Antibiotic Susceptibility Profiles and Frequency of Resistance Genes in Clinical Shiga Toxin-Producing Escherichia coli Isolates from Michigan over a 14-Year Period.

Shiga toxin-producing Escherichia coli (STEC) is an important foodborne pathogen that contributes to over 250,000 infections in the United States each year. Because antibiotics are not recommended for STEC infections, resistance in STEC has not been widely researched despite an increased likelihood for the transfer of resistance genes from STEC to opportunistic pathogens residing within the same microbial community. From 2001 to 2014, 969 STEC isolates were collected from Michigan patients. Antibiotic susceptibility profiles to clinically relevant antibiotics were determined using disc diffusion, while epidemiological data were used to identify factors associated with resistance. Whole-genome sequencing was used for serotyping, examining genetic relatedness, and identifying genetic determinants and mechanisms of resistance in the non-O157 isolates. Increasing frequencies of resistance to at least one antibiotic were observed over the 14 years (P = 0.01). While the non-O157 serogroups were more commonly resistant than O157 (odds ratio, 2.4; 95% confidence interval,1.43 to 4.05), the frequency of ampicillin resistance among O157 isolates was significantly higher in Michigan than the national average (P = 0.03). Genomic analysis of 321 non-O157 isolates uncovered 32 distinct antibiotic resistance genes (ARGs). Although mutations in genes encoding resistance to ciprofloxacin and ampicillin were detected in four isolates, most of the horizontally acquired ARGs conferred resistance to aminoglycosides, ß-lactams, sulfonamides, and/or tetracycline. This study provides insight into the mechanisms of resistance in a large collection of clinical non-O157 STEC isolates and demonstrates that antibiotic resistance among all STEC serogroups has increased over time, prompting the need for enhanced surveillance.

Antimicrobial Drug-Resistant Shiga Toxin-Producing Escherichia coli Infections, Michigan, USA.

High frequencies of antimicrobial drug resistance were observed in O157 and non-O157 Shiga toxin-producing E. coli strains recovered from patients in Michigan during 2010-2014. Resistance was more common in non-O157 strains and independently associated with hospitalization, indicating that resistance could contribute to more severe disease outcomes.

Governance and Public Health Decision-Making During the COVID-19 Pandemic: A Scoping Review.

Objective: We provide an in-depth understanding of how governance and decision-making during the COVID-19 pandemic has been empirically characterized in the literature to identify gaps in research and highlight areas that require further inquiry. Methods: We searched peer-reviewed publications using empirical data published between Jan 1, 2020 and Jan 31, 2022 in three electronic databases to examine the process of governance and decision-making during the COVID-19 pandemic. Two authors independently screened the records and 24 publications were extracted for the review. Results: Governance is analyzed by its level at national, sub-national, community and by its aspects of process, determinants and performance. While different methodological approaches are used, governance is conceptualized in four ways 1) characteristics and elements, 2) leadership, 3) application of power and 4) models or arrangements of governance. Conclusion: For future pandemic preparedness, there is a need for more empirical research using a unified conceptual approach to governance, which integrates decision-making processes and can guide governance structures and mechanisms across different countries and contexts. We call for more inclusivity in who performs the research on governance and where.

Singapore's COVID-19 crisis decision-making through centralization, legitimacy, and agility: an empirical analysis.

Background: Decision-making during health crises differs from routine decision-making and is constrained by ambiguity about evolving epidemiological situations, urgency of response, lack of evidence, and fear. Recent analyses of governance and decision-making during COVID-19, focusing on leadership qualities, involvement of specific stakeholders, and effective resource management, do not adequately address a persisting gap in understanding the determinants of decision-making during health crises at the national level. Methods: We undertook a study to understand the processes and characteristics of decision-making during the COVID-19 pandemic in Singapore. We used a case study approach and collected empirical evidence about public health decision-making, using a combination of key informant interviews and focus group discussions with stakeholders from government, academia and civil society organizations. Findings: We argue that administrative centralization and political legitimacy played important roles in agile governance and decision-making during the pandemic in Singapore. We demonstrate the role of the Singapore government's centralization in creating a unified and coherent governance model for emergency response and the People's Action Party's (PAP) legitimacy in facilitating people's trust in the government. Health system resilience and financial reserves further facilitated an agile response, yet community participation and prioritization of vulnerable migrant populations were insufficient in the governance processes. Interpretation: Our analysis contributes to the theory and practice of crisis decision-making by highlighting the role of political and administrative determinants in agile crisis decision-making. Funding: This study is funded by the U.S. Centers for Disease Control and Prevention through a Cooperative Research Agreement (NU2HGH2020000037).

