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Abstract Background Zoonotic transmission of simian retroviruses in Central Africa is ongoing and can result in pandemic human infection. While simian foamy virus (SFV) infection was reported in primate hunters in Cameroon and Gabon, little is known about the distribution of SFV in Africa and whether human-to-human transmission and disease occur. We screened 3,334 plasmas from persons living in rural villages in central Democratic Republic of Congo (DRC) using SFV-specific EIA and Western blot (WB) tests. PCR amplification of SFV polymerase sequences from DNA extracted from buffy coats was used to measure proviral loads. Phylogenetic analysis was used to define the NHP species origin of SFV. Participants completed questionnaires to capture NHP exposure information. Results Sixteen (0.5%) samples were WB-positive; 12 of 16 were from women (75%, 95% confidence limits 47.6%, 92.7%). Sequence analysis detected SFV in three women originating from Angolan colobus or red-tailed monkeys; both monkeys are hunted frequently in DRC. NHP exposure varied and infected women lived in distant villages suggesting a wide and potentially diverse distribution of SFV infections across DRC. Plasmas from 22 contacts of 8 WB-positive participants were all WB negative suggesting no secondary viral transmission. Proviral loads in the three women ranged from 14 – 1,755 copies/105 cells. Conclusions Our study documents SFV infection in rural DRC for the first time and identifies infections with novel SFV variants from Colobus and red-tailed monkeys. Unlike previous studies, women were not at lower risk for SFV infection in our population, providing opportunities for spread of SFV both horizontally and vertically. However, limited testing of close contacts of WB-positive persons did not identify human-to-human transmission. Combined with the broad behavioral risk and distribution of NHPs across DRC, our results suggest that SFV infection may have a wider geographic distribution within DRC. These results also reinforce the potential for an increased SFV prevalence throughout the forested regions of Africa where humans and simians co-exist. Our finding of endemic foci of SFV infection in DRC will facilitate longitudinal studies to determine the potential for person-to-person transmissibility and pathogenicity of these zoonotic retroviral infections.

Abstract Background Preterm birth is a major cause of neonatal mortality, responsible for 28% of neonatal deaths overall. The administration of antenatal corticosteroids to women at high risk of preterm birth is a powerful perinatal intervention to reduce neonatal mortality in resource rich environments. The effect of antenatal steroids to reduce mortality and morbidity among preterm infants in hospital settings in developed countries with high utilization is well established, yet they are not routinely used in developing countries. The impact of increasing antenatal steroid use in hospital or community settings with low utilization rates and high infant mortality among premature infants due to lack of specialized services has not been well researched. There is currently no clear evidence about the safety of antenatal corticosteroid use for community-level births. Methods We hypothesize that a multi country, two-arm, parallel cluster randomized controlled trial to evaluate whether a multifaceted intervention to increase the use of antenatal corticosteroids, including components to improve the identification of pregnancies at high risk of preterm birth and providing and facilitating the appropriate use of steroids, will reduce neonatal mortality at 28 days of life in preterm newborns, compared with the standard delivery of care in selected populations of six countries. 102 clusters in Argentina, Guatemala, Kenya, India, Pakistan, and Zambia will be randomized, and around 60,000 women and newborns will be enrolled. Kits containing vials of dexamethasone, syringes, gloves, and instructions for administration will be distributed. Improving the identification of women at high risk of preterm birth will be done by (1) diffusing recommendations for antenatal corticosteroids use to health providers, (2) training health providers on identification of women at high risk of preterm birth, (3) providing reminders to health providers on the use of the kits, and (4) using a color-coded tape to measure uterine height to estimate gestational age in women with unknown gestational age. In both intervention and control clusters, health providers will be trained in essential newborn care for low birth weight babies. The primary outcome is neonatal mortality at 28 days of life in preterm infants. Trial registration ClinicalTrials.gov. Identifier: NCT01084096

Abstract Background Nearly half the world’s babies are born at home. We sought to evaluate the training, knowledge, skills, and access to medical equipment and testing for home birth attendants across 7 international sites. Methods Face-to-face interviews were done by trained interviewers to assess level of training, knowledge and practices regarding care during the antenatal, intrapartum and postpartum periods. The survey was administered to a sample of birth attendants conducting home or out-of-facility deliveries in 7 sites in 6 countries (India, Pakistan, Guatemala, Democratic Republic of the Congo, Kenya and Zambia). Results A total of 1226 home birth attendants were surveyed. Less than half the birth attendants were literate. Eighty percent had one month or less of formal training. Most home birth attendants did not have basic equipment (e.g., blood pressure apparatus, stethoscope, infant bag and mask manual resuscitator). Reporting of births and maternal and neonatal deaths to government agencies was low. Indian auxilliary nurse midwives, who perform some home but mainly clinic births, were far better trained and differed in many characteristics from the birth attendants who only performed deliveries at home. Conclusions Home birth attendants in low-income countries were often illiterate, could not read numbers and had little formal training. Most had few of the skills or access to tests, medications and equipment that are necessary to reduce maternal, fetal or neonatal mortality.

Abstract Background Because of a physician shortage in many low-income countries, the use of nonphysicians to classify perinatal mortality (stillbirth and early neonatal death) using verbal autopsy could be useful. Objective To determine the extent to which underlying perinatal causes of deaths assigned by nonphysicians in Guatemala, Pakistan, Zambia, and the Democratic Republic of the Congo using a verbal autopsy method are concordant with underlying perinatal cause of death assigned by physician panels. Methods Using a train-the-trainer model, 13 physicians and 40 nonphysicians were trained to determine cause of death using a standardized verbal autopsy training program. Subsequently, panels of two physicians and individual nonphysicians from this trained cohort independently reviewed verbal autopsy data from a sample of 118 early neonatal deaths and 134 stillbirths. With the cause of death assigned by the physician panel as the reference standard, sensitivity, specificity, positive and negative predictive values, and cause-specific mortality fractions were calculated to assess nonphysicians' coding responses. Robustness criteria to assess how well nonphysicians performed were used. Results Causes of early neonatal death and stillbirth assigned by nonphysicians were concordant with physician-assigned causes 47% and 57% of the time, respectively. Tetanus filled robustness criteria for early neonatal death, and cord prolapse filled robustness criteria for stillbirth. Conclusions There are significant differences in underlying cause of death as determined by physicians and nonphysicians even when they receive similar training in cause of death determination. Currently, it does not appear that nonphysicians can be used reliably to assign underlying cause of perinatal death using verbal autopsy.

