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  • 1
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    Integrating de novo and inherited variants in 42,607 autism cases identifies mutations in new moderate-risk genes
    Springer Science and Business Media LLC ; 2022
    In:  Nature Genetics Vol. 54, No. 9 ( 2022-09), p. 1305-1319
    Details
    In: Nature Genetics, Springer Science and Business Media LLC, Vol. 54, No. 9 ( 2022-09), p. 1305-1319
    Abstract: To capture the full spectrum of genetic risk for autism, we performed a two-stage analysis of rare de novo and inherited coding variants in 42,607 autism cases, including 35,130 new cases recruited online by SPARK. We identified 60 genes with exome-wide significance ( P   〈  2.5 × 10 −6 ), including five new risk genes ( NAV3 , ITSN1 , MARK2 , SCAF1 and HNRNPUL2 ). The association of NAV3 with autism risk is primarily driven by rare inherited loss-of-function (LoF) variants, with an estimated relative risk of 4, consistent with moderate effect. Autistic individuals with LoF variants in the four moderate-risk genes ( NAV3 , ITSN1 , SCAF1 and HNRNPUL2 ; n  = 95) have less cognitive impairment than 129 autistic individuals with LoF variants in highly penetrant genes ( CHD8, SCN2A, ADNP, FOXP1 and SHANK3 ) (59% vs 88%, P  = 1.9 × 10 −6 ). Power calculations suggest that much larger numbers of autism cases are needed to identify additional moderate-risk genes.
    Type of Medium: Online Resource
    ISSN: 1061-4036 , 1546-1718
    URL: Article
    DOI: 10.1038/s41588-022-01148-2
    RVK:
    XA 10000
    Language: English
    Publisher: Springer Science and Business Media LLC
    Publication Date: 2022
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  • 2
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    Increasing frailty is associated with higher prevalence and reduced recognition of delirium in older hospitalised inpatients: results of a multi-centre study
    Springer Science and Business Media LLC ; 2023
    In:  European Geriatric Medicine Vol. 14, No. 2 ( 2023-01-25), p. 325-332
    Details
    In: European Geriatric Medicine, Springer Science and Business Media LLC, Vol. 14, No. 2 ( 2023-01-25), p. 325-332
    Abstract: Delirium is a neuropsychiatric disorder delineated by an acute change in cognition, attention, and consciousness. It is common, particularly in older adults, but poorly recognised. Frailty is the accumulation of deficits conferring an increased risk of adverse outcomes. We set out to determine how severity of frailty, as measured using the CFS, affected delirium rates, and recognition in hospitalised older people in the United Kingdom. Methods Adults over 65 years were included in an observational multi-centre audit across UK hospitals, two prospective rounds, and one retrospective note review. Clinical Frailty Scale (CFS), delirium status, and 30-day outcomes were recorded. Results The overall prevalence of delirium was 16.3% (483). Patients with delirium were more frail than patients without delirium (median CFS 6 vs 4). The risk of delirium was greater with increasing frailty [OR 2.9 (1.8–4.6) in CFS 4 vs 1–3; OR 12.4 (6.2–24.5) in CFS 8 vs 1–3]. Higher CFS was associated with reduced recognition of delirium (OR of 0.7 (0.3–1.9) in CFS 4 compared to 0.2 (0.1–0.7) in CFS 8). These risks were both independent of age and dementia. Conclusion We have demonstrated an incremental increase in risk of delirium with increasing frailty. This has important clinical implications, suggesting that frailty may provide a more nuanced measure of vulnerability to delirium and poor outcomes. However, the most frail patients are least likely to have their delirium diagnosed and there is a significant lack of research into the underlying pathophysiology of both of these common geriatric syndromes.
