Mechanically ventilated critically ill patients frequently develop ventilator-associated pneumonia (VAP), a life-threatening complication. Proposed preventive measures against VAP include, but are not restricted to, selective decontamination of the digestive tract (SDD), selective oropharyngeal decontamination (SOD) and the use of probiotics. Probiotics are live bacteria that could have beneficial effects on the host by altering gastrointestinal flora. Similar to SDD and SOD, a prescription of probiotics aims at the prevention of secondary colonization of the upper and/or lower digestive tract.We performed a literature review to describe the differences and similarities between SDD/SOD and probiotic preventive strategies, focusing on (a) efficacy, (b) risks, and (c) the routing of these strategies.Reductions in the incidence of VAP have been achieved with SDD and SOD. Two large randomized controlled trials even showed reduced mortality with these preventive strategies. Randomized controlled trials of probiotic strategies also showed a reduction of the incidence of VAP, but trials were too small to draw firm conclusions. Preventive strategies with antibiotics and probiotics may be limited due to the risk of emerging resistance to the locally applied antibiotics and the risk of probiotic-related infections, respectively. The majority of trials of SDD and SOD did not exhaustively address the issue of emerging resistance. Likewise, trials of probiotic strategies did not adequately address the risk of colonization with probiotics and probiotic-related infection. In studies of SDD and SOD the preventive strategy aimed at decontamination of the oral cavity, throat, stomach and intestines, and the oral cavity and throat, respectively. In the vast majority of studies of probiotic therapy the preventive strategy aimed at decontamination of the stomach and intestines.Prophylactic use of antibiotics in critically ill patients is effective in reducing the incidence of VAP. Probiotic strategies deserve consideration in future well-powered trials. Future studies are needed to determine if preventive antibiotic and probiotic strategies are safe with regard to development of antibiotic resistance and probiotic infections. It should be determined whether the efficacy of probiotics improves when these agents are provided to the mouth and the intestines simultaneously. Ventilator-associated pneumonia (VAP) frequently complicates the course of intubated and mechanically ventilated critically ill patients -3. VAP iPrevention of colonization of the upper and/or lower digestive tract is another approach for the prevention of VAP. This approach is built on the theory that the gastrointestinal flora changes with acute illness. In particular, it assumes that the normal flora disappears and is replaced by an overgrowth of so-called potentially pathogenic microorganisms (PPM), followed by aspiration of PPM, which could finally result in VAP.There are roughly two approaches for the prevention of colonization of the upper and/or lower digestive tract. One strategy includes topical application of non-absorbable antibiotics. Prevention of VAP has been achieved in trials of selective decontamination of the digestive tract (SDD) and trials of selective oropharyngeal decontamination (SOD). Another strategy uses topically applied probiotics, live bacteria that could alter gastrointestinal flora. Recent trials of different probiotic formulas suggest this strategy also to be effective in the prevention of VAP.This manuscript describes the rationale behind prophylactic antibiotic and probiotic strategies in critically ill patients. This is followed by a review dealing with the beneficial effects, risks, and routing of prophylactic antibiotic or probiotic therapy. This manuscript does not deal with oropharyngeal decontamination with chlorhexidine, which has the same principles as SOD. Isolated interventions for the prevention of tracheal aspiration are also not discussed.Two methods were used to identify relevant manuscripts in the medical literature on SDD, SOD and probiotic (or synbiotic) strategies. First, an electronic search in the databases of Medline, Embase, the Cochrane Library, the Cochrane Database of Systematic Reviews and Sumsearch was conducted. Second, reference lists of identified and selected manuscripts were reviewed for additional relevant manuscripts. The search was restricted to manuscripts published from 1980 until now, and manuscripts written in English.The following keywords were used to identity relevant manuscripts: "critical care", "intensive care", "ventilator-associated pneumonia", "nosocomial pneumonia", "SDD", "selective decontamination of the digestive tract", "selective gut decontamination", "SOD", selective oropharyngeal decontamination", "synbiotic", "prebiotic", and "probiotic".and intestines, and a short course of systemic antibiotics. We restricted inclusion of manuscripts of SOD to those studies that evaluated an SOD-regimen consisting of the administration of non-absorbable antibiotics solely in the mouth. We included all manuscripts of probiotic therapy, .Titles and abstracts of identified manuscripts were reviewed on: a) population , b) intervention , c) outcome , and d) type of study . In case of uncertainty the complete manuscript was obtained and evaluated. We did not restrict inclusion of manuscripts on methodological quality or any other critically appraisal criteria other than the criteria we formulated for data extraction. We restricted inclusion of manuscripts of SDD to those studies that evaluated an SDD-regimen consisting of administration of non-absorbable antibiotics in the mouth Finally, we restricted inclusion of manuscripts to those that dealt with the general ICU population .Manuscripts were criticized along three subjects: 1) Is prophylactic use of antibiotics or probiotics preventing VAP and reducing mortality? 2) What are the risks of preventive use of antibiotics or probiotics in critically ill patients? 3) What is the optimal route of administration of preventive antibiotics or probiotics?Critical illness-associated infections have been hypothesized to be either primary endogenous or secondary endogenous in their origin . In thisA second theory concerns the pathogenicity of microorganisms . PathogeIn addition, disturbance or loss of the intact anaerobic intestinal flora have been hypothesized to increase colonization with subsequent higher infection rates . DisturbSDD consists of selective eradication of PPM in the oral cavity and decontamination of the stomach and intestines by local administration of non-absorbable antibiotics, - the first is reached by application of a paste, gel or lozenge to the oral cavity, the second by administration of a suspension through a nasogastric tube. Systemic prophylaxis is provided by a short course of an intravenous antimicrobial agent, to prevent respiratory infections caused by commensal respiratory flora. Notably, the classical design of SDD also includes hand hygiene by health care workers, and frequent surveillance cultures.SOD consists of selective eradication of PPM in the oral cavity by local administration of non-absorbable antibiotics. SOD has been combined inconsistently with systemic prophylaxis by a short course of an intravenous antimicrobial agent.The concept of selective decontamination with probiotics, with or without prebiotics, is at least in part based on colonization resistance. Probiotics are live bacteria that could have a beneficial effect on the host by altering gastrointestinal flora. Prebiotics are non-digestible sugars that selectively stimulate the growth of certain colonic bacteria. When administered in combination, prebiotics could enhance the survival of probiotic strains as well as stimulate the activity of the endogenous flora. The combination of pre- and probiotics has been termed "synbiotics".Lactobacillus spp.) plus prebiotics, or a single-agent probiotic (Lactobacillus spp.).Administration of probiotics is not expected to eradicate the PPM as antibiotics would do, but delaying the time to colonization while the patients are intubated and ventilated could be beneficial. Several probiotic and synbiotic formulas are known and used. They usually are a combination of lactic acid bacteria  [On a pre-specified subgroup analysis, Barraud to 0.93) . In contWith SDD, non-absorbable antibiotics are administered in the mouth and intestines ; as such it should selectively eradicate of PPM in the oral cavity, throat, stomach and the intestines Figure . With SOOne conclusion that can be drawn from the retrieved randomized controlled trials of SDD in critically ill patients is that this strategy is an effective measure against VAP. Indeed, a vast majority of studies of SDD showed reduction of VAP rates with this strategy. SOD also seems an effective strategy against VAP. Notably, SDD and SOD were found equally efficient strategies with respect to prevention of mortality in critically ill patients. The preventive effects against VAP of probiotics are less certain. Additional studies are needed to confirm whether this strategy protects against VAP or not.Although not all trials of SDD showed a beneficial effect, meta-analyses strongly suggested this prophylactic strategy to be a very effective measure against VAP -45. UnfoWhile only four trials of probiotics showed benefits in critically ill patients, a recent meta-analysis suggested this prophylactic strategy to be an effective measure against VAP . By contConsidering the rationale for antibiotics or probiotics as a preventive strategy against VAP, several remarks must be made. The suggestion that critical illness-associated infections are preceded by colonization of the digestive tract with PPM has never been adequately proven, let alone whether there is causality between colonization and infection. Furthermore, it is important to realize that the concept of colonization resistance has been demonstrated only in gnotobiotic mice (mice in which only certain known strains of bacteria and other microorganisms are present), and its relevance has never been documented in critically ill patients. Also, none of the beneficial effects of probiotics with respect to colonization prevention have been unequivocally demonstrated in critically ill patients. Further remarks include the fact that there are no studies that support the claim that a short course of systemic antibiotics prevents primary endogenous infections. Finally, while in the classical design of SDD it was claimed that secondary endogenous infections arise mostly from other patients via the hands of caregivers (necessitating