In this paper, a wideband small cavity-backed magneto-electric (ME) antenna is proposed. This antenna is linearly polarized and designed to cover all the Global Navigation Satellite System (GNSS) ...bands. It exhibits small external dimensions of 90 × 90 × 40 mm3 (0.34 × 0.34 × 0.15 λ3 at lowest frequency) and achieves a wide impedance bandwidth of 40.5% (from 1.14 to 1.72 GHz) due to the excitation of a third resonance of the ME structure. It also provides a regular broadside gain of 5.2 dBi and stable radiation pattern in both E and H planes of the antenna.
Ocular developmental anomalies (ODA) such as anophthalmia/microphthalmia (AM) or anterior segment dysgenesis (ASD) have an estimated combined prevalence of 3.7 in 10,000 births. Mutations in SOX2 are ...the most frequent contributors to severe ODA, yet account for a minority of the genetic drivers. To identify novel ODA loci, we conducted targeted high-throughput sequencing of 407 candidate genes in an initial cohort of 22 sporadic ODA patients. Patched 1 (PTCH1), an inhibitor of sonic hedgehog (SHH) signaling, harbored an enrichment of rare heterozygous variants in comparison to either controls, or to the other candidate genes (four missense and one frameshift); targeted resequencing of PTCH1 in a second cohort of 48 ODA patients identified two additional rare nonsynonymous changes. Using multiple transient models and a CRISPR/Cas9-generated mutant, we show physiologically relevant phenotypes altering SHH signaling and eye development upon abrogation of ptch1 in zebrafish for which in vivo complementation assays using these models showed that all six patient missense mutations affect SHH signaling. Finally, through transcriptomic and ChIP analyses, we show that SOX2 binds to an intronic domain of the PTCH1 locus to regulate PTCH1 expression, findings that were validated both in vitro and in vivo. Together, these results demonstrate that PTCH1 mutations contribute to as much as 10% of ODA, identify the SHH signaling pathway as a novel effector of SOX2 activity during human ocular development, and indicate that ODA is likely the result of overactive SHH signaling in humans harboring mutations in either PTCH1 or SOX2.
The rate of unknown glaucoma is around 50% in industrialized countries. The purpose of our study was to estimate the prevalence of unknown cases of ocular hypertension, glaucoma suspects, and ...glaucoma in patients consulting for refractive disorders in France.
A retrospective study in the Point Vision ophthalmology center was led in Toulouse, France. All participants consulting for refractive disorders between June 2015 and June 2017 in the ophthalmology center were included. The cases were identified by the assessment of intraocular pressure, optic nerve head structure, and visual field. Ocular hypertension was defined as an intraocular pressure >21 mm Hg. Glaucoma was defined as the association of a glaucomatous papilla and two successive pathological visual fields. Glaucoma suspect was defined as the association of a glaucomatous papilla without visual field defect. The primary endpoint was the prevalence of unknown ocular hypertension, glaucoma suspects, and glaucoma in patients seen in an ophthalmology center.
A total of 66,068 patients (mean age = 37 years) consulted for a refraction visual assessment during the study period. Among them, 234 had a visual field and a retinal nerve fiber layer assessment for ocular hypertension and/or suspicious papilla. The prevalence of unknown cases of ocular hypertension, glaucoma suspect, and glaucoma was 2.6, 0.8, and 0.5 per 1,000 consultants, respectively. Median age at diagnosis of ocular hypertension, glaucoma suspect, and glaucoma was 52, 53, and 65 years, respectively.
The present study highlights the importance of glaucoma screening in people over 40 years old with the measurement of intraocular pressure and an optic nerve head assessment.
Background
We previously showed that supernatants of
Lactobacillus
biofilms induced an anti-inflammatory response by affecting the secretion of macrophage-derived cytokines, which was abrogated upon ...immunodepletion of the stress protein GroEL.