The United States Food and Drug Administration (FDA) regulatory response to combat neglected tropical diseases (NTDs): A review.

The availability and accessibility of safe and effective drugs, vaccines, and diagnostics are essential to reducing the immense global burden of neglected tropical diseases (NTDs). National regulatory authorities, such as the United States Food and Drug Administration (FDA), play an essential role in this effort to ensure access to safe and effective medical products by working within a set of legal frameworks and regulatory functions. However, medical product development for NTDs remains neglected, as combating NTDs is not a viable commercial market for pharmaceutical companies. To spur research and development (R&D) of NTD products, the US government has authorized various programs and policies to engage pharmaceutical companies, many of which provide FDA with the legal authority to implement NTD programs and pathways. Thus, this review provides a clear overview of the various regulatory pathways and programs employed by the FDA to increase the availability of NTD drugs, vaccines, and diagnostics. The review assesses the available information on various regulatory considerations and their impact on NTD product development as a first step in estimating the importance of such programs. Next, findings related to currently approved NTD products through these programs are discussed. Lastly, gaps in NTD R&D are identified and suggestions on how to address these are presented. The available data shows that while such incentive programs are factored into companies' decisions to pursue NTD R&D, approved products for NTDs remains vastly insufficient. Most approved products that utilize these NTD regulatory pathways and programs are overwhelmingly for tuberculosis and malaria-both of which are not considered NTDs by the World Health Organization (WHO). Dedicated efforts are needed to facilitate and accelerate NTD product including employing multiple incentive programs, regular assessment of such programs, and leveraging on public-private partnerships.

Expanding global vaccine manufacturing capacity: Strategic prioritization in small countries.

The COVID-19 pandemic highlighted significant gaps in equitable access to essential medical countermeasures such as vaccines. Manufacturing capacity for pandemic vaccines, therapeutics, and diagnostics is concentrated in too few countries. One of the major hurdles to equitable vaccine distribution was "vaccine nationalism", countries hoarded vaccines to vaccinate their own populations first which significantly reduced global vaccine supply, leaving significant parts of the world vulnerable to the virus. As part of equitably building global capacity, one proposal to potentially counter vaccine nationalism is to identify small population countries with vaccine manufacturing capacity, as these countries could fulfill their domestic obligations quickly, and then contribute to global vaccine supplies. This cross-sectional study is the first to assesses global vaccine manufacturing capacity and identifies countries with small populations, in each WHO region, with the capacity and capability to manufacture vaccines using various manufacturing platforms. Twelve countries were identified to have both small populations and vaccine manufacturing capacity. 75% of these countries were in the European region; none were identified in the African Region and South-East Asia Region. Six countries have facilities producing subunit vaccines, a platform where existing facilities can be repurposed for COVID-19 vaccine production, while three countries have facilities to produce COVID-19 mRNA vaccines. Although this study identified candidate countries to serve as key vaccine manufacturing hubs for future health emergencies, regional representation is severely limited. Current negotiations to draft a Pandemic Treaty present a unique opportunity to address vaccine nationalism by building regional capacities in small population countries for vaccine research, development, and manufacturing.

National and subnational governance and decision-making processes during the COVID-19 pandemic in Nigeria: an empirical analysis.

