The progressive neurometabolic disorder X-linked adrenoleukodystrophy (ALD) is caused by pathogenic variants in the
gene, which encodes the peroxisomal ATP-binding transporter for very-long-chain ...fatty acids. The clinical spectrum of ALD includes adrenal insufficiency, myelopathy, and/or leukodystrophy. A complicating factor in disease management is the absence of a genotype-phenotype correlation in ALD. Since 1999, most
(likely) pathogenic and benign variants have been reported in the
Variant Database. In 2017, following the expansion of ALD newborn screening, the database was rebuilt. To add an additional level of confidence with respect to pathogenicity, for each variant, it now also reports the number of cases identified and, where available, experimental data supporting the pathogenicity of the variant. The website also provides information on a number of ALD-related topics in several languages. Here, we provide an updated analysis of the known variants in
. The order of pathogenic variant frequency, overall clustering of disease-causing variants in exons 1-2 (transmembrane domain spanning region) and 6-9 (ATP-binding domain), and the most commonly reported pathogenic variant p.Gln472Argfs*83 in exon 5 are consistent with the initial reports of the mutation database. Novel insights include nonrandom clustering of high-density missense variant hotspots within exons 1, 2, 6, 8, and 9. Perhaps more importantly, we illustrate the importance of collaboration and utility of the database as a scientific, clinical, and ALD-community-wide resource.
Objectives
Early presentation and workup for acute infectious (IE) and autoimmune encephalitis (AE) are similar. This study aims to identify routine laboratory markers at presentation that are ...associated with IE or AE.
Methods
This was a multi‐center retrospective study at three tertiary care hospitals in New York City analyzing demographic and clinical data from patients diagnosed with definitive encephalitis based on a confirmed pathogen and/or autoantibody and established criteria for clinical syndromes.
Results
Three hundred and thirty‐three individuals with confirmed acute meningoencephalitis were included. An infectious‐nonbacterial (NB) pathogen was identified in 151/333 (45.40%), bacterial pathogen in 95/333 (28.50%), and autoantibody in 87/333 (26.10%). NB encephalitis was differentiated from AE by the presence of fever (NB 62.25%, AE 24.10%; p < 0.001), higher CSF white blood cell (WBC) (median 78 cells/μL, 8.00 cells/μL; p < 0.001), higher CSF protein (76.50 mg/dL, 40.90 mg/dL; p < 0.001), lower CSF glucose (58.00 mg/dL, 69.00 mg/dL; p < 0.001), lower serum WBC (7.80 cells/μL, 9.72 cells/μL; p < 0.050), higher erythrocyte sedimentation rate (19.50 mm/HR, 13.00 mm/HR; p < 0.05), higher C‐reactive protein (6.40 mg/L, 1.25 mg/L; p = 0.005), and lack of antinuclear antibody titers (>1:40; NB 11.54%, AE 32.73%; p < 0.001). CSF‐to‐serum WBC ratio was significantly higher in NB compared to AE (NB 11.3, AE 0.99; p < 0.001). From these findings, the association of presenting with fever, CSF WBC ≥50 cells/μL, and CSF protein ≥75 mg/dL was explored in ruling‐out AE. When all three criteria are present, an AE was found to be highly unlikely (sensitivity 92%, specificity 75%, negative predictive value 95%, and positive predictive value 64%).
Interpretations
Specific paraclinical data at initial presentation may risk stratify which patients have an IE versus AE.
Purpose of Review
Lennox-Gastaut syndrome (LGS) is an epileptic encephalopathy that is challenging to treat, with >80% of patients remaining refractory to therapy. Patient-oriented clinical outcome ...measures are essential for treatment guidance and the development of new therapies. Here, we provide a comprehensive review of outcome measures used in clinical trials targeting patients with LGS, in order to inform future studies, develop, and implement targeted patient and caregiver-relevant outcome measures.
Recent Findings
Published clinical trials that include, or specifically target, individuals with LGS are reviewed, and primary and secondary outcome measurements are examined. Outcome measures are grouped and discussed as (1) seizure-related, (2) cognitive, (3) functional, (4) quality of life, and (5) psychosocial for both the LGS patient and caregiver. In patients with LGS, seizure frequency is the most common outcome measured by clinicians, while quality of life and psychosocial effect of treatments are often most important to families.
Summary
Therefore, a disconnect exists between outcome measurements used in clinical trials and those rated important by families. Furthermore, cognitive, functional, and psychosocial outcome measures are often insufficiently sensitive for many LGS patients, and thus, using better targeted measures may result in an increased availability of treatment options.
