2023
Lokki, A Inkeri | Ren, Zhen | Triebwasser, Michael | Daly, Emma | | Perola, Markus | Auro, Kirsi | Burwick, Richard | Salmon, Jane E | Daly, Mark | Laivuori, Hannele | Atkinson, John P | Java, Anuja | Meri, Seppo
Identification of complement factor H variants that predispose to pre-eclampsia: A genetic and functional study Journal Article
In: BJOG, vol. 130, no. 12, pp. 1473–1482, 2023, ISSN: 1471-0528.
Abstract | Links | BibTeX | Tags:
@article{pmid37156755,
title = {Identification of complement factor H variants that predispose to pre-eclampsia: A genetic and functional study},
author = {A Inkeri Lokki and Zhen Ren and Michael Triebwasser and Emma Daly and and Markus Perola and Kirsi Auro and Richard Burwick and Jane E Salmon and Mark Daly and Hannele Laivuori and John P Atkinson and Anuja Java and Seppo Meri},
doi = {10.1111/1471-0528.17529},
issn = {1471-0528},
year = {2023},
date = {2023-11-01},
journal = {BJOG},
volume = {130},
number = {12},
pages = {1473--1482},
abstract = {OBJECTIVE: The objective of the study was to investigate the role of genetic variants in complement proteins in pre-eclampsia.nnDESIGN: In a case-control study involving 609 cases and 2092 controls, five rare variants in complement factor H (CFH) were identified in women with severe and complicated pre-eclampsia. No variants were identified in controls.nnSETTING: Pre-eclampsia is a leading cause of maternal and fetal morbidity and mortality. Immune maladaptation, in particular, complement activation that disrupts maternal-fetal tolerance leading to placental dysfunction and endothelial injury, has been proposed as a pathogenetic mechanism, but this remains unproven.nnPOPULATION: We genotyped 609 pre-eclampsia cases and 2092 controls from FINNPEC and the national FINRISK cohorts.nnMETHODS: Complement-based functional and structural assays were conducted in vitro to define the significance of these five missense variants and each compared with wild type.nnMAIN OUTCOME MEASURES: Secretion, expression and ability to regulate complement activation were assessed for factor H proteins harbouring the mutations.nnRESULTS: We identified five heterozygous rare variants in complement factor H (L3V, R127H, R166Q, C1077S and N1176K) in seven women with severe pre-eclampsia. These variants were not identified in controls. Variants C1077S and N1176K were novel. Antigenic, functional and structural analyses established that four (R127H, R166Q, C1077S and N1176K) were deleterious. Variants R127H and C1077S were synthesised, but not secreted. Variants R166Q and N1176K were secreted normally but showed reduced binding to C3b and consequently defective complement regulatory activity. No defect was identified for L3V.nnCONCLUSIONS: These results suggest that complement dysregulation due to mutations in complement factor H is among the pathophysiological mechanisms underlying severe pre-eclampsia.},
keywords = {},
pubstate = {published},
tppubtype = {article}
}
OBJECTIVE: The objective of the study was to investigate the role of genetic variants in complement proteins in pre-eclampsia.nnDESIGN: In a case-control study involving 609 cases and 2092 controls, five rare variants in complement factor H (CFH) were identified in women with severe and complicated pre-eclampsia. No variants were identified in controls.nnSETTING: Pre-eclampsia is a leading cause of maternal and fetal morbidity and mortality. Immune maladaptation, in particular, complement activation that disrupts maternal-fetal tolerance leading to placental dysfunction and endothelial injury, has been proposed as a pathogenetic mechanism, but this remains unproven.nnPOPULATION: We genotyped 609 pre-eclampsia cases and 2092 controls from FINNPEC and the national FINRISK cohorts.nnMETHODS: Complement-based functional and structural assays were conducted in vitro to define the significance of these five missense variants and each compared with wild type.nnMAIN OUTCOME MEASURES: Secretion, expression and ability to regulate complement activation were assessed for factor H proteins harbouring the mutations.nnRESULTS: We identified five heterozygous rare variants in complement factor H (L3V, R127H, R166Q, C1077S and N1176K) in seven women with severe pre-eclampsia. These variants were not identified in controls. Variants C1077S and N1176K were novel. Antigenic, functional and structural analyses established that four (R127H, R166Q, C1077S and N1176K) were deleterious. Variants R127H and C1077S were synthesised, but not secreted. Variants R166Q and N1176K were secreted normally but showed reduced binding to C3b and consequently defective complement regulatory activity. No defect was identified for L3V.nnCONCLUSIONS: These results suggest that complement dysregulation due to mutations in complement factor H is among the pathophysiological mechanisms underlying severe pre-eclampsia.
