Variation in CFHR3 determines susceptibility to meningococcal disease by controlling factor H concentrations.

Neisseria meningitidis protects itself from complement-mediated killing by binding complement factor H (FH). Previous studies associated susceptibility to meningococcal disease (MD) with variation in CFH, but the causal variants and underlying mechanism remained unknown. Here we attempted to define the association more accurately by sequencing the CFH-CFHR locus and imputing missing genotypes in previously obtained GWAS datasets of MD-affected individuals of European ancestry and matched controls. We identified a CFHR3 SNP that provides protection from MD (rs75703017, p value = 1.1 × 10-16) by decreasing the concentration of FH in the blood (p value = 1.4 × 10-11). We subsequently used dual-luciferase studies and CRISPR gene editing to establish that deletion of rs75703017 increased FH expression in hepatocyte by preventing promotor inhibition. Our data suggest that reduced concentrations of FH in the blood confer protection from MD; with reduced access to FH, N. meningitidis is less able to shield itself from complement-mediated killing.

Group A streptococcal disease in paediatric inpatients: a European perspective.

Group A streptococcal (GAS) disease shows increasing incidence worldwide. We characterised children admitted with GAS infection to European hospitals and studied risk factors for severity and disability. This is a prospective, multicentre, cohort study (embedded in EUCLIDS and the Swiss Pediatric Sepsis Study) including 320 children, aged 1 month to 18 years, admitted with GAS infection to 41 hospitals in 6 European countries from 2012 to 2016. Demographic, clinical, microbiological and outcome data were collected. A total of 195 (61%) patients had sepsis. Two hundred thirty-six (74%) patients had GAS detected from a normally sterile site. The most common infection sites were the lower respiratory tract (LRTI) (22%), skin and soft tissue (SSTI) (23%) and bone and joint (19%). Compared to patients not admitted to PICU, patients admitted to PICU more commonly had LRTI (39 vs 8%), infection without a focus (22 vs 8%) and intracranial infection (9 vs 3%); less commonly had SSTI and bone and joint infections (p < 0.001); and were younger (median 40 (IQR 21-83) vs 56 (IQR 36-85) months, p = 0.01). Six PICU patients (2%) died. Sequelae at discharge from hospital were largely limited to patients admitted to PICU (29 vs 3%, p < 0.001; 12% overall) and included neurodisability, amputation, skin grafts, hearing loss and need for surgery. More patients were recruited in winter and spring (p < 0.001). CONCLUSION: In an era of observed marked reduction in vaccine-preventable infections, GAS infection requiring hospital admission is still associated with significant severe disease in younger children, and short- and long-term morbidity. Further advances are required in the prevention and early recognition of GAS disease. WHAT IS KNOWN: • Despite temporal and geographical variability, there is an increase of incidence of infection with group A streptococci. However, data on the epidemiology of group A streptococcal infections in European children is limited. WHAT IS NEW: • In a large, prospective cohort of children with community-acquired bacterial infection requiring hospitalisation in Europe, GAS was the most frequent pathogen, with 12% disability at discharge, and 2% mortality in patients with GAS infection. • In children with GAS sepsis, IVIG was used in only 4.6% of patients and clindamycin in 29% of patients.

Hemostasis Proteins in Invasive Meningococcal and Nonmeningococcal Infections: A Prospective Multicenter Study.

