MORA and EnsembleTFpredictor: An ensemble approach to reveal functional transcription factor regulatory networks.

MOTIVATION: Our study aimed to identify biologically relevant transcription factors (TFs) that control the expression of a set of co-expressed or co-regulated genes. RESULTS: We developed a fully automated pipeline, Motif Over Representation Analysis (MORA), to detect enrichment of known TF binding motifs in any query sequences. MORA performed better than or comparable to five other TF-prediction tools as evaluated using hundreds of differentially expressed gene sets and ChIP-seq datasets derived from known TFs. Additionally, we developed EnsembleTFpredictor to harness the power of multiple TF-prediction tools to provide a list of functional TFs ranked by prediction confidence. When applied to the test datasets, EnsembleTFpredictor not only identified the target TF but also revealed many TFs known to cooperate with the target TF in the corresponding biological systems. MORA and EnsembleTFpredictor have been used in two publications, demonstrating their power in guiding experimental design and in revealing novel biological insights.

Overexpressing low-density lipoprotein receptor reduces tau-associated neurodegeneration in relation to apoE-linked mechanisms.

APOE is the strongest genetic risk factor for late-onset Alzheimer's disease. ApoE exacerbates tau-associated neurodegeneration by driving microglial activation. However, how apoE regulates microglial activation and whether targeting apoE is therapeutically beneficial in tauopathy is unclear. Here, we show that overexpressing an apoE metabolic receptor, LDLR (low-density lipoprotein receptor), in P301S tauopathy mice markedly reduces brain apoE and ameliorates tau pathology and neurodegeneration. LDLR overexpression (OX) in microglia cell-autonomously downregulates microglial Apoe expression and is associated with suppressed microglial activation as in apoE-deficient microglia. ApoE deficiency and LDLR OX strongly drive microglial immunometabolism toward enhanced catabolism over anabolism, whereas LDLR-overexpressing microglia also uniquely upregulate specific ion channels and neurotransmitter receptors upon activation. ApoE-deficient and LDLR-overexpressing mice harbor enlarged pools of oligodendrocyte progenitor cells (OPCs) and show greater preservation of myelin integrity under neurodegenerative conditions. They also show less reactive astrocyte activation in the setting of tauopathy.

A Comparison of Treatment Effects for Nonsurgical Therapies and the Minimum Clinically Important Difference in Knee Osteoarthritis: A Systematic Review.

BACKGROUND: The minimum clinically important difference (MCID) was developed to ascertain the smallest change in an outcome that patients perceive as beneficial. The objectives of the present review were (1) to compare the MCIDs for pain assessments used among guidelines and meta-analyses investigating different nonsurgical therapies for knee osteoarthritis and (2) to compare the effect estimates of different nonsurgical interventions against a single commonly-utilized MCID threshold. METHODS: Systematic and manual searches were conducted to identify guidelines and meta-analyses evaluating pain outcomes for nonsurgical knee osteoarthritis interventions. Individual treatment effects for pain were presented on a common scale (the standardized mean difference [SMD]). To evaluate the perception of the relative benefit of each nonsurgical treatment, the variation in MCIDs selected from the published MCID literature was assessed. RESULTS: Thirty-seven guidelines and meta-analyses were included. MCIDs were often presented as an SMD or a mean difference (MD) on a validated scale and varied in magnitude across sources. This analysis demonstrated that intra-articular hyaluronic acid, intra-articular corticosteroids, and acetaminophen all had relatively larger effect sizes than topical nonsteroidal anti-inflammatory drugs (NSAIDs). Higher-molecular-weight intra-articular hyaluronic acid had a greater relative effect compared with both non-selective and cyclooxygenase-2-selective oral NSAIDs. Evaluating the treatment effect estimates against a commonly utilized MCID revealed similarities in which observations attained clinical significance among treatments; however, this observation varied across the range of reported MCIDs. CONCLUSIONS: The present review confirmed the variability in the MCIDs for pain assessments that are used across guidelines and meta-analyses evaluating nonsurgical interventions for knee osteoarthritis. This variability may yield conflicting treatment recommendations, ranging from rejecting treatments that are indeed efficacious to accepting treatments that may not be beneficial. Additional research is required to determine why some nonsurgical therapies are more consistently recommended in knee osteoarthritis guidelines than others as these findings suggest similarities in their effect estimates for pain. Relevant stakeholders need to reach a consensus on a standard approach to determining the MCIDs for these therapies to ensure that appropriate and effective treatment options are available to patients prior to invasive surgical intervention. LEVEL OF EVIDENCE: Therapeutic Level IV. See Instructions for Authors for a complete description of levels of evidence.