Abstract Background In many developing countries, the majority of births are attended by traditional birth attendants, who lack formal training in neonatal resuscitation and other essential care required by the newly born infant. In these countries, the major causes of neonatal mortality are birth asphyxia, infection, and low-birth-weight/prematurity. Death from these causes is potentially modifiable using low-cost interventions, including neonatal resuscitation training. The purpose of this study was to evaluate the effect on perinatal mortality of training birth attendants in a rural area of the Democratic Republic of Congo (DRC) using two established programs. Methods This study, a secondary analysis of DRC-specific data collected during a multi-country study, was conducted in two phases. The effect of training using the WHO Essential Newborn Care (ENC) program was evaluated using an active baseline design, followed by a cluster randomized trial of training using an adaptation of a neonatal resuscitation program (NRP). The perinatal mortality rates before ENC, after ENC training, and after randomization to additional NRP training or continued care were compared. In addition, the influence of time following resuscitation training was investigated by examining change in perinatal mortality during sequential three-month increments following ENC training. Results More than two-thirds of deliveries were attended by traditional birth attendants and occurred in homes; these proportions decreased after ENC training. There was no apparent decline in perinatal mortality when the outcome of all deliveries prior to ENC training was compared to those after ENC but before NRP training. However, there was a gradual but significant decline in perinatal mortality during the year following ENC training (RR 0.73; 95% CI: 0.56-0.96), which was independently associated with time following training. The decline was attributable to a decline in early neonatal mortality. NRP training had no demonstrable effect on early neonatal mortality. Conclusion Training DRC birth attendants using the ENC program reduces perinatal mortality. However, a period of utilization and re-enforcement of training may be necessary before a decline in mortality occurs. ENC training has the potential to be a low cost, high impact intervention in developing countries. Trial registration This trial has been registered at http://www.clinicaltrials.gov (identifier NCT00136708).

Abstract Background In many malaria-endemic countries, increasing resistance may soon compromise the efficacy of sulphadoxine-pyrimethamine (SP) for intermittent preventative treatment (IPT) of malaria in pregnancy. Artemisinin-based IPT regimens represent a promising potential alternative to SP. Pharmacokinetic and safety data supporting the use of artemisinin derivatives in pregnancy are urgently needed. Methods Subjects included pregnant women with asymptomatic falciparum parasitaemia between 22-26 weeks (n = 13) or 32-36 weeks gestation (n = 13), the same women at three months postpartum, and 25 non-pregnant parasitaemic controls. All subjects received 200 mg orally administered AS. Plasma total and free levels of AS and its active metabolite DHA were determined using a validated LC-MS method. Non-compartmental pharmacokinetic analysis was performed using standard methods. Results All pregnant women delivered live babies. The median birth weight was 3025 grams [range 2130, 3620]; 2 of 26 babies had birth weights less than 2500 grams. Rates of parasite clearance by 12 hours post-dose were high and comparable among the groups. Rapid elimination of AS was observed in all three groups. The 90% CI for the pregnancy:postpartum ratio of geometric means for total and free AUC fell within the pre-specified 0.66 - 1.50 therapeutic equivalence interval. However, more pronounced pharmacokinetic differences were observed between the pregnancy and control subjects, with the 90% CI for the pregnancy:control ratio of geometric means for both total 0.68 (90% CI 0.57-0.81) and free AUC 0.78 (90% CI 0.63-0.95) not fully contained within the 0.66 - 1.50 interval. All subjects cleared parasites rapidly, and there was no difference in the percentage of women who were parasitaemic 12 hours after dosing. Conclusions A single dose of orally administered AS was found to be both effective and without adverse effects in this study of second and third trimester pregnant women in the DRC. Although DHA AUC during pregnancy and postpartum were similar, the AUC for the pregnant group was less than the non-pregnant controls. The findings of this study suggest that additional studies on the pharmacokinetics of AS in pregnant women are needed. Trial Registration ClinicalTrials.gov: NCT00538382

Abstract Background Inadequate and inappropriate complementary feeding are major factors contributing to excess morbidity and mortality in young children in low resource settings. Animal source foods in particular are cited as essential to achieve micronutrient requirements. The efficacy of the recommendation for regular meat consumption, however, has not been systematically evaluated. Methods/Design A cluster randomized efficacy trial was designed to test the hypothesis that 12 months of daily intake of beef added as a complementary food would result in greater linear growth velocity than a micronutrient fortified equi-caloric rice-soy cereal supplement. The study is being conducted in 4 sites of the Global Network for Women's and Children's Health Research located in Guatemala, Pakistan, Democratic Republic of the Congo (DRC) and Zambia in communities with toddler stunting rates of at least 20%. Five clusters per country were randomized to each of the food arms, with 30 infants in each cluster. The daily meat or cereal supplement was delivered to the home by community coordinators, starting when the infants were 6 months of age and continuing through 18 months. All participating mothers received nutrition education messages to enhance complementary feeding practices delivered by study coordinators and through posters at the local health center. Outcome measures, obtained at 6, 9, 12, and 18 months by a separate assessment team, included anthropometry; dietary variety and diversity scores; biomarkers of iron, zinc and Vitamin B12 status (18 months); neurocognitive development (12 and 18 months); and incidence of infectious morbidity throughout the trial. The trial was supervised by a trial steering committee, and an independent data monitoring committee provided oversight for the safety and conduct of the trial. Discussion Findings from this trial will test the efficacy of daily intake of meat commencing at age 6 months and, if beneficial, will provide a strong rationale for global efforts to enhance local supplies of meat as a complementary food for young children. Trial registration NCT01084109

