Measuring the unknown: An estimator and simulation study for assessing case reporting during epidemics

The fraction of cases reported, known as ‘reporting’, is a key performance indicator in an outbreak response, and an essential factor to consider when modelling epidemics and assessing their impact on populations. Unfortunately, its estimation is inherently difficult, as it relates to the part of an epidemic which is, by definition, not observed. We introduce a simple statistical method for estimating reporting, initially developed for the response to Ebola in Eastern Democratic Republic of the Congo (DRC), 2018–2020. This approach uses transmission chain data typically gathered through case investigation and contact tracing, and uses the proportion of investigated cases with a known, reported infector as a proxy for reporting. Using simulated epidemics, we study how this method performs for different outbreak sizes and reporting levels. Results suggest that our method has low bias, reasonable precision, and despite sub-optimal coverage, usually provides estimates within close range (5–10%) of the true value. Being fast and simple, this method could be useful for estimating reporting in real-time in settings where person-to-person transmission is the main driver of the epidemic, and where case investigation is routinely performed as part of surveillance and contact tracing activities.     

Genetic influences in self-reported symptoms of obstructive sleep apnoea and restless legs: a twin study.

Sleep disorders, such as obstructive sleep apnoea (OSA) and restless legs syndrome (RLS), are very common. The relative importance of genetic and nongenetic (environmental) influences on the symptomatology of these conditions has not been well studied. This study uses the twin design to examine this by evaluating OSA and RLS symptoms in monozygotic (MZ) and dizygotic (DZ) twins. Six thousand six hundred unselected female twin pairs, identified from a national volunteer twin register, were asked to complete a medical questionnaire. This questionnaire included questions on OSA and RLS symptoms, as well as questions on subject demographics, past medical history, smoking history and menopausal status. Responses were obtained from 4503 individuals (68% response rate). A total of 1937 twin pairs were evaluable: 933 MZ pairs (mean [range] age 51 [20-76] years) and 1004 DZ pairs (age 51 [20-80] years). Concordance rates were higher for MZ than DZ twins for OSA and RLS symptoms. Multifactorial liability threshold modeling suggests that additive genetic effects combined with unique environmental factors provide the best model for OSA and RLS symptoms. Heritability was estimated to be 52% (95% confidence interval 36% to 68%) for disruptive snoring, 48% (37% to 58%) for daytime sleepiness, 54% (44% to 63%) for restless legs, and 60% (51% to 69%) for legs jerking. These estimates dropped only slightly after adjustment for potential confounding influences on the symptoms of snoring and daytime sleepiness. These results suggest a substantial genetic contribution to the symptomatology of OSA and RLS. More research is needed to identify the genes responsible, and may ultimately lead to new therapies.     

Optimization of a series of quinazolinone-derived antagonists of CXCR3

The evaluation of the CXCR3 antagonist AMG 487 in clinic trials was complicated due to the formation of an active metabolite. In this Letter, we will discuss the further optimization of the quinazolinone series that led to the discovery of compounds devoid of the formation of the active metabolite that was seen with AMG 487. In addition, these compounds also feature increased potency and good pharmacokinetic properties. We will also discuss the efficacy of the lead compound 34 in a mouse model of cellular recruitment induced by bleomycin.     

Estimating Fundamental Host Range: a Host-Specificity Study of a Potential Biocontrol Agent for Prosopis Species (Leguminosae)

One approach to predicting non-target attack by potential biological control agents is to first describe their fundamental host ranges and then to predict how it will be expressed under postrelease field conditions. In this paper, we illustrate how the fundamental host range can be estimated experimentally by excluding possible limiting factors such as time-dependent effects. The example we use is a host-specificity study of a leaf-tying moth (Gelechiidae: Evippe sp. #1) which was being assessed for the biological control of mesquite (Leguminosae: Prosopis spp.) in Australia. Females oviposited all eggs on plants, mostly into cracks and fissures. First instar larvae leaf-mined and subsequent instars leaf-tied. Oviposition was not host-specific in cage trials, although ten times more eggs were laid on Prosopis than on non-targets. The fundamental host range for initiation of larval feeding was restricted to Prosopis and Leucaena leucocephala which both belong to the same tribe, and the fundamental host range for complete larval development was restricted to Prosopis . We predict that if released in Australia Evippe sp. #1 will only attack Prosopis spp., although low levels of 'indiscriminate' oviposition might occur on other taxa, and might result in initiation of feeding on L. leucocephala .     

