Interparental conflict is detrimental to the development of children. Only few methods for quantifying the degree of interparental conflict exist and this produces controversies about what is detrimental to child well-being and what is not. This is particularly critical in cases where there is a form of child abuse or maltreatment that cannot be diagnosed because of the lack of standards or criteria. The present study describes a method for quantifying the degree of interparental conflict on the basis of a generalizable measure which is scalable, robust, and reproducible. The method is developed on the data basis of a survey study, in which 1146 parents reported 46,720 items on the topic of hostile-aggressive parenting. The algorithm can estimate the degree of child abuse and child maltreatment which is particularly relevant for assessments of non-sexual forms of child maltreatment or abuse. The present methodology differs from classical psychometric approaches and available instruments in that its application yields the practically interpretable measure of a ‘loss of child well-being’ and that this measure can be dynamically adapted to child welfare standards changing in a society over the years. The approach identifies criteria which family courts or child welfare agencies should use for assessing interparental conflicts in a standardized and reproducible manner.

Isoxazolines are oral insecticidal drugs currently licensed for ectoparasite control in companion animals. Here we propose their use in humans for the reduction of vector-borne disease incidence. Fluralaner and afoxolaner rapidly killed Anopheles, Aedes, and Culex mosquitoes and Phlebotomus sand flies after feeding on a drug-supplemented blood meal, with IC50 values ranging from 33 to 575 nM, and were fully active against strains with preexisting resistance to common insecticides. Based on allometric scaling of preclinical pharmacokinetics data, we predict that a single human median dose of 260 mg (IQR, 177-407 mg) for afoxolaner, or 410 mg (IQR, 278-648 mg) for fluralaner, could provide an insecticidal effect lasting 50-90 days against mosquitoes and Phlebotomus sand flies. Computational modeling showed that seasonal mass drug administration of such a single dose to a fraction of a regional population would dramatically reduce clinical cases of Zika and malaria in endemic settings. Isoxazolines therefore represent a promising new component of drug-based vector control.

Purpose: Our primary purpose was to assess the clinical (predictive) validity of central retinal thickness (CRT) and best corrected visual acuity (BCVA) at 1 week and 1 month after starting treatment with ranibizumab for central retinal vein occlusion. The authors also assessed detectability of response to treatment.Methods: The authors used data from 325 participants in the CRUISE study, which included measurement of time-domain CRT and BCVA at baseline, 1 week, 1 month, and 6 months postrandomization. Analysis of covariance models were fitted to assess clinical validity, and distributions of change were constructed to assess detectability of response.Results: There was no evidence that 1-week CRT, and very strong evidence that 1-week BCVA were associated with baseline-adjusted BCVA at 6 months (P = 0.17 and P < 0.001, respectively). There was strong evidence that both 1-month CRT and 1-month BCVA were associated with baseline-adjusted 6-month BCVA (P = 0.005 and P < 0.001, respectively), but simultaneous adjustment found evidence of independent association only for BCVA (P = 0.71 and P < 0.001 for CRT and BCVA, respectively). Detectability of response tended to be higher for CRT than BCVA at 1 week and 1 month but by 6 months these were equivalent for CRT and BCVA.Conclusion: In this study, BCVA monitoring of treated central retinal vein occlusion patients seemed more informative than time-domain optical coherence tomography monitoring.

Eradication of malaria requires a novel type of drug that blocks transmission from the human to the mosquito host, but selection of such a drug is hampered by a lack of translational models. Experimental mosquito infections yield infection intensities that are substantially higher than observed in natural infections and, as a consequence, underestimate the drug effect on the proportion of mosquitoes that become infected. Here we introduce a novel experimental and computational method to adequately describe drug efficacy at natural parasite densities. Parameters of a beta-binomial infection model were established and validated using a large number of experimental mosquito infections at different parasite densities. Analyses of 15 experimental and marketed drugs revealed a class-specific ability to block parasite transmission. Our results highlight the parasite’s elongation factor EF2, PI4 kinase and the ATP4 sodium channel as key targets for interruption of transmission, and compounds DDD107498 and KAE609 as most advanced drug candidates.

