The GBA variant E326K is associated with alpha-synuclein aggregation and lipid droplet accumulation in human cell lines.

Sequence variants or mutations in the GBA gene are numerically the most important risk factor for Parkinson disease (PD). The GBA gene encodes for the lysosomal hydrolase enzyme, glucocerebrosidase (GCase). GBA mutations often reduce GCase activity and lead to the impairment of the autophagy-lysosomal pathway, which is important in the turnover of alpha-synuclein, accumulation of which is a key pathological hallmark of PD. Although the E326K variant is one of the most common GBA variants associated with PD, there is limited understanding of its biochemical effects. We have characterized homozygous and heterozygous E326K variants in human fibroblasts. We found that E326K variants did not cause a significant loss of GCase protein or activity, endoplasmic reticulum (ER) retention or ER stress, in contrast to the L444P GBA mutation. This was confirmed in human dopaminergic SH-SY5Y neuroblastoma cell lines overexpressing GCase with either E326K or L444P protein. Despite no loss of the GCase activity, a significant increase in insoluble alpha-synuclein aggregates in E326K and L444P mutants was observed. Notably, SH-SY5Y overexpressing E326K demonstrated a significant increase in the lipid droplet number under basal conditions, which was exacerbated following treatment with the fatty acid oleic acid. Similarly, a significant increase in lipid droplet formation following lipid loading was observed in heterozygous and homozygous E326K fibroblasts. In conclusion, the work presented here demonstrates that the E326K mutation behaves differently to the common loss of function GBA mutations; however, lipid dyshomeostasis and alpha-synuclein pathology are still evident.

Antigen stasis and airway nitrosative stress in human primary ciliary dyskinesia.

Nasal nitric oxide (nNO) is low in most patients with primary ciliary dyskinesia (PCD). Decreased ciliary motion could lead to antigen stasis, increasing oxidant production and NO oxidation in the airways. This could both decrease gas phase NO and increase nitrosative stress. We studied primary airway epithelial cells from healthy controls (HCs) and patients with PCD with several different genotypes. We measured antigen clearance in fenestrated membranes exposed apically to the fluorescently labeled antigen Dermatophagoides pteronyssinus (Derp1-f). We immunoblotted for 3-nitrotyrosine (3-NT) and for oxidative response enzymes. We measured headspace NO above primary airway cells without and with a PCD-causing genotype. We measured nNO and exhaled breath condensate (EBC) H2O2 in vivo. Apical Derp1-f was cleared from HC better than from PCD cells. DUOX1 expression was lower in HC than in PCD cells at baseline and after 24-h Derp1-f exposure. HC cells had less 3-NT and NO3- than PCD cells. However, NO consumption by HC cells was less than that by PCD cells; NO loss was prevented by superoxide dismutase (SOD) and by apocynin. nNO was higher in HCs than in patients with PCD. EBC H2O2 was lower in HC than in patients with PCD. The PCD airway epithelium does not optimally clear antigens and is subject to oxidative and nitrosative stress. Oxidation associated with antigen stasis could represent a therapeutic target in PCD, one with convenient monitoring biomarkers.NEW & NOTEWORTHY The PCD airway epithelium does not optimally clear antigens, and antigen exposure can lead to NO oxidation and nitrosative stress. Oxidation caused by antigen stasis could represent a therapeutic target in PCD, and there are convenient monitoring biomarkers.

Resting-state EEG signatures of Alzheimer's disease are driven by periodic but not aperiodic changes.

Electroencephalography (EEG) has shown potential for identifying early-stage biomarkers of neurocognitive dysfunction associated with dementia due to Alzheimer's disease (AD). A large body of evidence shows that, compared to healthy controls (HC), AD is associated with power increases in lower EEG frequencies (delta and theta) and decreases in higher frequencies (alpha and beta), together with slowing of the peak alpha frequency. However, the pathophysiological processes underlying these changes remain unclear. For instance, recent studies have shown that apparent shifts in EEG power from high to low frequencies can be driven either by frequency specific periodic power changes or rather by non-oscillatory (aperiodic) changes in the underlying 1/f slope of the power spectrum. Hence, to clarify the mechanism(s) underlying the EEG alterations associated with AD, it is necessary to account for both periodic and aperiodic characteristics of the EEG signal. Across two independent datasets, we examined whether resting-state EEG changes linked to AD reflect true oscillatory (periodic) changes, changes in the aperiodic (non-oscillatory) signal, or a combination of both. We found strong evidence that the alterations are purely periodic in nature, with decreases in oscillatory power at alpha and beta frequencies (AD < HC) leading to lower (alpha + beta) / (delta + theta) power ratios in AD. Aperiodic EEG features did not differ between AD and HC. By replicating the findings in two cohorts, we provide robust evidence for purely oscillatory pathophysiology in AD and against aperiodic EEG changes. We therefore clarify the alterations underlying the neural dynamics in AD and emphasize the robustness of oscillatory AD signatures, which may further be used as potential prognostic or interventional targets in future clinical investigations.

