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Background Global vaccine development efforts have been accelerated in response to the devastating coronavirus disease 2019 (COVID-19) pandemic. We evaluated the impact of a 2-dose COVID-19 vaccination campaign on reducing incidence, hospitalizations, and deaths in the United States. Methods We developed an agent-based model of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) transmission and parameterized it with US demographics and age-specific COVID-19 outcomes. Healthcare workers and high-risk individuals were prioritized for vaccination, whereas children under 18 years of age were not vaccinated. We considered a vaccine efficacy of 95% against disease following 2 doses administered 21 days apart achieving 40% vaccine coverage of the overall population within 284 days. We varied vaccine efficacy against infection and specified 10% preexisting population immunity for the base-case scenario. The model was calibrated to an effective reproduction number of 1.2, accounting for current nonpharmaceutical interventions in the United States. Results Vaccination reduced the overall attack rate to 4.6% (95% credible interval [CrI]: 4.3%–5.0%) from 9.0% (95% CrI: 8.4%–9.4%) without vaccination, over 300 days. The highest relative reduction (54%–62%) was observed among individuals aged 65 and older. Vaccination markedly reduced adverse outcomes, with non-intensive care unit (ICU) hospitalizations, ICU hospitalizations, and deaths decreasing by 63.5% (95% CrI: 60.3%–66.7%), 65.6% (95% CrI: 62.2%–68.6%), and 69.3% (95% CrI: 65.5%–73.1%), respectively, across the same period. Conclusions Our results indicate that vaccination can have a substantial impact on mitigating COVID-19 outbreaks, even with limited protection against infection. However, continued compliance with nonpharmaceutical interventions is essential to achieve this impact.

Significance An individual’s decision to vaccinate can be motivated by both self-interest and prosociality, making it difficult to delineate the contribution of prosociality to vaccination uptake. A silent polio epidemic in Israel in which the primary purpose of vaccination was to avert transmission to the general community provides a unique case study through which we quantify, using game-theoretical models, the contribution of prosociality to vaccination decisions. We find that prosociality was a significant driver to rapidly achieving a high coverage of polio vaccination. To further boost coverage, public health communication efforts should be directed toward allaying fears about vaccine risks. Our approach is useful for enhancing participation in diverse disease control measures, Regions with insufficient vaccination have hindered worldwide poliomyelitis eradication, as they are vulnerable to sporadic outbreaks through reintroduction of the disease. Despite Israel’s having been declared polio-free in 1988, a routine sewage surveillance program detected polio in 2013. To curtail transmission, the Israel Ministry of Health launched a vaccine campaign to vaccinate children—who had only received the inactivated polio vaccine—with the oral polio vaccine (OPV). Determining the degree of prosocial motivation in vaccination behavior is challenging because vaccination typically provides direct benefits to the individual as well as indirect benefits to the community by curtailing transmission. However, the Israel OPV campaign provides a unique and excellent opportunity to quantify and model prosocial vaccination as its primary objective was to avert transmission. Using primary survey data and a game-theoretical model, we examine and quantify prosocial behavior during the OPV campaign. We found that the observed vaccination behavior in the Israeli OPV campaign is attributable to prosocial behavior and heterogeneous perceived risk of paralysis based on the individual’s comprehension of the prosocial nature of the campaign. We also found that the benefit of increasing comprehension of the prosocial nature of the campaign would be limited if even 24% of the population acts primarily from self-interest, as greater vaccination coverage provides no personal utility to them. Our results suggest that to improve coverage, communication efforts should also focus on alleviating perceived fears surrounding the vaccine.

ImportanceRandomized clinical trials have shown that the COVID-19 vaccines currently approved in the US are highly efficacious. However, more evidence is needed to understand the population-level impact of the US vaccination rollout in the face of the changing landscape of COVID-19 pandemic in the US, including variants with higher transmissibility and immune escape.ObjectiveTo quantify the population-level impact of the US vaccination campaign in averting cases, hospitalizations and deaths from December 12, 2020 to June 28, 2021.DesignAge-stratified agent-based model which included transmission dynamics of the Alpha, Gamma and Delta variants in addition to the original Wuhan-1 variant.SettingOur model was calibrated to COVID-19 outbreak and vaccine rollout in the US. Model predictions were made at the country level.ParticipantsSimulated age-stratified population representing US demographics.Main Outcomes and MeasuresCases, hospitalizations and deaths averted by vaccination against COVID-19 in the US, compared to the counterfactuals of no vaccination and vaccination administered at half the actual pace.ResultsThe swift vaccine rollout in the US curbed a potential resurgence of cases in April 2021, which would have been otherwise fuelled by the Alpha variant. Compared to the scenario without vaccines, we estimated that the actual vaccination program averted more than 26 million cases, 1.2 million hospitalizations and saved 279,000 lives. A vaccination campaign with half the actual rollout rate would have led to an additional 460,000 hospitalizations and 121,000 deaths.Conclusions and RelevanceThe COVID-19 vaccination campaign in the US has had an extraordinary impact on reducing disease burden despite the emergence of highly transmissible variants. These findings highlight that the pace of vaccination was essential for mitigating COVID-19 in the US, and underscore the urgent need to close the vaccine coverage gaps in communities across the country.Key PointsQuestionHow effective was the United States (US) vaccination campaign in suppressing COVID-19 burden?FindingsThe vaccination campaign was highly effective in curbing the COVID-19 outbreak in the US. We estimated that the vaccine rollout saved over 275,000 lives and averted 1.2 million hospitalizations.MeaningThe swift vaccine rollout in the US averted a remarkable number of cases, hospitalizations and deaths despite the emergence of highly transmissible variants.

Since the emergence of coronavirus disease 2019 (COVID-19), unprecedented movement restrictions and social distancing measures have been implemented worldwide. The socioeconomic repercussions have fueled calls to lift these measures. In the absence of population-wide restrictions, isolation of infected individuals is key to curtailing transmission. However, the effectiveness of symptom-based isolation in preventing a resurgence depends on the extent of presymptomatic and asymptomatic transmission. We evaluate the contribution of presymptomatic and asymptomatic transmission based on recent individual-level data regarding infectiousness prior to symptom onset and the asymptomatic proportion among all infections. We found that the majority of incidences may be attributable to silent transmission from a combination of the presymptomatic stage and asymptomatic infections. Consequently, even if all symptomatic cases are isolated, a vast outbreak may nonetheless unfold. We further quantified the effect of isolating silent infections in addition to symptomatic cases, finding that over one-third of silent infections must be isolated to suppress a future outbreak below 1% of the population. Our results indicate that symptom-based isolation must be supplemented by rapid contact tracing and testing that identifies asymptomatic and presymptomatic cases, in order to safely lift current restrictions and minimize the risk of resurgence.

