Therapeutic Content of Mobile Phone Applications for Substance Use Disorders: An Umbrella Review.

Mobile phone applications (MPAs) for substance use disorder (SUD) treatment are increasingly used by patients. Although pilot studies have shown promising results, multiple previous systematic reviews noted insufficient evidence for MPA use in SUD treatment-many of the previously published reviews evaluated different trials. Subsequently, we aimed to conduct an umbrella review of previously published reviews investigating the efficacy of MPAs for SUD treatment, excluding nicotine/tobacco because umbrella reviews have been done in this population and the nicotine/tobacco MPA approach often differs from SUD-focused MPAs. No previous reviews have included a statistical meta-analysis of clinical trials to quantify an estimated overall effect. Seven reviews met inclusion criteria, and 17 unique studies with available data were taken from those reviews for the meta-analysis. Overall, reviews reported a lack of evidence for recommending MPAs for SUD treatment. However, MPA-delivered recovery support services, cognitive behavioral therapy, and contingency management were identified across multiple reviews as having promising evidence for SUD treatment. Hedges g effect size for an MPA reduction in substance use-related outcomes relative to the control arm was insignificant (0.137; 95% CI, -0.056 to 0.330; P=.16). In subgroup analysis, contingency management (1.29; 95% CI, 1.088-1.482; τ 2=0; k=2) and cognitive behavioral therapy (0.02; 95% CI, 0.001-0.030; τ 2=0; k=2) were significant. Although contingency management's effect was large, both trials were small (samples of 40 and 30). This review includes an adapted framework for the American Psychiatric Association's MPA guidelines that clinicians can implement to review MPAs critically with patients.

Congenital Eyelid Imbrication and Floppy Eyelid Syndromes Complicated by Eversion due to Prostaglandin E Infusion in a Patient With Trisomy 21 and Tetralogy of Fallot.

Congenital eyelid imbrication syndrome is a rare eyelid finding where a long upper lid overlaps the lower lid when the eyes are closed. To date, congenital eyelid imbrication syndrome has been described in the literature less than 10 times. We present a case of congenital eyelid imbrication syndrome in a patient with trisomy 21 and tetralogy of Fallot on a prostaglandin E infusion to maintain a patent ductus arteriosus prior to definitive heart surgery. While on the infusion, the patient developed peripheral edema and flushing due to vasodilation. This coincided with eyelid swelling, conjunctival chemosis, and eversion of the eyelids. Upon cessation of the prostaglandin E1 infusion, his eyelid eversion resolved.

TPL2 kinase activity regulates microglial inflammatory responses and promotes neurodegeneration in tauopathy mice.

Tumor progression locus 2 (TPL2) (MAP3K8) is a central signaling node in the inflammatory response of peripheral immune cells. We find that TPL2 kinase activity modulates microglial cytokine release and is required for microglia-mediated neuron death in vitro. In acute in vivo neuroinflammation settings, TPL2 kinase activity regulates microglia activation states and brain cytokine levels. In a tauopathy model of chronic neurodegeneration, loss of TPL2 kinase activity reduces neuroinflammation and rescues synapse loss, brain volume loss, and behavioral deficits. Single-cell RNA sequencing analysis indicates that protection in the tauopathy model was associated with reductions in activated microglia subpopulations as well as infiltrating peripheral immune cells. Overall, using various models, we find that TPL2 kinase activity can promote multiple harmful consequences of microglial activation in the brain including cytokine release, iNOS (inducible nitric oxide synthase) induction, astrocyte activation, and immune cell infiltration. Consequently, inhibiting TPL2 kinase activity could represent a potential therapeutic strategy in neurodegenerative conditions.

Characterization of vision in pediatric retinoblastoma survivors beyond visual acuity.

BACKGROUND: Retinoblastoma (RB) and its associated treatments can significantly impact visual acuity. However, little is known regarding other measures of vision, such as contrast sensitivity or saccades. The aim of this study was to describe contrast sensitivity and saccades in children treated for retinoblastoma. METHODS: This cross-sectional study included children aged 5-17 years who had completed treatment for RB. Visual acuity, saccades via fixation analysis, and contrast sensitivity by Cardiff contrast sensitivity were assessed, and multivariable linear regression was performed. RESULTS: Eleven children were enrolled (mean age, 10.7 ± 3.9 years). Treatment included enucleation (8 children [73%]) and chemotherapy (10 [91%]). Of the 11, one participant was unable to complete testing of saccades, and another was unable to complete contrast sensitivity testing. Decreased saccade parameters (velocity, latency, or accuracy) and impaired contrast sensitivity were observed in all 10 participants who underwent visual testing. Multivariable analysis revealed that worse logMAR visual acuity (B, -4.54 [-6.8, -2.2]; P = 0.004) and bilateral disease (B, -3.9 [-6.4, -1.4]; P = 0.009) were associated with worse contrast sensitivity. Germline disease was associated with decreased vertical saccade accuracy (P = 0.02). CONCLUSIONS: Decreased contrast sensitivity and impaired saccades were universally observed in this cohort of RB survivors. Comprehensive visual evaluation should be considered for all RB survivors to provide optimal rehabilitative services for these patients.