Abstract Background Maternal and newborn mortality rates remain unacceptably high, especially where the majority of births occur in home settings or in facilities with inadequate resources. The introduction of emergency obstetric and newborn care services has been proposed by several organizations in order to improve pregnancy outcomes. However, the effectiveness of emergency obstetric and neonatal care services has never been proven. Also unproven is the effectiveness of community mobilization and community birth attendant training to improve pregnancy outcomes. Methods/Design We have developed a cluster-randomized controlled trial to evaluate the impact of a comprehensive intervention of community mobilization, birth attendant training and improvement of quality of care in health facilities on perinatal mortality in low and middle-income countries where the majority of births take place in homes or first level care facilities. This trial will take place in 106 clusters (300-500 deliveries per year each) across 7 sites of the Global Network for Women's and Children's Health Research in Argentina, Guatemala, India, Kenya, Pakistan and Zambia. The trial intervention has three key elements, community mobilization, home-based life saving skills for communities and birth attendants, and training of providers at obstetric facilities to improve quality of care. The primary outcome of the trial is perinatal mortality. Secondary outcomes include rates of stillbirth, 7-day neonatal mortality, maternal death or severe morbidity (including obstetric fistula, eclampsia and obstetrical sepsis) and 28-day neonatal mortality. Discussion In this trial, we are evaluating a combination of interventions including community mobilization and facility training in an attempt to improve pregnancy outcomes. If successful, the results of this trial will provide important information for policy makers and clinicians as they attempt to improve delivery services for pregnant women and newborns in low-income countries. Trial Registration ClinicalTrials.gov NCT01073488

Background:Previous studies suggest that cases of Ebola virus disease (EVD) may go unreported because they are asymptomatic or unrecognized, but evidence is limited by study designs and sample size. Methods:A large population-based survey was conducted (n = 3415) to assess animal exposures and behaviors associated with Ebolavirus antibody prevalence in rural Kasai Oriental province of the Democratic Republic of Congo (DRC). Fourteen villages were randomly selected and all healthy individuals ≥1 year of age were eligible. Results:Overall, 11% of subjects tested positive for Zaire Ebolavirus (EBOV) immunoglobulin G antibodies. Odds of seropositivity were higher for study participants older than 15 years of age and for males. Those residing in Kole (closer to the outbreak site) tested positive at a rate 1.6× higher than Lomela, with seropositivity peaking at a site located between Kole and Lomela. Multivariate analyses of behaviors and animal exposures showed that visits to the forest or hunting and exposure to rodents or duikers predicted a higher likelihood of EBOV seropositivity. Conclusions:These results provide serologic evidence of Ebolavirus exposure in a population residing in non-EBOV outbreak locations in the DRC and define statistically significant activities and animal exposures that associate with EBOV seropositivity.

ObjectiveTo evaluate the temperature distribution among moderately preterm (MPT, 29-33 weeks) and extremely preterm (EPT, 37.5°C (4.2% vs 6.2%). For EPT infants in 2012-2013 compared with 2002-2003, the percentage of temperatures between 36.5°C and 37.5°C more than doubled and the percentage of temperatures >37.5°C more than tripled. Admission temperature was inversely associated with in-hospital mortality.ConclusionsLow and high admission temperatures are more frequent among EPT than MPT infants. Compared with a decade earlier, fewer EPT infants experience low admission temperatures but more have elevated temperatures. In spite of a change in distribution of NICU admission temperature, an inverse association between temperature and mortality risk persists.

ObjectiveTo estimate risk of necrotizing enterocolitis (NEC) for extremely low birth weight (ELBW) infants as a function of preterm formula (PF) and maternal milk intake and calculate the impact of suboptimal feeding on the incidence and costs of NEC.Study designWe used aORs derived from the Glutamine Trial to perform Monte Carlo simulation of a cohort of ELBW infants under current suboptimal feeding practices, compared with a theoretical cohort in which 90% of infants received at least 98% human milk.ResultsNEC incidence among infants receiving ≥98% human milk was 1.3%; 11.1% among infants fed only PF; and 8.2% among infants fed a mixed diet (P = .002). In adjusted models, compared with infants fed predominantly human milk, we found an increased risk of NEC associated with exclusive PF (aOR = 12.1, 95% CI 1.5, 94.2), or a mixed diet (aOR 8.7, 95% CI 1.2-65.2). In Monte Carlo simulation, current feeding of ELBW infants was associated with 928 excess NEC cases and 121 excess deaths annually, compared with a model in which 90% of infants received ≥98% human milk. These models estimated an annual cost of suboptimal feeding of ELBW infants of $27.1 million (CI $24 million, $30.4 million) in direct medical costs, $563 655 (CI $476 191, $599 069) in indirect nonmedical costs, and $1.5 billion (CI $1.3 billion, $1.6 billion) in cost attributable to premature death.ConclusionsAmong ELBW infants, not being fed predominantly human milk is associated with an increased risk of NEC. Efforts to support milk production by mothers of ELBW infants may prevent infant deaths and reduce costs.

BackgroundThe positive effects of early developmental intervention (EDI) on early child development have been reported in numerous controlled trials in a variety of countries. An important aspect to determining the efficacy of EDI is the degree to which dosage is linked to outcomes. However, few studies of EDI have conducted such analyses. This observational cohort study examined the association between treatment dose and children's development when EDI was implemented in three low and low-middle income countries as well as demographic and child health factors associated with treatment dose.MethodsInfants (78 males, 67 females) born in rural communities in India, Pakistan, and Zambia received a parent-implemented EDI delivered through biweekly home visits by trainers during the first 36 months of life. Outcome was measured at age 36 months with the Mental (MDI) and Psychomotor (PDI) Development Indices of the Bayley Scales of Infant Development-II. Treatment dose was measured by number of home visits completed and parent-reported implementation of assigned developmental stimulation activities between visits. Sociodemographic, prenatal, perinatal, and child health variables were measures as correlates.ResultsAverage home visits dose exceeded 91% and mothers engaged the children in activities on average 62.5% of days. Higher home visits dose was significantly associated with higher MDI (mean for dose quintiles 1-2 combined = 97.8, quintiles 3-5 combined = 103.4, p = 0.0017). Higher treatment dose was also generally associated with greater mean PDI, but the relationships were non-linear. Location, sociodemographic, and child health variables were associated with treatment dose.ConclusionsReceiving a higher dose of EDI during the first 36 months of life is generally associated with better developmental outcomes. The higher benefit appears when receiving ≥91% of biweekly home visits and program activities on ≥67% of days over 3 years. It is important to ensure that EDI is implemented with a sufficiently high dose to achieve desired effect. To this end groups at risk for receiving lower dose can be identified and may require special attention to ensure adequate effect.

Monkeypox virus is a zoonotic virus endemic to Central Africa. Although active disease surveillance has assessed monkeypox disease prevalence and geographic range, information about virus diversity is lacking. We therefore assessed genome diversity of viruses in 60 samples obtained from humans with primary and secondary cases of infection from 2005 through 2007. We detected 4 distinct lineages and a deletion that resulted in gene loss in 10 (16.7%) samples and that seemed to correlate with human-to-human transmission (p = 0.0544). The data suggest a high frequency of spillover events from the pool of viruses in nonhuman animals, active selection through genomic destabilization and gene loss, and increased disease transmissibility and severity. The potential for accelerated adaptation to humans should be monitored through improved surveillance.

