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Study aim: The aim of the study was to determine whether there are differences in performance analysis in high-sport handball matches between Pre-COVID-19, during COVID-19, and Post-COVID-19 seasons in the home and away matches.

Larvae of the goldenrod gall fly, Eurosta solidaginis, rely on a freeze tolerance strategy to survive the sub‐zero temperatures of Canadian winter. Critical to their survival is the accumulation of polyol cryoprotectants and global metabolic rate depression, both of which require the regulation of glycolysis and reorganization of carbohydrate metabolism. This study explored the role that pyruvate kinase (PK) regulation plays in this metabolic reorganization. PK was purified from control (5 °C‐acclimated) and frozen (−15 °C‐acclimated) larvae and enzyme kinetic properties, structural stability, and post‐translational modifications were examined in both enzyme forms. The Km phosphoenolpyruvate (PEP) of frozen PK was 20% higher than that of control PK, whereas the Vmax of frozen PK was up to 50% lower than that of control PK at the lowest assay temperature, suggesting inhibition of the enzyme during the winter. Additionally, the activity and substrate affinity of both forms of PK decreased significantly at low assay temperatures, and both forms were regulated allosterically by a number of metabolites. Pro‐Q™ Diamond phosphoprotein staining and immunoblotting experiments demonstrated significantly higher threonine phosphorylation of PK from frozen animals while acetylation and methylation levels remained constant. Together, these results indicate that PK exists in two structurally distinct forms in E. solidaginis. In response to conditions mimicking the transition to winter, PK appears to be regulated to support metabolic rate depression, the accumulation of polyol cryoprotectants, and the need for extended periods of anaerobic carbohydrate metabolism to allow the animal to survive whole‐body freezing. [ABSTRACT FROM AUTHOR]

Background: The proliferation of digital disease-detection systems has led to an increase in earlier warning signals, which subsequently have resulted in swifter responses to emerging threats. Such highly sensitive systems can also produce weak signals needing additional information for action. The delays in the response to a genuine health threat are often due to the time it takes to verify a health event. It was the delay in outbreak verification that was the main impetus for creating EpiCore., Objective: This paper describes the potential of crowdsourcing information through EpiCore, a network of voluntary human, animal, and environmental health professionals supporting the verification of early warning signals of potential outbreaks and informing risk assessments by monitoring ongoing threats., Methods: This paper uses summary statistics to assess whether EpiCore is meeting its goal to accelerate the time to verification of identified potential health events for epidemic and pandemic intelligence purposes from around the world. Data from the EpiCore platform from January 2018 to December 2022 were analyzed to capture request for information response rates and verification rates. Illustrated use cases are provided to describe how EpiCore members provide information to facilitate the verification of early warning signals of potential outbreaks and for the monitoring and risk assessment of ongoing threats through EpiCore and its utilities., Results: Since its launch in 2016, EpiCore network membership grew to over 3300 individuals during the first 2 years, consisting of professionals in human, animal, and environmental health, spanning 161 countries. The overall EpiCore response rate to requests for information increased by year between 2018 and 2022 from 65.4% to 68.8% with an initial response typically received within 24 hours (in 2022, 94% of responded requests received a first contribution within 24 h). Five illustrated use cases highlight the various uses of EpiCore., Conclusions: As the global demand for data to facilitate disease prevention and control continues to grow, it will be crucial for traditional and nontraditional methods of disease surveillance to work together to ensure health threats are captured earlier. EpiCore is an innovative approach that can support health authorities in decision-making when used complementarily with official early detection and verification systems. EpiCore can shorten the time to verification by confirming early detection signals, informing risk-assessment activities, and monitoring ongoing events., (©Nomita Divi, Jaś Mantero, Marlo Libel, Onicio Leal Neto, Marinanicole Schultheiss, Kara Sewalk, John Brownstein, Mark Smolinski. Originally published in JMIR Public Health and Surveillance (https://publichealth.jmir.org), 15.03.2024.)

