Pervasive Sharing of Causal Genetic Risk Factors Contributes to Clinical and Molecular Overlap between Sjögren's Disease and Systemic Lupus Erythematosus.

SjD (Sjögren's Disease) and SLE (Systemic Lupus Erythematosus) are similar diseases. There is extensive overlap between the two in terms of both clinical features and pathobiologic mechanisms. Shared genetic risk is a potential explanation of this overlap. In this study, we evaluated whether these diseases share causal genetic risk factors. We compared the causal genetic risk for SLE and SjD using three complementary approaches. First, we examined the published GWAS results for these two diseases by analyzing the predicted causal gene protein-protein interaction networks of both diseases. Since this method does not account for overlapping risk intervals, we examined whether such intervals also overlap. Third, we used two-sample Mendelian randomization (two sample MR) using GWAS summary statistics to determine whether risk variants for SLE are causal for SjD and vice versa. We found that both the putative causal genes and the genomic risk intervals for SLE and SjD overlap 28- and 130-times more than expected by chance (p < 1.1 × 10-24 and p < 1.1 × 10-41, respectively). Further, two sample MR analysis confirmed that alone or in aggregate, SLE is likely causal for SjD and vice versa. [SjD variants predicting SLE: OR = 2.56; 95% CI (1.98-3.30); p < 1.4 × 10-13, inverse-variance weighted; SLE variants predicting SjD: OR = 1.36; 95% CI (1.26-1.47); p < 1.6 × 10-11, inverse-variance weighted]. Notably, some variants have disparate impact in terms of effect size across disease states. Overlapping causal genetic risk factors were found for both diseases using complementary approaches. These observations support the hypothesis that shared genetic factors drive the clinical and pathobiologic overlap between these diseases. Our study has implications for both differential diagnosis and future genetic studies of these two conditions.

Speech intelligibility loss due to amyotrophic lateral sclerosis: the effect of tongue movement reduction on vowel and consonant acoustic features.

The purpose of this study was to identify aspects of impaired tongue motor performance that limit the ability to produce distinct speech sounds and contribute to reduced speech intelligibility in individuals with dysarthria secondary to amyotrophic lateral sclerosis (ALS). We analyzed simultaneously recorded tongue kinematic and acoustic data from 22 subjects during three target words (cat, dog, and took). The subjects included 11 participants with ALS and 11 healthy controls from the X-ray microbeam dysarthria database (Westbury, 1994). Novel measures were derived based on the range and speed of relative movement between two quasi-independent regions of the tongue - blade and dorsum - to characterize the global pattern of tongue dynamics. These "whole tongue" measures, along with the range and speed of single tongue regions, were compared across words, groups (ALS vs. control), and measure types (whole tongue vs. tongue blade vs. tongue dorsum). Reduced range and speed of both global and regional tongue movements were found in participants with ALS relative to healthy controls, reflecting impaired tongue motor performance in ALS. The extent of impairment, however, varied across words and measure types. Compared with the regional tongue measures, the whole tongue measures showed more consistent disease-related changes across the target words and were more robust predictors of speech intelligibility. Furthermore, these whole tongue measures were correlated with various word-specific acoustic features associated with intelligibility decline in ALS, suggesting that impaired tongue movement likely contributes to reduced phonetic distinctiveness of both vowels and consonants that underlie speech intelligibility decline in ALS.

Effect of prosodic manipulation on articulatory kinematics and second formant trajectories in children.

This study investigated effects of rate reduction and emphatic stress cues on second formant (F2) trajectories and articulatory movements during diphthong production in 11 typically developing school-aged children. F2 extent increased in slow and emphatic stress conditions, and tongue and jaw displacement increased in the emphatic stress condition compared to habitual speech. Tongue displacement significantly predicted F2 extent across speaking conditions. Results suggest that slow rate and emphatic stress cues induce articulatory and acoustic changes in children that may enhance clarity of the acoustic signal. Potential clinical implications for improving speech in children with dysarthria are discussed.

Additional evidence for a therapeutic effect of dextromethorphan/quinidine on bulbar motor function in patients with amyotrophic lateral sclerosis: A quantitative speech analysis.

