Abstract
Turbulence plays a key role in forming the complex geometry of the large-scale current sheet (CS) and fast energy release in a solar eruption. In this paper, we present full 3D ...high-resolution simulations for the process of a moderate coronal mass ejection (CME) and the thermodynamical evolution of the highly confined CS. Copious elongated blobs are generated owing to tearing and plasmoid instabilities, giving rise to a higher reconnection rate, and undergo the splitting, merging, and kinking processes in a more complex way in 3D. A detailed thermodynamical analysis shows that the CS is mainly heated by adiabatic and numerical viscous terms, and thermal conduction is the dominant factor that balances the energy inside the CS. Accordingly, the temperature of the CS reaches to a maximum of about 20 MK, and the range of temperatures is relatively narrow. From the face-on view in the synthetic Atmospheric Imaging Assembly 131 Å, the downflowing structures with similar morphology to supra-arcade downflows are mainly located between the post-flare loops and loop top, while moving blobs can extend spikes higher above the loop top. The downward-moving plasmoids can keep the twisted magnetic field configuration until the annihilation at the flare loop top, indicating that plasmoid reconnection dominates in the lower CS. Meanwhile, the upward-moving ones turn into turbulent structures before arriving at the bottom of the CME, implying that turbulent reconnection dominates in the upper CS. The spatial distributions of the turbulent energy and anisotropy are addressed, which show a significant variation in the spectra with height.
This Viewpoint describes the limitations of regulatory oversight for over-the-counter eye care products and challenges in providing clinical recommendations.
Background
Cataract surgery is the most common ambulatory incisional surgery performed in the USA. Cystoid macular edema (CME), the accumulation of fluid in the central retina due to leakage from ...dilated capillaries, is the most common cause of vision impairment following cataract surgery. Acute CME, defined as CME of less than four months' duration, often resolves spontaneously. CME that persists for four months or longer is termed chronic CME. Non‐steroidal anti‐inflammatory drugs (NSAIDs) have been used to treat CME. This update adds new evidence and analyses to the previously published review.
Objectives
To examine the effectiveness of NSAIDs in the treatment of CME following cataract surgery.
Search methods
We searched the CENTRAL (2022, Issue 3); Ovid MEDLINE; Embase; PubMed; LILACS; mRCT (discontinued in 2014, last searched August 2011), ClinicalTrials.gov, and WHO ICTRP databases. We did not use any date or language restrictions in the electronic search for trials. We last searched the electronic databases on 20 March 2022.
Selection criteria
We included randomized controlled trials evaluating the effects of NSAIDs for CME following cataract surgery.
Data collection and analysis
Two review authors independently screened all titles and s, reviewed full‐text publications against eligibility criteria, independently extracted data from newly included trials and assessed risk of bias for each included trial. We contacted trial authors for clarification or to request missing information. We provided a narrative synthesis of all included trials and their results. For continuous and dichotomous outcomes, we separately performed pooled analysis and reported mean difference (MD) and risk ratio (RR) as well as the associated 95% confidence interval (CI) whenever feasible. Two review authors independently graded the overall certainty of the evidence for each outcome using the GRADE approach.
Main results
We included nine trials with a total of 390 participants (393 eyes). Study participants' mean age was 72.2 years (interquartile range IQR 68.8 to 73.6) and 72% were women (IQR 69% to 74%). Three trials included participants with acute CME, and four included participants with chronic CME; the remaining two trials enrolled both participants with acute and chronic CME or participants with unknown CME duration. We assessed trials as having unclear (33%) or high risk of bias (67%).
Visual improvement of two or more lines at the end of treatment
Data from one trial in participants with acute CME show no treatment effect of topical ketorolac compared to placebo (RR 2.00, 95% CI 0.46 to 8.76; 22 participants). Data from a three‐arm trial in participants with acute CME demonstrate that, when compared with topical prednisolone, topical ketorolac (RR 1.33, 95% CI 0.58 to 3.07; 17 participants) or topical ketorolac and prednisolone combination therapy (RR 1.78, 95% CI 0.86 to 3.69; 17 participants) may have little or no effect on visual improvement. Results of subgroup analysis from two studies in participants with chronic CME suggest that, after treatment for 90 days or longer, NSAIDs may increase participants' likelihood of visual improvement by 1.87 fold (RR 2.87, 95% CI 1.58 to 5.22; I2 = 33%; 2 trials, 121 participants) relative to placebo. However, there was no evidence of treatment effects in the subgroup with two months of treatment or less (RR 0.72, 95% CI 0.30 to 1.73; P = 0.19, I2 = 41%; 2 trials, 34 participants). Overall, this evidence is very low certainty.
A single‐study estimate in patients with mixed CME indicates that topical diclofenac may increase the likelihood of visual improvement by 40% when compared to topical ketorolac (RR 1.40, 95% CI 1.02 to 1.94; 68 participants). However, the same trial reported no difference between the groups in mean final visual acuity in Snellen lines (MD 0.40, 95% CI −0.93 to 1.73). A three‐arm trial in patients with mixed CME reporting visual changes in ETDRS letters in comparisons between ketorolac and diclofenac (34 participants) or bromfenac (34 participants) suggests no evidence of effects. Overall, NSAIDs may slightly improve visual acuity in participants with mixed CME but the evidence is very uncertain.