Climate change is predicted to result in changes in the geographic ranges and local prevalence of infectious diseases, either through direct effects on the pathogen, or indirectly through range shifts in vector and reservoir species. To better understand the occurrence of monkeypox virus (MPXV), an emerging Orthopoxvirus in humans, under contemporary and future climate conditions, we used ecological niche modeling techniques in conjunction with climate and remote-sensing variables. We first created spatially explicit probability distributions of its candidate reservoir species in Africa's Congo Basin. Reservoir species distributions were subsequently used to model current and projected future distributions of human monkeypox (MPX). Results indicate that forest clearing and climate are significant driving factors of the transmission of MPX from wildlife to humans under current climate conditions. Models under contemporary climate conditions performed well, as indicated by high values for the area under the receiver operator curve (AUC), and tests on spatially randomly and non-randomly omitted test data. Future projections were made on IPCC 4(th) Assessment climate change scenarios for 2050 and 2080, ranging from more conservative to more aggressive, and representing the potential variation within which range shifts can be expected to occur. Future projections showed range shifts into regions where MPX has not been recorded previously. Increased suitability for MPX was predicted in eastern Democratic Republic of Congo. Models developed here are useful for identifying areas where environmental conditions may become more suitable for human MPX; targeting candidate reservoir species for future screening efforts; and prioritizing regions for future MPX surveillance efforts.

Although the incidence of human monkeypox has greatly increased in Central Africa over the last decade, resources for surveillance remain extremely limited. We conducted a geospatial analysis using existing data to better inform future surveillance efforts. Using active surveillance data collected between 2005 and 2007, we identified locations in Sankuru district, Democratic Republic of Congo (DRC) where there have been one or more cases of human monkeypox. To assess what taxa constitute the main reservoirs of monkeypox, we tested whether human cases were associated with (i) rope squirrels (Funisciurus sp.), which were implicated in monkeypox outbreaks elsewhere in the DRC in the 1980s, or (ii) terrestrial rodents in the genera Cricetomys and Graphiurus, which are believed to be monkeypox reservoirs in West Africa. Results suggest that the best predictors of human monkeypox cases are proximity to dense forests and associated habitat preferred by rope squirrels. The risk of contracting monkeypox is significantly greater near sites predicted to be habitable for squirrels (OR = 1.32; 95% CI 1.08-1.63). We recommend that semi-deciduous rainforests with oil-palm, the rope squirrel's main food source, be prioritized for monitoring.

Abstract Background In many malaria-endemic countries, increasing resistance may soon compromise the efficacy of sulphadoxine-pyrimethamine (SP) for intermittent preventative treatment (IPT) of malaria in pregnancy. Artemisinin-based IPT regimens represent a promising potential alternative to SP. Pharmacokinetic and safety data supporting the use of artemisinin derivatives in pregnancy are urgently needed. Methods Subjects included pregnant women with asymptomatic falciparum parasitaemia between 22-26 weeks (n = 13) or 32-36 weeks gestation (n = 13), the same women at three months postpartum, and 25 non-pregnant parasitaemic controls. All subjects received 200 mg orally administered AS. Plasma total and free levels of AS and its active metabolite DHA were determined using a validated LC-MS method. Non-compartmental pharmacokinetic analysis was performed using standard methods. Results All pregnant women delivered live babies. The median birth weight was 3025 grams [range 2130, 3620]; 2 of 26 babies had birth weights less than 2500 grams. Rates of parasite clearance by 12 hours post-dose were high and comparable among the groups. Rapid elimination of AS was observed in all three groups. The 90% CI for the pregnancy:postpartum ratio of geometric means for total and free AUC fell within the pre-specified 0.66 - 1.50 therapeutic equivalence interval. However, more pronounced pharmacokinetic differences were observed between the pregnancy and control subjects, with the 90% CI for the pregnancy:control ratio of geometric means for both total 0.68 (90% CI 0.57-0.81) and free AUC 0.78 (90% CI 0.63-0.95) not fully contained within the 0.66 - 1.50 interval. All subjects cleared parasites rapidly, and there was no difference in the percentage of women who were parasitaemic 12 hours after dosing. Conclusions A single dose of orally administered AS was found to be both effective and without adverse effects in this study of second and third trimester pregnant women in the DRC. Although DHA AUC during pregnancy and postpartum were similar, the AUC for the pregnant group was less than the non-pregnant controls. The findings of this study suggest that additional studies on the pharmacokinetics of AS in pregnant women are needed. Trial Registration ClinicalTrials.gov: NCT00538382

Studies on the burden of human monkeypox in the Democratic Republic of the Congo (DRC) were last conducted from 1981 to 1986. Since then, the population that is immunologically naïve to orthopoxviruses has increased significantly due to cessation of mass smallpox vaccination campaigns. To assess the current risk of infection, we analyzed human monkeypox incidence trends in a monkeypox-enzootic region. Active, population-based surveillance was conducted in nine health zones in central DRC. Epidemiologic data and biological samples were obtained from suspected cases. Cumulative incidence (per 10,000 population) and major determinants of infection were compared with data from active surveillance in similar regions from 1981 to 1986. Between November 2005 and November 2007, 760 laboratory-confirmed human monkeypox cases were identified in participating health zones. The average annual cumulative incidence across zones was 5.53 per 10,000 (2.18-14.42). Factors associated with increased risk of infection included: living in forested areas, male gender, age < 15, and no prior smallpox vaccination. Vaccinated persons had a 5.2-fold lower risk of monkeypox than unvaccinated persons (0.78 vs. 4.05 per 10,000). Comparison of active surveillance data in the same health zone from the 1980s (0.72 per 10,000) and 2006-07 (14.42 per 10,000) suggests a 20-fold increase in human monkeypox incidence. Thirty years after mass smallpox vaccination campaigns ceased, human monkeypox incidence has dramatically increased in rural DRC. Improved surveillance and epidemiological analysis is needed to better assess the public health burden and develop strategies for reducing the risk of wider spread of infection.

