Fertility History and Physical and Mental Health Changes in European Older Adults

Previous studies have shown that aspects of reproductive history, such as earlier parenthood and high parity, are associated with poorer health in mid and later life. However, it is unclear which dimensions of health are most affected by reproductive history, and whether the pattern of associations varies for measures of physical, psychological and cognitive health. Such variation might provide more insight into possible underlying mechanisms. We use longitudinal data for men and women aged 50–79 years in ten European countries from the Survey of Health, Ageing and Retirement in Europe to analyse associations between completed fertility history and self-reported and observed health indicators measured 2–3 years apart (functional limitations, chronic diseases, grip strength, depression and cognition), adjusting for socio-demographic, and health factors at baseline. Using multiple imputation and pattern mixture modelling, we tested the robustness of estimates to missing data mechanisms. The results are partly consistent with previous studies and show that women who became mothers before age 20 had worse functional health at baseline and were more likely to suffer functional health declines. Parents of 4 or more children had worse physical, psychological and cognitive health at baseline and were more likely to develop circulatory disease over the follow-up period. Men who delayed fatherhood until age 35 or later had better health at baseline but did not experience significantly different health declines. This study improves our understanding of linkages between fertility histories and later life health and possible implications of changes in fertility patterns for population health. However, research ideally using prospective life course data is needed to further elucidate possible mechanisms, considering interactions with partnership histories, health behaviour patterns and socio-economic trajectories

31st Annual Meeting and Associated Programs of the Society for Immunotherapy of Cancer (SITC 2016) : part two

Background The immunological escape of tumors represents one of the main ob- stacles to the treatment of malignancies. The blockade of PD-1 or CTLA-4 receptors represented a milestone in the history of immunotherapy. However, immune checkpoint inhibitors seem to be effective in specific cohorts of patients. It has been proposed that their efficacy relies on the presence of an immunological response. Thus, we hypothesized that disruption of the PD-L1/PD-1 axis would synergize with our oncolytic vaccine platform PeptiCRAd. Methods We used murine B16OVA in vivo tumor models and flow cytometry analysis to investigate the immunological background. Results First, we found that high-burden B16OVA tumors were refractory to combination immunotherapy. However, with a more aggressive schedule, tumors with a lower burden were more susceptible to the combination of PeptiCRAd and PD-L1 blockade. The therapy signifi- cantly increased the median survival of mice (Fig. 7). Interestingly, the reduced growth of contralaterally injected B16F10 cells sug- gested the presence of a long lasting immunological memory also against non-targeted antigens. Concerning the functional state of tumor infiltrating lymphocytes (TILs), we found that all the immune therapies would enhance the percentage of activated (PD-1pos TIM- 3neg) T lymphocytes and reduce the amount of exhausted (PD-1pos TIM-3pos) cells compared to placebo. As expected, we found that PeptiCRAd monotherapy could increase the number of antigen spe- cific CD8+ T cells compared to other treatments. However, only the combination with PD-L1 blockade could significantly increase the ra- tio between activated and exhausted pentamer positive cells (p= 0.0058), suggesting that by disrupting the PD-1/PD-L1 axis we could decrease the amount of dysfunctional antigen specific T cells. We ob- served that the anatomical location deeply influenced the state of CD4+ and CD8+ T lymphocytes. In fact, TIM-3 expression was in- creased by 2 fold on TILs compared to splenic and lymphoid T cells. In the CD8+ compartment, the expression of PD-1 on the surface seemed to be restricted to the tumor micro-environment, while CD4 + T cells had a high expression of PD-1 also in lymphoid organs. Interestingly, we found that the levels of PD-1 were significantly higher on CD8+ T cells than on CD4+ T cells into the tumor micro- environment (p < 0.0001). Conclusions In conclusion, we demonstrated that the efficacy of immune check- point inhibitors might be strongly enhanced by their combination with cancer vaccines. PeptiCRAd was able to increase the number of antigen-specific T cells and PD-L1 blockade prevented their exhaus- tion, resulting in long-lasting immunological memory and increased median survival

