Site-Specific Antimicrobial Activity of a Dual-Responsive Ciprofloxacin Prodrug.

Bacterial infections create distinctive microenvironments with a unique mix of metabolites and enzymes compared with healthy tissues that can be used to trigger the activation of antibiotic prodrugs. Here, a single and dual prodrug masking the C3 carboxylate and C7 piperazine of the fluoroquinolone, ciprofloxacin, responsive to nitroreductase (NTR) and/or hydrogen sulfide (H2S), was developed. Masking both functional groups reduced the activity of the prodrug against Staphylococcus aureus and Escherichia coli, increasing its minimum inhibitory concentration (MIC) by ∼512-fold (S. aureus) and ∼8000-fold (E. coli strains), while masking a single group only increased the MIC by ∼128-fold. Bacteria subjected to prolonged prodrug exposure did not show any increase in resistance. Triggering assays demonstrated the conversion of prodrugs to ciprofloxacin, and in a murine infection model, responsive prodrugs showed antibacterial activity comparable to that of ciprofloxacin, suggesting in vivo activation of prodrugs. Thus, the potential for site-specific antibiotic treatment with reduced threat of resistance is demonstrated.

Proteome-scale movements and compartment connectivity during the eukaryotic cell cycle.

Cell cycle progression relies on coordinated changes in the composition and subcellular localization of the proteome. By applying two distinct convolutional neural networks on images of millions of live yeast cells, we resolved proteome-level dynamics in both concentration and localization during the cell cycle, with resolution of ∼20 subcellular localization classes. We show that a quarter of the proteome displays cell cycle periodicity, with proteins tending to be controlled either at the level of localization or concentration, but not both. Distinct levels of protein regulation are preferentially utilized for different aspects of the cell cycle, with changes in protein concentration being mostly involved in cell cycle control and changes in protein localization in the biophysical implementation of the cell cycle program. We present a resource for exploring global proteome dynamics during the cell cycle, which will aid in understanding a fundamental biological process at a systems level.

Mapping of DDX11 genetic interactions defines sister chromatid cohesion as the major dependency.

DDX11/Chl1R is a conserved DNA helicase with roles in genome maintenance, DNA replication, and chromatid cohesion. Loss of DDX11 in humans leads to the rare cohesinopathy Warsaw breakage syndrome. DDX11 has also been implicated in human cancer where it has been proposed to have an oncogenic role and possibly to constitute a therapeutic target. Given the multiple roles of DDX11 in genome stability and its potential as an anticancer target, we set out to define a complete genetic interaction profile of DDX11 loss in human cell lines. Screening the human genome with clustered regularly interspaced short palindromic repeats (CRISPR) guide RNA drop out screens in DDX11-wildtype (WT) or DDX11-deficient cells revealed a strong enrichment of genes with functions related to sister chromatid cohesion. We confirm synthetic lethal relationships between DDX11 and the tumor suppressor cohesin subunit STAG2, which is frequently mutated in several cancer types and the kinase HASPIN. This screen highlights the importance of cohesion in cells lacking DDX11 and suggests DDX11 may be a therapeutic target for tumors with mutations in STAG2.

Emergency research without prior consent in the United States, Canada, European Union and United Kingdom: How regulatory differences affect study design and implementation in cardiac arrest trials.

Aim: A major barrier to performing cardiac arrest trials is the requirement for prospective informed consent, which is often infeasible during individual medical emergencies. In an effort to improve outcomes, some governments have adopted legislation permitting research without prior consent (RWPC) in these circumstances. We aimed to outline key differences between legislation in four Western locations and explore the effects of these differences on trial design and implementation in cardiac arrest research. Data sources: We performed a narrative review of RWPC legislation in the United States (US), Canada, the European Union (EU) and the United Kingdom (UK). Results: The primary criteria required to perform RWPC was similar across locations: the study must involve an individual medical emergency during which neither the prospective subject nor their authorized representative can provide informed consent. The US regulations were unique in their requirements for performing Community Consultation and Public Disclosure in the communities in which the research takes place. Another major difference was the requirement for consent for ongoing participation in Canada, the EU and the UK, while only notification of enrollment and the opportunity to discontinue participation are required in the US. Additionally, only Canada and the EU explicitly state that the subject or their representative may request withdrawal of their data. Conclusion: Regulations governing RWPC in the US, Canada, the EU and the UK have similar goals and protections for vulnerable populations during medical emergencies. Differences in the qualifying criteria and implementation procedures exist across locations and may affect study design.

