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  1. Article ; Online: Integrating Foundational and Clinical Science Remotely by Combining Team-Based Learning and Simulation.

    Roberts, Joel / Zhong, Qing / Linger, Rachel

    Medical science educator

    2023  Volume 33, Issue 4, Page(s) 925–934

    Abstract: Integrating foundational and clinical science in medical and other professional healthcare degree programs has been well established as a means to enhance learning. However, implementation remains challenging, and a significant gap exists in guidance for ...

    Abstract Integrating foundational and clinical science in medical and other professional healthcare degree programs has been well established as a means to enhance learning. However, implementation remains challenging, and a significant gap exists in guidance for non-professional degree programs to effectively accomplish both types of integration. Additionally, many modalities described in the literature are resource-intensive, scale poorly to larger groups, and are widely inaccessible. We present an online modality combining team-based learning and a simulation-based learning experience that fosters vertical and horizontal integration of physiology, pharmacology, and clinical science. The tools utilized include a vital sign simulator, video conferencing software, and a document-sharing platform. The activity demonstrated improved knowledge comparing pre- and posttests and evidence that the activity helped students integrate physiology, pharmacology, and clinical medicine. The novel structure is effective and accessible, uses open-source software and standard equipment available to most undergraduate and graduate faculty, and is adaptable to in-person, hybrid-remote, and fully remote delivery.
    Supplementary information: The online version contains supplementary material available at 10.1007/s40670-023-01817-9.
    Language English
    Publishing date 2023-06-15
    Publishing country United States
    Document type Journal Article
    ISSN 2156-8650
    ISSN (online) 2156-8650
    DOI 10.1007/s40670-023-01817-9
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  2. Article ; Online: The White House's Strategic Plan to Address the Opioid Crisis.

    Michel, Nastassja / McGough, Julianne E G / Linger, Rachel M A

    JAMA

    2023  Volume 329, Issue 24, Page(s) 2194

    MeSH term(s) Humans ; Federal Government ; Health Planning ; Health Policy ; Opioid Epidemic/prevention & control ; Public Health Practice
    Language English
    Publishing date 2023-07-04
    Publishing country United States
    Document type Letter ; Comment
    ZDB-ID 2958-0
    ISSN 1538-3598 ; 0254-9077 ; 0002-9955 ; 0098-7484
    ISSN (online) 1538-3598
    ISSN 0254-9077 ; 0002-9955 ; 0098-7484
    DOI 10.1001/jama.2023.8239
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  3. Article: Editorial: Emerging talents in pharmacology: Drugs outcomes research and policies 2022.

    Linger, Rachel M A / Fadare, Joseph O / Shen, Ye / Van Winkle, Lon J

    Frontiers in pharmacology

    2023  Volume 14, Page(s) 1162703

    Language English
    Publishing date 2023-03-02
    Publishing country Switzerland
    Document type Editorial
    ZDB-ID 2587355-6
    ISSN 1663-9812
    ISSN 1663-9812
    DOI 10.3389/fphar.2023.1162703
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  4. Article ; Online: The compound effect of irradiation and familial pseudohyperkalemia on potassium leak from red blood cells.

    Meli, Athinoula / Linger, Rachel / Stevens-Hernandez, Christian J / Gyongyver, Gyorffy / Marks, Denese C / Aung, Htet Htet / Tan, Joanne C G / Cardigan, Rebecca / Bruce, Lesley J / New, Helen V

    Transfusion

    2022  Volume 62, Issue 12, Page(s) 2587–2595

    Abstract: Background: Familial pseudohyperkalemia (FP) is a rare asymptomatic condition characterized by an increased rate of potassium leak from red blood cells (RBC) on refrigeration. Gamma irradiation compromises RBC membrane integrity and accelerates ... ...

