Vaccine Take of RV3-BB Rotavirus Vaccine Observed in Indonesian Infants Regardless of HBGA Status.

BACKGROUND: Histo-blood group antigen (HBGA) status may affect vaccine efficacy due to rotavirus strains binding to HBGAs in a P genotype-dependent manner. This study aimed to determine if HBGA status affected vaccine take of the G3P[6] neonatal vaccine RV3-BB. METHODS: DNA was extracted from stool samples collected in a subset (n = 164) of the RV3-BB phase IIb trial in Indonesian infants. FUT2 and FUT3 genes were amplified and sequenced, with any single-nucleotide polymorphisms analyzed to infer Lewis and secretor status. Measures of positive cumulative vaccine take were defined as serum immune response (immunoglobulin A or serum-neutralizing antibody) and/or stool excretion of RV3-BB virus. Participants were stratified by HBGA status and measures of vaccine take. RESULTS: In 147 of 164 participants, Lewis and secretor phenotype were determined. Positive vaccine take was recorded for 144 (97.9%) of 147 participants with the combined phenotype determined. Cumulative vaccine take was not significantly associated with secretor status (relative risk, 1.00 [95% CI, .94-1.06]; P = .97) or Lewis phenotype (relative risk, 1.03 [95% CI, .94-1.14]; P = .33), nor was a difference observed when analyzed by each component of vaccine take. CONCLUSIONS: The RV3-BB vaccine produced positive cumulative vaccine take, irrespective of HBGA status in Indonesian infants.

Intermittent screening and treatment for malaria complementary to routine immunisation in the first year of life in Papua, Indonesia: a cluster randomised superiority trial.

BACKGROUND: In Papua (Indonesia), infants with P. falciparum and/or P. vivax malaria are at risk of severe anaemia and death. We hypothesized that in an area of high malaria transmission, intermittent screening and treatment of infants with malaria (ISTi) will reduce morbidity compared to passive case detection (PCDi). METHODS: We conducted a cluster randomised, open label, superiority trial. A total of 21 clusters of village health posts (VHP) were randomised 1:1 to either IST for infants coinciding with 4 routine immunisation visits or PCDi. Healthy term infants born to consenting mothers enrolled into a maternal malaria cluster randomised trial were included in the study and followed for 12 months. Point of care malaria rapid diagnostic tests were used to detect peripheral parasitaemia at 2, 3, 4 and 9 months old in all infants in ISTi clusters and when symptomatic in PCDi clusters. Infants with detected peripheral parasitaemia were treated with dihydroartemisinin-piperaquine. The co-primary outcomes were the incidence rate of clinical malaria in the first year of life and the prevalence of parasitaemia at age 12 months. The incidence rate ratio and prevalence ratio between ISTi and PCDi were estimated using mixed-effects Poisson and log-binomial regression modelling (accounting for clustering at VHP level). RESULTS: Between May 2014 and February 2017, 757 infants were enrolled into the study, 313 into 10 ISTi clusters, and 444 into 11 PCDi clusters. Overall, 132 episodes of parasitaemia were detected, of whom 17 (12.9%) were in symptomatic infants. Over 12 months, the incidence rate (IR) of clinical malaria was 24 [95% CI, 10-50] per 1000 children-years at risk in the ISTi arm and 19 [95% CI, 8,38] per 1000 children-years in the PCDi arm (adjusted incidence rate ratio [aIRR] 1.77 [95% CI, 0.62-5.01]; p = 0.280). The prevalence of parasitaemia at 12 months was 13% (33/254) in the IST clusters and 15% (57/379) in the PCD clusters (adjusted prevalence ratio (aPR) = 0.92 (95% CI, 0.70-1.21), p = 0.55). There was no difference in the risk of anaemia between treatment arms. CONCLUSIONS: In high malaria transmission area outside of Africa, our study suggests that compared to PCDi, ISTi offers no significant benefit in reducing the risk of clinical malaria in infants born to women receiving effective protection from malaria during pregnancy. TRIAL REGISTRATION: ClinicalTrials.gov NCT02001428 , registered on 20 Nov 2013.

Risk factors for healthcare-associated infection among children in a low-and middle-income country.

