Extent of investigation and management of cases of 'unexplained' mismatch repair deficiency (u-dMMR): a UK Cancer Genetics Group consensus.

BACKGROUND: Mismatch repair deficiency (dMMR) is a characteristic feature of cancers linked to Lynch syndrome. However, in most cases, it results from sporadic somatic events rather than hereditary factors. The term 'Lynch-like syndrome' (LLS) has been used to guide colorectal cancer surveillance for relatives of individuals with a dMMR tumour when somatic and germline genomic testing is uninformative. As the assessment of mismatch repair through immunohistochemistry and/or microsatellite instability is increasingly applied across various tumour types for treatment planning, dMMR is increasingly detected in tumours where suspicion of hereditary aetiology is low. Our objective was to establish current practices and develop national guidance for investigating, and managing relatives of, patients with cancers demonstrating unexplained dMMR. METHODS: This was achieved through a virtual consensus meeting involving key stakeholders from the UK, through premeeting surveys, structured discussions and in-meeting polling to formulate best practice guidance. RESULTS: We identified variability in the availability of diagnostic technologies across specialist centres. It was agreed that equitable access to baseline testing is required, acknowledging the need for a pragmatic approach to investigating dMMR cancers not traditionally associated with Lynch syndrome. Factors such as family history, age, tumour type, protein loss pattern and extent of the investigation were deemed crucial in guiding family management. The term 'unexplained dMMR' was recommended over LLS. CONCLUSION: Decisions regarding investigations and future cancer risk management in patients and relatives should be nuanced, considering factors like clinical suspicion of hereditary predisposition to allocate limited resources efficiently and avoid unnecessary investigations in low-suspicion families.

The Trauma Activation Review Committee: Response to Undertriage During a Period of Rapid Growth at a Level II Trauma Center.

Trauma triage criteria are constantly being refined for improved identification of severely injured patients. When errors occur, they should be tracked, and triage criteria adjusted to minimize these events. Two time periods of trauma registry data at a single rural level II trauma center were retrospectively compared to evaluate demographics, injuries, and outcomes to identify triage errors. In 300 activated trauma patients during 2011, overtriage was 23% and undertriage was 3.7%. In 1035 activated trauma patients during 2019, overtriage was 20.5% and undertriage was 2.2%. Mortality decreased over time overall. In 2019, Trauma I patients were older, spent more time on the ventilator, and in the ICU (all P < .001). Trauma II patients were also older, had lower ISS, hospital days, and ventilator days (all P < .001). During rapid growth, evaluation of overtriage and undertriage can provide useful feedback for hospital staff to refine triage choices and improve patient outcomes.

Extensive phylogenies of human development inferred from somatic mutations.

Starting from the zygote, all cells in the human body continuously acquire mutations. Mutations shared between different cells imply a common progenitor and are thus naturally occurring markers for lineage tracing1,2. Here we reconstruct extensive phylogenies of normal tissues from three adult individuals using whole-genome sequencing of 511 laser capture microdissections. Reconstructed embryonic progenitors in the same generation of a phylogeny often contribute to different extents to the adult body. The degree of this asymmetry varies between individuals, with ratios between the two reconstructed daughter cells of the zygote ranging from 60:40 to 93:7. Asymmetries pervade subsequent generations and can differ between tissues in the same individual. The phylogenies resolve the spatial embryonic patterning of tissues, revealing contiguous patches of, on average, 301 crypts in the adult colonic epithelium derived from a most recent embryonic cell and also a spatial effect in brain development. Using data from ten additional men, we investigated the developmental split between soma and germline, with results suggesting an extraembryonic contribution to primordial germ cells. This research demonstrates that, despite reaching the same ultimate tissue patterns, early bottlenecks and lineage commitments lead to substantial variation in embryonic patterns both within and between individuals.

Chemical Vapor Deposited Mixed Metal Halide Perovskite Thin Films.

