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  • 1
    In: Nature, Springer Science and Business Media LLC, Vol. 600, No. 7889 ( 2021-12-16), p. 472-477
    Abstract: The genetic make-up of an individual contributes to the susceptibility and response to viral infection. Although environmental, clinical and social factors have a role in the chance of exposure to SARS-CoV-2 and the severity of COVID-19 1,2 , host genetics may also be important. Identifying host-specific genetic factors may reveal biological mechanisms of therapeutic relevance and clarify causal relationships of modifiable environmental risk factors for SARS-CoV-2 infection and outcomes. We formed a global network of researchers to investigate the role of human genetics in SARS-CoV-2 infection and COVID-19 severity. Here we describe the results of three genome-wide association meta-analyses that consist of up to 49,562 patients with COVID-19 from 46 studies across 19 countries. We report 13 genome-wide significant loci that are associated with SARS-CoV-2 infection or severe manifestations of COVID-19. Several of these loci correspond to previously documented associations to lung or autoimmune and inflammatory diseases 3–7 . They also represent potentially actionable mechanisms in response to infection. Mendelian randomization analyses support a causal role for smoking and body-mass index for severe COVID-19 although not for type II diabetes. The identification of novel host genetic factors associated with COVID-19 was made possible by the community of human genetics researchers coming together to prioritize the sharing of data, results, resources and analytical frameworks. This working model of international collaboration underscores what is possible for future genetic discoveries in emerging pandemics, or indeed for any complex human disease.
    Type of Medium: Online Resource
    ISSN: 0028-0836 , 1476-4687
    RVK:
    RVK:
    RVK:
    Language: English
    Publisher: Springer Science and Business Media LLC
    Publication Date: 2021
    detail.hit.zdb_id: 120714-3
    detail.hit.zdb_id: 1413423-8
    SSG: 11
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  • 2
    In: The Lancet Infectious Diseases, Elsevier BV, Vol. 22, No. 5 ( 2022-05), p. 622-635
    Type of Medium: Online Resource
    ISSN: 1473-3099
    Language: English
    Publisher: Elsevier BV
    Publication Date: 2022
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  • 3
    In: The Lancet, Elsevier BV, Vol. 394, No. 10215 ( 2019-12), p. 2165-2172
    Type of Medium: Online Resource
    ISSN: 0140-6736
    RVK:
    Language: English
    Publisher: Elsevier BV
    Publication Date: 2019
    detail.hit.zdb_id: 2067452-1
    detail.hit.zdb_id: 3306-6
    detail.hit.zdb_id: 1476593-7
    SSG: 5,21
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  • 4
    In: Open Forum Infectious Diseases, Oxford University Press (OUP), Vol. 8, No. Supplement_1 ( 2021-12-04), p. S142-S143
    Abstract: Up to 40% of hospitalized patients receive unnecessary or inappropriately broad antibiotics despite a low risk of multidrug-resistant organism (MDRO) infection. Empiric standard spectrum antibiotic use would reduce extended-spectrum (ES) antibiotic exposure and future resistance. We evaluated whether computerized prescriber order entry prompts providing patient-specific MDRO risk estimates could reduce ES antibiotic use compared to routine stewardship practices in patients hospitalized with urinary tract infection (UTI). Methods This 59-hospital cluster randomized trial compared: 1) INSPIRE prompts providing patient-specific MDRO UTI risk estimates at order entry and recommended standard spectrum antibiotics for risk & lt; 10% versus 2) routine stewardship practices. Prompt used an absolute MDRO risk algorithm based on a 140 hospital data set. Trial population included adults treated with antibiotics for UTI in ED or non-ICU wards in first 3 days of admission (empiric days); prompt was triggered if ES antibiotics were ordered. Prescribers received feedback on prompt response. Trial periods: 18-month Baseline (Apr 2017–Sept 2018); 6-month Phase-in (Oct 2018–Mar 2019); 15-month Intervention (Apr 2019 – June 2020). Primary outcome was ES antibiotic days of therapy (ES-DOT) per empiric day; secondary outcomes were a) vancomycin and b) anti-pseudomonal DOT per empiric day. Unadjusted, as-randomized analyses used generalized linear mixed effects models to assess differences in ES-DOT rates between the intervention vs baseline period across arms (difference in differences), while clustering by patient and hospital. Results Results: We randomized 59 