Five years later, with double the demographic data, naked mole-rat mortality rates continue to defy Gompertzian laws by not increasing with age.

The naked mole-rat (Heterocephalus glaber) is a mouse-sized rodent species, notable for its eusociality and long lifespan. Previously, we reported that demographic aging, i.e., the exponential increase of mortality hazard that accompanies advancing age in mammals and other organisms, does not occur in naked mole-rats (Ruby et al., 2018), a finding that has potential implications for human healthy aging. The demographic data supporting that conclusion had taken over three decades to accumulate, starting with the original rearing of H. glaber in captivity. This finding was controversial since many of the animals in that study were relatively young. In the 5 years following that study, we have doubled our quantity of demographic data. Here, we re-evaluated our prior conclusions in light of these new data and found them to be not only supported but indeed strengthened. We additionally provided insight into the social dynamics of captive H. glaber with data and analyses of body weight and colony size versus mortality. Finally, we provide a phylogenetically proximal comparator in the form of lifespan data from our Damaraland mole-rat (Fukomys damarensis) colony and demographic meta-analysis of those data along with published data from Ansell's mole-rat (Fukomys anselli). We found Fukomys mortality hazard to increase gradually with age, an observation with inferences on the evolution of exceptional lifespan among mole-rats and the ecological factors that may have accompanied that evolution.

Assessing social disparities in inpatient vs. outpatient arthroplasty: a in-state database analysis.

INTRODUCTION: Given the growing emphasis on patient outcomes, including postoperative complications, in total joint arthroplasty (TJA), investigating the rise of outpatient arthroplasty is warranted. Concerns exist over the safety of discharging patients home on the same day due to increased readmission and complication rates. However, psychological benefits and lower costs provide an incentive for outpatient arthroplasty. The influence of social determinants of health disparities on outpatient arthroplasty remains unexplored. One metric that assesses social disparities, including the following individual components: socioeconomic status, household composition, minority status, and housing and transportation, is the Social Vulnerability Index (SVI). As such, we aimed to compare: (1) mean overall SVI and mean SVI for each component and (2) risk factors for total complications between patients undergoing inpatient and outpatient arthroplasty. METHODS: Patients who underwent TJA between January 1, 2022 and December 31, 2022 were identified. Data were drawn from the Maryland State Inpatient Database (SID). A total of 7817 patients had TJA within this time period. Patients were divided into inpatient arthroplasty (n = 1429) and outpatient arthroplasty (n = 6338). The mean SVI was compared between inpatient and outpatient procedures for each themed score. The SVI identifies communities that may need support cause by external stresses on human health based on four themed scores: socioeconomic status; household composition and disability; minority status and language; and housing and transportation. The SVI uses the United States Census data to rank census tracts for each individual theme, as well as an overall social vulnerability score. The higher the SVI, the more social vulnerability, or resources needed to thrive in that area. Multivariate logistic regression analyses were performed to identify independent risk factors for total complications following TJA after controlling for risk factors and patient comorbidities. Total complications included: infection, aseptic loosening, dislocation, arthrofibrosis, mechanical complication, pain, and periprosthetic fracture. RESULTS: Patients who had inpatient arthroplasty had higher overall SVI scores (0.45 vs. 0.42, P < 0.001). The SVI scores were higher for patients who had inpatient arthroplasty for socioeconomic status (0.36 vs. 0.32, P < 0.001), minority status and language (0.76 vs. 0.74, P < 0.001), and housing and transportation (0.53 vs. 0.50, P < 0.001) compared to outpatient arthroplasty, respectively. There was no difference between inpatient and outpatient arthroplasty for household composition and disability (0.41 vs. 0.41, P = 0.99). When controlling for comorbidities, inpatient arthroplasty [Odds Ratio (OR) 1.91, 95% Confidence Interval (CI) 1.23-2.95, P = 0.004], hypertension (OR 2.11, 95% CI 1.23-3.62, P = 0.007), and housing and transportation (OR 2.00, 95% CI 1.17-3.42, P = 0.012) were independent risk factors for total complications. CONCLUSION: Inpatient arthroplasty was associated with increased social disparities across several components of deprivation as well as an independent risk factor total complications following TJA. To the best of our knowledge, this study is the first to examine the negative repercussions of inpatient arthroplasty through the lens of social disparities and can target specific areas for intervention.

