Storage and export of microbial biomass across the western Greenland Ice Sheet.

The Greenland Ice Sheet harbours a wealth of microbial life, yet the total biomass stored or exported from its surface to downstream environments is unconstrained. Here, we quantify microbial abundance and cellular biomass flux within the near-surface weathering crust photic zone of the western sector of the ice sheet. Using groundwater techniques, we demonstrate that interstitial water flow is slow (~10-2 m d-1), while flow cytometry enumeration reveals this pathway delivers 5 × 108 cells m-2 d-1 to supraglacial streams, equivalent to a carbon flux up to 250 g km-2 d-1. We infer that cellular carbon accumulation in the weathering crust exceeds fluvial export, promoting biomass sequestration, enhanced carbon cycling, and biological albedo reduction. We estimate that up to 37 kg km-2 of cellular carbon is flushed from the weathering crust environment of the western Greenland Ice Sheet each summer, providing an appreciable flux to support heterotrophs and methanogenesis at the bed.

The effect of a multicomponent multidisciplinary bundle of interventions on sleep and delirium in medical and surgical intensive care patients.

Sleep deprivation is common among intensive care patients and may be associated with delirium. We investigated whether the implementation of a bundle of non-pharmacological interventions, consisting of environmental noise and light reduction designed to reduce disturbing patients during the night, was associated with improved sleep and a reduced incidence of delirium. The study was divided into two parts, before and after changing our practice. One hundred and sixty-seven and 171 patients were screened for delirium pre- and post-intervention, respectively. Compliance with the interventions was > 90%. The bundle of interventions led to an increased mean (SD) sleep efficiency index (60.8 (3.5) before vs 75.9 (2.2) after, p = 0.031); reduced mean sound (68.8 (4.2) dB before vs 61.8 (9.1) dB after, p = 0.002) and light levels (594 (88.2) lux before vs 301 (53.5) lux after, p = 0.003); and reduced number of awakenings caused by care activities overnight (11.0 (1.1) before vs 9.0 (1.2) after, p = 0.003). In addition, the introduction of the care bundle led to a reduced incidence of delirium (55/167 (33%) before vs 24/171 (14%) after, p < 0.001), and less time spent in delirium (3.4 (1.4) days before vs 1.2 (0.9) days after, p = 0.021). Increases in sleep efficiency index were associated with a lower odds ratio of developing delirium (OR 0.90, 95% CI 0.84-0.97). The introduction of an environmental noise and light reduction programme as a bundle of non-pharmacological interventions in the intensive care unit was effective in reducing sleep deprivation and delirium, and we propose a similar programme should be implemented more widely.

Evaluation of the impact of fetal fibronectin test implementation on hospital admissions for preterm labour in Ontario: a multiple baseline time-series design.

OBJECTIVE: To determine the impact of a health system-wide fetal fibronectin (fFN) testing programme on the rates of hospital admission for preterm labour (PTL). DESIGN: Multiple baseline time-series design. SETTING: Canadian province of Ontario. POPULATION: A retrospective population-based cohort of antepartum and delivered obstetrical admissions in all Ontario hospitals between 1 April 2002 and 31 March 2010. METHODS: International Classification of Diseases codes in a health system-wide hospital administrative database were used to identify the study population and define the outcome measure. An aggregate time series of monthly rates of hospital admissions for PTL was analysed using segmented regression models after aligning the fFN test implementation date for each institution. MAIN OUTCOME MEASURE: Rate of obstetrical hospital admission for PTL. RESULTS: Estimated rates of hospital admission for PTL following fFN implementation were lower than predicted had pre-implementation trends prevailed. The reduction in the rate was modest, but statistically significant, when estimated at 12 months following fFN implementation (-0.96 hospital admissions for PTL per 100 preterm births; 95% confidence interval [CI], -1.02 to -0.90, P = 0.04). The statistically significant reduction was sustained at 24 and 36 months following implementation. CONCLUSIONS: Using a robust quasi-experimental study design to overcome confounding as a result of underlying secular trends or concurrent interventions, we found evidence of a small but statistically significant reduction in the health system-level rate of hospital admissions for PTL following implementation of fFN testing in a large Canadian province.