hospitals in 12 states, with 87,749 and 66,996 non-ICU UTI admissions in baseline and intervention periods, respectively. Intervention group had a a 21% reduction in ES-DOT compared to routine care. Vancomycin and anti-pseudomonal DOT were similarly reduced in the intervention group by 17% and 23%, respectively (Table). Conclusion Conclusion: INSPIRE order entry prompts providing real-time, patient-specific MDRO risk estimates with recommendation to use standard spectrum antibiotics in low risk patients significantly reduced empiric ES prescribing in adults admitted with UTI. Disclosures Shruti K. Gohil, MD, MPH, Medline (Other Financial or Material Support, Co-Investigator in studies in which participating hospitals and nursing homes received contributed antiseptic and cleaning products)Molnycke (Other Financial or Material Support, Co-Investigator in studies in which participating hospitals and nursing homes received contributed antiseptic and cleaning products)Stryker (Sage) (Other Financial or Material Support, Co-Investigator in studies in which participating hospitals and nursing homes received contributed antiseptic and cleaning products) Edward Septimus, MD, Medline (Other Financial or Material Support, Conducted studies in which participating hospitals received contributed antiseptic products)Molnlycke (Other Financial or Material Support, Conducted studies in which participating hospitals received contributed antiseptic products) Ken Kleinman, PhD, Medline (Other Financial or Material Support, Conducted studies in which participating hospitals received contributed antiseptic products)Molnlycke (Other Financial or Material Support, Conducted studies in which participating hospitals received contributed antiseptic products) Lauren Heim, MPH, Medline (Other Financial or Material Support, Conducted clinical trials and studies in which participating hospitals and nursing homes received contributed antiseptic and cleaning products)Molnlycke (Other Financial or Material Support, Conducted studies in which participating hospitals received contributed antiseptic product)Stryker (Sage) (Other Financial or Material Support, Conducted clinical trials and studies in which participating hospitals and nursing homes received contributed antiseptic product)Xttrium (Other Financial or Material Support, Conducted clinical trials and studies in which participating hospitals and nursing homes received contributed antiseptic product) Syma Rashid, MD, Medline (Other Financial or Material Support, Conducted studies in which participating hospitals received contributed antiseptic product)Stryker (Sage) (Other Financial or Material Support, Conducted clinical trials and studies in which participating hospitals and nursing homes received contributed antiseptic product)Xttrium (Other Financial or Material Support, Conducted clinical trials and studies in which participating hospitals and nursing homes received contributed antiseptic product) Taliser R. Avery, MS, Medline (Other Financial or Material Support, Conducted studies in which participating hospitals received contributed antiseptic product)Molnlycke (Other Financial or Material Support, Conducted studies in which participating hospitals received contributed antiseptic product) Kenneth Sands, MD, MPH, Medline (Other Financial or Material Support, Conducted studies in which participating hospitals received contributed antiseptic product) Julia Moody, MS, Medline (Other Financial or Material Support, Conducted studies in which participating hospitals received contributed antiseptic product)Molnlycke (Other Financial or Material Support, Conducted studies in which participating hospitals received contributed antiseptic product) Kimberly N. Smith, MBA, Medline (Other Financial or Material Support, Conducted studies in which participating hospitals received contributed antiseptic product) Brandon Carver, BA, Medline (Other Financial or Material Support, Conducted studies in which participating hospitals received contributed antiseptic product) Caren Spencer-Smith, MS, Medline (Other Financial or Material Support, Conducted studies in which participating hospitals received contributed antiseptic product)Molnlycke (Other Financial or Material Support, Conducted studies in which participating hospitals received contributed antiseptic product) Russell Poland, PhD, Medline (Other Financial or Material Support, Conducted studies in which participating hospitals received contributed antiseptic product) Jason Hickok, MBA, Medline (Other Financial or Material Support, Conducted studies in which participating hospitals received contributed antiseptic