Background: Seasonal respiratory viruses had lower incidence during their 2019-2020 and 2020-2021 seasons, which overlapped with the COVID-19 pandemic. The widespread implementation of precautionary measures to prevent transmission of SARS-CoV-2 has been seen to also mitigate transmission of seasonal influenza. The COVID-19 pandemic also led to changes in care seeking and access. Participatory surveillance systems have historically captured mild illnesses that are often missed by surveillance systems that rely on encounters with a health care provider for detection., Objective: This study aimed to assess if a crowdsourced syndromic surveillance system capable of detecting mild influenza-like illness (ILI) also captured the globally observed decrease in ILI in the 2019-2020 and 2020-2021 influenza seasons, concurrent with the COVID-19 pandemic., Methods: Flu Near You (FNY) is a web-based participatory syndromic surveillance system that allows participants in the United States to report their health information using a brief weekly survey. Reminder emails are sent to registered FNY participants to report on their symptoms and the symptoms of household members. Guest participants may also report. ILI was defined as fever and sore throat or fever and cough. ILI rates were determined as the number of ILI reports over the total number of reports and assessed for the 2016-2017, 2017-2018, 2018-2019, 2019-2020, and 2020-2021 influenza seasons. Baseline season (2016-2017, 2017-2018, and 2018-2019) rates were compared to the 2019-2020 and 2020-2021 influenza seasons. Self-reported influenza diagnosis and vaccination status were captured and assessed as the total number of reported events over the total number of reports submitted. CIs for all proportions were calculated via a 1-sample test of proportions., Results: ILI was detected in 3.8% (32,239/848,878) of participants in the baseline seasons (2016-2019), 2.58% (7418/287,909) in the 2019-2020 season, and 0.27% (546/201,079) in the 2020-2021 season. Both influenza seasons that overlapped with the COVID-19 pandemic had lower ILI rates than the baseline seasons. ILI decline was observed during the months with widespread implementation of COVID-19 precautions, starting in February 2020. Self-reported influenza diagnoses decreased from early 2020 through the influenza season. Self-reported influenza positivity among ILI cases varied over the observed time period. Self-reported influenza vaccination rates in FNY were high across all observed seasons., Conclusions: A decrease in ILI was detected in the crowdsourced FNY surveillance system during the 2019-2020 and 2020-2021 influenza seasons, mirroring trends observed in other influenza surveillance systems. Specifically, the months within seasons that overlapped with widespread pandemic precautions showed decreases in ILI and confirmed influenza. Concerns persist regarding respiratory pathogens re-emerging with changes to COVID-19 guidelines. Traditional surveillance is subject to changes in health care behaviors. Systems like FNY are uniquely situated to detect disease across disease severity and care seeking, providing key insights during public health emergencies., (©Autumn Gertz, Benjamin Rader, Kara Sewalk, Tanner J Varrelman, Mark Smolinski, John S Brownstein. Originally published in JMIR Public Health and Surveillance (https://publichealth.jmir.org), 28.12.2023.)

Purpose: Snoring may cause a number of problems such as tiredness, obesity, and even severe diseases, but the correlation between snoring and insulin secretion, which has important clinical significance, has rarely been studied. The objective of this study was to evaluate the correlation between snoring frequency and insulin secretion and discuss the potential mechanisms, thereby estimating the health condition of β-cells of individuals who snore., Methods: The analyses used data from National Health and Nutrition Examination Survey (NHANES) from 2015 to 2018. A regression analysis was performed for snoring frequency and insulin concentration, and then multiple regression analyses excluded various factors related to insulin secretion, including age, sex, race, body mass index (BMI), factors indicating patients' nutritional condition, and symptoms possibly implying obstructive sleep apnea. Subsequently, three hierarchical multiple regression analyses were carried out respectively based on sex, race, and BMI., Results: After adjusting for confounding variables, snoring frequency was correlated with insulin concentration especially when snoring was at relatively high frequencies (e.g., more than 5 nights per week) (β = 1.77, 95%CI = 0.42-3.13, P = 0.010). The stratification analyses showed that high snoring frequency increased insulin secretion among women (β = 1.83, 95%CI = 0.05-3.62, P = 0.044), Hispanics (β = 3.28, 95%CI = 0.05-6.51, P = 0.047), and participants with BMI in the range > 30 kg/m 2 (β = 3.77, 95%CI = 0.52-7.03, P = 0.023)., Conclusion: Our results suggest that snoring is likely to relate to an increase in insulin when severe, especially in women, Hispanics, and people with a BMI of more than 30 kg/m 2 ., (© 2022. The Author(s), under exclusive licence to Springer Nature Switzerland AG.)