AIMS: A recent double-blind placebo-controlled crossover 70-day trial demonstrated that a fixed combination of dextromethorphan and quinidine (DM/Q) improves speech and swallowing function in most patients with amyotrophic lateral sclerosis. In this study, a subset of participants, many of whom did not substantially improve while on DM/Q, were re-evaluated using computer-based speech analyses and expert clinician ratings of the overall severity of speech impairment. METHODS: Speech samples were recorded from the subset of 10 patients at four visits made at approximately 30-day intervals. The recordings were analysed by automated computer-based analysis of speech pausing patterns. Severity of speech impairment was rated by three experienced speech-language pathologists using direct magnitude estimation. Scores on patient-reported and clinician-administered scales of bulbar motor involvement were obtained at each visit. RESULTS: The effects of DM/Q were detected on several of the objective speech measures, including total pause duration (s) (Cohen's d = 0.73, 95% confidence interval (CI) -1.70, 0.24), pause time (%) (d = 0.77, 95% CI -1.75, 0.21), and mean speech event duration (s) (d = 0.52, 95% CI -0.44, 1.47), but not on clinician ratings of speech or the speech components of the self-report or clinician-administered scales. CONCLUSIONS: These findings suggest that even patients with modest improvement while on DM/Q may experience quantifiable improvements in speech when assessed using sensitive and objective measures. This study provides additional evidence of the positive impact of DM/Q on one or more of the neural systems that control bulbar motor function and production of speech.

A model-specific role of microRNA-223 as a mediator of kidney injury during experimental sepsis.

Sepsis outcomes are heavily dependent on the development of septic organ injury, but no interventions exist to interrupt or reverse this process. microRNA-223 (miR-223) is known to be involved in both inflammatory gene regulation and host-pathogen interactions key to the pathogenesis of sepsis. The goal of this study was to determine the role of miR-223 as a mediator of septic kidney injury. Using miR-223 knockout mice and multiple models of experimental sepsis, we found that miR-223 differentially influences acute kidney injury (AKI) based on the model used. In the absence of miR-223, mice demonstrated exaggerated AKI in sterile models of sepsis (LPS injection) and attenuated AKI in a live-infection model of sepsis (cecal ligation and puncture). We demonstrated that miR-223 expression is induced in kidney homogenate after cecal ligation and puncture, but not after LPS or fecal slurry injection. We investigated additional potential mechanistic explanations including differences in peritoneal bacterial clearance and host stool virulence. Our findings highlight the complex role of miR-223 in the pathogenesis of septic kidney injury, as well as the importance of differences in experimental sepsis models and their consequent translational applicability.

Alignment of classification paradigms for communication abilities in children with cerebral palsy.

AIM: We examined three communication ability classification paradigms for children with cerebral palsy (CP): the Communication Function Classification System (CFCS), the Viking Speech Scale (VSS), and the Speech Language Profile Groups (SLPG). Questions addressed interjudge reliability, whether the VSS and the CFCS captured impairments in speech and language, and whether there were differences in speech intelligibility among levels within each classification paradigm. METHOD: Eighty children (42 males, 38 females) with a range of types and severity levels of CP participated (mean age 60mo, range 50-72mo [SD 5mo]). Two speech-language pathologists classified each child via parent-child interaction samples and previous experience with the children for the CFCS and VSS, and using quantitative speech and language assessment data for the SLPG. Intelligibility scores were obtained using standard clinical intelligibility measurement. RESULTS: Kappa values were 0.67 (95% confidence interval [CI] 0.55-0.79) for the CFCS, 0.82 (95% CI 0.72-0.92) for the VSS, and 0.95 (95% CI 0.72-0.92) for the SLPG. Descriptively, reliability within levels of each paradigm varied, with the lowest agreement occurring within the CFCS at levels II (42%), III (40%), and IV (61%). Neither the CFCS nor the VSS were sensitive to language impairments captured by the SLPG. Significant differences in speech intelligibility were found among levels for all classification paradigms. INTERPRETATION: Multiple tools are necessary to understand speech, language, and communication profiles in children with CP. Characterization of abilities at all levels of the International Classification of Functioning, Disability and Health will advance our understanding of the ways that speech, language, and communication abilities present in children with CP.

Relation of Speech-Language Profile and Communication Modality to Participation of Children With Cerebral Palsy.

