Seasonal effects in the elimination of trachoma

The World Health Organization currently recommends annual mass antibiotic treatment to eliminate the ocular chlamydia that cause blinding trachoma. Active trachoma is believed to be seasonal in many areas of the world, and the optimal season in which to treat has not as yet been established. Here we use mathematical models of disease transmission to demonstrate that ideally, treatment should be administered before the low season to have the greatest chance of locally eliminating infection.     

Efficacy of delayed administration of post-chemotherapy granulocyte colony-stimulating factor: evidence from murine studies of bone marrow cell kinetics

The optimal schedule of post-chemotherapy granulocyte colony-stimulating factor (G-CSF) administration has not been determined. G-CSF is customarily started 24 hours after chemotherapy; however, clinical data demonstrated that delaying G-CSF until 5 days after completion of chemotherapy has not resulted in a longer duration of neutropenia. Here, we examined the optimal timing of post-chemotherapy G-CSF administration in a mouse model, to show that delayed administration does not postpone the appearance of mature granulocytes in the peripheral blood. We also investigated the mechanism of decreased efficacy of the early G-CSF application after chemotherapy by characterizing the changes in bone marrow cellular composition. To our knowledge, we demonstrate for the first time, that early after chemotherapy, the bone marrow is predominantly composed of mature residual granulocytes and very few progenitors and precursors, on which G-CSF would act to generate granulocytes. The point when immature progenitors reappear does not occur in murine bone marrow until 48 hours after a single dose of cyclophosphamide. Our results indicate that the bone marrow cellular composition early after discontinuation of chemotherapy is not optimal for G-CSF action on acceleration of myeloid recovery. Given the high cost of G-CSF prophylaxis, its delayed administration may potentially result in substantial economic benefits.     

Development of trachoma control programs and the involvement of national resources

Trachoma, one of the commonest eye diseases in developing countries, is associated with adverse living conditions and low socioeconomic status. The control of trachoma as a blinding disease has been the target of many national campaigns. The strategy of such campaigns has usually been based on intermittent topical treatment on a mass or selective basis, together with services for trichiasis surgery and health education. National campaigns against trachoma have often been successful on a short-term basis but have not always achieved their long-term goals. Sustained efforts are needed to maintain trachoma control, an area of endeavor that lends itself well to integration with general health services, particularly on a primary health care basis. In addition to logistic aspects, treatment compliance and behavioral patterns related to living conditions must be considered in the design of trachoma control programs.     

Sociomedical contributions to trachoma research and intervention

Although the importance of human factors in the transmission and control of blinding trachoma has long been recognized, little sociomedical research has been undertaken on this disease. The trachoma literature contains considerable anecdotal information and a few reports relating to human behavioral, cultural, social, and economic factors, but systematic study in this area is needed. The potential range of sociomedical contributions to trachoma research is wide, including studies on the transmission of the disease, its consequences (especially blindness), and the planning, logistics, monitoring, and evaluation of intervention programs.     

The natural history of endemic trachoma: a longitudinal study.

A longitudinal study of trachoma was conducted among 100 members of nine families living in a hyperendemic area of Tanzania. Family members were examined for trachoma every three months for one year and conjunctival specimens were collected for antigen detection, which was performed either by direct fluorescent antibody cytologic analysis or enzyme immunoassay. The serovar specificity of tear antibodies was determined. Overall, young children tended to form a core of those with persistent, often severe, disease who consistently shed Chlamydia. These children are a potential source of infection in their family. Chlamydia could be identified early in the course of presumed recently acquired infections, but not later in resolving infections. This temporal change may account for the discrepancies between demonstrable organisms and clinical disease seen in cross-sectional studies. Several children were identified who did not develop trachoma despite having Chlamydia identified in conjunctival scrapings. Their ability to resist infection may offer clues for vaccine development. The study of serovar specificity is consistent with the intrafamily transmission of trachoma, but was confounded by the large family size and the potential for separate transmission units to occur within large extended families. These observations give further understanding of the natural history and kinetics of the transmission of trachoma that should be of use in developing and evaluating intervention studies.     

