Low back pain (LBP) is a common disease that imposes a huge social and economic burden on people. Intervertebral disc (IVD) degeneration (IVDD) is often considered to be the leading cause of LBP and further aggravate and cause serious spinal problems. The established treatment strategy for IVDD consists of physiotherapy, pain medication by drug therapy, and, if necessary, surgery, but none of them can be treated from the etiology; that is, it cannot fundamentally reverse IVD and reconstruct the mechanical function of the spine. With the development of nanotechnology and regenerative medicine, nano-drug delivery systems (NDDSs) have improved treatment results because of their good biodegradability, biocompatibility, precise targeted specific drug delivery, prolonged drug release time, and enhanced drug efficacy, and various new NDDSs for drugs, proteins, cells, and genes have brought light and hope for the treatment of IVDD. This review summarizes the research progress of NDDSs in the treatment of IVDD and provides prospects for using NDDSs to address the challenges of IVDD. We hope that the ideas generated in this review will provide insight into the precise treatment of IVDD.
Metformin (MET) is the most prescribed antidiabetic drug, but its mechanisms of action remain elusive. Recent data point to the gut as MET's primary target. Here, we explored the effect of MET on the gut glucose transport machinery. Using human enterocytes (Caco-2/TC7 cells) in vitro, we showed that MET transiently reduced the apical density of sodium-glucose transporter 1 (SGLT1) and decreased the absorption of glucose, without changes in the mRNA levels of the transporter. Administered 1 h before a glucose challenge in rats (Wistar, GK), C57BL6 mice and mice pigs, oral MET reduced the post-prandial glucose response (PGR). This effect was abrogated in SGLT1-KO mice. MET also reduced the luminal clearance of 2-(18F)-fluoro-2-deoxy-D-glucose after oral administration in rats. In conclusion, oral metformin transiently lowers post-prandial glucose response by reducing the apical expression of SGLT1 in enterocytes, which may contribute to the clinical effects of the drug.
Measurements of a new type of substrate for the integration of the trap-rich interface passivation solution with the below-buried oxide functionalities required in fully-depleted (FD) Silicon-on-Insulator (SOI) nodes is presented. This is achieved by adding a second thin buried oxide (BOX2) layer in between the substrate and the trap-rich/BOX1/SOI stack. It is shown that the trap-rich layer above BOX2 can effectively passivate the parasitic surface conduction that would be induced below BOX2 if BOX2 remains thinner than 20 nm. This is proven through measurements of substrate losses and non-linearity of coplanar waveguide transmission lines, comparing the fabricated double-BOX samples to reference trap-rich and unpassivated high-resistivity substrates.
In view of the observed ﬂat rotation curves of spiral galaxies and motivated by the simple fact that within newtonian gravity a stationary axisymmetric mass distribution or dark matter vortex of ﬁnite extent readily displays a somewhat ﬂattened out velocity rotation curve up to distances comparable to the extent of such a vortex transverse to the galaxy’s disk, the possibility that such a ﬂattening out of rotation curves may rather be a manifestation of some stationary axisymmetric space-time curvature of purely gravitational character, without the need of some dark matter particles, is considered in the case of the gravimagnetic dipole carrying opposite NUT charges and in the tensionless limit of its Misner string, as an exact vacuum solution to Einstein’s equations. Aiming for a ﬁrst assessment of the potential of such a suggestion easier than a full ﬂedged study of its geodesics, the situation is analysed within the limits of weak ﬁeld gravito-electromagnetism and nonrelativistic dynamics. Thereby leading indeed to interesting and encouraging results.
Bicuspid aortic valve (BAV), the most common cardiovascular malformation occurs in 0.5–1.2% of the population. Although highly heritable, few causal mutations have been identified in BAV patients. Here, we report the targeted sequencing of HOXA1 in a cohort of BAV patients and the identification of rare indel variants in the homopolymeric histidine tract of HOXA1. In vitro analysis shows that disruption of this motif leads to a significant reduction in protein half-life and defective transcriptional activity of HOXA1. In zebrafish, targeting hoxa1a ortholog results in aortic valve defects. In vivo assays indicates that these variants behave as dominant negatives leading abnormal valve development. In mice, deletion of Hoxa1 leads to BAV with a very small, rudimentary non-coronary leaflet. We also show that 17% of homozygous Hoxa1−1His knock-in mice present similar phenotype. Genetic lineage tracing in Hoxa1−/− mutant mice reveals an abnormal reduction of neural crest-derived cells in the valve leaflet, which is caused by a failure of early migration of these cells.