PURPOSE: This study aimed to examine the contribution of speech motor impairment (SMI), language impairment, and communication modality to communicative and overall participation outcomes in school-age children with cerebral palsy (CP). METHOD: Eighty-one caregivers of children with CP provided information about their child's speech and language skills, communication modality, and participation through a web-based survey. Caregiver responses to two validated scales were used to quantify children's communicative participation and overall participation. Children were classified into four speech-language profile groups and three communication modality groups for comparison, based on caregiver-reported information regarding their child's communication skills. RESULTS: Children with CP who had co-occurring SMI and language impairment had significantly lower levels of communicative participation and involvement in activities overall, compared to children with SMI alone. Among children with SMI, augmentative and alternative communication (AAC) use was associated with greater overall frequency of participation and involvement in life activities. CONCLUSION: Children with CP who have both SMI and language impairment and those who are nonspeaking communicators should be prioritized early for communication interventions focused on maximizing participation, including consideration of AAC.

Effects of SPEAK OUT! & LOUD Crowd on Functional Speech Measures in Parkinson's Disease.

PURPOSE: This study investigated the effects of the SPEAK OUT! & LOUD Crowd therapy program on speaking rate, percent pause time, intelligibility, naturalness, and communicative participation in individuals with Parkinson's disease (PD). METHOD: Six adults with PD completed 12 individual SPEAK OUT! sessions across four consecutive weeks followed by group-based LOUD Crowd sessions for five consecutive weeks. Most therapy sessions were conducted via telehealth, with two participants completing the SPEAK OUT! portion in person. Speech samples were recorded at six time points: three baseline time points prior to SPEAK OUT!, two post-SPEAK OUT! time points, and one post-LOUD Crowd time point. Acoustic measures of speaking rate and percent pause time and listener ratings of speech intelligibility and naturalness were obtained for each time point. Participant self-ratings of communicative participation were also collected at pre- and posttreatment time points. RESULTS: Results showed significant improvement in communicative participation scores at a group level following completion of the SPEAK OUT! & LOUD Crowd treatment program. Two participants showed a significant decrease in speaking rate and increase in percent pause time following treatment. Changes in intelligibility and naturalness were not statistically significant. CONCLUSIONS: These findings provide preliminary support for the effectiveness of the SPEAK OUT! & LOUD Crowd treatment program in improving communicative participation for people with mild-to-moderate hypokinetic dysarthria secondary to PD. This study is also the first to demonstrate positive effects of this treatment program for people receiving the therapy via telehealth.

Motor Speech Phenotypes in Children With Epilepsy: Preliminary Findings.

PURPOSE: This exploratory study aimed to characterize motor speech impairments in a small sample of children with epilepsy, both with and without a known seizure etiology. A secondary aim was to evaluate the validity of the Profile for Childhood Apraxia of speech and Dysarthria (ProCAD), a newly developed tool for differential diagnosis of childhood apraxia of speech and dysarthria. METHOD: Thirteen children with seizure disorders completed a comprehensive speech and language assessment. Three expert speech-language pathologists rated the presence of auditory-perceptual features of motor speech impairment using the ProCAD. Motor speech features, diagnoses, and standardized test scores were compared between children with a known seizure etiology and children with idiopathic epilepsy. RESULTS: Nine of the 13 children exhibited motor speech impairment; dysarthria was the most common diagnosis. Most children (11/13) exhibited language impairment. Group comparisons showed that children with a known seizure etiology had more atypical motor speech features and lower language scores than children with idiopathic seizures. CONCLUSION: These preliminary findings suggest a high rate of motor speech impairment among children with epilepsy.

Inhibiting efferocytosis reverses macrophage-mediated immunosuppression in the leukemia microenvironment.

