Testing the Impact of Phone Texting Reminders for Children's Immunization Appointments in Rural Cameroon: Protocol for a Nonrandomized Controlled Trial.

BACKGROUND: Globally, over 20 million children are unvaccinated and over 25 million missed their follow-up doses during the COVID-19 pandemic; thus, they face vaccine-preventable diseases and unnecessary deaths. This is especially the case for those with HIV or living in vulnerable settings. Using cell phones to send reminders to parents has been shown to improve vaccination rates. OBJECTIVE: We aim to determine whether implementation of an automated SMS reminder will improve child vaccination rates in a turbulent, semiurban/semirural setting in a low-income country. METHODS: This will be a nonrandomized controlled trial that will be conducted at Azire Integrated Health Centre, Bamenda, Cameroon. RESULTS: A total of 200 parents per study group (aged over 18 years) who are registered at the clinic at least one month prior to the study will be recruited. The intervention group will receive 2 reminders: 1 week and 2 days prior to the scheduled vaccination. For those who miss their appointments, a reminder will be sent 1 week after their missed appointment. The control group will receive the regular care provided at the clinic. Baseline information, clinical visit data, and vaccination records will be collected for both groups. Descriptive statistics will be used to summarize baseline characteristics between and within clusters and groups. The Fisher exact test will be used to compare parent-child units who return for follow-up visits (as a percentage) and children vaccinated as scheduled (as a percentage) between the study groups. Finally, we will compare how many members of both study groups return for 1 follow-up visit using Kaplan-Meier survival analysis. CONCLUSIONS: Due to limited effective child vaccination interventions in unstable settings, this study will be of high importance for suggesting a holistic approach to improve child vaccination and public health. INTERNATIONAL REGISTERED REPORT IDENTIFIER (IRRID): DERR1-10.2196/47018.

Scaling the Children Immunization App (CIMA) to Support Child Refugees and Parents in the Time of the COVID-19 Pandemic: A Social Capital Approach to Scale a Smartphone Application in Zaatari Camp, Jordan.

BACKGROUND: Children vaccination is a key intervention for their survival, especially among refugees. Yet, children vaccination registration is done manually in refugees camps and there is no possibility to send reminders to parents to come back on time. We aimed to boost the parental registration of children's vaccination records on a Children Immunization app (CIMA) while also availing the parents with useful parenting skills under COVID-19-related stress. METHODS: We incorporated United Nations Office on Drugs and Crime (UNODC) Parenting Skills under COVID-19 information material, through CIMA in Arabic and English languages. We recruited 1100 children in February-March 2021, through a community health promotion dissemination approach. A team of two nurses from the local population and two volunteers (one trained nurse and one trained social worker), from the camp, was formed. They promoted the CIMA app at two clinics and through households visits in Zaatari refugee camp. Qualitative data on impressions and observations of the interactions with the Zaatari camp community were also collected. RESULTS: A total of 1100 children, up to 15 months of age, eligible for vaccination were enrolled in CIMA, whereby the staff explained the content of the app in terms of vaccination schedule, health promotion materials for vaccination and parenting skills to their caregivers. During the household visits, the volunteers identified a total of 70 children that have incomplete history of vaccination records (n = 42/70 girls, 60%). Also, opportunities and challenges for scaling the app were documented. CONCLUSION: The scaling of CIMA as an innovative means of dissemination of risk and health information in challenging context such as refugee camps was feasible. In the context of vaccination needs for children, in refugee settings, such a need is more eminent, particularly in the context of COVID-19.

Family Health Days program contributions in vaccination of unreached and under-immunized children during routine vaccinations in Uganda.

