Chemoprophylaxis is recommended for at-risk travellers visiting malaria endemic regions. The majority of travellers with imported malaria have not used this, and travellers visiting friends and relatives have the largest burden of malaria and the lowest compliance to chemoprophylaxis. In 1995, the UK’s Department of Health (DH) implemented a policy to make travellers fully responsible for the cost when purchasing chemoprophylaxis. This policy was not implemented in three Primary Care Trusts (PCTs) in London due to concern about the potential increase of imported malaria in their residents, and they maintained the public subsidy. An impact evaluation of the policy change was undertaken to determine if the continued subsidy reduced the incidence of imported malaria in one of the boroughs where the subsidy was maintained when compared to a borough where no subsidy was provided.
Between 2007 and 2010 prescriptions for malaria chemoprophylaxis were collected from pharmacy records and PCTs, and all cases of imported malaria reported from the tertiary hospital in each of the two boroughs were compared.
The dispensed chemoprophylaxis prescriptions were nearly 8.8 times higher in Lambeth (where subsidized drugs were provided), than in Hackney. A Poisson model revealed significantly fewer reports of imported malaria per capita were made in Lambeth compared to Hackney (p = 0.042).
The difference in malaria reports between the boroughs only just reached statistical significance, despite the considerable difference in chemoprophylaxis prescribing between the boroughs. Some travellers may not consider using chemoprophylaxis, irrespective of the cost. Regular evaluations of the recent policy changes in areas where malaria is subsidized will be important.
Imported malaria; Chemoprophylaxis; Subsidized costs; Evaluation
Antenatal preventive administration of sulfadoxine-pyrimethamine did not potentiate pregnancy-associated malaria morbidity despite expansion and fixation of drug-resistant malaria parasites. Sulfadoxine-pyrimethamine may be a safe component of malaria prevention programs without causing adverse effects on birth outcomes.
Background. Antenatal intermittent preventive therapy with 2 doses of sulfadoxine-pyrimethamine (IPTp-SP) is the mainstay of efforts in sub-Saharan Africa to prevent pregnancy-associated malaria (PAM). Recent studies report that drug resistance may cause IPTp-SP to exacerbate PAM morbidity, raising fears that current policies will cause harm as resistance spreads.
Methods. We conducted a serial, cross-sectional analysis of the relationships between IPTp-SP receipt, SP-resistant Plasmodium falciparum, and PAM morbidity in delivering women during a period of 9 years at a single site in Malawi. PAM morbidity was assessed by parasite densities, placental histology, and birth outcomes.
Results. The prevalence of parasites with highly SP-resistant haplotypes increased from 17% to 100% (P < .001), and the proportion of women receiving full IPTp (≥2 doses) increased from 25% to 82% (P < .001). Women who received full IPTp with SP had lower peripheral (P = .018) and placental (P < .001) parasite densities than women who received suboptimal IPTp (<2 doses). This effect was not significantly modified by the presence of highly SP-resistant haplotypes. After adjustment for covariates, the receipt of SP in the presence of SP-resistant P. falciparum did not exacerbate any parasitologic, histologic, or clinical measures of PAM morbidity.
Conclusions. In this longitudinal study of malaria at delivery, the receipt of SP as IPTp did not potentiate PAM morbidity despite the increasing prevalence and fixation of SP-resistant P. falciparum haplotypes. Even when there is substantial resistance, SP may be used in modified IPTp regimens as a component of comprehensive antenatal care.
Food-processing conditions may alter the allergenicity of food proteins by different means. In this study, the effect of the glycosylation as a result of thermal treatment on the digestibility and IgE-binding of codfish parvalbumin is investigated. Native and glycosylated parvalbumins were digested with pepsin at various conditions relevant for the gastrointestinal tract. Intact proteins and peptides were analysed for apparent molecular weight and IgE-binding. Glycosylation did not substantially affect the digestion. Although the peptides resulting from digestion were relatively large (3 and 4 kDa), the IgE-binding was strongly diminished. However, the glycosylated parvalbumin had a strong propensity to form dimers and tetramers, and these multimers bound IgE intensely, suggesting stronger IgE-binding than monomeric parvalbumin. We conclude that glycosylation of codfish parvalbumin does not affect the digestibility of parvalbumin and that the peptides resulting from this digestion show low IgE-binding, regardless of glycosylation. Glycosylation of parvalbumin leads to the formation of higher order structures that are more potent IgE binders than native, monomeric parvalbumin. Therefore, food-processing conditions applied to fish allergen can potentially lead to increased allergenicity, even while the protein's digestibility is not affected by such processing.
