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Pathogens that persist in environmental reservoirs represent a major and underappreciated risk for humans and animals (1). Bacillus anthracis, the causative agent of anthrax, is an extreme example of environmental [...]

This secondary data analysis of 620 hospitals examined how hospital capabilities and resources (for example, intensive care unit types and bed availability) influenced COVID-19 volume–outcome relationships. The analysis found that, regardless of hospital capability, as patient volumes surged, survival decreased. The article suggests that strategies to balance caseload surges across hospitals may help ensure patient safety. Visual Abstract. Association Between Hospital Type and Resilience During Caseload Stress: A Natural Quality-of-Care Experiment From the COVID-19 Pandemic This secondary data analysis of 620 hospitals examined how hospital capabilities and resources (for example, intensive care unit types and bed availability) influenced COVID-19 volume–outcome relationships. The analysis found that, regardless of hospital capability, as patient volumes surged, survival decreased. The article suggests that strategies to balance caseload surges across hospitals may help ensure patient safety. Background: Imbalances between hospital caseload and care resources that strained U.S. hospitals during the pandemic have persisted after the pandemic amid ongoing staff shortages. Understanding which hospital types were more resilient to pandemic overcrowding-related excess deaths may prioritize patient safety during future crises. Objective: To determine whether hospital type classified by capabilities and resources (that is, extracorporeal membrane oxygenation [ECMO] capability, multiplicity of intensive care unit [ICU] types, and large or small hospital) influenced COVID-19 volume–outcome relationships during Delta wave surges. Design: Retrospective cohort study. Setting: 620 U.S. hospitals in the PINC AI Healthcare Database. Participants: Adult inpatients with COVID-19 admitted July to November 2021. Measurements: Hospital-months were ranked by previously validated surge index (severity-weighted COVID-19 inpatient caseload relative to hospital bed capacity) percentiles. Hierarchical models were used to evaluate the effect of log-transformed surge index on the marginally adjusted probability of in-hospital mortality or discharge to hospice. Effect modification was assessed for by 4 mutually exclusive hospital types. Results: Among 620 hospitals recording 223 380 inpatients with COVID-19 during the Delta wave, there were 208 ECMO-capable, 216 multi-ICU, 36 large (≥200 beds) single-ICU, and 160 small (<200 beds) single-ICU hospitals. Overall, 50 752 (23%) patients required admission to the ICU, and 34 274 (15.3%) died. The marginally adjusted probability for mortality was 5.51% (95% CI, 4.53% to 6.50%) per unit increase in the log surge index (strain attributable mortality = 7375 [CI, 5936 to 8813] or 1 in 5 COVID-19 deaths). The test for interaction showed no difference (P  = 0.32) in log surge index–mortality relationship across 4 hospital types. Results were consistent after excluding transferred patients, restricting to patients with acute respiratory failure and mechanical ventilation, and using alternative strain metrics. Limitation: Residual confounding. Conclusion: Comparably detrimental relationships between COVID-19 caseload and survival were seen across all hospital types, including highly advanced centers, and well beyond the pandemic's learning curve. These lessons from the pandemic heighten the need to minimize caseload surges and their effects across all hospital types during public health and staffing crises. Primary Funding Source: Intramural Research Program of the National Institutes of Health Clinical Center. [ABSTRACT FROM AUTHOR]

Tyrosine kinase domain (TKD) mutations contribute to acquired resistance to FMS-like tyrosine kinase 3 (FLT3) inhibitors used to treat FLT3-mutant acute myeloid leukemia (AML). We report a cocrystal structure of FLT3 with a type I inhibitor, NCGC1481, that retained potent binding and activity against FLT3 TKD and gatekeeper mutations. Relative to the current generation of advanced FLT3 inhibitors, NCGC1481 exhibited superior antileukemic activity against the common, clinically relevant FLT3-mutant AML cells in vitro and in vivo., Introduction Acute myeloid leukemia (AML) is associated with mutations in FMS-like tyrosine kinase 3 (FLT3) in approximately 30% of cases, including internal tandem duplications (ITDs) and point mutations in the [...]

