Development of a Second-Generation, Chemical Probe for PIKfyve.

We optimized our highly potent and cell-active chemical probe for phosphatidylinositol-3-phosphate 5-kinase (PIKfyve), SGC-PIKFYVE-1, resulting in compounds with improved potency and demonstrated stability. Use of an in-cell, kinome-wide selectivity panel allowed for confirmation of excellent in-cell selectivity of our lead compound, , and another promising analogue, . Evaluation of the pharmacokinetic (PK) profiles of these two compounds revealed that both are well tolerated systemically and orally bioavailable.

Diagnostic features of functional/ dissociative seizures in the first presentation of transient loss of consciousness.

Objectives: Previous studies have identified features in patient's history and seizure descriptions supporting a clinical diagnosis of functional / dissociative seizures (FDS). However, most studies involved patients with chronic seizure disorders. This study explores the value of reported features for a clinical diagnosis of FDS in an adult population with a first presentation of transient loss of consciousness (TLoC).

Targeting Oestrogen Receptor Signalling in Breast Cancer Therapy.

There has been over 130 years of research into the treatment of breast cancer using approaches that target oestrogen receptor signalling. Here, we summarise the development of the key pillars of such endocrine therapy, namely, oestrogen deprivation, achieved through ovarian suppression and/or aromatase inhibition, and oestrogen receptor blockade, through selective oestrogen receptor modulators, downregulators and novel compounds entering early phase development. The translation of these compounds from advanced to early breast cancer settings is discussed with a focus on the placebo-controlled breast cancer prevention studies to most accurately describe the side effect profiles of the main approaches.

Electrical Heterogeneity in Hispanic Background Subpopulations: The HCHS/SOL.

Background: The Hispanic/Latino population is not uniform. Prevalence and clinical outcomes of cardiac arrhythmias in ethnic background subgroups are variable, but the reasons for differences are unclear. Vectorcardiographic Global Electrical Heterogeneity (GEH) has been shown to be associated with adverse cardiovascular outcomes.

Development and Evaluation of a Remote Monitoring Regional Adjuvant Abemaciclib Service for Patients With High-Risk Early Breast Cancer.

Introduction: Adjuvant abemaciclib was recently approved in high-risk early breast cancer, leading to an increase in oncology resource utilisation. We thus developed a regional, remote monitoring clinical service. The set-up, delivery processes and outcomes from the first 6 months' consecutive patients are presented.

Medial Deviation of a 6° Prosthetic Trochlear Groove After Kinematically Aligned Total Knee Arthroplasty Occurs in Four Types of Coronal Plane Alignment of the Knee (CPAK) and Decreases the Forgotten Joint Score.

Background: The study focused on kinematically aligned total knee arthroplasty (KA TKA). It identified which coronal plane alignment of the knee (CPAK) types are associated with a higher proportion of medial deviation of the 6° prosthetic trochlear groove (PTG) relative to the quadriceps' line of pull and whether medial deviation adversely affected the Forgotten Joint Score (FJS). The research calculated the minimum PTG angle required to prevent medial deviation by at least 2° in all patients.

Neighborhood-level measures of socioeconomic status impact healthcare utilization and surgical outcomes in cervical spondylotic myelopathy patients in the Deep South.

Objective: The aim of this study was to evaluate the association of neighborhood-level and individual-level measures of socioeconomic status with readmission, complication rates, and postoperative length of stay of patients with cervical spondylotic myelopathy (CSM) in the Deep South.

Methods: The authors identified all patients undergoing surgical intervention for the treatment of CSM from November 2010 to February 2022 using Current Procedural Terminology and ICD-9/ICD-10 codes. Patient demographic, socioeconomic, perioperative, and postoperative data for each patient were collected via review of the electronic medical record.

In silico pace mapping identifies pacing sites more accurately than inverse body surface potential mapping.

Background: Electrocardiographic imaging (ECGi) is a noninvasive technique for ventricular tachycardia ablation planning. However, it is limited to reconstructing epicardial surface activation. In silico pace mapping combines a personalized computational model with clinical electrocardiograms (ECGs) to generate a virtual 3-dimensional pace map.

Polygenic score distribution differences across European ancestry populations: implications for breast cancer risk prediction.

Background: The 313-variant polygenic risk score (PRS) provides a promising tool for clinical breast cancer risk prediction. However, evaluation of the PRS across different European populations which could influence risk estimation has not been performed.

Methods: We explored the distribution of PRS across European populations using genotype data from 94,072 females without breast cancer diagnosis, of European-ancestry from 21 countries participating in the Breast Cancer Association Consortium (BCAC) and 223,316 females without breast cancer diagnosis from the UK Biobank.

A new tibial insert design with ball-in-socket medial conformity and posterior cruciate ligament retention has low tibial baseplate migration after unrestricted kinematically aligned total knee arthroplasty: a cohort study using radiostereometric analysis.

Background And Purpose:  In total knee arthroplasty (TKA), an insert with ball-in-socket (BS) medial conformity (MC) and posterior cruciate ligament (PCL) retention restores kinematics closer to native than an insert with intermediate (I) MC. However, high medial conformity might compromise baseplate stability as indicated by maximum total point motion (MTPM). Using the BS MC insert with PCL retention, we aimed to determine whether (i) the baseplate is stable as indicated by mean MTPM < 0.

Testosterone Effects on Short-Term Physical, Hormonal, and Neurodevelopmental Outcomes in Infants with 47,XXY/Klinefelter Syndrome: The TESTO Randomized Controlled Trial.

Context: 47,XXY/Klinefelter syndrome (XXY) is associated with impaired testicular function and differences in physical growth, metabolism, and neurodevelopment. Clinical features of XXY may be attributable to inadequate testosterone during the mini-puberty period of infancy.

