Clinical Research Environment in India: Challenges and Proposed Solutions.

India has compelling need and keen aspirations for indigenous clinical research. Notwithstanding this need and previously reported growth the expected expansion of Indian clinical research has not materialized. We reviewed the scientific literature, lay press reports, and ClinicalTrials.gov data for information and commentary on projections, progress, and impediments associated with clinical trials in India. We also propose targeted solutions to identified challenges. The Indian clinical trial sector grew by (+) 20.3% CAGR (compound annual growth rate) between 2005 and 2010 and contracted by (-) 14.6% CAGR between 2010 and 2013. Phase-1 trials grew by (+) 43.5% CAGR from 2005-2013, phase-2 trials grew by (+) 19.8% CAGR from 2005-2009 and contracted by (-) 12.6% CAGR from 2009-2013, and phase-3 trials grew by (+) 13.0% CAGR from 2005-2010 and contracted by (-) 28.8% CAGR from 2010-2013. This was associated with a slowing of the regulatory approval process, increased media coverage and activist engagement, and accelerated development of regulatory guidelines and recuperative initiatives. We propose the following as potential targets for restorative interventions: Regulatory overhaul (leadership and enforcement of regulations, resolution of ambiguity in regulations, staffing, training, guidelines, and ethical principles [e.g., compensation]).Education and training of research professionals, clinicians, and regulators.Public awareness and empowerment. After a peak in 2009-2010, the clinical research sector in India appears to be experiencing a contraction. There are indications of challenges in regulatory enforcement of guidelines; training of clinical research professionals; and awareness, participation, partnership, and the general image amongst the non-professional media and public. Preventative and corrective principles and interventions are outlined with the goal of realizing the clinical research potential in India.

Distribution, ecology, life history, genetic variation, and risk of extinction of nonhuman primates from Costa Rica

We examined the association between geographic distribution, ecological traits, life history, genetic diversity, and risk of extinction in nonhuman primate species from Costa Rica. All of the current nonhuman primate species from Costa Rica are included in the study; spider monkeys (Ateles geoffroyi), howling monkeys (Alouatta palliata), capuchins (Cebus capucinus), and squirrel monkeys (Saimiri oerstedii). Geographic distribution was characterized accessing existing databases. Data on ecology and life history traits were obtained through a literature review. Genetic diversity was characterized using isozyme electrophoresis. Risk of extinction was assessed from the literature. We found that species differed in all these traits. Using these data, we conducted a Pearson correlation between risk of extinction and ecological and life history traits, and genetic variation, for widely distributed species. We found a negative association between risk of extinction and population birth and growth rates; indicating that slower reproducing species had a greater risk of extinction. We found a positive association between genetic variation and risk of extinction; i.e., species showing higher genetic variation had a greater risk of extinction. The relevance of these traits for conservation efforts is discussed.

Contracting Freedom: Governance and East Indian Indenture in the British Atlantic, 1838-1917

This is a dissertation about identity and governance, and how they are mutually constituted. Between 1838 and 1917, the British brought approximately half a million East Indian laborers to the Atlantic to work on sugar plantations. The dissertation argues that contrary to previous historiographical assumptions, indentured East Indians were an amorphous mass of people drawn from various regions of British India. They were brought together not by their innate "Indian-ness" upon their arrival in the Caribbean, but by the common experience of indenture recruitment, transportation and plantation life. Ideas of innate "Indian-ness" were products of an imperial discourse that emerged from and shaped official approaches to governing East Indians in the Atlantic. Government officials and planters promoted visions of East Indians as "primitive" subjects who engaged in child marriage and wife murder. Officials mobilized ideas about gender to sustain racialized stereotypes of East Indian subjects. East Indian women were thought to be promiscuous, and East Indian men were violent and depraved (especially in response to East Indian women's promiscuity). By pointing to these stereotypes about East Indians, government officials and planters could highlight the promise of indenture as a civilizing mechanism. This dissertation links the study of governance and subject formation to complicate ideas of colonial rule as static. It uncovers how colonial processes evolved to handle the challenges posed by migrant populations.

The primary architects of indenture, Caribbean governments, the British Colonial Office, and planters hoped that East Indian indentured laborers would form a stable and easily-governed labor force. They anticipated that the presence of these laborers would undermine the demands of Afro-Creole workers for higher wages and shorter working hours. Indenture, however, was controversial among British liberals who saw it as potentially hindering the creation of a free labor market, and abolitionists who also feared that indenture was a new form of slavery. Using court records, newspapers, legislative documents, bureaucratic correspondence, memoirs, novels, and travel accounts from archives and libraries in Britain, Guyana, and Trinidad and Tobago, this dissertation explores how indenture was envisioned and constantly re-envisioned in response to its critics. It chronicles how the struggles between the planter class and the colonial state for authority over indentured laborers affected the way that indenture functioned in the British Atlantic. In addition to focusing on indenture's official origins, this dissertation examines the actions of East Indian indentured subjects as they are recorded in the imperial archive to explore how these people experienced indenture.

