Tepotinib plus osimertinib in patients with EGFR-mutated non-small-cell lung cancer with MET amplification following progression on first-line osimertinib (INSIGHT 2): a multicentre, open-label, phase 2 trial.

BACKGROUND: Patients with EGFR-mutated non-small-cell lung cancer (NSCLC) and MET amplification as a mechanism of resistance to first-line osimertinib have few treatment options. Here, we report the primary analysis of the phase 2 INSIGHT 2 study evaluating tepotinib, a highly selective MET inhibitor, combined with osimertinib in this population. METHODS: This open-label, phase 2 study was conducted at 179 academic centres and community clinics in 17 countries. Eligible patients were aged 18 years or older with an Eastern Cooperative Oncology Group performance status of 0 or 1 and advanced or metastatic EGFR-mutated NSCLC of any histology, with MET amplification by tissue biopsy fluorescence in-situ hybridisation (FISH; MET gene copy number of ≥5 or MET-to-CEP7 ratio of ≥2) or liquid biopsy next-generation sequencing (MET plasma gene copy number of ≥2·3), following progression on first-line osimertinib. Patients received oral tepotinib 500 mg plus oral osimertinib 80 mg once daily. The primary endpoint was independently assessed objective response in patients with MET amplification by central FISH treated with tepotinib plus osimertinib with at least 9 months of follow-up. Safety was analysed in patients who received at least one study drug dose. This study is registered with ClinicalTrials.gov, NCT03940703 (enrolment complete). FINDINGS: Between Feb 13, 2020, and Nov 4, 2022, 128 patients (74 [58%] female, 54 [42%] male) were enrolled and initiated tepotinib plus osimertinib. The primary activity analysis population included 98 patients with MET amplification confirmed by central FISH, previous first-line osimertinib and at least 9 months of follow-up (median 12·7 months [IQR 9·9-20·3]). The confirmed objective response rate was 50·0% (95% CI 39·7-60·3; 49 of 98 patients). The most common treatment-related grade 3 or worse adverse events were peripheral oedema (six [5%] of 128 patients), decreased appetite (five [4%]), prolonged electrocardiogram QT interval (five [4%]), and pneumonitis (four [3%]). Serious treatment-related adverse events were reported in 16 (13%) patients. Deaths of four (3%) patients were assessed as potentially related to either trial drug by the investigator due to pneumonitis (two [2%] patients), decreased platelet count (one [1%]), respiratory failure (one [1%]), and dyspnoea (one [1%]); one death was attributed to both pneumonitis and dyspnoea. INTERPRETATION: Tepotinib plus osimertinib showed promising activity and acceptable safety in patients with EGFR-mutated NSCLC and MET amplification as a mechanism of resistance to first-line osimertinib, suggesting a potential chemotherapy-sparing oral targeted therapy option that should be further investigated. FUNDING: Merck (CrossRef Funder ID: 10.13039/100009945).

Blood safety markers in Dutch donors after relaxation of deferral for men who have sex with men: re-emergence of syphilis and HIV pre-exposure prophylaxis use.

BACKGROUND: Less discriminatory donor selection policies for men who have sex with men (MSM) may impact transfusion safety in terms of higher residual risks for known transfusion-transmitted infections (TTIs), increased vulnerability toward new TTIs that are also transmitted via sex, and HIV infections masked by pre-exposure prophylaxis (PrEP). STUDY DESIGN AND METHODS: TTI trends in Dutch donors were studied over a 13-year period (2011-2023), characterized by successive relaxations of MSM deferral criteria. Structured posttest counseling was performed to determine risk factors in TTI-positive donors. PrEP drug levels were measured in 9977 donations from male donors living in urban areas and in 67 donors with active or resolved syphilis. RESULTS: HIV incidence (from 5.8 to 1.5 per 1,000,000 donor years (DY)) and HBV incidence (from 12.4 to 4.5 per 1,000,000 DY) in Dutch donors decreased with less stringent MSM deferral criteria, while syphilis prevalence (from 26.4 to 44.1 per 100,000 new donors) and syphilis incidence (from 18.3 to 46.3 per 1,000,000 DY) increased over time. The proportion of MSM-related syphilis rose from 2% to 32% in new donors and from 12% to 27% in repeat donors. PrEP was detected in 2 of 9977 (0.02%) donations from male donors living in urban areas, and in 1 of 39 (2.6%) male donors with syphilis. DISCUSSION: To date, phasing out donor deferral for MSM had no significant impact on transfusion safety in the Netherlands. However, rising syphilis rates and (recent) PrEP use in the blood donor population, albeit rare, suggest an influx of donors with higher sexual risk profiles and requires intensified TTI surveillance in donors.

