The Efficacy and Safety of Bisphosphonate Therapy for Osteopenia/Osteoporosis in Patients With Chronic Kidney Disease: A Systematic Review and Individual Patient-Level Meta-Analysis of Placebo-Controlled Randomized Trials.

Background: The efficacy and safety of bisphosphonate therapy for the treatment of osteoporosis and osteopenia in the setting of chronic kidney disease (CKD) is unclear. Objective: To determine the effect of bisphosphonate therapy on fractures, bone mineral density (BMD), and adverse events in adults across the spectrum of CKD and dialysis. Design: Systematic review and individual patient-level meta-analysis. Setting: Searches of Ageline, CINAHL, the Cochrane Library, EMBASE, and Medline from inception to August 25, 2016, supplemented with manual screening and clinicalstudydatarequest.com. Authors were contacted for individual patient-level data. Patients: Randomized, placebo-controlled trials with 100 or more participants that evaluated the treatment of primary osteoporosis/osteopenia in adult men and women with bisphosphonate therapy. Measurements: Study characteristics, quality, and data were assessed independently by 2 reviewers. Outcome measures were fractures, BMD, and adverse events including decline in estimated glomerular filtration rate (eGFR) and hypocalcemia (calcium <2.00 mmol/L). Methods: Single-stage individual patient-level meta-analysis. Results: Of 39 eligible studies, individual patient-level data was available for 7 studies, all of which were studies of ibandronate. Of 7428 participants (5010 ibandronate, 2418 placebo), 100% were female, 98.6% were white, the mean body mass index was 25.7 kg/m2 (SD 3.9), 18.9% were smokers and there were 740 fracture events. The mean eGFR was 69.1 mL/min/1.73 m2 (SD 15.9) including 14.5%, 54.9%, 27.5%, 3.0%, and 0.2% stages G1, G2, G3A, G3B, and G4 CKD. Ibandronate increased hip and lumbar spine BMD and decreased the risk of fracture in the overall population (hazard ratio (HR) 0.871, 95% confidence interval (CI) 0.746, 1.018) but in patients with stage G3B CKD, it increased the risk of fracture (HR 3.862, 95% CI 1.156, 12.903). Ibandronate did not impact eGFR over 12 months but increased the risk of hypocalcemia (HR 1.324, 95% CI 1.056, 1.660) with no evidence of any effect modification by CKD stage (all tests of interaction p > 0.05). Limitations: Clinically significant heterogeneity among studies, lack of long-term follow-up and bone biopsy results, limited representation of stage G4 and G5 CKD patients. Conclusions: Chronic kidney disease potentially modifies the efficacy but not the safety of bisphosphonate therapy in osteopenia and osteoporosis. Registration: PROSPERO CRD42020145613.

