The effect of demographic stochasticity on Zika virus transmission dynamics: Probability of disease extinction, sensitivity analysis, and mean first passage time.

Viral infections spread by mosquitoes are a growing threat to human health and welfare. Zika virus (ZIKV) is one of them and has become a global worry, particularly for women who are pregnant. To study ZIKV dynamics in the presence of demographic stochasticity, we consider an established ZIKV transmission model that takes into consideration the disease transmission from human to mosquito, mosquito to human, and human to human. In this study, we look at the local stability of the disease-free and endemic equilibriums. By conducting the sensitivity analysis both locally and globally, we assess the effect of the model parameters on the model outcomes. In this work, we use the continuous-time Markov chain (CTMC) process to develop and analyze a stochastic model. The main distinction between deterministic and stochastic models is that, in the absence of any preventive measures such as avoiding travel to infected areas, being careful from mosquito bites, taking precautions to reduce the risk of sexual transmission, and seeking medical care for any acute illness with a rash or fever, the stochastic model shows the possibility of disease extinction in a finite amount of time, unlike the deterministic model shows disease persistence. We found that the numerically estimated disease extinction probability agrees well with the analytical probability obtained from the Galton-Watson branching process approximation. We have discovered that the disease extinction probability is high if the disease emerges from infected mosquitoes rather than infected humans. In the context of the stochastic model, we derive the implicit equation of the mean first passage time, which computes the average amount of time needed for a system to undergo its first state transition.

A Comparison of Deterministic and Stochastic Plant-Vector-Virus Models Based on Probability of Disease Extinction and Outbreak.

In this investigation, we formulate and analyse a stochastic epidemic model using the continuous-time Markov chain model for the propagation of a vector-borne cassava mosaic disease in a single population. The stochastic model is based upon a pre-existing deterministic plant-vector-virus model. To see how demographic stochasticity affects the vector-borne cassava mosaic disease dynamics, we compare the disease dynamics of both deterministic and stochastic models through disease extinction process. The probability of disease extinction and therefore the major outbreak are estimated analytically using the multitype Galton-Watson branching process (GWbp) approximation. Also, we have found the approximate probabilities of disease extinction numerically based on 30000 sample paths, and it is shown to be good estimate with the calculated probabilities from GWbp approximation. In particular, it is observed that there is a very high probability of disease extinction when the disease is introduced via the infected vectors rather than through infected plants.

Stochastic sensitivity analysis and early warning signals of critical transitions in a tri-stable prey-predator system with noise.

Near a tipping point, small changes in a certain parameter cause an irreversible shift in the behavior of a system, called critical transitions. Critical transitions can be observed in a variety of complex dynamical systems, ranging from ecology to financial markets, climate change, molecular bio-systems, health, and disease. As critical transitions can occur suddenly and are hard to manage, it is important to predict their occurrence. Although it is very tough to predict such critical transitions, various recent works suggest that generic early warning signals can detect the situation when systems approach a critical point. The most important indicator that predicts the risk of an upcoming critical transition is critical slowing down (CSD). CSD indicates a slow recovery rate from external perturbations of the stable state close to a bifurcation point. In this contribution, we study a two dimensional prey-predator model. Without any noise, the prey-predator model shows bistability and tri-stability due to the Allee effect in predators. We explore the critical transitions when external noise is added to the prey-predator system. We investigate early warning indicators, e.g., recovery rate, lag-1 autocorrelation, variance, and skewness to predict the critical transition. We explore the confidence domain method using the stochastic sensitivity function (SSF) technique near a stable equilibrium point to find a threshold value of noise intensity for a transition. The SSF technique in a two stage transition through confidence ellipse is described. We also show that the possibility of a transition to the predator-free state is independent of initial conditions. Our result may serve as a paradigm to understand and predict the critical transition in a two dimensional system.

Impact of demographic variability on the disease dynamics for honeybee model.