In this article, we used a two-step chemical vapor deposition (CVD) method to synthesize methylammonium lead-tin triiodide perovskite films, MAPb1-xSnxI3, with x varying from 0 to 1. We successfully controlled the concentration of Sn in the perovskite films and used Rutherford backscattering spectroscopy (RBS) to quantify the composition of the precursor films for conversion into perovskite films. According to the RBS results, increasing the SnCl2 source amount in the reaction chamber translate into an increase in Sn concentration in the films. The crystal structure and the optical properties of perovskite films were examined by X-ray diffraction (XRD) and UV-Vis spectrometry. All the perovskite films depicted similar XRD patterns corresponding to a tetragonal structure with I4cm space group despite the precursor films having different crystal structures. The increasing concentration of Sn in the perovskite films linearly decreased the unit volume from about 988.4 Å3 for MAPbI3 to about 983.3 Å3 for MAPb0.39Sn0.61I3, which consequently influenced the optical properties of the films manifested by the decrease in energy bandgap (Eg) and an increase in the disorder in the band gap. The SEM micrographs depicted improvements in the grain size (0.3-1 µm) and surface coverage of the perovskite films compared with the precursor films.

Induced secretion system mutation alters rhizosphere bacterial composition in Sorghum bicolor (L.) Moench.

MAIN CONCLUSION: A novel inducible secretion system mutation in Sorghum named Red root has been identified. The mutant plant root exudes pigmented compounds that enriches Actinobacteria in its rhizosphere compared to BTx623. Favorable plant-microbe interactions in the rhizosphere positively influence plant growth and stress tolerance. Sorghum bicolor, a staple biomass and food crop, has been shown to selectively recruit Gram-positive bacteria (Actinobacteria) in its rhizosphere under drought conditions to enhance stress tolerance. However, the genetic/biochemical mechanism underlying the selective enrichment of specific microbial phyla in the sorghum rhizosphere is poorly known due to the lack of available mutants with altered root secretion systems. Using a subset of sorghum ethyl methanesulfonate (EMS) mutant lines, we have isolated a novel Red root (RR) mutant with an increased accumulation and secretion of phenolic compounds in roots. Genetic analysis showed that RR is a single dominant mutation. We further investigated the effect of root-specific phenolic compounds on rhizosphere microbiome composition under well-watered and water-deficit conditions. The microbiome diversity analysis of the RR rhizosphere showed that Actinobacteria were enriched significantly under the well-watered condition but showed no significant change under the water-deficit condition. BTx623 rhizosphere showed a significant increase in Actinobacteria under the water-deficit condition. Overall, the rhizosphere of RR genotype retained a higher bacterial diversity and richness relative to the rhizosphere of BTx623, especially under water-deficit condition. Therefore, the RR mutant provides an excellent genetic resource for rhizosphere-microbiome interaction studies as well as to develop drought-tolerant lines. Identification of the RR gene and the molecular mechanism through which the mutant selectively enriches microbial populations in the rhizosphere will be useful in designing strategies for improving sorghum productivity and stress tolerance.

Limited Role for Antibiotics in COVID-19: Scarce Evidence of Bacterial Coinfection

BackgroundThere is currently a paucity of data describing bacterial coinfections, related antibiotic prescribing patterns, and the potential role of antimicrobial stewardship in the care of patients infected with SARS-CoV-2. MethodsThis prospective, observational study was conducted from March 10, 2020 to April 21, 2020 in admitted patients with confirmed COVID-19. Patients were included if [≥] 18 years old and admitted to the hospital for further treatment. Data was collected via chart review from the enterprise electronic health record database. Data collected include factors driving antibiotic choice, indication, and duration of therapy as well as microbiological data. FindingsAntibiotics were initiated on admission in 87/147 (59%) patients. Of these, 85/87 (98%) prescriptions were empiric. The most common indication for empiric antibiotics was concern for community-acquired pneumonia (76/85, 89%) with the most prescribed antibiotics being ceftriaxone and azithromycin. The median duration of antibiotic therapy was two days (interquartile range 1-5). No patients had a community-acquired bacterial respiratory coinfection, but 10/147 (7%) of patients were found to have concurrent bacterial infections from a non-respiratory source, and one patient was diagnosed with active pulmonary tuberculosis at the time of admission for COVID-19. InterpretationBacterial coinfection in patients with COVID-19 was infrequent. Antibiotics are likely unnecessary in patients with mild symptoms. There is little role for broad-spectrum antibiotics to empirically treat multidrug resistant organisms in patients with COVID-19, regardless of disease severity. Antimicrobial stewardship remains important in patients infected with SARS-CoV-2. FundingThe authors received no funding for this work.