Human p38 mitogen-activated protein kinase inhibitor drugs inhibit Plasmodium falciparum replication

We recently demonstrated that human p38 mitogen-activated protein kinase (MAPK) inhibitors reduced in vitro and in vivo replication of the protozoan parasites Toxoplasma gondii and Encephalitozoon cuniculi. In this study, we assessed the efficacy of five p38 MAPK inhibitors to block the replication of Plasmodium falciparum in human erythrocytes cultured ex vivo and demonstrate that the pyridinylimidazole RWJ67657 and the pyrrolobenzimidazole RWJ68198 reduced P. falciparum replication, yielded trophozoites that were greatly diminished in size at 24 h, and that these two agents interfered with stage differentiation. Interestingly, the chloroquine-resistant strain W2 was significantly more sensitive to these drugs than was the chloroquine-sensitive strain HB3. These results suggest that pyridinylimidazoles and pyrrolobenzimidazoles designed to inhibit human p38 MAPK activation can be developed to treat malaria.     

Chilling outweighs photoperiod in preventing precocious spring development

It is well known that increased spring temperatures cause earlier onset dates of leaf unfolding and flowering. However, a temperature increase in winter may be associated with delayed development when species' chilling requirements are not fulfilled. Furthermore, photosensitivity is supposed to interfere with temperature triggers. To date, neither the relative importance nor possible interactions of these three factors have been elucidated. In this study, we present a multispecies climate chamber experiment to test the effects of chilling and photoperiod on the spring phenology of 36 woody species. Several hypotheses regarding their variation with species traits (successional strategy, floristic status, climate of their native range) were tested. Long photoperiods advanced budburst for one‐third of the studied species, but magnitudes of these effects were generally minor. In contrast to prior hypotheses, photosensitive responses were not restricted to climax or oceanic species. Increased chilling length advanced budburst for almost all species; its effect greatly exceeding that of photoperiod. Moreover, we suggest that photosensitivity and chilling effects have to be rigorously disentangled, as the response to photoperiod was restricted to individuals that had not been fully chilled. The results indicate that temperature requirements and successional strategy are linked, with climax species having higher chilling and forcing requirements than pioneer species. Temperature requirements of invasive species closely matched those of native species, suggesting that high phenological concordance is a prerequisite for successful establishment. Lack of chilling not only led to a considerable delay in budburst but also caused substantial changes in the chronological order of species' budburst. The results reveal that increased winter temperatures might impact forest ecosystems more than formerly assumed. Species with lower chilling requirements, such as pioneer or invasive species, might profit from warming winters, if late spring frost events would in parallel occur earlier.     

Inhibition of mitochondrial fusion by α‐synuclein is rescued by PINK1, Parkin and DJ‐1

Aggregation of α‐synuclein (αS) is involved in the pathogenesis of Parkinson's disease (PD) and a variety of related neurodegenerative disorders. The physiological function of αS is largely unknown. We demonstrate with in vitro vesicle fusion experiments that αS has an inhibitory function on membrane fusion. Upon increased expression in cultured cells and in Caenorhabditis elegans, αS binds to mitochondria and leads to mitochondrial fragmentation. In C. elegans age‐dependent fragmentation of mitochondria is enhanced and shifted to an earlier time point upon expression of exogenous αS. In contrast, siRNA‐mediated downregulation of αS results in elongated mitochondria in cell culture. αS can act independently of mitochondrial fusion and fission proteins in shifting the dynamic morphologic equilibrium of mitochondria towards reduced fusion. Upon cellular fusion, αS prevents fusion of differently labelled mitochondrial populations. Thus, αS inhibits fusion due to its unique membrane interaction. Finally, mitochondrial fragmentation induced by expression of αS is rescued by coexpression of PINK1, parkin or DJ‐1 but not the PD‐associated mutations PINK1 G309D and parkin Δ1–79 or by DJ‐1 C106A.