Contexte: L'efficacité et l'innocuité du traitement de l'ostéoporose et de l'ostéopénie par les bisphosphonates en contexte d'insuffisance rénale chronique (IRC) sont mal connues. Objectif: Déterminer l'effet du traitement par bisphosphonates sur les fractures, la densité minérale osseuse (DMO) et les événements indésirables chez les adultes dans tout le spectre de l'IRC et de la dialyse. Conception: Revue systématique et méta-analyse individuelle au niveau du patient. Cadre: Recherches sur Ageline, CINAHL, la bibliothèque Cochrane, EMBASE et Medline depuis leur création jusqu'au 25 août 2016, complétées par une sélection manuelle et la consultation de clinicalstudydatarequest.com. Les auteurs ont été contactés pour l'obtention des données individuelles des patients. Sujets: Les essais randomisés contrôlés contre placebo qui ont été menés auprès d'au moins 100 sujets et qui ont évalué le traitement de l'ostéoporose/ostéopénie primaire chez des hommes et femmes adultes prenant des bisphosphonates. Mesures: Les caractéristiques, la qualité et les données de l'étude ont été examinées de manière indépendante par deux évaluateurs. Les critères d'évaluation étaient les fractures, la DMO et les événements indésirables, y compris la réduction du débit de filtration glomérulaire estimé (DFGe) et l'hypocalcémie (calcium < 2,00 mmol/L). Méthodologie: Méta-analyse en une seule étape au niveau du patient. Résultats: Sur les 39 études admissibles, seules 7 études présentaient des données individuelles au niveau des patients et celles-ci portaient toutes sur l'ibandronate. Les 7428 sujets (5010 ibandronate, 2418 placebo) inclus étaient des femmes (98,6 % étaient de race blanche) avec un indice de masse corporelle moyen de 25,7 kg/m2 (écart-type : 3,9), 18,9 % étaient fumeuses et on comptait 740 fractures. Le DFGe moyen était de 69,1 ml/min/1,73 m2 (écart-type : 15,9) pour des sujets atteints d'IRC de stades G1 (14,5 %), G2 (54,9 %), G3 (27,5 %), G3B (3,0 %) et G4 (0,2 %). L'ibandronate a amélioré la DMO de la hanche et du rachis lombaire et diminué le risque de fracture dans l'ensemble de la population (RR : 0,871; IC 95 % : 0,746-1,018), mais a augmenté le risque de fractures chez les sujets atteints d'IRC de stade G3B (RR : 3,862; IC95 % : 1,156-12,903). Sur une période de 12 mois, le DFGe n'a pas semblé affecté par le traitement à l'ibandronate, mais on a observé une augmentation du risque d'hypocalcémie (RR : 1,324; IC95 % : 1,056-1,660) sans modification de l'effet selon le stade de l'IRC (p>0,05 pour tous les tests d'interaction). Limites: Hétérogénéité cliniquement significative entre les études; absence de suivi à long terme et de résultats de biopsies osseuses; représentation limitée des patients atteints d'IRC de stade G4 et G5. Conclusion: L'IRC peut modifier l'efficacité, mais non l'innocuité, des bisphosphonates pour le traitement de l'ostéopénie et de l'ostéoporose.

Feasibility of an environmental scan-based approach to collecting information about factors impacting cancer genetics services in Latin American countries.

OBJECTIVE: Clinical cancer genetics services are expanding globally, but national policy and health care systems influence availability and implementation. Understanding the environmental factors within a country is required to appropriately implement, adapt, and evaluate cancer genetics service delivery models. An environmental scan (ES) is an approach used in business, public health, health care and other sectors to collect information about an environment or system for strategic decision making and program planning. An ES has been previously used to assess cancer genetics clinic-level factors to inform quality improvement efforts in the United States. We assessed the feasibility of using an ES to collect information about factors that may influence cancer genetics service delivery in the outer-most socio-ecological model environmental levels (policy, national agencies, healthcare systems, cultural considerations) in three Latin American countries. METHODS: Oncology and Genetics care team members at three participating sites used publicly available sources and personal experiences to complete a data collection form (DCF) that included questions about subtopics: laws and policies, relevant agencies and regulations, health care systems and insurance, and cultural considerations. Time to complete the DCF and DCF completeness were used to measure ES feasibility. RESULTS: Participating sites completed the DCF in 3 months, and most questions (average, 87.0%) were answered. Questions in the cultural considerations subtopic had the fewest answers (average, 77.8%). CONCLUSIONS: Overall, the ES was feasible and identified a lack of published literature related to cultural considerations impacting health care and genetics services uptake in Latin America. Environmental factors impact cancer genetics services, and identification of these factors will facilitate future collaborative research and genetics service delivery dissemination efforts.

The Role of Transoral Robotic Palatine and Lingual Tonsillectomy in the Diagnosis of Carcinoma of Unknown Primary in the Head and Neck Region.

