First report of an imported case of haemorrhagic fever with renal syndrome in South Africa.

Haemorrhagic fever with renal syndrome (HFRS) is caused by hantavirus infection. Hantaviruses are not endemic to South Africa, and we report the first detection of an imported case of HFRS in the country. The case involved a traveller from Croatia who presented to a Johannesburg hospital with an acute febrile illness with renal dysfunction. The patient reported visiting rurally located horse stables in Croatia before falling ill, and that a worker in the stables with similar illness was diagnosed with HFRS. Given the exposure history and clinical findings of the case, a clinical diagnosis of HFRS was made and confirmed by laboratory testing.

Prostate cancer treatment and the relationship of androgen deprivation therapy to cognitive function

Prostate cancer is the second most common form of cancer in men. For advanced, high risk prostate cancer, androgen deprivation therapy (ADT) is the preferred treatment and can induce remission, but resistance to ADT brings biochemical recurrence and progression of cancer. ADT brings adverse effects such as erectile dysfunction, decreased libido, and diminished physical strength. It is estimated that between 25 and 50% of men on ADT manifest some form of cognitive dysfunction that may be self-reported or reported by a family member. There is concern that impaired cognitive function with ADT is due to loss of testosterone support. Testosterone and its metabolites are known to possess neuroprotective properties. While a direct causal relationship between ADT and cognitive decline in prostate cancer patients has not been established, this review describes the controversy surrounding the possible connection between ADT and neurocognitive deterioration. The cellular and molecular mechanisms believed to underlie the protection of neuronal integrity by androgens are discussed. Results from animal models and human clinical studies are presented. Finally, we call attention to lifestyle modifications that may minimize cognitive issues in prostate cancer patients.

Prostate cancer treatment and the relationship of androgen deprivation therapy to cognitive function.

Prostate cancer is the second most common form of cancer in men. For advanced, high risk prostate cancer, androgen deprivation therapy (ADT) is the preferred treatment and can induce remission, but resistance to ADT brings biochemical recurrence and progression of cancer. ADT brings adverse effects such as erectile dysfunction, decreased libido, and diminished physical strength. It is estimated that between 25 and 50% of men on ADT manifest some form of cognitive dysfunction that may be self-reported or reported by a family member. There is concern that impaired cognitive function with ADT is due to loss of testosterone support. Testosterone and its metabolites are known to possess neuroprotective properties. While a direct causal relationship between ADT and cognitive decline in prostate cancer patients has not been established, this review describes the controversy surrounding the possible connection between ADT and neurocognitive deterioration. The cellular and molecular mechanisms believed to underlie the protection of neuronal integrity by androgens are discussed. Results from animal models and human clinical studies are presented. Finally, we call attention to lifestyle modifications that may minimize cognitive issues in prostate cancer patients.

[Renal cell carcinoma diagnosis and prognosis within the context of the WHO classification 2016]. / Histopathologische Diagnose und Prognose des Nierenzellkarzinoms im Kontext der WHO-Klassifikation 2016.

BACKGROUND: Histological classification of renal cell carcinoma (RCC) has become more and more important for clinical management, but relatively few is known regarding the swiftness with which the 2016 World Health Organization (WHO) classification of RCC was adopted in the daily routine diagnostics. AIM: To retrospectively review the histological diagnosis of RCC within the context of 2016 WHO classification followed by survival analysis. MATERIAL AND METHODS: Retrospective register based analysis of RCC diagnosis between 1998 and 2017 and survival analysis. RESULTS: 1440 RCC cases were registered between 1998 and 1917. According to 2016 WHO classification, 77.7% clear cell RCC and 22.3% non-clear cell RCC were diagnosed. A total of 37 rare subtypes were recorded, among those 1% MiT family translocation RCC, 0.35% acquired cystic disease-associated RCC, 0.35% multilocular cystic renal neoplasm of low malignant potential, 0.35% collecting duct carcinoma, 0.3% mucinous tubular and spindle cell carcinoma, 0.1% clear cell papillary RCC and 0.1% RCC with (angio)leiomyomatous stroma. Cox regression analysis showed significant different overall survival and progression-free survival between the histological subtypes. DISCUSSION: The complexity of the 2016 WHO classification of RCC put high demands on histopathological diagnostics. At University Medicine Center Rostock morphological distinct RCC entities have been mostly diagnosed by conventional means via hematoxillin and eosin stained slides, but beyond immunohistochemistry additionally molecular techniques were established. The histologic subtyping of RCC according to 2016 WHO classification has prognostic significance and might have predictive significance for unique therapeutic approaches.

