Safer and targeted use of antipsychotics in youth: an embedded, pragmatic randomized trial.

Background: Antipsychotic medications (AP) are inappropriately prescribed to young people. The goal of this pragmatic trial was to test a four-component approach to improved targeting of antipsychotic prescribing to people aged ≥3 and <18 years.

Methods: Clinicians in four health systems were cluster randomized by the number of previous AP orders and service line - specialty mental health and all others.

Observations from a national sample exchange program for molecular haematology testing.

External quality assessment programs (EQAP) for molecular haematology generally only assess the analytical phase of laboratory testing or provide limited evaluation of post-analytical components. We incorporated comprehensive post-analytical evaluation into an existing national inter-laboratory sample exchange program for molecular haematology due to the increasing complexity of diagnostic molecular testing and interpretation. We report key findings from four years of longitudinal data using this approach.

Cost Effectiveness of Molecular Diagnostic Testing Algorithms for the Treatment Selection of Frontline Ibrutinib for Patients with Chronic Lymphocytic Leukemia in Australia.

Background: Clinical indications for ibrutinib reimbursement in Australia should consider the inclusion of patients with chronic lymphocytic leukemia (CLL) harboring prognostically unfavorable TP53/IGHV genomic aberrations. This study assessed the cost effectiveness of five first-line treatment strategies in CLL for young (aged ≤ 65 years), fit patients without significant comorbidities: (1) no testing (fludarabine, cyclophosphamide and rituximab [FCR] for all), (2) test for del(17p) only, (3) test for TP53 gene mutation status, (4) test for TP53 and IGHV gene mutation status and (5) no testing (ibrutinib for all).

Method: A decision analytic model (decision tree and partitioned survival model) was developed from the Australian healthcare system perspective with a lifetime horizon.

Patient Pathway to Diagnosis of Myelin Oligodendrocyte Glycoprotein Antibody-Associated Disease (MOGAD): Findings from a Multinational Survey of 204 Patients.

Introduction: Myelin oligodendrocyte glycoprotein antibody-associated disease (MOGAD) is a rare demyelinating disorder of the central nervous system. Despite increased recognition of MOGAD as a distinct disease and the availability of sensitive methods of MOG antibody testing, diagnostic challenges remain. We conducted a survey to explore the patient experience from the start of symptoms to final MOGAD diagnosis.

A patient-centered nurse-supported primary care-based collaborative care program to treat opioid use disorder and depression: Design and protocol for the MI-CARE randomized controlled trial.

Background: Opioid use disorder (OUD) contributes to rising morbidity and mortality. Life-saving OUD treatments can be provided in primary care but most patients with OUD don't receive treatment. Comorbid depression and other conditions complicate OUD management, especially in primary care.

Acquired mutations in BAX confer resistance to BH3-mimetic therapy in acute myeloid leukemia.

Randomized trials in acute myeloid leukemia (AML) have demonstrated improved survival by the BCL-2 inhibitor venetoclax combined with azacitidine in older patients, and clinical trials are actively exploring the role of venetoclax in combination with intensive chemotherapy in fitter patients with AML. As most patients still develop recurrent disease, improved understanding of relapse mechanisms is needed. We find that 17% of patients relapsing after venetoclax-based therapy for AML have acquired inactivating missense or frameshift/nonsense mutations in the apoptosis effector gene BAX.

Clinically relevant variation in FLT3-ITD quantitation as a result of PCR cycle number and ITD insertion size.

FLT3 internal tandem duplication (ITD) quantitation is key to prognostication in acute myeloid leukaemia (AML). One potential source of variability in the allelic ratio (AR) is the number of polymerase chain reaction (PCR) cycles used. Using 30 archived samples of varying ITD lengths and AR, we compared two FLT3-ITD assays (Huang and RATIFY), evaluated the effect of PCR cycle number on each assay, and examined the potential clinical consequences.

SOHO State of the Art Updates and Next Questions | Mechanisms of Resistance to BCL2 Inhibitor Therapy in Chronic Lymphocytic Leukemia and Potential Future Therapeutic Directions.

Chronic lymphocytic leukaemia (CLL) constitutively overexpresses B-cell lymphoma 2 (BCL2) with consequent dysregulation of intrinsic apoptosis leading to abnormal cellular survival. Therapeutic use of BCL2 inhibitors (BCL2i, eg, venetoclax) in CLL, as both continuous monotherapy or in fixed duration combination, has translated scientific rationale into clinical benefit with significant rates of complete responses, including those without detectable minimal residual disease. Unlike with chemotherapy, response rates to venetoclax do not appear to be influenced by pre-existing chromosomal abnormalities or somatic mutations present, although the duration of response observed remains shorter for those with traditional higher risk genetic aberrations.

Decision-making among adolescents prescribed antipsychotic medications: Interviews to gain perspectives of youth without psychosis or mania.

Objectives: This study aimed to understand the experiences of youth who had been prescribed antipsychotics but did not have psychosis, mania, autism spectrum disorder, or developmental disability.

Methods: Twenty-three qualitative telephone interviews were conducted with youth aged 11-18 who had been prescribed an antipsychotic medication but did not have a diagnosis of psychotic disorder, bipolar disorder, autism spectrum disorder, or developmental disability. Participants were recruited from four U.