BACKGROUND: The use of transoral robotic surgery (TORS) lingual tonsillectomy in the diagnostic algorithm for head and neck carcinoma of unknown primary (CUP) has gained recent popularity. The primary aim of our study was to determine the identification rate of primary tumors in our cohort undergoing lingual ± palatine tonsillectomy for the workup of head and neck CUP. METHODS: This was a retrospective study of all patients undergoing diagnostic TORS for head and neck CUP over an eight-year period, across four centers in two countries. RESULTS: Fifty-six patients undergoing TORS to aid diagnosis of a primary site were included. Overall, TORS lingual ± palatine tonsillectomy identified a primary tumor in 41 (73.2%) patients. Over half were T1 tumors, with 25% measuring under 10 mm. Among those with human papilloma virus (HPV)+ nodal disease, the identification rate was 82.6%. CONCLUSIONS: TORS lingual tonsillectomy is an effective addition to the diagnostic workup of CUP, particularly in those with HPV+ nodal disease.

Novel linkage of the Society of Thoracic Surgeons database and hospital electronic health records.

BACKGROUND: Society of Thoracic Surgeons Congenital Heart Surgery Database is the largest congenital heart surgery database worldwide but does not provide information beyond primary episode of care. Linkage to hospital electronic health records would capture complications and comorbidities along with long-term outcomes for patients with CHD surgeries. The current study explores linkage success between Society of Thoracic Surgeons Congenital Heart Surgery Database and electronic health record data in North Carolina and Georgia. METHODS: The Society of Thoracic Surgeons Congenital Heart Surgery Database was linked to hospital electronic health records from four North Carolina congenital heart surgery using indirect identifiers like date of birth, sex, admission, and discharge dates, from 2008 to 2013. Indirect linkage was performed at the admissions level and compared to two other linkages using a "direct identifier," medical record number: (1) linkage between Society of Thoracic Surgeons Congenital Heart Surgery Database and electronic health records from a subset of patients from one North Carolina institution and (2) linkage between Society of Thoracic Surgeons data from two Georgia facilities and Georgia's CHD repository, which also uses direct identifiers for linkage. RESULTS: Indirect identifiers successfully linked 79% (3692/4685) of Society of Thoracic Surgeons Congenital Heart Surgery Database admissions across four North Carolina hospitals. Direct linkage techniques successfully matched Society of Thoracic Surgeons Congenital Heart Surgery Database to 90.2% of electronic health records from the North Carolina subsample. Linkage between Society of Thoracic Surgeons and Georgia's CHD repository was 99.5% (7,544/7,585). CONCLUSIONS: Linkage methodology was successfully demonstrated between surgical data and hospital-based electronic health records in North Carolina and Georgia, uniting granular procedural details with clinical, developmental, and economic data. Indirect identifiers linked most patients, consistent with similar linkages in adult populations. Future directions include applying these linkage techniques with other data sources and exploring long-term outcomes in linked populations.

A scoping review of evidence of naturally occurring Japanese encephalitis infection in vertebrate animals other than humans, ardeid birds and pigs.

Japanese encephalitis virus (JEV) is the leading cause of human encephalitis in Asia. JEV is a vector-borne disease, mainly transmitted by Culex mosquitoes, with Ardeidae birds as maintenance hosts and pigs as amplifying hosts. Other vertebrate animal hosts have been suggested to play a role in the epidemiology of JEV. This scoping review followed PRISMA guidelines to identify species in which evidence of naturally occurring JEV infection was detected in vertebrates other than ardeid birds, pigs and people. Following systematic searches, 4372 records were screened, and data were extracted from 62 eligible studies. Direct evidence (virus, viral antigen or viral RNA) of JEV infection was identified in a variety of mammals and birds (not always identified to the species level), including bats, passerine birds (family Turdidae), livestock (cattle [Bos taurus] and a goat [Capra hircus]), carnivores (two meerkats [Suricata suricatta]), and one horse (Equus caballus). Bat families included Pteropodidae, Vespertilionidae, Rhinolophidae, Miniopteridae, Hipposideridae. Indirect evidence (antibodies) was identified in several mammalian and avian orders, as well as reported in two reptile species. However, a major limitation of the evidence of JEV infection identified in this review was diagnostic test accuracy, particularly for serological testing. Studies generally did not report diagnostic sensitivity or specificity which is critical given the potential for cross-reactivity in orthoflavivirus detection. We hypothesise that bats and passerine birds could play an underappreciated role in JEV epidemiology; however, development of diagnostic tests to differentiate JEV from other orthoflaviviruses will be essential for effective surveillance in these, as well as the companion and livestock species that could be used to evaluate JEV control measures in currently endemic regions.