By analyzing vesicle fluids and crusted scabs from 136 persons with suspected monkeypox, we identified 51 cases of monkeypox by PCR, sequenced the hemagglutinin gene, and confirmed 94% of cases by virus culture. PCR demonstrated chickenpox in 61 patients. Coinfection with both viruses was found in 1 additional patient.

We conducted a theory-driven process evaluation of a cluster randomized controlled trial comparing two types of complementary feeding (meat versus fortified cereal) on infant growth in Guatemala, Pakistan, Zambia and the Democratic Republic of Congo. We examined process evaluation indicators for the entire study cohort (N = 1236) using chi-square tests to examine differences between treatment groups. We administered exit interviews to 219 caregivers and 45 intervention staff to explore why caregivers may or may not have performed suggested infant feeding behaviors. Multivariate regression analysis was used to determine the relationship between caregiver scores and infant linear growth velocity. As message recall increased, irrespective of treatment group, linear growth velocity increased when controlling for other factors (P < 0.05), emphasizing the importance of study messages. Our detailed process evaluation revealed few differences between treatment groups, giving us confidence that the main trial's lack of effect to reverse the progression of stunting cannot be explained by differences between groups or inconsistencies in protocol implementation. These findings add to an emerging body of literature suggesting limited impact on stunting of interventions initiated during the period of complementary feeding in impoverished environments. The early onset and steady progression support the provision of earlier and comprehensive interventions.

Objective To quantify maternal, fetal and neonatal mortality in low-and middle-income countries, to identify when deaths occur and to identify relationships between maternal deaths and stillbirths and neonatal deaths. Methods A prospective study of pregnancy outcomes was performed in 106 communities at seven sites in Argentina, Guatemala, India, Kenya, Pakistan and Zambia. Pregnant women were enrolled and followed until six weeks postpartum. Findings Between 2010 and 2012, 214070 of 220235 enrolled women (97.2%) completed follow-up. The maternal mortality ratio was 168 per 100000 live births, ranging from 69 per 100000 in Argentina to 316 per 100000 in Pakistan. Overall, 29% (98/336) of maternal deaths occurred around the time of delivery: most were attributed to haemorrhage (86/336), pre-eclampsia or eclampsia (55/336) or sepsis (39/336). Around 70% (4349/6213) of stillbirths were probably intrapartum; 34% (1804/5230) of neonates died on the day of delivery and 14% (755/5230) died the day after. Stillbirths were more common in women who died than in those alive six weeks postpartum (risk ratio, RR: 9.48; 95% confidence interval, CI: 7.97-11.27), as were perinatal deaths (RR: 4.30; 95% CI: 3.26-5.67) and 7-day (RR: 3.94; 95% CI: 2.74-5.65) and 28-day neonatal deaths (RR: 7.36; 95% CI: 5.54-9.77). Conclusion Most maternal, fetal and neonatal deaths occurred at or around delivery and were attributed to preventable causes. Maternal death increased the risk of perinatal and neonatal death. Improving obstetric and neonatal care around the time of birth offers the greatest chance of reducing mortality. Objectif Quantifier la mortalite maternelle, foetale et neonatale dans les pays a revenus faible et intermediaire pour identifier a quel moment survient le deces et pour analyser les relations entre les deces maternels et les mortinaissances/deces neonataux. Methodes Une etude prospective sur des grossesses a ete effectuee dans 106 collectivites sur 7 sites: Argentine, Guatemala, Inde, Kenya, Pakistan et Zambie. Les femmes enceintes ont ete inscrites et suivies jusqu'a 6 semaines apres leur accouchement. Resultats Entre 2010 et 2012, 214 070 femmes inscrites sur 220 235 (97,2%) ont participe au suivi. Le taux de mortalite maternelle etait de 168 pour 100 000 naissances d'enfants vivants, allant de 69 pour 100 000 en Argentine a 316 pour 100 000 au Pakistan. Dans I'ensemble, 29% (98/336) des deces maternels ont eu lieu au moment de la naissance: la plupart des deces ont ete dus a une hemorragie (86/336), une preeclampsie ou une eclampsie (55/336), ou encore une septicemle (39/336). Environ 70% (4349/6213) des enfants sont mortnes intrapartum; 34% (1804/5230) des nouveau-nes sont morts le jour de leur naissance et 14% (755/5230) le lendemain. Les mortlnaissances etaient plus frequentes chez les femmes qul ont aussi perdu la vie que chez celles qui ont survecu 6 semaines apres l'accouchement (risque relatif, RR: 9,48; intervalle de confiance a 95%, IC: 7,97-11,27), pour les deces perinatals (RR: 4,30; IC a 95%: 3,26-5,67), a 7 jours (RR: 3,94; IC a 95%: 2,74-5,65), et a 28 jours (RR: 7,36; IC a 95%: 5,54-9,77). Conclusion La plupart des cas de mortalite maternelle, foetale et neonatale se sont produits pendant ou peu avant ou apres la naissance et ont ete attribues a des causes evitables. La mortalite maternelle a augmente le risque de mort perinatale et neonatale. L'amelioration des soins obstetrlcaux et neonatals au moment de la naissance offre les meilleures chances de reduire cette mortalite. Objetivo Cuantificar la mortalidad materna, fetal y neonatal en paises de ingresos bajos y medios a fin de identificar cuando se producen muertes y las relaciones entre las muertes maternas y la mortalidad prenatal y neonatal. Metodos Se realizo un estudio prospectivo de los resultados del embarazo en 106 comunidades en siete lugares en Argentina, Guatemala, India, Kenya, Pakistan y Zambia. Se inscribieron mujeres embarazadas, de las que se hizo un seguimiento hasta seis semanas tras el parto. Resultados Entre 2010 y 2012,214 070 de las 220 235 mujeres inscritas (97,2%) completaron el seguimiento. La tasa de mortalidad materna fue de 168 por 100000 nacidos vivos, con una variacion que va desde 69 por 100 000 en Argentina a 316 por 100 000 en Pakistan. En general, el 29% (98/336) de las muertes maternas se produjo en torno al momento del parto: la mayoria se atribuyo a hemorragias (86/336), preeclampsia o eclampsia (55/336), o sepsis (39/336). Alrededor del 70% (4349/6213) de las muertes prenatales se produjo probablemente en el parto; el 34% (1804/5230) de los recien nacidos murieron el dia del parto y el 14% (755/5230), al dia siguiente. Las muertes prenatales fueron mas comunes en las mujeres que fallecieron que en aquellas con vida seis semanas despues del parto (riesgo relativo, RR: 9,48; intervalo de confianza 95%, IC: 7,97-11,27), al igual que las muertes perinatales (RR: 4,30; IC del 95%: 3,26-5,67) y las muertes de neonatos a 7 dias (RR: 3,94; IC del 95%: 2,74-5,65) y a 28 dias (RR: 7,36; IC del 95%: 5,54-9,77). Conclusion La mayoria de las muertes maternas, prenatales y neonatales ocurrieron en o en torno al parto y se atribuyeron a causas evitables. La muerte materna aumento el riesgo de muerte perinatal y neonatal. Mejorar la atencion obstetrica y neonatal en el momento del nacimiento ofrece las mayores posibilidades para reducir la mortalidad., Introduction An estimated 340000 maternal deaths, 2.7 million stillbirths and 3.1 million neonatal deaths occur worldwide each year --almost all in low-income countries. (1-4) In some parts of sub-Saharan Africa, [...]