Sodium arsenite toxicity on hematology indices and reproductive parameters in Teddy goat bucks and their amelioration with vitamin C.

Arsenic is a major environmental toxicant of concern, affecting both female and male reproductive systems. The present study was conducted to investigate the toxic effects of arsenic on semen quality and reproductive hormones of Teddy bucks, an important domestic species in regions of Pakistan. In addition to arsenic, vitamin C was fed to a subset of animals to determine if there were ameliorative effects on reproductive parameters. Sixteen adult Teddy bucks were randomly divided into four experimental groups: A (control), B (arsenic 5 mg/kg BW/day orally), and C (arsenic 5 mg/kg BW/day plus vitamin C of an oral dose of 200 mg/kg BW/day). The animals in experimental group D were given only vitamin C (oral dose of 200 mg/kg BW/day). Animals were fed treated food once a day for 12 weeks. Semen quality parameters (volume, motility, count, sperm morphology, live dead ratio, sperm membrane integrity, and sperm DNA integrity) of bucks from each experimental group were evaluated on a weekly basis. Hematology and the level of arsenic in the blood were assessed every 2 weeks. Serum was collected fortnightly to measure reproductive and stress hormones (testosterone, luteinizing hormone, follicle-stimulating hormones, and cortisol). At the end of the study, all the animals were slaughtered, and the testes of all the animals were collected and evaluated for histopathology. Semen parameters in arsenic-treated bucks were significantly reduced (p < 0.05) compared with controls. Moreover, the levels of male hormones (testosterone, luteinizing hormone, and follicle-stimulating hormone) were significantly decreased in arsenic-treated animals, while cortisol was significantly increased with arsenic exposure. The histopathological lesions in the testes were present in the form of the loss of germinal epithelium and atrophy of Leydig cells. Supplementation of vitamin C however ameliorated the adverse effects of arsenic on semen quality and hormones. The histopathological lesions were also ameliorated due to vitamin C treatment. This study demonstrates that arsenic can adversely affect reproductive endpoints in Teddy goat bucks and supports the hypothesis that vitamin C is an effective treatment in arsenic-induced toxicosis. This study has high significance for Pakistan, as water contaminated with arsenic is a top health concern and is a recurring issue for both domestic animals and humans.

Quantifying Microsatellite Mutation Rates from Intestinal Stem Cell Dynamics in Msh2-Deficient Murine Epithelium.

Microsatellite sequences have an enhanced susceptibility to mutation, and can act as sentinels indicating elevated mutation rates and increased risk of cancer. The probability of mutant fixation within the intestinal epithelium is dictated by a combination of stem cell dynamics and mutation rate. Here, we exploit this relationship to infer microsatellite mutation rates. First a sensitive, multiplexed, and quantitative method for detecting somatic changes in microsatellite length was developed that allowed the parallel detection of mutant [CA]n sequences from hundreds of low-input tissue samples at up to 14 loci. The method was applied to colonic crypts in Mus musculus, and enabled detection of mutant subclones down to 20% of the cellularity of the crypt (∼50 of 250 cells). By quantifying age-related increases in clone frequencies for multiple loci, microsatellite mutation rates in wild-type and Msh2-deficient epithelium were established. An average 388-fold increase in mutation per mitosis rate was observed in Msh2-deficient epithelium (2.4 × 10-2) compared to wild-type epithelium (6.2 × 10-5).

Vertical alignment of polyaniline nanofibers on electrode surface for high-performance microbial fuel cells.

Electrode modifications with conductive and nanostructured polyaniline (PANI) were recognized as efficient approach to improve interaction between electrode surface and electrogenic bacteria for boosting the performance of microbial fuel cell (MFC). However, it still showed undesirable performance because of the challenge to control the orientation (such as vertical alignment) of PANI nanostructure for extracellular electron transfer (EET). In this work, vertically aligned polyaniline (VA-PANI) on carbon cloth electrode surface were prepared by in-situ polymerization method (simply tuning the ratio of tartaric acid (TA) dopant). Impressively, the VA-PANI greatly improved the EET due to the increased opportunity to connect with conductive proteins. Eventually, MFC equipped with the VA-PANI electrodes delivered a power output of 853 mW/m2, which greatly outperformed those electrodes modified with un-oriented PANI. This work provided the possibility to control the orientation of PANI for EET and promise to harvest energy from wastewater with MFC.