BackgroundNumerous countries imposed strict travel restrictions, contributing to the large socioeconomic burden during the COVID-19 pandemic. The long quarantines that apply to contacts of cases may be excessive for travel policy.MethodsWe developed an approach to evaluate imminent countrywide COVID-19 infections after 0–14-day quarantine and testing. We identified the minimum travel quarantine duration such that the infection rate within the destination country did not increase compared to a travel ban, defining this minimum quarantine as “sufficient.”FindingsWe present a generalised analytical framework and a specific case study of the epidemic situation on November 21, 2021, for application to 26 European countries. For most origin-destination country pairs, a three-day or shorter quarantine with RT-PCR or antigen testing on exit suffices. Adaptation to the European Union traffic-light risk stratification provided a simplified policy tool. Our analytical approach provides guidance for travel policy during all phases of pandemic diseases.InterpretationFor nearly half of origin-destination country pairs analysed, travel can be permitted in the absence of quarantine and testing. For the majority of pairs requiring controls, a short quarantine with testing could be as effective as a complete travel ban. The estimated travel quarantine durations are substantially shorter than those specified for traced contacts.FundingEasyJet (JPT and APG), the Elihu endowment (JPT), the Burnett and Stender families’ endowment (APG), the Notsew Orm Sands Foundation (JPT and APG), the National Institutes of Health (MCF), Canadian Institutes of Health Research (SMM) and Natural Sciences and Engineering Research Council of Canada EIDM-MfPH (SMM).Research in contextEvidence before this studyEvidence from early in the pandemic indicates that border closures at the epicentre slowed global dissemination of COVID-19. As community transmission became established in many nations, studies have suggested that the benefit of strict border closures in mitigating the transmission of disease from travellers diminished. Research for community settings has shown that testing later during quarantine, rather than upon entry into quarantine, can substantially shorten the duration of quarantine needed to reduce post-quarantine transmission. In particular for international air travellers, a 14-day quarantine can effectively be shortened to five or seven days. The number of infectious COVID-19 cases that escape from these quarantines depends on the prevalence of disease in the country the traveller originated as well as the travel volume into the country.Added value of this studyWe developed a framework to identify quarantine and testing strategies that enable travel from specific origins without increasing their infection rates per capita within destinations. No prior study has evaluated the appropriate duration of quarantine necessary to prevent any rise in infection rates per capita in the destination countries as a result of travel. By accounting for prevalence, daily incidence, vaccine coverage, immunity, age demographics, and travel flow between countries, we quantified the contribution of travel towards within-country the imminent infections in the destination country under different quarantine and testing strategies. For travel between 26 European countries, our results for the pandemic situation observed on November 21, 2021 demonstrate that there are often less burdensome quarantine and testing strategies that can serve as effective alternatives to strict border closure. Specifically, these estimated sufficient quarantine durations are especially dependent on COVID-19 prevalence and immunity within the two countries. We also found that asymmetry in the travel flow, just not the volume of travel flow, can also influence the estimated sufficient quarantine durations. Using data on variants of concern, including Omicron, we found that the adequacy of a border control strategy to limit variant spread depends strongly on the geographical distribution of the variant. While our results pertain to European countries, we also provide an interactive spreadsheet that can be used to determine appropriate quarantine durations between any two countries. Moreover, our framework can also be applied at any spatial or population scale within which movement restrictions could feasibly be implemented.Implications of all available evidenceTravel quarantine and testing strategies can effectively mitigate importation and onward transmission within a country. Identifying sufficient strategies can allow countries to permit travel to and from other countries, without risking a short-term increase in infection rates. As long as the community transmission is occurring, the long-term epidemic trend within the destination country is more apt to be determined by other disease control measures, e.g., contact tracing, vaccination, and non-pharmaceutical interventions. Together, travel quarantine and other related control measures can mitigate the risk of transmission between countries, limiting the threat of variants of concern.

BackgroundGlobal vaccine development efforts have been accelerated in response to the devastating COVID-19 pandemic. We evaluated the impact of a 2-dose COVID-19 vaccination campaign on reducing incidence, hospitalizations, and deaths in the United States (US).MethodsWe developed an agent-based model of SARS-CoV-2 transmission and parameterized it with US demographics and age-specific COVID-19 outcomes. Healthcare workers and high-risk individuals were prioritized for vaccination, while children under 18 years of age were not vaccinated. We considered a vaccine efficacy of 95% against disease following 2 doses administered 21 days apart achieving 40% vaccine coverage of the overall population within 284 days. We varied vaccine efficacy against infection, and specified 10% pre-existing population immunity for the base-case scenario. The model was calibrated to an effective reproduction number of 1.2, accounting for current non-pharmaceutical interventions in the US.ResultsVaccination reduced the overall attack rate to 4.6% (95% CrI: 4.3% - 5.0%) from 9.0% (95% CrI: 8.4% - 9.4%) without vaccination, over 300 days. The highest relative reduction (54-62%) was observed among individuals aged 65 and older. Vaccination markedly reduced adverse outcomes, with non-ICU hospitalizations, ICU hospitalizations, and deaths decreasing by 63.5% (95% CrI: 60.3% - 66.7%), 65.6% (95% CrI: 62.2% - 68.6%), and 69.3% (95% CrI: 65.5% - 73.1%), respectively, across the same period.ConclusionsOur results indicate that vaccination can have a substantial impact on mitigating COVID-19 outbreaks, even with limited protection against infection. However, continued compliance with non-pharmaceutical interventions is essential to achieve this impact.Key pointsVaccination with a 95% efficacy against disease could substantially mitigate future attack rates, hospitalizations, and deaths, even if only adults are vaccinated. Non-pharmaceutical interventions remain an important part of outbreak response as vaccines are distributed over time.

Socioeconomic status is consistently linked to population health and specifically to the finding that there is decreasing health associated with decreasing social position. Despite the substantial literature, an analogous literature that is focused on clinical practice, and especially consideration of the individual, is almost nonexistent. Even in the absence of these data, physicians routinely incorporate patient life experience (biography) into their estimation of a patient's clinical trajectory (prognosis) and when making therapeutic decisions. Some advances have occurred that strengthen the evidence base, such as the US Food and Drug Administration decision to show all results from randomized controlled trials on newly approved drugs by age, sex, and race. In this article we review the current status of research on the impact of social determinants of treatment response and illustrate the important role of the therapeutic context in both research and practice. Examples are provided in which a patient's "biography" alters treatment response in subgroups of the population studied. We also provide examples in which multi-omic data and biographical information in a single individual can illuminate the clinical expression of disease. Finally, we suggest a research agenda that would better support physicians who use social and behavioral features as important elements in their decision making in clinical care.

The efficacy of influenza vaccines varies from one year to the next, with efficacy during the 2017-2018 season anticipated to be lower than usual. However, the impact of low-efficacy vaccines at the population level and their optimal age-specific distribution have yet to be ascertained. Applying an optimization algorithm to a mathematical model of influenza transmission and vaccination in the United States, we determined the optimal age-specific uptake of low-efficacy vaccine that would minimize incidence, hospitalization, mortality, and disability-adjusted life-years (DALYs), respectively. We found that even relatively low-efficacy influenza vaccines can be highly impactful, particularly when vaccine uptake is optimally distributed across age groups. As vaccine efficacy declines, the optimal distribution of vaccine uptake shifts toward the elderly to minimize mortality and DALYs. Health practitioner encouragement and concerted recruitment efforts are required to achieve optimal coverage among target age groups, thereby minimizing influenza morbidity and mortality for the population overall.

