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

Conservation tillage and residue management improve soil health and crop productivity—Evidence from a rice-maize cropping system in Bangladesh.

The rice-maize (R-M) system is rapidly expanding in Bangladesh due to its greater suitability for diverse soil types and environments. The present conventional method of cultivating puddled transplanted rice and maize is input-intensive, decreases soil health through intense ploughing, and ultimately reduces farm profitability. There is a need to investigate alternatives. Accordingly, we conducted a replicated 2-year (2020–2021) field study to investigate the effects of conservation agriculture (CA) based tillage and crop establishment (TCE) techniques and residue management practices on the physical, chemical, and biological properties of soil along with crop productivity and the profitability of rice-maize systems in the sandy loam soil of Northwest Bangladesh. Two TCE techniques Puddled transplanted rice (PTR) followed by Conventional tillage maize (CTM) and strip tillage direct-seeded rice (STDSR) followed by strip-tilled maize (STM) were assigned to the main plots and different percentages of crop residue retention (0, 25, and 50% by height) were allocated to the subplots. Results showed that a reduction in bulk density (BD), soil penetration resistance (SPR), and increased soil porosity were associated with STDSR/STM-based scenarios (strip tillage coupled with 25 and 50% residue retention). The soil organic carbon (SOC) fractions, such as dissolved organic C (DOC), light and heavy particulate organic matter C (POM-C), MAOM, and microbial biomass C (MBC) levels in the 0–10 cm layer under ST based treatments were 95, 8, 6, 2 and 45% greater, respectively, compared to CT with no residue treatment. When compared to the CT treatment, the DOC, light POM-C, heavy POM-C, and MAOM in the 10–20 cm layer with ST treatment were 8, 34, 25, 4 and 37% higher, respectively. Residue retention in ST increased average rice, maize, and system yields by 9.2, 14.0, and 14.12%, respectively, when compared to CT. The system gross margin and benefit-cost ratio (BCR) were $1,515 ha−1 and 1.90 under conventional tillage to$1,696 ha−1 and 2.15 under strip-tillage practices. Thus, our study suggests that CA could be an appropriate practice for sustaining soil fertility and crop yield under R-M systems in light-textured soils or other similar soils in Bangladesh

Phenylbutyrate Counteracts Shigella Mediated Downregulation of Cathelicidin in Rabbit Lung and Intestinal Epithelia: A Potential Therapeutic Strategy

BACKGROUND: Cathelicidins and defensins are endogenous antimicrobial peptides (AMPs) that are downregulated in the mucosal epithelia of the large intestine in shigellosis. Oral treatment of Shigella infected rabbits with sodium butyrate (NaB) reduces clinical severity and counteracts the downregulation of cathelicidin (CAP-18) in the large intestinal epithelia. AIMS: To develop novel regimen for treating infectious diseases by inducing innate immunity, we selected sodium 4-phenylbutyrate (PB), a registered drug for a metabolic disorder as a potential therapeutic candidate in a rabbit model of shigellosis. Since acute respiratory infections often cause secondary complications during shigellosis, the systemic effect of PB and NaB on CAP-18 expression in respiratory epithelia was also evaluated. METHODS: The readouts were clinical outcomes, CAP-18 expression in mucosa of colon, rectum, lung and trachea (immunohistochemistry and real-time PCR) and release of the CAP-18 peptide/protein in stool (Western blot). PRINCIPAL FINDINGS: Significant downregulation of CAP-18 expression in the epithelia of rectum and colon, the site of Shigella infection was confirmed. Interestingly, reduced expression of CAP-18 was also noticed in the epithelia of lung and trachea, indicating a systemic effect of the infection. This suggests a causative link to acute respiratory infections during shigellosis. Oral treatment with PB resulted in reduced clinical illness and upregulation of CAP-18 in the epithelium of rectum. Both PB and NaB counteracted the downregulation of CAP-18 in lung epithelium. The drug effect is suggested to be systemic as intravenous administration of NaB could also upregulate CAP-18 in the epithelia of lung, rectum and colon. CONCLUSION: Our results suggest that PB has treatment potential in human shigellosis. Enhancement of CAP-18 in the mucosal epithelia of the respiratory tract by PB or NaB is a novel discovery. This could mediate protection from secondary respiratory infections that frequently are the lethal causes in dysentery

