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| 2. |
- Aad, G., et al.
(author)
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- 2015
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Journal article (peer-reviewed)
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| 3. |
- Aad, G., et al.
(author)
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- 2015
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Journal article (peer-reviewed)
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| 4. |
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| 5. |
- Fresard, Laure, et al.
(author)
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Identification of rare-disease genes using blood transcriptome sequencing and large control cohorts
- 2019
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In: Nature Medicine. - : NATURE PUBLISHING GROUP. - 1078-8956 .- 1546-170X. ; 25:6, s. 911-919
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Journal article (peer-reviewed)abstract
- It is estimated that 350 million individuals worldwide suffer from rare diseases, which are predominantly caused by mutation in a single gene(1). The current molecular diagnostic rate is estimated at 50%, with whole-exome sequencing (WES) among the most successful approaches(2-5). For patients in whom WES is uninformative, RNA sequencing (RNA-seq) has shown diagnostic utility in specific tissues and diseases(6-8). This includes muscle biopsies from patients with undiagnosed rare muscle disorders(6,9), and cultured fibroblasts from patients with mitochondrial disorders(7). However, for many individuals, biopsies are not performed for clinical care, and tissues are difficult to access. We sought to assess the utility of RNA-seq from blood as a diagnostic tool for rare diseases of different pathophysiologies. We generated whole-blood RNA-seq from 94 individuals with undiagnosed rare diseases spanning 16 diverse disease categories. We developed a robust approach to compare data from these individuals with large sets of RNA-seq data for controls (n = 1,594 unrelated controls and n = 49 family members) and demonstrated the impacts of expression, splicing, gene and variant filtering strategies on disease gene identification. Across our cohort, we observed that RNA-seq yields a 7.5% diagnostic rate, and an additional 16.7% with improved candidate gene resolution.
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| 6. |
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| 7. |
- Gatzounis, Rena, et al.
(author)
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Taking a break in response to pain : An experimental investigation of the effects of interruptions by pain on subsequent activity resumption
- 2017
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In: Scandinavian Journal of Pain. - : Elsevier. - 1877-8860 .- 1877-8879. ; 16, s. 52-60
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Journal article (peer-reviewed)abstract
- BACKGROUND AND AIMS: Interrupting ongoing activities with the intention to resume them again later is a natural response to pain. However, such interruptions might have negative consequences for the subsequent resumption and performance of the interrupted activity. Activity interruptions by pain may be more impairing than interruptions by non-painful stimuli, and also be subjectively experienced as such. These effects might be more pronounced in people high in pain catastrophizing. These hypotheses were investigated in two experiments.METHODS: In Experiment 1, healthy volunteers (n=24) performed an ongoing task requiring a sequence of joystick movements. Occasionally, they received either a painful electrocutaneous or a non-painful vibrotactile stimulus, followed by suspension of the ongoing task and temporary engagement in a different task (interruption task). After performing the interruption task for 30s, participants resumed the ongoing task. As the ongoing task of Experiment 1 was rather simple, Experiment 2 (n=30) included a modified, somewhat more complex version of the task, in order to examine the effects of activity interruptions by pain.RESULTS: Participants made more errors and were slower to initiate movements (Experiment 1 & 2) and to complete movements (Experiment 2) when they resumed the ongoing task after an interruption, indicating that interruptions impaired subsequent performance. However, these impairments were not larger when the interruption was prompted by painful than by non-painful stimulation. Pain catastrophizing did not influence the results.CONCLUSIONS: Results indicate that activity interruptions by pain have negative consequences for the performance of an activity upon its resumption, but not more so than interruptions by non-painful stimuli. Potential explanations and avenues for future research are discussed.IMPLICATIONS: Interrupting ongoing activities is a common response to pain. In two experiments using a novel paradigm we showed that activity interruptions by pain impair subsequent activity resumption and performance. However, this effect seems to not be specific to pain.
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| 8. |
- Peaceman, Alan M., et al.
