Genetic copy number variants, cognition and psychosis: a meta-analysis and a family study

The burden of large and rare copy number genetic variants (CNVs) as well as certain specific CNVs increase the risk of developing schizophrenia. Several cognitive measures are purported schizophrenia endophenotypes and may represent an intermediate point between genetics and the illness. This paper investigates the influence of CNVs on cognition. We conducted a systematic review and meta-analysis of the literature exploring the effect of CNV burden on general intelligence. We included ten primary studies with a total of 18,847 participants and found no evidence of association. In a new psychosis family study, we investigated the effects of CNVs on specific cognitive abilities. We examined the burden of large and rare CNVs (>200 kb, <1% MAF) as well as known schizophrenia-associated CNVs in patients with psychotic disorders, their unaffected relatives and controls (N = 3428) from the Psychosis Endophenotypes International Consortium (PEIC). The carriers of specific schizophrenia-associated CNVs showed poorer performance than non-carriers in immediate (P = 0.0036) and delayed (P = 0.0115) verbal recall. We found suggestive evidence that carriers of schizophrenia-associated CNVs had poorer block design performance (P = 0.0307). We do not find any association between CNV burden and cognition. Our findings show that the known high-risk CNVs are not only associated with schizophrenia and other neurodevelopmental disorders, but are also a contributing factor to impairment in cognitive domains such as memory and perceptual reasoning, and act as intermediate biomarkers of disease risk.This work was supported by the Medical Research Council (G0901310) and the Wellcome Trust (grants 085475/B/08/Z, 085475/Z/08/Z). This study was supported by the NIHR Biomedical Research Centre at University College London Hospitals NHS Foundation Trust and University College London and by the NIHR Biomedical Research Centre for Mental Health at the South London and Maudsley NHS Foundation Trust at King’s College London. Further support to EB: Mental Health Research UK’s John Grace QC award, BMA Margaret Temple grants 2016 and 2006, MRC—Korean Health Industry Development Institute Partnering Award (MC_PC_16014), MRC New Investigator Award and a MRC Centenary Award (G0901310), National Institute of Health Research UK post-doctoral fellowship, the Psychiatry Research Trust, the Schizophrenia Research Fund, the Brain and Behaviour Research foundation’s NARSAD Young Investigator Awards 2005, 2008, Wellcome Trust Research Training Fellowship, the NIHR Biomedical Research Centre at UCLH, and the NIHR Biomedical Research Centre for Mental Health at the South London and Maudsley NHS Foundation Trust and Institute of Psychiatry King’s College London. Further support to co-authors: The Brain and Behaviour Research foundation’s (NARSAD’s) Young Investigator Award (Grant 22604, awarded to CI). The BMA Margaret Temple grant 2016 to JT. A 2014 European Research Council Marie Curie award to A Díez-Revuelta. HI has received funding from the European Union’s Horizon 2020 research and innovation programme under the Marie Sklodowska-Curie grant agreement No 747429. A Medical Research Council doctoral studentship to JH-S, IA-Z and AB. A Mental Health Research UK studentship to RM. VB is supported by a Wellcome Trust Seed Award in Science (200589/Z/16/Z). FWO Senior Clinical Fellowship to RvW. The infrastructure for the GROUP consortium is funded through the Geestkracht programme of the Dutch Health Research Council (ZON-MW, grant number 10-000-1001), and matching funds from participating pharmaceutical companies (Lundbeck, AstraZeneca, Eli Lilly, Janssen Cilag) and universities and mental health care organisations (Amsterdam: Academic Psychiatric Centre of the Academic Medical Centre and the mental health institutions: GGZ Ingeest, Arkin, Dijk en Duin, GGZ Rivierduinen, Erasmus Medical Centre, GGZ Noord Holland Noord. Groningen: University Medical Centre Groningen and the mental health institutions: Lentis, GGZ Friesland, GGZ Drenthe, Dimence, Mediant, GGNet Warnsveld, Yulius Dordrecht and Parnassia psycho-medical centre The Hague. Maastricht: Maastricht University Medical Centre and the mental health institutions: GGZ Eindhoven en De Kempen, GGZ Breburg, GGZ Oost-Brabant, Vincent van Gogh voor Geestelijke Gezondheid, Mondriaan, Virenze riagg, Zuyderland GGZ, MET ggz, Universitair Centrum Sint-Jozef Kortenberg, CAPRI University of Antwerp, PC Ziekeren Sint-Truiden, PZ Sancta Maria Sint-Truiden, GGZ Overpelt, OPZ Rekem. Utrecht: University Medical Centre Utrecht and the mental health institutions Altrecht, GGZ Centraal and Delta). The Santander cohort was supported by Instituto de Salud Carlos III (PI020499, PI050427, PI060507), SENY Fundació (CI 2005-0308007), Fundacion Ramón Areces and Fundacion Marqués de Valdecilla (API07/011, API10/13). We thank Valdecilla Biobank for providing the biological PAFIP samples and associated data included in this study and for its help in the technical execution of this work; we also thank IDIVAL Neuroimaging Unit for its help in the acquisition and processing of imaging PAFIP data