Methods
We purified GroEL from
L. reuteri
and analysed its anti-inflammatory properties in vitro in human macrophages isolated from buffy coats, ex vivo in explants from human biopsies and in vivo in a mouse model of DSS induced intestinal inflammation. As a control, we used GroEL purified (LPS-free) from
E. coli
.
Results
We found that
L. reuteri
GroEL (but not
E. coli
GroEL) inhibited pro-inflammatory M1-like macrophages markers, and favored M2-like markers. Consequently,
L. reuteri
GroEL inhibited pro-inflammatory cytokines (TNFα, IL-1β, IFNγ) while favouring an anti-inflammatory secretome. In colon tissues from human biopsies,
L. reuteri
GroEL was also able to decrease markers of inflammation and apoptosis (caspase 3) induced by LPS. In mice, we found that rectal administration of
L. reuteri
GroEL (but not
E. coli
GroEL) inhibited all signs of haemorrhagic colitis induced by DSS including intestinal mucosa degradation, rectal bleeding and weight loss. It also decreased intestinal production of inflammatory cytokines (such as IFNγ) while increasing anti-inflammatory IL-10 and IL-13. These effects were suppressed when animals were immunodepleted in macrophages. From a mechanistic point of view, the effect of
L. reuteri
GroEL seemed to involve TLR4, since it was lost in TRL4
−/−
mice, and the activation of a non-canonical TLR4 pathway.
Conclusions
L. reuteri
GroEL, by affecting macrophage inflammatory features, deserves to be explored as an alternative to probiotics.
Although direct-acting antivirals have been used extensively to treat patients with chronic hepatitis C virus (HCV) infection, their clinical effectiveness has not been well reported. We compared the ...incidence of death, hepatocellular carcinoma, and decompensated cirrhosis between patients treated with direct-acting antivirals and those untreated, in the French ANRS CO22 Hepather cohort.
We did a prospective study in adult patients with chronic HCV infection enrolled from 32 expert hepatology centres in France. We excluded patients with chronic hepatitis B, those with a history of decompensated cirrhosis, hepatocellular carcinoma, or liver transplantation, and patients who were treated with interferon-ribavirin with or without first-generation protease inhibitors. Co-primary study outcomes were incidence of all-cause mortality, hepatocellular carcinoma, and decompensated cirrhosis. The association between direct-acting antivirals and these outcomes was quantified using time-dependent Cox proportional hazards models. This study is registered with ClinicalTrials.gov, number NCT01953458.
Between Aug 6, 2012, and Dec 31, 2015, 10 166 patients were eligible for the study. 9895 (97%) patients had available follow-up information and were included in analyses. Median follow-up was 33·4 months (IQR 24·0–40·7). Treatment with direct-acting antivirals was initiated during follow-up in 7344 patients, and 2551 patients remained untreated at the final follow-up visit. During follow-up, 218 patients died (129 treated, 89 untreated), 258 reported hepatocellular carcinoma (187 treated, 71 untreated), and 106 had decompensated cirrhosis (74 treated, 32 untreated). Exposure to direct-acting antivirals was associated with increased risk for hepatocellular carcinoma (unadjusted hazard ratio HR 2·77, 95% CI 2·07–3·71) and decompensated cirrhosis (3·83, 2·29–6·42). After adjustment for variables (age, sex, body-mass index, geographical origin, infection route, fibrosis score, HCV treatment-naive, HCV genotype, alcohol consumption, diabetes, arterial hypertension, biological variables, and model for end-stage liver disease score in patients with cirrhosis), exposure to direct-acting antivirals was associated with a decrease in all-cause mortality (adjusted HR 0·48, 95% CI 0·33–0·70) and hepatocellular carcinoma (0·66, 0·46–0·93), and was not associated with decompensated cirrhosis (1·14, 0·57–2·27).
Treatment with direct-acting antivirals is associated with reduced risk for mortality and hepatocellular carcinoma and should be considered in all patients with chronic HCV infection.