BACKGROUND: Healthcare-associated infections (HAI) are one of significant causes of morbidity and mortality. Evaluating risk factors associated with HAI are important to improve clinical outcomes. We aimed to evaluate the risk factors of HAI in children in a low-to middle-income country. METHODS: A prospective cohort study was conducted during 43 months at a teaching hospital in Yogyakarta, Indonesia. All consecutive patients admitted to pediatric ICU and pediatric wards > 48 h were eligible. Those eligible patients were observed daily to identify the presence of HAI based on CDC criteria. The risk factors of HAI were identified. Multivariable logistic regression was used to identify independent risk factors. RESULTS: Total of 2612 patients were recruited. Of 467 were diagnosed as HAI. The cumulative incidence of HAI was 17.9%. In the multivariable analysis; length of stay > 7 days, severe sepsis, use of urine catheter, central venous catheter (CVC), non-standardized antibiotics, and aged < 1 year were independently associated with increased risk of HAI with adjusted OR (95%CI): 5.6 (4.3-7.3), 1.9 (1.3-2.9), 1.9 (1.3-2.6), 1.8 (1.1-2.9), 1.6 (1.2-2.0), and 1.4 (1.1-1.8), respectively. CONCLUSIONS: This study found that length of stay > 7 days, use of urine catheter and CVC, non-standardized antibiotic use, aged < 1 year, and had a diagnosis of severe sepsis increased risk of HAI.

Direct and indirect costs of acute diarrhea in children under five years of age in Indonesia: Health facilities and community survey.

BACKGROUND: Diarrhea remains a major cause of child morbidity and mortality in low- and middle-income countries. Reliable data on the economic burden of diarrhea is required to support the selection of appropriate health intervention programs. This study aimed to estimate the costs of acute diarrhea in children under five years of age in Indonesia, a large middle-income country with a substantial diarrheal burden. METHODS: Direct medical cost data were extracted retrospectively for 1050 children under five years of age with acute diarrhea receiving inpatient care across 45 health facilities in seven Indonesian provinces during 2017-2020. Direct medical costs for children treated in outpatient settings were estimated by collecting unit costs associated with standard diarrhea case management in children. A structured interview of 240 caregivers of inpatients was also conducted retrospectively to estimate direct non-medical costs as well as indirect costs from caregiver income loss. RESULTS: The weighted average direct medical cost for treatment of acute diarrhea as an inpatient and outpatient across health facility types was US$99.8 (SD±$56.8)(35% room costs, 29% professional fees, 26% medication costs, 10% diagnostic costs) and US$7.6 (SD±$4.3) (34% diagnostic costs, 28% medication costs, 27% professional fees, 10% registration fees), respectively. The average direct non-medical household cost for an acute diarrheal admission was US$4.90 and the indirect cost was US$9.90. CONCLUSION: There is a significant economic burden associated with acute diarrhea in children in Indonesia. This study, based on a wide variety of health care settings and geographical regions, provides data to inform the economic evaluation of rotavirus vaccines and other diarrheal prevention programs. FUNDING: This work was supported by a research grant from the Murdoch Children's Research Institute (MCRI) and PATH; and the Indonesian Technical Advisory Group on Immunization (ITAGI).

Predictive Factors for Cardiopulmonary Resuscitation Failure.

OBJECTIVES: Patients with chronic diseases are often admitted to the hospital through the emergency room of the hospital because of complaints of dyspnoea, urinary retention, decreased consciousness and cardiac arrest requiring resuscitation. The purpose of this study is to find predictive factors for failure of cardiopulmonary resuscitation (CPR) in patients of chronic diseases. MATERIALS AND METHODS: This cross-sectional study took medical records of patients who were carried out from primary healthcare center in Yogyakarta from 2017 to 2019. Bivariate statistical analysis used Fisher's exact test to determine the relative risk; if P < 0.25, then multivariate analysis with logistic regression continued with the backward method to obtain the odds ratio (OR). RESULTS: The results indicate that cardiac arrest patients with sepsis are most likely to fail at CPR, whereas male patients are 9.1 times (OR 9.1); patients with acidosis, 8.1 times (OR 8.1); and patients with asystole heart rhythm, 7.8 times (OR 7.8, P < 0.05). We can conclude that male patients with sepsis, acidosis or asystole heart rhythm will almost certainly fail to receive resuscitation. CONCLUSION: Sepsis or septic shock, the male gender, acidosis, and asystole rhythm can be determinants of mortality in patients with chronic diseases who undergo CPR. It is necessary for one to test the application of the checklist or data from other hospitals and score the predictive factors to make the determination of the success of CPR easier.

Safety and immunogenicity of human neonatal RV3 rotavirus vaccine (Bio Farma) in adults, children, and neonates in Indonesia: Phase I Trial.

