Age Factors , Central Nervous System Viral Diseases/cerebrospinal fluid , Central Nervous System Viral Diseases/therapy , Child , Child, Preschool , Enterovirus D, Human , Female , Hospitalization , Hospitals, Pediatric , Humans , Infant , International Classification of Diseases , Magnetic Resonance Imaging , Male , Myelitis/cerebrospinal fluid , Myelitis/therapy , Neuromuscular Diseases/cerebrospinal fluid , Neuromuscular Diseases/therapy , Retrospective Studies , Seasons , United States
10.
Zootaxa ; 4459(3): 565-574, 2018 Aug 15.
Article in English | MEDLINE | ID: mdl-30314126

ABSTRACT

Type specimens were located in the Macleay Museum for five species described by F.L. de Castelnau: Kurtus gulliveri (syntype), Pseudoambassis macleayi (lectotype and two paralectotypes), Pseudoambassis elongatus (lectotype and paralectotype), Acanthoperca gulliveri (syntype) and Engraulis nasutus (syntypes). The last-named is shown to be a senior subjective synonym of Anchovia aestuaria Ogibly 1910, and is referred to the genus Thryssa Cuvier 1829.


Subject(s)
Fishes , Animals , Museums , Rivers
11.
Article in English | MEDLINE | ID: mdl-28223393

ABSTRACT

The novel bacterial topoisomerase inhibitor class is an investigational type of antibacterial inhibitor of DNA gyrase and topoisomerase IV that does not have cross-resistance with the quinolones. Here, we report the evaluation of the in vitro properties of a new series of this type of small molecule. Exemplar compounds selectively and potently inhibited the catalytic activities of Escherichia coli DNA gyrase and topoisomerase IV but did not block the DNA breakage-reunion step. Compounds showed broad-spectrum inhibitory activity against a wide range of Gram-positive and Gram-negative pathogens, including biodefence microorganisms and Mycobacterium tuberculosis No cross-resistance with fluoroquinolone-resistant Staphylococcus aureus and E. coli isolates was observed. Measured MIC90 values were 4 and 8 µg/ml against a panel of contemporary multidrug-resistant isolates of Acinetobacter baumannii and E. coli, respectively. In addition, representative compounds exhibited greater antibacterial potency than the quinolones against obligate anaerobic species. Spontaneous mutation rates were low, with frequencies of resistance typically <10-8 against E. coli and A. baumannii at concentrations equivalent to 4-fold the MIC. Compound-resistant E. coli mutants that were isolated following serial passage were characterized by whole-genome sequencing and carried a single Arg38Leu amino acid substitution in the GyrA subunit of DNA gyrase. Preliminary in vitro safety data indicate that the series shows a promising therapeutic index and potential for low human ether-a-go-go-related gene (hERG) inhibition (50% inhibitory concentration [IC50], >100 µM). In summary, the compounds' distinct mechanism of action relative to the fluoroquinolones, whole-cell potency, low potential for resistance development, and favorable in vitro safety profile warrant their continued investigation as potential broad-spectrum antibacterial agents.


Subject(s)
Acinetobacter baumannii/drug effects , Anti-Bacterial Agents/pharmacology , DNA Topoisomerase IV/antagonists & inhibitors , Escherichia coli/drug effects , Mycobacterium tuberculosis/drug effects , Staphylococcus aureus/drug effects , Topoisomerase II Inhibitors/pharmacology , Ciprofloxacin/pharmacology , Drug Resistance, Multiple, Bacterial/drug effects , Humans , Microbial Sensitivity Tests
12.
Pediatr Neurol ; 66: 76-81, 2017 01.
Article in English | MEDLINE | ID: mdl-27847180

ABSTRACT

BACKGROUND: To determine the cost and efficacy of admitting patients for intravenous dihydroergotamine treatment and to identify factors associated with a higher likelihood of response to treatment. METHODS: We performed a retrospective review of all pediatric hospitalizations from 2001 to 2010 for intravenous dihydroergotamine therapy for headache. Data were collected using the REDcap database and consisted of multiple variables, including preadmission demographics, headache duration, use of prophylactic medications, inpatient therapies including dihydroergotamine dosing, procedures, consultations, total hospital cost, and headache severity at discharge and at follow-up. RESULTS: Seventy-four percent of the 145 individuals who were hospitalized were female. Mean age was 14.9 years. Headache was described as chronic or daily in almost all patients and 28 (19%) had status migrainosus. Sixty-six percent had a first-degree relative with migraine. The average length of stay was 3.7 days, and the average cost was $7569 per hospitalization. Patients received an average of eight doses of dihydroergotamine. At the time of discharge, 63% of patients reported improvement. Follow-up information was available for 68% of the cohort at a median of 42 days after discharge, and 21 of 99 patients (21%) experienced sustained relief of headache. Response to dihydroergotamine was correlated with a lower rate of comorbid diagnoses, lumbar puncture, and outpatient neuroimaging. Response also correlated to less expensive hospitalizations with an average cost of $5379 per hospitalization versus $7105 per hospitalization without positive response. Response was also correlated with a patient receiving more doses of intravenous dihydroergotamine. CONCLUSIONS: Although intravenous dihydroergotamine is an effective abortive medication for intractable migraine, it may provide only short-term headache relief in many pediatric patients. Hospitalization is relatively costly with only modest long-term benefit, especially in patients with chronic migraine or chronic daily headache.


