The National Diabetes Prevention Program  is rapidly expanding in an effort to help those at high risk of type 2 diabetes prevent or delay the disease. In 2012, the Centers for Disease Control and Prevention funded six national organizations to scale and sustain multistate delivery of the National DPP lifestyle change intervention (LCI). This study aims to describe reach, adoption, and maintenance during the 4-year funding period and to assess associations between site-level factors and program effectiveness regarding participant attendance and participation duration.The Reach, Effectiveness, Adoption, Implementation, and Maintenance (RE-AIM) framework was used to guide the evaluation from October 2012 to September 2016. Multilevel linear regressions were used to examine associations between participant-level demographics and site-level strategies and number of sessions attended, attendance in months 7–12, and duration of participation.The six funded national organizations increased the number of participating sites from 68 in 2012 to 164 by 2016 across 38 states and enrolled 14,876 eligible participants. By September 2016, coverage for the National DPP LCI was secured for 42 private insurers and 7 public payers. Nearly 200 employers were recruited to offer the LCI on site to their employees. Site-level strategies significantly associated with higher overall attendance, attendance in months 7–12, and longer participation duration included using self-referral or word of mouth as a recruitment strategy, providing non-monetary incentives for participation, and using cultural adaptations to address participants’ needs. Sites receiving referrals from healthcare providers or health systems also had higher attendance in months 7–12 and longer participation duration. At the participant level, better outcomes were achieved among those aged 65+ (vs. 18–44 or 45–64), those who were overweight (vs. obesity), those who were non-Hispanic white , and those eligible based on a blood test or history of gestational diabetes mellitus (vs. screening positive on a risk test).In a time of rapid dissemination of the National DPP LCI the findings of this evaluation can be used to enhance program implementation and translate lessons learned to similar organizations and settings.The online version of this article (10.1186/s13012-019-0928-9) contains supplementary material, which is available to authorized users. More than 30 million U.S. adults have diabetes , with 90The Diabetes Prevention Program (DPP) randomized clinical trial, initiated in 1996, found that a yearlong intensive lifestyle intervention aimed at reducing risk through healthy eating, physical activity, and stress reduction helped participants lose 5–7% of their body weight and reduce the risk of developing type 2 diabetes by 58% among high risk adults aged ≥ 25 and 71% for those aged ≥ 60 . Since tIn response to this need, CDC established the National DPP—a partnership of public and private organizations working to reduce the burden of type 2 diabetes by building the infrastructure for nationwide delivery of the evidence-based lifestyle change intervention (LCI) . The NatEvaluation of the first 4 years of the program, describing the experience of 14,747 participants, found an average weight loss of 4.2%, with 35.5% of participants achieving ≥ 5% weight loss . In addiNational Diabetes Prevention Program: Preventing Type 2 Diabetes Among People at High Risk (1212)) to scale and sustain multistate networks to deliver the structured, evidence-based LCI consistent with DPRP Standards in communities nationwide. Funding for the cooperative agreement was allocated based on the organizations’ capacity to reach large numbers of people at risk in multiple states, while working to also obtain health benefit coverage by employers and insurers [In 2012, CDC funded six U.S. national organizations through a 5-year cooperative agreement   frameworThe present work describes the results of the evaluation of funded organizations’ collective efforts and subsequent lessons learned in scaling up and sustaining the National DPP. The primary objective of this study is to describe program reach, adoption, and maintenance. This study also aims to assess associations between site-level factors and program effectiveness in terms of three outcomes: overall program attendance, attendance in months 7–12, and duration of participation.A total of 165 CDC-recognized organizations  were established by the six funded national organizations across the 4-year implementation period ; one site closed without submitting program data, and 28 sites did not submit data during the study period, leaving 136 sites for evaluation : Fig. 2.n = 164 sites), progress reports , and data from participants who attended their first session during the implementation period . Multilevel analyses include data from sites that had implemented the National DPP LCI for at least 12 months before the end of the evaluation period (n = 132) and from participants who attended their first session no later than 1 year before the end of the evaluation period , to evaluate their performance over the yearlong program.Descriptive analyses include program data from the evaluation  offering the LCI, the number of classes offered, the number of new employers offering the LCI on site, the number of employers offering the program as a covered health or wellness benefit for eligible employees, and the number of employees covered by the benefit. Implementation was assessed by key features of program delivery: participant recruitment strategies, adaptations made during delivery to meet specific needs of participants, and incentives or behavioral techniques to engage participants or remove barriers. Maintenance was defined as the extent to which programs had potential for sustainability, measured by the number of delivery sites achieving full CDC recognition, the number of sites continuing to deliver the program without cooperative agreement funding, and organizational and financial support or program reimbursement from private or public payers. Reach was defined as the absolute number and diversity of individuals participating in the program. Characteristics of participant reach included age, gender, race/ethnicity, body mass index (BMI), and eligibility determination. Effectiveness was measured by overall participant attendance (number of sessions attended in months 1–12), participant attendance in months 7–12, and duration of participation (days from first to last session within the 12-month program) among eligible participants attending at least one session at sites that offered the LCI for at least 12 months.The five dimensions of RE-AIM were operationalized for this evaluation as follows. Participant characteristics were stratified based on sex , age category at enrollment , race/ethnicity , prediabetes eligibility , and baseline BMI category . The “other” race/ethnicity category includes multiracial, non-Hispanic Asian, non-Hispanic Native Hawaiian/Pacific Islander, non-Hispanic American Indian or Alaska Native, and not reported.Findings presented in this paper are from program evaluation data and progress reports submitted annually by the six funded national organizations and their affiliated CDC-recognized organizations and from corresponding participant-level data submitted by the funded sites as part of the CDC recognition process. Evaluation data were extracted and validated by two independent evaluators (KN and SJ), who also provided evaluation technical assistance on data reporting and submission via webinars and ongoing consultation  as its contractor—was determined by CDC’s and RTI’s Institutional Review Boards not to be research involving human subjects.Descriptive statistics  were used to describe program characteristics and outcomes of interest based on the five dimensions of the RE-AIM evaluation framework. Multilevel mixed-effects linear regression analyses, with robust standard error and accounting for national organization-level clustering using a compound symmetry correlation matrix, were used to examine the association between participant-level demographics and site-level implementation strategies and the three primary outcomes . Forward selection was used to select parsimonious models. Interactions were also tested, and those that were statistically significant at The results are presented according to the principles of the RE-AIM framework. We present data on program adoption, implementation, and maintenance as well as information on program reach to participants and program effectiveness regarding site-level factors associated with participant overall attendance, attendance in months 7–12, and duration of participation.There was an increase in the number of sites from 68 in year 1 to 132 in year 4, with a total of 164 sites, funded ; delivering the program bilingually or in a language other than English (20.6%); or making other adaptations, such as addressing different preferences among male and female participants (11.2%).Many sites reported using different types of program-funded incentives that were not supported by federal funding, to increase participant enrollment and retention. Three categories of incentives used were non-monetary incentives, such as gym memberships, pedometers, food-measuring devices, or cookbooks (78.7%); monetary incentives, such as coupons or gift cards  (21.3%); and incentives to remove barriers to program access, such as providing child care or transportation passes (19.3%).By September 2016, 33 (25%) of the 132 sites with 12 or more months of participant data had achieved full CDC recognition, and 34 sites were no longer funded, 30 of which because they were self-sustaining and no longer needed cooperative agreement funding , attendance in months 7–12 (increased by 0.6 session), and duration of participation (increased by 23 days) over the yearlong LCI, compared with sites that did not use this strategy Table . Sites rAt the participant level, those who were younger vs. age 65+), were not non-Hispanic white, and were eligible based on a risk test (vs. a blood test or previous