product)Molnlycke (Other Financial or Material Support, Conducted studies in which participating hospitals received contributed antiseptic product) Arjun Srinivasan, MD, Nothing to disclose John A. Jernigan, MD, MS, Nothing to disclose Jonathan B. Perlin, MD, PhD, Medline (Other Financial or Material Support, Conducted studies in which participating hospitals received contributed antiseptic product)Molnlycke (Other Financial or Material Support, Conducted studies in which participating hospitals received contributed antiseptic product) Richard Platt, MD, MSc, Medline (Research Grant or Support, Other Financial or Material Support, Conducted studies in which participating hospitals received contributed antiseptic product)Molnlycke (Other Financial or Material Support, Conducted studies in which participating hospitals received contributed antiseptic product) Susan S. Huang, MD, MPH, Medline (Other Financial or Material Support, Conducted studies in which participating hospitals and nursing homes received contributed antiseptic and cleaning products)Molnlycke (Other Financial or Material Support, Conducted studies in which participating hospitals and nursing homes received contributed antiseptic and cleaning products)Stryker (Sage) (Other Financial or Material Support, Conducted studies in which participating hospitals and nursing homes received contributed antiseptic and cleaning products)Xttrium (Other Financial or Material Support, Conducted studies in which participating hospitals and nursing homes received contributed antiseptic and cleaning products)
    Type of Medium: Online Resource
    ISSN: 2328-8957
    Language: English
    Publisher: Oxford University Press (OUP)
    Publication Date: 2021
    detail.hit.zdb_id: 2757767-3
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  • 5
    In: Open Forum Infectious Diseases, Oxford University Press (OUP), Vol. 8, No. Supplement_1 ( 2021-12-04), p. S9-S10
    Abstract: Up to 40% of hospitalized patients receive unnecessary or inappropriately broad antibiotics despite a low risk of multidrug-resistant organism (MDRO) infection. Empiric standard spectrum antibiotic use would reduce extended-spectrum (ES) antibiotic exposure and future resistance. We evaluated whether computerized prescriber order entry prompts providing patient-specific MDRO risk estimates could reduce ES antibiotic use compared to routine stewardship practices in patients hospitalized with pneumonia. Methods This 59 hospital cluster-randomized trial compared: 1) INSPIRE prompts providing patient-specific MDRO pneumonia risk estimates at order entry and recommended standard spectrum antibiotics for risk & lt; 10% versus 2) routine stewardship practices. Prompt used an absolute MDRO risk algorithm based on a 140 hospital data set. Trial population included adults treated with antibiotics for pneumonia in ED or non-ICU wards in first 3 days of admission (empiric days); prompt was triggered if ES antibiotics were ordered. Prescribers received feedback on prompt response. Trial periods: 18-month Baseline (Apr 2017–Sept 2018); 6-month Phase-in (Oct 2018–Mar 2019); 15-month Intervention (Apr 2019 – June 2020). Primary outcome was ES antibiotic days of therapy (ES-DOT) per empiric day; secondary outcomes were a) vancomycin and b) anti-pseudomonal DOT per empiric day. Unadjusted, as-randomized analyses used generalized linear mixed effects models to assess differences in ES-DOT rates between the intervention vs baseline period across arms (difference in differences), while clustering by patient and hospital. Results We randomized 59 hospitals in 12 states, with 59,897 and 51,486 non-ICU pneumonia admissions in baseline and intervention periods, respectively. Intervention group had a 33% reduction in ES-DOT compared to routine care. Vancomycin and anti-pseudomonal DOT were similarly reduced in the intervention group by 27% and 33%, respectively (Table). Conclusion INSPIRE order entry prompts providing real-time, patient-specific MDRO risk estimates with recommendation to use standard spectrum antibiotics in low risk patients significantly reduced empiric ES prescribing in adults admitted with pneumonia. Disclosures Shruti K. Gohil, MD, MPH, Medline (Other Financial or Material Support, Co-Investigator in studies in which participating hospitals and nursing homes received contributed antiseptic and cleaning products)Molnycke (Other Financial or Material Support, Co-Investigator in studies in which participating hospitals and nursing homes received contributed antiseptic and cleaning products)Stryker (Sage) (Other Financial or Material Support, Co-Investigator in studies