Plasma biomarkers of small intestine adaptations in obesity-related metabolic alterations

Background: Evidence suggests that pathophysiological conditions such as obesity and type 2 diabetes (T2D) are associated with morphologic and metabolic alterations in the small intestinal mucosa. Exploring these alterations generally requires invasive methods, limiting data acquisition to subjects with enteropathies or undergoing bariatric surgery. We aimed to evaluate small intestine epithelial cell homeostasis in a cohort of men covering a wide range of adiposity and glucose homoeostasis statuses. Methods: Plasma levels of citrulline, a biomarker of enterocyte mass, and I-FABP, a biomarker of enterocyte death, were measured by UHPLC‑MS and ELISA in 154 nondiabetic men and 67 men with a T2D diagnosis. Results: Plasma citrulline was signifcantly reduced in men with insulin resistance and T2D compared to insulin sensi‑ tive men. Decreased citrulline levels were, however, not observed in men with uncontrolled metabolic parameters during T2D. Plasma I-FABP was signifcantly higher in men with T2D, especially in presence of uncontrolled glycemic and lipid profle parameters. Integration of both parameters, which estimate enterocyte turnover, was associated with glucose homeostasis as well as with T2D diagnosis. Diferences in biomarkers levels were independent of age and BMI and glucose fltration rates. Conclusions: Our study supports a decreased functional enterocyte mass and an increased enterocyte death rate in presence of metabolic alterations but emphasizes that epithelial cell homeostasis is especially altered in presence of severe insulin resistance and T2D. The marked changes in small intestine cellularity observed in obesity and diabe‑ tes are thus suggested to be part of gut dysfunctions, mainly at an advanced stage of the disease

Rural-urban disparities in the management and health issues of chronic diseases in Quebec (Canada) in the early 2000s

Abstract: Introduction: The ‘Commission on the Future of Health Care in Canada’ recognized that people living in rural and remote areas of Canada are at a disadvantage in health status, access to care and health professionals, and it considers the fight against these problems as a national priority. Although some attention has been paid to the prevalence of chronic diseases, very few studies have studied specifically the management and health issues in populations with chronic diseases in relation to rurality. The objective of this study was to describe systematic gaps across rural and urban populations in incidence, mortality, morbidity, material and human resources utilization, and drug management for three important chronic diseases: atherosclerosis, osteoporosis and diabetes. Methods: Three retrospective population-based cohort studies were used. Three study populations were selected: an atherosclerotic population including patients newly hospitalized for a myocardial infarction (MI), an osteoporotic population including the at risk population who have suffered from a fragility fracture (FF) and, finally, a diabetic population that includes only incident cases of diabetes patients. For each of the three chronic diseases, variables were selected and classified in six categories: incidence, mortality, morbidity, material resources utilization, physician consultation and drug treatment. The Statistical Area Classification (SAC) was used as the rurality definition and contains six categories including two urban areas − Census Metropolitan Areas (CMA), or metropolitan areas, and Census Agglomeration (CA), or small towns − and four rural areas: Strong, Moderate, Weak and No Metropolitan influenced zones (MIZ), depending on the proportion of the workforce that commutes to urban areas. Each disease-related variable was described using age- and sex-adjusted rates. For comparing rates between rurality classes, the adjusted relative risks were calculated using the CMA as the reference group. The χ2 was used to test for the equality of risks. Results: A common pattern was identified from this study: for all three studied diseases, the material resources utilization rates and the specialist (other than internist) consultation rates were almost always statistically lower in small towns and rural areas when compared with metropolitan areas. Mortality rates and drug utilization rates were very similar among regions, except for hormone replacement therapy in women where utilization rates were higher in small towns and rural areas compared with metropolitan areas. Among observations that were not common to all three chronic diseases, the first is that MI incidence was greater in small towns and in Weak MIZ compared with metropolitan areas, fragility fractures seem to be marginally more frequent in small towns but less frequent in rural areas compared with metropolitan areas, while an increased incidence rate of diabetes is observed in remote region and a smaller risk in moderate MIZ compared with metropolitan areas. For both atherosclerosis and diabetes, morbidity rates were always statistically higher in small towns and in rural areas. This was not the case for patients with osteoporotic fractures where similar morbidity rates across regions were observed, except in strong MI which show the lowest morbidity rate. Conclusions: There was substantially lower utilization of specialized services in non-metropolitan areas for all three diseases (myocardial infarction, osteoporosis, and diabetes). However, this did not translate into consistent differences in mortality and morbidity outcomes. This suggests that the impact of differential care utilization is specific to each disease, with indications that some important services may be under-utilized in rural areas, while others may be over-utilized in urban areas without improvement in outcomes

A modified self‐controlled case series method for event‐dependent exposures and high event‐related mortality, with application to COVID‐19 vaccine safety

