Paradigm lost: milton connects kinesin heavy chain to miro on mitochondria

The kinesin motor typically binds to cargo through its light chains. In this issue Glater et al. (p. 545) demonstrate a new type of linkage through the adapter protein, milton, and the mitochondrial membrane GTPase, miro. This is an important result because it represents a new mechanism of cargo binding and because miro's ability to bind GTP and calcium suggests that it is involved in the regulation of mitochondrial transport

Prevalence of Polypharmacy and associated adverse Outcomes and Risk Factors among Children With asthma in the Usa: a Cross-Sectional Study

OBJECTIVE: to estimate the prevalence of polypharmacy, identify risk factors and examine related adverse outcomes in the US children with asthma. DESIGN, SETTING AND PARTICIPANTS: This population-based, cross-sectional study included 1776 children with asthma from the 2011-2020 National Health and Nutrition Examination Surveys. EXPOSURES: Polypharmacy is defined as taking ≥2 medications concurrently for ≥1 day over the past 30 days. MAIN OUTCOMES AND MEASURES: (1) Weighted prevalence estimates of polypharmacy in children with asthma; (2) asthma attacks and emergency department (ED) visits. RESULTS: The estimated prevalence of polypharmacy in the US children with asthma was 33.49% (95% CI 31.81% to 35.17%). 15.53% (95% CI 14.31% to 16.75%), 12.63% (95% CI 11.37% to 13.88%) and 5.33% (95% CI) of participants were taking 2, 3-4, and 5 prescription medications, respectively. In addition to asthma medications, the most common sources of polypharmacy included antihistamines (20.17%, 95% CI 16.07% to 24.28%), glucocorticoids (16.67%, 95% 12.57% to 20.78%), and anti-infectives (14.28%, 95% CI 10.29 to 18.28). Risk factors for the increased number of medications included age 5-11 years old (vs 1-4 years: adjusted incidence rate ratio (aIRR) 1.38, 95% CI 1.10 to 1.72), fair-to-poor health (vs excellent or very good: aIRR 1.42, 95% CI 1.05 to 1.92), or ≥6 healthcare utilisation encounters over the last year (vs 0-5 encounters: aIRR 1.45, 95% CI 1.26 to 1.66). Polypharmacy increased the odds of an asthma attack (adjusted OR (aOR) 2.80, 95% CI 1.99 to 3.93) and ED visit (aOR 2.41, 95%1.59-3.63) after adjusting for demographics, insurance and health status. CONCLUSIONS: Every one in three US children with asthma experienced polypharmacy. Although it may reflect the treatment guidelines that various asthma medications are needed for maintenance therapy, our results suggested that polypharmacy increased the odds of asthma attacks or ED visits. This may be due to the concurrent use with other non-asthma medications indicating that there is an opportunity to improve medication management in children with asthma

Adverse Drug Events Related to Common asthma Medications in Us Hospitalized Children, 2000-2016

BACKGROUND: The reduction in adverse drug events is a priority in healthcare. Medications are frequently prescribed for asthmatic children, but epidemiological trends of adverse drug events related to anti-asthmatic medications have not been described in hospitalized children. OBJECTIVE: The objective of this study was to report incidence trends, risk factors, and healthcare utilization of adverse drug events related to anti-asthmatic medications by major drug classes in hospitalized children in the USA from 2000 to 2016. METHODS: A population-based temporal analysis included those aged 0-20 years who were hospitalized with asthma from the 2000 to 2016 Kids Inpatient Database. Age-stratified weighted temporal trends of the inpatient incidence of adverse drug events related to anti-asthmatic medications (i.e., corticosteroids and bronchodilators) were estimated. Stepwise multivariate logistic regression models generated risk factors for adverse drug events. RESULTS: From 2000 to 2016, 12,640 out of 698,501 pediatric asthma discharges (1.7%) were associated with adverse drug events from anti-asthmatic medications. 0.83% were adverse drug events from corticosteroids, resulting in a 1.14-fold increase in the length of stay (days) and a 1.42-fold increase in hospitalization charges (dollars). The overall incidence (per 1000 discharges) of anti-asthmatic medication adverse drug events increased from 5.3 (95% confidence interval [CI] 4.6-6.1) in 2000 to 21.6 (95% CI 18.7-24.6) in 2016 (p-trend = 0.024). Children aged 0-4 years had the most dramatic increase in the incidence of bronchodilator adverse drug events from 0.2 (95% CI 0.1-0.4) to 19.3 (95% CI 15.2-23.4) [p-trend ≤ 0.001]. In general, discharges among asthmatic children with some comorbidities were associated with an approximately two to five times higher odds of adverse drug events. CONCLUSIONS: The incidence of adverse drug events from common anti-asthmatic medications quadrupled over the past decade, particularly among preschool-age children who used bronchodilators, resulting in substantial increased healthcare costs. Those asthmatic children with complex medical conditions may benefit the most from adverse drug event monitoring

Intrathecal B-cell activation in LGI1 antibody encephalitis.