For the last few years, annual honeybee colony losses have been center of key interest for many researchers throughout the world. The spread of the parasitic mite and its interaction with specific honeybee viruses carried by Varroa mites has been linked to the decline of honeybee colonies. In this investigation, we consider honeybee-virus and honeybee-infected mite-virus models. We perform sensitivity analysis locally and globally to see the effect of the parameters on the basic reproduction number for both models and to understand the disease dynamics in detail. We use the continuous-time Markov chain model to develop and analyze stochastic epidemic models corresponding to both deterministic models. By using the disease extinction process, we compare both deterministic and stochastic models. We have observed that the numerically approximated probability of disease extinction based on 30 000 sample paths agrees well with the calculated probability using multitype branching process approximation. In particular, it is observed that the disease extinction probability is higher when infected honeybees spread the disease instead of infected mites. We conduct a sensitivity analysis for the stochastic model also to examine how the system parameters affect the probability of disease extinction. We have also derived the equation for the expected time required to reach disease-free equilibrium for stochastic models. Finally, the effect of the parameters on the expected time is represented graphically.

The potential impact of preventive therapy against tuberculosis in the WHO South-East Asian Region: a modelling approach.

BACKGROUND: The prevention of tuberculosis (TB) is key for accelerating current, slow declines in TB burden. The 2018 World Health Organization (WHO) guidelines on eligibility for preventive therapy to treat latent TB infection (LTBI) include people living with human immunodeficiency virus (PLHIV), household contacts of TB patients including children, and those with clinical conditions including silicosis, dialysis, transplantation, etc. and other country-specific groups. We aimed to estimate the potential impact of full implementation of these guidelines in the WHO South-East Asian (SEA) Region, which bears the largest burden of TB and LTBI amongst the WHO regions. METHODS: We developed mathematical models of TB transmission dynamics, calibrated individually to each of the 11 countries in the region. We modelled preventive therapy in the absence of other TB interventions. As an alternative comparator, reflecting ongoing developments in TB control in the region, we also simulated improvements in the treatment cascade for active TB, including private sector engagement and intensified case-finding. Relative to both scenarios, for each country in the region, we projected TB cases and deaths averted between 2020 and 2030, by full uptake of preventive therapy, defined as comprehensive coverage amongst eligible populations as per WHO guidelines, and assuming outcomes consistent with clinical trials. We also performed sensitivity analysis to illustrate impact under less-than-optimal conditions. RESULTS: At the regional level, full uptake of preventive therapy amongst identified risk groups would reduce annual incidence rates in 2030 by 8.30% (95% CrI 6.48-10.83) relative to 2015, in the absence of any additional interventions. If implemented against a backdrop of improved TB treatment cascades, preventive therapy would achieve an incremental 6.93 percentage points (95% CrI 5.81-8.51) of reduction in annual incidence rates, compared to 2015. At the regional level, the numbers of individuals with latent TB infection that need to be treated to avert 1 TB case is 64 (95% CrI 55-74). Sensitivity analysis illustrates that results for impact are roughly proportional to 'effective coverage' (the product of actual coverage and effectiveness of the regimen). CONCLUSIONS: Full implementation of WHO guidelines is important for ending TB in the SEA Region. Although future strategies will need to be expanded to the population level, to achieve large declines in TB incidence, the uptake of current tools can offer a valuable step in this direction.

Strategies for ending tuberculosis in the South-East Asian Region: A modelling approach.

Background & objectives: To support recent political commitments to end tuberculosis (TB) in the World Health Organization South-East Asian Region (SEAR), there is a need to understand by what measures, and with what investment, these goals could be reached. These questions were addressed by using mathematical models of TB transmission by doing the analysis on a country-by-country basis in SEAR. Methods: A dynamical model of TB transmission was developed, in consultation with each of the 11 countries in the SEAR. Three intervention scenarios were examined: (i) strengthening basic TB services (including private sector engagement), (ii) accelerating TB case-finding and notification, and (iii) deployment of a prognostic biomarker test by 2025, to guide mass preventive therapy of latent TB infection. Each scenario was built on the preceding ones, in successive combination. Results: Comprehensive improvements in basic TB services by 2020, in combination with accelerated case-finding to increase TB detection by at least two-fold by 2020, could lead to a reduction in TB incidence rates in SEAR by 67.3 per cent [95% credible intervals (CrI) 65.3-69.8] and TB deaths by 80.9 per cent (95% CrI 77.9-84.7) in 2035, relative to 2015. These interventions alone would require an additional investment of at least US$ 25 billion. However, their combined effect is insufficient to reach the end TB targets of 80 per cent by 2030 and 90 per cent by 2035. Model projections show how additionally, deployment of a biomarker test by 2025 could end TB in the region by 2035. Targeting specific risk groups, such as slum dwellers, could mitigate the coverage needed in the general population, to end TB in the Region. Interpretation & conclusions: While the scale-up of currently available strategies may play an important role in averting TB cases and deaths in the Region, there will ultimately be a need for novel, mass preventive measures, to meet the end TB goals. Achieving these impacts will require a substantial escalation in funding for TB control in the Region.

