Childhood Abuse and Age at Menarche

Purpose—Physical and sexual abuse are prevalent social hazards. We sought to examine the association between childhood physical and sexual abuse and age at menarche. Methods—Among 68,505 participants enrolled in the Nurses’ Health Study II we investigated the association between childhood physical abuse and sexual abuse on menarche prior to age 11 (early) or after age 15 (late) using multivariate logistic regression analysis, mutually adjusting for both types of abuse. Results—Fifty-seven percent of respondents reported some form of physical or sexual abuse in childhood. We found a positive dose-response association between severity of sexual abuse in childhood and risk for early menarche. Compared to women who reported no childhood sexual abuse, the adjusted odds ratio [AOR] for early menarche was 1.20 (95% confidence interval [CI], 1.10, 1.37) for sexual touching and 1.49 (95% CI, 1.34, 1.66) for forced sexual activity. Only severe physical abuse predicted early menarche (AOR=1.22, 95% CI, 1.10–1.37). Childhood physical abuse had a dose-response association with late age at menarche: AOR 1.17 (95% CI, 1.04, 1.32) for mild, 1.20 (95% CI, 1.08, 1.33) for moderate, and 1.50 (95% CI, 1.27, 1.77) for severe physical abuse. Sexual abuse was not associated with late menarche. Conclusion—Childhood abuse was very prevalent in this large cohort of U.S. women. Severity of childhood sexual abuse was associated with risk for early onset of menarche, and physical abuse was associated with both early and late onset menarche. Implications and Contribution—The severity of childhood sexual abuse and severe physical abuse were associated with risk for accelerated menarche, while severity of childhood physical was associated with risk for delayed onset of menarche. The nature of the association between different forms of childhood adversities and reproductive lifespan may vary

Management of adult-onset Still's disease:evidence- and consensus-based recommendations by experts

Objectives: Adult-onset Still's disease (AOSD) is a rare condition characterized by fevers, rash, and arthralgia/arthritis; most doctors treating AOSD in the Netherlands treat &lt;5 patients per year. Currently, there is no internationally accepted treatment guideline for AOSD. The objectives of this study were to conduct a Delphi panel aimed at reaching consensus about diagnostic and treatment strategies for patients with AOSD and to use the outcomes as a basis for a treatment algorithm. Methods: The Delphi panel brought together 18 AOSD experts: rheumatologists, internists and paediatricians. The Delphi process consisted of three rounds. In the first two rounds, online lists of questions and statements were completed. In the third round, final statements were discussed during a virtual meeting and a final vote took place. Consensus threshold was set at 80%. Two targeted literature searches were performed identifying the level of evidence of the consensus-based statements. Results: Consensus was reached on 29 statements, including statements related to diagnosis and diagnostic tests, definition of response and remission, the therapy, the use of methotrexate and tapering of treatment. The panel consented on reduction of the use of glucocorticoids to avoid side effects, and preferred the use of biologics over conventional treatment. The role of IL-1 and IL-6 blocking agents was considered important in the treatment of AOSD. Conclusion: In this Delphi panel, a high level of consensus was achieved on recommendations for diagnosis and therapy of AOSD that can serve as a basis for a treatment guideline.</p

Management of adult-onset Still's disease:evidence- and consensus-based recommendations by experts

Objectives: Adult-onset Still's disease (AOSD) is a rare condition characterized by fevers, rash, and arthralgia/arthritis; most doctors treating AOSD in the Netherlands treat &lt;5 patients per year. Currently, there is no internationally accepted treatment guideline for AOSD. The objectives of this study were to conduct a Delphi panel aimed at reaching consensus about diagnostic and treatment strategies for patients with AOSD and to use the outcomes as a basis for a treatment algorithm. Methods: The Delphi panel brought together 18 AOSD experts: rheumatologists, internists and paediatricians. The Delphi process consisted of three rounds. In the first two rounds, online lists of questions and statements were completed. In the third round, final statements were discussed during a virtual meeting and a final vote took place. Consensus threshold was set at 80%. Two targeted literature searches were performed identifying the level of evidence of the consensus-based statements. Results: Consensus was reached on 29 statements, including statements related to diagnosis and diagnostic tests, definition of response and remission, the therapy, the use of methotrexate and tapering of treatment. The panel consented on reduction of the use of glucocorticoids to avoid side effects, and preferred the use of biologics over conventional treatment. The role of IL-1 and IL-6 blocking agents was considered important in the treatment of AOSD. Conclusion: In this Delphi panel, a high level of consensus was achieved on recommendations for diagnosis and therapy of AOSD that can serve as a basis for a treatment guideline.</p