Association between anaesthetic technique and unplanned admission to intensive care after thoracic lung resection surgery: the second Association of Cardiothoracic Anaesthesia and Critical Care (ACTACC) National Audit.

Unplanned intensive care admission is a devastating complication of lung resection and is associated with significantly increased mortality. We carried out a two-year retrospective national multicentre cohort study to investigate the influence of anaesthetic and analgesic technique on the need for unplanned postoperative intensive care admission. All patients undergoing lung resection surgery in 16 thoracic surgical centres in the UK in the calendar years 2013 and 2014 were included. We defined critical care admission as the unplanned need for either tracheal intubation and mechanical ventilation or renal replacement therapy, and sought an association between mode of anaesthesia (total intravenous anaesthesia vs. volatile) and analgesic technique (epidural vs. paravertebral) and need for intensive care admission. A total of 253 out of 11,208 patients undergoing lung resection in the study period had an unplanned admission to intensive care in the postoperative period, giving an incidence of intensive care unit admission of 2.3% (95%CI 2.0-2.6%). Patients who had an unplanned admission to intensive care unit had a higher mortality (29.00% vs. 0.03%, p < 0.001), and hospital length of stay was increased (26 vs. 6 days, p < 0.001). Across univariate, complete case and multiple imputation (multivariate) models, there was a strong and significant effect of both anaesthetic and analgesic technique on the need for intensive care admission. Patients receiving total intravenous anaesthesia (OR 0.50 (95%CI 0.34-0.70)), and patients receiving epidural analgesia (OR 0.56 (95%CI 0.41-0.78)) were less likely to have an unplanned admission to intensive care after thoracic surgery. This large retrospective study suggests a significant effect of both anaesthetic and analgesic technique on outcome in patients undergoing lung resection. We must emphasise that the observed association does not directly imply causation, and suggest that well-conducted, large-scale randomised controlled trials are required to address these fundamental questions.

[Injuries in Karate Sports: A Survey Performed During the World Championship 2014]. / Verletzungen im Karatesport ­ eine Umfrage während der Weltmeisterschaft 2014.

Background: In literature, the competitive sport of modern karate is almost always characterised as a combat sport involving injuries caused by impact effects and physical contact with opponents. There is a lack of data regarding the outcome after karate injuries, specifically with a view to the contact-free Kata karate. Methods: Performing a random test using a questionnaire, we collected data concerning regular medical treatment, prior surgeries of the locomotor system, and medical care. This study included 300 athletes from 65 countries (average age: 24.1 years; 176 male, 124 female) participating in the Karate World Cup 2014. Seven participants competed in both disciplines, 87 only in the Kata discipline, and 206 only in Kumite (the discipline involving physical contact with opponents). The statistical analysis was performed using a two-sided Chi-square test and the Fisher's exact test. Results: Recurrent medical treatment was most commonly required for the knee region (Kata 28.7 %, Kumite 26.7 %). In Kata the shoulder region came second (22.9 %), in Kumite the ankle region (21.8 %), followed by hand and foot in both groups. Medical treatment of the elbow area was more frequent in the Kata Group (p = 0.033), while in Kumite athletes' hand (p = 0.002) and foot injuries (p = 0.007) prevailed. Prior surgeries of athletes of both disciplines most commonly concerned the knee, followed by the ankle region in the Kata group and by the hand and head region in the Kumite group. Statistically significant differences between the two disciplines were found in head injuries (p = 0.004), which commonly do not occur in the Kata discipline. During the World Cup, 56.0 % of the athletes had no individual medical care and 24.6 % received no sports-related medical care in their home countries. Conclusion: Although the risk of injuries in Kumite Karate has been reduced by the introduction of gumshields, hand and foot protectors as well as a reform of the scoring system, the potential for chronic physical damage should not be underestimated. Since in athletes competing in the Kata discipline the rate of surgeries and injuries is only slightly lower than in the Kumite group, Kumite Karate may be regarded as a martial arts competitive sport with a relatively low risk of injuries. In contrast, the risk of chronic musculoskeletal damage in Kata athletes seems to be underestimated thus far. Suggested improvements concern the training techniques and conditions (i. e. the tatami material), and there is a need for regular medical care, including preventative care, to be provided for these athletes.

