Tracking daily fatigue fluctuations in multiple sclerosis : ecological momentary assessment provides unique insights

The preparation of this manuscript was supported by a UK Economic and Social Research Council (ESRC) PhD studentship (ES/1026266/1) awarded to DP. The study was funded by the Psychology Unit at the University of Southampton. The authors declare that they have no conflict of interest. The authors thank all participants of this study. Open access via Springer Compact Agreement.Peer reviewedPublisher PD

Identification and nucleotide sequences of mxaA, mxaC, mxaK, mxaL, and mxaD genes from Methylobacterium extorquens AM1

The DNA sequence for a 4.4-kb HindIII-XhoI Methylobacterium extorquens AM1 DNA fragment that is known to contain three genes (mxaAKL) involved in incorporation of calcium into methanol dehydrogenase (I. W. Richardson and C. Anthony, Biochem. J. 287:709-7115, 1992) was determined. Five complete open reading frames and two partial open reading frames were found, suggesting that this region contains previously unidentified genes. A combination of sequence analysis, mutant complementation data, and gene expression studies showed that these genes correspond to mxaSACKLDorf1. Of the three previously unidentified genes (mxaC, mxaD, and orf1), mutant complementation studies showed that mxaC is required for methanol oxidation, while the function of the other two genes is still unknown

Joint Application of the Target Trial Causal Framework and Machine Learning Modeling to Optimize Antibiotic Therapy: Use Case on Acute Bacterial Skin and Skin Structure Infections due to Methicillin-resistant Staphylococcus aureus

Bacterial infections are responsible for high mortality worldwide. Antimicrobial resistance underlying the infection, and multifaceted patient's clinical status can hamper the correct choice of antibiotic treatment. Randomized clinical trials provide average treatment effect estimates but are not ideal for risk stratification and optimization of therapeutic choice, i.e., individualized treatment effects (ITE). Here, we leverage large-scale electronic health record data, collected from Southern US academic clinics, to emulate a clinical trial, i.e., 'target trial', and develop a machine learning model of mortality prediction and ITE estimation for patients diagnosed with acute bacterial skin and skin structure infection (ABSSSI) due to methicillin-resistant Staphylococcus aureus (MRSA). ABSSSI-MRSA is a challenging condition with reduced treatment options - vancomycin is the preferred choice, but it has non-negligible side effects. First, we use propensity score matching to emulate the trial and create a treatment randomized (vancomycin vs. other antibiotics) dataset. Next, we use this data to train various machine learning methods (including boosted/LASSO logistic regression, support vector machines, and random forest) and choose the best model in terms of area under the receiver characteristic (AUC) through bootstrap validation. Lastly, we use the models to calculate ITE and identify possible averted deaths by therapy change. The out-of-bag tests indicate that SVM and RF are the most accurate, with AUC of 81% and 78%, respectively, but BLR/LASSO is not far behind (76%). By calculating the counterfactuals using the BLR/LASSO, vancomycin increases the risk of death, but it shows a large variation (odds ratio 1.2, 95% range 0.4-3.8) and the contribution to outcome probability is modest. Instead, the RF exhibits stronger changes in ITE, suggesting more complex treatment heterogeneity.Comment: This is the Proceedings of the KDD workshop on Applied Data Science for Healthcare (DSHealth 2022), which was held on Washington D.C, August 14 202

Brn-3b enhances the pro-apoptotic effects of p53 but not its induction of cell cycle arrest by cooperating in trans-activation of bax expression

The Brn-3a and Brn-3b transcription factor have opposite and antagonistic effects in neuroblastoma cells since Brn-3a is associated with differentiation whilst Brn-3b enhances proliferation in these cells. In this study, we demonstrate that like Brn-3a, Brn-3b physically interacts with p53. However, whereas Brn-3a repressed p53 mediated Bax expression but cooperated with p53 to increase p21(cip1/waf1), this study demonstrated that co-expression of Brn-3b with p53 increases trans-activation of Bax promoter but not p21(cip1/waf1). Consequently co-expression of Brn-3b with p53 resulted in enhanced apoptosis, which is in contrast to the increased survival and differentiation, when Brn-3a is co-expressed with p53. For Brn-3b to cooperate with p53 on the Bax promoter, it requires binding sites that flank p53 sites on this promoter. Furthermore, neurons from Brn-3b knock-out (KO) mice were resistant to apoptosis and this correlated with reduced Bax expression upon induction of p53 in neurons lacking Brn-3b compared with controls. Thus, the ability of Brn-3b to interact with p53 and modulate Bax expression may demonstrate an important mechanism that helps to determine the fate of cells when p53 is induced

A novel patient-derived intra-femoral xenograft model of bone metastatic prostate cancer that recapitulates mixed osteolytic and osteoblastic lesions

