Evaluation of Scaling Invariance Embedded in Short Time Series

Scaling invariance of time series has been making great contributions in diverse research fields. But how to evaluate scaling exponent from a real-world series is still an open problem. Finite length of time series may induce unacceptable fluctuation and bias to statistical quantities and consequent invalidation of currently used standard methods. In this paper a new concept called correlation-dependent balanced estimation of diffusion entropy is developed to evaluate scale-invariance in very short time series with length . Calculations with specified Hurst exponent values of show that by using the standard central moving average de-trending procedure this method can evaluate the scaling exponents for short time series with ignorable bias () and sharp confidential interval (standard deviation ). Considering the stride series from ten volunteers along an approximate oval path of a specified length, we observe that though the averages and deviations of scaling exponents are close, their evolutionary behaviors display rich patterns. It has potential use in analyzing physiological signals, detecting early warning signals, and so on. As an emphasis, the our core contribution is that by means of the proposed method one can estimate precisely shannon entropy from limited records.     

Safety and immunogenicity of 2-dose heterologous Ad26.ZEBOV,MVA-BN-Filo Ebola vaccination in children and adolescents in Africa: A randomised,placebo-controlled,multicentre Phase II clinical trial

BackgroundReoccurring Ebola outbreaks in West and Central Africa have led to serious illness and death in thousands of adults and children. The objective of this study was to assess safety, tolerability, and immunogenicity of the heterologous 2-dose Ad26.ZEBOV, MVA-BN-Filo vaccination regimen in adolescents and children in Africa.Methods and findingsIn this multicentre, randomised, observer-blind, placebo-controlled Phase II study, 131 adolescents (12 to 17 years old) and 132 children (4 to 11 years old) were enrolled from Eastern and Western Africa and randomised 5:1 to receive study vaccines or placebo. Vaccine groups received intramuscular injections of Ad26.ZEBOV (5 × 10¹⁰ viral particles) and MVA-BN-Filo (1 × 10⁸ infectious units) 28 or 56 days apart; placebo recipients received saline. Primary outcomes were safety and tolerability. Solicited adverse events (AEs) were recorded until 7 days after each vaccination and serious AEs (SAEs) throughout the study. Secondary and exploratory outcomes were humoral immune responses (binding and neutralising Ebola virus [EBOV] glycoprotein [GP]-specific antibodies), up to 1 year after the first dose. Enrolment began on February 26, 2016, and the date of last participant last visit was November 28, 2018. Of the 263 participants enrolled, 217 (109 adolescents, 108 children) received the 2-dose regimen, and 43 (20 adolescents, 23 children) received 2 placebo doses. Median age was 14.0 (range 11 to 17) and 7.0 (range 4 to 11) years for adolescents and children, respectively. Fifty-four percent of the adolescents and 51% of the children were male. All participants were Africans, and, although there was a slight male preponderance overall, the groups were well balanced. No vaccine-related SAEs were reported; solicited AEs were mostly mild/moderate. Twenty-one days post-MVA-BN-Filo vaccination, binding antibody responses against EBOV GP were observed in 100% of vaccinees (106 adolescents, 104 children). Geometric mean concentrations tended to be higher after the 56-day interval (adolescents 13,532 ELISA units [EU]/mL, children 17,388 EU/mL) than the 28-day interval (adolescents 6,993 EU/mL, children 8,007 EU/mL). Humoral responses persisted at least up to Day 365.A limitation of the study is that the follow-up period was limited to 365 days for the majority of the participants, and so it was not possible to determine whether immune responses persisted beyond this time period. Additionally, formal statistical comparisons were not preplanned but were only performed post hoc.ConclusionsThe heterologous 2-dose vaccination was well tolerated in African adolescents and children with no vaccine-related SAEs. All vaccinees displayed anti-EBOV GP antibodies after the 2-dose regimen, with higher responses in the 56-day interval groups. The frequency of pyrexia after vaccine or placebo was higher in children than in adolescents. These data supported the prophylactic indication against EBOV disease in a paediatric population, as licenced in the EU.Trial registrationClinicalTrials.gov {"type":"clinical-trial","attrs":{"text":"NCT02564523","term_id":"NCT02564523"}}NCT02564523.

Zacchaeus Anywaine and co-workers study safety and immunogenicity of an Ebola vaccine among children and adolescents across four African countries.     