Drug-resistant bacteria remain an ever-present danger to patients and patient safety. Understanding whether and how clinicians use recently approved gram-negative antibiotics might help prioritize the patient in future antibiotic development. This study sought to determine use patterns of recently approved gram-negative antibiotics and identify factors associated with their preferential use in patients with gram-negative infections. The study found that despite approval of 7 next-generation gram-negative antibiotics, clinicians still frequently treat resistant gram-negative infections with older, generic antibiotics with suboptimal safety–efficacy profiles. Visual Abstract. Assessing Clinician Utilization of Next-Generation Antibiotics Against Resistant Gram-Negative Infections in U.S. Hospitals: Drug-resistant bacteria remain an ever-present danger to patients and patient safety. Understanding whether and how clinicians use recently approved gram-negative antibiotics might help prioritize the patient in future antibiotic development. This study sought to determine use patterns of recently approved gram-negative antibiotics and identify factors associated with their preferential use in patients with gram-negative infections. The study found that despite approval of 7 next-generation gram-negative antibiotics, clinicians still frequently treat resistant gram-negative infections with older, generic antibiotics with suboptimal safety–efficacy profiles. Background: The U.S. antibiotic market failure has threatened future innovation and supply. Understanding when and why clinicians underutilize recently approved gram-negative antibiotics might help prioritize the patient in future antibiotic development and potential market entry rewards. Objective: To determine use patterns of recently U.S. Food and Drug Administration (FDA)-approved gram-negative antibiotics (ceftazidime–avibactam, ceftolozane–tazobactam, meropenem–vaborbactam, plazomicin, eravacycline, imipenem–relebactam–cilastatin, and cefiderocol) and identify factors associated with their preferential use (over traditional generic agents) in patients with gram-negative infections due to pathogens displaying difficult-to-treat resistance (DTR; that is, resistance to all first-line antibiotics). Design: Retrospective cohort. Setting: 619 U.S. hospitals. Participants: Adult inpatients. Measurements: Quarterly percentage change in antibiotic use was calculated using weighted linear regression. Machine learning selected candidate variables, and mixed models identified factors associated with new (vs. traditional) antibiotic use in DTR infections. Results: Between quarter 1 of 2016 and quarter 2 of 2021, ceftolozane–tazobactam (approved 2014) and ceftazidime–avibactam (2015) predominated new antibiotic usage whereas subsequently approved gram-negative antibiotics saw relatively sluggish uptake. Among gram-negative infection hospitalizations, 0.7% (2551 [2631 episodes] of 362 142) displayed DTR pathogens. Patients were treated exclusively using traditional agents in 1091 of 2631 DTR episodes (41.5%), including "reserve" antibiotics such as polymyxins, aminoglycosides, and tigecycline in 865 of 1091 episodes (79.3%). Patients with bacteremia and chronic diseases had greater adjusted probabilities and those with do-not-resuscitate status, acute liver failure, and Acinetobacter baumannii complex and other nonpseudomonal nonfermenter pathogens had lower adjusted probabilities of receiving newer (vs. traditional) antibiotics for DTR infections, respectively. Availability of susceptibility testing for new antibiotics increased probability of usage. Limitation: Residual confounding. Conclusion: Despite FDA approval of 7 next-generation gram-negative antibiotics between 2014 and 2019, clinicians still frequently treat resistant gram-negative infections with older, generic antibiotics with suboptimal safety–efficacy profiles. Future antibiotics with innovative mechanisms targeting untapped pathogen niches, widely available susceptibility testing, and evidence demonstrating improved outcomes in resistant infections might enhance utilization. Primary Funding Source: U.S. Food and Drug Administration; NIH Intramural Research Program. [ABSTRACT FROM AUTHOR]