Background: Previous studies show that the spleen and bone marrow can serve as leukemia microenvironments in which macrophages play a significant role in immune evasion and chemoresistance. We hypothesized that the macrophage driven tolerogenic process of efferocytosis is a major contributor to the immunosuppressive leukemia microenvironment and that this was driven by aberrant phosphatidylserine expression from cell turnover and cell membrane dysregulation. Methods: Since MerTK is the prototypic efferocytosis receptor, we assessed whether the MerTK inhibitor MRX2843, which is currently in clinical trials, would reverse immune evasion and enhance immune-mediated clearance of leukemia cells. Results: We found that inhibition of MerTK decreased leukemia-associated macrophage expression of M2 markers PD-L1, PD-L2, Tim-3, CD163 and Arginase-1 compared to vehicle-treated controls. Additionally, MerTK inhibition led to M1 macrophage repolarization including elevated CD86 and HLA-DR expression, and increased production of T cell activating cytokines, including IFN-ß, IL-18, and IL-1ß through activation of NF-κB. Collectively, this macrophage repolarization had downstream effects on T cells within the leukemia microenvironment, including decreased PD-1+Tim-3+ and LAG3+ checkpoint expression, and increased CD69+CD107a+ expression. Discussion: These results demonstrate that MerTK inhibition using MRX2843 altered the leukemia microenvironment from tumor-permissive toward immune responsiveness to leukemia and culminated in improved immune-mediated clearance of AML.

Development of an International SMA Bulbar Assessment for Inter-professional Administration.

BACKGROUND: Progressive weakness can affect bulbar muscles in individuals with moderate to severe forms of spinal muscular atrophy (SMA). The paucity of standardized, valid bulbar assessments capturing clinically significant deficits in SMA impedes the ability to monitor function, facilitate intervention, or detect treatment response. OBJECTIVE: To fill this void, an international multidisciplinary team gathered to develop an agreed upon consensus-derived assessment of bulbar function in SMA for inter-professional administration to enhance our ability to monitor disease progression, support clinical management, and evaluate treatment effects. METHODS: Fifty-six international clinicians experienced in SMA were invited and engaged using the Delphi method over multiple rounds of web-based surveys to establish consensus. RESULTS: Serial virtual meetings occurred with 42 clinicians (21 speech and language therapists, 11 physical therapists, 5 neurologists, 4 occupational therapists, and 1 dentist). Seventy-two validated assessments of bulbar function were identified for potential relevance to individuals with SMA (32 accessible objective, 11 inaccessible objective, 29 patient-reported outcomes). Delphi survey rounds (n = 11, 15, 15) achieved consensus on individual items with relevance and wording discussed. Key aspects of bulbar function identified included: oral intake status, oral facial structure and motor strength, swallowing physiology, voice & speech, and fatigability. CONCLUSIONS: Multidisciplinary clinicians with expertise in bulbar function and SMA used Delphi methodology to reach consensus on assessments/items considered relevant for SMA across all age groups. Future steps include piloting the new scale moving towards validation/reliability. This work supports the advancement of assessing bulbar function in children and adults with SMA by a variety of professionals.

Outcomes of a clinic-based pediatric constraint-induced movement therapy program.

A single-group pre- and post-test design was used to evaluate functional outcomes of a constraint-induced movement therapy (CIMT) protocol implemented in an outpatient therapy center. The participants were 29 children with hemiplegia, ages 1.6-19.1 years old. The less-involved upper limb was placed in a cast that was worn 24 hr a day, 7 days a week. Individual therapy sessions took place 5 days/week. Children received 3 or 6 hr therapy sessions for 16-19 days followed by 2-5 days in which bimanual tasks were performed. Outcomes were assessed at baseline and following CIMT. Statistically significant gains were made on the Melbourne Assessment of Unilateral Upper Limb Function, Quality of Upper Extremity Skills Test (except the Protective Extension subtest), Assisting Hand Assessment, and the Canadian Occupational Performance Measure. The effect sizes varied from 0.46 to 0.70 indicating a moderate effect size. The results support the effectiveness of CIMT provided through a center-based program.

Use of Automated Kinematic Diadochokinesis Analysis to Identify Potential Indicators of Speech Motor Involvement in Children With Cerebral Palsy.

