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Id Subject Object Predicate Lexical cue
T1 0-165 Sentence denotes Periconceptional exposure to lopinavir, but not darunavir, impairs decidualization: a potential mechanism leading to poor birth outcomes in HIV-positive pregnancies.
T1 0-165 Sentence denotes Periconceptional exposure to lopinavir, but not darunavir, impairs decidualization: a potential mechanism leading to poor birth outcomes in HIV-positive pregnancies.
T2 166-181 Sentence denotes STUDY QUESTION:
T2 166-181 Sentence denotes STUDY QUESTION:
T3 182-379 Sentence denotes Does HIV protease inhibitor (PI)-based combination antiretroviral therapy (cART) initiated at periconception affect key events in early pregnancy, i.e. decidualization and spiral artery remodeling?
T3 182-379 Sentence denotes Does HIV protease inhibitor (PI)-based combination antiretroviral therapy (cART) initiated at periconception affect key events in early pregnancy, i.e. decidualization and spiral artery remodeling?
T4 380-395 Sentence denotes SUMMARY ANSWER:
T4 380-395 Sentence denotes SUMMARY ANSWER:
T5 396-700 Sentence denotes Two PIs, lopinavir and darunavir, currently offered as cART options in HIV-positive pregnancies were evaluated, and we found that lopinavir-based cART, but not darunavir-based cART, impaired uterine decidualization and spiral artery remodeling in both human ex vivo and mouse in vivo experimental models.
T5 396-700 Sentence denotes Two PIs, lopinavir and darunavir, currently offered as cART options in HIV-positive pregnancies were evaluated, and we found that lopinavir-based cART, but not darunavir-based cART, impaired uterine decidualization and spiral artery remodeling in both human ex vivo and mouse in vivo experimental models.
T6 701-723 Sentence denotes WHAT IS KNOWN ALREADY:
T6 701-723 Sentence denotes WHAT IS KNOWN ALREADY:
T7 724-799 Sentence denotes Early initiation of cART is recommended for pregnant women living with HIV.
T7 724-799 Sentence denotes Early initiation of cART is recommended for pregnant women living with HIV.
T8 800-959 Sentence denotes However, poor birth outcomes are frequently observed in HIV-positive pregnancies exposed to PI-based cART, especially when it is initiated prior to conception.
T8 800-959 Sentence denotes However, poor birth outcomes are frequently observed in HIV-positive pregnancies exposed to PI-based cART, especially when it is initiated prior to conception.
T9 960-1212 Sentence denotes The correlation between early initiation of PI-cART and adverse birth outcomes is poorly understood, due to lack of data on the specific effects of PI-cART on the early stages of pregnancy involving uterine decidualization and spiral artery remodeling.
T9 960-1212 Sentence denotes The correlation between early initiation of PI-cART and adverse birth outcomes is poorly understood, due to lack of data on the specific effects of PI-cART on the early stages of pregnancy involving uterine decidualization and spiral artery remodeling.
T10 1213-1242 Sentence denotes STUDY DESIGN, SIZE, DURATION:
T10 1213-1242 Sentence denotes STUDY DESIGN, SIZE, DURATION:
T11 1243-1482 Sentence denotes Lopinavir and darunavir were evaluated in clinically relevant combinations using an ex vivo human first-trimester placenta-decidua explant model, an in vitro human primary decidual cell culture system, and an in vivo mouse pregnancy model.
T11 1243-1482 Sentence denotes Lopinavir and darunavir were evaluated in clinically relevant combinations using an ex vivo human first-trimester placenta-decidua explant model, an in vitro human primary decidual cell culture system, and an in vivo mouse pregnancy model.
T12 1483-1648 Sentence denotes The first-trimester (gestational age, 6-8 weeks) human placenta-decidua tissue was obtained from 11 to 15 healthy women undergoing elective termination of pregnancy.
T12 1483-1648 Sentence denotes The first-trimester (gestational age, 6-8 weeks) human placenta-decidua tissue was obtained from 11 to 15 healthy women undergoing elective termination of pregnancy.
T13 1649-1837 Sentence denotes C57Bl/6 female mice (four/treatment group) were administered either lopinavir-cART, darunavir-cART or water by oral gavage once daily starting on the day of plug detection until sacrifice.
T13 1649-1837 Sentence denotes C57Bl/6 female mice (four/treatment group) were administered either lopinavir-cART, darunavir-cART or water by oral gavage once daily starting on the day of plug detection until sacrifice.
T14 1838-1879 Sentence denotes PARTICIPANTS/MATERIALS, SETTING, METHODS:
T14 1838-1879 Sentence denotes PARTICIPANTS/MATERIALS, SETTING, METHODS:
T15 1880-1886 Sentence denotes Human:
T15 1880-1886 Sentence denotes Human:
T16 1887-2019 Sentence denotes Spiral artery remodeling was assessed by immunohistochemical analysis of first-trimester placenta-decidua explant co-culture system.
T16 1887-2019 Sentence denotes Spiral artery remodeling was assessed by immunohistochemical analysis of first-trimester placenta-decidua explant co-culture system.
