Adalimumab as treatment for neurosarcoidosis: A case series.

Sarcoidosis is a disease characterized by non-caseating granulomas that can involve the central nervous system as neurosarcoidosis. This challenging disease is currently managed with high dose steroids, and sometimes the addition of infliximab. Other TNA-alpha inhibitors have not been studied as rigorously. We discovered ten neurosarcoidosis patients who were on an alternative TNA-alpha inhibitor, adalimumab. Eight patients had a positive response clinically and radiographically to adalimumab.

Disparities in Race and Ethnicity Reporting and Representation for Clinical Trials in Stroke: 2010 to 2020.

BACKGROUND: Racial and ethnic minority groups are at a higher stroke risk and have poor poststroke outcomes. The aim of this study was to assess the frequency of race reporting and proportions of race and ethnicity representation in stroke-related clinical trials. METHODS AND RESULTS: This is a descriptive study of stroke-related clinical trials completed between January 1, 2010 and December 31, 2020, and registered on ClinicalTrials.gov. Trials conducted in the United States, related to stroke and enrolling participants ≥18 years, were considered eligible. Trials were reviewed for availability of published results, data on race and ethnicity distribution, and trial characteristics. Overall, 60.1% of published trials reported race or ethnicity of participants, with a 2.6-fold increase in reporting between 2010 and 2020. White patients represented 65.0% of the participants, followed by 24.8% Black, 2.4% Asian or Pacific Islander, and <1% Native American and multiracial participants; 9.0% were of Hispanic ethnicity. These trends remained consistent throughout the study period, except in 2018, when a higher proportion of Black participants (53.1%) was enrolled compared with White participants (35.8%). Trials with the National Institutes of Health/federal funding had higher enrollment of Black (28.1%) and Hispanic (13.8%) participants compared with other funding sources. Behavioral intervention trials had the most diverse enrollment with equal enrollment of Black and White participants (41.1%) and 14.5% Hispanic participants. CONCLUSIONS: Despite the increase in race and ethnicity reporting between 2010 and 2020, the representation of racial and ethnic minority groups remains low in stroke trials. Funding initiatives may influence diversity efforts in trial enrollment.

Neurosarcoidosis causing hydrocephalus: A case series.

Sarcoidosis is a granulomatous inflammatory disease that rarely affects the central nervous system as neurosarcoidosis. Neurosarcoidosis can affect any part of the nervous system causing a wide variety of clinical presentations ranging from seizures to optic neuritis. Here, we highlight rare cases of obstructive hydrocephalus in patients with neurosarcoidosis to make clinicians aware of this potential disease complication.

Neurosarcoidosis: Diagnostic Challenges and Mimics A Review.

PURPOSE OF REVIEW: Neurosarcoidosis is a rare manifestation of sarcoidosis that is challenging to diagnose. Biopsy confirmation of granulomas is not sufficient, as other granulomatous diseases can present similarly. This review is intended to guide the clinician in identifying key conditions to exclude prior to concluding a diagnosis of neurosarcoidosis. RECENT FINDINGS: Although new biomarkers are being studied, there are no reliable tests for neurosarcoidosis. Advances in serum testing and imaging have improved the diagnosis for key mimics of neurosarcoidosis in certain clinical scenarios, but biopsy remains an important method of differentiation. Key mimics of neurosarcoidosis in all cases include infections (tuberculosis, fungal), autoimmune disease (vasculitis, IgG4-related disease), and lymphoma. As neurosarcoidosis can affect any part of the nervous system, patients should have a unique differential diagnosis tailored to their clinical presentation. Although biopsy can assist with excluding mimics, diagnosis is ultimately clinical.

Empiric treatment for persistent fever from suspected autoinflammatory disease: Experience from an undiagnosed diseases program.

