Biomarkers in autism Goldani, Andre A S; Downs, Susan R; Widjaja, Felicia ...
Frontiers in psychiatry,
08/2014, Letnik:
5
Journal Article
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Autism spectrum disorders (ASDs) are complex, heterogeneous disorders caused by an interaction between genetic vulnerability and environmental factors. In an effort to better target the underlying ...roots of ASD for diagnosis and treatment, efforts to identify reliable biomarkers in genetics, neuroimaging, gene expression, and measures of the body's metabolism are growing. For this article, we review the published studies of potential biomarkers in autism and conclude that while there is increasing promise of finding biomarkers that can help us target treatment, there are none with enough evidence to support routine clinical use unless medical illness is suspected. Promising biomarkers include those for mitochondrial function, oxidative stress, and immune function. Genetic clusters are also suggesting the potential for useful biomarkers.
Seven mycobacteriophages from distinct geographical locations were isolated, using
mc
155 as the host, and then purified and sequenced. All of the genomes are related to cluster A mycobacteriophages, ...BobSwaget and Lokk in subcluster A2; Fred313, KADY, Stagni, and StepMih in subcluster A3; and MyraDee in subcluster A18, the first phage to be assigned to that subcluster.
Uptake of treat-to-target (TTT) strategies for rheumatoid arthritis (RA) management is low. Our objective was to understand the heterogeneity in patients' conceptualisation of RA treatment to inform ...interventions improving TTT uptake.
Eligible participants recruited from an online research registry rated 56 items (on 5-point scales) reflecting concepts raised from patient interviews. Using items describing adhering to physician recommendations to create a binary criterion variable for medication adherence, we conducted a principal components analysis on the remaining items using Varimax rotation, describing how these factors predict adherence over and above demographic characteristics. We further use optimal sets in regression to identify the individual concepts that are most predictive of medication adherence.
We found significant heterogeneity in patients' conceptualisation of RA treatment among 621 persons with RA. A scree plot revealed a four-factor solution explained 38.4% of the variance. The four factors expected to facilitate TTT uptake were (% variance explained): (1) Access to high quality care and support (11.3%); (2) low decisional conflict related to changing disease-modifying antirheumatic drugs (DMARDs) (10.1%); (3) endorsement of a favourable DMARD risk/benefit ratio (9.9%); and (4) confidence that testing reflects disease activity (7.2%). These factors account for 13.8% of the variance in full medication adherence, fully explaining the only significant demographic predictor, age of the patient. The individual items most predictive of poor adherence centre on the lack of effective patient-physician communication, specifically insufficient access to information from rheumatologists, along with the need to seek information elsewhere.
Patients' conceptualisation of RA treatment varies; however, almost all patients have difficulty escalating DMARDs, even with access to quality information and an understanding of the benefits of TTT. Tailored interventions are needed to address patient hesitancy to escalate DMARDs.
Familial dysautonomia (FD) is an autosomal recessive neurodegenerative disease that affects the development and survival of sensory and autonomic neurons. FD is caused by an mRNA splicing mutation in ...intron 20 of the IKBKAP gene that results in a tissue-specific skipping of exon 20 and a corresponding reduction of the inhibitor of kappaB kinase complex-associated protein (IKAP), also known as Elongator complex protein 1. To date, several promising therapeutic candidates for FD have been identified that target the underlying mRNA splicing defect, and increase functional IKAP protein. Despite these remarkable advances in drug discovery for FD, we lacked a phenotypic mouse model in which we could manipulate IKBKAP mRNA splicing to evaluate potential efficacy. We have, therefore, engineered a new mouse model that, for the first time, will permit to evaluate the phenotypic effects of splicing modulators and provide a crucial platform for preclinical testing of new therapies. This new mouse model, TgFD9; Ikbkap(Δ20/flox) was created by introducing the complete human IKBKAP transgene with the major FD splice mutation (TgFD9) into a mouse that expresses extremely low levels of endogenous Ikbkap (Ikbkap(Δ20/flox)). The TgFD9; Ikbkap(Δ20/flox) mouse recapitulates many phenotypic features of the human disease, including reduced growth rate, reduced number of fungiform papillae, spinal abnormalities, and sensory and sympathetic impairments, and recreates the same tissue-specific mis-splicing defect seen in FD patients. This is the first mouse model that can be used to evaluate in vivo the therapeutic effect of increasing IKAP levels by correcting the underlying FD splicing defect.
