Increases in pneumococcal meningitis were reported from Ghanaian regions that lie in the meningitis belt in 2016-2017, despite introduction of 13-valent pneumococcal conjugate vaccine (PCV13) in 2012 ...using a 3-dose schedule (6, 10, and 14 weeks). We describe pneumococcal meningitis epidemiology in the Ghanaian Northern and Upper West regions across two meningitis seasons.
Suspected meningitis cases were identified using World Health Organization standard definitions. Pneumococcal meningitis was confirmed if pneumococcus was the sole pathogen detected by polymerase chain reaction, culture, or latex agglutination in cerebrospinal fluid collected from a person with suspected meningitis during December 2015-March 2017. Pneumococcal serotyping was done using PCR. Annual age-specific pneumococcal meningitis incidence (cases per 100,000 population) was calculated, adjusting for suspected meningitis cases lacking confirmatory testing.
Among 153 pneumococcal meningitis cases, 137 (89.5%) were serotyped; 100 (73.0%) were PCV13-type, including 85 (62.0%) that were serotype 1, a PCV13-targeted serotype. Persons aged ≥5 years accounted for 96.7% (148/153) of cases. Comparing 2015-2016 and 2016-2017 seasons, the proportion of non-serotype 1 PCV13-type cases decreased from 20.0% (9/45) to 4.1% (3/74) (p = 0.008), whereas the proportion that was serotype 1 was stable (71.1% (32/45) vs. 58.1% (43/74); p = 0.16). Estimated adjusted pneumococcal meningitis incidence was 1.8 in children aged <5 years and ranged from 6.8-10.5 in older children and adults.
High pneumococcal meningitis incidence with a large proportion of serotype 1 disease in older children and adults suggests infant PCV13 vaccination has not induced herd protection with this schedule in this high-transmission setting.
The development of stereoselective and efficient reactions for the construction of conjugated dienes and polyenes has remained at the forefront of organic chemistry, due to their key roles in ...medicinal chemistry, organic synthesis, and material science. The synthesis of conjugated dienes and polyenes is typically accomplished in a multistep manner by the sequential installation of individual CC bonds because it allows for control of stereoselectivity and efficiency of formation of each double bond. A conceptually distinct dienylation approach entails a stereoselective appendage of a four-carbon unit, shortcutting diene synthesis. Dienylation with sulfolene provided a direct route to E-dienes, but the synthesis of substantially more challenging Z-dienes remained elusive. Here, we report that a highly Z-selective dienylation can now be achieved by a simple adjustment of a ligand, enabling stereodivergent synthesis of E- and Z-dienes from one reagent and in one step. A detailed mechanistic investigation of the E- and Z-selective dienylation provided insight into the divergent behavior of the two catalytic systems and revealed that differences in relative stabilities of catalytically active palladium phosphine complexes have a major impact on the stereochemical outcomes of the dienylation.
IntroductionWomen with twin pregnancies and a short cervix are at increased risk for preterm birth (PTB). Given the burden of prematurity and its attendant risks, the quest for effective ...interventions in twins has been an area of considerable research. Studies investigating the effectiveness of cervical cerclage, cervical pessary and vaginal progesterone in preventing PTB have yielded conflicting results. The aim of this study is to compare the effectiveness of cervical pessary and cervical cerclage with or without vaginal progesterone to prevent PTB in women with twin pregnancies and a cervical length (CL) ≤ 28 mm.Methods and analysisThis multicentre, randomised clinical trial will be conducted at My Duc Hospital and My Duc Phu Nhuan Hospital, Vietnam. Asymptomatic women with twin pregnancies and a CL ≤28 mm, measured at 16–22 weeks’ gestation, will be randomised in a 1:1:1:1 ratio to receive a cerclage, pessary, cerclage plus progesterone or pessary plus progesterone. Primary outcome will be PTB <34 weeks. Secondary outcomes will be maternal and neonatal complications. We preplanned a subgroup analysis according to CL from all women after randomisation and divided into four quartiles. Analysis will be conducted on an intention-to-treat basis. The rate of PTB <34 weeks’ gestation in women with twin pregnancies and a cervix ≤28 mm and treated with pessary in our previous study at My Duc Hospital was 24.2%. A sample size of 340 women will be required to show or refute that cervical cerclage decreases the rate of PTB <34 weeks by 50% compared with pessary (from 24.2% to 12.1%, α level 0.05, power 80%, 5% lost to follow-up and protocol deviation). This study is not to be powered to assess interactions between interventions.Ethics and disseminationEthical approval was obtained from the Institutional Ethics Committee of My Duc Hospital and informed patient consent was obtained before study enrolment. Results of the study will be submitted for publication in a peer-reviewed journal.Trial registration numberNCT03863613 (date of registration: 4 March 2019).