Management of adult-onset Still's disease: evidence- and consensus-based recommendations by experts

Objectives: Adult-onset Still's disease (AOSD) is a rare condition characterized by fevers, rash, and arthralgia/arthritis; most doctors treating AOSD in the Netherlands treat <5 patients per year. Currently, there is no internationally accepted treatment guideline for AOSD. The objectives of this study were to conduct a Delphi panel aimed at reaching consensus about diagnostic and treatment strategies for patients with AOSD and to use the outcomes as a basis for a treatment algorithm. Methods: The Delphi panel brought together 18 AOSD experts: rheumatologists, internists and paediatricians. The Delphi process consisted of three rounds. In the first two rounds, online lists of questions and statements were completed. In the third round, final statements were discussed during a virtual meeting and a final vote took place. Consensus threshold was set at 80%. Two targeted literature searches were performed identifying the level of evidence of the consensus-based statements. Results: Consensus was reached on 29 statements, including statements related to diagnosis and diagnostic tests, definition of response and remission, the therapy, the use of methotrexate and tapering of treatment. The panel consented on reduction of the use of glucocorticoids to avoid side effects, and preferred the use of biologics over conventional treatment. The role of IL-1 and IL-6 blocking agents was considered important in the treatment of AOSD. Conclusion: In this Delphi panel, a high level of consensus was achieved on recommendations for diagnosis and therapy of AOSD that can serve as a basis for a treatment guideline

Discovery and functional prioritization of Parkinson's disease candidate genes from large-scale whole exome sequencing.

BACKGROUND: Whole-exome sequencing (WES) has been successful in identifying genes that cause familial Parkinson's disease (PD). However, until now this approach has not been deployed to study large cohorts of unrelated participants. To discover rare PD susceptibility variants, we performed WES in 1148 unrelated cases and 503 control participants. Candidate genes were subsequently validated for functions relevant to PD based on parallel RNA-interference (RNAi) screens in human cell culture and Drosophila and C. elegans models. RESULTS: Assuming autosomal recessive inheritance, we identify 27 genes that have homozygous or compound heterozygous loss-of-function variants in PD cases. Definitive replication and confirmation of these findings were hindered by potential heterogeneity and by the rarity of the implicated alleles. We therefore looked for potential genetic interactions with established PD mechanisms. Following RNAi-mediated knockdown, 15 of the genes modulated mitochondrial dynamics in human neuronal cultures and four candidates enhanced α-synuclein-induced neurodegeneration in Drosophila. Based on complementary analyses in independent human datasets, five functionally validated genes-GPATCH2L, UHRF1BP1L, PTPRH, ARSB, and VPS13C-also showed evidence consistent with genetic replication. CONCLUSIONS: By integrating human genetic and functional evidence, we identify several PD susceptibility gene candidates for further investigation. Our approach highlights a powerful experimental strategy with broad applicability for future studies of disorders with complex genetic etiologies

Concerns, quality of life, access to care and productivity of the general population during the first 8 weeks of the coronavirus lockdown in Belgium and the Netherlands

Abstract Background The COVID-19 pandemic has a disruptive impact on our society. We therefore conducted a population survey to describe: 1) stress, concerns and quality of life 2) access to healthcare and cancelled/delayed healthcare and 3) productivity during the first 8 weeks of the coronavirus lockdown in the general population. Methods An online cross-sectional survey was conducted in a representative sample after 8 weeks of the coronavirus lockdown in Belgium and the Netherlands. The survey included a series of three validated questionnaires about quality of life delayed/cancelled medical care and productivity loss using validated questionnaires. Results In total, 2099 Belgian and 2058 Dutch respondents completed the survey with a mean age of 46.4 and 42.0 years, respectively. Half of the respondents were female in both countries. A small proportion tested positive for COVID-19, 1.4% vs 4.7%, respectively. The majority of respondents with a medical condition was worried about their current health state due to the pandemic (53%) vs (63%), respectively. Respondents experienced postponed/cancelled care (26%) and were concerned about the availability of medication (32%) for both countries. Productivity losses due to the COVID-19 restrictions were calculated in absenteeism (36%) and presenteeism (30%) for Belgium, and (19%) and (35%) for the Netherlands. Most concerns and productivity losses were reported by respondents with childre

