Explainable deep learning for disease activity prediction in chronic inflammatory joint diseases.

Analysing complex diseases such as chronic inflammatory joint diseases (CIJDs), where many factors influence the disease evolution over time, is a challenging task. CIJDs are rheumatic diseases that cause the immune system to attack healthy organs, mainly the joints. Different environmental, genetic and demographic factors affect disease development and progression. The Swiss Clinical Quality Management in Rheumatic Diseases (SCQM) Foundation maintains a national database of CIJDs documenting the disease management over time for 19'267 patients. We propose the Disease Activity Score Network (DAS-Net), an explainable multi-task learning model trained on patients' data with different arthritis subtypes, transforming longitudinal patient journeys into comparable representations and predicting multiple disease activity scores. First, we built a modular model composed of feed-forward neural networks, long short-term memory networks and attention layers to process the heterogeneous patient histories and predict future disease activity. Second, we investigated the utility of the model's computed patient representations (latent embeddings) to identify patients with similar disease progression. Third, we enhanced the explainability of our model by analysing the impact of different patient characteristics on disease progression and contrasted our model outcomes with medical expert knowledge. To this end, we explored multiple feature attribution methods including SHAP, attention attribution and feature weighting using case-based similarity. Our model outperforms temporal and non-temporal neural network, tree-based, and naive static baselines in predicting future disease activity scores. To identify similar patients, a k-nearest neighbours regression algorithm applied to the model's computed latent representations outperforms baseline strategies that use raw input features representation.

Comprehensive analyses of the occurrence of a fungicide resistance marker and the genetic structure in Erysiphe necator populations.

Genetically distinct groups of Erysiphe necator, the fungus causing grapevine powdery mildew infect grapevine in Europe, yet the processes sustaining stable genetic differences between those groups are less understood. Genotyping of over 2000 field samples from six wine regions in Hungary collected between 2017 and 2019 was conducted to reveal E. necator genotypes and their possible differentiation. The demethylase inhibitor (DMI) fungicide resistance marker A495T was detected in all wine regions, in 16% of the samples. Its occurrence differed significantly among wine regions and grape cultivars, and sampling years, but it did not differ between DMI-treated and untreated fields. Multilocus sequence analyses of field samples and 59 in vitro maintained isolates revealed significant genetic differences among populations from distinct wine regions. We identified 14 E. necator genotypes, of which eight were previously unknown. In contrast to the previous concept of A and B groups, European E. necator populations should be considered genetically more complex. Isolation by geographic distance, growing season, and host variety influence the genetic structuring of E. necator, which should be considered both during diagnoses and when effective treatments are planned.

Shear-stress sensing by PIEZO1 regulates tendon stiffness in rodents and influences jumping performance in humans.

Athletic performance relies on tendons, which enable movement by transferring forces from muscles to the skeleton. Yet, how load-bearing structures in tendons sense and adapt to physical demands is not understood. Here, by performing calcium (Ca2+) imaging in mechanically loaded tendon explants from rats and in primary tendon cells from rats and humans, we show that tenocytes detect mechanical forces through the mechanosensitive ion channel PIEZO1, which senses shear stresses induced by collagen-fibre sliding. Through tenocyte-targeted loss-of-function and gain-of-function experiments in rodents, we show that reduced PIEZO1 activity decreased tendon stiffness and that elevated PIEZO1 mechanosignalling increased tendon stiffness and strength, seemingly through upregulated collagen cross-linking. We also show that humans carrying the PIEZO1 E756del gain-of-function mutation display a 13.2% average increase in normalized jumping height, presumably due to a higher rate of force generation or to the release of a larger amount of stored elastic energy. Further understanding of the PIEZO1-mediated mechanoregulation of tendon stiffness should aid research on musculoskeletal medicine and on sports performance.

Focus on time: dynamic imaging reveals stretch-dependent cell relaxation and nuclear deformation.

