Rewiring cancer drivers to activate apoptosis.

Genes that drive the proliferation, survival, invasion and metastasis of malignant cells have been identified for many human cancers1-4. Independent studies have identified cell death pathways that eliminate cells for the good of the organism5,6. The coexistence of cell death pathways with driver mutations suggests that the cancer driver could be rewired to activate cell death using chemical inducers of proximity (CIPs). Here we describe a new class of molecules called transcriptional/epigenetic CIPs (TCIPs) that recruit the endogenous cancer driver, or a downstream transcription factor, to the promoters of cell death genes, thereby activating their expression. We focused on diffuse large B cell lymphoma, in which the transcription factor B cell lymphoma 6 (BCL6) is deregulated7. BCL6 binds to the promoters of cell death genes and epigenetically suppresses their expression8. We produced TCIPs by covalently linking small molecules that bind BCL6 to those that bind to transcriptional activators that contribute to the oncogenic program, such as BRD4. The most potent molecule, TCIP1, increases binding of BRD4 by 50% over genomic BCL6-binding sites to produce transcriptional elongation at pro-apoptotic target genes within 15 min, while reducing binding of BRD4 over enhancers by only 10%, reflecting a gain-of-function mechanism. TCIP1 kills diffuse large B cell lymphoma cell lines, including chemotherapy-resistant, TP53-mutant lines, at EC50 of 1-10 nM in 72 h and exhibits cell-specific and tissue-specific effects, capturing the combinatorial specificity inherent to transcription. The TCIP concept also has therapeutic applications in regulating the expression of genes for regenerative medicine and developmental disorders.

Characteristics of Pharmacists' Interventions Related to Proton-Pump Inhibitors in French Hospitals: An Observational Study.

Methods: The study was based on a retrospective analysis of pharmacist interventions for DRPs detected during the medication order review and documented into the French Act-IP© database over a 12-year period. DRPs and PIs were analyzed, and independent factors of physician acceptance were assessed via multiple logistic regression. Results: Out of the 620,620 PIs registered, 29,694 targeted a PPI (4.8%). PPI's DRPs were mostly related to the prescription of a "drug not available at the hospital" (26.1%) and a "drug use without indication" (18.3%); PIs were mostly "drug switch" (35.9%) and "drug discontinuation" (26.1%). In all, 18,919 PIs were accepted by physicians (63.7%). Acceptance was significantly associated with patient age: less accepted for the 18-75 years group (OR = 0.59, 95 CI [0.46-0.76]), and the >75 years group (OR = 0.57, 95 CI [0.44-0.73]) vs. <18 years group; for the type of DRP, "drug use without indication" was the less accepted (OR = 0.73, 95 CI [0.63-0.85]); for the type of PI, "dose adjustment" was the less accepted (OR = 0.32, 95 CI [0.23-0.45]). Conclusion: Pharmacists contribute to preventing DRPs associated with PPI prescriptions during the medication order review process. Moreover, they often detect PPIs used without indication and they propose drug discontinuation, which contributes to the PPI deprescribing process. PIs should be further developed in the future to reduce PPI overprescription.

Catatonia with schizophrenia: From ECT to rTMS.

BACKGROUND: Electroconvulsive therapy is indicated in cases of catatonic schizophrenia following a failure of the challenge test with lorazepam or Zolpidem®. Some patients need maintenance treatment with ECT. Repetitive Transcranial Magnetic Stimulation (rTMS) and anodal Transcranial direct-current stimulation (tDCS) might be effective against catatonia. OBJECTIVE: Consider an alternative to ECT for a refractory patient. REVIEW: Twenty-one articles were identified mainly based on case reports series were found using search on Medline, Google Scholar, PsychInfo, CAIRNS. Key words were:"catatonia", and "rTMS", and more generally with"ECT","tDCS","Zolpidem®". At the end there were only six case reports with rTMS and three with tDCS. We discussed the alternative to ECT and follow up rTMS strategies illustrated by these case reports. FINDINGS: Patients mean age was 35; numbers of previous ECT vary from zero to 556; the most common motor threshold (MT) is 80%, with two patients with 110%, the most common treatment placement is L DLPFC. In one of them, ECT was the only acute-state or maintenance treatment effective in this patient, who underwent 556 ECT sessions over 20 years. High-frequency rTMS was considered as a possible alternative, given the potential adverse effects of chronic maintenance ECT in a patient with comorbid epilepsy. rTMS treatment was 3-4×/week and over time extended to once every two weeks. A persistent objective improvement in catatonia was observed on the Bush-Francis Catatonia Rating Scale. CONCLUSION: rTMS is helpful for acute and maintenance treatment for catatonic schizophrenia who both failed multiple pharmacologic interventions and had safety concerns with continuing maintenance ECT. Clinicians should consider rTMS as a potential treatment option for refractory catatonia.