Development of a machine learning model to predict mild cognitive impairment using natural language processing in the absence of screening.

Background: Patients and their loved ones often report symptoms or complaints of cognitive decline that clinicians note in free clinical text, but no structured screening or diagnostic data are recorded. These symptoms/complaints may be signals that predict who will go on to be diagnosed with mild cognitive impairment (MCI) and ultimately develop Alzheimer's Disease or related dementias. Our objective was to develop a natural language processing system and prediction model for identification of MCI from clinical text in the absence of screening or other structured diagnostic information.

Health economic evidence for the use of molecular biomarker tests in hematological malignancies: A systematic review.

Objectives: Molecular biomarker tests can inform the clinical management of genomic heterogeneous hematological malignancies, yet their availability in routine care largely depends on the supporting health economic evidence. This study aims to systematically review the economic evidence for recent molecular biomarker tests in hematological malignancies.

Methods: We conducted a systematic search in five electronic databases for studies published between January 2010 and October 2020.

What Are We Missing?: Evaluating an Intimate Partner Violence Screening Program in a Pediatric Emergency Department.

Objectives: Our study sought to explore and assess pediatric emergency department (ED) health care providers' knowledge, attitudes, and behaviors surrounding an existing intimate partner violence (IPV) screening program 4 years after initial implementation.

Methods: We used anonymous electronic surveys and telephone interviews to obtain provider perspectives using a mixed-methods analysis. We used χ2 tests to analyze the quantitative survey results, and an unstructured qualitative approach to analyze the telephone interviews.

Integration of tumour sequencing and case-control data to assess pathogenicity of RAD51C missense variants in familial breast cancer.

While protein-truncating variants in RAD51C have been shown to predispose to triple-negative (TN) breast cancer (BC) and ovarian cancer, little is known about the pathogenicity of missense (MS) variants. The frequency of rare RAD51C MS variants was assessed in the BEACCON study of 5734 familial BC cases and 14,382 population controls, and findings were integrated with tumour sequencing data from 21 cases carrying a candidate variant. Collectively, a significant enrichment of rare MS variants was detected in cases (MAF < 0.

Single-cell sequencing demonstrates complex resistance landscape in CLL and MCL treated with BTK and BCL2 inhibitors.

The genomic landscape of resistance to targeted agents (TAs) used as monotherapy in chronic lymphocytic leukemia (CLL) is complex and often heterogeneous at the patient level. To gain insight into the clonal architecture of acquired genomic resistance to Bruton tyrosine kinase (BTK) inhibitors and B-cell lymphoma 2 (BCL2) inhibitors in CLL, particularly in patients carrying multiple resistance mutations, we performed targeted single-cell DNA sequencing of 8 patients who developed progressive disease (PD) on TAs (either class). In all cases, analysis of single-cell architecture revealed mutual exclusivity between multiple resistance mutations to the same TA class, variable clonal co-occurrence of multiple mutations affecting different TAs in patients exposed to both classes, and a phenomenon of multiple independent emergences of identical nucleotide changes leading to canonical resistance mutations.

Design and methods of a randomized trial testing the novel Wellness Intervention for Smokers Living with HIV (WISH).

Smoking rates are disproportionately high among people living with HIV. Smokers living with HIV (SLWH) are also largely unaware of the HIV-specific deleterious effects of smoking and often lack motivation and confidence in their ability to quit tobacco. To address these issues, we developed the Wellness Intervention for Smokers Living with HIV (WISH).

An Update on the Current Genomic Landscape of Breast Implant-Associated Anaplastic Large Cell Lymphoma.

Breast implant-associated lymphoma (BIA-ALCL) is a rare subtype of anaplastic large-cell lymphoma associated with breast prostheses. Most patients present with a localised periprosthetic effusion and are managed with removal of the implant and surrounding capsule. Less commonly, the lymphoma can form a mass associated with the capsule and rarely can present with disseminated disease.

Outcomes of patients with CLL sequentially resistant to both BCL2 and BTK inhibition.

Covalent Bruton tyrosine kinase inhibitors (BTKi's) and the B-cell lymphoma 2 (BCL2) inhibitor venetoclax have significantly improved outcomes for patients with chronic lymphocytic leukemia (CLL), especially those with biologically adverse disease. Patients with CLL resistant to their first targeted agent (TA) can be effectively treated with the alternative class. However, relapses are expected with second-line TA therapy, and the clinical challenge of double class-resistant disease is now emerging with increasing frequency.

Clonal hematopoiesis, myeloid disorders and BAX-mutated myelopoiesis in patients receiving venetoclax for CLL.

The BCL2 inhibitor venetoclax has established therapeutic roles in chronic lymphocytic leukemia (CLL) and acute myeloid leukemia (AML). As BCL2 is an important determinant of survival of both myeloid progenitor and B cells, we investigated whether clinical and molecular abnormalities arise in the myeloid compartment during long-term continuous venetoclax treatment of CLL in 89 patients (87 with relapsed/refractory CLL). Over a median follow-up of 75 (range 21-98) months, persistent cytopenias (≥1 of neutropenia, thrombocytopenia, anemia) lasting ≥4 months and unrelated to CLL occurred in 25 patients (28%).