Among the stimuli to which cells are exposed in vivo, it has been shown that tensile deformations induce specific cellular responses in musculoskeletal, cardiovascular, and stromal tissues. However, the early response of cells to sustained substrate-based stretch has remained elusive because of the short timescale at which it occurs. To measure the tensile mechanical properties of adherent cells immediately after the application of substrate deformations, we have developed a dynamic traction force microscopy method that enables subsecond temporal resolution imaging of transient subcellular events. The system employs a novel, to our knowledge, tracking approach with minimal computational overhead to compensate substrate-based, stretch-induced motion/drift of stretched single cells in real time, allowing capture of biophysical phenomena on multiple channels by fluorescent multichannel imaging on a single camera, thus avoiding the need for beam splitting with the associated loss of light. Using this tool, we have characterized the transient subcellular forces and nuclear deformations of single cells immediately after the application of equibiaxial strain. Our experiments reveal significant differences in the cell relaxation dynamics and in the intracellular propagation of force to the nuclear compartment in cells stretched at different strain rates and exposes the need for time control for the correct interpretation of dynamic cell mechanics experiments.

The Protein Mat(ters)-Revealing the Biologically Relevant Mechanical Contribution of Collagen- and Fibronectin-Coated Micropatterns.

Understanding cell-material interactions requires accurate characterization of the substrate mechanics, which are generally measured by indentation-type atomic force microscopy. To facilitate cell-substrate interaction, model extracellular matrix coatings are used although their tensile mechanical properties are generally unknown. In this study, beyond standard compressive stiffness estimation, we performed a novel tensile mechanical characterization of collagen- and fibronectin-micropatterned polyacrylamide hydrogels. We further demonstrate the impact of the protein mat on the tensile stiffness characterization of adherent cells. To our knowledge, our study is the first to uncover direction-dependent mechanical behavior of the protein coatings and to demonstrate that it affects cellular response relative to substrate mechanics.

Green Fluorescent Protein Transformation Sheds More Light on a Widespread Mycoparasitic Interaction.

Powdery mildews, ubiquitous obligate biotrophic plant pathogens, are often attacked in the field by mycoparasitic fungi belonging to the genus Ampelomyces. Some Ampelomyces strains are commercialized biocontrol agents of crop pathogenic powdery mildews. Using Agrobacterium tumefaciens-mediated transformation (ATMT), we produced stable Ampelomyces transformants that constitutively expressed green fluorescent protein (GFP) to (i) improve the visualization of the mildew-Ampelomyces interaction and (ii) decipher the environmental fate of Ampelomyces fungi before and after acting as a mycoparasite. Detection of Ampelomyces structures, and especially hyphae, was greatly enhanced when diverse powdery mildew, leaf, and soil samples containing GFP transformants were examined with fluorescence microscopy compared with brightfield and differential interference contrast optics. We showed for the first time, to our knowledge, that Ampelomyces strains can persist up to 21 days on mildew-free host plant surfaces, where they can attack powdery mildew structures as soon as these appear after this period. As saprobes in decomposing, powdery mildew-infected leaves on the ground and also in autoclaved soil, Ampelomyces strains developed new hyphae but did not sporulate. These results indicate that Ampelomyces strains occupy a niche in the phyllosphere where they act primarily as mycoparasites of powdery mildews. Our work has established a framework for a molecular genetic toolbox for the genus Ampelomyces using ATMT.

Modified technique of endocapsular lens aspiration for severely subluxated lenses.

PurposeSeverely subluxated crystalline lenses pose a difficult situation to anterior segment surgeons and can only be managed surgically by removal of the lens as well as the capsular bag. Several techniques have been described in literature for the management of such cases. We describe a modified technique of endocapsular lens aspiration by the limbal route for lens extraction through small incisions on the cornea.Patients and methodsThirty-two eyes of 16 consecutive patients with severely subluxated crystalline lenses were recruited in the study. All eyes underwent a modified technique of lens aspiration within the capsular bag using a single instrument, vitrectomy cutter, and irrigation cannula, followed by sacrificing of the capsular bag. The patients were either left aphakic or implanted with an open loop anterior chamber intraocular lens (ACIOL Kelman Multiflex) and prospectively followed up for a period of 3 months.ResultsThe mean age of the patients was 9 years 3 months±3 years (range 5-15 yrs). All eyes underwent complete lens aspiration within the capsular bag with no dislocation of the lens matter. ACIOL was inserted in 22 eyes (68.7%) and 10 eyes (31.2%) were left aphakic. All the surgeries were uneventful. The mean best corrected visual acuity (BCVA) at 3 months post surgery was 0.47±0.11 logMAR which was significantly better than pre-operative BCVA (P=0.001). The percentage endothelial cell loss at 3 months was 7.1%. There was no evidence of glaucoma, corneal decompensation, or retinal detachment. The astigmatism which increased from 1.45D±086 preoperatively to 3.76D±2.02 1 week post-operatively due to sutures reduced to 1.97D±0.81 post suture removal at 3 months.ConclusionThe modified technique of endocapsular lens aspiration proves to be a simple and effective method of removal of the lens-capsular bag complex in severely subluxated lenses.