The terminology for human papillomavirus(HPV)–associated squamous lesions of the lower anogenital tract has a long history marked by disparate diagnostic terms derived from multiple specialties. It ...often does not reflect current knowledge of HPV biology and pathogenesis. A consensus process was convened to recommend terminology unified across lower anogenital sites. The goal was to create a histopathologic nomenclature system that reflects current knowledge of HPV biology, optimally uses available biomarkers, and facilitates clear communication across different medical specialties. The Lower Anogenital Squamous Terminology (LAST) Project was co-sponsored by the College of American Pathologists and the American Society for Colposcopy and Cervical Pathology and included 5 working groups; 3 work groups performed comprehensive literature reviews and developed draft recommendations. Another work group provided the historical background and the fifth will continue to foster implementation of the LAST recommendations. After an open comment period, the draft recommendations were presented at a consensus conference attended by LAST work group members, advisors, and representatives from 35 stakeholder organizations including professional societies and government agencies. Recommendations were finalized and voted on at the consensus meeting. The final, approved recommendations standardize biologically relevant histopathologic terminology for HPV-associated squamous intraepithelial lesions and superficially invasive squamous carcinomas across all lower anogenital tract sites and detail the appropriate use of specific biomarkers to clarify histologic interpretations and enhance diagnostic accuracy. A plan for disseminating and monitoring recommendation implementation in the practicing community was also developed. The implemented recommendations will facilitate communication between pathologists and their clinical colleagues and improve accuracy of histologic diagnosis with the ultimate goal of providing optimal patient care.
Objective
Despite proven benefits, less than half of patients with rheumatoid arthritis (RA) are treated using a treat‐to‐target (TTT) strategy. Our objective was to identify critical discrepancies ...between rheumatologist and patient mental models related to the treatment of RA to inform interventions designed to increase implementation of TTT.
Methods
We developed rheumatologist and patient mental models using the Mental Models Approach to Risk Communication. We conducted semistructured interviews to elicit views related to RA treatment decisions with 14 rheumatologists and 30 patients with RA. We also included responses (n = 284) to an open‐ended question on a survey fielded to augment qualitative descriptions from the interviews. Interviews were transcribed and coded independently by two members of the research team.
Results
Rheumatologist and patient mental models for RA treatment are significantly more complex than the TTT model. Both consider domains (system factors and patient readiness) outside of disease activity measurement, target setting, and risk versus benefit assessment in their decision‐making. Furthermore, specific factors were found to be unique to each model. For example, the physician model stresses the importance of evaluating disease activity over time and patient adherence. In contrast, patients discussed the impact of chronic disease weariness, medication‐related fatigue, the importance of feeling adequately informed, and stress associated with changing medications.
Conclusion
We found several discrepancies primarily related to information gaps and differences in how patients and physicians value trade‐offs that can serve as specific targets to improve patient–physician communication and ultimately inform interventions to improve uptake of TTT.
The optimal first-line mode of noninvasive respiratory support following extubation of critically ill children is not known.
To evaluate the noninferiority of high-flow nasal cannula (HFNC) therapy ...as the first-line mode of noninvasive respiratory support following extubation, compared with continuous positive airway pressure (CPAP), on time to liberation from respiratory support.
This was a pragmatic, multicenter, randomized, noninferiority trial conducted at 22 pediatric intensive care units in the United Kingdom. Six hundred children aged 0 to 15 years clinically assessed to require noninvasive respiratory support within 72 hours of extubation were recruited between August 8, 2019, and May 18, 2020, with last follow-up completed on November 22, 2020.