    Abstract Background: Familial pseudohyperkalemia (FP) is a rare asymptomatic condition characterized by an increased rate of potassium leak from red blood cells (RBC) on refrigeration. Gamma irradiation compromises RBC membrane integrity and accelerates potassium leakage. Here, we compared the effect of irradiation, applied early or late in storage, on FP versus non-FP RBC.
    Study design: Five FP and 10 non-FP individuals from the National Institute for Health Research Cambridge BioResource, UK, and three FP and six non-FP individuals identified by Australian Red Cross Lifeblood consented to the study. Blood was collected according to standard practice in each center, held overnight at 18-24°C, leucocyte-depleted, and processed into red cell concentrates (RCC) in Saline Adenine Glucose Mannitol. On Day 1, RCC were split equally into six Red Cell Splits (RCS). Two RCS remained non-irradiated, two were irradiated on Day 1 and two were irradiated on Day 14. RBCs were tested over cold storage for quality parameters.
    Results: As expected, non-irradiated FP RCS had significantly higher supernatant potassium levels than controls throughout 28 days of storage (p < .001). When irradiated early, FP RCS released potassium at similar rates to control. When irradiated late, FP RCS supernatants had higher initial post-irradiation potassium concentration than controls but were similar to controls by the end of storage (14 days post-irradiation). No other parameters studied showed a significant difference between FP and control.
    Discussion: FP does not increase the rate of potassium leak from irradiated RBCs. Irradiation may cause a membrane defect similar to that in FP RBCs.
    MeSH term(s) Humans ; Potassium ; Australia ; Erythrocytes
    Chemical Substances Potassium (RWP5GA015D)
    Language English
    Publishing date 2022-10-26
    Publishing country United States
    Document type Journal Article
    ZDB-ID 208417-x
    ISSN 1537-2995 ; 0041-1132
    ISSN (online) 1537-2995
    ISSN 0041-1132
    DOI 10.1111/trf.17159
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    Zs.A 284: Show issues Location:
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  5. Article ; Online: Antibody Responses to Influenza Vaccination are Diminished in Patients With Inflammatory Bowel Disease on Infliximab or Tofacitinib.

    Liu, Zhigang / Alexander, James L / Yee Eng, Kai / Ibraheim, Hajir / Anandabaskaran, Sulak / Saifuddin, Aamir / Constable, Laura / Castro Seoane, Rocio / Bewshea, Claire / Nice, Rachel / D'Mello, Andrea / Jones, Gareth R / Balarajah, Sharmili / Fiorentino, Francesca / Sebastian, Shaji / Irving, Peter M / Hicks, Lucy C / Williams, Horace R T / Kent, Alexandra J /
    Linger, Rachel / Parkes, Miles / Kok, Klaartje / Patel, Kamal V / Teare, Julian P / Altmann, Daniel M / Boyton, Rosemary J / Hart, Ailsa L / Lees, Charlie W / Goodhand, James R / Kennedy, Nicholas A / Pollock, Katrina M / Ahmad, Tariq / Powell, Nick

    Journal of Crohn's & colitis

    2023  Volume 18, Issue 4, Page(s) 560–569

    Abstract: Background and aims: We sought to determine whether six commonly used immunosuppressive regimens were associated with lower antibody responses after seasonal influenza vaccination in patients with inflammatory bowel disease [IBD].: Methods: We ... ...