Haemoglobinopathies variously reduce the risk of developing malaria syndromes. Quantifying these relationships may strengthen the foundation for translational studies of malaria pathogenesis and immunity.
The databases of MEDLINE and Embase (1950 – September 9, 2011) were searched to identify studies that estimated the risk of malaria in patients with and without haemoglobinopathies. Additional studies were identified from reference lists. Included outcomes were Plasmodium falciparum-related outcomes of severe malaria, uncomplicated malaria, asymptomatic parasitaemia, or pregnancy-associated malaria, and P. vivax malaria. Two independent reviewers identified studies, assessed their quality, and extracted data; data were meta-analyzed when outcomes were reported in more than one study.
Of 62 identified studies, 44 reported on HbAS, 19 on HbAC and HbCC, and 18 on α-thalassaemia. Case-control studies showed a decreased risk of severe malaria for HbAS (summary Odds Ratio [OR] 0.09; 95% confidence interval [CI] 0.06 – 0.12), HbCC (summary OR 0.27; 95% CI 0.11 – 0.63), homozygous α-thalassaemia (summary OR 0.63; 95% CI 0.48 – 0.83), HbAC (summary OR 0.83; 95% CI 0.74 – 0.92), and heterozygous α-thalassaemia (summary OR 0.83; 95% CI 0.74 – 0.92). Only HbAS was consistently associated with protection from uncomplicated malaria (summary Incidence Rate Ratio 0.69; 95% CI 0.61 – 0.79); none demonstrated protection from asymptomatic parasitaemia. There was a paucity of clinical studies investigating β-thalassaemia, HbE, P. vivax malaria, and pregnancy-associated malaria.
Protection from severe malaria syndromes is significant for HbAS, HbCC, HbAC, and homozygous and heterozygous α-thalassaemia, but these haemoglobinopathies differ substantially in the degrees of protection. Protection from uncomplicated malaria and asymptomatic parasitaemia is mild or absent. By attenuating the severity of malaria, haemoglobinopathies serve as a model for investigating the mechanisms of malaria pathogenesis and immunity.
Plasmodium falciparum malaria kills over 500,000 children every year and has been a scourge of humans for millennia. Owing to the co-evolution of humans and P. falciparum parasites, the human genome is imprinted with polymorphisms that not only confer innate resistance to falciparum malaria, but also cause hemoglobinopathies. These genetic traits—including hemoglobin S (HbS), hemoglobin C (HbC), and α-thalassemia—are the most common monogenic human disorders and can confer remarkable degrees of protection from severe, life-threatening falciparum malaria in African children: the risk is reduced 70% by homozygous HbC and 90% by heterozygous HbS (sickle-cell trait). Importantly, this protection is principally present for severe disease and largely absent for P. falciparum infection, suggesting that these hemoglobinopathies specifically neutralize the parasite's in vivo mechanisms of pathogenesis. These hemoglobin variants thus represent a “natural experiment” to identify the cellular and molecular mechanisms by which P. falciparum produces clinical morbidity, which remain partially obscured due to the complexity of interactions between this parasite and its human host. Multiple lines of evidence support a restriction of parasite growth by various hemoglobinopathies, and recent data suggest this phenomenon may result from host microRNA interference with parasite metabolism. Multiple hemoglobinopathies mitigate the pathogenic potential of parasites by interfering with the export of P. falciparum erythrocyte membrane protein 1 (PfEMP1) to the surface of the host red blood cell. Few studies have investigated their effects upon the activation of the innate and adaptive immune systems, although recent murine studies suggest a role for heme oxygenase-1 in protection. Ultimately, the identification of mechanisms of protection and pathogenesis can inform future therapeutics and preventive measures. Hemoglobinopathies slice the “Gordian knot” of host and parasite interactions to confer malaria protection, and offer a translational model to identify the most critical mechanisms of P. falciparum pathogenesis.
