Health Systems Preparedness for Infectious Disease Outbreaks: Relevance for Nephrology.

The coronavirus disease (COVID-19) crisis glaringly highlighted the critical need to develop resilient health care systems that are better prepared for epidemics. Millions of people died from COVID-19 itself, but almost three times as many died from health system disruptions. People living with kidney disease are highly vulnerable during outbreaks and pandemics and their needs must be included in preparedness planning. Health systems preparedness requires not only early identification and containment of outbreaks and maintenance of critical services during crises, but also bolstering population resilience and ensuring the safety of both health personnel and patients. Planning for surge capacity in an outbreak must include provision for both acute and chronic dialysis, and ensure access to medications for people with kidney diseases. Quality of care should not be compromised and must be monitored and improved where necessary. Technology, such as telemedicine, can support quality and continuity of care and minimize infection risks. Communication at all levels is crucial to ensure all stakeholders, including communities, have the necessary information to support cooperation and collaboration in effective outbreak responses. Research is important during and after pandemics to improve knowledge and build resilience at all levels, from outbreak detection to the development of therapeutics and optimizing equity in access to interventions. Only with adequate preparation and more resilient health systems can we hope, as a global community, to build on the harsh lessons learned during COVID-19, and improve the response to the next infectious disease outbreak, epidemic, or even pandemic.

Efficacy of a travelers' diarrhea vaccine system in travelers to India.

BACKGROUND: A patch vaccine containing heat-labile toxin (LT) from enterotoxigenic Escherichia coli (ETEC) has demonstrated to be beneficial in reducing the rate and severity of travelers' diarrhea in Latin America. To evaluate the efficacy of this transdermal vaccine system in an area with a different diarrheal pathogen profile, an additional phase 2 study was conducted in European travelers to India. METHODS: For this multicenter, randomized, double-blinded, placebo-controlled field study 723 subjects were recruited; 603 (299 LT vaccine, 304 placebo) were included in the per-protocol-population (PPP). RESULTS: Although the LT patch induced a measurable LT immune response in recipients, it failed to protect against LT ETEC or all-cause diarrhea. In the PPP the incidence rate of diarrhea as per primary endpoint was 6.0% (18 of 299) in the vaccine group and 5.9% (18 of 304) in the placebo group. Additionally, lower than expected rates of LT ETEC diarrheas were observed in India. The vaccine delivery system frequently produced rash and pruritus at the site of application, long term hyperpigmentation persisted in a minority of LT recipients, and also few site reactions were noted in the placebo group. CONCLUSIONS: The evaluated patch vaccine failed to satisfy mainly with respect to protective efficacy. Noninvasive prophylactic agents against travelers' diarrhea, particularly vaccines against the most frequent pathogens, thus continue to be badly needed.

Modelling platelet-blood flow interaction using the subcellular element Langevin method.

In this paper, a new three-dimensional modelling approach is described for studying fluid-viscoelastic cell interaction, the subcellular element Langevin (SCEL) method, with cells modelled by subcellular elements (SCEs) and SCE cells coupled with fluid flow and substrate models by using the Langevin equation. It is demonstrated that: (i) the new method is computationally efficient, scaling as (N) for N SCEs; (ii) cell geometry, stiffness and adhesivity can be modelled by directly relating parameters to experimentally measured values; (iii) modelling the fluid-platelet interface as a surface leads to a very good correlation with experimentally observed platelet flow interactions. Using this method, the three-dimensional motion of a viscoelastic platelet in a shear blood flow was simulated and compared with experiments on tracking platelets in a blood chamber. It is shown that the complex platelet-flipping dynamics under linear shear flows can be accurately recovered with the SCEL model when compared with the experiments. All experimental details and electronic supplementary material are archived at http://biomath.math.nd.edu/scelsupplementaryinformation/.

Study of elastic collisions of Myxococcus xanthus in swarms.