Governance of the COVID-19 pandemic required decision-makers to make and implement decisions amidst uncertainty, public pressure and time constraints. However, few studies have attempted to assess these decision-making processes empirically during health emergencies. Thus, we aimed to understand governance, defined as the process of decision-making and implementation of decisions, during the COVID-19 pandemic in Nigeria. We conducted key informant interviews and focus group discussions with national and subnational government officials, civil society organisation (CSO) members, development partners and academic experts. Our study identified several themes on governance and decision-making processes. First, Nigeria established high-level decision-making structures at the federal and state levels, providing clear and integrated multisectoral decision-making mechanism. However, due to the emergence of conflicts between government levels, there is a need to strengthen intergovernmental arrangements. Second, while decision-makers relied on input from academic experts and CSOs, additional efforts are required to engage such stakeholders in decision-making processes, especially during the early stages of health emergencies. Third, Nigeria's previous experiences responding to disease outbreaks aided the overall response, as many capacities and coordination mechanisms for cohesive action were present. Fourth, while decision-makers took a holistic view of scientific, social and economic factors for decision-making, this process was also adaptive to account for rapidly evolving information. Lastly, more efforts are needed to ensure decisions are inclusive, equitable and transparent, and improve overall public trust in governance processes. This study provides insights and identifies opportunities to enhance governance and decision-making processes in health emergency responses, aiding future pandemic preparedness efforts.

Pangenomic analyses of antibiotic-resistant Campylobacter jejuni reveal unique lineage distributions and epidemiological associations.

Application of whole-genome sequencing (WGS) to characterize foodborne pathogens has advanced our understanding of circulating genotypes and evolutionary relationships. Herein, we used WGS to investigate the genomic epidemiology of Campylobacter jejuni, a leading cause of foodborne disease. Among the 214 strains recovered from patients with gastroenteritis in Michigan, USA, 85 multilocus sequence types (STs) were represented and 135 (63.1 %) were phenotypically resistant to at least one antibiotic. Horizontally acquired antibiotic resistance genes were detected in 128 (59.8 %) strains and the genotypic resistance profiles were mostly consistent with the phenotypes. Core-gene phylogenetic reconstruction identified three sequence clusters that varied in frequency, while a neighbour-net tree detected significant recombination among the genotypes (pairwise homoplasy index P<0.01). Epidemiological analyses revealed that travel was a significant contributor to pangenomic and ST diversity of C. jejuni, while some lineages were unique to rural counties and more commonly possessed clinically important resistance determinants. Variation was also observed in the frequency of lineages over the 4 year period with chicken and cattle specialists predominating. Altogether, these findings highlight the importance of geographically specific factors, recombination and horizontal gene transfer in shaping the population structure of C. jejuni. They also illustrate the usefulness of WGS data for predicting antibiotic susceptibilities and surveillance, which are important for guiding treatment and prevention strategies.

State laws that authorize pharmacists to prescribe naloxone are associated with increased naloxone dispensing in retail pharmacies.

BACKGROUND: The opioid crisis in the United States continues to worsen. Several states have passed laws granting pharmacists the authority to independently prescribe (not just dispense) naloxone. Since pharmacists are accessible healthcare providers, enhancing their ability to prescribe naloxone, an effective opioid overdose reversal agent, may help combat the ongoing opioid overdose epidemic. METHOD: Using a nationally representative database on drug dispensing in 2010 to 2018 from Symphony Health, we conducted a cross-sectional study to assess whether state laws authorizing pharmacists to prescribe naloxone were associated with increased naloxone dispensing from retail pharmacies. RESULTS: The number of naloxone prescriptions dispensed from retail pharmacies increased from 2010 to 2018 and doubled from 2017 to 2018. The presence of state laws authorizing pharmacists to prescribe naloxone is associated with an average increase of 331(95% CI = 43.56, 618.49) prescription dispensed per state per quarter. This represents an approximately 53% increase in naloxone dispensed compared to pharmacies in states where there were no such laws. CONCLUSIONS: Our study suggests that state laws that allow pharmacists to prescribe and not just dispense naloxone at retail pharmacies can increase the availability and accessibility of naloxone. Adopting and implementing such laws may help reduce serious and life-threatening opioid overdoses.

Nanopore chip with self-aligned transverse tunneling junction for DNA detection.