    Abstract Background and aims: We sought to determine whether six commonly used immunosuppressive regimens were associated with lower antibody responses after seasonal influenza vaccination in patients with inflammatory bowel disease [IBD].
    Methods: We conducted a prospective study including 213 IBD patients and 53 healthy controls: 165 who had received seasonal influenza vaccine and 101 who had not. IBD medications included infliximab, thiopurines, infliximab and thiopurine combination therapy, ustekinumab, vedolizumab, or tofacitinib. The primary outcome was antibody responses against influenza/A H3N2 and A/H1N1, compared to controls, adjusting for age, prior vaccination, and interval between vaccination and sampling.
    Results: Lower antibody responses against influenza A/H3N2 were observed in patients on infliximab (geometric mean ratio 0.35 [95% confidence interval 0.20-0.60], p = 0.0002), combination of infliximab and thiopurine therapy (0.46 [0.27-0.79], p = 0.0050), and tofacitinib (0.28 [0.14-0.57], p = 0.0005) compared to controls. Lower antibody responses against A/H1N1 were observed in patients on infliximab (0.29 [0.15-0.56], p = 0.0003), combination of infliximab and thiopurine therapy (0.34 [0.17-0.66], p = 0.0016), thiopurine monotherapy (0.46 [0.24-0.87], p = 0.017), and tofacitinib (0.23 [0.10-0.56], p = 0.0013). Ustekinumab and vedolizumab were not associated with reduced antibody responses against A/H3N2 or A/H1N1. Vaccination in the previous year was associated with higher antibody responses to A/H3N2. Vaccine-induced anti-SARS-CoV-2 antibody concentration weakly correlated with antibodies against H3N2 [r = 0.27; p = 0.0004] and H1N1 [r = 0.33; p < 0.0001].
    Conclusions: Vaccination in both the 2020-2021 and 2021-2022 seasons was associated with significantly higher antibody responses to influenza/A than no vaccination or vaccination in 2021-2022 alone. Infliximab and tofacitinib are associated with lower binding antibody responses to influenza/A, similar to COVID-19 vaccine-induced antibody responses.
    MeSH term(s) Humans ; Piperidines/therapeutic use ; Female ; Male ; Influenza Vaccines/immunology ; Pyrimidines/therapeutic use ; Infliximab/therapeutic use ; Adult ; Prospective Studies ; Inflammatory Bowel Diseases/drug therapy ; Inflammatory Bowel Diseases/immunology ; Middle Aged ; Antibody Formation/drug effects ; Antibody Formation/immunology ; Immunosuppressive Agents/therapeutic use ; Influenza, Human/prevention & control ; Influenza, Human/immunology ; Influenza A Virus, H1N1 Subtype/immunology ; Influenza A Virus, H3N2 Subtype/immunology ; Antibodies, Viral/blood ; Case-Control Studies
    Chemical Substances tofacitinib (87LA6FU830) ; Piperidines ; Influenza Vaccines ; Pyrimidines ; Infliximab (B72HH48FLU) ; Immunosuppressive Agents ; Antibodies, Viral
    Language English
    Publishing date 2023-11-09
    Publishing country England
    Document type Journal Article
    ZDB-ID 2390120-2
    ISSN 1876-4479 ; 1873-9946
    ISSN (online) 1876-4479
    ISSN 1873-9946
    DOI 10.1093/ecco-jcc/jjad182
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  6. Article ; Online: COVID-19 vaccine-induced antibody and T-cell responses in immunosuppressed patients with inflammatory bowel disease after the third vaccine dose (VIP): a multicentre, prospective, case-control study.

    Alexander, James L / Liu, Zhigang / Muñoz Sandoval, Diana / Reynolds, Catherine / Ibraheim, Hajir / Anandabaskaran, Sulak / Saifuddin, Aamir / Castro Seoane, Rocio / Anand, Nikhil / Nice, Rachel / Bewshea, Claire / D'Mello, Andrea / Constable, Laura / Jones, Gareth R / Balarajah, Sharmili / Fiorentino, Francesca / Sebastian, Shaji / Irving, Peter M / Hicks, Lucy C /
    Williams, Horace R T / Kent, Alexandra J / Linger, Rachel / Parkes, Miles / Kok, Klaartje / Patel, Kamal V / Teare, Julian P / Altmann, Daniel M / Goodhand, James R / Hart, Ailsa L / Lees, Charlie W / Boyton, Rosemary J / Kennedy, Nicholas A / Ahmad, Tariq / Powell, Nick

    The lancet. Gastroenterology & hepatology

    2022  Volume 7, Issue 11, Page(s) 1005–1015

    Abstract: Background: COVID-19 vaccine-induced antibody responses are reduced in patients with inflammatory bowel disease (IBD) taking anti-TNF or tofacitinib after two vaccine doses. We sought to assess whether immunosuppressive treatments were associated with ... ...