Nationwide integrated mapping of three neglected tropical diseases in Togo: countrywide implementation of a novel approach

Objective To conduct a nationwide integrated neglected tropical disease (NTD) prevalence survey to define the need for public health interventions using an innovative mapping protocol. Methods Two villages were selected in every peripheral health unit in endemic districts: 29 districts for schistosomiasis and STH, 15 of them for trachoma. In each village, 15 children aged 6–9 years at a randomly selected school were tested. An additional convenience sample of 35 children aged 1–5 years underwent an eye examination for trachoma. This integrated mapping was followed by a 20‐cluster trachoma survey in each district that surpassed the WHO‐defined threshold of 10% prevalence of trachomatous inflammation‐follicular (TF). Results A total of 1096 villages were surveyed in <6 weeks. The district prevalence of schistosomiasis ranged from 2 to 49% and of STH from 5 to 70%, with prevalence at the village level ranging from 0 to 100% for both diseases. Two districts passed the threshold of 10% for active trachoma, but the cluster survey indicated this was because of misclassification bias and that the real prevalence was <1%. Conclusion Results of this mapping were used by the MoH and partners to plan integrated mass drug administration (MDA). Mass drug administration for trachoma was not implemented as no district passed the threshold requiring public health intervention.     

Determinants of success in national programs to eliminate lymphatic filariasis: a perspective identifying essential elements and research needs

The Global Programme to Eliminate Lymphatic Filariasis (GPELF) was launched in 2000. To understand why some national programs have been more successful than others, a panel of individuals with expertise in LF elimination efforts met to assess available data from programs in 8 countries. The goal was to identify: 1) the factors determining success for national LF elimination programs (defined as the rapid, sustained reduction in microfilaremia/antigenemia after repeated mass drug administration [MDA]); 2) the priorities for operational research to enhance LF elimination efforts. Of more than 40 factors identified, the most prominent were 1) initial level of LF endemicity; 2) effectiveness of vector mosquitoes; 3) MDA drug regimen; 4) population compliance. Research important for facilitating program success was identified as either biologic (i.e., [1] quantifying differences in vectorial capacity; [2] identifying seasonal variations affecting LF transmission) or programmatic (i.e., [1] identifying quantitative thresholds, especially the population compliance levels necessary for success, and the antigenemia or microfilaremia prevalence at which MDA programs can stop with minimal risk of resumption of transmission; [2] defining optimal drug distribution strategies and timing; [3] identifying those individuals who are "persistently non-compliant" during MDAs, the reasons for this non-compliance and approaches to overcoming it). While addressing these challenges is important, many key determinants of program success are already clearly understood; operationalizing these as soon as possible will greatly increase the potential for national program success.     

Trachoma: transmission, infection, and control

Mass antibiotic treatment and facial cleanliness are central to WHO's strategy for the elimination of blindness caused by trachoma. Recent studies have highlighted the heterogeneous response of communities to mass treatment and the complex relation between infection with Chlamydia trachomatis and clinical disease. It is important to be able to explain these findings to predict and maximise the effect of treatment on active trachoma disease and blindness in the community. Here we review the immunobiology of trachoma and provide a simple conceptual model of disease pathogenesis. We show how incorporating this model into a mathematical framework leads to an explanation of the observed community distribution of infection, bacterial load, and disease with age. The predictions of the model and empirical data show some differences that underscore the importance of individual heterogeneity in response to infection. The implications of disease transmission and pathogenesis for trachoma control programmes are discussed.     

When is a patient safe for discharge after procedural sedation? The timing of adverse effect events in 1367 pediatric procedural sedations

STUDY OBJECTIVES: The optimal timing of discharge from the emergency department (ED) after pediatric procedural sedation and analgesia has not been well studied. Because concern about delayed adverse effects commonly delays discharge after sedation, we attempted to establish the timing of adverse effects in our cohort of procedural sedations. METHODS: We analyzed data from a prospectively generated database comprising consecutive sedation events throughout a 2-year period. We determined the timing of serious (eg, hypoxia, stridor, hypotension) and other adverse effects from final medication administration and calculated adverse effect risk ratios in relation to sedation characteristics. RESULTS: In 1341 sedation events, there were 184 (13.7%) adverse effects, of which 159 (11.9%) were serious. The median age of children with and without adverse effects was similar (64 months in both groups). Most adverse effects occurred during the procedure (92%) rather than after the procedure (8%). Serious adverse effects occurred a median of 2 minutes after final medication dose (range -106 to +40 minutes). One hypoxic episode occurred each at 26, 30, and 40 minutes after final medication administration; all were repeated occurrences in children who had experienced previous hypoxia during the expected peak drug effect. CONCLUSION: Adverse effects were common; however, serious adverse effects rarely occurred after 25 minutes from the final medication administration. Those that did occur this late were all preceded by a separate similar adverse effect during the expected peak drug effect, which suggests that when similar medication regimens are used, discharge from the ED may be safe at approximately 30 minutes after final sedation medication administration if no adverse effects have occurred.     