Interactive Big Data Resource to Elucidate Human Immune Pathways and Diseases.

Many functionally important interactions between genes and proteins involved in immunological diseases and processes are unknown. The exponential growth in public high-throughput data offers an opportunity to expand this knowledge. To unlock human-immunology-relevant insight contained in the global biomedical research effort, including all public high-throughput datasets, we performed immunological-pathway-focused Bayesian integration of a comprehensive, heterogeneous compendium comprising 38,088 genome-scale experiments. The distillation of this knowledge into immunological networks of functional relationships between molecular entities (ImmuNet), and tools to mine this resource, are accessible to the public at http://immunet.princeton.edu. The predictive capacity of ImmuNet, established by rigorous statistical validation, is easily accessed by experimentalists to generate data-driven hypotheses. We demonstrate the power of this approach through the identification of unique host-virus interaction responses, and we show how ImmuNet complements genetic studies by predicting disease-associated genes. ImmuNet should be widely beneficial for investigating the mechanisms of the human immune system and immunological diseases.

Optimal photoelectron circular dichroism of a model chiral system.

We optimize the internuclear geometry and electronic structure of a model chiral system to achieve a maximal photoelectron circular dichroism (PECD) in its one-photon ionization by circularly polarized light. The electronic structure calculations are performed by the single center method, while the optimization is done using quantum alchemy employing a Taylor series expansion. Thereby, the effect of bond lengths and uncompensated charge distributions on the chiral response of the model is investigated theoretically in some detail. It is demonstrated that manipulating a chiral asymmetry of the ionic potential may enhance the dichroic parameter (i.e., the PECD) of the randomly oriented model system well beyond ß1 = 25%. Furthermore, we demonstrate that quantum alchemy is applicable to PECD despite the unusually strong coupling of spatial and electronic degrees of freedom and discuss the relative impact of the individual degrees of freedom in this model system. We define the necessary conditions for the computational design of PECD for real (non-model) chiral molecules using our approach.

Mad dephosphorylation at the nuclear pore is essential for asymmetric stem cell division.

Stem cells divide asymmetrically to generate a stem cell and a differentiating daughter cell. Yet, it remains poorly understood how a stem cell and a differentiating daughter cell can receive distinct levels of niche signal and thus acquire different cell fates (self-renewal versus differentiation), despite being adjacent to each other and thus seemingly exposed to similar levels of niche signaling. In the Drosophila ovary, germline stem cells (GSCs) are maintained by short range bone morphogenetic protein (BMP) signaling; the BMP ligands activate a receptor that phosphorylates the downstream molecule mothers against decapentaplegic (Mad). Phosphorylated Mad (pMad) accumulates in the GSC nucleus and activates the stem cell transcription program. Here, we demonstrate that pMad is highly concentrated in the nucleus of the GSC, while it quickly decreases in the nucleus of the differentiating daughter cell, the precystoblast (preCB), before the completion of cytokinesis. We show that a known Mad phosphatase, Dullard (Dd), is required for the asymmetric partitioning of pMad. Our mathematical modeling recapitulates the high sensitivity of the ratio of pMad levels to the Mad phosphatase activity and explains how the asymmetry arises in a shared cytoplasm. Together, these studies reveal a mechanism for breaking the symmetry of daughter cells during asymmetric stem cell division.

Distances and angles in standing long-leg radiographs: comparing conventional radiography, digital radiography, and EOS.

OBJECTIVE: Distances and angles measured from long-leg radiographs (LLR) are important for surgical decision-making. However, projectional radiography suffers from distortion, potentially generating differences between measurement and true anatomical dimension. These phenomena are not uniform between conventional radiography (CR) digital radiography (DR) and fan-beam technology (EOS). We aimed to identify differences between these modalities in an experimental setup. MATERIALS AND METHODS: A hemiskeleton was stabilized using an external fixator in neutral, valgus and varus knee alignment. Ten images were acquired for each alignment and each modality: one CR setup, two different DR systems, and an EOS. A total of 1680 measurements were acquired and analyzed. RESULTS: We observed great differences for dimensions and angles between the 4 modalities. Femoral head diameter measurements varied in the range of > 5 mm depending on the modality, with EOS being the closest to the true anatomical dimension. With functional leg length, a difference of 8.7% was observed between CR and EOS and with the EOS system being precise in the vertical dimension on physical-technical grounds, this demonstrates significant projectional magnification with CR-LLR. The horizontal distance between the medial malleoli varied by 20 mm between CR and DR, equating to 21% of the mean. CONCLUSIONS: Projectional distortion resulting in variations approaching 21% of the mean indicate, that our confidence on measurements from standing LLR may not be justified. It appears likely that among the tested equipment, EOS-generated images are closest to the true anatomical situation most of the time.

