Analytical Validation of a 37-Gene Next-Generation Sequencing Panel for Myeloid Malignancies and Review of Initial Findings Incorporating Updated 2022 Diagnostic and Prognostic Guidelines.

Myeloid neoplasms are clonal disorders that arise via acquisition of genetic mutations leading to excessive proliferation and defective differentiation. Mutational profiling is vital as it has implications for diagnosis, prognosis, and therapeutic decision-making. Next-generation sequencing (NGS) has become a mainstay in the evaluation of myeloid malignancies, as it enables efficient characterization of multiple genetic changes. Herein, the analytical validation of the 37-gene Archer VariantPlex Core Myeloid panel is reported, using 58 DNA specimens with 87 single-nucleotide variants and 23 insertions/deletions. The panel achieved good depth of coverage, 100% analytical sensitivity and specificity for single-nucleotide variants and insertions/deletions ≤21 bp, and 100% reproducibility, with a reportable limit of detection determined as 5%. The Archer NGS panel can accurately and reproducibly detect variants of clinical significance in myeloid neoplasms. A retrospective analysis of 535 clinical specimens tested with the Archer NGS panel showed a frequency and pattern of mutations across myeloid malignancies that were similar to other published studies. A review of the diagnostic classification of patients with acute myeloid leukemia and myelodysplastic syndrome using the World Health Organization 2017/2022 and International Consensus Classification 2022 guidelines, in addition to European LeukemiaNet 2017/2022 risk stratification of patients with acute myeloid leukemia, was also performed to assess the utility of the molecular information provided by the Archer NGS panel.

Treatment of multiple synchronous canine mast cell tumours using intratumoural tigilanol tiglate.

Mast cell tumours (MCTs) are common canine skin neoplasia. While they generally occur as single tumours, multiple synchronous MCTs (msMCTs) of de novo/non-metastatic origin are reported in a proportion of the patient population. Where there is no evidence of metastasis or lymphatic spread, MCTs are effectively controlled by surgery and other local therapies. However, treatment of de novo msMCTs can be more challenging, especially when they occur in surgically difficult locations. Here, we report the use of tigilanol tiglate, a novel small molecule registered as a veterinary pharmaceutical for the local treatment of non-metastatic MCTs, in the treatment of patients with msMCTs presenting at three Australian specialist referral centres. We also present a meta-analysis of the literature to provide a better understanding of the prevalence of canine msMCTs. Notably, nine patients with a total of 32 MCTs were treated during the study. A complete response was recorded in 26 (81%) of the individual MCTs on Day 28 after a single tigilanol tiglate injection. Of the 6 initially non-responsive MCTs, one achieved a complete response after a further tigilanol tiglate treatment. A complete response was reported at 6 months in all 22 of the tumours that were evaluable and that had recorded a complete response at Day 84. For the literature meta-analysis, 22 studies were found with prevalence estimates of msMCTs ranging from 3 to 40%; when combined, these studies yielded 3,745 patients with a prevalence of 13% (95% CI 10; 16). Overall, the results demonstrate the utility of intratumoural tigilanol tiglate as an option for the treatment of multiple MCTs where multiple surgical resections would have been required.

Passing the Threshold of One Justice System to the Next: Challenges of Emerging Young Adults in Hong Kong's Adult Criminal Justice Process.

In many criminal justice systems, there is a clear separation for juvenile and adult defendants. However, those in between, referred to as emerging young adult defendants (ages 18-25 years), are treated as adult defendants despite a growing recognition that emerging adulthood is a distinct period in the life course. The aim of this present study is to investigate the experiences and challenges faced by emerging young adult defendants ( N = 25) in Hong Kong's adult criminal justice process. Through in-depth semistructured interviews, it was found that emerging young adult defendants demonstrated a lack of understanding regarding their rights and the legal procedures, faced stress in being caught up in the criminal justice process, and were susceptible to influence by others, particularly family members, in making legal decisions. Implications and future directions of study are discussed.

Cardiovascular risk profile in burn survivors.