Sulfadoxine-pyrimethamine (SP) has been widely deployed in Africa for malaria control and molecular evidence of parasite drug-resistance is prevalent. However, the temporal effects on the selection of Plasmodium falciparum are not well understood. We conducted a retrospective serial cross-sectional study between 1997 and 2006 to investigate changes in drug-resistant malaria among pregnant women delivering at a single hospital in Blantyre, Malawi. P. falciparum parasites were genotyped for parasite clone multiplicity and drug-resistance mutations, and the strength of selection upon mutant genotypes was quantified. Five mutations in the dihydrofolate reductase and dihydropteroate synthase genes began at moderate frequencies and achieved fixation by 2005; the frequency of the highly-SP-resistant “quintuple mutant” haplotype increased from 19% to 100%. The selective advantage of alleles and haplotypes were quantified with selection coefficients: Selection was positive on all mutant alleles and haplotypes associated with SP resistance, and the relative fitness of the quintuple mutant haplotype was 0.139 (95% C.I. 0.067 – 0.211), indicating a substantial positive selective advantage. Mutations that confer higher levels of resistance to SP did not emerge. SP-resistant haplotypes were rapidly selected for and fixed in P. falciparum populations infecting pregnant women while SP was widely deployed in Malawi. These results underscore the pressing need for new preventive measures for pregnancy-associated malaria and provide a real-world model of the selection landscape malaria parasites.
malaria; pregnancy-associated malaria; drug resistance; parasite evolution
Pneumocystis jirovecii is an important opportunistic infection in HIV-infected patients. In the developed world, P. jirovecii epidemiology is marked by frequent colonization in immunosuppressed patients, but data on the prevalence of colonization is very limited in sub-Saharan Africa, where the majority of persons living with HIV reside. Our objective was to describe the epidemiology of P. jirovecii colonization among HIV-positive patients in a cross-sectional, hospital-based study of patients admitted with suspected pneumonia in Kampala, Uganda. P. jirovecii was detectable in bronchoalveolar lavage fluid from 7 of 124 (6%) consecutive patients with non-Pneumocystis pneumonia. Colonization was not associated with patient demographic or clinical information. This prevalence is substantially lower than in published studies in the developed world, and suggests that there is a limited reservoir of organisms for clinical infections in this Ugandan population. These findings may partially explain the low incidence of Pneumocystis pneumonia in Uganda and other sub-Saharan African countries.
Pneumocystis jirovecii; colonization; pneumonia; AIDS
Understanding the spatial clustering of Plasmodium falciparum populations can assist efforts to contain drug-resistant parasites and maintain the efficacy of future drugs. We sequenced single nucleotide polymorphisms (SNPs) in the dihydropteroate synthase gene (dhps) associated with sulfadoxine resistance and 5 microsatellite loci flanking dhps in order to investigate the genetic backgrounds, genetic relatedness, and geographic clustering of falciparum parasites in the Democratic Republic of the Congo (DRC). Resistant haplotypes were clustered into subpopulations: one in the northeast DRC, and the other in the balance of the DRC. Network and clonal lineage analyses of the flanking microsatellites indicate that geographically-distinct mutant dhps haplotypes derive from separate lineages. The DRC is therefore a watershed for haplotypes associated with sulfadoxine resistance. Given the importance of central Africa as a corridor for the spread of antimalarial resistance, the identification of the mechanisms of this transit can inform future policies to contain drug-resistant parasite strains.
Background. Pregnancy-associated malaria (PAM) produces poor birth outcomes, but its prevalence is commonly estimated in convenience samples.
Methods. We assessed the prevalence of malaria using real-time polymerase chain reaction (PCR) and estimated the consequences of infection on birth outcomes, using specimens from a nationally representative sample of 4570 women of childbearing age (WOCBA) responding to the 2007 Demographic and Health Survey in Democratic Republic of the Congo (DRC).
Results. Overall, 31.2% (95% confidence interval [CI], 29.2–33.1) of WOCBA were parasitemic, which was significantly more common in pregnant (37.2% [31.0–43.5]) than nonpregnant women (30.4% [CI, 28.4–32.5], prevalence ratio [PR] 1.22 [1.02–1.47]). Plasmodium falciparum was highest among pregnant women (36.6% vs 28.8%, PR 1.27 [1.05–1.53]). By contrast, P malariae was less common in pregnant (0.6%) compared with nonpregnant women (2.7%, PR 0.23 [0.09–0.56]). Extrapolation of the prevalence estimate to the population at risk of malaria in DRC suggests 1.015 million births are affected by P falciparum infection annually, and that adherence to preventive measures could prevent up to 549 000 episodes of pregnancy-associated malaria and 47 000 low-birth-weight births.