Dairy product consumption, eating habits, sedentary behaviour and physical activity association with bone mineral density among adolescent boys: a cross-sectional observational study.

BACKGROUND: During childhood and adolescence, skeletal microarchitecture and bone mineral density (BMD) undergo significant changes. Peak bone mass is built and its level significantly affects the condition of bones in later years of life. Understanding the modifiable factors that improve bone parameters at an early age is necessary to early prevent osteoporosis. To identify these modifiable factors we analysed the relationship between dairy product consumption, eating habits, sedentary behaviour, and level of physical activity with BMD in 115 young boys (14-17 years). METHODS: Bone parameters were measured by dual energy x-ray absorptiometry using paediatric specific software to compile the data. Dairy product consumption and eating habits were assessed by means of a dietary interview. Sedentary behaviour and physical activity was assessed in a face-to-face interview conducted using the International Physical Activity Questionnaire. Data collection on total physical activity level was performed by collecting information on the number of days and the duration of vigorous and moderate intensity (MVPA) and average daily time spent in sitting (SIT time). RESULTS: The strongest relationships with BMD in distal part of forearm were found for moderate plus vigorous activity, sit time, and intake of dairy products, intake of calcium, protein, vitamin D, phosphorus from diet. Relationships between BMD, bone mineral content (BMC) in the distal and proximal part of the forearm and PA, sit time and eating parameters were evaluated using the multiple forward stepwise regression. The presented model explained 48-67% (adjusted R2 = 0.48-0.67; p < 0.001) of the variance in bone parameters. The predictor of interactions of three variables: protein intake (g/person/day), vitamin D intake (µg/day) and phosphorus intake (mg/day) was significant for BMD dis (adjusted R2 = 0.59; p < 0.001). The predictor of interactions of two variables: SIT time (h/day) and dairy products (n/day) was significant for BMD prox (adjusted R2 = 0.48; p < 0.001). Furthermore, the predictor of interactions dairy products (n/day), protein intake (g/person/day) and phosphorus intake (mg/day) was significant for BMC prox and dis (adjusted R2 = 0.63-0.67; p < 0.001). CONCLUSIONS: High physical activity and optimal eating habits especially adequate intake of important dietary components for bone health such as calcium, protein, vitamin D and phosphorus affect the mineralization of forearm bones.

The Impact of Rationing Nursing Care on Patient Safety: A Systematic Review.

BACKGROUND Rationing of nursing care (RONC) has been associated with poor patient outcomes and is a growing concern in healthcare. The aim of this systematic study was to investigate the connection between patient safety and the RONC. MATERIAL AND METHODS A thorough search of electronic databases was done to find research that examined the relationship between restricting nurse services and patient safety. The systematic review followed the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines. Two reviewers (M.L. and A.P.) independently screened the titles and abstracts, and full-text articles were assessed for eligibility. Data were extracted, and a quality assessment was performed using appropriate techniques. RESULTS A total of 15 studies met the inclusion criteria. The studies included in the review demonstrated a correlation between rationing of nursing care and patient safety. The results of these studies revealed that there is an inverse relationship between rationing of nursing care and patient safety. The review found that when nursing care is rationed, there is a higher incidence of falls, medication errors, pressure ulcers, infections, and readmissions. In addition, the review identified that the work characteristics of nurses, such as workload, staffing levels, and experience, were associated with RONC. CONCLUSIONS RONC has a negative impact on patient safety outcomes. It is essential for healthcare organizations to implement effective strategies to prevent the RONC. Improving staffing levels, workload management, and communication amo0ng healthcare providers are some of the strategies that can support this.

Rationing of nursing care in Internal Medicine Departments-a cross-sectional study.

