[Clinicopathological features of low-grade oncocytic renal tumor (CD117-negative, cytokeratin 7-positive): report of seven cases].

Objective: To explore clinicopathological features of low-grade oncocytic tumor (LOT) of the kidney and to analyze its relationship to hybrid oncocytic/chromophobe tumor (HOCT) of the kidney, renal oncocytoma (RO), and chromophobe renal cell carcinoma (chRCC). Methods: Seven LOTs were identified from the pathologic archives of two hospitals, including Xiangya Hospital (5 cases) and the Second Xiangya Hospital (2 cases) of Central South University between 2012 and 2019. Clinical data of the LOTs were collected. The tumor morphology was analyzed and immunohistochemistry was performed. Results: All LOTs occurred in adults, aged from 49 to 72 years (median 56.0 years, mean 60.7 years). The tumor size ranged from 2.5 to 6.0 cm (median 4.3 cm, mean 4.3 cm). There were three male and four female patients. Three cases occurred in the left kidney and four in the right. All the tumors were solitary lesions without the clinicopathologic background of Birt-Hogg-Dubé (BHD) syndrome or oncocytosis. Five patients had available follow-up data (follow-up period 23-95 months, median 69.0 months, mean 64.6 months) and all were alive without disease. Microscopically, all LOTs were well-circumscribed (7/7). Three LOTs were partly encapsulated. The tumors demonstrated a predominant growth pattern comprising prominently compact small nests surrounded by delicately branching thin-walled blood vessels, imparting an organoid architecture (7/7), but variable numbers of glandular or gland-like structures were often seen among the small nests (7/7). There were frequently areas with loose, edematous stroma, and the tumor cells exhibited reticular, trabecular, or single cell arrangements (6/7). Focal hemorrhage was also commonly present in both compact and loose areas (5/7). In addition, focally cystic formation and ossification occurred in the compact area of one case and in the loose area of another case. The tumor cells in LOT showed intermediate cytologic characteristics between RO and chRCC, including abundantly eosinophilic granular cytoplasm, ovoid to round nuclei with mostly smooth contours, discernable small nucleoli (RO features), frequently delicate perinuclear halos, and occasional binucleation (chRCC features). The tumors were typically CK7-positive and CD117-negative (7/7), and variable staining for PAX8 (5/7), P504s (2/7), and vimentin (1/7). They were negative for CK20, CD10 and FOXI1. All tumors retained SDHB immunostaining. Conclusions: LOT is a rare and indolent oncocytic renal tumor with homogeneously intermediate cytologic features between RO and chRCC. There are some clinicopathologic overlaps between LOT and sporadic HOCT. The distinctive morphology and immunophenotype of LOT suggest that it is potentially a distinct tumor entity.

Linking Branch Lengths across Sets of Loci Provides the Highest Statistical Support for Phylogenetic Inference.

Evolution leaves heterogeneous patterns of nucleotide variation across the genome, with different loci subject to varying degrees of mutation, selection, and drift. In phylogenetics, the potential impacts of partitioning sequence data for the assignment of substitution models are well appreciated. In contrast, the treatment of branch lengths has received far less attention. In this study, we examined the effects of linking and unlinking branch-length parameters across loci or subsets of loci. By analyzing a range of empirical data sets, we find consistent support for a model in which branch lengths are proportionate between subsets of loci: gene trees share the same pattern of branch lengths, but form subsets that vary in their overall tree lengths. These models had substantially better statistical support than models that assume identical branch lengths across gene trees, or those in which genes form subsets with distinct branch-length patterns. We show using simulations and empirical data that the complexity of the branch-length model with the highest support depends on the length of the sequence alignment and on the numbers of taxa and loci in the data set. Our findings suggest that models in which branch lengths are proportionate between subsets have the highest statistical support under the conditions that are most commonly seen in practice. The results of our study have implications for model selection, computational efficiency, and experimental design in phylogenomics.

Physical activity and sleep differences between osteoarthritis, rheumatoid arthritis and non-arthritic people in China: objective versus self report comparisons.