Preterm human milk contains a large pool of latent TGF-ß, which can be activated by exogenous neuraminidase.

Human milk contains substantial amounts of transforming growth factor (TGF)-ß, particularly the isoform TGF-ß2. We previously showed in preclinical models that enterally administered TGF-ß2 can protect against necrotizing enterocolitis (NEC), an inflammatory bowel necrosis of premature infants. In this study we hypothesized that premature infants remain at higher risk of NEC than full-term infants, even when they receive their own mother's milk, because preterm human milk contains less bioactive TGF-ß than full-term milk. Our objective was to compare TGF-ß bioactivity in preterm vs. full-term milk and identify factors that activate milk-borne TGF-ß. Mothers who delivered between 23 0/7 and 31 6/7 wk or at ≥37 wk of gestation provided milk samples at serial time points. TGF-ß bioactivity and NF-κB signaling were measured using specific reporter cells and in murine intestinal tissue explants. TGF-ß1, TGF-ß2, TGF-ß3, and various TGF-ß activators were measured by real-time PCR, enzyme immunoassays, or established enzymatic activity assays. Preterm human milk showed minimal TGF-ß bioactivity in the native state but contained a large pool of latent TGF-ß. TGF-ß2 was the predominant isoform of TGF-ß in preterm milk. Using a combination of several in vitro and ex vivo models, we show that neuraminidase is a key regulator of TGF-ß bioactivity in human milk. Finally, we show that addition of bacterial neuraminidase to preterm human milk increased TGF-ß bioactivity. Preterm milk contains large quantities of TGF-ß, but most of it is in an inactive state. Addition of neuraminidase can increase TGF-ß bioactivity in preterm milk and enhance its anti-inflammatory effects.

HIV TB coinfection - perspectives from India.

Introduction: HIV and tuberculosis (TB) are two of the most challenging infections faced by humanity and place immense burden on health care systems worldwide. Both HIV and TB impact one another's progression.Areas covered: HIV is the most important risk factor for progression of latent TB to active disease. TB is the most common cause of death among People Living with HIV (PLHIV). Timely detection of TB among PLHIV and screening for HIV among TB patients, early initiation of ART and ATT among coinfected persons, provision of CPT and TB Preventive therapy along with control of air-borne infection are some of the key activities to reduce morbidity and mortality among coinfected persons. Despite many challenges, the collaboration between two programs has yielded good results and globally more than 7.3 million lives of PLHIV have been saved globally through scale-up of collaborative TB/HIV activities since 2005. The review looked into key features of both programs that are the collaboration strategies and challenges that still need to be addressed.Expert opinion: The overarching principle for effective implementation of collaborative activities is integration of the TB and HIV national programs right from policy making to service delivery and monitoring.

Thyroid function in patients with idiopathic nephrotic syndrome.