Quantitative assessment of central and limbal epithelium after long-term wear of soft contact lenses and in patients with dry eyes: a pilot study.

PurposeAnalysis of microstructural alterations of corneal and limbal epithelial cells in healthy human corneas and in other ocular conditions.Patients and methodsUnilateral eyes of three groups of subjects include healthy volunteers (G1, n=5), contact lens wearers (G2, n=5), and patients with dry eyes (G3, n=5) were studied. Imaging of basal (BC) and intermediate (IC) epithelial cells from central cornea (CC), corneal limbus (CL) and scleral limbus (SL) was obtained by in vivo confocal microscopy (IVCM). An appropriate image analysis algorithm was used to quantify morphometric parameters including mean cell area, compactness, solidity, major and minor diameter, and maximum boundary distance.ResultsThe morphometric parameters of BC and IC demonstrated no significant differences (P>0.05) between groups. Comparison between three corneal locations (CC, CL, and SL) within the groups showed significant differences (P<0.05) with mean values of cell area, compactness, solidity, and major and minor diameter of BC that increase from CC to limbus. The BC were round and regular in the central cornea (P<0.05) compared with CL and SL.ConclusionsIVCM enables high-quality confocal images from central corneal and limbal epithelium. This quantitative study demonstrated morphological differences in the basal and intermediate epithelium between limbus and central cornea, and found no differences between contact lens wearers, dry eyes, and normal subjects.

The role of specimen radiography in breast-conserving therapy of ductal carcinoma in situ.

BACKGROUND: To assess the role of intraoperative specimen radiography (SR) and to define risk factors for positive margins in breast-conserving therapy (BCT) of ductal carcinoma in situ (DCIS). METHODS: In a retrospective study in calcification-associated DCIS treated with BCT between January 2009 and December 2011, digital mammographs and SR were reviewed and radiological margin width was determined. Clinical, radiological, and histological data were correlated with surgical histological data, and a histologically free margin of at least 2 mm was taken as evidence of successful BCT. RESULTS: 47/91 patients (51.6%) fulfilling the inclusion criteria had histologically involved surgical margins. Univariate analyses revealed DCIS size, mammographic extension of calcification, presence of comedo necrosis, negative progesterone receptor status, and a small radiological margin on SR to be risk factors for unsuccessful BCT. Receiver Operating Characteristic (ROC) analysis showed a radiological margin width of 4 mm to be optimal, with a sensitivity of 72.3% and specificity of 52.3%. The likelihood of surgical free margins was increased 2.9-fold with a radiological margin width ≥4 mm. On multivariate logistic regression analysis, only histological DCIS size >20 mm clearly emerged as an independent predictive factor for surgically involved margins (p < 0.001), while an SR margin <4 mm trended toward significance (p = 0.066). CONCLUSIONS: SR is a reliable method for predicting free surgical margins in non-invasive breast cancer where a minimum radiological free margin of 4 Fmm is achieved. However, histological DCIS size remains the most important factor determining successful BCT.