Comparison of 2 Sets of Immunoassays Used in Modified 2-Tiered Testing Algorithms for the Diagnosis of Lyme Disease.

BACKGROUND: Since 2019, modified 2-tiered testing (MTTT) algorithms have been available for the diagnosis of Lyme disease. MTTTs replaced the standard algorithms that utilized enzyme immunoassays and immunoblots with sequential enzyme immunoassays that detect different antigens. METHODS: We compared the performance of serological assays from ZEUS Scientific Inc. and DiaSorin Inc. that are used for the diagnosis of Lyme disease. Serological results were compared with clinical information gathered by chart review. RESULTS: Percent positive agreement (PPA) and percent negative agreement (PNA) for total immunoglobulin G (IgG)/immunoglogulin M (IgM) (n = 120) were 64% (95% confidence interval 54% to 73%) and 100% (87% to 100%), respectively. PPA and PNA for IgG (n = 93) were 91% (80% to 97%) and 66% (52% to 78%), respectively. PPA and PNA for IgM (n = 93) were 75% (62% to 85%) and 95% (82% to 99%), respectively. Fewer positive total IgG/IgM results confirmed positive for either IgG or IgM for ZEUS compared to DiaSorin. Overall MTTT algorithm interpretation was concordant in 58% (55/95) of samples, and concordance improved when the results were limited to IgM in patients with symptom duration <30 days. Treatment with antibiotics was most strongly associated with IgM positivity. CONCLUSIONS: This analysis highlights differences in the performance characteristics between commercially available diagnostic assays for Lyme disease. Our data suggest that the DiaSorin assays would result in fewer positive total IgG/IgM tests, decreasing the required number of confirmatory IgG and IgM tests. This would potentially lead to fewer patients treated with antibiotics.

Lingual frenotomy for ankyloglossia in infants with breastfeeding difficulties: a longitudinal observational study.

Ankyloglossia, or tongue-tie, is a variation in the anatomy of the lingual frenulum that restricts tongue movement. It is recognised as a cause of breastfeeding difficulty. We prospectively collected data from a specialist tongue-tie assessment clinic and evaluated mothers' experience using a questionnaire. We prospectively collected data from the specialist tongue-tie assessment clinic from January 2023 to October 2023 to assess factors that may influence a lingual frenotomy in an infant. Mothers were invited to complete two questionnaires, one baseline in the clinic waiting room and one follow-up, 4 weeks after their clinic visit. These self-reported questionnaires assessed breastfeeding challenges, the mother's motivation for seeking an opinion regarding ankyloglossia, and the continuity of breastfeeding 4 weeks following the clinic visit. During these 10 months, 157 infants attended the clinic, and 96 frenotomies were performed. One hundred one participants completed baseline questionnaires, and 34 participants completed follow-up questionnaires. When mothers were asked why they wanted their baby assessed for a tongue-tie, the most common answers were difficulty with latch and nipple pain, reported by 45% and 40%, respectively. The average reported pain while breastfeeding was scored at 2.53, graded from 0 to 5 in the baseline questionnaire. This improved to 1.47 amongst women whose infants had a frenotomy. Conclusion: Our study suggests that performing a frenotomy in infants diagnosed with ankyloglossia may positively impact breastfeeding.

Clinical and Neuropathological Correlates of Substance Use in American Football Players.