diagnosis of GDM) tended to have lower attendance and duration  continued to offer the National DPP LCI and maintain their CDC recognition after funding ended. Additionally, the funded national organizations influenced nearly 50 insurers to cover the program. Beyond the nearly 15,000 people directly served by the funded sites, these changes in coverage have the potential to reach many more people with prediabetes or at high risk for type 2 diabetes.Although participants were racially diverse , the reach into some underserved population groups was limited . While this study did not address specific recruitment strategies for men, it showed no statistically significant difference in attendance and duration of participation among men and women. This finding is similar to a systematic review and meta-analysis of gender-specific differences in diabetes prevention, which found no significant differences in incidence of type 2 diabetes and weight change between men and women who received lifestyle interventions . SeveralTo address the gender gap and other priority populations, in 2017 CDC began funding ten national/regional organizations with affiliate program delivery sites in at least three states to start new CDC-recognized organizations in underserved areas through a 5-year cooperative agreement (1705). This new project incorporates lessons learned from the current evaluation to address gaps and aims to identify and evaluate strategies to enroll populations currently under-represented in the program relative to their estimated numbers and disease burden, such as men, Medicare beneficiaries, African-Americans, Asian-Americans, Hispanics, American Indians, Alaska Natives, Pacific Islanders, and people with visual impairment or physical disabilities.The RE-AIM model provided a solid framework to assess the implementation of this project, and offers a unique contribution to the type 2 diabetes prevention literature. It allowed simultaneous examination of both participant-level outcome data and detailed organizational and site-level data. Although this evaluation focuses on implementation of the National DPP LCI based on the work of six national organizations in the U.S., it provides a practical evaluation framework and pragmatic measures, which can help address gaps in current evaluations of global diabetes prevention interventions . This evProgram-funded incentives, non-CDC funded, were frequently used by sites and were effective in increasing program utilization and retaining participants. We also found that non-monetary incentives such as access to physical activity, pedometers, food measuring devices, or cookbooks were significantly associated with better outcomes. Similarly, recent findings from the 2017 “We Can Prevent Diabetes” trial , a collaFunded sites frequently implemented cultural adaptations to address participants’ needs or preferences, which were positively associated with participants’ overall attendance, attendance in months 7–12, and duration of participation. This finding is consistent with Chesla et al., who adapted the CDC-approved Group Lifestyle Balance curriculum for Chinese Americans with prediabetes, resulting in greater achievement of the 5% weight loss goal when compared to Chinese Americans receiving a non-adapted curriculum . We did While few sites (29.9%) reported using self-referral or word of mouth as a recruitment strategy, those that did found it to be effective in retaining participants. In addition, sites receiving referrals from healthcare providers/systems had higher participant attendance and longer duration of participation. However, detailed information on how sites implemented these referral strategies was not collected in this study. These results support a systematic review from the Community Preventive Services Task Force  and subsAt the participant-level, those who were younger (18–44 and 45–64) had significantly lower overall attendance, attendance in months 7–12, and duration of participation than those 65 years and older. This finding is consistent with a study of a multisite diabetes prevention translational project among American Indians and Alaska Natives showing that younger participants were at higher risk for both short-term  and long-term (loss to follow-up) retention failure . This fiAlthough Hispanics and non-Hispanic blacks had lower overall attendance than non-Hispanic whites, those who attended the LCI at sites that used cultural adaptations actually had higher attendance compared with those who attended at sites that did not use cultural adaptations. This finding is consistent with a study on community-based translation of the DPP’s lifestyle intervention in an underserved Latino population . RuggierFinally, this study found that participants who were overweight had significantly higher overall attendance, attendance in months 7–12, and duration of participation, compared with those who had obesity. This finding is consistent with a study of an intensive behavioral intervention for weight management, which found that lower baseline BMI was independently associated with higher retention . It is aThere are several limitations of this study. First, program implementation data were self-reported by the funded organizations and their delivery sites; however, data reported were rigorously assessed for data quality and completeness through a series of validation checks Additional file 2:RE-AIM Evaluation Instrument for DP12-1212 Affiliate Sites. (XLSX 32 kb)Additional file 3:DP12-1212 Grantee and Affiliate Site Data Review and Validation Process. (DOCX 26 kb)Additional file 4:2015 Diabetes Prevention Recognition Program (DPRP) Standards for Data Collection and Validation Process. 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This study analyzes the short‐term impact of an exogenous, positive income shock on caregivers’ subjective well‐being (SWB) in Malawi using panel data from 3,365 households targeted to receive Malawi's Social Cash Transfer Program that provides unconditional cash to ultra‐poor, labor‐constrained households. The study consists of a cluster‐randomized, longitudinal design. After the baseline survey, half of these village clusters were randomly selected to receive the transfer and a follow‐up was conducted 17 months later. We find that the short‐term impact of household income increases from the cash transfer leads to substantial SWB gains among caregivers. After a year's worth of transfers, caregivers in beneficiary households have higher life satisfaction and are more likely to believe in a better future. We examine whether program impacts on consumption, food security, resilience, and hopefulness could explain the increase in SWB but do not find that any of these mechanisms individually mediate our results. The importance of income for individual subjective well‐being (SWB), often described as “happiness” or “life satisfaction,” has been debated for decades  were randomly assigned to either the treatment or control group after the baseline survey. We use two rounds of longitudinal data—collected at baseline (pre‐program in 2013) and after 17 months (at the end of 2014). The random assignment to treatment and control status provides exogenous variation in income that allows us to identify the impact of such increases on SWB.We find that increases in household income from the cash transfer have substantial SWB effects among caregivers in the short term. There are large, significant effects of treatment on both life satisfaction and future outlooks, which are robust across empirical specifications. Specifically, after about a year's worth of transfers, caregivers in beneficiary households score higher on the QoL Scale (0.5 SD) and are more likely to believe in a better future in two years (around 20 percentage points) using panel data specifications. Moreover, we examine whether other program impacts on consumption, food security, resilience, and hopefulness explain the total effect of the program but do not find that any of these mechanisms individually mediate our results.SWB can be defined as an individual's evaluation of his or her life from both emotional and cognitive perspectives  SCTP is an unconditional cash transfer program targeted to ultra‐poor, labor‐constrained households. The main objectives of the program are to alleviate hunger and poverty among households and to improve children's well‐being and human capital through education, nutrition, health, and household productivity. The program began as a pilot in the Mchinji district in 2006, and since that time, the program has expanded to 18 districts and reaches 756,000 individuals in 175,000 households as of May 2016.SCTP beneficiary selection is made through a community‐based approach with oversight provided by local and national government. Appointed community members are responsible for identifying households that meet the eligibility criteria of being ultra‐poor and labor constrained. After further screening of households identified by the GoM, including a proxy means test to meet the ultra‐poor eligibility condition, the recipient list is generated. The program's goal is that these lists target the bottom 10 percent of each community  and Malawi's National Commission for Science and Technology (IRB Study No. RTT/2/20).The impact evaluation was designed around the GoM's plans to extend and expand coverage of the SCTP within Malawi, starting in 2013. In order to integrate the impact evaluation with early expansion plans in 2013, two districts, Salima and Mangochi, were chosen for the evaluation study. Random selection was included at all possible levels, including the two smaller levels within these districts, Traditional Authorities (TAs) and VCs. First, two TAs in each district were randomly selected to participate in the evaluation study, and the GoM subsequently carried out program targeting based on established operation guidelines. The targeting procedure generated eligibility lists in each VC in the designated study sites. Within each TA, VCs were ordered randomly by the study team using the random number generator in excel, and these randomly