A pragmatic, open-label, randomized controlled trial of Plasma-Lyte-148 versus standard intravenous fluids in children receiving kidney transplants (PLUTO).

Acute electrolyte and acid-base imbalance is experienced by many children following kidney transplant. This is partly because doctors give very large volumes of artificial fluids to keep the new kidney working. When severe, fluid imbalance can lead to seizures, cerebral edema and death. In this pragmatic, open-label, randomized controlled trial, we randomly assigned (1:1) pediatric kidney transplant recipients to Plasma-Lyte-148 or standard of care perioperative intravenous fluids (predominantly 0.45% sodium chloride and 0.9% sodium chloride solutions). We then compared clinically significant electrolyte and acid-base abnormalities in the first 72 hours post-transplant. The primary outcome, acute hyponatremia, was experienced by 53% of 68 participants in the Plasma-Lyte-148 group and 58% of 69 participants in the standard fluids group (odds ratio 0·77 (0·34 - 1·75)). Five of 16 secondary outcomes differed with Plasma-Lyte-148: hypernatremia was significantly more frequent (odds ratio 3·5 (1·1 - 10·8)), significantly fewer changes to fluid prescriptions were made (rate ratio 0·52 (0·40-0·67)), and significantly fewer participants experienced hyperchloremia (odds ratio 0·17 (0·07 - 0·40)), acidosis (odds ratio 0·09 (0·04 - 0·22)) and hypomagnesemia (odds ratio 0·21 (0·08 - 0·50)). No other secondary outcomes differed between groups. Serious adverse events were reported in 9% of participants randomized to Plasma-Lyte-148 and 7% of participants randomized to standard fluids. Thus, perioperative Plasma-Lyte-148 did not change the proportion of children who experienced acute hyponatremia compared to standard fluids. However fewer fluid prescription changes were made with Plasma-Lyte-148, while hyperchloremia and acidosis were less common.

Delineating mechanisms underlying parvalbumin neuron impairment in different neurological and neurodegenerative disorders: the emerging role of mitochondrial dysfunction.

Given the current paucity of effective treatments in many neurological disorders, delineating pathophysiological mechanisms among the major psychiatric and neurodegenerative diseases may fuel the development of novel, potent treatments that target shared pathways. Recent evidence suggests that various pathological processes, including bioenergetic failure in mitochondria, can perturb the function of fast-spiking, parvalbumin-positive neurons (PV+). These inhibitory neurons critically influence local circuit regulation, the generation of neuronal network oscillations and complex brain functioning. Here, we survey PV+ cell vulnerability in the major neuropsychiatric, and neurodegenerative diseases and review associated cellular and molecular pathophysiological alterations purported to underlie disease aetiology.

Science and the 'emancipation of the mind': dreams, the mind, and slavery.

Dreams were a subject of interest to philosophers thinking about the connection between the mind and the body in the nineteenth century. Many scholars have pointed out that the mind and the body were intimately linked and affected each other. Although science was on its way to becoming more technical and numbers focused in its investigatory practices, medical students and other physician-philosophers investigated the nature of sleep and dreams. Medical students and advanced researchers speculated on the nature of consciousness and mused on where the mind travels to during the sleep processes. Other romantic figures like Dr Polydori speculated on the nature of sleep walking in their medical dissertations. Dreams also had a powerful moral and motivational component, as dreams and activities in dreams, drove people like Benjamin Rush to embrace abolition. Other promoters of abolition used the nature of dreams to discusses the dreadfulness and suffering of slavery.