the need for hand hygiene), this has never been supported by studies. Also, it is uncertain whether frequent surveillance cultures are needed to monitor the effectiveness of decontamination.What should be noted is that almost all publications of trials of prophylactic antibiotics or probiotics lack a discussion on standard preventive measures against VAP. Such measures could include early weaning from mechanical ventilation, hand hygiene, aspiration precautions, and prevention of contamination, at times summarized with the acronym "WHAP" . In a siAlthough every literature review aims to find all studies addressing the question of the review, finding all studies is not always possible. It has been shown that those studies with significant results are easier to find than those without significant results. Also, studies with "positive" results are easier published than those with "negative" results. Over-representation of studies with significant results and "positive" studies in reviews may cause bias toward a positive result. We cannot exclude this to be the case in our review of antibiotics or probiotics against VAP.Lactobacillus as opposed to killed Lactobacillus for the prevention of postoperative infections did not add any effect [It is yet unclear whether probiotics offer their benefits merely by preventing the colonization with PPM . In one y effect . The mecOne recently published trial evaluated the effectiveness of SDD and SOD in a crossover study using cluster randomization in 13 ICUs in The Netherlands . MortaliOf course, one could (and should) consider the costs of each strategy: $12 for SDD and $1 for SOD . And theProphylactic use may induce antimicrobial resistance. Many trials of SDD (and SOD) have been performed in The Netherlands, a country with low endemicity of resistant bacteria. Dutch settings, however, may not be representative for other settings. Without doubt, additional research is mandatory to determine whether SDD and SOD are safe strategies with respect to antimicrobial resistance in countries with higher endemicity of resistant pathogens.Since probiotics are live bacteria, patients could become colonized and eventually develop probiotic-related infection. The currently available trials of probiotic therapy did not exhaustively address this issue, as they were not specifically designed for this outcome and were far too underpowered for that. Reports on VAP, endocarditis and bacteremia caused by probiotics -67, as wIt should be realized that studies of probiotics so far used different (combinations of) strains of live bacteria, sometimes combined with prebiotics. Each strain of probiotics may have additional, unique properties and actions towards specific targets. Present knowledge on these properties and actions, in particular in critically ill patients, is insufficient.and in the intestines , or only in the intestines.Furthermore, there is a need for further clarifications regarding doses, schedules and timing of probiotics for prevention of VAP and colonization, as to-date a great variability exists in the literature. Indeed, what should be noted is that in most trials probiotics were solely administered in the stomach. In only one trial the investigators applied probiotics simultaneously to the mouth and the intestines . InteresSDD and SOD seem efficient preventive measures against VAP. SDD and SOD are equally effective with respect to the prevention of mortality. Future studies of SDD and SOD should address the issue of emerging resistance with increased antimicrobial pressure. Given the increasing antimicrobial resistance, probiotics deserve consideration in new trials. Such trials should be well-powered, and investigators should carefully consider where to administer the probiotics: in the mouth, in the intestines, or both. Finally, studies of probiotics in critically ill patients should have active surveillance for probiotic-induced diseases.• SDD and SOD are efficient preventive measures against VAP and equally efficient strategies with respect to prevention of mortality in critically ill patients.• The majority of trials of SDD/SOD did not exhaustively address the issue of emerging resistance, as most were not specifically designed for this outcome and were far too underpowered for that; use of SDD/SOD may be limited due to the risk of emerging resistance to the locally applied antibiotics.• Trials of probiotic therapy did not adequately address the risk of colonization with probiotics and probiotic-related infection.• Probiotic therapy deserves consideration in future trials.• Trials of probiotic therapy should be well-powered, and investigators should carefully consider where to administer the probiotics.ICU: intensive care unit; IPI: intrinsic pathogenicity index; PPM: potentially pathogenic microorganisms; SDD: selective decontamination of the digestive tract; SOD: selective oropharyngeal decontamination; VAP: ventilator-associated pneumonia.The authors declare that they have no competing interests.MJS was responsible for concept and design, analysis and interpretation of data, and critical revision of the manuscript for important intellectual content. LH was responsible for search of the literature, analysis and interpretation of data, and critical revision of the manuscript for important intellectual content. All authors read and approved the final manuscript.


Median nerve neuropathy caused by compression from a tumor in the forearm is rare. Cases with anterior wrist ganglion have high recurrence rates despite surgical treatment. Here, we report the recurrence of an anterior wrist ganglion that originated from the Scaphotrapezial joint due to incomplete resection and that caused median nerve neuropathy in the distal forearm.A 47-year-old right-handed housewife noted the appearance of soft swelling on the volar aspect of her left distal forearm, and local resection surgery was performed twice at another hospital. One year after the last surgery, the swelling reappeared and was associated with numbness and pain in the radial volar aspect of the hand. Magnetic resonance imaging revealed that the multicystic lesion originated from the Scaphotrapezial joint and had expanded beyond the wrist. Exploration of the left median nerve showed that it was compressed by a large ovoid cystic lesion at the distal forearm near the proximal end of the carpal tunnel. We resected the cystic lesion to the Scaphotrapezial joint. Her symptoms disappeared 1 week after surgery, and complications or recurrent symptoms were absent 13 months after surgery.A typical median nerve compression was caused by incomplete resection of an anterior wrist ganglion, which may have induced widening of the cyst. Cases with anterior wrist ganglion have high recurrence rates and require extra attention in their treatment. Anterior wrist ganglion, which mainly originates from the radiocarpal joint, accounts for 15%-20% of wrist ganglions , and we A 47-year-old right-handed housewife noted a soft swelling on the volar aspect of her left distal forearm 3 years ago. She was diagnosed with a ganglion, and local resection surgery was performed twice at another hospital. Similar methods were used to perform both operations, which involved intralesional resections of the cyst with 1-cm skin incisions of the volar aspect of the forearm without following the stalk of the cyst. However, 1 year after the last surgery, the swelling reappeared and was associated with numbness and pain in the radial volar aspect of the hand, thumb, index finger, and middle finger. She came to our hospital and a physical examination revealed decreased sensitivity of the left median nerve area associated with a positive Tinel's sign on the volar aspect of the distal forearm. The patient had no evidence of polyneuropathy, vasculitis, tuberculosis, hypertrophic tenosynovitis, sarcoidosis, gout, or other systemic disorders. She did not give history of previous trauma except for the surgeries at the other hospital, and her wrist joint showed no signs of carpometacarpal arthrosis or instability. The nerve conduction velocity (44.2 m/s) and terminal latency (5.94 ms) of the left median nerve were prolonged and delayed respectively, compared with those of the contralateral nerve . A radiograph of her left forearm showed no space-occupying lesions around the median nerve and carpal tunnel, and significant osteoarthritic changes of the carpal bones were not observed. Magnetic resonance imaging revealed that the multi-cystic lesion originated from the Scaphotrapezial joint and had expanded beyond the wrist (Figure We decided to perform surgery. Exploration of the left median nerve showed that it was compressed by a large ovoid cystic lesion at the distal forearm near the proximal end of the carpal tunnel Figure . We reseCarpal tunnel syndrome is a common compressive neuropathy of the upper extremities and occasionally caused by ganglion cysts . KerrigaAnterior wrist ganglion is a common soft-tissue tumor in the wrist and may originate from the radioscaphoid or scapholunate joint ,3. GanglOn the basis of the findings in this case and those in the previous reports, we suggest that primary total resection of the anterior wrist ganglion with a wide incision to identify structures at risk, such as the radial artery, and allow sufficient exposure to identify the stalk of the ganglion following it down to its capsular attachment. In addition, preoperative detection of the origin of the wrist ganglion by MRI or ultrasound is useful to avoid incomplete surgery. The necessity of carpal tunnel release when the median nerve is compressed in the forearm is controversial, but we believe that carpal tunnel release contributes in special cases where the ganglion expands beyond the wrist and may compress the median nerve in the forearm.Cases with anterior wrist ganglion have high recurrence rates and require extra attention during their treatment. This case suggests that anterior wrist ganglion should be completely excised during primary surgery. Incomplete resection may induce widening of the cyst and cause several disorders including median nerve compression.Written informed consent was obtained from the patient for publication of this case report and any accompanying images. A copy of the written consent is available for review by the editor-in-chief of this journal.The authors declare that they have no competing interests.KO performed the surgery, performed all pertinent literature reviews on the subject, and drafted the manuscript. JM assisted KO in the surgery. TK, HM, TM, and HY helped to draft the manuscript. All authors read and approved the final manuscript.