Comparison of Biological Augmentation in Rotator Cuff Repair Using Inflamed Versus Noninflamed Bursal Tissue in Rats.

PURPOSE: To examine how augmentation of a rotator cuff repair with inflamed versus noninflamed bursal tissue affects tendon-to-bone healing in a rat model of rotator cuff repair. METHODS: A total of 136 Sprague-Dawley rats were randomly assigned to an inflamed or noninflamed bursal tissue application group. After detachment, the supraspinatus tendon was reattached with bursal tissue sewn onto the tendon-to-bone interface. The specimens were analyzed biomechanically 6 and at 7 weeks and immunohistologically at 1 and at 7 weeks after surgery. RESULTS: Immunohistological results showed no significant difference in the percentage of collagen type II in the tendon-to-bone interface at 1 (P = .87) and 7 weeks (P = .42) when using autologous noninflamed bursal tissue in comparison with inflamed bursal tissue specimens. The inflamed bursa group also showed no significant difference in collagen I to III quotient (P = .14) after surgery in comparison with noninflamed bursa groups after surgery. Biomechanical assessment showed that tendon stiffness (P = .87 inflamed versus noninflammed (resp.) P = .1) and the tendon viscoelasticity (P = .12 resp. P = .07) was the same after 6 and 7 weeks when we compared the inflamed bursa with the noninflamed bursa group. There was no significant difference (P = .8 resp. P = .87) in load to failure between in both inflamed and noninflamed bursa groups after 6 and 7 weeks. CONCLUSIONS: Autologous inflamed bursal tissue derived from the Achilles bursa and implanted to the tendon-to-bone interface after rotator cuff repair facilitates the same histologic and biomechanical healing response as using a noninflamed bursa interposition in rats. CLINICAL RELEVANCE: During augmentation of a rotator cuff repair, it is irrelevant whether the bursa tissue is inflamed.

Weighted power summation and contrast normalization mechanisms account for short-latency eye movements to motion and disparity of sine-wave gratings and broadband visual stimuli in humans.

In this paper, we show that the model we proposed earlier to account for the disparity vergence eye movements (disparity vergence responses, or DVRs) in response to horizontal and vertical disparity steps of white noise visual stimuli also provides an excellent description of the short-latency ocular following responses (OFRs) to broadband stimuli in the visual motion domain. In addition, we reanalyzed the data and applied the model to several earlier studies that used sine-wave gratings (single or a combination of two or three gratings) and white noise stimuli. The model provides a very good account of all of these data. The model postulates that the short-latency eye movements-OFRs and DVRs-can be accounted for by the operation of two factors: an excitatory drive, determined by a weighted sum of contributions of stimulus Fourier components, scaled by a global contrast normalization mechanism. The output of the operation of these two factors is then nonlinearly scaled by the total contrast of the stimulus. Despite different roles of disparity (horizontal and vertical) and motion signals in visual scene analyses, the earliest processing stages of these different signals appear to be very similar.

The Effectiveness of Growth Modulation Using Tension Band Plates in Children With Achondroplasia in Comparison to Children With Idiopathic Frontal Axial Deformities of the Knee.

