Smaller sample sizes for phase II trials based on exact tests with actual error rates by trading-off their nominal levels of significance and power

Background: Sample sizes for single-stage phase II clinical trials in the literature are often based on exact (binomial) tests with levels of significance (alpha (α) 80%). This is because there is not always a sample size where α and power are exactly equal to 5% and 80%, respectively. Consequently, the opportunity to trade-off small amounts of α and power for savings in sample sizes may be lost. Methods: Sample-size tables are presented for single-stage phase II trials based on exact tests with actual levels of significance and power. Trade-off in small amounts of α and power allows the researcher to select from several possible designs with potentially smaller sample sizes compared with existing approaches. We provide SAS macro coding and an R function, which for a given treatment difference, allow researchers to examine all possible sample sizes for specified differences are provided. Results: In a single-arm study with P0 (standard treatment)=10% and P1 (new treatment)=20%, and specified α=5% and power=80%, the A’Hern approach yields n=78 (exact α=4.53%, power=80.81%). However, by relaxing α to 5.67% and power to 77.7%, a sample size of 65 can be used (a saving of 13 patients). Interpretation: The approach we describe is especially useful for trials in rare disorders, or for proof-of-concept studies, where it is important to minimise the trial duration and financial costs, particularly in single-arm cancer trials commonly associated with expensive treatment options

What Is the Best Option for Treating Venous Leg Ulcer Infection? Is It Systemic or Local Antimicrobials or a Combination of Both? A Retrospective Cohort Study

Study aimed to find out best option (systemic or local antimicrobial or combination of both) for treating venous leg ulcer infection. Patients’ files were reviewed retrospectively. Participants were divided into three groups. First group was treated by systemic antibiotics only (SABG). Second group received local antibiotics only (LABG). Third group was treated by combination of both (SLABG). Treatment strategies were compared based on multiple parameters using Pearson chi-squared test & relative risk (RR). 456 participants identified: 153 in SABG, 152 in LABG and 151 in SLABG. It was found that SLABG group was statistically significantly better than other single treatment strategies regarding all parameters (except bacterial resistance): (i) ulcer healing within usual duration (10-14 days) was 2.4 time higher (RR 2.4, 95% CI: 1.84, 3.12), (ii) probability of not recurring ulcer was 2.6 time higher (iii) probability of not getting increased wound size, abscess,cellulites was 5 times higher (iv) probability of not developing septicemia was 40% higher (v) probability of not requiring surgical intervention was 30% higher (vi) fewer patients needed prolonged hospitalization & lower cost was 8 times more likely (vii) patients were 3 times more satisfied during treatment.Probability of bacterial resistance was six times higher with SLABG and 5 times higher with SABG compared to LABG. For RR & CI values for all above parameters, see results below Ultimately, combination of both systemic and local antimicrobials may be best option to treat venous leg ulcer infection with out- weight with emergence of antibiotic-resistance microorganism

Is abdominal drainage after open emergency appendectomy for complicated appendicitis beneficial or waste of money? A single centre retrospective cohort study

