Wessels MW, Willems PJ. Genetic factors in non‐syndromic congenital heart malformations.
The genetic defect in most patients with non‐syndromic congenital heart malformations (CHM) is unknown, ...although more than 40 different genes have already been implicated. Only a minority of CHM seems to be due to monogenetic mutations, and the majority occurs sporadically. The multifactorial inheritance hypothesis of common diseases suggesting that the cumulative effect of multiple genetic and environmental risk factors leads to disease, might also apply for CHM.
We review here the monogenic disease genes with high‐penetrance mutations, susceptibility genes with reduced‐penetrance mutations, and somatic mutations implicated in non‐syndromic CHM.
Proton-nucleus (p+A) collisions have long been recognized as a crucial component of the physics program with nuclear beams at high energies, in particular for their reference role to interpret and ...understand nucleus-nucleus data as well as for their potential to elucidate the partonic structure of matter at low parton fractional momenta (small-x). Here, we summarize the main motivations that make a proton-nucleus run a decisive ingredient for a successful heavy-ion program at the Large Hadron Collider (LHC) and we present unique scientific opportunities arising from these collisions. We also review the status of ongoing discussions about operation plans for the p+A mode at the LHC.
Human Precision-cut intestinal slices (hPCIS) are used to study intestinal physiology, pathophysiology, drug efficacy, toxicology, kinetics, and metabolism. However, the use of this ex vivo model is ...restricted to approximately a 24 h timeframe because of declining viability of the hPCIS during traditional culture. We hypothesized that we could extend the hPCIS viability by using organoid medium. Therefore, we cultured hPCIS for up to 72 h in organoid media expansion medium (Emed) and differentiation medium (Dmed). After incubation, we assessed culture-induced changes on viability markers, specific cell type markers and we assessed the metabolic activity of enterocytes by measuring midazolam metabolite formation. We show that the adenosine triphosphate (ATP)/protein ratio of Emed-cultured hPCIS and morphology of both Emed- and Dmed-cultured hPCIS was improved compared to WME-cultured hPCIS. Emed-cultured hPCIS showed an increased expression of proliferation and stem cell markers, whereas Dmed-cultured hPCIS showed an increased expression of proliferation and enterocyte markers, along with increased midazolam metabolism. Using the Emed, the viability of hPCIS could be extended for up to 72 h, and proliferating stem cells remained preserved. Using Dmed, hPCS also remained viable for up to 72 h, and specifically rescued the metabolizing enterocytes during culture. In conclusion, by using two different organoid culture media, we could extend the hPCIS viability for up to 72 h of incubation and specifically steer stem cells or enterocytes towards their original function, metabolism, and proliferation, potentially allowing pharmacokinetic and toxicology studies beyond the 24 h timeframe.
After 53 years of quiescence, Mount Agung awoke in August 2017, with intense seismicity, measurable ground deformation, and thermal anomalies in the summit crater. Although the seismic unrest peaked ...in late September and early October, the volcano did not start erupting until 21 November. The most intense explosive eruptions with accompanying rapid lava effusion occurred between 25 and 29 November. Smaller infrequent explosions and extrusions continue through the present (June 2019). The delay between intense unrest and eruption caused considerable challenges to emergency responders, local and national governmental agencies, and the population of Bali near the volcano, including over 140,000 evacuees. This paper provides an overview of the volcanic activity at Mount Agung from the viewpoint of the volcano observatory and other scientists responding to the volcanic crisis. We discuss the volcanic activity as well as key data streams used to track it. We provide evidence that magma intruded into the mid-crust in early 2017, and again in August of that year, prior to intrusion of an inferred dike between Mount Agung and Batur Caldera that initiated an earthquake swarm in late September. We summarize efforts to forecast the behavior of the volcano, to quantify exclusion zones for evacuations, and to work with emergency responders and other government agencies to make decisions during a complex and tense volcanic crisis.
Extended interval dosing (EID) of natalizumab is a promising strategy to optimise treatment in multiple sclerosis (MS). Personalised EID by therapeutic drug monitoring can enable further extension of ...treatment intervals.
The NEXT-MS trial is an investigator-initiated prospective phase IV non-randomised study. Adults with a diagnosis of relapsing-remitting MS who received ≥6 natalizumab infusions were included in three groups: personalised EID with a target drug trough concentration of 10 µg/mL (EID10), an exploratory group of personalised EID with a target of 5 µg/mL (EID5) and standard interval dosing (SID) of 4 weeks. The primary outcome is radiological disease activity (new/newly enlarged T2 lesions) comparing the EID10 group to a historical cohort of SID (HSID).