Ivermectin mass drug administration to humans disrupts malaria parasite transmission in Senegalese villages

Ivermectin mass drug administration (MDA) to humans is used to control onchocerciasis and lymphatic filariasis. Recent field studies have shown an added killing effect of ivermectin MDA against malaria vectors. We report that ivermectin MDA reduced the proportion of Plasmodium falciparum infectious Anopheles gambiae sensu stricto (s.s.) in treated villages in southeastern Senegal. Ivermectin MDA is a different delivery method and has a different mode of action from current malaria control agents. It could be a powerful and synergistic new tool to reduce malaria transmission in regions with epidemic or seasonal malaria transmission, and the prevalence and intensity of neglected tropical diseases.     

Cell Therapy for Acute Myocardial Infarction—Where Do We Go From Here?

Multiple clinical trials have been performed to test the hypothesis that administration of bone-marrow-derived progenitor and stem cells (BMCs) may improve left-ventricular (LV) function following acute myocardial infarction (AMI). These studies have generally confirmed that cell therapy administration can be safely administered; however, consensus has not been reached on whether this approach results in an improvement in LV function or clinical outcomes. Although many of the published studies have been randomized, placebo-controlled trials, many important questions regarding patient selection, methodology and trial design still exist. To date, almost no information has been obtained in regard to optimal dosing and cell type, timing of administration and preferred method of delivery. As a result, current cell therapy administration for AMI finds itself at the crossroads. In this review we have highlighted some of the important questions that remain unanswered in the field of cell therapy after AMI. We believe that future cell therapy trials should attempt to incorporate these important issues in designing upcoming clinical trials in order for the field to move forward.     

Review: Intermittent preventive treatment--a new approach to the prevention of malaria in children in areas with seasonal malaria transmission

Intermittent preventive treatment, the administration of a full course of an anti-malarial treatment to a population at risk at specified time points regardless of whether or not they are known to be infected, is now a recommended approach to the prevention of malaria in pregnancy and is being explored as a potential way of preventing malaria in infants. However, in many malaria endemic areas, the main burden of malaria is in older children and increasing use of insecticide treated bednets is likely to increase further the proportion of episodes of malaria that occur in older children. Recently, it has been shown in Senegal and in Mali that intermittent preventive treatment given to older children during the malaria transmission season can be remarkably effective in preventing malaria. This approach to malaria control is likely to be most effective in areas with a high level of malaria transmission concentrated in a short period of the year. However, several issues need to be addressed before intermittent preventive treatment in children can be advocated for use in malaria control programmes. These include: (1) determination of whether intermittent preventive treatment adds to the protection afforded by other control measures such as insecticide-treated bednets; (2) whether an effective and sustainable delivery system can be found; (3) choice of drug to be used; (4) optimum timing of drug administration; (5) the requisite interval between treatments. The potential benefits of intermittent preventive treatment in children are substantial; more research is needed to determine if this is a practical approach to malaria control.     

Trachoma in Jimma Zone, South Western Ethiopia.