BACKGROUND: Patients with persistent fevers of undetermined etiology often undergo extensive evaluation without a diagnosis. Autoinflammatory syndromes may not always be considered in the differential, as these are rare entities, there are no consensus clinical criteria and genetic testing can only capture a few of these diseases. We aimed to describe the experience and value of an undiagnosed diseases program in the evaluation and management of patients who present with persistent fevers. METHODS: A retrospective analysis was performed on eleven patients who presented with persistent fevers to the Undiagnosed Diseases Program (UDP) at University of Alabama at Birmingham. All patients received extensive testing prior to referral and were seen by multiple subspecialists. The primary outcome of complete remission was resolution of episodes of fever and malaise in response to empiric biological anti-inflammatory treatment. RESULTS: All patients received genetic testing and further diagnostic evaluation by the UDP. Even without confirmed genetic testing, they were empirically started on anti-inflammatory therapies (including colchicine, IL-1 inhibitors, IL-6 inhibitors). Ten patients have achieved complete remission on empiric treatment. Three patients were given formal diagnoses. No patients have had any major adverse events from therapy. CONCLUSIONS: This is a pilot study suggesting the role for empiric treatment trials of biologics for patients with suspected autoinflammatory diseases. As the differential diagnosis of patients with persistent fevers is broad, and the diagnosis of autoinflammatory diseases often comes with some degree of uncertainty, evaluation by a center with expertise in diagnosing these conditions can help determine which patients should have empiric trials of biologics.

Rural-urban differences in functional outcomes after acute stroke therapy within the stroke belt.

INTRODUCTION: The Southeastern United States (US) has the highest stroke mortality rate in the country. A high proportion of its population lives in rural areas. Rural patients with stroke have worse outcomes than their urban counterparts. We compared 90-day modified Rankin Score (mRS) between patients living in urban versus rural areas who received endovascular intervention for acute stroke. METHODS: We performed a retrospective analysis of patients who received acute stroke therapy at a comprehensive stroke center in the Southeastern US from 2014 to 2018. Individuals were classified as rural or urban dwellers based on 2010 Rural-Urban Commuting Area Codes. Stepwise logistic regression models were performed using clinical and demographic characteristics to compare good (mRS 0-1) vs poor (mRS 2-6) functional outcomes between urban and rural patients. RESULTS: 232 patients were included (185 urban and 47 rural). Urban and rural groups had similar composition of age, gender, and proportion of African-Americans. Mean baseline NIH stroke scale was higher in rural patients (17.0 vs 14.8 respectively, p-value=0.03.). Our model for poor functional outcome at 90-days revealed only older age as a significant risk factor (OR 0.97, 95% CI 0.95-0.99). CONCLUSIONS: Our study found that for patients receiving acute therapy for ischemic stroke, there were no significant differences in functional outcome between urban versus rural patients. Only older age predicted poor functional outcome at 90 days. Our study demonstrates that patients from rural areas may not have worse mortality rates or poor outcomes and can recover similarly to those from urban areas.

NKX3.1 Identifies Prostatic Origin of Dural Metastasis in the Setting of Negative Prostate-Specific Antigen Stain.

No clear guidelines exist for the appropriate diagnostic workup of an intracranial mass suspected to be a metastasis from unknown primary origin. Dural metastasis from prostatic origin is very rare. Patients with a known history of metastatic prostate cancer who present with a newly discovered lesion on brain imaging require neurosurgical biopsy to confirm diagnosis prior to initiating treatment. Intracranial metastasis from prostate cancer is rare, and dural metastasis is rarer than intraparenchymal metastasis. Current consensus guidelines support immunohistochemical staining with classic markers such as prostate-specific antigen (PSA) to identify prostatic origin. However, PSA detection of prostate metastases declines with higher Gleason scores and in patients undergoing androgen deprivation therapy. NKX3.1 is another stain that is highly sensitive and specific for prostate. Our patient was a 54-year-old man with a history of metastatic prostate cancer who presented with new-onset seizures. Brain imaging revealed a dural-based lesion with surrounding vasogenic edema and midline shift. The patient underwent resection of the lesion, which was stained with multiple cancer markers. Prostate-specific antigen was negative, but NKX3.1 was positive indicating a prostatic origin for the mass. He underwent a craniectomy to remove the lesion and was given steroids. However, he succumbed to his illness several months later. Here, we document the first report to our knowledge of a patient with prostate metastasis to the dura that is PSA negative, but NKX3.1 positive.