Huanglongbing (HLB) is a bacterial infection of citrus trees transmitted by the Asian citrus psyllid Diaphorina citri. Mitigation of HLB has focused on spraying of insecticides to reduce the psyllid population and removal of trees when they first show symptoms of the disease. These interventions have been only marginally effective, because symptoms of HLB do not appear on leaves for months to years after initial infection. Limited knowledge about disease spread during the asymptomatic phase is exemplified by the heretofore unknown length of time from initial infection of newly developing cluster of young leaves, called flush, by adult psyllids until the flush become infectious. We present experimental evidence showing that young flush become infectious within 15 d after receiving an inoculum of Candidatus Liberibacter asiaticus (bacteria). Using this critical fact, we specify a microsimulation model of asymptomatic disease spread and intensity in a grove of citrus trees. We apply a range of psyllid introduction scenarios to show that entire groves can become infected with up to 12,000 psyllids per tree in less than 1 y, before most of the trees show any symptoms. We also show that intervention strategies that reduce the psyllid population by 75% during the flushing periods can delay infection of a full grove, and thereby reduce the amount of insecticide used throughout a year. This result implies that psyllid surveillance and control, using a variety of recently available technologies, should be used from the initial detection of invasion and throughout the asymptomatic period.

As the global human population continues to grow, so too does our impact on the environment. The ingenuity with which our species has harnessed natural resources to fulfill our needs is dazzling. Even as we tighten our grip on the environment, however, the escalating extent of anthropogenic actions destabilizes long-standing ecological balances (1, 2). The dangers of mining, refining, and fossil fuel consumption now extend beyond occupational or proximate risks to global climate change (3). Among a plethora of environmental problems, extreme climate events are intensifying (4, 5). Storms, droughts, and floods cause direct destruction, but also have pervasive repercussions on food security, infectious disease transmission, and economic stability that take their toll for many years. For example, within weeks of the catastrophic wind and flood damage from the 2016 Hurricane Matthew in Haiti, there was a dramatic surge in cholera, among other devastating repercussions (6, 7). In a world where 1% of the population possesses 50% of the wealth (8), those worst affected by extreme climatic events and the aftermath are also the least able to rebound. Compounding the impact of natural disasters, our progressively more intimate interactions with fragmented environments (9) have given rise to an era of disease emergence and re-emergence at unprecedented rates, as exemplified by recent outbreaks of the Ebola and Zika viruses. Furthermore, globalization to an extent that includes the airline travel of over eight million people every day has enabled such disease outbreaks to disseminate rapidly and pose a threat far beyond their areas of origin (10). Addressing these challenges requires an understanding of coupled human–environment dynamics, whereby human activity modifies an environmental system (often detrimentally), and the resulting environmental repercussions then impact humans. In turn, these impacts can potentially spur a shift in human activity toward protection and restoration. … [↵][1]1To whom correspondence should be addressed. Email: alison.galvani{at}yale.edu. [1]: #xref-corresp-1-1

This study provides a response to Springer and Hauser’s claim that the Ryff Scales of Psychological Well-Being do not comprise six dimensions. We show that their analyses support the theoryguided six-factor model, although their interpretations of the data reveal a lack of understanding of the construct-oriented approach to personality assessment. We also review evidence from five categories of studies (i.e., factorial validity, psychological correlates, sociodemographic correlates, biological correlates, and intervention studies) that document the distinctiveness of the six dimensions of well-being, including among subscales that are highly correlated. We conclude with an examination of the methodological corrections (negative items, adjacent items, and redundant items) employed by Springer and Hauser, finding all to be problematic, either in terms of scientific rationale or method of implementation, or both. Correlations among latent constructs resulting from these analyses are thus highly questionable.

The purpose of this paper is to characterize the interrelationships between macropolitical, social and economic policies, human migration, agricultural development, and malaria transmission on the Amazon frontier. We focus our analysis on a recent colonization project, POLONOROESTE, in the state of Rondonia. Employing data from field surveys in 1985-1987 and 1995, we use spatial statistical methodologies linked to a geographical information system (GIS) to describe the patterns of human settlement in the area, the ecological transformations induced by forest clearance practices, and the manner in which these factors determine gradations of malaria risk. Our findings show that land use patterns, linked to social organization of the community and the structure of the physical environment, played a key role in promoting malaria transmission. In addition, the location of each occupied area is itself an important determinant of the pattern of malaria risk. Based on lessons learned from our spatial and temporal characterization of malaria risk, we propose policies for malaria mitigation in the Brazilian Amazon.

Japanese encephalitis (JE) is a disease caused by an arbovirus that is spread by marsh birds, amplified by pigs, and mainly transmitted by the bite of infected Culex tritaeniorhynchusmosquitoes. The estimated annual incidence and mortality rates are 30,000–50,000 and 10,000, respectively, and the estimated global burden to JE in 2002 was 709,000 disability-adjusted life years lost. Here, we discuss the contextual determinants of JE, and systematically examine studies assessing the relationship between irrigated rice agriculture and clinical parameters of JE. Estimates of the sizes of the rural population and population in irrigated areas are presented, and trends of the rural population, the rice-irrigated area, and the rice production are analyzed from 1963 to 2003. We find that approximately 1.9 billion people currently live in rural JE-prone areas of the world. Among them 220 million people live in proximity to rice-irrigation schemes. In 2003, the total rice harvested area of all JE-endemic countries (excluding the Russian Federation and Australia) was 1,345,000 km 2 . This is an increase of 22% over the past 40 years. Meanwhile, the total rice production in these countries has risen from 226 millions of tonnes to 529 millions of tonnes (+134%). Finally, we evaluate the effect of different vector control interventions in rice fields, including environmental measures (i.e. alternate wet and dry irrigation (AWDI)), and biological control approaches (i.e. bacteria, nematodes, invertebrate predators, larvivorous fish, fungi and other natural products). We conclude that in JE-endemic rural settings, where vaccination rates are often low, an integrated vector management approach with AWDI and the use of larvivorous fish as its main components can reduce vector populations, and hence has the potential to reduce the transmission level and the burden of JE. 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28

Human-made ecologic transformations have occurred at an unprecedented rate over the past 50 years. Prominent among them are water resource development projects. An estimated 40,000 large dams and 800,000 small dams have been built, and 272 million hectares of land are currently under irrigation worldwide. The establishment and operation of water projects has had a history of facilitating a change in the frequency and transmission dynamics of malaria, but analyses of these environmental risk factors are sparse. Here, we present a comprehensive review of studies that assessed the impact of irrigation and dam building on malaria prevalence or incidence, stratified by the World Health Organization's (WHO) sub-regions of the world, and link these studies with the latest statistics on disability adjusted life years, irrigated agriculture, and large dams. We also present estimates of the population at risk due to proximity to irrigation schemes and large dam reservoirs. In WHO sub-regions 1 and 2, which have 87.9% of the current global malaria burden, only 9.4 million people are estimated to live near large dams and irrigation schemes. In contrast, the remaining sub-regions concentrate an estimated 15.3 million people near large dams and up to 845 million near irrigation sites, while here only 12.1% of the global malaria burden is concentrated. Whether an individual water project triggers an increase in malaria transmission depends on the contextual determinants of malaria, including the epidemiologic setting, socioeconomic factors, vector management, and health seeking behavior. We conclude that in unstable malaria endemic areas, integrated malaria control measures, coupled with sound water management, are mandatory to mitigate the current burden of malaria in locations near irrigation or dam sites.