To achieve better signal quality and resolution in nanopore sequencing, there has been strong interest in quantum tunneling based detection which requires integration of tunneling junctions in nanopores. However, there has been very limited success due to precision and reproducibility issues. Here we report a new strategy based on feedback-controlled electrochemical processes in a confined nanoscale space to construct nanopore devices with self-aligned transverse tunneling junctions, all embedded on a nanofluidic chip. We demonstrate high-yield (>93%) correlated detection of translocating DNAs from both the ionic channel and the tunneling junction with enriched event rate. We also observed events attributed to non-translocating DNA making contact with the transverse electrodes. Existing challenges for precise sequencing are discussed, including fast translocation speed, and interference from transient electrostatic signals from fast-moving DNAs. Our work can serve as a first step to provide an accessible, and reproducible platform enabling further optimizations for tunneling-based DNA detection, and potentially sequencing.

Contents of US Food and Drug Administration Refuse-to-File Letters for New Drug Applications and Efficacy Supplements and Their Public Disclosure by Applicants.

Importance: Before reviewing drug applications, the US Food and Drug Administration (FDA) conducts "filing reviews" to assess whether they are complete enough for full review. If the applications are incomplete, the FDA issues refuse-to-file (RTF) letters identifying deficiencies. The FDA does not make these RTF letters public at the time of issuance. Why the FDA issues RTF letters and how often the letters and their contents are made publicly available are unknown. Objectives: To quantitatively analyze the FDA's reasons for issuing RTF letters and assess the public transparency of RTF letters and their contents. Design and Setting: This cross-sectional study analyzes RTF letters issued in response to new drug applications and efficacy supplements (applications for new indications or patient populations for already approved drugs) submitted to the FDA between January 1, 2008, and December 31, 2017. Statistical analysis was conducted in July 2019. Main Outcomes and Measures: Two types of information were extracted and cataloged from RTF letters: (1) the reasons why the FDA refused to file applications and (2) the FDA comments that, while not a basis for RTF letters, conveyed important information to applicants. The extent to which applicants publicly disclosed the FDA's refusal reasons were also assessed. Results: The study included 103 RTF letters containing a total of 644 identified FDA refusal reasons. Among the 2475 applications that the FDA received during the study time frame, 98 (4.0%) received RTF letters. Overall, 84.5% (544 of 644) of the refusal reasons were for scientific deficiencies; most reasons were related to drug efficacy and safety (196 [30.4%]) and drug quality (125 [19.4%]). The remaining 15.5% of refusal reasons (100 of 644) were for application organization deficiencies or legal issues. A total of 26.2% of the RTF letters (27 of 103) identified presubmission advice from the FDA that applicants did not follow; the most frequently ignored advice was related to clinical trial design (33.3% [9 of 27]), followed by product chemistry and manufacturing (25.9% [7 of 27]). Applicants publicly disclosed the existence of 16 of 103 RTF letters (15.5%); however, only 5.4% of applicant-disclosed reasons (35 of 644) matched the refusal reasons that the FDA had provided in the RTF letters. Conclusions and Relevance: This cross-sectional study found that the FDA refused to file applications for substantive reasons related to quality, safety, and efficacy, and applicants' disclosure of those reasons was incomplete. This work sheds light on the FDA's regulatory decision-making processes and the RTF reasons that could delay availability of therapies to patients.

Epidemiologic Associations Vary Between Tetracycline and Fluoroquinolone Resistant Campylobacter jejuni Infections.