Patients were randomized 1:1 to start either HFNC at a flow rate based on patient weight (n = 299) or CPAP of 7 to 8 cm H2O (n = 301).
The primary outcome was time from randomization to liberation from respiratory support, defined as the start of a 48-hour period during which the child was free from all forms of respiratory support (invasive or noninvasive), assessed against a noninferiority margin of an adjusted hazard ratio (HR) of 0.75. There were 6 secondary outcomes, including mortality at day 180 and reintubation within 48 hours.
Of the 600 children who were randomized, 553 children (HFNC, 281; CPAP, 272) were included in the primary analysis (median age, 3 months; 241 girls 44%). HFNC failed to meet noninferiority, with a median time to liberation of 50.5 hours (95% CI, 43.0-67.9) vs 42.9 hours (95% CI, 30.5-48.2) for CPAP (adjusted HR, 0.83; 1-sided 97.5% CI, 0.70-∞). Similar results were seen across prespecified subgroups. Of the 6 prespecified secondary outcomes, 5 showed no significant difference, including the rate of reintubation within 48 hours (13.3% for HFNC vs 11.5 % for CPAP). Mortality at day 180 was significantly higher for HFNC (5.6% vs 2.4% for CPAP; adjusted odds ratio, 3.07 95% CI, 1.1-8.8). The most common adverse events were abdominal distension (HFNC: 8/281 2.8% vs CPAP: 7/272 2.6%) and nasal/facial trauma (HFNC: 14/281 5.0% vs CPAP: 15/272 5.5%).
Among critically ill children requiring noninvasive respiratory support following extubation, HFNC compared with CPAP following extubation failed to meet the criterion for noninferiority for time to liberation from respiratory support.
isrctn.org Identifier: ISRCTN60048867.
To evaluate the association of subretinal hyperreflective material (SHRM) with visual acuity (VA), geographic atrophy (GA), and scar in the Comparison of Age-Related Macular Degeneration Treatments ...Trials (CATT).
Prospective cohort study within a randomized clinical trial.
The 1185 CATT participants.
Masked readers graded scar and GA on fundus photography and fluorescein angiography and graded SHRM on time-domain and spectral-domain (SD) optical coherence tomography (OCT) throughout 104 weeks. Measurements of SHRM height and width in the fovea, within the center 1 mm(2), or outside the center 1mm(2) were obtained on SD OCT images at 56 (n = 76) and 104 (n = 66) weeks.
Presence of SHRM, as well as location and size, and associations with VA, scar, and GA.
Among CATT participants, the percentage with SHRM at enrollment was 77%, decreasing to 68% at 4 weeks after treatment and to 54% at 104 weeks. At 104 weeks, scar was present more often in eyes with persistent SHRM than in eyes with SHRM that resolved (64% vs. 31%; P < 0.0001). Among eyes with detailed evaluation of SHRM at weeks 56 (n = 76) and 104 (n = 66), mean VA letter score was 73.5 (standard error SE, 2.8), 73.1 (SE, 3.4), 65.3 (SE, 3.5), and 63.9 (SE, 3.7) when SHRM was absent, present outside the central 1 mm(2), present within the central 1 mm(2) but not the foveal center, or present at the foveal center (P = 0.02), respectively. When SHRM was present, the median maximum height under the fovea, within the central 1 mm(2) including the fovea and anywhere within the scan, was 86 μm, 120 μm, and 122 μm, respectively. Visual acuity was decreased with greater SHRM height and width (P < 0.05).
In eyes with neovascular age-related macular degeneration (AMD), SHRM is common and often persists after anti-vascular endothelial growth factor treatment. At 2 years, eyes with scar were more likely to have SHRM than other eyes. Greater SHRM dimensions were associated with worse VA. In eyes with neovascular AMD, SHRM is an important morphologic biomarker.