BACKGROUND: Achondroplasia is the most common form of rhizomelic dwarfism. Aside from disproportionally short extremities, frontal knee malalignments are common. We assessed the effectiveness of guided growth via tension band plates in children with achondroplasia in comparison to patients with idiopathic knee deformities using radiography. METHODS: Twenty children with achondroplasia (8 valgus/31 varus knees) and 35 children with idiopathic knee malalignments (53 valgus/12 varus knees) which underwent temporary hemiepiphysiodesis at the distal femur and/or proximal tibia were retrospectively compared. Radiographic outcomes (mechanical lateral distal femoral angle, medial proximal tibial angle, and mechanical axis deviation) were compared before surgery and plate removal. Correction rates according to plate location were compared as change per implant duration and per growth in leg length. RESULTS: Achondroplasia patients were younger (9±2 vs.12±2 y), femoral and tibial growth rate was 43.3% and 48.5% lower and implant duration lasted longer: 36.9±8.9 months in valgus knees and 23.0±14.3 months in varus knees versus 13.4±7.9 months in idiopathic valgus and 11.7±4.6 months in idiopathic varus knees. Significant improvements in joint orientation angles and mechanical axis deviation were achieved but femoral and tibial plates achieved slower correction per months in achondroplasia (P≤0.031). When normalized to bone growth, the rate of correction in joint orientation angles was no longer significantly different for the femur (P=0.241), with a trend for slower correction in the tibia (P=0.066). The corrections in MAD per leg growth (mm/mm) remained smaller (P=0.001). In achondroplasia, older age correlated with slower MAD correction (r=-0.36, P=0.022), femoral plates corrected faster than tibial (P=0.024) and treatment of valgus was less successful than varus involving longer treatments (P=0.009). More complications occurred in achondroplastic knees (P=0.012). CONCLUSIONS: Skeletally immature patients with achondroplasia can benefit from growth modulations, but they need longer treatments and face more complications. Their slower growth does not solely determine the more tenacious success. LEVEL OF EVIDENCE: Therapeutic Level III-case-control study.

Management zones in transboundary aquifers: A review of delineation methods under a new framework of cross-border groundwater impacts.

Attention on the use of transboundary aquifers (TBAs) and their cross-border impacts is growing as countries become increasingly concerned about their long-term water security. Cross-border impacts, in groundwater quality and quantity, tend to concentrate in specific parts of TBAs, as they largely depend on the transboundary flow dynamics where anthropogenic actions operate. Thus, there is a growing consensus that strategies intended to prevent or mitigate such impacts should be implemented in strategic zones rather than in the whole TBA. These transboundary groundwater management zones (TGMZs) are relatively recent but have become a prominent topic in TBA management. However, until now, limited effort has been put into exploring the concept of TGMZs and the methods for their delineation. This research aims to fill these gaps and provide a basis for the delineation of TGMZs, thus helping neighbouring countries meet international responsibilities regarding the right to use and enjoy groundwater in TBAs. By reviewing academic and grey literature accessible from public sources, we present an overview of the concept and terminology of TGMZs, the approaches proposed for their delineation, and current operating examples. Additionally, we build a conceptual framework for assessing cross-border groundwater impacts by identifying their typologies and causal factors. We then apply our framework to evaluate and compare three reported methods which identify and delineate TGMZs from distinct perspectives, thereby gaining insights into their principles, performances, and limitations. Finally, we provide recommendations for further research towards optimising methods for delineating TGMZs.

Relation of Streptococcus Pyogenes tonsillitis isolate to antimicrobial agents and its infection treatment.

We reported the case of tonsillitis treatment in a 17-years-old boy with use of chemical non-antibiotic preparations, plant derived products and antibiotic benzathine phenoxymethylpenicillin. The antimicrobial agents for treatment were selected on the basis of their activity against a disease agent, the group A ß-hemolytic strain Streptococcus pyogenes BS1 isolated from a patient. The bacterium was susceptible in vitro to ß-lactams, with largest zones conditioned by penicillin G and benzathine phenoxymethylpenicillin discs, to fluoroquinolones and to cephems, with exception of cefazolin. Lincosamide clindamycin, macrolide spiramycin, aminoglycoside gentamicin, erythromycin, tetracycline and combination of sulfamethoxazole and trimethoprim were inactive against this bacterium. The Streptococcus pyogenes BS1 demonstrated intermediate susceptibility to the cephalosporin cephalexin, fluoroquinolone lomefloxacin and glycopeptide vancomycin. Non-antibiotic preparations were evaluated against Streptococcus pyogenes BS1 also. Among them "Stomatidin", "Chlorophyllipt", and phages of "Pyofag" were more effective than "Decatylen", "Decasan" and "Furadonin" in vitro. The antimicrobial applications of "Stomatidin", "Chlorophyllipt" and phages of "Pyofag" in the patient were less effective compared to the result of antibiotic benzathine phenoxymethylpenicillin treatment. Complete recovery of the patient was achieved with use of this antibiotic and Calendula flower extract as an local anti-inflammatory agent.

