Myelodysplastic Neoplasms (MDS) with Ring Sideroblasts or Mutations: The Improved Clinical Utility of World Health Organization and International Consensus Classification 2022 Definitions, a Single-Centre Retrospective Chart Review.

Myelodysplastic neoplasms (MDS) with ring sideroblasts (RS) are diagnosed via bone marrow aspiration in the presence of either (i) ≥15% RS or (ii) 5-14% RS and an mutation. In the MEDALIST trial and in an interim analysis of the COMMANDS trial, lower-risk MDS-RS patients had decreased transfusion dependency with luspatercept treatment. A total of 6817 patients with suspected hematologic malignancies underwent molecular testing using a next-generation-sequencing-based genetic assay and 395 MDS patients, seen at our centre from 1 January 2018 to 31 May 2023, were reviewed.

Double Duty: Complete Pathologic Response of Two Colonic Primaries with Mosaicism of a Novel Mutation to Neoadjuvant Pembrolizumab.

We present a fascinating case of a 57-year-old male with a novel mutation in MLH1 (), who presented with two synchronous colonic tumours, initially deemed unresectable, and experienced a complete pathological response on neoadjuvant pembrolizumab. Extensive genetic testing revealed post-zygotic mosaicism from the novel mutation.

Complexity in Genetic Epilepsies: A Comprehensive Review.

Epilepsy is a highly prevalent neurological disorder, affecting between 5-8 per 1000 individuals and is associated with a lifetime risk of up to 3%. In addition to high incidence, epilepsy is a highly heterogeneous disorder, with variation including, but not limited to the following: severity, age of onset, type of seizure, developmental delay, drug responsiveness, and other comorbidities. Variable phenotypes are reflected in a range of etiologies including genetic, infectious, metabolic, immune, acquired/structural (resulting from, for example, a severe head injury or stroke), or idiopathic.

A dedicated cytoplasmic container collects extrachromosomal DNA away from the mammalian nucleus.

Expression from transfected plasmid DNA is generally transient, but it is unclear what process terminates it. We show that DNA entering mammalian cells is rapidly surrounded by a double membrane in the cytoplasm, in some cases after leaving the nucleus. This cytoplasmic container, termed exclusome, frequently also contains extrachromosomal telomeric DNA, and is maintained by the cell over several division cycles.

Clinical validation of a single NGS targeted panel pipeline using the KAPA HyperChoice system for detection of germline, somatic and mitochondrial sequence and copy number variants.

Background: Comprehensive molecular diagnostics are highly dependent on the technical performance of next-generation sequencing (NGS) pipelines, which are assessed by data quality, cost, turnaround time, and accuracy of detecting a range of sequence and copy number variants.

Methods: A dataset of 285 clinically validated cases (205 retrospective and 80 prospective), carrying complex sequence and copy number variants and thousands of genetic polymorphisms underwent a clinical validation of the KAPA HyperChoice target enrichment system with parallel sample fidelity assessment across a number of NGS panels. The analysis included assessment of peripheral blood, urine, muscle and FFPE tissues.

Genotypic analysis of a large cohort of patients with suspected atypical hemolytic uremic syndrome.

Atypical hemolytic uremic syndrome (aHUS) is characterized by microangiopathic hemolytic anemia, thrombocytopenia, and renal impairment. Complement and coagulation gene variants have been associated with aHUS susceptibility. We assessed the diagnostic yield of a next-generation sequencing (NGS) panel in a large cohort of Canadian patients with suspected aHUS.

Evaluation of DNA Methylation Array for Glioma Tumor Profiling and Description of a Novel Epi-Signature to Distinguish IDH1/IDH2 Mutant and Wild-Type Tumors.

Unlabelled: Molecular biomarkers, such as mutations and 1p19q co-deletion, are included in the histopathological and clinical criteria currently used to diagnose and classify gliomas. mutation is a common feature of gliomas and is associated with a glioma-CpG island methylator phenotype (CIMP). Aberrant genomic methylation patterns can also be used to extrapolate information about copy number variation in a tumor.

