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Passive antibodies, maternal or transfusion-acquired, make serologic determination of pretransplant cytomegalovirus (CMV) status unreliable. We evaluated 3 assays unaffected by passive antibodies, in assignment of CMV infection status in children awaiting solid organ transplant and in controls: (1) CMV nucleic acid amplification testing (NAAT), (2) quantification of CMV-specific CD4+ T cells, and (3) quantification of CD27-CD28-CD4+ T cells. Our results highlight that CMV NAAT, from urine and oropharynx, is useful in confirming positive CMV status. Detection of CMV-specific CD4+ T cells was sensitive and specific in children >18 months but was less sensitive in children <12 months. CD27-CD28-CD4+ T cells are not likely useful in CMV risk stratification in children.

Background: A classification scheme and general set of criteria for diagnosing mild cognitive impairment (MCI) were recently proposed by a multidisciplinary group of experts who met at an international symposium on MCI. One of the proposed criteria included preserved basic activities of daily living and minimal impairment in complex instrumental activities of daily living (IADLs). Objective: To investigate whether older adults with MCI classified according to the subtypes identified by the Working Group (i.e. amnestic, single non-memory domain, and multiple domain with or without a memory component) differed from cognitively intact older adults on a variety of measures indexing IADLs and to examine how well measures of IADL predict concurrent MCI status. Methods: Two hundred and fifty community-dwelling older adults, ranging in age from 66 to 92, completed self-report measures of IADLs (Lawton and Brody IADL Scale, Scales of Independent Behaviour-Revised – SIB-R) and a measure of everyday problem solving indexing IADLs (Everyday Problems Test – EPT). Ratings of participants’ IADL functioning were also obtained from informants (e.g. spouse, adult child and friend). Results: Older adults with multiple-domain MCI demonstrated poorer IADL functioning than older adults with no cognitive impairment on the EPT and the SIB-R (both self- and informant-report versions). The multiple-domain MCI participants also demonstrated poorer IADLs than MCI participants with impairments in a single cognitive domain on the self-reported SIB-R and EPT. The single-domain MCI groups demonstrated poorer IADLs than older adults without cognitive impairment on the informant-reported SIB-R and EPT. No significant group differences were found on the Lawton and Brody IADL Scale. Using the EPT and SIB-R as predictors in a multinomial regression analysis, MCI group status was reliably predicted, but the classification rate was poor. Conclusion: Individuals with MCI demonstrated poorer IADL functioning compared to cognitively intact older adults. However, the changes in IADL functioning observed in MCI may be too subtle to be detected by certain measures, such as the Lawton and Brody IADL Scale.

Background Group A streptococci (Strep A) or Streptococcus pyogenes is a major human pathogen causing an estimated 500,000 deaths worldwide each year. Disease can range from mild pharyngitis to more severe infections, such as necrotizing fasciitis, septicemia, and toxic shock syndrome. Untreated, Strep A infection can lead to the serious post streptococcal pathologies of rheumatic fever/rheumatic heart disease and post-streptococcal glomerulonephritis. An effective vaccine against Strep A would have great benefits worldwide. Here, we test two products, J8 and p*17—both peptide derivatives of a highly conserved region in the M protein, in combination with the protein subunit K4S2 of SpyCEP, an IL-8 protease associated with neutrophil chemoattraction. Each peptide is individually conjugated to cross reacting material (CRM 197 ), and the conjugated peptide vaccines are abbreviated as J8-K4S2 or p*17-K4S2. Methods This single-site phase I, two-stage clinical trial in Edmonton, Alberta, Canada, aims to recruit a total of 30 healthy volunteers, aged 18–45 years, without any evidence of pre-existing valvular heart disease. The trial is divided into the initial unblinded safety test dose stage (stage 1) and the randomized, double-blinded, controlled trial stage (stage 2). Stage 1 will recruit 10 volunteers—5 each to receive either J8-K4S2 or p*17-K4S2 in an unblinded, staggered fashion, whereby volunteers are dosed with intentional spacing of at least 2 days in between doses to monitor for any immediate side effects before dosing the next. Once all 5 volunteers have received 3 doses of the first test vaccine, a similar process will follow for the second test vaccine. Once safety is established in stage 1, we will proceed to stage 2, which will recruit 20 volunteers to our 3-arm randomized controlled trial (RCT), receiving either of the trial vaccines, J8-K4S2 or p*17-K4S2, or comparator (rabies) vaccine. All product dosing will be at 0, 3, and 6 weeks. The primary outcome is vaccine safety; the secondary outcome is immunogenicity and comparative analyses of the different vaccine regimens. Discussion This Strep A vaccine clinical trial aims to investigate safety and immunogenicity of two novel conjugated peptide-based vaccines, J8-KS42 and p*17-K4S2. If one or both vaccine products demonstrate favorable primary and secondary outcomes, the product(s) will move into phase II and III studies. Trial registration ClinicalTrials.gov Identifier: NCT04882514. Registered on 2021–05-12, https://clinicaltrials.gov/study/NCT04882514 .

