Genesis and pathogenesis of the 1918 pandemic H1N1 influenza A virus

The source, timing, and geographical origin of the 1918–1920 pandemic influenza A virus have remained tenaciously obscure for nearly a century, as have the reasons for its unusual severity among young adults. Here, we reconstruct the origins of the pandemic virus and the classic swine influenza and (postpandemic) seasonal H1N1 lineages using a host-specific molecular clock approach that is demonstrably more accurate than previous methods. Our results suggest that the 1918 pandemic virus originated shortly before 1918 when a human H1 virus, which we infer emerged before ∼1907, acquired avian N1 neuraminidase and internal protein genes. We find that the resulting pandemic virus jumped directly to swine but was likely displaced in humans by ∼1922 by a reassortant with an antigenically distinct H1 HA. Hence, although the swine lineage was a direct descendent of the pandemic virus, the post-1918 seasonal H1N1 lineage evidently was not, at least for HA. These findings help resolve several seemingly disparate observations from 20th century influenza epidemiology, seroarcheology, and immunology. The phylogenetic results, combined with these other lines of evidence, suggest that the highmortality in 1918 among adults aged ∼20 to ∼40 y may have been due primarily to their childhood exposure to a doubly heterosubtypic putative H3N8 virus, which we estimate circulated from ∼1889–1900. All other age groups (except immunologically naive infants) were likely partially protected by childhood exposure to N1 and/or H1-related antigens. Similar processes may underlie age-specific mortality differences between seasonal H1N1 vs. H3N2 and human H5N1 vs. H7N9 infections

'It is like a tomato stall where someone can pick what he likes': structure and practices of female sex work in Kampala, Uganda.

BACKGROUND: Effective interventions among female sex workers require a thorough knowledge of the context of local sex industries. We explore the organisation of female sex work in a low socio-economic setting in Kampala, Uganda. METHODS: We conducted a qualitative study with 101 participants selected from an epidemiological cohort of 1027 women at high risk of HIV in Kampala. Repeat in-depth life history and work practice interviews were conducted from March 2010 to June 2011. Context specific factors of female sex workers' day-to-day lives were captured. Reported themes were identified and categorised inductively. RESULTS: Of the 101 women, 58 were active self-identified sex workers operating in different locations within the area of study and nine had quit sex work. This paper focuses on these 67 women who gave information about their involvement in sex work. The majority had not gone beyond primary level of education and all had at least one child. Thirty one voluntarily disclosed that they were HIV-positive. Common sex work locations were streets/roadsides, bars and night clubs. Typically sex occurred in lodges near bars/night clubs, dark alleyways or car parking lots. Overall, women experienced sex work-related challenges at their work locations but these were more apparent in outdoor settings. These settings exposed women to violence, visibility to police, a stigmatising public as well as competition for clients, while bars provided some protection from these challenges. Older sex workers tended to prefer bars while the younger ones were mostly based on the streets. Alcohol consumption was a feature in all locations and women said it gave them courage and helped them to withstand the night chill. Condom use was determined by clients' willingness, a woman's level of sobriety or price offered. CONCLUSIONS: Sex work operates across a variety of locations in the study area in Kampala, with each presenting different strategies and challenges for those operating there. Risky practices are present in all locations although they are higher on the streets compared to other locations. Location specific interventions are required to address the complex challenges in sex work environments

Evaluation design of a systematic, selective, internet-based, Chlamydia screening implementation in the Netherlands, 2008-2010: implications of first results for the analysis

A selective, systematic, Internet-based, Chlamydia Screening Implementation for 16 to 29-year-old residents started in three regions in the Netherlands in April 2008: in the cities of Amsterdam and Rotterdam and a more rural region, South Limburg. This paper describes the evaluation design and discusses the implications of the findings from the first screening round for the analysis. The evaluation aims to determine the effects of screening on the population prevalence of Chlamydia trachomatis after multiple screening rounds. A phased implementation or 'stepped wedge design' was applied by grouping neighbourhoods (hereafter: clusters) into three random, risk-stratified blocks (A, B and C) to allow for impact analyses over time and comparison of prevalences before and after one or two screening rounds. Repeated simulation of pre- and postscreening Chlamydia prevalences was used to predict the minimum detectable decline in prevalence. Real participation and positivity rates per region, block, and risk stratum (high, medium, and low community risk) from the 1st year of screening were used to substantiate predictions. The results of the 1st year show an overall participation rate of 16% of 261,025 invitees and a positivity rate of 4.2%, with significant differences between regions and blocks. Prediction by simulation methods adjusted with the first-round results indicate that the effect of screening (minimal detectable difference in prevalence) may reach significance levels only if at least a 15% decrease in the Chlamydia positivity rate in the cities and a 25% decrease in the rural region after screening can be reached, and pre- and postscreening differences between blocks need to be larger. With the current participation rates, the minimal detectable decline of Chlamydia prevalence may reach our defined significance levels at the regional level after the second screening round, but will probably not be significant between blocks of the stepped wedge design. Evaluation will also include other aspects and prediction models to obtain rational advice about future Chlamydia screening in the Netherland