BACKGROUND: Despite safe and effective WHO prequalified rotavirus vaccines, at least 84 million children remain unvaccinated. A birth dose schedule of the RV3-BB vaccine was reported to be highly efficacious against severe rotavirus disease in Indonesian infants and is under further development at PT Bio Farma, Indonesia. The aim is to develop a rotavirus vaccine starting from birth that could improve the implementation, safety, and effectiveness of vaccines. METHODS: A multi-site phase I study of a human neonatal RV3 rotavirus vaccine (Bio Farma) in adults, children, neonates in Indonesia from April 2018 to March 2019. The adult and child cohorts were open-labeled single-dose, while the neonatal cohort was randomized, double-blind, and placebo-controlled three-doses at the age of 0-5 days, 8-10 weeks, and 12-14 weeks. The primary objective was to assess the safety of vaccines with the immunogenicity and vaccine virus fecal shedding as the secondary endpoints in neonates. RESULTS: Twenty-five adults, 25 children, and 50 neonates were recruited, and all but one in the neonatal cohort completed all study procedures. Three serious adverse events were reported (1 adult & 2 neonates), but none were assessed related to investigational product (IP). The neonatal vaccine group had a significantly higher positive immune response (cumulative seroconverted SNA and IgA) 28 days after three doses than those in the placebo group (72% vs. 16.7%, respectively). The GMT of serum IgA in the vaccine group was significantly higher at post IP dose 1 (p < 0.05) and post IP dose 3 (p < 0.001) compared to the placebo group. CONCLUSION: The trial results show that the RV3 rotavirus vaccine (Bio Farma) is well tolerated in all participant cohorts (adults, children, and neonates). Three doses of this vaccine administered in a neonatal schedule were immunogenic. These promising results support further clinical development of the RV3 rotavirus vaccine (Bio Farma).

Vitamin D deficiency and severity of pneumonia in Indonesian children.

OBJECTIVE: To determine the prevalence of vitamin D deficiency in Indonesian children hospitalized with pneumonia and evaluate the association between vitamin D status and severity of pneumonia. METHODS: A hospital-based cross-sectional study was conducted from February 2016 to July 2017 in two district hospitals in Yogyakarta province, Indonesia. Infants and young children aged 2-59 months hospitalized with pneumonia were recruited. Serum blood samples were collected on admission and analyzed for total serum 25-hydroxyvitamin D3 and 25-hydroxyvitamin D2 concentrations using liquid chromatography-tandem mass spectrometry. Vitamin D deficiency was defined as a level of serum vitamin D <50 nmol/L. The association between vitamin D deficiency and severity of hospitalized pneumonia according to WHO criteria, including the presence of danger signs, hypoxemia (SpO2 in air below 90%), duration of hospitalization, and admission to Intensive Care Unit (ICU), was analyzed using logistic regression. RESULTS: 133 children with WHO-defined pneumonia were enrolled in the study and 127 (96%) had their vitamin D status determined. The mean vitamin D concentration was 67 (± 24 SD) nmol/L and 19% of participants were vitamin D deficient. Age younger than 6 months was associated with prolonged hospitalization (> 5 days) and low birth weight and poor nutritional status on admission were risk factors for hypoxemia. However, vitamin D status was not associated with the presence of danger signs, duration of hospitalization, or hypoxemia. CONCLUSIONS: One in every five children hospitalized with pneumonia was vitamin D deficient. Vitamin D status was not associated with the severity of pneumonia.

The incidence of acute respiratory infection in Indonesian infants and association with vitamin D deficiency.

BACKGROUND: Vitamin D deficiency has been associated with acute respiratory infection (ARI) in early life, but this has not been evaluated in Indonesia. We aimed to determine the incidence of ARI in Indonesian infants, and to evaluate the association with vitamin D deficiency. METHODS: From 23 December 2015 to 31 December 2017, we conducted a community-based prospective cohort study in Yogyakarta province. We enrolled 422 pregnant women and followed their infants from birth until 12 months of age for ARI episodes. Vitamin D status was measured at birth and at age six months. We performed Cox proportional hazard regression analysis to evaluate the association between vitamin D deficiency and pneumonia incidence. RESULTS: At study completion, 95% (400/422) of infants retained with a total of 412 child years of observation (CYO). The incidence of all ARI and of WHO-defined pneumonia was 3.89 (95% CI 3.70-4.08) and 0.25 (95% CI 0.21-0.30) episodes per CYO respectively. Vitamin D deficiency at birth was common (90%, 308/344) and associated with more frequent episodes of ARI non-pneumonia (adjusted odds ratio 4.48, 95% CI:1.04-19.34). Vitamin D status at birth or six months was not associated with subsequent pneumonia incidence, but greater maternal sun exposure during pregnancy was associated with a trend to less frequent ARI and pneumonia in infants. CONCLUSION: ARI, pneumonia, and vitamin D deficiency at birth were common in Indonesian infants. Minimising vitamin D deficiency at birth such as by supplementation of mothers or safe sun exposure during pregnancy has the potential to reduce ARI incidence in infants in this setting.