    Type of Medium: Online Resource
    ISSN: 1878-7657
    URL: Article
    DOI: 10.1007/s41999-022-00737-y
    Language: English
    Publisher: Springer Science and Business Media LLC
    Publication Date: 2023
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  • 3
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    Abatacept, Cenicriviroc, or Infliximab for Treatment of Adults Hospitalized With COVID-19 Pneumonia : A Randomized Clinical Trial
    American Medical Association (AMA) ; 2023
    In:  JAMA Vol. 330, No. 4 ( 2023-07-25), p. 328-
    Details
    In: JAMA, American Medical Association (AMA), Vol. 330, No. 4 ( 2023-07-25), p. 328-
    Abstract: Immune dysregulation contributes to poorer outcomes in COVID-19. Objective To investigate whether abatacept, cenicriviroc, or infliximab provides benefit when added to standard care for COVID-19 pneumonia. Design, Setting, and Participants Randomized, double-masked, placebo-controlled clinical trial using a master protocol to investigate immunomodulators added to standard care for treatment of participants hospitalized with COVID-19 pneumonia. The results of 3 substudies are reported from 95 hospitals at 85 clinical research sites in the US and Latin America. Hospitalized patients 18 years or older with confirmed SARS-CoV-2 infection within 14 days and evidence of pulmonary involvement underwent randomization between October 2020 and December 2021. Interventions Single infusion of abatacept (10 mg/kg; maximum dose, 1000 mg) or infliximab (5 mg/kg) or a 28-day oral course of cenicriviroc (300-mg loading dose followed by 150 mg twice per day). Main Outcomes and Measures The primary outcome was time to recovery by day 28 evaluated using an 8-point ordinal scale (higher scores indicate better health). Recovery was defined as the first day the participant scored at least 6 on the ordinal scale. Results Of the 1971 participants randomized across the 3 substudies, the mean (SD) age was 54.8 (14.6) years and 1218 (61.8%) were men. The primary end point of time to recovery from COVID-19 pneumonia was not significantly different for abatacept (recovery rate ratio [RRR], 1.12 [95% CI, 0.98-1.28] ; P  = .09), cenicriviroc (RRR, 1.01 [95% CI, 0.86-1.18]; P  = .94), or infliximab (RRR, 1.12 [95% CI, 0.99-1.28]; P  = .08) compared with placebo. All-cause 28-day mortality was 11.0% for abatacept vs 15.1% for placebo (odds ratio [OR], 0.62 [95% CI, 0.41-0.94] ), 13.8% for cenicriviroc vs 11.9% for placebo (OR, 1.18 [95% CI 0.72-1.94]), and 10.1% for infliximab vs 14.5% for placebo (OR, 0.59 [95% CI, 0.39-0.90] ). Safety outcomes were comparable between active treatment and placebo, including secondary infections, in all 3 substudies. Conclusions and Relevance Time to recovery from COVID-19 pneumonia among hospitalized participants was not significantly different for abatacept, cenicriviroc, or infliximab vs placebo. Trial Registration ClinicalTrials.gov Identifier: NCT04593940
    Type of Medium: Online Resource
    ISSN: 0098-7484
    URL: Article
    DOI: 10.1001/jama.2023.11043
    RVK:
    XA 10000
    Language: English
    Publisher: American Medical Association (AMA)
    Publication Date: 2023
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    detail.hit.zdb_id: 2018410-4
    SSG: 5,21
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  • 4
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    Decision making and support available to individuals considering and undertaking electroconvulsive therapy (ECT): a qualitative, consumer-led study
    Springer Science and Business Media LLC ; 2018
    In:  BMC Psychiatry Vol. 18, No. 1 ( 2018-12)
    Details
    In: BMC Psychiatry, Springer Science and Business Media LLC, Vol. 18, No. 1 ( 2018-12)
    Type of Medium: Online Resource
    ISSN: 1471-244X
    URL: Article
    DOI: 10.1186/s12888-018-1813-9
    Language: English
    Publisher: Springer Science and Business Media LLC
    Publication Date: 2018
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  • 5
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    Eating Disorders, Perfectionism, and Quality of Life : Maladaptive Perfectionism as a Mediator Between Symptoms of Disordered Eating and Quality of Life