Background Infectious diseases and ophthalmology professional societies have disagreed regarding ocular screening in patients with candidemia. We aimed to summarize the current evidence on the prevalence of ocular candidiasis (OC) and Candida endophthalmitis (CE) according to the standardized definitions. Methods A literature search was conducted from the inception date through 16 October 2022 using PubMed, Embase, and SCOPUS. Pooled prevalence of ocular complications was derived from generalized linear mixed models (PROSPERO CRD42022326610). Results A total of 70 and 35 studies were included in the meta-analysis for OC and concordant CE (chorioretinitis with vitreous involvement), respectively. This study represented 8599 patients with candidemia who underwent ophthalmologic examination. Pooled prevalences (95% CI) of OC, overall CE, concordant CE, and discordant CE were 10.7% (8.4–13.5%), 3.1% (2.1–4.5%), 1.8% (1.3–2.6%), and 7.4% (4.5–12%) of patients screened, respectively. Studies from Asian countries had significantly higher concordant CE prevalence (95% CI) of patients screened (3.6%; 2.9–4.6%) compared with studies from European countries (1.4%;.4–5%) and American countries (1.4%;.9–2.2%) (P <.01). Presence of total parenteral nutrition and Candida albicans was associated with CE, with pooled odds ratios (95% CI) of 6.92 (3.58–13.36) and 3.02 (1.67–5.46), respectively. Conclusions Prevalence of concordant CE overall and among Asian countries was 2 and 4 times higher than the prevalence previously reported by the American Academy of Ophthalmology (AAO) of <0.9%, respectively. There is an urgent need to study optimal screening protocols and to establish joint recommendations by the Infectious Diseases Society of America and AAO. [ABSTRACT FROM AUTHOR]

Anthrax is a serious zoonosis caused by Bacillus anthracis, which primarily affects wild herbivorous animals with spillover into humans. The disease occurs nearly worldwide but is poorly reported in Southeast Asian countries. In Vietnam, anthrax is underreported, and little is known about its temporal and spatial distributions. This paper examines the spatio-temporal distribution and epidemiological characteristics of human and livestock anthrax from Dien Bien province, Vietnam from 2010 to 2019. We also aim to define the role of livestock vaccination in reducing human cases. Historical anthrax data were collected by local human and animal health sectors in the province. Spatial rate smoothing and spatial clustering analysis, using Local Moran's I in GeoDa and space-time scan statistic in SaTScan, were employed to address these objectives. We found temporal and spatial overlap of anthrax incidence in humans and livestock with hotspots of human anthrax in the east. We identified three significant space-time clusters of human anthrax persisting from 2010 to 2014 in the east and southeast, each with high relative risk. Most of the human cases were male (69%), aged 15–59 years (80%), involved in processing, slaughtering, or eating meat of sick or dead livestock (96.9%) but environmental and unknown exposure were reported. Animal reports were limited compared to humans and at coarser spatial scale, but in areas with human case clusters. In years when livestock vaccination was high (>~25%), human incidence was reduced, with the opposite effect when vaccine rates dropped. This indicates livestock vaccination campaigns reduce anthrax burden in both humans and livestock in Vietnam, though livestock surveillance needs immediate improvement. These findings suggest further investigation and measures to strengthen the surveillance of human and animal anthrax for other provinces of Vietnam, as well as in other countries with similar disease context. Author summary: Anthrax is a bacterial disease, cause by Bacillus anthracis, that can transmit from herbivorous animals to humans through close contact, eating meat of infected animals, or through environmental contamination. Anthrax can be a severe disease requiring early diagnosis and treatment to avoid fatal outcomes, disability, or financial burden to patients and their families. The disease also affects human well-being when livestock is their livelihood and an important part in agricultural practice. Anthrax is preventable by vaccine but effective strategy for vaccine distribution should be built on the characteristics of the disease in both human communities and the local animal populations. This study provides evidence on the space-time distribution and other characteristics of anthrax applying a One Health approach and geographical information analysis techniques. We show that hotspots of human disease correspond to areas of animal case reporting. We also show human incidence is reduced with livestock vaccination rates are relatively high. The study results are useful for researchers to foster investigation on other aspects of the disease and control efforts. It also provides scientific evidence for advocacy and communication on the importance of anthrax vaccination and strategic planning on vaccine production and distribution in Vietnam and other countries with similar context. [ABSTRACT FROM AUTHOR]

Source Citation: Dulhunty JM, Brett SJ, De Waele JJ, et al; BLING III Study Investigators. Continuous vs intermittent β-lactam antibiotic infusions in critically ill patients with sepsis: the BLING III randomized clinical trial. JAMA. 12 June 2024. [Epub ahead of print.] 38864155 Clinical Impact Ratings: GIM/FP/GP: 5 out of 7 Infectious Disease: 6 out of 7 Critical Care: 7 out of 7 [ABSTRACT FROM AUTHOR]

