Immunogenicity of third dose COVID-19 vaccine strategies in patients who are immunocompromised with suboptimal immunity following two doses (OCTAVE-DUO): an open-label, multicentre, randomised, controlled, phase 3 trial.

BACKGROUND: The humoral and T-cell responses to booster COVID-19 vaccine types in multidisease immunocompromised individuals who do not generate adequate antibody responses to two COVID-19 vaccine doses, is not fully understood. The OCTAVE DUO trial aimed to determine the value of third vaccinations in a wide range of patients with primary and secondary immunodeficiencies. METHODS: OCTAVE-DUO was a prospective, open-label, multicentre, randomised, controlled, phase 3 trial investigating humoral and T-cell responses in patients who are immunocompromised following a third vaccine dose with BNT162b2 or mRNA-1273, and of NVX-CoV2373 for those with lymphoid malignancies. We recruited patients who were immunocompromised from 11 UK hospitals, aged at least 18 years, with previous sub-optimal responses to two doses of SARS-CoV-2 vaccine. Participants were randomly assigned 1:1 (1:1:1 for those with lymphoid malignancies), stratified by disease, previous vaccination type, and anti-spike antibody response following two doses. Individuals with lived experience of immune susceptibility were involved in the study design and implementation. The primary outcome was vaccine-specific immunity defined by anti-SARS-CoV-2 spike antibodies (Roche Diagnostics UK and Ireland, Burgess Hill, UK) and T-cell responses (Oxford Immunotec, Abingdon, UK) before and 21 days after the third vaccine dose analysed by a modified intention-to-treat analysis. The trial is registered with the ISRCTN registry, ISRCTN 15354495, and the EU Clinical Trials Register, EudraCT 2021-003632-87, and is complete. FINDINGS: Between Aug 4, 2021 and Mar 31, 2022, 804 participants across nine disease cohorts were randomly assigned to receive BNT162b2 (n=377), mRNA-1273 (n=374), or NVX-CoV2373 (n=53). 356 (45%) of 789 participants were women, 433 (55%) were men, and 659 (85%) of 775 were White. Anti-SARS-CoV-2 spike antibodies measured 21 days after the third vaccine dose were significantly higher than baseline pre-third dose titres in the modified intention-to-treat analysis (median 1384 arbitrary units [AU]/mL [IQR 4·3-7990·0] compared with median 11·5 AU/mL [0·4-63·1]; p<0·001). Of participants who were baseline low responders, 380 (90%) of 423 increased their antibody concentrations to more than 400 AU/mL. Conversely, 166 (54%) of 308 baseline non-responders had no response after the third dose. Detectable T-cell responses following the third vaccine dose were seen in 494 (80%) of 616 participants. There were 24 serious adverse events (BNT612b2 eight [33%] of 24, mRNA-1273 12 [50%], NVX-CoV2373 four [17%]), two (8%) of which were categorised as vaccine-related. There were seven deaths (1%) during the trial, none of which were vaccine-related. INTERPRETATION: A third vaccine dose improved the serological and T-cell response in the majority of patients who are immunocompromised. Individuals with chronic renal disease, lymphoid malignancy, on B-cell targeted therapies, or with no serological response after two vaccine doses are at higher risk of poor response to a third vaccine dose. FUNDING: Medical Research Council, Blood Cancer UK.

Assessing Student-Reported Perceptions of Prerequisite Usefulness in Preparation for Didactic Physician Assistant Education.

INTRODUCTION: To gain admittance to a physician assistant (PA) school, applicants must complete program-specific prerequisite courses and experiences. The lack of standardization contributes to complexity, expense, and limits diversity. This research assessed current didactic PA students' perceptions of prerequisite courses, course delivery methods, and direct patient care (DPC) experiences to determine which were perceived as the most useful in preparation for didactic PA education. METHODS: An online cross-sectional survey was sent to eligible PA students across the United States. The survey collected opinions on the usefulness of commonly required prerequisite courses, course delivery methods, and DPC experiences. Collected data underwent statistical analysis and qualitative analysis for open-response questions. RESULTS: A total of 527 students completed the survey. Greater than 50% reported prerequisite courses in science and psychology as well as speech, ethics, cardiopulmonary resuscitation (CPR), medical ethics, medical terminology, and nutrition "prepared them well" or "extremely well." The most frequently recommended educational delivery method was "in person." The DPC experiences reported to best prepare students were Medical Assistant, Certified Nursing Assistant, and Scribe. The reported recommended number of DPC hours was 1000 to 1499. Chi-square tests for courses that prepared students "well" and "extremely well" revealed that in-person delivery had a statistically significant association with anatomy, physiology, ethics, CPR, medical ethics, and Spanish. DISCUSSION: These significant findings should be considered by PA programs when evaluating their requirements for admission. Furthermore, PA education associations should consider universal requirements to reduce applicant barriers, complexity, and expense, which may lead to improved diversity.