Background: Antimicrobial resistance (AMR) in Gram-negative bacteria-causing bloodstream infections (BSIs), such as Klebsiella pneumoniae and non-typhoidal Salmonella (NTS), is a major public health concern. Nonetheless, AMR surveillance remains scarce in sub-Saharan Africa, where BSI treatment is largely empirical. The aim of the study was to determine the distribution and AMR patterns of BSI-causing NTS, K. pneumoniae , and other Gram-negative bacteria in Ghana., Methods: A cross-sectional study was conducted between April and December 2021 at eleven sentinel health facilities across Ghana as part of a pilot study on the feasibility and implementation of the human sector AMR surveillance harmonized protocol in sub-Saharan Africa. Gram-negative bacteria recovered from blood specimens of febrile patients were identified using MALDI-TOF and evaluated for antimicrobial resistance using the BD Phoenix M50 analyzer and Kirby-Bauer disc diffusion. The Department of Medical Microbiology at the University of Ghana served as the reference laboratory., Results: Out of 334 Gram-negative blood isolates, there were 18 (5.4%) NTS, 85 (25.5%) K. pneumoniae , 88 (26.4%) Escherichia coli , 40 (12.0%) Acinetobacter baumannii , 25 (7.5%) Pseudomonas aeruginosa , and 77 (23.1%) other Gram-negative bacteria. As a composite, the isolates displayed high resistance to the antibiotics tested-amoxicillin (89.3%), tetracycline (76.1%), trimethoprim-sulfamethoxazole (71.5%), and chloramphenicol (59.7%). Resistance to third-generation cephalosporins [ceftriaxone (73.7%), cefotaxime (77.8%), and ceftazidime (56.3%)] and fluoroquinolones [ciprofloxacin (55.3%)] was also high; 88% of the isolates were multidrug resistant, and the rate of extended-spectrum beta-lactamase (ESBL) production was 44.6%. Antibiotic resistance in K. pneumoniae followed the pattern of all Gram-negative isolates. Antibiotic resistance was lower in NTS blood isolates, ranging between 16.7-38.9% resistance to the tested antibiotics. Resistance rates of 38.9%, 22.2%, and 27.8% were found for cefotaxime, ceftriaxone, and ceftazidime, respectively, and 27.8% and 23.8% for ciprofloxacin and azithromycin, respectively, which are used in the treatment of invasive NTS. The prevalence of multidrug resistance in NTS isolates was 38.9%., Conclusions: Multicenter AMR surveillance of Gram-negative blood isolates from febrile patients was well-received in Ghana, and the implementation of a harmonized protocol was feasible. High resistance and multidrug resistance to first- or second-choice antibiotics, including penicillins, third-generation cephalosporins, and fluoroquinolones, were found, implying that these antibiotics might have limited effectiveness in BSI treatment in the country. Continuation of AMR surveillance in Gram-negative blood isolates is essential for a better understanding of the extent of AMR in these pathogens and to guide clinical practice and policymaking.

Introduction: Previous studies have observed the association between caffeine intake and depression, but few have considered the potential threshold effect of this issue. Therefore, the study aimed to examine the association between caffeine consumption and depression in patients aged 20 years or older using curve fitting analysis., Methods: The population was 3,263 patients from the 2017 to 2018 National Health and Nutrition Examination Survey (NHANES) with reliable answers to questions of caffeine intake and depression. Participants' depression levels were assessed using the 9-item Patient Health Questionnaire (PHQ-9) depression scale and the caffeine consumption were investigated in a private room of NHANES. The confounding variables of this study included level of education, monthly sleepiness, age, marital status, race, cigarette smoking, sex and recreational activities., Results: In linear regression analysis, patients with a higher PHQ-9 score tend to have less caffeine intake. A similar conclusion was drawn in logistic regression model using PHQ-9 ≥ 10 as a cut-off score for depression. But when caffeine intake exceeded 90 mg, there was no significant association between caffeine intake and depression based on the curve fitting analysis., Discussion: These results suggest that people can consume some caffeine to reduce depression. But further study is needed to examine the precise causal relationship between these factors., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Bao, Li, Guo, Zheng, Smolinski and He.)

Competing Interests: Divon Mordechai Lan reports a PhD scholarship from the University of Adelaide. The rest of the authors declare that they have no conflicts of interest.

Background: Participatory surveillance systems augment traditional surveillance systems through bidirectional community engagement. The digital platform evolution has enabled the expansion of participatory surveillance systems, globally, for the detection of health events impacting people, animals, plants, and the environment, in other words, across the entire One Health spectrum., Objective: The aim of this landscape was to identify and provide descriptive information regarding system focus, geography, users, technology, information shared, and perceived impact of ongoing participatory surveillance systems across the One Health spectrum., Methods: This landscape began with a systematic literature review to identify potential ongoing participatory surveillance systems. A survey was sent to collect standardized data from the contacts of systems identified in the literature review and through direct outreach to stakeholders, experts, and professional organizations. Descriptive analyses of survey and literature review results were conducted across the programs., Results: The landscape identified 60 ongoing single-sector and multisector participatory surveillance systems spanning five continents. Of these, 29 (48%) include data on human health, 26 (43%) include data on environmental health, and 24 (40%) include data on animal health. In total, 16 (27%) systems are multisectoral; of these, 9 (56%) collect animal and environmental health data; 3 (19%) collect human, animal, and environmental health data; 2 (13%) collect human and environmental health data; and 2 (13%) collect human and animal health data. Out of 60 systems, 31 (52%) are designed to cover a national scale, compared to those with a subnational (n=19, 32%) or multinational (n=10, 17%) focus. All systems use some form of digital technology. Email communication or websites (n=40, 67%) and smartphones (n=29, 48%) are the most common technologies used, with some using both. Systems have capabilities to download geolocation data (n=31, 52%), photographs (n=29, 48%), and videos (n=6, 10%), and can incorporate lab data or sample collection (n=15, 25%). In sharing information back with users, most use visualization, such as maps (n=43, 72%); training and educational materials (n=37, 62%); newsletters, blogs, and emails (n=34, 57%); and disease prevention information (n=32, 53%). Out of the 46 systems responding to the survey regarding perceived impacts of their systems, 36 (78%) noted "improved community knowledge and understanding" and 31 (67%) noted "earlier detection.", Conclusions: The landscape demonstrated the breadth of applicability of participatory surveillance around the world to collect data from community members and trained volunteers in order to inform the detection of events, from invasive plant pests to weekly influenza symptoms. Acknowledging the importance of bidirectionality of information, these systems simultaneously share findings back with the users. Such directly engaged community detection systems capture events early and provide opportunities to stop outbreaks quickly., (©Carrie McNeil, Sarah Verlander, Nomita Divi, Mark Smolinski. Originally published in JMIR Public Health and Surveillance (https://publichealth.jmir.org), 05.08.2022.)