A population-based survey on trachoma was carried out in Jimma zone. The survey showed that trachoma is hyperendemic: of 7,423 people examined, 33.02% had signs of trachoma, 28.9% of males and 37.01% of females; 26.13% of the urban and 34.09% of the rural population had clinical signs of trachoma. Active trachoma (TF/TI) was seen in 24.5% of the study population (an estimated half million people). The prevalence of signs of active trachoma among children 0–10 years of age was 35.7%. Blinding trachoma (CO/TT) was seen in 3.81% of the population: 6.86% of the female population aged 15 years had trichiasis and/or entropion.
Both active and critical trachoma were significantly associated with the female gender ( P < 0.0000001 for each), living in rural areas ( P < 0.0001 for each type), parental illiteracy ( P < 0.0000001 for each) and absence of a latrine ( P < 0.01 for each). Shorter distance of the household water supply was associated with a higher prevalence of both active and cicatricial trachoma. This was significant only for cases of active trachoma living in households within 16 to 30 minutes walking distance from the water source ( P < 0.03).
An estimated 17000 people in the zone are blind; 3500 of these from trachoma. About 52,000 people are in danger of blindness from trichiasis. Primary eye care activities such as promoting health education (face washing) among community members, especially women and children, mass chemotherapy for trachoma, training of health workers and establishment of community-based surgical services are recommended. These are to be executed by the Zonal Health Department in close collaboration with the community, governmental and non-governmental organisations.     

Assessment of biological responses: what to measure and when

During the past several years, increasing attention has been devoted to the use of biological response modifiers (BRMs) for the treatment of cancer. Phase I trials of BRMs must be designed to provide information not only regarding toxic effects, pharmacokinetics, and antitumor activities, but also on the many immunomodulatory effects. Biological monitoring must be carefully planned to enable meaningful conclusions to be drawn as to the optimal dose, schedule, and route of administration. Important considerations include selection of assays for the various biological effects, timing of testing following BRM administration, and methods for data interpretations.     

Early and late angiotensin-converting enzyme inhibition in acute myocardial infarction

Studies in animals and humans have shown that angtotensin-converting enzyme (ACE) inhibitors can prevent or at least attenuate ventricular dilation and remodeling following acute myocardial infarction (MI) and can improve subsequent left ventricular dysfunction, a strong predictor of survival. The question as to which patients will benefit most from ACE inhibitor therapy and the optimal timing of administration of such intervention after the onset of symptoms is still matter of debate, even if it is hypothesized that a greater benefit in terms of remodeling prevention may occur after early administration. However, while it is currently accepted that patients with asymptomatic postinfarctual left ventricular dysfunction can benefit from long-term administration of an ACE inhibitor when therapy is started late, the usefulness of an early administration is still to be clarified. In this setting, the question of early versus late ACE inhibitor treatment has to be related to the different evolving pattern of myocardial infarction with regard to the different degrees of postinfarction ventricular dysfunction and neurohormonal activation, whose extent could influence the effect of ACE inhibition. For example, not all patients with acute MI show progressive ventricular dilation. Early dilation is frequent in patients with anterior localization of necrosis, whereas it is usually not relevant in patients with acute inferior MI. Thus, different postinfarction patterns may differently influence the clinical success of therapeutic interventions, which can be instituted at various stages following acute Ml. The results of large clinical trials that are investigating the hypothesis of a benefit following early treatment with ACE inhibitors (ISIS-4, GISSI-3, SMILE) will provide clinical information on this Important Issue in the very near future and will better focus on the correct timing for ACE inhibition in these patients.     

Timing of maternal and neonatal dosing of nevirapine and the risk of mother-to-child transmission of HIV-1: HIVNET 024

OBJECTIVE: Despite a growing emphasis worldwide on complex and potent antiretroviral drug regimens for the prevention of mother-to-child transmission of HIV-1 (MTCT), two-dose nevirapine (NVP) prophylaxis remains an important choice in many settings. We analyzed data from a multicenter clinical trial to determine whether timing of maternal or infant NVP was associated with MTCT between delivery and 6 weeks of age (intrapartum/early postnatal transmission; I/EP). METHODS: HIVNET 024 was a placebo-controlled, double-blind trial of empiric antibiotics to reduce chorioamnionitis-associated MTCT. This secondary analysis used data collected in the original randomized trial. Enrolled women were instructed to self-administer NVP at labor onset; infants were to receive a dose within 72 h of birth. RESULTS: Data regarding 1491 mother-infant pairs were analyzed. The overall I/EP HIV-1 transmission rate was 8.1% at 6 weeks. Almost all women (93%) ingested NVP within 24 h of delivery; 90% of infants were given NVP within 48 h after delivery. Variations in mother or infant dose timing did not influence transmission rates, even when the combined pattern of both was taken into account through multivariate analysis. In the subset of women ingesting NVP or= 4 h). CONCLUSION: Variations in the timing of maternal and infant NVP doses (within reasonable proximity to delivery) do not appear to affect the risk of MTCT.     