Eye-related quality of life and activities of daily living in pediatric retinoblastoma patients: A single-center, non-controlled, cross-sectional analysis.

INTRODUCTION: Childhood retinoblastoma (RB) survivors are known to experience long-term morbidity; however, eye-related quality of life (QoL), which may significantly impact activities of daily living (ADL), has not been extensively studied in this population. The purpose of this cross-sectional study was to assess QoL and ADL morbidity among school-age RB survivors. METHODS: The Pediatric Eye Questionnaire (PedEyeQ) and Roll Evaluation Activities of Life (REAL) were administered to childhood RB survivors between ages 5 and 17 followed at St. Louis Children's Hospital. Visual outcomes and demographic predictors of ADL and QoL were examined. RESULTS: Total 23 patients (mean age 9.6 years) consented for participation in this study. All children experienced at least one domain on the PedEyeQ ≤ 80%. Subjects and parents marked functional vision to be the most impacted domain with a median score of 82.5 and 83.4, respectively. Only 10.5% of participants scored above 75% on the ADL percentile rank. On multivariable analysis, decreased visual acuity (VA) was associated with worse "Child Functional" (odds ratio [OR] -59.2, p = .004) and "Parent Worry Function" (OR -66.5, p = .03) metrics. Decreased contrast sensitivity was associated with worse "Parent Impact" (OR 21.0, p = .02) and "Parent Worry Function" (OR 3.70, p = .04) metrics. Longer saccade horizontal latency was associated with a worse "Parent Worry Function" metric (OR 43.0, p = .009). On multivariable analysis, no variable was significantly associated with ADL. CONCLUSION: RB survivors have impaired QoL and ADL. Screening for such difficulties should strongly be considered for all RB patients. Additional studies may help predict morbidity based on visual metrics and demographic data.

The Type I Interferon Signature Reflects Multiple Phenotypic and Activity Measures in Dermatomyositis.

OBJECTIVE: The type 1 interferon (IFN) pathway is up-regulated in dermatomyositis (DM). We sought to define how organ-specific disease activity as well as autoantibodies and other clinical factors are independently associated with systemic type I IFN activity in adult patients with DM. METHODS: RNA sequencing was performed on 355 whole blood samples collected from 202 well-phenotyped DM patients followed up during the course of their clinical care. A previously defined 13-gene type I IFN score was modeled as a function of demographic, serologic, and clinical variables using both cross-sectional and longitudinal data. RESULTS: The pattern of type I IFN-driven transcriptional response was stereotyped across samples with a sequential modular activation pattern strikingly similar to systemic lupus erythematosus. The median type I IFN score was higher or lower in patients with anti-melanoma differentiation-associated protein 5 (anti-MDA-5) or anti-Mi-2 antibodies, respectively, compared to patients without these antibodies. Absolute type I IFN score was independently associated with muscle and skin disease activity, interstitial lung disease, and anti-MDA-5 antibodies. Changes in the type I IFN score over time were significantly associated with changes in skin or muscle disease activity. Stratified analysis accounting for heterogeneity in organ involvement and antibody class revealed high correlation between changes in the type I IFN score and skin disease activity (Spearman's ρ = 0.84-0.95). CONCLUSION: The type I IFN score is independently associated with skin and muscle disease activity as well as certain clinical and serologic features in DM. Accounting for the effect of muscle disease and anti-MDA-5 status revealed that the type I IFN score is strongly correlated with skin disease activity, providing support for type I IFN blockade as a therapeutic strategy for DM.

Trachoma, the world's leading infectious cause of blindness: The remaining gap in care and access to basic handwashing facilities.