Background: Chronic traumatic encephalopathy (CTE) is a neurodegenerative tauopathy more frequently found in deceased former football players. CTE has heterogeneous clinical presentations with multifactorial causes. Previous literature has shown substance use (alcohol/drug) can contribute to Alzheimer's disease and related tauopathies pathologically and clinically. Objective: To examine the association between substance use and clinical and neuropathological endpoints of CTE. Methods: Our sample included 429 deceased male football players. CTE was neuropathologically diagnosed. Informant interviews assessed features of substance use and history of treatment for substance use to define indicators: history of substance use treatment (yes vs no, primary variable), alcohol severity, and drug severity. Outcomes included scales that were completed by informants to assess cognition (Cognitive Difficulties Scale, BRIEF-A Metacognition Index), mood (Geriatric Depression Scale-15), behavioral regulation (BRIEF-A Behavioral Regulation Index, Barratt Impulsiveness Scale-11), functional ability (Functional Activities Questionnaire), as well as CTE status and cumulative p-tau burden. Regression models tested associations between substance use indicators and outcomes. Results: Of the 429 football players (mean age = 62.07), 313 (73%) had autopsy confirmed CTE and 100 (23%) had substance use treatment history. Substance use treatment and alcohol/drug severity were associated with measures of behavioral regulation (FDR-p-values<0.05, ΔR2 = 0.04-0.18) and depression (FDR-p-values<0.05, ΔR2 = 0.02-0.05). Substance use indicators had minimal associations with cognitive scales, whereas p-tau burden was associated with all cognitive scales (p-values <0.05). Substance use treatment had no associations with neuropathological endpoints (FDR-p-values>0.05). Conclusions: Among deceased football players, substance use was common and associated with clinical symptoms.

Peptide-MHC-targeted retroviruses enable in vivo expansion and gene delivery to tumor-specific T cells.

Tumor-infiltrating-lymphocyte (TIL) therapy has demonstrated that endogenous T cells can be harnessed to initiate an effective anti-tumor response. Despite clinical promise, current TIL production protocols involve weeks-long ex vivo expansions which can affect treatment efficacy. Therefore, additional tools are needed to engineer endogenous tumor-specific T cells to have increased potency while mitigating challenges of manufacturing. Here, we present a strategy for pseudotyping retroviral vectors with peptide-major histocompatibility complexes (pMHC) for antigen-specific gene delivery to CD8 T cells and examine the efficacy of these transduced cells in immunocompetent mouse models. We demonstrate that pMHC-targeted viruses are able to specifically deliver function-enhancing cargoes while simultaneously activating and expanding anti-tumor T cells. The specificity of these viral vectors enables in vivo engineering of tumor-specific T cells, circumventing ex vivo manufacturing processes and improving overall survival in B16F10-bearing mice. Altogether, we have established that pMHC-targeted viruses are efficient vectors for reprogramming and expanding tumor-specific populations of T cells directly in vivo , with the potential to substantially streamline engineered cell therapy production for a variety of applications.

Radiation-Associated Secondary Cancer in Patients With Breast Cancer Harboring TP53 Germline Variants.

This cohort study examines the risk of radiation-associated sarcoma in patients with breast cancer harboring germline TP53 variants.

Update on Recommendations for Cancer Screening and Surveillance in Children with Genomic Instability Disorders.

Genomic instability disorders are characterized by DNA or chromosomal instability resulting in various clinical manifestations including developmental anomalies, immunodeficiency, and increased risk to develop cancers beginning in childhood. Many of these genomic instability disorders also present with exquisite sensitivity to anticancer treatments such as ionizing radiation and chemotherapy, which may further increase the risk of second cancers. In July 2023, the American Association of Cancer Research held the second Childhood Cancer Predisposition Workshop where multidisciplinary international experts discussed, reviewed, and updated recommendations for children with cancer predisposition syndromes. This article will discuss childhood cancer risks and surveillance recommendations for the group of genomic instability disorders with predominantly recessive inheritance, including the DNA repair disorders ataxia telangiectasia, Nijmegen breakage syndrome, Fanconi anemia, Xeroderma Pigmentosum, Bloom syndrome, and Rothmund-Thomson syndrome, as well as the telomere biology disorders and mosaic variegated aneuploidy. Recognition of children with genomic instability disorders is important in order to make the proper diagnosis, enable genetic counseling, and inform cancer screening, cancer risk reduction, and choice of anti-cancer therapy.

Everyday ageism experienced by community-dwelling older people with frailty.

