Mixtures of co-occurring chemicals in freshwater systems across the continental US.

Trace chemicals are common in marine and freshwater ecosystems globally. It is recognized that in the environment, individual chemicals are rarely found in isolation. Insufficient work has examined which chemicals co-occur and which methods best identify these mixtures. Using an existing data set, we found evidence that simple correlation analysis is better at identifying mixtures of commonly co-occurring trace chemicals than more commonly used PCA methods. Moreover, simple correlation analysis, unlike PCA, can be used in cases with unbalanced designs and with data points below reportable limits. Application of this approach allowed identification of 10 groups of chemicals commonly found together in freshwaters of the continental US, representing common "chemical syndromes." Better identification of co-occurring chemical combinations could aid in our understanding of biological and ecological effects of aquatic contaminants. This research provides evidence of correlation analyses as a more effective method for identifying commonly co-occurring aquatic contaminants. We also examined the patterns of these mixtures with a dataset consisting of concentrations of 406 trace chemicals from 38 sample locations across the continental US.

Overnight auto-adjusting continuous airway pressure + standard care compared with standard care alone in the prevention of morbidity in sickle cell disease phase II (POMS2b): study protocol for a randomised controlled trial.

BACKGROUND: In addition to pain, sickle cell anaemia (HbSS) complications include neurocognitive difficulties in attention and processing speed associated with low daytime and night-time oxygen saturation compounded by obstructive sleep apnoea (OSA). In the general population OSA is treated with continuous positive airways pressure (CPAP). The aim of this single-blind, randomised, controlled phase II trial is to compare auto-adjusting CPAP (APAP) with standard care to standard care alone in individuals with HbSS to determine whether the intervention improves attention and processing speed, brain structure, pain and quality of life. METHODS/DESIGN: Eligibility criteria include: ability to provide informed consent; age > 8 years; diagnosis of HbSS; and mean overnight saturation of < 90% for < 30% of the night (i.e. not meeting current criteria for overnight oxygen therapy). Key exclusion criteria are: overnight respiratory support; respiratory or decompensated cardiac failure; chronic transfusion; or contraindications to APAP therapy or magnetic resonance imaging (MRI). Sixty individuals with HbSS (30 children and 30 adults) will be randomised to standard care + APAP or standard care alone for six months. Minimisation factors are: age group (8-11, 12-15, 16-22 and > 23 years); silent infarction on MRI; minimum overnight oxygen saturation > 90% or < 90%; and hydroxyurea use. For APAP individuals, the intervention is administered at home. Adherence and effectiveness are recorded using software documenting hours of use each night and overnight oximetry. Participant support in terms of appropriate facemask and facilitating adherence are provided by an unblinded sleep physiologist. The primary outcome is change in the cancellation subtest from the Wechsler scales. Secondary outcomes include general cognitive functioning, quantitative brain MRI, blood and urine chemistry, quality of life and daily pain via a smartphone App (GoMedSolutions, Inc) and, where possible MRI heart, echocardiography, and 6-min walk. These outcomes will be assessed at baseline and after six months of treatment by assessors blind to treatment assignment. DISCUSSION: Altering oxygen saturation in HbSS may lead to bone marrow suppression. This risk will be reduced by monitoring full blood counts at baseline, two weeks, three months and six months, providing treatment as appropriate and reporting as safety events. TRIAL REGISTRATION: ISRCTN46012373 . Registered on 10 July 2015. Protocol Version: 6.0 Date: 24th December 2015 Sponsor: University Hospital Southampton. Sponsor's protocol code: RHMCHIOT53.

Prostate cancer screening in Primary Health Care: the current state of affairs.

