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Plasma cells (PC) are found in the CNS of multiple sclerosis (MS) patients, yet their source and role in MS remains unclear. We find that some PC in the CNS of mice with experimental autoimmune encephalomyelitis (EAE) originate in the gut and produce immunoglobulin A (IgA). Moreover, we show that IgA+ PC are dramatically reduced in the gut during EAE, and likewise, a reduction in IgA-bound fecal bacteria is seen in MS patients during disease relapse. Removal of plasmablast (PB) plus PC resulted in exacerbated EAE that was normalized by the introduction of gut-derived IgA+ PC. Furthermore, mice with an over-abundance of IgA+ PB and/or PC were specifically resistant to the effector stage of EAE, and expression of interleukin (IL)-10 by PB plus PC was necessary and sufficient to confer resistance. Our data show that IgA+ PB and/or PC mobilized from the gut play an unexpected role in suppressing neuroinflammation.

BackgroundHealthcare-associated infection (HAI) remains a significant risk for hospitalized patients and a challenging burden for the healthcare system. This study presents a clinical decision support tool that can be used in clinical workflows to proactively engage secondary assessments of pre-symptomatic and at-risk infection patients, thereby enabling earlier diagnosis and treatment.MethodsThis study applies machine learning, specifically ensemble-based boosted decision trees, on large retrospective hospital datasets to develop an infection risk score that predicts infection before obvious symptoms present. We extracted a stratified machine learning dataset of 36,782 healthcare-associated infection patients. The model leveraged vital signs, laboratory measurements and demographics to predict HAI before clinical suspicion, defined as the order of a microbiology test or administration of antibiotics.ResultsOur best performing infection risk model achieves a cross-validated AUC of 0.88 at 1 h before clinical suspicion and maintains an AUC >0.85 for 48 h before suspicion by aggregating information across demographics and a set of 163 vital signs and laboratory measurements. A second model trained on a reduced feature space comprising demographics and the 36 most frequently measured vital signs and laboratory measurements can still achieve an AUC of 0.86 at 1 h before clinical suspicion. These results compare favorably against using temperature alone and clinical rules such as the quick sequential organ failure assessment (qSOFA) score. Along with the performance results, we also provide an analysis of model interpretability via feature importance rankings.ConclusionThe predictive model aggregates information from multiple physiological parameters such as vital signs and laboratory measurements to provide a continuous risk score of infection that can be deployed in hospitals to provide advance warning of patient deterioration.

ObjectivesThis study aimed to investigate COVID-19-related disparities in clinical presentation and patient outcomes in hospitalized Native American individuals.MethodsThe study was performed within 30 hospitals of the Banner Health system in the Southwest United States and included 8,083 adult patients who tested positive for SARS-CoV-2 infection and were hospitalized between 1 March 2020 and 4 September 2020. Bivariate and multivariate analyses were used to assess racial and ethnic differences in clinical presentation and patient outcomes.ResultsCOVID-19-related hospitalizations in Native American individuals were over-represented compared with non-Hispanic white individuals. Native American individuals had fewer symptoms at admission; greater prevalence of chronic lung disease in the older adult; two times greater risk for ICU admission despite being younger; and 20 times more rapid clinical deterioration warranting ICU admission. Compared with non-Hispanic white individuals, Native American individuals had a greater prevalence of sepsis, were more likely to require invasive mechanical ventilation, had a longer length of stay, and had higher in-hospital mortality.ConclusionNative American individuals manifested greater case-fatality rates following hospitalization than other races/ethnicities. Atypical symptom presentation of COVID-19 included a greater prevalence of chronic lung disease and a more rapid clinical deterioration, which may be responsible for the observed higher hospital mortality, thereby underscoring the role of pulmonologists in addressing such disparities.

Cardiogenic shock (CS) is a severe condition with in-hospital mortality of up to 50%. Patients who develop CS may have previous cardiac history, but that may not always be the case, adding to the challenges in optimally identifying and managing these patients. Patients may present to a medical facility with CS or develop CS while in the emergency department (ED), in a general inpatient ward (WARD) or in the critical care unit (CC). While different clinical pathways for management exist once CS is recognized, there are challenges in identifying the patients in a timely manner, in all settings, in a timeframe that will allow proper management. We therefore developed and evaluated retrospectively a machine learning model based on the XGBoost (XGB) algorithm which runs automatically on patient data from the electronic health record (EHR). The algorithm was trained on 8 years of de-identified data (from 2010 to 2017) collected from a large regional healthcare system. The input variables include demographics, vital signs, laboratory values, some orders, and specific pre-existing diagnoses. The model was designed to make predictions 2 h prior to the need of first CS intervention (inotrope, vasopressor, or mechanical circulatory support). The algorithm achieves an overall area under curve (AUC) of 0.87 (0.81 in CC, 0.84 in ED, 0.97 in WARD), which is considered useful for clinical use. The algorithm can be refined based on specific elements defining patient subpopulations, for example presence of acute myocardial infarction (AMI) or congestive heart failure (CHF), further increasing its precision when a patient has these conditions. The top-contributing risk factors learned by the model are consistent with existing clinical findings. Our conclusion is that a useful machine learning model can be used to predict the development of CS. This manuscript describes the main steps of the development process and our results.

