Clinical and laboratory characteristics of children with venous thromboembolism and protein C‐deficiency: an observational Israeli‐German cohort study

Venous thromboembolism [TE] is a multifactorial disease and protein C deficiency [PCD] constitutes a major risk factor. In the present study the prevalence of PCD and the clinical presentation at TE onset, including neonatal purpura fulminans, in a cohort of children are reported. In 367 unselected children (0·1–19 years) recruited between July 1996 and December 2013, a comprehensive thrombophilia screening was performed along with recording of anamnestic data. Twenty‐five of 338 children (7·4%) had PCD. Mean age at first TE onset was 10 years (range 0·1–18). Leading thromboembolic manifestations were neonatal purpura fulminans (n = 5), TE of cerebral veins (n = 3), stroke (n = 2) deep veinthrombosis (DVT) of the leg (n = 10), DVT & pulmonary embolism (n = 2) and DVT & pelvic veins (n = 3). Concomitant risk factors for TE were identified in 12 patients, whereas 13 children spontaneously developed TE. A positive family history of DVT was found in 10 children. In this unselected cohort of paediatric patients with symptomatic TE the overall prevalence of PCD was 7·4%; 1·5% presented with neonatal purpura fulminans. Given its clinical implication for patients and family members, thrombophilia testing should be performed and the benefit of medical or educational interventions should be evaluated in this high‐risk population.     

How Many Have Died from Undiagnosed Human Immunodeficiency Virus–Associated Histoplasmosis,A Treatable Disease? Time to Act

Human immunodeficiency virus (HIV)–associated disseminated Histoplasma capsulatum capsulatum infection often mimics tuberculosis. This disease is well know in the United States but is dramatically underdiagnosed in Central and South America. In the Amazon region, given the available incidence data and the regional HIV prevalence, it is expected that, every year, 1,500 cases of histoplasmosis affect HIV patients in that region alone. Given the mortality in undiagnosed patients, at least 600 patients would be expected to die from an undiagnosed but treatable disease. The lack of a simple diagnostic tool and the lack of awareness by clinicians spiral in a vicious cycle and made a major problem invisible for 30 years. The HIV/acquired immunodeficiency syndrome community should tackle this problem now to prevent numerous avoidable deaths from HIV-associated histoplasmosis in the region and elsewhere.In the Guianas and the Amazon Basin, the prevalence of human immunodeficiency virus (HIV) is approximately 1%. There have been some decreases in incidence in some states in this region, but recent increases in incidence in northern states of Brazil have been reported.^1–3 The population of the Amazon basin is estimated to be approximately 10 million persons,⁴ which would imply that approximately 100,000 persons are HIV positive in the Amazon Basin.The Amazonian environment is suitable for the growth of Histoplasma capsulatum.⁵ For immunocompetent patients, this organism causes mostly benign infections, but in severely immunodepressed HIV-infected patients, infection with this organism leads to a fatal disease in the absence of diagnosis and treatment. There lies the problem. Clinical symptoms are unspecific and often mimic those of tuberculosis.^6,7 Diagnosis is difficult and requires invasive procedures (biopsies, bone marrow smears), and trained staff to detect H. capsulatum, often after weeks of culture.⁸ Severe infections are often fatal within days.⁹ However, death often occurs after long delays in which patients are unsuccessfully treated for unconfirmed tuberculosis. Patients die because they are not treated for a treatable disease and because there is no diagnosis test. With no diagnosis, this possibility is not included in the diagnostic and treatment algorithms of clinicians who, despite unknowingly encountering this disease on a regular basis, have never seen a case because it was never diagnosed. In this context, then why give presumptive treatment of a disease that is not present?It is tragic but it makes total sense. It is even frighteningly tragic when one crunches the numbers to estimate what it means that after 30 years of the HIV epidemic, one of the leading causes of acquired immunodeficiency syndrome (AIDS) in the Amazon¹⁰ still goes largely unrecognized and evolves under the radar of national plans and international funding efforts.The only incidence data available for this region suggests that the incidence of histoplasmosis during the highly active antiretroviral therapy era was 1.5 cases/100 person-years.¹⁰ The historical mortality rate of disseminated histoplasmosis was > 30% despite mycology expertise.^7,8 This finding indicates that for 100,000 HIV patients, there would be 1,500 cases of histoplasmosis/year and 600 deaths/year, and probably more if undiagnosed. This finding also indicates that for more than 30 years the cumulated death rate in the region must have been huge, in the tens of thousands.A rational sceptic could rightly doubt this claim from the generalization of data from the smallest South American territory to the entire Amazon and elsewhere. However, when one reviews the literature, it becomes evident that histoplasmosis is present throughout the region, this fact has been known for decades, and that we should have been paying more attention.⁵ The high prevalence of histoplasmin test reactivity in the region was known even before AIDS was identified in 1981.¹¹ Histoplasmosis has been an AIDS-defining illness since 1993. We should have connected the dots earlier.How could something so huge escape the attention of the HIV/AIDS community in the region? One explanation for this dramatic blind spot is that in the region, the diagnostic capacity for mycology has been insufficient. It has been long argued that medical mycology is a neglected area of biology, and that the often low incidence of mycoses is caused by a lack of medical mycologists rather than the absence of the mycoses.¹² Another explanation is that the standard conceptualization of HIV/AIDS, the usual indicators, and the Joint United Nations Programme on HIV/AIDS terminology and framework did not explicitly entail disseminated histoplasmosis or the regional AIDS-defining illnesses. The anesthetic effect of the familiarity of vertical concepts and vertical programs can make it difficult to reframe the problem and see what was always there.For better diagnostic and treatment, we should know what AIDS is to direct diagnostic hypotheses when caring for individual patients. Misdiagnosing histoplasmosis as tuberculosis, not only delays a life-saving treatment of the individual patient, but it can confound tuberculosis statistics (incidence, resistance, mortality) and make it difficult to evaluate tuberculosis program results.The current financial difficulties should not stand in the way of building the diagnostic capacity for detection of histoplasmosis. It does not necessarily cost much to do the diagnosis. Treatment relies on amphotericin B for severe forms and itraconazole for non-severe forms and prophylaxis.⁷ Both drugs are generic drugs that are perfectly affordable. The toxicity of amphotericin B leads industrialized countries to use the costly liposomal version of the drug. However, The Drugs for Neglected Disease Initiative is releasing a cheap alternative that was developed for treatment of cryptococcosis.¹³ This is an opportunity for resource-limited countries in disease-endemic areas for treatment of histoplasmosis. We should not wait any longer. Every year wasted to build capacity for diagnosis and treatment of histoplasmosis in the Amazon Basin and elsewhere leads to hundreds of deaths that could have been avoided. This is not acceptable.     