Atopic dermatitis can be due to a variety of causes from nonatopic triggers to food allergy. Control of egress of water and protection from ingress of irritants and allergens are key components of cutaneous barrier function. Current research suggests that a degraded barrier function of the skin allows the immune system inappropriate access to environmental allergens. Epidermal aeroallergen exposure may allow sensitization to allergen possibly initiating the atopic march. Further research into connections between epidermal barrier function and possible allergen sensitization will be important to undertake. Future clinical trials focused on skin barrier protection may be of value as a possible intervention in prevention of the initiation of the atopic march. The atopic march refers to the natural progression of atopic diseases from atopic dermatitis in infancy to atopic asthma in school age children. Recent research has uncovered exciting data concerning the initiation of the atopic march. A previously little valued component of the epidermis, the strateum corneum, has become an area of scientific attention in the study of the allergic diathesis. This focus on epidermal barrier function potentially provides a heightened understanding of both atopic dermatitis and the initiation of the atopic march. Improving barrier function with reduced water loss and minimized ingress of allergens might become an important tool to controlling the onset of the atopic march.Atopic dermatitis is one of the most significant and common skin diseases of childhood. Studies from Japan suggest that the prevalence for atopic dermatitis in childhood may be as high as 11–25% . A US-poStaphylococcus aureus. Infectious sequelae frequently result in atopic dermatitis exacerbations. These and other developments in atopic dermatitis are exciting. However, the emphasis of this paper will be confined to defining the importance of altered strateum corneum function and its possible link to the atopic march.Atopic dermatitis is an inflammatory cutaneous disease characterized by erythema, pruritus, altered barrier function, and immune dysfunction resulting in IgE sensitization. Dysfunction of antimicrobial peptides such as defensins, psoriasins, and cathelicidins is associated with the development of atopic dermatitis –8. FunctEpidermal layers of the skin include, the stratum corneum, stratum lucidum, stratum granulosum, stratum spinosum, and stratum basale. The structure of these layers is demonstrated in H2 biomarker expression [Each corneocyte in the stratum corneum is held together by tight junctions and scaffolding proteins. Claudins are a family of proteins that are important components of the tight junctions between corneocytes that help to maintain the skin barrier. Claudin-deficient patients have aberrant formation of tight junctions that cause disruption of the bioelectric barrier . Claudinpression . This suSimilar tight junction dysfunction has been found in desmoglein transgenic mice. Desmogleins play a role in the formation of desmosomes that promotes cell-to-cell tight junction adhesion in the stratum corneum. Mice without desmoglein were ultimately found to die from dehydration presumably due to increased transepidermal water loss mediated by lack of corneocyte adhesion .A different genetic knock-out mouse model of atopic dermatitis examined the relationship between scaffolding proteins and skin barrier function. Scaffolding proteins are required to overlaying tight junction linked corneocytes with cross-linked proteins and lipids to form an effective epidermal barrier. Loss of epidermal scaffolding proteins such as involucrin, envoplakin, and periplakin is associated with alterations in epidermal barrier function such as filaggrin and desmoglein-1 processing with formation of an abnormal cornified epidermal envelope . Immune Another factor allowing proper function of the epidermis is the control of the on or off activity of skin proteases. SPINK is a protein that inhibits serine protease action in the skin. The SPINK gene is absent in Netherton's syndrome. This syndrome is characterized by severe atopic dermatitis, scaling, and an elevated serum IgE . In thisIncreased protease functioning also occurs in atopic dermatitis patients. Allergens such as dust mite, cockroach and mold can activate serine proteases, adversely affecting the epidermal barrier . In factFilaggrin is an important protein found in lamellar bodies of stratum granulosum corneocytes. When these granules are released they become a vital component of the extracellular matrix of the stratum corneum. Mutations of the filaggrin gene have been associated with ichthyosis vulgaris and persistent atopic dermatitis , 19. FilThe lipid lamellar matrix is an integral component in controlling the barrier function of the skin. Decreased protein-bound omega-hydroxyceramides are found in the lesional skin of atopic dermatitis patients as compared to control patients . In thisin vitro study has demonstrated that ceramide inhibits mast cell production of IL-5, IL-10, and IL-13 [A murine model of atopic dermatitis illustrates the importance of ceramide in preventing allergen-induced atopic dermatitis. In this model, a synthetic ceramide was applied to the skin of mice noted for the ability to develop atopic dermatitis . In thisnd IL-13 . These mFilaggrin is another key protein in protecting against water loss through the strateum corneum and is present in the epidermis as early as 3 months of age . FilaggrIn vitro models of skin demonstrate that urocanic acid is a key filaggrin-derived amino acid linked to skin acidity [Degradation products of filaggrin have been found to contribute to the formation of the epidermal barrier by providing acidity. This critical function of acidification and hydration of the skin has been linked to filaggrin gene defects in atopic dermatitis . In vitr acidity . In thisIn studies of filaggrin-deficient children, increased transepidermal water loss along with development of specific IgE antibody to dust mite and cat was found with asthma , 37. A rin vivo. Dye penetration was deepest with severity of atopic dermatitis and correlated to increasing serum IgE as compared to control patients [This reduction in barrier function may allow for the development of inflammation due to increased penetration of allergen through the skin allowing IgE sensitization. In a filaggrin-deficient murine model, allergen exposure over lesional skin was linked to the development of allergen-specific IgE and Th17 expression . Facilitpatients , 35.Children with atopic dermatitis have a significant risk of going on to develop other atopic diseases such as allergic sensitization and asthma. Whether eczema precedes or postdates the development of allergic sensitization is not clear for all children . Thirty The allergic march has a pattern of allergic sensitization that changes as children age. In a study with 262 children with atopic dermatitis, IgE sensitization to food was common under 2 years of age. Between 2 and 5 years of age the children had food allergy but also started to develop inhalant allergy. After 5 years of age the children had mostly inhalant allergy as a significant allergic factor associated with their atopic dermatitis .Alternaria allergy eventually develops in 56% of atopic dermatitis children by 12 years of age [Dust mite and cockroach are allergens associated with atopic dermatitis . Alternas of age . When 30s of age . This suStudies suggest that a significant number of these children develop atopic dermatitis first and subsequently become sensitized to aeroallergens. Allergic rhinitis and asthma then follow. Suggested risk factors for this chain of events include atopic parents, possibly cat ownership , and preIdentification of ceramide as a critical element in barrier function has led to the development of ceramide-based emollients. In a study of mild-moderate atopic dermatitis patients, application of ceramide emollient resulted in 69% of patients having no symptoms of eczema and skin hydrations scores improving significantly . CeramidStrategies for possible prevention of atopic dermatitis include encouraging the natural acidification of the skin. Treating mice with lactobionic acid was associated with normal barrier function in addition to normalization of atopic inflammatory markers such as serum IgE . These aImmediate barrier repair can even be implemented on a delipidized stratum corneum with petrolatum without application of ceramide . A preliMurine models suggest that allergen penetration through the skin barrier is important to the development of atopic dermatitis. Human studies show a link between barrier protein dysfunction and development of atopic dermatitis and possibly asthma. Clinical trials have not yet directly looked at allergen penetration through a disordered skin barrier and subsequent development of asthma. Controlled trials with a significant number of patients would be important in determining whether prevention strategies for decreasing allergic sensitization and atopic dermatitis are effective. Longer-term follow-up studies determining whether the onset of allergic rhinitis and asthma is decreased by decreasing the incidence of eczema would also be exciting.It is apparent that not all patients with filaggrin deficiency go on to develop atopic dermatitis . In factResearch in the alteration and prevention of loss of stratum corneum barrier function may provide answers to questions raised regarding the development of atopic dermatitis and asthma.  Early identification of at-risk individuals and developing treatment strategies allowing retention of good skin barrier function may assist in the prevention of allergic sensitization in some individuals. The atopic march may not be inevitable for certain genetically predisposed individuals. Research into maintenance of barrier function in patients at risk for atopy may elucidate the ability to control skin barrier function and prevent onset of atopic dermatitis, and, hopefully, asthma.