Background: Technology-based innovations that are created collaboratively by local technology specialists and health experts can optimize the addressing of priority needs for disease prevention and control. An EpiHack is a distinct, collaborative approach to developing solutions that combines the science of epidemiology with the format of a hackathon. Since 2013, a total of 12 EpiHacks have collectively brought together over 500 technology and health professionals from 29 countries., Objective: We aimed to define the EpiHack process and summarize the impacts of the technology-based innovations that have been created through this approach., Methods: The key components and timeline of an EpiHack were described in detail. The focus areas, outputs, and impacts of the twelve EpiHacks that were conducted between 2013 and 2021 were summarized., Results: EpiHack solutions have served to improve surveillance for influenza, dengue, and mass gatherings, as well as laboratory sample tracking and One Health surveillance, in rural and urban communities. Several EpiHack tools were scaled during the COVID-19 pandemic to support local governments in conducting active surveillance. All tools were designed to be open source to allow for easy replication and adaptation by other governments or parties., Conclusions: EpiHacks provide an efficient, flexible, and replicable new approach to generating relevant and timely innovations that are locally developed and owned, are scalable, and are sustainable., (©Nomita Divi, Mark Smolinski. Originally published in the Journal of Medical Internet Research (https://www.jmir.org), 15.12.2021.)

An automated vendor-independent system for dose monitoring in computed tomography (CT) medical examinations involving ionizing radiation is presented in this paper. The system provides precise size-specific dose estimates (SSDE) following the American Association of Physicists in Medicine regulations. Our dose management can operate on incomplete DICOM header metadata by retrieving necessary information from the dose report image by using optical character recognition. For the determination of the patient's effective diameter and water equivalent diameter, a convolutional neural network is employed for the semantic segmentation of the body area in axial CT slices. Validation experiments for the assessment of the SSDE determination and subsequent stages of our methodology involved a total of 335 CT series (60 352 images) from both public databases and our clinical data. We obtained the mean body area segmentation accuracy of 0.9955 and Jaccard index of 0.9752, yielding a slice-wise mean absolute error of effective diameter below 2 mm and water equivalent diameter at 1 mm, both below 1%. Three modes of the SSDE determination approach were investigated and compared to the results provided by the commercial system GE DoseWatch in three different body region categories: head, chest, and abdomen. Statistical analysis was employed to point out some significant remarks, especially in the head category., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reporeted in this paper., (Copyright © 2020 Elsevier B.V. All rights reserved.)

Background: With the evolution of digital media, areas such as public health are adding new platforms to complement traditional systems of epidemiological surveillance. Participatory surveillance and digital epidemiology have become innovative tools for the construction of epidemiological landscapes with citizens' participation, improving traditional sources of information. Strategies such as these promote the timely detection of warning signs for outbreaks and epidemics in the region., Objective: This study aims to describe the participatory surveillance platform Guardians of Health, which was used in a project conducted during the 2016 Olympic and Paralympic Games in Rio de Janeiro, Brazil, and officially used by the Brazilian Ministry of Health for the monitoring of outbreaks and epidemics., Methods: This is a descriptive study carried out using secondary data from Guardians of Health available in a public digital repository. Based on syndromic signals, the information subsidy for decision making by policy makers and health managers becomes more dynamic and assertive. This type of information source can be used as an early route to understand the epidemiological scenario., Results: The main result of this research was demonstrating the use of the participatory surveillance platform as an additional source of information for the epidemiological surveillance performed in Brazil during a mass gathering. The platform Guardians of Health had 7848 users who generated 12,746 reports about their health status. Among these reports, the following were identified: 161 users with diarrheal syndrome, 68 users with respiratory syndrome, and 145 users with rash syndrome., Conclusions: It is hoped that epidemiological surveillance professionals, researchers, managers, and workers become aware of, and allow themselves to use, new tools that improve information management for decision making and knowledge production. This way, we may follow the path for a more intelligent, efficient, and pragmatic disease control system., (©Onicio Batista Leal Neto, Oswaldo Cruz, Jones Albuquerque, Mariana Nacarato de Sousa, Mark Smolinski, Eduarda Ângela Pessoa Cesse, Marlo Libel, Wayner Vieira de Souza. Originally published in JMIR Public Health and Surveillance (http://publichealth.jmir.org), 07.04.2020.)