We propose a modified self‐controlled case series (SCCS) method to handle both event‐dependent exposures and high event‐related mortality. This development is motivated by an epidemiological study undertaken in France to quantify potential risks of cardiovascular events associated with COVID‐19 vaccines. Event‐dependence of vaccinations, and high event‐related mortality, are likely to arise in other SCCS studies of COVID‐19 vaccine safety. Using this case study and simulations to broaden its scope, we explore these features and the biases they may generate, implement the modified SCCS model, illustrate some of the properties of this model, and develop a new test for presence of a dose effect. The model we propose has wider application, notably when the event of interest is death

All-Solid-State 2.45-to-2.78-THz Source

Sources in the THz range are required in order for NASA to implement heterodyne instruments in this frequency range. The source that has been demonstrated here will be used for an instrument on the SOFIA platform as well as for upcoming astrophysics missions. There are currently no electronic sources in the 2 3- THz frequency range. An electronically tunable compact source in this frequency range is needed for lab spectroscopy as well as for compact space-deployable heterodyne receivers. This solution for obtaining useful power levels in the 2 3- THz range is based on utilizing power-combined multiplier stages. Utilizing power combining, the input power can be distributed between different multiplier chips and then recombined after the frequency multiplication. A continuous wave (CW) coherent source covering 2.48 2.75 THz, with greater than 10 percent instantaneous and tuning bandwidth, and having l 14 W of output power at room temperature, has been demonstrated. This source is based on a 91.8 101.8-GHz synthesizer followed by a power amplifier and three cascaded frequency triplers. It demonstrates that purely electronic solid-state sources can generate a useful amount of power in a region of the electromagnetic spectrum where lasers (solid-state or gas) were previously the only available coherent sources. The bandwidth, agility, and operability of this THz source has enabled wideband, high-resolution spectroscopic measurements of water, methanol, and carbon monoxide with a resolution and signal-to-noise ratio unmatched by other existing systems, providing new insight in the physics of these molecules. Further - more, the power and optical beam quality are high enough to observe the Lamb-dip effect in water. The source frequency has an absolute accuracy better than 1 part in 1012, and the spectrometer achieves sub-Doppler frequency resolution better than 1 part in 108. The harmonic purity is better than 25 dB. This source can serve as a local oscillator for a variety of heterodyne systems, and can be used as a method for precision control of more powerful but much less frequency-agile quantum mechanical terahertz sources

Baraitser-Winter cerebrofrontofacial syndrome: Delineation of the spectrum in 42 cases

Baraitser-Winter, Fryns-Aftimos and cerebrofrontofacial syndrome types 1 and 3 have recently been associated with heterozygous gain-of-function mutations in one of the two ubiquitous cytoplasmic actin-encoding genes ACTB and ACTG1 that encode β- and γ-actins. We present detailed phenotypic descriptions and neuroimaging on 36 patients analyzed by our group and six cases from the literature with a molecularly proven actinopathy (9 ACTG1 and 33 ACTB). The major clinical anomalies are striking dysmorphic facial features with hypertelorism, broad nose with large tip and prominent root, congenital non-myopathic ptosis, ridged metopic suture and arched eyebrows. Iris or retinal coloboma is present in many cases, as is sensorineural deafness. Cleft lip and palate, hallux duplex, congenital heart defects and renal tract anomalies are seen in some cases. Microcephaly may develop with time. Nearly all patients with ACTG1 mutations, and around 60% of those with ACTB mutations have some degree of pachygyria with anteroposterior severity gradient, rarely lissencephaly or neuronal heterotopia. Reduction of shoulder girdle muscle bulk and progressive joint stiffness is common. Early muscular involvement, occasionally with congenital arthrogryposis, may be present. Progressive, severe dystonia was seen in one family. Intellectual disability and epilepsy are variable in severity and largely correlate with CNS anomalies. One patient developed acute lymphocytic leukemia, and another a cutaneous lymphoma, indicating that actinopathies may be cancer-predisposing disorders. Considering the multifaceted role of actins in cell physiology, we hypothesize that some clinical manifestations may be partially mutation specific. Baraitser-Winter cerebrofrontofacial syndrome is our suggested designation for this clinical entity

Complete exon sequencing of all known Usher syndrome genes greatly improves molecular diagnosis

<p>Abstract</p> <p>Background</p> <p>Usher syndrome (USH) combines sensorineural deafness with blindness. It is inherited in an autosomal recessive mode. Early diagnosis is critical for adapted educational and patient management choices, and for genetic counseling. To date, nine causative genes have been identified for the three clinical subtypes (USH1, USH2 and USH3). Current diagnostic strategies make use of a genotyping microarray that is based on the previously reported mutations. The purpose of this study was to design a more accurate molecular diagnosis tool.</p> <p>Methods</p> <p>We sequenced the 366 coding exons and flanking regions of the nine known USH genes, in 54 USH patients (27 USH1, 21 USH2 and 6 USH3).</p> <p>Results</p> <p>Biallelic mutations were detected in 39 patients (72%) and monoallelic mutations in an additional 10 patients (18.5%). In addition to biallelic mutations in one of the USH genes, presumably pathogenic mutations in another USH gene were detected in seven patients (13%), and another patient carried monoallelic mutations in three different USH genes. Notably, none of the USH3 patients carried detectable mutations in the only known USH3 gene, whereas they all carried mutations in USH2 genes. Most importantly, the currently used microarray would have detected only 30 of the 81 different mutations that we found, of which 39 (48%) were novel.</p> <p>Conclusions</p> <p>Based on these results, complete exon sequencing of the currently known USH genes stands as a definite improvement for molecular diagnosis of this disease, which is of utmost importance in the perspective of gene therapy.</p