ordered lists were provided to the government. After the baseline survey was completed, the lists were taken to the District Commissioner's Office in each district where a public coin toss was conducted to determine whether the top half or the bottom half of the list of VCs in each TA would enter the program first, with the remaining VCs entering at a later date. In each district, the District Commissioner designated which half of the list was heads and which was tails, and the result of the coin toss indicated the treatment group. Ultimately, 14 clusters were assigned to the treatment arm and the remaining 15 to the control arm.The study team computed power for the three key program outcomes of consumption, school enrollment, and child nutritional status using intra‐class correlation estimates from the most recent Malawi Demographic and Health Survey for nutrition and the latest Malawi Integrated Household Survey for consumption and schooling. These calculations led to a sample size of 3,500 households in 29 VCs for an average of 121 households per cluster. Within each VC, households were randomly sorted using a random number generator, and the first 122 households were selected for inclusion in the study. The final sample for the study was 3,531 households , approximately 47 percent of all eligible households from the four TAs  regression adjusted for TA stratification with standard errors (SEs) clustered at the VC level  were interviewed at follow‐up—an attrition rate of 5 percent. The evaluation examined 162 individual and household measures for statistical differences between study arms of the retained households and finds less than 1 percent are different at the 5 percent significance level , consisting of only those households with the same respondent in both surveys.SWB in this analysis is measured using constructs of QoL, future expectations, and relative well‐being. QoL measures are constructed from a series of questions gauging individuals’ perceptions of their life  to strongly disagree (1):These questions are drawn from the Satisfaction with Life Scale (SWLS)  in one, two, and three years from now. Binary indicators measure whether individuals feel their life in the future will be better, the same, or worse, compared to what it is now. As compared to life satisfaction, which is an assessment of one's current circumstances, these questions on future well‐being have respondents gauge the unknown future and tap into concepts of expectation and optimism. Psychological theory proposes that as a personality trait, optimism would affect SWB through expectations about the future  to rich (6). Respondents are asked to place themselves on one of these steps, in addition to their neighbors and friends. We generated two binary variables, one that measures relative well‐being in comparison to friends and the other in comparison to neighbors. The variables measure if individuals perceive themselves to be either the same or better off (compared to worse off) than their friends and neighbors.Additionally, we tested the relationship between negative shocks and SWB to ensure that our measures are sensitive to negative shocks and respond appropriately. If increases in income increase happiness, shocks that would reduce income, such as the death of an income earner, should analogously have a negative impact on happiness. Respondents were asked about negative shocks that occurred within the previous 12 months. We tested two measures: total number of shocks and an indicator for the death of an income earner. In addition, respondents were asked to assess the likelihood of experiencing negative shocks in the upcoming year: a food shortage and needing financial assistance. We created indicators for whether the respondent believes there is a likely or very likely chance that they will experience each shock in the future.Table To ensure that the initial balance achieved still holds for the panel sample used in this analysis, we compared baseline characteristics of caregiver respondents  across treatment and control groups. We tested for differences in means between treatment (T) and control (C) study arms, adjusting for the stratification variable (TA residence) and clustering SEs at the VC level Table . All varThe baseline characteristics presented in Table For future well‐being, the majority of eligible households (53 percent) think that their life will be better in one year. The proportion believing life will be better decreases below 50 percent, however, when respondents think about their life two or three years in the future. A larger percentage of respondents from ineligible households believe life will be better in one year (67 percent) but responses follow the same pattern of decreasing in the more distant future.For relative well‐being, Table We additionally examined individual and household determinants of our SWB measures. In general, positive correlates to SWB include income, self‐perceived good health, and marital status (being married), while female gender and age are more likely to be negative correlates  captures individual differences in reporting  but it is not predictive of relative well‐being. Results also indicate that health status and being married have important relationships with SWB. Having a chronic illness is significantly predictive of lower QoL scores by 1.5 points and is associated with being less positive about the future. Being married, on the other hand, is a positive determinant of QoL. Married caregivers have scores 1.2 points higher than non‐married caregivers. Indeed, being married is the only significant determinant across all outcomes.Table Other significant determinants of QoL at baseline include a caregiver's age (negatively associated) and household composition variables (both positive and negative). Future and relative well‐being display a similar pattern of relationships to determinants but compared to the QoL Scale, they have fewer significant coefficients. Notably, female gender is only predictive of relative well‐being (a negative association). The heavy saturation of female caregivers in the sample, however, means there is not much gender variation to test.Overall, determinant analysis reveals that the QoL Scale is more strongly predicted by individual and household variables than both future and relative well‐being. Consumption, poor health, and being married are the most significant predictors of SWB outcomes and have expected relationships, in line with the literature.itY is an individual, time‐specific measure of SWB, iPtT is an indicator for cash transfer receipt in the second wave and represents the DD treatment effect, which is the product of treatment status (iT) and the post period (tP).To estimate the average treatment effect of the cash transfer on our outcomes we use panel data and a Differences‐in‐differences (DD) regression model. Equation itX). Dummy variables for TA residence, however, are included in all models to account for randomized sampling procedures stratified by TA. The adjustments in itX consist of individual correlates of SWB including age, age‐squared, gender, marital status, education, and chronic health issues  to the total effects to determine whether there is any attenuation of the program impact after taking into account the mediator. Any observed attenuation is evidence the program indirectly works through that pathway to impact SWB.We then provide some additional analysis with sensitivity and robustness checks, and conclude with an examination of potential pathways through which the Malawi SCTP could affect SWB. We assess six objective program impacts that improve household welfare and could have been affected within the study time frame: number of meals per day, consumption , ability to respond to shocks, and likelihood of future shocks. Number of meals is operationalized with an indicator for whether the household eats two or more meals per day and consumption variables are operationalized as P‐values based on the wild bootstrap method  and consequently regular cluster adjusted SEs may be too small leading to an over‐rejection of the null or no effect. We therefore report both cluster‐robust SEs (CRSE) and Since the expectation is that a positive income shock can increase happiness, it is important to understand how consumption impacts SWB. Figure As mentioned earlier, consumption is much lower at follow‐up due to data collection occurring during the lean season. Therefore, the control group is the key to our estimation strategy as it accounts for this seasonality. Overall, the relationship is mostly flat across expenditure levels for both T and C groups. At follow‐up, however, scores increase horizontally for the T group but also for C at lower levels of consumption. Nevertheless, T scores are clearly higher than C scores across all levels of consumption at follow‐up.Estimates of the average treatment effects of the Malawi SCTP on caregiver SWB are displayed in Table t‐bootstrap test; both provide P‐values < 0.01.The unadjusted results indicate that there is a significant treatment effect for two outcomes, the QoL Scale (column 1) and future well‐being (column 4). Caregivers in treatment households score 3.3 points higher on the QoL Scale, which is 19 percent of the mean baseline score and translates to 0.48 of an SD increase. Additionally, these caregivers are 19 percentage points more likely to believe in a better future over their counterparts in the control group. For both of these outcomes, there is no difference between the significance of CRSEs and the wild P‐value < 0.01) across both the CRSE and wild bootstrap test for each model. The magnitude of the point estimate is slightly reduced after the inclusion of controls in the household panel (column 2) but point estimates are larger for the individual panel (column 3). Effect sizes remain around 0.5 SD, which is larger than the impacts from the GiveDirectly study that reported a 0.26 SD increase in an index measure of psychological well‐being, including a 0.16 SD effect on happiness and a 0.17 SD effect on life satisfaction , is still strongly significant . Lastly, while