Patients' perceptions and experiences of the prevention of hospital-acquired thrombosis : a qualitative study

Objective To examine patients' understanding of hospital-associated thrombosis, and their experiences of thromboprophylaxis. Design Qualitative study using semi-structured interviews with 31 patients requiring venous thromboembolism (VTE) prophylaxis following a recent hospital admission. Interviews were audio-recorded, transcribed verbatim and analysed thematically using framework analysis. Setting 4 hospitals in Birmingham and Oxford. Results All the participants received thromboprophylaxis following surgical procedures. Participants were aware of a risk of blood clots; however, they lacked a good understanding of VTE and its components. Experiences of VTE prophylaxis were characterised with good adherence to heparin injections and poor adherence to elastic compression stockings, largely due to perceived lack of clarity in guidance from health professionals. Participants had limited knowledge of the signs and symptoms of VTE and would value improved education on VTE. Conclusions Findings suggest that patient education is often inadequate and impacts negatively on patients' involvement in VTE prevention. An enhanced patient education programme incorporating a consistent message on the appropriate use of elastic compression stockings and description of VTE symptoms is likely to optimise the effectiveness of the prevention of hospital-associated thrombosis. Physicians may use the results of this study to improve individual patient education

Tracking Cancer Evolution through the Disease Course.

During cancer evolution, constituent tumor cells compete under dynamic selection pressures. Phenotypic variation can be observed as intratumor heterogeneity, which is propagated by genome instability leading to mutations, somatic copy-number alterations, and epigenomic changes. TRACERx was set up in 2014 to observe the relationship between intratumor heterogeneity and patient outcome. By integrating multiregion sequencing of primary tumors with longitudinal sampling of a prospectively recruited patient cohort, cancer evolution can be tracked from early- to late-stage disease and through therapy. Here we review some of the key features of the studies and look to the future of the field. SIGNIFICANCE: Cancers evolve and adapt to environmental challenges such as immune surveillance and treatment pressures. The TRACERx studies track cancer evolution in a clinical setting, through primary disease to recurrence. Through multiregion and longitudinal sampling, evolutionary processes have been detailed in the tumor and the immune microenvironment in non-small cell lung cancer and clear-cell renal cell carcinoma. TRACERx has revealed the potential therapeutic utility of targeting clonal neoantigens and ctDNA detection in the adjuvant setting as a minimal residual disease detection tool primed for translation into clinical trials

An Inverted Mass Hierarchy for Hot Dark Matter and the Solar Neutrino Problem.

The cosmological model in which 20% of the dark matter is shared by two nearly equal mass neutrinos fits the structure of the universe on all scales. This has been motivated a $\nu_\mu$-$\nu_{\tau}$ oscillation explanation of the deficit of atmospheric muon neutrinos. If the observed ratio of atmospheric $nu_\mu$ to $\nu_e$ has an alternative explanation, the cosmological model can be retained if the deficit of solar neutrinos is explained by $\nu_e$-$\nu_{\tau}$ oscillation. In this case an inverted mass hierarchy is required with $m_{\nu_{\mu}}\ll m_{\nu_e} \simeq m_{\nu_\tau}\approx 2.4$ eV. We show that if there exists an $L_e- L_{\tau}$ symmetry in nature, both the near mass degeneracy of \nue\ and \nut\ as well as the consistency of the above values for neutrino masses with the negative results for neutrinoless double beta decay search experiments are easily understood. We show that this symmetry implemented in the context of a high-scale left-right symmetric theory with the see-saw mechanism can lead to a simple theoretical understanding of the desired form of the mass matrix.Comment: Tex file; no figures; 10 page

Rare disruptive mutations in ciliary function genes contribute to testicular cancer susceptibility

Testicular germ cell tumour (TGCT) is the most common cancer in young men. Here we sought to identify risk factors for TGCT by performing whole-exome sequencing on 328 TGCT cases from 153 families, 634 sporadic TGCT cases and 1,644 controls. We search for genes that are recurrently affected by rare variants (minor allele frequency <0.01) with potentially damaging effects and evidence of segregation in families. A total of 8.7% of TGCT families carry rare disruptive mutations in the cilia-microtubule genes (CMG) as compared with 0.5% of controls (P=2.1 × 10¯⁸). The most significantly mutated CMG is DNAAF1 with biallelic inactivation and loss of DNAAF1 expression shown in tumours from carriers. DNAAF1 mutation as a cause of TGCT is supported by a dnaaf1hu²⁵⁵h(+/−) zebrafish model, which has a 94% risk of TGCT. Our data implicate cilia-microtubule inactivation as a cause of TGCT and provide evidence for CMGs as cancer susceptibility genes

Mesothelial Cell HIF1 alpha Expression Is Metabolically Downregulated by Metformin to Prevent Oncogenic Tumor-Stromal Crosstalk

The tumor microenvironment (TME) plays a pivotal role in cancer progression, and, in ovarian cancer (OvCa), the primary TME is the omentum. Here, we show that the diabetes drug metformin alters mesothelial cells in the omental microenvironment. Metformin interrupts bidirectional signaling between tumor and mesothelial cells by blocking OvCa cell TGF-beta signaling and mesothelial cell production of CCL2 and IL-8. Inhibition of tumor-stromal crosstalk by metformin is caused by the reduced expression of the tricarboxylic acid (TCA) enzyme succinyl CoA ligase (SUCLG2). Through repressing this TCA enzyme and its metabolite, succinate, metformin activated prolyl hydroxylases (PHDs), resulting in the degradation of hypoxia-inducible factor 1 alpha (HIF1 alpha) in mesothelial cells. Disruption of HIF1 alpha-driven IL-8 signaling in mesothelial cells by metformin results in reduced OvCa invasion in an organotypic 3D model. These findings indicate that tumor-promoting signaling between mesothelial and OvCa cells in the TME can be targeted using metformin