Germline mismatch repair (MMR) gene analyses from English NHS regional molecular genomics laboratories 1996-2020: development of a national resource of patient-level genomics laboratory records.

OBJECTIVE: To describe national patterns of National Health Service (NHS) analysis of mismatch repair (MMR) genes in England using individual-level data submitted to the National Disease Registration Service (NDRS) by the NHS regional molecular genetics laboratories. DESIGN: Laboratories submitted individual-level patient data to NDRS against a prescribed data model, including (1) patient identifiers, (2) test episode data, (3) per-gene results and (4) detected sequence variants. Individualised per-laboratory algorithms were designed and applied in NDRS to extract and map the data to the common data model. Laboratory-level MMR activity audit data from the Clinical Molecular Genetics Society/Association of Clinical Genomic Science were used to assess early years' missing data. RESULTS: Individual-level data from patients undergoing NHS MMR germline genetic testing were submitted from all 13 English laboratories performing MMR analyses, comprising in total 16 722 patients (9649 full-gene, 7073 targeted), with the earliest submission from 2000. The NDRS dataset is estimated to comprise >60% of NHS MMR analyses performed since inception of NHS MMR analysis, with complete national data for full-gene analyses for 2016 onwards. Out of 9649 full-gene tests, 2724 had an abnormal result, approximately 70% of which were (likely) pathogenic. Data linkage to the National Cancer Registry demonstrated colorectal cancer was the most frequent cancer type in which full-gene analysis was performed. CONCLUSION: The NDRS MMR dataset is a unique national pan-laboratory amalgamation of individual-level clinical and genomic patient data with pseudonymised identifiers enabling linkage to other national datasets. This growing resource will enable longitudinal research and can form the basis of a live national genomic disease registry.

Nudging During Pediatric Intensive Care Conferences With Family Members: Retrospective Analysis of Transcripts From a Single-Center, 2015-2019.

OBJECTIVES: Nudging, a behavioral economics concept, subtly influences decision-making without coercion or limiting choice. Despite its frequent use, the specific application of nudging techniques by clinicians in shared decision-making (SDM) is understudied. Our aim was to analyze clinicians' use of nudging in a curated dataset of family care conferences in the PICU. DESIGN: Between 2019 and 2020, we retrospectively studied and coded 70 previously recorded care conference transcripts that involved physicians and families from 2015 to 2019. We focused on decision-making discussions examining instances of nudging, namely salience, framing, options, default, endowment, commission, omission, recommend, expert opinion, certainty, and social norms. Nudging instances were categorized by decision type, including tracheostomy, goals of care, or procedures. SETTING: Single-center quaternary pediatric facility with general and cardiac ICUs. PATIENTS: None. INTERVENTIONS: None. MEASUREMENTS: We assessed the pattern and frequency of nudges in each transcript. MAIN RESULTS: Sixty-three of the 70 transcripts contained SDM episodes. These episodes represented a total of 11 decision categories based on the subject matter of nudging instances, with 308 decision episodes across all transcripts (median [interquartile range] 5 [4-6] per conference). Tracheostomy was the most frequently discussed decision. A total of 1096 nudging instances were identified across the conferences, with 8 (6-10) nudge types per conference. The most frequent nudging strategy used was gain frame (203/1096 [18.5%]), followed by loss frame (150/1096 [13.7%]). CONCLUSIONS: Nudging is routinely employed by clinicians to guide decision-making, primarily through gain or loss framing. This retrospective analysis aids in understanding nudging in care conferences: it offers insight into potential risks and benefits of these techniques; it highlights ways in which their application has been used by caregivers; and it may be a resource for future trainee curriculum development.

Experiences of Living With the Nonmotor Symptoms of Parkinson's Disease: A Photovoice Study.