Non-sexual forms of child abuse and maltreatment are difficult to define because they range on a continuous scale between forms of impairment, neglect, endangering, acute danger, etc. Methods to treat this quasi-continuous problem are required to allow for reliable and reproducible decision making in the fields between child welfare and child protection. An empirical list of 151 items on hostile-aggressive parenting has been assessed by 13 experts from various disciplines by means of a Delphi procedure. Assessments show large rater variability and rater bias which can be attributed, among other factors, to differing experiences and different background among raters. We present a method by which assessments can be projected on a continuous scale of a 'relative loss of child well-being'. As a solution for decision makers we provide threshold values and reference ranges for this loss of child well-being. The quantifications suggested by the present approach can support decision making at family courts and child protection agencies and the results can be used by professionals as well as by parents to comparatively evaluate own assessments of family or custody issues.

The elimination of infectious diseases requires reducing transmission below a certain threshold. The Visceral Leishmaniasis (VL) Elimination Initiative in Southeast Asia aims to reduce the annual VL incidence rate below 1 case per 10,000 inhabitants in endemic areas by 2015 via a combination of case management and vector control. Using a previously developed VL transmission model, we investigated transmission thresholds dependent on measures reducing the sand fly density either by killing sand flies (e.g., indoor residual spraying and long-lasting insecticidal nets) or by destroying breeding sites (e.g., environmental management). Model simulations suggest that elimination of VL is possible if the sand fly density can be reduced by 67% through killing sand flies, or if the number of breeding sites can be reduced by more than 79% through measures of environmental management. These results were compared to data from two recent cluster randomised controlled trials conducted in India, Nepal and Bangladesh showing a 72% reduction in sand fly density after indoor residual spraying, a 44% and 25% reduction through the use of long-lasting insecticidal nets and a 42% reduction after environmental management. Based on model predictions, we identified the parameters within the transmission cycle of VL that predominantly determine the prospects of intervention success. We suggest further research to refine model-based predictions into the elimination of VL.

Background: Pentavalent antimonials have been the mainstay of antileishmanial therapy for decades, but increasing failure rates under antimonial treatment have challenged further use of these drugs in the Indian subcontinent. Experimental evidence has suggested that parasites which are resistant against antimonials have superior survival skills than sensitive ones even in the absence of antimonial treatment.Methods and Findings: We use simulation studies based on a mathematical L. donovani transmission model to identify parameters which can explain why treatment failure rates under antimonial treatment increased up to 65% in Bihar between 1980 and 1997. Model analyses suggest that resistance to treatment alone cannot explain the observed treatment failure rates. We explore two hypotheses referring to an increased fitness of antimony-resistant parasites: the additional fitness is (i) disease-related, by causing more clinical cases (higher pathogenicity) or more severe disease (higher virulence), or (ii) is transmission-related, by increasing the transmissibility from sand flies to humans or vice versa.Conclusions: Both hypotheses can potentially explain the Bihar observations. However, increased transmissibility as an explanation appears more plausible because it can occur in the background of asymptomatically transmitted infection whereas disease-related factors would most probably be observable. Irrespective of the cause of fitness, parasites with a higher fitness will finally replace sensitive parasites, even if antimonials are replaced by another drug.

Control of onchocerciasis in Africa is currently based on annual community-directed treatment with ivermectin (CDTI) which has been assumed to be not efficient enough to bring about elimination. However, elimination has recently been reported to have been achieved by CDTI alone in villages of Senegal and Mali, reviving debate on the eradicability of onchocerciasis in Africa. We investigate the eradicability of onchocerciasis by examining threshold shifts and breakpoints predicted by a stochastic transmission model that has been fitted extensively to data. We show that elimination based on CDTI relies on shifting the threshold biting rate to a level that is higher than the annual biting rate. Breakpoints become relevant in the context of when to stop CDTI. In order for the model to predict a good chance for CDTI to eliminate onchocerciasis, facilitating factors such as the macrofilaricidal effect of ivermectin must be assumed. A chart predicting the minimum efficacy of CDTI required for elimination, dependent on the annual biting rate, is provided. Generalisable recommendations into strategies for the elimination of onchocerciasis are derived, particularly referring to the roles of vectors, the residual infection rate under control, and a low-spreader problem originating from patients with low parasite burdens.