Conclusions. Pregnancy-associated malaria and its consequences are highly prevalent in the DRC. Increasing the uptake of malaria preventive measures represents a significant opportunity to improve birth outcomes and neonatal health.
Pneumocystis jirovecii pneumonia (PCP) is an important opportunistic infection in patients infected with HIV, but its burden is incompletely characterized in those areas of sub-Saharan Africa where HIV is prevalent. We explored the prevalence of both PCP in HIV-infected adults admitted with pneumonia to a tertiary-care hospital in Uganda and of putative P. jirovecii drug resistance by mutations in fungal dihydropteroate synthase (dhps) and dihydrofolate reductase (dhfr). In 129 consecutive patients with sputum smears negative for mycobacteria, 5 (3.9%) were diagnosed with PCP by microscopic examination of Giemsa-stained bronchoalveolar lavage fluid. Concordance was 100% between Giemsa stain and PCR (dhps and dhfr). PCP was more prevalent in patients newly-diagnosed with HIV (11.4%) than in patients with known HIV (1.1%; p = 0.007). Mortality at 2 months after discharge was 29% overall: 28% among PCP-negative patients, and 60% (3 of 5) among PCP-positive patients. In these 5 fungal isolates and an additional 8 from consecutive cases of PCP, all strains harbored mutant dhps haplotypes; all 13 isolates harbored the P57S mutation in dhps, and 3 (23%) also harbored the T55A mutation. No non-synonymous dhfr mutations were detected. PCP is an important cause of pneumonia in patients newly-diagnosed with HIV in Uganda, is associated with high mortality, and putative molecular evidence of drug resistance is prevalent. Given the reliability of field diagnosis in our cohort, future studies in sub-Saharan Africa can investigate the clinical impact of these genotypes.
Malaria is highly endemic in the Democratic Republic of Congo (DRC), but the limits and intensity of transmission within the country are unknown. It is important to discern these patterns as well as the drivers which may underlie them in order for effective prevention measures to be carried out.
By applying high-throughput PCR analyses on leftover dried blood spots from the 2007 Demographic and Health Survey (DHS) for the DRC, prevalence estimates were generated and ecological drivers of malaria were explored using spatial statistical analyses and multilevel modelling.
Of the 7,746 respondents, 2268 (29.3%) were parasitaemic; prevalence ranged from 0-82% within geographically-defined survey clusters. Regional variation in these rates was mapped using the inverse-distance weighting spatial interpolation technique. Males were more likely to be parasitaemic than older people or females (p < 0.0001), while wealthier people were at a lower risk (p < 0.001). Increased community use of bed nets (p = 0.001) and community wealth (p < 0.05) were protective against malaria at the community level but not at the individual level. Paradoxically, the number of battle events since 1994 surrounding one's community was negatively associated with malaria risk (p < 0.0001).
This research demonstrates the feasibility of using population-based behavioural and molecular surveillance in conjunction with DHS data and geographic methods to study endemic infectious diseases. This study provides the most accurate population-based estimates to date of where illness from malaria occurs in the DRC and what factors contribute to the estimated spatial patterns. This study suggests that spatial information and analyses can enable the DRC government to focus its control efforts against malaria.
MicroRNAs are small RNA species that regulate gene expression post-transcriptionally and are aberrantly expressed in many cancers including hematological malignancies. However, the role of microRNAs in the pathogenesis of multiple myeloma (MM) is only poorly understood. We therefore used microarray analysis to elucidate the complete miRNome (miRBase version 13.0) of purified tumor (CD138+) cells from 33 patients with MM, 5 patients with monoclonal gammopathy of undetermined significance (MGUS) and 9 controls.