Opposing effects of 5-HT1A receptor agonist buspirone on supraspinal abdominal pain transmission in normal and visceral hypersensitive rats.

The serotonergic 5-HT1A receptors are implicated in the central mechanisms of visceral pain, but their role in these processes is controversial. Considering existing evidences for organic inflammation-triggered neuroplastic changes in the brain serotonergic circuitry, the ambiguous contribution of 5-HT1A receptors to supraspinal control of visceral pain in normal and post-inflammatory conditions can be assumed. In this study performed on male Wistar rats, we used microelectrode recording of the caudal ventrolateral medulla (CVLM) neuron responses to colorectal distension (CRD) and electromyography recording of CRD-evoked visceromotor reactions (VMRs) to evaluate post-colitis changes in the effects of 5-HT1A agonist buspirone on supraspinal visceral nociceptive transmission. In rats recovered from trinitrobenzene sulfonic acid colitis, the CRD-induced CVLM neuronal excitation and VMRs were increased compared with those in healthy animals, revealing post-inflammatory intestinal hypersensitivity. Intravenous buspirone (2 and 4 mg/kg) under urethane anesthesia dose-dependently suppressed CVLM excitatory neuron responses to noxious CRD in healthy rats, but caused dose-independent increase in the already enhanced nociceptive activation of CVLM neurons in post-colitis animals, losing also its normally occurring faciliatory effect on CRD-evoked inhibitory medullary neurotransmission and suppressive action on hemodynamic reactions to CRD. In line with this, subcutaneous injection of buspirone (2 mg/kg) in conscious rats, which attenuated CRD-induced VMRs in controls, further increased VMRs in hypersensitive animals. The data obtained indicate a shift from anti- to pronociceptive contribution of 5-HT1A-dependent mechanisms to supraspinal transmission of visceral nociception in intestinal hypersensitivity conditions, arguing for the disutility of buspirone and possibly other 5-HT1A agonists for relieving post-inflammatory abdominal pain.

Cost-Effectiveness of Tepotinib Versus Capmatinib for the Treatment of Adult Patients With Metastatic Non-Small Cell Lung Cancer Harboring Mesenchymal-Epithelial Transition Exon 14 Skipping.

OBJECTIVES: From the US Medicare perspective, this study compared the cost-effectiveness of tepotinib and capmatinib for treating metastatic non-small cell lung cancer with tumors harboring mesenchymal-epithelial transition factor gene exon 14 skipping. METHODS: A 3-state partitioned survival model assessed outcomes over a lifetime horizon. Parametric survival analysis of the phase 2 VISION trial informed clinical inputs for tepotinib. Capmatinib inputs were captured using hazard ratios derived from an unanchored matching-adjusted indirect comparison study and published literature. National cost databases, trial data, and literature furnished drug, treatment monitoring, and disease/adverse event management expenditures (2021 US dollars) and utility inputs. Outcomes were discounted at 3% annually. RESULTS: In the base case, tepotinib dominated capmatinib in frontline settings (incremental discounted quality-adjusted life-years [QALYs] and costs of 0.2127 and -$47 756, respectively) while realizing an incremental cost-effectiveness ratio of $274 514/QALY in subsequent lines (incremental QALYs and costs of 0.3330 and $91 401, respectively). In a line agnostic context, tepotinib produced an incremental cost-effectiveness ratio of $105 383/QALY (incremental QALYs and costs of 0.2794 and $29 447, respectively). Sensitivity and scenarios analyses for individual lines typically supported the base case, whereas those for the line agnostic setting suggested sensitivity to drug acquisition costs and efficacy inputs. CONCLUSIONS: Tepotinib could be cost-effective versus capmatinib in frontline and line agnostic contexts, considering the range of willingness-to-pay thresholds recommended by the Institute for Clinical and Economic Review ($100 000-$150 000/QALY). Tepotinib could be cost-effective in subsequent lines at higher willingness-to-pay levels. These results are to be interpreted cautiously, considering uncertainty in key model inputs.

Theoretical study of spin polarization in multiphoton ionization of Xe.