Non-antibiotic medication use in an Indonesian community cohort 0-18 months of age.

BACKGROUND: Rational medication use for treatment is mandatory, particularly in children as they are vulnerable to possible hazards of drugs. Understanding the medication use pattern is of importance to identify the problems of drug therapy and to improve the appropriate use of medication among this population. METHODS: A post-hoc study of the RV3-BB Phase IIb trial to children aged 0-18 months which was conducted in Indonesia during January 2013 to July 2016. Any concomitant medication use and health events among 1621 trial participants during the 18 months of follow-up were documented. Information on medication use included the frequency, formulation, indication, duration of usage, number of regimens, medication types, and therapeutic classes. RESULTS: The majority of participants (N = 1333/1621; 82.2%) used at least one non-antibiotic medication for treatment during the 18-month observation period. A total of 7586 medication uses were recorded, mostly in oral formulation (90.5%). Of all illnesses recorded, 24.7% were treated with a single drug regimen of non-antibiotic medication. The most common therapeutic classes used were analgesics/antipyretics (30.1%), antihistamines for systemic use (17.4%), cough and cold preparations (13.5%), vitamins (8.6%), and antidiarrheals (6.6%). The main medication types used were paracetamol (29.9%), chlorpheniramine (16.8%), guaifenesin (8.9%), zinc (4.6%), and ambroxol (4.1%). Respiratory system disorder was the most common reason for medication use (51.9%), followed by gastrointestinal disorders (19.2%), pyrexia (16.9%), and skin disorders (7.0%). CONCLUSION: A large number of children were exposed to at least one medication during their early life, including those where evidence of efficacy and safety in a pediatric population is lacking. This supports the need for further research on pediatric drug therapy to improve the appropriate use of medication in this population.

The prevalence and determinants of vitamin D deficiency in Indonesian infants at birth and six months of age.

BACKGROUND: Vitamin D deficiency in infants has been associated with an increased risk of a number of diseases but there are limited data on the prevalence and determinants of vitamin D deficiency from tropical settings with high infant morbidity and mortality. OBJECTIVE: To determine the prevalence and determinants of vitamin D deficiency in infants at birth and at six months of age in Yogyakarta province, Indonesia. DESIGN: Serum vitamin D of eligible infants was measured in cord blood at birth and at six months of age. Factors associated with vitamin D deficiency (serum 25-hydroxyvitamin D <50 nmol/L) were collected prospectively monthly from birth and concentrations measured by liquid chromatography-tandem mass spectrometry. Independent risk factors were identified by multiple logistic regression. RESULTS: Between December 2015 to December 2017, 350 maternal-newborn participants were recruited and followed up. Vitamin D deficiency was detected in 90% (308/344) of cord blood samples and 13% (33/255) of venous blood samples at six months. Longer time outdoors (≥2 hours per day) and maternal multivitamin intake containing vitamin D during pregnancy were protective against vitamin D deficiency at birth (AOR: 0.10, 95% CI: 0.01-0.90 and AOR: 0.21, 95% CI: 0.06-0.68, respectively). Risk factors for vitamin D deficiency at six months included lower cumulative skin-sun exposure score (AOR: 1.12, 95% CI: 1.04-1.20), severe vitamin D deficiency at birth (AOR: 7.73, 95% CI: 1.20-49.60) and exclusive breastfeeding (AOR: 2.64, 95% CI: 1.07-6.49) until six months. Among exclusively breast fed (EBF) infants, a higher skin-sun exposure score was associated with reduced vitamin D deficiency risk. CONCLUSION: In equatorial regions, the role of 'safe' morning sun exposure in infants and mothers in populations with medium to dark brown skin pigmentation and effective interventions to prevent vitamin D deficiency in newborns and EBF infants, need further consideration and evaluation.

Multifaceted interventions for healthcare-associated infections and rational use of antibiotics in a low-to-middle-income country: Can they be sustained?