PURPOSE: Ageism encapsulates stereotypes, prejudice and discrimination towards others or oneself based on age. While identified as the most frequent form of discrimination, relatively little work has captured the problem of day-to-day ageism faced by older people with frailty in community settings. The aim of this study therefore was to examine the prevalence of everyday ageism experienced by older people attending hospital-based ambulatory care services, and to clarify its association with measures of quality of life (QOL) and frailty. METHODS: A consecutive series (n = 100) of patients aged ≥ 70 years attending ambulatory care completed focused interviews. Day-to-day experience of ageism was measured with the everyday ageism scale, QOL was measured with the control autonomy self-realisation pleasure scale. RESULTS: Just over half of participants reported exposure to ageist messages; over 5/6 reported experiencing ageism in interpersonal interactions and 2/3 held some ageist beliefs themselves. Logistic regression demonstrated that experiencing ageism in interpersonal interactions was associated with a higher likelihood of internalised ageism [Adjusted Odds Ratio 6.02 (95% CI 1.70, 21.34); p = 0.005)]. Both ageism in interpersonal interactions [ß = -5.22 (95% CI -9.52, -0.91); p = 0.018] and internalised ageism [ß = -5.36 (95% CI -8.75, -1.97); p = 0.002] were associated with significantly lower QOL. DISCUSSION: This study highlights the striking prevalence of everyday ageism experienced by a cohort of community-dwelling older people with frailty and multimorbidity. In the context of further projected demographic changes in coming decades, with increasingly higher proportions of older people worldwide, these findings highlight an important societal issue that needs to be addressed.

Human in vivo baseline intrarenal pressure, peristaltic activity and response to ureteric stenting.

OBJECTIVES: To assess human in vivo intrarenal pressure (IRP) and peristaltic activity at baseline and after ureteric stent placement, using a narrow calibre pressure guidewire placed retrogradely in the renal pelvis. PATIENTS AND METHODS: A prospective, multi-institutional study recruiting consenting patients undergoing ureteroscopy was designed with ethical approval. Prior to ureteroscopy, the urinary bladder was emptied and the COMET™ II pressure guidewire (Boston Scientific) was advanced retrogradely via the ureteric orifice to the renal pelvis. Baseline IRPs were recorded for 1-2 min. At procedure completion, following ureteric stent insertion, IRPs were recorded for another 1-2 min. Statistical analysis of mean baseline IRP, peristaltic waveforms and frequency of peristaltic contractions was performed, thereby analysing the influence of patient variables and ureteric stenting. RESULTS: A total of 100 patients were included. Baseline mean (±SD) IRP was 16.76 (6.4) mmHg in the renal pelvis, with maximum peristaltic IRP peaks reaching a mean (SD) of 25.75 (17.9) mmHg. Peristaltic activity generally occurred in a rhythmic, coordinated fashion, with a mean (SD) interval of 5.63 (3.08) s between peaks. On univariate analysis, higher baseline IRP was observed with male sex, preoperative hydronephrosis, and preoperative ureteric stenting. On linear regression, male sex was no longer statistically significant, whilst the latter two variables remained significant (P = 0.004; P < 0.001). The mean (SD) baseline IRP in the non-hydronephrotic, unstented cohort was 14.19 (4.39) mmHg. Age, α-blockers and calcium channel blockers did not significantly influence IRP, and no measured variables influenced peristaltic activity. Immediately after ureteric stent insertion, IRP decreased (mean [SD] 15.18 [5.28] vs 16.76 [6.4] mmHg, P = 0.004), whilst peristaltic activity was maintained. CONCLUSIONS: Human in vivo mean (SD) baseline IRP is 14.19 (4.39) mmHg in normal kidneys and increases with both hydronephrosis and preoperative ureteric stenting. Mean (SD) peristaltic peak IRP values of 25.75 (17.9) mmHg are reached in the renal pelvis every 3-7 s and maintained in the early post-stent period.

Glucocorticoid Minimization in Anti-Neutrophil Cytoplasmic Antibody-Associated Vasculitis: An International Survey of Clinicians.