Spin polarization in the multiphoton above-threshold ionization of 5p3/2- and 5p1/2-electrons of Xe with intense 395nm, circularly polarized laser pulses, is investigated theoretically. For this purpose, we solve the time-dependent Schrödinger equation on the basis of spherical spinors. We, thus, simultaneously propagate the spin-up and spin-down single-active-electron wave packets, driven by the laser pulses in the ionic potential, which includes the spin-orbit interaction explicitly. The present theoretical results are in good agreement with the recent experimental results [D. Trabert et al., Phys. Rev. Lett. 120, 043202 (2018)].

Manipulating the Fourier spectra of stimuli comprising a two-frame kinematogram to study early visual motion-detecting mechanisms: Perception versus short latency ocular-following responses.

Two-frame kinematograms have been extensively used to study motion perception in human vision. Measurements of the direction-discrimination performance limits (Dmax) have been the primary subject of such studies, whereas surprisingly little research has asked how the variability in the spatial frequency content of individual frames affects motion processing. Here, we used two-frame one-dimensional vertical pink noise kinematograms, in which images in both frames were bandpass filtered, with the central spatial frequency of the filter manipulated independently for each image. To avoid spatial aliasing, there was no actual leftward-rightward shift of the image: instead, the phases of all Fourier components of the second image were shifted by ±» wavelength with respect to those of the first. We recorded ocular-following responses (OFRs) and perceptual direction discrimination in human subjects. OFRs were in the direction of the Fourier components' shift and showed a smooth decline in amplitude, well fit by Gaussian functions, as the difference between the central spatial frequencies of the first and second images increased. In sharp contrast, 100% correct perceptual direction-discrimination performance was observed when the difference between the central spatial frequencies of the first and second images was small, deteriorating rapidly to chance when increased further. Perceptual dependencies moved closer to the OFR ones when subjects were allowed to grade the strength of perceived motion. Response asymmetries common for perceptual judgments and the OFRs suggest that they rely on the same early visual processing mechanisms. The OFR data were quantitatively well described by a model which combined two factors: (1) an excitatory drive determined by a power law sum of stimulus Fourier components' contributions, scaled by (2) a contrast normalization mechanism. Thus, in addition to traditional studies relying on perceptual reports, the OFRs represent a valuable behavioral tool for studying early motion processing on a fine scale.

Phenolic Compounds from Sour Cherry Pomace: Microencapsulation, in Vitro Digestion, and Cell Growth Activities.

The objective of this work was the valorisation of sour cherry (Prunus cerasus L.) pomace as a source of biologically active compounds. To formulate microcapsules, polyphenolic compounds were extracted and encapsulated with maltodextrin as wall material, by freeze-drying. An in vitro digestion study was carried out on obtained encapsulates but also on sour cherry pomace extract and sour cherry pomace freeze-dried powder. The results indicated that encapsulation, as well as freeze-drying, provided a good protective effect on bioactive compounds during digestion. Furthermore, the potential antiproliferative and cytotoxic activities of encapsulates and sour cherry pomace extract were evaluated using breast adenocarcinoma MCF7 cell lines, colon adenocarcinoma HT-29 cell lines, and noncancer cell line. Encapsulates and sour cherry pomace extract showed variable anti-proliferative activity towards all cell lines. Obtained results showed that encapsulation of sour cherry pomace could be useful for improving the stability of polyphenolic compounds in the gastrointestinal tract. The results highlight the bioactive potential of sour cherry pomace as a nutraceutical resource and the protective effects of microencapsulation on the digestion of bioactive compounds.

THE ROLE OF LEFT VENTRICULAR HYPERTROPHY, RS1801253 AND RS1801252 ALLELIC POLYMORPHISMS OF ADRB1 IN ASSESSING THE RISK OF SUDDEN CARDIAC DEATH IN PATIENTS WITH ARTERIAL HYPERTENSION.

OBJECTIVE: The aim: To study the association of left ventricular hypertrophy (LVH) and polymorphisms rs1801253 and rs1801252 of the ADRB1 gene with the risk of sudden cardiac death (SCD). PATIENTS AND METHODS: Materials and methods: The study included 179 patients which underwent clinical investigation, echocardiography, elektrokardiography. The examined were divided into groups with a low (110 people) and high risk (69 people) of SCD. The distribution of allelic polymorphisms was investigated with polymerase chain reaction (PCR). RESULTS: Results: All patients of group with high-risk cardiovascular mortality showed a decrease in heart rate variability (RV) due to an increase in sympathetic activity (p=0.013). Also, in the group of patients with LVH, predictors of sudden cardiac death and arrhythmogenic substrate, were observed. The variability of the allele C1165G rs1801253 of the ADRB1 gene was associated with an increased risk (2.55-fold increase) of SCD and LVH. Also, the associations of polymorphic locus A145G (rs1801252) of the ADRB1 gene proved the presence of a permanent difference for the "risky" allele A in patients with a high risk of SCD. CONCLUSION: Conclusions: It was set the probable association of alleles rs1801253 (C1165G) and rs1801252 (A145G) ADRB1 at the patients with a high risk of SCD compared to the control group.