[Quality of Outcome after Primary Total Hip Replacement at a Maximum Care Hospital in Relation to Preoperative Influencing Factors]. / Ergebnisqualität nach Hüftendoprothesen-Erstimplantation an einem Krankenhaus der Maximalversorgung in Bezug auf präoperative Einflussfaktoren.

BACKGROUND: As the need for joint replacements will continue to rise, the outcome of primary total hip replacement (THR) must be improved and stabilised at a high level. In this study, we investigated whether pre-operative risk factors, such as gender, age and body weight at the time of the surgery or a restricted physical status (ASA-Status > 2 or Kellgren and Lawrence grade > 2) have a negative influence on the post-operative results or on patient satisfaction. MATERIAL AND METHODS: Retrospective data collection and a prospective interview were performed with 486 patients who underwent primary total hip replacement between January 2007 and December 2010 in our hospital. The patients' satisfaction and quality of life were surveyed with the WOMAC-Score, SF-36 and EuroQol-5. Differences between more than two independent spot tests were tested with the non-parametric Kruskal-Wallis test. Differences between two independent spot tests were tested with the non-parametric Mann-Whitney U test. The frequencies were reported and odds ratios calculated. The confidence interval was set at 95 %. The level of significance was p < 0.05. RESULTS: The average WOMAC-Score was 77.1 and the total score of the SF-36 was 66.9 points. The patients declared an average EuroQol Index of 0.81. Our data show that the patients' gender did not influence the duration of surgery or the scores. However, female patients tended to exhibit more postoperative complications. However, increased patient age at the time of surgery was associated with an increased OR for duration of surgery, length of stay and risk of complications. Patients who had a normal body weight at time of the surgery showed better peri- and post-operative results. We showed that the preoperative estimated Kellgren and Lawrence grade had a significant influence on the duration of surgery. The ASA classification influenced the duration of surgery as well the length of stay and the rate of complications. CONCLUSION: The quality of results after primary THR depends on preoperative factors. Existing comorbidities have a significant influence on the duration of surgery and therefore on the perioperative rate of complications and the postoperative outcome. Despite improvements in the functional and subjective outcome after primary THR, an adverse preoperative symptomatic status is associated with less favourable postoperative results.

Patient-Report Satisfaction and Health-Related Quality of Life in TiLOOP® Bra-Assisted or Implant-Based Breast Reconstruction Alone.

INTRODUCTION: Implant-based breast reconstructions (IBBR) using alternatives to acellular dermal matrixes are increasing. Data on complications are limited, and information concerning health-related quality of life (HR-QoL) following the use of these synthetic meshes do not exist. METHODS: Between January 2006 and January 2013, patients undergoing immediate or delayed-immediate IBBR with or without titanium covered polypropylene mesh (TiLOOP® Bra) were investigated. HR-QoL was assessed using the validated self-reporting BREAST-Q questionnaire. Patient demographics and complications were evaluated retrospectively. Stepwise regression backward elimination analysis was performed to identify influential factors on each BREAST-Q domain. RESULTS: Of the 90 women, 42 had IBBR alone and 48 in combination with TiLOOP® Bra. The mean follow-up was 18 months in the TiLOOP® Bra and 17.5 months in the implant alone group (p = 0.827). The overall complication rate was 21.1 %, with 14.6 % in the TiLOOP® Bra and in 28.6 % in the implant alone group (p = 0.105). Capsular contraction rate was 4.4 % in the TiLOOP® Bra and 16.7 % in the implant alone group (p = 0.052). The analysis of the HR-QoL showed no significant differences between the groups. Surgeries prior to IBBR had a positive influence on HR-QoL. TiLOOP® Bra was associated with a negative effect on "satisfaction with breast" (ß = -5.72; p < 0.001), as it was no longer observed for "satisfaction with outcome" and other domains.

