Development and assessment of a daily time-step continuous simulation modelling approach for design flood estimation at ungauged locations: ACRU model and Thukela Catchment case study

The estimation of design floods is necessary for the design of hydraulic structures. Commonly used event-based approaches to design flood estimation have several limitations, which include the estimation of antecedent soil moisture conditions and the assumption that the exceedance probability of the design flood is the same as the exceedance probability of the design rainfall. Many of the limitations of event-based approaches may be overcome by the use of continuous simulation modelling for design flood estimation. This paper contains a brief summary on the development and assessment of a continuous simulationmodelling system for design flood estimation in ungauged catchments. These developments include an investigation into the appropriate spatial scale of model configuration for optimum performance of the system, the temporal disaggregation of daily rainfall for hydrograph generation, flood routing in ungauged catchments and the use of radar information and rain-gauge data to improve the estimation of catchment rainfall. Results from the application of the system for design flood estimation in the Thukela Catchment in South Africa are presented and discussed. The results from the study highlight the challenges of hydrological modelling in an operational catchment and the need for reliable rainfall and runoff data. From the results obtained, it is concluded that reasonable and consistent estimates of design floods in the Thukela Catchment, particularly in smaller sub-catchments, can be obtained using the ACRU model.Keywords: Design flood estimation; continuous simulation modelling, Thukela Catchmen

Failure of A Novel, Rapid Antigen and Antibody Combination Test to Detect Antigen-Positive HIV Infection in African Adults with Early HIV Infection

BACKGROUND: Acute HIV infection (prior to antibody seroconversion) represents a high-risk window for HIV transmission. Development of a test to detect acute infection at the point-of-care is urgent. METHODS: Volunteers enrolled in a prospective study of HIV incidence in four African cities, Kigali in Rwanda and Ndola, Kitwe and Lusaka in Zambia, were tested regularly for HIV by rapid antibody test and p24 antigen ELISA. Five subgroups of samples were also tested by the Determine Ag/Ab Combo test 1) Antigen positive, antibody negative (acute infection); 2) Antigen positive, antibody positive; 3) Antigen negative, antibody positive; 4) Antigen negative, antibody negative; and 5) Antigen false positive, antibody negative (HIV uninfected). A sixth group included serial dilutions from a p24 antigen-positive control sample. Combo test results were reported as antigen positive, antibody positive, or both. RESULTS: Of 34 group 1 samples with VL between 5x105 and >1.5x107 copies/mL (median 3.5x106), 1 (2.9%) was detected by the Combo antigen component, 7 (20.6%) others were positive by the Combo antibody component. No group 2 samples were antigen positive by the Combo test (0/18). Sensitivity of the Combo antigen test was therefore 1.9% (1/52, 95% CI 0.0, 9.9). One false positive Combo antibody result (1/30, 3.3%) was observed in group 4. No false-positive Combo antigen results were observed. The Combo antigen test was positive in group 6 at concentrations of 80 pg/mL, faintly positive at 40 and 20 pg/mL, and negative thereafter. The p24 ELISA antigen test remained positive at 5 pg/mL. CONCLUSIONS: Although the antibody component of the Combo test detected antibodies to HIV earlier than the comparison antibody tests used, less than 2% of the cases of antigen-positive HIV infection were detected by the Combo antigen component. The development of a rapid point-of-care test to diagnose acute HIV infection remains an urgent goal

TIMP-2 Fusion Protein with Human Serum Albumin Potentiates Anti-Angiogenesis-Mediated Inhibition of Tumor Growth by Suppressing MMP-2 Expression