Understanding Treatment Decision-Making in Older Women With Breast Cancer: A Survey-Based Study.

INTRODUCTION: For women ≥70 y old with early-stage hormone receptor-positive, human epidermal growth factor receptor 2-negative breast cancer, the national guidelines recommend the omission of sentinel lymph node biopsy (SLNB) and post-lumpectomy radiotherapy. However, national-level data suggest these treatments remain common. We utilized a survey-based approach to explore patient-level factors driving overutilization. METHODS: We recruited women ≥70 y old with early-stage hormone receptor-positive/human epidermal growth factor receptor 2-negative breast cancer within 6 mo of surgery. An exploratory cross-sectional survey captured information on offered and pursued treatments, the importance of patient-centered outcomes, and the influence of each outcome on treatment decision-making. Descriptive statistics were used for analysis. RESULTS: 31/51 patients completed the survey with a response rate of 61%. Most patients (86%) received a lumpectomy. Twenty-eight percent of patients received SLNB, and 56% of lumpectomy patients underwent adjuvant radiotherapy. When considering treatment options, the patient-centered outcomes, most important for decision-making, were overall survival, breast-specific survival, and preventing local recurrence, while breast appearance, financial costs, and avoiding the need for pills (endocrine therapy) were the least important. CONCLUSIONS: Patients' treatment decisions align with their values. The correlation between patient-stated values and treatment decisions suggests a perceived mortality benefit of low-value SLNB and radiotherapy. These findings can inform targeted efforts to deimplement low-value care in breast cancer through patient-focused tools and education.

Isatuximab Monotherapy for Desensitization in Highly Sensitized Patients Awaiting Kidney Transplant.

SIGNIFICANCE STATEMENT: There is no standardized desensitization regimen for kidney transplant candidates. CD38, expressed by plasma cells, could be targeted for desensitization to deplete plasma cells producing alloantibodies and donor-specific antibodies. Few studies and case reports are available regarding the use of CD38 antibodies for desensitization in patients awaiting kidney transplant. This study shows that isatuximab, a CD38-targeting therapy, was well tolerated in kidney transplant candidates, with a durable decrease in anti-HLA antibodies and partial desensitization activity. The short treatment period and long follow-up of this study allowed for the understanding of the mechanism and timing for any antibody rebound. Isatuximab could be further investigated as an option for adjunct therapy to existing desensitization for patients on the kidney transplant waitlist. BACKGROUND: Patients with calculated panel reactive antibody (cPRA) ≥80.00%, particularly those with cPRA ≥99.90%, are considered highly sensitized and underserved by the Kidney Allocation System. Desensitization removes circulating reactive antibodies and/or suppresses antibody production to increase the chances of a negative crossmatch. CD38 is expressed highly on plasma cells, thus is a potential target for desensitization. METHODS: This was an open-label single-arm phase 1/2 study investigating the safety, pharmacokinetics, and preliminary efficacy of isatuximab in patients awaiting kidney transplantation. There were two cohorts, cohorts A and B, which enrolled cPRA ≥99.90% and 80.00% to <99.90%, respectively. RESULTS: Twenty-three patients (12 cohort A, 11 cohort B) received isatuximab 10 mg/kg weekly for 4 weeks then every 2 weeks for 8 weeks. Isatuximab was well tolerated with pharmacokinetic and pharmacodynamic profiles that indicated similar exposure to multiple myeloma trials. It resulted in decreases in CD38 + plasmablasts, plasma cells, and NK cells and significant reductions in HLA-specific IgG-producing memory B cells. Overall response rate, on the basis of a predefined composite desensitization end point, was 83.3% and 81.8% in cohorts A and B. Most responders had decreases in anti-HLA antibodies that were maintained for 26 weeks after the last dose. Overall, cPRA values were minimally affected, however, with only 9/23 patients (39%) having cPRA decreases to target levels. By study cutoff (median follow-up of 68 weeks), six patients received transplant offers, of which four were accepted. CONCLUSIONS: In this open-label trial, isatuximab was well tolerated and resulted in a durable decrease in anti-HLA antibodies with partial desensitization activity. CLINICAL TRIAL REGISTRATION NUMBER: NCT04294459 .