[How to act when an alpha-blocker is associated with a potent inhibitor of CYP3A4]. / Conduite à tenir en cas d'association d'un alpha-bloquant et d'un inhibiteur puissant du cytochrome 3A4.

OBJECTIVE: Combination of alpha-blockers with potent CYP3A4 inhibitors is either contra-indicated or not recommended. We searched data supporting this classification and guiding prescribers when such an interaction occurs. METHODS: We analyzed reports published by the French agency for drug safety, reference books and performed search in databases of pharmacokinetics studies and case or case series related with these interactions. RESULTS: The classification of the potential severity of these interactions defined by the French agency for drug safety evolved over time. Our literature search did not identify any cases or case series reporting serious clinical consequences of such interactions and no pharmacoepidemiological studies on the association between alpha-blockers and inhibitors of CYP3A4. The content of the summaries of product characteristics indicate that the combination of ketoconazole with alfuzosin, silodosin and tamsulosin increases the area under the curve of the alpha-blocker 3 fold. CONCLUSION: Data demonstrating the clinical consequences of an association between alpha-blocker and a potent CYP3A4 inhibitor are lacking. The 3 fold increase of the area under the curve for alfuzosin, silodosin and tamsulosin associated with ketoconazole while the association with the two first is contra-indicated and is not recommended with the third raises questions. This lack of data leaves doctors and pharmacists in a situation of uncertainty on how to proceed when such an interaction occurs.

Trends in pharmacists' medication order review in French hospitals from 2006 to 2009: analysis of pharmacists' interventions from the Act-IP© website observatory.

WHAT IS KNOWN AND OBJECTIVES: The French Society of Clinical Pharmacy has developed a website, named Act-IP©, enabling hospital pharmacists to document and analyse pharmacists' interventions (PIs) proposed during medication order review when a drug-related problem is detected. This study analyses PIs documented in Act-IP© and assesses factors associated with physicians' acceptance of PIs. METHODS: PIs documented into Act-IP© over a 30-month period were analysed. Independent predictors of physicians' acceptance were assessed using multiple logistic regression. RESULTS AND DISCUSSION: A total of 34,522 PIs were registered by 201 pharmacists working in 59 hospitals. PIs were mostly related to 'dose adjustment' (25%), 'drug discontinuation' (20%) and 'drug switch' (19%). Of the 43,343 medications involved, 28% targeted drugs acting on the central nervous system, 17% anti-infective drugs and 16% cardiovascular drugs. Sixty-eight per cent of PIs were accepted by physicians (15% refusals and 17% non-assessable). Physicians' acceptance was significantly associated with 1/ drug group: antineoplastics and immunomodulators (OR = 2.29, CI 95[1.94-2.69]), anti-infectives (OR = 1.19, CI 95 [1.11-1.28]); 2/ type of intervention: drug switch (OR = 1.54, CI 95 [1.43-1.65]), drug discontinuation (OR = 1.38, CI 95 [1.29-1.48]), administration modality optimization (OR = 1.19, CI 95 [1.11-1.29]), addition of a new drug (OR = 1.12, CI 95 [1.00-1.24]); 3/ ward specialty: paediatrics (OR = 1.83, CI 95 [1.24-2.70]) and intensive care (OR = 1.34, CI 95 [1.10-1.64]); 4/ level of pharmacist integration in the ward: higher when the pharmacist is regularly in the ward compared with occasionally (OR = 0.74, CI 95 [0.70-0.79]) or never (OR = 0.68, CI 95 [0.60-0.75]) present. WHAT IS NEW AND CONCLUSION: This study highlights the role of routine pharmacist review of medication orders to prevent drug-related problems and gives new insights for a successful collaboration between physicians and pharmacists.

