Venous thromboembolism in multiple myeloma: Increasing evidence in support of direct oral anticoagulants.

Venous thromboembolism (VTE) continues to cause significant morbidity and excess mortality in patients with multiple myeloma. The report by Costa and colleagues demonstrates superiority of direct oral anticoagulants over aspirin in terms of VTE prevention, without increased bleeding complications seen. Commentary on: Costa et al. Direct oral anticoagulants versus aspirin for primary thromboprophylaxis in patients with multiple myeloma undergoing outpatient therapy: A systematic review and updated meta-analysis. Br J Haematol 2023;203:395-403.

CyBorD-DARA in Newly Diagnosed Transplant-Eligible Multiple Myeloma: Results from the 16-BCNI-001/CTRIAL-IE 16-02 Study Show High Rates of MRD Negativity at End of Treatment.

The phase 1b 16-BCNI-001/CTRIAL-IE 16-02 CyBorD-DARA trial investigated the combination of Daratumumab with cyclophosphamide, bortezomib and dexamethasone in patients with newly diagnosed multiple myeloma (NDMM), followed by autologous stem cell transplantation and Daratumumab maintenance. CR/sCR rates were 50% after transplant and 62.5% at end of treatment. The overall percentage of patients achieving complete response or better was 77.8%. Progression-free survival rate at end of maintenance was 81.3% and estimated 2-year overall survival was 88.9%. 37.5% of patients demonstrated sustained MRD negativity to a level of 10-5 from transplant to analysis at EOT. In this phase 1b study, we have shown CyBorD-DARA to be an effective and well-tolerated immunomodulatory agent-free regiment in transplant-eligible NDMM.

Vaccine-induced thrombosis and thrombocytopenia (VITT) in Ireland: A review of cases and current practices.

Since the beginning of the Severe Acute Respiratory Syndrome Coronavirus-2 (SARS CoV-2) virus pandemic, several highly effective and safe vaccines have been produced at remarkable speed. Following global implementation of vaccination programmes, cases of thrombosis with thrombocytopenia following administration of adenoviral vector-based vaccines started being reported. In this review we discuss the known pathogenesis and epidemiology of so-called vaccine induced thrombocytopenia and thrombosis (VITT). We consider the available guidelines, diagnostic laboratory tests and management options for these patients. Finally, we discuss important unanswered questions and areas for future research in this novel pathoclinical entity.

Coupled virus - bacteria interactions and ecosystem function in an engineered microbial system.

Viruses are thought to control bacterial abundance, affect community composition and influence ecosystem function in natural environments. Yet their dynamics have seldom been studied in engineered systems, or indeed in any system, for long periods of time. We measured virus abundance in a full-scale activated sludge plant every week for two years. Total bacteria and ammonia oxidising bacteria (AOB) abundances, bacterial community profiles, and a suite of environmental and operational parameters were also monitored. Mixed liquor virus abundance fluctuated over an order of magnitude (3.18 × 108-3.41 × 109 virus's mL-1) and that variation was statistically significantly associated with total bacterial and AOB abundance, community composition, and effluent concentrations of COD and NH4+- N and thus system function. This suggests viruses play a far more important role in the dynamics of activated sludge systems than previously realised and could be one of the key factors controlling bacterial abundance, community structure and functional stability and may cause reactors to fail. These findings are based on statistical associations, not mechanistic models. Nevertheless, viral associations with abiotic factors, such as pH, make physical sense, giving credence to these findings and highlighting the role that physical factors play in virus ecology. Further work is needed to identify and quantify specific bacteriophage and their hosts to enable us to develop mechanistic models of the ecology of viruses in wastewater treatment systems. However, since we have shown that viruses can be related to effluent quality and virus quantification is simple and cheap, practitioners would probably benefit from quantifying viruses now.

Cutaneous Vasculitis: An Unusual Presentation of a Biclonal Nodal Plasma Cell Dyscrasia.

We describe an unusual case of a biclonal nodal plasma cell dyscrasia, presenting with a vasculitic rash, end-organ damage, and cytopenias. Serum protein electrophoresis demonstrated a biclonal kappa-restricted paraprotein, with a negative skeletal survey and no bone marrow disease. Fluorodeoxyglucose-PET-CT (FDG-PET-CT) revealed nodal involvement, which was not appreciable clinically, and facilitated biopsy, confirming the diagnosis of a nodal plasmacytoma. Complete biochemical response and resolution of the vasculitic rash were achieved with bortezomib-based therapy.