    Ovid Technologies (Wolters Kluwer Health) ; 2020
    In:  Journal of Nervous & Mental Disease Vol. 208, No. 10 ( 2020-10), p. 771-776
    Details
    In: Journal of Nervous & Mental Disease, Ovid Technologies (Wolters Kluwer Health), Vol. 208, No. 10 ( 2020-10), p. 771-776
    Abstract: Individuals with disordered eating behaviors exhibit significantly impaired quality of life (QoL). Maladaptive perfectionism is consistently associated with both eating disorders (EDs) and QoL, but its role in the relationship between eating pathology and QoL has remained largely unexplored. The current study investigated whether maladaptive perfectionism mediates the ED-QoL relationship. A total of 286 university students completed an online survey that consisted of self-report questionnaires assessing ED symptomology, QoL, maladaptive perfectionism, and anxiety and depression symptoms. Maladaptive perfectionism mediated the relationship between ED symptomology and QoL, but this effect did not persist when body mass index, depression, and anxiety were controlled for. The results suggest the mediatory effect of maladaptive perfectionism is masked by depression and anxiety symptomology. Recommendations for further research are proposed to clarify the role of maladaptive perfectionism in the ED-QoL relationship and to explore the mediatory role of depression and anxiety in this relationship.
    Type of Medium: Online Resource
    ISSN: 1539-736X , 0022-3018
    URL: Article
    DOI: 10.1097/NMD.0000000000001241
    RVK:
    XA 10000
    Language: English
    Publisher: Ovid Technologies (Wolters Kluwer Health)
    Publication Date: 2020
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  • 6
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    Attraction of Culex pipiens to uropygial gland secretions does not explain feeding preference for American robins
    Society for Vector Ecology ; 2018
    In:  Journal of Vector Ecology Vol. 43, No. 1 ( 2018-06), p. 110-116
    Details
    In: Journal of Vector Ecology, Society for Vector Ecology, Vol. 43, No. 1 ( 2018-06), p. 110-116
    Type of Medium: Online Resource
    ISSN: 1081-1710
    URL: Issue
    URL: Article
    DOI: 10.1111/jvec.2018.43.issue-1
    DOI: 10.1111/jvec.12290
    Language: English
    Publisher: Society for Vector Ecology
    Publication Date: 2018
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    SSG: 12
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  • 7
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    Selinexor in Combination with Induction and Consolidation Therapy in Older Adults with AML Is Highly Active
    American Society of Hematology ; 2019
    In:  Blood Vol. 134, No. Supplement_1 ( 2019-11-13), p. 1388-1388
    Details
    In: Blood, American Society of Hematology, Vol. 134, No. Supplement_1 ( 2019-11-13), p. 1388-1388
    Abstract: Background: Acute myeloid leukemia (AML) is an aggressive myeloid cancer of the hematopoietic system that primarily affects older adults and is characterized by therapy resistance and dismal outcomes. Novel approaches to treat AML are desperately needed. Selinexor is a small-molecule inhibitor of the nuclear export protein XPO1. Treatment of AML cells with selinexor was shown to sensitize them to chemotherapy in part by blocking the nuclear export of topoisomerase II, resulting in increased DNA strand breaks when an anthracycline is present. Furthermore, selinexor has shown encouraging results when combined with chemotherapy in the relapsed setting. This abstract reports on the initial results of a randomized phase II study of induction and consolidation with or without selinexor in newly diagnosed patients with AML 60 years of age or older. Methods: Patients 60 years of age or older with newly diagnosed de novo AML were randomized between 7+3 or 7+3+selinexor induction. Responding patients could then go on to high dose cytarabine consolidation with or without selinexor as per their initial treatment assignment. Patients in the selinexor arm who completed all planned consolidation could then move to maintenance therapy with selinexor alone. During induction cytarabine was dosed at 100 mg/m2 by