After age 6 me, the combination of breast-feeding and unfortified plant-based complementary feeding provides inadequate zinc (Zn). Additionally, high phytate intakes compromise the bioavailability of zinc. Our principal objective in this randomized controlled, doubly masked trial was to determine the effect of substituting Iow-phytate maize, a daily 5-mg zinc supplement, or both, in infants between ages 6-12 mo on impaired linear growth velocity, a common feature of zinc deficiency. In the Western Highlands of Guatemala, 412 infants were randomized to receive Iow-phytate or control maize. Within each maize group, infants were further randomized to receive a zinc supplement or placebo. Length, weight, and head circumference were measured at 6, 9, and 12 mo of age. There were no significant differences between the 2 maize groups or between the Zn supplement and placebo groups and no treatment interaction was observed for length-for-age (LAZ), weight-for-length (WLZ) or head circumference Z-scores. Overall mean ([+ or -] SD) Z-scores at 6 mo for combined treatment groups were: LAZ, -2.1 [+ or -] 1.1 ; WLZ, 0.7 [+ or -] 1.0; and head circumference Z-score, -0.7.0 [+ or -] 1.0. At 12 mo, these had declined further to: LAZ, -2.5 [+ or -] 1.1; WLZ, -0.0 [+ or -] 0.9; and head circumference Z-score, 0.9 [+ or -] 1.1; 83.3% were stunted and 2% were wasted. Low linear growth in older Guatemalan infants was not improved with either Iow-phytate maize or a daily 5-mg zinc supplement. Low contribution of maize to the complementary food of the infants negated any potential advantage of feeding low-phytate maize. doi: 10.3945/jn.109.115154.

The study attempts to evaluate the efficacy of newborn-care training in reducing the rate of perinatal mortality in developing countries. The results indicate that programs like Essential Newborn Care training of community-based attendants as well as subsequent training did not result in a reduction in neonatal death within 7 days after birth, but did result in a reduction in stillbirths.

Background: Few studies have examined the relationship between antenatal depression, anxiety and domestic violence in pregnant women in developing countries, despite the World Health Organization's estimates that depressive disorders will be the second leading cause of the global disease burden by 2020. There is a paucity of research on mood disorders, their predictors and sequelae among pregnant women in Pakistan. Aims: To determine the prevalence of anxiety and depression and evaluate associated factors, including domestic violence, among pregnant women in an urban community in Pakistan. Methods: All pregnant women living in identified areas of Hyderabad, Pakistan were screened by government health workers for an observational study on maternal characteristics and pregnancy outcomes. Of these, 1,368 (76%) of eligible women were administered the validated Aga Khan University Anxiety Depression Scale at 20-26 weeks of gestation. Results: Eighteen per cent of the women were anxious and/or depressed. Psychological distress was associated with husband unemployment (p = 0.032), lower household wealth (p = 0.027), having 10 or more years of formal education (p = 0.002), a first (p = 0.002) and an unwanted pregnancy (p < 0.001). The strongest factors associated with depression/anxiety were physical/sexual and verbal abuse; 42% of women who were physically and/or sexually abused and 23% of those with verbal abuse had depression/anxiety compared to 8% of those who were not abused. Conclusions: Anxiety and depression commonly occur during pregnancy in Pakistani women; rates are highest in women experiencing sexual/physical as well as verbal abuse, but they are also increased among women with unemployed spouses and those with lower household wealth. These results suggest that developing a screening and treatment programme for domestic violence and depression/anxiety during pregnancy may improve the mental health status of pregnant Pakistani women. Key words: pregnancy, depression, anxiety, Pakistan, measurement