School nurses are afforded minimal resources related to assessing pain in students with intellectual disability (ID) and have called for continuing education. The purpose of this study was to measure the effectiveness of an education program regarding best practices for assessing pain in students with ID. Educational sessions were presented to 248 school nurses. Pre-, post-, and follow-up surveys measured (1) difficulty school nurses face when assessing pain, (2) knowledge and use of pain assessment methods, and (3) intent to change and actual changes to professional practices. Participants experienced less difficulty assessing pain following the educational program. Almost all participants intended to change pain assessment practices, but large caseloads limited new practice adoption. Policy makers must consider population size and acuity when determining school nurse staffing. Trainings and other resources should be made available to school nurses in order to make pain assessments for students with ID more thorough and efficient.

Cross-border disease transmission is a key challenge for prevention and control of outbreaks. Variation in surveillance structure and national guidelines used in different countries can affect their data quality and the timeliness of outbreak reports. This study aimed to evaluate timeliness and data quality of national outbreak reporting for four countries in the Mekong Basin Disease Surveillance network (MBDS). Data on disease outbreaks occurring from 2010 to 2015 were obtained from the national disease surveillance reports of Cambodia, Lao PDR, Myanmar, and Vietnam. Data included total cases, geographical information, and dates at different timeline milestones in the outbreak detection process. Nine diseases or syndromes with public health importance were selected for the analysis including: dengue, food poisoning & diarrhea, severe diarrhea, diphtheria, measles, H5N1 influenza, H1N1 influenza, rabies, and pertussis. Overall, 2,087 outbreaks were reported from the four countries. The number of outbreaks and number of cases per outbreak varied across countries and diseases, depending in part on the outbreak definition used in each country. Dates on index onset, report, and response were >95% complete in all countries, while laboratory confirmation dates were 10%-100% incomplete in most countries. Inconsistent and out of range date data were observed in 1%-5% of records. The overall timeliness of outbreak report, response, and public communication was within 1-15 days, depending on countries and diseases. Diarrhea and severe diarrhea outbreaks showed the most rapid time to report and response, whereas diseases such as rabies, pertussis and diphtheria required a longer time to report and respond. The hierarchical structure of the reporting system, data collection method, and country's resources could affect the data quality and timeliness of the national outbreak reporting system. Differences in data quality and timeliness of outbreak reporting system among member countries should be considered when planning data sharing strategies within a regional network.

Background: The 2005 International Health Regulations (IHRs) established parameters for event assessments and notifications that may constitute public health emergencies of international concern. These requirements and parameters opened up space for the use of nonofficial mechanisms (such as websites, blogs, and social networks) and technological improvements of communication that can streamline the detection, monitoring, and response to health problems, and thus reduce damage caused by these problems. Specifically, the revised IHR created space for participatory surveillance to function, in addition to the traditional surveillance mechanisms of detection, monitoring, and response. Participatory surveillance is based on crowdsourcing methods that collect information from society and then return the collective knowledge gained from that information back to society. The spread of digital social networks and wiki-style knowledge platforms has created a very favorable environment for this model of production and social control of information., Objective: The aim of this study was to describe the use of a participatory surveillance app, Healthy Cup, for the early detection of acute disease outbreaks during the Fédération Internationale de Football Association (FIFA) World Cup 2014. Our focus was on three specific syndromes (respiratory, diarrheal, and rash) related to six diseases that were considered important in a mass gathering context (influenza, measles, rubella, cholera, acute diarrhea, and dengue fever)., Methods: From May 12 to July 13, 2014, users from anywhere in the world were able to download the Healthy Cup app and record their health condition, reporting whether they were good, very good, ill, or very ill. For users that reported being ill or very ill, a screen with a list of 10 symptoms was displayed. Participatory surveillance allows for the real-time identification of aggregates of symptoms that indicate possible cases of infectious diseases., Results: From May 12 through July 13, 2014, there were 9434 downloads of the Healthy Cup app and 7155 (75.84%) registered users. Among the registered users, 4706 (4706/7155, 65.77%) were active users who posted a total of 47,879 times during the study period. The maximum number of users that signed up in one day occurred on May 30, 2014, the day that the app was officially launched by the Minister of Health during a press conference. During this event, the Minister of Health announced the special government program Health in the World Cup on national television media. On that date, 3633 logins were recorded, which accounted for more than half of all sign-ups across the entire duration of the study (50.78%, 3633/7155)., Conclusions: Participatory surveillance through community engagement is an innovative way to conduct epidemiological surveillance. Compared to traditional epidemiological surveillance, advantages include lower costs of data acquisition, timeliness of information collected and shared, platform scalability, and capacity for integration between the population being served and public health services., (©Onicio Leal Neto, George Santiago Dimech, Marlo Libel, Wayner Vieira de Souza, Eduarda Cesse, Mark Smolinski, Wanderson Oliveira, Jones Albuquerque. Originally published in JMIR Public Health and Surveillance (http://publichealth.jmir.org), 04.05.2017.)