Neuralgic Amyotrophy Presenting with Multifocal Myonecrosis and Rhabdomyolysis.

Neuralgic amyotrophy (NA), also known as Parsonage-Turner syndrome, is an idiopathic disorder characterized by rapid-onset unilateral upper extremity pain, paralysis, and sensory disturbance in the distribution of the brachial plexus. The etiology is unknown, and there is a multitude of alternative clinical presentations as well as secondary triggers, which make the diagnosis challenging. To date, there has been no report of NA presenting with frank myonecrosis. In this report, we document the first case of NA presenting with multifocal myonecrosis of the shoulder girdle muscles and rhabdomyolysis. This case posed a unique challenge in the diagnostic workup and management as many causes of myonecrosis present similarly to NA, and NA is a diagnosis of exclusion. Our patient underwent exhaustive testing and several trials of therapy before diagnosis could be made. Such evaluations are expensive and carry risks for patients. As such, it is important that physicians recognize this unique presentation of NA.

Induction of autophagy in Cx3cr1+ mononuclear cells limits IL-23/IL-22 axis-mediated intestinal fibrosis.

Intestinal fibrosis is an excessive proliferation of myofibroblasts and deposition of collagen, a condition frequently seen in Crohn's disease (CD). The mechanism underlying myofibroblast hyper-proliferation in CD needs to be better understood. In this report, we found that mTOR inhibitor rapamycin or mTOR deletion in CX3Cr1+ mononuclear phagocytes inhibits expression of interleukin (IL)-23, accompanied by reduced intestinal production of IL-22 and ameliorated fibrosis in the TNBS-induced fibrosis mouse model. This inhibition of IL-23 expression is associated with elevated autophagy activity. Ablating the autophagy gene Atg7 increases the expression of IL-23, leading to increased expression of IL-22 and increased fibrosis. Both induction of IL-22 and intestinal fibrosis occurred in RAG-/- mice and depletion of innate lymphoid cells (ILCs) attenuates the fibrotic reaction, suggesting that the pro-fibrotic process is independent of T and B cells. Moreover, IL-22 facilitates the transformation of fibroblasts into myofibroblasts. Finally, the fibrotic reaction was attenuated upon neutralization of either IL-23 or IL-22. Altogether, this study elucidated a signaling cascade underlying intestinal fibrosis in which altered mTOR/autophagy in CX3Cr1+ mononuclear phagocytes up-regulates the IL-23/IL-22 axis, leading to an excessive fibrotic response. Thus, our findings suggest that this cascade could be a therapeutic target for alleviation of CD fibrosis.

Optimization of Laboratory Ordering Practices for Complete Blood Count With Differential.

Objectives: To investigate the utilization of CBC and CBC with differential (CBC w/diff) tests at University of Alabama at Birmingham Hospital, and to determine if a reduction in CBC w/diff tests could be achieved without negatively impacting patient care. Methods: The quantity of testing and distribution of repeated tests before, during, and after an educational intervention were compared. Results: CBC w/diff tests were ordered 10-fold more frequently than CBC tests. The trauma burn intensive care unit ordered the most CBC w/diff tests, with repeat tests done every 4 or 12 hours. The educational intervention reduced the number of CBC w/diff tests ordered and tests repeated every 12 hours. Conclusions: The educational intervention changed the ordering practices of CBC w/diff and CBC tests. This was sustained after the intervention and no negative effects on patient care were noted. Similar interventions may lead to optimization of ordering practices of other laboratory tests.

Association Between Genetic Traits for Immune-Mediated Diseases and Alzheimer Disease.