Subject(s)
Analgesics, Non-Narcotic/administration & dosage , Dihydroergotamine/administration & dosage , Headache Disorders/economics , Headache Disorders/therapy , Health Care Costs , Hospitalization/economics , Administration, Intravenous/economics , Adolescent , Analgesics, Non-Narcotic/economics , Child , Dihydroergotamine/economics , Female , Follow-Up Studies , Hospitals, Pediatric/economics , Humans , Inpatients/education , Male , Retrospective Studies , Severity of Illness Index , Treatment Outcome , Young Adult
13.
Orphanet J Rare Dis ; 11(1): 169, 2016 12 07.
Article in English | MEDLINE | ID: mdl-27927234

ABSTRACT

BACKGROUND: Canavan disease is a devastating autosomal recessive leukodystrophy leading to spongiform degeneration of the white matter. There is no cure or treatment for Canavan disease, and disease progression is poorly understood. RESULTS: We report a new presentation of a patient found to have Canavan disease; brain magnetic resonance imaging (MRI) revealed white matter cytotoxic edema, indicative of an acute active destructive process. We performed a comprehensive review of published cases of Canavan disease reporting brain MRI findings, and found that cytotoxic brain edema is frequently reported in early Canavan disease. CONCLUSIONS: Our results and the literature review support the notion of an acute phase in Canavan disease progression. These findings suggest that there is a window available for therapeutic intervention and support the need for early identification of patients with Canavan disease.


Subject(s)
Brain/diagnostic imaging , Brain/pathology , Canavan Disease/diagnostic imaging , Canavan Disease/pathology , Biomarkers , Humans
14.
Bioorg Med Chem Lett ; 26(17): 4179-83, 2016 09 01.
Article in English | MEDLINE | ID: mdl-27499455

ABSTRACT

There is an urgent and unmet medical need for new antibacterial drugs that tackle infections caused by multidrug-resistant (MDR) pathogens. During the course of our wider efforts to discover and exploit novel mechanism of action antibacterials, we have identified a novel series of isothiazolone based inhibitors of bacterial type II topoisomerase. Compounds from the class displayed excellent activity against both Gram-positive and Gram-negative bacteria with encouraging activity against a panel of MDR clinical Escherichia coli isolates when compared to ciprofloxacin. Representative compounds also displayed a promising in vitro safety profile.


Subject(s)
Anti-Bacterial Agents/chemistry , DNA Topoisomerases, Type II/metabolism , Thiazoles/chemistry , Thiazolidines/chemistry , Topoisomerase II Inhibitors/chemistry , Anti-Bacterial Agents/chemical synthesis , Anti-Bacterial Agents/pharmacology , Cell Survival/drug effects , DNA Topoisomerases, Type II/chemistry , Drug Evaluation, Preclinical , Drug Resistance, Multiple, Bacterial/drug effects , Escherichia coli/drug effects , Escherichia coli/genetics , Escherichia coli/isolation & purification , Gram-Negative Bacteria/drug effects , Gram-Positive Bacteria/drug effects , Hep G2 Cells , Humans , Microbial Sensitivity Tests , Mutation , Structure-Activity Relationship , Thiazoles/chemical synthesis , Thiazoles/pharmacology , Thiazolidines/chemical synthesis , Thiazolidines/pharmacology , Topoisomerase II Inhibitors/chemical synthesis , Topoisomerase II Inhibitors/pharmacology
16.
J Child Neurol ; 31(11): 1320-3, 2016 10.
Article in English | MEDLINE | ID: mdl-27306884

ABSTRACT

In 2011, the American Academy of Neurology (AAN) released guidelines for return seizure visits detailing 8 points that should be addressed during such visits. These guidelines are designed to improve routine follow-up care for epilepsy patients. The authors performed a quality improvement project aimed at increasing compliance with these guidelines after educating providers about them. The authors performed a chart review before and after an intervention which included: education regarding the guidelines, providing materials to remind providers of the guidelines, and templates to facilitate compliance. The authors reviewed charts at 2 and 6 months after the intervention. Significant improvement in documentation of 4 of the 8 measures was observed after this educational intervention. This suggests that simple educational interventions may help providers change practice and can improve compliance with new guidelines while requiring minimal time and resources to implement.