Self-monitoring of blood glucose in patients with diabetes who do not use insulin--are guidelines evidence-based?

AIMS: To evaluate if clinical practice guideline recommendations regarding self-monitoring of blood glucose in patients with diabetes not using insulin follow the principles of evidence-based medicine. METHODS: After a search from 1999 to 2011, 18 clinical practice guidelines were included. Recommendations regarding self-monitoring of blood glucose were graded on a scale from one (strongly against self-monitoring) to four (strongly in favour of self-monitoring) and compared with the similarly graded conclusions of systematic reviews that were cited by the clinical practice guidelines. We also investigated how clinical practice guideline characteristics, for example funding sources, and quality of references cited could be related to the guideline recommendations. RESULTS: The clinical practice guidelines cited in total 15 systematic reviews, 14 randomized controlled trials, 33 non-randomized controlled trials papers and 18 clinical practice guidelines or position statements. The clinical practice guideline recommendations had an average grade of 3.4 (range 2.0-4.0). Higher grades were seen for clinical practice guidelines that acknowledged industry funding (mean value 4.0) or were issued by organizations depending on private funding (mean value 3.6 vs. 3.0 for governmental funding). The conclusions of the 15 systematic reviews had a mean grade of 2.2 (range 1.0-3.8). Systematic reviews with low grades were less cited. In total, 21 randomized controlled trials were included in the systematic reviews. Approximately half of these evaluated an educational intervention where the effect of self-monitoring of blood glucose could not be clearly isolated. CONCLUSIONS: Clinical practice guidelines were more in favour of self-monitoring use than the systematic reviews that were cited. The citation practice was non-systematic and industry funding seemingly led to a more positive attitude towards use of self-monitoring of blood glucose.

Multicentre audit of the treatment of uncomplicated urinary tract infection in South Thames.

A regional audit report on the management of uncomplicated urinary tract infections (UTIs) in genitourinary (GU) medicine clinics in the UK in South Thames (South London, Kent, Surrey and Sussex). The majority of centres use trimethoprim as first-line treatment for uncomplicated UTIs. The incidence of trimethoprim resistance was 22.6%. The group has therefore recommended that cephalexin should be the first choice antibiotic for suspected UTIs within GU medicine.

The role of serial free/total prostate-specific antigen ratios in a watchful observation protocol for men with localized prostate cancer.

OBJECTIVE: To examine the change in the free/total prostate specific antigen ratio (f/tPSA) with time and to assess the potential value of serial measurements of f/tPSA as a determinant of disease progression in untreated, low-to-intermediate grade prostate cancer (T1b-T2b N0M0, Gleason score < or = 7 and PSA < or = 15 ng/mL). PATIENTS AND METHODS: In a prospective single-arm cohort study from November 1995, patients were conservatively managed with watchful observation alone unless they met arbitrarily defined criteria (clinical, histological and biochemical) of disease progression. Patients were followed regularly and underwent blood tests including PSA and f/tPSA. The initial and mean f/tPSA and the rate of change of f/tPSA with time were evaluated against the rate constant for the PSA doubling time (PSATd). Correlation analyses were used to evaluate any association between baseline clinical variables and either the rate of change of f/tPSA or initial f/tPSA. RESULTS: As of December 2000, 161 of a total of 206 accrued patients had three or more f/tPSA measurements and formed the basis of the study (median age 70 years; median follow-up 2.7 years). The median initial f/tPSA was 0.16; there was a significant negative correlation between this value and the initial total PSA. The mean f/tPSA and rate of change of f/tPSA with time were significantly negatively correlated with the rate constant for PSATd. Also, the rate of change of f/tPSA correlated negatively with clinical T stage, but not with other baseline variables, including initial PSA, age and Gleason score. CONCLUSION: The f/tPSA in men with untreated, clinically localized prostate cancer varied widely. The negative correlation between the rate of change of f/tPSA with time and rate constant for PSATd suggests that both might provide valuable information to allow clinicians to develop a strategy for optimizing the timing of therapeutic intervention for those patients choosing watchful observation alone.

