Tibial plateau fractures in older adults are associated with a clinically significant deterioration in health-related quality of life

Aims To investigate health-related quality of life (HRQoL) of older adults (aged ≥ 60 years) after tibial plateau fracture (TPF) compared to preinjury and population matched values, and what aspects of treatment were most important to patients. Methods We undertook a retrospective, case-control study of 67 patients at mean 3.5 years (SD 1.3; 1.3 to 6.1) after TPF (47 patients underwent fixation, and 20 nonoperative management). Patients completed EuroQol five-dimension three-level (EQ-5D-3L) questionnaire, Lower Limb Function Scale (LEFS), and Oxford Knee Scores (OKS) for current and recalled prefracture status. Propensity score matching for age, sex, and deprivation in a 1:5 ratio was performed using patient level data from the Health Survey for England to obtain a control group for HRQoL comparison. The primary outcome was the difference in actual (TPF cohort) and expected (matched control) EQ-5D-3L score after TPF. Results TPF patients had a significantly worse EQ-5D-3L utility (mean difference (MD) 0.09, 95% confidence interval (CI) 0.00 to 0.16; p &lt; 0.001) following their injury compared to matched controls, and had a significant deterioration (MD 0.140, 95% CI 0 to 0.309; p &lt; 0.001) relative to their preoperative status. TPF patients had significantly greater pre-fracture EQ-5D-3L scores compared to controls (p = 0.003), specifically in mobility and pain/discomfort domains. A decline in EQ-5D-3L greater than the minimal important change of 0.105 was present in 36/67 TPF patients (53.7%). Following TPF, OKS (MD -7; interquartile range (IQR)-1 to-15) and LEFS (MD -10; IQR -2 to -26) declined significantly (p &lt; 0.001) from pre-fracture levels. Of the 12 elements of fracture care assessed, the most important to patients were getting back to their own home, having a stable knee, and returning to normal function. Conclusion TPFs in older adults were associated with a clinically significant deterioration in HRQoL compared to preinjury level and age, sex, and deprivation matched controls for both undisplaced fractures managed nonoperatively and displaced or unstable fractures managed with internal fixation.</p

The Importance of Grey and Qualitative Literature in Developing Domestic Violence and Abuse and Child Maltreatment Core Outcome Sets: A Brief Report

Purpose: Core Outcome Sets (COS) are agreed sets of outcomes to be used in all trials that evaluate the effect of interventions. This report considers the added value of including grey and qualitative literature in a study to identify COSs of family-focused interventions for CM and DVA. / Methods: We identified outcomes of interventions for DVA or CM through systematically searching 12 academic databases and 86 organisation websites, leading to the inclusion of 485 full-text reports across 6 reviews. We developed a candidate outcome longlist comprising 347 extracted outcomes. / Results: We identified 87% (282/347) of candidate outcomes from the grey and qualitative literature, and 37% (127/347) from the trial literature. Of the candidate outcomes on the longlist, 22% (75/347) were identified solely from the grey or qualitative literature and 7% (26/347) from trial literature. Three of the eight outcomes in the final core outcome sets may have been missed if grey or qualitative literature had not been searched. / Conclusions: The qualitative and grey literature adds DVA and CM outcomes that are relevant to survivor perspectives but not reported in trials; this had an impact on the final COSs. It is important for COS developers to consider what they may be missing if they do not search the qualitative and grey literature

Tibial plateau fractures in older adults are associated with a clinically significant deterioration in health-related quality of life: a propensity score matched study