Unsupervised cluster analysis revealed that MM and MGUS samples have a distinct microRNA expression profile from control CD138+ cells. The majority of microRNAs aberrantly expressed in MM (109/129) were up-regulated. A comparison of these microRNAs with those aberrantly expressed in other B-cell and T-cell malignancies revealed a surprising degree of similarity (~40%) suggesting the existence of a common lymphoma microRNA signature. We identified 39 microRNAs associated with the pre-malignant condition MGUS. Twenty-three (59%) of these were also aberrantly expressed in MM suggesting common microRNA expression events in MM progression. MM is characterized by multiple chromosomal abnormalities of varying prognostic significance. We identified specific microRNA signatures associated with the most common IgH translocations (t(4;14) and t(11;14)) and del(13q). Expression levels of these microRNAs were distinct between the genetic subtypes (by cluster analysis) and correctly predicted these abnormalities in > 85% of cases using the support vector machine algorithm. Additionally, we identified microRNAs associated with light chain only myeloma, as well as IgG and IgA-type MM. Finally, we identified 32 microRNAs associated with event-free survival (EFS) in MM, ten of which were significant by univariate (logrank) survival analysis.
In summary, this work has identified aberrantly expressed microRNAs associated with the diagnosis, pathogenesis and prognosis of MM, data which will prove an invaluable resource for understanding the role of microRNAs in this devastating disease.
This article was reviewed by Prof. Neil Smalheiser, Prof. Yuriy Gusev, and an unknown reviewer.
Epidemiologic data on malaria are scant in many high-burden countries including the Democratic Republic of the Congo (DRC), which suffers the second-highest global burden of malaria. Malaria control efforts in regions with challenging infrastructure require reproducible and efficient surveillance. We employed new high-throughput molecular testing to characterize the state of malaria control in the DRC and estimate childhood mortality attributable to excess malaria transmission.
Methods and Findings
The Demographic and Health Survey was a cross-sectional, population-based cluster household survey of adults aged 15–59 years in 2007 employing structured questionnaires and dried blood spot collection. Parasitemia was detected by real-time PCR, and survey responses measured adoption of malaria control measures and under-5 health indices. The response rate was 99% at the household level, and 8,886 households were surveyed in 300 clusters; from 8,838 respondents molecular results were available. The overall prevalence of parasitemia was 33.5% (95% confidence interval [C.I.] 32–34.9); P. falciparum was the most prevalent species, either as monoinfection (90.4%; 95% C.I. 88.8–92.1) or combined with P. malariae (4.9%; 95% C.I. 3.7–5.9) or P. ovale (0.6%; 95% C.I. 0.1–0.9). Only 7.7% (95% CI 6.8–8.6) of households with children under 5 owned an insecticide-treated bednet (ITN), and only 6.8% (95% CI 6.1–7.5) of under-fives slept under an ITN the preceding night. The overall under-5 mortality rate was 147 deaths per 1,000 live births (95% C.I. 141–153) and between clusters was associated with increased P. falciparum prevalence; based on the population attributable fraction, 26,488 yearly under-5 deaths were attributable to excess malaria transmission.
Adult P. falciparum prevalence is substantial in the DRC and is associated with under-5 mortality. Molecular testing offers a new, generalizable, and efficient approach to characterizing malaria endemicity in underserved countries.
New diagnostic tools for malaria are required owing to the changing epidemiology of malaria, particularly among pregnant women in sub-Saharan Africa. Real-time PCR assays targeting Plasmodium falciparum lactate dehydrogenase (pfldh) gene may facilitate the identification of a high proportion of pregnant women with a P. falciparum parasitaemia below the threshold of microscopy. These molecular methods will enable further studies on the effects of these submicroscopic infections on maternal health and birth outcomes.
The pfldh real-time PCR assay and conventional microscopy were compared for the detection of P. falciparum from dried blood spots and blood smears collected from the peripheral blood of 475 Malawian women at delivery. A cycle threshold (Ct) of the real-time PCR was determined optimizing the sensitivity and specificity of the pfldh PCR assay compared to microscopy. A real-time PCR species-specific assay was applied to identify the contribution to malaria infections of three Plasmodium species (P. falciparum P. ovale and P. malariae) in 44 discordant smear and pfldh PCR assay results.
Of the 475 women, P. falciparum was detected in 11 (2.3%) by microscopy and in 51 (10.7%) by real-time PCR; compared to microscopy, the sensitivity of real-time PCR was 90.9% and the specificity 91.2%. If a Ct value of 38 was used as a cut-off, specificity improved to 94.6% with no change in sensitivity. The real-time PCR species-specific assay detected P. falciparum alone in all but four samples: two samples were mixed infections with P. falciparum and P. malariae, one was a pure P. malariae infection and one was a pfldh PCR assay-positive/species-specific assay-negative sample. Of three P. malariae infections detected by microscopy, only one was confirmed by the species-specific assay.