<p>Abstract</p> <p/> <p>Prostate cancer metastasizes to bone in the majority of patients with advanced disease leading to painfully debilitating fractures, spinal compression and rapid decline. In addition, prostate cancer bone metastases often become resistant to standard therapies including androgen deprivation, radiation and chemotherapy. There are currently few models to elucidate mechanisms of interaction between the bone microenvironment and prostate cancer. It is, thus, essential to develop new patient-derived, orthotopic models. Here we report the development and characterization of PCSD1 (Prostate Cancer San Diego 1), a novel patient-derived intra-femoral xenograft model of prostate bone metastatic cancer that recapitulates mixed osteolytic and osteoblastic lesions.</p> <p>Methods</p> <p>A femoral bone metastasis of prostate cancer was removed during hemiarthroplasty and transplanted into <it>Rag2^-/-;γ_c^-/-</it>mice either intra-femorally or sub-cutaneously. Xenograft tumors that developed were analyzed for prostate cancer biomarker expression using RT-PCR and immunohistochemistry. Osteoblastic, osteolytic and mixed lesion formation was measured using micro-computed tomography (microCT).</p> <p>Results</p> <p>PCSD1 cells isolated directly from the patient formed tumors in all mice that were transplanted intra-femorally or sub-cutaneously into <it>Rag2^-/-;γ_c^-/-</it>mice. Xenograft tumors expressed human prostate specific antigen (PSA) in RT-PCR and immunohistochemical analyses. PCSD1 tumors also expressed AR, NKX3.1, Keratins 8 and 18, and AMACR. Histologic and microCT analyses revealed that intra-femoral PCSD1 xenograft tumors formed mixed osteolytic and osteoblastic lesions. PCSD1 tumors have been serially passaged in mice as xenografts intra-femorally or sub-cutaneously as well as grown in culture.</p> <p>Conclusions</p> <p>PCSD1 xenografts tumors were characterized as advanced, luminal epithelial prostate cancer from a bone metastasis using RT-PCR and immunohistochemical biomarker analyses. PCSD1 intra-femoral xenografts formed mixed osteoblastic/osteolytic lesions that closely resembled the bone lesions in the patient. PCSD1 is a new primary prostate cancer bone metastasis-derived xenograft model to study metastatic disease in the bone and to develop novel therapies for inhibiting prostate cancer growth in the bone-niche.</p

Exposure and impact of a mass media campaign targeting sexual health amongst Scottish men who have sex with men: an outcome evaluation

Background: This paper explores the exposure and impact of a Scottish mass media campaign: Make Your Position Clear. It ran from October 2009 to July 2010, targeted gay men and other men who have sex with men (MSM), and had two key aims: to promote regular sexual health and HIV testing every 6 months, and to promote the use of appropriate condoms and water-based lubricant with each episode of anal intercourse. Methods: A cross-sectional survey (anonymous and self-report) was conducted 10 months after the campaign was launched (July 2010). Men were recruited from commercial venues. Outcome measures included use of lubricant, testing for sexually transmitted infections and HIV, and intentions to seek HIV testing within the following six months. Linear-by-linear chi-square analysis and binary logistic regressions were conducted to explore the associations between the outcome measures and campaign exposure. Results: The total sample was 822 men (62.6% response rate). Men self-identifying as HIV positive were excluded from the analysis (n = 38). Binary logistic analysis indicated that those with mid or high campaign exposure were more likely to have been tested for HIV in the previous six months when adjusted for age, area of residence and use of the “gay scene” (AOR = 1.96, 95% CI = 1.26 to 3.06, p = .003), but were not more likely to be tested for STIs (AOR = 1.37, 95% CI = 0.88 to 2.16, p = .167). When adjusted for previous HIV testing, those with mid or high campaign exposure were not more likely to indicate intention to be tested for HIV in the following six months (AOR = 1.30, 95% CI = 0.73 to 2.32, p = .367). Those with no campaign exposure were less likely than those with low exposure to have used appropriate lubricant with anal sex partners in the previous year (AOR = 0.42, 95% CI = 0.23 to 0.77, p = .005). Conclusions: The campaign had demonstrable reach. The analysis showed partial support for the role of mass media campaigns in improving sexual health outcomes. This suggests that a role for mass media campaigns remains within combination HIV prevention

Transcriptional profiling of MnSOD-mediated lifespan extension in Drosophila reveals a species-general network of aging and metabolic genes.

BACKGROUND: Several interventions increase lifespan in model organisms, including reduced insulin/insulin-like growth factor-like signaling (IIS), FOXO transcription factor activation, dietary restriction, and superoxide dismutase (SOD) over-expression. One question is whether these manipulations function through different mechanisms, or whether they intersect on common processes affecting aging. RESULTS: A doxycycline-regulated system was used to over-express manganese-SOD (MnSOD) in adult Drosophila, yielding increases in mean and maximal lifespan of 20%. Increased lifespan resulted from lowered initial mortality rate and required MnSOD over-expression in the adult. Transcriptional profiling indicated that the expression of specific genes was altered by MnSOD in a manner opposite to their pattern during normal aging, revealing a set of candidate biomarkers of aging enriched for carbohydrate metabolism and electron transport genes and suggesting a true delay in physiological aging, rather than a novel phenotype. Strikingly, cross-dataset comparisons indicated that the pattern of gene expression caused by MnSOD was similar to that observed in long-lived Caenorhabditis elegans insulin-like signaling mutants and to the xenobiotic stress response, thus exposing potential conserved longevity promoting genes and implicating detoxification in Drosophila longevity. CONCLUSION: The data suggest that MnSOD up-regulation and a retrograde signal of reactive oxygen species from the mitochondria normally function as an intermediate step in the extension of lifespan caused by reduced insulin-like signaling in various species. The results implicate a species-conserved net of coordinated genes that affect the rate of senescence by modulating energetic efficiency, purine biosynthesis, apoptotic pathways, endocrine signals, and the detoxification and excretion of metabolites.RIGHTS : This article is licensed under the BioMed Central licence at http://www.biomedcentral.com/about/license which is similar to the 'Creative Commons Attribution Licence'. In brief you may : copy, distribute, and display the work; make derivative works; or make commercial use of the work - under the following conditions: the original author must be given credit; for any reuse or distribution, it must be made clear to others what the license terms of this work are