BACKGROUND: Appendicitis is a medical condition that causes painful inflammation of the appendix. For acute appendicitis, appendectomy is immediately required as any delay may lead to serious complications such as gangrenous or perforated appendicitis with or without localized abscess formation. Patients who had appendectomy for complicated appendicitis are more prone to develop post-operative complications such as peritoneal abscess or wound infection. Sometimes, abdominal drainage is used to reduce these complications. However, the advantage of the abdominal drainage to minimize post-operative complications is not clear. Therefore, the aim of this study was to investigate whether the use of abdominal drainage after open emergency appendectomy for complicated appendicitis (perforated appendicitis with localized abscess formation only) can prevent or significantly reduce post-operative complications such as intra-peritoneal abscess formation or wound infection. METHODS: In this retrospective cohort study, files and notes were reviewed retrospectively for patients who had open emergency appendectomy for complicated appendicitis (perforated appendicitis with localized abscess formation only) and who had already been admitted and discharged from the surgical wards of Kerbala medical university/Imam Hussein medical city hospital/Kerbala/Iraq. Patients were selected according to specific inclusion and exclusion criteria. Patients were divided into two groups; drainage and non-drainage groups. The drainage group had intra-abdominal drain inserted after the surgery, while the non-drainage group had no drain placed post-operatively. A comparison between both groups was done in terms of these parameters; (i) the development of post operative intra-peritoneal abscess and or wound infection. (ii) The length and cost of hospital stay. (iii) The mortality outcomes. Statistical analysis was done using Pearson Chi-square test, Independent sample t-test and Mann-Whitney U Test. RESULTS: Of 227 patients with open emergency appendectomy for complicated appendicitis, 114 had received abdominal drain after the surgery. Fifty out of 114 patients (43.9%) with abdominal drainage developed post-operative intra-peritoneal abscess (abdominal or pelvic) while 53 out of 113 patients (46.9%) without drainage developed the same complication (P = 0.65). It was also revealed that for patients with drainage, 42 patients (36.8%) had post-operative wound infection, whereas this number was 38 (33.6%) for patients without drainage (P = 0.61). On the other hand, the patients with drain had significantly longer length of hospital stay (mean length of stay: 4.99 days versus 2.12 days, P < 0.001) and significantly higher cost (median cost per patient: $120 versus$60, P < 0.001). CONCLUSION: Installation of abdominal drainage after open emergency appendectomy for complicated appendicitis did not bring any considerable advantage in terms of prevention or significant reduction of post-operative intra-peritoneal abscess and wound infection. Rather, it lengthened the hospital stay and doubled the cost of operation

The sedimentology of river confluences

This is the author accepted manuscript. The final version is available from Wiley via the DOI in this record.Channel confluences are key nodes within large river networks, and yet surprisingly little is known about their spatial and temporal evolution. Moreover, because confluences are associated with vertical scour that typically extends to several times the mean channel depth, the deposits associated with such scours should have a high preservation potential within the rock record. Paradoxically, such scours are rarely observed, and their preservation and sedimentological interpretation are poorly understood. The present study details results from a physically‐based morphodynamic model that is applied to simulate the evolution and alluvial architecture of large river junctions. Boundary conditions within the model were defined to approximate the junction of the Ganges and Jamuna rivers, Bangladesh, with the model output being supplemented by geophysical datasets collected at this junction. The numerical simulations reveal several distinct styles of sedimentary fill that are related to the morphodynamic behaviour of bars, confluence scour downstream of braid bars, bend scour and major junction scour. Comparison with existing, largely qualitative, conceptual models reveals that none of these can be applied simply, although elements of each are evident in the deposits generated by the numerical simulation and observed in the geophysical data. The characteristics of the simulated scour deposits are found to vary according to the degree of reworking caused by channel migration, a factor not considered adequately in current conceptual models of confluence sedimentology. The alluvial architecture of major junction scours is thus characterized by the prevalence of erosion surfaces in conjunction with the thickest depositional sets. Confluence scour downstream of braid bar and bend scour sites may preserve some large individual sets, but these locations are typically characterized by lower average set thickness compared to major junction scour and by a lack of large‐scale erosional surfaces. Areas of deposition not related to any of the specific scour types highlighted above record the thinnest depositional sets. This variety in the alluvial architecture of scours may go some way towards explaining the paradox of ancient junction scours, that while abundant large scours are likely in the rock record, they have been reported rarely. The present results outline the likely range of confluence sedimentology and will serve as a new tool for recognizing and interpreting these deposits in the ancient fluvial record.This work was funded by a UK Natural Environment Research Council award to Sambrook Smith (NE/I023228/1), Bull (NE/I023864/1) and Nicholas (NE/I023120/1)

The planform mobility of river channel confluences: Insights from analysis of remotely sensed imagery