ObjectiveTo study intrathecal B-cell activity in leucine-rich, glioma-inactivated 1 (LGI1) antibody encephalitis. In patients with LGI1 antibodies, the lack of CSF lymphocytosis or oligoclonal bands and serum-predominant LGI1 antibodies suggests a peripherally initiated immune response. However, it is unknown whether B cells within the CNS contribute to the ongoing pathogenesis of LGI1 antibody encephalitis.MethodsPaired CSF and peripheral blood (PB) mononuclear cells were collected from 6 patients with LGI1 antibody encephalitis and 2 patients with other neurologic diseases. Deep B-cell immune repertoire sequencing was performed on immunoglobulin heavy chain transcripts from CSF B cells and sorted PB B-cell subsets. In addition, LGI1 antibody levels were determined in CSF and PB.ResultsSerum LGI1 antibody titers were on average 127-fold higher than CSF LGI1 antibody titers. Yet, deep B-cell repertoire analysis demonstrated a restricted CSF repertoire with frequent extensive clusters of clonally related B cells connected to mature PB B cells. These clusters showed intensive mutational activity of CSF B cells, providing strong evidence for an independent CNS-based antigen-driven response in patients with LGI1 antibody encephalitis but not in controls.ConclusionsOur results demonstrate that intrathecal immunoglobulin repertoire expansion is a feature of LGI1 antibody encephalitis and suggests a need for CNS-penetrant therapies

Factors Influencing Sleep Difficulty and Sleep Quantity in the Citizen Pscientist Psoriatic Cohort.

IntroductionSleep is essential for overall health and well-being, yet more than one-third of adults report inadequate sleep. The prevalence is higher among people with psoriasis, with up to 85.4% of the psoriatic population reporting sleep disruption. Poor sleep among psoriasis patients is particularly concerning because psoriasis is independently associated with many of the same comorbidities as sleep dysfunction, including cardiovascular disease, obesity, and depression. Given the high prevalence and serious consequences of disordered sleep in psoriasis, it is vital to understand the nature of sleep disturbance in this population. This study was designed to help meet this need by using survey data from Citizen Pscientist, an online patient portal developed by the National Psoriasis Foundation.MethodsOur analysis included 3118 participants who identified as having a diagnosis by a physician of psoriasis alone or psoriasis with psoriatic arthritis. Demographic information, psoriasis severity and duration, sleep apnea status, smoking and alcohol consumption, itch timing, and sleep characteristics were included. Two separate multivariate logistic regression models in STATA were used to determine whether the presence of psoriatic arthritis, age, gender, body mass index, comorbid sleep apnea, psoriasis severity, timing of worst itch, smoking status, or high-risk alcohol consumption were associated with sleep difficulty or low sleep quantity, defined by the American Academy of Sleep Medicine as less than 7 h of sleep per night on average.ResultsResults from the multivariate logistic regressions found that sleep difficulty was associated with psoriatic arthritis (OR 2.15, 95% CI [1.79-2.58]), female gender (2.03 [1.67-2.46]), obese body mass index (BMI ≥ 30) (1.25 [1.00-1.56]), sleep apnea (1.41 [1.07-1.86]), psoriasis severity of moderate (1.59 [1.30-1.94]) or severe (2.40 [1.87-3.08]), and smoking (1.60 [1.26-2.02]). Low sleep quantity was associated with obese BMI (1.62 [1.29-2.03]), sleep apnea (1.30 [1.01-1.68]), psoriasis severity of moderate (1.41 [1.16-1.72]) or severe (1.40 [1.11-1.76]), and smoking (1.62 [1.31-2.00]). Sleep difficulty and low sleep quantity were not associated with age, alcohol consumption, or timing of worst itch.ConclusionThese results are potentially meaningful in several aspects. We identify an important distinction between sleep difficulty and sleep quantity in psoriatic disease, whereby having psoriatic arthritis and being female are each associated with sleep difficulty despite no association with low sleep quantity. Furthermore, there is conflicting evidence from prior studies as to whether psoriasis severity is associated with sleep difficulty, but this well-powered, large study revealed a strong, graded relationship between psoriasis severity and both sleep difficulty and low sleep quantity. Overall, our results show that both sleep difficulty and low sleep quantity were associated with multiple factors in this analysis of a large psoriatic cohort. These findings suggest that dermatologists may gather clinically useful information by screening psoriatic patients for trouble sleeping and low sleep quantity to identify potential comorbidities and to more effectively guide disease management