OBJECTIVES: We aimed to describe the variation of hemostasis proteins in children with bacterial infections due to different pathogens ( Neisseria meningitidis, Streptococcus pneumoniae, Staphylococcus aureus , and group A streptococcus [GAS]) and to study hemostasis proteins in relation to mortality. DESIGN: Preplanned analysis in prospective cohort study. SETTING: Hospitals in five European countries (Austria, The Netherlands, Spain, Switzerland, and the United Kingdom). PATIENTS: Admitted children (2012-2016) with community-acquired infections due to meningococci ( n = 83), pneumococci ( n = 64), S. aureus (n = 50), and GAS ( n = 44) with available serum samples collected less than 48 hours after admission. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: Fibronectin, plasminogen activator inhibitor type 1 (PAI-1), thrombomodulin, and a disintegrin and metalloproteinase with a thrombospondin type 1 motif, member 13 (ADAMTS-13) were measured in serum in 2019-2020. Additionally, von Willebrand factor, protein C, protein S, and factor IX were measured in citrate plasma available from a subset of patients. Outcome measures included in-hospital mortality and disease severity (need for ventilation/inotropes, Pediatric Index of Mortality score).Of 241 children, 21 (8.7%) died and 177 (73.5%) were admitted to PICU. Mortality rate was similar for the pathogen groups. Levels of fibronectin and thrombomodulin differed for the different pathogens ( p < 0.05). Fibronectin levels were lower in GAS infections than in S. pneumoniae and S. aureus infections but did not differ from meningococcal infections. Thrombomodulin levels in meningococcal infections were higher than in S. aureus and pneumococcal infections. Overall, the area under the curve for mortality was 0.81 (95% CI, 0.70-0.92) for thrombomodulin and 0.78 (95% CI, 0.69-0.88) for ADAMTS-13. The association of each hemostasis protein did not vary across pathogens for any of the outcome measures. CONCLUSIONS: Hemostatic disturbances in childhood bacterial infections are not limited to meningococcal sepsis but occur with a comparable severity across nonmeningococcal infections. High thrombomodulin and high ADAMTS-13 had good discriminative ability for mortality. Our results emphasize the importance of hemostatic disturbances in meningococcal and nonmeningococcal pediatric bacterial infections.

The Lisbon Agreement on femoroacetabular impingement imaging-part 2: general issues, parameters, and reporting.

OBJECTIVES: Imaging assessment for the clinical management of femoroacetabular impingement (FAI) is controversial because of a paucity of evidence-based guidance and notable variability among practitioners. Hence, expert consensus is needed because standardised imaging assessment is critical for clinical practice and research. We aimed to establish expert-based statements on FAI imaging by using formal methods of consensus building. METHODS: The Delphi method was used to formally derive consensus among 30 panel members from 13 countries. Forty-four questions were agreed upon, and relevant seminal literature was circulated and classified in major topics to produce answering statements. The level of evidence was noted for all statements, and panel members were asked to score their level of agreement (0-10). This is the second part of a three-part consensus series and focuses on 'General issues' and 'Parameters and reporting'. RESULTS: Forty-seven statements were generated and group consensus was reached for 45. Twenty-five statements pertaining to 'General issues' (9 addressing diagnosis, differential diagnosis, and postoperative imaging) and 'Parameters and reporting' (16 addressing femoral/acetabular parameters) were produced. CONCLUSIONS: The available evidence was reviewed critically, recommended criteria for diagnostic imaging highlighted, and the roles/values of different imaging parameters assessed. Radiographic evaluation (AP pelvis and a Dunn 45° view) is the cornerstone of hip-imaging assessment and the minimum imaging study that should be performed when evaluating adult patients for FAI. In most cases, cross-sectional imaging is warranted because MRI is the 'gold standard' imaging modality for the comprehensive evaluation, differential diagnosis assessment, and FAI surgical planning. KEY POINTS: • Diagnostic imaging for FAI is not standardised due to scarce evidence-based guidance on which imaging modalities and diagnostic criteria/parameters should be used. • Radiographic evaluation is the cornerstone of hip assessment and the minimum study that should be performed when assessing suspected FAI. Cross-sectional imaging is justified in most cases because MRI is the 'gold standard' modality for comprehensive FAI evaluation. • For acetabular morphology, coverage (Wiberg's angle and acetabular index) and version (crossover, posterior wall, and ischial spine signs) should be assessed routinely. On the femoral side, the head-neck junction morphology (α° and offset), neck morphology (NSA), and torsion should be assessed.

The Lisbon Agreement on Femoroacetabular Impingement Imaging-part 3: imaging techniques.