A Phase I Double Blind,Placebo-Controlled,Randomized Study of the Safety and Immunogenicity of Electroporated HIV DNA with or without Interleukin 12 in Prime-Boost Combinations with an Ad35 HIV Vaccine in Healthy HIV-Seronegative African Adults

Background

Strategies to enhance the immunogenicity of DNA vaccines in humans include i) co-administration of molecular adjuvants, ii) intramuscular administration followed by in vivo electroporation (IM/EP) and/or iii) boosting with a different vaccine. Combining these strategies provided protection of macaques challenged with SIV; this clinical trial was designed to mimic the vaccine regimen in the SIV study.

Methods

Seventy five healthy, HIV-seronegative adults were enrolled into a phase 1, randomized, double-blind, placebo-controlled trial. Multi-antigenic HIV (HIVMAG) plasmid DNA (pDNA) vaccine alone or co-administered with pDNA encoding human Interleukin 12 (IL-12) (GENEVAX IL-12) given by IM/EP using the TriGrid Delivery System was tested in different prime-boost regimens with recombinant Ad35 HIV vaccine given IM.

Results

All local reactions but one were mild or moderate. Systemic reactions and unsolicited adverse events including laboratory abnormalities did not differ between vaccine and placebo recipients. No serious adverse events (SAEs) were reported. T cell and antibody response rates after HIVMAG (x3) prime—Ad35 (x1) boost were independent of IL-12, while the magnitude of interferon gamma (IFN-γ) ELISPOT responses was highest after HIVMAG (x3) without IL-12. The quality and phenotype of T cell responses shown by intracellular cytokine staining (ICS) were similar between groups. Inhibition of HIV replication by autologous T cells was demonstrated after HIVMAG (x3) prime and was boosted after Ad35. HIV specific antibodies were detected only after Ad35 boost, although there was a priming effect with 3 doses of HIVMAG with or without IL-12. No anti-IL-12 antibodies were detected.

Conclusion

The vaccines were safe, well tolerated and moderately immunogenic. Repeated administration IM/EP was well accepted. An adjuvant effect of co-administered plasmid IL-12 was not detected.

Trial Registration

ClinicalTrials.gov NCT01496989     

Creating an African HIV Clinical Research and Prevention Trials Network: HIV Prevalence,Incidence and Transmission

HIV epidemiology informs prevention trial design and program planning. Nine clinical research centers (CRC) in sub-Saharan Africa conducted HIV observational epidemiology studies in populations at risk for HIV infection as part of an HIV prevention and vaccine trial network. Annual HIV incidence ranged from below 2% to above 10% and varied by CRC and risk group, with rates above 5% observed in Zambian men in an HIV-discordant relationship, Ugandan men from Lake Victoria fishing communities, men who have sex with men, and several cohorts of women. HIV incidence tended to fall after the first three months in the study and over calendar time. Among suspected transmission pairs, 28% of HIV infections were not from the reported partner. Volunteers with high incidence were successfully identified and enrolled into large scale cohort studies. Over a quarter of new cases in couples acquired infection from persons other than the suspected transmitting partner.     

Safety and adherence to intermittent pre-exposure prophylaxis (PrEP) for HIV-1 in African men who have sex with men and female sex workers

Background

Little is known about safety of and adherence to intermittent HIV PrEP regimens, which may be more feasible than daily dosing in some settings. We present safety and adherence data from the first trial of an intermittent PrEP regimen among Kenyan men who have sex with men (MSM) and female sex workers (FSW).

Methods/Principal Findings

MSM and FSW were randomized to daily oral FTC/TDF or placebo, or intermittent (Monday, Friday and within 2 hours after sex, not to exceed one dose per day) oral FTC/TDF or placebo in a 2∶1∶2∶1 ratio; volunteers were followed monthly for 4 months. Adherence was assessed with the medication event monitoring system (MEMS). Sexual activity data were collected via daily text message (SMS) queries and timeline followback interviews with a one-month recall period. Sixty-seven men and 5 women were randomized into the study. Safety was similar among all groups. Median MEMS adherence rates were 83% [IQR: 63–92] for daily dosing and 55% [IQR:28–78] for fixed intermittent dosing (p = 0.003), while adherence to any post-coital doses was 26% [IQR:14–50]. SMS response rates were low, which may have impaired measurement of post-coital dosing adherence. Acceptability of PrEP was high, regardless of dosing regimen.