PSA doubling time of prostate carcinoma managed with watchful observation alone.

PURPOSE: To study prostate-specific antigen (PSA) doubling time of untreated, favorable grade, prostate carcinoma. METHODS AND MATERIALS: A prospective single-arm cohort study has been in progress to assess the feasibility of a watchful observation protocol with selective delayed intervention using clinical, histologic, or PSA progression as treatment indication in untreated, localized, favorable grade prostate adenocarcinoma (T1b-T2bN0 M0, Gleason Score < or = 7, and PSA < or = 15 ng/mL). Patients are conservatively managed with watchful observation alone, as long as they do not meet the arbitrarily defined disease progression criteria. Patients are followed regularly and undergo blood tests including PSA at each visit. PSA doubling time (Td) is estimated from a linear regression of ln(PSA) on time, assuming a simple exponential growth model. RESULTS: As of March 2000, 134 patients have been on the study for a minimum of 12 months (median, 24; range, 12-52) and have a median frequency of PSA measurement of 7 times (range, 3-15). Median age is 70 years. Median PSA at enrollment is 6.3 (range, 0.5-14.6). The distribution of Td is as follows: <2 years, 19 patients; 2-5 years, 46; 5-10 years, 25; 10-20 years, 11; 20-50 years, 6; > 50 years, 27. The median Td is 5.1 years. In 44 patients (33%), Td is greater than 10 years. There was no correlation between Td and patient age, clinical T stage, Gleason score, or initial PSA level. CONCLUSION: Td of untreated prostate cancer varies widely. In our cohort, 33% have Td > 10 years. Td may be a useful tool to guide treatment intervention for patients managed conservatively with watchful observation alone.

Human kallikrein 10: a novel tumor marker for ovarian carcinoma?

BACKGROUND: Human kallikrein 10 (hK10, encoded by KLK10 gene) is a recently discovered member of the human kallikrein family. hK10 is a secreted serine protease. With the development of a highly sensitive and specific immunoassay for hK10, quantification of hK10 in the circulation is now feasible. Our aim was to investigate whether hK10 concentration in serum changes in various malignancies. METHODS: We used a highly specific and sensitive immunofluorometric assay to quantify hK10 protein in 374 serum samples from healthy individuals and patients with various malignancies. RESULTS: Serum hK10 concentration was found to be significantly elevated in 56% of the ovarian cancer patients and such an increase was not observed in serum of healthy individuals or in serum of patients with other types of cancer, with the exception of approximately 15% of patients with gastrointestinal cancer. This hK10 elevation does not correlate well with CA 125. We have further demonstrated that hK10 concentration changes during ovarian cancer progression. CONCLUSION: This is the first report describing that hK10 serum concentration is significantly elevated in the majority of ovarian cancer patients. Our results indicate that hK10 may be a potential new serological marker for ovarian cancer diagnosis and monitoring.

Human kallikrein 6 (zyme/protease M/neurosin): a new serum biomarker of ovarian carcinoma.

BACKGROUND: There is an urgent need for discovery and validation of new serum biomarkers for ovarian carcinoma. Early diagnosis of ovarian cancer with serologic analysis may improve clinical outcomes through administration of effective treatment. Human kallikrein 6 (hK6, encoded by the KLK6 gene) is a serine protease of the kallikrein gene family. Recently, we were able to develop an immunofluorometric procedure for the quantitative measurement of hK6 in biologic fluids, including serum. METHODS: We have used an hK6-specific immunofluorometric assay to quantify hK6 protein in a large number of serum samples from normal individuals, as well as from patients with various malignancies. RESULTS: We report for the first time, significant increase of serum hK6 concentration in a large proportion of patients with ovarian carcinoma. The elevations of hK6 appear to be relatively specific for ovarian cancer because other malignancies did not cause any increase in the concentration of this biomarker in serum. Serial hK6 measurements appear to correlate with CA125 levels in patients monitored postsurgery. CONCLUSIONS: This is the first report describing significant elevations of hK6 concentration in serum of ovarian cancer patients. These data suggest that hK6 may represent a potential new biomarker for diagnosis and monitoring of ovarian carcinoma.