BACKGROUND: Objectively measured differences in physical activity (PA) and sleep have been documented among people with osteoarthritis (OA) and rheumatoid arthritis (RA) compared to non-arthritic controls. However, it is not clear whether OA and RA subgroups also differ on these indexes or the extent to which distinct arthritis subgroups versus controls can be accurately identified on the basis of objective PA and sleep indexes compared to self-report responses on questionnaires. This study addressed these gaps. METHODS: This case-control study comprised Chinese adults with OA (N = 40) or RA (N = 40) diagnoses based on physician assessments as well as a control group of adults without chronic pain (N = 40). All participants wore a Sensewear Armband (SWA) for consecutive 7 days and completed the International Physical Activity Questionnaire Short Form-Chinese as well as Pittsburgh Sleep Diary to obtain objective and subjective PA and sleep data, respectively. RESULTS: There were no differences between the three groups on any self-report indexes of PA or sleep. Conversely, OA and RA subgroups displayed significantly lower PA levels and more sleep problems than controls did on a majority of SWA indexes, though arthritis subgroups were not differentiated from one another on these measures. Logistic regression analyses indicated four non-multicollinear SWA indexes (i.e., steps, active energy expenditure, vigorous activity, time awake after sleep onset) correctly identified the subgroup membership of 75.0-82.5% of participants with RA or OA while classification accuracy results were attenuated for controls. CONCLUSIONS: Where possible, objective measures should be used to assess PA and sleep of adults with OA and RA while particular self-report PA questionnaires should be used sparingly.

Recalibration of the insect evolutionary time scale using Monte San Giorgio fossils suggests survival of key lineages through the End-Permian Extinction.

Insects are a highly diverse group of organisms and constitute more than half of all known animal species. They have evolved an extraordinary range of traits, from flight and complete metamorphosis to complex polyphenisms and advanced eusociality. Although the rich insect fossil record has helped to chart the appearance of many phenotypic innovations, data are scarce for a number of key periods. One such period is that following the End-Permian Extinction, recognized as the most catastrophic of all extinction events. We recently discovered several 240-million-year-old insect fossils in the Mount San Giorgio Lagerstätte (Switzerland-Italy) that are remarkable for their state of preservation (including internal organs and soft tissues), and because they extend the records of their respective taxa by up to 200 million years. By using these fossils as calibrations in a phylogenomic dating analysis, we present a revised time scale for insect evolution. Our date estimates for several major lineages, including the hyperdiverse crown groups of Lepidoptera, Hemiptera: Heteroptera and Diptera, are substantially older than their currently accepted post-Permian origins. We found that major evolutionary innovations, including flight and metamorphosis, appeared considerably earlier than previously thought. These results have numerous implications for understanding the evolution of insects and their resilience in the face of extreme events such as the End-Permian Extinction.

A comparison of methods for estimating substitution rates from ancient DNA sequence data.

BACKGROUND: Phylogenetic analysis of DNA from modern and ancient samples allows the reconstruction of important demographic and evolutionary processes. A critical component of these analyses is the estimation of evolutionary rates, which can be calibrated using information about the ages of the samples. However, the reliability of these rate estimates can be negatively affected by among-lineage rate variation and non-random sampling. Using a simulation study, we compared the performance of three phylogenetic methods for inferring evolutionary rates from time-structured data sets: regression of root-to-tip distances, least-squares dating, and Bayesian inference. We also applied these three methods to time-structured mitogenomic data sets from six vertebrate species. RESULTS: Our results from 12 simulation scenarios show that the three methods produce reliable estimates when the substitution rate is high, rate variation is low, and samples of similar ages are not all grouped together in the tree (i.e., low phylo-temporal clustering). The interaction of these factors is particularly important for least-squares dating and Bayesian estimation of evolutionary rates. The three estimation methods produced consistent estimates of rates across most of the six mitogenomic data sets, with sequence data from horses being an exception. CONCLUSIONS: We recommend that phylogenetic studies of ancient DNA sequences should use multiple methods of inference and test for the presence of temporal signal, among-lineage rate variation, and phylo-temporal clustering in the data.

Radioembolisation of hepatocellular carcinoma: a primer.

Transarterial radioembolisation (TARE) has gained increasing acceptance as an additional/alternative locoregional treatment option for hepatocellular carcinoma, and colorectal hepatic metastases that present beyond potentially curative options. This is a catheter-based transarterial selective internal brachytherapy that involves injection of radioactive microspheres (usually Y-90) that are delivered selectively to the liver tumours. Owing to the combined radioactive and microembolic effect, the findings at follow-up imaging are significantly different from that seen with other transarterial treatment options. Considering increasing confidence among clinicians, refinement in techniques and increasing number of ongoing trials, TARE is expected to gain further acceptance and become an important tool in the armamentarium for the treatment of liver malignancies. So it is imperative that all radiologists involved in the management of liver malignancies are well versed with TARE to facilitate appropriate discussion at multidisciplinary meetings to direct further management. In this article, we provide a comprehensive review on various aspects of radioembolisation with Y-90 for hepatocellular carcinoma including the patient selection, treatment planning, radiation dosimetry and treatment, side effects, follow-up imaging and future direction.

