Light intensity preferences of broiler chickens: implications for welfare.

There is considerable debate as to the optimal light intensities for growing chickens. This is influencing regulations and industry practices. The present study examines the preference of broiler chickens for light intensity. A choice system was developed to allow determination of the preferences of broiler chickens for light intensity. This system had three light proof pens each with feeders or waterers but different light intensities. There was a connecting transit pen with a light intensity of 1 to 2 lux. This allowed birds access to the pens each with feeders or waterers. There were markedly more chickens observed in the pens each with feeders or waterers and a light intensity of 20 lux than 5 lux. Moreover, more feed was consumed in the 20 lux pens than 5 pens. There were also high numbers of chickens in the transit compartment with its low light intensity (1 to 2 lux) and no feeders or waterers. Broiler chickens exhibited a preference for 20 lux light intensity for feeding compared to 5 lux light intensity. The present study supports the view that there should be a light intensity of at least 20 lux for the areas around the feeders and also suggests that light intensity may be reduced in other areas for resting and other activities.

Modeling underwater noise propagation from marine hydrokinetic power devices through a time-domain, velocity-pressure solution.

Marine hydrokinetic (MHK) devices generate electricity from the motion of tidal and ocean currents, as well as ocean waves, to provide an additional source of renewable energy available to the United States. These devices are a source of anthropogenic noise in the marine ecosystem and must meet regulatory guidelines that mandate a maximum amount of noise that may be generated. In the absence of measured levels from in situ deployments, a model for predicting the propagation of sound from an array of MHK sources in a real environment is essential. A set of coupled, linearized velocity-pressure equations in the time-domain are derived and presented in this paper, which are an alternative solution to the Helmholtz and wave equation methods traditionally employed. Discretizing these equations on a three-dimensional (3D), finite-difference grid ultimately permits a finite number of complex sources and spatially varying sound speeds, bathymetry, and bed composition. The solution to this system of equations has been parallelized in an acoustic-wave propagation package developed at Sandia National Labs, called Paracousti. This work presents the broadband sound pressure levels from a single source in two-dimensional (2D) ideal and Pekeris wave-guides and in a 3D domain with a sloping boundary. The paper concludes with demonstration of Paracousti for an array of MHK sources in a simple wave-guide.

Six-year clinical performance of etch-and-rinse and self-etch adhesives.

OBJECTIVE: To evaluate the 6-year clinical performance of Xeno IV, Xeno III, and XP Bond adhesives in the restoration of non-carious cervical lesions (NCCLs). METHODS: This was a randomized controlled clinical trial where 39 participants met the inclusion/exclusion criteria and were enrolled. Lesions restored were notch-shaped NCCLs. Prior to adhesive procedures, NCCLs were roughened. No enamel bevel was placed and no mechanical retention was created. Adhesive systems were applied following manufacturer's instructions and the NCCLs were restored with composite resin (TPH(3)). Restorations were finished immediately after placement and scored with regard to retention, marginal discoloration, marginal adaptation, sensitivity, and secondary caries using modified USPHS criteria. Descriptive statistics were performed. Logistic regression models were performed for each outcome separately with compound symmetry correlation structure where teeth were clustered by participants. All analyses were conducted using SAS 9.2. RESULTS: The 6-year recall rate was 77.5% of the restorations (76.9% of the participants). No statistical differences were found between adhesives for retention, marginal discoloration, and marginal adaptation. Restorations failed by loss of retention (16.7%, 27.6%, and 11.8% of Xeno IV, Xeno III, and XP Bond restorations, respectively) and marginal discoloration (7.4% of Xeno IV restorations). For every unit increase in restoration volume it was 1.31 (95%C.I. 1.05, 1.63, P=0.01) times more likely that the restoration retention would be maintained. SIGNIFICANCE: The tested adhesive systems presented similar clinical performance after six years of service, with annual failure rates of 2.8%, 4.6%, and 2.0% for Xeno IV, Xeno III, and XP Bond, respectively.

Three-year clinical evaluation of a silorane composite resin.