TIMP-2 protein has been intensively studied as a promising anticancer candidate agent, but the in vivo mechanism underlying its anticancer effect has not been clearly elucidated by previous works. In this study, we investigated the mechanism underlying the anti-tumor effects of a TIMP-2 fusion protein conjugated with human serum albumin (HSA/TIMP-2). Systemic administration of HSA/TIMP-2 effectively inhibited tumor growth at a minimum effective dose of 60 mg/kg. The suppressive effect of HSA/TIMP-2 was accompanied by a marked reduction of in vivo vascularization. The anti-angiogenic activity of HSA/TIMP-2 was directly confirmed by CAM assays. In HSA/TIMP-2-treated tumor tissues, MMP-2 expression was profoundly decreased without a change in MT1-MMP expression of PECAM-1-positive cells. MMP-2 mRNA was also decreased by HSA/TIMP-2 treatment of human umbilical vein endothelial cells. Zymographic analysis showed that HSA/TIMP-2 substantially decreased extracellular pro-MMP-2 activity (94–99% reduction) and moderately decreased active MMP-2 activity (10–24% reduction), suggesting MT1-MMP-independent MMP-2 modulation. Furthermore, HSA/TIMP-2 had no effect on in vitro active MMP-2 activity and in vivo MMP-2 activity. These studies show that HSA/TIMP-2 potentiates anti-angiogenic activity by modulating MMP-2 expression, but not MMP-2 activity, to subsequently suppress tumor growth, suggesting an important role for MMP-2 expression rather than MMP-2 activity in anti-angiogenesis

Life Quality Impairment Caused by Hookworm-Related Cutaneous Larva Migrans in Resource-Poor Communities in Manaus, Brazil

Hookworm-related cutaneous larva migrans (CLM) is a parasitic skin disease common in developing countries with hot climates. In resource-poor settings, CLM is associated with considerable morbidity. The disease is caused by animal hookworm larvae that penetrate the skin and migrate aimlessly in the epidermis as they cannot penetrate the basal membrane. Particularly in the rainy season, the intensity of infection is high with up to 40 larval tracks in an affected individual. Tracks are very itchy and are surrounded by a significant inflammation of the skin. Bacterial superinfection is common and intensifies the inflammation. The psychosocial consequences caused by CLM have never been investigated. We showed that CLM causes skin disease-associated life quality impairment in 91 patients with CLM. Skin disease-associated life quality was significantly impaired. The degree of impairment correlated to the intensity of infection and the number of body areas affected. After treatment with ivermectin, life quality was rapidly restored

Resectable pancreatic small cell carcinoma

Primary pancreatic small cell carcinoma (SCC) is rare, with just over 30 cases reported in the literature. Only 7 of these patients underwent surgical resection with a median survival of 6 months. Prognosis of SCC is therefore considered to be poor, and the role of adjuvant therapy is uncertain. Here we report two institutions' experience with resectable pancreatic SCC. Six patients with pancreatic SCC treated at the Johns Hopkins Hospital (4 patients) and the Mayo Clinic (2 patients) were identified from prospectively collected pancreatic cancer databases and re-reviewed by pathology. All six patients underwent a pancreaticoduodenectomy. Clinicopathologic data were analyzed, and the literature on pancreatic SCC was reviewed. Median age at diagnosis was 50 years (range 27–60). All six tumors arose in the head of the pancreas. Median tumor size was 3 cm, and all cases had positive lymph nodes except for one patient who only had five nodes sampled. There were no perioperative deaths and three patients had at least one postoperative complication. All six patients received adjuvant therapy, five of whom were given combined modality treatment with radiation, cisplatin, and etoposide. Median survival was 20 months with a range of 9–173 months. The patient who lived for 9 months received chemotherapy only, while the patient who lived for 173 months was given chemoradiation with cisplatin and etoposide and represents the longest reported survival time from pancreatic SCC to date. Pancreatic SCC is an extremely rare form of cancer with a poor prognosis. Patients in this surgical series showed favorable survival rates when compared to prior reports of both resected and unresectable SCC. Cisplatin and etoposide appears to be the preferred chemotherapy regimen, although its efficacy remains uncertain, as does the role of combined modality treatment with radiation

Gastric cancers of Western European and African patients show different patterns of genomic instability