OBJECTIVES: Imaging diagnosis of femoroacetabular impingement (FAI) remains controversial due to a lack of high-level evidence, leading to significant variability in patient management. Optimizing protocols and technical details is essential in FAI imaging, although challenging in clinical practice. The purpose of this agreement is to establish expert-based statements on FAI imaging, using formal consensus techniques driven by relevant literature review. Recommendations on the selection and use of imaging techniques for FAI assessment, as well as guidance on relevant radiographic and MRI classifications, are provided. METHODS: The Delphi method was used to assess agreement and derive consensus among 30 panel members (musculoskeletal radiologists and orthopedic surgeons). Forty-four questions were agreed on and classified into five major topics and recent relevant literature was circulated, in order to produce answering statements. The level of evidence was assessed for all statements and panel members scored their level of agreement with each statement during 4 Delphi rounds. Either "group consensus," "group agreement," or "no agreement" was achieved. RESULTS: Forty-seven statements were generated and group consensus was reached for 45. Twenty-two statements pertaining to "Imaging techniques" were generated. Eight statements on "Radiographic assessment" and 12 statements on "MRI evaluation" gained consensus. No agreement was reached for the 2 "Ultrasound" related statements. CONCLUSION: The first international consensus on FAI imaging was developed. Researchers and clinicians working with FAI and hip-related pain may use these recommendations to guide, develop, and implement comprehensive, evidence-based imaging protocols and classifications. KEY POINTS: • Radiographic evaluation is recommended for the initial assessment of FAI, while MRI with a dedicated protocol is the gold standard imaging technique for the comprehensive evaluation of this condition. • The MRI protocol for FAI evaluation should include unilateral small FOV with radial imaging, femoral torsion assessment, and a fluid sensitive sequence covering the whole pelvis. • The definite role of other imaging methods in FAI, such as ultrasound or CT, is still not well defined.

Rheumatic heart disease in The Gambia: clinical and valvular aspects at presentation and evolution under penicillin prophylaxis.

BACKGROUND: Rheumatic heart disease (RHD) remains the leading cause of cardiac-related deaths and disability in children and young adults worldwide. In The Gambia, the RHD burden is thought to be high although no data are available and no control programme is yet implemented. We conducted a pilot study to generate baseline data on the clinical and valvular characteristics of RHD patients at first presentation, adherence to penicillin prophylaxis and the evolution of lesions over time. METHODS: All patients registered with acute rheumatic fever (ARF) or RHD at two Gambian referral hospitals were invited for a clinical review that included echocardiography. In addition, patients were interviewed about potential risk factors, disease history, and treatment adherence. All clinical and echocardiography information at first presentation and during follow-up was retrieved from medical records. RESULTS: Among 255 registered RHD patients, 35 had died, 127 were examined, and 111 confirmed RHD patients were enrolled, 64% of them females. The case fatality rate in 2017 was estimated at 19.6%. At first presentation, median age was 13 years (IQR [9; 18]), 57% patients had late stage heart failure, and 84.1% a pathological heart murmur. Although 53.2% of them reported history of recurrent sore throat, only 32.2% of them had sought medical treatment. A history suggestive of ARF was reported by 48.7% patients out of whom only 15.8% were adequately treated. Two third of the patients (65.5%) to whom it was prescribed were fully adherent to penicillin prophylaxis. Progressive worsening and repeated hospitalisation was experienced by 46.8% of the patients. 17 patients had cardiac surgery, but they represented only 18.1% of the 94 patients estimated eligible for cardiac surgery. CONCLUSION: This study highlights for the first time in The Gambia the devastating consequences of RHD on the health of adolescents and young adults. Our findings suggest a high burden of disease that remains largely undetected and without appropriate secondary prophylaxis. There is a need for the urgent implementation of an effective national RHD control programto decrease the unacceptably high mortality rate, improve case detection and management, and increase community awareness of this disease.

Correction to: The Lisbon Agreement on Femoroacetabular Impingement Imaging-part 1: overview.

The original version of this article, published on 14 May 2020, unfortunately contained a mistake.

The Lisbon Agreement on Femoroacetabular Impingement Imaging-part 1: overview.

OBJECTIVES: Imaging assessment for the clinical management of femoroacetabular impingement (FAI) syndrome remains controversial because of a paucity of evidence-based guidance and notable variability in clinical practice, ultimately requiring expert consensus. The purpose of this agreement is to establish expert-based statements on FAI imaging, using formal techniques of consensus building. METHODS: A validated Delphi method and peer-reviewed literature were used to formally derive consensus among 30 panel members (21 musculoskeletal radiologists and 9 orthopaedic surgeons) from 13 countries. Forty-four questions were agreed on, and recent relevant seminal literature was circulated and classified in five major topics ('General issues', 'Parameters and reporting', 'Radiographic assessment', 'MRI' and 'Ultrasound') in order to produce answering statements. The level of evidence was noted for all statements, and panel members were asked to score their level of agreement with each statement (0 to 10) during iterative rounds. Either 'consensus', 'agreement' or 'no agreement' was achieved. RESULTS: Forty-seven statements were generated, and group consensus was reached for 45 (95.7%). Seventeen of these statements were selected as most important for dissemination in advance. There was no agreement for the two statements pertaining to 'Ultrasound'. CONCLUSION: Radiographic evaluation is the cornerstone of hip evaluation. An anteroposterior pelvis radiograph and a Dunn 45° view are recommended for the initial assessment of FAI although MRI with a dedicated protocol is the gold standard imaging technique in this setting. The resulting consensus can serve as a tool to reduce variability in clinical practices and guide further research for the clinical management of FAI. KEY POINTS: • FAI imaging literature is extensive although often of low level of evidence. • Radiographic evaluation with a reproducible technique is the cornerstone of hip imaging assessment. • MRI with a dedicated protocol is the gold standard imaging technique for FAI assessment.