Results of the first phase of the NEXT-MS trial are reported here (n=376) as the study will continue with an amended protocol. In the EID10 group (n=251), incidence rate of radiological activity was 10.0 per 1000 person-years, which was non-inferior to the HSID cohort (24.7 per 1000 person-years (n=87), incidence rate difference 14.7, 90% CI -4.5 to 34.0). Incidence rate of radiological activity was 10.0 per 1000 person-years in the EID5 group (n=65), and 47.0 per 1000 person-years in the SID group (n=60). Serum neurofilament light levels did not increase over time within the EID groups. There were no cases of progressive multifocal leukoencephalopathy.
MS disease activity is adequately controlled with personalised natalizumab EID. Interval extension to a drug trough concentration of 5 µg/mL is likely a safe target to extend natalizumab treatment intervals >6 weeks.
NCT04225312.
Abstract
Background
Birt-Hogg-Dubé syndrome (BHD) is an inherited disease caused by pathogenic variants in the
FLCN
gene. One of the characteristics is the increased risk for spontaneous ...pneumothorax, likely due to the presence of pulmonary cysts mainly distributed under the carina. Due to variable expression and lack of awareness, BHD is likely to be underdiagnosed
.
We aimed to examine the prevalence of BHD in patients presenting with an apparent primary spontaneous pneumothorax and to evaluate the contribution of chest CT in establishing the diagnosis.
Methods
Patients who presented with apparent primary spontaneous pneumothorax between 2004 and 2017 in a large Dutch teaching hospital were enrolled in this quantitative cross-sectional study. A questionnaire was sent to eligible patients. Patients who completed the questionnaire and consented to further participation were invited to visit the hospital for genetic testing and low dose, volumetric chest CT.
Results
Genetic testing was performed in 88 patients with apparent primary spontaneous pneumothorax. Three patients were found to have a pathogenic variant in the
FLCN
gene (3.4%). No variants of unknown significance were detected. Pulmonary cysts were detected in 14 out of 83 participants with an available chest CT, six had more than one cyst. All three patients with BHD had multiple pulmonary cysts.
Conclusions
Based on previous literature and the present study, we believe that performing a chest CT in every patient presenting with primary spontaneous pneumothorax is justified. Subsequent genetic testing of the FLCN gene should be considered when multiple pulmonary cysts are present.
Trial registration
The study was registered at clinicaltrials.gov with reference NCT02916992.
Summary at a glance
Three out of 88 patients with an apparent primary spontaneous pneumothorax were diagnosed with Birt-Hogg-Dubé syndrome in this study and all three had multiple pulmonary cysts. We believe that performing a chest CT in every patient with an apparent primary spontaneous pneumothorax is justified to identify underlying diseases.
Purpose
To investigate whether locoregional staging of colon cancer by experienced radiologists can be improved by training and feedback to minimize the risk of over-staging into the context of ...patient selection for neoadjuvant therapy and to identify potential pitfalls of CT staging by characterizing pathologic traits of tumors that remain challenging for radiologists.
Methods
Forty-five cases of stage I-III colon cancer were included in this retrospective study. Five experienced radiologists evaluated the CTs; 5 baseline scans followed by 4 sequential batches of 10 scans. All radiologists were trained after baseline scoring and 2 radiologists received feedback. The learning curve, diagnostic performance, reader confidence, and reading time were evaluated with pathologic staging as reference. Pathology reports and H&E slides of challenging cases were reviewed to identify potential pitfalls.
Results
Diagnostic performance in distinguishing T1-2 vs. T3-4 improved significantly after training and with increasing number of reviewed cases. Inaccurate staging was more frequently related to under-staging rather than over-staging. Risk of over-staging was minimized to 7% in batch 3–4. N-staging remained unreliable with an overall accuracy of 61%. Pathologic review identified two tumor characteristics causing under-staging for T-stage in 5/7 cases: (1) very limited invasive part beyond the muscularis propria and (2) mucinous composition of the invading part.
Conclusion
The high accuracy and specificity of T-staging reached in our study indicate that sufficient training and practice of experienced radiologists can ensure high validity for CT staging in colon cancer to safely use neoadjuvant therapy without significant risk of over-treatment, while N-staging remained unreliable.