Assessment of Ultrasound Features Predicting Axillary Nodal Metastasis in Breast Cancer: The Impact of Cortical Thickness.

PURPOSE: To evaluate the accuracy of axillary ultrasound (AUS) in detecting nodal metastasis in patients with early-stage breast cancer and to identify AUS features with high predictive power. MATERIALS AND METHODS: Prospective single-center preliminary study in 105 patients with a primary diagnosis of breast cancer and clinically negative axilla. AUS was performed using a 12 MHz linear-array transducer before ultrasound-guided needle biopsy. Nodal characteristics (shape, longitudinal-transverse [LT] axis ratio, margins, cortical thickness, hyperechoic hilum) were correlated with histopathological nodal status after SLNB or axillary lymph node dissection (ALND). RESULTS: Nodal metastases were present in 42/105 patients (40.0%). Univariate analyses showed that absence of hyperechoic hilum, round shape, LT axis ratio<2, sharp margins and cortical thickness>3 mm were associated with lymph node metastasis. Multivariate logistic regression analysis revealed cortical thickness > 3 mm as an independent predictive parameter for nodal involvement. Sensitivity, specificity, positive predictive value, negative predictive value and accuracy were 66.7, 74.6, 63.6, 77.0% and 71.4% respectively when cortical thickness > 3 mm was applied as the criterion for AUS positivity. Axillary tumor volume was low in patients with pT1/2 tumors and negative AUS, since only 3.2% of patients had > 2 metastatic lymph nodes. CONCLUSION: Cortical thickness>3 mm is a reliable predictor of nodal metastatic involvement. Negative AUS does not exclude lymph node metastases, but extensive axillary tumor volume is rare.

Titration of the gap junction protein Connexin43 reduces atherogenesis.

Ubiquitous reduction of the gap junction protein Connexin43 (Cx43) in mice provides beneficial effects on progression and composition of atherosclerotic lesions. Cx43 is expressed in multiple atheroma-associated cells but its function in each cell type is not known. To examine specifically the role of Cx43 in immune cells, we have lethally irradiated low-density lipoprotein receptor-deficient mice and reconstituted with Cx43+/+, Cx43+/- or Cx43-/- haematopoietic fetal liver cells. Progression of atherosclerosis was significantly lower in aortic roots of Cx43+/- chimeras compared with Cx43+/+ and Cx43-/- chimeras, and their plaques contained significantly less neutrophils. The relative proportion of circulating leukocytes was similar between the three groups. Interestingly, the chemoattraction of neutrophils, which did not express Cx43, was reduced in response to supernatant secreted by Cx43+/- macrophages in comparison with the ones of Cx43+/+ and Cx43-/- macrophages. Cx43+/- macrophages did not differ from Cx43+/+ and Cx43-/- macrophages in terms of M1/M2 polarisation but show modified gene expression for a variety chemokines and complement components. In conclusion, titration of Cx43 expression in bone marrow-derived macrophages reduces atherosclerotic plaque formation and chemoattraction of neutrophils to the lesions.

Anti-viral therapy for prevention of perinatal HBV transmission: extending therapy beyond birth does not protect against post-partum flare.

