PurposeTo investigate the ocular surface microbiome of patients with unilateral or asymmetric glaucoma being treated with topical ophthalmic medications in one eye and to determine whether microbial ...community changes were related to measures of ocular surface disease. MethodsV3-V4 16S rRNA sequencing was conducted on ocular surface swabs collected from both eyes of 17 subjects: 10 patients with asymmetric/unilateral glaucoma using topical glaucoma therapy on only one eye and seven age-matched, healthy controls with no history of ocular disease or eyedrop use. Samples were categorized into three groups: patients' glaucomatous eye treated with eyedrops, patients' contralateral eye without eyedrops, and healthy control eyes. Comparisons were made for microbial diversity and composition, with differences in composition tested for association with ocular surface disease measures including tear meniscus height, tear break-up time, and Dry Eye Questionnaire. ResultsSamples obtained from the patients' treated and untreated eyes both had significantly greater alpha-diversity and relative abundance of gram-negative organisms compared to healthy controls. The microbial composition of patient eyes was associated with decreased tear meniscus height and tear break-up time, whereas metagenomic predictions, based on 16S rRNA data, suggested increased synthesis of lipopolysaccharide. ConclusionsThe ocular surface microbiome of patients taking unilateral preserved glaucoma drops is characterized by a highly diverse array of gram-negative bacteria that is significantly different from the predominantly gram-positive microbes detected on healthy control eyes. These compositional differences were associated with decreased tear film measures and distinct inferred protein synthesis pathways, suggesting a potential link between microbial alterations and ocular surface inflammation.
Pathogenic variants in the GAP activity towards RAGs 1 (GATOR1) complex genes (DEPDC5, NPRL2, NPRL3) cause focal epilepsy through hyperactivation of the mechanistic target of rapamycin pathway. We ...report our experience using everolimus in patients with refractory GATOR1-related epilepsy.
We performed an open-label observational study of everolimus for drug-resistant epilepsy caused by variants in DEPDC5, NPRL2 and NPRL3. Everolimus was titrated to a target serum concentration (5-15ng/mL). The primary outcome measure was change in mean monthly seizure frequency compared with baseline.
Five patients were treated with everolimus. All had highly active (median baseline seizure frequency, 18/month) and refractory focal epilepsy (failed 5-16 prior anti-seizure medications). Four had DEPDC5 variants (three loss-of-function, one missense) and one had a NPRL3 splice-site variant. All patients with DEPDC5 loss-of-function variants had significantly reduced seizures (74.3-86.1%), although one stopped everolimus after 12 months due to psychiatric symptoms. Everolimus was less effective in the patient with a DEPDC5 missense variant (43.9% seizure frequency reduction). The patient with NPRL3-related epilepsy had seizure worsening. The most common adverse event was stomatitis.
Our study provides the first human data on the potential benefit of everolimus precision therapy for epilepsy caused by DEPDC5 loss-of-function variants. Further studies are needed to support our findings.
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BFBNIB, FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SAZU, SBCE, SBMB, UL, UM, UPUK
To explore the phenotypic spectrum of
-related disorders and specifically to determine whether patients fulfill criteria for alternating hemiplegia of childhood (AHC), we report the clinical features ...of 11 affected individuals.
Individuals with
-related disorders were identified through a movement disorder clinic at a specialist pediatric center, with additional cases identified through collaboration with other centers internationally. Clinical data were acquired through retrospective case-note review.
Eleven affected patients were identified. All had heterozygous missense variants involving exon 9 of
, confirmed as de novo in 9 cases. All had a complex motor phenotype, including at least 2 different kinds of movement disorder, e.g., ataxia and dystonia. Many patients demonstrated several features fulfilling the criteria for AHC: 10 patients had a movement disorder including paroxysmal elements, and 8 experienced hemiplegic episodes. In contrast to classic AHC, commonly caused by mutations in
, these events were reported later only in
mutation-positive patients from 20 months of age. Seven patients had epilepsy, but of these, 4 patients achieved seizure freedom. All patients had intellectual disability, usually moderate to severe. Other features include episodes of marked skin color change and gastrointestinal symptoms, each in 4 patients.