Although microscopy remains the most appropriate method for clinical malaria diagnosis in field settings, molecular diagnostics such as real-time PCR offer a more reliable means to detect malaria parasites, particularly at low levels. Determination of the possible contribution of these submicroscopic infections to poor birth outcomes and maternal health is critical. For future studies to investigate these effects, this pfldh real-time PCR assay offers a reliable detection method.
The effectiveness of radiotherapy treatment could be significantly improved if tumour cells could be rendered more sensitive to ionizing radiation without altering the sensitivity of normal tissues. However many of the key, therapeutically exploitable mechanisms that determine intrinsic tumour radiosensitivity are largely unknown. We have conducted a siRNA screen of 200 genes involved in DNA damage repair aimed at identifying genes whose knockdown increased tumour radiosensitivity. Parallel siRNA screens were conducted in irradiated and unirradiated tumour cells (SQ20B) and irradiated normal tissue cells (MRC5). Using γH2AX foci at 24 hours after ionising radiation we identified several genes such as BRCA2, Lig IV and XRCC5, whose knockdown is known to cause increased cell radiosensitivity thereby validating the primary screening endpoint. In addition we identified POLQ (DNA polymerase theta) as a potential tumour-specific target. Subsequent investigations demonstrated that POLQ knockdown resulted in radiosensitisation of a panel of tumour cell lines from different primary sites, whilst having little or no effect on normal tissue cell lines. These findings raise the possibility that POLQ inhibition might be used clinically to cause tumour specific radiosensitisation.
High-throughput Screen; siRNA; DNA-repair; POLQ; Tumour Radiosensitivity
Molecular assays can provide critical information for malaria diagnosis, speciation, and drug resistance, but their cost and resource requirements limit their application to clinical malaria studies. This study describes the application of a resource-conserving testing algorithm employing sample pooling for real-time PCR assays for malaria in a cohort of 182 pregnant women in Kinshasa. A total of 1,268 peripheral blood samples were collected during the study. Using a real-time PCR assay that detects all Plasmodium species, microscopy-positive samples were amplified individually; the microscopy-negative samples were amplified after pooling the genomic DNA (gDNA) of four samples prior to testing. Of 176 microscopy-positive samples, 74 were positive by the real-time PCR assay; the 1,092 microscopy-negative samples were initially amplified in 293 pools, and subsequently, 35 samples were real-time PCR positive (3%). With the real-time PCR result as the referent standard, microscopy was 67.9% sensitive (95% confidence interval [CI], 58.3% to 76.5%) and 91.2% specific (95% CI, 89.4% to 92.8%) for malaria. In total, we detected 109 parasitemias by real-time PCR and, by pooling samples, obviated over 50% of reactions and halved the cost of testing. Our study highlights both substantial discordance between malaria diagnostics and the utility and parsimony of employing a sample pooling strategy for molecular diagnostics in clinical and epidemiologic malaria studies.
Botulism developed in a patient following surgical repair of an open radial fracture. Symptoms resolved after treatment with antitoxin and antibiotics, and hardware excision was deferred. Subsequent osteomyelitis necessitated hardware exchange, and wound cultures grew Clostridium argentinense. This case highlights the management of botulism associated with orthopedic hardware.
To examine endoscopic retrograde cholangio‐pancreatography (ERCP) services and training in the UK.
Prospective multicentre survey.
Five regions of England.
Hospitals with an ERCP unit.
Adherence to published guidelines, technical success rates, complications and mortality.
Organisation questionnaires were returned by 76 of 81 (94%) units. Personal questionnaires were returned by 190 of 213 (89%) ERCP endoscopists and 74 of 91 (81%) ERCP trainees, of whom 45 (61%) reported participation in <50 ERCPs per annum. In all, 66 of 81 (81%) units collected prospective data on 5264 ERCPs, over a mean period of 195 days. Oximetry was used by all units, blood pressure monitoring by 47 of 66 (71%) and ECG monitoring by 37 of 66 (56%) units; 1484 of 4521 (33%) patients were given >5 mg of midalozam. Prothrombin time was recorded in 4539 of 5264 (86%) procedures. Antibiotics were given in 1021 of 1412 (72%) cases, where indicated. Patients' American Society of Anesthesiology (ASA) scores were 3–5 in 670 of 5264 (12.7%) ERCPs, and 4932 of 5264 (94%) ERCPs were scheduled with therapeutic intent. In total, 140 of 182 (77%) trained endoscopists demonstrated a cannulation rate ⩾80%. The recorded cannulation rate among senior trainees (with an experience of >200 ERCPs) was 222/338 (66%). Completion of intended treatment was done in 3707 of 5264 (70.4%) ERCPs; 268 of 5264 (5.1%) procedures resulted in a complication. Procedure‐related mortality was 21/5264 (0.4%). Mortality correlated with ASA score.