Concerns, quality of life, access to care and productivity of the general population during the first 8 weeks of the coronavirus lockdown in Belgium and the Netherlands

Abstract Background The COVID-19 pandemic has a disruptive impact on our society. We therefore conducted a population survey to describe: 1) stress, concerns and quality of life 2) access to healthcare and cancelled/delayed healthcare and 3) productivity during the first 8 weeks of the coronavirus lockdown in the general population. Methods An online cross-sectional survey was conducted in a representative sample after 8 weeks of the coronavirus lockdown in Belgium and the Netherlands. The survey included a series of three validated questionnaires about quality of life delayed/cancelled medical care and productivity loss using validated questionnaires. Results In total, 2099 Belgian and 2058 Dutch respondents completed the survey with a mean age of 46.4 and 42.0 years, respectively. Half of the respondents were female in both countries. A small proportion tested positive for COVID-19, 1.4% vs 4.7%, respectively. The majority of respondents with a medical condition was worried about their current health state due to the pandemic (53%) vs (63%), respectively. Respondents experienced postponed/cancelled care (26%) and were concerned about the availability of medication (32%) for both countries. Productivity losses due to the COVID-19 restrictions were calculated in absenteeism (36%) and presenteeism (30%) for Belgium, and (19%) and (35%) for the Netherlands. Most concerns and productivity losses were reported by respondents with childre

Association between dexamethasone treatment and the host response in COVID-19 patients admitted to the general ward

Dexamethasone improves clinical outcomes in COVID-19 patients requiring supplementary oxygen. We investigated possible mechanisms of action by comparing sixteen plasma host response biomarkers in general ward patients before and after implementation of dexamethasone as standard of care. 48 patients without and 126 patients with dexamethasone treatment were sampled within 48 h of admission. Endothelial cell and coagulation activation biomarkers were comparable. Dexamethasone treatment was associated with lower plasma interleukin (IL)-6 and IL-1 receptor antagonist levels, whilst other inflammation parameters were not affected. These data argue against modification of vascular-procoagulant responses as an early mechanism of action of dexamethasone in COVID-19

Delaying aging and the aging-associated decline in protein homeostasis by inhibition of tryptophan degradation

Toxicity of aggregation-prone proteins is thought to play an important role in aging and age-related neurological diseases like Parkinson and Alzheimer's diseases. Here, we identify tryptophan 2,3-dioxygenase (tdo-2), the first enzyme in the kynurenine pathway of tryptophan degradation, as a metabolic regulator of age-related α-synuclein toxicity in a Caenorhabditis elegans model. Depletion of tdo-2 also suppresses toxicity of other heterologous aggregation-prone proteins, including amyloid-β and polyglutamine proteins, and endogenous metastable proteins that are sensors of normal protein homeostasis. This finding suggests that tdo-2 functions as a general regulator of protein homeostasis. Analysis of metabolite levels in C. elegans strains with mutations in enzymes that act downstream of tdo-2 indicates that this suppression of toxicity is independent of downstream metabolites in the kynurenine pathway. Depletion of tdo-2 increases tryptophan levels, and feeding worms with extra L-tryptophan also suppresses toxicity, suggesting that tdo-2 regulates proteotoxicity through tryptophan. Depletion of tdo-2 extends lifespan in these worms. Together, these results implicate tdo-2 as a metabolic switch of age-related protein homeostasis and lifespan. With TDO and Indoleamine 2,3-dioxygenase as evolutionarily conserved human orthologs of TDO-2, intervening with tryptophan metabolism may offer avenues to reducing proteotoxicity in aging and age-related diseases