Small-molecule activation of OGG1 increases oxidative DNA damage repair by gaining a new function

Oxidative DNA damage is recognised by 8-oxoguanine (8-oxoG) DNA glycosylase 1 (OGG1), which excises 8-oxoG, leaving a substrate for apurinic endonuclease 1 (APE1), initiating repair. Here, we describe a small molecule (TH10785) that interacts with the Phe319 and Gly42 amino acids of OGG1, increases the enzyme activity 10-fold and generates a novel β,δ-lyase enzymatic function. TH10785 controls the catalytic activity mediated by a nitrogen base within its molecular structure. In cells, TH10785 increases OGG1 recruitment to and repair of oxidative DNA damage. This alters the repair process, which no longer requires APE1 but instead is dependent on polynucleotide kinase phosphatase (PNKP1) activity. The increased repair of oxidative DNA lesions with a small molecule may have therapeutic applications in various diseases and ageing.European Research Council TAROX-695376Swedish Research Council 2015-00162 and 2018-03406Ministry of Science and Innovation, Spain/State Research Agency, Spain/10.13039/501.100011033European Regional Development Fund (ERDF) BFU2017-83900-PCrafoord Foundation 20190532Alfred Osterlund FoundationSwedish Pain Relief FoundationSwedish Cancer Society CAN 2018/0658 and CAN 2017/716Torsten and Ragnar Soderberg foundationDr. Ake-Olsson Foundation for Hematological Research 2020-00306Thomas Helleday Foundation for medical research postdoctoral stipendsNTNU Enabling Technology Programme on BiotechnologyEMBO Short-Term Fellowship 9005FEBS Short-Term FellowshipScandinavian ExchangeGerman Research Foundation (DFG) 239748522Sonderforschungsbereich (SFB) 1127Leibniz AwardNorwegian Research Council 303369Karolinska Institutet Research Foundation 2020-02186Lars Hiertas Minne StiftelseAsociacion Espanola Contra Cancer grant Postdoctoral AECC 2020 POSTD20042BENIInstituto de Salud Carlos III CP19/00063, PI20/00329 and PI19/00640European Social Fund (ESF)Innovative Medicines Initiative 2 Joint Undertaking (JU) 875510European Union's Horizon 2020 research and innovation program, Marie Sklodowska-Curie 722729Accepte

Nucleobase catalysts for the enzymatic activation of 8-oxoguanine DNA glycosylase 1

: Bifunctional DNA glycosylases employ an active site lysine or the N-terminus to form a Schiff base with the abasic site (AP site) base excision repair (BER) intermediate. Cleaving this reversible structure is the rate-determining step in the initiation of 8-oxoguanine (8-oxoG) repair for 8-oxoguanine DNA glycosylase 1 (OGG1). The OGG1 AP lyase activity can be increased using small molecule binders, called organocatalytic switches, to cleave the DNA backbone in a similar manner as a bifunctional DNA glycosylase. In search for novel organocatalytic switches we here identify 8-Substituted 6 thioguanines and 6-amino-pyrazolo-[3,4-d]-pyrimidine derivatives as potent and selective scaffolds enabling OGG1 to cleave AP sites opposite any canonical nucleobase by β-elimination, shaping a complete, artificial AP-lyase function. These new tool compounds enhance the cellular repair of 8-oxoG and AP sites, activating a rudimentary but canonical enzymatic activity

