Longitudinal profiling identifies co-occurring BRCA1/2 reversions, TP53BP1, RIF1 and PAXIP1 mutations in PARP inhibitor-resistant advanced breast cancer.

Background: Resistance to therapies that target homologous recombination deficiency (HRD) in breast cancer limits their overall effectiveness. Multiple, preclinically validated, mechanisms of resistance have been proposed, but their existence and relative frequency in clinical disease are unclear, as is how to target resistance.

Patients And Methods: Longitudinal mutation and methylation profiling of circulating tumour (ct)DNA was carried out in 47 patients with metastatic BRCA1-, BRCA2- or PALB2-mutant breast cancer treated with HRD-targeted therapy who developed progressive disease-18 patients had primary resistance and 29 exhibited response followed by resistance.

Neonatal Brain Temperature Monitoring Based on Broadband Near-Infrared Spectroscopy.

We present here the initial development of a novel algorithm based on broadband near-infrared spectroscopy (bNIRS) data to estimate the changes in brain temperature (BT) in neonates. We first explored the validity of the methodology on a simple numerical phantom and reported good agreements between the theoretical and retrieved values of BT and hemodynamic parameters changes, which are the parameters usually targeted by bNIRS. However, we noted an underestimation of the absolute values of temperature and haemoglobins' concentration changes when large variations of tissue saturation were induced, probably due to a crosstalk between the species in this specific case.

Renal replacement and extracorporeal therapies in critical care: current and future directions.

There are a wide number of indications for extracorporeal therapies in the critical care environment. A common indication seen by the acute physician is continuous renal replacement therapy (CRRT) in a proportion of patients with acute kidney injury. It is therefore important that acute physicians have a sound understanding of the principles of CRRT in the acutely unwell patient.

The Extracellular Vesicle Citrullinome and Signature in a Piglet Model of Neonatal Seizures.

Neonatal seizures are commonly associated with acute perinatal brain injury, while understanding regarding the downstream molecular pathways related to seizures remains unclear. Furthermore, effective treatment and reliable biomarkers are still lacking. Post-translational modifications can contribute to changes in protein function, and post-translational citrullination, which is caused by modification of arginine to citrulline via the calcium-mediated activation of the peptidylarginine deiminase (PAD) enzyme family, is being increasingly linked to neurological injury.

Early assessment of injury with optical markers in a piglet model of neonatal encephalopathy.

Background: Opportunities for adjunct therapies with cooling in neonatal encephalopathy are imminent; however, robust biomarkers of early assessment are lacking. Using an optical platform of broadband near-infrared spectroscopy and diffuse correlation spectroscopy to directly measure mitochondrial metabolism (oxCCO), oxygenation (HbD), cerebral blood flow (CBF), we hypothesised optical indices early (1-h post insult) after hypoxia-ischaemia (HI) predicts insult severity and outcome.

Methods: Nineteen newborn large white piglets underwent continuous neuromonitoring as controls or following moderate or severe HI.

Systemic Therapy for Hereditary Breast Cancers.

Approximately 5% to 10% of all breast cancers are hereditary; many of which are caused by pathogenic variants in genes required for homologous recombination, including BRCA1 and BRCA2. Here we discuss systemic treatment for such breast cancers, including approved chemotherapeutic approaches and also targeted treatment approaches using poly-(ADP ribose) polymerase inhibitors. We also discuss experimental approaches to treating hereditary breast cancer, including new small molecule DNA repair inhibitors and also immunomodulatory agents.

Brain temperature monitoring in newborn infants: Current methodologies and prospects.

Brain tissue temperature is a dynamic balance between heat generation from metabolism, passive loss of energy to the environment, and thermoregulatory processes such as perfusion. Perinatal brain injuries, particularly neonatal encephalopathy, and seizures, have a significant impact on the metabolic and haemodynamic state of the developing brain, and thereby likely induce changes in brain temperature. In healthy newborn brains, brain temperature is higher than the core temperature.

Optical Monitoring in Neonatal Seizures.