Objective To evaluate sociodemographic and clinical factors associated with clinical outcomes in patients hospitalized with neuroinfectious diseases at three tertiary care centers in New York City. ...Methods This retrospective cohort study was conducted at three large urban tertiary care centers between January 1, 2010 and December 31, 2017. Poor clinical outcome was defined as length of hospital stay (LOS) ≥2 weeks and/or discharge to a location other than home. Sociodemographic and clinical factors were obtained from electronic medical records and descriptively analyzed. Multivariate logistic regression analysis investigated relationships between sociodemographic and clinical factors, and outcomes. Results Among 205 patients with definitive neuroinfectious diagnoses, older patients were more likely to have a LOS ≥2 weeks (odds ratio OR: 1.03; 95% confidence interval CI: 1.01-1.05) and less likely to be discharged home (OR: 0.96; 95% CI: 0.94-0.98) than younger patients. Patients with an immunocompromised state were more likely to have a LOS ≥2 weeks (OR: 2.80; 95% CI: 1.17-6.69). Additionally, patients admitted to the intensive care unit (ICU) were more likely to have a LOS ≥2 weeks (OR: 4.65; 95% CI: 2.13-10.16) and less likely to be discharged home (OR: 0.14; 95% CI: 0.06-0.34). There were no statistically significant associations between sex, race, ethnicity, English proficiency, substance use, or poverty index, and clinical outcome. Conclusions In this multicenter cohort of hospitalized neuroinfectious diseases, older age, history of immunocompromised state, and admission to the ICU were significantly associated with poor clinical outcome.
Hepatosteatosis, defined as excessive intrahepatic lipid accumulation, represents the first step of NAFLD. When combined with additional cellular stress, this benign status progresses to local and ...systemic pathological conditions such as NASH and insulin resistance. However, the molecular events directly caused by hepatic lipid build-up, in terms of its impact on liver biology and peripheral organs, remain unclear. Carnitine palmitoyltransferase 1A (CPT1A) is the rate limiting enzyme for long chain fatty acid beta-oxidation in the liver. Here we utilise hepatocyte-specific
knockout (LKO) mice to investigate the physiological consequences of abolishing hepatic long chain fatty acid metabolism.
Compared to the wild-type (WT) littermates, high fat diet (HFD)-fed LKO mice displayed more severe hepatosteatosis but were otherwise protected against diet-induced weight gain, insulin resistance, hepatic ER stress, inflammation and damage. Interestingly, increased energy expenditure was observed in LKO mice, accompanied by enhanced adipose tissue browning. RNAseq analysis revealed that the peroxisome proliferator activator alpha (PPARα)- fibroblast growth factor 21 (FGF21) axis was activated in liver of LKO mice. Importantly, antibody-mediated neutralization of FGF21 abolished the healthier metabolic phenotype and adipose browning in LKO mice, indicating that the elevation of FGF21 contributes to the improved liver pathology and adipose browning in HFD-treated LKO mice.
Liver with deficient CPT1A expression adopts a healthy steatotic status that protects against HFD-evoked liver damage and potentiates adipose browning in an FGF21-dependent manner. Inhibition of hepatic CPT1A may serve as a viable strategy for the treatment of obesity and NAFLD.
With increasing attention on the role of parenting stress on family functioning and children’s development, one area that has been neglected is how such relations differ across cultures. Although ...sometimes viewed as homogeneous, Asian countries often have markedly different belief systems. Cross-cultural studies require instruments that have been validated in different socio-cultural contexts. The widely used parenting stress index-short form (PSI-SF) has been used in several locations. However, results regarding its factorial structure have been mixed. Furthermore, there are only a few cross-cultural comparison studies. This study examined the factorial structure of an abridged version of the PSI-SF with data from Hong Kong (
N
= 258) and Thailand (
N
= 190). The results from confirmatory factor analyses indicated that, in both cultures, a three-factorial structure provides the best model fit. Furthermore, we found evidence for partial metric invariance, suggesting that the test scores can be compared directly. Tests for convergent and discriminant validity revealed that the three factors were correlated with parent general distress, authoritative, authoritarian, and permissive parenting behaviors, in both cultures. These findings suggest that the abridged PSI-SF can provide a meaningful comparison of parenting stress between Hong Kong and Thailand.
University of Houston Libraries established a new organizational structure in October 2021 and created the new Collections Strategies & Services department. This unit undertakes a more programmatic, ...collaborative approach to collections and begins to address the need for a broad, enterprise-wide document that clearly articulates its philosophy and priorities. In order to learn from other libraries and help develop collection plan or policy, an investigation about Association of Research Libraries (ARL) member institutions' collections policies was conducted. This paper detailed the methodology used to collect these policies, different types of policies and guidelines found on ARL member institutions' websites, and indications and suggestions for future policy development. The authors also called for collective efforts to build and maintain a collections policies bank for the broad library information science community to facilitate further collaboration and communication across institutions.
Optical microresonators with high quality (Q) factors are essential to a wide range of integrated photonic devices. Steady efforts have been directed towards increasing microresonator Q factors ...across a variety of platforms. With success in reducing microfabrication process-related optical loss as a limitation of Q, the ultimate attainable Q, as determined solely by the constituent microresonator material absorption, has come into focus. Here, we report measurements of the material-limited Q factors in several photonic material platforms. High-Q microresonators are fabricated from thin films of SiO
, Si
N
, Al
Ga
As, and Ta
O
. By using cavity-enhanced photothermal spectroscopy, the material-limited Q is determined. The method simultaneously measures the Kerr nonlinearity in each material and reveals how material nonlinearity and ultimate Q vary in a complementary fashion across photonic materials. Besides guiding microresonator design and material development in four material platforms, the results help establish performance limits in future photonic integrated systems.
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