STATEMENT OF PROBLEM: Composite resins are still outperformed by amalgams in the clinical practice with secondary caries and fractures being their most common failures. A material that suffers less polymerization shrinkage might improve the clinical performance of composite resins. PURPOSE: To evaluate the clinical performance of a low-shrink silorane-based composite resin (Filtek LS Low Shrink Posterior Restorative, 3M ESPE, St. Paul, MN, USA) in comparison with a methacrylate-based composite resin (Tetric EvoCeram, Ivoclar Vivadent, Schaan, Principality of Liechtenstein) over time. MATERIALS AND METHODS: Candidates in need of Class II composite resin restorations participated in this randomized controlled clinical trial. Those were 25 female and six male subjects with average age of 44.3 ± 12.7 years. Participants received 82 restorations, being 54 in premolars and 28 in molars. Procedures, which included the restoration of primary caries lesions or replacement of failing restorations, were done using modified preparations with no bevels or additional retention. Restorations were placed using Filtek LS (and dedicated self-etch adhesive) or Tetric EvoCeram (with AdheSE, Ivoclar Vivadent), following manufacturers' instructions. Incremental placement technique was applied and the restorations were immediately finished. Follow-up evaluations occurred at six, 12, 24, and 36 months and were done using the Fédération Dentaire Internationale criteria. Statistical analysis was performed using generalized estimating equations. RESULTS: The recall rate at 36 months was 89%. All interaction terms were not significant. CONCLUSIONS: Filtek LS performs as well as Tetric EvoCeram performs in the clinical setting at 36 months. CLINICAL SIGNIFICANCE: The silorane-based composite resin Filtek LS and the conventional methacrylate-based composite resin Tetric EvoCeram performed similarly well in posterior restorations over at least 36 months of clinical service.

Cultivation of zebra mussels (Dreissena polymorpha) within their invaded range to improve water quality in reservoirs.

Algal and cyanobacterial blooms in reservoirs are driven by nutrient enrichment and may present economic and conservation challenges for water managers. Current approaches such as suppression of algal growth with barley straw, ferric dosing or manipulation of fish stocks have not yielded long term successes. A possibility that has sparked growing interest is the encouragement and cultivation of natural filter feeders, such as mussels, which remove suspended matter from the water and reduce nutrient levels through biodeposition and assimilation. This review focusses on the zebra mussel (Dreissena polymorpha) as a tool for enhancement of water quality in reservoirs. Native to the Ponto-Caspian region, this species has invaded many lakes and reservoirs across North America and Western Europe, where it occurs in very high densities. While purposeful introduction of a non-native species into new sites is socially unacceptable, we investigate the possible benefits of encouraging increased abundance of zebra mussels in sites where the species is already established. We estimate that the annual nitrogen and phosphorus input into a large UK reservoir (Grafham Water) could be assimilated into zebra mussel biomass by encouraging settlement onto 3075 m and 1400 m of commercial mussel ropes, respectively. While zebra mussel cultivation has an incredible capacity to push eutrophic systems towards a clear water state, there are many risks associated with encouraging an invasive species, even within sites where it has already established. The zebra mussel is a prominent biofouler of native unionid mussels and raw water pipes, it changes the physical characteristics of the places it inhabits, in sites low in phosphorus it can be responsible for toxic cyanobacterial blooms, it alters nutrient cycling and community structure and it can have negative impacts on amenity value. Increased propagule pressure from elevated numbers of veliger larvae in the water column may increase the risk of spread to other locations. This may render some reservoir systems, such as dammed rivers which have outflows to downstream watercourses, unsuitable for cultivation. Such reservoirs are especially common in North America. We consider the practicalities of putting a zebra mussel cultivation system into place and identify gaps in knowledge. We conclude that zebra mussel cultivation offers an attractive tool for managing nutrient-enriched reservoirs, but that the benefits and costs must be balanced on a site-by-site basis.

Wear of a dental composite in an artificial oral environment: A clinical correlation.