Congenitally Corrected Transposition of the Great Arteries in Utero: Morphological Spectrum, Outcomes and Pitfalls in Fetal Diagnosis.

Congenitally corrected transposition of the great arteries (ccTGA) is a rare malformation with diverse morphology. We assessed features of fetuses with ccTGA and evaluated neonatal and pediatric outcomes. This was a retrospective review of fetuses with ccTGA at Birmingham Women's and Children's Hospital born from 2005 to 2019. Of thirty-six fetuses identified, six had unavailable prenatal data, one was postnatally diagnosed with isomerism and 29 fetuses were evaluated. ccTGA without associated cardiac lesions was found in 28% (8/29), ccTGA with significant VSD in 31% (9/29), ccTGA with pulmonary obstruction in 24% (7/29) and ccTGA with complex anomalies in 17% (5/29). Tricuspid regurgitation (TR) was observed in 17% (5/29) and heart block (HB) in 10% (3/29) prenatally. Six, that is 21% underwent genetic testing of which one was abnormal. Five extra-cardiac anomalies were reported prenatally and postnatally. Pregnancy was discontinued in five, of which two had moderate TR. There were thirty-one liveborn. Coarctation of the aorta was found in five postnatally but not suspected prenatally. In one, pulmonary stenosis was underestimated; otherwise, prenatal morphology was confirmed. Cardiac interventions were performed in 77% (24/31) liveborn with 39% (12/31) undergoing neonatal intervention. Overall, 6/31 liveborn died including all three with prenatal heart block and one with TR. Estimated survival for all liveborn at 1, 5 and 10 years was 87% (95% CI 76-100%), 83% (95% CI 72-98%) and 80% (95% CI 66-96%) respectively. Accurate prenatal diagnosis of ccTGA is critical for counseling. Early outcomes are favorable with 77% of liveborn undergoing surgery. Fetuses with prenatal diagnosis of complex associated abnormalities, HB and TR appear to do less well.

SARS-CoV-2-specific immune responses and clinical outcomes after COVID-19 vaccination in patients with immune-suppressive disease.

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) immune responses and infection outcomes were evaluated in 2,686 patients with varying immune-suppressive disease states after administration of two Coronavirus Disease 2019 (COVID-19) vaccines. Overall, 255 of 2,204 (12%) patients failed to develop anti-spike antibodies, with an additional 600 of 2,204 (27%) patients generating low levels (<380 AU ml-1). Vaccine failure rates were highest in ANCA-associated vasculitis on rituximab (21/29, 72%), hemodialysis on immunosuppressive therapy (6/30, 20%) and solid organ transplant recipients (20/81, 25% and 141/458, 31%). SARS-CoV-2-specific T cell responses were detected in 513 of 580 (88%) patients, with lower T cell magnitude or proportion in hemodialysis, allogeneic hematopoietic stem cell transplantation and liver transplant recipients (versus healthy controls). Humoral responses against Omicron (BA.1) were reduced, although cross-reactive T cell responses were sustained in all participants for whom these data were available. BNT162b2 was associated with higher antibody but lower cellular responses compared to ChAdOx1 nCoV-19 vaccination. We report 474 SARS-CoV-2 infection episodes, including 48 individuals with hospitalization or death from COVID-19. Decreased magnitude of both the serological and the T cell response was associated with severe COVID-19. Overall, we identified clinical phenotypes that may benefit from targeted COVID-19 therapeutic strategies.

p53 inhibitor iASPP is an unexpected suppressor of KRAS and inflammation-driven pancreatic cancer.