results are positive for relative well‐being across specifications, the only significant estimate is for the individual panel at the 10 percent level (column 9)—caregivers are 12 percentage points more likely to believe that they are the same or better off than their neighbors.Columns 5 and 6 in Table P‐value < 0.01) using either the CRSEs or the wild bootstrap test, signifying that regression SEs are unbiased. Given the robustness of the treatment effect across specifications, we focus on the individual panel sample for our subsequent analyses as this sample reduces concerns about different reporting scales across individuals over time.Overall, Table Our analysis so far has demonstrated high internal validity. Estimates of the treatment effect are consistent and robust across specifications. Internal validity, however, is also dependent on the ability of the measure to correctly represent the concept it defines. In particular, construct validity is a relevant concern for the QoL Scale, as it is generated from a series of response items, some of which cover positive effect as well as life satisfaction. We first tested each QoL item individually for a program effect, and except for item 5 , we find significant effects of around half a point for each measure. Results can be found in the Appendix Table .10Additionally, as a sensitivity analysis to test the construct validity of the QoL Scale, we examine whether the scale predicts negative shocks in the expected negative direction (opposite to a positive income shock) to confirm that it incorporates appropriate emotional effect in response to one's experiences. Using our preferred model specification, we test the effect of three measures of negative shocks on QoL including the number of shocks and household death (both in the previous 12 months), and the anticipation of a future shock  in the next 12 months. We also include the treatment effect as a control in a second model to further see whether the cash transfer is protective of life satisfaction above these negative shocks.Shocks could arguably be endogenous to treatment and we thus depart from causal analysis to validate this construct. In Table Results in Table While our analysis points to the clear conclusion that Malawi's SCTP has a positive impact on caregiver SWB, there could be a variety of reasons for this result. Increased expenditures on food and non‐food items is one likely mechanism. As food shares constitute upwards of 80 percent of our study sample's expenditure, increased food consumption might have an important impact on QoL by reducing hunger and worry over food. Expenditure on non‐food items such as clothes, toiletries, and housing improvements can also affect well‐being by improving individuals’ self‐esteem and feeling of pride or dignity (Bastagli et al., We extend analysis in this last section to examine whether other program impacts might be mediating the total treatment effect on SWB. Given that the immediate impacts of the cash transfer programs mostly go towards alleviating chronic issues of hunger, purchasing essential non‐food goods, and managing shocks—we focus on measures of food security, consumption, and self‐reliance to respond to shocks. Table Results in Table The program increases both per capita total and food expenditure, helps households ensure that they eat more than one meal per day, improves perceptions about future shocks, and increases their reliance on their own money to deal with negative shocks.To test whether these outcomes help explain some or all of the total treatment effect of the program on SWB, we employ a brief mediation analysis by modeling the impact of each mediator on the treatment effect (for a review of the causal mediation framework to identify direct and indirect effects of policy interventions, see Keele, Tingley, & Yamamoto, Table Similar to findings on the relationship between QoL scores and per capita consumption Figure , one posThis study reveals that in just about a year's time, Malawi's cash transfer can have a profound effect on the SWB of caregivers in beneficiary households. We find a strong, positive impact of the income shock on individuals’ QoL and perception of future well‐being but do not find a similar strong impact on their perception of relative well‐being. This finding lines up with evidence of positive impacts on objective measures of well‐being at the household and individual levels. For example, the cash importantly helps to increase food expenditures and the number of meals eaten compared to the control group, showing that the program was particularly protective for households during the lean season when the survey was conducted. However, we find no evidence that these increases in objective well‐being measures explain the direct program effect on subjective outcomes.This quantitative evidence from Malawi is also substantiated by qualitative evidence from in‐depth caregiver interviews collected at follow‐up, which also give some insight on how the program has changed their lives (Malawi SCTP Evaluation Team, In addition to corroborating evidence from the objective measures and qualitative data, we find that the results of the cash transfer program on SWB are robust across all specifications and models. Moreover, results show that negative and positive shocks together can have strong, independent impacts on QoL, possibly reflecting how positive and negative psychological states can exist simultaneously (Diener, Larsen, & Emmons, Interestingly, while results are strongly positive for measures of QoL and future well‐being, we find no impact on relative well‐being. According to the literature, people's happiness is judged relative to an internal reference point, which is determined by their past experiences and environments. Therefore, the perception of low relative economic standing in a community reflects lower happiness because, compared to others, there is potential to be happier. As we reported earlier, for most households transfer size as a share of pre‐program household consumption is lower than the generally accepted 20 percent threshold. It might be that this modest increase in income is not enough for households to consume as much as their friends and neighbors and so, relative to their community, they are still worse off. Therefore, the absolute income effect is likely driving the positive results we see for QoL and future well‐being. The null effect seems to align with prior work in Malawi that found no impact of income on relative well‐being among the poorest communities (Ravallion & Lokshin, While all of these positive impacts would in most respects appear to be good news, there is a concern amongst some that such programs could result in “leapfrogging.” In the context of cash transfer programs, leapfrogging refers to a situation when program beneficiaries quickly move to a higher standard of living that leaves behind other community members who were nearly as poor but did not receive the program Ellis, . In thisDespite the strength of our results, the positive time trend is an anomaly. It is unclear why control households report higher life satisfaction and future outlooks at the second wave. There was no concurrent rise in external economic circumstances, and in fact follow‐up data collection occurred during the lean season when consumption was much lower for all households, a decline of around 25 percent from baseline (Malawi SCTP Evaluation Team, Individual heterogeneities could also present a problem when making interpersonal comparisons. However, we find trivial differences between the household and individual panels suggesting that personality biases are not a problem; a result that is consistent with the literature (Beegle, Himelein, & Ravallion, This study shows that even small income increases are immensely valuable to the very poor. Caregivers use the money to improve their families’ livelihoods, ensuring provision of their basic needs including food, shelter, and clothing. The reduction of these daily stresses makes caregivers happier about their current situations and gives them hope that the future will continue to improve. Future research will be needed to understand if the absolute income effect will continue to have an impact on SWB in Malawi or if happiness flattens out as people adapt to their new circumstances. In Kenya, Haushofer, Reisinger, and Shapiro  find somCash transfers and other poverty alleviation program evaluations should continue to include SWB metrics to add to this evidence base. The use of self‐reported well‐being captures a more holistic picture of well‐being than would reliance only on objective measures and helps us answer questions about whether greater SWB can influence enhanced decisionmaking among the poor. With the growth of cash transfer programs across Africa, it will be important to understand whether there is an association between growth in these metrics and successful transition out of the poverty cycle. This critical knowledge can be used to enhance the effectiveness of social protection policy for the poor across Africa.


Accessing places outside home where activities are performed provides both benefits (e.g. participation in activities), and challenges (e.g. finding one’s way) for people with cognitive deficits. Participation in these places appears to depend on various factors such as the living situation of the person, availability of commodities and supporting social networks, or preserved ability to drive. However, clear patterns of participation remain scarcely documented. This study addresses the need for understanding of participation outside home among people with dementia through the places they visit. The aim is to describe how the outside world may be shrinking for them. People with and without dementia (n=70), aged 65+, were interviewed using the Participation in ACTivities and Places OUTside the Home (ACT-OUT) questionnaire across Switzerland. Results show that people with dementia participate significantly less in commercial, social and cultural places, but visit medical care places at a higher level, than those without dementia.