PURPOSE: This study examined multiple variables obtained from an automated measure of lip movement during a diadochokinesis (DDK) task to identify those with potential to detect mild speech motor involvement in school-age children diagnosed with cerebral palsy (CP). METHOD: Eight children with CP and high speech intelligibility and a matched group of eight children with typical development (TD) completed a DDK task while their lip and jaw movements were recorded. A custom MATLAB algorithm was used to automatically extract 23 kinematic measures of children's lip movements during production of the DDK sequences. Mann-Whitney U tests were used to compare groups on the kinematic measures, and receiver operating characteristic (ROC) analysis was used to evaluate the diagnostic accuracy of measures that significantly differed between groups. RESULTS: Five of the 23 kinematic variables differed significantly between the CP and TD groups. These were two measures of overall DDK performance (i.e., duration of the DDK sequence and number of cycles) and three spatial and temporal measures of lip movement. Duration of the DDK sequence and the mean displacement of the lips across cycles had the highest diagnostic accuracy, differentiating CP and TD groups with 88% sensitivity and 88% specificity. CONCLUSIONS: Automatically derived kinematic measures of DDK sequences differentiated children with CP and high intelligibility from typically developing children. Future research is needed to determine the clinical utility of these measures for detecting speech motor impairment.

Impact of the COVID-19 pandemic on therapy service delivery and functioning for school-aged children with disabilities in the United States.

BACKGROUND: The COVID-19 pandemic caused wide-scale disruptions to therapy services for children with disabilities in the United States. OBJECTIVE/HYPOTHESIS: We evaluated changes in therapy service delivery during the first four months of the pandemic, examined the impact of these changes on children's functioning, and analyzed factors predicting the loss of in-person services and receipt of teletherapy services. METHODS: We undertook an anonymous cross-sectional online survey of parents/caregivers of children with a disability aged 5-17 years. Changes in therapy service delivery and children's functioning were descriptively summarized. Logistic regressions examined individual and contextual predictors of loss of therapy services or receipt of teletherapy services. RESULTS: 402 parents of children aged 5-17 years old with one or more disabilities participated; 42% of children lost access to all therapy services, and 34% of children received at least one therapy service via telehealth. Children receiving a greater number of services pre-COVID and having access to more technological devices pre-COVID were significantly more likely to receive teletherapy. Over 40% of parents attributed declines in their child's motor, behavior, social, and communication skills to changes in therapy services; this impact was greater for children with multiple diagnoses. CONCLUSIONS: Findings underscore the negative impact of therapy service disruptions on children with disabilities.

A Tool for Differential Diagnosis of Childhood Apraxia of Speech and Dysarthria in Children: A Tutorial.

PURPOSE: While there has been mounting research centered on the diagnosis of childhood apraxia of speech (CAS), little has focused on differentiating CAS from pediatric dysarthria. Because CAS and dysarthria share overlapping speech symptoms and some children have both motor speech disorders, differential diagnosis can be challenging. There is a need for clinical tools that facilitate assessment of both CAS and dysarthria symptoms in children. The goals of this tutorial are to (a) determine confidence levels of clinicians in differentially diagnosing dysarthria and CAS and (b) provide a systematic procedure for differentiating CAS and pediatric dysarthria in children. METHOD: Evidence related to differential diagnosis of CAS and dysarthria is reviewed. Next, a web-based survey of 359 pediatric speech-language pathologists is used to determine clinical confidence levels in diagnosing CAS and dysarthria. Finally, a checklist of pediatric auditory-perceptual motor speech features is presented along with a procedure to identify CAS and dysarthria in children with suspected motor speech impairments. Case studies illustrate application of this protocol, and treatment implications for complex cases are discussed. RESULTS: The majority (60%) of clinician respondents reported low or no confidence in diagnosing dysarthria in children, and 40% reported they tend not to make this diagnosis as a result. Going forward, clinicians can use the feature checklist and protocol in this tutorial to support the differential diagnosis of CAS and dysarthria in clinical practice. CONCLUSIONS: Incorporating this diagnostic protocol into clinical practice should help increase confidence and accuracy in diagnosing motor speech disorders in children. Future research should test the sensitivity and specificity of this protocol in a large sample of children with varying speech sound disorders. Graduate programs and continuing education trainings should provide opportunities to practice rating speech features for children with dysarthria and CAS. SUPPLEMENTAL MATERIAL: https://doi.org/10.23641/asha.19709146.

Polygenic autoimmune disease risk alleles impacting B cell tolerance act in concert across shared molecular networks in mouse and in humans.