Comparison of new motorized injector vs manual injector for implantation of foldable intraocular lenses on wound integrity: an ASOCT study.

PURPOSE: To compare intraocular lens implantation using a motorized injector vs standard manual injector through a 2.2-mm clear corneal incision. METHODS: Patients underwent standard phacoemulsification using a 2.2-mm clear corneal incision. Hydrophobic acrylic aspheric intraocular lens (Acrysof SN60WF intraocular lens (IOL)) was inserted using D cartridge with manual monarch injector or autosert motorized injector. IOL safety, final incision size and wound integrity in terms of anterior and posterior wound gape, and descemet's membrane detachment were compared between the two groups at post-operative day 1 and at 1 month using Anterior Segment Optical Coherence Tomography. RESULTS: The study recruited 32 patients in the group I (manual injector) and 30 patients in group II (motorized injector). In group I, the final incision after IOL insertion increased by 0.12 mm (95% CI: 0.134-0.106) (P<0.0001), which was seen in 100% of the patients. In group II, the incision enlarged by 0.01 (95% CI: 0.021-0.0.001) (P=0.07) and was seen in only 6.67% of the cases. IOL nicks were seen in 9.37% of the cases in group I only. Although the incidence of descemet's membrane detachment and anterior wound gape was similar for both groups, posterior wound gape was seen more often with the manual injector in the immediate post-operative period. (P=0.018) CONCLUSION: The motorized insertion system was gentle and safe for the IOLs with lesser incidence of IOL nicks. Regarding wound safety, it caused significantly less incision enlargement and better posterior wound integrity.

Simultaneous specific in planta visualization of root-colonizing fungi using fluorescence in situ hybridization (FISH).

In planta detection of mutualistic, endophytic, and pathogenic fungi commonly colonizing roots and other plant organs is not a routine task. We aimed to use fluorescence in situ hybridization (FISH) for simultaneous specific detection of different fungi colonizing the same tissue. We have adapted ribosomal RNA (rRNA) FISH for visualization of common mycorrhizal (arbuscular- and ectomycorrhiza) and endophytic fungi within roots of different plant species. Beside general probes, we designed and used specific ones hybridizing to the large subunit of rRNA with fluorescent dyes chosen to avoid or reduce the interference with the autofluorescence of plant tissues. We report here an optimized efficient protocol of rRNA FISH and the use of both epifluorescence and confocal laser scanning microscopy for simultaneous specific differential detection of those fungi colonizing the same root. The method could be applied for the characterization of other plant-fungal interactions, too. In planta FISH with specific probes labeled with appropriate fluorescent dyes could be used not only in basic research but to detect plant colonizing pathogenic fungi in their latent life-period.

The BRENDA model: integrating psychosocial treatment and pharmacotherapy for the treatment of alcohol use disorders.

While the U.S. Food and Drug Administration has approved several medications for the treatment of alcohol-related problems, their use has not gained wide acceptance in the United States. Typically, patients with alcohol use disorders are only referred to psychosocial support (e.g., Alcoholics Anonymous). However, the use of pharmacotherapy may complement psychosocial treatments, as evidence shows that pharmacotherapy can improve treatment outcomes. The effectiveness of pharmacotherapy depends on patient compliance with taking the medication and the context in which the medication is administered. BRENDA is a psychosocial program designed specifically to be used by many types of healthcare providers, including primary care clinicians. Designed to enhance medication and treatment compliance, BRENDA is an ideal approach for use in conjunction with pharmacotherapy. The BRENDA approach has 6 components: 1) a biopsychosocial evaluation; 2) a report of findings from the evaluation given to the patient; 3) empathy; 4) addressing patient needs; 5) providing direct advice; and 6) assessing patient reaction to advice and adjusting the treatment plan as needed. This paper describes these components and discusses how the empirical support for each component is linked to the enhancement of medication compliance and the improvement of treatment outcomes.

