Infliximab treatment for steroid-refractory acute graft-versus-host disease

Background and Objectives. Tumor necrosis factor \u3b1 is one of the principal cytokines involved in the pathogenesis of acute graft-versus-host- disease (GVHD). Infliximab is an antibody to this cytokine. Design and Methods. We performed a retrospective analysis to evaluate the activity of infliximab in 32 patients with severe steroid-refractory acute GVHD. The patients received a median of 3 weekly courses of infliximab. The main organs involved in the patients were skin (n=2) liver (n=1), bowel (n=19), liver and bowel at the same stage (n=10). Results. Nineteen out 32 patients (59%) responded to infliximab with 6 (19%) complete and 13 (40%) partial responses. Age younger than 35 years, intestinal involvement and a longer time between hematopoietic stem cell transplantation and infliximab administration were factors predicting a favorable response. Infective episodes developed in 23/32 (72%) patients. All the 13 unresponsive patients died of GVHD shortly after infliximab. Thirteen of 19 responsive patients were alive at a median follow-up of 449 days (range 155-842) after infliximab, with no signs of chronic GVHD (n=5), limited (n=5) or extensive involvement (n=3). Six patients who responded subsequently died, one of chronic lung GVHD, the others of vascular complications or infections (2 fungal diseases). Interpretation and Conclusions. We conclude that infliximab is active in the treatment of severe steroid-refractory acute GVHD, particularly when the intestine is involved. Infections commonly followed its administration. The clinical activity of infliximab and the possibility that it increases the risk of infections are worth investigating in prospective trials

Inter- and intra-rater reliabilities of the Beighton Score compared to the Contompasis Score to assess Generalised Joint Hypermobility

Objectives: Generalized Joint Hypermobility [GJH] is a common connective tissue disorder associated with a range of musculoskeletal complaints. An effective screening tool to assess GJH may influence our understanding and choice of management. Diagnosis is clinical, using tools such as the Beighton Hypermobility Score and the Contompasis Scoring System. The comparable reliability of these tools has not been previously reported. The aim of the present study was to compare the intra- and the inter-rater reliability of the Beighton Score to the Contompasis Score to assess GJH. Methods: This was an observational study assessing 36 pain-free participants; 27 females and nine males; aged 18–32 years. Participants were assessed in random order, by two researchers over two sessions to determine intra- and inter-rater analyses. Intraclass Correlation Coefficient [ICC] and weighted Kappa statistics were used to calculate the level of agreement. Results: The intra- [ICC: 0.71–0.82] and the inter- [ICC: 0.72–0.80] rater reliability of the Beighton Score was substantial to almost perfect. The Contompasis Score displayed substantial to almost perfect intra-rater [ICC: 0.73–0.82] reliability and moderate to substantial inter-rater [ICC: 0.58–0.62] reliability. Conclusions: The present study provides an indication of the measurement capabilities of the Beighton and Contompasis Scores. The Beighton score appears to be superior compared with the Contompasis score particularly based on inter-rater reliability

Donor Lymphocyte Infusions After Allogeneic Stem Cell Transplantation in Acute Leukemia: A Survey From the Gruppo Italiano Trapianto Midollo Osseo (GITMO)

We conducted a retrospective multicenter study including pediatric and adult patients with acute leukemia (AL) who received donor lymphocyte infusions (DLIs) after allogeneic hematopoietic stem cell transplantation (HCT) between January 1, 2010 and December 31, 2015, in order to determine the efficacy and toxicity of the immune treatment. Two hundred fifty-two patients, median age 45.1 years (1.6\u201373.4), were enrolled from 34 Italian transplant centers. The underlying disease was acute myeloid leukemia in 180 cases (71%). Donors were HLA identical or 1 locus mismatched sibling (40%), unrelated (40%), or haploidentical (20%). The first DLI was administered at a median time of 258 days (55\u20133,784) after HCT. The main indication for DLI was leukemia relapse (73%), followed by mixed chimerism (17%), and pre-emptive/prophylactic use (10%). Ninety-six patients (38%) received one single infusion, whereas 65 (26%), 42 (17%), and 49 patients (19%) received 2, 3, or 654 infusions, respectively, with a median of 31 days between two subsequent DLIs. Forty percent of evaluable patients received no treatment before the first DLI, whereas radiotherapy, conventional chemotherapy or targeted treatments were administered in 3, 39, and 18%, respectively. In informative patients, a few severe adverse events were reported: grade III\u2013IV graft versus host disease (GVHD) (3%), grade III\u2013IV hematological toxicity (11%), and DLI-related mortality (9%). Forty-six patients (18%) received a second HCT after a median of 232 days (32\u20131,390) from the first DLI. With a median follow-up of 461 days (2\u20133,255) after the first DLI, 1-, 3-, and 5- year overall survival (OS) of the whole group from start of DLI treatment was 55, 39, and 33%, respectively. In multivariate analysis, older recipient age, and transplants from haploidentical donors significantly reduced OS, whereas DLI for mixed chimerism or as pre-emptive/prophylactic treatment compared to DLI for AL relapse and a schedule including more than one DLI significantly prolonged OS. This GITMO survey confirms that DLI administration in absence of overt hematological relapse and multiple infusions are associated with a favorable outcome in AL patients. DLI from haploidentical donors had a poor outcome and may represent an area of further investigation