Contrast-induced acute kidney injury (CI-AKI) is associated with increased morbidity and mortality after percutaneous coronary interventions and is a patient safety objective of the National Quality ...Forum. However, no formal quality improvement program to prevent CI-AKI has been conducted. Therefore, we sought to determine whether a 6-year regional multicenter quality improvement intervention could reduce CI-AKI after percutaneous coronary interventions.
We conducted a prospective multicenter quality improvement study to prevent CI-AKI (serum creatinine increase ≥0.3 mg/dL within 48 hours or ≥50% during hospitalization) among 21 067 nonemergent patients undergoing percutaneous coronary interventions at 10 hospitals between 2007 and 2012. Six intervention hospitals participated in the quality improvement intervention. Two hospitals with significantly lower baseline rates of CI-AKI, which served as benchmark sites and were used to develop the intervention, and 2 hospitals not receiving the intervention were used as controls. Using time series analysis and multilevel poisson regression clustering to the hospital level, we calculated adjusted risk ratios for CI-AKI comparing the intervention period to baseline. Adjusted rates of CI-AKI were significantly reduced in hospitals receiving the intervention by 21% (risk ratio, 0.79; 95% confidence interval: 0.67-0.93; P=0.005) for all patients and by 28% in patients with baseline estimated glomerular filtration rate <60 mL/min per 1.73 m(2) (risk ratio, 0.72; 95% confidence interval: 0.56-0.91; P=0.007). Benchmark hospitals had no significant changes in CI-AKI. Key qualitative system factors associated with improvement included multidisciplinary teams, limiting contrast volume, standardized fluid orders, intravenous fluid bolus, and patient education about oral hydration.
Simple cost-effective quality improvement interventions can prevent ≤1 in 5 CI-AKI events in patients with undergoing nonemergent percutaneous coronary interventions.
Combination therapy with alendronate and estrogen for 2 years increases bone mineral density at the spine and hip more than does therapy with either agent alone. Changes in bone mineral density after ...discontinuation of therapy have not been compared directly.
To determine the rate of bone loss when therapy with alendronate, estrogen, or both agents is discontinued.
Double-blind, placebo-controlled discontinuation trial.
18 U.S. centers.
244 postmenopausal, hysterectomized women 44 to 77 years of age.
2 years of therapy with alendronate, 10 mg/d (n = 92); conjugated estrogen, 0.625 mg/d (n = 143); alendronate and conjugated estrogen (n = 140); or placebo (n = 50). At year 3, women were allocated into five groups: Twenty-eight women continued to take placebo and 44 women continued to take combination therapy, but 50 women taking alendronate, 81 taking conjugated estrogen, and 41 taking combination therapy were switched to placebo.
Bone mineral density and biochemical markers of bone turnover.
Women taking alendronate or combination therapy who were switched to placebo for year 3 of the study maintained bone mass. Bone mineral density in these women was 4.1% (CI, 2.6% to 5.7%) and 6.6% (CI, 5.0% to 8.2%) higher, respectively, at the spine (P < 0.001 for both treatment comparisons) and 3.5% (CI, 2.3% to 4.6%) and 3.0% (CI, 1.8% to 4.2%) higher, respectively, at the trochanter (P < 0.001 for both treatment comparisons) than that in women previously taking estrogen who were switched to placebo. In contrast, women who were taking estrogen and were switched to placebo during year 3 experienced a 4.5% decrease at the spine (95% CI, -5.0% to -4.0%) and a 2.4% decrease at the trochanter (CI, -2.7% to -2.1%) (P < 0.001 for both changes). Compared with women who took placebo for 3 years, women who took estrogen for 2 years and were then switched to placebo had a bone mineral density that was 2.9% higher (CI, 1.2% to 4.6%) at the spine (P < 0.05) and 2.9% higher (CI, 1.6% to 4.2%) at the trochanter (P < 0.001). Changes in biochemical markers during year 3 did not differ among the groups that discontinued active treatment.
Accelerated bone loss is seen after withdrawal of estrogen therapy but not after withdrawal of alendronate or combination therapy. The differential effects after withdrawal of therapy should be considered in the management of postmenopausal osteoporosis.