BACKGROUND: Albumin is the major protein excreted in urine in patients with nephrotic syndrome (NS). However, low-molecular-weight proteins including some binding proteins are also excreted. Thyroid hormone and its binding globulins are excreted in urine in excess in nephrotic syndrome. Therefore, it has been postulated that patients with nephrotic syndrome may show hypothyroidism, subclinical or overt. METHODS: In this prospective observational study, patients of idiopathic nephrotic syndrome aged 1-40 years of both gender were included. Serum T3, T4 and TSH were assayed at diagnosis and repeated at 12 weeks or at remission whichever was earlier. Renal biopsy was performed as required. RESULTS: Among 100 patients taken for analysis (42 children, 58 adult), 30 cases were of first episode, 40 were of frequent relapse/steroid-dependent NS, and 30 patients had steroid-resistant NS (SRNS). Three (3%) cases had overt hypothyroidism and 18 (18%) patients had subclinical hypothyroidism. Most hypothyroid cases belonged to SRNS subgroup. Mean Serum T3, T4 and TSH values showed significant improvement in remission in comparison to nephrosis state (P < 0.01). Serum TSH had significant positive correlation (r = 0.391, P < 0.01) with 24-h proteinuria and negative correlation with serum albumin (r = - 0.303, P < 0.01) in nephrosis. CONCLUSION: Hypothyroidism is common among nephrotic syndrome patients especially in SRNS subgroup. Therefore, routine screening is recommended in steroid-resistant nephrotic syndrome patients.

Mitigating the impact of the COVID-19 pandemic on progress towards ending tuberculosis in the WHO South-East Asia Region.

Almost half of the deaths worldwide caused by tuberculosis in 2018 occurred in the World Health Organization (WHO) South-East Asia Region, home to around a quarter of the global population. Maintaining robust progress in this region is therefore essential if the global goal of ending the tuberculosis epidemic is to be realized. Substantial gains have been made in the region, but the threat to health worldwide posed by the coronavirus disease 2019 (COVID-19) pandemic includes not only the direct effects of the pandemic but also the potential eclipsing of the global tuberculosis emergency. The results of modelling studies present stark warnings of a reversal of years of progress and a significant resurgence in deaths from tuberculosis. The COVID-19 pandemic has had variable impacts in the WHO South-East Asia Region to date, but in the countries most affected there has been targeted diversion and repurposing of tuberculosis services, health-care workers and diagnostic equipment. The combined effects of COVID-19, containment measures and fragmentation of tuberculosis services have resulted in delays in diagnosis or non-diagnosis and disruption in treatment resulting in increased morbidity, mortality, transmission and drug resistance. Countries of the region have made attempts to ensure continuity of services and civil society and nongovernmental organizations have instituted a range of innovative mechanisms to support national programmes. However, a comprehensive approach - including scaling up successful initiatives, empowering community leadership, harnessing digital tools, and implementing easily accessible cash transfers and nutrition support - will be critical to success. As COVID-19 recedes, countries will need "catch-up plans" to deploy supplementary measures to address the increased tuberculosis burden. Urgent, targeted and agile responses have the potential to mitigate and reverse the impact of the COVID-19 pandemic on tuberculosis in South-East Asia.

Ending TB in Southeast Asia: current resources are not enough.

The Southeast Asia Region continues to battle tuberculosis (TB) as one of its most severe health and development challenges. Unless there is a substantial increase in investments for TB prevention, diagnosis, care and treatment, there will be catastrophic effects for the region. The uncontrolled TB burden impacts socioeconomic development and increase of drug resistance in the region. Based on epidemiological inputs from a mathematical model, a costing analysis estimates that the desired targets of ending TB are achievable with additional interventions, and critical thresholds require an increase in spending by almost double the current levels. The data source for financial allocation to TB programmes is the report submitted by countries to WHO, while projections are based on modelling. The model accounts for funding needs for all strategies based on published data and accounts for programme and patient costs. This paper delineates the resource needs, availability and gaps of ending TB in the region. It is estimated that close to US$2 billion per year are needed in the region for TB-related activities for a meaningful bending of the incidence curve towards ending TB.

Clinical profile and visual outcome in cluster endophthalmitis following cataract surgery in Central India.