A Floating Thrombus Anchored at the Proximal Anastomosis of a Woven Thoracic Graft Mimicking a Genuine Aortic Dissection

An aortoesophageal fistula following surgery for a ruptured 6.6-cm thoracic aneurysm in a 69-yearold female was repaired using a 34-mm woven prosthetic graft. A follow-up computed tomography (CT) scan at 10 days postoperatively revealed a dissection-like picture in the region of the graft, which was treated conservatively. The patient eventually died from sepsis and multiorgan failure. At autopsy, the graft was retrieved in situ and studied by detailed gross, microscopy, and scanning electron microscopy (SEM) examination. Gross observation confirmed that the dissection resulted from the rolling of the internal capsule downstream. A massive thrombus anchored at the proximal anastomosis and held by a narrow head was also noted. The thrombus demonstrated reorganization in the area of the anastomosis, with a false lumen in its distal half. The reminder of the thrombus consisted of layered fibrin. After gross examination, the fabric graft was found to be flawless. Additional detailed studies were also done using microscopy, SEM, and gross examination

Development and Validation of a Symptom-Based Activity Index for Adults With Eosinophilic Esophagitis

Standardized instruments are needed to assess the activity of eosinophilic esophagitis (EoE), to provide endpoints for clinical trials and observational studies. We aimed to develop and validate a patient-reported outcome (PRO) instrument and score, based on items that could account for variations in patients’ assessments of disease severity. We also evaluated relationships between patients’ assessment of disease severity and EoE-associated endoscopic, histologic, and laboratory findings

A Solve-RD ClinVar-based reanalysis of 1522 index cases from ERN-ITHACA reveals common pitfalls and misinterpretations in exome sequencing

Purpose Within the Solve-RD project (https://solve-rd.eu/), the European Reference Network for Intellectual disability, TeleHealth, Autism and Congenital Anomalies aimed to investigate whether a reanalysis of exomes from unsolved cases based on ClinVar annotations could establish additional diagnoses. We present the results of the “ClinVar low-hanging fruit” reanalysis, reasons for the failure of previous analyses, and lessons learned. Methods Data from the first 3576 exomes (1522 probands and 2054 relatives) collected from European Reference Network for Intellectual disability, TeleHealth, Autism and Congenital Anomalies was reanalyzed by the Solve-RD consortium by evaluating for the presence of single-nucleotide variant, and small insertions and deletions already reported as (likely) pathogenic in ClinVar. Variants were filtered according to frequency, genotype, and mode of inheritance and reinterpreted. Results We identified causal variants in 59 cases (3.9%), 50 of them also raised by other approaches and 9 leading to new diagnoses, highlighting interpretation challenges: variants in genes not known to be involved in human disease at the time of the first analysis, misleading genotypes, or variants undetected by local pipelines (variants in off-target regions, low quality filters, low allelic balance, or high frequency). Conclusion The “ClinVar low-hanging fruit” analysis represents an effective, fast, and easy approach to recover causal variants from exome sequencing data, herewith contributing to the reduction of the diagnostic deadlock

Influence of a magnetic guide field on wakefield acceleration

Enhancement of the trapping and optimization of the beam quality are two key issues of Laser Wake Field Acceleration (LWFA). The influence of stochastic acceleration on the trapping of electrons is compared to the one of cold injection. It is shown that when considering a high intensity wave perturbed by a low intensity counter-propagating wave, in the non-linear blowout regime, the influence of the colliding pulses polarizations (either parallel linear or positive circular) on the beam quality seems weak when the electron density is below $\sim 10^{-3}$ critical density. The effect of a homogenous constant magnetic field $B_0$, parallel to the direction of propagation of the pump pulse, is studied in the blowout regime. Transverse currents are generated at the rim of the bubble, which results in the amplification of the $B_0$ field at the rear of the bubble. Without $B_0$ field the beam periodically explodes and re-confines, this phenomenon is suppressed when $B_0$ reaches some threshold, which is a function of the laser pulses parameters (intensity, waist, duration). Therefore the dynamics of the beam is modified, its maximum energy is slightly boosted and above all transverse emittance reduced. Moreover the low energy tail, observed in the non magnetized case, can be completely suppressed leading to very sharp mono-energetic beam when $B_0$ is applied. If the available $B_0$ field is limited then one has to fine-tune the spatio-temporal shape and intensity of the colliding pulse in order to get an acute control on the beam quality