In very low density situations where a single myxobacterial cell is isolated from direct contact with other cells, the slime capsule interaction with the substrate or slime tracks on the substrate produce a viscous drag that results in a smooth gliding motion. Viscoelastic interactions of myxobacteria cells in a low-density domain close to the edge of a swarm are studied using a combination of a cell-based three-dimensional computational model and cell-tracking experiments. The model takes into account the flexible nature of Myxococcus xanthus as well as the effects of adhesion between cells arising from the interaction of the capsular polysaccharide covering two cells in contact with each other. New image and dynamic cell curvature analysis algorithms are used to track and measure the change in cell shapes that occur as flexible cells undergo significant bending during collisions resulting in direct calibration of the model parameters. Like aspect-ratio and directional reversals, the flexibility of cells and the adhesive cell-cell and cell-substrate interactions of M. xanthus play an important role in smooth gliding and more efficient swarming.

In vitro antimicrobial susceptibility of bacterial enteropathogens isolated from international travelers to Mexico, Guatemala, and India from 2006 to 2008.

The incidence rates of travelers' diarrhea (TD) have remained high for the last 50 years. More recently, there have been increasing recommendations for self-initiated therapy and use of prophylactic drugs for TD. We last examined the in vitro susceptibilities of commonly used antibiotics against TD pathogens in 1997. We now examine 456 enteropathogens isolated from adult travelers to Mexico, India, and Guatemala with diarrhea acquired between 2006 and 2008 to determine changes in susceptibility against 10 different antimicrobials by the agar dilution method. Traditional antibiotics, such as ampicillin, trimethoprim-sulfamethoxazole, and doxycycline, continue to show high levels of resistance. Current first-line antibiotic agents, including fluoroquinolones and azithromycin, showed significantly higher MICs than in our earlier study, and MIC(90) levels were above the Clinical and Laboratory Standards Institute cutoffs for resistance. There were significant geographical differences in resistance patterns when Central America was compared with India. Entertoxigenic Escherichia coli (ETEC) isolates showed increased resistance to ciprofloxacin (P = 0.023) and levofloxacin (P = 0.0078) in India compared with Central America. Enteroaggregative E. coli (EAEC) isolates from Central America showed increased resistance to nearly all of the antibiotics tested. Compared to MICs of isolates 10 years prior, there were 4- to 10-fold increases in MIC(90) values for ceftriaxone, ciprofloxacin, levofloxacin, and azithromycin for both ETEC and EAEC. There were no significant changes in rifaximin MICs. Rising MICs over time imply the need for continuous surveillance of susceptibility patterns worldwide and geographically specific recommendations in TD therapy.

Modeling conformational ensembles of slow functional motions in Pin1-WW.

Protein-protein interactions are often mediated by flexible loops that experience conformational dynamics on the microsecond to millisecond time scales. NMR relaxation studies can map these dynamics. However, defining the network of inter-converting conformers that underlie the relaxation data remains generally challenging. Here, we combine NMR relaxation experiments with simulation to visualize networks of inter-converting conformers. We demonstrate our approach with the apo Pin1-WW domain, for which NMR has revealed conformational dynamics of a flexible loop in the millisecond range. We sample and cluster the free energy landscape using Markov State Models (MSM) with major and minor exchange states with high correlation with the NMR relaxation data and low NOE violations. These MSM are hierarchical ensembles of slowly interconverting, metastable macrostates and rapidly interconverting microstates. We found a low population state that consists primarily of holo-like conformations and is a "hub" visited by most pathways between macrostates. These results suggest that conformational equilibria between holo-like and alternative conformers pre-exist in the intrinsic dynamics of apo Pin1-WW. Analysis using MutInf, a mutual information method for quantifying correlated motions, reveals that WW dynamics not only play a role in substrate recognition, but also may help couple the substrate binding site on the WW domain to the one on the catalytic domain. Our work represents an important step towards building networks of inter-converting conformational states and is generally applicable.

Travelling to India for the Delhi XIX Commonwealth Games 2010.

The 19th Commonwealth Games, conducted once in every four years since 1930, will be held in New Delhi from the 3rd through until the 14th of October, 2010. There will be approximately 17 sports on display and there will also be 15 para-sporting events. This paper focuses on health and safety issues for travellers to India in general, although it provides specific references to advice for visiting Commonwealth Games athletes and team staff, who will be travelling to the games. Whilst it needs be remembered that travel health advice can change, travellers are advised to seek up-to-date travel health advice for India, from their professional providers, closer to their departure.

MDLab: a molecular dynamics simulation prototyping environment.