[Pharmacists' interventions conducted by hospital pharmacists on psychotropic drugs pharmacotherapy]. / Interventions pharmaceutiques émises par les pharmaciens sur les médicaments psychotropes.

INTRODUCTION: The French Society of Clinical Pharmacy (SFPC) through the special interest group "standardization and optimization of clinical pharmacy activities" stated that the study of pharmacists' interventions (PIs) conducted during prescription analysis was a priority. The SFPC developed an internet website named Act-IP(®) (http://www.sfpc.eu/fr/) where French speaking pharmacists were able to document PIs using a normalized codification. The objective of this study was to analyze medication-related problems linked to psychotropic drugs in hospital and to investigate PIs performed during prescription analysis. MATERIALS AND METHODS: This is a multicenter, retrospective, observational study using PIs involving psychotropic medications recorded between September 2006 and February 2009 on the Act-IP(®) website. RESULTS: Four thousand six hundred and twenty PIs recorded by 165 pharmacists in 57 hospitals were related to psychotropic drugs. Patients concerned by these drug-related problems were 64 years old on average. Seven categories of medication-related problems represented more than 69% of PIs (1.1-Non Conformity of the drug choice compared to the formulary; 4.1 Supratherapeutic dose; 5.3 Therapeutic redundancy; 6.2 Drug interaction (all levels of severity); 7.0 Adverse drug reaction; 8.3 Inappropriate drug form; 8.5 Inappropriate timing of administration). The PIs related to 9.2 Patient's non compliance, 2.0 Untreated indication and 3.2 Length of the treatment too short were infrequent (less than 1%). The most common type of intervention was the dose adjustment. Almost 45% of these PIs involved Zopiclone or Zolpidem prescription in elderly patients. Seven hundred and nine drug interactions were identified by pharmacists. The most common type of drug interaction considered the risk of cardiac arrhythmias due to antipsychotic medications. One hundred and thirty-three PIs concerned adverse drug reaction. The most frequent adverse drug reactions were a fall (36 PIs), hemorrhage/bleeding (32 PIs), drowsiness (12 PIs) and extrapyramidal syndrome (12 PIs). Antidepressant drugs were the greatest pharmacological class concerning adverse drug reaction. The overall acceptance rate was 57%. Eight hundred and seventy-four PIs (19%) were refused and 1111 (24%) were non-assessable. DISCUSSION: PIs avoids drug-related problems, such as the polyprescription of benzodiazepine or supratherapeutic dose. However, few PIs concern compliance to therapy or polyprescription of antipsychotic drugs. These two categories of medication-related problems are known to be an issue in mental health therapy. The lack of guidelines describing mental health pathology (such as the HAS guideline) is an obstacle for performing evidence-based PIs. The lack of information describing the context of the prescription is a limitation of this study. In order to improve their practice, pharmacists have to focus more on the context in which patients are evolving, and to take into account its entire situation based on Anglo-Saxon approaches. A second way is to identify clinical settings where PIs are useful and to describe PIs needed. Doctors and pharmacists should get together and talk about these clinical situations and PIs, because some may be misunderstood or disapproved by prescribers. This collaboration could take the form of a thesaurus combining clinical situation and PIs. CONCLUSION: It appears important for pharmacists to show their daily involvement in the quality of medical care. This feedback on medication problems encountered and PIs proposed should help prescribers to identify clinical situations at risk. Nevertheless, this study also suggests that progress is possible. Dialogue must allow pharmacists and physicians to delete misunderstandings about their practices.

Overdosed paracetamol (acetaminophen) prescriptions and subsequent pharmacist interventions in French hospitals.

