Nucleic acid amplification tests for diagnosis of smear-negative TB in a high HIV-prevalence setting: a prospective cohort study

Background

Nucleic acid amplification tests are sensitive for identifying Mycobacterium tuberculosis in populations with positive sputum smears for acid-fast bacilli, but less sensitive in sputum-smear-negative populations. Few studies have evaluated the clinical impact of these tests in low-income countries with high burdens of TB and HIV.

Methods

We prospectively enrolled 211 consecutive adults with cough ≥2 weeks and negative sputum smears at Mulago Hospital in Kampala, Uganda. We tested a single early-morning sputum specimen for Mycobacterium tuberculosis DNA using two nucleic acid amplification tests: a novel in-house polymerase chain reaction targeting the mycobacterial secA1 gene, and the commercial Amplified® Mycobacterium tuberculosis Direct (MTD) test (Gen-Probe Inc, San Diego, CA). We calculated the diagnostic accuracy of these index tests in reference to a primary microbiologic gold standard (positive mycobacterial culture of sputum or bronchoalveolar lavage fluid), and measured their likely clinical impact on additional tuberculosis cases detected among those not prescribed initial TB treatment.

Results

Of 211 patients enrolled, 170 (81%) were HIV-seropositive, with median CD4+ T-cell count 78 cells/µL (interquartile range 29-203). Among HIV-seropositive patients, 94 (55%) reported taking co-trimoxazole prophylaxis and 29 (17%) reported taking antiretroviral therapy. Seventy-five patients (36%) had culture-confirmed TB. Sensitivity of MTD was 39% (95% CI 28–51) and that of secA1 was 24% (95% CI 15–35). Both tests had specificities of 95% (95% CI 90–98). The MTD test correctly identified 18 (24%) TB patients not treated at discharge and led to a 72% relative increase in the smear-negative case detection rate.

Conclusions

The secA1 and MTD nucleic acid amplification tests had moderate sensitivity and high specificity for TB in a predominantly HIV-seropositive population with negative sputum smears. Although newer, more sensitive nucleic acid assays may enhance detection of Mycobacterium tuberculosis in sputum, even currently available tests can provide substantial clinical impact in smear-negative populations.     

A prospective study to evaluate the accuracy of rapid diagnostic tests for diagnosis of human leptospirosis: Result from THAI-LEPTO AKI study

BackgroundRapid diagnostic tests (RDTs) have become widely used in low-resource settings for leptospirosis diagnostic. This study aims to evaluate the diagnostic performance of the five commercially available RDTs to detect human IgM against Leptospira spp. in Thai population.Methodology/Principal findingsNinety-nine serum samples from Leptospirosis suspicious patients were tested with five RDTs, including Medical Science Public Health, Leptocheck-WB, SD bioline, TRUSTline, and J.Mitra. The case definition was based on MAT, qPCR, and culture results. Diagnostic accuracy was determined based on the first day of enrollment in an overall analysis and stratified according to days post-onset of fever. The five RDTs had overall sensitivity ranging from 1.8% to 75% and specificity ranging from 52.3% to 97.7%. Leptocheck-WB had high sensitivity of 75.0%. The sensitivity of five RDTs increased on days 4–6 post-onset of fever, while the specificity of all tests remained relatively stable at different days post-onset of fever.Conclusions/SignificanceThe tested RDTs showed low sensitivity. Therefore, based on the present study, five commercially available RDTs might not be an appropriate test for acute leptospirosis screening in the Thai population.     

Comparing the clinical and histological diagnosis of leprosy and leprosy reactions in the INFIR cohort of Indian patients with multibacillary leprosy

Background

The ILEP Nerve Function Impairment in Reaction (INFIR) is a cohort study designed to identify predictors of reactions and nerve function impairment in leprosy. The aim was to study correlations between clinical and histological diagnosis of reactions.