Source Citation: Abdul-Aziz MH, Hammond NE, Brett SJ, et al. Prolonged vs intermittent infusions of β-lactam antibiotics in adults with sepsis or septic shock: a systematic review and meta-analysis. JAMA. 12 June 2024. [Epub ahead of print.] 38864162 Clinical Impact Ratings: GIM/FP/GP: 6 out of 7 Infectious Disease: 7 out of 7 Critical Care: 6 out of 7 [ABSTRACT FROM AUTHOR]

The shape of 3d-orbitals often governs the electronic and magnetic properties of correlated transition metal oxides. In the superconducting cuprates, the planar confinement of the d x 2 − y 2 orbital dictates the two-dimensional nature of the unconventional superconductivity and a competing charge order. Achieving orbital-specific control of the electronic structure to allow coupling pathways across adjacent planes would enable direct assessment of the role of dimensionality in the intertwined orders. Using Cu L3 and Pr M5 resonant x-ray scattering and first-principles calculations, we report a highly correlated three-dimensional charge order in Pr-substituted YBa2Cu3O7, where the Pr f-electrons create a direct orbital bridge between CuO2 planes. With this we demonstrate that interplanar orbital engineering can be used to surgically control electronic phases in correlated oxides and other layered materials. External perturbations can induce 3D charge order in cuprates, but the 3D correlation length is limited and the mechanism is not well understood. Ruiz et al. show that Pr substitution in YBa2Cu3O7 enhances interplanar orbital coupling and stabilizes coherent 3D charge order that coexists with superconductivity. [ABSTRACT FROM AUTHOR]

Background: In March 2020, an influx of admissions in COVID-19 positive patients threatened to overwhelm healthcare facilities in East Baton Rouge Parish, Louisiana. Exacerbating this problem was an overall shortage of diagnostic testing capability at that time, resulting in a delay in time-to-result return. An improvement in diagnostic testing availability and timeliness was necessary to improve the allocation of resources and ultimate throughput of patients. The management of a COVID-19 positive patient or patient under investigation requires infection control measures that can quickly consume personal protective equipment (PPE) stores and personnel available to treat these patients. Critical shortages of both PPE and personnel also negatively impact care in patients admitted with non-COVID-19 illnesses. Methods: A multisectoral partnership of healthcare providers, facilities and academicians created a molecular diagnostic lab within an academic research facility dedicated to testing inpatients and healthcare personnel for SARS-CoV-2. The purpose of the laboratory was to provide a temporary solution to the East Baton Rouge Parish healthcare community until individual facilities were self-sustaining in testing capabilities. We describe the partnership and the impacts of this endeavor by developing a model derived from a combination of data sources, including electronic health records, hospital operations, and state and local resources. Findings: Our model demonstrates two important principles: the impact of reduced turnaround times (TAT) on potential differences in inpatient population numbers for COVID-19 and savings in PPE attributed to the more rapid TAT. [ABSTRACT FROM AUTHOR]

Anthrax is a zoonosis caused by the spore-forming bacterium Bacillus anthracis, with potential for high fatality rate, especially in herbivores. Upon host death, spores can enter the soil surrounding the carcass and be ingested by other animals feeding in the same location. Accordingly, surveillance to quickly identify and decontaminate anthrax carcasses is crucial to outbreak prevention. In endemic anthrax areas such as Texas and Africa, vultures are used as a surveillance tool for identifying presence and location of dead animals. However, many anthrax outbreaks in the United States have occurred in areas outside the ranges of both black and turkey vultures. Here, we used a longitudinal camera trap survey at carcass sites in southwestern Montana to investigate the utility of facultative avian scavengers on disease and carcass surveillance in a reemerging anthrax risk zone. From August 2016 to September 2018, camera traps at 11 carcass sites were triggered 1996 times by avian scavengers. While the majority were facultative avian scavengers such as corvids and eagles, our results suggest that facultative scavengers cannot replace vultures as a surveillance tool in this ecosystem due to their absence during the anthrax risk period (June to August), reduced search efficiency, or low flight patterns. We found that the conditions in Montana likely parallel systems elsewhere in the continental United States. Using ecological niche models of B. anthracis distribution overlaid with relative abundance maps of turkey vultures, we found that much of North Dakota, South Dakota, Minnesota, Wyoming, Nebraska, and Iowa have areas of anthrax risk, but low or absent turkey vulture populations. Without vultures in these areas, surveillance capacity is reduced, and it becomes more difficult to identify anthrax cases, meaning fewer carcasses are decontaminated, and consequently, outbreaks could become more frequent or severe. [ABSTRACT FROM AUTHOR]