In this paper we review the evidence of the effect of health interventions on mortality reduction from hypertensive diseases in pregnancy (HDP). We chose HDP because they represent a major cause of death in low income countries and evidence of effect on maternal mortality from randomised studies is available for some interventions.We used four approaches to review the evidence of the effect of interventions to prevent or treat HDP on mortality reduction from HDP. We first reviewed the Cochrane Library to identify systematic reviews and individual trials of the efficacy of single interventions for the prevention or treatment of HDP. We then searched the literature for articles quantifying the impact of maternal health interventions on the reduction of maternal mortality at the population level and describe the approaches used by various authors for interventions related to HDP. Third, we examined levels of HDP-specific mortality over time or between regions in an attempt to quantify the actual or potential reduction in mortality from HDP in these regions or over time. Lastly, we compared case fatality rates in women with HDP-related severe acute maternal morbidity with those reported historically in high income countries before any effective treatment was available.The Cochrane review identified 5 effective interventions: routine calcium supplementation in pregnancy, antiplatelet agents during pregnancy in women at risk of pre-eclampsia, Magnesium sulphate (MgS04) for the treatment of eclampsia, MgS04 for the treatment of pre-eclampsia, and hypertensive drugs for the treatment of mild to moderate hypertension in pregnancy.We found 10 studies quantifying the effect of maternal health interventions on reducing maternal mortality from HDP, but the heterogeneity in the methods make it difficult to draw uniform conclusions for effectiveness of interventions at various levels of the health system. Most authors include a health systems dimension aimed at separating interventions that can be delivered at the primary or health centre level from those that require hospital treatment, but definitions are rarely provided and there is no consistency in the types of interventions that are deemed effective at the various levels.The low levels of HDP related mortality in rural China and Sri Lanka suggest that reductions of 85% or more are within reach, provided that most women give birth with a health professional who can refer them to higher levels of care when necessary. Results from studies of severe acute maternal morbidity in Indonesia and Bolivia also suggest that mortality in women with severe pre-eclampsia or eclampsia in hospital can be reduced by more than 84%, even when the women arrive late.The increasing emphasis on the rating of the quality of evidence has led to greater reliance on evidence from randomised controlled trials to estimate the effect of interventions. Yet evidence from randomised studies is often not available, the effects observed on morbidity may not translate in to mortality, and the distinction between efficacy and effectiveness may be difficult to make. We suggest that more use should be made of observational evidence, particularly since such data represent the actual effectiveness of packages of interventions in various settings. The fifth Millennium Development Goal has set targets for the reduction of maternal mortality by 2015, but progress has been slow . Where rWHO estimates that 88 to 98 percent of maternal deaths are avoidable with moderate levels of health care . This deIn this paper we review the evidence of the effect of health interventions on mortality reduction from hypertensive diseases in pregnancy (HDP). We chose HDP because they represent a major cause of death in low income countries  and evidWe used four approaches to review the evidence of the effect of interventions to prevent or treat HDP on mortality reduction from HDP. We first reviewed the Cochrane Library to identify systematic reviews and individual trials of the efficacy of single interventions for the prevention or treatment of HDP. We then searched the literature for articles quantifying the impact of maternal health interventions on the reduction of maternal mortality at the population level and describe the approaches used by various authors for interventions related to HDP. Third, we examined levels of HDP-specific mortality over time or between regions in an attempt to quantify the actual or potential reduction in mortality from HDP in these regions or over time. Lastly, we compared case fatality rates in women with HDP-related severe acute maternal morbidity with those reported historically in high income countries before any effective treatment was available.The Cochrane database of Systematic Reviews (June 2010) was searched using the terms hypertension during pregnancy, pre-eclampsia and eclampsia. Reviews were included if they reported the effect of an intervention on any of the following HDP-related maternal outcomes: maternal or HDP-related death, recurring convulsions, eclampsia, pre-eclampsia, placental abruption, intra- or postpartum bleeding, and hypertension. Studies from all countries were considered because few or no data are available from low-income countries. Reviews with no evidence of effect on any of the HDP-related maternal outcomes  were excluded. Reviews with evidence of effect on at least one of the HDP-related maternal outcomes but with less than 50 outcome events were also excluded. We also searched the Cochrane Central Register of Controlled Trials (June 2010) for trials published from 2000 onwards using the same search criteria as above. We selected single interventions for which no Cochrane review had been performed by June 2010. We followed the standard recommended steps for data extraction, summary of the evidence and effect estimates .We searched PubMed for articles quantifying the impact of maternal health interventions on the reduction of maternal mortality at the population level, using the terms interventions, maternal mortality and effectiveness in our search. Reference lists from all relevant articles were checked. We included articles reporting the effect of preventive or curative interventions on HDP-related mortality, regardless of the definitions used. Information was extracted on interventions, the health systems level at which the intervention was delivered, the mortality outcome, the reported risk reduction on mortality outcomes, the methods for estimating effect sizes, and the references quoted.To obtain HDP-specific maternal mortality ratios by region we applied the proportion of deaths from HDP by region  We also Lastly, we used two recent reviews of severe acute maternal morbidity (SAMM) in high and low income countries ,16 and aTwenty nine reviews reported the effect of interventions on HDP-related health outcomes. Eighteen interventions (reported in 19 reviews) were excluded because there was no evidence of effect on any of the maternal outcomes listed. Excluded interventions were supplementation or prophylactic administration of: antoxidants , zinc 1, VitaminTwo further reviews had evidence of effect on at least one of the HDP-related maternal outcomes, but the number of events was insufficient to warrant inclusion. Women with severe hypertension allocated calcium channel blockers rather than hydralazine were less likely to have persistent high blood pressure , but the total number of women with persistent high blood pressure was only 31. Rest andWe read 251 abstracts reported in the Cochrane Central Register of Controlled Trials between 2000 and June 2010. Two interventions had evidence of effect on HDP-related outcomes. One trial assessed the effect of Coenzyme Q10 supplementation during pregnancy in women at increased risk of pre-eclampsia and found a 44% reduction in pre-eclampsia  . AnotherThe results of included reviews are shown in Additional File There is no doubt that treating women with eclampsia with MgS04 reduces the risk of maternal death compared to diazepam (RR 0.59 95% CI 0.37-0.94), though the effect against placebo is not known. MgS04 is also effective for the treatment of pre-eclampsia: treating women with pre-eclampsia with MgS04 reduces their risk of eclampsia (RR 0.41 95% CI 0.29-0.58) and placental abruption (RR 0.64 95% CI 0.50-0.83), though there is insufficient evidence to draw conclusions with regard to the risk of death. The efficacy of the treatment of hypertension in pregnancy is less clear. Antihypertensive drugs in women with mild to moderate hypertension do not lower the risk of pre-eclampsia and there are insufficient numbers of events to assess their effect on risk of eclampsia or maternal death. Antihypertensive drugs do halve the risk of developing severe hypertension (RR 0.50 95% CI 0.41-0.61) .Routine calcium supplementation during pregnancy halves the risk of pre-eclampsia (RR 0.45 95% CI 0.31-0.65), and reduces the occurrence of a composite outcome of death or serious morbidity (RR 0.80 95% CI 0.65-0.97). The reduction in the risk of pre-eclampsia is greatest for women at high risk of pre-eclampsia , and for those with low baseline calcium intake . There is a 17% reduction in the risk of pre-eclampsia with the use of antiplatelet agents – mostly low dose aspirin - during pregnancy in women at risk of pre-eclampsia (RR 0.83 95% CI 0.77-0.89). However, there are no significant differences between antiplatelet agents and placebo in the risk of eclampsia or maternal death.We found 15 studies quantifying the effect of maternal health interventions on reducing maternal mortality at the population level, ten of which are included here   separateHDP-related mortality outcomes range from deaths due to eclampsia to deaths from eclampsia and pre-eclampsia or hypertensive disorders of pregnancy. No definitions are provided.The approach to estimating effect sizes includes reliance on evidence from expert opinion, previous models, a single trial or systematic reviews. Four reviews rely on expert opinion, but the authors do not specify the characteristics or the numbers of experts involved nor how the expert opinion is arrived at .56]57][57]56][5[57]56]5 WHO .Table Our recommended estimates for the LiST model are shown in Table This study highlights the complexity in quantifying the effect of interventions to prevent or treat HDP on mortality from HDP. First, evidence based on the accepted scientific standard - randomised controlled trials - is only available for a small number of single interventions, and no randomised trial evidence is available for interventions which have been highly effective in reducing HDP-related mortality in high income countries, such as caesarean sections. Second, only one intervention (MgS04 for eclampsia) has been shown to have an effect on mortality. Third, the magnitude of effect on severe outcomes is not always consistent with that seen in less severe outcomes . Fourth, estimates of effectiveness of comprehensive intervention packages – whether extrapolated from trends in HDP mortality over time or between regions, or from case fatality rates from SAMM due to HDP in high and low income countries – vary greatly, and interpretation is hampered by lack of knowledge on the content of these intervention packages. Existing models have tried to circumvent these problems by seeking advice from “experts” and/or by narrowly focusing on the efficacy of single interventions, but the inconsistencies, ambiguity and lack of transparency in the assumptions underlying the models call into question the validity of reported effect estimates.The 98% fall in HDP related mortality in the UK and Sweden over fifty years suggests that HDP-related deaths are highly avoidable. The fall in mortality from HDP has been largely attributed to a reduction in the number of cases of eclampsia, while the incidence of pre-eclampsia has been more resistant to change ,67. The Can these findings be applied to low income countries? The low levels of HDP related mortality in rural China and Sri Lanka suggest that reductions of 85% or more are within reach, provided that most women give birth with a health professional who can refer them to higher levels of care when necessary. Results from SAMM studies in Indonesia and Bolivia also suggest that mortality in women with severe pre-eclampsia or eclampsia in hospital can be reduced by more than 84%, even when the women arrive