The study objective was to correlate wear between an in vitro method for simulating wear and in vivo wear of a posterior dental composite. Ten subjects (12 restorations) were selected from a five-year clinical study (University of North Carolina, School of Dentistry) that assessed wear of SureFil composite (Caulk, Dentsply). Subject casts were digitized and changes in volume and mean depth with time were calculated from the 3D digital models for contact and contact-free wear. SureFil composite disks were mounted in the University of Minnesota's Artificial Oral Environment, opposed by natural enamel, subjected to mandibular-like movements for 150 K, 300 K, 600 K, 1.2 M, and 1.5 M cycles, and loaded with peak forces of 13 N (n = 7) or 30 N (n = 3). Wear rates were calculated as the slope of the linear regressions fitting the wear data. Data were analyzed using one-way ANOVAs and post hoc t-tests where appropriate (p = 0.05). Clinical restorations included contact wear on seven restorations and contact-free wear on all restorations. Contact-free wear was less than contact wear (p < 0.01). SureFil clinical wear rates were 0.012 mm/year (mean depth) and 0.023 mm(3)/year (volume). Clinical restorations expanded slightly during the first year. Using a conversion rate of one year equals 3 × 10(5) cycles, there were no significant differences between the clinical and simulated data except depths at Year 5 and 13 N volume at Year 4. The 30 N simulation reproduced the clinical data if contact-free wear was taken into account. Good agreement between simulated and clinical wear implies that in vitro simulation can screen new composite formulations.

Control of biofouling by Cordylophora caspia in freshwater using one-off, pulsed and intermittent dosing of chlorine: laboratory evaluation.

Cordylophora caspia is a hydrozoan which causes biofouling in power plants and is an increasing problem in UK drinking water treatment works. Thermal control is not usually feasible without a ready source of hot water so laboratory experiments were conducted to assess whether using pulsed doses of chlorine is an alternative solution. C. caspia polyps disintegrated after a single 20 min dose (the length of one backwash cycle in water treatment work filter beds) of 2.5 ppm chlorine. Without further treatment colonies regenerated within 3 days, but repeated dosing with chlorine for 20 min each day inhibited this regeneration. The resistance of surviving colonies to chlorine increased over time, although colony size and polyp regeneration continued to fall. These results suggest pulsed treatment with chlorinated backwashes at 2 ppm could be used to control C. caspia biofouling in rapid gravity filters and this may have relevance to other settings where thermal control is not feasible.

Biofouling by bryozoans, Cordylophora and sponges in UK water treatment works.

In recent years biofouling from native (bryozoans, sponges) and non-native (Cordylophora) animals has increased in UK water treatment works (WTW). A survey of six UK water companies and eight WTWs revealed that these taxa were more widespread and abundant than previously recognised. Primary problems related to the occlusion of underfloor nozzles and tailpipes in rapid gravity filter beds (RGFs). These cost the UK water industry pound 1.49 m between 2005 and 2009. Additional impacts came from skin irritation to operatives from sponge spicules and the potential for elevated bacterial pathogen levels. Sponges penetrated the furthest through the water treatment process, reaching the point of final chlorination at one WTW. A monitoring plate study showed pronounced seasonality in fouling, with most taxa peaking in mid to late summer before a winter die-off. Control options, including the use of chlorine, and the importance of resistant stages for each taxon are discussed.

Effects of duration of whitening strip treatment on tooth color: a randomized, placebo-controlled clinical trial.

OBJECTIVES: A randomized, double-blind, placebo-controlled clinical trial was conducted to evaluate efficacy and safety of 6% hydrogen peroxide whitening strip used twice daily over an extended, 6-week period. METHODS: After informed consent, 40 eligible adults were randomly assigned to 6% hydrogen peroxide whitening strips (Crest Whitestrips, The Procter & Gamble Company, USA) or placebo strips without peroxide. Treatment was twice daily for 30min, and response was evaluated biweekly after initial (Week 2) and extended (Weeks 4 and 6) use. Tooth color was measured under standardized lighting conditions using digital image analysis, and safety was assessed from clinical examination and interview. Whitening was measured using data derived from digital images taken at baseline compared to post-treatment, with outcomes reported using the CIELAB color notation system. Analysis of variance and covariance were used to assess initial response, and repeated measures regression analysis was used to model color change during sustained use. RESULTS: Forty subjects (25-58 years old) started the study. At baseline, L* ranged from 68.0 to 76.8, a* ranged from 8.0 to 11.8, and b* ranged from 16.4 to 23.1. Groups differed significantly (p<0.001) on all color parameters at Week 2 and thereafter, favoring the 6% hydrogen peroxide strips. Week 2 adjusted means+/-SE were -2.1+/-0.2 for Deltab* and 1.9+/-0.2 for DeltaL* for the peroxide group compared to -0.3+/-0.2 for Deltab* and 0.4+/-0.2 for the placebo group. With sustained use (Weeks 2-6), the slope for the peroxide strip was estimated as -0.3 for Deltab* and +0.2 for DeltaL* per week, with both slopes differing significantly from zero (p<0.0001), while slopes for the placebo strip were not significant (p=0.22) and nearly zero. Treatment was generally well tolerated, with adverse events confined to symptoms only. CONCLUSIONS: Twice-daily use of 6% hydrogen peroxide whitening strips resulted in teeth becoming lighter and less yellow versus baseline and placebo during initial 2-week use, with no evidence of placebo response during sustained (Weeks 2-6) use.