The purpose of this study was to determine clinical presentation, microbiological spectrum and visual outcome of cluster endophthalmitis patients after cataract surgery in central India. The records of cluster endophthalmitis patients were retrospectively reviewed. Three clusters of patients were identified who had undergone vitreous biopsy followed by three-port pars plana vitrectomy with intraocular antibiotics and steroids. Good visual outcome was seen in eight (33%) of 24 patients. Six patients had corneal infiltration. Smear positivity was 58% and culture positivity was 42%. There was significant association ( P P = 0.006) with poor visual outcome. The association between type of surgery ( P = 0.6), duration of symptoms ( P = 0.64) and corneal infiltration ( P = 0.06) with visual outcome was not significant. Pseudomonas aeruginosa was the organism isolated in vitreous cultures. Thirty three percent patients benefit after appropriate vitreoretinal intervention in cluster endophthalmitis.

Development of nested polymerase chain reaction-based diagnosis of duck enteritis virus and detection of DNA polymerase gene from non-descriptive duck breeds of West Bengal, India.

AIM: The study was undertaken to detect the clinical signs, postmortem lesions of embryonated duck plague (DP) infected eggs, and histopathological changes of chorioallantoic membrane (CAM) in non-descriptive ducks of West Bengal with special reference to standardize nested polymerase chain reaction (PCR). MATERIALS AND METHODS: After postmortem of suspected carcasses, samples were collected for virus isolation and identification through specific pathogen free (Khaki Campbell) embryonated duck eggs. PCR was also done as confirmatory test after doing postmortem of duck embryos. DP specific nested PCR was standardized for better confirmation of the disease. Sensitivity of nested primers was also tested for DP virus. RESULTS: Gross, postmortem and histopathological changes were prominent in dead embryos. First set of primer was able to detect 602 bp fragments of DNA polymerase gene of duck enteritis virus from infected CAM. Subsequently, a DP specific nested PCR which was very much sensitive for very small amount of viral genome was successfully standardized. After NCBI blast nucleotide sequence of nested PCR product (Accession No. HG425076) showed homology with the sequences data available in GenBank. CONCLUSION: The study concludes that PCR assay is very much helpful to diagnose DP disease and developed nested PCR is a double confirmatory diagnostic tool for DP.

Topological quantum phase transition from mirror to time reversal symmetry protected topological insulator.

Topological insulators constitute a new phase of matter protected by symmetries. Time-reversal symmetry protects strong topological insulators of the Z2 class, which possess an odd number of metallic surface states with dispersion of a Dirac cone. Topological crystalline insulators are merely protected by individual crystal symmetries and exist for an even number of Dirac cones. Here, we demonstrate that Bi-doping of Pb1-x Sn x Se (111) epilayers induces a quantum phase transition from a topological crystalline insulator to a Z2 topological insulator. This occurs because Bi-doping lifts the fourfold valley degeneracy and induces a gap at [Formula: see text], while the three Dirac cones at the [Formula: see text] points of the surface Brillouin zone remain intact. We interpret this new phase transition as caused by a lattice distortion. Our findings extend the topological phase diagram enormously and make strong topological insulators switchable by distortions or electric fields.Transitions between topological phases of matter protected by different symmetries remain rare. Here, Mandal et al. report a quantum phase transition from a topological crystalline insulator to a Z2 topological insulator by doping Bi into Pb1-x Sn x Se (111) thin films.

Giant Rashba Splitting in Pb1-x Snx Te (111) Topological Crystalline Insulator Films Controlled by Bi Doping in the Bulk.

The topological properties of lead-tin chalcogenide topological crystalline insulators can be widely tuned by temperature and composition. It is shown that bulk Bi doping of epitaxial Pb1-x Snx Te (111) films induces a giant Rashba splitting at the surface that can be tuned by the doping level. Tight binding calculations identify their origin as Fermi level pinning by trap states at the surface.

Transport Gap Opening and High On-Off Current Ratio in Trilayer Graphene with Self-Aligned Nanodomain Boundaries.