Methodology/Principal Findings

Three hundred and three newly diagnosed patients with World Health Organization multibacillary (MB) leprosy from two centres in India were enrolled in the study. Skin biopsies taken at enrolment were assessed using a standardised proforma to collect data on the histological diagnosis of leprosy, leprosy reactions and the certainty level of the diagnosis. The pathologist diagnosed definite or probable Type 1 Reactions (T1R) in 113 of 265 biopsies from patients at risk of developing reactions whereas clinicians diagnosed skin only reactions in 39 patients and 19 with skin and nerve involvement. Patients with Borderline Tuberculoid (BT) leprosy had a clinical diagnosis rate of reactions of 43% and a histological diagnosis rate of 61%; for patients with Borderline Lepromatous (BL) leprosy the clinical and histological diagnosis rates were 53.7% and 46.2% respectively. The sensitivity and specificity of clinical diagnosis for T1R was 53.1% and 61.9% for BT patients and 61.1% and 71.0% for BL patients. Erythema Nodosum Leprosum (ENL) was diagnosed clinically in two patients but histologically in 13 patients. The Ridley-Jopling classification of patients (n = 303) was 42.8% BT, 27.4% BL, 9.4% Lepromatous Leprosy (LL), 13.0% Indeterminate and 7.4% with non-specific inflammation. This data shows that MB classification is very heterogeneous and encompasses patients with no detectable bacteria and high immunological activity through to patients with high bacterial loads.

Conclusions/Significance

Leprosy reactions may be under-diagnosed by clinicians and increasing biopsy rates would help in the diagnosis of reactions. Future studies should look at sub-clinical T1R and ENL and whether they have impact on clinical outcomes.     

Autonomic neuropathy in Fabry disease: a prospective study using the Autonomic Symptom Profile and cardiovascular autonomic function tests

Background  

Fabry patients have symptoms and signs compatible with autonomic dysfunction. These symptoms and signs are considered to be due to impairment of the peripheral nervous system, but findings indicative of autonomic neuropathy in other diseases, such as orthostatic intolerance and male sexual dysfunction, are infrequently reported in Fabry disease. The aim of our study was to investigate autonomic symptoms and cardiovascular autonomic function in a large cohort of male and female Fabry patients.     

Prognosis of angina with and without a diagnosis: 11 year follow up in the Whitehall II prospective cohort study

Objective To investigate the prognosis of angina among people with and without diagnosis by a doctor and an abnormal cardiovascular test result.Design Prospective cohort study with a median follow up of 11 years.Setting 20 civil service departments originally located in London.Participants 10 308 civil servants aged 35-55 years at baseline.Main outcome measures Recurrent reports of angina; quality of life (SF-36 physical functioning); non-fatal myocardial infarction; death from any cause (n = 344).Results 1158 (11.4%) participants developed angina, and 813 (70%) had no evidence of diagnosis by a doctor at the time of the initial report. Participants without a diagnosis had an increased risk of impaired physical functioning (age and sex adjusted odds ratio of 2.36 (95% confidence interval 1.91 to 2.90)) compared with those who had neither angina nor myocardial infarction throughout follow up. Among reported cases of angina without a diagnosis, the 15.5% with an abnormality on a study electrocardiogram had an increased risk of death (hazard ratio 2.37 (1.16 to 4.87)). These effects were similar in magnitude to those in participants with a diagnosis of angina.Conclusion Undiagnosed angina was common and had an adverse impact on prognosis comparable to that of diagnosed angina, particularly among people with electrocardiographic abnormalities. Efforts to improve prognosis among people with angina should take account of this submerged clinical iceberg.     

Research of the Holiday kind: Tabulating Ingestion of Mocha Solution (TIMS): a longitudinal prospective cohort study

The annual "Roll Up the Rim to Win" contest at Tim Hortons restaurants provides customers the opportunity to win prizes. This study investigated win ratios, prize types and patterns of coffee consumption.     

Risk factors for congenital cryptorchidism in a prospective birth cohort study

Background

Risk factors for congenital cryptorchidism were investigated in a prospective birth cohort study in Denmark and Finland from 1997 to 2001.