in which participating hospitals and nursing homes received contributed antiseptic and cleaning products) Edward Septimus, MD, Medline (Other Financial or Material Support, Conducted studies in which participating hospitals received contributed antiseptic products)Molnlycke (Other Financial or Material Support, Conducted studies in which participating hospitals received contributed antiseptic products) Ken Kleinman, PhD, Medline (Other Financial or Material Support, Conducted studies in which participating hospitals received contributed antiseptic products)Molnlycke (Other Financial or Material Support, Conducted studies in which participating hospitals received contributed antiseptic products) Lauren Heim, MPH, Medline (Other Financial or Material Support, Conducted clinical trials and studies in which participating hospitals and nursing homes received contributed antiseptic and cleaning products)Molnlycke (Other Financial or Material Support, Conducted studies in which participating hospitals received contributed antiseptic product)Stryker (Sage) (Other Financial or Material Support, Conducted clinical trials and studies in which participating hospitals and nursing homes received contributed antiseptic product)Xttrium (Other Financial or Material Support, Conducted clinical trials and studies in which participating hospitals and nursing homes received contributed antiseptic product) Syma Rashid, MD, Medline (Other Financial or Material Support, Conducted studies in which participating hospitals received contributed antiseptic product)Stryker (Sage) (Other Financial or Material Support, Conducted clinical trials and studies in which participating hospitals and nursing homes received contributed antiseptic product)Xttrium (Other Financial or Material Support, Conducted clinical trials and studies in which participating hospitals and nursing homes received contributed antiseptic product) Taliser R. Avery, MS, Medline (Other Financial or Material Support, Conducted studies in which participating hospitals received contributed antiseptic product)Molnlycke (Other Financial or Material Support, Conducted studies in which participating hospitals received contributed antiseptic product) Kenneth Sands, MD, MPH, Medline (Other Financial or Material Support, Conducted studies in which participating hospitals received contributed antiseptic product) Julia Moody, MS, Medline (Other Financial or Material Support, Conducted studies in which participating hospitals received contributed antiseptic product)Molnlycke (Other Financial or Material Support, Conducted studies in which participating hospitals received contributed antiseptic product) Micaela H. Coady, MS, Medline (Other Financial or Material Support, Conducted studies in which participating hospitals received contributed antiseptic product)Molnlycke (Other Financial or Material Support, Conducted studies in which participating hospitals received contributed antiseptic product) Kimberly N. Smith, MBA, Medline (Other Financial or Material Support, Conducted studies in which participating hospitals received contributed antiseptic product) Brandon Carver, BA, Medline (Other Financial or Material Support, Conducted studies in which participating hospitals received contributed antiseptic product) Caren Spencer-Smith, MS, Medline (Other Financial or Material Support, Conducted studies in which participating hospitals received contributed antiseptic product)Molnlycke (Other Financial or Material Support, Conducted studies in which participating hospitals received contributed antiseptic product) Russell Poland, PhD, Medline (Other Financial or Material Support, Conducted studies in which participating hospitals received contributed antiseptic product) Jason Hickok, MBA, Medline (Other Financial or Material Support, Conducted studies in which participating hospitals received contributed antiseptic product)Molnlycke (Other Financial or Material Support, Conducted studies in which participating hospitals received contributed antiseptic product) Arjun Srinivasan, MD, Nothing to disclose John A. Jernigan, MD, MS, Nothing to disclose Jonathan B. Perlin, MD, PhD, Medline (Other Financial or Material Support, Conducted studies in which participating hospitals received contributed antiseptic product)Molnlycke (Other Financial or Material Support, Conducted studies in which participating hospitals received contributed antiseptic product) Richard Platt, MD, MSc, Medline (Research Grant or Support, Other Financial or Material Support, Conducted studies in which participating hospitals received contributed antiseptic product)Molnlycke (Other Financial