Monte Carlo simulation of the transmission of measles: Beyond the mass action principle

We present a Monte Carlo simulation of the transmission of measles within a population sample during its growing and equilibrium states by introducing two different vaccination schedules of one and two doses. We study the effects of the contact rate per unit time $\xi$ as well as the initial conditions on the persistence of the disease. We found a weak effect of the initial conditions while the disease persists when $\xi$ lies in the range 1/L-10/L ($L$ being the latent period). Further comparison with existing data, prediction of future epidemics and other estimations of the vaccination efficiency are provided. Finally, we compare our approach to the models using the mass action principle in the first and another epidemic region and found the incidence independent of the number of susceptibles after the epidemic peak while it strongly fluctuates in its growing region. This method can be easily applied to other human, animals and vegetable diseases and includes more complicated parameters.Comment: 15 pages, 4 figures, 1 table, Submitted to Phys.Rev.

Traditional Underground Grain Storage in Clay Soils in Sudan Improved by Recent Innovations

In the central clay plain of the Sudan, traditional subsistence farmers and small farmers that also produce for local markets want to keep the region near food self-sufficiency. They combine annual production of sorghum with underground pit storage of part of the harvest. With increasing climate variability this food security is coming more and more under pressure. Farmers recently experimented with pit innovations that would allow storage for more than one season. These innovations were quantified and further improvements were suggested. It was found that in the most abundantly occurring cracking clay soils, wide shallow pits, using thick chaff linings, with wider above ground soil caps, are most suitable for longer term storage

Predictors of survival in frontotemporal lobar degeneration syndromes

After decades of research, large-scale clinical trials in patients diagnosed with frontotemporal lobar degeneration (FTLD) are now underway across multiple centres worldwide. As such, refining the determinants of survival in FTLD represents a timely and important challenge. Specifically, disease outcome measures need greater clarity of definition to enable accurate tracking of therapeutic interventions in both clinical and research settings. Multiple factors potentially determine survival, including the clinical phenotype at presentation; radiological patterns of atrophy including markers on both structural and functional imaging; metabolic factors including eating behaviour and lipid metabolism; biomarkers including both serum and cerebrospinal fluid markers of underlying pathology; as well as genetic factors, including both dominantly inherited genes, but also genetic modifiers. The present review synthesises the effect of these factors on disease survival across the syndromes of frontotemporal dementia, with comparison to amyotrophic lateral sclerosis, progressive supranuclear palsy and corticobasal syndrome. A pathway is presented that outlines the utility of these varied survival factors for future clinical trials and drug development. Given the complexity of the FTLD spectrum, it seems unlikely that any single factor may predict overall survival in individual patients, further suggesting that a precision medicine approach will need to be developed in predicting disease survival in FTLD, to enhance drug target development and future clinical trial methodologies

Pathophysiology and Treatment of Non-motor Dysfunction in Amyotrophic Lateral Sclerosis

Amyotrophic lateral sclerosis is a progressive and fatal neurodegenerative disease typically presenting with bulbar or limb weakness. There is increasing evidence that amyotrophic lateral sclerosis is a multisystem disease with early and frequent impacts on cognition, behaviour, sleep, pain and fatigue. Dysfunction of normal physiological and metabolic processes also appears common. Evidence from pre-symptomatic studies and large epidemiological cohorts examining risk factors for the future development of amyotrophic lateral sclerosis have reported a high prevalence of changes in behaviour and mental health before the emergence of motor weakness. This suggests that changes beyond the motor system are underway at an early stage with dysfunction across brain networks regulating a variety of cognitive, behavioural and other homeostatic processes. The full impact of non-motor dysfunction continues to be established but there is now sufficient evidence that the presence of non-motor symptoms impacts overall survival in amyotrophic lateral sclerosis, and with up to 80% reporting non-motor symptoms, there is an urgent need to develop more robust therapeutic approaches. This review provides a contemporary overview of the pathobiology of non-motor dysfunction, offering readers a practical approach with regard to assessment and management. We review the current evidence for pharmacological and non-pharmacological treatment of non-motor dysfunction in amyotrophic lateral sclerosis and highlight the need to further integrate non-motor dysfunction as an important outcome measure for future clinical trial design

Genetic Affinities within a Large Global Collection of Pathogenic Leptospira: Implications for Strain Identification and Molecular Epidemiology

Leptospirosis is an important zoonosis with widespread human health implications. The non-availability of accurate identification methods for the individualization of different Leptospira for outbreak investigations poses bountiful problems in the disease control arena. We harnessed fluorescent amplified fragment length polymorphism analysis (FAFLP) for Leptospira and investigated its utility in establishing genetic relationships among 271 isolates in the context of species level assignments of our global collection of isolates and strains obtained from a diverse array of hosts. In addition, this method was compared to an in-house multilocus sequence typing (MLST) method based on polymorphisms in three housekeeping genes, the rrs locus and two envelope proteins. Phylogenetic relationships were deduced based on bifurcating Neighbor-joining trees as well as median joining network analyses integrating both the FAFLP data and MLST based haplotypes. The phylogenetic relationships were also reproduced through Bayesian analysis of the multilocus sequence polymorphisms. We found FAFLP to be an important method for outbreak investigation and for clustering of isolates based on their geographical descent rather than by genome species types. The FAFLP method was, however, not able to convey much taxonomical utility sufficient to replace the highly tedious serotyping procedures in vogue. MLST, on the other hand, was found to be highly robust and efficient in identifying ancestral relationships and segregating the outbreak associated strains or otherwise according to their genome species status and, therefore, could unambiguously be applied for investigating phylogenetics of Leptospira in the context of taxonomy as well as gene flow. For instance, MLST was more efficient, as compared to FAFLP method, in clustering strains from the Andaman island of India, with their counterparts from mainland India and Sri Lanka, implying that such strains share genetic relationships and that leptospiral strains might be frequently circulating between the islands and the mainland