This study aims to examine the current practice of General practitioners (GPs)/primary care physicians in opportunistic screening for prostate cancer (PC) by digital rectal examination(DRE) and Prostate Specific Antigen(PSA) testing and identify any difference in screening practice. Printed copies and/or electronic versions of a survey was distributed amongst 438 GPs throughout Australia in 2012. Statistical analyses (Wilcoxon rank-sum test, Fisher's exact test or Pearson chi-square test)were performed by outcomes and GP characteristics.There were a total of 149 responses received (34%), with similar gender distribution in rural and metropolitan settings. 74% GPs believed PSA testing was at least 'somewhat effective' in reducing PC mortality with annual PSA screening being conducted by more GPs in the metropolitan setting compared to the rural GPs (35% vs 18.4%), while 25% of rural GPs would not advocate routine PSA screening. When examining the concordance between DRE and PSA testing by gender of GP, the male GPs reported performing PSA testing more frequently than DRE in patients between ages 40 to 69 (p = 0.011). Urology Society guidelines (77.2%) and College of GPs (73.2%) recommendations for PC screening were thought to be at least 'somewhat useful'. Although reference ranges for PSA tests were felt to be useful, the majority (65.8%) found it easier to refer to an urologist due to the disagreements in guidelines. In conclusion, the current guidelines for PSA screening appear to cause more confusion due to their conflicting advice, leaving GPs to formulate their own practice methods, calling for an urgent need for uniform collaborative guidelines.

Patients' responses to transient ischaemic attack symptoms: a cross-sectional questionnaire study in Australian general practices.

BACKGROUND: Consensus guidelines for transient ischaemic attack (TIA) recommend urgent investigation and management, but delays in management occur and are attributable to patient and health system factors. AIM: To establish general practice patients' anticipated responses to TIA symptoms, and associations of appropriate responses. DESIGN AND SETTING: A cross-sectional questionnaire-based study in Australian general practices. METHOD: Consecutive patients attending general practices completed questionnaires that contained the Stroke Action Test (STAT) adapted for TIA about demographic, health system use, and stroke risk factors. STAT elicits appropriate or inappropriate anticipated responses to 28 symptom complexes. Anticipated actions in-hours and out-of-hours were elicited. Associations of independent variables with adapted-STAT scores were tested with multiple linear regression. RESULTS: There were 854 participants (response rate 76.9%). Urgent healthcare-seeking responses to transient neurological symptoms ranged from 96.8% for right-sided weakness with dysphasia to 59.1% for sudden dizziness. Associations of higher adapted-STAT scores were older age, Indigenous status, previous after-hours services use, self-perception of health as poor, and familiarity with a stroke public awareness campaign. A personal or family history of stroke, smoking status, and time of event (in-hours/out-of-hours) were not significantly associated with adapted-STAT scores. CONCLUSION: Most general practice attendees expressed intentions to seek health care urgently for most symptoms suggestive of TIA, with highest levels of urgency observed in high stroke-risk scenarios. Intentions were not associated with a number of major risk factors for TIA and might be improved by further educational interventions, either targeted or at population level.

Redox state of pentraxin 3 as a novel biomarker for resolution of inflammation and survival in sepsis.

In an endotoxaemic mouse model of sepsis, a tissue-based proteomics approach for biomarker discovery identified long pentraxin 3 (PTX3) as the lead candidate for inflamed myocardium. When the redox-sensitive oligomerization state of PTX3 was further investigated, PTX3 accumulated as an octamer as a result of disulfide-bond formation in heart, kidney, and lung-common organ dysfunctions seen in patients with sepsis. Oligomeric moieties of PTX3 were also detectable in circulation. The oligomerization state of PTX3 was quantified over the first 11 days in critically ill adult patients with sepsis. On admission day, there was no difference in the oligomerization state of PTX3 between survivors and non-survivors. From day 2 onward, the conversion of octameric to monomeric PTX3 was consistently associated with a greater survival after 28 days of follow-up. For example, by day 2 post-admission, octameric PTX3 was barely detectable in survivors, but it still constituted more than half of the total PTX3 in non-survivors (p < 0.001). Monomeric PTX3 was inversely associated with cardiac damage markers NT-proBNP and high-sensitivity troponin I and T. Relative to the conventional measurements of total PTX3 or NT-proBNP, the oligomerization of PTX3 was a superior predictor of disease outcome.