Most B cells produced in the bone marrow have some level of autoreactivity. Despite efforts of central tolerance to eliminate these cells, many escape to periphery, where in healthy individuals, they are rendered functionally non-responsive to restimulation through their antigen receptor via a process termed anergy. Broad repertoire autoreactivity may reflect the chances of generating autoreactivity by stochastic use of germline immunoglobulin gene segments or active mechanisms may select autoreactive cells during egress to the naïve peripheral B cell pool. Likewise, it is unclear why in some individuals autoreactive B cell clones become activated and drive pathophysiologic changes in autoimmune diseases. Both of these remain central questions in the study of the immune system(s). In most individuals, autoimmune diseases arise from complex interplay of genetic risk factors and environmental influences. Advances in genome sequencing and increased statistical power from large autoimmune disease cohorts has led to identification of more than 200 autoimmune disease risk loci. It has been observed that autoantibodies are detectable in the serum years to decades prior to the diagnosis of autoimmune disease. Thus, current models hold that genetic defects in the pathways that control autoreactive B cell tolerance set genetic liability thresholds across multiple autoimmune diseases. Despite the fact these seminal concepts were developed in animal (especially murine) models of autoimmune disease, some perceive a disconnect between human risk alleles and those identified in murine models of autoimmune disease. Here, we synthesize the current state of the art in our understanding of human risk alleles in two prototypical autoimmune diseases - systemic lupus erythematosus (SLE) and type 1 diabetes (T1D) along with spontaneous murine disease models. We compare these risk networks to those reported in murine models of these diseases, focusing on pathways relevant to anergy and central tolerance. We highlight some differences between murine and human environmental and genetic factors that may impact autoimmune disease development and expression and may, in turn, explain some of this discrepancy. Finally, we show that there is substantial overlap between the molecular networks that define these disease states across species. Our synthesis and analysis of the current state of the field are consistent with the idea that the same molecular networks are perturbed in murine and human autoimmune disease. Based on these analyses, we anticipate that murine autoimmune disease models will continue to yield novel insights into how best to diagnose, prognose, prevent and treat human autoimmune diseases.

Reliability of Perceptual Judgments of Phonetic Accuracy and Hypernasality Among Speech-Language Pathologists for Children With Dysarthria.

Purpose The objectives of this study were to: (a) compare interrater reliability of practicing speech-language pathologists' (SLPs) perceptual judgments of phonetic accuracy and hypernasality between children with dysarthria and those with typical development, and (b) to identify speech factors that influence reliability of these perceptual judgments for children with dysarthria. Method Ten SLPs provided ratings of speech samples from twenty 5-year-old children with dysarthria and twenty 5-year-old children with typical development on two tasks via a web-based platform: a hypernasality judgment task and a phonetic accuracy judgment task. Interrater reliability of SLPs' ratings on both tasks was compared between children with dysarthria and children with typical development. For children with dysarthria, four acoustic speech measures, intelligibility, and a measure of phonetic accuracy (percent stops correct) were examined as predictors of reliability of SLPs' perceptual judgments. Results Reliability of SLPs' phonetic accuracy judgments and hypernasality ratings was significantly lower for children with dysarthria than for children with typical development. Among children with dysarthria, interrater reliability of perceptual judgments ranged from strong to weak. Percent stops correct was the strongest predictor of interrater reliability for both phonetic accuracy judgments and hypernasality ratings. Conclusions Reliability of perceptual phonetic accuracy judgments and hypernasality ratings among practicing SLPs for children with dysarthria is reduced compared to ratings for children with typical development. Findings underscore the need for more reliable methods to assess phonetic accuracy and hypernasality for children with dysarthria.

Prazosin versus quetiapine for nighttime posttraumatic stress disorder symptoms in veterans: an assessment of long-term comparative effectiveness and safety.