Persistence of improvement of vision one month after discontinuation of treatment
One trial of participants with chronic CME tested oral indomethacin (RR 0.40, 95% CI 0.10 to 1.60; 20 participants) and the other compared topical ketorolac to placebo (RR 4.00, 95% CI 0.51 to 31.1; 26 participants). While there is no evidence of treatment effects, evidence suggests substantial between‐group heterogeneity (P = 0.07, I2 = 69.9%; very low‐certainty evidence). None of the trials in patients with acute or mixed CME reported this outcome.
Proportion of participants with improvement in leakage on fundus fluorescein angiography
One three‐arm trial in participants with acute CME shows that, when compared with topical prednisolone, there is no treatment benefit of topical ketorolac (RR 1.11, 95% CI 0.45 to 2.75; 17 participants) or topical ketorolac and topical prednisolone combination therapy (RR 1.56, 95% CI 0.72 to 3.38; 17 participants). This evidence is very low certainty.
The combined estimate from two trials in participants with chronic CME indicates NSAIDs have little to no effect over placebo on improving leakage (RR 1.93, 95% CI 0.62 to 6.02; 40 participants; very low‐certainty evidence). Neither of the trials in patients with mixed CME reported this outcome.
Proportion of participants with improved contrast sensitivity
Very low‐certainty evidence from one trial in participants with acute CME shows no treatment benefit of ketorolac (RR 1.11, 95% CI 0.45 to 2.75; 17 participants) or ketorolac and prednisolone combination therapy (RR 1.78, 95% CI 0.86 to 3.69; 17 participants) compared with topical prednisolone. None of the trials in patients with chronic or mixed CME reported this outcome.
Proportion of participants with improved central macular thickness on optical coherence tomography; measures of quality of life
No included trial reported these outcomes.
Adverse effects
Most trials observed no differences in ocular adverse events, such as corneal toxicity or elevated intraocular pressure, between comparison groups.
Authors' conclusions
Evidence on effects of NSAIDs in patients with CME is very uncertain and further investigation is warranted. Our findings are limited by small sample sizes, and heterogeneity in interventions, assessments, and reporting of clinically important outcomes.
Differential scanning calorimetry (DSC) can indicate changes in structure and/or concentration of the most abundant proteins in a biological sample via heat denaturation curves (HDCs). In blood serum ...for example, HDC changes result from either concentration changes or altered thermal stabilities for 7-10 proteins and has previously been shown capable of differentiating between sick and healthy human subjects. Here, we compare HDCs and proteomic profiles of 50 patients experiencing joint-inflammatory symptoms, 27 of which were clinically diagnosed with rheumatoid arthritis (RA). The HDC of all 50 subjects appeared significantly different from expected healthy curves, but comparison of additional differences between the RA and the non-RA subjects allowed more specific understanding of RA samples. We used mass spectrometry (MS) to investigate the reasons behind the additional HDC changes observed in RA patients. The HDC differences do not appear to be directly related to differences in the concentrations of abundant serum proteins. Rather, the differences can be attributed to modified thermal stability of some fraction of the human serum albumin (HSA) proteins in the sample. By quantifying differences in the frequency of artificially induced post translational modifications (PTMs), we found that HSA in RA subjects had a much lower surface accessibility, indicating potential ligand or protein binding partners in certain regions that could explain the shift in HSA melting temperature in the RA HDCs. Several low abundance proteins were found to have significant changes in concentration in RA subjects and could be involved in or related to binding of HSA. Certain amino acid sites clusters were found to be less accessible in RA subjects, suggesting changes in HSA structure that may be related to changes in protein-protein interactions. These results all support a change in behavior of HSA which may give insight into mechanisms of RA pathology.
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DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Cell lineages of the early human gonad commit to one of the two mutually antagonistic organogenetic fates, the testis or the ovary. Some individuals with a 46,XX karyotype develop testes or ovotestes ...(testicular or ovotesticular disorder of sex development; TDSD/OTDSD), due to the presence of the testis-determining gene, SRY Other rare complex syndromic forms of TDSD/OTDSD are associated with mutations in pro-ovarian genes that repress testis development (e.g. WNT4); however, the genetic cause of the more common non-syndromic forms is unknown. Steroidogenic factor-1 (known as NR5A1) is a key regulator of reproductive development and function. Loss-of-function changes in NR5A1 in 46,XY individuals are associated with a spectrum of phenotypes in humans ranging from a lack of testis formation to male infertility. Mutations in NR5A1 in 46,XX women are associated with primary ovarian insufficiency, which includes a lack of ovary formation, primary and secondary amenorrhoea as well as early menopause. Here, we show that a specific recurrent heterozygous missense mutation (p.Arg92Trp) in the accessory DNA-binding region of NR5A1 is associated with variable degree of testis development in 46,XX children and adults from four unrelated families. Remarkably, in one family a sibling raised as a girl and carrying this NR5A1 mutation was found to have a 46,XY karyotype with partial testicular dysgenesis. These unique findings highlight how a specific variant in a developmental transcription factor can switch organ fate from the ovary to testis in mammals and represents the first missense mutation causing isolated, non-syndromic 46,XX testicular/ovotesticular DSD in humans.