New South Wales and Australian Capital Territory Researcher Development Program 2005-07: modest investment, considerable outcomes.

This evaluation of the Researcher Development Program (RDP) in NSW and ACT aimed to determine whether the RDP was effective in assisting novice researchers to undertake primary health care research. In mid-2008, 47 participants of the NSW and ACT RDP during 2005-07 were invited to participate in a postal survey. The survey included questions regarding previous research training and experience, outcomes during and after participation in the program, and organisational aspects of the program. Follow-up interviews were conducted with selected participants. Interview questions covered time in the program, supervision, organisational support and placement outcomes. Thirty-seven participants responded to the survey and 23 (62%) participants took part in the semi-structured interviews. Seventy-eight per cent of survey respondents felt that the RDP helped them move from novice to a more experienced researcher with effective supervision identified by participants as a key element in determining the success of the program. Many felt that time allocation was inadequate and 20% thought their capacity to maintain their workload was adversely affected by participating. Outcomes were considerable given the modest nature of the program. Notable outcomes were that most participants published their research and presented their research at a conference. Furthermore, one-fifth of survey respondents had enrolled in higher degrees. Several interviewees reported that their research led to changes in practice. Most respondents found the RDP valuable and considered that undertaking the program increased their research knowledge.

Enuresis associated with sleep disordered breathing in children with sickle cell anemia.

PURPOSE: Enuresis and sleep disordered breathing are common among children with sickle cell anemia. We evaluated whether enuresis is associated with sleep disordered breathing in children with sickle cell anemia. MATERIALS AND METHODS: Baseline data were used from a multicenter prospective cohort study of 221 unselected children with sickle cell anemia. A questionnaire was used to evaluate, by parental report during the previous month, the presence of enuresis and its severity. Overnight polysomnography was used to determine the presence of sleep disordered breathing by the number of obstructive apneas and/or hypopneas per hour of sleep. Logistic and ordinal regression models were used to evaluate the association of sleep disordered breathing and enuresis. RESULTS: The mean age of participants was 10.1 years (median 10.0, range 4 to 19). Enuresis occurred in 38.9% of participants and was significantly associated with an obstructive apnea-hypopnea index of 2 or more per hour after adjusting for age and gender (OR 2.19; 95% CI 1.09, 4.40; p = 0.03). Enuresis severity was associated with obstructive apneas and hypopneas with 3% or more desaturation 2 or more times per hour with and without habitual snoring (OR 3.23; 95% CI 1.53, 6.81; p = 0.001 and OR 2.07; 95% CI 1.09, 3.92; p = 0.03, respectively). CONCLUSIONS: In this unselected group of children with sickle cell anemia, sleep disordered breathing was associated with enuresis. Results of this study support that children with sickle cell anemia who present with enuresis should be evaluated by a pulmonologist for sleep disordered breathing.

How generalisable are results of studies conducted in practice-based research networks? A cross-sectional study of general practitioner demographics in two New South Wales networks.

