No abstract

A subgroup of severe combined immunodeficiencies (SCID) is characterized by lack of T and B cells and is caused by defects in genes required for T- and B-cell receptor gene rearrangement. Several of these genes are also involved in nonhomologous end joining of DNA double-strand break repair, the largest subgroup consisting of patients with T−B−NK+SCID due to DCLRE1C/ARTEMIS defects. We postulated that in patients with ARTEMIS deficiency, early and late complications following hematopoietic cell transplantation might be more prominent compared with patients with T−B−NK+SCID caused by recombination activating gene 1/2 (RAG1/2) deficiencies. We analyzed 69 patients with ARTEMIS and 76 patients with RAG1/2 deficiencies who received transplants from either HLA-identical donors without conditioning or from HLA-nonidentical donors without or with conditioning. There was no difference in survival or in the incidence or severity of acute graft-versus-host disease regardless of exposure to alkylating agents. Secondary malignancies were not observed. Immune reconstitution was comparable in both groups, however, ARTEMIS-deficient patients had a significantly higher occurrence of infections in long-term follow-up. There is a highly significant association between poor growth in ARTEMIS deficiency and use of alkylating agents. Furthermore, abnormalities in dental development and endocrine late effects were associated with alkylation therapy in ARTEMIS deficiency.

The PCT level is a strong predictor for distinguishing between bacterial and aseptic meningitis in children in the emergency department. Its combination with other parameters in an effective clinical decision rule could be helpful.

INSERM/Reacting, the French Ebola Task Force, and Institut de Recherche pour le Développement.

BACKGROUNDAn efavirenz-based regimen (with a 600-mg dose of efavirenz, known as EFV600) was the World Health Organization preferred first-line treatment for human immunodeficiency virus type 1 (HIV-1) infection until June 2018. Given concerns about side effects, dolutegravir-based and low-dose efavirenz-based combinations have been considered as first-line treatments for HIV-1 in resource-limited settings. METHODSWe conducted an open-label, multicenter, randomized, phase 3 noninferiority trial in Cameroon. Adults with HIV-1 infection who had not received antiretroviral therapy and had an HIV-1 RNA level (viral load) of at least 1000 copies per milliliter were randomly assigned to receive either dolutegravir or the reference treatment of lowdose efavirenz (a 400-mg dose, known as EFV400), combined with tenofovir and lamivudine. The primary end point was the proportion of participants with a viral load of less than 50 copies per milliliter at week 48, on the basis of the Food and Drug Administration snapshot algorithm. The difference between treatment groups was calculated, and noninferiority was tested with a margin of 10 percentage points. RESULTSA total of 613 participants received at least one dose of the assigned regimen. At week 48, a viral load of less than 50 copies per milliliter was observed in 231 of 310 participants (74.5%) in the dolutegravir group and in 209 of 303 participants (69.0%) in the EFV400 group, with a difference of 5.5 percentage points (95% confidence interval [CI], −1.6 to 12.7; P<0.001 for noninferiority). Among those with a baseline viral load of at least 100,000 copies per milliliter, a viral load of less than 50 copies per milliliter was observed in 137 of 207 participants (66.2%) in the dolutegravir group and in 123 of 200 participants (61.5%) in the EFV400 group, with a difference of 4.7 percentage points (95% CI, −4.6 to 14.0). Virologic failure (a viral load of >1000 copies per milliliter) was observed in 3 participants in the dolutegravir group (with none acquiring drug-resistance mutations) and in 16 participants in the EFV400 group. More weight gain was observed in the dolutegravir group than in the EFV400 group (median weight gain, 5.0 kg vs. 3.0 kg; incidence of obesity, 12.3% vs. 5.4%). CONCLUSIONSIn HIV-1-infected adults in Cameroon, a dolutegravir-based regimen was noninferior to an EFV400-based reference regimen with regard to viral suppression at week 48. Among participants who had a viral load of at least 100,000 copies per milliliter when antiretroviral therapy was initiated, fewer participants than expected had viral suppression.

No abstract

Agelastatin A, isolated from the axinellid sponge Agelas dendromorpha of the Coral Sea, is a new-skeleton alkaloid with, unusually for the oroidin family to which it belongs, marked cytotoxicity toward tumour cells in culture.

Bone marrow transplantation has resulted in life-saving sustained T cell reconstitution in many SCID infants, but correction of B cell function has been more problematic. At the annual meeting of the Primary Immunodeficiency Treatment Consortium held in Boston, MA on April 27, 2012, a debate was held regarding the use of pre-transplant conditioning versus no pre-transplant conditioning in an effort to address this problem. Reviews of the literature were made by both debaters and there was agreement that there was a higher rate of B cell chimerism and a lower number of patients who required ongoing IG replacement therapy in centers that used pretransplant conditioning. However, there were still patients who required IG replacement in those centers, so pre-transplant conditioning did not guarantee development of B cell function. RB presented data on B cell function according to the molecular defect of the patient, and showed that patients with IL7Rα, ADA and CD3 chain gene mutations can have normal B cell function posttransplantation with only host B cells. EH presented a statistical analysis of B cell function in published reports and showed that only a conditioning regimen that contained busulfan was significantly associated with better B cell function post-transplantation. The question is whether the risk of immediate and longterm toxicity in using busulfan is justified, particularly in SCID patients with DNA repair defects and in very young SCID newborns who will be detected by newborn screening. KeywordsSevere combined immunodeficiency; conditioning regimen; haematopoietic stem cell transplantation; B cell function; immunoglobulin therapy © 2013 Elsevier Inc. All rights reserved. Publisher's Disclaimer: This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final citable form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain. Table 1 shows the number and percentages with donor B cell chimerism and the number and percentages of patients of each molecular type who currently require IVIG treatment. The molecular defects with the highest percentages of donor B cell chimerism were X-linked SCIDs, of which twenty-one (36%) had donor B cells, and ADA-Def SCIDs of which 6 (33%) had donor B cell chimerism, with smaller percentages of donor B cell chimerism found among the other molecular types. Eighty-nine (71%) of the patients do not have donor B cell chimerism. Nevertheless, only 61 (48.8%) of the 125 survivors require immunoglobulin (IG) replacement therapy. Thus, 28 of the survivors without B cell chimerism do not require IG replacement. Sixty-two percent of those requiring IG replacement are X-linked SCIDs; 38 of the 58 X-SCID patients are currently receiving it ...