Attraction of Culex pipiens to House Sparrows Is Influenced by Host Age but Not Uropygial Gland Secretions.

Culex pipiens serves as the endemic vector of West Nile virus (WNV) in eastern North America, where house sparrows (HOSP, Passer domesticus) serve as a reservoir host. We tested the hypotheses that: (1) Attraction of Cx. pipiens to HOSP is influenced by bird age and (2) that age-specific variation in chemical profiles of bird uropygial gland secretions informs this choice. We conducted mosquito choice trials in an olfactometer and found that Cx. pipiens were more often attracted to adult sparrows over nestlings, however, they demonstrated no preference for adults over fledglings. Using gas chromatography-mass spectrometry we observed age-specific differences in the semi-volatile chemical profiles of house sparrow uropygial gland secretions. Contrary to our hypothesis, we found no significant difference in mosquito feeding preference between the secretions of adults and those of either nestlings or fledglings. We suggest that other chemical cues influence the feeding preference of Cx. pipiens, either independently of uropygial gland secretions, or synergistically with them.

Guidelines of care for the management of acne vulgaris.

Acne is one of the most common disorders treated by dermatologists and other health care providers. While it most often affects adolescents, it is not uncommon in adults and can also be seen in children. This evidence-based guideline addresses important clinical questions that arise in its management. Issues from grading of acne to the topical and systemic management of the disease are reviewed. Suggestions on use are provided based on available evidence.

Translating psoriasis guidelines into practice: Important gaps revealed.

BACKGROUND: There is a well-established lack of adherence to evidence-based clinical guidelines. The American Academy of Dermatology (AAD) developed educational sessions entitled Translating Evidence into Practice based on the published guidelines for psoriasis and psoriatic arthritis. OBJECTIVE: We sought to determine the effectiveness of Translating Evidence into Practice sessions in improving patient care. METHODS: Pre- and post-session surveys were administered at Translating Evidence into Practice sessions. A follow-up was administered 6 months after completion of the most recent session, which was 2.5 years after the first session. RESULTS: At both post-session and follow-up, more than 92% of participants believed the sessions had improved their knowledge. The proportion of participants that self-reported assessing disease severity, comorbidities, and quality of life increased at follow-up. Participants' self-reported counseling of patients and confidence in treating psoriasis and psoriatic arthritis also increased at post-session and follow-up. Greater than 97% of participants thought the sessions would have a positive impact on their practice whereas 50% reported making a change in practice. LIMITATIONS: Lack of a control group, the self-reported nature of the data, and potential participant bias are limitations. CONCLUSION: The AAD's Translating Evidence into Practice sessions are effective and well received for improving knowledge and practice and can be useful to determine self-reported practice gaps.

Prevention of Orthopaedic Implant Infection in Patients Undergoing Dental Procedures.

The Prevention of Orthopaedic Implant Infection in Patients Undergoing Dental Procedures evidence-based clinical practice guideline was codeveloped by the American Academy of Orthopaedic Surgeons (AAOS) and the American Dental Association. This guideline replaces the previous AAOS Information Statement, "Antibiotic Prophylaxis in Bacteremia in Patients With Joint Replacement," published in 2009. Based on the best current evidence and a systematic review of published studies, three recommendations have been created to guide clinical practice in the prevention of orthopaedic implant infections in patients undergoing dental procedures. The first recommendation is graded as Limited; this recommendation proposes that the practitioner consider changing the long-standing practice of routinely prescribing prophylactic antibiotic for patients with orthopaedic implants who undergo dental procedures. The second, graded as Inconclusive, addresses the use of oral topical antimicrobials in the prevention of periprosthetic joint infections. The third recommendation, a Consensus statement, addresses the maintenance of good oral hygiene.