Background Moyamoya angiopathy (MMA) is a rare cerebrovascular condition leading to stroke. Mutations in 15 genes have been identified in Mendelian forms of MMA, but they explain only a very small proportion of cases. Our aim was to investigate the genetic basis of MMA in consanguineous patients having unaffected parents in order to identify genes involved in autosomal recessive MMA. Methods Exome sequencing (ES) was performed in 6 consecutive consanguineous probands having MMA of unknown etiology. Functional consequences of variants were assessed using western blot and protein 3D structure analyses. Results Causative homozygous variants of NOS3, the gene encoding the endothelial nitric oxide synthase (eNOS), and GUCY1A3, the gene encoding the alpha1 subunit of the soluble guanylate cyclase (sGC) which is the major nitric oxide (NO) receptor in the vascular wall, were identified in 3 of the 6 probands. One NOS3 variant (c.1502 + 1G > C) involves a splice donor site causing a premature termination codon and leads to a total lack of eNOS in endothelial progenitor cells of the affected proband. The other NOS3 variant (c.1942 T > C) is a missense variant located into the flavodoxine reductase domain; it is predicted to be destabilizing and shown to be associated with a reduction of eNOS expression. The GUCY1A3 missense variant (c.1778G > A), located in the catalytic domain of the sGC, is predicted to disrupt the tridimensional structure of this domain and to lead to a loss of function of the enzyme. Both NOS3 mutated probands suffered from an infant-onset and severe MMA associated with posterior cerebral artery steno-occlusive lesions. The GUCY1A3 mutated proband presented an adult-onset MMA associated with an early-onset arterial hypertension and a stenosis of the superior mesenteric artery. None of the 3 probands had achalasia. Conclusions We show for the first time that biallelic loss of function variants in NOS3 is responsible for MMA and that mutations in NOS3 and GUCY1A3 are causing fifty per cent of MMA in consanguineous patients. These data pinpoint the essential role of the NO pathway in MMA pathophysiology.
Patients with chronic liver disease (CLD) and cirrhosis present a rebalanced hemostatic system in the three phases of haemostasis. This balance is however unstable and can easily tip towards bleeding or thrombosis. Management of both spontaneous bleeding and bleeding during invasive procedures remains a challenge in this patient population. Transfusion of blood products can result in circulatory overload and thereby worsen portal hypertension. As an alternative to fresh frozen plasma (FFP), prothrombin complex concentrates (PCC) may have merit in patients with liver disease because of their low volume. The impact of PCC in in-vitro spiking experiments of cirrhotic plasma is promising, but also warrants cautious use in light of thromboembolic risk. The majority of existing studies carried-out in CLD patients are retrospective or do not have an adequate control arm. A prospective study (the PROTON trial) was set up in 2013 to investigate the utility of PCC in patients undergoing liver transplantation. However, the study has never recruited the planned number of patients. Robust data on PCC safety in CLD is also required. The limited existing evidence does not seem to indicate an excessive thromboembolic risk. Currently, the utilisation of PCC in CLD cannot be routinely recommended but can provide an option for carefully selected cases in which other measures were not sufficient to control bleeding and after delicately weighing risks and benefits.
Humans exhibit lateralization such that most individuals typically show a preference for using one arm over the other for a range of movement tasks. The computational aspects of movement control leading to these differences in skill are not yet understood. It has been hypothesized that the dominant and non-dominant arms differ in terms of the use of predictive or impedance control mechanisms. However, previous studies present confounding factors that prevented clear conclusions: either the performances were compared across two different groups, or in a design in which asymmetrical transfer between limbs could take place. To address these concerns, we studied a reach adaptation task during which healthy volunteers performed movements with their right and left arms in random order. We performed two experiments. Experiment 1 (18 participants) focused on adaptation to the presence of a perturbing force field and Experiment 2 (12 participants) focused on rapid adaptations in feedback responses. The randomization of the left and right arm led to simultaneous adaptation, allowing us to study lateralization in single individuals with symmetrical and minimal transfer between limbs. This design revealed that participants could adapt control of both arms, with both arms showing similar performance levels. The non-dominant arm initially presented a slightly worst performance but reached similar levels of performance in late trials. We also observed that the non-dominant arm showed a different control strategy compatible with robust control when adapting to the force field perturbation. EMG data showed that these differences in control were not caused by differences in co-contraction across the arms. Thus, instead of assuming differences in predictive or reactive control schemes, our data show that in the context of optimal control, both arms can adapt, and that the non-dominant arm uses a more robust, model-free strategy likely to compensate for less accurate internal representations of movement dynamics. Significance statement We studied a reach adaptation task during which volunteers performed the task with their right and left arm randomly. The randomization of the arms allowed us to study lateralization in single individuals with symmetrical and minimal transfer between limbs. We observed similar performance levels after adaptation of both arms in the force applied to counter the perturbation. Moreover, the non-dominant arm showed a more robust control strategy when adapting to the force field perturbation, which enabled similar deviations despite faster movements. These interlimb differences were not caused by differences in co-contraction across the two arms. Our results suggest that both arms can adapt to the presence of a force field but the non-dominant arm uses a more robust, model-free strategy.