Oncogenic KRAS activation, inflammation and p53 mutation are key drivers of pancreatic cancer (PC) development. Here we report iASPP, an inhibitor of p53, as a paradoxical suppressor of inflammation and oncogenic KRASG12D-driven PC tumorigenesis. iASPP suppresses PC onset driven by KRASG12D alone or KRASG12D in combination with mutant p53R172H. iASPP deletion limits acinar-to-ductal metaplasia (ADM) in vitro but accelerates inflammation and KRASG12D-induced ADM, pancreatitis and PC tumorigenesis in vivo. KRASG12D/iASPPΔ8/Δ8 tumours are well-differentiated classical PCs and their derivative cell lines form subcutaneous tumours in syngeneic and nude mice. Transcriptomically, either iASPP deletion or p53 mutation in the KRASG12D background altered the expression of an extensively overlapping gene set, comprised primarily of NF-κB and AP1-regulated inflammatory genes. All these identify iASPP as a suppressor of inflammation and a p53-independent oncosuppressor of PC tumorigenesis.

Additive Manufacturing of Multimaterial Composites for Radiation Shielding and Thermal Management.

The harsh radiation environment of space induces the degradation and malfunctioning of electronic systems. Current approaches for protecting these microelectronic devices are generally limited to attenuating a single type of radiation or require only selecting components that have undergone the intensive and expensive process to be radiation-hardened by design. Herein, we describe an alternative fabrication strategy to manufacture multimaterial radiation shielding via direct ink writing of custom tungsten and boron nitride composites. The additively manufactured shields were shown to be capable of attenuating multiple species of radiation by tailoring the composition and architecture of the printed composite materials. The shear-induced alignment during the printing process of the anisotropic boron nitride flakes provided a facile method for introducing favorable thermal management characteristics to the shields. This generalized method offers a promising approach for protecting commercially available microelectronic systems from radiation damage and we anticipate this will vastly enhance the capabilities of future satellites and space systems.

Substance Use Among Physician Assistant Students: A National Study on the Prevalence of Alcohol, Tobacco, Illicit Substances, and Medication Use.

INTRODUCTION: The purpose of this study was to discover the substance use prevalence among physician assistant students (PA-S) compared with the age-relevant general US population and to examine the frequency of stress, burnout, anxiety, and depression during the didactic and clinical phases, while accounting for the impact of the COVID-19 pandemic. METHODS: A 20-item survey instrument was created. Self-reported data included demographics, anxiety, burnout, tobacco, illicit substances, and prescription medication use. Outcome-based inventories included a modified Perceived Stress Scale, Patient Health Questionnaire-2 (PHQ-2), and Alcohol Use Disorder Identification Test-Concise. The survey was emailed to all US programs (∼270 programs; ∼25,000 students), with 54 programs approving dissemination to their students (n∼4,760). RESULTS: Of the 1432 responses (30% response rate, 96% completion rate), the final validated sample was 1378 students (56.1% didactic, 43.8% clinical). When compared with the national population, PA-S prevalence for tobacco (5.2%) and illicit substance use (9.9%) were notably lower; alcohol (53.5%) was comparable; and prescription medication (7.0%) is only reported for PA students due to the lack of a national comparison. A higher frequency of substance use was observed during the didactic (52.5%) vs clinical (47.5%) phases. Stress was the dominant factor in both phases (93.5% didactic, 86.1% clinical). Respondents reported that the COVID-19 pandemic had minimal impact on reported rates, other than alcohol. DISCUSSION: Although PA-S substance use prevalence is at or below the national population, PA programs are encouraged to review their policies and provide conversations and resources for students who may have one or more risk factors and experience a negative effect from current substance use.

Medium-term Outcome of Prenatally Diagnosed Hypoplastic Left-Heart Syndrome and Impact of a Restrictive Atrial Septum Diagnosed in-utero.

OBJECTIVE: Surgical outcome data differs from overall outcomes of prenatally diagnosed fetuses with hypoplastic left heart syndrome (HLHS). Our aim was to describe outcome of prenatally diagnosed fetuses with this anomaly. METHODS: Retrospective review of prenatally diagnosed classical HLHS at a tertiary hospital over a 13-year period, estimated due dates 01/08/2006 to 31/12/2019. HLHS-variants and ventricular disproportion were excluded. RESULTS: 203 fetuses were identified with outcome information available for 201. There were extra-cardiac abnormalities in 8% (16/203), with genetic variants in 14% of those tested (17/122). There were 55 (27%) terminations of pregnancy, 5 (2%) intrauterine deaths and 10 (5%) babies had prenatally planned compassionate care. There was intention to treat (ITT) in the remaining 131/201(65%). Of these, there were 8 neonatal deaths before intervention, two patients had surgery in other centers. Of the other 121 patients, Norwood procedure performed in 113 (93%), initial hybrid in 7 (6%), and 1 had palliative coarctation stenting. Survival for the ITT group from birth at 6-months, 1-year and 5-years was 70%, 65%, 62% respectively. Altogether of the initial 201 prenatally diagnosed fetuses, 80 patients (40%) are currently alive. A restrictive atrial septum (RAS) is an important sub-category associated with death, HR 2.61, 95%CI 1.34-5.05, p = 0.005, with only 5/29 patients still alive. CONCLUSION: Medium-term outcomes of prenatally diagnosed HLHS have improved however it should be noted that almost 40% do not get to surgical palliation, which is vital to those doing fetal counselling. There remains significant mortality particularly in fetuses with in-utero diagnosed RAS.