Methodology and Principal Findings

In total, 2,496 boys were examined for cryptorchidism at birth (cryptorchid/healthy: 128/2,368) and three months old (33/2,215). Information on risk factors was obtained antenatally (questionnaire/interview) or at birth from birth records. Use of nicotine substitutes during pregnancy (n = 40) and infertility treatment by intrauterine insemination (n = 49) were associated with an increased risk for cryptorchidism, adjusted odds ratio (95% confidence interval) (OR (95%CI)) 3.04 (95%CI 1.00–9.27) and 3.01 (95%CI 1.27–7.15), respectively. No association was seen for mothers (n = 79) who had infertility treatment in form of intracytoplasmic sperm injection (ICSI) or in vitro fertilization (IVF) treatment (OR 0.71 95%CI 0.21–2.38). In total, 728 (29%) reported to have smoked during pregnancy, however, no increased risk among maternal smokers was found. Furthermore, we found statistically significant associations between cryptorchidism and low birth weight, prematurity, being small for gestational age, substantial vaginal bleeding, and breech presentation, which are in accordance with other studies.

Conclusions and Significance

Our study revealed two novel risk factors for cryptorchidism: intrauterine insemination and the use of nicotine substitutes in pregnancy. This suggests that cryptorchidism may not only be associated to genetic factors, but also to maternal lifestyle and exposure.     

Low lipoprotein(a) concentration is associated with cancer and all-cause deaths: a population-based cohort study (the JMS cohort study)

Background

Experimental studies support the anti-neoplastic effect of apo(a), but several clinical studies have reported contradictory results. The purpose of this study was to determine whether a low lipoprotein(a) [Lp(a)] concentration is related to mortality from major causes of death, especially cancer.

Methods

The subjects were 10,413 participants (4,005 men and 6,408 women) from a multi-center population-based cohort study in Japan (The Jichi Medical School cohort study). The average age at registration was 55.0 years, and the median observation period was 4,559 days. As the estimated hazard ratio was high for both the low and very high Lp(a) levels, we defined two Lp(a) groups: a low Lp(a) group [Lp(a)<80 mg/L] and an intermediate-to-high Lp(a) group [Lp(a)≥80]. Participants who died from malignant neoplasms (n = 316), cardiovascular disease (202), or other causes (312) during the observation period were examined.

Results

Cumulative incidence plots showed higher cumulative death rates for the low Lp(a) group than for the intermediate-to-high Lp(a) group for all-cause, cancer, and miscellaneous-cause deaths (p<0.001, p = 0.03, and p = 0.03, respectively). Cox proportional hazards analyses with the sex and age of the participants, body mass index, and smoking and drinking histories as covariates showed that a low Lp(a) level was a significant risk for all-cause, cancer, and miscellaneous-cause deaths (p<0.001, p = 0.003, and p = 0.01, respectively). The hazard ratio (95% CI) [1.48, 1.15–1.92] of a low Lp(a) level for cancer deaths was almost the same as that for a male sex (1.46, 1.00–2.13).

Conclusions

This is the first report to describe the association between a low Lp(a) level and all-cause or cancer death, supporting the anti-neoplastic effect of Lp(a). Further epidemiological studies are needed to confirm the present results.     

Risk of diagnosis of ovarian cancer after raised serum CA 125 concentration: a prospective cohort study.

OBJECTIVE: To determine the risk of invasive epithelial ovarian cancer and fallopian tube cancer associated with a raised concentration of the tumour marker CA 125 in asymptomatic postmenopausal women. DESIGN: Serum CA 125 concentration was measured annually in study participants for one to four years. Participants with a concentration > or = 30 U/ml were recalled for abdominal ultrasonography. Follow up was by annual postal questionnaire. SETTING: General practice, occupational health departments, ovarian cancer screening unit in a teaching hospital. SUBJECTS: 22,000 volunteers, all postmenopausal women > or = 45 years of age; recruited between 1 June 1986 and 1 May 1990. INTERVENTION: Surgical investigation if the ultrasound examination was abnormal. MAIN OUTCOME MEASURES: Cumulative and relative risk of developing an index cancer (invasive epithelial cancer of the ovary or fallopian tube) after a specified CA 125 result. RESULTS: 49 index cancers developed in the study population during a mean follow up of 6.76 years. The overall cumulative risk of developing an index cancer was 0.0022 for the entire study population and was lower for women with a serum CA 125 concentration < 30 U/ml (cumulative risk 0.0012) but was appreciably increased for women with a concentration > or = 30 U/ml (0.030) and > 100 U/ml (0.149). Compared with the entire study population the relative risk of developing an index cancer within one year and five years was increased 35.9-fold (95% confidence interval 18.3 to 70.4) and 14.3-fold (8.5 to 24.3) respectively after a serum CA 125 concentration > or = 30 U/ml and 204.8-fold (79.0 to 530.7) and 74.5-fold (31.1 to 178.3) respectively after a concentration > or = 100 U/ml. CONCLUSION: CA 125 is a powerful index of risk of ovarian and fallopian tube cancer in asymptomatic postmenopausal women.     

