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Myasthenia gravis is an autoimmune disorder of the neuromuscular junction. Treatment typically includes symptomatic oral cholinesterase inhibitors, immunosuppression, and immunomodulation. In addition to corticosteroids, azathioprine and mycophenolate mofetil are the most frequently used immunosuppressants in North America. We aimed to evaluate the comparative effectiveness of these two drugs, and to assess the effect of the dose and duration of treatment. We did a prospective cohort study at 19 academic centres in Canada and the USA. We included patients (aged ≥18 years) with autoimmune myasthenia gravis, who were never treated with immunosuppressants. Treating clinicians determined the choice of medication, dose, follow-up intervals, and drug monitoring. Outcome measures and adverse events were recorded at each visit. We assessed two co-primary outcomes. The first was the patient-reported Myasthenia Gravis-Quality of Life 15-revised (MGQOL-15r) score, measured as the mean change from treatment initiation to the follow-up visit with the lowest score. A clinically meaningful reduction (CMR) in MGQOL-15r was defined as a 5-point decrease. The second was a composite clinical outcome of disease improvement (Myasthenia Gravis Foundation of America Post-Intervention Status Minimal Manifestations or better) and low adverse event burden (defined as grade ≤1 Common Terminology Criteria for Adverse Events). We also compared these outcomes in patients receiving an adequate dose and duration of azathioprine (≥2 mg/kg per day for at least 12 months) or mycophenolate mofetil (≥2 g per day for at least 8 months) and a lower dose or shorter duration of these agents. We used propensity score weighting with generalised linear regression models. This study is registered with ClinicalTrials.gov (NCT03490539). Between May 1, 2018, and Aug 31, 2020, 167 patients were enrolled; 85 did not receive azathioprine or mycophenolate mofetil and were excluded. Four were excluded from outcome analyses because they had scores of 0 on an outcome measure at treatment initiation. Of the 78 patients included in analyses, 47 received mycophenolate mofetil (median follow-up 25 months [IQR 13·5–31·5]) and 31 received azathioprine (median follow-up 20 months [IQR 13–30]). The mean change in MG-QOL15r was –10·4 (95% CI –18·9 to –1·3) with mycophenolate mofetil and –6·8 (–17·2 to 3·6) with azathioprine (mean difference –3·3, 95% CI –7·7 to 1·2; p=0·15). 38 (81%) of 47 patients receiving mycophenolate mofetil and 18 (57%) of 31 receiving azathioprine had a CMR in MG-QOL15r (risk difference 24·0%; 95% CI –0·2 to 48·0; p=0·052). The clinical composite outcome was achieved in 22 (47·7%) of 47 patients who received mycophenolate mofetil and nine (28·1%) of 31 who received azathioprine (risk difference 19·6%, 95% CI –4·9 to 44·2; p=0·12). Descriptive analysis did not find a difference in the proportion of patients reaching a CMR in MG-QOL15r between the adequate dose and duration group and the lower dose or shorter duration group. Adverse events occurred in 11 (32%) of 34 patients who received azathioprine and nine (19%) of 48 who received mycophenolate mofetil. The most frequent adverse events were hepatotoxicity with azathioprine (five [15%] of 34) and gastrointestinal disturbances (seven [15%] of 48) with mycophenolate mofetil. There were no study-related deaths. More than half of patients treated with azathioprine and mycophenolate mofetil felt their quality of life improved; no difference in clinical outcomes was noted between the two drugs. Adverse events associated with azathioprine were potentially more serious than those with mycophenolate mofetil, although mycophenolate mofetil is teratogenic. Lower than recommended doses of azathioprine might be effective, with reduced dose-dependent adverse events. More comparative effectiveness studies are required to inform treatment choices in myasthenia gravis. Patient-Centered Outcomes Research Institute, Myasthenia Gravis Foundation of America.