INTRODUCTION: Little is known about the manner in which hospital pharmacists intervene for overdosed paracetamol prescriptions. The aim of this retrospective study was to describe the number and nature of pharmacists' interventions (PIs) for overdosed paracetamol adult prescriptions in hospitals. METHODS: We studied PIs that had been documented by pharmacists on the French Society of Clinical Pharmacy website tool between 2007 and 2010. We identified PIs that were related to paracetamol-containing prescriptions of one brand name only (type 1) particularly for patients with body weight ≤ 50 kg who were prescribed 4 g/day, and PIs that concerned the co-prescription of two paracetamol-containing products (type 2). RESULTS: Among 60 hospitals, seven did not report any paracetamol overdose-related PIs. Of the 53 hospitals that had at least one PI, 16 did not report any type 1 PIs. Bodyweight, liver disease, cirrhosis and chronic alcoholism were absent recorded criterion by most of the hospitals included in this study. DISCUSSION: Previously published studies have highlighted that the most frequent PIs are type 1, especially for patients whose body weight is ≤ 50 kg. We observed a broad variability in the number or type of PI that were related to overdosed paracetamol prescriptions compared with the total of all recorded types of PI. These data suggest that a significant number of hospital pharmacists are unaware of the risks that adult patients with low body weight are exposed to when receiving four grams paracetamol/day over several days. CONCLUSION: Pharmacist educational programs are needed.

Borrowing Transcriptional Kinases to Activate Apoptosis.

Protein kinases are disease drivers whose therapeutic targeting traditionally centers on inhibition of enzymatic activity. Here chemically induced proximity is leveraged to convert kinase inhibitors into context-specific activators of therapeutic genes. Bivalent molecules that link ligands of the transcription factor B-cell lymphoma 6 (BCL6) to ATP-competitive inhibitors of cyclin-dependent kinases (CDKs) were developed to re-localize CDK to BCL6-bound loci on chromatin and direct phosphorylation of RNA Pol II. The resulting BCL6-target proapoptotic gene expression translated into killing of diffuse large B-cell lymphoma (DLBCL) cells at 72 h with EC50s of 0.9 - 10 nM and highly specific ablation of the BCL6-regulated germinal center response in mice. The molecules exhibited 10,000-fold lower cytotoxicity in normal lymphocytes and are well tolerated in mice. Genomic and proteomic evidence corroborated a gain-of-function mechanism where, instead of global enzyme inhibition, a fraction of total kinase activity is borrowed and re-localized to BCL6-bound loci. The strategy demonstrates how kinase inhibitors can be used to context-specifically activate transcription, accessing new therapeutic space.

Preferences of owners of overweight dogs when buying commercial pet food.

Most pet dogs in developed countries are fed commercial diets. The aim of this study was to evaluate the preferences of owners of overweight dogs when buying commercial pet food. The study was a descriptive observational multi-centre study on a group of 198 owners of urban household dogs. Personal interviews were conducted to examine the owners' opinions with questions rating the importance of certain qualities of prepared dog food. Bivariate analyses for comparisons of absolute means between groups of owners of dogs with excess weight (n = 137) and owners of normal weight dogs (n = 61) were made using the Mann-Whitney U-test. A low price (p < 0.001) and special offers (p = 0.008) of commercial dog food were more important for owners of dogs with excess weight than for owners of normal weight dogs. The quality of ingredients (p = 0.007) and the nutritional composition (p < 0.001) were more important for owners of normal weight dogs than for owners of dogs with excess weight. The veterinarian was the most important source of information on dog nutrition for both groups (83.6% for owners of normal weight dogs and 83.2% for owners of dogs with excess weight) (p = 0.88). The owners of dogs with excess weight had less interest in corrected dog nutrition than owners of normal weight dogs (p < 0.001).

[Opportunities for medication errors and pharmacist's interventions in the context of computerized prescription order entry: a review of data published by French hospital pharmacists]. / Opportunités d'erreurs médicamenteuses et interventions pharmaceutiques dans le cadre de la prescription informatisée : revue des données publiées par les pharmaciens hospitaliers français.

INTRODUCTION: Computerized prescription order entry (CPOE) is accelerating in France. CPOE has been shown to reduce the occurrence of some medication errors, but evidence of a beneficial effect on clinical outcomes remains limited. In some cases, new error types have arisen with its use. The aim of this study was to investigate the French data on the nature and frequency of medication errors opportunities generated by the computer use, which led pharmacists to alert prescribers. METHODS: We performed a search on PubMed and CAT-INIST databases completed by a manual one. RESULTS: Ten publications, 11 abstracts and three personal communications were analysed. As part of the analysis of computerized prescriptions, the rate of pharmaceutical interventions due to CPOE ranges from 5.9 to 35% depending on the study. Duplicate orders, unit errors, the use of free text, parameterization flaws and poor usability of software are probably the root of many prescribing errors. Errors generated by the tool can have serious potential consequences. DISCUSSION: Pharmacist's interventions due to CPOE are common. It is not known whether variability of the percentage of pharmacist's interventions is due to software used or to conditions by witch studies were carried out. With implementation of CPOE in hospital, pharmacists must acquire new knowledge and new skills in order to prevent prescription errors generated by these tools and its misuse. CONCLUSION: Studies are urgently needed in order to identify the safest tools and to discard the most dangerous.