Regulation of immunological tolerance by the p53-inhibitor iASPP.

Maintenance of immunological homeostasis between tolerance and autoimmunity is essential for the prevention of human diseases ranging from autoimmune disease to cancer. Accumulating evidence suggests that p53 can mitigate phagocytosis-induced adjuvanticity thereby promoting immunological tolerance following programmed cell death. Here we identify Inhibitor of Apoptosis Stimulating p53 Protein (iASPP), a negative regulator of p53 transcriptional activity, as a regulator of immunological tolerance. iASPP-deficiency promoted lung adenocarcinoma and pancreatic cancer tumorigenesis, while iASPP-deficient mice were less susceptible to autoimmune disease. Immune responses to iASPP-deficient tumors exhibited hallmarks of immunosuppression, including activated regulatory T cells and exhausted CD8+ T cells. Interestingly, iASPP-deficient tumor cells and tumor-infiltrating myeloid cells, CD4+, and γδ T cells expressed elevated levels of PD-1H, a recently identified transcriptional target of p53 that promotes tolerogenic phagocytosis. Identification of an iASPP/p53 axis of immune homeostasis provides a therapeutic opportunity for both autoimmune disease and cancer.

The expanding spectrum and utility of antigens in membranous nephropathy.

PURPOSE OF REVIEW: Multiple antigenic targets were discovered in membranous nephropathy, representing distinct autoimmune diseases with a similar morphologic pattern of injury. An overview of recent developments, including antigen types, clinical associations, serologic monitoring, and advancements in understanding disease pathogenesis are provided. RECENT FINDINGS: Several new antigenic targets have defined subtypes of membranous nephropathy, including Neural epidermal growth factor-like 1, protocadherin 7, HTRA1, FAT1, SEMA3B, NTNG1, NCAM1, exostosin 1/2, transforming growth factor beta receptor 3, CNTN1, proprotein convertase subtilisin/kexin type 6, and neuron-derived neurotrophic factor. Autoantigens in membranous nephropathy may demonstrate unique clinical associations, assisting the nephrologist to identify potential disease etiologies and triggers, such as autoimmune disease, cancer, medications, and infections. SUMMARY: We are entering an exciting era for which an antigen-based approach will further define subtypes of membranous nephropathy, allow for development of noninvasive diagnostics, and improve care for patients.

EXT1 and NCAM1-associated membranous lupus nephritis in a cohort of patients undergoing repeat kidney biopsies.