OBJECTIVE: To compare the demographics of general practitioners in two practice-based research networks (PBRNs) and to explore the generalisability of research findings from these PBRNs. DESIGN, SETTING AND PARTICIPANTS: Cross-sectional questionnaire-based study of two geographically-based PBRNs--Hunter New England Central Coast Network of Research General Practices (NRGP) and Primary Healthcare Research Network-General Practice (PHReNet-GP)--during August-September 2010. All 183 GP members of both PBRNs were invited to participate; of these, 140 (77%) participated. MAIN OUTCOME MEASURES: GPs' demographics, use of languages other than English in consultations, and previous participation in research. Practices' use of practice nurses. Socioeconomic status and rurality or urbanicity of practice location. RESULTS: Compared with PHReNet-GP GPs, NRGP GPs were more likely to work in a practice employing a practice nurse (100% v 53.8%; 95% CI for difference, 30.5%-61.8%; P < 0.001), worked in larger practices (2.9 more full-time-equivalent GPs per practice; 95% CI, 2.1-3.6; P < 0.001), and were less likely to work in a major city (33.7% v 89.7%; 95% CI for difference, 42.8%-69.3%; P < 0.001). NRGP GPs also worked in practices with a different spectrum of socioeconomic disadvantage, and were less likely to have been involved in research as a researcher (35.4% v 76.9%; 95% CI for difference, 25.3%-57.8%; P < 0.001). Fewer NRGP GPs consulted in languages other than English (8.9% v 64.1%; 95% CI for difference, 39.1%-71.2%; P < 0.001). There were also differences between these and national general practice statistics. CONCLUSIONS: These results suggest possible lack of generalisability of findings from some types of studies conducted in single PBRNs. In such circumstances, collaboration of PBRNs may produce more generalisable results.

Auto-adjusting positive airway pressure in children with sickle cell anemia: results of a phase I randomized controlled trial.

Low nocturnal oxygen saturation (SpO(2)) is implicated in complications of Sickle Cell Anemia (SCA). Twenty-four children with SCA were randomized to receive overnight auto-adjusting continuous positive airway pressure (auto-CPAP) with supplemental oxygen, if required, to maintain SpO(2) >or=94% or as controls. We assessed adherence, safety, sleep parameters, cognition and pain. Twelve participants randomized to auto-CPAP (3 with oxygen) showed improvement in Apnea/Hypopnea Index (p<0.001), average desaturation events >3%/hour (p=0.02), mean nocturnal SpO(2) (p=0.02) and cognition. Primary efficacy endpoint (Processing Speed Index) showed no group differences (p=0.67), but a second measure of processing speed and attention (Cancellation) improved in those receiving treatment (p=0.01). No bone marrow suppression, rebound pain or serious adverse event resulting from auto-CPAP use was observed. Six weeks of auto-CPAP therapy is feasible and safe in children with SCA, significantly improving sleep-related breathing disorders and at least one aspect of cognition.

Protein phosphatase 2A contributes to the cardiac dysfunction induced by endotoxemia.

AIMS: Sepsis-associated cardiac dysfunction represents an intrinsic impairment of cardiomyocyte function due in part to a decrease in myofilament Ca(2+) sensitivity associated with a sustained increase in cardiac troponin I (cTnI) phosphorylation at Ser23/24. Dephosphorylation of cTnI is under regulatory control. Thus, muscarinic and adenosine A(1)-receptor agonists antagonize beta-adrenergic stimulation via activation of protein phosphatase 2A (PP2A). The aim of this study was to determine whether modulation of PP2A and thus cTnI phosphorylation could improve sepsis-induced contractile dysfunction. METHODS AND RESULTS: Cardiomyocytes were isolated from control or septic mice 16-18 h after an injection of vehicle or lipopolysaccharide (LPS; 9 mg/kg ip) respectively. Protein expression and phosphatase activity were determined in homogenates of control and septic hearts. Our data showed that LPS significantly increased cTnI phosphorylation at Ser23/24 in cardiomyocytes and reduced contraction amplitude without affecting Ca(2+)-transients. Treatment of cardiomyocytes with the A(1) agonist cyclopentyladenosine (CPA) or the protein kinase A inhibitor H89 significantly attenuated the LPS-induced contractile dysfunction without effect on Ca(2+)-transients. Co-treatment with CPA and H89 completely reversed the contractile dysfunction. Increased cTnI phosphorylation in septic hearts was associated with a significant reduction in the protein expression of both the catalytic and regulatory subunits (B56 alpha) of PP2A and a decrease in PP2A activity. CPA treatment of septic hearts increased PP2A activity. An increase in the protein expression of demethylated PP2A and a decrease in the PP2A-methyltransferase (PPMT; the methyltransferase that catalyses this reaction) were also observed. CONCLUSION: These data support the hypothesis that sustained cTnI phosphorylation underlies the contractile dysfunction seen in sepsis.