BACKGROUND: Antepartum anti-viral therapy (AVT) is often administered to prevent perinatal transmission of hepatitis B virus (HBV) infection. Little is known about the effect of AVT on post-partum flare rates and severity. AIM: To examine whether extending AVT beyond birth influences the post-partum course. METHODS: One hundred and one pregnancies in 91 women with HBV DNA levels ≥log 7 IU/mL were included. AVT (initially lamivudine, later tenofovir disoproxil fumarate) was commenced from 32 weeks gestation and stopped soon after birth and at 12 weeks post-partum. Outcomes according to post-partum treatment duration were examined: Group 1 = AVT ≤4 weeks (n = 44), Group 2 = AVT >4 weeks (n = 43), Group 3 = no AVT (n = 14). RESULTS: The majority of women were HBeAg+ (97%), median age 29 years, baseline HBV DNA log 8.0 IU/mL and follow-up 48 weeks post-partum. Post-partum treatment duration was 2 weeks for Group 1 and 12 weeks for Group 2, P < 0.01. Flare rates were not significantly different: Group 1 = 22/44 (50%), Group 2 = 17/43 (40%) and Group 3 = 4/14 (29%), P = 0.32. Onset of flare was similar at 8/10/9 weeks post-partum for Groups 1/2/3 respectively, P = 0.34. The majority of flares spontaneously resolved. HBeAg seroconversion (n = 1/5/1 in Groups 1/2/3, P = 0.27) was not associated with treatment duration or the occurrence of a post-partum flare. CONCLUSIONS: Post-partum flares are common and usually arise early after delivery. They are often mild in severity and most spontaneously resolve. Extending anti-viral therapy does not protect against post-partum flares or affect HBeAg seroconversion rates.

Short duration of lamivudine for the prevention of hepatitis B virus transmission in pregnancy: lack of potency and selection of resistance mutations.

This study sought to assess the antiviral efficacy of lamivudine (LMV) administered during third trimester to reduce maternal viraemia and to identify the emergence of LMV resistance. A prospective observational analysis was performed on 26 mothers with high viral load (>107 IU/mL). Twenty-one women received LMV (treated group) for an average of 53 days (range 22-88 days), and the remaining five formed the untreated control group. Serum samples from two time points were used to measure HBV DNA levels and antiviral drug resistance. The LMV-treated women achieved a median HBV DNA reduction of 2.6-log10 IU/mL. Although end-of-treatment (EOT) HBV DNA in four (18%) LMV-treated women remained at >10(7) IU/mL (± 0.5 log IU/mL), no mother-to-baby transmission was observed. In contrast, a baby from the untreated mother was HBsAg positive at 9 months postpartum. Four technologies were used for drug resistance testing. Only ultra-deep pyrosequencing (UDPS) was sufficiently sensitive to detect minor viral variants down to <1%. UDPS showed that LMV therapy resulted in increased viral quasispecies diversity and positive selection of HBV variants with reverse transcriptase amino acid substitutions at sites associated with primary LMV resistance (rtM204I/V and rtA181T) in four (19%) women. These viral variants were detected mostly at low frequencies (0.63-5.92%) at EOT, but one LMV-treated mother had an rtA181T variant that increased from 2.2% pretherapy to 25.59% at EOT. This mother was also infected with the vaccine escape variant (sG145R), which was inhibited by LMV treatment. LMV therapy during late pregnancy only reduced maternal viraemia moderately, and drug-resistant viral variants emerged.

Recurrence of endometriosis after hysterectomy.

AIM: Persistent or recurrent pain after hysterectomy is one of the most frustrating clinical scenarios in benign gynaecology. We attempt to review the current evidence regarding the recurrence of pelvic pain after hysterectomy for endometriosis. The impact of ovarian conservation, type of hysterectomy and the extent of surgical excision were analysed. METHODS: Peer reviewed published manuscripts in the English language in the period between 1980 and 2014 were reviewed using Pubmed and science direct regarding the incidence, causes and recurrence of endometriosis. RESULTS: Sixty-seven articles were identified. Incomplete excision of endometriosis is the most predominant reason in the literature for the recurrence of endometriosis, and the type of Hysterectomy affects the recurrent symptoms mainly by impacting the extent of excision of the lesion. Ovarian cyst drainage is associated with the highest rate of ovarian cyst reformation within three to six months after surgery. The use of hormone replacement therapy is associated with recurrence of pelvic pain in 3.5% of cases. No studies addressed the recurrence of endometriosis after standard vs robotic assisted hysterectomy. CONCLUSION: A high recurrence rate of 62% is reported in advanced stages of endometriosis in which the ovaries were conserved. Ovarian conservation carries a 6 fold risk of recurrent pain and 8 folds risk of reoperation. The decision has to be weighed taking into consideration the patient's age and the impact of early menopause on her life style. The recurrence of endometriosis symptoms and pelvic pain are directly correlated to the surgical precision and removal of peritoneal and deeply infiltrated disease. Surgical effort should always aim to eradicate the endometriotic lesions completely to keep the risk of recurrence as low as possible.