BACKGROUND: Exostosin 1/2 (EXT1/2) and neural cell adhesion molecule 1 (NCAM1) associated membranous lupus nephritis (MLN) may represent distinct disease phenotypes with prognostic significance. METHODS: We searched our archives for patients with systemic lupus erythematous (SLE) and at least two kidney biopsies demonstrating MLN. Each biopsy was stained for EXT1 and NCAM1 and scored as positive or negative. Histopathologic and clinical data were reviewed. RESULTS: We identified 31 patients with a clinical diagnosis of SLE and at least two kidney biopsies with MLN. A total of 28 patients (90%) showed concordant staining for EXT1 and NCAM1 in both biopsies; 8 patients (26%) were EXT1 positive and NCAM1 negative, 18 patients (58%) were EXT1 negative and NCAM1 negative and 2 patients (7%) were EXT1 negative and NCAM1 positive. A total of three patients (10%) had discordant EXT1 staining between their first and last biopsies; two patients (7%) were EXT1 positive in their first biopsy and EXT1 negative in the last biopsy and one patient (3%) was EXT1 negative in his first biopsy and EXT1 positive in the last biopsy. Compared with the EXT1-negative cohort at the time of the first biopsy, the EXT1-positive cohort had a higher average estimated glomerular filtration rate (eGFR; 141 versus 108 mL/min/1.73 m2; P = 0.04), lower average percent global glomerulosclerosis (0.5 versus 12%; P = 0.05), lower average interstitial fibrosis and tubular atrophy (2.5 versus 11.7%; P = 0.06) and lower average total National Institutes of Health (NH) chronicity scores (0.75 versus 2.33; P = 0.05). On long-term follow-up, the rate of change in eGFR did not significantly differ between the two groups (P = 0.24). One EXT1-positive patient (12.5%) developed stage 4 chronic kidney disease (CKD) or end-stage kidney disease (ESKD) compared with four patients (20%) in the EXT-negative group and two of the three EXT1-discordant patients (P = 0.38). CONCLUSIONS: We performed the largest retrospective repeat-biopsy study to evaluate EXT1 and NCAM1 autoantigens in MLN. Our data demonstrate that EXT1 positivity is associated with better kidney function at the time of diagnosis and raises the possibility that EXT1 status may change throughout the disease course of MLN.

Common arterial trunk in functionally univentricular hearts: a case series.

INTRODUCTION: The association of a univentricular heart defect with common arterial trunk is extremely rare. There is a lack of population-based outcome studies reported in the literature. METHODS: The hospital records, echocardiographic and other imaging modality data, outpatients' records, operation notes, and other electronic data were reviewed. Patients were reviewed, and the final outcomes of surgery were observed. RESULTS: Six cases (two males) with common arterial trunk presented over a 30-year period. Five had a complete unbalanced atrioventricular septal defect (83%) and one (17%) had tricuspid atresia associated with common arterial trunk. All had antenatal diagnosis. Two cases (33%) were excluded from initial surgical palliation due to Trisomy 21 in one and severe truncal valve regurgitation in one. Initial surgical palliation was performed in four cases (67%) at median age of 31 days (2-60) and consisted of disconnection and reconstruction of the pulmonary arteries and establishing controlled pulmonary blood flow. There were no early deaths. Conversion to cavopulmonary shunt was not possible in two due to severe airway problems in one and pulmonary arteries anatomy in one. They died at 11 and 16 months, respectively. Two patients (33%) underwent cavopulmonary shunt with 1 (17%) being alive at 18 months - 12 months after cavopulmonary shunt. The second patient proceeded to Fontan completion at 19 months but required catheter takedown 3 months later and died 3.5 years later. CONCLUSIONS: Univentricular hearts with common arterial trunk carry extremely poor short- to medium-term outcomes. This should inform antenatal and postnatal counselling and decision-making.

Mutant Ras and inflammation-driven skin tumorigenesis is suppressed via a JNK-iASPP-AP1 axis.

Concurrent mutation of a RAS oncogene and the tumor suppressor p53 is common in tumorigenesis, and inflammation can promote RAS-driven tumorigenesis without the need to mutate p53. Here, we show, using a well-established mutant RAS and an inflammation-driven mouse skin tumor model, that loss of the p53 inhibitor iASPP facilitates tumorigenesis. Specifically, iASPP regulates expression of a subset of p63 and AP1 targets, including genes involved in skin differentiation and inflammation, suggesting that loss of iASPP in keratinocytes supports a tumor-promoting inflammatory microenvironment. Mechanistically, JNK-mediated phosphorylation regulates iASPP function and inhibits iASPP binding with AP1 components, such as JUND, via PXXP/SH3 domain-mediated interaction. Our results uncover a JNK-iASPP-AP1 regulatory axis that is crucial for tissue homeostasis. We show that iASPP is a tumor suppressor and an AP1 coregulator.

Proceedings of the 2022 Santa Fe Bone Symposium: Current Concepts in the Care of Patients with Osteoporosis and Metabolic Bone Diseases.