Abstract Drosophila seminal fluid proteins (SFPs) are often cited as an example of interlocus sexual conflict, wherein the proteins increase male fitness while decreasing female fitness, spurring recurring female counter-adaptations and rapid molecular evolution. This model predicts that male-expressed genetic variation in the accessory gland, which produces seminal fluid, should generate counter-evolving genetic pathways in females, resulting in sexual coevolution. Using a trio of D. melanogaster populations exhibiting substantial SFP expression divergence due to recent selection, we test for coevolution in the female post-mating transcriptome in the lower reproductive tract and head. Contrasting predictions of sexual antagonism, female post-mating gene expression is indifferent to male population of origin. Instead, our results better support the alternative hypotheses that environmental variation is the source of selection on male SFP gene expression and that population differentiation in the female post-mating transcriptome is generated by female-expressed genotypic differentiation.

Whiteflies ( Bemisia tabaci) and the diseases they transmit are a major detriment to crop yields and a significant contributor to world hunger. The highly evolved interactions of host plant, phloem-feeding insect vector with endosymbionts and persistently transmitted virus represent a tremendous challenge for interdisciplinary study. Presented here is the establishment of a colony of axenic whiteflies on tissue-cultured plants. Efficient colony establishment was achieved by a surface sterilization of eggs laid on axenic phototrophically tissue-cultured plants. The transfer of emerging whiteflies through coupled tissue culture vessels to new axenic plants facilitates robust subculturing and produces hundreds of whitefly adults per month. Whitefly proliferation on more than two dozen plant species is shown as well as in vitro testing of whitefly preference for different plants. This novel multi-organism system provides the high-level of biocontainment required by Federal permitting to conduct virus transmission experiments. Axenic whitefly adults were able to acquire and transmit a begomovirus into tissue-cultured plants, indicating that culturable gut microorganisms are not required for virus transmission. The approach described enables a wide range of hypotheses regarding whitefly phytopathology without the expense, facilities, and contamination ambiguity associated with current approaches.

Background: Headache is one of the most common debilitating chronic pain conditions in patients with mild traumatic brain injury. Conventional pharmacological treatments have not been shown to be effective in alleviating debilitating mild traumatic brain injury related headaches (MTBI-HA). Therefore, the development of an innovative non-invasive therapy in managing MTBI-HA is needed in the field of pain management. Repetitive transcranial magnetic stimulation (rTMS) utilizes a basic electromagnetic coupling principle in which a rapid discharge of electrical current is converted into dynamic magnetic flux, allowing the induction of a localized current in the brain for neuromodulation. The treatment is currently FDA approved for treating depression in the United States. Recent meta-analysis studies have implicated its usage in chronic pain management. Objective: The objective of the prospective case series is to assess the potential application of rTMS in alleviating MTBI-HA. Study Design: A prospective evaluation was conducted in patients with established diagnoses of MTBIHA and treated with neuronavigational guided rTMS. Setting: The study was conducted at the Veteran Administration San Diego Healthcare System where over 400 patients with MTBI were being evaluated annually by the Rehabilitation Medicine Service. A fraction of this patient population was referred and evaluated in the Anesthesia Pain Clinic for the consideration of rTMS for their headaches. Methods: A prospective case series was conducted with human subject protection committee approval. Patients with established diagnoses of MTBI and constant headaches rated at ≥ 4 on a 0 – 10 Numerical Rating Pain Scale (NRPS), and on stable headache medication regimens were selected to receive the treatment. Four sessions of rTMS were delivered to specific areas of cortices over a 2-month period. Patients’ average intensities of lingering constant headaches (defined as duration of headache lasting more than 48 hours), and the average frequency (number of severe headache episodes per day), intensity (NRPS), and duration (hours) of headache exacerbations were assessed before and after the rTMS treatment protocol. Results: Six men (average age of 50) with MTBI-HA received the rTMS treatment protocol. Average pre and post-rTMS constant headache scores (± SD) on the NRPS were 5.50 (± 1.38) and 2.67 (± 1.75), respectively, with an average post-rTMS headache intensity reduction of 53.05% (± 19.90). The average headache exacerbation frequency (episodes per week) was reduced by 78.97% (± 19.88) with 2 patients reporting complete cessation of severe headache episodes. For those (N = 4) with persistent headache exacerbations, the average duration and intensity of these exacerbations were reduced by 50.0% and 31.7%, respectively. Limitations: This prospective evaluation provides the initial insight that rTMS may be beneficial in alleviating a debilitating chronic pain condition in patients with MTBI-HA. More controlled randomized studies should be conducted to validate its efficacy. Other co-existing cognitive and mood dysfunction should be assessed as well. Conclusions: rTMS offers a non-invasive treatment option for MTBI-HA. The tested treatment protocol was well tolerated by the patients and can be adopted for future randomized controlled studies in further validating the treatment efficacy. Key words: Transcranial magnetic stimulation, MTBI, mild traumatic rrain injury, headaches, pain neuromodulation