FReDA – The German Family Demography Panel Study

The study programme “FReDA – The German Family Demography Panel” is a cooperative project of the German Federal Institute for Population Research, GESIS – Leibniz Institute for the Social Sciences, and – as representatives of the pairfam consortium – the University of Cologne and the Friedrich Schiller University Jena. FReDA is a longitudinal study on family and demography with an international perspective and a dyadic multi-actor design. As part of the international Generations and Gender Programme (GGP), the FReDA-GGS sample allows for comparisons with several other European countries. From wave 2 onwards, the pairfam sample, which was first recruited in 2008, will be integrated into the FReDA panel as the FReDA-pairfam sample and will be followed with a joint FReDA survey instrument. FReDA focuses thematically on family life and intimate relationships. The questionnaires for the first wave of FReDA have a modular design and comprise the following main topics: • Demography • Health, well-being, and personality • Work and income • Family planning and fertility • Couples’ relationships and partnerships • Parent–child and intergenerational relationships • Attitudes and values • COVID-19 pandemic For the recruitment of the FReDA-GGS sample, a probability-based sample of 108,256 anchor persons aged between 18 and 49 years and resident in Germany was drawn from the population registers of municipalities in Germany. The first FReDA wave, W1, was conducted in multiple subwaves consisting of the recruitment wave W1R and the two subwaves W1A and W1B. The interviews were conducted in a self-administered web-based (CAWI) or paper-based (PAPI) mode by the infas Institute for Applied Social Science. Data for the first FReDA wave were collected from April to June 2021 (W1R), July to September 2021 (W1A), and November 2021 to January 2022 (W1B). Additionally, data on anchor persons’ partners were collected from August to November 2021 (W1Apartner). A comprehensive overview of the methodological and conceptual principles of the FReDA study is provided in the FReDA reference paper by Schneider et al. (2021) .Recruitment subwave W1R: Value orientation and attitudes: traditional marriage concept (Unmarried cohabitation is permissible, marriage for life, divorce is permissible); traditional family (women need children to be fulfilled, men need children to be fulfilled, homosexual couple rights); gender role (pre-school child suffers if mother works, working mother can establish warm and secure relationship with child, women should care for family and less for career); intergenerational care values (parents provide financial help, children should care for parents, children should provide financial help for parents); gender values (better political leaders, for whom is a university education most important, for whom is having a job more important, for whom is housework and looking after children more important, better at caring for children). Corona: experience during the COVID-19 pandemic (personally heavily burdened, fear of falling ill, can also see the positive side, financial losses, difficulty restricting personal contact); assessment of political measures to fight the Corona virus (too much, just enough, too little). Demography: sex; sex according to register data; age; date of birth (month, year); current marital status; respondent has a partner; respondent has a partner for at least three months, living with partner; place first met current partner; satisfaction with the current romantic relationship; no children; number of biological children with current partner and with former partner; number of adopted children and of stepchildren; household size; highest school-leaving certificate; highest vocational qualification; years of education; education (ISCED-11); current situation; satisfaction with the actual employment situation; date school-leaving certificate reached (month, year); type of academic institution; date vocational education reached (month, year); degree of urbanization; currently living in eastern Germany; place of birth (federal state); country of birth; citizenships; language spoken at home; migration background: born in Germany; German citizenship; additional citizenship; date of immigration (month, year); financial situation of household (subjective); total household net income (last month, categories); internet connection; frequency of internet use; satisfaction with life as a whole. Additionally coded: respondent ID (anchor); subwave; sample (FReDA-GGS); interview date (day, month, year); mode; device used by respondent; total duration of web interview in seconds; contact strategy; number of mailings; interview assessment (the questionnaire was interesting, varied, important for research, long, difficult, too personal); panel consent; Flag variables: inconsistency with register data; partial interviews; unusually short interview duration; weight: design weight; design weight scaled to net sample size; start of survey field period; end of survey field period. Paradata: respondent ID (anchor); subwave; time and date of first access to questionnaire (absolute cumulated duration); time and date of last access to questionnaire (absolute cumulated duration); viewport width first page (in pixels); viewport height first page (in pixels); viewport width last page (in pixels); viewport height last page (in pixels); last page processed in questionnaire; number of interruptions; absolute cumulated duration for pages (milliseconds); soft prompt for page consent. Wave W1A: Employment: employment status; paid employment in the last week, full-time/part-time employment; hours worked per week, commuting between home and work (duration in hours and minutes); perceived stress during the last three months (too tired to do housework, difficulty meeting family obligations, too tired at work, difficulty concentrating because of family obligations, private conflicts affect performance); current situation; continuing education measures in the last twelve months. Information on children, ex-partners, and household members of the anchor in repeat loops. For respondents in paper-based mode, the number of loop variables is limited to four children, four ex-partners, and four household members. For respondents in web-based mode, the maximum number of blocks of loop variables is higher. Partner and partnership information: partner´s education: highest general education degree, highest vocational education degree, years of education; ISCED 2011; type of college/institution; current situation; paid job in the last week; hours worked per week; health restrictions in the last six months; country of birth; citizenships; country of birth Germany; German citizenship; other citizenship; federal state at birth; moved to Germany (month and year); duration of current partnership/ marriage in months; date of beginning relationship with current partner (month, year); married to current partner; date of marriage (month, year); registered civil partnership with current partner; date of registration of civil partnership (month, year); ever married to current partner(s); date of divorce from current partner (month, year); date of moving in with current partner (month, year), choice or circumstances of living apart; reason for living apart (anchor and partner; circumstances of living apart; distance from current partner´s home (duration in hours and minutes); number of days of face-to-face meetings and contacts with current partner(s) per week, month, or year; Intention to move in together in the next three years; intention to marry; intention to move in together and marry; frequency of disagreements about housework, money, leisure activities, relationship with friends, with parents, family planning, and child rearing issues; behavior in case of serious disagreements; serious thoughts about separation or divorce. Information on previous partnerships: Previous partnerships of at least three months duration; number of previous partnerships; number of cohabitations or marriages in previous partnerships; sex and age (date of birth month, year) of ex-partner; way of getting to know ex-partner; date of beginning of relationship (month, year); date of moving in together (month, year); married to ex-partner; date of marriage (month, year); type of end partnership (separation/death of partner); divorce from ex-partner), date of divorce (month, year); partner who filed for divorce. Information on children: child living, status of child; other natural parent of child; sex of child; date of birth (month year); date of death (month, year); child lives in same household; place of residence of child if not in same household; number of days per week, month, or year with care of child; number of overnights of child per week in respondent´s household; current situation; health limitations; general health; child has ever lived in the same household for more than three months; number of days per week, month, or year with face-to-face meetings with child; number of days per week, month, or year with other contact with child; distance to child´s other residence (duration in hours and minutes); satisfaction with relationship with child. Natural children with ex-partner; number of natural children with respective former partner; stepchildren with ex-partner; number of stepchildren with respective former partner; natural children of ex-partner; number of natural children with respective former partner; children with someone else; number of children with someone else. Pregnancies and family planning: current pregnancy of respondent or partner; other woman pregnant by respondent; expected date of birth (month, year); pregnancy with youngest child was planned; timing of pregnancy earlier/later than planned or just right; previous pregnancy was planned; timing of previous pregnancy earlier/later than planned or just right; problems getting pregnant for at least twelve months; purely physically able to have a child or to to conceive (anchor and partner); unable to have a child due to sterilization or surgery; diagnosis for infertility or not seen a doctor; time of attempt to become pregnant (month and year); type of fertility treatment; type of contraceptive methods used; sexual intercourse in the last four weeks; desire to have children in the next three years; general desire to have children; intended number of children; ideal number of children for respondent and in general; desired sex of first or next child; age at first menstruation or age at voice change; age at first sexual intercourse. Housing situation: number of rooms in the apartment or house; living space (in square meters); date of moving in (month and year); owner or tenant of the apartment or house; monthly cold rent (in euros); monthly incidental rental costs (in euros); satisfaction with the apartment or house; place of residence three years ago; reason for moving; intended move within Germany; intended move to another country. Household composition: other household members; number of other persons in the household; for the other household members was asked: relationship to this household member; sex; date of birth (month and year); current situation; satisfaction with the relationship to this person; health restrictions of this person in the last six months. Division of household chores between partners; satisfaction with division of chores; assessment of fairness of division of household