Aims To investigate health-related quality of life (HRQoL) of older adults (aged ≥ 60 years) after tibial plateau fracture (TPF) compared to preinjury and population matched values, and what aspects of treatment were most important to patients. Methods We undertook a retrospective, case-control study of 67 patients at mean 3.5 years (SD 1.3; 1.3 to 6.1) after TPF (47 patients underwent fixation, and 20 nonoperative management). Patients completed EuroQol five-dimension three-level (EQ-5D-3L) questionnaire, Lower Limb Function Scale (LEFS), and Oxford Knee Scores (OKS) for current and recalled prefracture status. Propensity score matching for age, sex, and deprivation in a 1:5 ratio was performed using patient level data from the Health Survey for England to obtain a control group for HRQoL comparison. The primary outcome was the difference in actual (TPF cohort) and expected (matched control) EQ-5D-3L score after TPF. Results TPF patients had a significantly worse EQ-5D-3L utility (mean difference (MD) 0.09, 95% confidence interval (CI) 0.00 to 0.16; p &lt; 0.001) following their injury compared to matched controls, and had a significant deterioration (MD 0.140, 95% CI 0 to 0.309; p &lt; 0.001) relative to their preoperative status. TPF patients had significantly greater pre-fracture EQ-5D-3L scores compared to controls (p = 0.003), specifically in mobility and pain/discomfort domains. A decline in EQ-5D-3L greater than the minimal important change of 0.105 was present in 36/67 TPF patients (53.7%). Following TPF, OKS (MD -7; interquartile range (IQR) -1 to -15) and LEFS (MD -10; IQR -2 to -26) declined significantly (p &lt; 0.001) from pre-fracture levels. Of the 12 elements of fracture care assessed, the most important to patients were getting back to their own home, having a stable knee, and returning to normal function. Conclusion TPFs in older adults were associated with a clinically significant deterioration in HRQoL compared to preinjury level and age, sex, and deprivation matched controls for both undisplaced fractures managed nonoperatively and displaced or unstable fractures managed with internal fixation. <br/

Functional assessment of gap junctions in monolayer and three-dimensional cultures of human tendon cells using fluorescence recovery after photobleaching

Gap junction-mediated intercellular communication influences a variety of cellular activities. In tendons, gap junctions modulate collagen production, are involved in strain-induced cell death, and are involved in the response to mechanical stimulation. The aim of the present study was to investigate gap junction-mediated intercellular communication in healthy human tendon-derived cells using fluorescence recovery after photobleaching (FRAP). The FRAP is a noninvasive technique that allows quantitative measurement of gap junction function in living cells. It is based on diffusion-dependent redistribution of a gap junction-permeable fluorescent dye. Using FRAP, we showed that human tenocytes form functional gap junctions in monolayer and three-dimensional (3-D) collagen I culture. Fluorescently labeled tenocytes following photobleaching rapidly reacquired the fluorescent dye from neighboring cells, while HeLa cells, which do not communicate by gap junctions, remained bleached. Furthermore, both 18 β-glycyrrhetinic acid and carbenoxolone, standard inhibitors of gap junction activity, impaired fluorescence recovery in tendon cells. In both monolayer and 3-D cultures, intercellular communication in isolated cells was significantly decreased when compared with cells forming many cell-to-cell contacts. In this study, we used FRAP as a tool to quantify and experimentally manipulate the function of gap junctions in human tenocytes in both two-dimensional (2-D) and 3-D cultures

High potential for weathering and climate effects of non-vascular vegetation in the Late Ordovician

It has been hypothesized that predecessors of today’s bryophytes significantly increased global chemical weathering in the Late Ordovician, thus reducing atmospheric CO2 concentration and contributing to climate cooling and an interval of glaciations. Studies that try to quantify the enhancement of weathering by non-vascular vegetation, however, are usually limited to small areas and low numbers of species, which hampers extrapolating to the global scale and to past climatic conditions. Here we present a spatially explicit modelling approach to simulate global weathering by non-vascular vegetation in the Late Ordovician. We estimate a potential global weathering flux of 2.8 (km3 rock) yr−1, defined here as volume of primary minerals affected by chemical transformation. This is around three times larger than today’s global chemical weathering flux. Moreover, we find that simulated weathering is highly sensitive to atmospheric CO2 concentration. This implies a strong negative feedback between weathering by non-vascular vegetation and Ordovician climate

HVPE growth and characterization of GaP on different substrates and patterned templates for frequency conversion devices

This article describes efforts to achieve fast deposition of thick Quasi-Phase-Matched (QPM) GaP structures with high surface and structural quality on oriented patterned (OP) templates in a Hydride Vapor Phase Epitaxial (HVPE) process. These QPM structures will be incorporated in devices for conversion of frequencies from the near infrared to the mid infrared and THz regions, where powerful and tunable sources are in great demand for both military and civilian applications. In contrast with GaAs—the most studied OP QPM material—the two-photon absorption of GaP is predicted to be extremely low, which allows pumping with a number of convenient sources between 1 – 1.7 µm. Unpatterned GaP layers up to 370 µm thick were grown with growth rates up to 93 µm/hr with high reproducibility on bare substrates. The layers demonstrated smooth surface morphology with RMS < 1 nm and high structural quality with FWHM equal to 39 arcsec for layers grown on GaP and 112 arcsec for those grown on GaAs. Growth on OP-GaP templates resulted in 142 µm thick QPM structures deposited at a growth rate of 71 µm/h with good vertical (normal to the layer surface) propagation of the initial pattern. When the growth was performed on OP-GaAs one of the domains showed a trend toward a faceting growth. Further investigations are in progress to equalize the vertical and lateral growth of the two domains, and determine the best orientation of the substrate and pattern in order to achieve structures thick enough for high power nonlinear applications