Background Chronic pain conditions are highly prevalent in patients with mild traumatic brain injury. Supraspinal diffuse axonal injury is known to dissociate brain functional connectivity in these patients. The effect of this dissociated state on supraspinal pain network is largely unknown. A functional magnetic resonance imaging study was conducted to compare the supraspinal pain network in patients with mild traumatic brain injury to the gender and age-matched healthy controls with the hypothesis that the functional connectivities of the medial prefrontal cortices, a supraspinal pain modulatory region to other pain-related sensory discriminatory and affective regions in the mild traumatic brain injury subjects are significantly reduced in comparison to healthy controls. Results The mild traumatic brain injury group (N = 15) demonstrated significantly (P < 0.01, cluster threshold > 150 voxels) less activities in the thalamus, pons, anterior cingulate cortex, insula, dorsolateral prefrontal cortex, and medial prefrontal cortices than the healthy control group (N = 15). Granger Causality Analyses (GCA) indicated while the left medial prefrontal cortices of the healthy control group cast a noticeable degree of outward (to affect) causality inference to multiple pain processing related regions, this outward inference pattern was not observed in the mild traumatic brain injury group. On the other hand, only patients’ bilateral anterior cingulate cortex received multiple inward (to be affected) causality inferences from regions including the primary and secondary somatosensory cortices and the inferior parietal lobe. Resting state functional connectivity analyses indicated that the medial prefrontal cortices of the mild traumatic brain injury group demonstrated a significantly (P < 0.01, F = 3.6, cluster size > 150 voxels) higher degree of functional connectivity to the inferior parietal lobe, premotor and secondary somatosensory cortex than the controls. Conversely, the anterior cingulate cortex of the healthy group demonstrated significantly (P < 0.01, F = 3.84, cluster size > 150 voxels) less degree of functional connectivities to the inferior parietal lobe and secondary somatosensory cortex than their mild traumatic brain injury counterparts. Conclusions In short, the current study demonstrates that patients with mild traumatic brain injury and headaches appear to have an altered state of supraspinal modulatory and affective functions related to pain perception.

Drosophila seminal fluid proteins (SFPs) are often cited as an example of interlocus sexual conflict, wherein the proteins increase male fitness while decreasing female fitness, spurring recurring female counter adaptations and rapid molecular evolution. This model predicts that male-expressed genetic variation in the accessory gland, which produces seminal fluid, should generate counter-evolving genetic pathways in females, resulting in sexual coevolution. Using a trio of populations exhibiting substantial SFP expression divergence due to recent selection, we test for coevolution in the female post-mating transcriptome in the lower reproductive tract and head. Contrasting predictions of sexual antagonism, female postmating gene expression is indifferent to male population of origin. Instead, our results better support the alternative hypotheses that environmental variation is the source of selection on male SFP gene expression, and that population differentiation in the female post-mating transcriptome is generated by female-expressed genotypic differentiation.