The 22nd Annual Santa Fe Bone Symposium (SFBS) was a hybrid meeting held August 5-6, 2022, with in-person and virtual attendees. Altogether, over 400 individuals registered, a majority of whom attended in-person, representing many states in the USA plus 7 other countries. The SFBS included 10 plenary presentations, 2 faculty panel discussions, satellite symposia, Bone Health & Osteoporosis Foundation Fracture Liaison Service Boot Camp, and a Project ECHO workshop, with lively interactive discussions for all events. Topics of interest included fracture prevention at different stages of life; how to treat and when to change therapy; skeletal health in cancer patients; advanced imaging to assess bone strength; the state of healthcare in the USA; osteosarcopenia; vitamin D update; perioperative bone health care; new guidelines for managing primary hyperparathyroidism; new concepts on bone modeling and remodeling; and an overview on the care of rare bone diseases, including hypophosphatasia, X-linked hypophosphatemia, tumor induced osteomalacia, osteogenesis imperfecta, fibrodysplasia ossificans progressiva, and osteopetrosis. The SFBS was preceded by the Santa Fe Fellows Workshop on Osteoporosis and Metabolic Bone Diseases, a collaboration of the Endocrine Fellows Foundation and the Osteoporosis Foundation of New Mexico. From the Workshop, 4 participating fellows were selected to give oral presentations at the bone symposium. These proceedings represent the clinical highlights of 2022 SFBS presentations and the discussions that followed, all with the aim of optimizing skeletal health and minimizing the consequences of fragile bones.

MAiD to Last: Creating a Care Ecology for Sustainable Medical Assistance in Dying Services.

This paper depicts a case study of an organizational strategy for the promotion of ethical practice when introducing a new, high-risk, ethically-charged medical practice like Medical Assistance in Dying (MAiD). We describe the development of an interprofessional program that enables the delivery of high-quality, whole-person MAiD care that is values-based and sustainable. A "care ecology" strategy recognizes the interconnected web of relationships and structures necessary to support a quality experience of MAiD for patients, families, and clinicians. This program exemplifies a care ecology approach that addresses common barriers to entry to MAiD practice, and also meets the needs of a variety of stakeholders through the creation of patient and family resources, team supports, standards of practice, professional development opportunities, organizational infrastructure, and community partnerships. We also describe how a thriving care ecology evolves to remain resilient, and to enable integration as the needs of the organization, team and program change over time. The design and development of this program may be adapted to other jurisdictions and organizations where MAiD is introduced, or where new patient populations become eligible for MAiD. This care ecology model may also be applicable to the creation of sustainable programs that provide other morally controversial or novel clinical services.

Getting Beyond Pros and Cons: Results of a Stakeholder Needs Assessment on Physician Assisted Dying in the Hospital Setting.

This study assessed the attitudes and needs of physicians and health professional staff at a tertiary care hospital in Canada regarding the introduction of physician assisted dying (PAD) during 2015-16. This research aimed to develop an understanding of the wishes, concerns and hopes of stakeholders related to handling requests for PAD; to determine what supports/structures/resources health care professionals (HCP) require in order to ensure high quality and compassionate care for patients requesting PAD, and a supportive environment for all healthcare providers across the moral spectrum. This study constituted a mixed methods design with a qualitative descriptive approach for the study's qualitative component. A total of 303 HCPs working in a tertiary care hospital completed an online survey and 64 HCPs working in hospital units with high mortality rates participated in 8 focus group discussions. Both focus group and survey data coalesced around several themes to support the implementation of PAD following the decriminalization of this practice: the importance of high quality care; honoring moral diversity; supporting values (such as autonomy, privacy, beneficence); and developing resources, including collaboration with palliative care, education, policies and a specialized team. This study provided the foundational evidence to support the development of the PAD program described in other papers in this collection, and can be a model for gathering evidence from stakeholders to inform the implementation of PAD in any healthcare organization.

The role of osteoanabolic agents in the management of patients with osteoporosis.

Reducing fracture risk is the objective of osteoporosis treatment. Bone-forming osteoporosis drugs increase bone mass, restore bone microarchitecture, and reduce fracture risk more effectively than oral bisphosphonates, providing strong justification for the use of these agents as the initial therapy or after anti-remodeling agents in patients at very high risk of fracture. At the end of a 12-to-24-month course of osteoanabolic therapy, transitioning to a potent anti-remodeling agent maintains and enhances the treatment benefit. This review describes the clinical applications of osteoanabolic therapy for osteoporosis.

Clinicopathologic features of non-lupus membranous nephropathy in a pediatric population.