Trilayer graphene exhibits exceptional electronic properties that are of interest both for fundamental science and for technological applications. The ability to achieve a high on-off current ratio is the central question in this field. Here, we propose a simple method to achieve a current on-off ratio of 10(4) by opening a transport gap in Bernal-stacked trilayer graphene. We synthesized Bernal-stacked trilayer graphene with self-aligned periodic nanodomain boundaries (NBs) on the technologically relevant vicinal cubic-SiC(001) substrate and performed electrical measurements. Our low-temperature transport measurements clearly demonstrate that the self-aligned periodic NBs can induce a charge transport gap greater than 1.3 eV. More remarkably, the transport gap of ∼0.4 eV persists even at 100 K. Our results show the feasibility of creating new electronic nanostructures with high on-off current ratios using graphene on cubic-SiC.

Mass primaquine preventive treatment for control of Plasmodium vivax malaria in the Democratic People's Republic of Korea: a country success story.

In 1998, the resurgence of Plasmodium vivax malaria in the Democratic People's Republic of Korea quickly increased to an epidemic, with 601 013 cases reported I during 1999-2001. The introduction of mass primaquine preventive treatment (MPPT) in 2002 was followed by a rapid reduction of malaria disease burden. The intervention has been well accepted by the community. Doctors were part of a strong functional health system with the ability to deliver interventions at the household J level. MPPT was considered for control of malaria after a study conducted in two J neighbouring endemic villages (ris) involving 320 healthy adults demonstrated that presence of parasitaemia was significantly lower among those receiving MPPT than those who did not. Similarly, in a mass blood survey conducted in the study sites during May, 2002 involving 5138 persons in study and 4215 in comparison areas, the total positive results were 7-10 times rarer in the treatment group both before and after the malaria transmission season. In addition, the number of malaria cases in the MPPT treatment ris was strikingly lower than control ris in every month during the malaria transmission season of 2002. The prevalence of G6PDD deficiency in DPR Korea is low, haemolytic events are rare and deaths due to MPPT have not been reported. MPPT in itself is a powerful intervention and the decision to deploy it depends on the epidemiology of malaria, urgency of malaria control and resources available in the country.

Mass primaquine preventive treatment for control of Plasmodium vivax malaria in the Democratic People’s Republic of Korea: a country success story.

In 1998, the resurgence of Plasmodium vivax malaria in the Democratic People’s Republic of Korea quickly increased to an epidemic, with 601 013 cases reported during 1999–2001. The introduction of mass primaquine preventive treatment (MPPT) in 2002 was followed by a rapid reduction of malaria disease burden. The intervention has been well accepted by the community. Doctors were part of a strong functional health system with the ability to deliver interventions at the household level. MPPT was considered for control of malaria after a study conducted in two neighbouring endemic villages (ris) involving 320 healthy adults demonstrated that presence of parasitaemia was significantly lower among those receiving MPPT than those who did not. Similarly, in a mass blood survey conducted in the study sites during May, 2002 involving 5138 persons in study and 4215 in comparison areas, the total positive results were 7–10 times rarer in the treatment group both before and after the malaria transmission season. In addition, the number of malaria cases in the MPPT treatment ris was strikingly lower than control ris in every month during the malaria transmission season of 2002. The prevalence of G6PDD deficiency in DPR Korea is low, haemolytic events are rare and deaths due to MPPT have not been reported. MPPT in itself is a powerful intervention and the decision to deploy it depends on the epidemiology of malaria, urgency of malaria control and resources available in the country.

Clinical profile and visual outcome in cluster endophthalmitis following cataract surgery in Central India.

The purpose of this study was to determine clinical presentation, microbiological spectrum and visual outcome of cluster endophthalmitis patients after cataract surgery in central India. The records of cluster endophthalmitis patients were retrospectively reviewed. Three clusters of patients were identified who had undergone vitreous biopsy followed by three-port pars plana vitrectomy with intraocular antibiotics and steroids. Good visual outcome was seen in eight (33%) of 24 patients. Six patients had corneal infiltration. Smear positivity was 58% and culture positivity was 42%. There was significant association ( P P = 0.006) with poor visual outcome. The association between type of surgery ( P = 0.6), duration of symptoms ( P = 0.64) and corneal infiltration ( P = 0.06) with visual outcome was not significant. Pseudomonas aeruginosa was the organism isolated in vitreous cultures. Thirty three percent patients benefit after appropriate vitreoretinal intervention in cluster endophthalmitis.