Conclusions/Significance

Adherence to intermittent dosing regimens, fixed doses, and in particular coitally-dependent doses, may be more difficult than adherence to daily dosing. However, intermittent dosing may still be appropriate for PrEP if intracellular drug levels, which correlate with prevention of HIV acquisition, can be attained with less than daily dosing and if barriers to adherence can be addressed. Additional drug level data, qualitative data on adherence barriers, and better methods to measure sexual activity are necessary to determine whether adherence to post-coital PrEP could be comparable to more standard regimens.

Trial Registration

ClinicalTrials.gov {"type":"clinical-trial","attrs":{"text":"NCT00971230","term_id":"NCT00971230"}}NCT00971230     

Reflooding the Faguibine floodplain system,northern Mali: potential benefits and challenges

The Faguibine system, northern Mali, consists of a series of interconnected floodplains of which the flooded surface area declined from about 1 000 km² in the late 19th century to only some 90 km² in 2010. Flood extent depends on the height of the Niger River flood peak at Diré. Satellite imagery analysis indicated that a phase shift may have occurred in the year 2000, probably as a delayed consequence of the Sahelian drought of the 1970s compounded by the collapse of societal controls on water use during recent civil conflict. An economic evaluation of the system in 2011 showed US$100 000 per year of net income per flooded km² in Lake Faguibine, allowing vulnerable people to practise recession agriculture, to fish and to graze livestock. An intensive investment phase, combined with an approach of rebuilding local governance systems and environmental management capacity, could yield net benefits to the user communities of the order of ten times the maintenance costs, contributing to human well-being. The system is currently threatened by the building of the Fomi Dam in Guinea and by the planned expansion of irrigation upstream. There is also a risk of the return of a prolonged drought linked to the Atlantic multi-decadal oscillation index.     

Reproductive Health Voucher Program and Facility Based Delivery in Informal Settlements in Nairobi: A Longitudinal Analysis

Introduction

In Kenya, the maternal mortality rate had ranged from 328 to 501 deaths per 100,000 live births over the last three decades. To reduce these rates, the government launched in 2006 a means-tested reproductive health output-based approach (OBA) voucher program that covers costs of antenatal care, a facility-based delivery (FBD) and a postnatal visit in prequalified healthcare facilities. This paper investigated whether women who bought the voucher for their index child and had a FBD were more likely to deliver a subsequent child in a facility compared to those who did not buy vouchers.

Methods and Findings

We used population-based cohort data from two Nairobi slums where the voucher program was piloted. We selected mothers of at least two children born between 2006 and 2012 and divided the mothers into two groups: Index-OBA mothers bought the voucher for the index child (N=352), and non-OBA mothers did not buy the voucher during the study period (N=514). The most complete model indicated that the adjusted odds-ratio of FBD of subsequent child when the index child was born in a facility was 3.89 (p<0.05) and 4.73 (p<0.01) in Group 2.

Discussion and Conclusion

The study indicated that the voucher program improved poor women access to FBD. Furthermore, the FBD of an index child appeared to have a persistent effect, as a subsequent child of the same mother was more likely to be born in a facility as well. While women who purchased the voucher have higher odds of delivering their subsequent child in a facility, those odds were smaller than those of the women who did not buy the voucher. However, women who did not buy the voucher were less likely to deliver in a good healthcare facility, negating their possible benefit of facility-based deliveries. Pathways to improve access to FBD to all near poor women are needed.     

Evidence of a Double Burden of Malnutrition in Urban Poor Settings in Nairobi,Kenya

Background

Many low- and middle-income countries are undergoing a nutrition transition associated with rapid social and economic transitions. We explore the coexistence of over and under- nutrition at the neighborhood and household level, in an urban poor setting in Nairobi, Kenya.

Methods

Data were collected in 2010 on a cohort of children aged under five years born between 2006 and 2010. Anthropometric measurements of the children and their mothers were taken. Additionally, dietary intake, physical activity, and anthropometric measurements were collected from a stratified random sample of adults aged 18 years and older through a separate cross-sectional study conducted between 2008 and 2009 in the same setting. Proportions of stunting, underweight, wasting and overweight/obesity were dettermined in children, while proportions of underweight and overweight/obesity were determined in adults.