or Material Support, Conducted studies in which participating hospitals received contributed antiseptic product) Susan S. Huang, MD, MPH, Medline (Other Financial or Material Support, Conducted studies in which participating hospitals and nursing homes received contributed antiseptic and cleaning products)Molnlycke (Other Financial or Material Support, Conducted studies in which participating hospitals and nursing homes received contributed antiseptic and cleaning products)Stryker (Sage) (Other Financial or Material Support, Conducted studies in which participating hospitals and nursing homes received contributed antiseptic and cleaning products)Xttrium (Other Financial or Material Support, Conducted studies in which participating hospitals and nursing homes received contributed antiseptic and cleaning products)
    Type of Medium: Online Resource
    ISSN: 2328-8957
    Language: English
    Publisher: Oxford University Press (OUP)
    Publication Date: 2021
    detail.hit.zdb_id: 2757767-3
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  • 6
    In: Journal for ImmunoTherapy of Cancer, BMJ, Vol. 8, No. 2 ( 2020-09), p. e001229-
    Abstract: C-type lectin-like molecule 1 (CLL-1) is highly expressed in acute myeloid leukemia (AML) but is absent in primitive hematopoietic progenitors, making it an attractive target for a chimeric antigen receptor (CAR) T-cell therapy. Here, we optimized our CLL-1 CAR for anti-leukemic activity in mouse xenograft models of aggressive AML. Methods First, we optimized the CLL-1 CAR using different spacer, transmembrane and costimulatory sequences. We used a second retroviral vector to coexpress transgenic IL15. We measured the effects of each construct on T cell phenotype and sequential (recursive) co culture assays with tumor cell targets to determine the durability of the anti tumor activity by flow cytometry. We administered CAR T cells to mice engrafted with patient derived xenografts (PDX) and AML cell line and determined anti tumor activity by bioluminescence imaging and weekly bleeding, measured serum cytokines by multiplex analysis. After euthanasia, we examined formalin-fixed/paraffin embedded sections. Unpaired two-tailed Student’s t-tests were used and values of p 〈 0.05 were considered significant. Survival was calculated using Mantel-Cox log-rank test. Results In vitro, CLL-1 CAR T cells with interleukin-15 (IL15) were less terminally differentiated (p 〈 0.0001) and had superior expansion compared with CD28z-CD8 CAR T cells without IL15 (p 〈 0.001). In both AML PDX and AML cell line animal models, CLL-1 CAR T coexpressing transgenic IL15 initially expanded better than CD28z-CD8 CAR T without IL15 (p 〈 0.0001), but produced severe acute toxicity associated with high level production of human tumor necrosis factor α (TNFα), IL15 and IL2. Histopathology showed marked inflammatory changes with tissue damage in lung and liver. This acute toxicity could be managed by two strategies, individually or in combination. The excessive TNF alpha secretion could be blocked with anti-TNF alpha antibody, while excessive T cell expansion could be arrested by activation of an inducible caspase nine safety switch by administration of dimerizing drug. Both strategies successfully prolonged tumor-free survival. Conclusion Combinatorial treatment with a TNFα blocking antibody and subsequent activation of the caspase-9 control switch increased the expansion, survival and antileukemic potency of CLL-1 CAR T-cells expressing transgenic IL15 while avoiding the toxicities associated with excessive cytokine production and long-term accumulation of activated T-cells.
    Type of Medium: Online Resource
    ISSN: 2051-1426
    Language: English
    Publisher: BMJ
    Publication Date: 2020
    detail.hit.zdb_id: 2719863-7
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  • 7
    Online Resource
    Online Resource
    Elsevier BV ; 2004
    In:  Molecular & Cellular Proteomics Vol. 3, No. 3 ( 2004-03), p. 250-256
    In: Molecular & Cellular Proteomics, Elsevier BV, Vol. 3, No. 3 ( 2004-03), p. 250-256
    Type of Medium: Online Resource
    ISSN: 1535-9476
    Language: English
    Publisher: Elsevier BV
    Publication Date: 2004
    detail.hit.zdb_id: 2071375-7
    SSG: 12
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  • 8
    In: JAMA, American Medical Association (AMA), Vol. 330, No. 14 ( 2023-10-10), p. 1337-