Sodium dodecyl sulfate reduces bacterial contamination in goat colostrum without negative effects on immune passive transfer in goat kids.

To investigate the use of sodium dodecyl sulfate (SDS) as a biocide on goat colostrum, 2 experiments were performed. In the first, 20 goat colostrum samples were divided into 3 aliquots. A different treatment was performed on each aliquot: pasteurization (56°C, 30 min) or addition of SDS to a final concentration of either 0.1 or 1% (36°C, 10 min). Immunoglobulin G and colony-forming units were evaluated before and after treatment. Both pasteurization and treatment with 1% SDS significantly reduced the colony-forming units in colostrum. Treatment with 0.1% SDS was not effective at reducing the colony-forming units in colostrum. The IgG concentration of pasteurized colostrum was significantly lower than that of untreated colostrum, whereas treatment with 1% SDS did not affect the colostrum IgG concentration. In the second experiment, the effects of SDS colostrum treatment on immune passive transfer were evaluated. Forty goat kids were fed either refrigerated colostrum or colostrum treated with 1% SDS twice daily for 2 d. Blood samples were obtained at birth and every day for 5 d. IgG, IgM, and IgA were measured in blood serum to monitor the passive immune transfer process. Creatinine, glucose, total cholesterol, blood urea nitrogen, bilirubin, and aspartate transaminase were also monitored to evaluate the health of kids. No differences in serum IgG, IgM, IgA, creatinine, glucose, total cholesterol, blood urea nitrogen, bilirubin, or aspartate transaminase levels were observed between groups. Our findings indicate that SDS is an efficient colostrum biocide that, unlike pasteurization, does not affect immune passive transfer or goat kid health.

[Designing a tool to describe drug interactions and adverse events for learning and clinical routine]. / Développement d'un outil d'aide à la description des interactions et des effets indésirables médicamenteux pour la formation et la routine clinique.

Pharmacists play an important role in prescription analysis. They are involved in therapeutic drug monitoring, particularly for drugs with a narrow therapeutic index, prevention and management of drug interactions, and may be called in to identify side effects and adverse events related to drug therapy. For the polymedicated patient, the medical file, the list of prescribed drugs and the history of their administration may be insufficient to adequately assign the responsibility of a given adverse effect to one or more drugs. Graphical representations can sometimes be useful to describe and clarify a sequence of events. In addition, as part of their academic course, students have many occasions to hear about "side effects" and "drug interactions". However, in the academic setting, there are few opportunities to observe the evolution and the consequences of these events. In the course of their hospital training, these students are required to perform patient follow-up for pharmacotherapeutic or educational purposes and to comment case reports to physicians. The aim of this paper is to present a tool facilitating the graphic display of drug interaction consequences and side effects. This tool can be a useful aid for causality assessment. It structures the students' training course and helps them better understand the commentaries pharmacists provide for physicians. Further development of this tool should contribute to the prevention of adverse drug events.

Diagnostic yield of active case finding for tuberculosis at human immunodeficiency virus testing in Haiti.