Therapeutic Assessment With Child Inpatients.

Growing evidence supports Therapeutic Assessment (TA), a collaborative and therapeutic approach to psychological assessment, as an effective method for enhancing motivation for and engagement with psychotherapy across a variety of clinical populations and treatment settings. However, to date there are no known studies assessing the use of TA in child psychiatric inpatient settings. This article briefly reviews the structure of child and family TA, enumerates the challenges and risks associated with short-term inpatient stays, and proposes a path for integrating TA into these units as a way to enhance the quality of care and reduce the risk of rapid rehospitalization. The authors provide three case examples from a child psychiatric inpatient unit, each using a modified version of TA and each integrating assessments into brief family interventions. The authors conclude with suggestions for best practice for child psychiatric inpatient TAs.

Human Dental Pulp Stem Cells Exhibit Different Biological Behaviours in Response to Commercial Bleaching Products.

The purpose of this study was to evaluate the diffusion capacity and the biological effects of different bleaching products on human dental pulp stem cells (hDPSCs). The bleaching gel was applied for 90, 30 or 15 min to enamel/dentine discs that adapted in an artificial chamber. The diffusion of hydrogen peroxide (HP) was analysed by fluorometry and the diffusion products were applied to hDPSCs. Cell viability, cell migration and cell morphology assays were performed using the eluates of diffusion products. Finally, cell apoptosis and the expression of mesenchymal stem cell markers were analysed by flow cytometry. Statistical analysis was performed using analysis of variance and Kruskal⁻Wallis or Mann⁻Whitney tests (α < 0.05). Significant reductions of approximately 95% in cell viability were observed for the 3 × 15 min groups (p < 0.001), while 1 × 30 min of PerfectBleach and 1 × 90 min of PolaNight resulted in reductions of 50% and 60% in cell viability, respectively (p < 0.001). Similar results were obtained in the migration assay. Moreover, the 3 × 15 min group was associated with cell morphology alterations and reductions of >70% in cell live. Finally, hDPSCs maintained their mesenchymal phenotype in all conditions. Similar concentrations of carbamide peroxide (CP) and HP in different commercial products exhibited different biological effects on hDPSCs.

The effect of environmental chemicals on the tumor microenvironment.

Potentially carcinogenic compounds may cause cancer through direct DNA damage or through indirect cellular or physiological effects. To study possible carcinogens, the fields of endocrinology, genetics, epigenetics, medicine, environmental health, toxicology, pharmacology and oncology must be considered. Disruptive chemicals may also contribute to multiple stages of tumor development through effects on the tumor microenvironment. In turn, the tumor microenvironment consists of a complex interaction among blood vessels that feed the tumor, the extracellular matrix that provides structural and biochemical support, signaling molecules that send messages and soluble factors such as cytokines. The tumor microenvironment also consists of many host cellular effectors including multipotent stromal cells/mesenchymal stem cells, fibroblasts, endothelial cell precursors, antigen-presenting cells, lymphocytes and innate immune cells. Carcinogens can influence the tumor microenvironment through effects on epithelial cells, the most common origin of cancer, as well as on stromal cells, extracellular matrix components and immune cells. Here, we review how environmental exposures can perturb the tumor microenvironment. We suggest a role for disrupting chemicals such as nickel chloride, Bisphenol A, butyltins, methylmercury and paraquat as well as more traditional carcinogens, such as radiation, and pharmaceuticals, such as diabetes medications, in the disruption of the tumor microenvironment. Further studies interrogating the role of chemicals and their mixtures in dose-dependent effects on the tumor microenvironment could have important general mechanistic implications for the etiology and prevention of tumorigenesis.

Demonstrating a correlation between the maturity of road safety practices and road safety incidents.

