The Role of Cytotoxic Therapy with Hematopoietic Stem Cell Transplantation in the Therapy of Acute Lymphoblastic Leukemia in Adults: An Evidence-based Review

AbstractEvidence supporting the role of hematopoietic stem cell transplantation (SCT) in the therapy of acute lymphoblastic leukemia in adults (≥15 years) is presented and critically evaluated in this systematic evidence-based review. Specific criteria were used for searching the published medical literature and for grading the quality and strength of the evidence, and the strength of the treatment recommendations. Treatment recommendations based on the evidence are presented and were reached unanimously by a panel of acute lymphoblastic leukemia experts. The priority areas of needed future research for adult acute lymphoblastic leukemia are: definition of patients at high risk in first complete remission, beyond Philadelphia chromosome positive; outcomes of SCT in older (>50 years) adults; determination if reduced intensity versus myeloablative conditioning regimens yield an equivalent graft-versus-leukemia effect with reduced toxicity; monitoring of minimal residual disease to achieve disease control before SCT; and the use of cord blood and other alternative sources of stem cells for use in adult SCT recipients

Stellar Coronal and Wind Models: Impact on Exoplanets

Surface magnetism is believed to be the main driver of coronal heating and stellar wind acceleration. Coronae are believed to be formed by plasma confined in closed magnetic coronal loops of the stars, with winds mainly originating in open magnetic field line regions. In this Chapter, we review some basic properties of stellar coronae and winds and present some existing models. In the last part of this Chapter, we discuss the effects of coronal winds on exoplanets.Comment: Chapter published in the "Handbook of Exoplanets", Editors in Chief: Juan Antonio Belmonte and Hans Deeg, Section Editor: Nuccio Lanza. Springer Reference Work

Defining the genotypic and phenotypic spectrum of X-linked MSL3-related disorder

Purpose We sought to delineate the genotypic and phenotypic spectrum of female and male individuals with X-linked, MSL3-related disorder (Basilicata-Akhtar syndrome). Methods Twenty-five individuals (15 males, 10 females) with causative variants in MSL3 were ascertained through exome or genome sequencing at ten different sequencing centers. Results We identified multiple variant types in MSL3 (ten nonsense, six frameshift, four splice site, three missense, one in-frame-deletion, one multi-exon deletion), most proven to be de novo, and clustering in the terminal eight exons suggesting that truncating variants in the first five exons might be compensated by an alternative MSL3 transcript. Three-dimensional modeling of missense and splice variants indicated that these have a deleterious effect. The main clinical findings comprised developmental delay and intellectual disability ranging from mild to severe. Autism spectrum disorder, muscle tone abnormalities, and macrocephaly were common as well as hearing impairment and gastrointestinal problems. Hypoplasia of the cerebellar vermis emerged as a consistent magnetic resonance image (MRI) finding. Females and males were equally affected. Using facial analysis technology, a recognizable facial gestalt was determined. Conclusion Our aggregated data illustrate the genotypic and phenotypic spectrum of X-linked, MSL3-related disorder (Basilicata-Akhtar syndrome). Our cohort improves the understanding of disease related morbidity and allows us to propose detailed surveillance guidelines for affected individuals

Defining the genotypic and phenotypic spectrum of X-linked MSL3-related disorder

PURPOSE: We sought to delineate the genotypic and phenotypic spectrum of female and male individuals with X-linked, MSL3-related disorder (Basilicata-Akhtar syndrome). METHODS: Twenty-five individuals (15 males, 10 females) with causative variants in MSL3 were ascertained through exome or genome sequencing at ten different sequencing centers. RESULTS: We identified multiple variant types in MSL3 (ten nonsense, six frameshift, four splice site, three missense, one in-frame-deletion, one multi-exon deletion), most proven to be de novo, and clustering in the terminal eight exons suggesting that truncating variants in the first five exons might be compensated by an alternative MSL3 transcript. Three-dimensional modeling of missense and splice variants indicated that these have a deleterious effect. The main clinical findings comprised developmental delay and intellectual disability ranging from mild to severe. Autism spectrum disorder, muscle tone abnormalities, and macrocephaly were common as well as hearing impairment and gastrointestinal problems. Hypoplasia of the cerebellar vermis emerged as a consistent magnetic resonance image (MRI) finding. Females and males were equally affected. Using facial analysis technology, a recognizable facial gestalt was determined. CONCLUSION: Our aggregated data illustrate the genotypic and phenotypic spectrum of X-linked, MSL3-related disorder (Basilicata-Akhtar syndrome). Our cohort improves the understanding of disease related morbidity and allows us to propose detailed surveillance guidelines for affected individuals

Undisclosed Antiretroviral Drug Use in a Multinational Clinical Trial (HIV Prevention Trials Network 052)

The HIV Prevention Trials Network 052 study enrolled serodiscordant couples. Index participants infected with human immunodeficiency virus reported no prior antiretroviral (ARV) treatment at enrollment. ARV drug testing was performed retrospectively using enrollment samples from a subset of index participants. ARV drugs were detected in 45 of 96 participants (46.9%) with an undetectable viral load, 2 of 48 (4.2%) with a low viral load, and 1 of 65 (1.5%) with a high viral load (P < .0001); they were also detected in follow-up samples from participants who were not receiving study-administered treatment. ARV drug testing may be useful in addition to self-report of ARV drug use in some clinical trial settings

Distinct Salmonella Enteritidis lineages associated with enterocolitis in high-income settings and invasive disease in low-income settings.