BACKGROUND: Implicit rationing of nursing care refers to a situation in which necessary nursing care is not performed to meet all of the patients' needs. PURPOSE: To examine the factors influencing the rationing of nursing care, nurses' assessment of the quality of patient care, and their job satisfaction in Internal Medicine Departments. METHODS: A cross-sectional descriptive study was undertaken. The study included 1164 nurses working in the Internal Medicine Departments in 8 hospitals (Lower Silesia, Poland). The Perceived Implicit Rationing of Nursing Care instrument was used. RESULTS: Respondents rarely ration nursing care, with a mean score of 1.12 (SD = 0.68). The mean score for quality of patient care was 6.99 (SD = 1.92). In contrast, the mean job satisfaction score was 6.07 points (SD = 2.22). The most important predictors of high rates of rationing of nursing care were work experience of 16-20 years (regression parameter: 0.387) and a Bachelor's degree in nursing (regression parameter: 0.139). Nurses' assessment of the quality of patient care ratings were increased by having a Master's degree in nursing (regression parameter: 0.41), and significantly decreased by work experience of 16-20 years (regression parameter: -1.332). Independent predictors of job satisfaction ratings in both univariate and multivariate analysis were Master's degree and long-shift working patterns. CONCLUSION: The factors that influence an increased level of nursing care rationing on medical wards are nurse seniority, exceeding 16 years and female gender. Obtaining a Master's degree in nursing indicates improved nurses' assessment of the quality of patient care.

Cell projection plots: A novel visualization of bone marrow aspirate cytology.

Deep models for cell detection have demonstrated utility in bone marrow cytology, showing impressive results in terms of accuracy and computational efficiency. However, these models have yet to be implemented in the clinical diagnostic workflow. Additionally, the metrics used to evaluate cell detection models are not necessarily aligned with clinical goals and targets. In order to address these issues, we introduce novel, automatically generated visual summaries of bone marrow aspirate specimens called cell projection plots (CPPs). Encompassing relevant biological patterns such as neutrophil maturation, CPPs provide a compact summary of bone marrow aspirate cytology. To gauge clinical relevance, CPPs were inspected by 3 hematopathologists, who decided whether corresponding diagnostic synopses matched with generated CPPs. Pathologists were able to match CPPs to the correct synopsis with a matching degree of 85%. Our finding suggests CPPs can represent clinically relevant information from bone marrow aspirate specimens and may be used to efficiently summarize bone marrow cytology to pathologists. CPPs could be a step toward human-centered implementation of artificial intelligence (AI) in hematopathology, and a basis for a diagnostic-support tool for digital pathology workflows.

Rationing in healthcare-a scoping review.

Healthcare rationing has been the subject of numerous debates and concerns in the field of health economics in recent years. It is a concept which refers to the allocation of scarce healthcare resources and involves the use of different approaches to the delivery of health services and patient care. Regardless of the approach used, healthcare rationing fundamentally involves withholding potentially beneficial programs and/or treatments from certain people. As the demands placed on health services continue to rise and with that significant increases to the cost, healthcare rationing has become increasingly popular and is deemed necessary for the delivery of affordable, patient-care services. However, public discourse on this issue has largely been centered on ethical considerations with less focus on economic rationality. Establishing the economic rationality of healthcare rationing is essential in healthcare decision-making and consideration of its adoption by healthcare authorities and organizations. This scoping review of seven articles demonstrates that the economic rationality of healthcare rationing is the scarcity of healthcare resources amidst increased demand and costs. Therefore, supply, demand, and benefits are at the core of healthcare rationing practices and influence decisions on its suitability. Given the increased costs of care and resource scarcity, healthcare rationing is a suitable practice towards ensuring healthcare resources are allocated to people in a rational, equitable, and cost-effective manner. The rising costs and demands for care place significant pressure on healthcare authorities to identify suitable strategies for the allocation of healthcare resources. Healthcare rationing as a priority-setting strategy would support healthcare authorities identify mechanisms to allocate scarce resources in a cost-effective manner. When used in the context of a priority-setting approach, healthcare rationing helps healthcare organizations and practitioners to ensure that patient populations achieve maximum benefits at reasonable costs. It represents a fair allocation of healthcare resources to all populations, especially in low-income settings.

Exploratory Study of Determinants of the Spread of COVID-19 before Shelter-in-Place Orders.