Caspase 3 cleavage of Pax7 inhibits self-renewal of satellite cells

Compensatory growth and regeneration of skeletal muscle is dependent on the resident stem cell population, satellite cells (SCs). Self-renewal and maintenance of the SC niche is coordinated by the paired-box transcription factor Pax7, and yet continued expression of this protein inhibits the myoblast differentiation program. As such, the reduction or removal of Pax7 may denote a key prerequisite for SCs to abandon self-renewal and acquire differentiation competence. Here, we identify caspase 3 cleavage inactivation of Pax7 as a crucial step for terminating the self-renewal process. Inhibition of caspase 3 results in elevated Pax7 protein and SC self-renewal, whereas caspase activation leads to Pax7 cleavage and initiation of the myogenic differentiation program. Moreover, in vivo inhibition of caspase 3 activity leads to a profound disruption in skeletal muscle regeneration with an accumulation of SCs within the niche. We have also noted that casein kinase 2 (CK2)-directed phosphorylation of Pax7 attenuates caspase-directed cleavage. Together, these results demonstrate that SC fate is dependent on opposing posttranslational modifications of the Pax7 protein

Volume Characteristics of Landslides Triggered by the MW 7.8 2016 Kaikōura Earthquake, New Zealand, Derived From Digital Surface Difference Modeling

We use a mapped landslide inventory coupled with a 2‐m resolution vertical difference model covering an area of 6,875 km2 to accurately constrain landslide volume‐area relationships. We use the difference model to calculate the source volumes for landslides triggered by the MW 7.8 Kaikōura, New Zealand, earthquake of 14 November 2016. Of the 29,519 mapped landslides in the inventory, 28,394 are within the analysis area, and of these, we have calculated the volume of 17,256 source areas that are ≥90% free of debris. Of the 28,394 landslides, about 80% are classified as soil or rock avalanches and the remainder as mainly translational slides. Our results show that both the soil avalanches and the rock avalanches, ignoring their source geology, have area to volume power‐law scaling exponents (γ) of 0.921 to 1.060 and 1.040 to 1.138, respectively. These are lower than the γ values of 1.1–1.3 (for soil) and 1.3–1.6 (for rock) reported in the literature for undifferentiated landslide types. They are, however, similar to those γ values estimated from other coseismic landslide inventories. In contrast, for 50 selected rotational, translational (planar slide surfaces), or compound slides, where much of the debris remains in the source area, we found γ values range between 1.46 and 1.47, indicating that their slide surfaces were considerably deeper than those landslides classified as avalanches. This study, like previous studies on coseismic landslides, shows that soil and rock avalanches (disrupted landslides) are the dominant landslide type triggered by earthquakes and that they tend to be shallow.Key PointsWe use a 2‐m resolution vertical difference model to estimate source volumes for 17,256 landslides with sources ≥90% free of debris triggered by the MW7.8 2016 Kaikōura EarthquakeThe model was derived by subtracting a tectonically adjusted pre‐EQ surface model from a post‐EQ model, covering an area of 6,875 km2Landslide trigger mechanism, type/failure mode, and source material are critical for accurate estimation of landslide volumes from source‐area geometriesPeer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/156166/2/jgrf21176.pdfhttp://deepblue.lib.umich.edu/bitstream/2027.42/156166/1/jgrf21176_am.pd

Total knee replacement after high tibial osteotomy: Time-to-event analysis and predictors

© 2021 Joule Inc. or its licensors. BACKGROUND: An important aim of high tibial osteotomy (HTO) is to prevent or delay the need for total knee replacement (TKR). We sought to estimate the frequency and timing of conversion from HTO to TKR and the factors associated with it. METHODS: We prospectively evaluated patients with osteoarthritis (OA) of the knee who underwent medial opening wedge HTO from 2002 to 2014 and analyzed the cumulative incidence of TKR in July 2019. The presence or absence of TKR on the HTO limb was identified from the orthopedic surgery reports and knee radiographs contained in the electronic medical records for each patient at London Health Sciences Centre. We used cumulative incidence curves to evaluate the primary outcome of time to TKR. We used multivariable Cox proportional hazards analysis to assess potential preoperative predictors including radiographic disease severity, malalignment, correction size, pain, sex, age, body mass index (BMI) and year of surgery. RESULTS: Among 556 patients who underwent 643 HTO procedures, the cumulative incidence of TKR was 5% (95% confidence interval [CI] 3%–7%) at 5 years and 21% (95% CI 17%–26%) at 10 years. With the Cox proportional hazards multivariable model, the following preoperative factors were significantly associated with an increased rate of conversion: radiographic OA severity (adjusted hazard ratio [HR] 1.96, 95% CI 1.12–3.45), pain (adjusted HR 0.85, 95% CI 0.75–0.96)], female sex (adjusted HR 1.67, 95% CI 1.08–2.58), age (adjusted HR 1.50 per 10 yr, 95% CI 1.17–1.93) and BMI (adjusted HR 1.31 per 5 kng/m2, 95% CI 1.12–1.53). INTERPRETATION: We found that 79% of knees did not undergo TKR within 10 years after undergoing medial opening wedge HTO. The strongest predictor of conversion to TKR is greater radiographic disease at the time of HTO