The VITAH Trial-Vitamin D Supplementation and Cardiac Autonomic Tone in Patients with End-Stage Kidney Disease on Hemodialysis: A Blinded, Randomized Controlled Trial

End-stage kidney disease (ESKD) patients are at increased cardiovascular risk. Vitamin D deficiency is associated with depressed heart rate variability (HRV), a risk factor depicting poor cardiac autonomic tone and risk of cardiovascular death. Vitamin D deficiency and depressed HRV are highly prevalent in the ESKD population. We aimed to determine the effects of oral vitamin D supplementation on HRV ((low frequency (LF) to high frequency (HF) spectral ratio (LF:HF)) in ESKD patients on hemodialysis. Fifty-six subjects with ESKD requiring hemodialysis were recruited from January 2013-March 2015 and randomized 1:1 to either conventional (0.25 mcg alfacalcidol plus placebo 3×/week) or intensive (0.25 mcg alfacalcidol 3×/week plus 50,000 international units (IU) ergocalciferol 1×/week) vitamin D for six weeks. The primary outcome was the change in LF:HF. There was no difference in LF:HF from baseline to six weeks for either vitamin D treatment (conventional: p = 0.9 vs. baseline; intensive: p = 0.07 vs. baseline). However, participants who remained vitamin D-deficient (25-hydroxyvitamin D < 20 ng/mL) after treatment demonstrated an increase in LF:HF (conventional: n = 13, ∆LF:HF: 0.20 ± 0.06, p < 0.001 vs. insufficient and sufficient vitamin D groups; intensive: n = 8: ∆LF:HF: 0.15 ± 0.06, p < 0.001 vs. sufficient vitamin D group). Overall, six weeks of conventional or intensive vitamin D only augmented LF:HF in ESKD subjects who remained vitamin D-deficient after treatment. Our findings potentially suggest that while activated vitamin D, with or without additional nutritional vitamin D, does not appear to improve cardiac autonomic tone in hemodialysis patients with insufficient or sufficient baseline vitamin D levels, supplementation in patients with severe vitamin D deficiency may improve cardiac autonomic tone in this higher risk sub-population of ESKD. TRIAL REGISTRATION: ClinicalTrials.gov, NCT01774812

Using a quantitative quadruple immunofluorescent assay to diagnose isolated mitochondrial Complex I deficiency

Isolated Complex I (CI) deficiency is the most commonly observed mitochondrial respiratory chain biochemical defect, affecting the largest OXPHOS component. CI is genetically heterogeneous; pathogenic variants affect one of 38 nuclear-encoded subunits, 7 mitochondrial DNA (mtDNA)-encoded subunits or 14 known CI assembly factors. The laboratory diagnosis relies on the spectrophotometric assay of enzyme activity in mitochondrially-enriched tissue homogenates, requiring at least 50 mg skeletal muscle, as there is no reliable histochemical method for assessing CI activity directly in tissue cryosections. We have assessed a validated quadruple immunofluorescent OXPHOS (IHC) assay to detect CI deficiency in the diagnostic setting, using 10 µm transverse muscle sections from 25 patients with genetically-proven pathogenic CI variants. We observed loss of NDUFB8 immunoreactivity in all patients with mutations affecting nuclear-encoding structural subunits and assembly factors, whilst only 3 of the 10 patients with mutations affecting mtDNA-encoded structural subunits showed loss of NDUFB8, confirmed by BN-PAGE analysis of CI assembly and IHC using an alternative, commercially-available CI (NDUFS3) antibody. The IHC assay has clear diagnostic potential to identify patients with a CI defect of Mendelian origins, whilst highlighting the necessity of complete mitochondrial genome sequencing in the diagnostic work-up of patients with suspected mitochondrial disease

Vacuum Stability, Perturbativity, and Scalar Singlet Dark Matter

We analyze the one-loop vacuum stability and perturbativity bounds on a singlet extension of the Standard Model (SM) scalar sector containing a scalar dark matter candidate. We show that the presence of the singlet-doublet quartic interaction relaxes the vacuum stability lower bound on the SM Higgs mass as a function of the cutoff and lowers the corresponding upper bound based on perturbativity considerations. We also find that vacuum stability requirements may place a lower bound on the singlet dark matter mass for given singlet quartic self coupling, leading to restrictions on the parameter space consistent with the observed relic density. We argue that discovery of a light singlet scalar dark matter particle could provide indirect information on the singlet quartic self-coupling.Comment: 25 pages, 10 figures; v2 - fixed minor typos; v3 - added to text discussions of other references, changed coloring of figures for easier black and white viewin

Neuronal network disintegration: common pathways linking neurodegenerative diseases

Neurodegeneration refers to a heterogeneous group of brain disorders that progressively evolve. It has been increasingly appreciated that many neurodegenerative conditions overlap at multiple levels and therefore traditional clinicopathological correlation approaches to better classify a disease have met with limited success. Neuronal network disintegration is fundamental to neurodegeneration, and concepts based around such a concept may better explain the overlap between their clinical and pathological phenotypes. In this Review, promoters of overlap in neurodegeneration incorporating behavioural, cognitive, metabolic, motor, and extrapyramidal presentations will be critically appraised. In addition, evidence that may support the existence of large-scale networks that might be contributing to phenotypic differentiation will be considered across a neurodegenerative spectrum. Disintegration of neuronal networks through different pathological processes, such as prion-like spread, may provide a better paradigm of disease and thereby facilitate the identification of novel therapies for neurodegeneration