Passive Versus Active Tuberculosis Case Finding and Isoniazid Preventive Therapy Among Household Contacts in a Rural District of Malawi.

SETTING: Thyolo district, rural Malawi. OBJECTIVES: To compare passive with active case finding among household contacts of smear-positive pulmonary tuberculosis (TB) patients for 1) TB case detection and 2) the proportion of child contacts aged under 6 years who are placed on isoniazid (INH) preventive therapy. DESIGN: Cross-sectional study. METHODS: Passive and active case finding was conducted among household contacts, and the uptake of INH preventive therapy in children was assessed. RESULTS: There were 189 index TB cases and 985 household contacts. Human immunodeficiency virus (HIV) prevalence among index cases was 69%. Prevalence of TB by passive case finding among 524 household contacts was 0.19% (191/100000), which was significantly lower than with active finding among 461 contacts (1.74%, 1735/100000, P = 0.01). Of 126 children in the passive cohort, 22 (17%) received INH, while in the active cohort 25 (22%) of 113 children received the drug. Transport costs associated with chest X-ray (CXR) screening were the major reason for low INH uptake. CONCLUSIONS: Where the majority of TB patients are HIV-positive, active case finding among household contacts yields nine times more TB cases and is an opportunity for reducing TB morbidity and mortality. The need for a CXR is an obstacle to the uptake of INH prophylaxis

Preindustrial and Postwar Economic Development: Is There a Link?

Everybody knows now that the “hardware” dimension of development—the physical infrastructure, for example—is a lot easier to put in place than the “software” to keep it operable, which depends on local skills and institutions. (United Nations Development Programme

WHO Clinical Staging of HIV Infection and Disease, Tuberculosis and Eligibility for Antiretroviral Treatment: Relationship to CD4 Lymphocyte Counts.

SETTING: Thyolo district, Malawi. OBJECTIVES: To determine in HIV-positive individuals aged over 13 years CD4 lymphocyte counts in patients classified as WHO Clinical Stage III and IV and patients with active and previous tuberculosis (TB). DESIGN: Cross-sectional study. METHODS: CD4 lymphocyte counts were determined in all consecutive HIV-positive individuals presenting to the antiretroviral clinic in WHO Stage III and IV. RESULTS: A CD4 lymphocyte count of < or = 350 cells/microl was found in 413 (90%) of 457 individuals in WHO Stage III and IV, 96% of 77 individuals with active TB, 92% of 65 individuals with a history of pulmonary TB (PTB) in the last year, 91% of 89 individuals with a previous history of PTB beyond 1 year, 81% of 32 individuals with a previous history of extra-pulmonary TB, 93% of 107 individuals with active or past TB with another HIV-related disease and 89% of 158 individuals with active or past TB without another HIV-related disease. CONCLUSIONS: In our setting, nine of 10 HIV-positive individuals presenting in WHO Stage III and IV and with active or previous TB have CD4 counts of < or = 350 cells/microl. It would thus be reasonable, in this or similar settings where CD4 counts are unavailable for clinical management, for all such patients to be considered eligible for antiretroviral therapy

Unrepeatered DPSK transmission over 360 km SMF-28 fibre using URFL based amplification

Unrepeatered 42.7 Gb/s per channel RZ-DPSK transmission over standard SMF-28 fibre with novel URFL based amplification using fibre Bragg gratings is investigated. OSNR and gain performance are studied experimentally and through simulations. Error free transmission for 16 channels across the full C-band with direct detection was experimentally demonstrated for 280 km span length, as well as 6-channel transmission at 340 km and single-channel transmission up to 360 km (75 dB) without employing ROPA or specialty fibres

Estimating the economic impact of a possible equine and human epidemic of West Nile virus infection in Belgium