Background In the Indian subcontinent, about 200 million people are at risk of developing visceral leishmaniasis (VL). In 2005, the governments of India, Nepal and Bangladesh started the first regional VL elimination program with the aim to reduce the annual incidence to less than 1 per 10,000 by 2015. A mathematical model was developed to support this elimination program with basic quantifications of transmission, disease and intervention parameters. This model was used to predict the effects of different intervention strategies. Methods and Findings Parameters on the natural history of Leishmania infection were estimated based on a literature review and expert opinion or drawn from a community intervention trial (the KALANET project). The transmission dynamic of Leishmania donovani is rather slow, mainly due to its long incubation period and the potentially long persistence of parasites in infected humans. Cellular immunity as measured by the Leishmanin skin test (LST) lasts on average for roughly one year, and re-infection occurs in intervals of about two years, with variation not specified. The model suggests that transmission of L. donovani is predominantly maintained by asymptomatically infected hosts. Only patients with symptomatic disease were eligible for treatment; thus, in contrast to vector control, the treatment of cases had almost no effect on the overall intensity of transmission. Conclusions Treatment of Kala-azar is necessary on the level of the individual patient but may have little effect on transmission of parasites. In contrast, vector control or exposure prophylaxis has the potential to efficiently reduce transmission of parasites. Based on these findings, control of VL should pay more attention to vector-related interventions. Cases of PKDL may appear after years and may initiate a new outbreak of disease; interventions should therefore be long enough, combined with an active case detection and include effective treatment.

Control of onchocerciasis currently focuses on community-directed treatment with the microfilaricide ivermectin which effectively kills Onchocerca volvulus microfilariae in the human host. The feasibility of elimination by this control strategy has recently been reported for some foci in Africa which has rekindled discussions on evaluating the threshold conditions of elimination of onchocerciasis. We developed a stochastic model based on a master equation which predicts, based on data from West and Central Africa, that elimination of savannah onchocerciasis can be expected around a threshold biting rate of 730 bites per person per year, ranging region-specifically roughly from 230 to 2300 bites per person and year. The threshold values give rise to optimism that elimination of onchocerciasis is feasible, but the associated measures of parasite prevalence and density suggest that onchocerciasis can remain endemic at very low infection intensities. Endemicity at a low level is a risk factor for elimination strategies, and we point to the necessity of investigating these issues on the basis of breakpoints which refer to threshold conditions based on parasite prevalence and density.

Background: When the first cases of a new infectious disease appear, questions arise about the further course of the epidemic and about the appropriate interventions to be taken to protect individuals and the public as a whole. Mathematical models can help answer these questions. In this article, the authors describe basic concepts in the mathematical modelling of infectious diseases, illustrate their use with a simple example, and present the results of influenza models. Method: Description of the mathematical modelling of infectious diseases and selective review of the literature. Results: The two fundamental concepts of mathematical modelling of infectious diseases-the basic reproduction number and the generation time-allow a better understanding of the course of an epidemic. Modelling studies based on past influenza epidemics suggest that the rise of the epidemic curve can be slowed at the beginning of the epidemic by isolating ill persons and giving prophylactic medications to their contacts. Later on in the course of the epidemic, restricting the number of contacts (e.g., by closing schools) may mitigate the epidemic but will only have a limited effect on the total number of persons who contract the disease. Conclusion: Mathematical modelling is a valuable tool for understanding the dynamics of an epidemic and for planning and evaluating interventions.