IMPORTANCE: Late-onset Alzheimer disease (AD), the most common form of dementia, places a large burden on families and society. Although epidemiological and clinical evidence suggests a relationship between inflammation and AD, their relationship is not well understood and could have implications for treatment and prevention strategies. OBJECTIVE: To determine whether a subset of genes involved with increased risk of inflammation are also associated with increased risk for AD. DESIGN, SETTING, AND PARTICIPANTS: In a genetic epidemiology study conducted in July 2015, we systematically investigated genetic overlap between AD (International Genomics of Alzheimer's Project stage 1) and Crohn disease, ulcerative colitis, rheumatoid arthritis, type 1 diabetes, celiac disease, and psoriasis using summary data from genome-wide association studies at multiple academic clinical research centers. P values and odds ratios from genome-wide association studies of more than 100 000 individuals were from previous comparisons of patients vs respective control cohorts. Diagnosis for each disorder was previously established for the parent study using consensus criteria. MAIN OUTCOMES AND MEASURES: The primary outcome was the pleiotropic (conjunction) false discovery rate P value. Follow-up for candidate variants included neuritic plaque and neurofibrillary tangle pathology; longitudinal Alzheimer's Disease Assessment Scale cognitive subscale scores as a measure of cognitive dysfunction (Alzheimer's Disease Neuroimaging Initiative); and gene expression in AD vs control brains (Gene Expression Omnibus data). RESULTS: Eight single-nucleotide polymorphisms (false discovery rate P < .05) were associated with both AD and immune-mediated diseases. Of these, rs2516049 (closest gene HLA-DRB5; conjunction false discovery rate P = .04 for AD and psoriasis, 5.37 × 10-5 for AD, and 6.03 × 10-15 for psoriasis) and rs12570088 (closest gene IPMK; conjunction false discovery rate P = .009 for AD and Crohn disease, P = 5.73 × 10-6 for AD, and 6.57 × 10-5 for Crohn disease) demonstrated the same direction of allelic effect between AD and the immune-mediated diseases. Both rs2516049 and rs12570088 were significantly associated with neurofibrillary tangle pathology (P = .01352 and .03151, respectively); rs2516049 additionally correlated with longitudinal decline on Alzheimer's Disease Assessment Scale cognitive subscale scores (ß [SE], 0.405 [0.190]; P = .03). Regarding gene expression, HLA-DRA and IPMK transcript expression was significantly altered in AD brains compared with control brains (HLA-DRA: ß [SE], 0.155 [0.024]; P = 1.97 × 10-10; IPMK: ß [SE], -0.096 [0.013]; P = 7.57 × 10-13). CONCLUSIONS AND RELEVANCE: Our findings demonstrate genetic overlap between AD and immune-mediated diseases and suggest that immune system processes influence AD pathogenesis and progression.

Systems biology approach to identify gene network signatures for colorectal cancer.

In this work, we integrated prior knowledge from gene signatures and protein interactions with gene set enrichment analysis (GSEA), and gene/protein network modeling together to identify gene network signatures from gene expression microarray data. We demonstrated how to apply this approach into discovering gene network signatures for colorectal cancer (CRC) from microarray datasets. First, we used GSEA to analyze the microarray data through enriching differential genes in different CRC-related gene sets from two publicly available up-to-date gene set databases - Molecular Signatures Database (MSigDB) and Gene Signatures Database (GeneSigDB). Second, we compared the enriched gene sets through enrichment score, false-discovery rate, and nominal p-value. Third, we constructed an integrated protein-protein interaction (PPI) network through connecting these enriched genes by high-quality interactions from a human annotated and predicted protein interaction database, with a confidence score labeled for each interaction. Finally, we mapped differential gene expressions onto the constructed network to build a comprehensive network model containing visualized transcriptome and proteome data. The results show that although MSigDB has more CRC-relevant gene sets than GeneSigDB, the integrated PPI network connecting the enriched genes from both MSigDB and GeneSigDB can provide a more complete view for discovering gene network signatures. We also found several important sub-network signatures for CRC, such as TP53 sub-network, PCNA sub-network, and IL8 sub-network, corresponding to apoptosis, DNA repair, and immune response, respectively.