Surgeons depend on fluid intake and output (I/O) measurements for assessment of resuscitation and fluid balance during the perioperative period. Frequently, these measurements are taken by Registered Nurses (RNs) and/or Patient Care Technicians (PCTs). There is variability in the accuracy and consistency of these measurements across nursing units. The goal of this study is to establish what barriers exist in obtaining accurate fluid measurements and potential solutions. A mixed-method, sequential study design was utilized. First, a survey was conducted at a tertiary care institution of 8 nonintensive care nursing units assessing the perceptions of RNs (n = 85) and PCTs (n = 38) regarding fluid intake and output measurements for surgical patients. Four focus groups were then conducted to expand upon the results of the survey. Fourteen participants (10 RNs and 4 PCTs) were interviewed, and transcripts were analyzed by three reviewers. Qualitative data were manually coded by reviewers using a hierarchical methodology. Survey response rate was 40.6%. The strongest barriers in the survey were patient load and staff time limitations. About half (49%) of the respondents acknowledged that fluid measurements were inaccurate half of the time. PCTs spend more time collecting and charting I/Os and have higher patient loads (P < 0.001) than RNs. PCTs noted more difficulty with complex patients (P = 0.017) and devices for outputs (P = 0.004). PCT's (94%) handwrite data prior to electronic entry. One-third of nurses reported direct electronic entry (P < 0.001). Overall, 71% would prefer to chart in patient's rooms. Most (80%) of respondents received <5 h of fluids-related training at the time they were hired. Cronbach's alpha for three focus group reviewers was 0.84 (95% CI 0.693-0.923). Themes included understaffing, lack of training, a high percentage of traveling nurses, and poor communication regarding new orders. Recommended solutions to improve I/Os included in-room kiosks for electronic entry and relief of staffing burdens. Fluid I/O measurement accuracy and efficiency may be improved by increased staffing, educational programs, and computer access, streamlining of order sets, simplicity of EMR data entry, and a standardized process for measuring, recording, and charting I/Os. • Nursing staff acknowledges I/O inaccuracies and are motivated to find solutions. • Understaffing and poor teamwork are major obstacles to accurate I/Os. • Hospital-wide educational opportunities are essential to improving I/O consistency. • Solutions include technology access and simplification of I/O recording system. [ABSTRACT FROM AUTHOR]

We link modern conceptualizations of maladaptive personality and psychopathy dimensions to music and movie genre preferences. Participants, N = 379, completed the Personality Inventory (5th ed.; PID-5), Triarchic Psychopathy Measure (TriPM), and music and movie preferences questionnaires. The structure of some, but not all, music preferences factors aligned with previous reports. Overall, maladaptive traits had meaningful, albeit modest links to entertainment media preferences, but not to the kinds of intense or rebellious music genres sometimes labeled as "problem" entertainment in prior literature. Support emerged for several a priori hypotheses, but some predictions based on the three- and five-factor normal personality trait and entertainment preferences literature did not generalize to a five-factor formulation of maladaptive personality. We discuss the findings' implications and several likely sources of inconsistencies in the literature on music and movie preferences and personality. [ABSTRACT FROM AUTHOR]