This study explores the impact of relevant characteristics of counties and their relationship with increases in COVID-19 cases before shelter-in-place (SIP) orders in the U.S. The recent emergence of COVID-19 occurs when there is little understanding of the related factors affecting the growth and spread of the disease. These relationships are examined through an analysis of 672 counties before SIP orders were issued. Areas that experienced the most significant transmission of disease are identified, and their characteristics are analyzed. A meaningful relationship was found between the increase of COVID-19 cases and several factors. Average commute time and the proportion of commuters using transit had a positive relationship. Along with other socio-economic factors, such as median house value and proportion of the Black population, several transportation-related factors had a significant association with the transmission of the disease. The decrease rate of total vehicle miles traveled (VMT) before and after SIP orders also had a solid and positive relationship with the expansion of the disease. The findings suggest that planners and transportation service providers must integrate evolving public health considerations into transportation services which affect the increase in the transmission of infectious diseases.

The Core Curriculum for Cardiovascular Nurses and Allied Professionals.

This 2023 update of the Core Curriculum in Cardiovascular Nursing (2015) embraces the formation of the Association of Cardiovascular Nursing and Allied Professionals and reflects the diverse professional backgrounds of our members, including nurses, allied health professionals, and healthcare scientists (in this document referred to collectively as Nurses and Allied Professionals).

Community consultation in the pediatric intensive care unit for an exception from informed consent Trial: A survey of patient caregivers.

Aim: To explore perspectives of families in the pediatric intensive care unit (PICU) about an emergency interventional trial on peri-arrest bolus epinephrine for acute hypotension using Exception From Informed Consent (EFIC). Methods: We performed face-to-face interviews with families whose children were hospitalized in the PICU. A research team member provided an educational presentation about the planned trial and administered a survey with open- and closed-ended items. Analyses included descriptive statistics for quantitative data and thematic analysis for qualitative data. Results: Sixty-seven participants contributed to 60 survey responses (53 individuals and 7 families for whom 2 family members participated). Most participants answered favorably toward the planned trial: 55/58 (95%) reported that the trial seemed "somewhat" or "very important"; 52/57 (91%) felt the use of EFIC was "somewhat" or "completely acceptable"; and 43/58 (74%) said they would be "somewhat" or "very likely" to allow their child to participate. Five themes emerged supporting participation in the planned trial: 1) trust in the clinical team; 2) familiarity with the study intervention (epinephrine); 3) study protocol being similar to standard care; 4) informed consent during an emergency was not feasible; and 5) importance of research. Barriers to potential participation included requests for additional time to decide about participating and misconceptions about study elements, especially eligibility. Conclusions: Families of PICU patients generally supported plans for an emergency interventional trial using EFIC. Future inpatient EFIC studies may benefit from highlighting the themes identified here in their educational materials.

Anxiety and Depressive Symptoms, Frailty and Quality of Life in Atrial Fibrillation.

Introduction: Symptoms of atrial fibrillation (AF) can significantly affect functioning in daily life and reduce patients' quality of life (QoL). The severity and type of AF symptoms affects not only patient's QoL, but can be a cause of the development of emotional and psychological disorders. In addition, frailty syndrome (FS) plays important role from the point of view of developing disability and dependence on others, as well as reducing QoL. Aim: To assess the symptoms of anxiety and depression, to evaluate the co-occurrence of frailty syndrome and the impact of these factors on the quality of life of patients with AF. Methods: The study used a Polish adaptation of the Arrhythmia-Specific questionnaire in Tachycardia and Arrhythmia part III (ASTA part III), the Tilburg Frailty Indicator (TFI) and the Hospital Anxiety Depression Scale (HADS). Results: Analysis showed that anxiety symptoms and depressive symptoms correlate significantly (p < 0.05) and positively with the physical (r = 0.24; p < 0.001, r = 0.29, p = 0.002, respectively), psychological (r = 0.34, p < 0.001, r = 0.49 p < 0.001, respectively) and total quality of life (r = 0.31, p = 0.001, r = 0.414; p < 0.001, respectively) ASTA III domains. A significant (p < 0.05) positive correlation was observed between the TFI total score and the physical (r = 0.34, p < 0.001), psychological (r = 0.36, p < 0.001) and overall quality of life (r = 0.38, p < 0.001) in ASTA III domains. Conclusions: Both FS and depressive and anxiety symptoms significantly affect QoL. Understanding the relationship between anxiety and depressive symptoms, FS and QoL may allow for a more targeted approach to the treatment and care of patients with AF.

