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National security decisions are driven by complex, interconnected contextual, individual, and strategic variables. Modeling and simulation tools are often used to identify relevant patterns, which can then be shaped through policy remedies. In the paper to follow, however, we argue that models of these scenarios may be prone to the complexity-scarcity gap, in which relevant scenarios are too complex to model from first principles and data from historical scenarios are too sparse-making it difficult to draw representative conclusions. The result are models that are either too simple or are unduly biased by the assumptions of the analyst. We outline a new method of quantitative inquiry-experimental wargaming-as a means to bridge the complexity-scarcity gap that offers human-generated, empirical data to inform a variety of model and simulation tasks (model building, calibration, testing, and validation). Below, we briefly describe SIGNAL-our first-of-a-kind experimental wargame designed to study strategic stability in conflict settings with nuclear weapons. We then highlight the potential utility of this data for modeling and simulation efforts in the future using this data.

In early 2020, the Medical Biology Laboratory of the Pasteur Institute of Cambodia isolated an unusually high number of fluoroquinolone-resistant Salmonella enterica subspecies enterica serovar Paratyphi A strains during its routine bacteriological surveillance activities in Phnom Penh, Cambodia. A public-health investigation was supported by genome sequencing of these Paratyphi A strains to gain insights into the genetic diversity and population structure of a potential outbreak of fluoroquinolone-resistant paratyphoid fever. Comparative genomic and phylodynamic analyses revealed the 2020 strains were descended from a previously described 2013-2015 outbreak of Paratyphi A infections. Our analysis showed sub-lineage 2.3.1 had remained largely susceptible to fluoroquinolone drugs until 2015, but acquired chromosomal resistance to these drugs during six separate events between late 2012 and 2015. The emergence of fluoroquinolone resistance was rapidly followed by the replacement of the original susceptible Paratyphi A population, which led to a dramatic increase of fluoroquinolone-resistant blood-culture-confirmed cases in subsequent years (2016-2020). The rapid acquisition of resistance-conferring mutations in the Paratyphi A population over a 3 year period is suggestive of a strong selective pressure on that population, likely linked with fluoroquinolone use. In turn, emergence of fluoroquinolone resistance has led to increased use of extended-spectrum cephalosporins like ceftriaxone that are becoming the drug of choice for empirical treatment of paratyphoid fever in Cambodia.

We develop a methodology for comparing agent-based models that are developed for the same domain, but may differ in the data sets (e.g., geographical regions) to which they are applied, and in the structure of the model. Our approach is to learn a response surface in the common parameter space of the models and compare the regions corresponding to qualitatively different behaviors in the models. As an example, we develop an active learning algorithm to learn phase shift boundaries in contagion processes in order to compare two agent-based models of rooftop solar panel adoption developed for different regions. We present results for 2D and 3D subspaces of the parameter space, though the approach scales to higher dimensions as well., Competing Interests: Conflict of interest The authors declare that they have no conflict of interest.

Background: Culture media are fundamental in clinical microbiology. In laboratories in low- and middle-income countries (LMICs), they are mostly prepared in-house, which is challenging., Objectives: This narrative review describes challenges related to culture media in LMICs, compiles best practices for in-house media preparation, gives recommendations to improve access to quality-assured culture media products in LMICs and formulates outstanding questions for further research., Sources: Scientific literature was searched using PubMed and predefined MeSH terms. In addition, grey literature was screened, including manufacturer's websites and manuals as well as microbiology textbooks., Content: Bacteriology laboratories in LMICs often face challenges at multiple levels: lack of clean water and uninterrupted power supply, high environmental temperatures and humidity, dust, inexperienced and poorly trained staff, and a variable supply of consumables (often of poor quality). To deal with this at a base level, one should be very careful in selecting culture media. It is recommended to look for products supported by the national reference laboratory that are being distributed by an in-country supplier. Correct storage is key, as is appropriate preparation and waste management. Centralized media acquisition has been advocated for LMICs, a role that can be taken up by the national reference laboratories, next to guidance and support of the local laboratories. In addition, there is an important role in tropicalization and customization of culture media formulations for private in vitro diagnostic manufacturers, who are often still unfamiliar with the LMIC market and the plethora of bacteriology products., Implication: The present narrative review will assist clinical microbiology laboratories in LMICs to establish best practices for handling culture media by defining quality, regulatory and research paths., (Copyright © 2021 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Objectives: Following the launch of the Global Antimicrobial Resistance Surveillance System (GLASS), antimicrobial resistance (AMR) rates in many countries remain poorly described. This review provides an overview of published AMR data from Cambodia in the context of recently initiated national human and food-animal surveillance., Methods: PubMed and the Cochrane Database of Systematic Reviews were searched for articles published from 2000 to 2018, which reported antimicrobial susceptibility testing (AST) data for GLASS specific organisms isolated from Cambodia. Articles were screened using strict inclusion/exclusion criteria. AST data was extracted, with medians and ranges of resistance rates calculated for specific bug-drug combinations., Results: Twenty-four papers were included for final analysis, with 20 describing isolates from human populations. Escherichia coli was the most commonly described organism, with median resistance rates from human isolates of 92.8% (n=6 articles), 46.4% (n=4), 55.4% (n=8), and 46.4% (n=5) to ampicillin, 3 rd generation cephalosporins, fluoroquinolones, and gentamicin respectively., Conclusions: Whilst resistance rates are high for several GLASS organisms, there were insufficient data to draw robust conclusions about the AMR situation in Cambodia. The recently implemented national AMR surveillance systems will begin to address this data gap., (Copyright © 2019 The Author(s). Published by Elsevier Ltd.. All rights reserved.)