Durkin, Jaclyn | Poe, Amy R | Belfer, Samuel J | Rodriguez, Anyara | Tang, Si Hao | Walker, James A | Kayser, Matthew S
regulates early developmental sleep in Journal Article
In: Neurobiol Sleep Circadian Rhythms, vol. 15, pp. 100101, 2023, ISSN: 2451-9944.
Abstract | Links | BibTeX | Tags:
@article{pmid37593040,
title = { regulates early developmental sleep in },
author = {Jaclyn Durkin and Amy R Poe and Samuel J Belfer and Anyara Rodriguez and Si Hao Tang and James A Walker and Matthew S Kayser},
doi = {10.1016/j.nbscr.2023.100101},
issn = {2451-9944},
year = {2023},
date = {2023-11-01},
journal = {Neurobiol Sleep Circadian Rhythms},
volume = {15},
pages = {100101},
abstract = {Sleep disturbances are common in neurodevelopmental disorders, but knowledge of molecular factors that govern sleep in young animals is lacking. Evidence across species, including , suggests that juvenile sleep has distinct functions and regulatory mechanisms in comparison to sleep in maturity. In flies, manipulation of most known adult sleep regulatory genes is not associated with sleep phenotypes during early developmental (larval) stages. Here, we examine the role of the neurodevelopmental disorder-associated gene () in sleep during numerous developmental periods. Mutations in () are associated with sleep and circadian disorders in humans and adult flies. We find in flies that acts to regulate sleep across the lifespan, beginning during larval stages. is required in neurons for this function, as is signaling via the Alk pathway. These findings identify as one of a small number of genes positioned to regulate sleep across developmental periods.},
keywords = {},
pubstate = {published},
tppubtype = {article}
}
Sleep disturbances are common in neurodevelopmental disorders, but knowledge of molecular factors that govern sleep in young animals is lacking. Evidence across species, including , suggests that juvenile sleep has distinct functions and regulatory mechanisms in comparison to sleep in maturity. In flies, manipulation of most known adult sleep regulatory genes is not associated with sleep phenotypes during early developmental (larval) stages. Here, we examine the role of the neurodevelopmental disorder-associated gene () in sleep during numerous developmental periods. Mutations in () are associated with sleep and circadian disorders in humans and adult flies. We find in flies that acts to regulate sleep across the lifespan, beginning during larval stages. is required in neurons for this function, as is signaling via the Alk pathway. These findings identify as one of a small number of genes positioned to regulate sleep across developmental periods.
McConkie-Rosell, Allyn | Spillmann, Rebecca C | Schoch, Kelly | Sullivan, Jennifer A | Walley, Nicole | McDonald, Marie | | Hooper, Stephen R | Shashi, Vandana
Unraveling non-participation in genomic research: A complex interplay of barriers, facilitators, and sociocultural factors Journal Article
In: J Genet Couns, vol. 32, no. 5, pp. 993–1008, 2023, ISSN: 1573-3599.
