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Unlike many viral hemorrhagic fevers (VHFs), Lassa fever (LF) is not a rare disease that emerges only as sporadic cases or in outbreak form. Although surveillance is inadequate to determine the true incidence, up to 300,000 infections and 5000 deaths from LF are estimated to occur yearly. The highest incidence is in the "Mano River Union (MRU) countries" of Sierra Leone, Liberia, and Guinea. Although civil unrest in this region over the past two decades has impeded capacity building and research, new-found peace in recent years presents new opportunities. In 2004, the Mano River Union Lassa Fever Network (MRU LFN) was established to assist MRU countries in the development of national and regional surveillance, diagnosis, treatment, control, and prevention of LF. Here, we review the present literature on treatment and pathogenesis of LF and outline priorities for future research in the field made possible by the improved research capacity of the MRU LFN.

In the late course of chronic pancreatitis (CP), weight loss is often seen because of reduced caloric intake and a reduction of pancreatic enzyme secretion, resulting in maldigestion. Most of these patients can be managed by dietary recommendations and pancreatic enzyme supplementation. However, approximately 5% of these patients are reported to be candidates for enteral nutrition support during their course of CP. Although small bowel access for enteral feeding can be easily obtained by percutaneous endoscopic gastrojejunostomy (PEG/J) or direct percutaneous endoscopic jejunostomy (DPEJ), to date there are no data regarding clinical outcome and safety of long-term jejunal feeding in CP.From January 1999 to October 2002, 57 patients receiving enteral nutrition by PEG/J or DPEJ were retrospectively analyzed during a follow-up period of 6 months. There were 38 females and 19 males, with an average age of 46.6 years.Small-bowel access was obtained by PEG/J in 53 patients and by DPEJ in 4. Duration of enteral feeding was 113 days. Average body weight significantly increased from 64.8 kg at day 1 to 69.1 kg at day 180 (p.001). The percentage of patients with abdominal pain decreased from 96% to 23%. One patient sustained a colon mesentery injury after DPEJ tube placement.Long-term nutrition support by PEG/J or DPEJ in patients with symptomatic, chronic pancreatitis increases patients' body weight and decreases the degree of malnutrition, abdominal pain, and other gastrointestinal symptoms. The underlying mechanisms for these observations are unclear and require further investigation. Small-bowel rest with reduced pancreatic gland stimulation might be a key component. Moderately to severely malnourished patients who do not respond to oral dietary interventions and who are candidates for elective pancreatic surgery might also be candidates for long-term preoperative jejunal feeding to reduce malnutrition-associated perioperative complications. In experienced hands, we feel that long-term jejunal feeding is safe, with minimal major complications.

PurposeCirculating cell-free DNA is present in increased amounts in the blood of cancer patients, but the clinical relevance of this phenomenon remains unclear. We conducted a clinical study to assess the value of circulating DNA as a prognostic marker in patients with non–small-cell lung cancer (NSCLC).Patients and MethodsA standard protocol for the quantification of circulating DNA by real-time polymerase chain reaction was set up and validated at two oncology units. One hundred eighty-five informed patients with NSCLC and 46 healthy controls were included in the study. DNA concentrations were determined in paired plasma and serum samples and analyzed for a relationship with leukocyte counts and lactate dehydrogenase (LDH) levels. DNA concentrations in healthy controls and in patients were compared, and cutoff levels for plasma and serum DNA were determined. Patient survival was analyzed relative to baseline DNA concentrations, and the relationship between tumor responses and changes in DNA concentrations was assessed in patients receiving chemotherapy.ResultsWe found a significant correlation between increased plasma DNA concentrations and elevated LDH levels (P = .009), advanced tumor stage (P < .003), and poor survival (P < .001). Tumor progression after chemotherapy was significantly (P = .006) associated with increasing plasma DNA concentrations. Serum DNA concentrations strongly correlated (P < .001) with leukocyte counts.ConclusionOur data demonstrate that quantification of plasma DNA is an accurate technique amenable to standardization, which might complement current methods for the prediction of patient survival. This approach might be considered for evaluation in large prospective studies.