Reordering based integrative expression profiling for microarray classification.

BACKGROUND: Current network-based microarray analysis uses the information of interactions among concerned genes/gene products, but still considers each gene expression individually. We propose an organized knowledge-supervised approach - Integrative eXpression Profiling (IXP), to improve microarray classification accuracy, and help discover groups of genes that have been too weak to detect individually by traditional ways. To implement IXP, ant colony optimization reordering (ACOR) algorithm is used to group functionally related genes in an ordered way. RESULTS: Using Alzheimer's disease (AD) as an example, we demonstrate how to apply ACOR-based IXP approach into microarray classifications. Using a microarray dataset - GSE1297 with 31 samples as training set, the result for the blinded classification on another microarray dataset - GSE5281 with 151 samples, shows that our approach can improve accuracy from 74.83% to 82.78%. A recently-published 1372-probe signature for AD can only achieve 61.59% accuracy in the same condition. The ACOR-based IXP approach also has better performance than the IXP approach based on classic network ranking, graph clustering, and random-ordering methods in an overall classification performance comparison. CONCLUSIONS: The ACOR-based IXP approach can serve as a knowledge-supervised feature transformation approach to increase classification accuracy dramatically, by transforming each gene expression profile to an integrated expression files as features inputting into standard classifiers. The IXP approach integrates both gene expression information and organized knowledge - disease gene/protein network topology information, which is represented as both network node weights (local topological properties) and network node orders (global topological characteristics).

High-resolution experimental and computational profiling of tissue-specific known and novel miRNAs in Arabidopsis.

Small non-coding RNAs (ncRNAs) are key regulators of plant development through modulation of the processing, stability, and translation of larger RNAs. We present small RNA data sets comprising more than 200 million aligned Illumina sequence reads covering all major cell types of the root as well as four distinct developmental zones. MicroRNAs (miRNAs) constitute a class of small ncRNAs that are particularly important for development. Of the 243 known miRNAs, 133 were found to be expressed in the root, and most showed tissue- or zone-specific expression patterns. We identified 66 new high-confidence miRNAs using a computational pipeline, PIPmiR, specifically developed for the identification of plant miRNAs. PIPmiR uses a probabilistic model that combines RNA structure and expression information to identify miRNAs with high precision. Knockdown of three of the newly identified miRNAs results in altered root growth phenotypes, confirming that novel miRNAs predicted by PIPmiR have functional relevance.

Outcomes and satisfaction of patients with orthopaedic implants left in-situ for more than three years: a retrospective study.

BACKGROUND: There are no clear guidelines on implant removal. Few have assessed the long-term outcomes of patients with implants left in-situ, or removed. Therefore, removal of implants after fracture fixation remains controversial. METHODS: In this retrospective study, we reviewed 53 patients with implant for fracture fixation in-situ for more than 3 years. All patients were younger than 60 years. Quality of life of each patient was assessed with the Chinese (Hong Kong) validated Short Form-36 and the pain was assessed with visual analogue scale (VAS). All patients were clinically examined and plain radiographs were taken. RESULTS: The total SF-36 score of the patients was not statistically different from the Hong Kong norm (P > 0.05). Mean score of VAS was 2.08. Thirty-three patients (62.3%) reported limited range of movement, 9 patients (17%) complained of cosmetic problems, and 10 patients (18.9%) complained of weakness. Clinically, 82.6% of patients had no scarring, 84.7% of patients had full range of movement and all had no tenderness on assessment. Radiologically, no abnormality was detected except for one patient with known avascular necrosis of the femoral head after screw fixation. CONCLUSION: As most patients were clinically and radiologically normal with quality of life scores comparable to the norm, removal of implants is not advisable as a routine practice.