Phytophthora root rot, caused by
, is an economically important disease on young apple trees. Limited information is available on the effect of different phosphonate application methods and dosages ...on disease control, fruit and root phosphite concentrations, and soil and root pathogen inoculum levels. Evaluation of phosphonate treatments in three apple orchard trials (two in the Grabouw and one in the Koue Bokkeveld region) showed that foliar sprays (ammonium or potassium phosphonate), trunk sprays and trunk paints, were equally effective at increasing trunk diameter in one trial and yield in a second trial over a 25-month period. Foliar ammonium and potassium phosphonate sprays (12 g of phosphorous acid/tree), and two different dosages of the ammonium phosphonate sprays (∼4.8 g or 12 g of phosphorous acid/tree) were all equally effective at improving tree growth. The addition of a bark penetrant (polyether-polymethylsiloxane-copolymer) to trunk sprays did not improve the activity of trunk sprays. The low dosage ammonium phosphonate foliar spray (∼4.8 g a.i./tree) was the only treatment that, in general, yielded significantly lower root phosphite concentrations than the other phosphonate treatments. Root phosphite concentrations were significantly positively correlated (
< 0.0001) with an increase in trunk diameter and negatively (
< 0.0001) with
root DNA quantities. Phosphite fruit residues were <31 ppm for all treatments, with the trunk paint treatment (80 g of phosphorous acid/tree applied annually) yielding significantly lower residues than the higher dosage foliar sprays (∼12 g a.i./tree). Twenty-one months posttreatment, most of the phosphonate treatments in all of the trials similarly significantly reduced
DNA quantities estimated directly from roots, but not from soil based on soil baiting DNA analysis. Pathogen quantities in fine feeder roots did not differ significantly from those in higher-order roots (<5 mm diameter).
DNA quantities estimated using DNA quantification directly from roots were significantly correlated (
< 0.0001) with those obtained through root leaf baiting DNA analysis and, to a lesser extent, with soil leaf baiting DNA quantities (
= 0.025).
Computed tomography (CT) is used for restaging of gastric cancer patients during neoadjuvant chemotherapy (NAC). The treatment strategy could be altered after detection of distant interval ...metastases, possibly leading to a reduction in unnecessary chemotherapy cycles, its related toxicity, and surgical procedures. The aim of this study was to evaluate the additive value of restaging-CT during NAC in guiding clinical decision making in gastric cancer.
This retrospective, multicenter cohort study identified all patients with surgically resectable gastric adenocarcinoma (cT1–4a-x, N0–3-x, M0-x), who started NAC with curative intent. Restaging-CT was performed after 2 out of 3 cycles of NAC. The primary outcome was treatment alterations made based on restaging-CT by a multidisciplinary tumor board. Confirmation of metastases was obtained by surgery or biopsy.
Between 2007 and 2015, CT-restaging was performed in 122 out of 152 included patients and timed after 2 cycles (n = 76) or after 3 cycles (n = 46) of NAC. Restaging-CT revealed a metastasis in 1 out of 122 restaged patients (1%) after which surgical resection was omitted, whereas 4 patients (3%) with distant interval metastases were not identified by restaging-CT and underwent a futile laparotomy. In 5 out of 76 patients (7%) disease progression was detected while undergoing NAC, leading to omission of the 3rd cycle of chemotherapy.
The additive value of restaging-CT during NAC in gastric cancer is limited in guiding clinical decision making and therefore not recommended. Further studies may identify subgroups that may benefit of alternative diagnostic modalities.
Apple replant disease (ARD) is a biological phenomenon that is encountered when old apple orchards are replanted, resulting in tree growth and yield reductions in young trees. Three ARD orchard ...trials were conducted, which showed that semiselective chemicals (fenamiphos, metalaxyl, imidacloprid, and phosphonates) used independently, two fumigant formulations (33.3% chloropicrin and 60.8% 1,3-dichloropropene Pic33-1,3D and 57.% chloropicrin and 38% 1,3 dichloropropene Pic57-1,3D), and semiselective chemicals combined with Pic33-1,3D or Pic57-1,3D all contributed to significant increases in tree growth (trunk diameter and shoot length) relative to the untreated control 3 to 4 years postplanting. The treatments did not differ significantly from each other in improving tree growth. Yield was more indicative of treatment efficacy, but this varied between the three orchards. The Pic33-1,3D fumigant in combination with semiselective chemistries was the most consistent in significantly increasing cumulative yields. The Pic57-1,3D treatment was superior in increasing yields relative to the Pic33-1,3D treatment, because (i) it significantly increased cumulative yields in comparison with the Pic33-1,3D treatment in one orchard and (ii) in another orchard, a significant increase in yield was obtained with Pic57-1,3D relative to the control treatment but not with the Pic33-1,3D treatment. The quantification of ARD causative agents 20 months postplant showed that
contributed to disease development in all three orchards; significant negative correlations existed between the quantity of
DNA detected in tree roots and tree growth and less often, yield. In two orchards, only some of the treatments that significantly reduced the quantity of
DNA in tree roots relative to the control also resulted in a significant increase in tree growth. Some of the aforementioned trends were also evident for
spp. root densities in two of the orchards. There was a significant positive correlation between
root DNA quantities and
spp. root densities.
spp. and "
"-like DNA quantities detected in tree roots typically were not indicative of treatment efficacy. However, a significant positive correlation existed between these two pathogen groups, suggesting complex interactions not associated with pathogen quantities per se.
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