Regulation of pH by Carbonic Anhydrase 9 Mediates Survival of Pancreatic Cancer Cells With Activated KRAS in Response to Hypoxia.

Background & Aims Most pancreatic ductal adenocarcinomas (PDACs) express an activated form of KRAS, become hypoxic and dysplastic, and are refractory to chemo and radiation therapies. To survive in the hypoxic environment, PDAC cells upregulate enzymes and transporters involved in pH regulation, including the extracellular facing carbonic anhydrase 9 (CA9). We evaluated the effect of blocking CA9, in combination with administration of gemcitabine, in mouse models of pancreatic cancer. Methods We knocked down expression of KRAS in human (PK-8 and PK-1) PDAC cells with small hairpin RNAs. Human and mouse (KrasG12D/Pdx1-Cre/Tp53/RosaYFP) PDAC cells were incubated with inhibitors of MEK (trametinib) or extracellular signal-regulated kinase (ERK), and some cells were cultured under hypoxic conditions. We measured levels and stability of the hypoxia-inducible factor 1 subunit alpha (HIF1A), endothelial PAS domain 1 protein (EPAS1, also called HIF2A), CA9, solute carrier family 16 member 4 (SLC16A4, also called MCT4), and SLC2A1 (also called GLUT1) by immunoblot analyses. We analyzed intracellular pH (pHi) and extracellular metabolic flux. We knocked down expression of CA9 in PDAC cells, or inhibited CA9 with SLC-0111, incubated them with gemcitabine, and assessed pHi, metabolic flux, and cytotoxicity under normoxic and hypoxic conditions. Cells were also injected into either immune-compromised or immune-competent mice and growth of xenograft tumors was assessed. Tumor fragments derived from patients with PDAC were surgically ligated to the pancreas of mice and the growth of tumors was assessed. We performed tissue microarray analyses of 205 human PDAC samples to measure levels of CA9 and associated expression of genes that regulate hypoxia with outcomes of patients using the Cancer Genome Atlas database. Results Under hypoxic conditions, PDAC cells had increased levels of HIF1A and HIF2A, upregulated expression of CA9, and activated glycolysis. Knockdown of KRAS in PDAC cells, or incubation with trametinib, reduced the posttranscriptional stabilization of HIF1A and HIF2A, upregulation of CA9, pHi, and glycolysis in response to hypoxia. CA9 was expressed by 66% of PDAC samples analyzed; high expression of genes associated with metabolic adaptation to hypoxia, including CA9, correlated with significantly reduced survival times of patients. Knockdown or pharmacologic inhibition of CA9 in PDAC cells significantly reduced pHi in cells under hypoxic conditions, decreased gemcitabine-induced glycolysis, and increased their sensitivity to gemcitabine. PDAC cells with knockdown of CA9 formed smaller xenograft tumors in mice, and injection of gemcitabine inhibited tumor growth and significantly increased survival times of mice. In mice with xenograft tumors grown from human PDAC cells, oral administration of SLC-0111 and injection of gemcitabine increased intratumor acidosis and increased cell death. These tumors, and tumors grown from PDAC patient-derived tumor fragments, grew more slowly than xenograft tumors in mice given control agents, resulting in longer survival times. In KrasG12D/Pdx1-Cre/Tp53/RosaYFP genetically modified mice, oral administration of SLC-0111 and injection of gemcitabine reduced numbers of B cells in tumors. Conclusions In response to hypoxia, PDAC cells that express activated KRAS increase expression of CA9, via stabilization of HIF1A and HIF2A, to regulate pH and glycolysis. Disruption of this pathway slows growth of PDAC xenograft tumors in mice and might be developed for treatment of pancreatic cancer