INSERM-ANRS (France Recherche Nord & Sud Sida-HIV Hépatites), ANR (Agence Nationale de la Recherche), DGS (Direction Générale de la Santé), MSD, Janssen, Gilead, AbbVie, Bristol-Myers Squibb, and Roche.
While there has been progress in our understanding of the origin and history of agriculture in sub-Saharan Africa, a unified perspective is still lacking on where and how major crops were ...domesticated in the region. Here, we investigated the domestication of African yam (
), a key crop in early African agriculture. Using whole-genome resequencing and statistical models, we show that cultivated yam was domesticated from a forest species. We infer that the expansion of African yam agriculture started in the Niger River basin. This result, alongside with the origins of African rice and pearl millet, supports the hypothesis that the vicinity of the Niger River was a major cradle of African agriculture.
Despite recent advances in the treatment of colorectal cancer (CRC), tumor resistance is a frequent cause of chemotherapy failure. Therefore, new treatment options are needed to improve survival of ...patients with irinotecan-refractory CRCs, particularly those bearing KRAS mutations that preclude the use of anti-EGFR therapies. In this study, we investigated whether sorafenib could reverse irinotecan resistance, thereby enhancing the therapeutic efficacy of routinely used irinotecan-based chemotherapy. We used both in vitro (the HCT116, SW48, SW620, and HT29 colon adenocarcinoma cell lines and four SN-38-resistant HCT-116 and SW48 clones) and in vivo models (nude mice xenografted with SN-38-resistant HCT116 cells) to test the efficacy of sorafenib alone or in combination with irinotecan or its active metabolite, SN-38. We have shown that sorafenib improved the antitumoral activity of irinotecan in vitro, in both parental and SN-38-resistant colon adenocarcinoma cell lines independently of their KRAS status, as well as in vivo, in xenografted mice. By inhibiting the drug-efflux pump ABCG2, sorafenib favors irinotecan intracellular accumulation and enhances its toxicity. Moreover, we found that sorafenib improved the efficacy of irinotecan by inhibiting the irinotecan-mediated p38 and ERK activation. In conclusion, our results show that sorafenib can suppress resistance to irinotecan and suggest that sorafenib could be used to overcome resistance to irinotecan-based chemotherapies in CRC, particularly in KRAS-mutated tumors.
Background & Aims Albumin infusion improves renal function and survival in cirrhotic patients with spontaneous bacterial peritonitis (SBP) but its efficacy in other types of infections remains ...unknown. We investigated this issue through a multicenter randomized controlled trial. Methods A total of 193 cirrhotic patients with a Child-Pugh score greater than 8 and sepsis unrelated to SBP were randomly assigned to receive antibiotics plus albumin (1.5 g/kg on day 1 and 1 g/kg on day 3; albumin group ALB: n = 96) or antibiotics alone (control group CG: n = 97). The primary endpoint was the 3-month renal failure rate (increase in creatinine ⩾50% to reach a final value ⩾133 μmol/L). The secondary endpoint was 3-month survival rate. Results Forty-seven (24.6%) patients died (ALB: n = 27 vs. CG: n = 20; 3-month survival: 70.2% vs. 78.3%; p = 0.16). Albumin infusion delayed the occurrence of renal failure (mean time to onset, ALB: 29.0 ± 21.8 vs. 11.7 ± 9.1 days, p = 0.018) but the 3-month renal failure rate was similar (ALB: 14.3% vs. CG: 13.5%; p = 0.88). By multivariate analysis, MELD score ( p <0.0001), pneumonia ( p = 0.0041), hyponatremia ( p = 0.031) and occurrence of renal failure ( p <0.0001) were predictors of death. Of note, pulmonary edema developed in 8/96 (8.3%) patients in the albumin group of whom two died, one on the day and the other on day 33 following albumin infusion. Conclusions In cirrhotic patients with infections other than SBP, albumin infusion delayed onset of renal failure but did not improve renal function or survival at 3 months. Infusion of large amounts of albumin should be cautiously administered in the sickest cirrhotic patients.