late ,79. The Various authors have attempted to identify interventions that can be delivered at health centre level in the absence of referral care, but the range of interventions varies greatly. Dietary supplementation with at least 1 g of calcium a day reduces the risk of death or serious morbidity from HDP by 20%, and the effect may be stronger for high risk women or those with low dietary calcium. Calcium is cheap and it should be possible to achieve high coverage antenatally through a health centre delivery strategy, though the intervention should be started early in pregnancy. Other interventions are not likely to work at the health centre level alone. Low dose aspirin reduces the risk of pre-eclampsia by 17%, but there is no evidence of an effect on eclampsia or death. Antihypertensive drugs in mild to moderate hypertension during pregnancy halve the risk of severe hypertension, but they do not prevent or delay progression to pre-eclampsia or eclampsia. TreatmenTable We have based our estimates of the effect of packages of interventions on observational data, comparing current HDP mortality or case fatality with that at times when no effective interventions were available. This approach has a number of limitations. First, we assume that variation in the incidence of HDP mortality or case fatality is entirely due to health service factors, while there is no biological or genetic variation between populations. This is clearly not true. The incidence of HDP varies by parity and maternal age, and variation in the demographic profile of the population will affect the incidence and mortality from HDP. Second, maternal mortality and SAMM are difficult to measure  and variations in case definitions may have affected the results. Eclampsia may be one of the more easily recognised clinical entities, however, and errors less marked than for other obstetric problems. Third, unlike SAMM from other diseases which have a case fatality rate close to 100% if untreated, women can survive eclampsia in the absence of treatment. We used historical data from the UK and Sweden to estimate the natural case fatality rate but such data are clearly imprecise, and results have to be interpreted with caution.The increasing emphasis on the rating of the quality of evidence has led to greater reliance on evidence from randomised controlled trials to estimate the effect of interventions. Yet evidence from randomised studies is often not available, the effects observed on morbidity may not translate in to mortality, and the distinction between efficacy and effectiveness may be difficult to make. We suggest that more use should be made of observational evidence, particularly since such data represent the actual effectiveness of packages of interventions in various settings.The authors declare no conflict of interest..xlsx. Efficacy of treatment and prevention of HDP based on Cochrane reviews.Click here for file.xlsx. Review of population models quantifying the effect of prevention and treatment of HDP on maternal mortality from HDP.Click here for file


Intractable seizures are a subgroup of epileptic disorders challenging the physicians’ skills to become controlled. Showing resistance towards common pharmacotherapy, they demand newer antiepileptic drugs acquired at higher costs. 0.06% of children around the world are estimated to suffer from epilepsy and its consequences. The aim of the present study has been to evaluate the cost-effectiveness of these drugs in the treatment of intractable seizures in children.Clinical and cost data were collected from medical and cost records preserved at a neurologist office and a referral pharmacy respectively. Based on the new AED which are accessible in Iran, regimens were categorized into eight groups. The first group consisting of conventional AEDs was considered as comparator and the effectiveness of other groups was compared with it. Incremental Cost-effectiveness Ratio (ICER) of adding-on each new antiepileptic drug was calculated in terms of Rials per consequence (Rls/consq) and compared with each other. Furthermore ICER of the regimens was compared with the GDP per capita (Gross Domestic Product) of the year (2010).the ICER of the adding-on regimens range from negative values for Gabapentin, Levetiracetam and Zonisamide to low values for Lamotrigine  and Oxcarbazepine (~7.7 mil Rls/consq) and followed by high values for Topiramate (~21 mil Rls/consq) and Vigabatrin (~43.7 mil Rls/consq) considering the three months of remaining on regimen. By increasing the limit of remaining time to six months, the previously mentioned regimens persist on negative values. However Oxcarbazepine (~28.7 mil Rls/consq) and Lamotrigine (~13.8 mil Rls/consq) show a steep increase. Topiramate (~23.6 mil Rls/consq) displays a less change. Opposite to other regimens, the ICER value of Vigabatrin (~17.26 mil Rls/consq) has shown an important increase.Adding-on new antiepileptics to conventional regimens are cost-effective and justified considering the GDP per capita. Epilepsy is defined as a neurological disorder of brain portrayed by persisting predisposition to develop epileptic seizures . A propoIn general, selecting an AED is performed on the basis of many factors including relative efficacy, drug-drug interactions, tolerability and cost . The acqThe aim of this study was to compare cost-effectiveness of newer AEDs being added to conventional regimens in treating intractable seizures in children.This study has been conducted in a cross sectional manner. Clinical data was obtained from medical records of patients archived at the office of a physician with well established expertise in pediatric neurology. Patients with seizures not being responsive to two or three conventional AEDs were included in the study . Cases oAn additional model comparing regimens composed of conventional AEDs and any of the seven new AEDs with the same assumptions mentioned above was set up in order to evaluate the cost-effectiveness of adding-on new AEDs in general Figure .Regarding the fact that either the inability of a regimen in controlling seizures or the inappropriate safety profile are the main reasons of switching the regimen by the clinical specialist, thus remaining on a regimen has been viewed as an acceptable indicator of effectiveness and safety for regimens. Receiving approval by the clinician, remaining on a regimen for three months and more was regarded as effectiveness endpoint (desired consequence).The proportion of seizure controlled patients to all the patients incorporated into the model was assumed as the effectiveness of the related regimen. The effectiveness of regimens was calculated for both arms within each model. Next the effectiveness of add-on regimens was subtracted from the comparator’s regimen effectiveness.Cost data was primarily obtained from the referral pharmacy of Tehran (Sizdah-e-Aban Pharmacy). Given the perspective of our study has been that of the patients, latest sales price were collected and split in two sets. The first set made up of the maximum prices consisting of brand name drugs that at most cases are imported and the second set comprised of the minimum prices which belong to the generic drugs. As availability of drugs has been the only determinant factor in purchasing drugs, an average of these prices was computed. Considering the variety of the dosage forms, standardizing the daily dose of each drug was necessary in order to compare the cost of each regimen. This was managed by calculating the prescribed daily dose (PDD) of each drug as an average of all the existing doses reported in the records.For example if Valproate was prescribed as 900 mg/day in two records and 600 mg/day in one record the weighted average of PDD would equal 800 mg/day. PDD of each AED was subsequently multiplied by the price of 1 mg of each drug -obtained by dividing the average price by the potency of the dosage form- as well as 365 days of year for further comparison with the GDP (Gross Domestic Product) per capita, resulting in the cost of each regimen. The cost of the comparator group  has not been calculated due to being mentioned in both arms of the decision trees. In other words the difference of costs of regimens (ΔC) was simplified as followed:In order to compare the cost effectiveness of add-on regimens the incremental cost-effectiveness ratio (ICER) was calculated as:.The final step was comparing the ICER of each new AED as add-on therapy with the GDP per capita of Iran, as a measure for assessing the cost-effectiveness of different regimens.It should be noted that all costs are reported as Rials (Rls) (1 United States of America’ Dollar (USD) ~ 10,000 Rls; 1 Euro ~ 15,000 Rls) in year 2010.Sensitivity analysis was performed at three cost levels  and the model was rerun with an effectiveness endpoint of six months.57 patients were approved with intractable seizures giving access to 284 records of regimens. The distribution of patients has been depicted Table .Table The incremental cost-effectiveness ratio of adding any of the new AEDs shows a positive value of 37 million Rials per a desired consequence. Changing the effectiveness endpoint from three to six months raises the ICER value to 42.4 mil Rls/consq  turns out to exhibit dramatic changes in the cost-effectiveness due to striking decrease in effectiveness, followed by Topiramate (ICER ~ 23.6 mil Rls/consq). The increase for Lamotrigine (ICER ~ 13.8 mil Rls/consq) has been less considerable. Opposite to the previous regimens Vigabatrin (ICER ~ 17.3 mil Rls/consq) has shown a substantial decrease.The results confirm that adding-on new AEDs to conventional regimens in controlling intractable seizures in children is cost-effective comparing to regimens composed entirely of conventional AEDs. However choosing certain AEDs added to the conventional regimen especially in long term requires extra consideration. Given the general advantages of monotherapy against polytherapy, physicians’ preference could be driven towards monotherapy by cost-effective regimens including newer AEDs such as Oxcarbazepine, Lamotrigine and Topiramate.Since the value that Iranian society recognize for health outcomes is unknown, interpreting the results express complicacy . WHO guiIf a specific regimen is causative of unacceptable side effects or is not efficient, the patient would have been quickly switched to an alternative regimen. Therefore retention rates of different regimens are appropriate indices for effectiveness. In addition actual clinical data used in this study instead of receiving abstract information by clinicians, improves realization of the results. While the study has much strength, cost and medical databanks not being available accounts for limitations through the study.Collecting clinical data from a referral but single center can be responsible for undesirable bias in the results. Indirect costs such as costs pertaining to side effects and clinical visits were not included in this economic evaluation and different types of epilepsy were not separated due to the low number of patients.Our results are quite different from Frew’s study that has demonstrated the newer and older antiepileptic drugs different in cost terms while equal in efficacy term . This coAdding-on new antiepileptics to conventional regimens is cost-effective and justified considering the GDP per capita. Among the new adding-on AEDs prescribed in Iran, Lamotrigine shows the best results in terms of cost-effectiveness in treating children with intractable seizures. As the same, Oxcarbazepine and Topiramate fall under the GDP per capita level, while Vigabatrin stands close to the standard. However, other adding-on medications; Gabapentin, Levetiracetam and Zonisamide; in treating the target population appears not to be cost-effective due to less effectiveness compared with older AEDs.The authors declare that they have no competing interests.ZG conceived and implemented the strategy, collected clinical and cost data, analyzed data and drafted paper, AK conceived the strategy of study and supervised the project, SN gave consultation on designing the study, conceived the strategy of study, revised the article and supervised the project, GZ gave consultation on designing the study and provided clinical data, AA gave consultation on designing the study and building the model. All authors read and approved the final manuscript.