BACKGROUND: Nonmotor symptoms (NMSs) are frequently experienced by people with Parkinson's disease (PD) and are often perceived as their most bothersome symptoms. However, these remain poorly understood with suboptimal clinical management. These unmet needs are an important determinant of health-related quality of life (QoL) in PD. OBJECTIVE: The aim of this study was to gain insights into the experience of living with the NMS of PD in real-time using participatory action methodology. METHOD: Using the photovoice method, 14 people with PD took photographs to document their experiences of living with the NMS of PD. They composed corresponding written narratives to capture the impact of NMS on their daily activities and QoL. In total, 152 photographs and corresponding narratives were analysed using thematic analysis with an inductive approach. RESULTS: Four interrelated themes were identified. Emotional well-being and sense of self encompassed a process of adjustment to living with PD. Engaging in valued activities, adopting a positive mindset and utilising coping strategies were thought to enhance confidence and self-esteem. Social support and societal awareness highlighted the importance of supportive relationships and socialising to aid participation and avoid isolation. Barriers to social engagement included the unpredictability of NMS and nonvisible NMS being neglected or misunderstood. CONCLUSION: Findings demonstrated the far-reaching impact of nonmotor aspects of PD on emotional, occupational and social dimensions. These needs could be addressed through person-centred and comprehensive approaches to care. PATIENT OR PUBLIC CONTRIBUTION: This study utilised a participatory research approach allowing participants to choose the subjects that mattered to them and how to present their results. Additionally, a group workshop was held with people with PD, their family members and healthcare professionals to guide theme development.

Real-world evidence of heparin and citrate use in extracorporeal photopheresis: A hypothesis-generating data review of device settings and performance.

Extracorporeal photopheresis (ECP) is widely used for the treatment of cutaneous T-cell lymphoma, graft-vs-host disease, and other immune-related conditions. To avoid clotting during treatment, the ECP system used must be effectively primed with an anticoagulant. Heparin is the recommended anticoagulant for the THERAKOS CELLEX System, but acid citrate dextrose-A (ACDA) is often used. We compared system performance between these two anticoagulants for this ECP system. Deidentified data for ECP device performance were obtained at each treatment session, from automatically logged Smart Cards or labels completed by device operators. We compared the effects of ACDA or heparin on overall treatment duration, buffy coat (leukocyte) collection time, photoactivation time and the number of alarms and warnings. The variability in these parameters was also assessed. Data from 23 334 treat sessions were analyzed; ACDA was used in 34.4% and heparin in 65.6%. Overall, the ECP procedure duration, buffy coat collection time and photoactivation time were numerically similar regardless of whether ACDA or heparin was used, and regardless of needle mode. Photoactivation time variability was lower with ACDA compared with heparin in all needle modes. Among treatments that were completed automatically without any operator intervention, total treatment duration and photoactivation time were significantly reduced with ACDA use in both the double- and single-needle modes. The data presented indicate that, in both double- and single-needle modes, the THERAKOS® CELLEX® integrated ECP system performed similarly with ACDA compared to heparin, although ACDA demonstrated potential benefits in reducing variability in photoactivation time.

A systematic review of vestibular stimulation in post-stroke visual neglect.

Unilateral visual neglect is a condition that negatively impacts the lives of many stroke survivors. Studies have investigated different forms of vestibular stimulation as a potential therapy, but evidence is yet to be systematically reviewed. We therefore reviewed the effects of vestibular stimulation on outcomes of neglect and activities of daily living (ADL) for people with visual neglect. We searched relevant databases up until September 2022. Eligible articles included any form of vestibular stimulation, study design, or control condition. Included participants were 18 years or older, presenting with neglect following a haemorrhagic or ischaemic stroke. Relevant outcomes were clinically validated measures of neglect and ADL. Cochrane risk of bias tools were used to assess study quality. Meta-analyses and narrative methods were used to synthesize the data. Our search returned 17 relevant studies comprising 180 participants. Meta-analyses showed no difference between galvanic vestibular stimulation and sham conditions on outcomes, whereas caloric vestibular stimulation led to improvement compared to pre-stimulation scores. Narrative syntheses showed mixed results. Clinical and methodological heterogeneity was found both within and between studies. Overall, results were inconsistent regarding the effects of vestibular stimulation as a treatment for neglect. Further trials are warranted but require more careful methodological planning.

Dissection, media portrayals, and reaction: Black bodies and medical education in nineteenth-century newspapers.