Background: Neonatal seizures remain a significant cause of morbidity and mortality worldwide. The past decade has resulted in substantial progress in seizure detection and understanding the impact seizures have on the developing brain. Optical monitoring such as cerebral near-infrared spectroscopy (NIRS) and broadband NIRS can provide non-invasive continuous real-time monitoring of the changes in brain metabolism and haemodynamics.

Pandemic or Not, Worker Subjective Wellbeing Pivots About the Living Wage Point: A Replication, Extension, and Policy Challenge in Aotearoa New Zealand.

Recent pre-pandemic research suggests that living wages can be pivotal for enhancing employee attitudes and subjective wellbeing. This article explores whether or not the present COVID-19 pandemic is impacting pivotal links between living wages and employee attitudes and subjective wellbeing, with replication indicating robustness. Twin cohorts each of 1,000 low-waged workers across New Zealand (NZ), one pre- (2018), and one present-pandemic (2020) were sample surveyed on hourly wage, job attitudes, and subjective wellbeing as linked to changes in the world of work associated with the pandemic (e.

New Roles of Poly(ADP-Ribose) Polymerase Inhibitors in the Treatment of Breast Cancer.

Since the proof of concept of synthetic lethality between poly(ADP-ribose) polymerase inhibition and loss of BRCA1/2 homologous recombination (HR) function in preclinical models and early phase clinical trials, poly(ADP-ribose) polymerase inhibitors (PARPi) are increasing part of standard-of-care treatment for advanced breast cancers with BRCA gene mutations. The field has also recently seen benefits for PARPi in early breast cancer in those with germline BRCA1 and BRCA2 pathogenic mutations, and signals that synthetic lethal affects may occur in tumors with deficiencies in HR caused by germline, somatic, or epigenetic dysregulation of a number of HR genes. Despite the evidence of the synthetic lethal effects of PARPi, they are not always effective in HR defective cancers, and as they become part of standard of care in breast cancer, the study of prevalence of distinct mechanisms of resistance to PARPi and cross-resistance with other DNA-damaging agents such as platinum in breast cancer will be important and may inform therapy choices.

Real-world outcomes associated with new cancer medicines approved by the Food and Drug Administration and European Medicines Agency: A retrospective cohort study.

Purpose: Real-World Data (RWD) studies are increasingly used to support regulatory approvals, reimbursement decisions, and changes in clinical practice for novel cancer drugs. However, few studies have systematically appraised their quality or compared outcomes to pivotal trials.

Methods: All RWD studies (2010-2019) for drugs approved by the Food and Drug Administration (FDA) and European Medicines Agency (EMA) from 2010 to 2015 for solid organ tumours in the non-curative setting were identified.

Safety and immunogenicity of one versus two doses of the COVID-19 vaccine BNT162b2 for patients with cancer: interim analysis of a prospective observational study.

Background: The efficacy and safety profiles of vaccines against SARS-CoV-2 in patients with cancer is unknown. We aimed to assess the safety and immunogenicity of the BNT162b2 (Pfizer-BioNTech) vaccine in patients with cancer.

Methods: For this prospective observational study, we recruited patients with cancer and healthy controls (mostly health-care workers) from three London hospitals between Dec 8, 2020, and Feb 18, 2021.

Role of Optical Neuromonitoring in Neonatal Encephalopathy-Current State and Recent Advances.

Neonatal encephalopathy (NE) in term and near-term infants is a significant global health problem; the worldwide burden of disease remains high despite the introduction of therapeutic hypothermia. Assessment of injury severity and effective management in the neonatal intensive care unit (NICU) relies on multiple monitoring modalities from systemic to brain-specific. Current neuromonitoring tools provide information utilized for seizure management, injury stratification, and prognostication, whilst systemic monitoring ensures multi-organ dysfunction is recognized early and supported wherever needed.

The impact of national non-pharmaceutical interventions ('lockdowns') on the presentation of cancer patients.

One of the most ignored aspects of the COVID-19 pandemic has been the impact of public health measures by governments on wider health and welfare. From March 2020, hospitals in the UK saw a dramatic reduction in patients with cancer presenting due to multifactorial reasons. The impact of the pandemic on patients with cancer in the South East London Cancer Alliance was studied.