Plain Language Summary We have collected, analyzed, and disseminated seasonal forecasts of September sea ice over 2008–2022. Here, we analyze the skill of these forecasts. We show that individual forecasts of September sea ice extent (SIE) have limited skill, but the median forecast shows skill that is at least as good as a statistical benchmark. Overall the skill is lower than expected from existing retrospective forecasts. Shorter‐term forecasts produced in early September show that many forecasts imply physically unprecedented rates of SIE change. The skill of spatial forecasts from individual models is also limited, but the multi‐model forecast is twice as skilled, showing the value of a multi‐model forecast ensemble. To explore the spread across forecasts we have assessed sea ice initial conditions and found large differences in the sea ice volume used to initialize forecasts, which has an impact on the forecast. We also find that summer weather has a modest impact on forecast error, which tends to underpredict September SIE during summers with circulation patterns that favor high September SIE and vice versa.
The permafrost active layer is a key supplier of soil organic carbon and mineral nutrients to Arctic rivers. In the active layer, sites of soil-water exchange are locations for organic carbon and nutrient mobilization. Previously these sites were considered as connected during summer months and isolated during winter months. Whether soil pore waters in active layer soils are connected during shoulder seasons is poorly understood. In this study, exceptionally heavy silicon isotope compositions in soil pore waters show that during late winter, there is no connection between isolated pockets of soil pore water in soils with a shallow active layer. However, lighter silicon isotope compositions in soil pore waters reveal that soils are biogeochemically connected for longer than previously considered in soils with a deeper active layer. We show that an additional 21% of the 0–1 m soil organic carbon stock is exposed to soil - water exchange. This marks a hot moment during a dormant season, and an engine for organic carbon transport from active layer soils. Our findings mark the starting point to locate earlier pathways for biogeochemical connectivity, which need to be urgently monitored to quantify the seasonal flux of organic carbon released from permafrost soils.
Introduction: The intermittent intrapulmonary deflation (IID) technique is a recent airway clearance technique that intends to delay the onset of expiratory flow limitation (EFL) during exhalation. We showed in a previous study that IID increased the expiratory volume of COPD patients compared to quiet breathing and positive expiratory pressure (PEP) therapy. We hypothesized that it was due to the attenuation of the EFL. Objectives: To verify the physiologic effects of IID and PEP techniques on EFL with a mechanical lung model. Methods: A mechanical lung model was created to assess the effects of IID and PEP techniques. The thorax was simulated by a plexiglas box in which an adult test lung was connected. A calibration syringe simulated the inspiratory phase. Later, with activation of the IID, the expiratory phase was driven by the deflation generated by the device. With PEP, the expiration occurred maintaining an expiratory pressure between 5-10 cmH2O. A pneumotachograph and a pressure transducer were placed in series for flow, volumes and pressure measurements. Results: The model reproduced physiological characteristics of EFL. However, the deflation of the model was slowed by IID and PEP, and flow remained almost constant, so flow limitation was reduced. Conclusion: The IID and PEP attenuate EFL and increase exhaled volume in the in vitro model.
California is a landmark setting for studying produce recovery efforts and policy implications because of its global relevance in agricultural production, its complex network of food recovery organizations, and its environmental and public health regulations. Through a series of focus groups with organizations involved in produce recovery (gleaning organizations) and emergency food operations (food banks, food pantries), this study aimed to deepen our understanding of the current produce recovery system and determine the major challenges and opportunities related to the produce recovery system. Operational and systematic barriers to produce recovery were highlighted by both gleaning and emergency food operations. Operational barriers, such as the lack of appropriate infrastructure and limited logistical support were found to be a challenge across groups and were directly tied to inadequate funding for these organizations. Systematic barriers, such as regulations related to food safety or reducing food loss and waste, were also found to impact both gleaning and emergency food organizations, but differences were observed in how each type of regulation impacted each stakeholder group. To support the expansion of food recovery efforts, participants expressed need for better coordination within and across food recovery networks and more positive and transparent engagement from regulators to increase understanding of the specifics of their unique operational constraints. The focus group participants also provided critiques on how emergency food assistance and food recovery are inscribed within the current food system and for longer term goals of reducing food insecurity and food loss and waste a systematic change will be required.