Objective To assess the current international representation of members of editorial and advisory boards and authors in the leading peer reviewed literature on tropical medicine. Design Systematic review. Main outcome measures Country affiliations, as classified by the human development index, of editorial and advisory board members of all tropical medicine journals referenced by the Institute of Scientific Information (ISI) as of late 2003 and of all contributing authors of full articles published in the six leading journals on tropical medicine in 2000-2. Results Sixteen (5.1%) of the 315 editorial and advisory board members from the 12 ISI referenced journals on tropical medicine are affiliated to countries with a low human development index and 223 (70.8%) to countries with a high index. Examination of the 2384 full articles published in 2000-2 in the six highest ranking tropical medicine journals showed that 48.1% of contributing authors are affiliated to countries with a high human development index, whereas the percentage of authors from countries with a low index was 13.7%. Articles written exclusively by authors from low ranked countries accounted for 5.0%. Our data indicate that research collaborations between a country with a high human development index and one that has either a medium or a low index are common and account for 26.5% and 16.1% of all full articles, respectively. Conclusion Current collaborations should be transformed into research partnerships, with the goals of mutual learning and institutional capacity strengthening in the developing world.

Poverty reduction policies guide development strategies. In economies that depend heavily on agriculture, in the face of rapid population growth, innovative approaches are required to satisfy food needs, increase household welfare and alleviate poverty. Irrigated agriculture is an important strategy to enhance crop production, but it must be well tailored to specific socio-ecological settings, as otherwise, it might increase the burden of water-related parasitic diseases and delay economic advance. The purpose of this study is to assess and quantify the effect of ill health, particularly malaria, on the performance of farm activity, with an emphasis on drip-irrigated vegetable farming in rural Côte d'Ivoire. Vegetable yields and revenues were monitored among 12 farmers and linked with longitudinal medical and entomological surveys. Over the course of 10 months, farmers were classified as sick, on average, for 14-15 days, with malaria accounting for 8-9 days (58%), confirming that malaria is the most important disease in this setting. There was a large heterogeneity among farmers, with malaria-related work losses ranging between 0 and 26 days. Work absenteeism correlated with overall yields and revenues. During a single cabbage production cycle, those farmers who were prescribed sick because of malaria for more than 2 days (mean: 4.2 days) had 47% lower yields and 53% lower revenues than farmers who missed a maximum of 2 days (mean: 0.3 days). This is consequential in an intensive cropping system, where substitutes for qualified workers are not readily available. We conclude that mitigating the burden of malaria is an important step towards reducing the vulnerability of people engaged in intensive agricultural production. This calls for targeted interventions to facilitate agriculture-based rural development that might spur social and economic development and reduce inequities in sub-Saharan Africa.

Background For 2 decades, the number of physician-scientists has not kept pace with the overall growth of the medical research community. Concomitantly, the number of women entering medical schools has increased markedly. We have explored the effect of the changing gender composition of medical schools on the present and future pipeline of young physician-scientists. Methods We analyzed data obtained from the Association of American Medical Colleges, the National Institutes of Health, and the Howard Hughes Medical Institute pertaining to the expressed research intentions or research participation of male and female medical students in the United States. Results A statistically significant decline in the percentage of matriculating and graduating medical students\Mboth men and women\Mwho expressed strong research career intentions occurred during the decade between 1987 and 1997. Moreover, matriculating and graduating women were significantly less likely than men to indicate strong research career intentions. Each of these trends has been observed for medical schools overall and for research-intensive ones. Cohort data obtained by tracking individuals from matriculation to graduation revealed that women who expressed strong research career intentions upon matriculation were more likely than men to decrease their research career intentions during medical school. Medical student participation in research supported the gender gap identified by assessing research intentions. Female medical student participation in the Medical Scientist Training Program and the Howard Hughes Medical Institute/National Institutes of Health-sponsored Cloisters Program has increased but lags far behind the growth in the female population in medical schools. Conclusion Three worrisome trends in the research career intentions and participation of the nation\'s medical students (a decade-long decline for both men and women, a large and persistent gender gap, and a negative effect of the medical school experience for women) presage a further decline in the physician-scientist pipeline unless they are reversed promptly and decisively.

Infections with Schistosoma mansoni and hookworms are widespread in sub-Saharan Africa and the burden of disease associated with both parasites is enormous. Although there is a large overlap in their geographic distribution, little is known about the association between S. mansoni and hookworm infections and the underlying mechanisms. We explored this association among 325 schoolchildren from Côte d'Ivoire, by screening multiple stool specimens over consecutive days. We found a highly significant positive association between S. mansoni and hookworm infections with an adjusted odds ratio of 2.25 (95% confidence interval: 1.31-3.85; P=0.003). Increasing infection intensity of S. mansoni was significantly correlated with an increased likelihood of concomitant hookworm infections (chi(2)=20.72; P0.001). Egg counts in stool specimens derived from a single day did not consistently reveal the positive association between the two parasites, which underlines the importance of repeated stool examinations. Several self-reported water contact patterns were significantly associated either with S. mansoni, hookworm or concomitant infections. Our findings are of considerable importance for tailoring effective health education messages that are readily adapted to the local epidemiological setting. Complemented with other control interventions, these measures might significantly reduce the burden caused by S. mansoni and hookworm infections.

One hundred years ago, Giemsa's stain was employed for the first time for malaria diagnosis. Giemsa staining continues to be the method of choice in most malarious countries, although, in the recent past, several alternatives have been developed that exhibit some advantages. Considerable progress has been made with fluorescent dyes, particularly with Acridine Orange (AO). The literature on the discovery, development and validation of the AO method for malaria diagnosis is reviewed here. Compared with conventional Giemsa staining, AO shows a good diagnostic performance, with sensitivities of 81.3%-100% and specificities of 86.4%-100%. However, sensitivities decrease with lower parasite densities, and species differentiation may occasionally be difficult. The most notable advantage of the AO method over Giemsa staining is its promptness; results are readily available within 3-10 min, whereas Giemsa staining may take 45 min or even longer. This is an important advantage for the organization of health services and the provision of effective treatment of malaria cases. The national malaria control programme of Tanzania, together with the Japan International Co-operation Agency, began to introduce the AO method in Tanzania in 1994. So far, AO staining has been introduced in 70 regional and district hospitals, and 400 laboratory technicians have been trained to use the method. The results of this introduction, which are reviewed here and have several important implications, indicate that AO is a viable alternative technique for the laboratory diagnosis of malaria in highly endemic countries.

Single species infections with schistosomes, geohelminths, and intestinal protozoans are common over large parts of sub-Saharan Africa, and it is expected that polyparasitism affects a considerable proportion of the population, hence posing a great toll on public health. However, few investigations have been carried out to quantify the extent of polyparasitism. Here, a detailed assessment is reported for the epidemiology of Schistosoma mansoni, geohelminths, and intestinal protozoan infections, with particular emphasis on polyparasitism among 260 community members in rural Cĵte d'Ivoire. Schistosoma mansoni, Entamoeba coli, and hookworm were the predominant species with prevalences of 71.5, 64.6, and 51.9%, respectively. Only 8 individuals displayed no infection, whereas two-thirds of the population harbored 3 or more parasites concurrently. There were a series of significant pairwise parasite co-occurrences, e.g., between S. mansoni and hookworms and between S. mansoni and E. coli. It is concluded that polyparasitism in the population studied here was very common, which is probably the case also in other areas of rural Cĵte d'Ivoire and elsewhere in sub-Saharan Africa. These findings call for integrated approaches to effectively control multiple parasitic and protozoan infections.