To the Editor: Lassa fever is endemic in West Africa, with

Despite substantial efforts to eradicate poliomyelitis by administering oral poliovirus vaccine through routine immunization and annual national immunization days (NIDs), Pakistan reported 22% (1147) of the worldwide cases in 1997. Reasons for continued high poliomyelitis incidence include failure to vaccinate, vaccine failure, or inadequate immunization strategies. A case-control study was conducted to measure vaccination status and reasons for undervaccination among 66 poliomyelitis cases and 130 age- and neighborhood-matched controls. Cases were undervaccinated through routine immunization (matched odds ratio [MOR], 0.3; 95% confidence interval [CI], 0.1-0.5); however, NID immunization was similar for cases and controls (MOR, 0.6; 95% CI, 0.3-1.2). Reasons for undervaccination included not being informed, considering vaccination unimportant, and long distances to vaccination sites. Failure to vaccinate through routine immunization was a major risk factor for poliomyelitis in Pakistan. Successful NIDs alone will not interrupt poliovirus circulation in Pakistan, and children remain at risk unless routine immunization is strengthened or additional supplementary immunization is provided.

To better define the contribution of human parainfluenza viruses (HPIVs) to lower respiratory tract infection in adults, we tested acute- and convalescent-phase serum specimens from hospitalized adults participating in a population-based prospective study of lower respiratory tract infection during 1991-1992. We tested all available specimens from the epidemic seasons for each virus and approximately 300 randomly selected specimens from the corresponding off-seasons for antibodies to HPIV-1, HPIV-2, or HPIV-3. During the respective epidemic season, HPIV-1 infection was detected in 18 (2.5%) of 721 and HPIV-3 infection in 22 (3.1%) of 705 patients with lower respiratory tract infection. Only 2 (0.2%) of 1,057 patients tested positive for HPIV-2 infection. No HPIV-1 infections and only 2 (0.7% of 281 patients tested) HPIV-3 infections were detected during the off-seasons. HPIV-1 and HPIV-3 were among the four most frequently identified infections associated with lower respiratory tract infection during their respective outbreak seasons.

In July 1995 we investigated a pneumonia outbreak in a Pennsylvania town. We conducted epidemiological and molecular microbiological studies to determine the outbreak source and interrupt transmission of disease. Legionnaires' disease (LD) was quickly identified by urine antigen testing, and a newly developed immunohistochemical stain confirmed nosocomial transmission to a hospital inpatient. LD was confirmed in 22 patients. Case-patients were more likely than controls to have been within 1,000 feet of the hospital (matched odds ratio, 21.0; 95% confidence interval, 2.9-368) during the 2 weeks prior to illness. Legionella pneumophila serogroup 1 (Lp-1) was isolated from hospital cooling towers (CTs) and rooftop air samples but not from hospital potable water or community CTs. Hospital CT and air Lp-1 isolates matched all five patient isolates by monoclonal antibody, arbitrarily primed polymerase chain reaction, and pulsed-field gel electrophoresis subtyping. Strategies to prevent LD must include minimizing transmission from CTs.

The associations found in the general populations of a number of different countries are suggestive and warrant an integrated program of laboratory and epidemiologic research to reject or confirm the magnesium-IHD hypothesis. Singling out this particular risk factor has two justifications. First, as would be the case with any epidemiologic risk factor for IHD whose attributable risk was large enough to be detectable through epidemiology, applying that attributable risk to the vast annual morbidity and mortality from IHD would translate into tens of thousands of lives benefited and millions of dollars in hospital costs avoided per year. Second, this particular risk factor could conceivably be eliminated by an inexpensive supplementation program. For example, a low-sodium, higher-magnesium and -potassium table salt has been recommended and used in Finland for many years, during a period when the prevalence of hypertension in population surveys was said to decrease (117). Interventions which do not require behavioral change have always been the most cost-effective in public health. We therefore urge funding agencies to give priority to studies determining whether there are unforeseen adverse effects of magnesium for some population subgroups and whether the apparent benefit derived from low doses of magnesium in the development of IHD or IHD death is real. Furthermore, researchers should determine which chemical form of magnesium is best absorbed and most effective. We need to better understand the interrelation of various water and food constituents, as well as individual risk factors, in the pathogenesis of IHD. Susceptible individuals who are at higher risk of being depleted of magnesium need to be identified, and potential untoward effects of magnesium should be studied. Future research must provide better answers about low level waterborne magnesium before recommendations to the public can be made.