BCR-ABL1 isoform and a novel BCR-ABL1 mutation, p.Y440C. The latter is in the C-terminal lobe of the kinase domain, which likely induces deviations in the protein structure and activity and destabilizes its inactive conformation. The treatment was substituted by bosutinib, which binds to the active conformation of the protein, prior to allogeneic bone marrow transplant to overcome the lack of a complete response to dasatinib. These findings strengthen the importance of BCR-ABL1 mutational screening in Ph+ patients, particularly for those who do not achieve complete molecular remission.Philadelphia chromosome-positive acute lymphoblastic leukemia (Ph+ ALL) represents the most common genetic subtype of adult ALL (20%–30%) and accounts for approximately 50% of all cases in the elderly. It has been considered the subgroup of ALL with the worst outcome. The introduction of tyrosine kinase inhibitors (TKIs) allows complete hematologic remission virtually in all patients, with improved disease-free survival and overall survival. Nevertheless, the emergence of resistant mutations in BCR-ABL1 may require different TKI strategies to overcome the patient’s resistance and disease relapse. Here, we report a Ph+B-ALL case with persistent minimal residual disease (MRD) after treatment with dasatinib. The patient expressed the P190 Acute lymphoblastic leukemia (ALL) is a clonal disease in which immature lymphoid cells accumulate mainly in the bone marrow and peripheral blood. The disease is very heterogenous, comprising several hematological, cytogenetic and molecular groups. The Philadelphia chromosome (Ph) is the most frequent genetic abnormality in adult ALL (Ph+ ALL), representing 20%–30% of the B-lineage cases (B-ALL) but only 5% of the pediatric cases. Ph+ ALL frequency increases with age, accounting for approximately 50% of all cases in the elderly.2BCR and ABL1. In Ph+ ALL, the most frequently expressed isoform of BCR-ABL1, accounting for 70% of the cases, is the P190, in which exon 1 of BCR is fused to exon 2 of ABL1 (e1a2).BCR-ABL1. The transforming potential of the P190 isoform is believed to result from the partial loss of BCR domains, namely, the guanine exchange factor/dbl-like domain that mediates the communication with several Ras proteins, which are crucial for the regulation of signaling pathways and processes, such as cell proliferation, differentiation, adhesion, apoptosis and migration.The translocation that characterizes the Ph chromosome, tq34;q11), involves the fusion of the following two genes: 4;q11, inABL1 domain of the chimeric transcript. Indeed, BCR-ABL1 variations are one of the mechanisms that lead to TKI resistance, may be due to pre-existent mutations (primary resistance accounts for one-third of the patients) or mutations that arise from TKI treatment pressure (acquired resistance).15In chronic myeloid leukemia (CML), in which all patients test positive for BCR-ABL1, tyrosine kinase inhibitor (TKI) therapy revolutionized prognosis. The same applies for Ph+ALL, in which complete remission can be achieved in 95% of the patients.BCR-ABL1 isoform and a novel BCR-ABL1 mutation in the region that encodes for the C-terminal lobe domain of the protein.Herein, we describe a Ph+ B-ALL patient expressing the P190−4 for BCR-ABL1 transcripts , characterized as Ph+ by cytogenetics  showed a point mutation in the ABL1 domain of the fusion transcript, c.1319A.G, which lies in the region that translates for the C-terminal lobe of the kinase domain, p.Tyr440Cys , and as an effort to achieve molecular remission, the TKI regimen was changed to bosutinib in post-induction therapy. After 7 weeks on bosutinib, asatinib . NeverthTKI regimens have greatly improved the therapeutic outcome of patients with Ph+ ALL. However, each individual’s sensitivity to each TKI must be considered for a successful therapeutic outcome. Similar to what is recommended for CML, Ph+ ALL patients who do not respond to one of the available TKIs should undergo mutational screening for an assessment of markers of drug resistance mechanisms.12BCR-ABL1 nucleotide substitution, c.1319A.G (codon TAC.TGC), results in the amino acid alteration, p.Tyr440Cys , according to the manufacturer’s instructions. A total of 100 nuclei were scored at diagnosis. This analysis was carried out using a fluorescence microscope , and image capture was performed using Isis FISH Imaging System V 5.7.1 .2, 10 mM NaCl and 10 mM Tris-HCl; pH 7) and centrifuged at 400× g for 5 minutes. The procedure was repeated to lyse residual red blood cells. White blood cell pellet was subjected to total RNA extraction using SV Total RNA Isolation System , according to the manufacturer’s instructions. RNA was resuspended in nuclease-free water and stored at −80°C until use. RNA concentration and purity were determined by UV spectrophotometry. Total RNA extracted (100 ng) was reverse transcribed into cDNA, using the NZY M-MuLV First-Strand cDNA Synthesis kit .RNA was extracted from bone marrow white blood cells. Briefly, 5 mL of sample was mixed with 10 mL of red blood cell lysis solution , 2.5 mM MgCl2, 0.15× Hi-Specific additive (Bioline), 200 µM dNTPs, 400 nM primers and 0.02 U/µL BIOTAQ DNA polymerase (Bioline). Outer PCR was performed using 3 µL of cDNA in a 50 µL reaction, under the following conditions: initial denaturation at 95°C for 5 minutes; 30 cycles of 94°C for 30 seconds, 55°C for 30 seconds, 72°C for 1.5 minutes; and a final extension step at 72°C for 10 minutes. Inner PCR was performed using 1 µL of outer PCR product in a 50 µL reaction, under the following conditions: initial denaturation at 95°C for 5 minutes; 30 cycles of 94°C for 15 seconds, 55°C for 30 seconds, 72°C for 1 minute; and a final extension step at 72°C for 10 minutes. A control PCR, for the amplification of ABL1, was also performed using primers depicted in Nested-PCR amplification of BCR-ABL1 e1a2 transcript was performed in bone marrow samples using a Corbett Rotor-Gene 6000 thermal cycler  and NZY qPCR Green Master Mix (Nzytech). The reaction mixture was prepared in a final volume of 10 µL with 1 µL of cDNA and 100 nM of each primer: outer PCR primers for BCR-ABL1 transcript identification or ABL1 control primers, specified in −ΔΔCt), in which relative gene expression is given by quantification of the gene of interest (BCR-ABL1) normalized to internal control gene (ABL1), relative to control condition (diagnostics sample).Quantitative monitoring of g; the supernatant was removed; and the dry pellet was resuspended in 100 µL of TE buffer. DNA concentration and purity were determined by UV spectrophotometry. DNA was stored at 4°C until use.Buccal epithelial cells were collected from the subject of this study by twirling a swab on the inner cheeks for 1 minute. The swab was separated from the stick and inserted into a microtube containing 440 µL of lysis buffer . The tube was vortexed for several minutes to promote the release of most epithelial cells. The swab was removed, and 20 µL of proteinase K  was mixed with the cell suspension and incubated for 10 minutes at 50°C. After adding 40 µL of 5 M NaCl, 500 µL of isopropanol was gently mixed with the DNA-containing solution and allowed to stand for 5 minutes at room temperature. The sample was centrifuged for 5 minutes at 12,000× ABL1 exon 8 of patient’s epithelial cells was performed using the following primers: forward 5′-CTCAAATAATCCTCCCACTTCA and reverse 5′-CCTGGAATGCCCACATATAC. PCR mixture components included 1× NH4 reaction buffer (Bioline), 2.5 mM MgCl2, 0.15× Hi-Spec additive (Bioline), 200 µM dNTPs, 400 nM primers, 0.02 U/µL BIOTAQ DNA polymerase (Bioline) and 20 ng of gDNA. PCR conditions included an initial denaturation at 95°C for 5 minutes; 30 cycles of 94°C for 30 seconds, 55°C for 30 seconds, 72°C for 1 minute; and a final extension step at 72°C for 10 minutes.PCR amplification of BCR-ABL1 e1a2 (GenBank AF113911.1) and ABL1 (GenBank NM005157.5).Basic Local Alignment Search Tool (BLAST), from the National Center for Biotechnology Information (NCBI), was used to align all obtained sequences, via Sanger sequencing, with the following reference sequences: Figure S1BCR-ABL1 e1a2 reference sequence from GenBank AF113911.1 (Seq 2).Alignment of Ph+ ALL patient e1a2 nucleotide sequence (Seq 1) with Note: Arrow indicates the breakpoint in this BCR-ABL1 isoform.Abbreviations: ALL, acute lymphoblastic leukemia; Ph+, Philadelphia chromosome positive.Figure S2DISOclust disorder prediction results.Note: Disorder probability score by residue number in BCR-ABL1 harboring the Y440C on the ABL1 domain.