(author)
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Lifestyle Interventions Limit Gestational Weight Gain in Women with Overweight or Obesity : LIFE-Moms Prospective Meta-Analysis
- 2018
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In: Obesity. - : Wiley. - 1930-7381 .- 1930-739X. ; 26:9, s. 1396-1404
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Journal article (peer-reviewed)abstract
- Objective: This study aimed to evaluate the effects of varied lifestyle intervention programs designed to ameliorate excess gestational weight gain (GWG) in pregnant women with overweight or obesity compared with standard care, including effects on pregnancy outcomes. Methods: Seven clinical centers conducted separate randomized clinical trials to test different lifestyle intervention strategies to modify GWG in diverse populations. Eligibility criteria, specific outcome measures, and assessment procedures were standardized across trials. The results of the separate trials were combined using an individual-participant data meta-analysis. Results: For the 1,150 women randomized, the percent with excess GWG per week was significantly lower in the intervention group compared with the standard care group (61.8% vs. 75.0%; odds ratio [95% CI]: 0.52 [0.40 to 0.67]). Total GWG from enrollment to 36 weeks' gestation was also lower in the intervention group (8.1 ± 5.2 vs. 9.7 ± 5.4 kg; mean difference: −1.59 kg [95% CI:−2.18 to −0.99 kg]). The results from the individual trials were similar. The intervention and standard care groups did not differ in preeclampsia, gestational diabetes, cesarean delivery, or birth weight. Conclusions: Behavioral lifestyle interventions focusing primarily on diet and physical activity among women with overweight and obesity resulted in a significantly lower proportion of women with excess GWG. This modest beneficial effect was consistent across diverse intervention modalities in a large, racially and socioeconomically diverse US population of pregnant women.
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| 9. |
- Phelan, Suzanne, et al.
(author)
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One-year postpartum anthropometric outcomes in mothers and children in the LIFE-Moms lifestyle intervention clinical trials
- 2020
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In: International Journal of Obesity. - : Springer Science and Business Media LLC. - 0307-0565 .- 1476-5497. ; 44, s. 57-68
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Journal article (peer-reviewed)abstract
- Background/objectives: Excess gestational weight gain (GWG) is a risk factor for maternal postpartum weight retention and excessive neonatal adiposity, especially in women with overweight or obesity. Whether lifestyle interventions to reduce excess GWG also reduce 12-month maternal postpartum weight retention and infant weight-for-length z score is unknown. Randomized controlled trials from the LIFE-Moms consortium investigated lifestyle interventions that began in pregnancy and tested whether there was benefit through 12 months on maternal postpartum weight retention (i.e., the difference in weight from early pregnancy to 12 months) and infant-weight-for-length z scores. Subjects/methods: In LIFE-Moms, women (N = 1150; 14.1 weeks gestation at enrollment) with overweight or obesity were randomized within each of seven trials to lifestyle intervention or standard care. Individual participant data were combined and analyzed using generalized linear mixed models with trial entered as a random effect. The 12-month assessment was completed by 83% (959/1150) of women and 84% (961/1150) of infants. Results: Compared with standard care, lifestyle intervention reduced postpartum weight retention (2.2 ± 7.0 vs. 0.7 ± 6.2 kg, respectively; difference of −1.6 kg (95% CI −2.5, −0.7; p = 0.0003); the intervention effect was mediated by reduction in excess GWG, which explained 22% of the effect on postpartum weight retention. Lifestyle intervention also significantly increased the odds (OR = 1.68 (95% CI, 1.26, 2.24)) and percentage of mothers (48.2% vs. 36.2%) at or below baseline weight at 12 months postpartum (yes/no) compared with standard care. There was no statistically significant treatment group effect on infant anthropometric outcomes at 12 months. Conclusions: Compared with standard care, lifestyle interventions initiated in pregnancy and focused on healthy eating, increased physical activity, and other behavioral strategies resulted in significantly less weight retention but similar infant anthropometric outcomes at 12 months postpartum in a large, diverse US population of women with overweight and obesity.
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| 10. |
- Redman, Leanne M., et al.