Throughout the nineteenth century, medical schools in both the Northern and Southern regions of the United States required a regular supply of bodies for medical study and experimentation. Physicians and medical students targeted the bodies of African Americans, both freedmen and the enslaved, to meet this demand. Simultaneously, the nation's booming newspaper market became a stage on which debates about the cruelty of slavery and the social consequences of pursuing medical knowledge played out in articles about the dissection of Black bodies. Such stories increased fears about dissection and mistrust towards the medical profession among African American communities, which manifested in riots against physicians, vandalism against medical schools, and corrective responses from African American newspaper editors and journalists. Through an extensive examination of nineteenth-century U.S. newspapers, this article identifies themes evident in the coverage of dissection during this period. Southern newspapers crafted stories of dissection that served the dual purpose of entertaining White readers and humiliating African Americans. This public humiliation fostered what became a popular genre of derogatory and vile humor that reinforced negative and inaccurate racialized stereotypes as well as racist science. Ultimately, such newspaper coverage provoked reactions within Black communities and among antislavery advocates that showcase how people often excluded from practicing medicine themselves viewed issues like medical education. Newspaper rhetoric around these themes amplified tensions between religious and scientific perspectives, reflected differences and similarities between the northern and southern areas of the United States, and fortified racist views in both cultural and scientific contexts.

Incorporating a Psychiatric Telehealth Simulation in a Family Nurse Practitioner Curriculum.

The prevalence of mental health disorders in primary care is high and challenges related to the COVID pandemic warrant further training of the family nurse practitioner. A telehealth simulation learning experience that included common primary care diagnoses in mental health-general anxiety, depression, and substance use disorder-was incorporated into a non-clinical behavioral health course. Formative evaluation provided by licensed nurse practitioners confirmed the need for improving interviewing techniques, engaging clients, and promoting safety among this population. Students' confidence during the encounter was measured using the Simulation Effectiveness Tool. Findings suggest a simulation learning experience is an effective resource for training nurse practitioner students to treat mental health disorders.

Formulation and acceptability of local nutrient-dense foods for young children: A formative study for the Child Health, Agriculture and Integrated Nutrition (CHAIN) Trial in rural Zimbabwe.

Stunting affects almost one-quarter of children globally, leading to reduced human capacity and increased long-term risk of chronic disease. Despite intensive infant and young child feeding (IYCF) interventions, many children do not meet their requirements for essential nutrients. This study aimed to assess the feasibility of implementing an IYCF intervention utilizing nutrient-dense powders from egg, biofortified sugar beans and Moringa oleifera leaf in rural Zimbabwe. A mixed-methods formative study was conducted comprising the following: (i) a recipe formulation trial, (ii) trials of improved practices to assess acceptability of the intervention, and (iii) a participatory message formulation process to develop counselling modules for the IYCF-plus intervention. Twenty-seven mother-baby pairs were recruited between November 2019 and April 2020. Key domains affecting IYCF practices that emerged were time, emotional and physical space, cultural and religious beliefs, indigenous knowledge systems and gender dynamics. Household observations and sensory evaluation indicated high acceptability of the new ingredients. Recipe formulation and participatory message formulation by participants instilled community ownership and served to demystify existing misconceptions about the new food products. Families noted the potential for intervention sustainability because the foods could be grown locally. Supplementing complementary foods with nutrient-dense local food ingredients as powders has the potential to sustainably address nutrient-gaps in the diets of young children living in rural lower- and middle-income countries. Comprehensive IYCF counselling utilizing a gender-lens approach, family support and indigenous knowledge systems or resources are key elements to support positive behaviour change in complementary feeding interventions.

Diagnosis and Management of Non-Metastatic Upper Tract Urothelial Carcinoma: AUA/SUO Guideline.

PURPOSE: The purpose of this guideline is to provide a useful reference on the effective evidence-based diagnoses and management of non-metastatic upper tract urothelial carcinoma (UTUC). MATERIALS/METHODS: The Pacific Northwest Evidence-based Practice Center of Oregon Health & Science University (OHSU) team conducted searches in Ovid MEDLINE (1946 to March 3rd, 2022), Cochrane Central Register of Controlled Trials (through January 2022), and Cochrane Database of Systematic Reviews (through January 2022). The searches were updated August 2022. When sufficient evidence existed, the body of evidence was assigned a strength rating of A (high), B (moderate), or C (low) for support of Strong, Moderate, or Conditional Recommendations. In the absence of sufficient evidence, additional information is provided as Clinical Principles and Expert Opinions (Table 1).[Table: see text]Results:This Guideline provides updated, evidence-based recommendations regarding diagnosis and management of non-metastatic UTUC including risk stratification, surveillance and survivorship. Treatments discussed include kidney sparing management, surgical management, lymph node dissection (LND), neoadjuvant/adjuvant chemotherapy and immunotherapy. CONCLUSION: This standardized guideline seeks to improve clinicians' ability to evaluate and treat patients with UTUC based on available evidence. Future studies will be essential to further support these statements for improving patient care. Updates will occur as the knowledge regarding disease biology, clinical behavior and new therapeutic options develop.

