Validation of PATHFx 2.0: An open-source tool for estimating survival in patients undergoing pathologic fracture fixation

Treatment decisions in patients with metastatic bone disease rely on accurate survival estimation. We developed the original PATHFx models using expensive, proprietary software and now seek to provide a more cost-effective solution. Using open-source machine learning software to create PATHFx version 2.0, we asked whether PATHFx 2.0 could be created using open-source methods and externally validated in two unique patient populations. The training set of a well-characterized, database records of 189 patients and the bnlearn package within R Version 3.5.1 (R Foundation for Statistical Computing), was used to establish a series of Bayesian belief network models designed to predict survival at 1, 3, 6, 12, 18, and 24 months. Each was externally validated in both a Scandinavian (n = 815 patients) and a Japanese (n = 261 patients) data set. Brier scores and receiver operating characteristic curves to assessed discriminatory ability. Decision curve analysis (DCA) evaluated whether models should be used clinically. DCA showed that the model should be used clinically at all time points in the Scandinavian data set. For the 1-month time point, DCA of the Japanese data set suggested to expect better outcomes assuming all patients will survive greater than 1 month. Brier scores for each curve demonstrate that the models are accurate at each time point. Statement of Clinical Significance: we successfully transitioned to PATHFx 2.0 using open-source software and externally validated it in two unique patient populations, which can be used as a cost-effective option to guide surgical decisions in patients with metastatic bone disease.     

Vesicoureteral reflux diagnosed in adulthood. Incidence of urinary tract infections, hypertension, proteinuria, back pain and renal calculi

Study purpose: To determine the incidence of urinary tract infections, hypertension, back pain, and renal calculi in adult patients with vesicoureteral reflux and reflux nephropathy. Methods: A group of 115 patients (16-60 years of age, median 28 years) with vesicoureteral reflux, combined with reflux nephropathy in 101 patients, first detected between 1967 and 1984, was studied retrospectively. The group comprised 99 women and 16 men. Results: Symptoms and findings associated with the urinary tract preceded the diagnosis of vesicoureteral reflux by median 14 years (1-60 years). Intravenous pyelography preceded investigation with micturating cystography in 99 patients. Fifteen patients had no urinary tract infections, 17 patients had only lower urinary tract infections, and 83 patients had upper with or without lower urinary tract infections. Females had 12 times more lower and seven times more upper urinary tract infections than males, whereas males had impairment of renal function and proteinuria more often than females. Hypertension was present in 39 patients (34%) and five times more frequent in patients with bilateral than in those with unilateral reflux nephropathy. The median age at the first recording of hypertension was 33 years (16-60 years). Malignant hypertension was uncommon and occurred in two patients. An older group (>45 years of age at presentation) of 19 patients showed a 90% incidence of hypertension compared with 23% in 96 patients in the younger group (⩽45 years of age at presentation). Back pain of varying type and severity was present in 48 patients (42%). A total of 38 renal calculi was found in 21 (18%) patients, of whom 14 were completely asymptomatic. Conclusions: The natural history of vesicoureteral reflux first detected in adulthood has shown a strikingly high incidence of urinary tract infections, arterial hypertension, back pain, and renal calculi.     

Perceived symptoms and quality of life in women with breast cancer receiving radiation therapy.

The purpose of this study was to describe symptoms, side-effects and quality of life (QoL) of women with breast cancer during and following treatment with radiation therapy. The sample consisted of 134 women with breast cancer. Symptoms were measured using a modified version of the Oncology Treatment Toxicity Tool (OTTAT) and QoL was measured using the Cancer Rehabilitation Evaluation System-short form (CARES-sf). The results showed an increase in experienced symptoms and their severity as the treatment progressed. QoL was perceived as poorest at baseline before treatment had started. During the treatment, QoL scores leveled out and an improvement could be seen after completion of treatment. The study findings provide directions and suggestions for assessment and management of perceived symptoms for women receiving radiation therapy for breast cancer from the second week and up to 2 weeks after completion of therapy is the critical time-period for targeting interventions for experienced symptoms and side-effects from radiation therapy.     