Abstract | Links | BibTeX | Tags:
@article{pmid37005744,
title = {Unraveling non-participation in genomic research: A complex interplay of barriers, facilitators, and sociocultural factors},
author = {Allyn McConkie-Rosell and Rebecca C Spillmann and Kelly Schoch and Jennifer A Sullivan and Nicole Walley and Marie McDonald and and Stephen R Hooper and Vandana Shashi},
doi = {10.1002/jgc4.1707},
issn = {1573-3599},
year = {2023},
date = {2023-10-01},
journal = {J Genet Couns},
volume = {32},
number = {5},
pages = {993--1008},
abstract = {Although genomic research offering next-generation sequencing (NGS) has increased the diagnoses of rare/ultra-rare disorders, populations experiencing health disparities infrequently participate in these studies. The factors underlying non-participation would most reliably be ascertained from individuals who have had the opportunity to participate, but decline. We thus enrolled parents of children and adult probands with undiagnosed disorders who had declined genomic research offering NGS with return of results with undiagnosed disorders (Decliners, n = 21) and compared their data to those who participated (Participants, n = 31). We assessed: (1) practical barriers and facilitators, (2) sociocultural factors-genomic knowledge and distrust, and (3) the value placed upon a diagnosis by those who declined participation. The primary findings were that residence in rural and medically underserved areas (MUA) and higher number of barriers were significantly associated with declining participation in the study. Exploratory analyses revealed multiple co-occurring practical barriers, greater emotional exhaustion and research hesitancy in the parents in the Decliner group compared to the Participants, with both groups identifying a similar number of facilitators. The parents in the Decliner group also had lower genomic knowledge, but distrust of clinical research was not different between the groups. Importantly, despite their non-participation, those in the Decliner group indicated an interest in obtaining a diagnosis and expressed confidence in being able to emotionally manage the ensuing results. Study findings support the concept that some families who decline participation in diagnostic genomic research may be experiencing pile-up with exhaustion of family resources - making participation in the genomic research difficult. This study highlights the complexity of the factors that underlie non-participation in clinically relevant NGS research. Thus, approaches to mitigating barriers to NGS research participation by populations experiencing health disparities need to be multi-pronged and tailored so that they can benefit from state-of -the art genomic technologies.},
keywords = {},
pubstate = {published},
tppubtype = {article}
}
Although genomic research offering next-generation sequencing (NGS) has increased the diagnoses of rare/ultra-rare disorders, populations experiencing health disparities infrequently participate in these studies. The factors underlying non-participation would most reliably be ascertained from individuals who have had the opportunity to participate, but decline. We thus enrolled parents of children and adult probands with undiagnosed disorders who had declined genomic research offering NGS with return of results with undiagnosed disorders (Decliners, n = 21) and compared their data to those who participated (Participants, n = 31). We assessed: (1) practical barriers and facilitators, (2) sociocultural factors-genomic knowledge and distrust, and (3) the value placed upon a diagnosis by those who declined participation. The primary findings were that residence in rural and medically underserved areas (MUA) and higher number of barriers were significantly associated with declining participation in the study. Exploratory analyses revealed multiple co-occurring practical barriers, greater emotional exhaustion and research hesitancy in the parents in the Decliner group compared to the Participants, with both groups identifying a similar number of facilitators. The parents in the Decliner group also had lower genomic knowledge, but distrust of clinical research was not different between the groups. Importantly, despite their non-participation, those in the Decliner group indicated an interest in obtaining a diagnosis and expressed confidence in being able to emotionally manage the ensuing results. Study findings support the concept that some families who decline participation in diagnostic genomic research may be experiencing pile-up with exhaustion of family resources - making participation in the genomic research difficult. This study highlights the complexity of the factors that underlie non-participation in clinically relevant NGS research. Thus, approaches to mitigating barriers to NGS research participation by populations experiencing health disparities need to be multi-pronged and tailored so that they can benefit from state-of -the art genomic technologies.
Perlis, Roy H | Fihn, Stephan D
Evaluating the Application of Large Language Models in Clinical Research Contexts Journal Article
In: JAMA Netw Open, vol. 6, no. 10, pp. e2335924, 2023, ISSN: 2574-3805.
@article{pmid37782501,
title = {Evaluating the Application of Large Language Models in Clinical Research Contexts},
author = {Roy H Perlis and Stephan D Fihn},
doi = {10.1001/jamanetworkopen.2023.35924},
issn = {2574-3805},
year = {2023},
date = {2023-10-01},
journal = {JAMA Netw Open},
volume = {6},
number = {10},
pages = {e2335924},
keywords = {},
pubstate = {published},
tppubtype = {article}
}
Rahmoune, Adline | Winkler, Marion F | Saxena, Richa | Compher, Charlene | Dashti, Hassan S
In: Nutr Clin Pract, 2023, ISSN: 1941-2452.