Campylobacter jejuni is the leading cause of bacterial gastroenteritis and antibiotic resistant C. jejuni are a serious threat to public health. Herein, we sought to evaluate trends in C. jejuni infections, quantify resistance frequencies, and identify epidemiological factors associated with infection. Campylobacter jejuni isolates (n = 214) were collected from patients via an active surveillance system at four metropolitan hospitals in Michigan between 2011 and 2014. The minimum inhibitory concentration for nine antibiotics was determined using microbroth dilution, while demographic and clinical data were used for the univariate and multivariate analyses. Over the 4-year period, a significant increase in the recovery of C. jejuni was observed (p ≤ 0.0001). Differences in infection rates were observed by hospital and several factors were linked to more severe disease. Patients residing in urban areas, for instance, were significantly more likely to be hospitalized than rural residents as were patients over 40 years of age and those self-identifying as non-White, highlighting potential disparities in disease outcomes. Among the 214 C. jejuni isolates, 135 (63.1%) were resistant to at least one antibiotic. Resistance was observed for all nine antibiotics tested yielding 11 distinct resistance phenotypes. Tetracycline resistance predominated (n = 120; 56.1%) followed by resistance to ciprofloxacin (n = 49; 22.9%), which increased from 15.6% in 2011 to 25.0% in 2014. Resistance to two antibiotic classes was observed in 38 (17.8%) isolates, while multidrug resistance, or resistance to three or more classes, was observed in four (1.9%). Notably, patients with ciprofloxacin resistant infections were more likely to report traveling in the past month (Odds Ratio (OR): 3.0; 95% confidence interval (CI): 1.37, 6.68) and international travel (OR: 9.8; 95% CI: 3.69, 26.09). Relative to patients with only tetracycline resistant infections, those with ciprofloxacin resistance were more likely to travel internationally, be hospitalized and have an infection during the fall or summer. Together, these findings show increasing rates of infection and resistance and highlight specific factors that impact both outcomes. Enhancing understanding of factors linked to C. jejuni resistance and more severe infections is critical for disease prevention, particularly since many clinical laboratories have switched to the use of culture-independent tests for the detection of Campylobacter.

Increasing Frequencies of Antibiotic Resistant Non-typhoidal Salmonella Infections in Michigan and Risk Factors for Disease.

Non-typhoidal Salmonella (NTS) are important enteric pathogens causing over 1 million foodborne illnesses in the U.S. annually. The widespread emergence of antibiotic resistance in NTS isolates has limited the availability of antibiotics that can be used for therapy. Since Michigan is not part of the FoodNet surveillance system, few studies have quantified antibiotic resistance frequencies and identified risk factors for NTS infections in the state. We obtained 198 clinical NTS isolates via active surveillance at four Michigan hospitals from 2011 to 2014 for classification of serovars and susceptibility to 24 antibiotics using broth microdilution. The 198 isolates belonged to 35 different serovars with Enteritidis (36.9%) predominating followed by Typhimurium (19.5%) and Newport (9.7%), though the proportion of each varied by year, residence, and season. The number of Enteritidis and Typhimurium cases was higher in the summer, while Enteritidis cases were significantly more common among urban vs. rural residents. A total of 30 (15.2%) NTS isolates were resistant to ≥1 antibiotic and 15 (7.5%) were resistant to ≥3 antimicrobial classes; a significantly greater proportion of Typhimurium isolates were resistant compared to Enteritidis isolates and an increasing trend in the frequency of tetracycline resistance and multidrug resistance was observed over the 4-year period. Resistant infections were associated with longer hospital stays as the mean stay was 5.9 days for patients with resistant isolates relative to 4.0 days for patients infected with susceptible isolates. Multinomial logistic regression indicated that infection with serovars other than Enteritidis [Odds ratio (OR): 3.8, 95% confidence interval (CI): 1.23-11.82] as well as infection during the fall (OR: 3.0; 95% CI: 1.22-7.60) were independently associated with resistance. Together, these findings demonstrate the importance of surveillance, monitoring resistance frequencies, and identifying risk factors that can aid in the development of new prevention strategies.

High production of erythritol from Candida sorbosivorans SSE-24 and its inhibitory effect on biofilm formation of Streptococcus mutans.

Amongst different isolates screened for erythritol production, isolate no. SSE-24 was found to be the best erythritol producer and identified as Candida sorbosivorans SSE-24. Statistical optimization was used to determine the optimum level of the significant variables for maximum erythritol production. The interactive effects of glucose, inoculum level and yeast extract were determined to be significant. The optimum medium composition for erythritol production was 160 g/L glucose, 12 g/L yeast extract, 10% inoculum level and 0.35 g/L FeSO4⋅7H2O. The production of erythritol was successfully scaled up to a 30 L level, where 60.20 g/L of erythritol was produced, with a yield of 0.38 g/g. The fermentation broth was purified by activated charcoal followed by vacuum concentration, ion exchange chromatography and crystallization. Purity of erythritol was further determined by NMR. Significant inhibitory effect of erythritol on growth (>78%) and biofilm formation (40.2%) of Streptococcus mutans enhances the importance of this study.