Modern metal-on-metal hip implants.

This Technology Overview was prepared using systematic review methodology and summarizes the findings of studies published as of July 15, 2011, on modern metal-on-metal hip implants. Analyses conducted on outcomes by two joint registries indicate that patients who receive metal-on-metal total hip arthroplasty (THA) and hip resurfacing are at greater risk for revision than are patients who receive THA using a different bearing surface combination. Data from these registries also indicate that larger femoral head components have higher revision rates and risk of revision and that older age is associated with increased revision risks of large-head metal-on-metal THA. Several studies noted a correlation between suboptimal hip implant positioning and higher wear rates, local metal debris release, and consequent local tissue reactions to metal debris. In addition, several studies reported elevated serum metal ion concentrations in patients with metal-on-metal hip articulations, although the clinical significance of these elevated ion concentrations remains unknown.

The treatment of pediatric supracondylar humerus fractures.

Based on the best current evidence and a systematic review of published studies, 14 recommendations have been created to guide clinical practice and management of supracondylar fractures of the humerus in children. Two each of these recommendations are graded Weak and Consensus; eight are graded Inconclusive. The two Moderate recommendations include nonsurgical immobilization for acute or nondisplaced fractures of the humerus or posterior fat pad sign, and closed reduction with pin fixation for displaced type II and III and displaced flexion fractures.

Optimizing the management of rotator cuff problems.

Of the 31 recommendations made by the work group, 19 were determined to be inconclusive because of the absence of definitive evidence. Of the remaining recommendations, four were classified as moderate grade, six as weak, and two as consensus statements of expert opinion. The four moderate-grade recommendations include suggestions that exercise and nonsteroidal anti-inflammatory drugs be used to manage rotator cuff symptoms in the absence of a full-thickness tear, that routine acromioplasty is not required at the time of rotator cuff repair, that non-cross-linked, porcine small intestine submucosal xenograft patches not be used to manage rotator cuff tears, and that surgeons can advise patients that workers' compensation status correlates with less favorable outcomes after rotator cuff surgery.

Diagnosis and treatment of osteochondritis dissecans.

This clinical practice guideline is based on a series of systematic reviews of published studies in the available literature on the diagnosis and treatment of osteochondritis dissecans of the knee. None of the 16 recommendations made by the work group is graded as strong; most are graded inconclusive; two are graded weak; and four are consensus statements. Both of the weak recommendations are related to imaging evaluation. For patients with knee symptoms, radiographs of the joint may be obtained to identify the lesion. For patients with radiographically apparent lesions, MRI may be used to further characterize the osteochondritis dissecans lesion or identify other knee pathology.

The treatment of symptomatic osteoporotic spinal compression fractures.

This clinical practice guideline is based on a series of systematic reviews of published studies on the treatment of symptomatic osteoporotic spinal compression fractures. Of 11 recommendations, one is strong; one, moderate; three, weak; and six, inconclusive. The strong recommendation is against the use of vertebroplasty to treat the fractures; the moderate recommendation is for the use of calcitonin for 4 weeks following the onset of fracture. The weak recommendations address the use of ibandronate and strontium ranelate to prevent additional symptomatic fractures, the use of L2 nerve root blocks to treat the pain associated with L3 or L4 fractures, and the use of kyphoplasty to treat symptomatic fractures in patients who are neurologically intact.

Diagnosis and treatment of acute Achilles tendon rupture.

This clinical practice guideline is based on a series of systematic reviews of published studies in the available literature on the diagnosis and treatment of acute Achilles tendon rupture. None of the 16 recommendations made by the work group was graded as strong; most are graded inconclusive; four are graded weak; two are graded as moderate strength; and two are consensus statements. The two moderate-strength recommendations include the suggestions for early postoperative protective weight bearing and for the use of protective devices that allow for postoperative mobilization.