Prostate-specific antigen testing in Ontario: reasons for testing patients without diagnosed prostate cancer.

BACKGROUND: The use of the prostate-specific antigen (PSA) test has been increasing rapidly in Canada since its introduction in 1988. The reasons for using the PSA test in patients without known prostate cancer are unclear. This paper reports on the first study in Canada to use physician records to assess the use of PSA testing. METHODS: A questionnaire was mailed to physicians attending 475 patients without diagnosed prostate cancer. The patients were randomly selected from 2 laboratory databases of PSA test records in the greater Toronto area during 1995. The physicians were asked to consult their patient records to avoid recall bias. Information obtained included physician's specialty, patient's age at time of PSA test and reason(s) for the test. RESULTS: There were 264 responses (56%), of which 240 (91%) were usable. Of these 240, 63% (95% confidence interval [Cl] 58%-70%) indicated that the test was conducted to screen for prostate cancer, 40% (95% Cl 34%-47%) said it was to investigate urinary symptoms, and 33% (95% Cl 27%-40%) responded that it was a follow-up to a medical procedure or drug therapy. More than one reason was permitted. Of 151 responses indicating screening as one reason for testing, 64% (95% Cl 56%-72%) stated that it was initiated by the patient, and 73% (95% Cl 65%-80%) stated that it was part of a routine examination. For 19%, both investigation of symptoms and screening asymptomatic patients were given as reasons for testing, and for another 19% both follow-up of a medical procedure and screening were given as reasons. Screening was recorded as a reason for testing far more commonly for patients seen by family physicians and general practitioners than for patients seen by urologists (67% v. 29%, p < 0.001). In contrast, the use of PSA testing to diagnose urinary symptoms was more common for patients seen by urologists than for those seen by family physicians and general practitioners (52% v. 37%, p = 0.044). No significant difference was found between physician groups in the use of PSA testing as a follow-up of a medical procedure (42% for urologists and 31% for family physicians and general practitioners). About 24% of the PSA test records were for patients younger than 50 and older than 70 years. PSA testing initiated by patients was more common in the practices of family physicians and general practitioners than in the practices of urologists (44% v. 13%, p < 0.001). INTERPRETATION: Screening for prostate cancer was the most common reason for PSA testing in our study group; it occurred most commonly in the family and general practice setting and was usually initiated by the patient. Differences in reasons for testing were identified by practice specialty. Although PSA screening for prostate cancer is sometimes recommended for men between 50 and 70 years of age, it is being conducted in men outside this age group.

Phase 2 studies of adenosine cardioplegia.

BACKGROUND: Laboratory evidence supports the use of adenosine-supplemented cardioplegia. An initial phase 1 dose-ranging clinical evaluation demonstrated that an adenosine concentration of 15 mumol/L could be safely administered with warm blood cardioplegia and suggested that phase 2 studies were warranted. METHODS AND RESULTS: Two separate double-blind, randomized, placebo-controlled trials were performed in patients undergoing primary, isolated, nonemergent coronary artery bypass graft surgery. Patients were randomized to receive adenosine 15 mumol/L versus placebo in the first study (n = 200) and adenosine 50 or 100 mumol/L versus placebo in the second study (n = 128). Adenosine was infused with both initial and final doses of warm antegrade blood cardioplegia. The data from the 2 trials were combined using the methods of Mantel and Haenszel, and the results of the meta-analysis are presented as the relative risk with their associated 95% confidence intervals (CI). The different study groups were comparable with respect to all preoperative clinical characteristics, angiographic findings, and intraoperative variables. In both trials 1 and 2, no differences were found between groups in the incidence of the individual primary or secondary outcomes. Similarly, when both studies were combined, there was no significant evidence of any consistent treatment benefit (primary: death: relative risk [RR] = 1.02, 95% CI = 0.06, 16.6; myocardial infarction by CK-MB: RR = 0.84, CI = 0.54, 1.31; low output syndrome: RR = 1.38, CI = 0.29, 6.42; any of the above: RR = 0.98, CI = 0.78, 1.25; secondary: Q-wave myocardial infarction: RR = 1.30, CI = 0.41, 4.13; myocardial infarction by troponin T: RR = 0.7, CI = 0.40, 1.21; inotrope requirement: RR = 0.9, CI = 0.46, 1.79; intra-aortic balloon pump requirement: RR = 0.6, CI = 0.07, 4.81; P > 0.20). CONCLUSIONS: Despite promising experimental data, adenosine supplementation of warm blood cardioplegia did not demonstrate any statistically significant benefit in patients undergoing elective coronary artery bypass graft surgery. Although sample sizes were relatively small, based on our interim analyses, it is unlikely that increased patient enrollment would reveal any substantive clinical differences between groups.