Posttraumatic stress disorder (PTSD) is an anxiety disorder experienced by combat veterans. Nighttime symptoms are often unrelieved by selective serotonin reuptake inhibitor therapy, and increased use of prazosin or quetiapine for treatment is seen. The purpose of this study was to determine the short- and long-term effectiveness and safety of prazosin versus quetiapine for treating nighttime symptoms in veteran PTSD patients. This is a historical prospective cohort study using retrospective chart review. Three hundred twenty-four patients with a diagnosis of PTSD, based on International Classification of Diseases, Ninth Revision coding, who were initially prescribed prazosin or quetiapine for nighttime symptoms were screened for inclusion. Short-term effectiveness was determined by documentation of symptomatic improvement within 6 months, and long-term effectiveness if patients continued therapy to study end date. Safety was assessed by comparing incidence of adverse drug effects causing discontinuation of either study drug. This study included 237 patients: 62 received prazosin, and 175 received quetiapine. Short-term effectiveness was similar for prazosin (61.3%) and quetiapine (61.7%; P = 0.54). However, patients prescribed prazosin were significantly more likely to continue their therapy to study end date compared with quetiapine (48.4% vs 24%; P < 0.001; odds ratio, 3.0; 95% confidence interval, 1.62-5.45), thus achieving long-term effectiveness. Alternatively, patients in the quetiapine group were more likely to discontinue therapy because of adverse effects compared with the prazosin group (34.9% vs 17.7%; P = 0.008). Because of similar rate of short-term effectiveness, superior long-term effectiveness, and lower incidence of events leading to discontinuation, compared with quetiapine, prazosin should be used first-line for treating nighttime PTSD symptoms in a veteran population.

Differential Diagnosis of Apraxia of Speech in Children and Adults: A Scoping Review.

Purpose Despite having distinct etiologies, acquired apraxia of speech (AOS) and childhood apraxia of speech (CAS) share the same central diagnostic challenge (i.e., isolating markers specific to an impairment in speech motor planning/programming). The purpose of this review was to evaluate and compare the state of the evidence on approaches to differential diagnosis for AOS and CAS and to identify gaps in each literature that could provide directions for future research aimed to improve clinical diagnosis of these disorders. Method We conducted a scoping review of literature published between 1997 and 2019, following the Preferred Reporting Items for Systematic Reviews and Meta-Analyses Extension for Scoping Reviews guidelines. For both AOS and CAS, literature was charted and summarized around four main methodological approaches to diagnosis: speech symptoms, quantitative speech measures, impaired linguistic-motor processes, and neuroimaging. Results Results showed that similar methodological approaches have been used to study differential diagnosis of apraxia of speech in adults and children; however, the specific measures that have received the most research attention differ between AOS and CAS. Several promising candidate markers for AOS and CAS have been identified; however, few studies report metrics that can be used to assess their diagnostic accuracy. Conclusions Over the past two decades, there has been a proliferation of research identifying potential diagnostic markers of AOS and CAS. In order to improve clinical diagnosis of AOS and CAS, there is a need for studies testing the diagnostic accuracy of multiple candidate markers, better control over language impairment comorbidity, more inclusion of speech-disordered control groups, and an increased focus on translational work moving toward clinical implementation of promising measures.

Muc5ac Expression Protects the Colonic Barrier in Experimental Colitis.

BACKGROUND: The mucus gel layer (MGL) lining the colon is integral to exclusion of bacteria and maintaining intestinal homeostasis in health and disease. Some MGL defects allowing bacteria to directly contact the colonic surface are commonly observed in ulcerative colitis (UC). The major macromolecular component of the colonic MGL is the secreted gel-forming mucin MUC2, whose expression is essential for homeostasis in health. In UC, another gel-forming mucin, MUC5AC, is induced. In mice, Muc5ac is protective during intestinal helminth infection. Here we tested the expression and functional role of MUC5AC/Muc5ac in UC biopsies and murine colitis. METHODS: We measured MUC5AC/Muc5ac expression in UC biopsies and in dextran sulfate sodium (DSS) colitis. We performed DSS colitis in mice deficient in Muc5ac (Muc5ac-/-) to model the potential functional role of Muc5ac in colitis. To assess MGL integrity, we quantified bacterial-epithelial interaction and translocation to mesenteric lymph nodes. Antibiotic treatment and 16S rRNA gene sequencing were performed to directly investigate the role of bacteria in murine colitis. RESULTS: Colonic MUC5AC/Muc5ac mRNA expression increased significantly in active UC and murine colitis. Muc5ac-/- mice experienced worsened injury and inflammation in DSS colitis compared with control mice. This result was associated with increased bacterial-epithelial contact and translocation to the mesenteric lymph nodes. However, no change in microbial abundance or community composition was noted. Antibiotic treatment normalized colitis severity in Muc5ac-/- mice to that of antibiotic-treated control mice. CONCLUSIONS: MUC5AC/Muc5ac induction in the acutely inflamed colon controls injury by reducing bacterial breach of the MGL.