Changes in quality of life after balloon treatment followed by gastric banding in severely obese patients--the use of two different quality of life questionnaires

Improvements in quality of life (QOL) obtained by weight loss have mainly been reported after bariatric surgery. QOL has not been investigated in surgical patients first losing weight by nonsurgical means followed by a surgical intervention and never simultaneously by two QOL-a generic and a disease-specific-questionnaires. Prospective data were obtained from 40 consecutive patients (mean age 36.6 years, body weight 142.4 kg, body mass index (BMI) 46.5 kg/m2). Two different QOL questionnaires, the generic Medical Outcomes Study Short Form-36 (SF-36) and the disease-specific Health-Related Quality of Life (HRQL) questionnaire, were evaluated at three points in time: at the start, 3 months after the placement of an intragastric balloon that remained in situ for 6 months, and 3 months after subsequent gastric banding. QOL scores revealed a significant improvement in many health domains, with an earlier improvement with the disease-specific HRQL, whereas the generic QOL questionnaire lagged behind. However, in the end, the SF-36 caught up completely to normal-weight levels, whereas some scales of the HRQL remained below these levels. Work productivity and involvement in sports improved significantly. BMI declined significantly over time, but no correlation with SF-36 and HRQL score changes was found. The QOL improved substantially independent of changes in BMI. Because of the divergent outcomes of generic and disease-specific QOL questionnaires, prospective studies should examine the sensitivity to changes of both kinds of QOL questionnaire

The Subjective Experience of Living with Parkinson's Disease:A Meta-Ethnography of Qualitative Literature

BACKGROUND: A better understanding of the subjective experience of living with Parkinson's disease (PD) and the factors that influence this experience can be used to improve wellbeing of people with PD (PwP). OBJECTIVE: To gain more insight in the subjective experience of PD from the PwP's perspective, and the factors that contribute to this experience. METHODS: In this qualitative review, we performed a systematic search of qualitative studies discussing the subjective experience of PD and extracted reported themes (first order themes). Using a meta-ethnographic approach, we categorized the first order themes into second order themes, and created a third order construct: a holistic model of the subjective experience of living with PD. RESULTS: We included 20 studies with a total sample of 279 PwP. Data-extraction yielded 227 first order themes, which were categorized into the second order themes: 1) Awareness, 2) Disruption, 3) Adjustment, 4) The external environment, and 5) The changing self. With these themes, we developed the "model of dialectic change" which conceptualizes life with PD as a transformative journey, wherein PwP employ strategies to stabilize their changeable relationship with their external environment, while simultaneously redefining their self-concept. CONCLUSION: Our findings indicate that not only the symptoms of PD, but also the manner in which these cause disruptions in the PwP's interaction with their personal environment and self-concept, determine the subjective experience of PD andquality of life. Some PwP experience problems with adjusting, resulting in psychological distress. This calls for a holistic, multidisciplinary and participatory approach of PD