3D mouse pose from single-view video and a new dataset.

We present a method to infer the 3D pose of mice, including the limbs and feet, from monocular videos. Many human clinical conditions and their corresponding animal models result in abnormal motion, and accurately measuring 3D motion at scale offers insights into health. The 3D poses improve classification of health-related attributes over 2D representations. The inferred poses are accurate enough to estimate stride length even when the feet are mostly occluded. This method could be applied as part of a continuous monitoring system to non-invasively measure animal health, as demonstrated by its use in successfully classifying animals based on age and genotype. We introduce the Mouse Pose Analysis Dataset, the first large scale video dataset of lab mice in their home cage with ground truth keypoint and behavior labels. The dataset also contains high resolution mouse CT scans, which we use to build the shape models for 3D pose reconstruction.

Genetics implicates overactive osteogenesis in the development of diffuse idiopathic skeletal hyperostosis.

Diffuse idiopathic skeletal hyperostosis (DISH) is a condition where adjacent vertebrae become fused through formation of osteophytes. The genetic and epidemiological etiology of this condition is not well understood. Here, we implemented a machine learning algorithm to assess the prevalence and severity of the pathology in ~40,000 lateral DXA scans in the UK Biobank Imaging cohort. We find that DISH is highly prevalent, above the age of 45, ~20% of men and ~8% of women having multiple osteophytes. Surprisingly, we find strong phenotypic and genetic association of DISH with increased bone mineral density and content throughout the entire skeletal system. Genetic association analysis identified ten loci associated with DISH, including multiple genes involved in bone remodeling (RUNX2, IL11, GDF5, CCDC91, NOG, and ROR2). Overall, this study describes genetics of DISH and implicates the role of overactive osteogenesis as a key driver of the pathology.

The Change of Practitioner's Self-Efficacy in Triple P Professional Training: Moderating Role of Practitioner Characteristics, Country, and Delivery Mode.

Two studies examined the change in self-efficacy of practitioners after attending Triple P training and the moderators that affect training outcomes. Study 1 used a large multidisciplinary sample of health, education, and welfare practitioners (N = 37,235) came from 30 countries around the world, which all participate in a Triple P professional training course during 2012-2019. This study assessed practitioners' overall self-efficacy and their consultation skills efficacy prior to training, immediately following training, and at six- to eight-weeks follow-up. Participants reported significant improvements of their overall self-efficacy and their consultation skills self-efficacy. There were significantly small differences based on practitioners' gender, disciplines, education levels, and country location. Study 2 examined the training outcomes of videoconference-based training (following the COVID-19 pandemic) compared to in-person training (N = 6867). No significant differences were found between videoconference and in-person training on any outcome measure. Implications for the global dissemination of evidence-based parenting programs as part of a comprehensive public health response to COVID-19 was discussed.

A potent bioactive fraction against colon cancer from Plectranthus vettiveroides.

Aim: This study was designed to investigate the anticancer efficacy of the organic leaf extracts of the plant, Plectranthus vettiveroides (P. vettiveroides), and to analyze the molecular mechanism of the anticancer activity. Methods: The leaf extracts were prepared by polarity-graded serial extraction of the dried leaf powder. The cytotoxic effect of the extracts was analyzed by the 3-(4, 5-dimethylthiazol-2-yl)-2, 5-diphenyltetrazolium bromide (MTT) assay. The most active ethyl acetate extract was subjected to bioactivity-guided fractionation by column chromatography, which yielded a cytotoxic fraction designated as the P. vettiveroides fraction (PVF). The anticancer property of PVF was confirmed further by clonogenic assay. The mechanism of PVF-induced cell death was analyzed by flow cytometry and fluorescence microscopy. Additionally, the effects of PVF on apoptotic and cell survival pathways were analyzed using western immunoblot analysis. Results: A bioactive fraction PVF, was isolated from the ethyl acetate leaf extract. PVF showed significant anticancer activity against colon cancer cells, whilst normal cells were comparatively less affected. PVF induced strong apoptotic stimuli in colorectal carcinoma cell line HCT116, involving both extrinsic and intrinsic pathways. Investigation into the molecular mechanism of anticancer activity of PVF in HCT116 cells revealed that the fraction activates the pro-apoptotic pathway via tumor suppressor protein 53 (p53) and inhibits the anti-apoptotic pathway by regulating phosphatidylinositol 3-kinase (PI3K) signaling. Conclusions: The findings of this study demonstrate, with mechanism-based evidence, the chemotherapeutic potential of a bioactive fraction PVF, derived from the leaves of the medicinal plant P. vettiveroides against colon cancer.