Roll back malaria (RBM) aims at halving the current burden of the disease by the year 2010. The focus is on sub-Saharan Africa, and it is proposed to implement efficacious and cost-effective control strategies. But the evidence base of such information is scarce, and a notable missing element is the discussion of the potential of environmental management. We reviewed the literature and identified multiple malaria control programmes that incorporated environmental management as the central feature. Prominent among them are programmes launched in 1929 and implemented for two decades at copper mining communities in Zambia. The full package of control measures consisted of vegetation clearance, modification of river boundaries, draining swamps, oil application to open water bodies and house screening. Part of the population also was given quinine and was sleeping under mosquito nets. Monthly malaria incidence rates and vector densities were used for surveillance and adaptive tuning of the environmental management strategies to achieve a high level of performance. Within 3-5 years, malaria-related mortality, morbidity and incidence rates were reduced by 70-95%. Over the entire 20 years of implementation, the programme had averted an estimated 4173 deaths and 161,205 malaria attacks. The estimated costs per death and malaria attack averted were US$ 858 and US$ 22.20, respectively. Over the initial 3-5 years start-up period, analogous to the short-duration of cost-effectiveness analyses of current studies, we estimated that the costs per disability adjusted life year (DALY) averted were US$ 524-591. However, the strategy has a track record of becoming cost-effective in the longer term, as maintenance costs were much lower: US$ 22-92 per DALY averted. In view of fewer adverse ecological effects, increased sustainability and better uses of local resources and knowledge, environmental management--integrated with pharmacological, insecticidal and bednet interventions--could substantially increase the chances of rolling back malaria.

We have examined data on six closely linked microsatellite loci on chromosome 9q34 from 59 Ashkenazi Jewish families with idiopathic torsion dystonia (ITD). Our data show that the vast majority (>90%) of early–onset ITD cases in the Ashkenazi population are due to a single founder mutation, which we estimate first appeared approximately 350 years ago. We also show that carriers preferentially originate from the northern part of the historic Jewish Pale of settlement (Lithuania and Byelorussia). The recent origin of this dominant mutation and its current high frequency (between 1/6,000 and 1/2,000) suggest that the Ashkenazi population descends from a limited group of founders, and emphasize the importance of genetic drift in determining disease allele frequencies in this population.

The citrus disease huanglongbing (HLB), associated with an uncultured bacterial pathogen, is threatening the citrus industry worldwide. A mathematical model of the transmission of HLB between its psyllid vector and citrus host has been developed to characterize the dynamics of the vector and disease development, focusing on the spread of the pathogen from flush to flush (a newly developing cluster of very young leaves on the expanding terminal end of a shoot) within a tree. This approach differs from that of prior models for vector-transmitted plant diseases where the entire plant is the unit of analysis. Dynamics of vector and host populations are simulated realistically as the flush population approaches complete infection. Model analysis indicates that vector activity is essential for initial infection but is not necessary for continued infection because infection can occur from flush to flush through internal movement in the tree. Flush production, within-tree spread, and latent period are the most important parameters influencing HLB development. The model shows that the effect of spraying of psyllids depends on time of initial spraying, frequency, and efficacy of the insecticides. Similarly, effects of removal of symptomatic flush depend on the frequency of removal and the time of initiation of this practice since the start of the epidemic. Within-tree resistance to spread, possibly affected by inherent or induced resistance, is a major factor affecting epidemic development, supporting the notion that alternate routes of transmission besides that by the vector can be important for epidemic development.

The authors examine some implications of current trends in life expectancy and morbidity in developed countries such as the United States. In particular they "demonstrate empirically that there is as yet no clear evidence supporting the idea of compression of mortality in either human populations or in experimental animal models; discuss statistical and mathematical modeling issues--including open research problems pertaining to the measurement of compression of mortality morbidity and disability; [and] relate debates about compression to population forecasting and health policy agendas." (EXCERPT)

Substance dependence or addiction is a complex environmental and genetic disorder that results in serious health and socio-economic consequences. Multiple substance dependence categories together, rather than any one individual addiction outcome, may explain the genetic variability of such disorder. In our study, we defined a composite substance dependence phenotype derived from six individual diagnoses: addiction to nicotine, alcohol, marijuana, cocaine, opiates or other drugs as a whole. Using data from several genomewide case-control studies, we identified a strong (Odds ratio = 1.77) and significant (p-value = 7E-8) association signal with a novel gene, PBX/knotted 1 homeobox 2 (PKNOX2), on chromosome 11 with the composite phenotype in European-origin women. The association signal is not as significant when individual outcomes for addiction are considered, or in males or African-origin population. Our findings underscore the importance of considering multiple addiction types and the importance of considering population and gender stratification when analyzing data with heterogeneous population.

Although there is agreement that climate change will result in population displacements and migration, there are differing views on the potential volume of flows, the likely source and destination areas, the relative role of climatic versus other factors in precipitating movements, and whether migration represents a failure of adaptation (1, 2). We argue that climate change mitigation and adaptation (M&A) actions, which will also result in significant population displacements, have not received sufficient attention. Given the emergence of resettlement as an adaptation response, it is critical to learn from research on development-forced displacement and resettlement (DFDR). We discuss two broad categories of potential displacement in response to (i) climate impacts themselves and (ii) large-scale M&A projects. We discuss policy approaches for facilitating migration and, where communities lack resources to migrate, suggest guidelines for organized resettlement.

In 1984 researchers spoke to 4670 people from 887 households in Para State Brazil to judge the effectiveness of perceived malaria illness reports as a methodology for determining the magnitude and distribution of the demand for malaria specific health services in frontier communities. They collected blood from 931 persons who were able to directly respond to the questionnaire. The tests verified exposure to Plasmodium falciparum in 212 of direct respondents who claimed to have had malaria (sensitivity 80.9%). Further 446 of the direct respondents who did not claim to have experienced a malarial episode indeed did not have anti P. falciparum antigens in their blood (66.7% specificity). 223 other direct respondents also claimed to have had malaria but the serologic tests did not prove exposure. This may be because they were exposed to P. vivax (which was also common in Para) instead of P. falciparum for which the tests were sensitive. Men had 2.5 more episodes/year than women. Gold miners had the highest annual parasite incidence (direct=431 vs. 190 for farmers and persons who cleared the forests) and highest exposure weighted illness rate (direct=898 vs. 606) of all occupational groups. This survey confirmed that it was basically infeasible to directly contact the majority of members of the households especially those at highest risk of malarial episodes. Therefore researchers need to conduct indirect illness reports to obtain population coverage. The methodology used in this study is the best current methodology to survey highly mobile nonimmune populations. Future research to better the methodology should include that with different prompts the interviewer gives to indirect respondents to considerably increase the accuracy of responses. In conclusion these results the rapid influx of nonimmune migrants to the Amazon and the need to minimize the number of days productive workers cannot work justifies rapid and defensible assessment of the demand for health services a high priority.