OBJECTIVE: The objective of this study is to demonstrate a correlation between the maturity of a country's road safety practices and road safety incidents. METHODS: Firstly, data on a number of road injuries and fatalities for 129 countries were extracted from the United Nations Global Status on Road Safety database. These data were subdivided according to road safety incident and accident causation factors and normalized based on vehicular fleet (per 1000 vehicles) and road network (per meter of paved road). Secondly, a road safety maturity model was developed based on an adaptation of the concept of process maturity modeling. The maturity of countries with respect to 10 road safety practices was determined through the identification of indicators recorded in the United Nations Global Status of Road Safety Database. Plots of normalized road safety performance of the 129 countries against their maturity scores for each road safety practice as well as an aggregation of the road safety practices were developed. An analysis of variance was done to determine the extent of the correlation between the road safety maturity of the countries and their performance. In addition, a full Bayesian analysis was done to confirm the correlation of each of the road safety practices with injuries and fatalities. RESULTS: Regression analysis for fatalities, injuries, and combined accidents identified maturity with respect to road safety practices associated with speed limits and use of alternative modes as being the most significant predictors of traffic fatalities. A full Bayesian regression confirms that there is a correlation between the maturity of road safety practices and road safety incidents. CONCLUSION: Road safety practices associated with enforcement of speed limits and promotion of alternative modes are the most significant road safety practices toward which mature countries have concentrated their efforts, resulting in a lower frequency of fatalities, injury rates, and property damage accidents. The authors argue that the use of gross domestic product (GDP) as a predictor of road safety incidents suffers from the presumptive assumption that the only criterion that matters is national income, therefore erroneously predicting that richer countries all perform approximately the same in fatalities and that developing nations are at various stages, with high variability and uncertainty in prediction. It is proposed that an aggregation of individual maturity scores from road safety practices will lead to a better indicator for policy because it connects externalities (fatalities/injuries) with intrinsic factors for which policies can be oriented.

Growing skin: A computational model for skin expansion in reconstructive surgery.

The goal of this manuscript is to establish a novel computational model for stretch-induced skin growth during tissue expansion. Tissue expansion is a common surgical procedure to grow extra skin for reconstructing birth defects, burn injuries, or cancerous breasts. To model skin growth within the framework of nonlinear continuum mechanics, we adopt the multiplicative decomposition of the deformation gradient into an elastic and a growth part. Within this concept, we characterize growth as an irreversible, stretch-driven, transversely isotropic process parameterized in terms of a single scalar-valued growth multiplier, the in-plane area growth. To discretize its evolution in time, we apply an unconditionally stable, implicit Euler backward scheme. To discretize it in space, we utilize the finite element method. For maximum algorithmic efficiency and optimal convergence, we suggest an inner Newton iteration to locally update the growth multiplier at each integration point. This iteration is embedded within an outer Newton iteration to globally update the deformation at each finite element node. To demonstrate the characteristic features of skin growth, we simulate the process of gradual tissue expander inflation. To visualize growth-induced residual stresses, we simulate a subsequent tissue expander deflation. In particular, we compare the spatio-temporal evolution of area growth, elastic strains, and residual stresses for four commonly available tissue expander geometries. We believe that predictive computational modeling can open new avenues in reconstructive surgery to rationalize and standardize clinical process parameters such as expander geometry, expander size, expander placement, and inflation timing.

A case of rituximab-induced hepatitis.

A case of hepatitis in a patient receiving rituximab for ITP is reported. After an extensive workup, no infectious or autoimmune etiology could be found. The authors believe that this represents a case of drug-induced hepatitis, which has not been reported for this agent in the past.

Assessment and classification of mechanical strength components of human femur trabecular bone using texture analysis and neural network.

In this work the mechanical strength components of human femur trabecular bone are analyzed and classified using planar radiographic images and neural network. The mechanical strength regions such as Primary Compressive, Primary Tensile, Secondary Tensile and Ward Triangle in femur trabecular bone images (N = 100) are delineated by semi-automatic image processing procedure. First and higher order texture parameters and parameters such as apparent mineralization and total area associated with the strength regions are derived for normal and abnormal images. The statistically derived significant parameters corresponding to the primary strength regions are fed to the neural network for training and validation. The classifications are carried out using feed forward network that is trained with standard back propagation algorithm. Results demonstrate that the apparent mineralization of normal samples is always high as (71%) compared to abnormal samples (64%). Entropy shows a high value (7.3) for normal samples and variation between the mean intensity and apparent mineralization for the primary strength zone is statistically significant (p < 0.0005). The classified outputs are validated by sensitivity and specificity measurements and are found to be 66.66% and 80% respectively. Further it appears that it is possible to differentiate normal and abnormal samples from the conventional radiographic images. As trabecular architecture in the human femur is an important factor contributing to bone strength, the procedure adopted here could be a useful supplement to the clinical observations for bone loss and fracture risk.