    Abstract Background: COVID-19 vaccine-induced antibody responses are reduced in patients with inflammatory bowel disease (IBD) taking anti-TNF or tofacitinib after two vaccine doses. We sought to assess whether immunosuppressive treatments were associated with reduced antibody and T-cell responses in patients with IBD after a third vaccine dose.
    Methods: VIP was a multicentre, prospective, case-control study done in nine centres in the UK. We recruited immunosuppressed patients with IBD and non-immunosuppressed healthy individuals. All participants were aged 18 years or older. The healthy control group had no diagnosis of IBD and no current treatment with systemic immunosuppressive therapy for any other indication. The immunosuppressed patients with IBD had an established diagnosis of Crohn's disease, ulcerative colitis, or unclassified IBD using standard definitions of IBD, and were receiving established treatment with one of six immunosuppressive regimens for at least 12 weeks at the time of first dose of SARS-CoV-2 vaccination. All participants had to have received three doses of an approved COVID-19 vaccine. SARS-CoV-2 spike antibody binding and T-cell responses were measured in all participant groups. The primary outcome was anti-SARS-CoV-2 spike (S1 receptor binding domain [RBD]) antibody concentration 28-49 days after the third vaccine dose, adjusted by age, homologous versus heterologous vaccine schedule, and previous SARS-CoV-2 infection. The primary outcome was assessed in all participants with available data.
    Findings: Between Oct 18, 2021, and March 29, 2022, 352 participants were included in the study (thiopurine n=65, infliximab n=46, thiopurine plus infliximab combination therapy n=49, ustekinumab n=44, vedolizumab n=50, tofacitinib n=26, and healthy controls n=72). Geometric mean anti-SARS-CoV-2 S1 RBD antibody concentrations increased in all groups following a third vaccine dose, but were significantly lower in patients treated with infliximab (2736·8 U/mL [geometric SD 4·3]; p<0·0001), infliximab plus thiopurine (1818·3 U/mL [6·7]; p<0·0001), and tofacitinib (8071·5 U/mL [3·1]; p=0·0018) compared with the healthy control group (16 774·2 U/mL [2·6]). There were no significant differences in anti-SARS-CoV-2 S1 RBD antibody concentrations between the healthy control group and patients treated with thiopurine (12 019·7 U/mL [2·2]; p=0·099), ustekinumab (11 089·3 U/mL [2·8]; p=0·060), or vedolizumab (13 564·9 U/mL [2·4]; p=0·27). In multivariable modelling, lower anti-SARS-CoV-2 S1 RBD antibody concentrations were independently associated with infliximab (geometric mean ratio 0·15 [95% CI 0·11-0·21]; p<0·0001), tofacitinib (0·52 [CI 0·31-0·87]; p=0·012), and thiopurine (0·69 [0·51-0·95]; p=0·021), but not with ustekinumab (0·64 [0·39-1·06]; p=0·083), or vedolizumab (0·84 [0·54-1·30]; p=0·43). Previous SARS-CoV-2 infection (1·58 [1·22-2·05]; p=0·0006) was independently associated with higher anti-SARS-CoV-2 S1 RBD antibody concentrations and older age (0·88 [0·80-0·97]; p=0·0073) was independently associated with lower anti-SARS-CoV-2 S1 RBD antibody concentrations. Antigen-specific T-cell responses were similar in all groups, except for recipients of tofacitinib without evidence of previous infection, where T-cell responses were significantly reduced relative to healthy controls (p=0·021).
    Interpretation: A third dose of COVID-19 vaccine induced a boost in antibody binding in immunosuppressed patients with IBD, but these responses were reduced in patients taking infliximab, infliximab plus thiopurine, and tofacitinib. Tofacitinib was also associated with reduced T-cell responses. These findings support continued prioritisation of immunosuppressed groups for further vaccine booster dosing, particularly patients on anti-TNF and JAK inhibitors.
    Funding: Pfizer.
    MeSH term(s) Antibodies, Viral ; COVID-19/prevention & control ; COVID-19 Vaccines/adverse effects ; Case-Control Studies ; Humans ; Immunosuppressive Agents/adverse effects ; Inflammatory Bowel Diseases/drug therapy ; Infliximab/therapeutic use ; Janus Kinase Inhibitors ; Prospective Studies ; SARS-CoV-2 ; T-Lymphocytes ; Tumor Necrosis Factor Inhibitors ; Ustekinumab
    Chemical Substances Antibodies, Viral ; COVID-19 Vaccines ; Immunosuppressive Agents ; Janus Kinase Inhibitors ; Tumor Necrosis Factor Inhibitors ; Infliximab (B72HH48FLU) ; Ustekinumab (FU77B4U5Z0)
    Language English
    Publishing date 2022-09-09
    Publishing country Netherlands
    Document type Journal Article ; Multicenter Study ; Research Support, Non-U.S. Gov't
    ISSN 2468-1253
    ISSN (online) 2468-1253
    DOI 10.1016/S2468-1253(22)00274-6
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  7. Article ; Online: COVID-19 vaccine-induced antibody responses in immunosuppressed patients with inflammatory bowel disease (VIP): a multicentre, prospective, case-control study.