continuous infusion for 7 days and daunorubicin was dosed at 60 mg/m2 on days 1-3. In consolidation cytarabine was dosed at 1.5 gm/m2 given Q12 hours on days 1, 3 and 5. Selinexor was dosed at 60 mg PO on days 1, 3, 8, 10, 15 and 17 during induction and consolidation and on days 1 and 8 every 21 days in maintenance. Optional blood samples were collected just prior to and at several time points after selinexor during induction. Mononuclear cells were isolated from these samples, lysed and lysates evaluated for protein pathway drug target activation mapping by reverse phase phosphoprotein array (RPPA). Results: Thirteen patients have been enrolled to date with 12 available for evaluation. Of the 12 evaluable patients 6 were randomized to each arm. Baseline demographics are listed in Table 1. Overall the combination was well tolerated with no patients discontinuing selinexor secondary to treatment related adverse events. In the standard arm 3 of 6 patients achieved a complete remission. Of the 3 responders 1 has relapsed, 1 has gone on to transplant and one has completed consolidation chemotherapy. In the selinexor arm 5 of 6 patients achieved a complete remission and 1 patient achieved a morphologic leukemia free state. All patients given selinexor achieved a response. Of the 5 responders 3 have gone on to transplant, 1 is on maintenance therapy (completed 14 cycles) and one is completing consolidation therapy. In the standard arm no patients died during induction and 3 of 6 patients have died from progressive disease. In the selinexor arm 1 patient died during induction and none of the remaining patients have progressed (Figure 1 and Table 2). No difference in the AE profile was noted between arms and no unexpected side effects were observed. The patient on long term maintenance selinexor is tolerating it without significant AEs to date. Blood samples were available from 3 patients from the selinexor arm. RPPA based protein pathway activation mapping analysis of PBMCs revealed a significant increase in phosphorylation of AMPK, BAD and LC3B at one-hour post treatment that returned to baseline by 2 hours suggesting a transient increase in these pathways that was subsequently suppressed (Figure 2). Conclusions: Selinexor in combination with standard induction and consolidation therapy appears highly active in older de novo AML patients. Selinexor may increase response by modulation of AMPK, autophagy and BAD phosphorylation. Enrollment is ongoing. Disclosures Pardee: Spherix Intellectual Property: Research Funding; CBM Bipharma: Membership on an entity's Board of Directors or advisory committees; Amgen: Speakers Bureau; Celgene: Speakers Bureau; Pharmacyclics/Janssen: Speakers Bureau; Karyopharm: Research Funding; Rafael Pharmaceuticals: Consultancy, Research Funding. Manuel:Novartis: Speakers Bureau; Jazz Pharmaceuticals: Speakers Bureau. Powell:Pfizer: Consultancy, Research Funding; Rafael Pharmaceuticals: Consultancy, Research Funding; Novartis: Consultancy, Speakers Bureau; Jazz Pharmaceuticals: Consultancy, Research Funding, Speakers Bureau; Janssen: Research Funding. OffLabel Disclosure: Selinexor is not approved for the treatment of AML
    Type of Medium: Online Resource
    ISSN: 0006-4971 , 1528-0020
    URL: Article
    DOI: 10.1182/blood-2019-129413
    RVK:
    XA 33000
    RVK:
    XA 10000
    Language: English
    Publisher: American Society of Hematology
    Publication Date: 2019
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  • 8
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    45. Large vessel vasculitis associated with common iliac artery aneurysm and limb ischaemia
    Oxford University Press (OUP) ; 2019
    In:  Rheumatology Advances in Practice Vol. 3, No. Supplement_1 ( 2019-09-01)
    Details
    In: Rheumatology Advances in Practice, Oxford University Press (OUP), Vol. 3, No. Supplement_1 ( 2019-09-01)