Active surveillance: does serial prostate biopsy increase histological inflammation?

BACKGROUND: Active surveillance (AS) is an appropriate management strategy for men with low-risk prostate cancer. Most protocols recommend repeated prostate biopsy every 12-24 months. The purpose of this paper is to describe histological inflammation patterns in men on AS who underwent serial prostate biopsy for disease monitoring. METHODS: We reviewed records of men on AS from January 1999 through February 2011 who had a diagnostic plus ≥1 repeat transrectal ultrasound-guided biopsies performed at our institution. The type and degree of inflammatory infiltrate were grossly reviewed and scored for each patient's biopsy by a single pathologist. Relationship of inflammation severity and number of serial biopsies was assessed using a repeated measures mixed model. Unpaired t-test and χ(2)-square analysis assessed variance in degree of inflammation and location of inflammation relative to cancer grade progression defined as Gleason sum increase. RESULTS: Fifty-six men met study inclusion criteria. Mean age was 62.1 (6.5) years, 71% were stage cT1c, 79% had a PSA level <10 ng ml(-1), and 98% had diagnostic Gleason sum ≤6. A small, statistically significant increase in maximum chronic inflammation (CI) scores with greater number of repeat biopsies was observed. CI scores were not associated with number of biopsies based on upgrade status. The main limitation to our study is our small sample size. Potential unmeasured confounders, such as unreported antibiotic use or symptomatic prostatitis, may have also affected our findings. CONCLUSIONS: In this pilot study of 56 men on AS for localized prostate cancer, degree of chronic histological inflammation increased with greater number of prostate biopsies, but was not associated with subsequent risk of grade progression.

[Evaluation of the self-tonometer Icare ONE in comparison to Goldmann applanation tonometry]. / Evaluation des Selbsttonometers Icare ONE im Vergleich mit der Goldmann-Applanationstonometrie.

OBJECTIVE: The aim of this clinical study was to demonstrate the practicability of self-measured intraocular pressure and to evaluate the reliability by comparing the data with those obtained by Goldmann applanation tonometry (GAT). METHODS: A total of 40 patients aged between 44 and 82 years with glaucoma were introduced to the handling of the tonometer. The self-measurements were done for 1-3 days following the medical measurement by GAT. The data were saved as "correct" or in the case of wrong handling as "false". The impressions of the patients were obtained by a questionnaire. RESULTS: A total number of 191 single measurements were registered by the Icare ONE and of these there were 97 (50.8%) signed "false". Of the patients 45% reached a maximum difference of ±5 mmHg between GAT and self-measurement in every single measurement. In the subgroup of under 60-year-old patients 70% reached this result. There were no indications of a systematic error. Of the probands 60% considered the handling of the Icare ONE as difficult. Nevertheless, 80% could imagine using the self-tonometer at home. CONCLUSIONS: The differences between the self-measurements and the GAT were highly fluctuating in some cases. In the group of patients younger than 60 years the agreement was better, so problems with the handling of the Icare ONE may be an important factor. However, the acceptance in the patients tested was high and continuous pressure measurements at home could be reasonable. Advancements in the handling and reliability are needed to improve clinical application of the measured values.

Effect of bile acid sequestrants on glucose metabolism, hepatic de novo lipogenesis, and cholesterol and bile acid kinetics in type 2 diabetes: a randomised controlled study.