In this study we aimed to produce the first detailed analysis of the epidemiology of the severe injury and mortality impacts of the 1931 Hawke’s Bay earthquake in New Zealand (NZ). This involved the compilation and analysis of archival data  including the examination of 324 death certificates. We found that there were 662 people for whom some hospitalisation data were available at four weeks post-earthquake: 54% were still in hospital, 4% were still classified as “serious”, and 5% had died (n = 28). Our classification of death certificate data indicated 256 earthquake-attributable deaths and for another five deaths the earthquake was estimated to have played an indirect role. There were 15 buildings associated with three or more deaths each (accounting for 58% of deaths with a known location). Many of these buildings were multi-storey and involved unreinforced masonry – with some of this falling into the street and killing people there (19% of deaths). In contrast, deaths in homes, which were typically of wood construction and single stories, comprised only 3% of deaths. In conclusion, this earthquake had a relatively high injury impact that appears partly related to the lack of regulations for building construction that would mitigate earthquake-related risk. Such regulations continue to be of relevance for New Zealand and for other countries in earthquake zones. It is also probably the worst sudden natural hazard event to strike New Zealand. The earthquake was of a high magnitude (MW 7.4–7.6)2 and a brief description of it follows:The Hawke’s Bay earthquake on 3 February 1931 is one of the top two sudden mass fatality events in the 1900 to 2015 period for New Zealand and is the highest mortality earthquake in the country’s recorded history3.“Occurring at 10:47 am (NZ Summer Time) on Tuesday, 3 February 1931, the Hawke’s Bay earthquake  is recorded as having caused the largest loss of life and most extensive damage of any quake in New Zealand’s history. The effects of the earthquake were greatest in the towns of Napier and Hastings, but other towns in the Hawke’s Bay also suffered major damage.” There was … “extensive fissuring, slumping and landslides occurring over much of Hawke’s Bay” …. “The earthquake was followed by fires in the business areas of both Napier and Hastings that became uncontrollable as water pressure dwindled because of broken water mains. The Ahuriri Lagoon in Napier was raised drastically in the earthquake, changing the coastline significantly ….”4.Also of note was the severe damage to local hospitals and the need to transfer patients to other hospitals around the lower North Island of New Zealand: “Napier’s hospitals were badly damaged and unusable, so patients were moved to the lawns of the Botanical Gardens, where a surgical station was set up. Emergency hospitals were set up at the Hastings racecourse and at Napier Park racecourse, where doctors operated beneath the grandstand. In the ensuing days, many injured people were evacuated to other centres”5; 2556; 2563; 2581; 260 (range: 256 to 266)7; and 261 (range: 257 to 273)8. Some individuals with earthquake-related injuries appeared to have died of injuries in subsequent weeks and their names were not included in the official records (often after being moved in an injured state to other cities/towns). Basic descriptive epidemiology of this disaster is also limited9 eg, with no description of the socio-demographic characteristics of those who died and with no consideration of death certificate data.Previous work suggests a range in the reported death toll for this earthquake, variously reported as: 251Given the above, we aimed to produce the first detailed analysis of the descriptive epidemiology of the severe injury and mortality impacts of this 1931 Hawke’s Bay earthquake. It was anticipated that this work should contribute to a richer understanding of this major disaster, and potentially help to improve the prevention and management of future disasters in New Zealand and other countries that still lack building regulations and are in earthquake zones.11. This included public hospital data from beyond Hawkes Bay, but did not cover those in private hospitals. Missing data  were obtained from other sources . Some extra detail on people hospitalised with injuries came from police and relief fund archival files13 along with contemporary newspaper articles.We obtained archival reports on patient status for all patients “admitted from earthquake area to departmental institutions” that were compiled four weeks after the earthquake10 and obtained death certificates for these cases. Additional information on the circumstances of some of the deaths  came from “Affidavits to Death” contained in Probate records held on a genealogical database site (https://www.familysearch.org). Published newspaper obituaries (identified in Papers Past)14 also provided additional information on selected cases.We obtained 324 electronic versions of death certificates, mainly from purchasing these from “Birth Deaths and Marriages” . These were for all names associated with the potential earthquake deaths as listed in various sources: contemporary newspapers, books on the earthquake with lists of names, the names on monuments in Napier and Hastings, and based on: the age at death, time, burial date and location, and family history information. We also identified deaths among hospitalised casesFrom the above data sources we were typically able to code the location of injury or death, to inside specific buildings or on the street outside specific buildings. Failing that, we used death certificate data which sometimes included site details, although this was also sometimes at non-specific levels of just a street name or at a whole suburb/town level.15 and in subsequent days and weeks (takotsubo cardiomyopathy)16. Also included were deaths for people reported as “officially missing” on death certificates and who were thought to have been in the earthquake area. This included names not definitively linked to an unidentified body or charred human remains.We classified deaths as being directly earthquake-related if the death certificate stated this or if the cause of death on the death certificate and other available information was suggestive that an earthquake-related cause was dominant “on the balance of probabilities” .We classified other deaths as Classification was performed by the two medical practitioners (NW and AT) in the research team and any disagreements in classification was resolved by further discussion. The process of refining our classification approach was iterative and required some discussion to achieve consensus on the final classification of cases, thus we did not attempt any formal assessment of inter-rater reliability.17. Given an absence of age-group/sex estimates for these areas, the following steps were performed:18, were used to interpolate the age-structure of the national population for 1931 .The age-distributions from the census results for 1926 and 1935 (since no census was held in 1931)These national data were then used to estimate the age and sex structure in 1931 for the urban population of Napier and Hastings.Results were analysed in EpiInfo and OpenEpi. We calculated severe injury and mortality rates per 1000 population for the combined urban area of Napier for Hastings and also the geographical area of Hawke’s Bay (as per the population estimates for April 1931 and including the Māori population)University of Otago Human Ethics Committee approval (reference number D18/342). We note that all the historical mortality data (including death certificates) are already publicly available. Nevertheless, we have only presented anonymised data in our results.The hospitalisation data reported by the Department of Health are shown in Tables The most common type of injury was fracture, followed by “shock”, and head injury Table . But theLower limb fractures were twice as common as upper limb ones Table  and 13% The median age of the injured people was 42.5 years Table  with theThe assumed geographical location of where the person was injured was dominated by Napier (69% for the modern-day Napier City Council area), followed by Hastings (22% for the Hastings District Council area) Table .19.There was one person hospitalised as a result of being injured during rescue work. A police report also indicated that some police officers were “slightly injured” in the rescue effortsThe analysis of the death certificate data suggested a total of 256 deaths occurred during earthquake shaking Table , S1–S3. The deaths occurred predominantly on the day of the earthquake (87%) and then in the subsequent week (6%) Table . There wThe median age of death was 37 years but with the range being from one day old to 92 years. For most age-groups, the mortality rate was fairly similar to the hospitalised injury rate, except the latter was generally higher in the 60+ age-group Fig. . The morTable Overall, there were 15 buildings with three or more deaths associated with them and these accounted for 58% 126/217) of all deaths for which a location was known , followed by being struck outside (19%) eg, from chimneys or masonry falling into the street Table . It is dNapier and its suburbs experienced the most deaths , followed by Hastings (36%) Table . Only 104. We found no evidence for deaths from any of the aftershocks.We identified two deaths among people who went into earthquake-damaged buildings to rescue others but then were killed themselves on the day of the earthquake. But another source reports that this fatal outcome also applied to students at the Napier Technical College: “several of those students had gone back into the school to rescue trapped classmates”23). Given that this earthquake is probably the highest mortality sudden natural hazard event for people in New Zealand, it suggests that policy-makers and research funders could do more to encourage such work on, or filling gaps in, the nation’s disaster epidemiology. This conclusion also arises from the work of others24.Despite New Zealand being at high risk from natural hazard events, the lack of the basic descriptive epidemiology of this major earthquake (until now) suggests a low focus on historical epidemiology for such disasters. This contrasts markedly with the epidemiology of the more slow-moving natural hazard event of the 1918/1919 influenza pandemic, for which there is detailed published New Zealand research . It was also able to identify five additional deaths that were