Development and implementation of a 'Mental Health Finder' software tool within an electronic medical record system.

BACKGROUND: In Ireland, as in many other healthcare systems, mental health service provision is being reconfigured with a move toward more care in the community, and particularly primary care. Recording and surveillance systems for mental health information and activities in primary care are needed for service planning and quality improvement. AIMS: We describe the development and initial implementation of a software tool ('mental health finder') within a widely used primary care electronic medical record system (EMR) in Ireland to enable large-scale data collection on the epidemiology and management of mental health and substance use problems among patients attending general practice. METHODS: In collaboration with the Irish Primary Care Research Network (IPCRN), we developed the 'Mental Health Finder' as a software plug-in to a commonly used primary care EMR system to facilitate data collection on mental health diagnoses and pharmacological treatments among patients. The finder searches for and identifies patients based on diagnostic coding and/or prescribed medicines. It was initially implemented among a convenience sample of six GP practices. RESULTS: Prevalence of mental health and substance use problems across the six practices, as identified by the finder, was 9.4% (range 6.9-12.7%). 61.9% of identified patients were female; 25.8% were private patients. One-third (33.4%) of identified patients were prescribed more than one class of psychotropic medication. Of the patients identified by the finder, 89.9% were identifiable via prescribing data, 23.7% via diagnostic coding. CONCLUSIONS: The finder is a feasible and promising methodology for large-scale data collection on mental health problems in primary care.

Treatment of moderate-to-severe atopic eczema in adults within the U.K.: results of a national survey of dermatologists.

BACKGROUND: Little is known about U.K. dermatologists' treatment approaches towards adult patients with recalcitrant moderate-to-severe atopic eczema. OBJECTIVES: We wanted to learn about (i) treatment approaches used for this disease in the U.K.; (ii) factors that influence treatment decisions and (iii) perceived gaps in evidence on treatment safety and efficacy, and priorities for future trials. METHODS: We conducted an online survey of consultant-level dermatologists in the U.K. RESULTS: Sixty-one respondents from over 30 centres reported on management of moderate-to-severe atopic eczema in adults, outwith the context of an acute flare. Phototherapy or psoralen-ultraviolet A was the most common therapeutic modality chosen first line (46%), and this was usually narrowband ultraviolet B. Systemic therapy was chosen as a first-line approach by 36% of dermatologists. Azathioprine was the commonest drug reported being used as first line followed by oral corticosteroids, ciclosporin and methotrexate. Methotrexate was the most common second-line treatment of respondents. The key factors that influenced decision making on the use of phototherapy and systemic agents were the respondent's clinical experience, results of baseline tests (systemic agents) and knowledge of both efficacy and acute and chronic side-effect profiles. The most important evidence gaps identified were the relative effectiveness of treatments, the alternatives to current approaches and the safety of long-term maintenance treatment. With regard to future trials, respondents suggested that priority should be given to studies involving methotrexate. CONCLUSIONS: While survey study designs have limitations, we found that phototherapy, in particular narrowband ultraviolet B, was respondents' preferred first-line treatment for adults with recalcitrant moderate-to-severe atopic eczema, perhaps reflecting access to, and clinical experience of, this approach. Azathioprine is widely used as a longer-term maintenance treatment.

Tolerogenic dendritic cells generated with dexamethasone and vitamin D3 regulate rheumatoid arthritis CD4+ T cells partly via transforming growth factor-ß1.

Tolerogenic dendritic cells (tolDC) are a new immunotherapeutic tool for the treatment of rheumatoid arthritis (RA) and other autoimmune disorders. We have established a method to generate stable tolDC by pharmacological modulation of human monocyte-derived DC. These tolDC exert potent pro-tolerogenic actions on CD4+ T cells. Lack of interleukin (IL)-12p70 production is a key immunoregulatory attribute of tolDC but does not explain their action fully. Here we show that tolDC express transforming growth factor (TGF)-ß1 at both mRNA and protein levels, and that expression of this immunoregulatory cytokine is significantly higher in tolDC than in mature monocyte-derived DC. By inhibiting TGF-ß1 signalling we demonstrate that tolDC regulate CD4+ T cell responses in a manner that is at least partly dependent upon this cytokine. Crucially, we also show that while there is no significant difference in expression of TGF-ßRII on CD4+ T cells from RA patients and healthy controls, RA patient CD4+ T cells are measurably less responsive to TGF-ß1 than healthy control CD4+ T cells [reduced TGF-ß-induced mothers against decapentaplegic homologue (Smad)2/3 phosphorylation, forkhead box protein 3 (FoxP3) expression and suppression of (IFN)-γ secretion]. However, CD4+ T cells from RA patients can, nonetheless, be regulated efficiently by tolDC in a TGF-ß1-dependent manner. This work is important for the design and development of future studies investigating the potential use of tolDC as a novel immunotherapy for the treatment of RA.