Background Exposure during pregnancy to malaria and sexually-transmitted infections is associated with adverse birth outcomes including low birth weight (LBW). This study aimed at assessing if the adjunction of two doses of azithromycin to sulfadoxine-pyrimethamine for the intermittent preventive treatment of malaria in pregnancy can reduce LBW. Methods A two parallel-groups, open-label randomized controlled trial involving pregnant women (16 to 35 years of age and 12 to 24 weeks of gestation as confirmed by last menstrual period or fundal height) was conducted in rural Burkina Faso. Women were assigned in a 1:1 ratio either to use azithromycin (1 g daily for 2 days) during the second and third trimesters of pregnancy plus monthly sulfadoxine-pyrimethamine (1500/75 mg) (SPAZ) (intervention) or to continue using a monthly sulfadoxine-pyrimethamine (1500/75 mg) (SP) (control). Primary outcome was a LBW (birth weight measured within 24 h after birth < 2500 g). Secondary outcomes including stillbirth, preterm birth or miscarriage are reported together with safety data. Results A total of 992 pregnant women underwent randomization (496 per group) and 898 (90.5%) valid birth weights were available (450 in SPAZ and 448 in SP). LBW incidence was 8.7% (39/450) in SPAZ and 9.4% (42/448) in controls (p-value = 0.79). Compared with controls, pregnant women with SPAZ showed a risk ratio (RR) of 1.16 (95% confidence interval (CI 0.64–2.08]) for preterm births, 0.75 (95% CI 0.17–3.35) for miscarriage and 0.64 (95% CI 0.25–1.64) for stillbirths. No treatment-related serious adverse events (SAEs) have been observed, and there was no significant difference in the number of SAEs (13.5% [67/496] in SPAZ, 16.7% [83/496] in SP, p-value = 0.18) or AEs (17.1% [85/496] in SPAZ, 18.8% [93/496] in SP, p-value = 0.56). Conclusion Adequate prevention regimen with monthly sulfadoxine-pyrimethamine given to all pregnant women has been proved to reduce the risk of LBW in malaria endemic areas. Adding azithromycin to the regimen does not offer further benefits, as far as women receive a malaria prevention regimen early enough during pregnancy. Trial registration Pan African Clinical Trial Registry ( https://pactr.samrc.ac.za/Search.aspx ): PACTR201808177464681. Registered 21 August 2018.
Background Despite their potential to undermine malaria control and elimination efforts, infected adults who live in endemic areas are an overlooked aspect of public health strategies. We aimed to estimate the prevalence of malaria, to identify underlying parasites species, and to assess predicting factors among adults residing in an endemic area from the Democratic Republic of Congo (DRC). Methods A community-based cross-sectional survey included subjects aged 18 years and above who were interviewed using a standard questionnaire and tested for malaria using a rapid diagnostic test and a nested polymerase chain reaction assay. Logistic regression models were fitted to assess the effect of potential predictive factors on malaria infection. Results The prevalence of malaria was estimated 60.2% [95%CI: 55.5; 64.8] in this population category. Parasite species identified included P. falciparum (87.4%), P. malariae (39.9), and P. ovale (7.5%) which occurred primarily as single species infections of P. falciparum ( 55.3% of malaria cases) and mixed P. falciparum/ P. malariae infections (26.1%). Putative episodes of clinical malaria dated back more than a month in 50% of participants whereas no episode was evoked within a 48-hours period interval prior to the survey. The likelihood of malaria infections decreased significantly with age (adjusted odds ratio, aOR = 0.98 [95%CI: 0.87; 0.98]; p = 0.006) and indoor insecticide spraying (aOR = 0.1 [95%CI: <0.01; 0.58]; p = 0.032). Conclusion Adults infected with malaria constitute a potentially important latent reservoir for the transmission of the disease in the study setting. They should specifically be taken into account in public health measures and translational research.