There is debate on whether the reported increase in the number of cases of childhood thyroid cancer in Belarus is real and attributable to radiation released following the Chernobyl nuclear accident, or rather an artefact due to incorrect histological diagnosis, more complete case reporting and mass screening of children after the accident. We have scrutinised the histological slides of 120 (75%) of the 160 cases reported among children aged up to 15 years to the Belarus tumour registry from 1986 to 1992 and examined time trends and geographical patterns in incidence and tumour characteristics. Incidence based on reported cases increased from 0.041 per 100,000 in 1986 to 2.548 in 1992. Carcinoma was confirmed in 94% of reviewed tumours. Except for one medullary carcinoma all histologies were of the papillary type. Most of the tumours had spread beyond the organ capsule and measured over 10 mm in diameter. There was a weak and statistically non-significant trend (p = 0.19) towards smaller tumours in the later years. The proportion of cases with lymphnode or distant metastasis remained unchanged. Incidence based on histologically confirmed cases was highest adjacent and to the west and north of Chernobyl, matching best estimates of iodine-131 contamination. Our data thus strongly suggest that the observed increase is real but more data are needed in order to assess the impact of mass screening and to clarify the possible association with radiation released at Chernobyl in 1986.

This article relates to two studies. In the first one all registered drug-related deaths (n = 649) in Switzerland from 1987 to 1989 were analyzed. In Study II a complete regional sample (n = 154) was further investigated. Data linkage to death certificates permitted tabulations according to place of residence and year of death, and the investigation of the migration of addicts. Drug-related mortality rate in urban areas was distinctly higher. Use of morphine/heroin was found in 80%. Consumption of cannabis started at age 11, of IV-applicated drugs at 13 years. Further results pertain to home situation, education, profession, cause, and circumstances of death.

BACKGROUND: Influenza outbreaks have been reported among travelers, but attack rates and incidence are unknown. METHODS: A cohort study was conducted. Travelers to subtropical and tropical countries recruited at the University of Zurich Travel Clinic (Switzerland), January 1998 to March 2000, were investigated with pre- and posttravel assessment of hemagglutination inhibition and by questionnaire. RESULTS: Among 1450 travelers recruited who completed questionnaires and provided serum samples before departure, 289 (19.9%) reported febrile illness during or after traveling abroad; of these, 211 (73.0%) provided paired serum samples. Additionally, paired serum samples were collected from 321 frequency-matched afebrile control subjects among the remaining 1161 subjects of the study population. Seroconversion for influenza virus infection was demonstrated in 40 (2.8%) of all travelers; 18 participants (1.2%) had a > or = 4-fold increase in antibody titers. This corresponds to an incidence of 1.0 influenza-associated events per 100 person-months abroad. Among the 211 febrile participants, 27 (12.8%) had seroconversion, 13 (6.2%) with a > or = 4-fold increase; among the 321 afebrile control subjects, 13 (4.0%) had seroconversion, 5 (1.6%) with a > or = 4-fold increase. Twenty-five seroconverters (62.5%; P = .747) acquired influenza outside of the European epidemic season. Sixteen patients (40.0%) sought medical attention either abroad or at home, and 32 (80.0%) were asymptomatic at the time of completion of the survey. CONCLUSIONS: This survey indicates that influenza is the most frequent vaccine-preventable infection among travelers to subtropical and tropical countries. Infections occur mainly outside the domestic epidemic season, and they have a considerable impact. Pretravel vaccination should be considered for travelers to subtropical and tropical countries.

Dr X is back from her annual leave. Dr Y, the locum doctor, reports on the patients he saw during her absence, including a 40 year old teacher who had sprained her right ankle. Returning from a conference, she had stumbled while walking down the stairs with a heavy bag. Examination revealed a moderately swollen lateral right ankle. The patient was able to walk but was clearly in pain. Her breath smelt of alcohol. Dr Y had applied the Ottawa ankle rules—decision rules designed to exclude fractures of the malleolus and the midfoot—and found no bone tenderness.1 He had previously visited the website of a centre for evidence based medicine2 and printed out a list of diagnostic tests that can rule out, or rule in, the condition in question without requiring further investigations. The probability of disease, given a positive or negative test result (post-test probability), is usually obtained by calculating the likelihood ratio of the test result and using formulas based on Bayes's theorem (see box 1), or a nomogram,3 to convert the estimated probability of the suspected diagnosis before the test result was known (pretest probability) into a post-test probability, which takes the result into account.4 Likelihood ratios indicate how many times more likely a test result is to be expected in a patient with the disease compared with a person free of the disease and thus measure a test's ability to modify pretest probabilities. David Sackett and others have argued that such calculations are unnecessary when a test is highly sensitive or highly specific.4–6 In this situation the likelihood ratio of a negative test will generally be very small, and the likelihood ratio of a positive test very large. A negative test will thus rule out, and a positive result …