PRINCIPLES:The evaluation of the capacity of a country's public health system in case of an influenza pandemic is essential for preparedness planning. Only few studies compare existing medical resources with those required during a severe pandemic. METHODS:We perform a sensitivity analysis with the freely available simulation tool InfluSim to explore the expected number of outpatient visits and the hospital bed occupancy in an influenza pandemic in Switzerland. We define plausible ranges for unknown parameter values and take random samples from these ranges. A set of four simulations is run for each parameter constellation, considering no intervention, contact reduction, antiviral treatment or a combination of both interventions. RESULTS:We find that the peak number of outpatient visits of influenza patients would still be manageable by the current number of active physicians with praxis in Switzerland, and that the demand of hospital beds would be only sustainable in the case of a good compliance of the combined interventions. On the other hand, the demand on intensive care unit beds is unsustainably high. CONCLUSIONS:The range of outcomes, resulting from parameter uncertainty, reaches from outpatient and hospitalization values which are half as high as the median to values which double the median. A combination of antiviral treatment and social distancing can considerably mitigate a severe pandemic, but will only bring it under control for the most optimistic parameter constellation combining (mild outbreaks with a high compliance of interventions).

BACKGROUND:Neuraminidase inhibitors (NI) and social distancing play a major role in plans to mitigate future influenza pandemics.METHODS:Using the freely available program InfluSim, the authors examine to what extent NI-treatment and prophylaxis promote the occurrence and transmission of a NI resistant strain.RESULTS:Under a basic reproduction number of R0 = 2.5, a NI resistant strain can only spread if its transmissibility (fitness) is at least 40% of the fitness of the drug-sensitive strain. Although NI drug resistance may emerge in treated patients in such a late state of their disease that passing on the newly developed resistant viruses is unlikely, resistant strains quickly become highly prevalent in the population if their fitness is high. Antiviral prophylaxis further increases the pressure on the drug-sensitive strain and favors the spread of resistant infections. The authors show scenarios where pre-exposure antiviral prophylaxis even increases the number of influenza cases and deaths.CONCLUSION:If the fitness of a NI resistant pandemic strain is high, any use of prophylaxis may increase the number of hospitalizations and deaths in the population. The use of neuraminidase inhibitors should be restricted to the treatment of cases whereas prophylaxis should be reduced to an absolute minimum in that case.

A variety of intervention measures exist to prevent and control diseases with pandemic potential like SARS or pandemic influenza. They differ in their approach and effectiveness in reducing the number of cases getting infected. The effects of different intervention measures were investigated by a mathematical modelling approach, with comparisons based on the effective reproduction number (Re). The analysis showed that early case detection followed by strict isolation could control a SARS outbreak. Tracing close contacts of cases and contacts of exposed health care workers additionally reduces the Re. Tracing casual contacts and measures aiming to decrease social interaction were less effective in reducing the number of SARS cases. The study emphasizes the importance of early identification and isolation of SARS cases to reduce the number of people getting infected. However, doing so transfers cases to health care facilities, making infection control measures in hospitals essential to avoid nosocomial spread. The modelling approach applied in this study is useful for analysing interactions of different intervention measures for reducing the Re of SARS.

Nodule palpation is the major diagnostic tool for determining the prevalence of infection in areas of the African Programme for Onchocerciasis Control (APOC) and is recommended for identifying communities at risk and selecting them for mass drug administration. The diagnostic value of palpation, however, has not been quantified in terms of sensitivity and predictive values. We derive these measures from the probability that a nodule is palpable, which has been estimated by stochastic simulations from an extensive pre-control database. We show that nodule palpation is only reliable in highly endemic areas and that false-positive diagnoses can lead to considerable misclassifications of regions where endemicity is actually low. Its diagnostic precision is poor because of large intra- and inter-individual variability. The findings underline the need for further development of available diagnostics that allow long-term monitoring when endemicity declines.

Neuraminidase inhibitors (NI) play a major role in plans to mitigate future influenza pandemics. Modeling studies suggested that a pandemic may be contained at the source by early treatment and prophylaxis with antiviral drugs. Here, we examine the influence of NI resistant influenza strains on an influenza pandemic. We extend the freely available deterministic simulation program InfluSim to incorporate importations of resistant infections and the emergence of de novo resistance. The epidemic with the fully drug sensitive strain leads to a cumulative number of 19,500 outpatients and 258 hospitalizations, respectively, per 100,000 inhabitants. Development of de novo resistance alone increases the total number of outpatients by about 6% and hospitalizations by about 21%. If a resistant infection is introduced into the population after three weeks, the outcome dramatically deteriorates. Wide-spread use of NI treatment makes it highly likely that the resistant strain will spread if its fitness is high. This situation is further aggravated if a resistant virus is imported into a country in the early phase of an outbreak. As NI-resistant influenza infections with high fitness and pathogenicity have just been observed, the emergence of drug resistance in treated populations and the transmission of drug resistant strains is an important public health concern for seasonal and pandemic influenza.