Practical Input on Bone Tumor Imaging: Pathological Fracture, Risk Features, and When to Contact Orthopaedics.

Awareness of risk factors associated with impending fracture and its radiologic appearance allows early diagnosis, supports prophylactic surgical treatment, and prevents the multiple complications of a pathologic fracture. Because the femur is the most common long bone affected by metastatic bone lesions, we address this clinically relevant site in this review. The key to early detection of risky bone lesions is familiarity with the possible clinical presentation, biomechanical effects of the anatomical site (femoral head and neck, intertrochanteric zone, proximal diaphysis), and the lesion types (lytic, blastic, or mixed). Awareness of the possible treatment strategies depending on the characteristics just listed allows high-quality targeted reporting.

Whole spine localizers of magnetic resonance imaging detect unexpected vertebral fractures.

BACKGROUND: Whole spine localizers (WS-loc) of magnetic resonance imaging (MRI) are performed for enumeration of the vertebrae but they can be also used for the evaluation of the spine. PURPOSE: To assess the accuracy of fracture detection using WS-locs of MRI and compare the findings with standard high-resolution short tau inversion recovery (STIR) sequences, and to determine whether the review of WS-locs is useful and if additional information can be gained by assessing the thoracic spine section of the WS-locs. MATERIAL AND METHODS: A total of 298 magnetic resonance (MR) examinations of the lumbar spine with WS-locs were evaluated. Two independent readers reviewed the images. In case of fracture detection, further characterization of the fracture was performed. To assess inter-reader agreement, unweighted Cohen's kappa with 95% confidence intervals (CI) and Phi coefficients were calculated. RESULTS: The study sample included 187 female and 111 male patients (age range = 65-94 years; median age = 75.0 years). The WS-locs detected 42 fractures of the lumbar spine and 36 of the thoracic spine. Inter-reader agreement for fracture detection in the lumbar and thoracic spine was strong (K = 0.87, 95% CI = 0.78-0.95, Phi = 0.87, and K = 0.88, 95% CI = 0.79-0.96, Phi = 0.88, respectively). CONCLUSION: WS-locs from MR examinations of the lumbar spine provide a good diagnostic tool for the detection and evaluation of unsuspected vertebral fractures. WS-locs show strong inter-reader agreement for fracture detection in the thoracic and lumbar spine.

Anatomy-based MRI assessment of the iliopsoas muscle complex after pertrochanteric femoral fracture.

OBJECTIVE: To evaluate the quality of the iliopsoas muscle complex after pertrochanteric femoral fracture, using MRI; to propose an anatomy-based evaluation of the iliopsoas muscle complex; and to determine the inter-reader reliability of two classifications of fatty muscle degeneration. MATERIALS AND METHODS: We included adult patients with a displaced lesser trochanter following pertrochanteric femoral fracture. Muscle quality was evaluated using the Goutallier and Slabaugh classifications at three levels (L4/L5, L5/S1, and the anterior inferior iliac spine). Two radiologists independently reviewed the MRIs, and force measurement was performed on both hips. Linear mixed-effects models were used to determine the effect of fracture on muscle quality and strength, and Cohen's kappa statistic was used to assess inter-reader agreement. RESULTS: In the 18 patients included, the iliopsoas muscle complex showed higher grades of fatty muscle degeneration on the fractured side than on the non-fractured side. The mean difference between muscle strength on the fractured vs the non-fractured side was -12 N (p > 0.05). Inter-reader agreement for the Goutallier and Slabaugh classifications was good and very good respectively (weighted K = 0.78 and 0.85 respectively). CONCLUSION: Fatty muscle degeneration of the iliopsoas muscle complex after pertrochanteric femoral fracture was evident using both classification systems; however, fatty muscle degeneration resulted in only a minimal reduction of muscle strength. To provide a thorough assessment of iliopsoas muscle complex quality, we suggest evaluating it at different anatomical levels. Regarding inter-reader agreement, the Slabaugh classification was superior to the Goutallier classification.