    Abstract: Universal nasal mupirocin plus chlorhexidine gluconate (CHG) bathing in intensive care units (ICUs) prevents methicillin-resistant S taphylococcus aureus (MRSA) infections and all-cause bloodstream infections. Antibiotic resistance to mupirocin has raised questions about whether an antiseptic could be advantageous for ICU decolonization. Objective To compare the effectiveness of iodophor vs mupirocin for universal ICU nasal decolonization in combination with CHG bathing. Design, Setting, and Participants Two-group noninferiority, pragmatic, cluster-randomized trial conducted in US community hospitals, all of which used mupirocin-CHG for universal decolonization in ICUs at baseline. Adult ICU patients in 137 randomized hospitals during baseline (May 1, 2015-April 30, 2017) and intervention (November 1, 2017-April 30, 2019) were included. Intervention Universal decolonization involving switching to iodophor-CHG (intervention) or continuing mupirocin-CHG (baseline). Main Outcomes and Measures ICU-attributable S aureus clinical cultures (primary outcome), MRSA clinical cultures, and all-cause bloodstream infections were evaluated using proportional hazard models to assess differences from baseline to intervention periods between the strategies. Results were also compared with a 2009-2011 trial of mupirocin-CHG vs no decolonization in the same hospital network. The prespecified noninferiority margin for the primary outcome was 10%. Results Among the 801 668 admissions in 233 ICUs, the participants’ mean (SD) age was 63.4 (17.2) years, 46.3% were female, and the mean (SD) ICU length of stay was 4.8 (4.7) days. Hazard ratios (HRs) for S aureus clinical isolates in the intervention vs baseline periods were 1.17 for iodophor-CHG (raw rate: 5.0 vs 4.3/1000 ICU-attributable days) and 0.99 for mupirocin-CHG (raw rate: 4.1 vs 4.0/1000 ICU-attributable days) (HR difference in differences significantly lower by 18.4% [95% CI, 10.7%-26.6%] for mupirocin-CHG, P   & amp;lt; .001). For MRSA clinical cultures, HRs were 1.13 for iodophor-CHG (raw rate: 2.3 vs 2.1/1000 ICU-attributable days) and 0.99 for mupirocin-CHG (raw rate: 2.0 vs 2.0/1000 ICU-attributable days) (HR difference in differences significantly lower by 14.1% [95% CI, 3.7%-25.5%] for mupirocin-CHG, P  = .007). For all-pathogen bloodstream infections, HRs were 1.00 (2.7 vs 2.7/1000) for iodophor-CHG and 1.01 (2.6 vs 2.6/1000) for mupirocin-CHG (nonsignificant HR difference in differences, −0.9% [95% CI, −9.0% to 8.0%]; P  = .84). Compared with the 2009-2011 trial, the 30-day relative reduction in hazards in the mupirocin-CHG group relative to no decolonization (2009-2011 trial) were as follows: S aureus clinical cultures (current trial: 48.1% [95% CI, 35.6%-60.1%]; 2009-2011 trial: 58.8% [95% CI, 47.5%-70.7%] ) and bloodstream infection rates (current trial: 70.4% [95% CI, 62.9%-77.8%]; 2009-2011 trial: 60.1% [95% CI, 49.1%-70.7%] ). Conclusions and Relevance Nasal iodophor antiseptic did not meet criteria to be considered noninferior to nasal mupirocin antibiotic for the outcome of S aureus clinical cultures in adult ICU patients in the context of daily CHG bathing. In addition, the results were consistent with nasal iodophor being inferior to nasal mupirocin. Trial Registration ClinicalTrials.gov Identifier: NCT03140423
    Type of Medium: Online Resource
    ISSN: 0098-7484
    RVK:
    Language: English
    Publisher: American Medical Association (AMA)
    Publication Date: 2023
    detail.hit.zdb_id: 2958-0
    detail.hit.zdb_id: 2018410-4
    SSG: 5,21
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  • 9
    Online Resource
    Online Resource
    American Psychiatric Association Publishing ; 2020
    In:  American Journal of Psychiatry Vol. 177, No. 7 ( 2020-07-01), p. 637-638
    In: American Journal of Psychiatry, American Psychiatric Association Publishing, Vol. 177, No. 7 ( 2020-07-01), p. 637-638
    Type of Medium: Online Resource
    ISSN: 0002-953X , 1535-7228
    RVK:
    Language: English
    Publisher: American Psychiatric Association Publishing
    Publication Date: 2020
    detail.hit.zdb_id: 1500554-9
    SSG: 5,2
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  • 10
    Online Resource
    Online Resource
    American Psychiatric Association Publishing ; 2014
    In:  The Journal of Neuropsychiatry and Clinical Neurosciences Vol. 26, No. 1 ( 2014-01), p. 51-56
    In: The Journal of Neuropsychiatry and Clinical Neurosciences, American Psychiatric Association Publishing, Vol. 26, No. 1 ( 2014-01), p. 51-56
    Type of Medium: Online Resource
    ISSN: 0895-0172 , 1545-7222
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    Language: English
    Publisher: American Psychiatric Association Publishing
    Publication Date: 2014
    detail.hit.zdb_id: 1474283-4
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