Avian eggshell membrane (ESM) is a natural biomaterial that has been used as an alternative natural bandage to cure wounds, and is available in large quantities from egg industries. We have ...previously demonstrated that processed eggshell membrane powder (PEP), aiming to be used in a low cost wound healing product, possesses anti-inflammatory properties. In this study, we further investigated effects of PEP on MMP activities in vitro (a dermal fibroblast cell culture system) and in vivo (a mouse skin wound healing model). Three days incubation with PEP in cell culture led to rearrangement of the actin-cytoskeleton and vinculin in focal adhesions and increased syndecan-4 shedding. In addition, we observed increased matrix metalloproteinase type 2 (MMP-2) enzyme activation, without effects on protein levels of MMP-2 or its regulators (membrane type 1 (MT1)-MMP and tissue inhibitor of matrix metalloproteinase type 2 (TIMP-2). Longer incubation (10 days) led to increased protein levels of MMP-2 and its regulators. We also observed an increased alpha-smooth muscle actin (α-SMA) production, suggesting an effect of PEP on myofibroblast differentiation. In vivo, using the mouse skin wound healing model, PEP treatment (3 days) increased MMP activity at the wound edges, along with increased MMP-2 and MMP-9 protein levels, and increased keratinocyte cell proliferation. Altogether, our data suggest PEP stimulates MMP activity, and with a positive effect on early cellular events during wound healing.
The Wnt family of secreted glycolipo-proteins signals through multiple signal transduction pathways and is essential for embryonic development and organ development and homeostasis. The Wnt-pathways ...are conserved and critical in all metazoans. Wnt signaling pathways comprise the canonical Wnt/β-catenin pathway and several non-canonical signaling branches, of which Wnt-Planar Cell Polarity (PCP) signaling and the Wnt/Calcium pathway have received the most attention and are best understood. nterestingly, all Wnt-pathways have a nuclear signaling branch and also can affect many cellular processes independent of its nuclear transcriptional regulation. Canonical Wnt/β-catenin signaling is the most critical for a nuclear transcriptional response, in both development and disease, yet the mechanism(s) on how the "business end" of the pathway, β-catenin, translocates to the nucleus to act as co-activator to the TCF/Lef transcription factor family still remains obscure. Here we discuss and compare the very different strategies on how the respective Wnt signaling pathways activate a nuclear transcriptional response. We also highlight some recent new insights into how β-catenin is translocated to the nucleus via an IFT-A, Kinesin-2, and microtubule dependent mechanism and how this aspect of canonical Wnt-signaling uses ciliary proteins in a cilium independent manner, conserved between Drosophila and mammalian cells.
•We combine various cutting-edge Machine Learning techniques to detect tuberculosis.•We propose an expert system that effectively classifies Chest X-ray images.•Our system significantly outperforms ...various state-of-the-art approaches.•It has been evaluated using different quality metrics.