The Indirect Effect of Peritraumatic Dissociation on the Relationship Between Childhood Maltreatment and Schizotypy.

Schizotypy is a multidimensional personality construct that is understood as a vulnerability for schizophrenia, often manifesting as more subtle and attenuated symptoms, referred to as schizotypic psychopathology. It has many well-established environmental risk factors, including experiencing childhood maltreatment (CM), but the intermediary mechanisms that relate CM to schizotypic psychopathology are unclear. Prior studies have demonstrated that trait dissociation may indirectly affect the relationship between CM and schizotypic psychopathology.

Selective Pharmaceutical Inhibition of PARP14 Mitigates Allergen-Induced IgE and Mucus Overproduction in a Mouse Model of Pulmonary Allergic Response.

The type 2 cytokines IL-4 and IL-13, which share use of an IL-4 receptor α-chain and its nuclear induction of the transcription factor STAT6, are crucial in elicitation and maintenance of allergic conditions including asthma. STAT6 binds poly(ADP-ribose) polymerase (PARP)14, an ADP-ribosyl monotransferase. Elimination of PARP14 by gene targeting led to attenuation of OVA-specific allergic lung inflammation.

Opioid-Free Anesthesia: Physico Chemical Stability Studies on Multi-Analyte Mixtures Intended for Use in Clinical Anesthesiology.

Opioid-free anesthesia is used increasingly often in hospitals around the world. In this type of anesthesia, opioids are replaced by other analgesics, such as ketamine, lidocaine, dexmedetomidine, and magnesium sulfate. Many clinicians prepare these agents as dual, triple, or quadruple admixtures within a single syringe.

Clinical Utility of Implementing a Frontline NGS-Based DNA and RNA Fusion Panel Test for Patients with Suspected Myeloid Malignancies.

Background: The use of molecular genetic biomarkers is rapidly advancing to aid diagnosis, prognosis, and clinical management of hematological disorders. We have implemented a next-generation sequencing (NGS) assay for detection of genetic variants and fusions as a frontline test for patients suspected with myeloid malignancy. In this study, we summarize the findings and assess the clinical impact in the first 1613 patients tested.

Theory of Mind and Alexithymia in Deaf and Hard-of-Hearing Young Adults.

The aim of the current study was to examine theory of mind (ToM), the ability to infer the mental states of others, in young adults who are deaf and hard-of-hearing (DHH), and to explore the influence of alexithymia, an inability to understand emotions of the self and others, on ToM performance in this group. Compared to participants with typical hearing, DHH participants displayed significantly lower affective ToM skills and greater alexithymia. After accounting for verbal intelligence quotient, hearing status and alexithymia significantly contributed to poorer ToM performance, accounting for over 14% of the variance.

Analysis of Sequence and Copy Number Variants in Canadian Patient Cohort With Familial Cancer Syndromes Using a Unique Next Generation Sequencing Based Approach.

Background: Hereditary cancer predisposition syndromes account for approximately 10% of cancer cases. Next generation sequencing (NGS) based multi-gene targeted panels is now a frontline approach to identify pathogenic mutations in cancer predisposition genes in high-risk families. Recent evolvement of NGS technologies have allowed simultaneous detection of sequence and copy number variants (CNVs) using a single platform.

Drugs in Pregnancy and Lactation - Medications used in Swiss Obstetrics.

Background: In order to improve the safety of drugs in pregnancy and lactation, it is imperative that data on clinical practice be collected and validated.

Methods: Data on routinely used medications were requested from 9 Swiss perinatal centres (5 university hospitals for obstetrics and 4 non-university centres). Furthermore, recommendations and guidelines from scientific societies for the fields of application were sought.