indirectly related to the earthquake. These differences are not surprising, given that some people were transferred to hospitals far from the earthquake area and also some deaths occurred many months to years later . But while this study has provided a more accurate assessment than past estimates, there is still some uncertainty around the precise numbers of deaths and severe injuries attributable to this earthquake. In particular, the evidence from the Canterbury earthquake of 201125 is that there may have been other cardiovascular disease-related hospital admissions and probably deaths in the year after the 1931 earthquake due to earthquake-related psychological stress.A key implication from this research is that death tolls and severe injury data for large disasters before the 21The deaths from this earthquake occurred predominantly on the day of the earthquake (87%) and then in the subsequent week (6%) Table . Of the 26, the typical male killed lost 32 years of life span and the typical female killed lost 43 years. This equates to 9456 lost life-years for the 256 deaths in this disaster. Furthermore, this figure does not capture lost quality-of-life for those who were left disabled eg, with amputated limbs or paralysis. Nevertheless, the total impact would still have been relatively small compared to the more slowly evolving disaster of the 1918 influenza pandemic (9000 deaths)20 and with the country’s involvement in the First World War 27.The median age of death was 37 years  and so using lifetable estimates for New ZealandThe similarity of death rates for males and females might seem surprising, given that more women might have been located in residential settings (where death rates were low) at this period in New Zealand society eg, in childcare and other caring roles. But this factor was probably countered by the high death rates amongst women working in the retail sector Table , amongstPerhaps the most striking feature of the mortality patterns is that there were six buildings that were associated with 10 or more deaths each (from collapse and fire) and there were 15 buildings associated with three or more deaths each . Many of these buildings were multi-storey and involved masonry – with some of this falling into the street and killing people on the street or who ran outside during the earthquake (19% of deaths – Table Table The time of day of the earthquake at 10.47am) probably contributed to the high mortality since people were working or shopping in the business districts of Napier and Hastings Tables  and 7. Sam probabVeronica), which meant that its crew could be deployed. It seems likely that such factors might have improved the efficiency of rescue efforts and with the operation of the field hospitals.There was no established emergency management system in New Zealand in 1931. Nevertheless, there were many citizens with military training and experience of the mass trauma events of the First World War . There was also an influx of health workers from outside the region , and the arrival of the Royal Navy at Napier on the day of the earthquake . There were also few tourists, with only one international traveller apparently being been killed. Another factor was that it was mid-summer with fine weather, which probably improved the survival for those who were extracted from the rubble after some time, and for the injured located in tents in field hospital settings. For example, a 91 year old man was pulled alive, three days after the event28 about the role of different building materials: “We may here remark that the damage has been sustained by those possessing brick and clay dwellings. Wooden houses in every instance have escaped”29. For this reason it was recommended at the time that “a public meeting of settlers should be convened, for the purpose of appointing a committee to report upon the late disastrous affliction, and to call upon the Executive to appoint an Inspector of Works so that in future buildings may be erected after some well matured and systematic plan”29. But this was not done, leading to the retrospective view that: “If the government of the day had taken heed of this advice it is likely that events such as the Hawke’s Bay earthquake would not have been nearly as disastrous”29.This question can be considered in the light of the history of documented earthquakes in New Zealand. First, it was known from the 1848 Marlborough earthquake 29. For this 1855 earthquake it was also reported that “most wooden houses, especially those of one storey, fared much better than those built of brick”30. A Commission after this earthquake did investigate building construction and did make recommendations for greater use of wooden framing in buildings . The Commission also highlighted that earthquakes were a problem for the whole of the country – and not just Wellington30. As a result it appears that “while memories of the 1848 and 1855 earthquakes were fresh, most of the new buildings in Wellington were constructed of wood”31. “However, it took only 25–30 years for awareness of building safety to fade. Masonry construction gradually returned, encouraged by city council regulations for fire resistance. By the beginning of the 20th century the earthquake hazard was largely discounted, and between 1913 and 1926 the New Zealand Official Yearbook included the comment that ‘earthquakes in New Zealand are rather a matter of scientific interest than a subject for alarm’”31.Many of the stone and brick buildings in Wellington that had been destroyed in the 1848 Marlborough earthquake were nevertheless, re-erected in wood. As a result it is thought that this was a factor in the low death toll of the 1855 Wairarapa earthquake, with only between five and nine deaths, despite the large geological impact32. There were reports of numerous landslides, widespread soil liquefaction and the opening of large fissures in the ground. Houses were shaken off their piles and some chimney bricks fell through rooves33. However, there is no evidence that this earthquake triggered any subsequent changes in local building construction practices.In 1863 a notable earthquake actually hit Hawke’s Bay (magnitude 7.5), striking near the town of Waipukurau34. A report after this earthquake also recommended that there be building standards to reduce earthquake damage, but again this advice was not substantively acted on before the 1931 Hawke’s Bay earthquake29.In 1929 the Murchison earthquake was felt in towns and cities throughout New ZealandGiven the above information, it does seem likely that if the citizens of New Zealand and their government had adequately learnt from history – they may have adopted relevant building regulations before the 1931 earthquake and that this would have reduced the injury and mortality burdens. While all regulations involve trade-offs , some of the regulations may have been particularly cost-effective. For example, regulations to stabilise brick chimneys and to minimise masonry above building entrances – might have cost relatively little and yet would have saved many lives.35, and there were deaths in streets in the central city area of Christchurch 36, primarily from falling masonry.Furthermore, if such earthquake-related building regulations were adequately adopted and implemented throughout New Zealand, the death toll in the 2011 Canterbury earthquake would probably have been less. This is because a majority (62%) of the 185 deaths were in a single inadequately constructed building (the CTV building)The earthquake-related injury burden associated with a lack of adequate building regulations (or their implementation and enforcement), is also of relevance to modern day low-income countries in earthquake zones. These settings may wish to prioritise applying such regulations particularly to multi-storey buildings and to addressing unreinforced masonry on buildings above busy streets. For such buildings policy-makers may also wish to promote greater use of wood as a building material .Particular strengths of this study included it being the first to comprehensively describe the injury epidemiology of this earthquake. The study also obtained death certificates and unpublished injury related records. Nevertheless, the severe injury data are limited due to incomplete documentation, especially for cases transferred to hospitals outside the region. But even when documented, it was sometimes unclear what particular injury terms meant . Furthermore, there was no information on the occurrence of minor injuries that did not require hospitalisations.Even though this study benefited from considering death certificate data, at this time in history these were still not particularly detailed, were not typewritten and often were not completed as required . They also lacked data on ethnicity. For the severe injury data we also frequently lacked occupational data and also information that linked injuries with the aftershocks that occurred in the subsequent weeks.While the mortality data were more robust than that for hospitalised injuries, it too had limitations including missing data for the details around the location of the injury and the mechanism of injury.This earthquake remains the worst sudden mass fatality event due to a natural hazard in New Zealand’s history. This mortality burden partly related to the lack of adequate regulations for building construction to reduce earthquake risk. This was despite evidence from prior earthquakes in New Zealand (since 1848) that indicated the risks of brick and stone vs wood as construction materials. Given the experience with the Canterbury earthquake in 2011, regulations around earthquake risk continue to be of relevance for New Zealand, as well as for other countries in earthquake zones.st century. This suggests there is a need to upgrade funding for disaster research in this country so as to ensure that the lessons of the past are appropriately learnt.This study also highlights the relative lack of research into the basic epidemiology of disaster events in this country before the 21Supplementary Material