Background: Flu Near You (FNY) is an Internet-based participatory surveillance system in the United States and Canada that allows volunteers to report influenza-like symptoms using a brief weekly symptom report., Objective: Our objective was to evaluate the representativeness of the FNY population compared with the general population of the United States, explore the demographic and behavioral characteristics associated with FNY's high-participation users, and summarize results from a user survey of a cohort of FNY participants., Methods: We compared (1) the representativeness of sex and age groups of FNY participants during the 2014-2015 flu season versus the general US population and (2) the distribution of Human Development Index (HDI) scores of FNY participants versus that of the general US population. We analyzed associations between demographic and behavioral factors and the level of participant follow-up (ie, high vs low). Finally, descriptive statistics of responses from FNY's 2015 and 2016 end-of-season user surveys were calculated., Results: During the 2014-2015 influenza season, 47,234 unique participants had at least one FNY symptom report that was either self-reported (users) or submitted on their behalf (household members). The proportion of female FNY participants was significantly higher than that of the general US population (n=28,906, 61.2% vs 51.1%, P<.001). Although each age group was represented in the FNY population, the age distribution was significantly different from that of the US population (P<.001). Compared with the US population, FNY had a greater proportion of individuals with HDI >5.0, signaling that the FNY user distribution was more affluent and educated than the US population baseline. We found that high-participation use (ie, higher participation in follow-up symptom reports) was associated with sex (females were 25% less likely than men to be high-participation users), higher HDI, not reporting an influenza-like illness at the first symptom report, older age, and reporting for household members (all differences between high- and low-participation users P<.001). Approximately 10% of FNY users completed an additional survey at the end of the flu season that assessed detailed user characteristics (3217/33,324 in 2015; 4850/44,313 in 2016). Of these users, most identified as being either retired or employed in the health, education, and social services sectors and indicated that they achieved a bachelor's degree or higher., Conclusions: The representativeness of the FNY population and characteristics of its high-participation users are consistent with what has been observed in other Internet-based influenza surveillance systems. With targeted recruitment of underrepresented populations, FNY may improve as a complementary system to timely tracking of flu activity, especially in populations that do not seek medical attention and in areas with poor official surveillance data., (©Kristin Baltrusaitis, Mauricio Santillana, Adam W Crawley, Rumi Chunara, Mark Smolinski, John S Brownstein. Originally published in JMIR Public Health and Surveillance (http://publichealth.jmir.org), 07.04.2017.)

Additivity of functional group contributions to protein-ligand binding is a very popular concept in medicinal chemistry as the basis of rational design and optimized lead structures. Most of the currently applied scoring functions for docking build on such additivity models. Even though the limitation of this concept is well known, case studies examining in detail why additivity fails at the molecular level are still very scarce. The present study shows, by use of crystal structure analysis and isothermal titration calorimetry for a congeneric series of thrombin inhibitors, that extensive cooperative effects between hydrophobic contacts and hydrogen bond formation are intimately coupled via dynamic properties of the formed complexes. The formation of optimal lipophilic contacts with the surface of the thrombin S3 pocket and the full desolvation of this pocket can conflict with the formation of an optimal hydrogen bond between ligand and protein. The mutual contributions of the competing interactions depend on the size of the ligand hydrophobic substituent and influence the residual mobility of ligand portions at the binding site. Analysis of the individual crystal structures and factorizing the free energy into enthalpy and entropy demonstrates that binding affinity of the ligands results from a mixture of enthalpic contributions from hydrogen bonding and hydrophobic contacts, and entropic considerations involving an increasing loss of residual mobility of the bound ligands. This complex picture of mutually competing and partially compensating enthalpic and entropic effects determines the non-additivity of free energy contributions to ligand binding at the molecular level., ((c) 2010 Elsevier Ltd. All rights reserved.)