PURPOSE: Trachoma, the world's leading infectious cause of blindness, has been targeted by the WHO for elimination through the SAFE strategy: surgery, antibiotics, facial cleanliness, and environmental improvement. Although significant progress has been made, there remains a gap in care. This project studied the association of geographical distribution of the remaining need for trachoma intervention and its association with access to basic handwashing facilities at home, as an indicator of water/sanitation infrastructure. We hypothesized that poor water sanitation would correspond to areas where trachoma intervention is still required. DESIGN: Retrospective analysis using the WHO Global Health Observatory. Spatial, correlation, and simple and multivariable regression analyses were used. METHODS: Using data from the WHO Global Health Observatory, a total of 194 countries were analyzed. Two choropleth maps were created, with inset maps focused on the South Pacific region, where the top 5 countries with the greatest population proportion requiring trachoma intervention are located. RESULTS: Correlations and the simple regression model of total population with access to handwashing facilities as the only risk factor were insignificant. However, the multivariable regression models with access to handwashing facilities (total, urban, and rural) and population density as risk factors for trachoma intervention were significant. CONCLUSION: Poor water/sanitation infrastructure correlates with trachoma burden. Therefore, water/sanitation infrastructure improvement is a worthwhile target in the efforts toward trachoma elimination, but further research on the association between these important public health indicators is warranted.

Retinopathy of prematurity: risk stratification by gestational age.

OBJECTIVE: To identify gestational age (GA) specific risk factors for severe ROP (sROP). STUDY DESIGN: Single-center cohort stratified by GA into <24 weeks, 24-26 weeks and ≥27 weeks. RESULTS: 132/1106 (11.9%) developed sROP. Time to full feeds was the only risk factor [HR 1.003 (1.001-1.006), p = 0.04] for infants<24 weeks GA. For infants 24-26 weeks GA, a higher GA was protective [HR 0.66 (0.51-0.85), p < 0.01], whereas steroids for bronchopulmonary dysplasia (BPD) [HR 2.21 (1.28-3.26), p < 0.01], patent ductus arteriosus (PDA) ligation [HR 1.99 (1.25-3.11), p < 0.01] and use of nitric oxide [HR 1.96 (1.11-3.30), p = 0.01] increased the hazard of sROP. Increasing birthweight was protective [HR 0.70 (0.54-0.89), p < 0.01] in infants ≥27 weeks GA. Cumulative hazard of sROP reached 1.0 by fifteen weeks for <24 weeks GA, 0.4 by twenty weeks for 24-26 weeks GA, and 0.05 by twenty weeks after birth for ≥27 weeks GA. CONCLUSIONS: Risk factors, cumulative hazard, and time to sROP vary by GA.

Factors impacting adherence to an exercise-based physical therapy program for individuals with low back pain.

BACKGROUND/OBJECTIVE: Exercise-based rehabilitation is a conservative management approach for individuals with low back pain. However, adherence rates for conservative management are often low and the reasons for this are not well described. The objective of this study was to evaluate predictors of adherence and patient-reported reasons for non-adherence after ceasing a supervised exercise-based rehabilitation program in individuals with low back pain. DESIGN: Retrospective observational study. METHODS: Data was retrospectively analyzed from 5 rehabilitation clinics utilizing a standardized exercise-based rehabilitation program. Baseline demographics, diagnosis and symptom specific features, visit number, and discontinuation profiles were quantified for 2,243 patients who underwent the program. RESULTS: Forty-three percent (43%) of participants were adherent to the program, with the majority (31.7%) discontinuing treatment prior to completion due to logistic and accessibility issues. Another 13.2% discontinued prior to the prescribed duration due to clinically significant improvements in pain and/or disability without formal discharge evaluation, whereas 8.3% did not continue due to lack of improvement. Finally, 6.0% were discharged for related and unrelated medical reasons including surgery. Individuals diagnosed with disc pathology were most likely to be adherent to the program. LIMITATIONS: This study was a retrospective chart review with missing data for some variables. Future studies with a prospective design would increase quality of evidence. CONCLUSIONS: The majority of individuals prescribed an in-clinic exercise-based rehabilitation program are non-adherent. Patient diagnosis was the most important predictor of adherence. For those who were not adherent, important barriers include personal issues, insufficient insurance authorization and lack of geographic accessibility.

Substitutions at a rheostat position in human aldolase A cause a shift in the conformational population.