Although heterozygous
mutations were originally described in early infantile epileptic encephalopathy type 64, our study confirms that they account for a more expansive clinical phenotype, including a complex polymorphic movement disorder with paroxysmal elements resembling AHC.
testing should therefore be considered in patients with an AHC-like phenotype, particularly those negative for
mutations.
The stellate ganglion block (SGB) procedure has been used successfully for over twelve years to treat thousands of patients suffering from posttraumatic stress disorder (PTSD). Level 1b evidence ...supports this use of SGB, but no studies to date have reported specifically on anxiety symptom improvements following SGB. We collected Generalized Anxiety Disorder questionnaire (GAD-7) scores pre-procedure and at 1-week and 1-month post-procedure from 285 patients. The mean baseline GAD-7 score of 15.9 (indicating severe anxiety) declined significantly following SGB treatment. Changes in GAD-7 scores ≥ 4 were considered clinically meaningful. From baseline to 1 week, the GAD-7 scores dropped by 9.0 points (95% CI = 8.3-9.7,
< 0.001, d = 1.8), with 211 (79.6%) patients demonstrating clinically meaningful improvement. Furthermore, from baseline to 1 month, the GAD-7 scores dropped by 8.3 points (95% CI = 7.6-9.0,
< 0.001, d = 1.7), with 200 (75.5%) patients demonstrating clinically meaningful improvement. The stellate ganglion block treatment resulted in a decrease of GAD-7 scores of over twice the minimal clinically important difference in treating anxiety for at least 1 month following SGB. Given the results from this retrospective observational study, larger prospective studies should be conducted to determine the effects of SGB treatment as a novel therapeutic treatment for generalized anxiety disorder and other anxiety disorders.
Our objective was to establish the rate of neurological involvement in Shiga toxin-producing
Escherichia coli
–hemolytic uremic syndrome (STEC-HUS) and describe the clinical presentation, management ...and outcome. A retrospective chart review of children aged ≤ 16 years with STEC-HUS in Children’s Health Ireland from 2005 to 2018 was conducted. Laboratory confirmation of STEC infection was required for inclusion. Neurological involvement was defined as encephalopathy, focal neurological deficit, and/or seizure activity. Data on clinical presentation, management, and outcome were collected. We identified 240 children with HUS; 202 had confirmed STEC infection. Neurological involvement occurred in 22 (11%). The most common presentation was seizures (73%). In the
neurological group
, 19 (86%) were treated with plasma exchange and/or eculizumab. Of the 21 surviving children with neurological involvement, 19 (91%) achieved a complete neurological recovery. A higher proportion of children in the
neurological group
had renal sequelae (27% vs. 12%,
P
= .031). One patient died from multi-organ failure.
Conclusion
: We have identified the rate of neurological involvement in a large cohort of children with STEC-HUS as 11%. Neurological involvement in STEC-HUS is associated with good long-term outcome (complete neurological recovery in 91%) and a low case-fatality rate (4.5%) in our cohort.
What is Known:
• HUS is associated with neurological involvement in up to 30% of cases.
• Neurological involvement has been reported as predictor of poor outcome, with associated increased morbidity and mortality.
What is New:
• The incidence of neurological involvement in STEC-HUS is 11%.
• Neurological involvement is associated with predominantly good long-term outcome (90%) and a reduced case-fatality rate (4.5%) compared to older reports.