High-resolution x-ray spectrometer for x-ray absorption fine structure spectroscopy.

Two extended x-ray absorption fine structure flat crystal x-ray spectrometers (EFX's) were designed and built for high-resolution x-ray spectroscopy over a large energy range with flexible, on-shot energy dispersion calibration capabilities. The EFX uses a flat silicon [111] crystal in the reflection geometry as the energy dispersive optic covering the energy range of 6.3-11.4 keV and achieving a spectral resolution of 4.5 eV with a source size of 50 µm at 7.2 keV. A shot-to-shot configurable calibration filter pack and Bayesian inference routine were used to constrain the energy dispersion relation to within ±3 eV. The EFX was primarily designed for x-ray absorption fine structure (XAFS) spectroscopy and provides significant improvement to the Laboratory for Laser Energetics' OMEGA-60 XAFS experimental platform. The EFX is capable of performing extended XAFS measurements of multiple absorption edges simultaneously on metal alloys and x-ray absorption near-edge spectroscopy to measure the electron structure of compressed 3d transition metals.

An Automated, Home-Cage, Video Monitoring-based Mouse Frailty Index Detects Age-associated Morbidity in C57BL/6 and Diversity Outbred Mice.

Frailty indexes (FIs) provide quantitative measurements of nonspecific health decline and are particularly useful as longitudinal monitors of morbidity in aging studies. For mouse studies, frailty assessments can be taken noninvasively, but they require handling and direct observation that is labor-intensive to the scientist and stress inducing to the animal. Here, we implement, evaluate, and provide a refined digital FI composed entirely of computational analyses of home-cage video and compare it to manually obtained frailty scores in both C57BL/6 and genetically heterogeneous Diversity Outbred mice. We show that the frailty scores assigned by our digital index correlate with both manually obtained frailty scores and chronological age. Thus, we provide an automated tool for frailty assessment that can be collected reproducibly, at scale, without substantial labor cost.

Patient Preferences and Satisfaction With Decisions in Stage-III Melanoma: A Mixed Methods Study.

INTRODUCTION: Rapid accumulation of data in surgical and medical oncology has changed the treatment landscape for patients with stage-III melanoma, introducing options for active surveillance and adjuvant systemic therapy; however, these options have increased the complexity of decision making. METHODS: We conducted an explanatory sequential mixed-methods study consisting of surveys and semistructured interviews among patients diagnosed with stage-III melanoma at a single institution from August 2019 to December 2021. The survey included the validated 30-point satisfaction with decision scale (SWD). The interview guide was developed using a shared decision-making framework. RESULTS: Twenty-six participants completed the survey (response rate 40%) and 17 were interviewed. In the survey, 69% of participants reported receiving a recommendation for active surveillance and 23% received a recommendation for adjuvant systemic therapy. Overall SWD for treatment of the lymph node basin and adjuvant systemic therapy was high at 27.94 and 26.21 out of 30, respectively. In the interviews, participants stressed the importance of the physician's recommendation as well as the desire to minimize intervention and avoid potential side effects in their decisions. However, they demonstrated persistent knowledge gaps in their understanding of the treatment options. CONCLUSIONS: Like other cancer types where the option for active surveillance exists, the physician's recommendation is influential in shaping decisions for patients with stage-III melanoma. Physicians can improve shared decision making in this complex treatment landscape through improved multidisciplinary collaboration and mechanisms for ensuring patients' understanding of the treatment options.

Challenges and promise of targeting miRNA in rheumatic diseases: a computational approach to identify miRNA association with cell types, cytokines, and disease mechanisms.