Killing two pathways with one inhibitor: Acute myeloid leukemia is an aggressive cancer that can be difficult to treat because of rapidly evolving therapeutic resistance. Melgar et al. focused on a subtype of acute myeloid leukemia characterized by mutations in a gene called FLT3. Although FLT3 inhibitors can target oncogenic signaling pathways in this cancer, their effects do not last. The authors identified a pathway involved in the innate immune stress response, whose activation promoted resistance to drugs targeting the FLT3 pathway, and then developed an inhibitor that targets both pathways at once. This multikinase inhibitor showed promising results in vitro and in animals, suggesting its potential for clinical translation. Targeted inhibitors to oncogenic kinases demonstrate encouraging clinical responses early in the treatment course; however, most patients will relapse because of target-dependent mechanisms that mitigate enzyme-inhibitor binding or through target-independent mechanisms, such as alternate activation of survival and proliferation pathways, known as adaptive resistance. Here, we describe mechanisms of adaptive resistance in FMS-like receptor tyrosine kinase (FLT3)–mutant acute myeloid leukemia (AML) by examining integrative in-cell kinase and gene regulatory network responses after oncogenic signaling blockade by FLT3 inhibitors (FLT3i). We identified activation of innate immune stress response pathways after treatment of FLT3-mutant AML cells with FLT3i and showed that innate immune pathway activation via the interleukin-1 receptor–associated kinase 1 and 4 (IRAK1/4) complex contributes to adaptive resistance in FLT3-mutant AML cells. To overcome this adaptive resistance mechanism, we developed a small molecule that simultaneously inhibits FLT3 and IRAK1/4 kinases. The multikinase FLT3-IRAK1/4 inhibitor eliminated adaptively resistant FLT3-mutant AML cells in vitro and in vivo and displayed superior efficacy as compared to current targeted FLT3 therapies. These findings uncover a polypharmacologic strategy for overcoming adaptive resistance to therapy in AML by targeting immune stress response pathways. [ABSTRACT FROM AUTHOR]

Abstract: Highly functionalized aminocyclopentadienes can be formed through the rearrangement of anions generated from readily prepared 6‐silyl‐1,2‐dihydropyridines by desilylation with fluoride. The scope and generality of the reaction was defined, and diverse transformations were performed on the highly functionalized products. A mechanism and driving force for the rearrangement were identified from experiments and DFT calculations. [ABSTRACT FROM AUTHOR]

A dynamic kinetic resolution of β-halo α-keto esters in an asymmetric homoenolate reaction is described. A chiral N-hetereocyclic carbene catalyzes the a³ → d³-umpolung addition of α,β-enals to racemic α-keto esters, forming γ-butyrolactones with three contiguous stereocenters. The addition occurs with high regio-, diastereo-, and enantiocontrol. This methodology constitutes an intermolecular DKR process to set three stereocenters during the key bond forming event. [ABSTRACT FROM AUTHOR]

This Note details experiments that probe the mechanism by which donor-acceptor norbornene systems epimerize. A number of mechanistic studies indicate that epimerization in these systems occurs via a Lewis acid catalyzed retro-Diels-Alder/Diels-Alder sequence, rather than bond rotation in an intimate ion pair. These results suggest that, under the reaction conditions examined, the ring strain present in norbornene is inadequate to induce zwitterion formation analogous to that observed with donor-acceptor cyclopropanes. [ABSTRACT FROM AUTHOR]

The lytic bacteriophage T4 employs multiple phage-encoded early proteins to takeover the Escherichia coli host. However, the functions of many of these proteins are not known. In this study, we have characterized the T4 early gene motB, located in a dispensable region of the T4 genome. We show that heterologous production of MotB is highly toxic to E. coli, resulting in cell death or growth arrest depending on the strain and that the presence of motB increases T4 burst size 2-fold. Previous work suggested that motB affects middle gene expression, but our transcriptome analyses of T4 motBam vs. T4 wt infections reveal that only a few late genes are mildly impaired at 5 min post-infection, and expression of early and middle genes is unaffected. We find that MotB is a DNA-binding protein that binds both unmodified host and T4 modified [(glucosylated, hydroxymethylated-5 cytosine, (GHme-C)] DNA with no detectable sequence specificity. Interestingly, MotB copurifies with the host histone-like proteins, H-NS and StpA, either directly or through cobinding to DNA. We show that H-NS also binds modified T4 DNA and speculate that MotB may alter how H-NS interacts with T4 DNA, host DNA, or both, thereby improving the growth of the phage. [ABSTRACT FROM AUTHOR]

A chiral N-heterocyclic carbene-catalyzed a3 → d3-umpolung addition of α,β-enals to racemic α-keto esters gives access to γ-butyrolactones with high regio-, diastereo-, and enantiocontrol. [ABSTRACT FROM AUTHOR]

The choice of the N-protecting group (Tbs) is crucial. [ABSTRACT FROM AUTHOR]