Prostate-specific antigen utilization in Ontario: extent of testing in patients with and without cancer.

OBJECTIVES: To ascertain the extent of prostate-specific antigen (PSA) testing in patients with prostate cancer (PC), with other cancers (OC), and with no cancer (NC) in two clinical laboratory databases. DESIGN AND METHODS: PSA test records were obtained from a tertiary care hospital, Sunnybrook Health Science Centre (SHSC) and from a private laboratory, Gamma-Dynacare Medical Laboratories (GDL), during the period 1988 to 1995. These records were linked with the Ontario Cancer Registry (OCR) to establish a diagnosis of PC, OC, or NC. Trends in PSA testing according to diagnostic category, testing laboratory, patient age (by decade), and PSA value (in microgram/L) were determined. RESULTS: Major cancer sites identified in the patients tested for PSA were prostate (60%), bladder and colon (7% each), lung (5%), kidney (3%), and rectum (3%). There were 11,867 patients (8.5%) with PC, 8,002 (5.9%) with OC, and 118,954 (86%) with NC. The total number of PSA tests performed on these patients was 230,756, of which 21% were on PC, 5% on OC, and 74% on NC; of these tests, 64% were performed through GDL and 36% through SHSC. The mean (median) number of tests per patient was: PC, 4.0 (2); OC, 1.4 (1); and NC, 1.5 (1). For PC 89% and for OC 72% of all tests occurred after diagnosis. Between 1990 and 1995 the number of PSA tests increased two-fold in PC and OC, and 20-fold in NC. We estimate that about one-half of the PSA tests in the NC group were for screening purposes. The proportion of PSA tests occurring in PC, OC, and NC for patients 50 to 70 years of age was 41%, 50%, and 63%, respectively; for patients over 70 years of age, this proportion was 58%, 46%, and 22% respectively; and for patients under 50 it was 1%, 4%, and 15%, respectively. Between 1990 and 1995, the largest increase in testing frequency was in the NC group, particularly in patients 50 to 70 years of age, which was accompanied by a decrease in patients over 70. Less than 10% of testing occurred in patients under 50 in all diagnostic groups. We estimate that about 26% of PSA screening tests in NC occurred outside the guidelines for patient age. Between 1988 and 1995, the proportion of PSA results below our detection limit (< 0.2 micrograms/L) showed a steady rise in the PC group, as did the proportion between 0.2 and 3.9 micrograms/L; these were accompanied by a fall in the proportion > 20.0 micrograms/L. However, the proportion of PSA results within these ranges did not change much during the same time period for the OC and NC groups. At cutoffs of PSA = 4.0 micrograms/L (or PSA = 10.0 micrograms/L), estimates of clinical specificity were 84.0% (or 96.3%), and of clinical sensitivity were 83.4% (or 47.1%). CONCLUSIONS: Most (86%) PSA testing occurred in men with NC, consistent with diagnosis or screening. There were more PSA tests per patient in PC than in OC, and most testing occurred after diagnosis. PSA testing in the NC group continues to increase rapidly. The proportion of PSA tests in patients over age 70 decreased in the order of PC > NC > OC. Between 1990 and 1995, there was an increase in the proportion of patients tested who were between 50 and 70 in the NC group, which may suggest more screening in this group. Over this same time period, there was an increase in the proportion of undetectable PSA values, possibly suggesting increased use of radical therapy; there was also a decrease in the proportion of PSA > 20 micrograms/L, possibly suggesting a decrease in the prevalence of advanced stage PC.