BACKGROUND: We explored the contributions of the Family Health Days (FHDs) concept, which was developed by the Uganda Ministry of Health (MOH) and UNICEF as a supplementary quarterly outreach program in addition to strengthening the routine expanded program for immunization (EPI), with the aim to increase coverage, through improved access to the unimmunized or unreached and under-immunized children under 5 years. METHOD: A cross-sectional descriptive study of the Uganda MOH, Health Management Information Systems (HMIS) and UNICEF in house FHDs data was conducted covering six quarterly implementations of the program between April 2012 and December 2013. The FHDs program was implemented in 31 priority districts with low routine vaccination coverage from seven sub-regions in Uganda in a phased manner using places of worship for service delivery. RESULTS: During the six rounds of FHDs in the 31 districts, a total of 178,709 and 191,223 children received measles and Diphtheria-Pertussis-Tetanus (DPT3) vaccinations, respectively. The FHDs' contributions were 126% and 144% for measles and 103% and 122% for DPT3 in 2012 and 2013, respectively of the estimated unreached annual target populations. All implementing sub-regions after two rounds in 2012 attained over and above the desired target for DPT3 (85%) and measles (90%). The same was true in 2013 after four rounds, except for Karamoja and West Nile sub-regions, where in some districts a substantial proportion of children remained unimmunized. The administrative data for both DPT3 and measles immunization showed prominent and noticeable increase in coverage trend in FHDS regions for the months when the program was implemented. CONCLUSION: The FHDs program improved vaccination equity by reaching the unreached and hard-to-reach children and bridging the gap in immunization coverage, and fast tracking the achievement of targets recommended by the Global Vaccine Action Plan (GVAP) for measles and DPT3 (85% and 90% respectively) in implementing sub-regions and districts. The FHDs is an innovative program to supplement routine immunizations designed to reach the unreached and under immunized children.

Type-1 interferons prolong the lifespan of neutrophils by interfering with members of the apoptotic cascade.

Polymorphonuclear Neutrophils (PMNs) are metabolically highly active phagocytes, present in abundant numbers in the circulation. These active cells take the onus of clearing invading pathogens by crowding at inflammatory sites in huge numbers. Though PMNs are extremely short living and die upon spontaneous apoptosis, extended lifespan has been observed among those cells arrive at the inflammation sites or tackle intracellular infections or face any microbial challenges. The delay/inhibition of spontaneous apoptosis of these short-living cells at the inflammatory core rather helps in combating pathogens. Like many candidates, type-1 interferons (type-1 IFNs) is a group of cytokines predominant at the inflammation site. Although there are some isolated reports, a systematic study is still lacking which addresses the impact of the predominant type of interferon on the spontaneous apoptosis of neutrophils. Here in, we have observed that exposure of these IFNs (IFN-ß, IFN-α & IFN-ω etc) on human neutrophils prevents the degradation of the Bfl1, an important anti-apoptotic partner in the apoptotic cascade. Treatment showed a significant reduction in the release of cytochrome-C in the cytosol, a critical regulator in the intrinsic apoptotic pathway. We also noticed a reduction in the conversion of procaspase -3 to active caspase-3, a crucial executioner caspase towards initiation of apoptosis. Taken together our results show that exposure to interferon interferes with apoptotic pathways of neutrophils and thereby delay its spontaneous apoptosis. These findings would help us further deciphering specific roles if these inflammatory agents are causing any immune-metabolomic changes on PMNs at the inflammatory and infection core.

Infection of neutrophil granulocytes with Leishmania major activates ERK 1/2 and modulates multiple apoptotic pathways to inhibit apoptosis.

Neutrophil granulocytes provide the first line of defense against bacterial, fungal, and parasitic infections. They phagocytose and kill many invading pathogens. Certain pathogenic microorganisms such as the intracellular protozoan parasite Leishmania major (L. major) can survive inside neutrophils. Mature neutrophils have a very short life span due to spontaneous apoptosis. Previously, we have reported that infections with L. major are able to delay spontaneous apoptosis. In the present study, we addressed the underlying mechanisms of regulation of both extrinsic and intrinsic apoptosis. We show that interaction with L. major transiently activates ERK1/2 phosphorylation. Pharmacological inhibition of ERK1/2 phosphorylation reversed the apoptosis delay. Moreover, infection leads to the enhanced and sustainable expression of the anti-apoptotic proteins Bcl-2 and Bfl-1, respectively. As downstream events, the release of cytochrome c from mitochondria and processing of caspase-6 were inhibited. We also confirm that infection with L. major results in reduced FAS expression on the surface of neutrophils. The presented data indicate that infection with L. major affects both intrinsic as well as extrinsic pathways of neutrophil apoptosis. Enhanced life span of host neutrophils enables the parasite to survive within neutrophils.

Chlamydia pneumoniae multiply in neutrophil granulocytes and delay their spontaneous apoptosis.