Reproductive health services for populations at high risk of HIV: Performance of a night clinic in Tete province, Mozambique

<p>Abstract</p> <p>Background</p> <p>Different models exist to provide HIV/STI services for most-at-risk populations (MARP). Along the Tete traffic corridor in Mozambique, linking Malawi and Zimbabwe, a night clinic opening between 4 and 10 PM was established targeting female sex workers (FSW) and long-distance truck drivers (LDD). The clinic offers free individual education and counselling, condoms, STI care, HIV testing, contraceptive services and outreach peer education. To evaluate this clinic model, we assessed relevance, service utilisation, efficiency and sustainability.</p> <p>Methods</p> <p>In 2007-2009, mapping and enumeration of FSW and LDD was conducted; 28 key informants were interviewed; 6 focus group discussions (FGD) were held with FSW from Mozambique and Zimbabwe, and LDD from Mozambique and Malawi. Clinic outputs and costs were analysed.</p> <p>Results</p> <p>An estimated 4,415 FSW work in the area, or 9% of women aged 15-49, and on average 66 trucks stay overnight near the clinic. Currently on average, 475 clients/month visit the clinic (43% for contraception, 24% for counselling and testing and 23% for STI care). The average clinic running cost is US$ 1408/month, mostly for human resources. All informants endorsed this clinic concept and the need to expand the services. FGD participants reported high satisfaction with the services and mentioned good reception by the health staff, short waiting times, proximity and free services as most important. Participants were in favour of expanding the range of services, the geographical coverage and the opening times.</p> <p>Conclusions</p> <p>Size of the target population, satisfaction of clients and endorsement by health policy makers justify maintaining a separate clinic for MARP. Cost-effectiveness may be enhanced by broadening the range of SRHR-HIV/AIDS services, adapting opening times, expanding geographical coverage and targeting additional MARP. Long-term sustainability remains challenging and requires private-public partnerships or continued project-based funding.</p

"One country, two systems": Sociopolitical implications for female migrant sex workers in Hong Kong

<p>Abstract</p> <p>Background</p> <p>Under the "two countries, one system" policy implemented by China to manage the return of Hong Kong's sovereignty, Hong Kong has maintained a comparatively prosperous economy within the Asian region. This has resulted in an environment which fosters migration from the mainland to Hong Kong, due largely to proximity, higher earning potential, common language, and a relaxing of border control measures. However not all mainland China citizens are equally able to access these new migration schemes and indeed a number of women such as sex workers are either migrating and/or working illegally and without occupational, legal and health protection within Hong Kong.</p> <p>Discussion</p> <p>Female migrant sex workers are exposed to a number of significant threats to their health, however their illegal status contributes to even greater vulnerability. The prevailing discourses which view these women as either "trafficked women" or as "illegal immigrants" do not adequately account for the complex situations which result in such women's employment in Hong Kong's sex industry. Rather, their position can best be understood within the broader frameworks provided by migration literature and the concept of "structural violence". This allows for a greater understanding of the socio-political issues which are systematically denying migrant sex workers adequate access to health care and other opportunities for social advancement. When these issues are taken into account, it becomes clear that the current relevant legislation regarding both immigration and sex work is perpetuating the marginalised and vulnerable status of migrant sex workers. Unless changes are made, structural barriers will remain in place which impede the ability of migrant sex workers to manage their own health needs and status.</p> <p>Conclusion</p> <p>Female migrant sex workers in Hong Kong are extremely vulnerable to a number of occupational health and safety hazards which have significantly detrimental effects on their health. These risks can best be understood within a broad framework of socio-political factors contributing to their vulnerability. Ensuring that migrant sex workers have adequate support for their health and legal rights requires require structural interventions such as decriminalisation and providing open and inclusive access to health service to counteract such factors.</p

Impaired Sprouting and Axonal Atrophy in Cerebellar Climbing Fibres following In Vivo Silencing of the Growth-Associated Protein GAP-43