An epidemiological paradox surrounds Salmonella enterica serovar Enteritidis. In high-income settings, it has been responsible for an epidemic of poultry-associated, self-limiting enterocolitis, whereas in sub-Saharan Africa it is a major cause of invasive nontyphoidal Salmonella disease, associated with high case fatality. By whole-genome sequence analysis of 675 isolates of S. Enteritidis from 45 countries, we show the existence of a global epidemic clade and two new clades of S. Enteritidis that are geographically restricted to distinct regions of Africa. The African isolates display genomic degradation, a novel prophage repertoire, and an expanded multidrug resistance plasmid. S. Enteritidis is a further example of a Salmonella serotype that displays niche plasticity, with distinct clades that enable it to become a prominent cause of gastroenteritis in association with the industrial production of eggs and of multidrug-resistant, bloodstream-invasive infection in Africa.This work was supported by the Wellcome Trust. We would like to thank the members of the Pathogen Informatics Team and the core sequencing teams at the Wellcome Trust Sanger Institute (Cambridge, UK). We are grateful to D. Harris for work in managing the sequence data

The Effect of Mindfulness-based Programs on Cognitive Function in Adults: A Systematic Review and Meta-analysis.

peer reviewedMindfulness-based programs (MBPs) are increasingly utilized to improve mental health. Interest in the putative effects of MBPs on cognitive function is also growing. This is the first meta-analysis of objective cognitive outcomes across multiple domains from randomized MBP studies of adults. Seven databases were systematically searched to January 2020. Fifty-six unique studies (n = 2,931) were included, of which 45 (n = 2,238) were synthesized using robust variance estimation meta-analysis. Meta-regression and subgroup analyses evaluated moderators. Pooling data across cognitive domains, the summary effect size for all studies favored MBPs over comparators and was small in magnitude (g = 0.15; [0.05, 0.24]). Across subgroup analyses of individual cognitive domains/subdomains, MBPs outperformed comparators for executive function (g = 0.15; [0.02, 0.27]) and working memory outcomes (g = 0.23; [0.11, 0.36]) only. Subgroup analyses identified significant effects for studies of non-clinical samples, as well as for adults aged over 60. Across all studies, MBPs outperformed inactive, but not active comparators. Limitations include the primarily unclear within-study risk of bias (only a minority of studies were considered low risk), and that statistical constraints rendered some p-values unreliable. Together, results partially corroborate the hypothesized link between mindfulness practices and cognitive performance. This review was registered with PROSPERO [CRD42018100904]

Evaluating the Effects of SARS-CoV-2 Spike Mutation D614G on Transmissibility and Pathogenicity.

Global dispersal and increasing frequency of the SARS-CoV-2 spike protein variant D614G are suggestive of a selective advantage but may also be due to a random founder effect. We investigate the hypothesis for positive selection of spike D614G in the United Kingdom using more than 25,000 whole genome SARS-CoV-2 sequences. Despite the availability of a large dataset, well represented by both spike 614 variants, not all approaches showed a conclusive signal of positive selection. Population genetic analysis indicates that 614G increases in frequency relative to 614D in a manner consistent with a selective advantage. We do not find any indication that patients infected with the spike 614G variant have higher COVID-19 mortality or clinical severity, but 614G is associated with higher viral load and younger age of patients. Significant differences in growth and size of 614G phylogenetic clusters indicate a need for continued study of this variant

Evaluating the Effects of SARS-CoV-2 Spike Mutation D614G on Transmissibility and Pathogenicity

Global dispersal and increasing frequency of the SARS-CoV-2 spike protein variant D614G are suggestive of a selective advantage but may also be due to a random founder effect. We investigate the hypothesis for positive selection of spike D614G in the United Kingdom using more than 25,000 whole genome SARS-CoV-2 sequences. Despite the availability of a large dataset, well represented by both spike 614 variants, not all approaches showed a conclusive signal of positive selection. Population genetic analysis indicates that 614G increases in frequency relative to 614D in a manner consistent with a selective advantage. We do not find any indication that patients infected with the spike 614G variant have higher COVID-19 mortality or clinical severity, but 614G is associated with higher viral load and younger age of patients. Significant differences in growth and size of 614G phylogenetic clusters indicate a need for continued study of this variant

Genomic epidemiology of SARS-CoV-2 in a UK university identifies dynamics of transmission

AbstractUnderstanding SARS-CoV-2 transmission in higher education settings is important to limit spread between students, and into at-risk populations. In this study, we sequenced 482 SARS-CoV-2 isolates from the University of Cambridge from 5 October to 6 December 2020. We perform a detailed phylogenetic comparison with 972 isolates from the surrounding community, complemented with epidemiological and contact tracing data, to determine transmission dynamics. We observe limited viral introductions into the university; the majority of student cases were linked to a single genetic cluster, likely following social gatherings at a venue outside the university. We identify considerable onward transmission associated with student accommodation and courses; this was effectively contained using local infection control measures and following a national lockdown. Transmission clusters were largely segregated within the university or the community. Our study highlights key determinants of SARS-CoV-2 transmission and effective interventions in a higher education setting that will inform public health policy during pandemics.</jats:p