    Abstract: An 81-year-old gentleman with no prior medical history presented with a 5-month history of gradual onset malaise and reduced appetite. Weight loss of 2 stone was noted. Mild intermittent headache was present. After 3 months, he developed intermittent claudication of the right leg. A diagnosis of giant cell arteritis (GCA) was made. Disease was corticosteroid resistant, on the basis of clinical findings, biochemistry and imaging. Tocilizumab was commenced. Imaging also revealed dissection of the proximal right common iliac artery. The intermittent claudication progressed to acute limb ischaemia, which responded well to conservative treatment with heparin. Case description Headache was unilateral, intermittent and lasted a few minutes only, although it was described as severe. There were no visual symptoms, no scalp tenderness and no jaw or tongue claudication.  His mobility was severely impacted by intermittent claudication. He was previously playing 3 rounds of golf per week but exercise tolerance reduced to fifty metres. There were no specific risk factors for atherosclerotic disease.  He was a retired head teacher and had never smoked. Alcohol intake was 3 units per week. He was not taking any medication. The predominant features in the history were systemic upset and weight loss and the initial focus was on ruling out malignancy. Extensive investigations were performed by the general practitioner (GP). Erythrocyte sedimentation rate (ESR) was 80 and C-reactive protein (CRP) 74. A full blood count and serum biochemistry were otherwise unremarkable. Immunoglobulins were normal with no paraprotein detected. Thyroid stimulating hormone (TSH) was within the normal range. Prostate specific antigen (PSA) was raised at 17.8 but urology investigations revealed no evidence of malignancy. Computed tomography (CT) of the thorax, abdomen and pelvis showed non-specific inflammation of jejunum & mesenteric fat. Subsequent magnetic resonance imaging (MRI) of the small bowel showed resolution of these changes but noted a chronic focal area of dissection at the proximal right common iliac artery. The GP commenced prednisolone 40mg daily, increased after twelve days to 60mg daily due to partial response. Review in rheumatology clinic two weeks later noted ongoing intermittent claudication. Headache had resolved and weight stabilised. The right temporal artery was difficult to palpate and the right ulnar pulse was absent. Temporal artery ultrasound scan (TA USS) in clinic demonstrated bilateral ongoing active inflammation. Three pulses of 500mg intravenous methylprednisolone were arranged. Discussion Whilst ESR had initially improved to 10 and CRP to  〈  3, they subsequently increased to 53 and 45 respectively. Subsequent positron emission tomography with computed tomography (PET-CT) showed diffuse metabolic activity in thoracic aorta, bilateral subclavian, axillary and femoral arteries. On the basis of bloods, ongoing claudicant symptoms and strongly positive TA-USS and PET-CT, the disease was felt to meet criteria for steroid non-responsiveness. As per NICE guidelines, permission was sought and granted from the local tertiary centre to commence tocilizumab. The patient was noted to have diverticulosis on the basis of imaging but had never been symptomatic. After appropriate patient counselling on the risks of gastrointestinal perforation, a decision was made to proceed with treatment. The finding of dissection at the proximal right common iliac artery prompted urgent referral to the vascular surgery team. However, whilst awaiting review, the patient developed acute limb ischaemia with pallor, weakness and pain of the right leg. He was admitted and managed conservatively with intravenous heparin, followed by subcutaneous heparin and clopidogrel. He responded well to medical therapy and remains under vascular follow up. Notably, the aneurysm was retrospectively noted on CT scan imaging, confirming that it predated corticosteroid treatment. Key learning points Whilst aneurysm formation is a recognised complication of giant cell arteritis, they are typically aortic and involvement of lower limb arteries is rare There is no consensus opinion on optimal surveillance of extra-aortic aneurysms in GCA; decisions should be made on a case by case basis Tocilizumab is an effective treatment for refractory GCA. The current NICE guideline on its usage is based on the GiACTA study findings Conflicts of interest The authors have declared no conflicts of interest.