    Alexander, James L / Kennedy, Nicholas A / Ibraheim, Hajir / Anandabaskaran, Sulak / Saifuddin, Aamir / Castro Seoane, Rocio / Liu, Zhigang / Nice, Rachel / Bewshea, Claire / D'Mello, Andrea / Constable, Laura / Jones, Gareth R / Balarajah, Sharmili / Fiorentino, Francesca / Sebastian, Shaji / Irving, Peter M / Hicks, Lucy C / Williams, Horace R T / Kent, Alexandra J /
    Linger, Rachel / Parkes, Miles / Kok, Klaartje / Patel, Kamal V / Teare, Julian P / Altmann, Daniel M / Boyton, Rosemary J / Goodhand, James R / Hart, Ailsa L / Lees, Charlie W / Ahmad, Tariq / Powell, Nick

    The lancet. Gastroenterology & hepatology

    2022  Volume 7, Issue 4, Page(s) 342–352

    Abstract: Background: The effects that therapies for inflammatory bowel disease (IBD) have on immune responses to SARS-CoV-2 vaccination are not yet fully known. Therefore, we sought to determine whether COVID-19 vaccine-induced antibody responses were altered in ...

    Abstract Background: The effects that therapies for inflammatory bowel disease (IBD) have on immune responses to SARS-CoV-2 vaccination are not yet fully known. Therefore, we sought to determine whether COVID-19 vaccine-induced antibody responses were altered in patients with IBD on commonly used immunosuppressive drugs.
    Methods: In this multicentre, prospective, case-control study (VIP), we recruited adults with IBD treated with one of six different immunosuppressive treatment regimens (thiopurines, infliximab, a thiopurine plus infliximab, ustekinumab, vedolizumab, or tofacitinib) and healthy control participants from nine centres in the UK. Eligible participants were aged 18 years or older and had received two doses of COVID-19 vaccines (either ChAdOx1 nCoV-19 [Oxford-AstraZeneca], BNT162b2 [Pfizer-BioNTech], or mRNA1273 [Moderna]) 6-12 weeks apart (according to scheduling adopted in the UK). We measured antibody responses 53-92 days after a second vaccine dose using the Roche Elecsys Anti-SARS-CoV-2 spike electrochemiluminescence immunoassay. The primary outcome was anti-SARS-CoV-2 spike protein antibody concentrations in participants without previous SARS-CoV-2 infection, adjusted by age and vaccine type, and was analysed by use of multivariable linear regression models. This study is registered in the ISRCTN Registry, ISRCTN13495664, and is ongoing.
    Findings: Between May 31 and Nov 24, 2021, we recruited 483 participants, including patients with IBD being treated with thiopurines (n=78), infliximab (n=63), a thiopurine plus infliximab (n=72), ustekinumab (n=57), vedolizumab (n=62), or tofacitinib (n=30), and 121 healthy controls. We included 370 participants without evidence of previous infection in our primary analysis. Geometric mean anti-SARS-CoV-2 spike protein antibody concentrations were significantly lower in patients treated with infliximab (156·8 U/mL [geometric SD 5·7]; p<0·0001), infliximab plus thiopurine (111·1 U/mL [5·7]; p<0·0001), or tofacitinib (429·5 U/mL [3·1]; p=0·0012) compared with controls (1578·3 U/mL [3·7]). There were no significant differences in antibody concentrations between patients treated with thiopurine monotherapy (1019·8 U/mL [4·3]; p=0·74), ustekinumab (582·4 U/mL [4·6]; p=0·11), or vedolizumab (954·0 U/mL [4·1]; p=0·50) and healthy controls. In multivariable modelling, lower anti-SARS-CoV-2 spike protein antibody concentrations were independently associated with infliximab (geometric mean ratio 0·12, 95% CI 0·08-0·17; p<0·0001) and tofacitinib (0·43, 0·23-0·81; p=0·0095), but not with ustekinumab (0·69, 0·41-1·19; p=0·18), thiopurines (0·89, 0·64-1·24; p=0·50), or vedolizumab (1·16, 0·74-1·83; p=0·51). mRNA vaccines (3·68, 2·80-4·84; p<0·0001; vs adenovirus vector vaccines) were independently associated with higher antibody concentrations and older age per decade (0·79, 0·72-0·87; p<0·0001) with lower antibody concentrations.
    Interpretation: For patients with IBD, the immunogenicity of COVID-19 vaccines varies according to immunosuppressive drug exposure, and is attenuated in recipients of infliximab, infliximab plus thiopurines, and tofacitinib. Scheduling of third primary, or booster, doses could be personalised on the basis of an individual's treatment, and patients taking anti-tumour necrosis factor and tofacitinib should be prioritised.
    Funding: Pfizer.
    MeSH term(s) Adolescent ; Adult ; Antibody Formation ; BNT162 Vaccine ; COVID-19/prevention & control ; COVID-19 Vaccines ; Case-Control Studies ; ChAdOx1 nCoV-19 ; Humans ; Inflammatory Bowel Diseases/drug therapy ; Prospective Studies ; SARS-CoV-2
    Chemical Substances COVID-19 Vaccines ; ChAdOx1 nCoV-19 (B5S3K2V0G8) ; BNT162 Vaccine (N38TVC63NU)
    Language English
    Publishing date 2022-02-04
    Publishing country Netherlands
    Document type Journal Article ; Multicenter Study ; Research Support, Non-U.S. Gov't
    ISSN 2468-1253
    ISSN (online) 2468-1253
    DOI 10.1016/S2468-1253(22)00005-X
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  8. Article ; Online: Neutralising antibody responses against SARS-CoV-2 Omicron BA.4/5 and wild-type virus in patients with inflammatory bowel disease following three doses of COVID-19 vaccine (VIP): a prospective, multicentre, cohort study.