Pathway-level information extractor (PLIER) for gene expression data.

A major challenge in gene expression analysis is to accurately infer relevant biological insights, such as variation in cell-type proportion or pathway activity, from global gene expression studies. We present pathway-level information extractor (PLIER) ( https://github.com/wgmao/PLIER and http://gobie.csb.pitt.edu/PLIER ), a broadly applicable solution for this problem that outperforms available cell proportion inference algorithms and can automatically identify specific pathways that regulate gene expression. Our method improves interstudy replicability and reveals biological insights when applied to trans-eQTL (expression quantitative trait loci) identification.

One-year follow-up-case report of secondary tension pneumothorax in a COVID-19 pneumonia patient.

PURPOSE: The Coronavirus Disease 2019 (COVID-19) may result not only in acute symptoms such as severe pneumonia, but also in persisting symptoms after months. Here we present a 1 year follow-up of a patient with a secondary tension pneumothorax due to COVID-19 pneumonia. CASE PRESENTATION: In May 2020, a 47-year-old male was admitted to the emergency department with fever, dry cough, and sore throat as well as acute chest pain and shortness of breath. Sputum testing (polymerase chain reaction, PCR) and computed tomography (CT) confirmed infection with the severe acute respiratory syndrome coronavirus type 2 (SARS-CoV-2). Eleven days after discharge, the patient returned to the emergency department with pronounced dyspnoea after coughing. CT showed a right-sided tension pneumothorax, which was relieved by a chest drain (Buelau) via mini open thoracotomy. For a period of 3 months following resolution of the pneumothorax the patient complained of fatigue with mild joint pain and dyspnoea. After 1 year, the patient did not suffer from any persisting symptoms. The pulmonary function and blood parameters were normal, with the exception of slightly increased levels of D-Dimer. The CT scan revealed only discrete ground glass opacities (GGO) and subpleural linear opacities. CONCLUSION: Tension pneumothorax is a rare, severe complication of a SARS-CoV-2 infection but may resolve after treatment without negative long-term sequelae. LEVEL OF EVIDENCE: V.

Different tissue phagocytes sample apoptotic cells to direct distinct homeostasis programs.

Recognition and removal of apoptotic cells by professional phagocytes, including dendritic cells and macrophages, preserves immune self-tolerance and prevents chronic inflammation and autoimmune pathologies. The diverse array of phagocytes that reside within different tissues, combined with the necessarily prompt nature of apoptotic cell clearance, makes it difficult to study this process in situ. The full spectrum of functions executed by tissue-resident phagocytes in response to homeostatic apoptosis, therefore, remains unclear. Here we show that mouse apoptotic intestinal epithelial cells (IECs), which undergo continuous renewal to maintain optimal barrier and absorptive functions, are not merely extruded to maintain homeostatic cell numbers, but are also sampled by a single subset of dendritic cells and two macrophage subsets within a well-characterized network of phagocytes in the small intestinal lamina propria. Characterization of the transcriptome within each subset before and after in situ sampling of apoptotic IECs revealed gene expression signatures unique to each phagocyte, including macrophage-specific lipid metabolism and amino acid catabolism, and a dendritic-cell-specific program of regulatory CD4+ T-cell activation. A common 'suppression of inflammation' signature was noted, although the specific genes and pathways involved varied amongst dendritic cells and macrophages, reflecting specialized functions. Apoptotic IECs were trafficked to mesenteric lymph nodes exclusively by the dendritic cell subset and served as critical determinants for the induction of tolerogenic regulatory CD4+ T-cell differentiation. Several of the genes that were differentially expressed by phagocytes bearing apoptotic IECs overlapped with susceptibility genes for inflammatory bowel disease. Collectively, these findings provide new insights into the consequences of apoptotic cell sampling, advance our understanding of how homeostasis is maintained within the mucosa and set the stage for development of novel therapeutics to alleviate chronic inflammatory diseases such as inflammatory bowel disease.