Rho Kinase (ROCK) is a serine/threonine kinase whose inhibition could prove beneficial in numerous therapeutic areas. We have developed a promising class of ATP-competitive inhibitors based upon a benzimidazole scaffold, which show excellent potency toward ROCK (IC(50)<10nM). This report details the optimization of selectivity for ROCK over other related kinases such as Protein kinase A (PKA)., (Copyright 2010 Elsevier Ltd. All rights reserved.)

Accurately predicting the binding affinity of ligands to their receptors by computational methods is one of the major challenges in structure-based drug design. One of the potentially significant errors in these predictions is the common assumption that the ligand binding affinity contributions of noncovalent interactions are additive. Herein we present data obtained from two separate series of thrombin inhibitors containing hydrophobic side chains of increasing size that bind in the S3 pocket and with, or without, an adjacent amine that engages in a hydrogen bond with Gly 216. The first series of inhibitors has a m-chlorobenzyl moiety binding in the S1 pocket, and the second has a benzamidine moiety. When the adjacent hydrogen bond is present, the enhanced binding affinity per A(2) of hydrophobic contact surface in the S3 pocket improves by 75% and 59%, respectively, over the inhibitors lacking this hydrogen bond. This improvement of the binding affinity per A(2) demonstrates cooperativity between the hydrophobic interaction and the hydrogen bond.

Successful design of potent and selective protein inhibitors, in terms of structure-based drug design, strongly relies on the correct understanding of the molecular features determining the ligand binding to the target protein. We present a case study of serine protease inhibitors with a bis(phenyl)methane moiety binding into the S3 pocket. These inhibitors bind with remarkable potency to the active site of thrombin, the blood coagulation factor IIa. A combination of X-ray crystallography and isothermal titration calorimetry provides conclusive insights into the driving forces responsible for the surprisingly high potency of these inhibitors. Analysis of six well-resolved crystal structures (resolution 1.58-2.25 A) along with the thermodynamic data allows an explanation of the tight binding of the bis(phenyl)methane inhibitors. Interestingly, the two phenyl rings contribute to binding affinity for very different reasons - a fact that can only be elucidated by a structure-based approach. The first phenyl moiety occupies the hydrophobic S3 pocket, resulting in a mainly entropic advantage of binding. This observation is based on the displacement of structural water molecules from the S3 pocket that are observed in complexes with inhibitors that do not bind in the S3 pocket. The same classic hydrophobic effect cannot explain the enhanced binding affinity resulting from the attachment of the second, more solvent-exposed phenyl ring. For the bis(phenyl)methane inhibitors, an observed adaptive rotation of a glutamate residue adjacent to the S3 binding pocket attracted our attention. The rotation of this glutamate into salt-bridging distance with a lysine moiety correlates with an enhanced enthalpic contribution to binding for these highly potent thrombin binders. This explanation for the magnitude of the attractive force is confirmed by data retrieved by a Relibase search of several thrombin-inhibitor complexes deposited in the Protein Data Bank exhibiting similar molecular features. Special attention was attributed to putative changes in the protonation states of the interaction partners. For this purpose, two analogous inhibitors differing mainly in their potential to change the protonation state of a hydrogen-bond donor functionality were compared. Buffer dependencies of the binding enthalpy associated with complex formation could be traced by isothermal titration calorimetry, which revealed, along with analysis of the crystal structures (resolution 1.60 and 1.75 A), that a virtually compensating proton interchange between enzyme, inhibitor and buffer is responsible for the observed buffer-independent thermodynamic signatures.

The overt DIC score of the DIC subcommittee of the ISTH includes a fibrin-related marker (FRM) as indicator of intravascular fibrin formation. The type of marker to be used has not been specified, but D-dimer antigen, or fibrin degradation products are used by most investigators. Soluble fibrin complexes have been suggested as more specific indicators of acute intravascular fibrin formation. The aim of the present study was to compare the predictive value of the overt DIC score concerning clinical outcome in a surgical intensive care cohort, using either D-dimer antigen, or soluble fibrin antigen as FRM. The cutoff values for 2 and 3 score points for the FRM were assigned on the basis of the 25% and 75% quartiles of 1870 plasma samples obtained from 359 ICU patients during a period of 6 months. For 331 patients with complete diagnostic workup and day 1 blood samples, the Iatro SF as FRM component of the overt DIC score displayed the highest prognostic power concerning clinical outcome. The 28-day mortality of patients with overt DIC at day 1, using Iatro SF as FRM assay was 50.0%, whereas 28-day mortality of patients without overt DIC was 14.0% (p <0.0001). Using MDA D-dimer, and TINAquant D-dimer, 28-day mortality was between 35.5% and 39.3% in patients with overt DIC, and 15.5% to 15.6% in patients without overt DIC. Selection of the FRM as component of the DIC score has a small, but relevant impact on the prognostic performance of the overt DIC score. The present data on the distribution of values may provide a basis for the selection of appropriate cutoff points for assigning 2, and 3 points in the score.