OBJECTIVE: Burn patients have prolonged derangements in metabolic, endocrine, cardiac and psychosocial systems, potentially impacting on their cardiovascular health. There are no studies on the risk of cardiovascular disease (CVD) after-burn. The aim of our study was to record lipid values and evaluate CVD risk in adult burn survivors. METHODS: In a cross-sectional study patients ≥18 years with burn injury between 18-80% total burn surface area (TBSA) from 1998 to 2012 had total cholesterol, low density lipoprotein (LDL), high density lipoprotein (HDL) and triglycerides measured via finger prick. Means were compared to optimal ranges. Multivariate regression models were performed to assess the association of lipids with age, years after-burn and total body surface area % (TBSA). A p value <0.05 was considered significant. The Framingham General Cardiovascular Risk Score (FGCRS) was calculated. RESULTS: Fifty patients were included in the study. Compared to optimal values, patients had low HDL and high triglycerides. Greater %TBSA was associated with statistically significant elevation of triglycerides (p=0.007) and total cholesterol/HDL ratio (p=0.027). The median FGCRS was 3.9% (low) 10-year risk of CVD with 82% of patients in the low-risk category. Patients involved in medium/high level of physical activity had optimal values of HDL, TC/HDL and triglycerides despite the magnitude of TBSA%. CONCLUSION: Adult burn survivors had alterations in lipid profile proportional to TBSA, which could be modified by exercise, and no increase in overall formally predicted CVD risk in this cross sectional study.

Risks of gestational diabetes and preeclampsia over the last decade in a cohort of Alberta women.

OBJECTIVES: The incidence of gestational diabetes mellitus (GDM) is increasing. However, less is known about the incidence of preeclampsia (PE) and whether it is affected by the presence of GDM. We sought to document the population-level incidence of GDM and PE during the last decade and examine the association between GDM and PE after accounting for established risk factors. METHODS: We selected a population-based cohort retrospectively using data from the Alberta Perinatal Health Program registry. Logistic regression was used to examine the association between GDM and PE after adjusting for baseline characteristics. RESULTS: Of 426 296 deliveries between 2000 and 2009, 422 672 were in women without pre-existing diabetes. Among these women, the incidence of GDM increased from 3.1% in 2000 to 4.6% in 2009 (P < 0.01), while the incidence of PE remained stable at approximately 1.3% per year. The incidence of PE was significantly higher in women with GDM than in those without GDM (2.6% vs. 1.2%; P < 0.01). After adjustment, women with GDM had a 90% higher risk of PE than those without GDM (OR 1.9; 95% CI 1.7 to 2.1). Other significant risk factors for PE were age, obesity, nulliparity, multifetal gestation, pre-existing hypertension, and chronic kidney disease. CONCLUSION: In this contemporary population-based study spanning 10 years, there was a significant increase in the incidence of GDM over time. The higher incidence of PE in women with GDM than in normoglycemic women suggests a need for heightened surveillance and monitoring of women with GDM for the development of PE.

Objectifs : L'incidence du diabète sucré gestationnel (DSG) est en hausse. Toutefois, nous en savons moins pour ce qui est de l'incidence de la prééclampsie (PE) et de la question de savoir si cette dernière est affectée par la présence d'un DSG. Nous avons cherché à documenter l'incidence populationnelle du DSG et de la PE au cours de la dernière décennie, ainsi qu'à examiner l'association entre le DSG et la PE à la suite de la neutralisation de l'effet des facteurs de risque établis. Méthodes : Nous avons, de façon rétrospective, sélectionné une cohorte en population générale au moyen de données issues du registre du Alberta Perinatal Health Program. Une régression logistique a été utilisée pour examiner l'association entre le DSG et la PE, à la suite de la neutralisation de l'effet des caractéristiques de base. Résultats : Des 426 296 accouchements s'étant déroulés entre 2000 et 2009, 422 672 ont été constatés chez des femmes ne présentant pas un diabète préexistant. Chez ces femmes, l'incidence du DSG est passée de 3,1 % en 2000 à 4,6 % en 2009 (P < 0,01), tandis que l'incidence de la PE est demeurée stable à environ 1,3 % par année. L'incidence de la PE était considérablement plus élevée chez les femmes présentant un DSG que chez les femmes qui n'en présentaient pas un (2,6 % vs 1,2 %; P < 0,01). À la suite de la neutralisation, les femmes présentant un DSG connaissaient une hausse du risque de PE de l'ordre de 90 %, par comparaison avec les femmes ne présentant pas un DSG (RC 1,9; IC à 95 %, 1,7 - 2,1). Parmi les autres facteurs de risque significatifs en matière de PE, on trouvait l'âge, l'obésité, la nulliparité, la gestation multifœtale, l'hypertension préexistante et la maladie rénale chronique. Conclusion : Dans le cadre de cette étude contemporaine en population générale couvrant une période de 10 ans, nous avons constaté une hausse considérable de l'incidence du DSG avec le temps. L'incidence accrue de la PE chez les femmes présentant un DSG, par comparaison avec les femmes normoglycémiques, semble indiquer la nécessité d'intensifier la surveillance et le monitorage de l'apparition d'une PE chez les femmes qui présentent un DSG.

Incidence of heart failure and mortality after acute coronary syndromes.