A 12-year clinical evaluation of a three-step dentin adhesive in noncarious cervical lesions.

BACKGROUND: The authors conducted a study to evaluate the clinical performance of a dual-cured, three-step dentin adhesive (OptiBond Dual Cure, Kerr, a subsidiary of Sybron Dental Specialties, Orange, Calif.; no longer on the market) at 12 years. METHODS: The authors restored 100 noncarious cervical lesions without use of macromechanical retention or enamel bevels. In one-half of the lesions (group A), the authors etched only the enamel; in the other half (group B), they etched both enamel and dentin. After etching, they applied a light-cured primer and dual-cured adhesive to enamel and dentin in both groups. They restored the preparations with a resin-based composite. They performed direct evaluations by using modified U.S. Public Health Service criteria at insertion (baseline) and at one year and 12 years after insertion. RESULTS: The 12-year retention rates were 93 percent in group A and 84 percent in group B, for an overall retention rate of 89 percent. Except for marginal discoloration in both groups and retention in group B, the restorations in both groups had Alfa ratings of 88 percent or greater in all of the direct clinical evaluation categories. CONCLUSIONS: The 12-year clinical performance, including retention rate, of a dual-cured dental adhesive was excellent and was not affected by dentin acid-etching. CLINICAL IMPLICATIONS: This clinical study provides additional evidence for the long-term durability of a three-step etch-and-rinse adhesive in non-carious cervical lesions.

An eight-year clinical evaluation of filled and unfilled one-bottle dental adhesives.

BACKGROUND: The strategies for accomplishing resin adhesion to dentin involve surface conditioning, priming and bonding. One-bottle adhesives combine the priming and bonding functions in a single solution. In this study, the authors compared the eight-year clinical performance of two one-bottle adhesives made by different manufacturers. METHODS: The authors placed a total of 99 Class V restorations using either a filled, ethanol-based adhesive (OptiBond Solo [OS], SDS Kerr, Orange, Calif.) or an unfilled, acetone-based adhesive (Prime & Bond 2.1 [PB] Dentsply Caulk, Milford, Del.) and a hybrid resin-based composite in 33 subjects with noncarious cervical lesions. The authors did not bevel the enamel margins and used no mechanical retention. They evaluated the restorations at baseline and for as long as eight years after placement using modified U.S. Public Health Service criteria. They analyzed differences between groups using appropriate statistical tests. RESULTS: The authors examined 56 restorations after eight years and found retention rates of 69 percent for OS and 59 percent for PB. These rates did not differ statistically (P = .449) and were not significantly affected by subject or lesion characteristics. The authors noted marginal discoloration on 55 percent of the retained OS restorations and on 31 percent of the retained PB restorations, but they detected no secondary caries around any restoration. They noted poor anatomical form and poor marginal adaptation in 15 percent and 40 percent of the retained OS restorations, respectively. CONCLUSIONS: The performance of both adhesives was good during this eight-year clinical trial. The filled, ethanol-based adhesive OS demonstrated slightly better bond durability than did the unfilled, acetone-based adhesive PB, but the difference between the two materials was not statistically significant. CLINICAL IMPLICATIONS: Despite a high incidence of marginal discoloration, the one-bottle adhesives evaluated in this study provided good clinical retention of Class V restorations without mechanical retention. When the materials are used properly, restorations are retained at an acceptable rate through at least eight years of clinical service.

Clinical evaluation of an all-in-one adhesive in non-carious cervical lesions with different degrees of dentin sclerosis.