Muscle alkali-soluble protein, carnitine, water and electrolytes in patients with persistent post-operative infection

The muscle contents of water, electrolytes, creatine, alkali-soluble protein (ASP) and carnitine were determined using percutaneous muscle biopsy technique. Seven patients with prolonged catabolic states and subsequent respiratory failure were studied. Twelve age- and sex-matched healthy subjects were used for comparison. The muscle content of alkali-soluble protein in relation to the content of DNA was less than half of control values, indicating a loss of more than 50% of muscle protein content. The muscle carnitine content was 25.9 +/- 6.5 mumol/g alkali-soluble protein, suggesting a preserved muscle carnitine concentration. Total muscle water was increased by over 20%, mainly due to an increase in extracellular water. Muscle sodium and chloride contents were doubled. The content of magnesium was slightly reduced but muscle potassium was normal. The marked depletion of muscle protein may have contributed to the requirements for artificial ventilation and the difficulties in weaning off the ventilator. The increase in muscle water masks the loss of metabolically active muscle tissue yielding low values for energy expenditure when relating to body weight. The benefit of the use of the ASP/DNA ratio in nutritional assessment is emphasised.     

Effect of carnitine supplemented TPN on turnover and muscle utilisation of free fatty acids in patients with persistent post-operative infection

The effect of L-carnitine on FFA turnover and regional utilisation over the leg was investigated using infusion of (14)C-oleic acid and measurement of the respiratory quotient (RQ) in eight artificially ventilated patients with severe post-operative infection and at least 2 weeks of carnitine free TPN. Carnitine or placebo was added to the daily infusion of lipid during two consecutive 4-day periods in a randomised cross-over fashion. The total dose of carnitine was 110 mg/kg over 4 days. Before carnitine supplementation, total plasma carnitine levels ranged between 39 and 152 mumol/l. The RQ was 0.87 +/- 0.02 (SEM). The turnover (185 +/- 64 mumol/min) and fractional turnover (0.39 +/- 0.04/min) of oleic acid as well as the uptake (31 +/- 10 mumol/min) and fractional uptake (0.46 +/- 0.05) over the leg were similar to previously reported values in healthy subjects. Carnitine supplementation, despite a doubling of the average plasma carnitine level, did not influence the RQ or the whole body turnover and regional exchange of oleic acid. The present results suggest that four days of carnitine supplementation in patients with persistent post-operative infection has no measurable effect on FFA utilisation, indicating that the patients' carnitine reserves were sufficient to maintain normal FFA utilisation.     

Tumour necrosis factor-alpha potentiates CR3-induced respiratory burst by activating p38 MAP kinase in human neutrophils

CR3 and Fc gamma Rs are the main receptors involved in the phagocytic process leading to engulfment and killing of microbes by production of reactive oxygen intermediates (ROI) and degranulation. Various inflammatory mediators, such as tumour necrosis factor-alpha (TNF-alpha) and lipopolysaccharide (LPS), are known to prime neutrophils leading to increased bactericidal responses, but the underlying mechanism of priming has only been partially elucidated. The purpose of this study was to investigate how TNF-alpha primes neutrophils for subsequent stimuli via either CR3 or Fc gamma R. The receptors were specifically activated with pansorbins (protein-A-positive Staphylococcus aureus) coated with anti-CR3, anti-Fc gamma RIIa, or anti-Fc gamma RIIIb monoclonal antibody. Activation of neutrophils with these particles resulted in ROI production as measured by chemiluminescence. Anti-CR3 pansorbins induced the most prominent ROI production in neutrophils. TNF-alpha potentiated the CR3-mediated respiratory burst but had little effect on that mediated by Fc gamma Rs. The priming effect of TNF-alpha on CR3-mediated ROI production is associated with an increased activation of p38 MAPK as well as tyrosine phosphorylation of p72(syk). Pretreatment of neutrophils with the inhibitors for p38 MAPK and p72(syk) markedly suppressed the respiratory burst induced by CR3. Furthermore, TNF-alpha induced about a three-fold increase in the expression of CR3 in neutrophils, an effect which is blocked by the p38 MAPK inhibitor. Taken together, these results showed that TNF-alpha potentiates the CR3-mediated respiratory burst in neutrophils not only by triggering a p38 MAPK-dependent up-regulation of CD11b/CD18 but also by modulating the signalling pathways.