Objective To evaluate the prevalence, sex distribution and causes of neonatal mortality, as well as its risk factors, in an urban Pakistani population with access to obstetric and neonatal care. Methods Study area women were enrolled at 20-26 weeks&apos; gestation in a prospective population-based cohort study that was conducted from 2003 to 2005. Physical examinations, antenatal laboratory tests and anthropometric measures were performed, and gestational age was determined by ultrasound to confirm eligibility. Demographic and health data were also collected on pretested study forms by trained female research staff. The women and neonates were seen again within 48 hours postpartum and at day 28 after the birth. All neonatal deaths were reviewed using the Pattinson et al. system to assign obstetric and final causes of death; the circumstances of the death were determined by asking the mother or family and by reviewing hospital records. Frequencies and rates were calculated, and 95% confidence intervals were determined for mortality rates. Relative risks were calculated to evaluate the associations between potential risk factors and neonatal death. Logistic regression models were used to compute adjusted odds ratios. Findings Birth outcomes were ascertained for 1280 (94%) of the 1369 women enrolled. The 28-day neonatal mortality rate was 47.3 per 1000 live births. Preterm birth, Caesarean section and intrapartum complications were associated with neonatal death. Some 45% of the deaths occurred within 48 hours and 73% within the first week. The primary obstetric causes of death were preterm labour (34%) and intrapartum asphyxia (21%). Final causes were classified as immaturity-related (26%), birth asphyxia or hypoxia (26%) and infection (23%). Neither delivery in a health facility nor by health professionals was associated with fewer neonatal deaths. The Caesarean section rate was 19%. Almost all (88%) neonates who died received treatment and 75% died in the hospital. Conclusion In an urban population with good access to professional care, we found a high neonatal mortality rate, often due to preventable conditions. These results suggest that, to decrease neonatal mortality, improved health service quality is crucial. Objectif Evaluer la prevalence, la distribution par sexes et les causes de la mortalite neonatale, ainsi que ses facteurs de risque, dans une population pakistanaise urbaine, ayant acces aux soins obstetricaux et neonatals. Methodes Des femmes de la zone etudiee ont ete recrutees 9, 20-26 semaines de grossesse pour participer a, une etude de cohorte prospective en population, realisee de 2003 a 2005. Des examens physiques, des examens de laboratoires antenatals et des mesures anthropometriques ont ete pratiques et l&apos;age gestationnel a ete determine par echographie pour confirmer I&apos;admissibilite dans I&apos;etude. Des donnees demographiques et sanitaires ont egalement ete recueillies au moyen de formulaires d&apos;etude prealabiement testes, par des membres feminins du personnel de recherche formes a cet effet. Les meres et les nouveau-nes ont ete revus dans les 48 heures suivant I&apos;accouchement et le 28e jour apres la naissance. Tous les deces neonatals ont ete analyses a I&apos;aide du systeme de Pattinson et al. pour leur affecter des causes obstetricales et finales ; leurs circonstances ont ete determinees en interrogeant la mere ou la famille et en examinant les dossiers hospitaliers. On a calcule, les frequences et les taux de mortalite, ainsi que les intervalles de confiance & 95 % associes a ces derniers. On a egalement determine les risques relatifs pour evaluer les associations entre les facteurs de risque eventuels et les deces neonatals. On a fait appel a des modeies de regression Iogistique pour calculer les odds ratios ajustes. Resultats On a determine I&apos;issue de I&apos;accouchement pour 1280 (94 %) des 1369 femmes participant & I&apos;etude. Le taux de mortalite neonatale a 28 jours etait de 47,3 pour 1000 naissances vivantes. li existait une association entre les naissances avant terme, les accouchements par cesarienne et les complications intrapartum, d&apos;une part, et les deces neonatals, d&apos;autre part. Res de 45 % des deces sont intervenus dans les 48 heures et 73 % dans la premiere semaine apres I&apos;accouchement. Les principales causes obstetricales de deces etaient le travail avant terme (34 %) et I&apos;asphyxie intrapartum (21%). Comme causes finales de deces, on relevait, dans I&apos;ordre, les causes liees a I&apos;immaturite (26 %), rasphyxie ou I&apos;hypoxie pendant I&apos;accouchement (26 %) et les infections (23 %). Ni le fait d&apos;accoucher dans un etablissement de soins, ni la realisation de I&apos;accouchement par un professionnel de sante, n&apos;etaient associes a une baisse du nombre de deces neonatals. Le taux d&apos;accouchement par cesarienne etait de 19 %. Presque tous les nouveau-nes decedes (88 %) avaient recu un traitement et 75% d&apos;entre eux etaient morts a I&apos;hopital. Conclusion Dans une poputation urbaine disposant d&apos;un acces satisfaisant aux soins de sante, nous avons releve un taux de mortalite neonatale eleve, souvent du a des affections evitables. Ces resultats laissent & penser qu&apos;il est essentiel d&apos;ameliorer la qualite des services de sante pour faire baisser la mortalite neonatale. Objetivo Evaluar la prevalencia, la distribucion por sexos y las causas de la mortalidad neonatal, asi como los factores de riesgo asociados, en una poblacion urbana del Pakistan con acceso a atencion obstetrica y neonatal. Metodos Entre 2003 y 2005 se realizo un estudio de cohortes prospectivo basado en la poblacion .con embarazadas que se encontraban entre la 20 y la 26 semana de gestacion. Se sometio a las mujeres a exploracion fisica, pruebas de laboratorio prenatales y mediciones antropometricas y se determino la edad gestacional mediante ecografia para confirmar la elegibilidad. Personal investigador femenino reunio tambien datos demograficos y sanitarios mediante formularios que se habian ensayado previamente. Las mujeres y los recien nacidos fueron examinados de nuevo en el termino de 48 horas tras el parto y a los 28 dias del nacimiento. Todas las defunciones neonatales fueron analizadas mediante el sistema ideado por Pattinson y col. para asignar las causas obstetricas y finales de la defuncion; las circunstancias de la muerte se determinaron interrogando a la madre u otros familiares y examinando las historias clinicas. Se calcularon las frecuencias y las tasas, y se determinaron los intervalos de confianza del 95% de las tasas de mortalidad. Se calcularon los riesgos relativos para evaluar la relacion entre los factores de riesgo potenciales y la mortalidad neonatal, y el calculo de las razones de posibilidades ajustadas se hizo mediante regresion Iogistica. Resultados Se determinaron los resultados obstetricos de 1280 (94%) de las 1369 mujeres participantes. La tasa de mortalidad neonatal a los 28 dias fue de 47,3 por 1000 nacidos vivos. Los nacimientos prematuros, las cesareas y las complicaciones durante el parto se asociaron a mortalidad neonatal. Un 45% de las defunciones se produjeron en el termino de las primeras 48 horas, y el 73% durante la primera semana. Las principales causas obstetricas de defuncion fueron el parto prematuro (34%) y la asfixia intraparto (21%). Las causas finales se clasificaron como relacionadas con la inmadurez (26%), con situaciones de asfixia o hipoxia en el parto (26%) y con infecciones (23%). El hecho de dar a luz en un centro de salud o con la asistencia de profesionales sanitarios no se asocio a un menor numero de muertes neonatales. La tasa de cesareas fue del 19%. Casi todos (88%) los recien nacidos que fallecieron habian recibido tratamiento, y el 75% murieron en el hospital. Conclusion En una poblacion urbana con buen acceso a atencion profesional, observamos una tasa de mortalidad neonatal elevada, debida con frecuencia a problemas prevenibles. Estos resultados llevan a pensar que la mejora de la calidad de los servicios de salud es fundamental para reducir la mortalidad neonatal., Introduction Of the estimated 130 million infants born each year worldwide, (1,4) million die in the first 28 days of life. Three-quarters of neonatal deaths occur in the first week, [...]

A study to ascertain the extent to which obstetric practices were used in the third stage of labor was conducted. Results revealed that use of oxytocin in the third stage of labor had many beneficial effects for the mother and this information needs to be disseminated among birth attendants.