Monogamy, the Protective Fallacy: Sexual versus Emotional Exclusivity and the Implication for Sexual Health Risk.

The authors examined the hypothesis that many individuals define monogamy based on emotional rather than sexual fidelity. Participants, 373 heterosexual college students and 282 gay men, read three vignettes of decreasing mitigation in which they imagined committing an act of infidelity against a hypothetical partner and where half the participants were cued to their emotional attachment toward the partner. Despite the infidelity, relationships in the emotional attachment-cued vignettes were rated as monogamous to a greater degree than relationships in the vignettes where emotional attachment was not cued. In addition, over one-third of the participants in our study reported infidelity in their current self-defined monogamous relationships yet also reported feeling more protected from sexual health risks and reported less condom use than individuals who defined their relationship as nonmonogamous. The implications for monogamy as a protective fallacy are discussed.

How social context impacts on the development, identification and treatment of mental and substance use disorders among young people - a qualitative study of health care workers.

Introduction Social context has a major influence on the detection and treatment of youth mental and substance use disorders in socioeconomically disadvantaged urban areas, particularly where gang culture, community violence, normalisation of drug use and repetitive maladaptive family structures prevail. This paper aims to examine how social context influences the development, identification and treatment of youth mental and substance use disorders in socioeconomically disadvantaged urban areas from the perspectives of health care workers. METHOD: Semi-structured interviews were conducted with health care workers (n=37) from clinical settings including: primary care, secondary care and community agencies and analysed thematically using Bronfenbrenner's Ecological Theory to guide analysis. RESULTS: Health care workers' engagement with young people was influenced by the multilevel ecological systems within the individual's social context which included: the young person's immediate environment/'microsystem' (e.g., family relationships), personal relationships in the 'mesosystem' (e.g., peer and school relationships), external factors in the young person's local area context/'exosystem' (e.g., drug culture and criminality) and wider societal aspects in the 'macrosystem' (e.g., mental health policy, health care inequalities and stigma). CONCLUSIONS: In socioeconomically disadvantaged urban areas, social context, specifically the micro-, meso-, exo-, and macro-system impact both on the young person's experience of mental health or substance use problems and services, which endeavour to address these problems. Interventions that effectively identify and treat these problems should reflect the additional challenges posed by such settings.

Development and evaluation of an educational intervention in youth mental health for primary care practitioners.

OBJECTIVES: Irish adolescents have one of the highest rates of suicide and self-harm in the European Union. Although primary care has been identified as an opportune environment in which to detect and treat mental health problems in adolescents, lack of training among primary care professionals (PCPs) is a barrier to optimum identification and treatment. We describe the development and evaluation of an educational intervention on youth mental health and substance misuse for PCPs. METHODS: Thirty general practitioners and other PCPs working in the Mid-West region participated in an educational session on youth-friendly consultations, and identification and treatment of mental ill-health and substance use. Learning objectives were addressed through a presentation, video demonstration, small group discussions, role play, question-and-answer sessions with clinical experts, and an information pack. Following the session, participants completed an evaluation form assessing knowledge gain and usefulness of different components of the session. RESULTS: A total of 71% of participants were involved in the provision of care to young people and 55% had no previous training in youth mental health or substance abuse. Participants rated knowledge gains as highest with regard to understanding the importance of early intervention, and primary care, in youth mental health. The components rated as most useful were case studies/small group discussion, the 'question-and-answer session' with clinical experts, and peer interaction. CONCLUSIONS: The educational session outlined in this pilot was feasible and acceptable and may represent an effective way to train professionals to help tackle the current crisis in youth mental health.

Agreement between amoA gene-specific quantitative PCR and fluorescence in situ hybridization in the measurement of ammonia-oxidizing bacteria in activated sludge.