IGFBP7 Induces Differentiation and Loss of Survival of Human Acute Myeloid Leukemia Stem Cells without Affecting Normal Hematopoiesis

Leukemic stem cells (LSCs) are thought to be the major cause of the recurrence of acute myeloid leukemia (AML) due to their potential for self-renewal. To identify therapeutic strategies targeting LSCs, while sparing healthy hematopoietic stem cells (HSCs), we performed gene expression profiling of LSCs, HSCs, and leukemic progenitors all residing within the same AML bone marrow and identified insulin-like growth factor-binding protein 7 (IGFBP7) as differentially expressed. Low IGFBP7 is a feature of LSCs and is associated with reduced chemotherapy sensitivity. Enhancing IGFBP7 by overexpression or addition of recombinant human IGFBP7 (rhIGFBP7) resulted in differentiation, inhibition of cell survival, and increased chemotherapy sensitivity of primary AML cells. Adding rhIGFBP7 reduced leukemic stem and/or progenitor survival and reversed a stem-like gene signature, but it had no influence on normal hematopoietic stem cell survival. Our data suggest a potential clinical utility of the addition of rhIGFBP7 to current chemotherapy regimens to decrease AML relapse rates

Antibody Response in Immunocompromised Patients With Hematologic Cancers Who Received a 3-Dose mRNA-1273 Vaccination Schedule for COVID-19.

Importance: It has become common practice to offer immunocompromised patients with hematologic cancers a third COVID-19 vaccination dose, but data substantiating this are scarce. Objective: To assess whether a third mRNA-1273 vaccination is associated with increased neutralizing antibody concentrations in immunocompromised patients with hematologic cancers comparable to levels obtained in healthy individuals after the standard 2-dose mRNA-1273 vaccination schedule. Design, Setting, and Participants: This prospective observational cohort study was conducted at 4 university hospitals in the Netherlands and included 584 evaluable patients spanning the spectrum of hematologic cancers and 44 randomly selected age-matched adults without malignant or immunodeficient comorbidities. Exposures: One additional mRNA-1273 vaccination 5 months after completion of the standard 2-dose mRNA-1273 vaccination schedule. Main Outcomes and Measures: Serum immunoglobulin G (IgG) antibodies to spike subunit 1 (S1) antigens prior to and 4 weeks after a third mRNA-1273 vaccination, and antibody neutralization capacity of wild-type, Delta, and Omicron variants in a subgroup of patients. Results: In this cohort of 584 immunocompromised patients with hematologic cancers (mean [SD] age, 60 [11.2] years; 216 [37.0%] women), a third mRNA-1273 vaccination was associated with median S1-IgG concentrations comparable to concentrations obtained by healthy individuals after the 2-dose mRNA-1273 schedule. The rise in S1-IgG concentration after the third vaccination was most pronounced in patients with a recovering immune system, but potent responses were also observed in patients with persistent immunodeficiencies. Specifically, patients with myeloid cancers or multiple myeloma and recipients of autologous or allogeneic hematopoietic cell transplantation (HCT) reached median S1-IgG concentrations similar to those obtained by healthy individuals after a 2-dose schedule. Patients receiving or shortly after completing anti-CD20 therapy, CD19-directed chimeric antigen receptor T-cell therapy recipients, and patients with chronic lymphocytic leukemia receiving ibrutinib were less responsive or unresponsive to the third vaccination. In the 27 patients who received cell therapy between the second and third vaccination, S1 antibodies were preserved, but a third mRNA-1273 vaccination was not associated with significantly enhanced S1-IgG concentrations except for patients with multiple myeloma receiving autologous HCT. A third vaccination was associated with significantly improved neutralization capacity per antibody. Conclusions and Relevance: Results of this cohort study support that the primary schedule for immunocompromised patients with hematologic cancers should be supplemented with a delayed third vaccination. Patients with B-cell lymphoma and allogeneic HCT recipients need to be revaccinated after treatment or transplantation. Trial Registration: EudraCT Identifier: 2021-001072-41

Quantitative analysis of mRNA-1273 COVID-19 vaccination response in immunocompromised adult hematology patients.