What constitutes responsiveness of physicians: A qualitative study in rural Bangladesh

Responsiveness entails the social actions by health providers to meet the legitimate expectations of patients. It plays a critical role in ensuring continuity and effectiveness of care within people centered health systems. Given the lack of contextualized research on responsiveness, we qualitatively explored the perceptions of outpatient users and providers regarding what constitute responsiveness in rural Bangladesh. An exploratory study was undertaken in Chuadanga, a southwestern Bangladeshi District, involving in-depth interviews of physicians (n = 17) and users (n = 7), focus group discussions with users (n = 4), and observations of patient provider interactions (three weeks). Analysis was guided by a conceptual framework of responsiveness, which includes friendliness, respecting, informing and guiding, gaining trust and optimizing benefits. In terms of friendliness, patients expected physicians to greet them before starting consultations; even though physicians considered this unusual. Patients also expected physicians to hold social talks during consultations, which was uncommon. With regards to respect patients expected physicians to refrain from disrespecting them in various ways; but also by showing respect explicitly. Patients also had expectations related to informing and guiding: they desired explanation on at least the diagnosis, seriousness of illness, treatment and preventive steps. In gaining trust, patients expected that physicians would refrain from illegal or unethical activities related to patients, e.g., demanding money against free services, bringing patients in own private clinics by brokers (dalals), colluding with diagnostic centers, accepting gifts from pharmaceutical representatives. In terms of optimizing benefits: patients expected that physicians should be financially sensitive and consider individual need of patients. There were multiple dimensions of responsiveness- for some, stakeholders had a consensus; context was an important factor to understand them. This being an exploratory study, further research is recommended to validate the nuances of the findings. It can be a guideline for responsiveness practices, and a tipping point for future research

Antenatal care in practice: an exploratory study in antenatal care clinics in the Kilombero Valley, south-eastern Tanzania

BACKGROUND: The potential of antenatal care for reducing maternal morbidity and improving newborn survival and health is widely acknowledged. Yet there are worrying gaps in knowledge of the quality of antenatal care provided in Tanzania. In particular, determinants of health workers' performance have not yet been fully understood. This paper uses ethnographic methods to document health workers' antenatal care practices with reference to the national Focused Antenatal Care guidelines and identifies factors influencing health workers' performance. Potential implications for improving antenatal care provision in Tanzania are discussed. METHODS: Combining different qualitative techniques, we studied health workers' antenatal care practices in four public antenatal care clinics in the Kilombero Valley, south-eastern Tanzania. A total of 36 antenatal care consultations were observed and compared with the Focused Antenatal Care guidelines. Participant observation, informal discussions and in-depth interviews with the staff helped to identify and explain health workers' practices and contextual factors influencing antenatal care provision. RESULTS: The delivery of antenatal care services to pregnant women at the selected antenatal care clinics varied widely. Some services that are recommended by the Focused Antenatal Care guidelines were given to all women while other services were not delivered at all. Factors influencing health workers' practices were poor implementation of the Focused Antenatal Care guidelines, lack of trained staff and absenteeism, supply shortages and use of working tools that are not consistent with the Focused Antenatal Care guidelines. Health workers react to difficult working conditions by developing informal practices as coping strategies or "street-level bureaucracy". CONCLUSIONS: Efforts to improve antenatal care should address shortages of trained staff through expanding training opportunities, including health worker cadres with little pre-service training. Attention should be paid to the identification of informal practices resulting from individual coping strategies and "street-level bureaucracy" in order to tackle problems before they become part of the organizational culture

Prevalence, Features and Risk Factors for Malaria Co-Infections amongst Visceral Leishmaniasis Patients from Amudat Hospital, Uganda