This randomized clinical trial compared the performance of an all-in-one adhesive (iBond) applied in sclerotic and non-sclerotic non-carious cervical lesions with that of a three-step etch-prime-bond adhesive (Gluma Solid Bond, SB). One-hundred and five lesions were randomly assigned to four groups according to adhesive, sclerosis scale and technique: 1) SB applied to lesions with sclerosis scale 1 and 2 (n=26); 2) iBond applied to lesions with sclerosis scale 1 and 2 (n=28); 3) iBond applied to lesions with sclerosis scale 3 and 4 (n=25) and 4) iBond applied with prior acid-etching to lesions with sclerosis scale 3 and 4 (n=26). A microfilled composite (Durafill VS) was used as the restorative material. The restorations were evaluated for retention, color match, marginal adaptation, anatomic form, cavosurface margin discoloration, secondary caries, pre- and post-operative sensitivity, surface texture and fracture at insertion (baseline), 6, 18 months and at 3 years using modified USPHS evaluation criteria (Alfa=excellent; Bravo=clinically acceptable; Charlie=clinically unacceptable). There was a high percentage of Bravo scores for marginal adaptation (4%-32%) and marginal discoloration (18%-60%) in Groups 2, 3 and 4, but all groups had <5% Charlie scores at 6 months and <10% Charlie scores at 18 months for retention and marginal discoloration, respectively. However, it should be noted that 13% of the restorations in Group 4 were not retained at three years.

36-month clinical evaluation of two adhesives and microhybrid resin composites in Class I restorations.

PURPOSE: To compare the clinical performance of a self-etching adhesive with that of a popular etch-and-rinse adhesive in Class I posterior composite restorations. METHODS: 60 Class I resin composite restorations (30 per group) were placed in matched pairs using either the self-etch adhesive Xeno III and the microhybrid resin composite Esthet-X or the etch-and-rinse adhesive OptiBond Solo Plus and Point 4 microhybrid resin composite. Subjects were interviewed via telephone 1 week after restoration placement to assess early post-operative sensitivity. In addition, the restorations were evaluated clinically for post-operative sensitivity, marginal quality, wear, and other characteristics immediately after placement and at 6, 12, 18, and 36 months from baseline. RESULTS: During the first week after placement, subjects reported that 23% of restorations in each group had post-operative sensitivity. Sensitivity decreased greatly with time, and differences between the two groups were never statistically significant. Marginal integrity and discoloration were similar for each group at each recall evaluation. Wear of both resin composites increased over time, but mean wear remained at less than 100 microm for each resin composite at 3 years.

Functionality or aesthetics? A pilot study of music therapy in the treatment of multiple sclerosis patients.

INTRODUCTION: Neuro-degenerative diseases are, and will remain, an enormous public health problem. Interventions that could delay disease onset even modestly will have a major public health impact. The aim of this study is to see which components of the illness are responsive to change when treated with music therapy in contrast to a group of patients receiving standard medical treatment alone. MATERIAL AND METHODS: Twenty multiple sclerosis patients (14 female, 6 male) were involved in the study, their ages ranging from 29 to 47 years. Ten participants formed the therapy group, and 10 the matched control group matched by age, gender and the standard neurological classification scheme Expanded Disability Status Scale (EDSS). Exclusion criteria were pregnancy and mental disorders requiring medication. Patients in the therapy group received three blocks of music therapy in single sessions over the course of the one-year project (8-10 sessions, respectively). Measurements were taken before therapy began (U1), and subsequently every three months (U2-U4) and within a 6-month follow-up without music therapy (U5) after the last consultation. Test battery included indicators of clinical depression and anxiety (Beck Depression Inventory and Hospital Anxiety and Depression Scale), a self-acceptance scale (SESA) and a life quality assessment (Hamburg Quality of Life Questionnaire in Multiple Sclerosis). In addition, data were collected on cognitive (MSFC) and functional (EDSS) parameters. RESULTS: There was no significant difference between the music-therapy treatment group and the control group. However, the effect size statistics comparing both groups show a medium effect size on the scales measuring self-esteem (d, 0.5423), depression HAD-D (d, 0.63) and anxiety HAD-A (d, 0.63). Significant improvements were found for the therapy group over time (U1-U4) in the scale values of self-esteem, depression and anxiety. In the follow-up, scale values for fatigue, anxiety and self-esteem worsen within the group treated with music therapy. DISCUSSION: A therapeutic concept for multiple sclerosis, which includes music therapy, brings an improvement in mood, fatigue and self-acceptance. When music therapy is removed, then scale scores worsen and this appears to intimate that music therapy has an influence.

Microleakage of Class V composites using different placement and curing techniques: an in vitro study.