Multiple evolutionary origins of Australian soil-burrowing cockroaches driven by climate change in the Neogene.

Parallel evolution is the independent appearance of similar derived phenotypes from similar ancestral forms. It is of key importance in the debate over whether evolution is stochastic and unpredictable, or subject to constraints that limit available phenotypic options. Nevertheless, its occurrence has rarely been demonstrated above the species level. Climate change on the Australian landmass over the last approximately 20 Myr has provided conditions conducive to parallel evolution, as taxa at the edges of shrinking mesic habitats adapted to drier biomes. Here, we investigate the phylogeny and evolution of Australian soil-burrowing and wood-feeding blaberid cockroaches. Soil burrowers (subfamily Geoscapheinae) are found in relatively dry sclerophyllous and scrubland habits, whereas wood feeders (subfamily Panesthiinae) are found in rainforest and wet sclerophyll. We sequenced and analysed mitochondrial and nuclear markers from 142 specimens, and estimated the evolutionary time scale of the two subfamilies. We found evidence for the parallel evolution of soil-burrowing taxa from wood-feeding ancestors on up to nine occasions. These transitions appear to have been driven by periods of aridification during the Miocene and Pliocene across eastern Australia. Our results provide an illuminating example of climate-driven parallel evolution among species.

Overcoming super-knock down resistance (super-kdr) mediated resistance: multi-halogenated benzyl pyrethroids are more toxic to super-kdr than kdr house flies.

Target site insensitivity because of mutations in the voltage-sensitive sodium channel gene (Vssc) is a major mechanism of resistance to pyrethroid insecticides in the house fly, Musca domestica. There are three known Vssc alleles that confer resistance to pyrethroids in the house fly: knock down resistance (kdr; L1014F), super-kdr (M918T + L1014F) and kdr-his (L1014H), but there has been no side-by-side comparison of the resistance levels that they confer. We compared the levels of resistance conferred by the three Vssc alleles in congenic strains to 19 structurally diverse pyrethroids, and compared the full-length Vssc cDNA sequences from each strain. Generally, the levels of resistance conferred were kdr-his < kdr < super-kdr. However, there was significant variation in this pattern, especially for super-kdr, for which both high and low resistance ratios were observed for several pyrethroids. We also examined the levels of resistance in heterozygotes. Resistance in each of the hybrids was generally inherited as an incompletely recessive trait, except for the kdr-his/kdr hybrids, which showed incompletely to completely dominant resistance (ie had resistance levels comparable to kdr homozygotes). The importance of these results to understanding the frequencies of these resistance alleles in natural populations, the evolution of insecticide resistance and resistance management strategies are discussed.

Mediating effects on health-related quality of life in adults with osteoporosis: a structural equation modeling.

UNLABELLED: Participants with physical limitation and high degree of pain had poor mental and physical health-related quality of life. In addition, the more support and exercise that the participants had, the more likely they were to report better health-related quality of life. INTRODUCTION: Osteoporosis is a public health threat worldwide. The aim of this study is to examine the effects of individual demographics, disease characteristics, and social support on health-related quality of life (HrQoL) of adults with osteoporosis. Most psychosocial studies focused on the relationships but not the specific construct of social support on HrQoL. METHODS: In a correlational design, face-to-face, structured interviews were employed to collect information. Study questionnaires included a demographic sheet, the modified Social Support Inventory, and the Short-Form 36 scales on a convenience sample of 161 individuals recruited from four outpatient centers. Using the structural equation modeling approach, all relationships among factors, mediators, and HrQoL were analyzed. RESULTS: The mean duration of osteoporosis was longer than 5 years. Participants who exercised more than three times per week had greater HrQoL than individuals who exercised less frequently. Participants with physical limitation and high degree of pain had poor mental and physical HrQoL. The more support that the participants perceived, the more likely they were to report better HrQoL. The best fitted structural equation modeling (SEM) model included individual demographics and physical function, and social support as significant predictors on HrQoL, with informational support and physical function acting as mediators in those relationships. Moreover, this structural model explained 35, 42, and 40 % of the variance on activity of daily living (ADL), physical, and mental health-related quality of life. CONCLUSIONS: The more informational support that individuals have, the more likely they were to report better HrQoL. Individuals with osteoporosis who have lower pain and more exercise are considered having better HrQoL. Further longitudinal research will help clarify the direction of these relationships.

Biogeographic calibrations for the molecular clock.