Impact of cross-protective vaccines on epidemiological and evolutionary dynamics of influenza

Large-scale immunization has profoundly impacted control of many infectious diseases such as measles and smallpox because of the ability of vaccination campaigns to maintain long-term herd immunity and, hence, indirect protection of the unvaccinated. In the case of human influenza, such potential benefits of mass vaccination have so far proved elusive. The central difficulty is a considerable viral capacity for immune escape; new pandemic variants, as well as viral escape mutants in seasonal influenza, compromise the buildup of herd immunity from natural infection or deployment of current vaccines. Consequently, most current influenza vaccination programs focus mainly on protection of specific risk groups, rather than mass prophylactic protection. Here, we use epidemiological models to show that emerging vaccine technologies, aimed at broad-spectrum protection, could qualitatively alter this picture. We demonstrate that sustained immunization with such vaccines could--through potentially lowering transmission rates and improving herd immunity--significantly moderate both influenza pandemic and seasonal epidemics. More subtly, phylodynamic models indicate that widespread cross-protective immunization could slow the antigenic evolution of seasonal influenza; these effects have profound implications for a transition to mass vaccination strategies against human influenza, and for the management of antigenically variable viruses in general.     

Seasonal and altitudinal variations in fly density and their association with the occurrence of trachoma, in the Gurage zone of central Ethiopia

In the Gurage zone of central Ethiopia, the association between fly density and the occurrence of trachoma has been investigated across varying altitudes. The seasonal pattern of fly density in the area was also explored. When, over short sampling periods (10 min/child indoors and 10 min/child outdoors), hand nets were used to collect flies from the eyes of children aged 2-8 years, only Musca sorbens and M. domestica were caught. Almost all of the 13,147 'eye-seeking' flies collected came from villages at low (<2000 m; 40.7%) or mid altitudes (2200-2500 m; 58.6%) with only 0.7% of them caught in the high-altitude villages investigated (at >3000 m). Musca sorbens predominated outdoors and M. domestica indoors. Almost all (99.3%) of the eye-seeking M. sorbens collected were caught outdoors whereas most (76.7%) of the M. domestica were caught indoors (P<0.0001 for each). The median numbers of flies caught, per child, per 10-min collection, in the low-, mid- and high-altitude villages were 9.5, six and zero, respectively, for M. sorbens, and eight, three and zero, respectively, for M. domestica. The altitudinal trends in these numbers of 'eye-seeking' flies matched those in the prevalences of active trachoma among children aged 1-10 years, which were high in the villages at low (81.6%) and mid altitude (78.7%) but much lower (1.7%) in the high-altitude villages. In conclusion, trachoma is a common disease of public-health importance only in the low- and mid-altitude villages in the Gurage zone, where there are large numbers of eye-seeking flies, and not in the villages that lie >3000 m above sea level, where there is a dearth of such flies.     

Review of the evidence base for the 'F' and 'E' components of the SAFE strategy for trachoma control

Community control of trachoma as a blinding disease is based on the SAFE strategy of Surgery, Antibiotic therapy, Facial cleanliness and Environmental improvement. Surgery and antibiotic therapy currently dominate most programmes. Blindness from trachoma results from frequent infections repeated over many years, so ultimate success requires the reduction of transmission. This is only likely to be sustainable through the F and E components of SAFE. Environmental improvement with access to water, enhanced hygiene and better sanitation reduces trachoma transmission and the blinding sequelae eventually disappear. Transmission routes and factors that cause this are not known and consequently no single specific tool for F and E is in place. Evidence from intervention studies shows that the promotion of face-washing gave modest gains for intense effort and a pilot study showed that trachoma transmission was reduced in the absence of eye-seeking flies. Other studies have shown that latrines and improved access to water are associated with a lower prevalence of active trachoma. There is likely to be a long-term beneficial effect of a combination of improved water supplies, provision of latrines, facial hygiene promotion through established infrastructure and control of eye-seeking flies. Each of these interventions offers additional public health and other benefits in its own right. Further research on the routes of transmission, the role of hygiene and means of sustainable fly control should be a priority.