chores; division of childcare chores; satisfaction with division of childcare chores; household decision-maker about routine household purchases, major household purchases, amount of time spent in own employment, and amount of time spent in partner´s employment; Organization of household income and expenses; length of time receiving Parental Benefit or Parental BenefitPlus for youngest child (in months, anchor, and partner); received regular child care assistance from acquaintances, friends, or relatives in the last 12 months; person providing child care assistance; number of days of child care assistance; payment of one of these persons; regular child care assistance from paid providers (e.g. B. child day care providers); type of child care services used; number of days per week, month, or year; monthly cost of child care; chore assistance from public or private providers; number of days per week, month, or year chore assistance is used; cost per week, month, or year of chore assistance; life satisfaction; self-assessment of health status; frequency of depression tendencies in the last week; net household income (in euros and categorized); assessment of the household´s financial situation; receipt of alimony in the last twelve months from a former partner; payment of alimony in the last twelve months to a former partner. Demography: sex; sex according to registry data; age; date of birth (month, year); age according to registry data; currently residing in East Germany; degree of urbanization; current marital status; current partnership status: same-sex partnership; current partnership status: relationship present; partnership for at least three months; living with partner; how did you meet current partner; satisfaction with current relationship; age and sex of partner; date of birth (month and year) of partner; number of all children, number of biological children, adopted children, and stepchildren born before the interview; number of all children still living, number of all children in the anchor´s household; age of youngest child, number of biological children, and number of adopted children with current partner; children of current partner with someone else and number of these children. Additionally coded were: ID anchor; wave data collection; identifier for sample membership; interview date (day, month, year); participation mode; terminal device; total duration of web interview in seconds; contact strategy; number of mailings; net equivalent income (GCEE); interview rating; consent to panel participation current partner; flag variables: Deviations from registry data, incomplete interviews, strikingly short interview duration, deviations from previous wave, missing information on children with (ex)partners, missing information on children (child loop); weighting factors; field start, field end. Wave W1B: Parents, origin, and childhood: birth mother still living, birth mother living in same household; birth father still living; birth father living in same household; distance to mother´s/father´s residence in hours and minutes; number of days of face-to-face meetings and contacts with mother and father per week, month, or year; satisfaction with relationship with birth mother/father; attachment to birth mother/father; asked for both parents: Age; country of birth; date of birth (month, year); date of death (month, year); country of birth Germany; federal state at birth; birth parents living in a common household; living with birth mother/father in a common household; ever lived apart from birth parents for at least 3 months; date of first separation from parents (month and year); intended change in living situation due to separation from parents in the next three years; parents were married; date of marriage (month and year); separation of parents; date of separation (month and year); siblings: Number of brothers and sisters; number of older siblings; year of birth of first child of birth mother and birth father; childhood in Germany; childhood abroad; federal state during childhood; lived with birth parents during childhood; lived with whom during childhood; quality of relationship between birth parents during childhood; ever lived abroad for more than three months during childhood; occupation (ISCO88) and occupational status of birth mother or of birth father at age 15; years of education of birth parents; highest general education degree (ISCED-11), highest vocational education degree; number of grandparents still living; number of birth children, adopted children, stepchildren, and foster children; grandchildren; number of grandchildren; date of birth of oldest grandchild (month and year). General well-being and health status: life satisfaction; regular need for care; type of health impairments or no diagnosis of health impairments; degree of limitations in activities of daily living in the last six months; limitations since when; infection with Corona virus since the beginning of the pandemic; body weight in kilograms; height in centimeters; happiness scale; loneliness (can rely on people for help with problems, feel general emptiness, miss people around me, can rely on many people, often feel rejected, feel close to people); contacts for important personal matters. Employment situation: current situation; satisfaction with employment status; date of beginning of current situation (month and year); paid employment in the last week; date of beginning of paid employment (month and year); employment full-time or part-time; hours worked per week; commuting between home and work (duration in hours and minutes); arrangement of work hours; flexibility in arrangement of work hours; frequency of working from home per week; frequency of working evenings or nights for at