Vaccination guidelines for patients treated for hematological diseases are typically conservative. Given their high risk for severe coronavirus infectious disease 2019 (COVID-19) it is important to identify those patients that benefit from vaccination. We prospectively quantified serum IgG antibodies to spike subunit 1 (S1)antigensduring and after 2-dose mRNA-1273 (Spikevax/Moderna) vaccination in hematology patients. Obtaining S1 IgG≥300 binding antibody units (BAU)/mlwas considered adequate as it represents the lower level of S1 IgG concentration obtained in healthy individuals andit correlates with potent virus neutralization. Selected patients (n=723) were severely immunocompromised due to their disease or treatment thereof. Nevertheless, more than 50% of patients obtained S1 IgG ≥300 BAU/ml after 2-dose mRNA-1273. All patients with sickle cell disease or chronic myeloid leukemia obtained adequate antibody concentrations.Around 70% ofpatients with chronic graftversushostdisease (GvHD), multiple myeloma, or untreated chronic lymphocytic leukemia (CLL) obtained S1 IgG≥300 BAU/ml.Ruxolitinib or hypomethylating therapy but not high-dose chemotherapy blunted responses in myeloid malignancies. Responses inlymphoma patients, CLL patients on ibrutinib, and chimeric antigen receptor T cell recipients were low.The minimal time-interval after autologous hematopoietic cell transplantation (HCT) to reach adequate concentrations was <2 months for multiple myeloma, 8 months for lymphoma, and 4-6 months after allogeneic HCT.Serum IgG4, absolute B and NK cell number and number of immunosuppressants predicted S1 IgG ≥300 BAU/ml. Hematology patients on chemotherapy, shortly after HCT, or with chronic GvHD should not be precluded from vaccination. Netherlands Trial Register NL9553

Quantitative analysis of mRNA-1273 COVID-19 vaccination response in immunocompromised adult hematology patients

Vaccination guidelines for patients treated for hematological diseases are typically conservative. Given their high risk for severe COVID-19, it is important to identify those patients that benefit from vaccination. We prospectively quantified serum immunoglobulin G (IgG) antibodies to spike subunit 1 (S1) antigens during and after 2-dose mRNA-1273 (Spikevax/Moderna) vaccination in hematology patients. Obtaining S1 IgG $300 binding antibody units (BAUs)/mL was considered adequate as it represents the lower level of S1 IgG concentration obtained in healthy individuals, and it correlates with potent virus neutralization. Selected patients (n 5 723) were severely immunocompromised owing to their disease or treatment thereof. Nevertheless, .50$ 300 BAUs/mL after 2-dose mRNA-1273. All patients with sickle cell disease or chronic myeloid leukemia obtained adequate antibody concentrations. Around 70% of patients with chronic graft-versus-host disease (cGVHD), multiple myeloma, or untreated chronic lymphocytic leukemia (CLL) obtained S1 IgG $300 BAUs/mL. Ruxolitinib or hypomethylating therapy but not high-dose chemotherapy blunted responses in myeloid malignancies. Responses in patients with lymphoma, patients with CLL on ibrutinib, and chimeric antigen receptor T-cell recipients were low. The minimal time interval after autologous hematopoietic cell transplantation (HCT) to reach adequate concentrations was,2 months for multiple myeloma, 8 months for lymphoma, and 4 to 6 months after allogeneic HCT. Serum IgG4, absolute B- and natural killer–cell number, and number of immunosuppressants predicted S1 IgG$ 300 BAUs/mL. Hematology patients on chemotherapy, shortly after HCT, or with cGVHD should not be precluded from vaccination. This trial was registered at Netherlands Trial Register as #NL9553