Primary health care systems are designed to provide comprehensive patient care. However, the ICD 9 coding system used for billing purposes in Canada neither characterizes nor captures the scope of clinical practice or complexity of physician-patient interactions. This study aims to describe the content of primary care clinical encounters and examine the limitations of using administrative data to capture the content of these visits. Although a number of U.S studies have described the content of primary care encounters, this is the first Canadian study to do so.Study-specific data collection forms were completed by 16 primary care physicians in community health and family practice clinics in Winnipeg, Manitoba, Canada. The data collection forms were completed immediately following the patient encounter and included patient and visit characteristics, such as primary reason for visit, topics discussed, actions taken, degree of complexity as well as diagnosis and ICD-9 codes.Data was collected for 760 patient encounters. The diagnostic codes often did not reflect the dominant topic of the visit or the topic requiring the most amount of time. Physicians often address multiple problems and provide numerous services thus increasing the complexity of care.This is one of the first Canadian studies to critically analyze the content of primary care clinical encounters. The data allowed a greater understanding of primary care clinical encounters and attests to the deficiencies of singular ICD-9 coding which fails to capture the comprehensiveness and complexity of the primary care encounter. As primary care reform initiatives in the U.S and Canada attempt to transform the way family physicians deliver care, it becomes increasingly important that other tools for structuring primary care data are considered in order to help physicians, researchers and policy makers understand the breadth and complexity of primary care. Primary care practice provides comprehensive patient care including assessment, diagnosis and management of both acute and chronic problems. However, the ICD 9 coding system used in Canada does not capture the scope of disease or recognize the complexity of physician patient interactions. Administrative claims data in Canada use a single ICD-9 or ICD-10 code which does not elaborate on the severity of the disease, complexity of care or describe the extent of clinical management provided by the physician . AdminisIn the U.S, numerous studies have investigated the wide array of problems addressed and treatments provided during primary care encounters -8. ThereThis study was initiated by a team of academic researchers and community-based family physicians with an interest in exploring the complexity of community-based care. In describing the content of primary care clinical encounters, this study's objectives were to identify the types of problems addressed by primary care physicians in a typical patient visit and to determine the kinds of actions taken and the various patient-related factors that influence visit complexity. These details are critically important in characterizing family practice, and in setting relevant educational, research, and policy priorities .A convenience sample comprised of 16 primary care physicians collected data from five different primary care clinics in an urban center. Two of the study sites are community health clinics funded on salary, one is a university-based student clinic with a blended funding mechanism, one is a teaching clinic with salaried physicians and one is a private fee for service practice. The study was approved by the University of Manitoba Health Research Ethics Board.This study utilized a specifically designed data collection form .The primary reasons for the visit are listed in Table According to the ICD-9 codes recorded, periodic health evaluations, depression, hypertension, anxiety, diabetes mellitus, and fertility control were the most commonly discussed topics. This is consistent with administrative claims data with nine of the ten most frequently reported diagnoses being common to the two data sources .In this study, the ICD-9 code submitted for administrative purposes was found to match what physicians considered being the "dominant topic of the visit" for only 71% of patient visits. The ICD-9 code only matched 61% of topics that were considered to be the "topic requiring the most time" and was consistent with both the "dominant topic of the visit" and the "topic requiring the most time" for 58% of encounters. Table Physicians considered 10% of patient visits to be very complex and 48% moderately complex. Logistic regression was conducted to determine the factors associated with visit complexity as determined by the physician. The independent variables included the clinic site, visit-related factors . The total number of topics discussed significantly increased the likelihood of a visit being evaluated as complex . Presence of social or cultural issues did not significantly increase the likelihood of a visit being evaluated as complex  nor was patient gender associated with perceived complexity.This study aimed to describe the content of a primary care clinical encounter and describe the breadth and complexity of primary care as well as the inadequacy of a single ICD-9 code required by and used in Canadian billing claims. The findings support previous research indicating that physicians commonly address multiple problems and provide numerous services during family practice outpatient visits. A mean of 2.56 topics were discussed per visit resulting in an average of over three actions. This finding corresponds with reports from previous studies in the US ,6. as weThe number of topics discussed per visit is associated with physicians reporting a clinical encounter to be complex. Considering that 90% of patients visiting their family physician have more than one chronic condition, and as many as 50% have five or more , primaryMost chronic conditions are managed within family practice with a small percentage of actions resulting in a referral to a specialist. Comorbidity is frequently addressed in the primary care encounter and primary care providers are the case managers for most patients with comorbidities as specialist care is sought for uncommon conditions . PrimaryOur data collection form gave the physicians an opportunity to list up to seven topics addressed during the visit, however only a single ICD code is submitted in most Canadian reimbursement systems and should reflect the primary problem addressed. The ICD-9 code did not consistently correspond to the problems considered dominant during the patient visit. They also did not consistently correspond to the problems that take the most time to address in a visit. In addition, episodic/acute visits were the most prevalent type of visits yet ICD-9 codes for general medical examinations or chronic disease management were the most frequently used diagnostic codes. This lack of congruence between codes and topics appears to be strongly related to whether visits were more complex visits (with multiple problems covered) rather than less complex or more symptom focused Table . HoweverICD coding originated for the purpose of categorizing and coding morbidity for public health purposes and until the mid 1970's was the most common means of classifying morbidity data within primary care. However, with its disease-based structure, many of the vague and/or ill defined symptoms and non-disease conditions that present in primary care are difficult to code with ICD codes. The disadvantages in using ICD spurred the World Organization of Family Doctors (WONCA) to design a classification specific to primary care. The International Classification of Primary Care (ICPC) provides a more comprehensive and patient centred structure while also ordering the data according to episodes of care (or first to last presentation of an illness or event) . StructuThe comprehensive care that is provided by family physicians is of particular relevance as we move toward care that is oriented toward the patient's overall health rather than disease-centered care. A broader view of patient care must be considered if primary care is to be properly understood. Effective multimorbidity case management requires an approach that cannot be neatly categorized into a discrete ICD diagnostic code. A more holistic approach to caring for patients with multiple morbidities requires moving beyond codes or labels and considering varying levels of severity and emotional distress that accompany their conditions . FurtherWhile a multi-method approach, such as one that combines direct observation, medical record review, patient survey, and/or billing data would likely provide a more comprehensive, unbiased view of primary care clinical encounters, our results are consistent with other U.S studies which have used direct observation ,7. The sThis is one of the first Canadian studies to critically analyze the content of primary care clinical encounters. The data allowed a greater understanding of primary care clinical encounters and attests to the deficiencies of singular ICD-9 or billing coding. Therefore, as primary care reform initiatives in the U.S and Canada attempt to transform the way family physicians deliver care, it becomes increasingly important that physicians, researchers and policy makers develop a thorough understanding of the breadth and complexity of primary care encounters.The authors declare that they have no competing interests.AK and MD were involved in the conception and design of the study. GH and JS were involved in data analysis and manuscript drafting with significant contributions from both AK and MD. All authors reviewed drafts, contributed to revisions and approved the final manuscript.The pre-publication history for this paper can be accessed here:http://www.biomedcentral.com/1471-2296/13/7/prepubAppendix A Data collection form.Click here for file