Associations between copper and zinc intakes from diet and mortality from cardiovascular disease in a large population-based prospective cohort study

Several studies have related cardiovascular disease (CVD) to serum concentrations of copper and zinc but not to their dietary intakes. We thought to examine the association between dietary intakes of copper and zinc with risk of mortality from CVD in a prospective study encompassing 58,646 healthy Japanese men and women aged 40-79 years. The intakes of copper and zinc were determined by a validated self-administered food frequency questionnaire, and their associations with risk of mortality from CVD were evaluated by Cox proportional hazard modelling. During 965, 970 person-years of follow-up between 1989-2009, we documented 3,388 CVD deaths [1,514 from stroke, 702 from coronary heart disease (CHD) and 1,172 from other CVD]. Copper intake was not associated with CHD mortality; however, the multivariable hazard ratios (HRs) with 95% confidence intervals (CIs) for mortality from stroke, other CVD and total CVD in the highest versus the lowest quintiles of copper intake among men were 1.78 (1.16-2.77; P-trend=0.007), 1.61 (1.01-2.81; P-trend =0.03) and 1.63 (1.21-2.33; P-trend=0.001), respectively, and those among women were 1.49 (1.00-2.19; P-trend=0.04), 1.59 (1.09-2.55; P-trend =0.02) and 1.36 (1.06-1.69; P-trend=0.01), respectively. Higher intakes of zinc was inversely associated with mortality from CHD in men; 0.68 (0.58-1.03; P-trend=0.05) but not women; 1.13 (0.71- 1.49; P-trend=0.61). No associations were observed with other mortality endpoints. In conclusion, dietary copper intake was positively associated with mortality from CVD in both genders; whereas, higher dietary zinc intake was inversely associated with mortality from CHD in men but not women.     

Effectiveness of the standard WHO recommended retreatment regimen (category II) for tuberculosis in Kampala, Uganda: a prospective cohort study

Background

Each year, 10%–20% of patients with tuberculosis (TB) in low- and middle-income countries present with previously treated TB and are empirically started on a World Health Organization (WHO)-recommended standardized retreatment regimen. The effectiveness of this retreatment regimen has not been systematically evaluated.

Methods and Findings

From July 2003 to January 2007, we enrolled smear-positive, pulmonary TB patients into a prospective cohort to study treatment outcomes and mortality during and after treatment with the standardized retreatment regimen. Median time of follow-up was 21 months (interquartile range 12–33 months). A total of 29/148 (20%) HIV-uninfected and 37/140 (26%) HIV-infected patients had an unsuccessful treatment outcome. In a multiple logistic regression analysis to adjust for confounding, factors associated with an unsuccessful treatment outcome were poor adherence (adjusted odds ratio [aOR] associated with missing half or more of scheduled doses 2.39; 95% confidence interval (CI) 1.10–5.22), HIV infection (2.16; 1.01–4.61), age (aOR for 10-year increase 1.59; 1.13–2.25), and duration of TB symptoms (aOR for 1-month increase 1.12; 1.04–1.20). All patients with multidrug-resistant TB had an unsuccessful treatment outcome. HIV-infected individuals were more likely to die than HIV-uninfected individuals (p<0.0001). Multidrug-resistant TB at enrolment was the only common risk factor for death during follow-up for both HIV-infected (adjusted hazard ratio [aHR] 17.9; 6.0–53.4) and HIV-uninfected (14.7; 4.1–52.2) individuals. Other risk factors for death during follow-up among HIV-infected patients were CD4<50 cells/ml and no antiretroviral treatment (aHR 7.4, compared to patients with CD4≥200; 3.0–18.8) and Karnofsky score <70 (2.1; 1.1–4.1); and among HIV-uninfected patients were poor adherence (missing half or more of doses) (3.5; 1.1–10.6) and duration of TB symptoms (aHR for a 1-month increase 1.9; 1.0–3.5).