Visceral leishmaniasis (VL) and malaria are two major parasitic diseases sharing a similar demographic and geographical distribution. In areas where both diseases are endemic, such as Sudan, Uganda, India and Bangladesh, co-infection cases have been reported, but features and risk factors associated with these co-morbidities remain poorly characterized. In the present study, routinely collected data of VL patients admitted to Amudat Hospital, Uganda, were used to investigate the magnitude of VL-malaria co-infections and identify possible risk factors. Nearly 20% of the patients included in this study were found to be co-infected with VL and malaria, indicating that this is a common condition among VL patients living in malaria endemic areas. Young age (≤9 years) was identified as an important risk factor for contracting the VL-malaria co-infection, while being anemic or carrying a skin infection appeared to negatively correlate with the co-morbidity. Co-infected patients presented with slightly more severe symptoms compared to mono-infected patients, but had a similar prognosis, possibly due to early diagnosis of malaria as a result of systematic testing. In conclusion, these results emphasize the importance of performing malaria screening amongst VL patients living in malaria-endemic areas and suggest that close monitoring of co-infected patients should be implemented

Studies on the antidiarrhoeal activity of Aegle marmelos unripe fruit: Validating its traditional usage

<p>Abstract</p> <p>Background</p> <p><it>Aegle marmelos </it>(L.) Correa has been widely used in indigenous systems of Indian medicine due to its various medicinal properties. However, despite its traditional usage as an anti-diarrhoeal there is limited information regarding its mode of action in infectious forms of diarrhoea. Hence, we evaluated the hot aqueous extract (decoction) of dried unripe fruit pulp of <it>A. marmelos </it>for its antimicrobial activity and effect on various aspects of pathogenicity of infectious diarrhoea.</p> <p>Methods</p> <p>The decoction was assessed for its antibacterial, antigiardial and antirotaviral activities. The effect of the decoction on adherence of enteropathogenic <it>Escherichia coli </it>and invasion of enteroinvasive <it>E. coli </it>and <it>Shigella flexneri </it>to HEp-2 cells were assessed as a measure of its effect on colonization. The effect of the decoction on production of <it>E. coli </it>heat labile toxin (LT) and cholera toxin (CT) and their binding to ganglioside monosialic acid receptor (GM1) were assessed by GM1-enzyme linked immuno sorbent assay whereas its effect on production and action of <it>E. coli </it>heat stable toxin (ST) was assessed by suckling mouse assay.</p> <p>Results</p> <p>The decoction showed cidal activity against <it>Giardia </it>and rotavirus whereas viability of none of the six bacterial strains tested was affected. It significantly reduced bacterial adherence to and invasion of HEp-2 cells. The extract also affected production of CT and binding of both LT and CT to GM1. However, it had no effect on ST.</p> <p>Conclusion</p> <p>The decoction of the unripe fruit pulp of <it>A. marmelos</it>, despite having limited antimicrobial activity, affected the bacterial colonization to gut epithelium and production and action of certain enterotoxins. These observations suggest the varied possible modes of action of <it>A. marmelos </it>in infectious forms of diarrhoea thereby validating its mention in the ancient Indian texts and continued use by local communities for the treatment of diarrhoeal diseases.</p

Snake Bite in South Asia: A Review

Snake bite is one of the most neglected public health issues in poor rural communities living in the tropics. Because of serious misreporting, the true worldwide burden of snake bite is not known. South Asia is the world's most heavily affected region, due to its high population density, widespread agricultural activities, numerous venomous snake species and lack of functional snake bite control programs. Despite increasing knowledge of snake venoms' composition and mode of action, good understanding of clinical features of envenoming and sufficient production of antivenom by Indian manufacturers, snake bite management remains unsatisfactory in this region. Field diagnostic tests for snake species identification do not exist and treatment mainly relies on the administration of antivenoms that do not cover all of the important venomous snakes of the region. Care-givers need better training and supervision, and national guidelines should be fed by evidence-based data generated by well-designed research studies. Poorly informed rural populations often apply inappropriate first-aid measures and vital time is lost before the victim is transported to a treatment centre, where cost of treatment can constitute an additional hurdle. The deficiency of snake bite management in South Asia is multi-causal and requires joint collaborative efforts from researchers, antivenom manufacturers, policy makers, public health authorities and international funders