It offers the possibility to analyze neoangiogenesis and vessel density in vivo. Angiogenetic switch is essential in cancer progression. Aim of the paper was to review the use of this imaging tool to analyze colorectal and gastric cancers vascularization in vivo. The aim is to provide the possibility of combining diagnostic evidences with vascularization and molecular profile to evaluate the efficacy of an antiangiogenic treatment in association with conventional therapy. pCLE can be considered a revolutionary method for real-time assessment of changes in vascularization pattern in this tumors and it may open the possibility to address the use of anti-angiogenic therapy in order to improve the outcome of the treatment. Probe-based Confocal Laser Endomicroscopy (pCLE) is a novel imaging technique for gastrointestinal endoscopy providing  We experienced with the probe-based confocal endomicroscopy system , in combination with videomosaicing which allows the reconstitution of panoramas of the tissues with the alignment of the input frames. We aimed therefore to use this new promising imaging tool to analyze the angiogenic process in colo-rectal and gastric cancer patients. This method discloses the possibility of a translational approach combining the confocal imaging not only with the diagnosis in vivo and the specific molecular profile of the patient, but also with the targeted antiangiogenic treatment.In recent years, endoscopic image quality has been highly improved thanks to very technologically advanced devices. One of these new gastrointestinal endoscopy methods is the confocal laser endomicroscopy (CLE) which has allowed for a confocal scanning microscope to be integrated into a conventional flexible endoscope. Potential applications include detection of neoplasia with targeting of biopsies, and the detection of inflammatory bowel disease, celiac sprue, and microscopic colitis . CLE proin vivo diagnosis of GI neoplasia and related precursor lesions during colonscopy. Based on characteristic morphological changes or due to characteristic single cells like globet cells in Barrett's esophagus, the promising technology of CLE enables already in vivo diagnosis of pathological mucosal conditions. However, confocal imaging holds the potential to go far beyond: the possibility to analyze the morphology and density of the blood vessels present on the surface of the tumors could also provide vital information for a more appropriate diagnosis and for a putative employment anti-angiogenic drugs during the treatment.The potential role of CLE has been explored in different pathologic conditions of the gastrointestinal (GI) tract, the possibility of diagnosing premalignant and malignant lesions of the GI tract being particularly important considering the prognostic implications. GI cancers represent a major cause of morbidity and mortality, with incomplete response to chemotherapy and poor prognosis in the advanced stages of the disease. Recently, CLE has been successfully applied in studies dedicated in particular to neoplastic Barrett's esophagus, and gastric and colorectal neoplasia. Since accurate diagnosis and staging are essential for therapeutic planning, CLE holds the potential for a strong impact in the screening and/or surveillance of GI tumors , 3. CLE β, and angiopoietins, thus enhancing angiogenesis [β1 molecule and was indeed found to be upregulated during neoangiogenesis [The development of new blood vessels from the preexisting vasculature (angiogenesis) is an indispensable event both in normal and pathological conditions, such as cancer growth and development. Tumors will not grow beyond 1-2 mm unless the angiogenic switch is turned on , thus thogenesis . Angiogeogenesis . To earlogenesis , 12. Endogenesis . Among togenesis . The proogenesis . MMRN2 iogenesis . MMRN2 cogenesis –18. The ogenesis . Prior togenesis  indicateogenesis . The useogenesis . Thus thin vivo imaging of human colorectal neoplasia and its use also allows the analysis of the vascular structure, morphology (irregular vessels) and leakiness (fluorescein outflow). Studies are currently underway to apply this new imaging tool for objective evaluation of the microvessel density in different stages of the neoplastic development and in conjunction with antiangiogenetic therapy. Preliminary data on the microvessel density for biliary cancers at the liver hilum [High-resolution confocal imaging is achieved by using an exogenous fluorescence technique. Fluorescein is intravenously administered for specific er hilum , 21, forer hilum , and forer hilum , 24, areEndoscopic imaging and monitoring of angiogenesis have the potential to be valuable biomarkers in preneoplastic, premalignant, and cancer stage in GI lesions. The “endoscopic angiogenesis” analysis on gastric and colo-rectal cancers was performed on the patients listed in in vivo assessment of the morphological alterations and the abnormal microvasculature of the cancer mucosa and the results correlated with the traditional conventional approach. pCLE can be considered a crucial and revolutionary method for real-time analysis of the vascularization pattern in colo-rectal and gastric cancer. These preliminary results indicate that pCLE in combination with immunological staining (CD31 and MMRN2) hold the potential for a significant impact both on basic research and clinical practice, suggesting a substantial possibility for a translational study.The use of pCLE allowed the R. Cannizzaro and M. Mongiat shared first authorship.


Malaria rapid diagnostic tests (RDTs) are increasingly used by remote health personnel with minimal training in laboratory techniques. RDTs must, therefore, be as simple, safe and reliable as possible. Transfer of blood from the patient to the RDT is critical to safety and accuracy, and poses a significant challenge to many users. Blood transfer devices were evaluated for accuracy and precision of volume transferred, safety and ease of use, to identify the most appropriate devices for use with RDTs in routine clinical care.Five devices, a loop, straw-pipette, calibrated pipette, glass capillary tube, and a new inverted cup device, were evaluated in Nigeria, the Philippines and Uganda. The 227 participating health workers used each device to transfer blood from a simulated finger-prick site to filter paper. For each transfer, the number of attempts required to collect and deposit blood and any spilling of blood during transfer were recorded. Perceptions of ease of use and safety of each device were recorded for each participant. Blood volume transferred was calculated from the area of blood spots deposited on filter paper.The overall mean volumes transferred by devices differed significantly from the target volume of 5 microliters (p < 0.001). The inverted cup (4.6 microliters) most closely approximated the target volume. The glass capillary was excluded from volume analysis as the estimation method used is not compatible with this device. The calibrated pipette accounted for the largest proportion of blood exposures ; exposures ranged from 2% to 6% for the other four devices. The inverted cup was considered easiest to use in blood collection ; the straw-pipette and calibrated pipette were rated lowest (143/225 [64%] and 135/225 [60%] respectively). Overall, the inverted cup was the most preferred device , followed by the loop .The performance of blood transfer devices varied in this evaluation of accuracy, blood safety, ease of use, and user preference. The inverted cup design achieved the highest overall performance, while the loop also performed well. These findings have relevance for any point-of-care diagnostics that require blood sampling. Malaria rapid diagnostic tests (RDTs) are recommended for use in areas where good-quality microscopy is not available, including peripheral health centers and community-based case management programmes,2. RDTs Most commercially available RDT kits are packaged with individual-use disposable blood transfer devices intended to collect, transfer and deposit a fixed volume of blood  from a finger-prick to the absorbent pad within a well on the RDT cassette. Available transfer devices include loops, straw-pipettes, squeezable calibrated pipettes and capillary tubes. Blood transfer devices should fulfill a number of basic requirements: first, they should transfer the correct volume of blood (avoiding inaccurate test results); second, the risk of exposure of the user to direct blood contact through design, poor technique or accident should be minimized; and third, they should be easy to manipulate.As RDT cassette design is fairly standardized, the parameters governing the appropriateness of design of the transfer device should be common to various RDT kits. Identifying the best design should therefore improve the overall diagnostic accuracy and safety of all RDT cassettes. Five devices were evaluated: four were typical examples of the main types of devices currently provided with commercially-available malaria RDTs, while the fifth was developed specifically for the study, based on an earlier promising design that had not been deployed with commercially-available tests. The study reported here evaluated blood transfer devices in terms of accuracy and consistency of blood volume transferred, blood safety, and ease of use in the hands of health workers, to identify the most appropriate blood transfer devices for use with malaria RDTs in routine clinical care.The study was conducted between August and November 2009 among 227 health workers in Nigeria, the Philippines and Uganda, drawn from staff of front-line health centers and community-based malaria programmes. Staff members with a patient care role were invited to participate irrespective of previous experience with RDTs, but information on previous experience with RDTs and blood transfer was recorded. Participants were unaware of the provenance of the devices evaluated, in order to avoid biasing the results. All participants provided written informed consent. The study protocol was approved by institutional review boards in each participating country.The five blood transfer devices evaluated were the loop (hard plastic), straw-pipette (soft plastic), inverted cup (hard plastic), calibrated pipette (soft plastic), and capillary tube (glass), as shown in Figure Prior to the evaluation, study staff demonstrated the correct use of each device to participating health workers, and allowed time for questions. Each participant then used each device under the observation of