The use of immediate bone grafting in reconstruction of clinically infected mandibular fractures: bone grafts in the presence of pus.

PURPOSE: Current approaches to the treatment of infected mandibular fractures include antibiotics, drainage, immobilization of the segments, and debridement followed by secondary bone grafting of residual defects once the infection is resolved and the wound healed. Over the past 30 years, the time from debridement to grafting has diminished from several months to a few weeks. We present our experience with a treatment model managing clinically infected fractures of the mandible with antibiotics, debridement, rigid internal fixation, and immediate autogenous bone grafting. MATERIALS AND METHODS: In this retrospective study, we present a series of 43 patients who demonstrated clinical/laboratory findings consistent with infection in one or more mandibular fractures (50 infected fractures). These patients underwent a combination of incision and drainage, fracture debridement, rigid internal fixation, and immediate bone grafting of the resulting defect in a single stage. Both transoral and transfacial approaches were used. RESULTS: Of the 50 fractures, 43 showed both resolution of infection and bony union of fractures with long-term follow-up of 2 months to 4 years. Four fractures developed recurrent infection but proved to have bony union and were successfully treated by hardware removal only. Three other patients were deemed failures with persistent infection, loss of graft, nonunion, and need for retreatment. Each of these patients was afflicted with underlying immunocompromise. CONCLUSIONS: Although careful patient selection is a must, immediate bone grafting of infected mandibular fractures, when used in conjunction with rigid internal fixation and appropriate intraoperative debridement, is an effective treatment modality which allows a single surgical procedure and dramatically shortens the course of treatment.

Complications of alpha-interferon therapy for aggressive central giant cell lesion of the maxilla.

Treatment of giant cell lesions of the jaws is currently a subject of acute interest in the maxillofacial community. Based on their presumptive histological and biological similarities to both the "brown tumors" of hyperparathyroidism as well as proliferative vascular lesions, both calcitonin and interferon alpha administration have been attempted in patients suffering from these lesions. We present a case report of one young female in which both of these treatment modalities were instituted. We also discuss a rarely reported complication consisting of drug-induced lupus erythematosis and pancreatitis secondary to interferon alpha use.

Effect of nitric oxide releasing paracetamol and flurbiprofen on cytokine production in human blood.

Exposure of anti-coagulated human blood to Escherichia coli lipopolysaccharide (50 ng/ml) resulted in the time-dependent (maximum at 5 h) biosynthesis of interleukin-1beta and tumour necrosis factor-alpha (TNF-alpha). Preincubation with nitroparacetamol or nitroflurbiprofen (but not paracetamol or flurbiprofen) caused dose-related inhibition of the formation of interleukin 1 beta (IC(50)s, 44.5 and 362 microM, n=12) and tumour necrosis factor-alpha (IC(50)s, 9.0 and 0.0009 microM, n=12). The inhibitory effect of nitroparacetamol was completely reversed by (2-(4-carboxyphenyl)-4,4,5,5-tetramethylimidazoline-1-oxyl-3-oxide; 2-(4-carboxyphenyl)-4,5-dihydro-4,4,5,5-tetramethyl-1H-imidazol-1-yloxy-3-oxide potassium (carboxy-PTIO, 100 microM; NO scavenging agent). Neither the nuclear factor-kappaB transduction inhibitor, pyrrolidinedithiocarbamate (10-1000 microM) nor the nitric oxide donor, 1-hydroxy-2-oxo-3-(3-aminopropyl)-3-isopropyl-1-triazene (NOC-5, 10-1000 microM), affected cytokine formation in these experiments.