Rationale & Objective: Research in anti-neutrophil cytoplasmic antibody-associated vasculitis (AAV) has focused on reducing treatment toxicities, notably through reduction of exposure to glucocorticoids. Glucocorticoid-sparing therapies such as avacopan are not widely available in many countries, and patients are exposed to high glucocorticoid doses. There is little data concerning what clinicians should accept as the lowest glucocorticoid dosing that can be used in induction therapy for AAV. Study Design: International, online survey. Setting & Participants: Clinicians in various countries with experience in managing vasculitis. Exposure and Outcomes: Survey questions to gauge interest and preferences in studying an induction of remission regimen for severe AAV using only 2 or 4 weeks of glucocorticoids without avacopan. Data collected included general opinions about standard of care for induction agents, glucocorticoids, and avacopan. Respondents were presented with 3 candidate trial designs, 2 of which proposed a combination of cyclophosphamide and rituximab induction. Analytical Approach: Using a 10-point Likert scale, respondents ranked each candidate trial on its usefulness in demonstrating whether a minimal glucocorticoid regimen would be safe and effective and their willingness to randomize into the trial. Results: There were 210 respondents to the survey. The candidate trials were rated moderate-to-high for usefulness to demonstrate safety and efficacy (scores 6-7/10), and moderate (scores 5-6/10) for willingness to randomize. Four-week glucocorticoid duration was preferred to 2 weeks, and combination cyclophosphamide-rituximab with 4-week glucocorticoids was the most preferred design. Forty-two percent of respondents felt avacopan had to be incorporated into a minimal GC trial design to want to recruit patients. Limitations: Representativeness of survey sample and generalizability of findings. Conclusions: Combination cyclophosphamide-rituximab may be the ideal way of studying minimal glucocorticoid use in severe AAV. Given its increasing uptake, incorporating avacopan into a potential trial design is important.

Research in anti-neutrophil cytoplasmic antibody-associated vasculitis (AAV) has focused on using less glucocorticoids to limit side effects. New drugs that drastically limit glucocorticoid use are not available in many countries. Studies are needed to find other ways of reducing glucocorticoid exposure to treat AAV, but it is unclear how best to achieve this. We administered a survey to doctors with experience in treating AAV and had them grade different combinations of widely available treatments with 2 or 4 weeks of glucocorticoids. We found that a combination of 2 doses cyclophosphamide with 2 doses rituximab and 4 weeks of glucocorticoids was the preferred treatment. The results will guide the development of a trial studying minimal use of glucocorticoids for the treatment of AAV.

Superconductor based, tomographic, neutron diagnostics for fusion power monitoring.

We propose a scalable system of compact, superconducting neutron monitors, which can be embedded in any existing cryogenic infrastructure of a fusion system. The pixel-based nature of the detectors allows them to be placed at intervals following the circumference of a cooled zone, e.g., a field coil, thus allowing for a tomographic measurement of the neutron flux surrounding the plasma. An early stage prototype of the superconducting bolometer is described, and the key results of a previous feasibility study of this prototype performed with cold neutrons are summarized. The bolometer can be adapted for use with fast neutrons by altering the composition and geometry of the neutron-to-heat conversion layer. This paper describes the initial feasibility considerations for implementation in a superconducting tokamak. The sensor is based on a high-temperature superconductor, making it possible to select the operation temperature in the range 1-90 K. Neutron flux numbers were found using the ITER MCNP reference model, and these were embedded in a TOPAS model to find the expected signal measured by the bolometer at the position of a toroidal field coil. The results at the coil position indicate suitable operation levels in terms of the magnitude of the measured signal, with a measurable signal of several ohm, which is much smaller than the saturation energy of the detector. Radiation hardness is estimated and found to be on the order of at least 40 years for the relevant radiation levels. The upcoming investigation activities of the project are described for both radiation testing and analytical modeling.

Cognition Mediates the Association Between Cerebrospinal Fluid Biomarkers of Amyloid and P-Tau and Neuropsychiatric Symptoms.