Objective: We tested the hypothesis that exogenous testosterone treatment positively effects short-term physical, hormonal, and neurodevelopmental outcomes in infants with XXY.

Optimizing outcomes from cardiac resynchronization therapy: what do recent data and insights say?

Introduction: Cardiac Resynchronization Therapy (CRT) is an effective treatment for heart failure (HF) in approximately two-thirds of recipients, with a third remaining CRT 'non-responders.' There is an increasing body of evidence exploring the reasons behind non-response, as well as ways to preempt or counteract it.

Areas Covered: This review will examine the most recent evidence regarding optimizing outcomes from CRT, as well as explore whether traditional CRT indeed remains the best first-line therapy for electrical resynchronization in HF.

Long term follow-up of women treated for screen detected atypical ductal hyperplasia or lobular neoplasia in a large UK screening centre.

Background: Atypical ductal hyperplasia (ADH) and lobular neoplasia (LN) increase subsequent breast cancer (BC) risk. However, optimal surveillance and risk reduction regimes remain uncertain. We report management and outcomes of women with ADH and LN to provide data on potential screening/prevention strategies.

Integration of personalised ultrasensitive ctDNA monitoring of patients with metastatic breast cancer to reduce imaging requirements.

Circulating tumour DNA (ctDNA) is an emerging biomarker for monitoring cancers. The personalised disease monitoring in metastatic breast cancer (PDM-MBC) study is an ongoing study instigated to evaluate ctDNA as a biomarker to individualise imaging requirements in patients with MBC. Patients receiving first-line endocrine therapy (aromatase inhibitor + cyclin-dependent kinase 4/6 inhibitor) had plasma samples collected pre-treatment, weeks 2 and 4, and concurrently with imaging until progressive disease (PD).

Population-based germline testing of , and in breast cancer patients in the United Kingdom: Evidence to support extended testing, and definition of groups who may not require testing.

Purpose: To assess the contribution of germline pathogenic variants (PVs) in population-based series of breast cancers and the best strategy to improve detection rates.

Methods: Three cohort studies were utilized, including a hospital-based series identified from new UK mainstream testing criteria (group-1), offering testing to all women (group-2-BReast CAncer [BRCA]-DIRECT), and a Greater Manchester cohort study recruited from the mammography screening population (group-3-Predicting Risk of Cancer at Screening). DNA samples from women with breast cancer were sequenced for PVs in , , and Partner and Localiser of BRCA2 ().

Does the posterior tibial slope in caliper-verified unrestricted kinematically aligned TKA using manual instruments match the slope in the contralateral healthy knee and improve function?

Purpose: Unrestricted kinematically aligned total knee arthroplasty (unKA TKA) strives to restore the pre-arthritic posterior tibial slope (PTS), however consistency of achieving this alignment target is unknown. The present study determined the proportion of subjects with differences in PTS less than 2° from the target and the improvement in patient-reported function after unKA TKA.

Methods: A review of 562 postoperative scanograms identified 99 patients (51 female) with a unKA TKA in one limb, a contralateral healthy limb, and a postoperative axial CT scan.

Preclinical Development of Tuspetinib for the Treatment of Acute Myeloid Leukemia.

This article reports preclinical development of TUS, an oral kinase inhibitor currently in clinical development for treatment of AML. The article covers the studies of TUS activities on cellular targets and the nonclinical studies that supported the advancement of TUS to a phase I/II trial of TUS/VEN in refractory AML and a phase I/II trial of TUS/VEN/5-azacytidine in newly diagnosed patients with AML (NCT03850574).

Sex differences in the intention and decision to use emergency medical services for acute coronary syndrome in Australia: a retrospective study.

Background: Sex-based disparities in acute coronary syndrome (ACS) presentations exist and women often have worse outcomes after an ACS event. Calling the emergency medical services (EMS) initiates prehospital diagnosis and treatment and reduces in-hospital time to treatment. This study aims to identify factors affecting the intention to call EMS and EMS usage in Australian women and men.

Can we utilise the circadian clock to target cancer stem cells?

The 24-hourly circadian clock has been implicated in the regulation of multiple cancer hallmarks and characteristics. Cancer stem cells (CSCs) are a small but significant population of cells within many cancers, characterised by their self-renewal and clonogenic capacities. Increasing evidence points to CSCs having prominent roles in metastasis and drug resistance.

A Covalent Chemical Probe for nsP2 Cysteine Protease with Antialphaviral Activity and Proteome-wide Selectivity.

RA-0003022 () was identified as a high-quality covalent chemical probe for nsP2 cysteine protease (nsP2pro). Isoxazole covalently captured the active site C478 and inactivated the enzyme with a / ratio of 6000 Ms. A negative control analog RA-0025453 () retained the covalent warhead but demonstrated >100-fold decrease in enzyme inhibition.

Experiences of a Digital Behavior Change Intervention to Prevent Weight Gain and Promote Risk-Reducing Health Behaviors for Women Aged 18 to 35 Years at Increased Risk of Breast Cancer: Qualitative Interview Study.

Background: Breast cancer is the most common form of cancer in women. Adult weight gain and modifiable health behaviors, including smoking, alcohol intake, and lack of physical activity, are well-known risk factors. Most weight gain in women occurs between the ages of 18 and 35 years.

The need for rigour in consensus statements and guidelines.

Clinical guidelines and consensus statements are an essential aid to clinical practice. However, they bring with them risks. Amongst these are the exclusion of key stakeholders, the creation of mutual self-citation networks, and a lack of rigour in implementing and documenting the consensus process.