Some protein positions play special roles in determining the magnitude of protein function: at such "rheostat" positions, varied amino acid substitutions give rise to a continuum of functional outcomes, from wild type (or enhanced), to intermediate, to loss of function. This observed range raises interesting questions about the biophysical bases by which changes at single positions have such varied outcomes. Here, we assessed variants at position 98 in human aldolase A ("I98X"). Despite being ~17 Å from the active site and far from subunit interfaces, substitutions at position 98 have rheostatic contributions to the apparent cooperativity (nH ) associated with fructose-1,6-bisphosphate substrate binding and moderately affected binding affinity. Next, we crystallized representative I98X variants to assess structural consequences. Residues smaller than the native isoleucine (cysteine and serine) were readily accommodated, and the larger phenylalanine caused only a slight separation of the two parallel helixes. However, the diffraction quality was reduced for I98F, and further reduced for I98Y. Intriguingly, the resolutions of the I98X structures correlated with their nH values. We propose that substitution effects on both nH and crystal lattice disruption arise from changes in the population of aldolase A conformations in solution. In combination with results computed for rheostat positions in other proteins, the results from this study suggest that rheostat positions accommodate a wide range of side chains and that structural consequences manifest as shifted ensemble populations and/or dynamics changes.

Inadequate Cerebrospinal Fluid Concentrations of Available Salvage Agents Further Impedes the Optimal Treatment of Multidrug-Resistant Enterococcus faecium Meningitis and Bacteremia.

BACKGROUND: Vancomycin-resistant Enterococcus faecium (VRE) in particular has evolved as an important cause of hospital acquired infection, especially in immunocompromised hosts. METHODS: We present a complex case of a patient with relapsed acute myeloid leukemia who underwent allogenic hematopoietic stem cell transplantation complicated by persistent VRE bacteremia and meningitis. To optimize therapy, various blood and cerebrospinal fluid (CSF) samples were sent to a research laboratory for extensive susceptibility testing, pharmacokinetic analyses, and time-kill experiments. RESULTS: In vitro testing revealed resistance to all first-line treatment options and CSF sampling demonstrated sub-optimal central nervous system concentrations achieved by each antimicrobial agent administered in relation to their respective MIC value. Time-kill analyses at observed CSF concentrations confirmed the lack of bactericidal activity despite use of a four-drug combination regimen. CONCLUSIONS: This work is the first to report CSF concentrations of oritavancin and tedizolid in humans and adds to the limited data regarding in vitro susceptibility of new antimicrobial agents such as eravacycline, omadacycline, and lefamulin against VRE. Our study provides new insights into various aspects of treatment of extensively drug-resistant Enterococcus faecium meningitis and bacteremia and supports the continued pursuit of precision medicine for these challenging cases.

Genotype‒Structurotype‒Phenotype Correlations in Patients with Pachyonychia Congenita.

Pachyonychia congenita (PC) is a genetic disorder of keratin that presents with nail dystrophy, painful palmoplantar keratoderma, and other clinical manifestations. We investigated the genotype‒structurotype‒phenotype correlations seen with mutations in keratin genes (keratin [K]6A, K6B, K6C, K16, K17) and utilized protein structure modeling of high-frequency mutations to examine the functional importance of keratin structural domains in PC pathogenesis. Participants of the International PC Research Registry underwent genetic testing and completed a standardized survey on their symptoms. Our results support previous reports associating oral leukokeratosis with K6A mutations and cutaneous cysts, follicular hyperkeratosis, and natal teeth with K17 mutations. Painful keratoderma was prominent with K6A and K16 mutations. Nail involvement was most common in patients with K6A mutation and least common in those with K6C mutation. Across keratin subtypes, patients with coil 2B mutations had the greatest impairment in ambulation, and patients with coil 1A mutations reported more emotional issues. Molecular modeling demonstrated that hotspot missense mutations in PC largely disrupted hydrophobic interactions or surface charge. The former may destabilize keratin dimers/tetramers, whereas the latter likely interferes with higher-order keratin filament formation. Understanding the pathologic alterations in keratin structure improves our knowledge of how PC genotype correlates with clinical phenotype, advancing insight into disease pathogenesis and therapeutic development.

Rheostat functional outcomes occur when substitutions are introduced at nonconserved positions that diverge with speciation.