Molecular estimates of evolutionary timescales have an important role in a range of biological studies. Such estimates can be made using methods based on molecular clocks, including models that are able to account for rate variation across lineages. All clock models share a dependence on calibrations, which enable estimates to be given in absolute time units. There are many available methods for incorporating fossil calibrations, but geological and climatic data can also provide useful calibrations for molecular clocks. However, a number of strong assumptions need to be made when using these biogeographic calibrations, leading to wide variation in their reliability and precision. In this review, we describe the nature of biogeographic calibrations and the assumptions that they involve. We present an overview of the different geological and climatic events that can provide informative calibrations, and explain how such temporal information can be incorporated into dating analyses.

Histologic classification of non-small-cell lung cancer over time: reducing the rates of not-otherwise-specified.

BACKGROUND: The importance of histologic classification in selecting the appropriate systemic therapy for non-small-cell lung cancer (nsclc) came to attention in 2007. In British Columbia, that information was communicated through international and national meetings, our centralized cancer care program, and to the medical community at large in multidisciplinary forums. We examined the effects of those education programs on the categorization of nsclc and associated systemic treatment practices. METHODS: The BC Cancer Agency provides cancer care to 4.6 million residents of British Columbia. A retrospective review of all stage iiib and ivnsclc patients referred in 2007 and 2011 collected baseline characteristics, treatment, and outcomes. Histology was classified using the International Classification of Diseases for Oncology, 3rd edition, for the Canadian Cancer Registry. RESULTS: In 2007, 671 patients were referred, and 170 received chemotherapy; in 2011, the relevant figures were 680 and 197 respectively. Baseline characteristics in the cohorts were not statistically significantly different in 2007 and 2011. Histologic classifications in 2007 were 41% nonsquamous, 13% squamous, and 46% not otherwise specified (nos); in 2011, they were 63%, 17%, and 20% respectively. Exposure to pemetrexed in any line of therapy in 2007 was 22% for nonsquamous, 17% for squamous, and 10% for nos; in 2011, exposure was 39%, 3%, and 37% respectively. Exposure to epidermal growth factor receptor tyrosine kinase inhibitor (egfrtki) in 2007 was 36%, 22%, and 33%; in 2011, it was 64%, 60%, and 63%. Median overall survival duration, 2007 versus 2011, was 3.25 months versus 3.57 months with best supportive care, and 11.31 months versus 11.54 months with chemotherapy. CONCLUSIONS: The specificity of nsclc histologic categorization improved in 2011 compared with 2007, with a reduction of 26 percentage points in the rate of nos disease. The proportion of patients treated with chemotherapy over time remained the same, but the use of pemetrexed and egfrtki increased. The increased accuracy in histologic classification resulted in more appropriate utilization of systemic drugs.

Development of a hybrid microwave-optical thermoregulation monitor for the muscle.

This paper presents the latest development of the hybrid microwave-optical thermoregulation monitor for the muscle. It is capable of warming the muscle and measuring the subsequent blood volume changes, using a novel microwave applicator with integrated optical probes. The challenge is to measure the thermoregulation response in deep tissue while minimizing any effect from the skin layer. We have introduced a skin cooling device, an additional integrated optical Laser Doppler flow monitoring probe and a temperature sensor to measure skin blood flow and temperature, respectively. The result shows that skin cooling is essential to minimize skin flow changes during microwave warming. The hybrid probe was placed on a human thigh to measure oxy/deoxy/total haemoglobin concentration changes (ΔHbO2/ΔHHb/ΔHbT), skin flux and temperature upon microwave warming. Without skin cooling, the skin temperature was elevated by 4 °C and both ΔHbO2/ΔHbT and skin flux increased, showing microwave warming occurring in both the skin and muscle. With skin cooling, the skin temperature was kept relatively constant. While ΔHbO2/ΔHbT increased, the skin flux was relatively stable, showing a preferential microwave warming in the muscle, rather than the skin.

Is polyethylene glycol loxenatide 100 µg the preferred glucagon-like peptide-1 receptor agonist for type 2 diabetes mellitus? A meta-analysis and trial sequential analysis.