(author)
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Attenuated early pregnancy weight gain by prenatal lifestyle interventions does not prevent gestational diabetes in the LIFE-Moms consortium
- 2021
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In: Diabetes Research and Clinical Practice. - : Elsevier BV. - 0168-8227. ; 171
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Journal article (peer-reviewed)abstract
- Aims: To examine the effect of lifestyle (diet and physical activity) interventions on the prevalence of GDM, considering the method of GDM ascertainment and its association with early pregnancy characteristics and maternal and neonatal outcomes in the LIFE-Moms consortium. Methods: LIFE-Moms evaluated the effects of lifestyle interventions to optimize gestational weight gain in 1148 pregnant women with BMI ≥ 25 kg/m2 and without known diabetes at enrollment, compared with standard care. GDM was assessed between 24 and 31-weeks gestation by a 2-hour, 75-gram OGTT or by local clinical practice standards. Results: Lifestyle interventions initiated prior to 16 weeks reduced early excess GWG compared with standard care (0.35 ± 0.24 vs 0.43 ± 0.26 kg per week, p=<0.0001) but did not affect GDM diagnosis (11.1% vs 11.6%, p = 0.91). Using the 75-gram, 2-hour OGTT, 13. 0% of standard care and 11.0% of the intervention group had GDM by the IADPSG criteria (p = 0.45). The ‘type of diagnostic test’ did not change the result (p = 0.86). Women who developed GDM were significantly heavier, more likely to have obesity, and more likely to have dysglycemia at baseline. Conclusion: Moderate-to-high intensity lifestyle interventions grounded in behavior change theory initiated between 9 and 16-weeks gestation did not affect the prevalence of GDM despite reducing early GWG. Clinicaltrials.gov: NCT01545934, NCT01616147, NCT01771133, NCT01631747, NCT01768793, NCT01610752, NCT01812694.
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| 11. |
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| 12. |
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| 13. |
- Gatzounis, Rena, et al.
(author)
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A break from pain! : Interruption management in the context of pain
- 2019
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In: Pain management. - : Future Medicine Ltd.. - 1758-1869 .- 1758-1877. ; 9:1, s. 81-91
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Journal article (peer-reviewed)abstract
- Activity interruptions, namely temporary suspensions of an ongoing task with the intention to resume it later, are common in pain. First, pain is a threat signal that urges us to interrupt ongoing activities in order to manage the pain and its cause. Second, activity interruptions are used in chronic pain management. However, activity interruptions by pain may carry costs for activity performance. These costs have recently started to be systematically investigated. We review the evidence on the consequences of activity interruptions by pain for the performance of the interrupted activity. Further, inspired by literature on interruptions from other research fields, we suggest ways to improve interruption management in the field of pain, and provide a future research agenda.
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| 14. |
- Gatzounis, Rena, et al.
(author)
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Activity interruptions by pain impair activity resumption, but not more than activity interruptions by other stimuli : an experimental investigation
- 2018
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In: Pain. - : Lippincott Williams & Wilkins. - 0304-3959 .- 1872-6623. ; 159:2, s. 351-358
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Journal article (peer-reviewed)abstract
- Interrupting ongoing activities whilst intending to resume them later is a natural response to pain. Whereas this response facilitates pain management, at the same time it may also disrupt task performance. Previous research has shown that activity interruptions by pain impair subsequent resumption of the activity, but not more than pain-irrelevant interruptions. Ongoing task complexity and pain threat value might influence interruption effects. In this experiment, we adjusted a paradigm from outside the field of pain to investigate how activity interruptions by pain affect task performance. Healthy participants (n=69) were required to answer a series of questions, in a specific sequence, about presented letter-digit combinations. This ongoing task was occasionally interrupted by painful electrocutaneous or non-painful vibrotactile stimulation (between-subjects) followed by a typing task. Upon interruption completion, participants were required to resume the ongoing task at the next step of the question sequence. Results indicate impaired sequence accuracy (less frequent resumption at the correct step of the sequence) but preserved non-sequence accuracy (similarly frequent correct responses to question content) immediately after an interruption. Effects were not larger for interruptions by pain, compared to non-pain. Further, participants in the two conditions reported similar task experience, namely task motivation, perceived difficulty, and confidence to resume the interrupted task. Pain catastrophizing did not influence the results. As in previous studies, activity interruptions by pain were shown to impair the resumption of a task that requires keeping to a step sequence, but not more than interruptions by non-painful stimuli. Potential explanations are discussed.