Indenture contracts were central to the justification of indenture and to the creation of a pliable labor force in the Atlantic. According to English common law, only free parties could enter into contracts. Indenture contracts limited the period of indenture and affirmed that laborers would be remunerated for their labor. While the architects of indenture pointed to contracts as evidence that indenture was not slavery, contracts in reality prevented laborers from participating in the free labor market and kept the wages of indentured laborers low. Further, in late nineteenth-century Britain, contracts were civil matters. In the British Atlantic, indentured laborers who violated the terms of their contracts faced criminal trials and their associated punishments such as imprisonment and hard labor. Officials used indenture contracts to exploit the labor and limit the mobility of indentured laborers in a manner that was reminiscent of slavery but that instead established indentured laborers as subjects with limited rights. The dissertation chronicles how indenture contracts spawned a complex inter-imperial bureaucracy in British India, Britain, and the Caribbean that was responsible for the transportation and governance of East Indian indentured laborers overseas.

Two Antarctic penguin genomes reveal insights into their evolutionary history and molecular changes related to the Antarctic environment.

BACKGROUND: Penguins are flightless aquatic birds widely distributed in the Southern Hemisphere. The distinctive morphological and physiological features of penguins allow them to live an aquatic life, and some of them have successfully adapted to the hostile environments in Antarctica. To study the phylogenetic and population history of penguins and the molecular basis of their adaptations to Antarctica, we sequenced the genomes of the two Antarctic dwelling penguin species, the Adélie penguin [Pygoscelis adeliae] and emperor penguin [Aptenodytes forsteri]. RESULTS: Phylogenetic dating suggests that early penguins arose ~60 million years ago, coinciding with a period of global warming. Analysis of effective population sizes reveals that the two penguin species experienced population expansions from ~1 million years ago to ~100 thousand years ago, but responded differently to the climatic cooling of the last glacial period. Comparative genomic analyses with other available avian genomes identified molecular changes in genes related to epidermal structure, phototransduction, lipid metabolism, and forelimb morphology. CONCLUSIONS: Our sequencing and initial analyses of the first two penguin genomes provide insights into the timing of penguin origin, fluctuations in effective population sizes of the two penguin species over the past 10 million years, and the potential associations between these biological patterns and global climate change. The molecular changes compared with other avian genomes reflect both shared and diverse adaptations of the two penguin species to the Antarctic environment.

Child work and labour among orphaned and abandoned children in five low and middle income countries.

BACKGROUND: The care and protection of the estimated 143,000,000 orphaned and abandoned children (OAC) worldwide is of great importance to global policy makers and child service providers in low and middle income countries (LMICs), yet little is known about rates of child labour among OAC, what child and caregiver characteristics predict child engagement in work and labour, or when such work infers with schooling. This study examines rates and correlates of child labour among OAC and associations of child labour with schooling in a cohort of OAC in 5 LMICs. METHODS: The Positive Outcomes for Orphans (POFO) study employed a two-stage random sampling survey methodology to identify 1480 single and double orphans and children abandoned by both parents ages 6-12 living in family settings in five LMICs: Cambodia, Ethiopia, India, Kenya, and Tanzania. Regression models examined child and caregiver associations with: any work versus no work; and with working <21, 21-27, and 28+ hours during the past week, and child labour (UNICEF definition). RESULTS: The majority of OAC (60.7%) engaged in work during the past week, and of those who worked, 17.8% (10.5% of the total sample) worked 28 or more hours. More than one-fifth (21.9%; 13% of the total sample) met UNICEF's child labour definition. Female OAC and those in good health had increased odds of working. OAC living in rural areas, lower household wealth and caregivers not earning an income were associated with increased child labour. Child labour, but not working fewer than 28 hours per week, was associated with decreased school attendance. CONCLUSIONS: One in seven OAC in this study were reported to be engaged in child labour. Policy makers and social service providers need to pay close attention to the demands being placed on female OAC, particularly in rural areas and poor households with limited income sources. Programs to promote OAC school attendance may need to focus on the needs of families as well as the OAC.

Correlates of poor health among orphans and abandoned children in less wealthy countries: the importance of caregiver health.