With the recent tragedy at Sandy Hook Elementary in Newtown, CT, the public and the government are looking for solutions to school violence. The National Rifle Association (NRA), a Second Amendment, pro-gun advocacy group, has proposed an “education and training emergency response program” called The National School Shield , which advocates the placement of armed security in schools. Although the program sounds provocative, serious questions complicate its plausibility, necessity, motive, and effectiveness. Furthermore, the potential policy and practical ramifications of encouraging armed security forces in U.S. schools are complex. The authors examined the proposal’s key elements from a public policy perspective and determined that the NRA program would be expensive in terms of both implementation and civil and/or criminal liability, would increase juvenile contact with the criminal justice system, would increase the potential for injuries and deaths from firearms, and would potentially only serve to increase profits for those invested in security industries. More potentially effective and safe policy alternatives are offered.

PurposeThe transition from school to higher education is a complex process. Peer mentoring is often used by institutions to facilitate this process. The purpose of this research, which was conducted at a South African university, was to determine whether a peer mentoring programme, which involved a large number of students and a limited number of mentors, could successfully assist students to adapt to the academic and psychosocial demands of university life.Design/methodology/approachA sequential explanatory mixed method design was implemented. In the first phase, a questionnaire was used to collect data to establish participants' experience of the programme. The findings from the questionnaire were used to inform the qualitative phase, in which the participants' perceptions of the benefits of the mentor programme were further explored by means of group interviews. The qualitative data were analysed using inductive qualitative content analysis.FindingsThe results indicate that a structured peer mentoring programme, in which a mentor works with up to 70 mentees in a group setting, can be a useful tool to assist with students' transition to university. The research found that the peer mentoring programme contributed to the students' academic, social and personal integration into the higher education environment.Research limitations/implicationsThe perspectives of mentors and faculty were not included. No comparative study with students who did not participate in the programme was conducted.Practical implicationsThis research illustrates that it is possible to mentor large groups of disadvantaged and vulnerable students notwithstanding limited resources.Originality/valueIn contrast to the existing literature on peer mentoring in higher education, which focuses on one-on-one or small-group mentoring, this research suggests that peer mentoring of larger groups can also play an important role in assisting students to transition to higher education. The description of the programme and the benefits students derived from it offer other institutions with limited resources some ideas about how a peer mentoring programme can be implemented.

In this case-based Learning Forum, Burton takes clinicians through the key steps in diagnosing and managing this patient.