Background: Cambodia, a lower middle-income country of about 16 million individuals in southeast Asia, endures a high burden of both tuberculosis and other lower respiratory infections. Differentiating tuberculosis from other causes of respiratory infection has important clinical implications yet may be challenging to accomplish in the absence of diagnostic microbiology facilities. Furthermore, co-infection of tuberculosis with other bacterial lower respiratory infections may occur. The objective of this study was to determine the prevalence and etiologies of tuberculosis and other bacterial co-infection and to analyze the clinical and radiographic characteristics of patients presenting with respiratory infection to a provincial referral hospital in Cambodia., Methods: We performed a retrospective, cross-sectional analysis of laboratory and clinical data, on patients presenting with respiratory symptoms to a chest clinic of a 260-bed provincial referral hospital in Cambodia. We analyzed mycobacterial and bacterial sputum test results, and demographics, medical history and chest radiography., Results: Among 137 patients whose treating clinicians ordered sputum testing for tuberculosis and other bacteria, the median age was 52 years, 54% were male, 3% had HIV infection, and 26% were current smokers. Nearly all had chronic respiratory symptoms (> 96%) and abnormal chest radiographs (87%). Sputum testing was positive for tuberculosis in 40 patients (30%) and for bacteria in 60 patients (44%); 13 had tuberculosis and bacterial co-infection (9% overall; 33% of tuberculosis patients). Clinical characteristics were generally similar across pulmonary infection types, although co-infection was identified in 43% of patients with one or more cavitary lesions on chest radiography. Among those with bacterial growth on sputum culture, Gram negative bacilli (Klebsiella and Pseudomonas spp.) were the most commonly isolated., Conclusions: Among patients with symptoms of respiratory infections whose treating clinicians ordered sputum testing for tuberculosis and other bacteria, 9% of all patients and 33% of tuberculosis patients had tuberculosis and bacterial co-infection. Greater availability of microbiologic diagnostics for pulmonary tuberculosis and bacterial infection is critical to ensure appropriate diagnosis and management.

Melioidosis infection, caused by Burkholderia pseudomallei, is increasingly reported in Cambodia. We hypothesized that implementation of an enhanced sputum testing protocol in a provincial hospital diagnostic microbiology laboratory would increase detection of B. pseudomallei. We tested 241 sputum specimens that were deemed acceptable for culture, comparing culture in selective enrichment broth followed by sub-culture on Ashdown's medium to standard culture methods. Two specimens (0.8%) were positive for B. pseudomallei using the enhanced protocol whereas one specimen (0.4%) was positive using standard methods. These findings demonstrate that B. pseudomallei is rarely detected in sputum at this hospital. The low frequency of B. pseudomallei in sputum specimens precludes drawing any conclusions about the relative benefits of an enhanced sputum testing protocol at this site. Promoting clinician awareness of the infection and encouraging utilization of diagnostic microbiology services are likely to be important factors in facilitating identification of melioidosis.

The ability to propagate embryonic stem cells (ESCs) while maintaining their pluripotency is critical if their potential use in regenerative medicine is to be realized. The mechanisms controlling ESC self-renewal are under intense investigation, and glycogen synthase kinase 3 (GSK-3) has been implicated in regulating both self-renewal and differentiation. To clarify its role in ESCs we have used chemical genetics. We synthesized a series of bisindolylmaleimides, a subset of which inhibit GSK-3 in murine ESCs and robustly enhance self-renewal in the presence of leukemia inhibitory factor (LIF) and serum, but not in the absence of LIF. Importantly, these molecules appear selective for GSK-3 and do not perturb other signaling pathways regulating self-renewal. Our study clarifies the functional importance of GSK-3 in regulation of ESC self-renewal and provides tools for investigating its role further.