Predictive value of C-reactive protein for tuberculosis, bloodstream infection or death among HIV-infected individuals with chronic, non-specific symptoms and negative sputum smear microscopy.

BACKGROUND: C-reactive protein (CRP) is an inflammatory biomarker that may identify patients at risk of infections or death. Mortality among HIV-infected persons commencing antiretroviral therapy (ART) is often attributed to tuberculosis (TB) or bloodstream infections (BSI). METHODS: In two district hospitals in southern Malawi, we recruited HIV-infected adults with one or more unexplained symptoms present for at least one month (weight loss, fever or diarrhoea) and negative expectorated sputum microscopy for TB. CRP determination for 452 of 469 (96%) participants at study enrolment was analysed for associations with TB, BSI or death to 120 days post-enrolment. RESULTS: Baseline CRP was significantly elevated among patients with confirmed or probable TB (52), BSI (50) or death (60) compared to those with no identified infection who survived at least 120 days (269). A CRP value of >10 mg/L was associated with confirmed or probable TB (adjusted odds ratio 5.7; 95% CI 2.6, 14.3; 87% sensitivity) or death by 30 days (adjusted odds ratio 9.2; 95% CI 2.2, 55.1; 88% sensitivity). CRP was independently associated with TB, BSI or death, but the prediction of these endpoints was enhanced by including haemoglobin (all outcomes), CD4 count (BSI, death) and whether ART was started (death) in logistic regression models. CONCLUSION: High CRP at the time of ART initiation is associated with TB, BSI and early mortality and so has potential utility for stratifying patients for intensified clinical and laboratory investigation and follow-up. They may also be considered for empirical treatment of opportunistic infections including TB.

Mortality and morbidity in community-acquired sepsis in European pediatric intensive care units: a prospective cohort study from the European Childhood Life-threatening Infectious Disease Study (EUCLIDS).

BACKGROUND: Sepsis is one of the main reasons for non-elective admission to pediatric intensive care units (PICUs), but little is known about determinants influencing outcome. We characterized children admitted with community-acquired sepsis to European PICUs and studied risk factors for mortality and disability. METHODS: Data were collected within the collaborative Seventh Framework Programme (FP7)-funded EUCLIDS study, which is a prospective multicenter cohort study aiming to evaluate genetic determinants of susceptibility and/or severity in sepsis. This report includes 795 children admitted with community-acquired sepsis to 52 PICUs from seven European countries between July 2012 and January 2016. The primary outcome measure was in-hospital death. Secondary outcome measures were PICU-free days censured at day 28, hospital length of stay, and disability. Independent predictors were identified by multivariate regression analysis. RESULTS: Patients most commonly presented clinically with sepsis without a source (n = 278, 35%), meningitis/encephalitis (n = 182, 23%), or pneumonia (n = 149, 19%). Of 428 (54%) patients with confirmed bacterial infection, Neisseria meningitidis (n = 131, 31%) and Streptococcus pneumoniae (n = 78, 18%) were the main pathogens. Mortality was 6% (51/795), increasing to 10% in the presence of septic shock (45/466). Of the survivors, 31% were discharged with disability, including 24% of previously healthy children who survived with disability. Mortality and disability were independently associated with S. pneumoniae infections (mortality OR 4.1, 95% CI 1.1-16.0, P = 0.04; disability OR 5.4, 95% CI 1.8-15.8, P < 0.01) and illness severity as measured by Pediatric Index of Mortality (PIM2) score (mortality OR 2.8, 95% CI 1.3-6.1, P < 0.01; disability OR 3.4, 95% CI 1.8-6.4, P < 0.001). CONCLUSIONS: Despite widespread immunization campaigns, invasive bacterial disease remains responsible for substantial morbidity and mortality in critically ill children in high-income countries. Almost one third of sepsis survivors admitted to the PICU were discharged with some disability. More research is required to delineate the long-term outcome of pediatric sepsis and to identify interventional targets. Our findings emphasize the importance of improved early sepsis-recognition programs to address the high burden of disease.

The retroneural approach: an alternative technique for lumbar transforaminal epidural steroid injections.