Biologically distinct subtypes of diffuse large B-cell lymphoma can be identified using gene-expression analysis to determine their cell of origin, corresponding to germinal centre or activated B cell. We aimed to investigate whether adding bortezomib to standard therapy could improve outcomes in patients with these subtypes. In a randomised evaluation of molecular guided therapy for diffuse large B-cell lymphoma with bortezomib (REMoDL-B), an open-label, adaptive, randomised controlled, phase 3 superiority trial, participants were recruited from 107 cancer centres in the UK (n=94) and Switzerland (n=13). Eligible patients had previously untreated, histologically confirmed diffuse large B-cell lymphoma with sufficient diagnostic material from initial biopsies for gene-expression profiling and pathology review; were aged 18 years or older; had ECOG performance status of 2 or less; had bulky stage I or stage II–IV disease requiring full-course chemotherapy; had measurable disease; and had cardiac, lung, renal, and liver function sufficient to tolerate chemotherapy. Patients initially received one 21-day cycle of standard rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisolone (R-CHOP; rituximab 375 mg/m2, cyclophosphamide 750 mg/m2, doxorubicin 50 mg/m2, and vincristine 1·4 mg/m2 [to a maximum of 2 mg total dose] intravenously on day 1 of the cycle, and prednisolone 100 mg orally once daily on days 1–5). During this time, we did gene-expression profiling using whole genome cDNA-mediated annealing, selection, extension, and ligation assay of tissue from routine diagnostic biopsy samples to determine the cell-of-origin subtype of each participant (germinal centre B cell, activated B cell, or unclassified). Patients were then centrally randomly assigned (1:1) via a web-based system, with block randomisation stratified by international prognostic index score and cell-of-origin subtype, to continue R-CHOP alone (R-CHOP group; control), or with bortezomib (RB-CHOP group; experimental; 1·3 mg/m2 intravenously or 1·6 mg/m2 subcutaneously) on days 1 and 8 for cycles two to six. If RNA extracted from the diagnostic tissues was of insufficient quality or quantity, participants were given R-CHOP as per the control group. The primary endpoint was 30-month progression-free survival, for the germinal centre and activated B-cell population. The primary analysis was on the modified intention-to-treat population of activated and germinal centre B-cell population. Safety was assessed in all participants who were given at least one dose of study drug. We report the progression-free survival and safety outcomes for patients in the follow-up phase after the required number of events occurred. This study was registered at ClinicalTrials.gov, number NCT01324596, and recruitment and treatment has completed for all participants, with long-term follow-up ongoing. Between June 2, 2011, and June 10, 2015, 1128 eligible patients were registered, of whom 918 (81%) were randomly assigned to receive treatment (n=459 to R-CHOP, n=459 to RB-CHOP), comprising 244 (26·6%) with activated B-cell disease, 475 (51·7%) with germinal centre B cell disease, and 199 (21·7%) with unclassified disease. At a median follow-up of 29·7 months (95% CI 29·0–32·0), we saw no evidence for a difference in progression-free survival in the combined germinal centre and activated B-cell population between R-CHOP and RB-CHOP (30-month progression-free survival 70·1%, 95% CI 65·0–74·7 vs 74·3%, 69·3–78·7; hazard ratio 0·86, 95% CI 0·65–1·13; p=0·28). The most common grade 3 or worse adverse event was haematological toxicity, reported in 178 (39·8%) of 447 patients given R-CHOP and 187 (42·1%) of 444 given RB-CHOP. However, RB-CHOP was not associated with increased haematological toxicity and 398 [87·1%] of 459 participants assigned to receive RB-CHOP completed six cycles of treatment. Grade 3 or worse neuropathy occurred in 17 (3·8%) patients given RB-CHOP versus eight (1·8%) given R-CHOP. Serious adverse events occurred in 190 (42·5%) patients given R-CHOP, including five treatment-related deaths, and 223 (50·2%) given RB-CHOP, including four treatment-related deaths. This is the first large-scale study in diffuse large B-cell lymphoma to use real-time molecular characterisation for prospective stratification, randomisation, and subsequent analysis of biologically distinct subgroups of patients. The addition of bortezomib did not improve progression-free survival. Janssen-Cilag, Bloodwise, and Cancer Research UK.