Most ERCPs in the UK are performed on low‐risk patients with therapeutic intent. Complication rates compare favourably with those reported internationally. However, quality suffers because there are too many trainees in too many low‐volume ERCP centres.
Food allergies are caused by immunological reactions in individuals sensitized to normal protein components of foods. For any given sensitized individual, the severity of a reaction is generally assumed to be proportional to the dose of allergenic protein. There is substantial clinical evidence that “threshold” doses exist for the elicitation of an allergic reaction; however, the threshold (i.e., lowest dose that elicits a reaction) varies substantially across the sensitized population. Current approaches to protecting sensitized individuals from exposure to food allergens are highly qualitative (i.e., they rely on food avoidance). The Key Events Dose-Response Framework is an analytical approach for refining understanding of the biological basis of the dose-response. Application of this approach to food allergy provides a foundation for a more rigorous quantitative understanding of variability in allergic response. This study reviews the allergic disease process and the current approaches to identifying thresholds for food allergens. The pathway of key biological events occurring between food intake and allergic response is considered, along with factors that may determine the nature and severity of response to food allergens. Data needs, as well as implications for identifying thresholds, and for characterizing variability in thresholds, are also discussed.
Low dose dose-response; food allergy; thresholds; minimal eliciting dose; Key Events Dose-Response Framework
Genes on different chromosomes can be spatially associated in the nucleus in several transcriptional and regulatory situations; however, the functional significance of such associations remains unclear. Using human erythropoiesis as a model, we show that five cotranscribed genes, which are found on four different chromosomes, associate with each other at significant but variable frequencies. Those genes most frequently in association lie in decondensed stretches of chromatin. By replacing the mouse α-globin gene cluster in situ with its human counterpart, we demonstrate a direct effect of the regional chromatin environment on the frequency of association, whereas nascent transcription from the human α-globin gene appears unaffected. We see no evidence that cotranscribed erythroid genes associate at shared transcription foci, but we do see stochastic clustering of active genes around common nuclear SC35-enriched speckles (hence the apparent nonrandom association between genes). Thus, association between active genes may result from their location on decondensed chromatin that enables clustering around common nuclear speckles.
BACKGROUND: Despite generally falling mortality and suicide rates, among young men the rates of violent death from accidents and suicide continue to rise. Most research has focused upon suicide, and the potential for effective interventions, particularly in primary care, remains controversial. AIMS: To compare health service contacts prior to suicidal and accidental deaths among young men. DESIGN OF STUDY: Examination of inquest data, postmortem and toxicology reports, and general practitioner (GP) and hospital records. SETTING: All sudden, unexpected, violent or unnatural deaths involving young men aged between 15 and 39 years and reported to the four coroner's offices of Merseyside and Cheshire during 1995. METHOD: We compared data on the timing and nature of final GP contacts before death among young men with a verdict of accident or misadventure and suicide or undetermined death. RESULTS: Out of a total of 268 violent deaths, 130 received verdicts of accident/misadventure and 97 received verdicts of suicide/undetermined death. Information on the final contact with a GP was available for 172 deaths. Although there was a significant difference between the proportion of suicide cases (56%) and that of cases of accidental death (41%) who had seen their GP during the 3 months before death, this was not significant at 1 month (38% versus 30%, respectively). Suicide cases were more likely to have seen a mental health professional at some time (27% for suicides versus 13% for accidental deaths). CONCLUSION: These findings confirm that relatively few young men consult their GP during the period before death from suicide or accidents. Prevention strategies must extend beyond suicide risk assessment, and consider ways to encourage young men to consult GPs when they are experiencing emotional distress or problems related to mental health or substance misuse.