study staff, who recorded information on ease of use  and safety  using a checklist. A single sample of fresh venous blood in EDTA, pre-screened for infectious agents, was provided each day. To simulate collection and transfer of finger-prick blood whilst ensuring standardization, study staff pipetted 8-10 μL of venous blood onto a gloved finger. After five practice transfers with each device, each participant was observed using three devices of each type to transfer blood from the gloved finger to absorbent filter paper (Whatman grade 3) to simulate the absorbent pad of an RDT. Transfer devices were presented to each health worker in a computer-generated randomized order.For each transfer attempt, the observer recorded whether a participant required more than one attempt to collect the desired amount of blood; whether blood was released unintentionally from the device at any time before reaching the target; whether the health worker required more than one attempt to deposit all the blood in the target area; and whether blood touched the health worker's gloves, skin or clothing at any time.After each health worker had been observed transferring blood three times with all five devices, s/he was interviewed using a standard questionnaire regarding ease of collection, transfer and deposition of blood, and the perceived risk of blood exposure. Each health worker ranked the devices in order of preference and stated reasons for her/his choices.The blood spots were dried and scanned, the area of each was measured using LineScale Plug-In version 1.80 (LineType Software Inc)  and the This method of volume estimation was used for four of the devices evaluated . However, the filter paper used in this assessment does not consistently draw blood from the glass capillary, and consequently a variable amount of blood remains in the capillary and the resulting blood spots do not accurately reflect its transfer volume; this phenomenon was confirmed with additional laboratory work at the Research Institute for Tropical Medicine (RITM) in the Philippines. Briefly, the full capacity of the glass capillary device was measured using a micropipettor and found to be 10 μL. Glass capillary devices were filled with EDTA-preserved blood and held steadily to RDT pads (n = 50) or filter paper (n = 50) for 10 seconds. The height of the blood column in each device was measured before and after the 10-second deposition time, and the difference was used to calculate the volume deposited onto each of the two surfaces. From a full starting volume of 10 μL, the mean volume transferred to the RDT pad was 6.59 μL, while the mean transferred to filter paper 2.23 μL, indicating a significant difference in the capacity of the two surfaces to wick blood out of the capillary tube. Therefore, the glass capillary results were disregarded from the analysis of blood volume transferred.Each day fresh venous blood was preserved in EDTA and study staff used a micropipette to make 20 reference blood spots of 5 μL each on filter paper. The area of each reference spot was measured with the LineScale software as above, and the mean was used as an area-to-volume coefficient for all spots produced that day from the same blood sample, ensuring that variations in haematocrit or other characteristics of the blood sample that could affect absorbance on filter paper did not bias results.Data were entered into a central database using Epi-Info version 6.04  and Microsoft Office Excel 2007, and analysed with Stata version 9 . Proportions for each endpoint were calculated independently for each site and for all sites combined. Repeated measures ANOVA was used to test for differences in mean blood volume transferred between and within individuals. Mean volumes transferred were compared to the goal volume of 5 μL using a one-sample t-test. These analyses were performed in SAS version 9 (SAS Institute Inc.).All participants in the Philippines were voluntary community health workers ; those in Nigeria included community health workers and facility-based health workers; most Ugandan participants were health workers employed at peripheral government health centers while the remainder were volunteer community health workers Table . A majorBlood volumes transferred using each device are presented in Table Overall, more than one-third of the health workers required at least one repeat attempt to collect blood with the loop 86/226, 38%), the straw-pipette  and the calibrated pipette , while the other two devices required fewer repeat attempts  and presentation of a broad surface area of retained blood for release onto the absorbent surface. In contrast, the loop presents a narrow contact surface unless tilted sideways . The straw-pipette and calibrated pipette also required further manipulation to ensure contact between the blood and the absorbent surface.et al [et al sensitivity was considerably reduced at parasite densities of 200 parasites/μL with volumes less than 3 μL for RDTs designed for 5 μL of blood[The need for improved blood transfer methods for use with RDTs has been identified in previous reports-12. The et al , assesseet al . Inadequ of blood. In the A limitation of this evaluation is the somewhat artificial condition created by using absorbent filter paper, rather than RDT pads, for blood deposition. This method allowed us to estimate the blood volumes transferred by each device in the hands of health workers, but provided unreliable results for transfer volume with the glass capillary due to the observed difference in the absorbent qualities of filter paper compared to an RDT pad. The same phenomenon, and the resultant difficulty in depositing blood onto the filter paper from a glass capillary, may also have contributed to health workers' less favorable perception of this device, although many participants also commented on unrelated features. Another artificial condition created for this study was the placement of a blood drop on a gloved finger, rather than pricking a patient's finger, to obtain a source of blood for each transfer. The devices tested may perform slightly differently when collecting blood from skin rather than the latex surface.The current study was specifically aimed at assessing the suitability of the devices for use by front-line health workers with limited laboratory training and limited facilities. Some workers may also have lesser capacity for fine manipulation. Clearly, specific training may overcome some of the apparent deficiencies illustrated here. For example, the capillary tube and calibrated pipette may perform better in laboratories with technicians accustomed to manipulating such devices. The results of this study show significant variation between study sites; differences in prior training or experience using certain types of devices are likely explanations for these variations. For example, Ugandan health workers who have considerable experience with RDT use made, in general, fewer observed errors with all devices than did less-experienced participants in the other two countries Table , althougAs RDT cassette design is essentially standard, blood transfer devices should be an exchangeable accessory. Careful selection of the blood transfer device should be a part of overall RDT kit selection. Flexibility in matching the most appropriate RDT  to the most appropriate transfer device for the field of intended use could improve the outcome of RDTs' introduction into malaria programmes.In addition to malaria RDTs, point-of-care tests based on sampling of small quantities of blood or serum are currently used at peripheral health care levels for a number of diseases , and will be of increasing importance as new tests are developed for other diseases. The results of this study are likely to be applicable to these tests, though they should be confirmed on different sample types and with different cadres of health or laboratory worker. It seems illogical to use a wide variety of device designs aimed at achieving essentially the same task, when required transfer volumes are similar, and accuracy, blood safety and ease of use are universally important issues. Establishing quality and consistency in the design of point-of-care diagnostic kits for different diseases will improve both diagnostic performance on the front lines of the health care system and ease of training and implementation.The performance of blood transfer devices varied in this evaluation, with the inverted cup design achieving the highest overall performance in terms of accuracy and precision of blood volume transferred, blood safety, ease of use, and user preference, while the loop also performed well in most respects. The relative appropriateness of the different device designs may vary in other settings and in the hands of personnel with different levels of training. These findings have relevance for any point-of-care diagnostics that require blood sampling, and the variability in device performance demonstrated here highlights the need to devote attention to this issue when implementing RDT-based diagnostic programmes.The authors declare that they have no competing interests.HH designed the study, contributed to development of the inverted cup device, coordinated field work in Uganda, analysed and interpreted the data, and drafted the manuscript. WO contributed to study design and coordinated field work in Nigeria. JL and MLM contributed to study design, coordinated field work in the Philippines, and conducted additional laboratory assessments at RITM. CA contributed to study design and participated in critical revision of the manuscript. AA and IG coordinated development of the inverted cup device, contributed to study design and participated in critical revision of the manuscript. MLG performed the statistical analysis for blood volumes transferred and participated in critical revision of the manuscript. DB conceived the study, contributed to development of the inverted cup device, contributed to the study design, and helped to draft and revise the manuscript. All authors read and approved the final manuscript.Table S1. Explanations given by participants for perceptions of ease of use, risk and appropriateness as summarized in Table 4 in the full manuscript.Click here for file