BACKGROUND: Transmission of infection between patients by health workers, and the irrational use of antibiotics are preventable causes for healthcare-associated infections (HAI) and multi-resistant organisms. A previous study implementing a hand hygiene campaign and antibiotic stewardship program significantly reduced these infections. Sustaining such interventions can be challenging. AIMS: To evaluate whether there was a sustained effect of a multifaceted infection control and antibiotic stewardship program on HAI and antibiotic use 5 years after it began. METHODS: A prospective evaluation study was conducted over 26 months (from February 2016 to April 2018) in a teaching hospital in Indonesia, 5 years after the implementation of an antibiotic stewardship and infection control program, which was successful when initially evaluated. All children admitted to the pediatric ICU and pediatric wards were observed daily. Assessment of HAI was made based on the criteria from the Centers for Disease Control and Prevention. Assessment of rational antibiotic use was based on the WHO Pocket Book of Hospital Care for Children. Multivariable logistic regression analysis was used to quantify the relationship between the HAI and the multifaceted intervention. RESULTS: We observed an increase in HAIs, from 8.6% (123/1419 patients) in the initial post-intervention period in 2011-2013 to 16.9% (314/1855) in the evaluation study (relative risk (RR) (95% CI) 1.95 (1.60 to 2.37)). After adjusting for potential confounders, we found that an increase in HAI in the evaluation period with adjusted OR 1.94 (95% CI 1.53 to 2.45). Inappropriate antibiotic use also increased, from 20.6% (182 of 882 patients who were prescribed antibiotics) to 48.6% (545/1855) (RR 2.35 (2.04 to 2.71)). Hand hygiene compliance also declined from 62.9% (1125/1789) observed moments requiring hand hygiene to 51% (1526/2993) (RR 3.33 (2.99 to 3.70)). CONCLUSIONS: Healthcare-associated infections and irrational use of antibiotics remain significant even after the implementation of a multifaceted infection control intervention and antibiotic stewardship program. There is a need for continuous input, ongoing surveillance and long-term monitoring of these interventions to sustain compliance and effectiveness and address problems as they emerge.

Rotavirus specific maternal antibodies and immune response to RV3-BB rotavirus vaccine in central java and yogyakarta, Indonesia.

BACKGROUND: Placental or breast milk maternal antibodies can potentially reduce oral rotavirus vaccine efficacy in developing countries. We aimed to examine the relationship between the level of rotavirus specific immunoglobulin A (IgA) and neutralising antibodies (NA) in colostrum and breast milk and cord IgG, with cumulative vaccine take following one and three doses of oral RV3-BB rotavirus vaccine within a Phase IIb trial in Indonesia. METHODS: 196 infants received three doses of RV3-BB in a randomized, double-blinded trial, using a neonatal schedule (first dose at 0-5 days of age, n = 61), an infant schedule (first dose at ~ 8 weeks of age, n = 67) or placebo (n = 68). Rotavirus specific IgA and NA in colostrum and breast milk, rotavirus specific cord IgG, Serum IgA and stool excretion were measured. RESULTS: There was little evidence of an association between IgA in colostrum or breast milk and cumulative vaccine take after three doses in the neonatal or infant groups. In the neonatal group, there was a negative association between IgG titre in cord blood and cumulative vaccine take (odds ratio [OR] 0.96; 95% confidence interval [CI] 0.92-1.00; p = 0.03) and serum IgA response (OR 0.94; 95%CI 0.89-0.99; p = 0.02) after one dose of vaccine, which were not evident after three doses in the neonatal or infant groups. CONCLUSIONS: Amongst Indonesian infants we did not find an association between IgA in colostrum or breast milk and vaccine take after 3 doses of RV3-BB vaccine. Maternal rotavirus antibodies in breast milk appear to have minimal impact on RV3-BB vaccine take when administered with a short delay in breast-feeding in settings with a high rotavirus disease burden.

Immunogenicity of four doses of oral poliovirus vaccine when co-administered with the human neonatal rotavirus vaccine (RV3-BB).