Examination of host flanking sequences revealed that they are orthologous, and despite being more than 96 million years old, their env reading frames are fully coding competent with evidence for strong purifying selection to maintain expression and for them likely being transcriptionally active. These make them the oldest EFVs discovered thus far and the first documented EFVs that may have been co-opted for potential cellular functions. Phylogenetic analyses revealed a complex virus–host co-evolutionary history and cross-species transmission routes of ancient FVs.A recent study reported the discovery of an endogenous reptilian foamy virus (FV), termed ERV-Spuma-Spu, found in the genome of tuatara. Here, we report two novel reptilian foamy viruses also identified as endogenous FVs (EFVs) in the genomes of panther gecko (ERV-Spuma-Ppi) and Schlegel’s Japanese gecko (ERV-Spuma-Gja). Their presence indicates that FVs are capable of infecting reptiles in addition to mammals, amphibians, and fish. Numerous copies of full length ERV-Spuma-Spu elements were found in the tuatara genome littered with in-frame stop codons and transposable elements, suggesting that they are indeed endogenous and are not functional. ERV-Spuma-Ppi and ERV-Spuma-Gja, on the other hand, consist solely of a foamy virus-like  Spumaretrovirinae subfamily) are a unique subgroup of retroviruses (family Retroviridae) comprising an independent lineage basal to all other exogenous retroviruses  NOT “partial” AND 500:100000[SLEN]’, which retrieved proteins that belong to the members of the Retroviridae family [NCBI: txid11632] with a length between 500 and 100,000 amino acids and were not annotated as partial . The second query was ‘txid186534[Organism:exp] NOT “partial” AND 500:100000[SLEN]’, which retrieved proteins that belong to the members of the Caulimoviridae family [NCBI: txid186534] with a length between 500 and 100,000 amino acids and were not annotated as partial (720 sequences). The last query was ‘txid186665[Organism:exp]’, which retrieved proteins that belong to the members of the Metaviridae family [NCBI: txid186665] (5 sequences). Out of 12,520 Pol hits, only 2757 exhibited the greatest similarity to FV proteins  was used to identify open reading frames, and tRNAScan (http://lowelab.ucsc.edu/tRNAscan-SE/) was used to identify the primer binding site. We also attempted to identify the internal promoter in ERV-Spuma-Spu by comparing its sequence to those of mammalian FVs. The consensus sequence is in The top 20 elements of the 165 ERV-Spuma-Spu elements that exhibited the greatest similarity to the concatenated CoeEFV Pol-Env protein sequence were aligned and used to reconstruct a consensus sequence. At the time of analysis, the quality of the tuatara genome was low, however, containing many large strings of undetermined nucleotides (‘N’s). Furthermore, the majority of the identified ERV-Spuma-Spu elements were also interrupted by transposable elements. Because of this, the standard protocol of consensus sequence reconstruction  inferred false gaps where they should not have been. To overcome this problem, we only allowed gaps in the consensus sequence if there were more than 15 sequences containing gaps in that particular position; otherwise, a consensus base pair from non-gap sequences would be inferred. Standard ambiguous bases were used in the case of base count ties. The consensus sequence of the virus internal region was inferred separately from the LTR portion , and thePol and Env protein sequences of the consensus ERV-Spuma-Spu and CoeEFV were used in a tBLASTn search against the NCBI Whole Genome Shotgun database restricted to reptiles and excluding the tuatara genome to examine if other reptile genomes had any EFVs.Numerous tBLASTn hits were returned from six reptile genomes showing similarity to the Pol protein sequences. From each genome, we selected one to five top hits  and examined if they were most similar to modern-day FVs. Reciprocal BLASTx analysis suggested that none of them were FV-like, however . We thusenv elements were found. One was found in the genome of the panther gecko , and the other was found in the genome of Schlegel’s Japanese gecko . Neither elements contained in-frame stop codons or transposable elements. Results from reciprocal BLASTx searchers , the brown spotted pitviper , and the green anole , were identified based on the genes found on LNDG01066615.1 and BDOT01000314.1 by using tBLASTn. AUGUSTUS , which was comparable to the one previously reported {R2 = 0.95 (0.91–0.99) [2 = 0.96 (0.91–0.99)]. They were then used to extrapolate in order to calculate the timescales of other nodes based on their Evolutionary timescales of reptile EFVs were estimated using the time dependent rate phenomenon (TDRP) model ,27. The er site) ,27. We tAnalyses of the Pol protein sequences suggested that the ERV-Spuma-Spu lineage diverged 232.50 (173.70–303.33) myr ago (mya), which was comparable to that estimated based on the Env protein sequences, which was 257.15 202.49–324.05) mya. These age estimates were, however, significantly lower than those of their hosts, which were estimated to be 324.7 (318–331.4) mya . The age9–324.05 This study reports two novel reptile EFVs that reside in the genomes of panther gecko (ERV-Spuma-Ppi) and Schlegel’s Japanese gecko (ERV-Spuma-Gja) and further characterizes ERV-Spuma-Spu . Togetheenv gene, and are present in only a single copy in each genome. We showed that they are orthologous, being present in the same host genomic location in both species. Based on the speciation date of their gecko hosts, we inferred that these EFVs are at least 96 (83–98) myr old [env genes. Additional analyses of transcriptomic data obtained directly from Gekko japonicas and Paroedura picta are thus required to confirm that the two gecko EFVs are transcriptionally active.ERV-Spuma-Ppi and ERV-Spuma-Gja are not full length ERVs, comprising only a full-length FV-like  myr old , making  myr old . Remarka myr old , we discenv genes are known to have been co-opted many times by various vertebrate hosts for a wide range of functions. The most well-known one is perhaps the syncytin genes, which was captured for a function in placental formation numerous times by various mammals  as an accessory gene [env gene and the 3’ LTR, which is typical for a mammalian FV [env gene. It is thus possible that the previously identified accessory gene in ERV-Spuma-Spu might have been an artifact. At face value, the observed lack of accessory genes is suggestive of ancient gene losses in ancestral exogenous reptile FVs. Alternatively, it could be that the ancestral exogenous tuatara FVs did possess accessory genes but lost them after becoming endogenous. This observation is also consistent with multiple acquisitions of accessory genes in other FVs at the same genomic location, which is perhaps less parsimonious but nevertheless possible. Discovery of other reptilian FVs or EFVs will help elucidate this issue.We were able to identify 165 ERV-Spuma-Spu elements in the tuatara genome. Examination of their consensus sequence revealed that ERV-Spuma-Spu only possessed the three main retroviral core genes, namely ory gene ; howeveralian FV ,6,42. Thgag gene was markedly shorter than those of typical simian FVs. Protein sequence comparison showed that the putative ERV-Spuma-Spu Gag protein had a full matrix domain essential for Gag–Gag interaction [284SAP domain), which mediates viral particle release [Furthermore, we found that the ERV-Spuma-Spu eraction ,44, Gag–eraction . The coneraction , could a release . Neverth release . Moreover, a region homologous to the C-terminus of the nucleocapsid domain (corresponding to aa 549–648 in the SFVpsc Gag protein) containing part of the glycine/arginine rich box (GR) II and the entire GR-III was also missing from the putative ERV-Spuma-Spu Gag protein. GR-I, a nucleolar localization signal  and is iBased on their observation that ERV-Spuma-Spu is more closely related to mammalian FVs than CoeEFV, Wei et al. proposed an ancient co-speciation of ERV-Spuma-Spu and mammalian FVs dating back more than 320 million years ago . This stOur phylogenetic analyses of Env proteins revealed that, while ERV-Spuma-Ppi and ERV-Spuma-Gja form a clade, they do not form a monophyletic clade with ERV-Spuma-Spu elements, with the two gecko EFVs being closer to mammalian FVs than ERV-Spuma-Spu (Bayesian posterior probability clade support = 1.00). We estimated the age of the gecko EFV lineage to be 208.54 (171.59–250.91) myr old. Again, this low age estimate is suggestive of a cross-species transmission origin for the gecko EFVs’ ancestor, one that is broadly contemporary but independent from the transmission that gave rise to the ancestor of ERV-Spuma-Spu elements.The phylogenetic placement of CoeEFV with respect to that of the ERV-Spuma-Spu lineage also suggests an evolutionary history of cross-species transmission. While the Pol protein of CoeEFV exhibits a sister relationship with that of ERV-Spuma-Spu viruses A, its Enenv gene) to share a most recent common ancestor with that of mammalian FVs 332.68 (236.13–451.42) mya. This age estimate is drastically older than that of the pol gene, suggesting that CoeEFV’s pol and env genes might have different evolutionary histories. We note however that this age estimate is conditioned on how the Env tree is rooted. In this study, we chose the mid-point rooting method, which placed NviFLERV-1 (the amphibian EFV) as the most basal lineage in the Env tree (pol and the env genes can have different evolutionary histories, then there would be no intrinsic reasons for the Pol and the Env tree topologies to closely resemble each other. Another possibility is to subjectively place CoeEFV as the most basal linage in the Env tree, in which case the estimated date would be the divergence date of NviFLERV-1 instead, which in turn would make it a lower bound estimate for the branching date of CoeEFV’s env gene. This nonetheless still supports the hypothesis that CoeEFV’s pol and env genes have different evolutionary histories. On the other hand, we estimated CoeEFV’s Env protein (and thus its Env tree B, consisEnv tree A. Howeveenv genes to have evolutionary histories that are strikingly different from the rest of the env gene and the pol gene [This finding mirrors observations from primate  and felipol gene ,60,61,62pol gene , which mOur analyses reveal a complex evolutionary history and ancient transmission routes of ancient FVs, likely involving host switches across the boundary between water and land, as well as the modular nature of their genomes. Our work also highlights the importance and the value of recombination analysis and temporal information in evolutionary inference as well as the pitfalls of tree-topology based virus–host co-speciation analysis. Discovery of additional EFVs will undoubtedly further our understanding and improve our knowledge of the complex and rich natural history of FVs.