SUMMARYIn May 2001, the World Health Assembly (WHA) passed a resolution which urged member states to attain, by 2010, a minimum target of regularly administering anthelminthic drugs to at least 75% and up to 100% of all school-aged children at risk of morbidity. The refined global strategy for the prevention and control of schistosomiasis and soil-transmitted helminthiasis was issued in the following year and large-scale administration of anthelminthic drugs endorsed as the central feature. This strategy has subsequently been termed ‘preventive chemotherapy’. Clearly, the 2001 WHA resolution led the way for concurrently controlling multiple neglected tropical diseases. In this paper, we recall the schistosomiasis situation in Africa in mid-2003. Adhering to strategic guidelines issued by the World Health Organization, we estimate the projected annual treatment needs with praziquantel among the school-aged population and critically discuss these estimates. The important role of geospatial tools for disease risk mapping, surveillance and predictions for resource allocation is emphasised. We clarify that schistosomiasis is only one of many neglected tropical diseases and that considerable uncertainties remain regarding global burden estimates. We examine new control initiatives targeting schistosomiasis and other tropical diseases that are often neglected. The prospect and challenges of integrated control are discussed and the need for combining biomedical, educational and engineering strategies and geospatial tools for sustainable disease control are highlighted. We conclude that, for achieving integrated and sustainable control of neglected tropical diseases, a set of interventions must be tailored to a given endemic setting and fine-tuned over time in response to the changing nature and impact of control. Consequently, besides the environment, the prevailing demographic, health and social systems contexts need to be considered.

Background As the population of Africa rapidly urbanizes, large populations could be protected from malaria by controlling aquatic stages of mosquitoes if cost-effective and scalable implementation systems can be designed. Methods A recently initiated Urban Malaria Control Programme in Dar es Salaam delegates responsibility for routine mosquito control and surveillance to modestly-paid community members, known as Community-Owned Resource Persons (CORPs). New vector surveillance, larviciding and management systems were designed and evaluated in 15 city wards to allow timely collection, interpretation and reaction to entomologic monitoring data using practical procedures that rely on minimal technology. After one year of baseline data collection, operational larviciding with Bacillus thuringiensis var. israelensis commenced in March 2006 in three selected wards. Results The procedures and staff management systems described greatly improved standards of larval surveillance relative to that reported at the outset of this programme. In the first year of the programme, over 65,000 potential Anopheles habitats were surveyed by 90 CORPs on a weekly basis. Reaction times to vector surveillance at observations were one day, week and month at ward, municipal and city levels, respectively. One year of community-based larviciding reduced transmission by the primary malaria vector, Anopheles gambiae s.l., by 31% (95% C.I. = 21.6–37.6%; p = 0.04). Conclusion This novel management, monitoring and evaluation system for implementing routine larviciding of malaria vectors in African cities has shown considerable potential for sustained, rapidly responsive, data-driven and affordable application. Nevertheless, the true programmatic value of larviciding in urban Africa can only be established through longer-term programmes which are stably financed and allow the operational teams and management infrastructures to mature by learning from experience.

Summary The public health and economic significance of malaria is enormous, and its control remains a great challenge. Many established malaria control methods are hampered by drug resistance and insecticide-resistant vectors. Malaria control measures built around environmental management are non-toxic, cost-effective, and sustainable. However, there has been no comprehensive review of the literature or meta-analysis examining the effect of these interventions. We therefore did a systematic literature review and identified 40 studies that emphasised environmental management interventions and reported clinical malaria variables as outcome measures. Of these 40 studies, environmental modification (measures aiming to create a permanent or long-lasting effect on land, water, or vegetation to reduce vector habitats—eg, the installation and maintenance of drains) was the central feature in 27 studies, environmental manipulation (methods creating temporary unfavourable conditions for the vector—eg, water or vegetation management) in four, and nine quantified the effect of modifications of human habitation. Most of the studies (n=34, 85%) were implemented before the Global Malaria Eradication Campaign (1955–69), which mainly relied on indoor residual spraying with dichlorodiphenyltrichloroethane (DDT). In 16 studies that applied environmental modification and in eight studies on modification of human habitation, the risk ratio of malaria was reduced by 88·0% (95% CI 81·7–92·1) and 79·5% (95% CI 67·4–87·2), respectively. We conclude that malaria control programmes that emphasise environmental management are highly effective in reducing morbidity and mortality. Lessons learned from these past successful programmes can inspire sound and sustainable malaria control approaches and strategies.

Background Concomitant parasitic infections are common in the developing world, yet most studies focus on a single parasite in a narrow age group. We investigated the extent of polyparasitism and parasite associations, and related these findings to self-reported morbidity. Methods Inhabitants of 75 randomly selected households from a single village in western Cote d’Ivoire provided multiple faecal specimens and a single finger prick blood sample. The Kato-Katz technique and a formol-ether concentration method were employed to screen faecal samples for Schistosoma mansoni, soil-transmitted helminths and intestinal protozoa. Giemsa-stained blood smears were analysed for malaria parasites. A questionnaire was administered for collection of demographic information and self-reported morbidity indicators. Results Complete parasitological data were obtained for 500/561 (89.1%) participants, similarly distributed among sex, with an age range from 5 days to 91 years. The prevalences of Plasmodium falciparum, hookworms, Entamoeba histolytica/E. dispar, and S. mansoni were 76.4%, 45.0%, 42.2%, and 39.8%, respectively. Threequarters of the population harboured three or more parasites concurrently. Multivariate analysis revealed significant associations between several pairs of parasites. Some parasitic infections and the total number of parasites were significantly associated with self-reported morbidity indicators. Conclusions Our data confirm that polyparasitism is very common in rural Cote d’Ivoire and that people have clear perceptions about the morbidity caused by some of these parasitic infections. Our findings can be used for the design and implementation of sound intervention strategies to mitigate morbidity and co-morbidity.

Schistosomes and soil-transmitted helminths currently infect a third of the world's human population. An important feature of these parasitic infections is their focal distribution, which has significant implications for control. Only a few studies have been carried out at the microepidemiological scale, comparing infection levels among individuals or households within a single village. In this study, data are presented from a cross-sectional survey, examining all children attending a primary school in rural Côte d'Ivoire over several consecutive days for Schistosoma mansoni, soil-transmitted helminths, and intestinal protozoa. All houses in the main village were mapped, and school children were linked to these households for small-area spatial analyses. Comparison between the 260 school children who live within the main village and the 89 children who reside in nearby settlements revealed significant differences in the overall prevalence and intensity of infections with S. mansoni and hookworm, confirming the focal nature of these 2 parasites. On the other hand, S. mansoni and hookworm infections exhibited random spatial patterns within the main village. The validity of these results is discussed in the context of this epidemiological setting, drawing attention to the issue of scale. Our findings have direct implications for intervention because they call for a uniform, community-wide approach to control schistosomiasis and soil-transmitted helminthiasis. Implementation can be relatively straightforward, and the proposed control approach might be cost-effective and prove sustainable.

The committee recommends 10 priority areas for research investment to integrate the behavioral, social, and biomedical sciences at the National Institutes of Health: Predisease pathways—identify early and long-term biological, behavioral, psychological, and social precursors to disease; Positive health—identify biological, behavioral, and psychosocial factors that contribute to resilience, disease resistance, and wellness; Gene expression—understand environmentally induced gene expression and its connection to positive and negative health outcomes; Personal ties—explicate the mechanisms by which proximal social interactions influence health and disease outcomes; Healthy communities—identify the collective properties of social and physical environments that influence health and disease outcomes; Inequality—clarify the mechanisms through which socioeconomic hierarchies, racism, discrimination, and stigmatization influence health and disease outcomes; Population health—understand macro-level trends in health status and evaluate the performance of the health care system; Interventions—expand the scope and effectiveness of strategies for social and behavioral interventions to improve health; Methodology—develop new measurement techniques and study designs to link information across levels of analysis (molecular, cellular, behavioral, psychosocial, community) and across time; Infrastructure—establish ways to maintain long-term study populations and to train scientists to integrate health-related knowledge across multiple disciplines.