BACKGROUND: The RV3-BB human neonatal rotavirus vaccine was developed to provide protection from severe rotavirus disease from birth. The aim of this study was to investigate the potential for mutual interference in the immunogenicity of oral polio vaccine (OPV) and RV3-BB. METHODS: A randomized, placebo-controlled trial involving 1649 participants was conducted from January 2013 to July 2016 in Central Java and Yogyakarta, Indonesia. Participants received three doses of oral RV3-BB, with the first dose given at 0-5 days (neonatal schedule) or ~8 weeks (infant schedule), or placebo. Two sub-studies assessed the immunogenicity of RV3-BB when co-administered with either trivalent OPV (OPV group, n = 282) or inactivated polio vaccine (IPV group, n = 333). Serum samples were tested for antibodies to poliovirus strains 1, 2 and 3 by neutralization assays following doses 1 and 4 of OPV. RESULTS: Sero-protective rates to poliovirus type 1, 2 or 3 were similar (range 0.96-1.00) after four doses of OPV co-administered with RV3-BB compared with placebo. Serum IgA responses to RV3-BB were similar when co-administered with either OPV or IPV (difference in proportions OPV vs IPV: sIgA responses; neonatal schedule 0.01, 95% CI -0.12 to 0.14; p = 0.847; infant schedule -0.10, 95% CI -0.21 to -0.001; p = 0.046: sIgA GMT ratio: neonatal schedule 1.23, 95% CI 0.71-2.14, p = 0.463 or infant schedule 1.20, 95% CI 0.74-1.96, p = 0.448). CONCLUSIONS: The co-administration of OPV with RV3-BB rotavirus vaccine in a birth dose strategy did not reduce the immunogenicity of either vaccine. These findings support the use of a neonatal RV3-BB vaccine where either OPV or IPV is used in the routine vaccination schedule.

Antimicrobial use in an Indonesian community cohort 0-18 months of age.

BACKGROUND: Antimicrobial resistance has become a global health emergency and is contributed to by inappropriate antibiotic use in community clinical settings. The aim of this study was to evaluate the antimicrobial use pattern in infants from birth until 18 months of age in Indonesia. METHODS: A post-hoc analysis was conducted in 1621 participants from the RV3BB Phase IIb trial conducted in Indonesia from January 2013 through July 2016. Any health events were documented in the trial as adverse events. Concomitant medication surveillance recorded all medications, including antibiotics during the 18 months of follow-up. Information included the frequency, duration of usage, formulation, classes, and their indications, including prophylactic antibiotic and perinatal use. RESULTS: Of 1621 participants, 551 (33.99%) received at least one antibiotic for treatment of infections during the 18 months observation period. Additionally, during the perinatal period, prophylactic antibiotics were used in 1244 (76.74%) participants and antibiotics consumed in 235 mothers of participants (14.50%). A total of 956 antibiotic consumptions were recorded for 18 months follow up, 67 (7.01%) as part of antimicrobial combinations. The average duration of antibiotic course was 4.92 days. Penicillin and sulfonamides were the most common antibiotic classes consumed (38.81% and 24.48%, respectively). CONCLUSIONS: Despite the low community consumption rate, the overuse of antibiotic in URTIs and non-bloody diarrhea in our setting represents a major opportunity for antimicrobial stewardship, particularly in early life.

Phylogenetic and immunoinformatic analysis of VP4, VP7, and NSP4 genes of rotavirus strains circulating in children with acute gastroenteritis in Indonesia.

Rotavirus is a major cause of diarrhea in Indonesian children. However, rotavirus vaccines have not been introduced in the national immunization program of Indonesia. Understanding the genetic diversity and conserved antigenic regions of circulating strains are therefore essential to assess the potential efficacy of rotavirus vaccines. We collected fecal samples from hospitalized children less than 5 years of age with acute diarrhea. Rotavirus genotyping was performed by reverse transcriptase polymerase chain reaction, followed by sequencing of the VP4, VP7, and NSP4 genes of representative strains. Phylogenetic analysis was performed to investigate their relationship with globally circulating strains. Conservational analysis, immunoinformatics, and epitope mapping in comparison to vaccine strains were also performed. The sequence analyses showed that differences of multiple amino acid residues existed between the VP4, VP7, and NSP4 antigenic regions of the vaccine strains and the Indonesian isolates. However, many predicted conserved epitopes with higher antigenicity were observed in the vaccine and Indonesian strains, conferring the importance of these epitopes. The identified epitopes showed a higher potential of rotavirus vaccine to be employed in Indonesia. It could also be helpful to inform the design of a peptide vaccine based on the conserved regions and epitopes in the viral proteins.

Malaria morbidity and mortality following introduction of a universal policy of artemisinin-based treatment for malaria in Papua, Indonesia: A longitudinal surveillance study.