Percent free prostate-specific antigen after radiotherapy for prostate cancer.

OBJECTIVES: The range of "normal" prostate-specific antigen (PSA) values compatible with cure following radiotherapy (RT) for prostate cancer (PCa) has yet to be established. Various thresholds, ranging from 0.5 to 4.0 ng/mL are used to define biochemical disease-free status. Because the proportion of free PSA is lower in men with PCa, the ratio of free PSA to total PSA could theoretically be useful in determining cancer-free status after RT. METHODS: One hundred two men treated with standard external beam RT from October 1988 to October 1994 (median dose, 66 Gy) were chosen for measurement of percent free PSA because they had a routine follow-up visit in November or December of 1996. All patients had undergone systematic transrectal ultrasound-guided biopsies after RT. Biopsies were negative in 66 patients, positive in 21, and indeterminate in 15 (rare, degenerated cancer cells with no evidence of proliferation by immunohistochemical stains). Stage distribution was T1b, 8; T1c, 9; T2a, 25; T2b/c, 40; and T3, 20. Median follow-up is 40 months. RESULTS: Total serum PSA ranged from 0. 1 to 10.0 ng/mL. Because the mean (+/-SD) percent free PSA for patients with negative (n = 66) and indeterminate (n = 15) biopsies were 29% +/- 18% and 25% +/- 7%, respectively (P = 0.13), these were combined. The mean (+/-SD) percent free PSA for those with positive biopsies (n = 21) was 15% +/- 8% and was significantly different from those with negative or indeterminate biopsies (P < 0.001). Patients with negative or indeterminate biopsies were grouped according to their total PSA as 0.1 to 0.5 ng/mL (n = 33), 0.6 to 1.0 ng/mL (n = 23), 1.1 to 2.0 ng/mL (n = 17), and greater than 2.0 ng/mL (n = 7). The mean percent free PSAs were 34%, 28%, 21%, and 12%, respectively. CONCLUSIONS: Percent free PSA may be a useful adjunct in diagnosing recurrent PCa after RT. The ratio is significantly different in patients of known biopsy status, distinguishing a group with positive biopsies from those with negative. However, there is overlap in individual values, and because patients with negative biopsies after RT may have subclinical distant disease, more follow-up is necessary before percent free PSA can be incorporated into a definition of biochemical disease-free status. Percent free PSA may be most useful for PSA from 0.6 to 2.0 ng/mL, where failure is common, but not universal.

The safety of topical anaesthetic and analgesic agents in a gel when used to provide pain relief at split skin donor sites.

Post operative pain from split skin donor sites is a recognised problem. This study was carried out to assess the safety of a 'depot' preparation of bupivacaine and ketoprofen when applied to denuded dermis of a split donor site. Two groups of six patients each received either bupivacaine gel (2.5 mg/ml) or ketoprofen gel (1.6 mg/ml). One patient from each group was excluded as protocol was not followed. The mean surface area for bupivacaine was 106 cm2 (range 64-160) and the mean for ketoprofen was 130 cm2 (range 64-180). Blood samples were obtained before application and at 10, 20, 30, 60, 120, 240 and 480 min after application. Serum levels were assayed using Gas Liquid Chromatography and High Pressure Liquid Chromatography. Bupivacaine levels peaked at 120 min, mean level obtained was 0.07 microgram/ml (range 0.03-0.1). Ketoprofen levels also peaked at 120 min and the mean level obtained was 0.20 microgram/ml (range 0.12-0.27). The reported toxic serum level for bupivacaine was 4 micrograms/ml and for ketoprofen is 1128 micrograms/ml. In conclusion, these preparations, when applied to denuded dermis of a split skin donor site, are unlikely to result in toxic levels.