The obligate intracellular bacterial pathogen Chlamydia pneumoniae (Cp) is responsible for a range of human diseases, including acute respiratory infection. Although experimental intratracheal infection with Cp results in a massive recruitment of neutrophil granulocytes (polymorphonuclear neutrophils (PMN)), the role of these cells in the defense against Cp is unclear. In this study the interactions of PMN with Cp were investigated. In vitro coincubation experiments showed that human granulocytes were able to internalize Chlamydia in an opsonin-independent manner. Importantly, phagocytosed Cp were not killed; the ingested bacteria survived and multiplied within PMN. Although uninfected granulocytes became apoptotic within 10 h, infected PMN survived up to 90 h. Coincubation with Cp significantly decreased the ratio of apoptotic PMN, as detected by morphological analysis, annexin V, and TUNEL staining. The observed antiapoptotic effect was associated with a markedly lower level of procaspase-3 processing and, consequently, reduced caspase-3 activity in infected PMN. LPS was found as a major, but not exclusive, component responsible for the observed antiapoptotic effect. Chlamydia LPS affected PMN apoptosis both by acting directly on the cells and by inducing the autocrine production of the antiapoptotic cytokine IL-8. These data show that, in contrast to other microbial pathogens that drive phagocytes into apoptosis to escape killing, Cp can extend the life span of neutrophil granulocytes, making them suitable host cells for survival and multiplication within the first hours/days after infection.

Highly purified lipoteichoic acid activates neutrophil granulocytes and delays their spontaneous apoptosis via CD14 and TLR2.

Lipoteichoic acid (LTA) is a major component of the cell membrane of gram-positive bacteria. Although LTA has become increasingly recognized as an immunomodulator, its effect on polymorphonuclear neutrophil granulocytes (PMN) is still not clear. The interaction between LTA and PMN, however, is of particular importance, as PMN are the first leukocytes that migrate to the site of infection and encounter bacterial pathogens. In the present study, the interaction of highly purified human PMN with endotoxin-free LTA from Staphylococcus aureus was investigated. After exposure to LTA, neutrophil granulocytes acquired typical activated cell morphology. LTA had a marked activating effect on the functions of PMN as well. Shedding of CD62L, degranulation, and priming for formyl-Met-Leu-Phe-mediated oxidative burst were induced in PMN upon exposure to LTA. Moreover, LTA treatment induced the release of proinflammatory cytokines such as interleukin-8, tumor necrosis factor alpha, and granulocyte-colony stimulating factor by PMN. The effects of LTA on PMN were found to be associated with nuclear factor-kappaB activation. Of particular interest was that LTA inhibited the spontaneous apoptosis and therefore, increased the lifespan of PMN. Experiments using blocking antibodies revealed that CD14 and Toll-like receptor 2 (TLR2) but not TLR4 play a major role in LTA-mediated effects on PMN. These data clearly show that LTA, a component of gram-positive bacteria, directly activates neutrophil granulocytes, the primary effector cells in the first line of defense against infectious challenge.

Inhibition of the spontaneous apoptosis of neutrophil granulocytes by the intracellular parasite Leishmania major.

Macrophages are the major target cell population of the obligate intracellular parasites Leishmania. Although polymorphonuclear neutrophil granulocytes (PMN) are able to internalize Leishmania promastigotes, these cells have not been considered to date as host cells for the parasites, primarily due to their short life span. In vitro coincubation experiments were conducted to investigate whether Leishmania can modify the spontaneous apoptosis of human PMN. Coincubation of PMN with Leishmania major promastigotes resulted in a significant decrease in the ratio of apoptotic neutrophils as detected by morphological analysis of cell nuclei, TUNEL assay, gel electrophoresis of low m.w. DNA fragments, and annexin V staining. The observed antiapoptotic effect was found to be associated with a significant reduction of caspase-3 activity in PMN. The inhibition of PMN apoptosis depended on viable parasites because killed Leishmania or a lysate of the parasites did not have antiapoptotic effect. L. major did not block, but rather delayed the programmed cell death of neutrophils by approximately 24 h. The antiapoptotic effect of the parasites could not be transferred by the supernatants, despite secretion of IL-8 by PMN upon coculture with L. major. In vivo, intact parasites were found intracellularly in PMN collected from the skin of mice 3 days after s.c. infection. This finding strongly suggests that infection with Leishmania prolongs the survival time of neutrophils also in vivo. These data indicate that Leishmania induce an increased survival of neutrophil granulocytes both in vitro and in vivo.