Microbial abundance is central to most investigations in microbial ecology, and its accurate measurement is a challenging task that has been significantly facilitated by the advent of molecular techniques over the last 20 years. Fluorescence in situ hybridization (FISH) is considered the gold standard of quantification techniques; however, it is expensive and offers low sample throughput, both of which limit its wider application. Quantitative PCR (qPCR) is an alternative that offers significantly higher throughput, and it is used extensively in molecular biology. The accuracy of qPCR can be compromised by biases in the DNA extraction and amplification steps. In this study, we compared the accuracy of these two established quantification techniques to measure the abundance of a key functional group in biological wastewater treatment systems, the ammonia-oxidizing bacteria (AOB), in samples from a time-series experiment monitoring a set of laboratory-scale reactors and a full-scale plant. For the qPCR analysis, we tested two different sets of AOB-specific primers, one targeting the 16SrRNA gene and one targeting the ammonia monooxygenase (amoA) gene. We found that there was a positive linear logarithmic relationship between FISH and the amoA gene-specific qPCR, where the data obtained from both techniques was equivalent at the order of magnitude level. The 16S rRNA gene-specific qPCR assay consistently underestimated AOB numbers.

Associations between maternal prepregnancy body mass index and child neurodevelopment at 2 years of age.

OBJECTIVE: Both underweight and obese mothers have an increased risk for adverse offspring outcomes. Few studies have examined the association between prepregnancy body mass index (BMI) and children's neurodevelopment. SUBJECTS: We used data from the nationally representative Early Childhood Longitudinal Study-Birth Cohort (ECLS-B; n=6850). Children were classified according to their mother's prepregnancy BMI (kg m(-2)) status: underweight (BMI <18.5), normal weight (BMI 18.5-24.9), overweight (BMI 25.0-29.9), obese class I (BMI 30.0-34.9), and obese class II and III (BMI ≥35.0). Children's age-adjusted mental development index (MDI) and psychomotor development index (PDI) T-scores (mean 50, s.d. 10) were obtained using a validated shortened version of the Bayley Scales of Infant Development-II at approximately 2 years of age. While adjusting for sociodemographics, we estimated the average MDI and PDI scores or the risk of delayed (<-1 s.d. vs >1 s.d.) mental or motor development, relative to children of normal weight mothers. RESULTS: Compared with children of normal weight mothers, MDI scores were lower among children of mothers of all other prepregnancy BMI categories, with the greatest adjusted difference among children of class II and III obese mothers (-2.13 (95% CI -3.32, -0.93)). The adjusted risk of delayed mental development was increased among children of underweight (risk ratio (RR) 1.36 (95% CI 1.04, 1.78)) and class II and III obese (RR 1.38 (95% CI 1.03, 1.84)) mothers. Children's PDI scores or motor delay did not differ by maternal prepregnancy BMI. CONCLUSION: In this nationally representative sample of 2-year-old US children, low and very-high maternal prepregnancy BMI were associated with increased risk of delayed mental development but not motor development.

Identification of the pathogenic pathways in osteoarthritic hip cartilage: commonality and discord between hip and knee OA.

OBJECTIVE: To define for the first time the transcriptomes of normal and end-stage osteoarthritis (OA) hip cartilage. MATERIALS AND METHODS: RNA was isolated from cartilage within 2h of joint replacement surgery. Gene expression was analyzed using Agilent GeneSpring GX 11 following hybridization to Illumina Human HT-12 V3 microarrays. Real-time reverse-transcription polymerase chain reaction (RT-PCR) was used to validate the expression of six genes identified by microarray as differentially expressed. Gene Set Enrichment Analysis (GSEA) and Ingenuity Pathway Analysis (IPA) were used to investigate enriched functions or canonical pathways amongst differentially expressed genes respectively. RESULTS: In total we identified 998 differentially expressed genes (fold change ≥ ±1.5, P-value ≤ 0.01) between neck of femur fracture (NOF) (n = 10) and OA hip (n = 9) patient cartilage. These differentially expressed genes were enriched within 71 canonical pathways. A comparison between a comparable knee dataset(20) only identified 229 genes similarly differentially expressed although remarkably 34 canonical pathways overlapped between experiments. CONCLUSIONS: This study is the first to report a comprehensive gene expression analysis of human hip OA cartilage compared to control (NOF) cartilage at the whole-genome level. Our differential gene expression dataset shows excellent correlation with similar defined studies using comparable tissue but reveals discord between hip and knee OA at the individual gene status but with commonality with regards the molecular pathways involved.

Smoking patterns, attitudes and motives: unique characteristics among 2-year versus 4-year college students.