When it's at: An examination of when cognitive change occurs during cognitive therapy for compulsive checking in obsessive-compulsive disorder

Abstract Background and objectives The cognitive theory of compulsive checking in OCD proposes that checking behaviour is maintained by maladaptive beliefs, including those related to inflated responsibility and those related to reduced memory confidence. This study examined whether and when specific interventions (as part of a new cognitive therapy for compulsive checking) addressing these cognitive targets changed feelings of responsibility and memory confidence. Methods Participants were nine adults with a primary or secondary diagnosis of OCD who reported significant checking symptoms (at least one hour per day) on the Yale-Brown Obsessive-Compulsive Scale. A single-case multiple baseline design was used, after which participants received 12 sessions of cognitive therapy. From the start of the baseline period through to the 1 month post-treatment follow-up assessment session, participants completed daily monitoring of feelings of responsibility, memory confidence, and their time spent engaging in compulsive checking. Results Results revealed that feelings of responsibility significantly reduced and memory confidence significantly increased from baseline to immediately post-treatment, with very high effect sizes. Multilevel modelling revealed significant linear changes in feelings of responsibility (i.e., reductions over time) and memory confidence (i.e., increases over time) occurred following the sessions when these were addressed. Finally, we found that improvements in these over the course of the treatment significantly predicted reduced time spent checking. Limitations The small sample size limits our ability to generalize our results. Conclusions Results are discussed in terms of a focus on the timing of change in cognitive therapy

Using PCR-Based Detection and Genotyping to Trace Streptococcus salivarius Meningitis Outbreak Strain to Oral Flora of Radiology Physician Assistant

We recently investigated three cases of bacterial meningitis that were reported from a midwestern radiology clinic where facemasks were not worn during spinal injection of contrast agent during myelography procedures. Using pulsed field gel electrophoresis we linked a case strain of S. salivarius to an oral specimen of a radiology physician assistant (RPA). We also used a real-time PCR assay to detect S. salivarius DNA within a culture-negative cerebrospinal fluid (CSF) specimen. Here we extend this investigation through using a nested PCR/sequencing strategy to link the culture-negative CSF specimen to the case strain. We also provide validation of the real-time PCR assay used, demonstrating that it is not solely specific for Streptococcus salivarius, but is also highly sensitive for detection of the closely related oral species Streptococcus vestibularis. Through using multilocus sequence typing and 16S rDNA sequencing we further strengthen the link between the CSF case isolate and the RPA carriage isolate. We also demonstrate that the newly characterized strains from this study are distinct from previously characterized S. salivarius strains associated with carriage and meningitis

Temporal Retinal Nerve Fiber Loss in Patients with Spinocerebellar Ataxia Type 1

BACKGROUND: Autosomal dominant spinocerebellar ataxia type 1 is an adult onset progressive disorder with well characterized neurodegeneration in the cerebellum and brainstem. Beyond brain atrophy, few data exist concerning retinal and optic nerve involvement. OBJECTIVE: To evaluate retinal changes in SCA1 patients compared to age and gender matched healthy controls. METHODOLOGY/PRINCIPAL FINDINGS: Nine patients with SCA1 were prospectively recruited from the ataxia clinic and were compared to nine age and gender matched healthy controls. Both cohorts received assessment of visually evoked potentials and eye examination by optical coherence tomography to determine retinal nerve fiber layer thickness and total macular volume. While no differences were found in visually evoked potentials, SCA1 patients showed a significant reduction of mean retinal nerve fiber layer thickness (RNFLT) compared to healthy controls (84±13 µm vs. 97±8 µm, p = 0.004). Temporal areas showed the most prominent RNFLT reduction with high statistical significances (temporal-inferior: p<0.001, temporal: p<0.001, temporal-superior: p = 0.005) whereas RNFLT in nasal areas was in the range of the control group. From six SCA1 patients an additional macular scan was obtained. The comparison to the corresponding healthy control showed a slight but not significant reduction in TMV (8.22±0.68 mm(3) vs. 8.61±0.41 mm(3), p = 0.15). CONCLUSION: In SCA1 patients, we found evidence for degeneration of retinal nerve fibers. The temporal focus of the observed retinal nerve fiber layer reduction suggests an involvement of the papillo-macular bundle which resembles pathology found in toxic or mitochondrial optic nerve disease such as Leber's hereditary optic neuropathy (LHON) or dominant optic atrophy (DOA)

Opposite-polarity motors activate one another to trigger cargo transport in live cells

Mechanical interactions between any two opposite-polarity motors are necessary and sufficient for bidirectional organelle transport in live cells