Characteristics and Outcomes of Cardiac Arrest in Adult Patients Admitted to Pediatric Services: A Descriptive Analysis of the American Heart Association's Get With The Guidelines-Resuscitation Data.

OBJECTIVES: Differences between adult and pediatric in-hospital cardiac arrest (IHCA) are well-described. Although most adults are cared for on adult services, pediatric services often admit adults, particularly those with chronic conditions. The objective of this study is to describe IHCA in adults admitted to pediatric services. DESIGN: Retrospective cohort analysis from the American Heart Association's Get With The Guidelines-Resuscitation registry of a subpopulation of adults with IHCA while admitted to pediatric services. Multivariable logistic regression was used to evaluate adjusted survival outcomes and compare outcomes between age groups (18-21, 22-25, and ≥26 yr old). SETTING: Hospitals contributing to the Get With The Guidelines-Resuscitation registry. PATIENTS: Adult-aged patients (≥ 18 yr) with an index pulseless IHCA while admitted to a pediatric service from 2000 to 2018. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: A total of 491 adult IHCAs were recorded on pediatric services at 17 sites, during the 19 years of review, and these events represented 0.1% of all adult IHCAs. In total, 221 cases met inclusion criteria with 139 events excluded due to an initial rhythm of bradycardia with poor perfusion. Median patient age was 22 years (interquartile range, 19-28 yr). Ninety-eight percent of patients had at least one pre-existing condition. Return of spontaneous circulation occurred in 63% of events and 30% of the patients survived to discharge. All age groups had similar rates of survival to discharge (range 26-37%; p = 0.37), and survival did not change over the study period (range 26-37%; p = 0.23 for adjusted survival to discharge). CONCLUSIONS: In this cohort of adults with IHCA while admitted to a pediatric service, we failed to find an association between survival outcomes and age. Additional research is needed to better understand resuscitation in this population.

Trends in Disease Severity Among Critically Ill Children With Severe Acute Respiratory Syndrome Coronavirus 2: A Retrospective Multicenter Cohort Study in the United States.

OBJECTIVES: To describe trends in critical illness from severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection in children over the course of the COVID-19 pandemic. We hypothesized that PICU admission rates were higher in the Omicron period compared with the original outbreak but that fewer patients needed endotracheal intubation. DESIGN: Retrospective cohort study. SETTING: This study took place in nine U.S. PICUs over 3 weeks in January 2022 (Omicron period) compared with 3 weeks in March 2020 (original period). PATIENTS: Patients less than or equal to 21 years old who screened positive for SARS-CoV-2 infection by polymerase chain reaction or hospital-based rapid antigen test and were admitted to a PICU or intermediate care unit were included. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: A total of 267 patients (239 Omicron and 28 original) were reviewed. Forty-five patients in the Omicron cohort had incidental SARS-CoV-2 and were excluded from analysis. The Omicron cohort patients were younger compared with the original cohort patients (median [interquartile range], 6 yr [1.3-13.3 yr] vs 14 yr [8.3-17.3 yr]; p = 0.001). The Omicron period, compared with the original period, was associated with an average increase in COVID-19-related PICU admissions of 13 patients per institution (95% CI, 6-36; p = 0.008), which represents a seven-fold increase in the absolute number admissions. We failed to identify an association between cohort period (Omicron vs original) and odds of intubation (odds ratio, 0.7; 95% CI, 0.3-1.7). However, we cannot exclude the possibility of up to 70% reduction in intubation. CONCLUSIONS: COVID-19-related PICU admissions were seven times higher in the Omicron wave compared with the original outbreak. We could not exclude the possibility of up to 70% reduction in use of intubation in the Omicron versus original epoch, which may represent differences in PICU/hospital admission policy in the later period, or pattern of disease, or possibly the impact of vaccination.

In-Hospital Cardiac Arrest in Adult Patients Admitted to a Quaternary Children's Center.