Given the previously documented higher rates of smoking among 2-year college students in comparison with 4-year university students, this study compares smoking patterns, attitudes and motives among 2-year and 4-year college students. Two thousand two hundred and sixty-five undergraduate students aged 18-25 years at a 2-year college and a 4-year university completed an online survey in 2008. Current (past 30-day) smoking was reported by 43.5% of 2-year and 31.9% of 4-year college students, and daily smoking was reported by 19.9% of 2-year and 8.3% of 4-year college students. Attending a 2-year college was associated with higher rates of current smoking [odds ratio (OR) = 1.72] and daily smoking (OR = 2.84), and with less negative attitudes regarding smoking, controlling for age, gender, ethnicity and parental education. Also, compared with 4-year college student smokers, 2-year college smokers had lower motivation to smoke for social reasons, but more motivation to smoke for affect regulation, after controlling for age, gender, ethnicity and parental education. Two- and 4-year college students report different smoking patterns, attitudes and motives. These distinctions might inform tobacco control messages and interventions targeting these groups of young adults.

Pattern recognition receptor expression is not impaired in patients with chronic mucocutanous candidiasis with or without autoimmune polyendocrinopathy candidiasis ectodermal dystrophy.

Patients with chronic mucocutaneous candidiasis (CMC) have an unknown primary immune defect and are unable to clear infections with the yeast Candida. CMC includes patients with AIRE gene mutations who have autoimmune polyendocrinopathy candidiasis ectodermal dystrophy (APECED), and patients without known mutations. CMC patients have dysregulated cytokine production, suggesting that defective expression of pattern recognition receptors (PRRs) may underlie disease pathogenesis. In 29 patients with CMC (13 with APECED) and controls, we assessed dendritic cell (DC) subsets and monocyte Toll-like receptor (TLR) expression in blood. We generated and stimulated monocyte-derived (mo)DCs with Candida albicans, TLR-2/6 ligand and lipopolysaccharide and assessed PRR mRNA expression by polymerase chain reaction [TLR-1-10, Dectin-1 and -2, spleen tyrosine kinase (Syk) and caspase recruitment domain (CARD) 9] in immature and mature moDCs. We demonstrate for the first time that CMC patients, with or without APECED, have normal blood levels of plasmocytoid and myeloid DCs and monocyte TLR-2/TLR-6 expression. We showed that in immature moDCs, expression levels of all PRRs involved in anti-Candida responses (TLR-1, -2, -4, -6, Dectin-1, Syk, CARD9) were comparable to controls, implying that defects in PRR expression are not responsible for the increased susceptibility to Candida infections seen in CMC patients. However, as opposed to healthy controls, both groups of CMC patients failed to down-regulate PRR mRNA expression in response to Candida, consistent with defective DC maturation, as we reported recently. Thus, impaired DC maturation and consequent altered regulation of PRR signalling pathways rather than defects in PRR expression may be responsible for inadequate Candida handling in CMC patients.

Comparative genome hybridization of Streptococcus mutans strains.

The basis for genotypic and phenotypic variation within Streptococcus mutans is poorly understood but the availability of the genome sequence of strain UA159 provides an opportunity for comparative studies. Genomic DNA prepared from nine strains of S. mutans was used to probe a microarray consisting of oligonucleotides representing 1948 open reading frames of S. mutans UA159. A total of 385 (20%) of the UA159 open reading frames were found to be absent from one or more of the test strains. Absent open reading frames frequently occurred in blocks of adjacent open reading frames and represented regions previously experimentally detected by polymerase chain reaction, predicted genomic islands and insertion sequence elements as well as novel open reading frames. Approximately half appear to involve foreign DNA acquired by horizontal transmission. The results indicate the existence of distinct core and dispensable genomes and may help explain the phenotypic and genotypic variation within S. mutans.

The EIF2AK3 gene region and type I diabetes in subjects from South India.

Mutations in the EIF2AK3 gene underlie susceptibility to the Wolcott-Rallison syndrome, which is a monogenic disease associated with insulin-deficient neonatal diabetes. Furthermore, suggestive evidence of linkage between type 1 diabetes (T1DM) and the EIF2KA3 chromosomal region has been reported in Scandinavian families. We have investigated the hypothesis that polymorphic variants in and around the EIF2AK3 gene might partially account for susceptibility to T1DM in South Indian subjects. Excess transmission of the common alleles of two polymorphic markers (D2S1786 and 15INDEL, located within the gene) downstream of EIF2AK3, either singly (D2S1786, P = 0.01) and 15INDEL (P = 0.02) or as a combination (P < 0.001), were found in 234 families with a T1DM proband. There was also a clear paternal effect for the 15INDEL marker (P = 0.005) on disease susceptibility. The presence of the common allele of both markers was found in decreased frequency in the subjects with normal glucose tolerance compared to probands with T1DM (both P