β‐site amyloid precursor protein‐cleaving enzyme 1 (BACE1) is required for the production of β‐amyloid peptides, which are implicated in the etiology of Alzheimer's disease. The safety and pharmacokinetics of the BACE1 inhibitor verubecestat have previously been studied in young adults aged 19–45 years. In this randomized, placebo‐controlled, phase I study (protocol MK‐8931‐006), we investigated the safety, tolerability, and pharmacokinetics of a single dose (100 mg) or multiple doses (30, 80, and 120 mg) once daily for 28 days of verubecestat in healthy elderly subjects. Safety end points were assessed at baseline and during the duration of the study period and indicated that verubecestat was generally well tolerated. Verubecestat pharmacokinetics were similar between healthy elderly male and female subjects and similar to those reported in healthy young males in previous studies. These data supported subsequent studies to assess the potential efficacy of verubecestat in subjects with Alzheimer's disease.

A Phase I, double-blind, randomized, crossover study in healthy males (N=106) was conducted between March 21, 2004, and May 17, 2004, to determine the magnitude and duration of the hemodynamic interaction of avanafil (a phosphodiesterase type-5 inhibitor for treating males with erectile dysfunction) when coadministered with glyceryl trinitrate (NTG) compared with sildenafil and placebo. Subjects received avanafil (200 mg), sildenafil (100 mg), and placebo (on separate days) via the oral route followed by NTG (0.4 mg) 12, 8, 4, 1, or 0.5 hours post-dose via the sublingual route. Blood pressure (BP) and heart rate (HR) were assessed at defined intervals.Throughout the study (after administration of the study drug, and including the period after NTG administration), the effects of avanafil and sildenafil on BP and HR were significantly greatest overall, at the shortest (0.5-hour) time interval compared with placebo. By the 8- and 12-hour time intervals, no significant difference in BP or HR was observed for avanafil (8 and 12 hours) or sildenafil (12 hours) (p>0.05, compared with placebo). Compared with avanafil, sildenafil had a significantly greater effect when dosed 0.5 hours before NTG on standing HR (p=0.05); 1 hour before NTG on standing systolic blood pressure (SBP) (p

People living with multiple sclerosis (MS) experience episodic CNS white matter lesions instigated by autoreactive T cells. With age, patients with MS show evidence of gray matter demyelination and experience devastating nonremitting symptomology. What drives progression is unclear and studying this has been hampered by the lack of suitable animal models. Here, we show that passive experimental autoimmune encephalomyelitis (EAE) induced by an adoptive transfer of young Th17 cells induced a nonremitting clinical phenotype that was associated with persistent leptomeningeal inflammation and cortical pathology in old, but not young, SJL/J mice. Although the quantity and quality of T cells did not differ in the brains of old versus young EAE mice, an increase in neutrophils and a decrease in B cells were observed in the brains of old mice. Neutrophils were also found in the leptomeninges of a subset of progressive MS patient brains that showed evidence of leptomeningeal inflammation and subpial cortical demyelination. Taken together, our data show that while Th17 cells initiate CNS inflammation, subsequent clinical symptoms and gray matter pathology are dictated by age and associated with other immune cells, such as neutrophils.

Subpial demyelination is a specific hallmark of multiple sclerosis and a correlate of disease progression. Although the mechanism(s) that mediate pathogenesis in the subpial compartment remain unclear, it has been speculated that inflammation in the overlying meninges may be associated with subpial injury. Here we show that adoptive transfer of proteolipid protein-primed Th17 cells into SJL/J recipient mice induces subpial demyelination associated with microglial/macrophage activation, disruption of the glial limitans, and evidence of an oxidative stress response. This pathology was topologically associated with foci of immune cells in the meninges and occurred in the absence of measurable anti-myelin oligodendrocyte glycoprotein IgM or IgG antibodies. To test the role of brain-infiltrating leukocytes on subpial injury, we modulated sphingosine 1-phosphate (S1P) receptor1,5 activity with BAF312 (siponimod) treatment. Administration of BAF312, even after adoptively transferred T cells had entered the brain, significantly ameliorated clinical experimental autoimmune encephalomyelitis and diminished subpial pathology, concomitant with a selective reduction in the capacity of transferred T cells to make Th17 cytokines. We conclude that sustained subpial cortical injury is associated with the capacity for brain-resident T cells to produce Th17 cytokines, and this pathological process occurs in an S1P receptor1,5-dependent manner.