Models to forecast changes in mortality, morbidity and disability in elderly populations are essential to national and state policies for health and welfare programmes. This volume presents a wide-ranging survey of the forecasting of health in elderly populations, including the modelling of the incidence of chronic diseases in the elderly, the differing perspectives of actuarial and health care statistics, and an assessment of the impact of new technologies on the elderly population. Amongst the topics covered are: uncertainties in projections from census and social security data and actuarial approaches to forecasting; plausible ranges for population growth using biological models and epidemiological time series data; the financing of long term care programmes; the effects of major disabling diseases on health expenditures and forecasting cancer risks and risk factors.

There is an extensive literature on cancer mortality trends and forecasts based on them (e.g., Davis and Hoel, 1990). A common feature of most forecasts is that they deal with trends in site-specific cancer mortality and/or incidence rates but ignore progression from the well-state, to tumor initiation, to detectable disease, to death. Analysis of mortality trends may be useful for determining how much progress the Naional Cancer Institute (NCI) has made toward its 1986 long-range goal of reducing cancer death rates (Bailar, 1990). More refined assessments, whether of public health interventions (e.g., advertising against smoking), screening programs, or new treatments such as chemotherapy for early breast cancer (Early Breast Cancer Trialists’ Collaborative Group, 1988; 1992 a,b) requires use of individual data and stochastic process models. In particular, biologically based models of cancer progression in birth cohorts are important (e.g., Cuzick, p. 85, and Hoel, p. 86 in Davis and Hoel, 1990) for analyzing trends, producing forecasts, and assessing interventions. Nevertheless, the use of cohort models is an exception (Manton and Stallard, 1982, 1988, 1992), not the rule, in forecasting.

A hybrid transmission/genetics model for the development of resistance by Plasmodium falciparum to anti-malarial drugs is set forth. Field data on pyrimethamine resistance are used to calibrate and test the model. Simulated consequences of different drug dosage and population coverage strategies are presented to illustrate an ethical dilemma. A strategy of maximally effective treatment for all infected individuals in the short term can be deleterious—in terms of rapid development of drug resistance—for a community in the longer term.

Background: Exponential growth in the population of older adults presents clinicians with special concerns about factors affecting risks for declines in cognitive and physical functioning. Objectives: To examine the hypothesis that risks for such declines and for disease outcomes, such as cardiovascular disease, are related to differences inallostatic load, the cumulative physiologic toll exacted on the body over time by efforts to adapt to life experiences. To present an operational definition of allostatic load, along with preliminary evidence of its predictive validity in relation to salient outcomes of aging. Methods: Data from a longitudinal, community-based study of successful aging were used to develop a measure of allostatic load based on 10 parameters reflecting levels of physiologic activity across a range of important regulatory systems. Allostatic load is the sum of the number of parameters for which the subject was rated in the highest-risk quartile. Results: Higher allostatic load scores were associated with poorer cognitive and physical functioning and predicted larger decrements in cognitive and physical functioning as well as being associated with an increased risk for the incidence of cardiovascular disease, independent of sociodemographic and health status risk factors. Conclusions: Findings are consistent with the conceptualization of allostatic load as an index of wear and tear on the body, with elevations in allostatic load predicting an increased risk for a decline in cognitive and physical functioning as well as cardiovascular disease in a cohort of older men and women. From a clinical perspective, the concept of allostatic load may provide the basis for a more comprehensive assessment of major risks in the aging process. Arch Intern Med. 1997;157:2259-2268

Grade of membership (GOM) representations are used to characterize and compare the health status of a very heterogeneous sample of blacks and whites in an elderly cohort of 2,806 noninstitutionalized men and women living in New Haven, Connecticut. They were interviewed in 1982 as part of the Established Populations for the Epidemiologic Study of the Elderly (EPESE). Ideal profiles based on functional disabilities, chronic diseases, and selected biomedical and behavioral risk factors are constructed empirically. Each individual in the sample is represented by a set of GOM scores, interpreted as degrees of similarity of his or her health record to each of the profiles. Four profiles emerge from GOM analyses: healthy elderly, elderly with cognitive impairment, elderly with impairment in mobility function and physical performance and with selected chronic conditions, and elderly with major limitations in activities of daily living and multiple chronic conditions. Although elderly blacks and whites generally have similar configurations of profiles, there are important differences, especially when chronic conditions are related to specific types of functional impairments. Questions about and claims for black/white mortality crossovers at older ages, usually addressed with aggregate data, are examined conditional on GOM scores that correspond to diverse combinations of disabilities (or lack thereof) together with housing characteristics of cohort members (e.g., whether they live in public housing for the elderly or in owned or rented housing in the community).

Randomized clinical trials are widely regarded as the method of choice for evaluating the efficacy of therapeutic treatments in medicine. For a critique of this attitude and a balanced discussion of alternative strategies, the reader should consult Feinstein (1985). Despite the rigorous nature of randomized trials, their domain of applicability is essentially restricted to studies where the investigator can control the structure of the population to be investigated and where the number of conditions (or circumstances) involved in comparisons is small in number. Programs in which voluntary self-selection for entry is an essential feature and in which the full treatment involves not only drug therapy but a variety of counseling services and an appropriate administrate structure do not lend themselves to evaluation by conventional randomized trials. In fact, the act of randomization into a program could destroy one of the central processes under investigation; namely, the process of voluntary self-selection.

Methodological issues involved in the analysis of longitudinally collected data are examined. Longitudinal studies are ideal for detecting patterns of change. Social scientists ask questions regarding distributional changes and forecasting the evolution of the respondent population along a certain variable continuum. The mathematical framework usually used for such analysis is discrete-time Markov chains. The limitations of this method of analysis to describe social processes are mentioned. Discrimination among alternative structures and use of fragmentary data are discussed. Occupational data is used illustratively.