MicroRNAs (miRNAs) are small non-coding RNAs that alter the expression of target genes at the post-transcriptional level, influencing diverse outcomes in metabolism, cell differentiation, proliferation, cell survival, and cell death. Dysregulated miRNA expression is implicated in various rheumatic conditions, including ankylosing spondylitis (AS), gout, juvenile idiopathic arthritis (JIA), osteoarthritis (OA), psoriatic arthritis, rheumatoid arthritis (RA), Sjogren's syndrome, systemic lupus erythematosus (SLE) and systemic sclerosis. For this review, we used an open-source programming language- PowerShell, to scan the massive number of existing primary research publications on PubMed on miRNAs in these nine diseases to identify and count unique co-occurrences of individual miRNAs and the disease name. These counts were used to rank the top seven most relevant immuno-miRs based on their research volume in each rheumatic disease. Individual miRNAs were also screened for publication with the names of immune cells, cytokines, and pathological processes involved in rheumatic diseases. These occurrences were tabulated into matrices to identify hotspots for research relevance. Based on this information, we summarize the basic and clinical findings for the top three miRNAs - miR-146, miR-155, and miR-21 - whose relevance spans across multiple rheumatic diseases. Furthermore, we highlight some unique miRNAs for each disease and why some rheumatic conditions lack research in this emerging epigenetics field. With the overwhelming number of publications on miRNAs in rheumatic diseases, this review serves as a 'relevance finder' to guide researchers in selecting miRNAs based on the compiled existing knowledge of their involvement in disease pathogenesis. This approach applies to other disease contexts with the end goal of developing miRNA-based therapeutics.

Incidence and Clinical Risk Factors of Post-Operative Complications following Primary Total Hip Arthroplasty: A 10-Year Population-Based Cohort Study.

Background: Total hip arthroplasty (THA) has become a growing treatment procedure for debilitating hip pathologies. Patients experienced post-operative complications and revision surgeries according to large THA registries. To fully understand the short-term and long-term post-operative outcomes following THA, the purpose of this study is to examine the incidence of post-operative complications following primary THA and to examine how this trend has changed over 10 years within community hospitals in the US using large databases. Methods: This study queried the State Inpatient Database (SID) for primary THA between 2006 and 2015. Individual patients were followed forward in time until the first instance of a post-operative complication. The multivariable logistic regression analyses were computed to examine which post-operative complications were independent predictors of pre-operative comorbidities. Results: Median age of patients was 67 years, and 56% of patients were female. Females with avascular necrosis (AVN) as an indication for THA had a 27% higher risk of complication. Females with osteoarthritis (OA) as an indication for THA had a 6% higher risk of complication. Post-operative complications occurred with higher frequencies in the first two months of THA and the highest risks of THA complications within the first 6 months. Conclusion: The most common indication is OA in elders with primary THA. Females and those of black ethnicity showed the greatest risks of THA complications. Data from our large study can be used to understand post-operative complications and readmissions after THA. Our study also provides data on risk factors associated with these complications.

Sub-bandgap trap sites for high-density photochemical electron storage in colloidal SrTiO3 nanocrystals.

We report facile and reversible electron storage in colloidal SrTiO3 nanocrystals using photochemical and redox titration methods. A very high electron storage capacity (∼180 e- per 7 nm nanocrystal) is achieved which we attribute to the localized nature of added electrons at sub-bandgap trap sites in these colloidal SrTiO3 nanocrystals. The rate of electron accumulation is also found to be much faster with ethylene glycol as the sacrificial reductant compared to ethanol. This work provides key insight and establishes a kinetic bottleneck in the charge trapping processes.

Calcification of the abdominal aorta is an under-appreciated cardiovascular disease risk factor in the general population.

Calcification of large arteries is a high-risk factor in the development of cardiovascular diseases, however, due to the lack of routine monitoring, the pathology remains severely under-diagnosed and prevalence in the general population is not known. We have developed a set of machine learning methods to quantitate levels of abdominal aortic calcification (AAC) in the UK Biobank imaging cohort and carried out the largest to-date analysis of genetic, biochemical, and epidemiological risk factors associated with the pathology. In a genetic association study, we identified three novel loci associated with AAC (FGF9, NAV9, and APOE), and replicated a previously reported association at the TWIST1/HDAC9 locus. We find that AAC is a highly prevalent pathology, with ~ 1 in 10 adults above the age of 40 showing significant levels of hydroxyapatite build-up (Kauppila score > 3). Presentation of AAC was strongly predictive of future cardiovascular events including stenosis of precerebral arteries (HR~1.5), myocardial infarction (HR~1.3), ischemic heart disease (HR~1.3), as well as other diseases such as chronic obstructive pulmonary disease (HR~1.3). Significantly, we find that the risk for myocardial infarction from elevated AAC (HR ~1.4) was comparable to the risk of hypercholesterolemia (HR~1.4), yet most people who develop AAC are not hypercholesterolemic. Furthermore, the overwhelming majority (98%) of individuals who develop pathology do so in the absence of known pre-existing risk conditions such as chronic kidney disease and diabetes (0.6% and 2.7% respectively). Our findings indicate that despite the high cardiovascular risk, calcification of large arteries remains a largely under-diagnosed lethal condition, and there is a clear need for increased awareness and monitoring of the pathology in the general population.