    Liu, Zhigang / Alexander, James L / Le, Kaixing / Zhou, Xin / Ibraheim, Hajir / Anandabaskaran, Sulak / Saifuddin, Aamir / Lin, Kathy Weitung / McFarlane, Leon R / Constable, Laura / Seoane, Rocio Castro / Anand, Nikhil / Bewshea, Claire / Nice, Rachel / D'Mello, Andrea / Jones, Gareth R / Balarajah, Sharmili / Fiorentino, Francesca / Sebastian, Shaji /
    Irving, Peter M / Hicks, Lucy C / Williams, Horace Rt / Kent, Alexandra J / Linger, Rachel / Parkes, Miles / Kok, Klaartje / Patel, Kamal V / Teare, Julian P / Altmann, Daniel M / Boyton, Rosemary J / Hart, Ailsa L / Lees, Charlie W / Goodhand, James R / Kennedy, Nicholas A / Pollock, Katrina M / Ahmad, Tariq / Powell, Nick

    EClinicalMedicine

    2023  Volume 64, Page(s) 102249

    Abstract: Background: Patients with inflammatory bowel disease (IBD) receiving anti-TNF and JAK-inhibitor therapy have attenuated responses to COVID-19 vaccination. We aimed to determine how IBD treatments affect neutralising antibody responses against the ... ...