Reduced incidence of slowly progressive Heymann nephritis in rats immunized with a modified vaccination technique.

A slowly progressive Heymann nephritis (SPHN) was induced in three groups of rats by weekly injections of a chemically modified renal tubular antigen in an aqueous medium. A control group of rats received the chemically unmodified version of the antigen in an aqueous solution. One group of SPHN rats were pre- and post-treated with weekly injections of IC made up of rKF3 and rarKF3 IgM antibody at antigen excess (MIC) (immune complexes [ICs] containing sonicated ultracentrifuged [u/c] rat kidney fraction 3 [rKF3] antigen and IgM antibodies specific against the antigen, at slight antigen excess). One group of SPHN rats were post-treated with MIC 3 weeks after the induction of the disease and one group of SPHN animals received no treatment. The control group of rats received pre- and post-treatment with sonicated u/c rKF3. The incidence of immune-complex glomerulonephritis (ICGN) in the untreated SPHN rats was 87%, in the pre- and post-treated animals 13%, and in the post-treated-only rats 20%. Rats receiving sonicated ultracentrifuged rKF3 antigen did not develop ICGN. The present experiment demonstrates that the development of SPHN can be not only prevented but also effectively terminated by our newly developed modified vaccination technique.

Cell immunofluorescence and brain extract based dot-immunobinding assay in identification of arboviruses.

Infected mouse brain homogenates were semi-purified and used in a dot-immunobinding assay to identify the corresponding arboviruses.

Postburn scar carcinoma.

A review of 20 patients with postburn scar carcinoma is presented. Eight early cases treated by wide excision and repair by skin grafting have been free of the tumour for the last 5-7 years. Nine patients treated by surgery and three patients who refused surgery and were treated by topical 5-fluorouracil developed metastasis and have since died.

Acute renal failure associated with ioxaglate, a low-osmolality radiocontrast agent.

Iodinated radiocontrast agents may cause acute renal failure, particularly in patients with preexisting renal failure, heart failure, or diabetes. The low-osmolality contrast agents cause less hypersensitivity, but substantial nephrotoxicity has not been noted. We report three high-risk patients who developed acute renal failure after one of these new agents, ioxaglate, was administered for coronary arteriography and ventriculography. The renal failure was severe: two of the patients required dialysis. We could find no previously reported cases of acute renal failure associated with ioxaglate. Despite their theoretical advantages, the low-osmolality contrast agents may cause acute renal failure in patients who are at risk and should be used with the same precautions as the conventional agents.

Serum angiotensin converting enzyme activity in normal adults and patients with different types of hypertension.

The serum converting enzyme activity (SCEA) was measured in 86 healthy individuals (1.44 +/- 0.82 u, mean +/- SD), 39 patients with essential hypertension (1.53 +/- 0.71 u), 7 patients with hypertension due to renal artery stenosis (1.76 +/- 0.77 u), 14 patients with chronic renal failure (2.10 +/- 0.57 u), 7 patients with renal failure and hypertension (2.62 +/- 0.35 u), 22 normotensive pregnant women (1.02 +/- 0.26 u) and 6 hypertensive pregnant women (1.1 +/- 0.3). No difference was detected between men and women or between normotensives and hypertensives. However, a significant rise in SCEA was found in patients with chromic renal failure (P less than 0.005), in whom an enlarged pulmonary vascular bed and accelerated cellular breakdown are thought to be the causes of the elevated SCEA. During pregnancy, subnormal SCEA was found (P less than 0.005), and this is thought to be due to the enzyme consumption in the kinin system, which is activated during pregnancy. We assume that converting enzyme is not a limiting factor in angiotensin conversion, and most probably it does not contribute significantly to the pathogenesis of hypertension.