Extracellular sulfatase-2 is overexpressed in rheumatoid arthritis and mediates the TNF-α-induced inflammatory activation of synovial fibroblasts.

Extracellular sulfatase-2 (Sulf-2) influences receptor-ligand binding and subsequent signaling by chemokines and growth factors, yet Sulf-2 remains unexplored in inflammatory cytokine signaling in the context of rheumatoid arthritis (RA). In the present study, we characterized Sulf-2 expression in RA and investigated its potential role in TNF-α-induced synovial inflammation using primary human RA synovial fibroblasts (RASFs). Sulf-2 expression was significantly higher in serum and synovial tissues from patients with RA and in synovium and serum from hTNFtg mice. RNA sequencing analysis of TNF-α-stimulated RASFs showed that Sulf-2 siRNA modulated ~2500 genes compared to scrambled siRNA. Ingenuity Pathway Analysis of RNA sequencing data identified Sulf-2 as a primary target in fibroblasts and macrophages in RA. Western blot, ELISA, and qRT‒PCR analyses confirmed that Sulf-2 knockdown reduced the TNF-α-induced expression of ICAM1, VCAM1, CAD11, PDPN, CCL5, CX3CL1, CXCL10, and CXCL11. Signaling studies identified the protein kinase C-delta (PKCδ) and c-Jun N-terminal kinase (JNK) pathways as key in the TNF-α-mediated induction of proteins related to cellular adhesion and invasion. Knockdown of Sulf-2 abrogated TNF-α-induced RASF proliferation. Sulf-2 knockdown with siRNA and inhibition by OKN-007 suppressed the TNF-α-induced phosphorylation of PKCδ and JNK, thereby suppressing the nuclear translocation and DNA binding activity of the transcription factors AP-1 and NF-κBp65 in human RASFs. Interestingly, Sulf-2 expression positively correlated with the expression of TNF receptor 1, and coimmunoprecipitation assays demonstrated the binding of these two proteins, suggesting they exhibit crosstalk in TNF-α signaling. This study identified a novel role of Sulf-2 in TNF-α signaling and the activation of RA synoviocytes, providing the rationale for evaluating the therapeutic targeting of Sulf-2 in preclinical models of RA.

The relationship between distress tolerance and symptoms of depression: Validation of the Distress Tolerance Scale (DTS) and short-form (DTS-SF).

OBJECTIVE: Distress tolerance (DT) has been found to be implicated in the development and maintenance of depressive symptomatology and various other significant psychological conditions. As such, it is critical to have measures of DT that are effective and easy to administer. This study aimed to examine the factor structure, psychometric properties, and clinical utility of the Distress Tolerance Scale (DTS) and the short-form version, the Distress Tolerance Scale Short-form (DTS-SF), in a large population of individuals with varying levels of self-reported depressive symptoms. METHOD: A total of 959 participants completed an online battery of questionnaires which included an assessment of depressive symptoms as well as the DTS and related measures. Results: Confirmatory factor analyses validated the four-factor structure of the DTS and the one-factor structure of the DTS-SF. Good construct validity and good internal consistency were observed across both the DTS and DTS-SF. CONCLUSION: Overall, this paper provides new evidence for the validity, reliability and discriminative ability of the DTS and the brief version of the questionnaire, the DTS-SF.

Navigating through perplex morphologic changes after exogenous hormone usage.