Implementation of Psychosocial Screening into Diabetes Clinics: Experience from the Type 1 Diabetes Exchange Quality Improvement Network.

PURPOSE OF REVIEW: Although advances in diabetes technology and pharmacology have significantly and positively impacted diabetes management and health outcomes for some, diabetes care remains burdensome and can be challenging to balance with other life priorities. The purpose of this article is to review the rationale for assessment of psychosocial domains in diabetes care settings and strategies for the implementation of psychosocial screening into routine practice. Survey data from the Type 1 Diabetes Exchange Quality Improvement Network is highlighted. RECENT FINDINGS: Implementation of psychosocial screening requires identifying the population; selecting validated tools to assess target domains; determining frequency of screening and mode of survey delivery; and scoring, interpreting, documenting, and facilitating referrals such that these processes are part of clinical workflows. Recognizing the influence of psychosocial factors for people with diabetes (PWD), professional society guidelines for comprehensive diabetes care recommend the integration of psychosocial screening into routine care.

Laparoscopic donor nephrectomy-Technique and peri-operative outcomes in an Australian transplant center.

INTRODUCTION: Demand for donor kidneys far exceeds the availability of organs from deceased donors. Living donor kidneys are an important part of addressing this shortfall, and laparoscopic nephrectomy is an important strategy to reduce donor morbidity and increase the acceptability of living donation. AIM: To retrospectively review the intraoperative and postoperative safety, technique, and outcomes of patients undergoing donor nephrectomy at a single tertiary hospital in Sydney, Australia. METHOD: Retrospective capture and analysis of clinical, demographic, and operative data for all living donor nephrectomies performed between 2007 and 2022 at a single University Hospital in Sydney, Australia. RESULTS: Four hundred and seventy-two donor nephrectomies were performed: 471 were laparoscopic, two of which were converted from laparoscopic to open and hand-assisted nephrectomy, respectively, and one (.2%) underwent primary open nephrectomy. The mean warm ischemia time was 2.8 min (±1.3 SD, median 3 min, range 2-8 min) and the mean length of stay (LOS) was 4.1 days (±1.0 SD). The mean renal function on discharge was 103 µmol/L (±23.0 SD). Seventy-seven (16%) patients had a complication with no Clavien Dindo IV or V complications seen. Outcomes demonstrated no impact of donor age, gender, kidney side, relationship to the recipient, vascular complexity; or surgeon experience, on complication rate or LOS. CONCLUSION: Laparoscopic donor nephrectomy is a safe and effective procedure with minimal morbidity and no mortality in this series.

Bortezomib and Vorinostat Therapy as Maintenance Therapy Post Autologous Transplant for Non-Hodgkin's Lymphoma Using R-BEAM or BEAM Transplant Conditioning Regimen.

INTRODUCTION: The success of autologous stem cell transplantation (ASCT) for treating non-Hodgkin's lymphoma (NHL) is limited by its high relapse rates. To reduce the risk of relapse, additional maintenance therapy can be added post-transplant. In a non-transplant setting at the time of initiation of this study, both bortezomib and vorinostat had been studied alone or in combination for some NHL histology and showed some clinical activity. At our center, this combination therapy post-transplant for Multiple Myeloma (MM) showed acceptable toxicity. Therefore, it seemed reasonable to study this combination therapy post-ASCT for NHL. METHODS: NHL patients underwent conditioning for ASCT with rituximab, carmustine, etoposide, cytarabine, melphalan (R-BEAM)/carmustine, etoposide, cytarabine, melphalan (BEAM). After recovery from the acute transplant-related toxicity, combination therapy with IV bortezomib and oral vorinostat (BV) was started and was given for a total of 12 (28-day) cycles. RESULTS: Nineteen patients received BV post ASCT. The most common toxicities were hematologic, gastrointestinal, metabolic, fatigue and peripheral neuropathy. With a median follow-up of 10.3 years, 11 patients (58%) are alive without disease progression and 12 patients (63%) are alive. CONCLUSIONS: BV can be given post-ASCT for NHL and produces excellent disease-free and overall survival rates.