Tuberculosis (TB) caused by Mycobacterium tuberculosis is a contagious disease which is among the top deadly diseases in the world. Research in Medical Imaging has been done to provide doctors with techniques and tools to early detect, monitor and diagnose the disease using Artificial Intelligence. Recently, many attempts have been made to automatically recognize TB from chest X-ray (CXR) images. Still, while the obtained performance is encouraging, according to our investigation, many of the existing approaches have been evaluated on small and undiverse datasets. We suppose that such a good performance might not hold for heterogeneous data sources, which originate from real world scenarios. Our present work aims to fill the gap and improve the prediction performance on larger datasets. In particular, we present a practical solution for the detection of tuberculosis from CXR images, making use of cutting-edge Machine Learning and Computer Vision algorithms. We conceptualize a framework by adopting three recent deep neural networks as the main classification engines, namely modified EfficientNet, modified original Vision Transformer, and modified Hybrid EfficientNet with Vision Transformer. Moreover, we also empower the learning process with various augmentation techniques. We evaluated the proposed approach using a large dataset which has been curated by merging various public datasets. The resulting dataset has been split into training, validation, and testing sets which account for 80%, 10%, and 10% of the original dataset, respectively. To further study our proposed approach, we compared it with two state-of-the-art systems. The obtained results are encouraging: the maximum accuracy of 97.72% with AUC of 100% is achieved with ViT_Base_EfficientNet_B1_224. The experimental results demonstrate that our conceived tool outperforms the considered baselines with respect to different quality metrics.
The endothelial glycocalyx (EG) is essential for proper function of the endothelium and for vascular integrity, but its role in premature atherogenesis in rheumatoid arthritis (RA) has not been ...studied yet. EG impairment can play a role in pathogenesis of vascular disease, and one of its characteristics is shedding of syndecan-1 from endothelial cells. Syndecan-1 shedding is mediated by matrix metalloproteinase-9 (MMP-9) and counteracted by tissue inhibitor of metalloproteinases (TIMP)-1. Cardiovascular disease risk in RA is reversible by disease modifying antirheumatic drugs (DMARDs), but the exact modes of action are still unclear. Therefore, we examined effects of DMARDs on syndecan-1, MMP-9 and TIMP-1 in RA patients, and searched for associations between these parameters and inflammatory activity. From the observational PSARA study, we examined 39 patients starting with methotrexate (MTX) monotherapy (in MTX naïve patients, n = 19) or tumor necrosis factor inhibitors (TNFi) in combination with MTX (in MTX non-responders, n = 20) due to active RA. Serum syndecan-1, MMP-9 and TIMP-1 were measured at baseline and after six weeks of treatment. Serum syndecan-1 (p = 0.008) and TIMP-1 (p<0.001) levels decreased after six weeks of anti-rheumatic treatment. Levels of MMP-9 also decreased, but the difference was not statistically significant. The improvement in syndecan-1 levels were independent of changes in inflammatory activity. There was no significant difference in changes in syndecan-1 levels from baseline to 6 weeks between the MTX and TNFi groups, however the change was significant within the MTX group. Six weeks of antirheumatic treatment was associated with reduction in serum levels of syndecan-1, which might reflect reduced syndecan-1 shedding from EG. Thus, it is possible that EG-preserving properties of DMARDs might contribute to their cardioprotective effects. These effects may be at least partly independent of their anti-inflammatory actions. Our findings do not support the notion that syndecan-1 shedding in RA is mediated mainly by increased MMP-9 or decreased TIMP-9 serum concentration.
The main protease, M
(or 3CL
) in SARS-CoV-2 is a viable drug target because of its essential role in the cleavage of the virus polypeptide. Feline infectious peritonitis, a fatal coronavirus ...infection in cats, was successfully treated previously with a prodrug GC376, a dipeptide-based protease inhibitor. Here, we show the prodrug and its parent GC373, are effective inhibitors of the M
from both SARS-CoV and SARS-CoV-2 with IC
values in the nanomolar range. Crystal structures of SARS-CoV-2 M
with these inhibitors have a covalent modification of the nucleophilic Cys145. NMR analysis reveals that inhibition proceeds via reversible formation of a hemithioacetal. GC373 and GC376 are potent inhibitors of SARS-CoV-2 replication in cell culture. They are strong drug candidates for the treatment of human coronavirus infections because they have already been successful in animals. The work here lays the framework for their use in human trials for the treatment of COVID-19.
We revisit the gradient projection method in the framework of nonlinear optimal control problems with bang–bang solutions. We obtain the strong convergence of the iterative sequence of controls and ...the corresponding trajectories. Moreover, we establish a convergence rate, depending on a constant appearing in the corresponding switching function and prove that this convergence rate estimate is sharp. Some numerical illustrations are reported confirming the theoretical results.
PDF