<p>Abstract</p> <p>Background</p> <p>Infection with <it>H. pylori </it>is important in the etiology of gastric cancer. Gastric cancer is infrequent in Africa, despite high frequencies of <it>H. pylori </it>infection, referred to as the African enigma. Variation in environmental and host factors influencing gastric cancer risk between different populations have been reported but little is known about the biological differences between gastric cancers from different geographic locations. We aim to study genomic instability patterns of gastric cancers obtained from patients from United Kingdom (UK) and South Africa (SA), in an attempt to support the African enigma hypothesis at the biological level.</p> <p>Methods</p> <p>DNA was isolated from 67 gastric adenocarcinomas, 33 UK patients, 9 Caucasian SA patients and 25 native SA patients. Microsatellite instability and chromosomal instability were analyzed by PCR and microarray comparative genomic hybridization, respectively. Data was analyzed by supervised univariate and multivariate analyses as well as unsupervised hierarchical cluster analysis.</p> <p>Results</p> <p>Tumors from Caucasian and native SA patients showed significantly more microsatellite instable tumors (p < 0.05). For the microsatellite stable tumors, geographical origin of the patients correlated with cluster membership, derived from unsupervised hierarchical cluster analysis (p = 0.001). Several chromosomal alterations showed significantly different frequencies in tumors from UK patients and native SA patients, but not between UK and Caucasian SA patients and between native and Caucasian SA patients.</p> <p>Conclusions</p> <p>Gastric cancers from SA and UK patients show differences in genetic instability patterns, indicating possible different biological mechanisms in patients from different geographical origin. This is of future clinical relevance for stratification of gastric cancer therapy.</p

Integrated genomic characterization of oesophageal carcinoma

Oesophageal cancers are prominent worldwide; however, there are few targeted therapies and survival rates for these cancers remain dismal. Here we performed a comprehensive molecular analysis of 164 carcinomas of the oesophagus derived from Western and Eastern populations. Beyond known histopathological and epidemiologic distinctions, molecular features differentiated oesophageal squamous cell carcinomas from oesophageal adenocarcinomas. Oesophageal squamous cell carcinomas resembled squamous carcinomas of other organs more than they did oesophageal adenocarcinomas. Our analyses identified three molecular subclasses of oesophageal squamous cell carcinomas, but none showed evidence for an aetiological role of human papillomavirus. Squamous cell carcinomas showed frequent genomic amplifications of CCND1 and SOX2 and/or TP63, whereas ERBB2, VEGFA and GATA4 and GATA6 were more commonly amplified in adenocarcinomas. Oesophageal adenocarcinomas strongly resembled the chromosomally unstable variant of gastric adenocarcinoma, suggesting that these cancers could be considered a single disease entity. However, some molecular features, including DNA hypermethylation, occurred disproportionally in oesophageal adenocarcinomas. These data provide a framework to facilitate more rational categorization of these tumours and a foundation for new therapies.ope

Global patient outcomes after elective surgery: prospective cohort study in 27 low-, middle- and high-income countries.

BACKGROUND: As global initiatives increase patient access to surgical treatments, there remains a need to understand the adverse effects of surgery and define appropriate levels of perioperative care. METHODS: We designed a prospective international 7-day cohort study of outcomes following elective adult inpatient surgery in 27 countries. The primary outcome was in-hospital complications. Secondary outcomes were death following a complication (failure to rescue) and death in hospital. Process measures were admission to critical care immediately after surgery or to treat a complication and duration of hospital stay. A single definition of critical care was used for all countries. RESULTS: A total of 474 hospitals in 19 high-, 7 middle- and 1 low-income country were included in the primary analysis. Data included 44 814 patients with a median hospital stay of 4 (range 2-7) days. A total of 7508 patients (16.8%) developed one or more postoperative complication and 207 died (0.5%). The overall mortality among patients who developed complications was 2.8%. Mortality following complications ranged from 2.4% for pulmonary embolism to 43.9% for cardiac arrest. A total of 4360 (9.7%) patients were admitted to a critical care unit as routine immediately after surgery, of whom 2198 (50.4%) developed a complication, with 105 (2.4%) deaths. A total of 1233 patients (16.4%) were admitted to a critical care unit to treat complications, with 119 (9.7%) deaths. Despite lower baseline risk, outcomes were similar in low- and middle-income compared with high-income countries. CONCLUSIONS: Poor patient outcomes are common after inpatient surgery. Global initiatives to increase access to surgical treatments should also address the need for safe perioperative care. STUDY REGISTRATION: ISRCTN5181700