BACKGROUND: The long-term incidence of heart failure (HF) in ST-elevation myocardial infarction (STEMI), non-ST-elevation myocardial infarction (NSTEMI), or unstable angina (UA) patients is uncertain. We examined the 1-year incidence of HF and its association with mortality among patients surviving their first acute coronary syndrome (ACS) hospitalization. METHODS AND RESULTS: A retrospective cohort study of patients, aged ≥20 years, with no prior HF, hospitalized for the first time with ACS between April 1, 2002, and December 31, 2008, in Alberta, Canada, and followed up for 1 year. Index HF was defined as HF that developed as a complication during the index ACS hospitalization, and post-discharge HF, as HF developing after discharge from the index ACS hospitalization. Among 9,406 STEMI, 11,008 NSTEMI, and 4,910 UA patients, 13.6%, 14.8%, and 5.2% had index HF, respectively (P < .01). At 1-year, cumulative HF rates were 23.4% in STEMI, 25.4% in NSTEMI, and 16% in UA patients. Among hospital survivors, 1-year mortality rate was 13.9% in patients with index HF, 10.6% in patients with postdischarge HF, and 2.4% in patients with no HF. In multivariable analysis, both index HF (adjusted hazard ratio 3.2, 95% CI 2.7-3.7) and postdischarge HF (adjusted hazard ratio 4.6, 95% CI 3.9-5.4) were associated with 1-year mortality. CONCLUSIONS: There are significant differences in the incidence of HF among STEMI, NSTEMI, and UA patients. The increased mortality risk associated with index HF and postdischarge HF suggests a need for vigilant follow-up of all ACS patients for prompt detection and treatment of HF.

Temporal trends in patient and treatment delay among men and women presenting with ST-elevation myocardial infarction.

BACKGROUND: over the last decade, there have been major changes in the treatment of ST-elevation myocardial infarction (STEMI). Whether these have resulted in changes in sex differences in time to treatment is unknown. We examined temporal trends in time to reperfusion therapy among men and women with STEMI. METHODS: the study includes 2 cohorts of STEMI patients presenting to a large metropolitan region during the periods August 24, 2000, to August 20, 2002 (Cohort1, n = 753), and August 25, 2006, to December 31, 2008 (Cohort2, n = 885). RESULTS: in both cohorts, compared with men, women were significantly older and had more comorbidities. Rate of emergency medical services use among women increased from 55% in Cohort1 to 66% in Cohort2 (P = .02). Median time from symptom onset to first medical contact was 84 minutes among men and 121 minutes among women (P < .01) in Cohort1 and 59 minutes among men and 81 minutes among women (P < .01) in Cohort2. Median door-to-balloon time was significantly longer among women compared with men in Cohort2. After multivariable adjustment, female sex was associated with a 34% (or 27-minute) increase in time from symptom onset to first medical contact and with a 23% (or 13-minute) increase in time from hospital arrival to reperfusion therapy. CONCLUSIONS: in the last decade, there have been significant reductions in patient and system delay, especially among women. However, women continue to have longer presentation and treatment times, suggesting that there continue to be opportunities for improvement.

Kinetic and thermodynamic assessment of binding of serotonin transporter inhibitors.

Several serotonin reuptake inhibitors are in clinical use for treatment of depression and anxiety disorders. However, to date, reported pharmacological differentiation of these ligands has focused mainly on their equilibrium binding affinities for the serotonin transporter. This study takes a new look at antidepressant binding modes using radioligand binding assays with [(3)H]S-citalopram to determine equilibrium and kinetic rate constants across multiple temperatures. The observed dissociation rate constants at 26 degrees C fall into a narrow range for all molecules. Conversely, association rate constants generally decreased with increasing equilibrium binding affinities. Consistent with this, the measured activation energy for S-citalopram association was relatively large (19.5 kcal . mol(-1)), suggesting conformational change upon ligand binding. For most of the drugs, including citalopram, the enthalpy (DeltaH(O)) and entropy (-TDeltaS(O)) contributions to reaction energetics were determined by van't Hoff analyses to be roughly equivalent (25-75% DeltaG(O)) and to correlate (positively for enthalpy) with the polar surface area of the drug. However, the binding of the drug fluvoxamine was predominantly entropically driven. When these data are considered in the context of the physicochemical properties of these ligands, two distinct binding modes can be proposed. The citalopram-type binding mode probably uses a polar binding pocket that allows charged or polar interactions between ligand and receptor with comparatively small loss in enthalpy due to dehydration. The fluvoxamine-type binding mode is fueled by energy released upon burying hydrophobic ligand moieties into a binding pocket that is flexible enough to suffer minimal loss in entropy from conformational constraint.