This is the author accepted manuscript. The final version is available from the publisher via the DOI in this record.River channel confluences are widely acknowledged as important geomorphological nodes that control the downstream routing of water and sediment, and which are locations for the preservation of thick fluvial deposits overlying a basal scour. Despite their importance, there has been little study of the stratigraphic characteristics of river junctions, or the role of confluence morphodynamics in influencing stratigraphic character and preservation potential. As a result, although it is known that confluences can migrate through time, models of confluence geomorphology and sedimentology are usually presented from the perspective that the confluence remains at a fixed location. This is problematic for a number of reasons, not least of which is the continuing debate over whether it is possible to discriminate between scour that has been generated by autocyclic processes (such as confluence scour) and that driven by allocyclic controls (such as sea-level change). This paper investigates the spatial mobility of river confluences by using the 40-year record of Landsat Imagery to elucidate the styles, rates of change and areal extent over which large river confluence scours may migrate. On the basis of these observations, a new classification of the types of confluence scour is proposed and applied to the Amazon and Ganges-Brahmaputra-Meghna (GBM) basins. This analysis demonstrates that the drivers of confluence mobility are broadly the same as those that drive channel change more generally. Thus in the GBM basin, a high sediment supply, large variability in monsoonal driven discharge and easily erodible bank materials result in a catchment where over 80% of large confluences are mobile over this 40-year window; conversely this figure is < 40% for the Amazon basin. These results highlight that: i) the potential areal extent of confluence scours is much greater than previously assumed, with the location of some confluences on the Jamuna (Brahmaputra) River migrating over a distance of 20 times the tributary channel width; ii) extensive migration in the confluence location is more common than currently assumed, and iii) confluence mobility is often tied to the lithological and hydrological characteristics of the drainage basins that determine sediment yield.This work was funded by NERC grant NE/I023228/1 to Sambrook Smith, Bull, Nicholas and Best

The Use of Transdermal Estrogen in Castrate-resistant, Steroid-refractory Prostate Cancer

BACKGROUND: Androgen-deprivation therapy is the mainstay of treatment for metastatic prostate cancer. Corticosteroids and estrogens are also useful agents in castration-resistant prostate cancer (CRPC). However, oral estrogens are associated with thromboembolic events, which limits their use, and transdermal estrogens may offer a safer alternative. This study was carried out to determine the safety and effectiveness of transdermal estrogens in CRPC. PATIENTS AND METHODS: Forty-one patients with CRPC and steroid-resistant prostate cancer were eligible for this dose-escalation study of transdermal estradiol. A starting dose of 50 mcg/24 hours was applied and increased if prostate-specific antigen (PSA) rose > 5 ng/mL in steps to 300 mcg/24 hours. The primary endpoint was PSA response, and secondary outcomes included incidence of thromboembolic events and progression-free survival. Patients who progressed were offered diethylstilbestrol. RESULTS: Five (13%) of 40 patients had > 50% PSA reduction for at least 1 month at any transdermal estradiol dose. No venous-thromboembolic events were observed, and responses plateaued at 200 mcg/24 hours. A correlation between PSA response and rising sex hormone binding globulin was seen. Fifty percent of patients subsequently responded to low-dose diethylstilbestrol. CONCLUSION: Transdermal estradiol appears to be a low toxicity treatment option to control CRPC after failure of steroid therapy. Modulation of sex hormone binding globulin by transdermal estradiol may be one mechanism of action of estrogens on CRPC. Oral estrogens remain effective after the use of transdermal estradiol

One-pot synthesis and negative ion mass spectrometric investigation of a densely functionalized cinnoline, 3-amino-5,7,8-trichloro-6-hydroxycinnoline-4-carbonitrile

Known densely substituted 3-amino-5,7,8-trichloro-6-hydroxycinnoline-4-carbonitrile was synthesized using a new synthetic protocol involving chloranil and malonitrile via quinone methide formation. This one-pot synthesis occurs under base mediated conditions in a polar medium. The method involves condensation of excess malononitrile with chloranil in ethanol at reflux to 2-(2,4,5-trichloro-3-hydroxy-6-oxocyclohexa-2,4-dien-1-ylidene) malononitrile. This is an atom efficient, simple and effective procedure for the preparation of a highly substituted cinnoline that can serve as a relay to antimalarial prototypes

Identification of novel clostridium perfringens type E strains that carry an iota toxin plasmid with a functional enterotoxin gene