OBJECTIVE: This study aimed to systematically evaluate the efficacy, safety and optimal dose of polyethylene glycol loxenatide (PEX168) for treating type 2 diabetes mellitus (T2DM). MATERIALS AND METHODS: Clinical trials of PEX168 for T2DM were identified in 8 databases, with a build time limit of January 2023. Included studies were subjected to meta-analysis and trial sequential analysis (TSA). RESULTS: On the efficacy endpoint, the meta-analysis showed that PEX168 100 µg significantly reduced 0.86% glycated hemoglobin type A1c (HbA1c) (MD -0.86, 95% CI -1.02 - -0.70,  p<0.00001), 1.11 mmol/L fasting plasma glucose (FPG) (MD -1.11, 95% CI -1.49 - -0.74, p<0.00001) and 1.91 mmol/L 2h postprandial glucose (PPG) (MD -1.91, 95% CI -3.35 - -0.46, p=0.01) compared with placebo. The TSA showed that all these benefits were conclusive. On safety endpoints, total adverse events (AEs), gastrointestinal (GI) AEs, serious AEs, and hypoglycemia were comparable to placebo for PEX168 100 µg (p>0.05). In the dose comparison, the HbA1c, FPG, and 2h PPG of PEX168 200 µg were comparable to 100 µg (p>0.05), while GI AEs were significantly higher than 100 µg (RR=2.84, 95% CI 1.64-4.93,  p=0.0002). CONCLUSIONS: PEX168 100 µg can significantly lower blood glucose and does not increase the risk of total AEs, GI AEs, and hypoglycemia, which may be a preferred glucagon-like peptide-1 receptor agonist for type 2 diabetes mellitus.

A Mendelian randomization study of the effect of selenium on autoimmune thyroid disease.

OBJECTIVE: The impact of selenium on autoimmune thyroid disease (AITD) is a subject of ongoing debate. This study aimed to analyze the causal correlations of selenium with autoimmune thyroiditis (AIT), autoimmune hyperthyroidism (AIH), and Graves' disease (GD) by Mendelian randomization (MR). MATERIALS AND METHODS: Single nucleotide polymorphisms related to selenium, AIT, AIH, and GD were sourced from the IEU Open GWAS project and FinnGen. Exposure-outcome causality was assessed using inverse variance weighted, MR-Egger, and weighted median. Horizontal pleiotropy was examined using the MR-Egger intercept, heterogeneity was evaluated with Cochran's Q test, and the robustness of the results was confirmed via leave-one-out sensitivity analysis. RESULTS: The MR analysis revealed that selenium did not exhibit a causal relationship with AIT (OR 0.993, 95% CI 0.786 to 1.108, p=0.432), AIH (OR 1.066, 95% CI 0.976 to 1.164, p=0.154), or GD (OR 1.052, 95% CI 0.984 to 1.126, p=0.138). Moreover, the MR-Egger intercept and Cochran's Q test demonstrated the absence of horizontal pleiotropy or heterogeneity in these results (p>0.05). Sensitivity analysis affirmed the robustness of these results. CONCLUSIONS: This MR analysis concluded that selenium was not linked to AIT, AIH, or GD risk. Therefore, indiscriminate selenium supplementation is not advisable for AITD patients without concurrent selenium deficiency.

Subtyping of triple-negative breast cancers: its prognostication and implications in diagnosis of breast origin.

BACKGROUND: Triple-negative breast cancer (TNBC) subtyping by gene profiling has provided valuable clinical information. Here, we aimed to evaluate the relevance of TNBC subtyping using immunohistochemistry (IHC), which could be a more clinically practical approach, for prognostication and applications in patient management. METHODS: A total of 123 TNBC cases were classified using androgen receptor (AR), CD8, Forkhead box C1 protein (FOXC1), and doublecortin-like kinase 1 (DCLK1) into luminal androgen receptor (LAR), basal-like immunosuppressive (BLIS), mesenchymal-like (MES), and immunomodulatory (IM) subtypes. The IM cases were further divided into the IM-excluded and IM-inflamed categories by CD8 spatial distribution. Their clinicopathological and biomarker profiles and prognoses were evaluated. RESULTS: LAR (28.6%) and MES (11.2%) were the most and least frequent subtypes. The IHC-TNBC subtypes demonstrated distinct clinicopathological features and biomarker profiles, corresponding to the reported features in gene profiling studies. IM-inflamed subtype had the best outcome, while BLIS had a significantly poorer survival. Differential breast-specific marker expressions were found. Trichorhinophalangeal syndrome type 1 (TRPS1) was more sensitive for IM-inflamed and BLIS, GATA-binding protein 3 (GATA3) for IM-excluded and MES, and gross cystic disease fluid protein 15 (GCDFP15) for LAR subtypes. CONCLUSIONS: Our findings demonstrated the feasibility of IHC surrogates to stratify TNBC subtypes with distinct features and prognoses. The IM subtype can be refined by its CD8 spatial pattern. Breast-specific marker expression varied among the subtypes. Marker selection should be tailored accordingly.