Conclusions

The recommended regimen for retreatment TB in Uganda yields an unacceptable proportion of unsuccessful outcomes. There is a need to evaluate new treatment strategies in these patients. Please see later in the article for the Editors'' Summary     

Human papillomavirus persistence in young unscreened women, a prospective cohort study

Objective

To evaluate hr-HPV persistence and associated risk factors in a prospective cohort of young unscreened women. Additionally, the relation between hr-HPV status and cytology/histology results is examined.

Methods and Principal Findings

Two year follow-up of 235 out of 2065 young women (18–29 years), participating in a large, one year epidemiological study, with questionnaires, self-collected cervico-vaginal samples (Vibabrush), and SPF₁₀LiPA for HPV detection. Only women hr-HPV positive at sample month 12 were invited for a second year of follow-up. After study follow-up, available cytology/histology data were requested from PALGA (the national network and registry of histo- and cytopathology in The Netherlands). These data were compared with available cytology/histology data of the month 12 hr-HPV negative women from the same cohort. 44.1% of the hr-HPV types detected at study month 12, persisted during follow-up. HPV types 45, 31, 16 and 18 were most likely to persist with percentages of 60.0%, 56.8%, 54.4%,and 50.0%, respectively. Compared to newly detected infections at month 12, infections present since 6 months or baseline had an increased risk to persist (OR 3.09 [95% CI: 1.74–5.51] and OR 4.99 [95% CI: 2.67–9.32], respectively). Other co-factors influencing persistence were, multiple HPV infections, smoking and multiple lifetime sexual partners. The percentage of women with a HSIL/CIN2+ (12.1%) in the persistent HPV group, was not significantly different (p = 0.107) from the 5.3% of the women who cleared the hr-HPV infection, but was significantly (p 0.000) higher than to the 1.6% of women in the hr-HPV negative control group.

Conclusion

We showed that HPV genotype, multiple infections, smoking, and multiple lifetime sexual partners are co-factors that increase the risk of hr-HPV persistency. Most importantly, we showed that hr-HPV infections are more likely to persist the longer they have been present and that women with a persistent hr-HPV infection have a high risk of HSIL/CIN2+ development.     

Perinatal mortality in eastern Uganda: a community based prospective cohort study

Background

To achieve a child mortality reduction according to millennium development goal 4, it is necessary to considerably reduce neonatal mortality. We report stillbirth and early neonatal mortality risks as well as determinants of perinatal mortality in Eastern Uganda.

Methods

A community-based prospective cohort study was conducted between 2006 and 2008. A total of 835 pregnant women were followed up for pregnancy outcome and survival of their children until 7 days after delivery. Mother''s residence, age, parity, bed net use and whether delivery took place at home were included in multivariable regression analyses to identify risk factors for perinatal death.

Results

The stillbirth risk was 19 per 1,000 pregnancies and the early neonatal death risk 22 per 1,000 live births. Overall, the perinatal mortality risk was 41 [95%CI: 27, 54] per 1,000 pregnancies. Of the deaths, 47% followed complicated deliveries and 24% preterm births. Perinatal mortality was 63/1,000 pregnancies among teenage mothers, 76/1,000 pregnancies among nulliparous women and 61/1,000 pregnancies among women delivering at home who, after controlling for potential confounders, had a 3.7 (95%CI: 1.8, 7.4) times higher perinatal mortality than women who gave birth in a health facility. This association was considerably stronger among nulliparous women [RR 8.0 (95%CI: 2.9, 21.6)] than among women with a previous live birth [RR 1.8 (95%CI: 0.7, 4.5)]. All perinatal deaths occurred among women who did not sleep under a mosquito net. Women living in urban slums had a higher risk of losing their babies than those in rural areas [RR: 2.7 (95%CI: 1.4, 5.3)].