Clostridium perfringens enterotoxin (CPE) is a major virulence factor for human gastrointestinal diseases, such as food poisoning and antibiotic associated diarrhea. The CPE-encoding gene (cpe) can be chromosomal or plasmid-borne. Recent development of conventional PCR cpe-genotyping assays makes it possible to identify cpe location (chromosomal or plasmid) in type A isolates. Initial studies for developing cpe genotyping assays indicated that all cpe-positive strains isolated from sickened patients were typable by cpe-genotypes, but surveys of C. perfringens environmental strains or strains from feces of healthy people suggested that this assay might not be useful for some cpe-carrying type A isolates. In the current study, a pulsed-field gel electrophoresis Southern blot assay showed that four cpe-genotype untypable isolates carried their cpe gene on a plasmid of ~65 kb. Complete sequence analysis of the ~65 kb variant cpe-carrying plasmid revealed no intact IS elements and a disrupted cytosine methyltransferase (dcm) gene. More importantly, this plasmid contains a conjugative transfer region, a variant cpe gene and variant iota toxin genes. The toxin genes encoded by this plasmid are expressed based upon the results of RT-PCR assays. The ~65 kb plasmid is closely related to the pCPF4969 cpe plasmid of type A isolates. MLST analyses indicated these isolates belong to a unique cluster of C. perfringens. Overall, these isolates carrying a variant functional cpe gene and iota toxin genes represent unique type E strains. © 2011 Miyamoto et al

Purpurogallin-A heme binding component of oak galls

Recently, it has been shown that Purpurogallin (PPG), an orange benztropolone constituent of oak galls and its derivative, CU-CPT22, can compete with the binding of the specific lipoprotein ligand to toll-like receptors (TLRs), which are type I transmembrane proteins. These recognize pathogen-derived macromolecules that play a key role in the innate immune system. This system provides an attractive target for the treatment of various immune disorders. Notably, PPG also interacts with various metals and its mode of action against HIV in vitro may involve inhibition of metal containing integrases. In the current study, an optimised synthesis of PPG is presented together with its gas phase behaviour (probed by mass spectrometry) as well as its redox behaviour with porphyrins such as heme. This interaction may also explain its effects at metal containing integrases within HIV in vitro as well as its action during processing of iron complexes within Plasmodia. This compound could serve as a novel prototype for the synthesis of novel redox active antimalarials

Isolation and Characterization of Antibacterial Compounds from <i>Aspergillus fumigatus:</i> An Endophytic Fungus from a Mangrove Plant of the Sundarbans.

The Sundarbans, a UNESCO world heritage site, is one of the largest mangrove forests in one stretch. Mangrove plants from this forest are little studied for their endophytic fungi. In this study, we isolated fourteen endophytic fungi from the plants Ceriops decandra and Avicennia officinalis collected from the Sundarbans. Five of them were identified as Aspergillus sp. and one as Penicillium sp. by macroscopic and microscopic observation. Antibacterial activity of the crude extracts obtained from these endophytes was determined against Staphylococcus aureus, Micrococcus luteus, Escherichia coli, and Pseudomonas aeruginosa using resazurin-based microtiter assay. The isolated endophytes showed varying degrees of antibacterial activity with MICs ranging between 5 and 0.078 mg/mL. Molecular identification of the most active endophyte revealed its identity as Aspergillus fumigatus obtained from the leaves of C. decandra. Acute toxicity study of the ethyl acetate extract of A. fumigatus in mice revealed no mortality even at the highest dose of 2000 mg/kg bodyweight, though some opposing results are found in the subacute toxicity study. The extract was subjected to silica gel and Sephadex column chromatography resulting in the isolation of three pure compounds. LC-MS analysis of these pure compounds revealed their identity as fumigaclavine C, azaspirofuran B, and fraxetin. This is the first report of fraxetin from A. fumigatus. All three identified compounds were previously reported for their antibacterial activity against different strains of both Gram-positive and Gram-negative bacteria. Therefore, the observed antibacterial activity of the ethyl acetate (EtOAc) extract of A. fumigatus could be due to the presence of these compounds. These results support the notion of investigating fungal endophytes from the Sundarbans for new antimicrobial compounds