Results

Of the 3335 children included in the analyses with a total of 6750 visits, 46% (51% boys, 40% girls) were stunted, 11% (13% boys, 9% girls) were underweight, 2.5% (3% boys, 2% girls) were wasted, while 9% of boys and girls were overweight/obese respectively. Among their mothers, 7.5% were underweight while 32% were overweight/obese. A large proportion (43% and 37%%) of overweight and obese mothers respectively had stunted children. Among the 5190 adults included in the analyses, 9% (6% female, 11% male) were underweight, and 22% (35% female, 13% male) were overweight/obese.

Conclusion

The findings confirm an existing double burden of malnutrition in this setting, characterized by a high prevalence of undernutrition particularly stunting early in life, with high levels of overweight/obesity in adulthood, particularly among women. In the context of a rapid increase in urban population, particularly in urban poor settings, this calls for urgent action. Multisectoral action may work best given the complex nature of prevailing circumstances in urban poor settings. Further research is needed to understand the pathways to this coexistence, and to test feasibility and effectiveness of context-specific interventions to curb associated health risks.     

Safety and immunogenicity of 2-dose heterologous Ad26.ZEBOV,MVA-BN-Filo Ebola vaccination in healthy and HIV-infected adults: A randomised,placebo-controlled Phase II clinical trial in Africa

BackgroundWe investigated safety, tolerability, and immunogenicity of the heterologous 2-dose Ebola vaccination regimen in healthy and HIV-infected adults with different intervals between Ebola vaccinations.Methods and findingsIn this randomised, observer-blind, placebo-controlled Phase II trial, 668 healthy 18- to 70-year-olds and 142 HIV-infected 18- to 50-year-olds were enrolled from 1 site in Kenya and 2 sites each in Burkina Faso, Cote d’Ivoire, and Uganda. Participants received intramuscular Ad26.ZEBOV followed by MVA-BN-Filo at 28-, 56-, or 84-day intervals, or saline. Females represented 31.4% of the healthy adult cohort in contrast to 69.7% of the HIV-infected cohort. A subset of healthy adults received booster vaccination with Ad26.ZEBOV or saline at Day 365. Following vaccinations, adverse events (AEs) were collected until 42 days post last vaccination and serious AEs (SAEs) were recorded from signing of the ICF until the end of the study. The primary endpoint was safety, and the secondary endpoint was immunogenicity. Anti-Ebola virus glycoprotein (EBOV GP) binding and neutralising antibodies were measured at baseline and at predefined time points throughout the study.The first participant was enrolled on 9 November 2015, and the date of last participant’s last visit was 12 February 2019. No vaccine-related SAEs and mainly mild-to-moderate AEs were observed among the participants. The most frequent solicited AEs were injection-site pain (local), and fatigue, headache, and myalgia (systemic), respectively. Twenty-one days post-MVA-BN-Filo vaccination, geometric mean concentrations (GMCs) with 95% confidence intervals (CIs) of EBOV GP binding antibodies in healthy adults in 28-, 56-, and 84-day interval groups were 3,085 EU/mL (2,648 to 3,594), 7,518 EU/mL (6,468 to 8,740), and 7,300 EU/mL (5,116 to 10,417), respectively. In HIV-infected adults in 28- and 56-day interval groups, GMCs were 4,207 EU/mL (3,233 to 5,474) and 5,283 EU/mL (4,094 to 6,817), respectively. Antibody responses were observed until Day 365. Ad26.ZEBOV booster vaccination after 1 year induced an anamnestic response.Study limitations include that some healthy adult participants either did not receive dose 2 or received dose 2 outside of their protocol-defined interval and that the follow-up period was limited to 365 days for most participants.ConclusionsAd26.ZEBOV, MVA-BN-Filo vaccination was well tolerated and immunogenic in healthy and HIV-infected African adults. Increasing the interval between vaccinations from 28 to 56 days improved the magnitude of humoral immune responses. Antibody levels persisted to at least 1 year, and Ad26.ZEBOV booster vaccination demonstrated the presence of vaccination-induced immune memory. These data supported the approval by the European Union for prophylaxis against EBOV disease in adults and children ≥1 year of age.Trial registrationClinicalTrials.gov {"type":"clinical-trial","attrs":{"text":"NCT02564523","term_id":"NCT02564523"}}NCT02564523

Houreratou Barry and co-workers report on safety and immunogenicity of an Ebola vaccine in adults across four African countries.