This study aimed at estimating, in a prospective scenario, the potential economic impact of a possible epidemic of WNV infection in Belgium, based on 2012 values for the equine and human health sectors, in order to increase preparedness and help decision-makers. Modelling of risk areas, based on the habitat suitable for Culex pipiens, the main vector of the virus, allowed us to determine equine and human populations at risk. Characteristics of the different clinical forms of the disease based on past epidemics in Europe allowed morbidity among horses and humans to be estimated. The main costs for the equine sector were vaccination and replacement value of dead or euthanised horses. The choice of the vaccination strategy would have important consequences in terms of cost. Vaccination of the country's whole population of horses, based on a worst-case scenario, would cost more than EUR 30 million; for areas at risk, the cost would be around EUR 16–17 million. Regarding the impact on human health, short-term costs and socio-economic losses were estimated for patients who developed the neuroinvasive form of the disease, as no vaccine is available yet for humans. Hospital charges of around EUR 3,600 for a case of West Nile neuroinvasive disease and EUR 4,500 for a case of acute flaccid paralysis would be the major financial consequence of an epidemic of West Nile virus infection in humans in Belgium. (Résumé d'auteur

New datings and elevations of a fossil reef in Lembetabe, southwest Madagascar: eustatic and tectonic implications

The study of geological sea-level proxies formed during previous interglacials is a common approach to assess how global sea level will evolve under warmer climate conditions. Over the last decades, technical advancements in both survey and geochronology have allowed improving our knowledge of past sea-level highstands. This is of prime importance to refine our understanding of processes contributing to sea-level changes, and ultimately to improve both local and global sea-level projections. Last Interglacial sea-level proxies in the Western Indian Ocean (and more specifically the island nation of Madagascar), have been less investigated than in other intertropical oceans over the last decades. As a result, paleo sea-level data in this region are less abundant and less precise than elsewhere. Here, we report the results of two field campaigns aimed at studying the site of Lembetabe, southwest Madagascar, where a fossil reef was first described by the researcher Rene ⠁ Battistini more than 50 years ago. We estimate paleo relative sea level history in space and time from 15 new U-series ages from a fossil reef platform mapped with differential GNSS and drone photogrammetry. Our data suggest that, between 129 ka and 115 ka, paleo relative sea level at this location was about 3.4 &amp; PLUSMN; 1.4 m above modern. Once corrected for glacial isostatic adjustment, we find that paleo global mean sea level did not exceed 3 m above modern. Only slight crustal subsidence would reconcile the peak Last Interglacial sea level measured at Lembetabe with the 5 e10 m range reported in the literature.&amp; COPY; 2023 Published by Elsevier Ltd

Revisiting battistini: Pleistocene coastal evolution of southwestern madagascar

The study of paleo shorelines, particularly of those formed during the late Quaternary, provides robust insights into past climate variability. Advances in surveying techniques and chronological methodologies have dramatically improved the inter-comparability of regional and basin-wide paleo shoreline surveys. However, these advances have been applied unevenly across the globe. This is especially true in southwestern Madagascar, where, in the 1960s and 1970s, emerged Pleistocene beach and reef facies were first described in detail and dated to Marine Isotope Stage (MIS) 5a using U–Th alpha activity counting by french geologist René Battistini. Now, 50 years on, no further analysis of the coastal sequence has been made. In this study, we present an updated late Pleistocene coastal evolution model for the southwestern Madagascar coast. Utilizing a combination of Structure-from-Motion/Multi-View Stereo techniques and differential Global Navigation Satellite System surveys, we have created five high-resolution 3D outcrop reconstructions that have, in turn, been chronologically constrained using 10 U-series ages from both in situ and reworked coral samples. Our data suggest that the emerged reef was deposited during MIS 5e (∼125 ka), then was covered by intertidal and beach sediment (including redeposited coral clasts of MIS 5e age), and finally capped off by thick eolianites. This sequence would suggest that the local sea level must have remained stable throughout MIS 5e in order to allow for the progradation of both the beach and reef environments

A phase I clinical and pharmacological study evaluating vinflunine in combination with doxorubicin as first line treatment in metastatic breast cancer