Tomato flavour is an important goal for breeders. Volatile organic compounds (VOCs) are major determinants of tomato flavour. Although most tomato varieties for fresh market are F1 hybrids, most ...studies on the genetic control of flavour-related traits are performed on lines. We quantified 46 VOCs in a panel of 121 small fruited lines and in a test cross panel of 165 hybrids (the previous panel plus 44 elite cherry tomato lines crossed with a common line). High and consistent heritabilities were assessed for most VOCs in the two panels, and 65% of VOC contents were strongly correlated between lines and hybrids. Additivity was observed for most VOCs. We performed genome wide association studies (GWAS) on the two panels separately, along with a third GWAS on the test cross subset carrying only F1 hybrids corresponding to the line panel. We identified 205, 183 and 138 associations, respectively. We identified numerous overlapping associations for VOCs belonging to the same metabolic pathway within each panel; we focused on seven chromosome regions with clusters of associations simultaneously involved in several key VOCs for tomato aroma. The study highlighted the benefit of testcross panels to create tasty F1 hybrid varieties.
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•One-third of the patients with cirrhosis and variceal bleeding are eligible for early-TIPS.•TIPS is restricted to 7% of patients displaying less severe cirrhosis.•Other studies are ...needed to confirm the benefit of early-TIPS on survival.
The Baveno VI consensus meeting concluded that an early transjugular intra-hepatic porto-systemic shunt (TIPS) must be considered in high-risk patients with cirrhosis, presenting with variceal bleeding (VB) (Child B + active bleeding at endoscopy or Child C10-13 patients). Whether this therapeutic approach is feasible in a real-life setting remains unclear. The aim of this study was to determine (i) the proportion of patients eligible for early-TIPS among patients with cirrhosis and VB, (ii) the proportion of these patients who underwent early-TIPS placement and the main reasons for discarding TIPS, and (iii) the outcomes of patients who experienced early-TIPS placement.
A large, national, prospective, multicentre audit of academic and non-academic centres, in which all French centres recruiting patients with gastrointestinal bleeding were invited to participate. All consecutive patients with cirrhosis and portal hypertension-related bleeding were included.
A total of 964 patients were included (58 centres: 26 academic, 32 non-academic; patient characteristics: male sex 77%; age 59.6 ± 12.1 years; aetiologies of cirrhosis (alcoholic 67%, viral 15%, other 18%); source of bleeding (oesophageal varices 80%, gastric varices 11%, other 9%); active bleeding at endoscopy 34%; Child A 21%, B 44%, C 35%. Overall, 35% of the patients were eligible for early-TIPS, but only 6.8%, displaying less severe cirrhosis underwent early-TIPS placement. The main reason for discarding TIPS was a lack of availability. The actuarial probability of survival at one year was significantly increased in early-TIPS patients (85.7 ± 0.07% vs. 58.9 ± 0.03%, p = 0.04). The severity of liver disease was the only parameter independently associated with improved one-year survival.
In this real-life study, one-third of the patients with cirrhosis, admitted for VB fulfilled the criteria for early-TIPS placement, whereas only 7% had access to TIPS. TIPS was restricted to patients displaying less severe cirrhosis. The severity of liver disease was the only parameter that influenced survival.
Bleeding from oesophageal or gastric varices is a severe complication of cirrhosis, related to an increased pressure in the portal vein perfusing the liver. Some patients are described as “severe”, either because their liver disease is already severe, or because the bleeding is very important. Those patients could benefit from a prothesis, placed inside the liver by an interventional radiologist, aiming to decrease the pressure in the portal vein, just after the control of bleeding by medications and endoscopic treatment. New studies are warranted to demonstrate a real beneficial effect of this therapeutic attitude, which is not adopted in real-life practice, as shown by this national French audit of practice.
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