least two hours; workplace evenings or nights at home or elsewhere); frequency of working weekends; workplace weekends at home or elsewhere; probability of job loss; type of organization of current business (private or public); type of current employment contract; flexible work arrangements by employer; additional employment or business; hours worked per week for the additional employment; possible to return to work after maternity or parental leave; intention to return to work after end of maternity or parental leave; intention to take a job or start a business within the next three years; job or business immediately before current situation; previous job situation; previous job position; previous number of supervised employees; reason for leaving previous job; current or most recent occupation (ISCO-08); current or most recent occupational position. Partnership: steady relationship; date of birth of partner; relationship existed at the time of last interview; satisfaction with partner relationship; information on partner´s current employment and daily activities: Current situation; paid job in the last week; reason for leaving previous job; current job (ISCO-88); job position; number of supervised employees; hours worked per week; work schedule arrangement; frequency of working from home per week; frequency of working in the evening or at night for at least two hours; workplace at home or elsewhere in the evening or at night); frequency of working on weekends; working weekends at home or elsewhere; likelihood of job loss; organizational form of current business (private or public); type of current employment contract; flexible work arrangements by employer; additional employment or business; hours worked per week for the additional employment. Financial situation of the household: estimated current market value of owned real estate and land; real estate loan; outstanding amount for this loan; amount of the household´s monthly payments for real estate loans; subjective assessment of the household´s financial situation; ever received money, valuables or possessions worth more than 5. 000 euros; received these financial transfers from whom; year of last gift or inheritance; household financially in arrears in the last twelve months; types of household income in the last month; household net income (in euros and categories); expected development of financial situation in the next three years. Attitudes and values: general trust in people; planning for the future; value orientation and attitudes: Traditional concept of marriage (unmarried cohabitation is okay, marriage is lifelong union, divorce is okay); traditional family (women need children for fulfilling life, men need children for fulfilling life, equal rights for homosexual couples); gender role (preschool child suffers when mother works, loving and stable mother-child relationship when mother works, women should care about family and less about career); intergenerational values (parents should financially support adult children, children should take responsibility for their parents´ care, children should financially support their parents), gender roles (better political leadership, for whom is university education more important, for whom is a job more important, for whom is household and child care more important, better care for young children); experiment on ideal employment status and ideal weekly work hours of mother and father by age of child; religious community; frequency of participation in religious events per week, month, or year; religiosity; experience of Corona pandemic (personally heavily burdened, fear of contracting COVID-19, time also had good sides, financial losses, difficulty limiting personal contacts). Demography: sex; sex according to registry data; age; date of birth (month, year); age according to registry data; migration background; currently residing in eastern Germany; degree of urbanization; current partnership status: relationship present; satisfaction with current relationship; age of partner; number of all children, number of biological children, number of adopted children, and stepchildren born before interview. Additionally coded: ID anchor; wave data collection; identifier for sample membership; interview date (day, month, year); mode of participation; terminal device; total duration of Web interview in seconds; contact strategy; incentive experiment; experimental groups work by age

The Life Journeys of Young Women Project: Objectives, design, and recruitment results

The Life Journeys of Young Women Project is the first population-based study to examine the role of economic uncertainty throughout early adulthood on age at first childbirth. A retrospective cross-sectional component was added to an existing cohort study that is based on a birth cohort of women born during 1973–1975 in Adelaide, South Australia (n ∼ 1,000). An event history calendar instrument was used to obtain data regarding a range of life domains including partnering, educational attainment, home ownership, higher education debt, employment, and pregnancies over a 20-year period (sometimes as detailed as at monthly intervals). Interviews were conducted between 2007 and 2009. An analysis framework applying time-varying and time-constant survival analysis techniques within a life-course framework was developed that will guide analyses to examine the role of duration and life-course timing of economic uncertainty on age at first childbirth. This paper discusses study objectives and design, fieldwork procedures, planned statistical analyses, and recruitment outcomes, focusing on novel features that would facilitate analogous epidemiologic research.Emily J. Steele, Lynne C. Giles, Michael J. Davies, and Vivienne M. Moor