BACKGROUND: More than 153 million children worldwide have been orphaned by the loss of one or both parents, and millions more have been abandoned. We investigated relationships between the health of orphaned and abandoned children (OAC) and child, caregiver, and household characteristics among randomly selected OAC in five countries. METHODOLOGY: Using a two-stage random sampling strategy in 6 study areas in Cambodia, Ethiopia, India, Kenya, and Tanzania, the Positive Outcomes for Orphans (POFO) study identified 1,480 community-living OAC ages 6 to 12. Detailed interviews were conducted with 1,305 primary caregivers at baseline and after 6 and 12 months. Multivariable logistic regression models describe associations between the characteristics of children, caregivers, and households and child health outcomes: fair or poor child health; fever, cough, or diarrhea within the past two weeks; illness in the past 6 months; and fair or poor health on at least two assessments. PRINCIPAL FINDINGS: Across the six study areas, 23% of OAC were reported to be in fair or poor health; 19%, 18%, and 2% had fever, cough, or diarrhea, respectively, within the past two weeks; 55% had illnesses within the past 6 months; and 23% were in fair or poor health on at least two assessments. Female gender, suspected HIV infection, experiences of potentially traumatic events, including the loss of both parents, urban residence, eating fewer than 3 meals per day, and low caregiver involvement were associated with poorer child health outcomes. Particularly strong associations were observed between child health measures and the health of their primary caregivers. CONCLUSIONS: Poor caregiver health is a strong signal for poor health of OAC. Strategies to support OAC should target the caregiver-child dyad. Steps to ensure food security, foster gender equality, and prevent and treat traumatic events are needed.

Victims of infanticide and conspecific bite wounding in a female-dominant primate: a long-term study.

The aggression animals receive from conspecifics varies between individuals across their lifetime. As poignantly evidenced by infanticide, for example, aggression can have dramatic fitness consequences. Nevertheless, we understand little about the sources of variation in received aggression, particularly in females. Using a female-dominant species renowned for aggressivity in both sexes, we tested for potential social, demographic, and genetic patterns in the frequency with which animals were wounded by conspecifics. Our study included 243 captive, ring-tailed lemurs (Lemur catta), followed from infancy to adulthood over a 35-year time span. We extracted injury, social, and life-history information from colony records and calculated neutral heterozygosity for a subset of animals, as an estimate of genetic diversity. Focusing on victims rather than aggressors, we used General Linear Models to explain bite-wound patterns at different life stages. In infancy, maternal age best predicted wounds received, as infants born to young mothers were the most frequent infanticide victims. In adulthood, sex best predicted wounds received, as males were three times more likely than females to be seriously injured. No relation emerged between wounds received and the other variables studied. Beyond the generally expected costs of adult male intrasexual aggression, we suggest possible additive costs associated with female-dominant societies - those suffered by young mothers engaged in aggressive disputes and those suffered by adult males aggressively targeted by both sexes. We propose that infanticide in lemurs may be a costly by-product of aggressively mediated, female social dominance. Accordingly, the benefits of female behavioral 'masculinization' accrued to females through priority of access to resources, may be partially offset by early costs in reproductive success. Understanding the factors that influence lifetime patterns of conspecific wounding is critical to evaluating the fitness costs associated with social living; however, these costs may vary substantially between societies.

Elucidation of hepatitis C virus transmission and early diversification by single genome sequencing.

A precise molecular identification of transmitted hepatitis C virus (HCV) genomes could illuminate key aspects of transmission biology, immunopathogenesis and natural history. We used single genome sequencing of 2,922 half or quarter genomes from plasma viral RNA to identify transmitted/founder (T/F) viruses in 17 subjects with acute community-acquired HCV infection. Sequences from 13 of 17 acute subjects, but none of 14 chronic controls, exhibited one or more discrete low diversity viral lineages. Sequences within each lineage generally revealed a star-like phylogeny of mutations that coalesced to unambiguous T/F viral genomes. Numbers of transmitted viruses leading to productive clinical infection were estimated to range from 1 to 37 or more (median = 4). Four acutely infected subjects showed a distinctly different pattern of virus diversity that deviated from a star-like phylogeny. In these cases, empirical analysis and mathematical modeling suggested high multiplicity virus transmission from individuals who themselves were acutely infected or had experienced a virus population bottleneck due to antiviral drug therapy. These results provide new quantitative and qualitative insights into HCV transmission, revealing for the first time virus-host interactions that successful vaccines or treatment interventions will need to overcome. Our findings further suggest a novel experimental strategy for identifying full-length T/F genomes for proteome-wide analyses of HCV biology and adaptation to antiviral drug or immune pressures.