This study compared three-dimensional (3-D) hip and knee kinematics and kinetics between lateral shuffle and side-step cutting movements to determine whether the simpler lateral shuffle movement can be used in place of cutting to assess knee injury risk. A total of 78 patients (52 female) and 34 controls (16 female) aged 8-19 years performed lateral shuffle and 45° side-step cutting movements. Hip and knee kinematics and kinetics between initial contact and peak knee flexion were calculated using the Plug-in-Gait model and compared between activities using Pearson's correlation and paired t-tests. Peak knee valgus angle correlated strongly (r=0.86, p<0.0001), while minimum (r=0.25, p=0.0001) and peak hip abduction (r=0.24, p=0.0003), and peak hip internal rotation (r=0.33, p<0.0001) correlated only weakly between the two activities. Peak external knee valgus moment (r=0.32, p<0.0001) and average external knee (r=0.42, p<0.0001) and hip (r=0.37, p<0.0001) flexion moments correlated weakly to moderately between activities. Subjects were more internally rotated (3.6°, p<0.0001) and less abducted (16.7° and 17.3° for minimum and maximum, p<0.0001) at the hip during cutting, with higher hip (0.12, p<0.0001) and lower knee (-0.02, p=0.0001) non-dimensional flexion moments. These results suggest that the lateral shuffle movement may be useful for evaluating knee valgus, particularly during initial visual assessment. However, the lateral shuffle may not be challenging enough to reveal poor neuromuscular control over hip ab/adduction and rotation, necessitating follow-up assessment of cutting, ideally using 3-D motion analysis., (Copyright © 2015 Elsevier B.V. All rights reserved.)

Purpose: To compare dynamic ankle-foot orthoses (DAFOs) and adjustable dynamic response (ADR) ankle-foot orthoses (AFOs) in children with cerebral palsy., Methods: A total of 10 children with cerebral palsy (4-12 years; 6 at Gross Motor Function Classification System level I, 4 at Gross Motor Function Classification System level III) and crouch and/or equinus gait wore DAFOs and ADR-AFOs, each for 4 weeks, in randomized order. Laboratory-based gait analysis, walking activity monitor, and parent-reported questionnaire outcomes were compared among braces and barefoot conditions., Results: Children demonstrated better stride length (11-12 cm), hip extension (2°-4°), and swing-phase dorsiflexion (9°-17°) in both braces versus barefoot. Push-off power (0.3 W/kg) and knee extension (5°) were better in ADR-AFOs than in DAFOs. Parent satisfaction and walking activity (742 steps per day, 43 minutes per day) were higher for DAFOs., Conclusions: ADR-AFOs produce better knee extension and push-off power; DAFOs produce more normal ankle motion, greater parent satisfaction, and walking activity. Both braces provide improvements over barefoot.

This study examined the impact of gait analysis on surgical outcomes in ambulatory children with cerebral palsy (CP) through a randomized controlled trial. 156 children with CP (94 male; age 10.2 ± 3.7 years) underwent gait analysis and were randomized to two groups: Gait Report group (N = 83), where the referring surgeon received the patient's gait analysis report, and Control group (N = 73), where the surgeon did not receive the gait report. Outcomes were assessed pre- and 1.3 ± 0.5 years post-operatively. An intent-to-treat analysis compared outcomes between the two groups. Outcome measures included the Gillette Functional Activity Questionnaire (FAQ), Gait Deviation Index (GDI), oxygen cost, gross motor function measure, Child Health Questionnaire (CHQ), Pediatric Outcomes Data Collection Instrument (PODCI), and Pediatric Evaluation and Disability Inventory. The outcomes that differed significantly between groups were change in health from the CHQ, which was rated as much better for 56% (46/82) of children in the Gait Report group compared with 38% (28/73) in the Control group (p = 0.04), and upper extremity physical function from the PODCI. Gait outcomes (FAQ and GDI) improved more when over half of the recommendations for a patient were followed or the recommended extent of surgery (none, single, or multi-level) was done (p ≤ 0.04). On average, however, only 42% of the recommendations were followed in the Gait Report group, compared with 35% in the Control group (p = 0.23). This is much less than the >85% reported in previous studies and may account for the lack of differences between groups for some of the outcome measures., (Copyright © 2012 Elsevier B.V. All rights reserved.)