OBJECTIVE: This study aimed to describe baseline and event characteristics and outcomes for adult patients who experience in-hospital cardiac arrest (IHCA) in a quaternary children's hospital and compare IHCA outcomes in younger (18-24 years) versus older (≥25 years) adults. We hypothesized that the rate of survival to hospital discharge would be lower in the older adult group. METHODS: We performed a retrospective single-center cohort study of inpatient areas of a quaternary children's center. Adult patients (≥18 years of age) with an index pulseless IHCA requiring at least 1 minute of cardiopulmonary resuscitation or defibrillation were included. RESULTS: Thirty-three events met the inclusion criteria with a median patient age of 23.9 years (interquartile range, 20.2-33.3 years). Twenty-one (64%) patients had congenital heart disease, and 25 (76%) patients had comorbidities involving ≥2 organ systems. The most common prearrest interventions were invasive mechanical ventilation (76%) and vasoactive infusions (55%). Seventeen patients (52%) survived to hospital discharge.Survival to discharge was lower in patients 25 years or older compared with patients aged 18 to 24 years old (3 of 15 [20%] vs 14 of 18 [78%], respectively; P = 0.002). CONCLUSIONS: The majority of adult patients with IHCA in our pediatric hospital had preexisting multisystem comorbidities, the most common of which was congenital heart disease. Overall survival to discharge after IHCA was 52%, similar to that reported for the general pediatric population. Survival to discharge was significantly lower in the subgroup of patients 25 years or older when compared with those between the ages of 18 and 24 years.

Automated bone marrow cytology using deep learning to generate a histogram of cell types.

Background: Bone marrow cytology is required to make a hematological diagnosis, influencing critical clinical decision points in hematology. However, bone marrow cytology is tedious, limited to experienced reference centers and associated with inter-observer variability. This may lead to a delayed or incorrect diagnosis, leaving an unmet need for innovative supporting technologies. Methods: We develop an end-to-end deep learning-based system for automated bone marrow cytology. Starting with a bone marrow aspirate digital whole slide image, our system rapidly and automatically detects suitable regions for cytology, and subsequently identifies and classifies all bone marrow cells in each region. This collective cytomorphological information is captured in a representation called Histogram of Cell Types (HCT) quantifying bone marrow cell class probability distribution and acting as a cytological patient fingerprint. Results: Our system achieves high accuracy in region detection (0.97 accuracy and 0.99 ROC AUC), and cell detection and cell classification (0.75 mean average precision, 0.78 average F1-score, Log-average miss rate of 0.31). Conclusions: HCT has potential to eventually support more efficient and accurate diagnosis in hematology, supporting AI-enabled computational pathology.

Peri-arrest bolus epinephrine practices amongst pediatric resuscitation experts.

AIM: To describe current practices of peri-arrest bolus epinephrine use amongst pediatric resuscitation experts in a multinational survey. METHODS: A 9-question survey was developed and electronically distributed to pediatric critical care physicians who are site investigators for the Pediatric Resuscitation Quality Collaborative (pediRES-Q) network. Institutional demographics were collected through the American Hospital Association 2018 Annual Survey and linked to responses. Descriptive statistics were used to characterize closed-ended responses, and qualitative content analysis to analyze open-ended responses. RESULTS: Of the 63 collaborative members invited to participate, 49 (78%) responded, representing 35 institutions in 9 countries. Forty-six of the 49 respondents (94%) reported that they would consider using peri-arrest bolus epinephrine during critical situations in patients not requiring cardiopulmonary resuscitation. Initial dosing strategies ranged from 0.1mcg/kg to 10mcg/kg, with the most commonly reported initial dose of 1mcg/kg by 25 of the 37 (68%) respondents who answered this question. Three of the 49 (6%) participants indicated that they would generally avoid using peri-arrest bolus epinephrine, citing lack of evidence to support its use. CONCLUSIONS: In this multinational survey of pediatric resuscitation experts, endorsement of peri-arrest bolus epinephrine use was nearly universal, though a few clinicians cited lack of evidence to support this practice. There was a 100-fold difference in the range of initial weight-based doses reported, as well as a minority of clinicians who reported using non-weight-based dosing. Further research is needed to determine best practices, standardization of initial dosing, clinical factors that may warrant dosing modifications and associations with clinically important outcomes.