SETTING: The Groupe Haïtien d'étude du Sarcome de Kaposi et des Infections Opportunistes (GHESKIO) Centres, Port-au-Prince, Haiti, facilitate "test and treat" strategies by screening all patients for tuberculosis (TB) at human immunodeficiency virus (HIV) testing.OBJECTIVE: 1) To determine the proportion of patients with chronic cough at HIV testing diagnosed with TB, stratified by HIV test results; and 2) to evaluate the additional diagnostic yield of Xpert® MTB/RIF vs. sputum microscopy.DESIGN: We conducted a retrospective cohort analysis including all adults tested for HIV at GHESKIO from August 2014 to July 2015.RESULTS: Of 29 233 adult patients tested for HIV, 2953 (10%) were diagnosed as HIV-positive. Chronic cough lasting ≥2 weeks was reported by 1116 (38%) HIV-positive patients; 984 (88%) were tested and 265 (27%) were diagnosed with TB. Chronic cough was reported by 5985 (23%) HIV-negative patients; 5654 (94%) were tested and 1179 (21%) were diagnosed with TB. Of all bacteriologically confirmed cases, 27% were smear-negative and Xpert-positive. Among all TB patients, 81% were HIV-negative.CONCLUSIONS: Screening for TB at HIV testing was high-yield, among both HIV-infected and HIV-negative individuals. Testing for both diseases should be conducted among patients who present with chronic cough at HIV testing.

Relationship between analytic values and canine obesity.

The objective of this study was to assess the relationship between canine body condition and metabolic parameters like serum lipids, blood glucose and alanine aminotransferase (ALT) concentrations. We selected 127 dogs (42 males and 85 females) that were taken to our veterinary medicine service during routine visits. The mean age was 6.67 +/- 5.24 years. Body condition (BC) was measured by Laflamme scale and dogs were considered as obese when BC score was over 6. The following variables were collected: total cholesterol, high-density lipoprotein cholesterol, triglycerides, basal glucose and ALT. 66.1% of the dog cohort were obese. Total cholesterol and triglycerides were found to be higher (p < 0.05) in obese dogs with respect to normal weight dogs. In conclusion, obesity in dogs is associated with higher serum lipid levels.

Blood transcriptomic markers of Mycobacterium tuberculosis load in sputum.

BACKGROUND: Peripheral blood transcriptome signatures that distinguish active pulmonary tuberculosis (TB) from control groups have been reported, but correlations of these signatures with sputum mycobacterial load are incompletely defined. METHODS: We assessed the performance of published TB transcriptomic signatures in Haiti, and identified transcriptomic biomarkers of TB bacterial load in sputum as measured by Xpert® MTB/RIF molecular testing. People in Port au Prince, Haiti, with untreated pulmonary TB (n = 51) formed the study cohort: 19 people with low and 32 with high sputum Mycobacterium tuberculosis load. Peripheral whole blood transcriptomes were generated using RNA sequencing. RESULTS: Twenty of the differentially expressed transcripts in TB vs. no TB were differentially expressed in people with low vs. high sputum mycobacterial loads. The difference between low and high bacterial load groups was independent of radiographic severity. In a published data set of transcriptomic response to anti-tuberculosis treatment, this 20-gene subset was more treatment-responsive at 6 months than the full active TB signature. CONCLUSION: We identified genes whose transcript levels in the blood distinguish active TB with high vs. low M. tuberculosis loads in the sputum. These transcripts may reveal mechanisms of mycobacterial control of M. tuberculosis during active infection, as well as identifying potential biomarkers for bacterial response to anti-tuberculosis treatment.

Prevalence of Canine Obesity, Obesity-Related Metabolic Dysfunction, and Relationship with Owner Obesity in an Obesogenic Region of Spain.

The main objective of this study was to evaluate the prevalence of canine obesity and obesity-related metabolic dysfunction (ORMD) in the obesogenic area in Spain. The prevalence of overweight/obesity among owners of obese pets was also evaluated. In the sample population studied (93 client-owned dogs), 40.9% of dogs presented obesity (body condition score 7-9/9), 40.9% of dogs presented hypertension, 20.4% of dogs presented fasting hypertriglyceridemia, 20.4% fasting hypercholesterolemia, and 5.4% of dogs presented fasting hyperglycemia. The overall prevalence of ORMD was of 22.6%. Seventy-eight percent of overweight/obese owners had overweight/obese dogs (P < 0.001) including all dogs diagnosed with ORMD. In conclusion, in the studied obesogenic region of Spain, the prevalence of canine obesity and ORMD was shown to be elevated and related to the presence of overweight/obesity in owners. All dogs with ORMD were owned by overweight/obese persons. These results provide new inputs for future studies highlighting the relationship between owner and pet obesity and indicating the need of further efforts to control and reduce obesity prevalence in both.

Diagnostic yield of active case finding for tuberculosis and HIV at the household level in slums in Haiti.