    Type of Medium: Online Resource
    ISSN: 2514-1775
    URL: Article
    DOI: 10.1093/rap/rkz028.014
    Language: English
    Publisher: Oxford University Press (OUP)
    Publication Date: 2019
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  • 9
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    233 Enhancing quality improvement capacity through the British Society for Rheumatology’s multi-region audit into the management of adults with systemic lupus erythematosus
    Oxford University Press (OUP) ; 2019
    In:  Rheumatology Vol. 58, No. Supplement_3 ( 2019-04-01)
    Details
    In: Rheumatology, Oxford University Press (OUP), Vol. 58, No. Supplement_3 ( 2019-04-01)
    Type of Medium: Online Resource
    ISSN: 1462-0324 , 1462-0332
    URL: Article
    DOI: 10.1093/rheumatology/kez107.049
    Language: English
    Publisher: Oxford University Press (OUP)
    Publication Date: 2019
    detail.hit.zdb_id: 1474143-X
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  • 10
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    O24 Risk of death during the 2020 UK COVID-19 epidemic and annual influenza seasons among people with vasculitis compared to the general population: a whole-population study using data from the NDRS and the RECORDER project
    Oxford University Press (OUP) ; 2021
    In:  Rheumatology Vol. 60, No. Supplement_1 ( 2021-04-25)
    Details
    In: Rheumatology, Oxford University Press (OUP), Vol. 60, No. Supplement_1 ( 2021-04-25)
    Abstract: Background/Aims  To quantify the risk of death among people with vasculitis during the UK 2020 COVID-19 epidemic compared with baseline risk, risk during annual influenza seasons and risk of death in the general population during COVID-19. Methods  We performed a cohort study using data from the National Congenital Anomaly and Rare Disease Registration Service (NCARDRS) under their legal permissions (CAG 10-02(d)/2015). Coded diagnoses for vasculitis (ANCA-associated vasculitis, Takayasu arteritis, Behçet's disease, and giant cell arteritis) were identified from Hospital Episode Statistics from 2003 onwards. Previous coding validation work demonstrated a positive predictive value & gt;85%. The main outcome measure was age-standardised mortality rates (ASMRs) for all-cause death. ONS published data were used for general population mortality rates. Results  We identified 55,110 people with vasculitis (median age 74.9 (IQR 64.1-82.7) years, 68.0% female) alive 01 March 2020. During March-April 2020, 892 (1.6%) died of any cause. The crude mortality rate was 9773.0 (95% CI 9152.3-10,435.9) per 100,000 person-years. The ASMR was 2567.5 per 100,000 person-years, compared to 1361.1 (1353.6-1368.7) in the general population (see table). The ASMR in March-April 2020 was 1.4 times higher than the mean ASMR for March-April 2015-2019 (1965.6). The increase in deaths during March-April 2020 occurred at a younger age than in the general population. We went on to investige the effect of previous influenza seasons. The 2014/15 season saw the greatest excess all-cause mortality nationally in recent years, and there were 624 deaths in 38,888 people (6472.5 person-years) with vasculitis in our data (crude mortality rate 9640.8 (8913.3-10427.7); The ASMR was 2657.6, which was marginally higher than the ASMR among people with vasculitis recorded during March-April 2020 during the COVID-19 pandemic. Conclusion  People with vasculitis are at increased risk of death during circulating COVID-19 and influenza epidemics. The ASMR among people with vasculitis was high both during the 2014/15 influenza season and during the first wave of the COVID-19 epidemic. COVID-19 vaccination and annual influenza vaccination for people with vasculitis are both important, regardless of patient age. Disclosure  M. Rutter: None. P.C. Lanyon: Grants/research support; PCL has received funding for research from Vifor Pharma.. M.J. Grainge: None. R.B. Hubbard: None. E.J. Peach: Grants/research support; EJP has received funding for research from Vifor Pharma. M. Bythell: None. J. Aston: None. S. Stevens: None. F.A. Pearce: Grants/research support; FAP has received funding for research from Vifor Pharma..
    Type of Medium: Online Resource
    ISSN: 1462-0324 , 1462-0332
    URL: Article
    DOI: 10.1093/rheumatology/keab246.023
    Language: English
    Publisher: Oxford University Press (OUP)
    Publication Date: 2021
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