BACKGROUND: Compared with other available injection techniques for lumbar transforaminal epidural steroid injections (LTFESIs), the traditionally performed subpedicular approach is associated with a higher risk of spinal cord infarction, a rare but catastrophic complication. PURPOSE: To assess the short-term efficacy of the retroneural approach for computed tomography (CT)-guided LTFESIs with respect to different needle-tip positions. MATERIAL AND METHODS: This retrospective analysis included 238 patients receiving 286 CT-guided LTFESIs from January 2013 to January 2016. Short-term outcomes in terms of pain relief were assessed using the visual analogue scale (VAS) at baseline and 30 min after. The needle-tip location was categorized as extraforaminal, junctional, or foraminal relative to the neural foramen. Additionally, the distance from the needle tip to the nerve root was measured. RESULTS: A mean pain reduction of 3.22 points (±2.17 points) on the VAS was achieved. The needle-tip location was extraforaminal in 48% (136/286), junctional in 42% (120/286), and foraminal in 10% (28/286) of the cases. The mean distance from the needle tip to the nerve root was 3.83 mm (±3.37 mm). There was no significant correlation between pain relief and needle-tip position in relation to the neural foramen. Therapy success was not dependent on the distance between the needle tip and the nerve root. No major complications were observed. CONCLUSION: In our population treated with LTFESIs, the retroneural approach was shown to be an effective technique, with no significant differences in pain relief following different needle-tip positions.

Lipidus migrans-a radiology imaging feature after ankle injury.

We present an uncommon imaging feature with fluid fat tracking within the tendon sheath of the flexor hallucis longus (FHL) after traumatic injury to the ankle joint. We propose a coined medical term "lipidus migrans" to define the presence of floating fat in a tendon sheath. This is due to lipohemarthrosis from intra-articular fracture of the ankle with leakage of fluid fat into the tendon sheath. Communication between the FHL tendon sheath and ankle joint can occur in up to 25% of patients. Radiologists should be aware of the presence of lipidus migrans as a potential posttraumatic complication after intra-articular ankle fracture and that fat in the tendon sheath may mimic fracture fragments or even a tendon sheath tumor.

No difference in flexion power despite iliopsoas fatty degeneration in healed hip fractures with large lesser trochanter displacement.

OBJECTIVE: To evaluate iliopsoas atrophy and loss of function after displaced lesser trochanter fracture of the hip. DESIGN: Cohort study. SETTING: District hospital. PATIENTS: Twenty consecutive patients with pertrochanteric fracture and displacement of the lesser trochanter of > 20 mm. INTERVENTION: Fracture fixation with either an intramedullary nail or a plate. OUTCOME MEASUREMENTS: Clinical scores (Harris hip, WOMAC), hip flexion strength measurements, and magnetic resonance imaging findings. RESULTS: Compared with the contralateral non-operated side, the affected side showed no difference in hip flexion force in the supine upright neutral position and at 30° of flexion (205.4 N vs 221.7 N and 178.9 N vs. 192.1 N at 0° and 30° flexion, respectively). However, the affected side showed a significantly greater degree of fatty infiltration compared with the contralateral side (global fatty degeneration index 1.085 vs 0.784), predominantly within the psoas and iliacus muscles. CONCLUSION: Severe displacement of the lesser trochanter (> 20 mm) in pertrochanteric fractures did not reduce hip flexion strength compared with the contralateral side. Displacement of the lesser trochanter in such cases can lead to fatty infiltration of the iliopsoas muscle unit. The amount of displacement of the lesser trochanter did not affect the degree of fatty infiltration. LEVEL OF EVIDENCE: II.

Diagnosis of childhood tuberculosis and host RNA expression in Africa.