Subject(s)
Education, Medical, Continuing , Epilepsy/therapy , Guideline Adherence , Practice Guidelines as Topic , Academies and Institutes , Adolescent , Child , Child, Preschool , Female , Humans , Male , Medical Records , Neurology , Quality Improvement , United States , Young Adult
17.
Pediatr Neurol ; 55: 17-21, 2016 Feb.
Article in English | MEDLINE | ID: mdl-26621554

ABSTRACT

BACKGROUND: In 2014-2015, several regions of the United States experienced an outbreak of acute flaccid myelitis in pediatric patients. A common, unique feature was disease localization to the gray matter of the spinal cord. METHODS: We report 11 children, ages 13 months to 14 years (median 9 years), in the Intermountain West who presented with extremity weakness (n = 10) or cranial neuropathy (n = 1) of varying severity without an apparent etiology. RESULTS: All children experienced acute paralysis, and 10 had symptoms or signs that localized to the spinal cord. Maximum paralysis occurred within 4 days of onset in all patients. All had spinal gray matter lesions consistent with acute myelitis detected by magnetic resonance imaging; no single infectious cause was identified. Despite therapy with intravenous immunoglobulin, corticosteroids, or plasma exchange, nine of 10 (90%) children had motor deficits at follow-up. CONCLUSIONS: Recognition of this disorder enables clinicians to obtain appropriate imaging and laboratory testing, initiate treatment, and provide families with accurate prognostic information. In contrast to other causes of acute flaccid paralysis in childhood, most children with acute flaccid myelitis have residual neurological deficits.


Subject(s)
Cranial Nerve Diseases/diagnosis , Gray Matter/pathology , Myelitis/diagnosis , Paralysis/diagnosis , Acute Disease , Adolescent , Child , Child, Preschool , Female , Humans , Infant , Magnetic Resonance Imaging , Male , Northwestern United States
18.
Transl Pediatr ; 4(4): 260-70, 2015 Oct.
Article in English | MEDLINE | ID: mdl-26835388

ABSTRACT

West syndrome, or infantile spasms syndrome is a frequently catastrophic infantile epileptic encephalopathy with a variety of etiologies. Despite the heterogeneous nature of causes of infantile spasms, a careful diagnostic evaluation can lead to diagnosis in many patients and may guide treatment choices. Magnetic resonance imaging (MRI) brain remains the highest yield initial study in determining the etiology in infantile spasms. Treatment of infantile spasms has little class I data, but adrenocorticotropic hormone (ACTH), prednisolone and vigabatrin have the best evidence as first-line medications. Other therapies including the ketogenic diet and other anti-epileptics medications may also prove useful in the treatment of infantile spasms. In general, more studies are needed to determine the best treatment regimen for this condition. Prognosis is generally poor, with the majority of patients having some or profound neurocognitive delays. Patients without delays at diagnosis and without an identifiable etiology, if treated appropriately, have the greatest likelihood of a normal outcome.

19.
Health Promot Pract ; 14(6): 885-92, 2013 Nov.
Article in English | MEDLINE | ID: mdl-23407061

ABSTRACT

Quality improvement (QI) and evaluation are frequently considered to be alternative approaches for monitoring and assessing program implementation and impact. The emphasis on third-party evaluation, particularly associated with summative evaluation, and the grounding of evaluation in the social and behavioral science contrast with an emphasis on the integration of QI process within programs or organizations and its origins in management science and industrial engineering. Working with a major philanthropic organization in Georgia, we illustrate how a QI model is integrated with evaluation for five asthma prevention and control sites serving poor and underserved communities in rural and urban Georgia. A primary foundation of this merged model of QI and evaluation is a refocusing of the evaluation from an intimidating report card summative evaluation by external evaluators to an internally engaged program focus on developmental evaluation. The benefits of the merged model to both QI and evaluation are discussed. The use of evaluation based logic models can help anchor a QI program in evidence-based practice and provide linkage between process and outputs with the longer term distal outcomes. Merging the QI approach with evaluation has major advantages, particularly related to enhancing the funder's return on investment. We illustrate how a Plan-Do-Study-Act model of QI can (a) be integrated with evaluation based logic models, (b) help refocus emphasis from summative to developmental evaluation, (c) enhance program ownership and engagement in evaluation activities, and (d) increase the role of evaluators in providing technical assistance and support.


Subject(s)
Asthma/therapy , Disease Management , Health Behavior , Health Education/organization & administration , Quality Improvement/organization & administration , Health Promotion/organization & administration , Humans
20.
Dent Clin North Am ; 57(1): 145-61, 2013 Jan.
Article in English | MEDLINE | ID: mdl-23174615

ABSTRACT

Procedural sedation offers an effective and humane way to deliver dental care to the young, anxious child and to those with extensive treatment needs. Delivery of sedation requires thorough understanding of its indications and contraindications, patient assessment, pharmacology, monitoring, and office protocol. Safe and successful outcomes depend on a systematic approach to care, and the ability to manage unintended cardiopulmonary events.


Subject(s)
Conscious Sedation , Dental Care for Children/methods , Airway Management , Anesthesia, Dental/methods , Anesthesia, General , Child , Child, Preschool , Conscious Sedation/methods , Emergencies , Humans , Medical History Taking , Monitoring, Physiologic , Personality Assessment
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