BACKGROUND: Malaria control activities can have a disproportionately greater impact on Plasmodium falciparum than on P. vivax in areas where both species are coendemic. We investigated temporal trends in malaria-related morbidity and mortality in Papua, Indonesia, before and after introduction of a universal, artemisinin-based antimalarial treatment strategy for all Plasmodium species. METHODS AND FINDINGS: A prospective, district-wide malariometric surveillance system was established in April 2004 to record all cases of malaria at community clinics and the regional hospital and maintained until December 2013. In March 2006, antimalarial treatment policy was changed to artemisinin combination therapy for uncomplicated malaria and intravenous artesunate for severe malaria due to any Plasmodium species. Over the study period, a total of 418,238 patients presented to the surveillance facilities with malaria. The proportion of patients with malaria requiring admission to hospital fell from 26.9% (7,745/28,789) in the pre-policy change period (April 2004 to March 2006) to 14.0% (4,786/34,117) in the late transition period (April 2008 to December 2009), a difference of -12.9% (95% confidence interval [CI] -13.5% to -12.2%). There was a significant fall in the mortality of patients presenting to the hospital with P. falciparum malaria (0.53% [100/18,965] versus 0.32% [57/17,691]; difference = -0.21% [95% CI -0.34 to -0.07]) but not in patients with P. vivax malaria (0.28% [21/7,545] versus 0.23% [28/12,397]; difference = -0.05% [95% CI -0.20 to 0.09]). Between the same periods, the overall proportion of malaria due to P. vivax rose from 44.1% (30,444/69,098) to 53.3% (29,934/56,125) in the community clinics and from 32.4% (9,325/28,789) to 44.1% (15,035/34,117) at the hospital. After controlling for population growth and changes in treatment-seeking behaviour, the incidence of P. falciparum malaria fell from 511 to 249 per 1,000 person-years (py) (incidence rate ratio [IRR] = 0.49 [95% CI 0.48-0.49]), whereas the incidence of P. vivax malaria fell from 331 to 239 per 1,000 py (IRR = 0.72 [95% CI 0.71-0.73]). The main limitations of our study were possible confounding from changes in healthcare provision, a growing population, and significant shifts in treatment-seeking behaviour following implementation of a new antimalarial policy. CONCLUSIONS: In this area with high levels of antimalarial drug resistance, adoption of a universal policy of efficacious artemisinin-based therapy for malaria infections due to any Plasmodium species was associated with a significant reduction in total malaria-attributable morbidity and mortality. The burden of P. falciparum malaria was reduced to a greater extent than that of P. vivax malaria. In coendemic regions, the timely elimination of malaria will require that safe and effective radical cure of both the blood and liver stages of the parasite is widely available for all patients at risk of malaria.

Religious and community leaders' acceptance of rotavirus vaccine introduction in Yogyakarta, Indonesia: a qualitative study.

BACKGROUND: In Indonesia, oral rotavirus vaccines are available but not funded on the National Immunization Program (NIP). New immunization program introduction requires an assessment of community acceptance. For religiously observant Muslims in Indonesia, vaccine acceptance is further complicated by the use of porcine trypsin during manufacturing and the absence of halal labeling. In Indonesia, religious and community leaders and the Majelis Ulama Indonesia (MUI) are important resources for many religiously observant Muslims in decisions regarding the use of medicines, including vaccines. This study aimed to explore the views of religious and community leaders regarding the rotavirus vaccine to inform future communication strategies. METHODS: Twenty semi-structured in-depth interviews were undertaken with religious leaders and community representatives from two districts of Yogyakarta Province, Indonesia. Thematic analysis was undertaken. RESULTS: Although there was recognition childhood diarrhoea can be severe and a vaccine was needed, few were aware of the vaccine. Participants believed a halal label was required for community acceptance, and maintenance of trust in their government and leaders. Participants considered themselves to be key players in promoting the vaccine to the community post-labeling. CONCLUSIONS: This study highlights the need for better stakeholder engagement prior to vaccine availability and the potentially important role of religious and community leaders in rotavirus vaccine acceptability in the majority Muslim community of Yogyakarta, Indonesia. These findings will assist with the development of strategies for new vaccine introduction in Indonesia.

Norovirus and rotavirus infections in children less than five years of age hospitalized with acute gastroenteritis in Indonesia.