When amino acids vary during evolution, the outcome can be functionally neutral or biologically-important. We previously found that substituting a subset of nonconserved positions, "rheostat" positions, can have surprising effects on protein function. Since changes at rheostat positions can facilitate functional evolution or cause disease, more examples are needed to understand their unique biophysical characteristics. Here, we explored whether "phylogenetic" patterns of change in multiple sequence alignments (such as positions with subfamily specific conservation) predict the locations of functional rheostat positions. To that end, we experimentally tested eight phylogenetic positions in human liver pyruvate kinase (hLPYK), using 10-15 substitutions per position and biochemical assays that yielded five functional parameters. Five positions were strongly rheostatic and three were non-neutral. To test the corollary that positions with low phylogenetic scores were not rheostat positions, we combined these phylogenetic positions with previously-identified hLPYK rheostat, "toggle" (most substitution abolished function), and "neutral" (all substitutions were like wild-type) positions. Despite representing 428 variants, this set of 33 positions was poorly statistically powered. Thus, we turned to the in vivo phenotypic dataset for E. coli lactose repressor protein (LacI), which comprised 12-13 substitutions at 329 positions and could be used to identify rheostat, toggle, and neutral positions. Combined hLPYK and LacI results show that positions with strong phylogenetic patterns of change are more likely to exhibit rheostat substitution outcomes than neutral or toggle outcomes. Furthermore, phylogenetic patterns were more successful at identifying rheostat positions than were co-evolutionary or eigenvector centrality measures of evolutionary change.

Dermatomyositis autoantibodies: how can we maximize utility?

The past 15 years has seen significant advances in the characterization of myositis-specific autoantibodies (MSAs) and their associated phenotypes in patients with dermatomyositis (DM). As more careful studies are performed, it is clear that unique combinations of clinical and pathological phenotypes are associated with each MSA, despite the fact that there is considerable heterogeneity within antibody classes as well as overlap across the groups. Because risk for interstitial lung disease (ILD), internal malignancy, adverse disease trajectory, and, potentially response to therapy differ by DM MSA group, a deeper understanding of MSAs and validation and standardization of assays used for detection are critical for optimizing diagnosis and treatment. Like any test, the diagnostic sensitivity and specificity of assays for various MSAs is not perfect. Currently tests for MSAs are helpful at minimum for a clinician to assess relative risk or contribute to diagnosis and perhaps counsel the appropriate patient about what to expect. With international standardization and larger studies it is likely that more antibody tests will make their way into formal schemata for diagnosis and actionable risk assessment in DM. In this review, we summarize key considerations for interpreting the clinical and pathologic associations with MSA in DM and identify critical gaps in knowledge and practice that will maximize their clinical utility and utility for understanding disease pathogenesis.

Congenital Thumb-Index Web Space Deficiency.

Background: There are several congenital hand differences that cause thumb-index (TI) web space deficiency. There is a knowledge gap in the literature about the hand differences that are associated with TI web space deficiency. We aimed to identify these congenital differences and the various specific reconstructive surgical procedures that are used for these conditions. Methods: We conducted a retrospective chart review of children treated operatively over a period of 30 years for congenital TI web space deficiency by the senior author (G.M.R.). We gathered data on demographics and associated congenital hand differences and compiled a list of all surgical procedures performed for the web space and the ipsilateral upper extremity. Results: We included 71 patients (77 hands) with 12 congenital hand differences (62 developmental and 9 spastic). The total number of upper extremity operations, (ie), anesthetics performed for these patients was 186, averaging 2.6 settings and 7.5 procedures for each patient. Cutaneous reconstructive procedures included first dorsal metacarpal artery pedicle flaps (49 patients), 4-flap Z-plasties (15), and transposition flaps (13). In addition, 16 different thumb reconstructive procedures were necessary. Ten patients required revision of their TI web space procedures for recurrence. Conclusions: The prevalence of TI web space deficiency is underappreciated. These patients often have multiple musculoskeletal anomalies of the hand and upper extremity that should be ruled out and require surgical treatment to optimize hand function. Consideration should be given to performing more than one procedure in one setting when possible.

Imatinib as a potentially effective therapeutic alternative in corticosteroid-resistant eosinophilic fasciitis.

Eosinophilic fasciitis (EF) is a rare condition in children that is typically treated with systemic corticosteroids. We present the case of a 9-year-old boy with biopsy-proven EF, refractory to systemic corticosteroids and methotrexate. The tyrosine kinase inhibitor imatinib was added as adjuvant therapy, leading to improvement in joint function and skin laxity. Our case is the first to suggest the anti-fibrotic properties of imatinib may benefit EF patients.

Trem2 Deletion Reduces Late-Stage Amyloid Plaque Accumulation, Elevates the Aß42:Aß40 Ratio, and Exacerbates Axonal Dystrophy and Dendritic Spine Loss in the PS2APP Alzheimer's Mouse Model.