BACKGROUND: Improved diagnostic tests for tuberculosis in children are needed. We hypothesized that transcriptional signatures of host blood could be used to distinguish tuberculosis from other diseases in African children who either were or were not infected with the human immunodeficiency virus (HIV). METHODS: The study population comprised prospective cohorts of children who were undergoing evaluation for suspected tuberculosis in South Africa (655 children), Malawi (701 children), and Kenya (1599 children). Patients were assigned to groups according to whether the diagnosis was culture-confirmed tuberculosis, culture-negative tuberculosis, diseases other than tuberculosis, or latent tuberculosis infection. Diagnostic signatures distinguishing tuberculosis from other diseases and from latent tuberculosis infection were identified from genomewide analysis of RNA expression in host blood. RESULTS: We identified a 51-transcript signature distinguishing tuberculosis from other diseases in the South African and Malawian children (the discovery cohort). In the Kenyan children (the validation cohort), a risk score based on the signature for tuberculosis and for diseases other than tuberculosis showed a sensitivity of 82.9% (95% confidence interval [CI], 68.6 to 94.3) and a specificity of 83.6% (95% CI, 74.6 to 92.7) for the diagnosis of culture-confirmed tuberculosis. Among patients with cultures negative for Mycobacterium tuberculosis who were treated for tuberculosis (those with highly probable, probable, or possible cases of tuberculosis), the estimated sensitivity was 62.5 to 82.3%, 42.1 to 80.8%, and 35.3 to 79.6%, respectively, for different estimates of actual tuberculosis in the groups. In comparison, the sensitivity of the Xpert MTB/RIF assay for molecular detection of M. tuberculosis DNA in cases of culture-confirmed tuberculosis was 54.3% (95% CI, 37.1 to 68.6), and the sensitivity in highly probable, probable, or possible cases was an estimated 25.0 to 35.7%, 5.3 to 13.3%, and 0%, respectively; the specificity of the assay was 100%. CONCLUSIONS: RNA expression signatures provided data that helped distinguish tuberculosis from other diseases in African children with and those without HIV infection. (Funded by the European Union Action for Diseases of Poverty Program and others).

TST positivity in household contacts of tuberculosis patients: a case-contact study in Malawi.

BACKGROUND: Screening household contacts of active tuberculosis (TB) patients is recommended for TB control. Due to resource constraints this rarely occurs in lower income countries. Demographic and clinical features of index cases may influence the likelihood of onwards TB transmission. It has also been proposed that accumulation of intracellular lipid bodies within M. tuberculosis cells may also enhance bacterial transmissibility. This study explored whether clinical and bacteriological observations recorded at baseline in TB cases in Malawi could help identify those with the highest risk of onwards transmission, to prioritise contact tracing. METHODS: In this case-contact study, data on clinical presentation, sputum bacterial load and the percentage of lipid body positive acid-fast bacilli (%LB + AFB) on sputum smears were recorded in adults with sputum smear and culture positive pulmonary TB before initiation of therapy. The Tuberculin Skin Test (TST) was used to detect infection with M. tuberculosis amongst household contacts under the age of 15 years. TST positivity of the child contacts was related to characteristics of the index case. RESULTS: Thirty four index cases brought 56 contacts (median: 1, range: 1-4 contacts each). 37 (66%) of contacts had a positive TST. Cavities or a high percentage of lung affected on index patient CXRs were associated with TST positivity. Multivariate analysis of non-radiological factors showed that male sex, HIV-negative status and raised peripheral blood white blood count (WBC) in index patients were also independent risk factors of TST positivity. Lower %LB + AFB counts were associated with TST positivity on univariate analysis only. CONCLUSION: TST positivity is common amongst household contacts of sputum smear positive adult TB patients in Malawi. Contact tracing in this high risk population could be guided by prioritising index cases with CXR cavities and extensive radiological disease or, in the absence of CXRs, those who are HIV-negative with a raised WBC.

Colloid Mobilization and Seasonal Variability in a Semiarid Headwater Stream.

Colloids can be important vectors for the transport of contaminants in the environment, but little is known about colloid mobilization at the watershed scale. We present colloid concentration, composition, and flux data over a large range of hydrologic conditions from a small watershed (Gordon Gulch) in the foothills of the Colorado Front Range. Colloids, consisting predominantly of Si, Fe, and Al, were present in most stream samples but were not detected in groundwater samples. Mineralogical and morphological analysis indicated that the colloids were composed of kaolinite and illite clays with lesser amounts of amorphous Fe-hydroxides. Although colloid composition remained relatively constant over the sampled flow conditions, colloid concentrations varied considerably and increased as ionic strength of stream water decreased. The highest concentrations occurred during precipitation events after extended dry periods. These observations are consistent with laboratory studies that have shown colloids can be mobilized by decreases in pore-water ionic strength, which likely occurs during precipitation events. Colloidal particles constituted 30 to 35% of the Si mass flux and 93 to 97% of the Fe and Al mass fluxes in the <0.45-µm fraction in the stream. Colloids are therefore a significant and often overlooked component of mass fluxes whose temporal variations may yield insight into hydrologic flowpaths in this semiarid catchment.