    Abstract Background: Patients with inflammatory bowel disease (IBD) receiving anti-TNF and JAK-inhibitor therapy have attenuated responses to COVID-19 vaccination. We aimed to determine how IBD treatments affect neutralising antibody responses against the Omicron BA.4/5 variant.
    Methods: In this multicentre cohort study, we prospectively recruited 340 adults (69 healthy controls and 271 IBD) at nine UK hospitals between May 28, 2021 and March 29, 2022. The IBD study population was established (>12 weeks therapy) on either thiopurine (n = 63), infliximab (n = 45), thiopurine and infliximab combination therapy (n = 48), ustekinumab (n = 45), vedolizumab (n = 46) or tofacitinib (n = 24). Patients were excluded if they were being treated with any other immunosuppressive therapies. Participants had two doses of either ChAdOx1 nCoV-19 or BNT162b2 vaccines, followed by a third dose of either BNT162b2 or mRNA1273. Pseudo-neutralisation assays against SARS-CoV-2 wild-type and BA.4/5 were performed. The half maximal inhibitory concentration (NT50) of participant sera was calculated. The primary outcome was anti-SARS-CoV-2 neutralising response against wild-type virus and Omicron BA.4/5 variant after the second and third doses of anti-SARS-CoV-2 vaccine, stratified by immunosuppressive therapy, adjusting for prior infection, vaccine type, age, and interval between vaccination and blood collection. This study is registered with ISRCTN (No. 13495664).
    Findings: Both heterologous (first two doses adenovirus vaccine, third dose mRNA vaccine) and homologous (three doses mRNA vaccine) vaccination strategies significantly increased neutralising titres against both wild-type SARS-CoV-2 virus and the Omicron BA.4/5 variant in healthy participants and patients with IBD. Antibody titres against BA.4/5 were significantly lower than antibodies against wild-type virus in both healthy participants and patients with IBD (p < 0.0001). Multivariable models demonstrated that neutralising antibodies against BA.4/5 after three doses of vaccine were significantly lower in patients with IBD on infliximab (Geometric Mean Ratio (GMR) 0.19 [0.10, 0.36], p < 0.0001), infliximab and thiopurine combination (GMR 0.25 [0.13, 0.49], p < 0.0001) or tofacitinib (GMR 0.43 [0.20, 0.91], p = 0.028), but not in patients on thiopurine monotherapy, ustekinumab, or vedolizumab. Breakthrough infection was associated with lower neutralising antibodies against wild-type (p = 0.037) and BA.4/5 (p = 0.045).
    Interpretation: A third dose of a COVID-19 mRNA vaccine based on the wild-type spike glycoprotein significantly boosts neutralising antibody titres in patients with IBD. However, responses are lower against the Omicron variant BA.4/5, particularly in patients taking anti-TNF and JAK-inhibitor therapy. Breakthrough infections are associated with lower neutralising antibodies and immunosuppressed patients with IBD may receive additional benefit from bivalent vaccine boosters which target Omicron variants.
    Funding: Pfizer.
    Language English
    Publishing date 2023-10-05
    Publishing country England
    Document type Journal Article
    ISSN 2589-5370
    ISSN (online) 2589-5370
    DOI 10.1016/j.eclinm.2023.102249
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  9. Article ; Online: Taking aim at Mer and Axl receptor tyrosine kinases as novel therapeutic targets in solid tumors.

    Linger, Rachel M A / Keating, Amy K / Earp, H Shelton / Graham, Douglas K

    Expert opinion on therapeutic targets

    2010  Volume 14, Issue 10, Page(s) 1073–1090

    Abstract: Importance of the field: Axl and/or Mer expression correlates with poor prognosis in several cancers. Until recently, the role of these receptor tyrosine kinases (RTKs) in development and progression of cancer remained unexplained. Studies demonstrating ...