TREM2 is an Alzheimer's disease (AD) risk gene expressed in microglia. To study the role of Trem2 in a mouse model of ß-amyloidosis, we compared PS2APP transgenic mice versus PS2APP mice lacking Trem2 (PS2APP;Trem2ko) at ages ranging from 4 to 22 months. Microgliosis was impaired in PS2APP;Trem2ko mice, with Trem2-deficient microglia showing compromised expression of proliferation/Wnt-related genes and marked accumulation of ApoE. Plaque abundance was elevated in PS2APP;Trem2ko females at 6-7 months; but by 12 or 19-22 months of age, it was notably diminished in female and male PS2APP;Trem2ko mice, respectively. Across all ages, plaque morphology was more diffuse in PS2APP;Trem2ko brains, and the Aß42:Aß40 ratio was elevated. The amount of soluble, fibrillar Aß oligomers also increased in PS2APP;Trem2ko hippocampi. Associated with these changes, axonal dystrophy was exacerbated from 6 to 7 months onward in PS2APP;Trem2ko mice, notwithstanding the reduced plaque load at later ages. PS2APP;Trem2ko mice also exhibited more dendritic spine loss around plaque and more neurofilament light chain in CSF. Thus, aggravated neuritic dystrophy is a more consistent outcome of Trem2 deficiency than amyloid plaque load, suggesting that the microglial packing of Aß into dense plaque is an important neuroprotective activity.SIGNIFICANCE STATEMENT Genetic studies indicate that TREM2 gene mutations confer increased Alzheimer's disease (AD) risk. We studied the effects of Trem2 deletion in the PS2APP mouse AD model, in which overproduction of Aß peptide leads to amyloid plaque formation and associated neuritic dystrophy. Interestingly, neuritic dystrophies were intensified in the brains of Trem2-deficient mice, despite these mice displaying reduced plaque accumulation at later ages (12-22 months). Microglial clustering around plaques was impaired, plaques were more diffuse, and the Aß42:Aß40 ratio and amount of soluble, fibrillar Aß oligomers were elevated in Trem2-deficient brains. These results suggest that the Trem2-dependent compaction of Aß into dense plaques is a protective microglial activity, limiting the exposure of neurons to toxic Aß species.

Low-Temperature Pack Aluminization Process on Pipeline Steel To Inhibit Asphaltene Deposition.

Asphaltene deposition in petroleum refineries is known to be problematic as it reduces efficiency and may lead to structural failure or production downtime. Though several successful approaches have been utilized to limit deposition through the addition of dispersants and inhibitors to petroleum, these methods require constant intervention and are often expensive. In this study, we demonstrate an innovative technique to engineer the surface chemistry of pipeline steels to inhibit asphaltene deposition. Pack aluminization, a standard industrial-scale chemical vapor deposition process, is employed at a low temperature of 600 °C to aluminize API 5L X65 high strength pipe steel substrates. The results showed deposit-free steel surfaces after high-pressure and high-temperature fouling experiments. The improvement is attributed to the formation of an aluminide intermetallic phase of Fe2Al5, which changes the native oxide chemistry to favor alumina over hematite. The continuous passivating oxide scale, acting as a protective barrier, mitigates asphaltene deposition and sulfidic corrosion. Because this process is based on alloying the surface of the steel and is not a coating with a weakly adhered interface, it is not prone to delamination, and it can be re-formed when damaged within the aluminized region. The combination of low-cost processing and improved antifouling characteristics makes surface chemistry modification of steel a promising preventative approach against asphaltene deposition.

Complement C3 Is Activated in Human AD Brain and Is Required for Neurodegeneration in Mouse Models of Amyloidosis and Tauopathy.

Complement pathway overactivation can lead to neuronal damage in various neurological diseases. Although Alzheimer's disease (AD) is characterized by ß-amyloid plaques and tau tangles, previous work examining complement has largely focused on amyloidosis models. We find that glial cells show increased expression of classical complement components and the central component C3 in mouse models of amyloidosis (PS2APP) and more extensively tauopathy (TauP301S). Blocking complement function by deleting C3 rescues plaque-associated synapse loss in PS2APP mice and ameliorates neuron loss and brain atrophy in TauP301S mice, improving neurophysiological and behavioral measurements. In addition, C3 protein is elevated in AD patient brains, including at synapses, and levels and processing of C3 are increased in AD patient CSF and correlate with tau. These results demonstrate that complement activation contributes to neurodegeneration caused by tau pathology and suggest that blocking C3 function might be protective in AD and other tauopathies.