PURPOSE: To evaluate microleakage at enamel and dentin margins of two composite resins, using bulk and incremental placement techniques, "rebonding", and facial and lingual curing methods. MATERIALS AND METHODS: One hundred standardized Class V cavity preparations were made on the facial surface of extracted human premolars and were randomly assigned to 10 groups. Single Bond was used as the dentin/enamel adhesive. A heavily filled composite resin, Z250, and a microfill, Silux Plus, were inserted and polymerized using five different techniques: (1) incremental placement and facial curing; (2) incremental placement, facial curing and rebonding; (3) bulk placement and facial curing; (4) bulk placement, facial curing and rebonding; (5) incremental placement and lingual and facial curing. After the restorations were finished and polished, the margins of those in the rebonded groups were etched, rinsed, and dried. The adhesive resin, Single Bond, was applied at the composite resin-tooth interface and light-cured. All the specimens were thermocycled, stained with 1% methylene blue, sectioned, and evaluated for leakage (0-4 scale) by two examiners. RESULTS: Almost no leakage occurred at enamel margins. At the cementum margins, differences in microleakage related to restorative material or technique were not statistically significant. However, leakage at the cementum margins was significantly greater than at the enamel margins for both composite resin materials.

Effects of temperature and aerial exposure on the BOD of waste zebra mussels removed from navigational locks.

This laboratory study evaluated the effects of temperature and aerial exposure on BOD5 (5-day BOD) of waste zebra mussels of the type generated by maintenance operations on dams and navigational locks. The term waste zebra mussels includes the mussels and their associated debris with the latter including sediment, feces, pseudofeces and other small aquatic organisms. The BOD5 of waste zebra mussel was evaluated after aerial exposure of 3 and 10 days at temperatures of 5, 10, and 20 degrees C. The mean BOD5 values for waste zebra mussels in this study ranged from 18,500 to 30,600 mg O2/l. Factorial ANOVA analysis revealed that both temperature and aerial exposure had a negative effect on waste zebra mussel BOD5 (P<0.05) but there was no significant interaction effect (P = 0.119). Multiple regression analysis predicted that for the range of treatment conditions used in this study each 1 degrees C increase in temperature reduced the waste zebra mussel BOD5 by 284mg O2/l or 0.93% of the maximum mean BOD5. Each I day increase in aerial exposure reduced waste zebra mussel BOD5 by 987 mg O2/l or 3.22% of the maximum mean BOD5. Aerial exposure of waste zebra mussels substantially reduces waste BOD5.

Social poetics as research and practice: living in and learning from the process of research.

This paper is both a report of research work carried out by one author of the paper with the other involved in a supervisory role, and a reflection on methodology that was an emergent property of the research process. The research question arose when professional preunderstandings about schizophrenia as a biological disturbance were bracketed as a Husserlian form of phenomenology was adopted. The initial study focused on the meanings three individuals attached to being diagnosed with a mental illness and being involved in psychiatric treatment systems. The exploration of meanings led to the researcher being guided by one study participant in relation to a suitable framework for making sense of her lived experience of being entangled in psychiatric systems. This involved an appreciation of the poetics of interpersonal interaction that was simultaneously fuelled by the researcher's reading of social poetics in psychology. Thus, the research became a hermeneutic inquiry, focused upon the text of one participant (Beth)1 and the psychiatric system that she and colleagues encountered. Beth's psychiatric predicament was described by a loss of 'self', psychiatric interrogation, and positive and negative features of immersion in the system. A byproduct of taking a poetic approach was that the participant found the research process therapeutic. Thus, social poetics encouraged a beneficial blurring of the boundaries between research and practice. In both arenas, social poetics can lead to a different level of understanding. This is contradictory to mainstream approaches to research that value objectivity with a strict division between the researcher and the subjects, with the aim of producing scientific knowledge.

Guidelines for clinical research in complementary medicine.

There are several stages in preparing clinical research studies. Stage 1 includes identifying the purpose of the inquiry and finding the essential financial resources. Careful thinking about the clinical practice to be investigated and the allocation of time for research is also necessary. Stage 2 involves assessing the feasibility of the study. Statistical decisions are best made before data are collected, and this means consultation with a statistician or methodologist. There has to be ethical approval from the cooperating institution. A thorough search of the literature is fundamental. In Stage 3, the final trial is designed, ethical approval obtained, and the proposal is submitted for funding. In the final stage, Stage 4, the trial is carried out, analyzed, and prepared for publication.