Acute flaccid paralysis (AFP) is a clinical syndrome characterized by rapid onset of weakness, including (less frequently) weakness of the muscles of respiration and swallowing, progressing to maximum severity within several days to weeks. The term "flaccid" indicates the absence of spasticity or other signs of disordered central nervous system motor tracts such as hyperreflexia, clonus, or extensor plantar responses (1). When applied to voluntary muscles, "paralysis" means loss of contraction due to interruption of motor pathways from the cortex to the muscle fiber. It is preferable to use the term "paresis" for slight loss of motor strength and "paralysis" or "plegia" for severe loss of motor strength (1). The differential diagnosis of AFP varies considerably with age. No single operational clinical case definition of AFP or paralytic poliomyelitis that combines both high sensitivity and high specificity has emerged (2-4). The currently used case definition increases sensitivity in detecting the existence of AFP but tends to decrease specificity in detecting paralytic poliomyelitis.

Croup is a common manifestation of respiratory tract infection in children, and human parainfluenza virus 1 (HPIV-1) is the agent most commonly associated with croup. In the United States, HPIV-1 produces a distinctive pattern of biennial epidemics of respiratory illness during the autumn months of odd-numbered years. National Hospital Discharge Survey data for croup hospitalizations among patients

Microscopic diagnosis of malaria is unreliable outside specialized centers. Rapid tests have become available in recent years, but their accuracy has not been assessed systematically.To determine the accuracy of rapid diagnostic tests for ruling out malaria in nonimmune travelers returning from malaria-endemic areas.The authors searched MEDLINE, EMBASE, CAB Health, and CINAHL (1988 to September 2004); hand-searched conference proceedings; checked reference lists; and contacted experts and manufacturers.Diagnostic accuracy studies in nonimmune individuals with suspected malaria were included if they compared rapid tests with expert microscopic examination or polymerase chain reaction tests.Data on study and patient characteristics and results were extracted in duplicate. The main outcome was the likelihood ratio for a negative test result (negative likelihood ratio) for Plasmodium falciparum malaria. Likelihood ratios were combined by using random-effects meta-analysis, stratified by the antigen targeted (histidine-rich protein-2 [HRP-2] or parasite lactate dehydrogenase [LDH]) and by test generation. Nomograms of post-test probabilities were constructed.The authors included 21 studies and 5747 individuals. For P. falciparum, HRP-2-based tests were more accurate than parasite LDH-based tests: Negative likelihood ratios were 0.08 and 0.13, respectively (P = 0.019 for difference). Three-band HRP-2 tests had similar negative likelihood ratios but higher positive likelihood ratios compared with 2-band tests (34.7 vs. 98.5; P = 0.003). For P. vivax, negative likelihood ratios tended to be closer to 1.0 for HRP-2-based tests than for parasite LDH-based tests (0.24 vs. 0.13; P = 0.22), but analyses were based on a few heterogeneous studies. Negative likelihood ratios for the diagnosis of P. malariae or P. ovale were close to 1.0 for both types of tests. In febrile travelers returning from sub-Saharan Africa, the typical probability of P. falciparum malaria is estimated at 1.1% (95% CI, 0.6% to 1.9%) after a negative 3-band HRP-2 test result and 97% (CI, 92% to 99%) after a positive test result.Few studies evaluated 3-band HRP-2 tests. The evidence is also limited for species other than P. falciparum because of the few available studies and their more heterogeneous results. Further studies are needed to determine whether the use of rapid diagnostic tests improves outcomes in returning travelers with suspected malaria.Rapid malaria tests may be a useful diagnostic adjunct to microscopy in centers without major expertise in tropical medicine. Initial decisions on treatment initiation and choice of antimalarial drugs can be based on travel history and post-test probabilities after rapid testing. Expert microscopy is still required for species identification and confirmation.