Summary This paper considers the formulation and estimation of continuous time social science duration models. The focus is on new issues that arise in applying statistical models developed in biostatistics to analyze economic data and formulate economic models. Both single spell and multiple spell models are discussed. In addition, we present a general time inhomogeneous multiple spell model which contains a variety of useful models as special cases. Four distinctive features of social science duration analysis are emphasized: (1) Because of the limited size of samples available in economics and because of an abundance of candidate observed explanatory variables and plausible omitted explanatory variables, standard nonparametric procedures used in biostatistics are of limited value in econometric duration analysis. It is necessary to control for observed and unobserved explanatory variables to avoid biasing inference about underlying duration distributions. Controlling for such variables raises many new problems not discussed in the available literature. (2) The environments in which economic agents operate are not the time homogeneous laboratory environments assumed in biostatistics and reliability theory. Ad hoc methods for controlling for time inhomogeneity produce badly biased estimates. (3) Because the data available to economists are not obtained from the controlled experimental settings available to biologists, doing econometric duration analysis requires accounting for the effect of sampling plans on the distributions of sampled spells. (4) Econometric duration models that incorporate the restrictions produced by economic theory only rarely can be represented by the models used by biostatisticians. The estimation of structural econometric duration models raises new statistical and computational issues. Because of (1) it is necessary to parameterize econometric duration models to control for both observed and unobserved explanatory variables. Economic theory only provides qualitative guidance on the matter of selecting a functional form for a conditional hazard, and it offers no guidance at all on the matter of choosing a distribution of unobservables. This is unfortunate because empirical estimates obtained from econometric duration models are very sensitive to assumptions made about the functional forms of these model ingredients. In response to this sensitivity we present criteria for inferring qualitative properties of conditional hazards and distributions of unobservables from raw duration data sampled in time homogeneous environments; i.e. from unconditional duration distributions. No parametric structure need be assumed to implement these procedures. We also note that current econometric practice overparameterizes duration models. Given a functional form for a conditional hazard determined up to a finite number of parameters, it is possible to consistently estimate the distribution of unobservables nonparametrically. We report on the performance of such an estimator and show that it helps to solve the sensitivity problem. We demonstrate that in principle it is possible to identify both the conditional hazard and the distribution of unobservables without assuming parametric functional forms for either. Tradeoffs in assumptions required to secure such model identification are discussed. Although under certain conditions a fully nonparametric model can be identified, the development of a consistent fully nonparametric estimator remains to be done. We also discuss conditions under which access to multiple spell data aids in solving the sensitivity problem. A superficially attractive conditional likelihood approach produces inconsistent estimators, but the practical significance of this inconsistency is not yet known. Conditional inference schemes for eliminating unobservables from multiple spell duration models that are based on sufficient or ancillary statistics require unacceptably strong assumptions about the functional forms of conditional hazards and so are not robust. Contrary to recent claims, they offer no general solution to the model sensitivity problem. The problem of controlling for time inhomogeneous environments (Point (2)) remains to be solved. Failure to control for time inhomogeneity produces serious biases in estimated duration models. Controlling for time inhomogeneity creates a potential identification problem. For a single spell data it is impossible to separate the effect of duration dependence from the effect of time inhomogeneity by a fully nonparametric procedure. Although it is intuitively obvious that access to multiple spell data aids in the solution of this identification problem, the development of precise conditions under which this is possible is a topic left for future research. We demonstrate how sampling schemes distort the functional forms of sample duration distributions away from the population duration distributions that are the usual object of econometric interest (Point (3)). Inference based on misspecified duration distributions is in general biased. New formulae for the densities of commonly used duration measures are produced for duration models with unobservables in time inhomogeneous environments. We show how access to spells that begin after the origin date of a sample aids in solving econometric problems created by the sampling schemes that are used to generate economic duration data. We also discuss new issues that arise in estimating duration models explicitly derived from economic theory (Point (4)). For a prototypical search unemployment model we discuss and resolve new identification problems that arise in attempting to recover structural economic parameters. We also consider nonstandard statistical problems that arise in estimating structural models that are not treated in the literature. Imposing or testing the restrictions implied by economic theory requires duration models that do not appear in the received literature and often requires numerical solution of implicit equations derived from optimizing theory.

Motivated by ecological and genetic phenomena, Karlin and McGregor [3] introduced the following model to describe the continued formation and growth of mutant biological populations. It is assumed that a new mutant population arises at each event time of a stochastic process (referred to as the input process) $\{v(t),t > 0\}$ whose state space is the non-negative integers. Each new mutant population begins its evolution with a fixed number of elements and evolves according to the laws of a continuous time Markov chain $\mathscr{P}$ with stationary transition probability function $P_{i,j}(t)\quad i,j = 0, 1, 2, \cdots; t \geqq 0.$ We assume that all populations evolve according to the same Markov Chain and independent of one another. In terms of this structure, the basic question which we consider in this work can be formulated in the following manner: (A) Given an input process $\{v(t),t > 0\}$ and the individual growing process $\mathscr{P}$, determine the asymptotic behavior as $t \rightarrow \infty$ of the mean and variance of $S(t) = \{$number of different sizes of mutant populations at time $t\}$ and determine the limit distribution as $t \rightarrow \infty$ of $S(t)$ appropriately normalized. $S(t)$ is a special functional of the vector process $N(t) = \{N_0(t), N_1(t), N_2(t), \cdots\}\quad t > 0$ where $N_k(t) = \text{number of mutant populations with exactly} k \text{members at time} t$ and may be interpreted as a measure of the fluctuations in population size. We have restricted our considerations to this special case because it serves as a model problem for more general situations and possesses all the subtle difficulties of the general case. The random variable $S(t)$ can also be identified as the number of distinct occupied states at time $t$ among all Markov Chains which have begun their evolution up to that time. In the subsequent discussion we will refer to $\{S(t), t > 0\}$ as the "occupied states" process generated by the input process $\{v(t),t > 0\}$ and the Markov Chain $\mathscr{P}$. Without loss of generality we identify the state 0 as the initial state of all evolving Markov Chains and $-1$ as an absorbing state if absorption is possible. In this paper we introduce "occupied states" processes generated by a class of null recurrent, transient, and absorbing barrier Birth and Death processes and a Poisson input process. The special feature of this class is that with the normalization $Y(t;u) = t^{-1} X(t^\alpha u),\quad\alpha > 0$ $(\{X(t), t > 0\}$ is the growing process $\mathscr{P}$), the process $Y(t;u)$ converges weakly in the Markov sense as $t \rightarrow \infty$ to a Bessel diffusion (see C. Stone [8]). The main idea (also applicable to more general growing processes $\mathscr{P}$ is that one requires local limit theorems, and under some circumstances, specification of the rate of convergence of the transition density of $Y(t;u)$ to the density of the limiting diffusion in order to prescribe exact asymptotic formulas for $ES(t)$ and $\operatorname{Var} S(t)$ and to prove a central limit theorem for $S(t)$. The results of this paper are in sharp contrast with the asymptotic formulas for $ES(t)$ and $\operatorname{Var} S(t)$ which appear in the companion paper [6], where the growing process $\mathscr{P}$ is a general positive recurrent Markov chain and the input process remains Poisson. Section 2 contains basic definitions, some intuitive discussion, and precise statements of the main results on asymptotic behavior of $ES(t)$ and $\operatorname{Var} S(t)$. In Section 3, we present detailed proofs of the theorems of Section 2, and we conclude with a central limit theorem for $S(t)$ in Section 4. The appendix contains some technical lemmas which are essential for asymptotic formulas that incorporate speed of convergence theorems.

We treat a model describing the continued formation and growth of mutant biological populations. At each transition time of a Poisson process a new mutant population begins its evolution with a fixed number of elements and evolves according to the laws of a continuous time positive recurrent Markov Chain $Y(t)$ with stationary transition probabilities $P_{ik}(t), i, k = 0,1,2,\cdots, t \geqq 0$. Our principal concern is the asymptotic behavior of moments and of the distribution function of the functional $S(t) = \{$number of different sizes of mutant populations at time $t\}$. When the recurrence time distribution to any state of the Markov Chain $Y(t)$ has a finite second moment, the moments of $S(t)$ and limit behavior of its distribution function are controlled by the stationary measure associated with $Y(t)$. When the second moment of the recurrence time distribution is infinite, then a local limit theorem and speed of convergence estimate for $P_{ik}(t)$ with $k = k(t) \rightarrow \infty, t \rightarrow \infty$ are required to establish asymptotic formulas for moments of $S(t)$.