Objective: An abnormality of the optical transmission waveform obtained during measurement of the activated partial thromboplastin time (aPTT) has been described in association with overt disseminated intravascular coagulation. This abnormality, a biphasic waveform, is caused by the in vitro formation of Ca2+-induced complexes between very low density lipoprotein and C-reactive protein. We have evaluated the diagnostic utility of aPTT waveform analysis for identifying patients with overt disseminated intravascular coagulation and sepsis., Design: Observational study investigating the predictive value of biphasic waveform for the diagnosis of sepsis and overt disseminated intravascular coagulation., Setting: Surgical intensive care unit of a university hospital., Subjects: We studied 331 consecutive patients admitted to the intensive care unit during a period of 6 months., Interventions: Laboratory analyses, including prothrombin time, aPTT, aPTT waveform analysis, fibrinogen, D-dimer antigen, and platelet count., Measurements and Main Results: At the most sensitive threshold value of the waveform variable for detection of the biphasic waveform (slope&#95;1 = -0.05 %T/sec), this abnormality was detected in 54 of 331 patients (16.3%) at admission and 95 of 331 patients (28.7%) during the entire course of intensive care unit treatment. At this threshold, 59.3% of patients with a biphasic waveform on admission and 45.3% with a biphasic waveform during the total intensive care unit course were diagnosed with sepsis. Depending on the threshold value of slope&#95;1, the sensitivity of aPTT waveform analysis for detection of sepsis varied between 22% and 55% at admission and between 48% and 74% during the entire intensive care unit stay. The specificity for sepsis varied between 92% and 98% and between 81% and 94%, for admission and total intensive care unit course, respectively. Biphasic waveform showed a comparable specificity for the diagnosis of overt disseminated intravascular coagulation, albeit at a lower sensitivity., Conclusions: As an adjunct to routine coagulation testing in intensive care unit patients, aPTT waveform analysis is an elegant means for the rapid and highly specific identification of patients with sepsis.

Objectives: To describe demographic characteristics, patterns of use, and symptoms associated with mercury poisoning among persons who used a Mexican beauty cream containing mercurous chloride and to estimate the prevalence of cream use in Texas near the Mexico border., Design: Case series and cross-sectional survey., Setting: Border communities of Arizona, California, New Mexico, and Texas., Participants: Persons who used the cream and contacted a health department in response to announcements about the cream and households that participated in the Survey of Health and Environmental Conditions in Texas Border Counties and Colonias, 1997., Main Outcome Measures: Urine mercury concentrations, self-reported symptoms, and prevalence of cream use among households., Results: Of 330 cream users who contacted their health department, 96% were women, and 95% were Hispanic. The mean urine mercury concentration was 146.7 microg/L (reference range : 0-20 microg/L). In 5% of 2,194 randomly selected Texas households near the Mexico border, at least 1 person had used "Crema de Belleza-Manning" (Laboratorios Vida Natural, S.A., Tampico, Tamaulipas, Mexico) in the previous year., Conclusions: Most cream users had increased urine mercury concentrations. Cream use was common in Texas near the Mexico border. Physicians should consider toxicity in patients with neurologic symptoms of unclear cause and use public health departments when investigating unusual illnesses.

Major depressive disorder is the most common diagnosis encountered in family practice, yet family physicians are relatively unlikely to make the diagnosis. This study compared physician ratings of depression with scores from the Center for Epidemiological Studies-Depression (CES-D) questionnaire and with telephone interview diagnoses of depression using the 3rd revised edition of the Diagnostic and Statistical Manual of Mental Disorders (DSM-III-R) criteria for major depressive disorder in a population of 266 patients in community-based family practices. Additional assessments were made of health status, stress, social support, prescribed psychotropic medication, and counseling. The prevalence of positive questionnaire scores in this population was 22.6 percent, and the prevalence of major depressive disorder (based on telephone interview) was 8 percent. Physician ratings of depression were relatively inaccurate when compared with either CES-D scores or telephone interview diagnoses. Optimum specificity (80 percent) and sensitivity (50 percent) with telephone interview diagnoses were achieved when physicians rated the patient as having any depression versus having no depression. Physician ratings of depression were correlated with their assessment of patient stress, social support, and physical health but not with more objective measures of these variables. When compared with telephone interview diagnosis, the sensitivity and specificity of the CES-D scores were relatively poor, suggesting that the CES-D is not useful as a screening tool for unselected populations. Finally, we found that family physicians base their assessments of depression more on distress than on depressive symptoms. Certain physician myths, barriers, and biases may exist that preclude the effective diagnosis of depression.