Molecular dynamics (MD) simulation involves solving Newton's equations of motion for a system of atoms, by calculating forces and updating atomic positions and velocities over a timestep Deltat. Despite the large amount of computing power currently available, the timescale of MD simulations is limited by both the small timestep required for propagation, and the expensive algorithm for computing pairwise forces. These issues are currently addressed through the development of efficient simulation methods, some of which make acceptable approximations and as a result can afford larger timesteps. We present MDLab, a development environment for MD simulations built with Python which facilitates prototyping, testing, and debugging of these methods. MDLab provides constructs which allow the development of propagators, force calculators, and high level sampling protocols that run several instances of molecular dynamics. For computationally demanding sampling protocols which require testing on large biomolecules, MDL includes an interface to the OpenMM libraries of Friedrichs et al. which execute on graphical processing units (GPUs) and achieve considerable speedup over execution on the CPU. As an example of an interesting high level method developed in MDLab, we present a parallel implementation of the On-The-Fly string method of Maragliano and Vanden-Eijnden. MDLab is available at http://mdlab.sourceforge.net.

Is there a relationship between elderly suicide rates and educational attainment? A cross-national study.

BACKGROUND: Suicides are associated with both high and low levels of intelligence and educational attainment in both individual-level and aggregate-level studies, but this has been rarely studied in the elderly. METHODS: A cross-national study examining the relationship between elderly suicide rates (y-axis) and educational attainment (x-axis) was undertaken with the 'a priori' hypothesis that the relationship would be curvilinear and follow a U-shaped curve with the quadratic equation Y = A + BX + CX(2), where A, B and C are constants. Data on suicide rates for both sexes in the age-bands 65-74 years and 75+ years, and the Education Index (a proxy measure of educational attainment) were ascertained from the World Health Organisation and the United Nations websites, respectively. RESULTS: The main finding was the predicted curvilinear relationship between suicide rates, in both sexes in both the elderly age-bands, and the Education Index fitting the quadratic equation Y = A + BX + CX(2). CONCLUSIONS: Given the cross-sectional study design, a causal relationship cannot be assumed. The impact of educational attainment on elderly suicide rates may occur through interaction with other factors, mediation of the effects of other factors, or by its effects being mediated by other factors, and require further study.

Epidemiology of travelers' diarrhea: details of a global survey.

BACKGROUND: Recent epidemiologic data on travelers' diarrhea (TD) are essential for the evaluation of conventional and future prophylactic and therapeutic measures. METHODS: To determine the epidemiology, including risk factors, impact and quality-of-life evaluation of TD, a cross-sectional survey was conducted over 12 months at the airports of Mombasa (Kenya), Goa (India), Montego Bay (Jamaica) and Fortaleza (Brazil) by distributing questionnaires to visitors just prior to their flying home. The study period was March 1996 to July 1998. RESULTS: Overall, 73,630 short-term visitors completed a questionnaire. The total diarrhea attack rate varied between a high of 54.6% in Mombasa and a low of 13.6% in Fortaleza, but only between 31.5% and 5.4% of all travelers had classic TD. The 14-day incidence rates varied between 19.5% and 65.7%. Few travelers meticulously avoided potentially dangerous food items, although in India and Kenya most travelers avoided those considered most dangerous. Risk factors were stays exceeding 1 week, age between 15 and 30 years, and residence in the UK. The impact, measured as incapacity or quality-of-life scores, was very considerable. CONCLUSIONS: TD continues to affect vacationers and business travelers as frequently as it did some 20 years ago. Compliance with recommendations to reduce exposure to pathogens by avoiding dangerous food items is poor among travelers from all countries. Implementation of food safety education programs may be difficult to achieve.

Irrational prescribing in South Asia: a case of fluoroquinolone-associated phototoxicity.

Prescribing habits in South Asian countries have been subjected to some scrutiny.1-6 Most studies conclude that the quality of prescribing is poor, with overuse of antimicrobials and irrational use of fixed-dose combination therapy, particularly in the private sector.1 Prescriptions for multiple drugs are the rule rather than the exception, with up to seven items being prescribed for a single disease entity. Analgesics, anti-inflammatories and drugs of uncertain pharmacologic efficacy, such as vitamins, minerals and glucose water, are also frequently prescribed.