Clinical application of exogenous hormone as a method of contraception and/or treatment of various gynecologic disorders is exceedingly common. Unfortunately, the concurrent use of these agents also complicates the interpretation of pathology specimens. Various studies have shown that morphologic changes induced by hormonal therapies are present in both non-neoplastic and neoplastic tissues within the women's reproductive tract. It is important to understand the exogenous hormone induced morphologic changes, as it helps the pathologists make the accurate diagnosis, and in turn, guide clinicians to make optimal clinical decisions. In this review, we summarize the morphologic changes in both neoplastic and non-neoplastic endometrial, cervical, and myometrial surgical specimens after hormonal therapies, particularly after progestin treatment. In the endometrium, particularly in the scenario of progestin-treated atypical endometrial hyperplasia/endometrioid intraepithelial neoplasia (AEH/EIN), there is notoriously poor interobserver agreement and difficulty in assessing for the residual disease. We summarize current literature and propose our recommended approach in assessing these challenging endometrial biopsies, including a diagnostic algorism, the use of PAX-2, PTEN, beta-catenin immunohistochemistry panel, as well as consistency in diagnostic wording of the report. In the cervix, progestin makes dysplastic lesions appear metaplastic, thus high-grade squamous dysplastic lesions may be easily missed. Within the myometrium, lesions such as adenomyosis may show various degree of decidualization, while smooth muscle neoplasms may show apoplectic changes, and stromal lesions including endometrial stromal sarcoma may show more eosinophilic cytoplasm. All such changes may pose more or less diagnostic challenges in our daily practice. However, most are readily recognizable when we understand particular hormone related scenarios.

Takinib Inhibits Inflammation in Human Rheumatoid Arthritis Synovial Fibroblasts by Targeting the Janus Kinase-Signal Transducer and Activator of Transcription 3 (JAK/STAT3) Pathway.

TGF ß-activated kinase 1 (TAK1) is an important participant in inflammatory pathogenesis for diseases such as rheumatoid arthritis (RA) and gouty arthritis. The central position it occupies between the mitogen activated protein kinase (MAPK) and nuclear factor kappa B (NF-κB) pathways makes it an attractive therapeutic target. As this field has developed in recent years, several novel inhibitors have been presented as having specific activity that reduces the TAK1 function either covalently as in the case of 5Z-7-oxozeanol (5Z7O) or reversibly (NG-25). However, the mechanism through which takinib elicits its anti-inflammatory activity remains elusive. While this inhibitor shows great promise, a thorough analysis of its inhibitor function and its potential off-target effects is necessary before addressing its clinical potential or its use in inflammatory conditions. An analysis through Western blot showed an unexpected increase in IL-1ß-induced TAK1 phosphorylation-a prerequisite for and indicator of its functional potential-by takinib while simultaneously demonstrating the inhibition of the JAK/STAT pathway in human rheumatoid arthritis synovial fibroblasts (RASFs) in vitro. In THP-1 monocyte-derived macrophages, takinib again led to the lipopolysaccharide-induced phosphorylation of TAK1 without a marked inhibition of the TAK1 downstream effectors, namely, of c-Jun N-terminal kinase (JNK), phospho-c-Jun, NF-κB phospho-p65 or phospho-IκBα. Taken together, these findings indicate that takinib inhibits inflammation in these cells by targeting multiple signaling pathways, most notably the JAK/STAT pathway in human RASFs.

The data-driven future of high-energy-density physics.

High-energy-density physics is the field of physics concerned with studying matter at extremely high temperatures and densities. Such conditions produce highly nonlinear plasmas, in which several phenomena that can normally be treated independently of one another become strongly coupled. The study of these plasmas is important for our understanding of astrophysics, nuclear fusion and fundamental physics-however, the nonlinearities and strong couplings present in these extreme physical systems makes them very difficult to understand theoretically or to optimize experimentally. Here we argue that machine learning models and data-driven methods are in the process of reshaping our exploration of these extreme systems that have hitherto proved far too nonlinear for human researchers. From a fundamental perspective, our understanding can be improved by the way in which machine learning models can rapidly discover complex interactions in large datasets. From a practical point of view, the newest generation of extreme physics facilities can perform experiments multiple times a second (as opposed to approximately daily), thus moving away from human-based control towards automatic control based on real-time interpretation of diagnostic data and updates of the physics model. To make the most of these emerging opportunities, we suggest proposals for the community in terms of research design, training, best practice and support for synthetic diagnostics and data analysis.