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DOBA, EMUNI, FIS, FZAB, GEOZS, GIS, IJS, IMTLJ, IZUM, KILJ, KISLJ, MFDPS, NLZOH, NUK, OILJ, PILJ, PNG, SAZU, SBCE, SBJE, SBMB, SBNM, SIK, UILJ, UKNU, UL, UM, UPUK, VKSCE, VSZLJ, ZAGLJ
Abstract
Background
There is widespread agreement that the integration of cessation services in lung cancer screening (LCS) is essential for achieving the full benefits of LCS with low-dose computed ...tomography (LDCT). There is a formidable knowledge gap about how to best design feasible, effective, and scalable cessation services in LCS facilities. A collective of NCI-funded clinical trials addressing this gap is the Smoking Cessation at Lung Examination (SCALE) Collaboration.
Methods
The Cessation and Screening to Save Lives (CASTL) trial seeks to advance knowledge about the reach, effectiveness, and implementation of tobacco treatment in lung cancer screening. We describe the rationale, design, evaluation plan, and interventions tested in this multiphase optimization strategy trial (MOST). A total of 1152 screening-eligible current smokers are being recruited from 18 LCS sites (
n
= 64/site) in both academic and community settings across the USA. Participants receive enhanced standard care (cessation advice and referral to the national Quitline) and are randomized to receive additional tobacco treatment components (motivational counseling, nicotine replacement patches/lozenges, message framing). The primary outcome is biochemically validated, abstinence at 6 months follow-up. Secondary outcomes are self-reported smoking abstinence, quit attempts, and smoking reduction at 3 and 6 months. Guided by the Implementation Outcomes Framework (IOF), our evaluation includes measurement of implementation processes (reach, fidelity, acceptability, appropriateness, sustainability, and cost).
Conclusion
We will identify effective treatment components for delivery by LCS sites. The findings will guide the assembly of an optimized smoking cessation package that achieves superior cessation outcomes. Future trials can examine the strategies for wider implementation of tobacco treatment in LDCT-LCS sites.
Trial registration
ClinicalTrials.gov
NCT03315910
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IZUM, KILJ, NUK, PILJ, PNG, SAZU, UL, UM, UPUK
Raman spectroscopy is a powerful non-destructive technique for the identification and characterization of plastics, but a major shortcoming of this technique is that environmental weathering, dyes, ...and additives in the material can generate a strong fluorescence background that overwhelms the Raman scattering. Here, we demonstrate that time-gated Raman spectroscopy can be used to successfully reduce the fluorescence signal and measure Raman spectra of recovered plastics. Time-gating removes a significant amount of background signal from the Raman spectra such that the polymers and color additives can be identified using similar measurement times compared to continuous-wave Raman spectroscopy. Examples of this are shown for a small subset of samples recovered from Hawaiian marine environments and a nonweathered commercial plastic. Time-gated Raman spectroscopy can also be used to characterize samples that are black in color due to carbon-based additives like graphite, which can be challenging to characterize via other common vibrational spectroscopic techniques.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
Movement disorders are increasingly identified in infantile encephalopathies due to single gene disorders (e.g. SCN2A, CDKL5, ARX). The associated movement disorder can be challenging to recognise ...and treat. We report a 2 year-old boy with a background history of Ohtahara syndrome due to a missense variant in ARX (the aristaless-related homeobox gene) who subsequently developed status dystonicus. ARX is a transcription factor that plays a critical role in cortical neuronal development and is associated with a range of important neurodevelopmental disorders depending on the site of the pathogenic variant. Cases of status dystonicus are described with variants affecting the polyalanine expansion region of ARX but have not been reported previously with variants affecting the aristaless domain of ARX as in this case. Dystonic episodes posed a challenge in recognition and treatment, including confusion with status epilepticus. We discuss the difficulties in diagnosis and management of status dystonicus, an underreported life-threatening emergency in children.
•Variants in ARX are an important cause of severe early-onset epilepsy, developmental delay and dystonia.•We report status dystonicus in male with Ohtahara syndrome due to a missense variant in ARX, expanding the genotype-phenotype.•Status dytonicus is a “medical emergency”, requiring early recognition, supportive and dystonia-specific treatments.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UL, UM, UPCLJ, UPUK, ZRSKP
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