T17 2020-2089 Sentence denotes Trophoblast migration was measured using a placental explant culture.
T17 2020-2089 Sentence denotes Trophoblast migration was measured using a placental explant culture.
T18 2090-2202 Sentence denotes A primary decidual cell culture was used to evaluate the viability of immune cell populations by flow cytometry.
T18 2090-2202 Sentence denotes A primary decidual cell culture was used to evaluate the viability of immune cell populations by flow cytometry.
T19 2203-2353 Sentence denotes Soluble factors, including biomarkers of decidualization and angiogenesis, were quantified by ELISA and Luminex assay using decidua-conditioned media.
T19 2203-2353 Sentence denotes Soluble factors, including biomarkers of decidualization and angiogenesis, were quantified by ELISA and Luminex assay using decidua-conditioned media.
T20 2354-2360 Sentence denotes Mouse:
T20 2354-2360 Sentence denotes Mouse:
T21 2361-2569 Sentence denotes In the mouse pregnancy model, gestational day 6.5 or 9.5 implantation sites were used to assess decidualization, spiral artery remodeling and uterine natural killer (uNK) cell numbers by immunohistochemistry.
T21 2361-2569 Sentence denotes In the mouse pregnancy model, gestational day 6.5 or 9.5 implantation sites were used to assess decidualization, spiral artery remodeling and uterine natural killer (uNK) cell numbers by immunohistochemistry.
T22 2570-2684 Sentence denotes Transcription factor STAT3 was assayed by immunohistochemistry in both human decidua and mouse implantation sites.
T22 2570-2684 Sentence denotes Transcription factor STAT3 was assayed by immunohistochemistry in both human decidua and mouse implantation sites.
T23 2685-2721 Sentence denotes MAIN RESULTS AND THE ROLE OF CHANCE:
T23 2685-2721 Sentence denotes MAIN RESULTS AND THE ROLE OF CHANCE:
T24 2722-2852 Sentence denotes Lopinavir-cART, but not darunavir-cART, impaired uterine decidualization and spiral artery remodeling in both experimental models.
T24 2722-2852 Sentence denotes Lopinavir-cART, but not darunavir-cART, impaired uterine decidualization and spiral artery remodeling in both experimental models.
T25 2853-2994 Sentence denotes Lopinavir-cART treatment was also associated with selective depletion of uNK cells, reduced trophoblast migration and defective placentation.
T25 2853-2994 Sentence denotes Lopinavir-cART treatment was also associated with selective depletion of uNK cells, reduced trophoblast migration and defective placentation.
T26 2995-3153 Sentence denotes The lopinavir-associated decidualization defects were attributed to a decrease in expression of transcription factor STAT3, known to regulate decidualization.
T26 2995-3153 Sentence denotes The lopinavir-associated decidualization defects were attributed to a decrease in expression of transcription factor STAT3, known to regulate decidualization.
T27 3154-3420 Sentence denotes Our results suggest that periconceptional initiation of lopinavir-cART, but not darunavir-cART, causes defective maturation of the uterine endometrium, leading to impairments in spiral artery remodeling and placentation, thus contributing to the poor birth outcomes.
T27 3154-3420 Sentence denotes Our results suggest that periconceptional initiation of lopinavir-cART, but not darunavir-cART, causes defective maturation of the uterine endometrium, leading to impairments in spiral artery remodeling and placentation, thus contributing to the poor birth outcomes.
T28 3421-3443 Sentence denotes LARGE SCALE DATA: N/A.
T28 3421-3443 Sentence denotes LARGE SCALE DATA: N/A.
T29 3444-3477 Sentence denotes LIMITATIONS, REASONS FOR CAUTION:
T29 3444-3477 Sentence denotes LIMITATIONS, REASONS FOR CAUTION:
T30 3478-3618 Sentence denotes The human first-trimester placenta/decidua samples could only be obtained from healthy females undergoing elective termination of pregnancy.
T30 3478-3618 Sentence denotes The human first-trimester placenta/decidua samples could only be obtained from healthy females undergoing elective termination of pregnancy.
T31 3619-3791 Sentence denotes As biopsy is the only way to obtain first-trimester decidua from pregnant women living with HIV on PI-cART, ethics approval and participant consent are difficult to obtain.
T31 3619-3791 Sentence denotes As biopsy is the only way to obtain first-trimester decidua from pregnant women living with HIV on PI-cART, ethics approval and participant consent are difficult to obtain.
T32 3792-3879 Sentence denotes Furthermore, our animal model is limited to the study of cART and does not include HIV.
T32 3792-3879 Sentence denotes Furthermore, our animal model is limited to the study of cART and does not include HIV.
T33 3880-4115 Sentence denotes HIV infection is also associated with immune dysregulation, inflammation, alterations in angiogenic factors and complement activation, all of which could influence decidual and placental vascular remodeling and modify any cART effects.
T33 3880-4115 Sentence denotes HIV infection is also associated with immune dysregulation, inflammation, alterations in angiogenic factors and complement activation, all of which could influence decidual and placental vascular remodeling and modify any cART effects.