Vinfunine (VFL) is a novel bifluorinated tubulin-targeted agent of the vinca alkaloids class active in advanced stage breast cancer. We conducted a phase I study combining VFL with doxorubicin (DXR) to define the recommended dose (RD), safety, pharmacokinetic (PK) interaction and efficacy. Two schedules (day 1 every 3weeks; days 1 and 8 every 3weeks) were investigated as first line chemotherapy in metastatic breast cancer patients. Thirty-two patients received a total of 162 cycles of the VFL-DXR combination (median 6). The RDs were VFL 250mg/m2/DXR 40mg/m2 every 3weeks for schedule 1 and VFL 120mg/m2/DXR 25mg/m2 days 1 and 8 every 3weeks for schedule 2. The main dose-limiting toxicity was neutropenia. The most frequent non-hematological adverse events were nausea, fatigue, constipation, vomiting, anorexia, stomatitis and dyspnea. Objective response rate was reached in 47.1% of the patients. No PK interaction was observed. VFL-DXR combination is feasible with manageable toxicity. The antitumor activity was promising and supports further evaluatio

Sustained correction of B-cell development and function in a murine model of X-linked agammaglobulinemia (XLA) using retroviral-mediated gene transfer

X-linked agammaglobulinemia (XLA) is a human immunodeficiency caused by mutations in Bruton tyrosine kinase (Btk) and characterized by an arrest in early B-cell development, near absence of serum immunoglobulin, and recurrent bacteria infections. Using Btk- and Tec-deficient mice (BtkTec-/-) as a model for XLA, we determined if Btk gene therapy could correct this disorder. Bone marrow (BM) from 5-fluorouracil (5FU)-treated BtkTec-/- mice was transduced with a retroviral vector expressing human Btk and transplanted into BtkTec-/- recipients. Mice engrafted with transduced hematopoietic cells exhibited rescue of both primary and peripheral B-lineage development, revocery of peritoneal B1 B cells, and correction of serum immunoglobulin M (IgM) and IgG3 levels. Gene transfer also restored T-independent type II immune responses, and B-cell antigen receptor (BCR) proliferative responses. B-cell progenitors derived from Btk-transduced stem cells exhibited higher levels of Btk expression than non-B cells; and marking studies demonstrated a selective advantage for Btk-transduced B-lineage cells. BM derived from primary recipients also rescued Btk-dependent function in secondary hosts that had received a transplant. Together, these data demonstrate that gene transfer into hematopoietic stem cells can reconstitute Btk-dependent B-cell development and function in vivo, and strongly support the feasibility of pursuing Btk gene transfer for XLA

Azacytidine Enhances Regulatory T-Cells In Vivo and Prevents Experimental Xenogeneic Graft-Versus-Host Disease

Background The demethylating agent 5-azacytidine (AZA) has proven its efficacy as treatment for myelodysplastic syndrome and acute myeloid leukemia. In addition, AZA can demethylate FOXP3 intron 1 (FOXP3i1) leading to the generation of regulatory T cells (Tregs). Objective We investigated the impact of AZA on xenogeneic graft-versus-host disease (xGVHD) in a humanized murine model of transplantation, and described the impact of the drug on human T cells in vivo. Methods In order to induce xGVHD, human peripheral blood mononuclear cells (huPBMC) were administered intravenously in NOD-scid IL-2Rγnull (NSG) mice. Results AZA successfully improved both survival (p&lt;0.0001) and xGVHD scores (p&lt;0.0001). Further, AZA significantly decreased human T-cell proliferation as well as INF-γ and TNF-α serum levels, and reduced the expression of GRANZYME B and PERFORIN 1 by cytotoxic T cells. In addition, AZA administration significantly increased the function, proliferation and frequency of Tregs through demethylation of FOXP3i1 and higher secretion of IL-2 by conventional T cells due to IL2 gene promoter site 1 demethylation. Interestingly, among AZA-treated mice surviving the acute phase of xGVHD, there was an inverse correlation between the presence of Tregs and signs of chronic GVHD. Finally, Tregs harvested from the spleen of AZA-treated mice were suppressive and stable over time since they persisted at high frequency in secondary transplant experiments. Conclusion These findings emphasize a potential role for AZA as prevention or treatment of GVHD