In clinical trials, treatment effects from binary outcomes, such as “alive” or “dead”, can be presented in various ways (eg, relative risk reduction [RRR] and absolute risk reduction [ARR]).1–2 (See glossary for definitions and calculations). Alternatively, the number needed to treat (NNT) is an expression of the number of patients who need to be treated to prevent one additional adverse event.2–4 Mathematically, the NNT equals the reciprocal of the ARR. Many journals now report results from clinical trials using the NNT, along with 95% confidence intervals (CIs).5 Since its introduction,3 a debate has ensued whether reporting NNTs from meta-analyses is misleading.4,6,7 ACP Journal Club and Evidence-Based Medicine have devoted attention to this debate, and methodological questions have been raised in various review discussions and commentaries.8–9 The objective of this editorial is to provide Evidence-Based Medicine readers with caveats and suggestions when applying NNTs from a meta-analysis to an individual patient. We highlight 2 problems. Firstly, NNTs from a meta-analysis are subject to variation in risk differences among the studies included in the meta-analysis as well as in baseline risks. Secondly, applying NNTs to an individual requires adjustment for their baseline risk. NNTs derived from meta-analyses are affected …

Summary The antigenic-toxic complex of B. abortus isolated in the phenol phase of phenol/water system, is a lipopolysaccharide (LPS)-protein macromolecule. The specific side chain was isolated from this complex by means of pronase treatment and mild HCl cleavage, followed by fractionation on Sephadex. The side chain thus isolated lost its capacity to coat erythrocytes but not that of neutralizing antibodies, as shown in the hemagglutination inhibition test. Esterification of the side chain with lauryl sulfat restored its erythrocyte coating capacity. In view of transforming this haptene into an immunogen, it was attached to S. minnesota Re cells. Immunization of rabbits with this conjugate engendered the formation of antibodies that agglutinated B. abortus and B. melitensis cells as well. As the side chain could only be isolated from the smooth strain, it proves that a defect in the synthesis of this moiety gave rise to the rough Brucella mutant. In the latter fraction glucose, mannose and quinovosamine were identified. Fraction II separated on Sephadex was identified as the core polysaccharide, present in the preparation obtained from smooth and rough strain. In the core region 2-keto-3-deoxy-octonate, glucose, glucosamine (from the smooth but not from the rough strain) and protein were identified. Following the mild HCl hydrolysis, the lipid-protein moiety i.e. region 3, is also split off but without precipitating and, during the fractionation on Sephadex, it adsorbs onto the gel. The absence of jS-hydroxymyristic acid and glucosamine in Brucella lipid dissociates it from the enteric lipid A. In the LPS-protein's toxicity a major role has the protein present only in the smooth strain.

The immunological activities of three purified preparations of enterobacterial common antigen (ECA) obtained by different procedures were studied. ECA-Ma (method of A. Marx) was from Salmonella typhimurium TV149 (Ra mutant), ECA-My (method of H. Mayer) was from S. montevideo , and ECA-Ro (method of E. Romanowska) was from Shigella sonnei phase I. These preparations, on a weight basis, neutralized similar amounts of ECA antibodies, indicating that the serological activities were comparable. Neither ECA-My nor ECA-Ro elicited specific delayed-type hypersensitivity skin reactions at 24 or 48 h in immunized guinea pigs. ECA-Ma, as well as the nonpurified preparations of the antigens used for immunization, elicited reactions at 24 h but not at 48 h. Thus, ECA-specific delayed-type hypersensitivity was not detected in immunized guinea pigs. Striking differences were noted in the immunogenicity of these antigens, ECA-Ma being highly immunogenic in the rabbit in contrast to ECA-My and ECA-Ro. ECA-Ma was a potent mitogen for guinea pig spleen cells, stimulating high levels of DNA synthesis; ECA-My was only slightly active. The three antigens were mitogenic to spleen cells from both CBA/J and C3H/HeJ mice, although not to the same degree, indicating that this effect is not due to contaminating lipopolysaccharide, since the latter strain of mice is resistant to endotoxin. Since an ECA-Ma extract made from an ECA-negative mutant proved to be mitogenic to murine spleen cells, the mitogenicity is not due to the ECA haptenic determinant. The mitogenic effect is polyclonal in nature, ECA-Ma producing a maximum response on day 3. Thus, the ECA preparations are both B-cell mitogens and polyclonal activators in murine spleen cells. From these studies it is evident that the biological and immunological activities of these purified antigens depend not only on the haptenic determinant but also on associated or bound components of the preparations.