SAI-CH-6: Development of a Short Form of the State Anxiety Inventory for Children At-Risk for Type 1 Diabetes.

OBJECTIVE: To develop a reliable and valid short form of the State Anxiety Subscale of the State-Trait Anxiety Inventory for Children (STAI-CH) in the Environmental Determinants of Diabetes in the Young (TEDDY) study. METHODS: A Development Sample of 842 10-year-old TEDDY children completed the STAI-CH State Subscale about their type 1 diabetes (T1D) risk. The best 6 items (three anxiety-present and three anxiety-absent) for use in a short form (SAI-CH-6) were identified via item-total correlations. SAI-CH-6 reliability was examined in a Validation Sample (n = 257) of children who completed the full 20-item STAI-CH State Subscale and then again in an Application Sample (n = 2,710) who completed only the SAI-CH-6. Expected associations between the children's SAI-CH-6 scores and country of residence, sex, T1D family history, accuracy of T1D risk perception, worry about getting T1D, and their parents' anxiety scores were examined. RESULTS: The SAI-CH-6 was reliable (α = 0.81-0.87) and highly correlated with the full 20-item STAI-CH State Subscale (Development Sample: r = 0.94; Validation Sample: r = 0.92). SAI-CH-6 scores detected significant differences in state anxiety symptoms associated with T1D risk by country, T1D family history, accuracy of T1D risk perception, and worry about getting T1D and were correlated with the child's parent's anxiety. CONCLUSION: The SAI-CH-6 appears useful for assessing children's state anxiety symptoms when burden and time limitations prohibit the use of the STAI-CH. The utility of the SAI-CH-6 in older children with and without chronic conditions needs to be assessed.

Homologous recombination deficiency in newly diagnosed FIGO stage III/IV high-grade epithelial ovarian cancer: a multi-national observational study.

OBJECTIVE: Olaparib plus bevacizumab maintenance therapy improves survival outcomes in women with newly diagnosed, advanced, high-grade ovarian cancer with a deficiency in homologous recombination. We report data from the first year of routine homologous recombination deficiency testing in the National Health Service (NHS) in England, Wales, and Northern Ireland between April 2021 and April 2022. METHODS: The Myriad myChoice companion diagnostic was used to test DNA extracted from formalin-fixed, paraffin-embedded tumor tissue in women with newly diagnosed International Federation of Gynecology and Obstetrics (FIGO) stage III/IV high-grade epithelial ovarian, fallopian tube, or primary peritoneal cancer. Tumors with homologous recombination deficiency were those with a BRCA1/2 mutation and/or a Genomic Instability Score (GIS) ≥42. Testing was coordinated by the NHS Genomic Laboratory Hub network. RESULTS: The myChoice assay was performed on 2829 tumors. Of these, 2474 (87%) and 2178 (77%) successfully underwent BRCA1/2 and GIS testing, respectively. All complete and partial assay failures occurred due to low tumor cellularity and/or low tumor DNA yield. 385 tumors (16%) contained a BRCA1/2 mutation and 814 (37%) had a GIS ≥42. Tumors with a GIS ≥42 were more likely to be BRCA1/2 wild-type (n=510) than BRCA1/2 mutant (n=304). The distribution of GIS was bimodal, with BRCA1/2 mutant tumors having a higher mean score than BRCA1/2 wild-type tumors (61 vs 33, respectively, χ2 test p<0.0001). CONCLUSION: This is the largest real-world evaluation of homologous recombination deficiency testing in newly diagnosed FIGO stage III/IV high-grade epithelial ovarian, fallopian tube, or primary peritoneal cancer. It is important to select tumor tissue with adequate tumor content and quality to reduce the risk of assay failure. The rapid uptake of testing across England, Wales, and Northern Ireland demonstrates the power of centralized NHS funding, center specialization, and the NHS Genomic Laboratory Hub network.