Ultrathin diamond films, or diamanes, are promising quasi-2D materials that are characterized by high stiffness, extreme wear resistance, high thermal conductivity, and chemical stability. Surface functionalization of multilayer graphene with different stackings of layers could be an interesting opportunity to induce proper electronic properties into diamanes. Combination of these electronic properties together with extraordinary mechanical ones will lead to their applications as field-emission displays substituting original devices with light-emitting diodes or organic light-emitting diodes. In the present study, we focus on the electronic properties of fluorinated and hydrogenated diamanes with (111), (110), (0001), (101̅0), and (2̅110) crystallographic orientations of surfaces of various thicknesses by using first-principles calculations and Bader analysis of electron density. We see that fluorine induces an occupied surface electronic state, while hydrogen modifies the occupied bulk state and also induces unoccupied surface states. Furthermore, a lower number of layers is necessary for hydrogenated diamanes to achieve the convergence of the work function in comparison with fluorinated diamanes, with the exception of fluorinated (110) and (2̅110) films that achieve rapid convergence and have the same behavior as other hydrogenated surfaces. This induces a modification of the work function with an increase of the number of layers that makes hydrogenated (2̅110) diamanes the most suitable surface for field-emission displays, better than the fluorinated counterparts. In addition, a quasi-quantitative descriptor of surface dipole moment based on the Tantardini-Oganov electronegativity scale is introduced as the average of bond dipole moments between the surface atoms. This new fundamental descriptor is capable of predicting a priori the bond dipole moment and may be considered as a new useful feature for crystal structure prediction based on artificial intelligence.
Atherosclerotic renovascular disease is the most frequent cause of renovascular hypertension and its prevalence increases with age and in specific subset of patients, such as those with end-stage chronic kidney disease, heart failure, and coronary artery disease. Besides hypertension, atherosclerotic renovascular disease is responsible for several clinical manifestations, including life-threatening conditions, such as recurrent flash pulmonary edema, rapidly progressive chronic kidney disease, or acute kidney injury. Atherosclerotic renovascular disease is usually part of a more diffuse atherosclerotic process and requires a combination therapy including antihypertensive, antiplatelet and lipid-lowering agents, as well as optimization of antidiabetic treatment, if needed. Besides medical therapy, percutaneous renal angioplasty was supposed to be the most effective therapy for atherosclerotic renovascular disease, by leading to blood flow restoration. However, despite an apparently solid rationale, several randomized clinical trials failed to confirm the favorable effects of percutaneous renal angioplasty on blood pressure control, kidney function, cardiovascular and renal outcomes, previously reported in observational, retrospective and single-center cohorts, switching off the enthusiasm for this procedure. Several studies' limitations may partly account for this failure, including heterogeneity of diagnostic techniques, overestimation of the degree of renal artery stenosis, inappropriate timing of revascularization, multiple protocol revisions, frequent crossovers, and most importantly exclusion of patients at higher likelihood to respond to angioplasty. The purpose of this review is to summarize studies' potential weaknesses and provide guidance to the clinician for identification of patients who may benefit most from revascularization.
Backg round Glioblastoma is an aggressive tumor that has a dismal prognosis even with multimodal treatment. However, some patients survive longer than expected. The objective of this study was to revisit patients diagnosed with glioblastoma according to the 2021 WHO classification and analyze clinical and molecular characteristics associated with long-term survival (LTS). Methods We retrospectively analyzed 120 IDH-wildtype glioblastomas operated on at our institution between 2013 and 2018. We divided them into LTS patients, surviving more than 3 years, and non-LTS patients, and then compared their features. Additionally, we performed DNA methylation-based brain tumor classification in LTS patients. Results Sixteen patients were long-term survivors. Age < 70 years, MGMT promoter methylation, extent of resection ≥ 95%, and administration of radiochemotherapy were associated with LTS (P = 0.005, P < 0.001, P = 0.048, and P = 0.008, respectively). In addition, when these factors were combined, the probability of LTS was 74% (95% CI: 62–-84). The methylome analysis confirmed the diagnosis of glioblastoma in the majority of the tested LTS patients. Regarding subtypes, 29% of cases were mesenchymal (MES), 43% were RTK1, and 29% were RTK2. Interestingly, RTK1 and RTK2 cases tended to have longer overall survival than MES cases (P = 0.057). Moreover, the only tested LTS patient with an unmethylated MGMT promoter had an “adult-type diffuse high-grade glioma, IDH-wildtype, subtype E” rather than a glioblastoma. This tumor was characterized by multinucleated giant cells and a somatic mutation in POLE. Conclusions We suggest that glioblastoma patients with a combination of favorable prognostic factors can achieve LTS in 74% of cases. In addition, methylome analysis is important to ascertain the type of glioma in LTS patients, especially when the MGMT promoter is unmethylated.
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