A potent and selective PARP14 inhibitor decreases protumor macrophage gene expression and elicits inflammatory responses in tumor explants.

PARP14 has been implicated by genetic knockout studies to promote protumor macrophage polarization and suppress the antitumor inflammatory response due to its role in modulating interleukin-4 (IL-4) and interferon-γ signaling pathways. Here, we describe structure-based design efforts leading to the discovery of a potent and highly selective PARP14 chemical probe. RBN012759 inhibits PARP14 with a biochemical half-maximal inhibitory concentration of 0.

Clinical epigenomics: genome-wide DNA methylation analysis for the diagnosis of Mendelian disorders.

Purpose: We describe the clinical implementation of genome-wide DNA methylation analysis in rare disorders across the EpiSign diagnostic laboratory network and the assessment of results and clinical impact in the first subjects tested.

Methods: We outline the logistics and data flow between an integrated network of clinical diagnostics laboratories in Europe, the United States, and Canada. We describe the clinical validation of EpiSign using 211 specimens and assess the test performance and diagnostic yield in the first 207 subjects tested involving two patient subgroups: the targeted cohort (subjects with previous ambiguous/inconclusive genetic findings including genetic variants of unknown clinical significance) and the screening cohort (subjects with clinical findings consistent with hereditary neurodevelopmental syndromes and no previous conclusive genetic findings).

DNA methylation epi-signature is associated with two molecularly and phenotypically distinct clinical subtypes of Phelan-McDermid syndrome.

Background: Phelan-McDermid syndrome is characterized by a range of neurodevelopmental phenotypes with incomplete penetrance and variable expressivity. It is caused by a variable size and breakpoint microdeletions in the distal long arm of chromosome 22, referred to as 22q13.3 deletion syndrome, including the SHANK3 gene.

Errors in identifying emotion in body postures and facial expressions among pediatric patients with bipolar disorder.

Introduction: Facial emotion processing impairments have been consistently demonstrated among patients with pediatric bipolar disorder (PBD). However, less is known about other domains of nonverbal emotion recognition in this group. Therefore, the aim of the current study was to investigate emotion identification for body postures in addition to facial expressions among PBD patients and matched healthy comparison (HC) subjects.

In Vitro and Cellular Probes to Study PARP Enzyme Target Engagement.

Poly(ADP-ribose) polymerase (PARP) enzymes use nicotinamide adenine dinucleotide (NAD) to modify up to seven different amino acids with a single mono(ADP-ribose) unit (MARylation deposited by PARP monoenzymes) or branched poly(ADP-ribose) polymers (PARylation deposited by PARP polyenzymes). To enable the development of tool compounds for PARP monoenzymes and polyenzymes, we have developed active site probes for use in in vitro and cellular biophysical assays to characterize active site-directed inhibitors that compete for NAD binding. These assays are agnostic of the protein substrate for each PARP, overcoming a general lack of knowledge around the substrates for these enzymes.

Attachment as a Moderator in the Relation Between Child Maltreatment and Symptoms of Depression.

Experiencing child maltreatment is a risk factor for later psychopathology; however, not all survivors of child maltreatment go on to develop mental health diagnoses. There are likely important risk factors that act as moderators interacting with child maltreatment to contribute to the development of psychopathology. The present study examined the attachment dimensions of anxiety and avoidance as potential moderators in the association between child maltreatment and depressive symptomatology in a sample of college students.

The effects of a staff-training program in behavior management and social-learning principles on staff-patient interactions within a psychiatric rehabilitation inpatient unit.

Despite the existence of effective behavioral interventions for people diagnosed with serious mental illness (SMI), these continue to be underutilized. Barriers to implementation include a low frequency of staff-patient interactions, as well as a lack of knowledge about, and negative attitudes toward, behavioral interventions. Therefore, we examined the effects of a mandatory behavioral staff-training program on staff-patient interactions on a long-term psychiatric inpatient program for individuals with SMI.