Strategies for the control of human parasitic diseases such as onchocerciasis and lymphatic filariasis require an understanding of how the parasite successfully infects and persists in humans. Despite the fact that the vast majority of infective larvae are eliminated after infection, this 'protection' is far from being an all-or-nothing response. The hypothesis presented here, which is based on epidemiological observations, suggests that the resistance against filarial parasites includes a time-dependent component, probably caused by an early immune response with short-term memory. Validating this hypothesis requires experimental studies with a longitudinal component. Such experiments would help to clarify whether the infection can be controlled by vaccination strategies at all.

BACKGROUND:Planning public health responses against pandemic influenza relies on predictive models by which the impact of different intervention strategies can be evaluated. Research has to date rather focused on producing predictions for certain localities or under specific conditions, than on designing a publicly available planning tool which can be applied by public health administrations. Here, we provide such a tool which is reproducible by an explicitly formulated structure and designed to operate with an optimal combination of the competing requirements of precision, realism and generality.RESULTS:InfluSim is a deterministic compartment model based on a system of over 1,000 differential equations which extend the classic SEIR model by clinical and demographic parameters relevant for pandemic preparedness planning. It allows for producing time courses and cumulative numbers of influenza cases, outpatient visits, applied antiviral treatment doses, hospitalizations, deaths and work days lost due to sickness, all of which may be associated with economic aspects. The software is programmed in Java, operates platform independent and can be executed on regular desktop computers.CONCLUSION:InfluSim is an online available software http://www.influsim.info which efficiently assists public health planners in designing optimal interventions against pandemic influenza. It can reproduce the infection dynamics of pandemic influenza like complex computer simulations while offering at the same time reproducibility, higher computational performance and better operability.

SUMMARY Planning adequate public health responses against emerging infectious diseases requires predictive tools to evaluate the impact of candidate intervention strategies. With current interest in pandemic influenza very high, modelling approaches have suggested antiviral treatment combined with targeted prophylaxis as an effective first-line intervention against an emerging influenza pandemic. To investigate how the effectiveness of such interventions depends on contact structure, we simulate the effects in networks with variable degree distributions. The infection attack rate can increase if the number of contacts per person is heterogeneous, implying the existence of high-degree individuals who are potential super-spreaders. The effectiveness of a socially targeted intervention suffers from heterogeneous contact patterns and depends on whether infection is predominantly transmitted to close or casual contacts. Our findings imply that the various contact networks' degree distributions as well as the allocation of contagiousness between close and casual contacts should be examined to identify appropriate strategies of disease control measures.

Background: Influenza pandemic preparedness plans are currently developed and refined on national and international levels. Much attention has been given to the administration of antiviral drugs, but contact reduction can also be an effective part of mitigation strategies and has the advantage to be not limited per se. The effectiveness of these interventions depends on various factors which must be explored by sensitivity analyses, based on mathematical models.Methods: We use the freely available planning tool Influ Sim to investigate how pharmaceutical and non-pharmaceutical interventions can mitigate an influenza pandemic. In particular, we examine how intervention schedules, restricted stockpiles and contact reduction (social distancing measures and isolation of cases) determine the course of a pandemic wave and the success of interventions.Results: A timely application of antiviral drugs combined with a quick implementation of contact reduction measures is required to substantially protract the peak of the epidemic and reduce its height. Delays in the initiation of antiviral treatment (e.g. because of parsimonious use of a limited stockpile) result in much more pessimistic outcomes and can even lead to the paradoxical effect that the stockpile is depleted earlier compared to early distribution of antiviral drugs.Conclusion: Pharmaceutical and non-pharmaceutical measures should not be used exclusively. The protraction of the pandemic wave is essential to win time while waiting for vaccine development and production. However, it is the height of the peak of an epidemic which can easily overtax general practitioners, hospitals or even whole public health systems, causing bottlenecks in basic and emergency medical care.