T34 4116-4151 Sentence denotes WIDER IMPLICATIONS OF THE FINDINGS:
T34 4116-4151 Sentence denotes WIDER IMPLICATIONS OF THE FINDINGS:
T35 4152-4364 Sentence denotes Our findings provide mechanistic insight with direct clinical implications, rationalizing why the highest adverse birth outcomes are reported in HIV-positive pregnancies exposed to lopinavir-cART from conception.
T35 4152-4364 Sentence denotes Our findings provide mechanistic insight with direct clinical implications, rationalizing why the highest adverse birth outcomes are reported in HIV-positive pregnancies exposed to lopinavir-cART from conception.
T36 4365-4541 Sentence denotes We demonstrate that dysregulation of decidualization is the mechanism through which lopinavir-cART, but not darunavir-cART, use in early pregnancy leads to poor birth outcomes.
T36 4365-4541 Sentence denotes We demonstrate that dysregulation of decidualization is the mechanism through which lopinavir-cART, but not darunavir-cART, use in early pregnancy leads to poor birth outcomes.
T37 4542-4701 Sentence denotes Although lopinavir is no longer a first-line regimen in pregnancy, it remains an alternate regimen and is often the only PI available in low resource settings.
T37 4542-4701 Sentence denotes Although lopinavir is no longer a first-line regimen in pregnancy, it remains an alternate regimen and is often the only PI available in low resource settings.
T38 4702-5215 Sentence denotes Our results highlight the need for reconsidering current guidelines recommending lopinavir use in pregnancy and indicate that lopinavir should be avoided especially in the first trimester, whereas darunavir is safe to use and should be the preferred PI in pregnancy.Further, in current times of the COVID-19 pandemic, lopinavir is among the top drug candidates which are being repurposed for inclusion in clinical trials world-over, to assess their therapeutic potential against the dangerous respiratory disease.
T38 4702-5215 Sentence denotes Our results highlight the need for reconsidering current guidelines recommending lopinavir use in pregnancy and indicate that lopinavir should be avoided especially in the first trimester, whereas darunavir is safe to use and should be the preferred PI in pregnancy.Further, in current times of the COVID-19 pandemic, lopinavir is among the top drug candidates which are being repurposed for inclusion in clinical trials world-over, to assess their therapeutic potential against the dangerous respiratory disease.
T39 5216-5364 Sentence denotes Current trials are also testing the efficacy of lopinavir given prophylactically to protect health care workers and people with potential exposures.
T39 5216-5364 Sentence denotes Current trials are also testing the efficacy of lopinavir given prophylactically to protect health care workers and people with potential exposures.
T40 5365-5516 Sentence denotes Given the current extraordinary numbers, these might include women with early pregnancies, who may or may not be cognizant of their gestational status.
T40 5365-5516 Sentence denotes Given the current extraordinary numbers, these might include women with early pregnancies, who may or may not be cognizant of their gestational status.
T41 5517-5667 Sentence denotes This is a matter of concern as it could mean that women with early pregnancies might be exposed to this drug, which can cause decidualization defects.
T41 5517-5667 Sentence denotes This is a matter of concern as it could mean that women with early pregnancies might be exposed to this drug, which can cause decidualization defects.
T42 5668-5897 Sentence denotes Our findings provide evidence of safety concerns surrounding lopinavir use in pregnancy, that women of reproductive age considering participation in such trials should be made aware of, so they can make a fully informed decision.
T42 5668-5897 Sentence denotes Our findings provide evidence of safety concerns surrounding lopinavir use in pregnancy, that women of reproductive age considering participation in such trials should be made aware of, so they can make a fully informed decision.
T43 5898-5934 Sentence denotes STUDY FUNDING/COMPETING INTEREST(S):
T43 5898-5934 Sentence denotes STUDY FUNDING/COMPETING INTEREST(S):
T44 5935-6061 Sentence denotes This work was supported by funding from the Canadian Institutes of Health Research (CIHR) (PJT-148684 and MOP-130398 to L.S.).
T44 5935-6061 Sentence denotes This work was supported by funding from the Canadian Institutes of Health Research (CIHR) (PJT-148684 and MOP-130398 to L.S.).
T45 6062-6132 Sentence denotes C.D. received support from CIHR Foundation (FDN143262 to Stephen Lye).
T45 6062-6132 Sentence denotes C.D. received support from CIHR Foundation (FDN143262 to Stephen Lye).
T46 6133-6179 Sentence denotes S.K. received a TGHRI postdoctoral fellowship.
T46 6133-6179 Sentence denotes S.K. received a TGHRI postdoctoral fellowship.
T47 6180-6240 Sentence denotes The authors declare that there are no conflicts of interest.
T47 6180-6240 Sentence denotes The authors declare that there are no conflicts of interest.
T48 6241-6345 Sentence denotes L.S. reports personal fees from ViiV Healthcare for participation in a Women and Transgender Think Tank.
T48 6241-6345 Sentence denotes L.S. reports personal fees from ViiV Healthcare for participation in a Women and Transgender Think Tank.