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| 15. |
- Gatzounis, Rena, et al.
(author)
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Effects of activity interruptions by pain on pattern of activity performance : An experimental investigation
- 2018
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In: Scandinavian Journal of Pain. - : Walter de Gruyter. - 1877-8860 .- 1877-8879. ; 18, s. 109-119
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Journal article (peer-reviewed)abstract
- Background and aims: Suspending an ongoing activity with the intention to resume it again later is a natural response to pain. This response facilitates coping with the pain, but it may also have negative consequences for the resumption and performance of the activity. For example, people with pain problems are often forced to take a break from doing their household chores because of their pain. They might delay resuming their chore, eventually needing longer time to finish it. We investigated how activity interruptions by pain influence the pattern of subsequent activity performance. We expected that when an activity is interrupted by pain (compared to non-pain), people spend longer time away from the activity, need longer time to complete it, and are less motivated to perform it.Methods: Sixty healthy volunteers performed an ongoing task that required them to make joystick movements in different directions according to a specific rule. Occasionally, participants received either a painful electrocutaneous stimulus or a non-painful and non-aversive auditory stimulus (between-subjects) as an interruption cue. The interruption cue was followed by the temporary suspension of the ongoing task and the initiation of a different activity (interruption task). The latter required the categorization of cards and had a maximum duration, but participants could also stop it earlier by pressing a button. We measured time away from the (interrupted) ongoing task, total time to complete the ongoing task (including the interruptions) and self-reported motivation to perform both the ongoing as well as the interruption task.Results: Groups did not differ in the time away from the ongoing task, total time to complete the ongoing task, or self-reported motivation to perform the two tasks.Conclusions: Activity interruptions by pain did not impair the pattern of activity performance more than activity interruptions by non-pain. Potential explanations and suggestions for future research are discussed.
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| 16. |
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| 17. |
- Shakur, Y, et al.
(author)
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Membrane localization of cyclic nucleotide phosphodiesterase 3 (PDE3). Two N-terminal domains are required for the efficient targeting to, and association of, PDE3 with endoplasmic reticulum
- 2000
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In: Journal of Biological Chemistry. - 1083-351X. ; 275:49, s. 38749-38761
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Journal article (peer-reviewed)abstract
- Subcellular localization of cyclic nucleotide phosphodiesterases (PDEs) may be important in compartmentalization of cAMP/cGMP signaling responses. In 3T3-L1 adipocytes, mouse (M) PDE3B was associated with the endoplasmic reticulum (ER) as indicated by its immunofluorescent colocalization with the ER protein BiP and subcellular fractionation studies. In transfected NIH 3006 or COS-7 cells, recombinant wild-type PDE3A and PDE3B isoforms were both found almost exclusively in the ER. The N-terminal portion of PDE3 can be arbitrarily divided into region 1 (aa 1-300), which contains a large hydrophobic domain with six predicted transmembrane helices, followed by region 2 (aa 301-500) containing a smaller hydrophobic domain (of approximately 50 aa). To investigate the role of regions 1 and 2 in membrane association, we examined the subcellular localization of a series of catalytically active, Flag-tagged N-terminal-truncated human (H) PDE3A and MPDE3B recombinants, as well as a series of fragments from regions 1 and 2 of MPDE3B synthesized as enhanced green fluorescent (EGFP) fusion proteins in COS-7 cells. In COS-7 cells, the localization of a mutant HPDE3A, lacking the first 189 amino acids (aa) and therefore four of the six predicted transmembrane helices (H3A-Delta189), was virtually identical to that of the wild type. M3B-Delta302 (lacking region 1) and H3A-Delta397 (lacking region 1 as well as part of region 2) retained, to different degrees, the ability to associate with membranes, albeit less efficiently than H3A-Delta189. Proteins that lacked both regions 1 and 2, H3A-Delta510 and M3B-Delta604, did not associate with membranes. Consistent with these findings, region 1 EGFP-MPDE3B fusion proteins colocalized with the ER, whereas region 2 EGFP fusion proteins were diffusely distributed. Thus, some portion of the N-terminal hydrophobic domain in region 1 plus a second domain in region 2 are important for efficient membrane association/targeting of PDE3.
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