OBJECTIVES. The objectives of this study were to assess whether (1) in-hospital growth velocity is predictive of neurodevelopmental and growth outcomes at 18 to 22 months' corrected age among extremely low birth weight (ELBW) infants and (2) in-hospital growth velocity contributes to these outcomes after controlling for confounding demographic and clinical variables. METHODS. Infants 501 to 1000 g birth weight from a multicenter cohort study were divided into quartiles of in-hospital growth velocity rates. Variables considered for the logistic-regression models included gender, race, gestational age, small for gestational age, mother's education, severe intraventricular hemorrhage, periventricular leukomalacia, age at regaining birth weight, necrotizing enterocolitis, late-onset infection, bronchopulmonary dysplasia, postnatal steroid therapy for pulmonary disease, and center. RESULTS. Of the 600 discharged infants, 495 (83%) were evaluated at 18 to 22 months' corrected age. As the rate of weight gain increased between quartile 1 and quartile 4, from 12.0 to 21.2 g/kg per day, the incidence of cerebral palsy, Bayley II Mental Developmental Index (MDI) <70 and Psychomotor Developmental Index (PDI) <70, abnormal neurologic examination, neurodevelopmental impairment, and need for rehospitalization fell significantly. Similar findings were observed as the rate of head circumference growth increased. The in-hospital rate of growth was associated with the likelihood of anthropometric measurements at 18 months' corrected age below the 10th percentile values of the Centers for Disease Control and Prevention 2000 growth curve. Logistic-regression analyses, controlling for potential demographic or clinical cofounders, and adjusted for center, identified a significant relationship between growth velocity and the likelihood of cerebral palsy, MDI and PDI scores of <70, and neurodevelopmenta] impairment. CONCLUSIONS. These analyses suggest that growth velocity during an ELBW infant's NICU hospitalization exerts a significant, and possibly independent, effect on neurodevelopmental and growth outcomes at 18 to 22 months' corrected age. Key Words extremely low birth weight infant, growth, neurodevelopmental outcome Abbreviations ELBW--extremely low birth weight MDI--Mental Developmental Index PDI--Psychomotor Developmental Index PMA--postmenstrual age CP--cerebral palsy NDI--neurodevelopmental impairment SGA--small for gestational age NEC--necrotizing enterocolitis IVH--intraventricular hemorrhage PVL--periventricular leukomalacia BPD--bronchopulmonary dysplasia OR--odds ratio CI--confidence interval, POSTNATAL GROWTH FAILURE is the norm for extremely low birth weight (ELBW) infants, especially the sickest infants. (1-4) The NICHD Growth Observational Study (1) demonstrated that, although the rate of […]

Objective. To compare multiple logistic regression and neural network models in predicting death for extremely low birth weight neonates at 5 time points with cumulative data sets, as follows: scenario A, limited prenatal data; scenario B, scenario A plus additional prenatal data; scenario C, scenario B plus data from the first 5 minutes after birth; scenario D, scenario C plus data from the first 24 hours after birth; scenario E, scenario D plus data from the first 1 week after birth. Methods. Data for all infants with birth weights of 401 to 1000 g who were born between January 1998 and April 2003 in 19 National Institute of Child Health and Human Development Neonatal Research Network centers were used (n = 8608). Twenty-eight variables were selected for analysis (3 for scenario A, 15 for scenario B, 20 for scenario C, 25 for scenario D, and 28 for scenario E) from those collected routinely. Data sets censored for prior death or missing data were created for each scenario and divided randomly into training (70%) and test (30%) data sets. Logistic regression and neural network models for predicting subsequent death were created with training data sets and evaluated with test data sets. The predictive abilities of the models were evaluated with the area under the curve of the receiver operating characteristic curves. Results. The data sets for scenarios A, B, and C were similar, and prediction was best with scenario C (area under the curve: 0.85 for regression; 0.84 for neural networks), compared with scenarios A and B. The logistic regression and neural network models performed similarly well for scenarios A, B, D, and E, but the regression model was superior for scenario C. Conclusions. Prediction of death is limited even with sophisticated statistical methods such as logistic regression and nonlinear modeling techniques such as neural networks. The difficulty of predicting death should be acknowledged in discussions with families and caregivers about decisions regarding initiation or continuation of care. logistic models, neural networks (computer), predictive value, receiver operating characteristic curve. ABBREVIATIONS. ELBW, extremely low birth weight; ROC, receiver operating characteristic; AUC, area under the curve; SNAP, Score for Neonatal Acute Physiology; PPV, positive predictive value; NPV, negative predictive value., Extremely low birth weight (ELBW) infants continue to have a disproportionately high mortality rate, compared with larger, more mature infants, despite advances in perinatal and neonatal care. (1-3) Decisions regarding [...]

Objective. A number of definitions of bronchopulmonary dysplasia (BPD), or chronic lung disease, have been used. A June 2000 National Institute of Child Health and Human Development/National Heart, Lung, and Blood Institute Workshop proposed a severity-based definition of BPD for infants Methods. Data from 4866 infants (birth weight [less than or equal to] 1000 g, GA Results. A total of 77% of the neonates met the 28-days definition, and 44% met the 36-weeks definition. Using the consensus BPD definition, 77% of the infants had BPD, similar to the cohort identified by the 28-days definition. A total of 46% of the infants met the moderate (30%) or severe (16%) consensus definition criteria, identifying a similar cohort of infants as the 36-weeks definition. Of infants who met the 28-days definition and 36-weeks definition and were seen at follow-up at 18 to 22 months&apos; corrected age, 40% had been treated with pulmonary medications and 35% had been rehospitalized for pulmonary causes. In contrast, as the severity of BPD identified by the consensus definition worsened, the incidence of those outcomes and of selected adverse neurodevelopmental outcomes increased in the infants who were seen at follow-up. Conclusion. The consensus BPD definition identifies a spectrum of risk for adverse pulmonary and neurodevelopmental outcomes in early infancy more accurately than other definitions. bronchopulmonary dysplasia, chronic lung disease, extremely preterm infants, neurodevelopmental. ABBREVIATIONS. BPD, bronchopulmonary dysplasia; CLD, chronic lung disease; PMA, postmenstrual age; VLBW, very low birth weight; GA, gestational age; ELBW, extremely low birth weight; NICHD, National Institute of Child Health and Human Development; CPAP, continuous positive airway pressure; RSV, respiratory syncytial virus; CP, cerebral palsy., Several definitions of bronchopulmonary dysplasia (BPD), or chronic lung disease (CLD), have been used since 1967, when Northway et al (1) first described the clinical, radiologic, and pathologic changes seen [...]