Genetic dissection of grain zinc concentration in spring wheat for mainstreaming biofortification in CIMMYT wheat breeding

Wheat is an important staple that acts as a primary source of dietary energy, protein, and essential micronutrients such as iron (Fe) and zinc (Zn) for the world’s population. Approximately two billion people suffer from micronutrient deficiency, thus breeders have crossed high Zn progenitors such as synthetic hexaploid wheat, T. dicoccum, T. spelta, and landraces to generate wheat varieties with competitive yield and enhanced grain Zn that are being adopted by farmers in South Asia. Here we report a genome-wide association study (GWAS) using the wheat Illumina iSelect 90 K Infinitum SNP array to characterize grain Zn concentrations in 330 bread wheat lines. Grain Zn phenotype of this HarvestPlus Association Mapping (HPAM) panel was evaluated across a range of environments in India and Mexico. GWAS analysis revealed 39 marker-trait associations for grain Zn. Two larger effect QTL regions were found on chromosomes 2 and 7. Candidate genes (among them zinc finger motif of transcription-factors and metal-ion binding genes) were associated with the QTL. The linked markers and associated candidate genes identified in this study are being validated in new biparental mapping populations for marker-assisted breeding

Antibiotic prophylaxis and infective endocarditis incidence following invasive dental procedures: a systematic review and meta-analysis

Importance: The association between antibiotic prophylaxis and infective endocarditis after invasive dental procedures is still unclear. Indications for antibiotic prophylaxis were restricted by guidelines beginning in 2007. Objective: To systematically review and analyze existing evidence on the association between antibiotic prophylaxis and infective endocarditis following invasive dental procedures. Data Sources: PubMed, Cochrane-CENTRAL, Scopus, Web of Science, Proquest, Embase, Dentistry and Oral Sciences Source, and ClinicalTrials.gov were systematically searched from inception to May 2023. Study Selection: Studies on the association between antibiotic prophylaxis and infective endocarditis following invasive dental procedures or time-trend analyses of infective endocarditis incidence before and after current antibiotic prophylaxis guidelines were included. Data Extraction and Synthesis: Study quality was evaluated using structured tools. Data were extracted by independent observers. A pooled relative risk (RR) of developing infective endocarditis following invasive dental procedures in individuals who were receiving antibiotic prophylaxis vs those who were not was computed by random-effects meta-analysis. Main Outcomes and Measures The outcome of interest was the incidence of infective endocarditis following invasive dental procedures in relation to antibiotic prophylaxis. Results: Of 11 217 records identified, 30 were included (1 152 345 infective endocarditis cases). Of them, 8 (including 12 substudies) were either case-control/crossover or cohort studies or self-controlled case series, while 22 were time-trend studies; all were of good quality. Eight of the 12 substudies with case-control/crossover, cohort, or self-controlled case series designs performed a formal statistical analysis; 5 supported a protective role of antibiotic prophylaxis, especially among individuals at high risk, while 3 did not. By meta-analysis, antibiotic prophylaxis was associated with a significantly lower risk of infective endocarditis after invasive dental procedures in individuals at high risk (pooled RR, 0.41; 95% CI, 0.29-0.57; P for heterogeneity = .51; I2, 0%). Nineteen of the 22 time-trend studies performed a formal pre-post statistical analysis; 9 found no significant changes in infective endocarditis incidence, 7 demonstrated a significant increase for the overall population or subpopulations (individuals at high and moderate risk, streptococcus-infective endocarditis, and viridans group streptococci–infective endocarditis), whereas 3 found a significant decrease for the overall population and among oral streptococcus-infective endocarditis. Conclusions and Relevance: While results from time-trend studies were inconsistent, data from case-control/crossover, cohort, and self-controlled case series studies showed that use of antibiotic prophylaxis is associated with reduced risk of infective endocarditis following invasive dental procedures in individuals at high risk, while no association was proven for those at low/unknown risk, thereby supporting current American Heart Association and European Society of Cardiology recommendations. Currently, there is insufficient data to support any benefit of antibiotic prophylaxis in individuals at moderate risk