Background: Neuropsychiatric symptoms (NPS) can be an early manifestation of Alzheimer's disease (AD). However, the associations among NPS, cognition, and AD biomarkers across the disease spectrum are unclear. Objective: We analyzed cross-sectional mediation pathways between cerebrospinal fluid (CSF) biomarkers of AD (Aß1-42, p-tau181), cognitive function, and NPS. Methods: Primary models included 781 participants from the National Alzheimer's Coordinating Center (NACC) data set who had CSF analyzed for AD biomarkers using Lumipulse. NPS were assessed with the Neuropsychiatric Inventory Questionnaire (NPI-Q). We assessed cognition with the harmonized MMSE/MoCA, as well as neuropsychological tests sensitive to AD pathology: story recall, naming, animal fluency, and Trails B. The Clinical Dementia Rating (CDR®) scale assessed dementia severity. Mediation models were estimated with Kemeny metric covariance in a structural equation model framework, controlling for age, education, sex, and APOEɛ4. Results: The sample was older adults (M = 73.85, SD = 6.68; 49.9% male, 390; 27.9% dementia, 218) who were predominantly white (n = 688, 88.1%). Higher p-tau181/Aß1-42 ratio predicted higher NPI-Q, which was partially mediated by the MMSE/MoCA and, in a second model, story recall. No other pathway was statistically significant. Both the MMSE/MoCA and NPI-Q independently mediated the association between p-tau181/Aß1-42 ratio and CDR global impairment. With dementia excluded, p-tau181/Aß1-42 ratio was no longer associated with the NPI-Q. Conclusions: NPS may be secondary to cognitive impairment and AD pathology through direct and indirect pathways. NPS independently predict dementia severity in AD. However, AD pathology likely plays less of a role in NPS in samples without dementia.

Implementation and Evaluation of a Multi-level, Place-Based Tobacco Prevention and Control Program at a Minority-Serving Institution in Texas.

Multi-level, place-based interventions have proven effective at promoting a range of health behaviors, including tobacco control and discouraging the uptake of tobacco products. This paper describes the implementation and impact of a 3-year, multi-level tobacco prevention and control program at a community-college minority-serving institution (MSI) on the Texas Gulf Coast within the context of a broader multi-sector, cross-functional health coalition. The intervention studied included a tobacco-free policy, a large-scale communication campaign highlighting parts of the intervention and prevention and cessation resources. The intervention was bolstered by the support of a community-led Steering Committee and tobacco control experts. Results from the first 3 years of implementation show that tobacco-free policies were largely supported by community members, awareness of the policy increased over time, and tobacco prevention and cessation resources were successfully embedded into campus norms. This multi-component approach shows how a community college was able to effectively reach students and staff on their campus to increase awareness of both the campus tobacco-free policy and the availability of tobacco prevention and cessation resources. Additionally, it also offers lessons for future tobacco prevention and control work in higher education.

Experiences of health services for adults with cerebral palsy, their support people, and service providers.

AIM: To explore the experiences of health services among adults with cerebral palsy (CP) in Ireland, from the perspectives of adults with CP, their support people, and service providers. METHOD: A qualitative descriptive study design was used. In-depth semi-structured interviews were conducted between March and August 2021 with adults with CP, people who supported them, and health professionals. Thematic analysis was used to evaluate the data. RESULTS: Twenty-one adults with CP, seven support people (family carer[s], spouse or partner, or friend), and 15 service providers participated in the study. Adults had a mean age of 38 years 5 months (range 22-58 years) and were classified in Gross Motor Function Classification System levels I to V. Five themes were identified from the data: (1) access challenges in adult services; (2) knowledge and understanding of CP; (3) support people's role and care burden; (4) communication and interaction in adult services; and (5) health system challenges. CONCLUSION: Adults with CP in Ireland face multiple challenges accessing the health services they need. Services were reported to be inadequate, with limited resources and understanding of CP. Participants highlighted a need for system-level interventions, including enhanced training for health professionals to effectively meet the needs of adults with CP.