Paroxetine in human milk

Aims The primary aims of the study were to estimate the exposure of infants to paroxetine via breast milk and to determine the maternal milk:plasma ratio (M/P) of paroxetine. Secondary aims were to compare single point and area under the curve (AUC) estimates of M/P, to assess variability of M/P in fore and hind milk, and to compare the observed M/P with that predicted by a model. Methods Two studies were performed. In one study, six nursing mothers who were being treated with paroxetine were studied over a 24 h dose interval at steady-state. The total amount of paroxetine in the milk was measured, which represented the &apos;dose&apos; to the infant. The M/P AUC was calculated and compared with a predicted value. In the second study, four nursing mothers who were being treated with paroxetine, were studied at steady-state, around a normal infant feeding time. A single plasma sample and a prefeed milk sample were taken approximately 3 h after the morning dose of paroxetine, and a postfeed milk sample taken around 1 h later. The dose received by the infant was estimated from the average milk concentrations of the pre and postfeed samples using standard assumptions, and M/P calculated directly. Plasma concentrations of paroxetine were measured in 8 of the 10 infants in the two studies. Results The mean dose of paroxetine received by the infants in the first study was 1.13% (range 0.5-1.7) of the weight adjusted maternal dose. The mean M/P AUC was 0.39 (range 0.32-0.51). The predicted M/P was 0.22. The mean dose of paroxetine received by the infants in the second study was 1.25% (range 0.38-2.24) of the weight adjusted maternal dose. The mean M/P was 0.96 (range 0.31-3.33) and did not differ between fore and hind milk. The drug was not detected in the plasma of seven of the infants studied and was detected but not quantifiable (&lt;4 mg l −1 ) in one infant. No adverse effects were observed in any of the infants. Conclusions Measured M/P and estimated infant dose were similar in the two studies, although the range was wider for the single point study. Paroxetine can be considered &apos;safe&apos; during breast feeding because the dose transferred to the infant is well below the recommended safety limit of 10% of the weight adjusted maternal dose, concentrations in the infants were generally undetectable, and no adverse effects were reported

Implementing natural capital credit risk assessment in agricultural lending

Agriculture has critical impacts and dependencies on natural capital, and agriculturallenders are therefore exposed to natural capital credit risk through their loans tofarmers. Currently, however, lenders lack any detailed guidance for assessing naturalcapital credit risk in agriculture and are challenged by the fact that the relevant material risks vary considerably by agricultural sector and geography. This paper developsa natural capital credit risk assessment framework based on a bottom‐up review ofthe material risks associated with natural capital impacts and dependencies forAustralian beef production. It demonstrates that implementing natural capital creditrisk assessment is feasible in agricultural lending, using a combination of quantitativeand qualitative inputs. Implementation challenges include the complexity and interconnectedness of natural capital processes, data availability and cost, spatial data analytical capacity, and the need for transformational change, both within lendingorganisations and across the banking sector

Immunogenomic profiling determines responses to combined PARP and PD-1 inhibition in ovarian cancer

Combined PARP and immune checkpoint inhibition has yielded encouraging results in ovarian cancer, but predictive biomarkers are lacking. We performed immunogenomic profiling and highly multiplexed single-cell imaging on tumor samples from patients enrolled in a Phase I/II trial of niraparib and pembrolizumab in ovarian cancer (NCT02657889). We identify two determinants of response; mutational signature 3 reflecting defective homologous recombination DNA repair, and positive immune score as a surrogate of interferon-primed exhausted CD8+T-cells in the tumor microenvironment. Presence of one or both features associates with an improved outcome while concurrent absence yields no responses. Single-cell spatial analysis reveals prominent interactions of exhausted CD8+T-cells and PD-L1+macrophages and PD-L1+tumor cells as mechanistic determinants of response. Furthermore, spatial analysis of two extreme responders shows differential clustering of exhausted CD8+T-cells with PD-L1+macrophages in the first, and exhausted CD8+T-cells with cancer cells harboring genomic PD-L1 and PD-L2 amplification in the second. A Phase I/II trial previously revealed variable anti-tumor efficacy of the PARP inhibitor niraparib in combination with the PD-1 inhibitor pembrolizumab in platinum-resistant ovarian cancer patients. Here, the authors perform an integrated genomic and immunomics analysis of tumor samples from the same patients and find potential predictive biomarkers of response to such combination therapy.Peer reviewe