SETTING: Haiti has the highest burden of tuberculosis (TB) in the Americas, with an estimated prevalence of 254 per 100 000 population. The Haitian Group for the Study of Kaposi's Sarcoma and Opportunistic Infections (Groupe Haïtien d'Etude du Sarcome de Kaposi et des Infections Opportunistes, GHESKIO) conducted active case finding (ACF) for TB at the household level in nine slums in Port-au-Prince. OBJECTIVE: We report on the prevalence of undiagnosed TB detected through GHESKIO's ACF campaign. DESIGN: From 1 August 2014 to 31 July 2015, we conducted a retrospective cohort analysis using GHESKIO's ACF campaign data. All individuals who reported chronic cough (cough 2 weeks) were tested for TB at GHESKIO, and those aged 10 years were included in the analyses. RESULTS: Of 104 097 individuals screened in the community, 5598 (5%) reported chronic cough and satisfied the study inclusion criteria. A total of 1110 (20%) were diagnosed with active TB disease (prevalence of 1066/100 000). Of the 5472 (98%) patients tested for human immunodeficiency virus (HIV), 528 (10%) were HIV-positive; 143 (3%) patients were diagnosed with both diseases. CONCLUSION: Household-level screening for cough with TB and HIV testing for symptomatic patients was a high-yield strategy, leading to the detection of a prevalence of undiagnosed disease exceeding national estimates by more than four-fold for TB, and by five-fold for HIV.

An outbreak of abortions and high neonatal mortality associated with Trypanosoma evansi infection in dromedary camels in the Canary Islands.

Trypanosoma evansi was diagnosed for the first time in the Canary Islands (Spain) in 1998 in a dromedary camel. Seroprevalences of 4.8% up to 9% have been observed using different diagnostic methods. Affected animals have been treated but the dissemination of the disease is unknown. This article presents an outbreak of abortions and high neonatal mortality attributable to T. evansi infection in camels as well as the clinical assessment of the affected animals. The patients were diagnosed by routine checking (three pregnant animals), after abortion (five dams), or after delivered premature or weak calves (eight dams). At clinical examination, 2 out of 16 affected animals showed moderate signs of chronic form, particularly hyporexia and intolerance to exercise. The aborted fetuses were aged 6-8 months of gestation, approximately. The main laboratorial findings were regenerative anemia (haemolytic anemia), lymphocytic and monocytic leukocytosis, hyperproteinemia, hyperglobulinemia, hypoglycaemia, serum urea increased and serum iron decreased. Treatment using trypanocidal drug (Cymelarsan) resulted highly effective. Massive treatment would be recommended in the entire camel population in the Canary Islands (less than 2000 animals), as therapeutic or preventive measure, in order to control and to achieve an eventual eradication of the disease.

CD4 deficit and tuberculosis risk persist with delayed antiretroviral therapy: 5-year data from CIPRA HT-001.

SETTING: Port-au-Prince, Haiti. OBJECTIVE: To determine long-term effects of early vs. delayed initiation of antiretroviral therapy (ART) on immune recovery and tuberculosis (TB) risk in human immunodeficiency virus (HIV) infected individuals. DESIGN: Open-label randomized controlled trial of immediate ART in HIV-infected adults with CD4 counts between 200 and 350 cells/mm(3) vs. deferring ART until the CD4 count was <200 cells/mm(3). The primary comparisons were CD4 counts over time and risk for incident TB, with 5 years of follow-up. RESULTS: A total of 816 participants were enrolled, with 408 in each treatment arm. The early treatment group started ART within 2 weeks, while the deferred treatment group started ART a median of 1.3 years after enrollment. After 5 years, the mean CD4 count in the early treatment group was significantly higher than in the deferred treatment group (496 cells/mm(3), 95% confidence interval [CI] 477-515 vs. 373 cells/mm(3), 95%CI 357-389; P < 0.0001). TB risk was higher in the deferred treatment group (unadjusted HR 2.41, 95%CI 1.56-3.74; P < 0.0001) and strongly correlated with lower CD4 counts in time-dependent multivariate analysis. CONCLUSION: Delays in ART initiation for HIV-infected adults with CD4 counts of 200-350 cells/mm(3) can result in long-term immune dysfunction and persistent increased risk for TB.