    Abstract Importance of the field: Axl and/or Mer expression correlates with poor prognosis in several cancers. Until recently, the role of these receptor tyrosine kinases (RTKs) in development and progression of cancer remained unexplained. Studies demonstrating that Axl and Mer contribute to cell survival, migration, invasion, metastasis and chemosensitivity justify further investigation of Axl and Mer as novel therapeutic targets in cancer.
    Areas covered in this review: Axl and Mer signaling pathways in cancer cells are summarized and evidence validating these RTKs as therapeutic targets in glioblastoma multiforme, NSCLC, and breast cancer is examined. A discussion of Axl and/or Mer inhibitors in development is provided.
    What the reader will gain: Potential toxicities associated with Axl or Mer inhibition are addressed. We propose that the probable action of Mer and Axl inhibitors on cells within the tumor microenvironment will provide a therapeutic opportunity to target both tumor cells and the stromal components that facilitate disease progression.
    Take home message: Axl and Mer mediate multiple oncogenic phenotypes and activation of these RTKs constitutes a mechanism of chemoresistance in a variety of solid tumors. Targeted inhibition of these RTKs may be effective as anti-tumor and/or anti-metastatic therapy, particularly if combined with standard cytotoxic therapies.
    MeSH term(s) Cell Line, Tumor ; Cell Movement/drug effects ; Cell Survival/drug effects ; Clinical Trials as Topic ; Humans ; Neoplasms/drug therapy ; Neoplasms/genetics ; Oncogene Proteins/genetics ; Oncogene Proteins/metabolism ; Protein Kinase Inhibitors/pharmacology ; Protein Kinase Inhibitors/therapeutic use ; Proto-Oncogene Proteins/antagonists & inhibitors ; Proto-Oncogene Proteins/metabolism ; Receptor Protein-Tyrosine Kinases/antagonists & inhibitors ; Receptor Protein-Tyrosine Kinases/genetics ; Receptor Protein-Tyrosine Kinases/metabolism ; Signal Transduction/drug effects ; Treatment Outcome ; Tumor Microenvironment ; Axl Receptor Tyrosine Kinase
    Chemical Substances Oncogene Proteins ; Protein Kinase Inhibitors ; Proto-Oncogene Proteins ; Receptor Protein-Tyrosine Kinases (EC 2.7.10.1) ; Axl Receptor Tyrosine Kinase ; AXL protein, human
    Language English
    Publishing date 2010-08-30
    Publishing country England
    Document type Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't ; Review
    ZDB-ID 2055208-7
    ISSN 1744-7631 ; 1472-8222
    ISSN (online) 1744-7631
    ISSN 1472-8222
    DOI 10.1517/14728222.2010.515980
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  10. Article ; Online: Targeting paediatric acute lymphoblastic leukaemia: novel therapies currently in development.

    Lee-Sherick, Alisa B / Linger, Rachel M A / Gore, Lia / Keating, Amy K / Graham, Douglas K

    British journal of haematology

    2010  Volume 151, Issue 4, Page(s) 295–311

    Abstract: Modifications to the treatment of acute lymphoblastic leukaemia (ALL) in children have led to a dramatic increase in survival in the past 40 years. Despite this success, a significant subset of paediatric leukaemia patients either relapse or fail to ever ...

    Abstract Modifications to the treatment of acute lymphoblastic leukaemia (ALL) in children have led to a dramatic increase in survival in the past 40 years. Despite this success, a significant subset of paediatric leukaemia patients either relapse or fail to ever achieve a complete remission. Additionally, some patients necessitate treatment with intensified chemotherapy regimens due to clinical or laboratory findings which identify them as high risk. These patients are unlikely to respond to further minor adjustments to the dosing or timing of administration of the same chemotherapy medications. Many novel targeted therapies for the treatment of childhood ALL provide potential mechanisms to further improve cure rates, and provide the possibility of minimizing toxicity to non-malignant cells, given their specificity to malignant cell phenotypes. This article explores many of the potential targeted therapies in varying stages of development, from those currently in clinical trials to those still being refined in the research laboratory.
    MeSH term(s) Antineoplastic Agents/pharmacology ; Antineoplastic Agents/therapeutic use ; Apoptosis/drug effects ; Child ; Enzyme Inhibitors/pharmacology ; Enzyme Inhibitors/therapeutic use ; Epigenesis, Genetic/drug effects ; Humans ; Molecular Targeted Therapy/methods ; Phosphotransferases/antagonists & inhibitors ; Precursor Cell Lymphoblastic Leukemia-Lymphoma/drug therapy ; Precursor Cell Lymphoblastic Leukemia-Lymphoma/pathology
    Chemical Substances Antineoplastic Agents ; Enzyme Inhibitors ; Phosphotransferases (EC 2.7.-)
    Language English
    Publishing date 2010-08-31
    Publishing country England
    Document type Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't ; Review
    ZDB-ID 80077-6
    ISSN 1365-2141 ; 0007-1048
    ISSN (online) 1365-2141
    ISSN 0007-1048
    DOI 10.1111/j.1365-2141.2010.08282.x
    Database MEDical Literature Analysis and Retrieval System OnLINE

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