Tuberculosis and Histoplasmosis among Human Immunodeficiency Virus–Infected Patients: A Comparative Study

In disease-endemic areas, histoplasmosis is the main differential diagnosis for tuberculosis among human immunodeficiency virus (HIV)–infected patients. However, no study has compared the two diseases. Thus, the objective of this study was to compare tuberculosis and histoplasmosis in HIV-infected patients. A population of 205 HIV-infected patients (99 with tuberculosis and 106 with histoplasmosis) hospitalized in Cayenne, French Guiana during January 1, 1997–December 31, 2008 were selected retrospectively from the French Hospital Database on HIV. Multivariate analysis showed that tuberculosis was associated with cough (adjusted odds ratio [AOR] = 0.20, 95% confidence interval [CI] = 0.05–0.73) and a C-reactive protein level > 70 mg/L (AOR = 0.98, 95% CI = 0.97–0.99). Variables associated with disseminated histoplasmosis were a γ-glutamyl transferase level > 72 IU/L (AOR = 4.99, 95% CI = 1.31–18.99), origin from French Guiana (AOR = 5.20, 95% CI = 1.30–20.73), disseminated localization (AOR = 6.40, 95% CI = 1.44–28.45), a concomitant opportunistic infection (AOR = 6.71, 95% CI = 1.50–29.96), a neutrophil count < 2,750 cells/mm³ (AOR = 10.54, 95% CI = 2.83–39.24), a CD4 cell count < 60 cells/mm³ (AOR = 11.62, 95% CI = 2.30–58.63), and a platelet count < 150,000/mm³ (AOR = 19.20, 95% CI = 3.35–110.14). Tuberculosis and histoplasmosis have similarities, but some factors show a greater association with one of these diseases. Thus, adapted therapeutic choices can be made by using simple clinical and paraclinical criteria.     

Statins and glycaemic control in individuals with diabetes: a systematic review and meta-analysis

Aims/hypotheses

Current evidence indicates that statins increase the risk of incident diabetes; however, the relationship between statins and glycaemic control in people with established diabetes has not been well characterised. To address this question, we conducted a meta-analysis of randomised controlled trials (RCTs) of statins in patients with diabetes for whom there was available data on glycaemic control.

Methods

We identified studies published between January 1970 and November 2013 by searching electronic databases and reference lists. We included RCTs in which the intervention group received statins and the control group received placebo or standard treatment, with >200 participants enrolled, with the intervention lasting >12 weeks and with pre- and post-intervention HbA_1c reported. We combined study-specific estimates using random-effects model meta-analysis.

Results

In a pooled analysis of nine trials involving 9,696 participants (4,980 statin, 4,716 control) and an average follow-up of 3.6 years, the mean HbA_1c of participants randomised to statins was higher than those randomised to the control group: mean difference (95% CI) was 0.12% (0.04, 0.20) or 1.3 mmol/mol (0.4, 2.2); p?=?0.003. There was moderate heterogeneity across the studies (I ²?=?54%, p?=?0.014) not explained by available study-level characteristics. This review was limited by the small number of studies, available data on only three statins and sparse reporting on changes in use of glucose-lowering medications.

Conclusions/interpretation

Statin treatment is associated with a modest increase in HbA_1c in patients with diabetes.     

Incidence of microcracks after preparation of straight and curved root canals with three different NiTi instrumentation techniques assessed by micro‐CT

This study evaluated the effect of three different NiTi instrumentation techniques on the incidence of microcracks after the preparation of straight and curved root canals using micro‐CT. Roots from mandibular premolars and maxillary molars (n = 66) with the same mean canal curvatures were assigned to three groups of straight and three groups of curved roots (n = 11). After preoperative micro‐CT scans, root canals were prepared with Reciproc, OneShape and ProTaper Next to size 25. Specimens were scanned again, and pre‐ and post‐operative cross‐sectional images (n = 75 263) were screened to identify the presence of dentinal microcracks. Overall, microcracks were detected in 2.97% (n = 2236) of the cross‐sectional images. No new dentinal microcracks were observed after root canal instrumentation of straight and curved canals with the tested NiTi systems. Instrumentation with Reciproc, OneShape and ProTaper Next did not induce the formation of dentinal microcracks irrespective of canal curvature.