AIMS/HYPOTHESIS: The primary aim of this completed multicentre randomised, parallel, double-blind placebo-controlled study was to elucidate the mechanisms of glucose-lowering with colesevelam and secondarily to investigate its effects on lipid metabolism (hepatic de novo lipogenesis, cholesterol and bile acid synthesis). METHODS: Participants with type 2 diabetes (HbA(1c) 6.7-10.0% [50-86 mmol/mol], fasting glucose <16.7 mmol/l, fasting triacylglycerols <3.9 mmol/l and LDL-cholesterol >1.55 mmol/l) treated with diet and exercise, sulfonylurea, metformin or a combination thereof, were randomised by a central coordinator to either 3.75 g/day colesevelam (n = 30) or placebo (n = 30) for 12 weeks at three clinical sites in the USA. The primary measure was the change from baseline in glucose kinetics with colesevelam compared to placebo treatment. Fasting and postprandial glucose, lipid and bile acid pathways were measured at baseline and post-treatment using stable isotope techniques. Plasma glucose, insulin, total glucagon-like peptide-1 (GLP-1), total glucose-dependent insulinotropic polypeptide (GIP), glucagon and fibroblast growth factor-19 (FGF-19) concentrations were measured during the fasting state and following a meal tolerance test. Data was collected by people blinded to treatment. RESULTS: Compared with placebo, colesevelam improved HbA(1c) (mean change from baseline of 0.3 [SD 1.1]% for placebo [n = 28] and -0.3 [1.1]% for colesevelam [n = 26]), glucose concentrations, fasting plasma glucose clearance and glycolytic disposal of oral glucose. Colesevelam did not affect gluconeogenesis or appearance rate (absorption) of oral glucose. Fasting endogenous glucose production and glycogenolysis significantly increased with placebo but were unchanged with colesevelam (treatment effect did not reach statistical significance). Compared with placebo, colesevelam increased total GLP-1 and GIP concentrations and improved HOMA-beta cell function while insulin, glucagon and HOMA-insulin resistance were unchanged. Colesevelam increased cholesterol and bile acid synthesis and decreased FGF-19 concentrations. However, no effect was seen on fractional hepatic de novo lipogenesis. CONCLUSIONS/INTERPRETATION: Colesevelam, a non-absorbed bile acid sequestrant, increased circulating incretins and improved tissue glucose metabolism in both the fasting and postprandial states in a manner different from other approved oral agents. TRIAL REGISTRATION: ClinicalTrials.gov NCT00596427 FUNDING: The study was funded by Daiichi Sankyo.

Evaluation of imbalance in stratified blocked randomization: some remarks on the range of validity of the model by Hallstrom and Davis.

OBJECTIVES: If in a clinical trial prognostic factors are known in advance, it is often recommended that randomization of patients should be stratified. The best-known method is permuted-block randomization within strata. But it suffers from the disadvantage that imbalance still occurs in the trial as a whole if there are a large number of strata, or/and the block sizes are too large for the number of patients. The results of Hallstrom and Davis are appropriate for evaluating the risk of such a troubled situation by using two special cases of their general variance formula. But it is merely generally argued for whichever practical situations these special cases are valid. Consequently, additional investigations are required to reveal the conditions for correct application. METHODS: We investigated the range of validity of special cases by performing computer simulations, varying a number of trial characteristics, and discuss the application of results for practical situations. RESULTS: The validity of special cases is not given in each situation. Depending on block size, a binomial distribution model is valid for a permitted average maximum number of patients per stratum between 36% and 57% of considered block sizes, whereas the uniform distribution model works adequately from at least 70%. In an intermediate range of invalidity, implementation of a simulation study is necessary to compute the probability distribution of differences. CONCLUSIONS: Our results are important if choosing the stratified permuted-block randomization to estimate the risk for an intolerable overall imbalance when planning a trial.