The adult mammalian central nervous system has a limited ability to establish new connections and to recover from traumatic or degenerative events. The olivo-cerebellar network represents an excellent model to investigate neuroprotection and repair in the brain during adulthood, due to its high plasticity and ordered synaptic organization. To shed light on the molecular mechanisms involved in these events, we focused on the growth-associated protein GAP-43 (also known as B-50 or neuromodulin). During development, this protein plays a crucial role in growth and in branch formation of neurites, while in the adult it is only expressed in a few brain regions, including the inferior olive (IO) where climbing fibres (CFs) originate. Following axotomy GAP-43 is usually up-regulated in association with regeneration. Here we describe an in vivo lentiviral-mediated gene silencing approach, used for the first time in the olivo-cerebellar system, to efficiently and specifically downregulate GAP-43 in rodents CFs. We show that lack of GAP-43 causes an atrophy of the CF in non-traumatic conditions, consisting in a decrease of its length, branching and number of synaptic boutons. We also investigated CF regenerative ability by inducing a subtotal lesion of the IO. Noteworthy, surviving CFs lacking GAP-43 were largely unable to sprout on surrounding Purkinje cells. Collectively, our results demonstrate that GAP-43 is essential both to maintain CFs structure in non-traumatic condition and to promote sprouting after partial lesion of the IO

Perceived control over condom use among sex workers in Madagascar: a cohort study

<p>Abstract</p> <p>Background</p> <p>Women's perceived control over condom use has been found to be an important determinant of actual condom use in some studies. However, many existing analyses used cross-sectional data and little quantitative information exists to characterize the relationships between perceived control and actual condom use among sex worker populations.</p> <p>Methods</p> <p>We assessed the association between measures of perceived condom use control and self-reported use of male condoms employing data from a longitudinal pilot study among 192 sex workers in Madagascar.</p> <p>Results</p> <p>In multivariable models, a lack of perceived control over condom use with a main partner and having a main partner ever refuse to use a condom when asked were both associated with an increased number of sex acts unprotected by condoms in the past week with a main partner (RR 1.86; 95% CI 1.21-2.85; RR 1.34; 95% CI 1.03-1.73, respectively). Conversely, no measure of condom use control was significantly associated with condom use with clients.</p> <p>Conclusion</p> <p>Perceived control over condom use was an important determinant of condom use with main partners, but not clients, among sex workers in Madagascar. Programs working with sex workers should reach out to main and commercial partners of sex workers to increase male condom use.</p

Cost-Effectiveness of an Intervention to Reduce HIV/STI Incidence and Promote Condom Use among Female Sex Workers in the Mexico–US Border Region

Previous research demonstrated efficacy of a brief behavioral intervention to reduce incidence of HIV and sexually transmitted infections (STIs) among female sex workers (FSWs) in Tijuana and Ciudad Juarez, Mexico, cities on Mexico's border with the US. We assessed this intervention's cost-effectiveness.A life-time Markov model was developed to estimate HIV cases prevented, changes in quality-adjusted life expectancy (QALE), and costs per additional quality-adjusted life year gained (QALY), comparing (in US$2,009) no intervention to a once-only and annual intervention. Future costs and health benefits were discounted annually at 3$183. For FSWs receiving the intervention annually, there were 29 additional HIV cases prevented and 4.5 additional months of QALE compared to the once-only intervention. The additional cost per QALY was US$1,075. When highly active antiretroviral therapy (HAART) was included in the model, the annual intervention strategy resulted in net savings and dominated both once-only and no intervention strategies, and remained robust across extensive sensitivity analyses. Even when considering clinical benefits from HAART, ignoring added costs, the cost per QALY gained remained below three times the Mexican GDP per capita, and below established cost-effectiveness thresholds.This brief intervention was shown to be cost-effective among FSWs in two Mexico-US border cities and may have application for FSWs in other resource-limited settings.ClinicalTrials.gov NCT00338845

Self-Organized Criticality in Developing Neuronal Networks

Recently evidence has accumulated that many neural networks exhibit self-organized criticality. In this state, activity is similar across temporal scales and this is beneficial with respect to information flow. If subcritical, activity can die out, if supercritical epileptiform patterns may occur. Little is known about how developing networks will reach and stabilize criticality. Here we monitor the development between 13 and 95 days in vitro (DIV) of cortical cell cultures (n = 20) and find four different phases, related to their morphological maturation: An initial low-activity state (≈19 DIV) is followed by a supercritical (≈20 DIV) and then a subcritical one (≈36 DIV) until the network finally reaches stable criticality (≈58 DIV). Using network modeling and mathematical analysis we describe the dynamics of the emergent connectivity in such developing systems. Based on physiological observations, the synaptic development in the model is determined by the drive of the neurons to adjust their connectivity for reaching on average firing rate homeostasis. We predict a specific time course for the maturation of inhibition, with strong onset and delayed pruning, and that total synaptic connectivity should be strongly linked to the relative levels of excitation and inhibition. These results demonstrate that the interplay between activity and connectivity guides developing networks into criticality suggesting that this may be a generic and stable state of many networks in vivo and in vitro