Conclusion

Our findings strengthen arguments for ensuring that pregnant women have access to and use adequate delivery facilities and bed nets.     

Charting the progression of disability in parkinson disease: study protocol for a prospective longitudinal cohort study

Background  

People with Parkinson disease (PD), even in the presence of symptomatic relief from medical, surgical, and rehabilitative interventions, face a persistent worsening of disability. This disability is characterized by diminished quality of life, reduced functional mobility, declining performance in activities of daily living and worsening neurological impairments. While evidence has emerged supporting the clinically meaningful benefits of short-term exercise programs on these underlying factors, assertions regarding the effects of sustained programs of exercise and physical activity on the trajectory of disablement in PD are made in the absence of direct evidence. Indeed, the natural decline in quality of life and functional mobility in people diagnosed with PD is poorly understood. Moreover, outcome measures commonly used in clinical exercise trials typically do not capture the full spectrum of disability as defined by the World Health Organization (WHO).     

Low job control and risk of coronary heart disease in Whitehall II (prospective cohort) study.

OBJECTIVE: To determine the association between adverse psychosocial characteristics at work and risk of coronary heart disease among male and female civil servants. DESIGN: Prospective cohort study (Whitehall II study). At the baseline examination (1985-8) and twice during follow up a self report questionnaire provided information on psychosocial factors of the work environment and coronary heart disease. Independent assessments of the work environment were obtained from personnel managers at baseline. Mean length of follow up was 5.3 years. SETTING: London based office staff in 20 civil service departments. SUBJECTS: 10,308 civil servants aged 35-55 were examined-6895 men (67%) and 3413 women (33%). MAIN OUTCOME MEASURES: New cases of angina (Rose questionnaire), severe pain across the chest, diagnosed ischaemic heart disease, and any coronary event. RESULTS: Men and women with low job control, either self reported or independently assessed, had a higher risk of newly reported coronary heart disease during follow up. Job control assessed on two occasions three years apart, although intercorrelated, had cumulative effects on newly reported disease. Subjects with low job control on both occasions had an odds ratio for any subsequent coronary event of 1.93 (95% confidence interval 1.34 to 2.77) compared with subjects with high job control at both occasions. This association could not be explained by employment grade, negative affectivity, or classic coronary risk factors. Job demands and social support at work were not related to the risk of coronary heart disease. CONCLUSIONS: Low control in the work environment is associated with an increased risk of future coronary heart disease among men and women employed in government offices. The cumulative effect of low job control assessed on two occasions indicates that giving employees more variety in tasks and a stronger say in decisions about work may decrease the risk of coronary heart disease.     

Prognostic significance of sealed-off perforation in colon cancer: a prospective cohort study

Background

Perforated colon cancer is a rare complication, but has a high risk of recurrence. However, most studies have not distinguished sealed-off perforation from free perforation, and the prognosis is unclear. The aim of this study was to evaluate the oncologic outcome of colon cancer with sealed-off perforation.

Methods

Eighty-six consecutive patients who underwent resection for colon cancer with sealed-off or free perforation were included. We defined sealed-off perforation as a colon perforation with localized abscess identified on operative, computed tomography, or pathologic findings, with no evidence of free perforation, including fecal contamination and dirty fluid collection in the peritoneal cavity. Oncologic outcomes were compared between patients with colon cancer with sealed-off perforation and free perforation using a log-rank test and Cox regression analysis.

Results

The sealed-off perforation group included 62 patients, and 24 patients were in the free perforation group. TNM stage and lymphatic, venous, and perineural invasion were similar between the groups. The median follow-up period was 28.9?months (range 0–159). The sealed-off perforation group had better prognosis compared with the free perforation group in terms of progression-free survival (PFS) and overall survival (OS), although there were no statistically significant differences in PFS (5-year PFS 53.7% vs. 40.5%, p?=?0.148; 5-year OS 53.6% vs. 22.9%, p?=?0.001). However, in multivariable analysis using the Cox progression test, sealed-off perforation did not show a significant effect on cancer progression (p =?0.138) and OS (p =?0.727).

Conclusions

Colon cancer with sealed-off perforation showed no difference in prognosis compared with free perforation.