Rotaviruses and noroviruses are the most important viral causes of acute gastroenteritis in children. While previous studies of acute gastroenteritis in Indonesia mainly focused on rotavirus, here, we investigated the burden and epidemiology of norovirus and rotavirus disease. Children less than five years of age hospitalized with acute gastroenteritis were enrolled in this study from January to December 2015 at three participating hospitals. Rotavirus was detected by enzyme immunoassay (EIA), followed by genotyping by reverse transcription PCR (RT-PCR). Norovirus genogroups were determined by TaqMan-based quantitative RT-PCR. Among 406 enrolled children, 75 (18.47%), 223 (54.93%) and 29 (7.14%) cases were positive for norovirus, rotavirus and both viruses (mixed infections), respectively. Most cases clinically presented with fever, diarrhea, vomiting and some degree of dehydration. The majority (n = 69/75 [92%]) of the noroviruses identified belonged to genogroup II, and several genotypes were identified by sequencing a subset of samples. Among 35 samples tested for rotavirus genotype, the most prevalent genotype was G3P[8] (n = 30/35 [85.6%]). Our study suggests that the burden of norovirus diseases in Indonesian children should not be underestimated. It also shows the emergence of rotavirus genotype G3P[8] in Indonesia.

Predictors of mortality in children with nosocomial bloodstream infection.

Background: Nosocomial bloodstream infection (BSI) is associated with high mortality rates. Evaluating factors to predict mortality is important for prevention and improving clinical outcomes. Aim: To evaluate the clinical predictors of mortality in paediatric nosocomial bloodstream infection. Methods: A prospective cohort study was conducted from 1 December 2010 until 28 February 2013 in a teaching hospital in Yogyakarta, Indonesia. All patients admitted consecutively to the paediatric ICU (PICU) and paediatric wards after > 48 h of hospitalisation were eligible. Patients were observed daily to identify the presence of nosocomial BSI based on Centers for Disease Control and Prevention (CDC) criteria. Patients were followed up until they were discharged or died, and predictors of mortality were identified. Logistic regression was used to identify independent predictors. Results: A total of 2646 patients were recruited, 170 developed nosocomial BSI (6.4%) and 70 of these children died (case fatality rate 41%). Nosocomial BSI was associated with increased mortality with an adjusted OR of 8.5 (95% CI 6.0-12.1). In multivariate analysis, malnutrition, admission to the PICU and use of a central line catheter were independently associated with an increased risk of death with adjusted ORs (95% CI), respectively, of 6.0 (1.6-22.6), 3.2 (1.6-6.7) and 3.1 (1.1-8.7). Conclusion: The study demonstrates that significant mortality is attributable to nosocomial bloodstream infection. An increased risk of death in children with nosocomial BSI can be identified by simple clinical predictors including malnutrition, admission to the PICU and use of a central line catheter.

The effect of zinc supplementation on pro-inflammatory cytokines (TNF-α, IL-1 AND IL-6) in mice with Escherichia coli LPS-induced diarrhea.

BACKGROUND AND OBJECTIVES: Inflammation in the intestine causes diarrhea due to an increased release of pro-inflammatory cytokines such as TNF-α, IL-1, and IL-6. These are triggered by the exposure of E. coli-LPS to epithelial cells of the intestinal mucosa as well as low concentration of zinc in plasma such as in infants or children who are experiencing diarrhea. This paper aims to determine the effects of zinc supplementation on pro-inflammatory cytokines (TNF-α, IL-1 and IL-6) in mice with E. coli-LPS-induced diarrhea. MATERIALS AND METHODS: This study used a controlled trial experimental design in the laboratory. A sample size of 20 mice were randomly divided into 4 groups: 1) Control group was given standard foods, 2) Trial group was given E. coli-LPS 2.5 mg/kg/oral once on day1, 3) Prevention group was given E. coli-LPS + 30 mg/kg/oral of zinc once daily for 12 days, 4) Therapeutic group was given E. coli-LPS, and were then given 30 mg/kg/oral of zinc once daily for 12 days if diarrhea occurred. Blood samples of mice were taken through the orbital sinus on the 0, 5th, 10th hour, and on the 4th, 8th and 12th days. RESULTS: Positive effects of zinc supplementation on levels of pro-inflammatory cytokines were observed, in which the higher levels of zinc were present, the lower levels of pro-inflammatory cytokines, especially TNF-α were observed. However, there was an increase of IL-1 and IL-6 levels on the 8th day in the prevention and therapeutic groups. CONCLUSION: Oral zinc supplementation had a significant positive effect on the levels of pro-inflammatory cytokines. Where there were higher levels of zinc, lower levels of pro-inflammatory cytokines TNF-α were present.