This qualitative narrative inquiry study explored students’ perceptions of intervention strategies used in the early alert program at an Arkansas two-year college. The problem addressed in this study was that student perceptions do not inform early alert program designs. By assessing the student’s perceptions of intervention strategies, improvements can be made to the effectiveness of the method of intentional support through these intervention strategies. The guiding theoretical framework that served as the basis for this study was Tinto’s (1993) theory of student integration. Interviews were conducted with current college students attending a public, two-year college in Arkansas to collect student perceptions regarding early alert intervention strategies used by the college. The seven participants in the study were derived, using stratified purposeful sampling, from a candidate pool list of 30 students that matched the overall demographics of the college’s early alert program. Questions were asked regarding the forms of intervention strategies experienced by the student, the impact and effectiveness of those strategies, and the associated perceptions and personal motivations that resulted from involvement in the early alert program. Data analysis consisted of a thematic analysis technique to organize the data into codes and themes. The following five themes were identified during the study: (a) positive perception of student support; (b) intervention strategies provided an avenue to seek help; (c) successful interventions offered an invitation to participate, support, or guidance; (d) personal and family motivation was considered a priority; and (e) text messaging was effective and preferred. The implications of this study show a preference for text messaging, a positive response to targeted outreach from the college, and a value for personal and family motivation. Recommendations for practice include utilizing a broad variety of intervention strategies, incorporating personal and family motivation, and striving to build personal connections within early alert program design. Future research should further explore student perceptions within specific demographic categories, explore the potential impact of personal and family motivation in early alert program design, and examine the relationship between preferred outreach, such as text messaging, and making personal connections.

Using a Burkitt lymphoma-like gene expression signature, we recently defined a high-risk molecular high-grade (MHG) group mainly within germinal centre B-cell like diffuse large B-cell lymphomas (GCB-DLBCL), which was enriched for MYC/BCL2 double-hit (MYC/BCL2-DH). The genetic basis underlying MHG-DLBCL and their aggressive clinical behaviour remain unknown. We investigated 697 cases of DLBCL, particularly those with MYC/BCL2-DH (n = 62) by targeted sequencing and gene expression profiling. We showed that DLBCL with MYC/BCL2-DH, and those with BCL2 translocation, harbour the characteristic mutation signatures that are associated with follicular lymphoma and its high-grade transformation. We identified frequent MYC hotspot mutations that affect the phosphorylation site (T58) and its adjacent amino acids, which are important for MYC protein degradation. These MYC mutations were seen in a subset of cases with MYC translocation, but predominantly in those of MHG. The mutations were more frequent in double-hit lymphomas with IG as the MYC translocation partner, and were associated with higher MYC protein expression and poor patient survival. DLBCL with MYC/BCL2-DH and those with BCL2 translocation alone are most likely derived from follicular lymphoma or its precursor lesion, and acquisition of MYC pathogenic mutations may augment MYC function, resulting in aggressive clinical behaviour.

MYC translocation occurs in 8–14% of diffuse large B-cell lymphoma (DLBCL), and may concur with BCL2 and/or BCL6 translocation, known as double-hit (DH) or triple-hit (TH). DLBCL- MYC / BCL2 -DH/TH are largely germinal centre B-cell like subtype, but show variable clinical outcome, with IG :: MYC fusion significantly associated with inferior survival. While DLBCL- MYC / BCL6 -DH are variable in their cell-of-origin subtypes and clinical outcome. Intriguingly, only 40-50% of DLBCL with MYC translocation show high MYC protein expression (>70%). We studied 186 DLBCLs with MYC translocation including 32 MYC/BCL2/BCL6 -TH , 75 MYC/BCL2 -DH and 26 MYC/BCL6 -DH. FISH revealed a MYC / BCL6 fusion in 59% of DLBCL- MYC/BCL2/BCL6 -TH and 27% of DLBCL- MYC / BCL6 -DH. Targeted NGS showed a similar mutation profile and LymphGen genetic subtype between DLBCL- MYC/BCL2/BCL6 -TH and DLBCL- MYC/BCL2 -DH, but variable LymphGen subtypes among DLBCL- MYC / BCL6 -DH. MYC protein expression is uniformly high in DLBCL with IG::MYC , but variable in those with non- IG::MYC including MYC / BCL6 -fusion. Translocation breakpoint analyses of 8 cases by TLC-based NGS showed no obvious genomic configuration that enables MYC transactivation in 3 of the 4 cases with non- IG: : MYC , while a typical promoter substitution or IGH super enhancer juxtaposition in the remaining cases. The findings potentially explain variable MYC expression in DLBCL with MYC translocation, and also bear practical implications in its routine assessment.