This study evaluates the visual assessment of gait using portions of the Physicians' Rating Scale (PRS). Thirty children with pathologic gait were evaluated "live" and using full- and slow-speed video. Interobserver reliability (weighted kappa) was 0.57 to 0.74 for foot contact, 0.69 to 0.71 for crouch, 0.30 to 0.40 for hip flexion, 0.57 to 0.65 for knee flexion, and 0.42 to 0.52 for dorsiflexion in stance. Intraobserver reliability (comparing the three conditions) was 0.50 to 0.78 for foot contact, 0.71 to 0.80 for crouch, 0.26 to 0.44 for hip flexion, 0.60 to 0.86 for knee flexion, and 0.39 to 0.61 for dorsiflexion. Observers were correct only 12% to 32% of the time when reporting less than 0 degrees of dorsiflexion and 0% to 29% of the time when reporting more than 20 degrees of hip flexion due to overestimation of hip flexion and underestimation of ankle dorsiflexion. These errors could lead some clinicians to presume the presence of contractures that do not actually exist. Visual assessment using the PRS does not appear to accurately measure what it is most commonly used to assess: ankle position in stance.

Preoperative and postoperative gait analyses were reviewed for 47 patients with cerebral palsy in an attempt to ascertain predictors of surgical outcome as measured by gait velocity. Higher postoperative velocity correlated with higher preoperative velocity and younger age. Observed velocities in older children were smaller than predicted values. Older children showed either an average decline in velocity from normal for age or no change. Younger children showed an average increase in velocity toward normal for their age. Diagnosis, type of surgery, number of procedures performed and level of ambulation preoperatively were not predictive of postoperative velocity. These results suggests that gait velocity cannot be reliably increased in all children with cerebral palsy undergoing surgery, especially those older than age 12.

The purpose of this study was to assess the reliability of interpretation of gait analysis data between physicians and institutions. Gait analysis data from seven patients were reviewed by 12 experienced gait laboratory physicians from six institutions. Reviewers identified problems and made treatment recommendations based on the data provided. Agreement among physicians for the most commonly diagnosed problems was slight to moderate (kappa range, 0.14-0.46). Physicians agreed on identification of soft tissue more than bony problems (intraclass correlation, 0.56 vs. 0.37). Variability regarding surgical recommendations for soft-tissue procedures (kappa range, 0.20-0.64) was similar to that for diagnosis of both soft-tissue and bone problems, although recommendation for hamstring lengthening showed substantial agreement (kappa = 0.64). There was less agreement in recommendation of osteotomies (kappa range, 0.13-0.22). Physicians agreed more on the number of soft-tissue procedures than bone procedures recommended (intraclass correlation, 0.65 vs. 0.19). There was an interinstitutional difference in the frequency of soft-tissue (p = 0.0152) and osseous problem identification (p = 0.0002), as well as in the frequency of recommendations for soft-tissue surgery (p = 0.0004) and osteotomies (p < 0.0001). Although gait analysis data are themselves objective, this study demonstrates some subjectivity in their interpretation. The interobserver variability reported here is similar to that reported for established classification systems of various orthopedic conditions.

Purpose: To determine the role of P-glycoprotein (Pgp) on the CNS penetration of the HIV protease inhibitor (PI) amprenavir (141W94) and to test the hypothesis that co-administration of a second HIV PI (ritonavir) could enhance amprenavir's brain penetration in vivo., Methods: Pgp-mediated efflux was investigated in vitro with Caco-2 cells and in vivo by whole-body autoradiography (WBA). "Genetic" mdr1a/1b double knockout mice, "chemical" Pgp knockout mice generated by administration of the Pgp inhibitor GF120918, and mice pretreated with ritonavir were used in WBA studies to investigate the effects of Pgp modulation on the CNS penetration of amprenavir., Results: Amprenavir, indinavir, ritonavir, and saquinavir had 2- to 23-fold higher transport rates from the basolateral to apical direction than from the apical to basolateral direction across Caco-2 monolayers. Incubation with GF120918 negated this difference, suggesting that the efflux was Pgp-mediated. WBA studies demonstrated a 13- and 27-fold increase in the brain and a 3.3-fold increase in the CSF concentrations of amprenavir in mice pretreated with GF120918 and in mdr1a/1b double knockout mice. In contrast, pretreatment with ritonavir did not alter the CNS exposure of amprenavir., Conclusions: These results provide evidence that amprenavir and other HIV PIs are Pgp substrates and that co-administration of a specific Pgp inhibitor will enhance amprenavir's CNS penetration in vivo. These results will have an important therapeutic impact in the treatment of AIDS dementia.