BACKGROUND: Membranous nephropathy is an uncommon cause of nephrotic syndrome in pediatrics. METHODS: We reviewed our kidney biopsy records for patients ≤ 20 years of age with membranous nephropathy without evidence of systemic lupus erythematosus within 6 months of biopsy (January 1995-September 2020). Staining for PLA2R, NELL1, THSD7A, SEMA3B, EXT2 (3 biopsies), and IgG-subclass were performed. RESULTS: Sixteen children (≤ 12 years) and 25 adolescents (13-20 years) were identified. Four children and 15 adolescents showed autoantigen positivity: PLA2R+/SEMA3B- (13), SEMA3B+/PLA2R+ (2), SEMA3B+/PLA2R- (1), NELL1 (1), EXT2+ (2), and THSD7A (0). Co-morbidities associated with PLA2R positivity included IPEX syndrome, active hepatitis B, Von Hippel Lindau syndrome, solitary kidney, type 1 diabetes, hyperuricemia, pregnancy (1), obesity (3), type II diabetes, H. pylori, viral prodrome, and nephrolithiasis. The SEMA3B+/PLA2R- adolescent was pregnant, the NELL1+ adolescent was obese, and the two EXT2+ adolescents eventually met the clinical criteria for lupus (4, 9 years post-biopsy). Co-morbidities among the remaining 24 patients included remote hepatitis B (2), Down's syndrome, lysinuric protein intolerance, recurrent UTIs, hypothyroidism, pregnancy (3), and obesity (2). Follow-up data was available for 12 children and 16 adolescents. Of the 12 children, 6 achieved complete remission, 4 achieved partial remission, and 2 had no response to treatment (1 transplant). Of the 16 adolescents, 4 achieved complete remission, 4 achieved partial remission, and 8 had no response to treatment (3 transplants). A child with "full-house" immunofluorescence staining achieved spontaneous disease remission. CONCLUSION: Our non-lupus membranous nephropathy cohort represents one of the largest pediatric studies to date. A higher resolution version of the Graphical abstract is available as Supplementary information.

Loss of MEN1 function impairs DNA repair capability of pancreatic neuroendocrine tumors.

Somatic MEN1 mutations occur in up to 50% of pancreatic neuroendocrine tumors (PanNETs). Clinical studies have shown that radiation therapy (IR) is effective in a subset of PanNETs, but it remains unclear why some patients respond better to IR than others. Herein, we study whether MEN1 loss of function increases radiosensitivity of PanNETs and determine its effect on DNA double-strand break (DSB) repair. After creating a MEN1 knockout PanNET cell line, we confirmed reduced DSB repair capacity in MEN1-deficient cells and linked these findings to a defect in homologous recombination, as well as reduced BRCA2 expression levels. Consistent with this model, we found that MEN1 mutant cells displayed increased sensitivity to the highly trapping poly (ADP-ribose) polymerase (PARP) 1 inhibitor talazoparib in vitro. Our results suggest that combining IR with PARP inhibition may be beneficial in patients with PanNETs and MEN1 loss of function.

Strategies and techniques for quality control and semantic enrichment with multimodal data: a case study in colorectal cancer with eHDPrep.

BACKGROUND: Integration of data from multiple domains can greatly enhance the quality and applicability of knowledge generated in analysis workflows. However, working with health data is challenging, requiring careful preparation in order to support meaningful interpretation and robust results. Ontologies encapsulate relationships between variables that can enrich the semantic content of health datasets to enhance interpretability and inform downstream analyses. FINDINGS: We developed an R package for electronic health data preparation, "eHDPrep," demonstrated upon a multimodal colorectal cancer dataset (661 patients, 155 variables; Colo-661); a further demonstrator is taken from The Cancer Genome Atlas (459 patients, 94 variables; TCGA-COAD). eHDPrep offers user-friendly methods for quality control, including internal consistency checking and redundancy removal with information-theoretic variable merging. Semantic enrichment functionality is provided, enabling generation of new informative "meta-variables" according to ontological common ancestry between variables, demonstrated with SNOMED CT and the Gene Ontology in the current study. eHDPrep also facilitates numerical encoding, variable extraction from free text, completeness analysis, and user review of modifications to the dataset. CONCLUSIONS: eHDPrep provides effective tools to assess and enhance data quality, laying the foundation for robust performance and interpretability in downstream analyses. Application to multimodal colorectal cancer datasets resulted in improved data quality, structuring, and robust encoding, as well as enhanced semantic information. We make eHDPrep available as an R package from CRAN (https://cran.r-project.org/package = eHDPrep) and GitHub (https://github.com/overton-group/eHDPrep).