Abstract The value of screening for cognitive impairment, including dementia and Alzheimer's disease, has been debated for decades. Recent research on causes of and treatments for cognitive ...impairment has converged to challenge previous thinking about screening for cognitive impairment. Consequently, changes have occurred in health care policies and priorities, including the establishment of the annual wellness visit, which requires detection of any cognitive impairment for Medicare enrollees. In response to these changes, the Alzheimer's Foundation of America and the Alzheimer's Drug Discovery Foundation convened a workgroup to review evidence for screening implementation and to evaluate the implications of routine dementia detection for health care redesign. The primary domains reviewed were consideration of the benefits, harms, and impact of cognitive screening on health care quality. In conference, the workgroup developed 10 recommendations for realizing the national policy goals of early detection as the first step in improving clinical care and ensuring proactive, patient-centered management of dementia.
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FZAB, GEOZS, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SAZU, SBCE, SBJE, SBMB, UL, UM, UPUK
•Pre-oxidation was combined with BAF to efficiently treat shale gas wastewater.•Pre-oxidation increased the biodegradability of organics.•Pre-oxidation enhanced the removal efficiency of organics in ...BAF.•Compared to BAF alone, pre-oxidation+BAF showed higher microbial activity.•Rehaibacterium and Methyloversatilis played a key role in organic degradation.
Biological treatment technology is increasingly explored in shale gas wastewater (SGW) treatment owing to its cost effectiveness and requires efforts to improve its efficacy. In this work, ozone and ferrate(VI) oxidation pre-treatment were evaluated to enhance the performance of the subsequent biologically active filtration (BAF) in the removal of organic contaminants. The oxidation improved the SGW biodegradability and organic composition under relative high salinity (~20 g/L). Due to the degradation activity of microorganisms, the organics removal efficiency in the BAF system was observed to gradually improve and then reaching stability in long-term continuous-mode operation. The removal rate of dissolved organic carbon (DOC) of the ozone-BAF (O3-BAF) and the ferrate(VI)-BAF (Fe(VI)-BAF) systems was 83.2% and 82.8% , respectively, higher than that of BAF alone (80.9%). This increase was attributed to higher activity and content of microorganisms in O3-BAF and Fe(VI)-BAF systems. Two uncultured bacterial species with high abundance of 7.2-21.0% and 2.24-22.31% in genus Rehaibacterium and genus Methyloversatilis were significantly correlated with DOC removal and fluorescent organics removal, respectively. More research is needed to understand whether the species were new and their specific function. This study provides valuable suggestions for extracting safe water from SGW with an efficient treatment train.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
Lower urinary tract symptoms (LUTS) are exceptionally common and debilitating, and they are likely caused or exacerbated by dysfunction of neural circuits controlling bladder function. An incomplete ...understanding of neural control of bladder function limits our ability to clinically address LUTS. Barrington’s nucleus (Bar) provides descending control of bladder and sphincter function, and its glutamatergic neurons expressing corticotropin releasing hormone (BarCrh/Vglut2) are implicated in bladder control. However, it remains unclear whether this subset of Bar neurons is necessary for voiding, and the broader circuitry providing input to this control center remains largely unknown. Here, we examine the contribution to micturition behavior of BarCrh/Vglut2 neurons relative to the overall BarVglut2 population. First, we identify robust, excitatory synaptic input to Bar. Glutamatergic axons from the periaqueductal gray (PAG) and lateral hypothalamic area (LHA) intensely innervate and are functionally connected to Bar, and optogenetic stimulation of these axon terminals reliably provokes voiding. Similarly, optogenetic stimulation of BarVglut2 neurons triggers voiding, whereas stimulating the BarCrh/Vglut2 subpopulation causes bladder contraction, typically without voiding. Next, we genetically ablate either BarVglut2 or BarCrh/Vglut2 neurons and found that only BarVglut2 ablation replicates the profound urinary retention produced by conventional lesions in this region. Fiber photometry recordings reveal that BarVglut2 neuron activity precedes increased bladder pressure, while activity of BarCrh/Vglut2 is phase delayed. Finally, deleting Crh from Bar neurons has no effect on voiding and related bladder physiology. Our results help identify the circuitry that modulates Bar neuron activity and identify subtypes that may serve different roles in micturition.
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•In vivo neuroscience techniques and thermography combined to study urinary continence•PAG and LHA neurons provide direct excitatory innervation of Barrington’s nucleus•Optogenetic stimulation of neural afferents leads to different void-behavior sequence•The glutamatergic Bar population is necessary and sufficient for micturition behavior
Verstegen et al. shine light on Barrington’s nucleus, in which neuron subpopulations have distinct activity patterns important for coordinating downstream bladder control. Furthermore, they identify nodes on the pathway to activate the micturition control center, with different roles, reflex, or voluntary behavior integration, for the afferent sites
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
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