Abstract | Links | BibTeX | Tags:
@article{pmid37777983,
title = {Comparison between self-reported and actigraphy-derived sleep measures in patients receiving home parenteral nutrition: Secondary analysis of observational data},
author = {Adline Rahmoune and Marion F Winkler and Richa Saxena and Charlene Compher and Hassan S Dashti},
doi = {10.1002/ncp.11077},
issn = {1941-2452},
year = {2023},
date = {2023-10-01},
journal = {Nutr Clin Pract},
abstract = {BACKGROUND: Patients receiving home parenteral nutrition (HPN) frequently report disrupted sleep. However, there are often inconsistencies between objectively measured and questionnaire-derived sleep measures. We compared sleep measures estimated from wrist actigraphy and self-report in adults receiving HPN.nnMETHODS: In this secondary analysis, we pooled data from two sleep-related studies enrolling adults receiving habitual HPN. We compared measures from 7-day averages of wrist actigraphy against comparable responses to a sleep questionnaire. Sleep measures included bedtime, wake time, time in bed, total sleep time, and sleep onset latency (SOL). Spearman correlation coefficients, Bland-Altman plots, and linear regression models for each set of sleep measures provided estimates of agreement.nnRESULTS: Participants (N = 35) had a mean age of 52 years, body mass index of 21.6 kg/m , and 77% identified as female. Correlation coefficients ranged from 0.35 to 0.90, were highest for wake time (r = 0.90) and bedtime (r = 0.74), and lowest for total sleep time (r = 0.35). Actigraphy overestimated self-reported bedtime, wake time, and total sleep time and underestimated self-reported time in bed and SOL. Regression coefficients indicated the highest calibration for bedtime and wake time and lower calibration for time in bed, total sleep time, and SOL.nnCONCLUSION: We observed strong-to-moderate agreement between sleep measures derived from wrist actigraphy and self-report in adults receiving HPN. Weaker correlations for total sleep time and SOL may indicate low wrist actigraphy sensitivity. Low-quality sleep resulting from sleep disruptions may have also contributed to an underreporting of perceived sleep quantity and lower concordance.},
keywords = {},
pubstate = {published},
tppubtype = {article}
}
BACKGROUND: Patients receiving home parenteral nutrition (HPN) frequently report disrupted sleep. However, there are often inconsistencies between objectively measured and questionnaire-derived sleep measures. We compared sleep measures estimated from wrist actigraphy and self-report in adults receiving HPN.nnMETHODS: In this secondary analysis, we pooled data from two sleep-related studies enrolling adults receiving habitual HPN. We compared measures from 7-day averages of wrist actigraphy against comparable responses to a sleep questionnaire. Sleep measures included bedtime, wake time, time in bed, total sleep time, and sleep onset latency (SOL). Spearman correlation coefficients, Bland-Altman plots, and linear regression models for each set of sleep measures provided estimates of agreement.nnRESULTS: Participants (N = 35) had a mean age of 52 years, body mass index of 21.6 kg/m , and 77% identified as female. Correlation coefficients ranged from 0.35 to 0.90, were highest for wake time (r = 0.90) and bedtime (r = 0.74), and lowest for total sleep time (r = 0.35). Actigraphy overestimated self-reported bedtime, wake time, and total sleep time and underestimated self-reported time in bed and SOL. Regression coefficients indicated the highest calibration for bedtime and wake time and lower calibration for time in bed, total sleep time, and SOL.nnCONCLUSION: We observed strong-to-moderate agreement between sleep measures derived from wrist actigraphy and self-report in adults receiving HPN. Weaker correlations for total sleep time and SOL may indicate low wrist actigraphy sensitivity. Low-quality sleep resulting from sleep disruptions may have also contributed to an underreporting of perceived sleep quantity and lower concordance.
Mazurek, Mercy H | Parasuram, Nethra R | Peng, Teng J | Beekman, Rachel | Yadlapalli, Vineetha | Sorby-Adams, Annabel J | Lalwani, Dheeraj | Zabinska, Julia | Gilmore, Emily J | Petersen, Nils H | Falcone, Guido J | Sujijantarat, Nanthiya | Matouk, Charles | Payabvash, Sam | Sze, Gordon | Schiff, Steven J | Iglesias, Juan Eugenio | Rosen, Matthew S | de Havenon, Adam | Kimberly, W Taylor | Sheth, Kevin N
Detection of Intracerebral Hemorrhage Using Low-Field, Portable Magnetic Resonance Imaging in Patients With Stroke Journal Article
In: Stroke, 2023, ISSN: 1524-4628.