Mortality due to cancer treatment delay: systematic review and meta-analysis.

Objective: To quantify the association of cancer treatment delay and mortality for each four week increase in delay to inform cancer treatment pathways.

Design: Systematic review and meta-analysis.

Data Sources: Published studies in Medline from 1 January 2000 to 10 April 2020.

Comparing the Westmead Posttraumatic Amnesia Scale, Galveston Orientation and Amnesia Test, and Confusion Assessment Protocol as Measures of Acute Recovery Following Traumatic Brain Injury.

Background: The duration of the acute period of recovery following traumatic brain injury (TBI) remains a widely used criterion for injury severity and clinical management. Consensus regarding its most appropriate definition and assessment method has yet to be established.

Objective: The present study compared the trajectory of recovery using 3 measures: the Westmead Post-Traumatic Amnesia Scale (WPTAS), the Galveston Orientation and Amnesia Test (GOAT), and the Confusion Assessment Protocol (CAP).

Structural and functional brain abnormalities in children with schizotypal disorder: a pilot study.

Schizotypal disorder lies in the schizophrenia spectrum and is widely studied in adult populations. Schizotypal disorder in children (SDc) is less well described. This study examined brain morphological and functional connectivity abnormalities in SDc (12 SDc and 9 typically developing children), focusing on the default mode and executive control brain networks.

Attentional set-shifting and social abilities in children with schizotypal and comorbid autism spectrum disorders.

Objective: While diagnostically independent, autism and schizotypal disorders can co-occur. Their concurrent impact on outcomes and phenotypes has not been investigated. We investigated the impact of comorbid autism and schizotypal disorders in children on executive functioning and socio-pragmatic skills - core features of both disorders.

Safety and Efficacy of Pazopanib Therapy Prior to Planned Nephrectomy in Metastatic Clear Cell Renal Cancer.

Importance: The role of cytoreductive nephrectomy in patients with metastatic renal cancer in the era of targeted therapy is uncertain.

Objective: To establish the safety and efficacy of upfront pazopanib therapy prior to cytoreductive nephrectomy in previously untreated patients with metastatic clear cell renal cancer.

Design, Setting, And Participants: Single-arm phase 2 study of 104 previously untreated patients with metastatic clear cell renal cancer recruited between June 2008 and October 2012 at cancer treatment centers with access to nephrectomy services.

Early cranial ultrasound findings among infants with neonatal encephalopathy in Uganda: an observational study.

Background: In sub-Saharan Africa, the timing and nature of brain injury and their relation to mortality in neonatal encephalopathy (NE) are unknown. We evaluated cranial ultrasound (cUS) scans from term Ugandan infants with and without NE for evidence of brain injury.

Methods: Infants were recruited from a national referral hospital in Kampala.

Gamification of Learning Deactivates the Default Mode Network.

We hypothesized that embedding educational learning in a game would improve learning outcomes, with increased engagement and recruitment of cognitive resources evidenced by increased activation of working memory network (WMN) and deactivation of default mode network (DMN) regions. In an fMRI study, we compared activity during periods of learning in three conditions that were increasingly game-like: Study-only (when periods of learning were followed by an exemplar question together with its correct answer), Self-quizzing (when periods of learning were followed by a multiple choice question in return for a fixed number of points) and Game-based (when, following each period of learning, participants competed with a peer to answer the question for escalating, uncertain rewards). DMN hubs deactivated as conditions became more game-like, alongside greater self-reported engagement and, in the Game-based condition, higher learning scores.

The Melbourne assessment of Schizotypy in kids: a useful measure of childhood schizotypal personality disorder.

Despite being identified as a high risk cohort for psychosis, there has been relatively little research on the clinical presentation and assessment of Schizotypal Personality Disorder (SPD) in childhood. The current study aimed to develop a measure of childhood SPD (Melbourne Assessment of Schizotypy in Kids (MASK)) and assess discriminant validity against another neurodevelopmental disorder, autism spectrum disorder (ASD). Sixty-eight children aged between 5 and 12 (21 SPD, 15 ASD, and 32 typically developing) and their parents were administered the MASK.