Epidemiology of Hypophosphatemia in Critical Illness: A Multicentre, Retrospective Cohort Study.

INTRODUCTION: Hypophosphatemia is common in critically ill patients. We have described the epidemiology of hypophosphatemia in patients admitted to the Intensive Care Units. METHODS: A multicentre, retrospective cohort study of 12 ICUs in Queensland, Australia from January 1st, 2015, to December 31st, 2021. Exclusions included readmissions, renal replacement therapy, end-stage renal disease, and palliative intent admissions and transfers from other ICUs. Patients were classified into four groups based on the severity of the first episode of low serum phosphate (PO4): "None" (PO4: ≥ 0.81 mmol/L, ``Mild" (PO4: ≥ 0.50 & < 0.81 mmol/L) "Moderate" (PO4: ≥ 0.30 & < 0.50 mmol/L) and "Severe" (PO4: < 0.30 mmol/L). A mixed-effect logistic regression model, including hospital as a random effect, was developed to examine factors associated with 90-day case fatality. RESULTS: Of the 89,776 patients admitted, 68,699 patients were included in this study, with 23,485 (34.2%) having hypophosphatemia with onset mostly on Day 2 of ICU admission and correcting to normal 3 days after hypophosphatemia was identified. There was substantial variation among participating ICUs in phosphate replacement; the threshold, and the route by which it was replaced. Day-90 case fatality increased with severity of hypophosphatemia (None: 3,974 (8.8%), Mild: 2,306 (11%), Moderate: 377 (14%); Severe: 108 (21%) (p < 0.001)). Multivariable regression analysis showed that compared to those without hypophosphatemia, patients with moderate (odds ratio (OR) 1.24; 95% confidence intervals (CI) 1.07-1.44; p = 0.004) or severe (OR 1.49; 95% CI 1.13-1.97; p = 0.005) hypophosphatemia had increased risk of 90-day case fatality. CONCLUSION: Hypophosphatemia was common, and mostly occurred on day 2 with early correction of serum phosphate. Phosphate replacement practices were variable among ICUs. Moderate and severe hypophosphatemia was associated with increased 90-day case fatality.

Sepsis-associated acute kidney injury in the intensive care unit: incidence, patient characteristics, timing, trajectory, treatment, and associated outcomes. A multicenter, observational study.

PURPOSE: The Acute Disease Quality Initiative (ADQI) Workgroup recently released a consensus definition of sepsis-associated acute kidney injury (SA-AKI), combining Sepsis-3 and Kidney Disease Improving Global Outcomes (KDIGO) AKI criteria. This study aims to describe the epidemiology of SA-AKI. METHODS: This is a retrospective cohort study carried out in 12 intensive care units (ICUs) from 2015 to 2021. We studied the incidence, patient characteristics, timing, trajectory, treatment, and associated outcomes of SA-AKI based on the ADQI definition. RESULTS: Out of 84,528 admissions, 13,451 met the SA-AKI criteria with its incidence peaking at 18% in 2021. SA-AKI patients were typically admitted from home via the emergency department (ED) with a median time to SA-AKI diagnosis of 1 day (interquartile range (IQR) 1-1) from ICU admission. At diagnosis, most SA-AKI patients (54%) had a stage 1 AKI, mostly due to the low urinary output (UO) criterion only (65%). Compared to diagnosis by creatinine alone, or by both UO and creatinine criteria, patients diagnosed by UO alone had lower renal replacement therapy (RRT) requirements (2.8% vs 18% vs 50%; p < 0.001), which was consistent across all stages of AKI. SA-AKI hospital mortality was 18% and SA-AKI was independently associated with increased mortality. In SA-AKI, diagnosis by low UO only, compared to creatinine alone or to both UO and creatinine criteria, carried an odds ratio of 0.34 (95% confidence interval (CI) 0.32-0.36) for mortality. CONCLUSION: SA-AKI occurs in 1 in 6 ICU patients, is diagnosed on day 1 and carries significant morbidity and mortality risk with patients mostly admitted from home via the ED. However, most SA-AKI is stage 1 and mostly due to low UO, which carries much lower risk than diagnosis by other criteria.

Burden of enteral supplement interactions with common antimicrobial agents: a single-centre observational analysis.

INTRODUCTION: Oral antimicrobials, including ciprofloxacin, levofloxacin and doxycycline, are susceptible to binding with enteral therapies such as calcium and iron therapies. Administered together, the bioavailability of these antimicrobials is expected to be reduced. METHODS: A retrospective case series of patients receiving oral antimicrobials (ciprofloxacin, levofloxacin and doxycycline) was analysed at a single-centre NHS acute hospital (April 2016-September 2019). Patient demographics, including concurrent enteral therapies, were recorded using medical records. Clinically important interactions were defined as doses administered within 2 hours of antimicrobial therapy. RESULTS: A total of 4067 prescriptions for the study antimicrobials (ciprofloxacin, n=1905; levofloxacin, n=538; and doxycycline, n=1624) were prescribed for 3584 patients. 1918/3583 (53.5%) of the patients were female, and the median age was 67 years (range 0.5-105.0 years). 810/4067 (19.3%) prescriptions reviewed had an interacting enteral therapy (calcium or iron salt) administered within 2 hours of the study medication. CONCLUSION: The concomitant administration of enteral calcium and iron with oral antimicrobials is common within the acute care hospital setting. Approximately one in five patients has a clinically important interaction which may impair oral bioavailability and limit treatment efficacy. As antimicrobial stewardship teams strive for increased intravenous-to-oral de-escalation, it is important that optimum dosing administration is followed to optimise patient outcomes.

Clinical Utility and Functionality of an Artificial Intelligence-Based App to Predict Mortality in COVID-19: Mixed Methods Analysis.

BACKGROUND: The artificial neural network (ANN) is an increasingly important tool in the context of solving complex medical classification problems. However, one of the principal challenges in leveraging artificial intelligence technology in the health care setting has been the relative inability to translate models into clinician workflow. OBJECTIVE: Here we demonstrate the development of a COVID-19 outcome prediction app that utilizes an ANN and assesses its usability in the clinical setting. METHODS: Usability assessment was conducted using the app, followed by a semistructured end-user interview. Usability was specified by effectiveness, efficiency, and satisfaction measures. These data were reported with descriptive statistics. The end-user interview data were analyzed using the thematic framework method, which allowed for the development of themes from the interview narratives. In total, 31 National Health Service physicians at a West London teaching hospital, including foundation physicians, senior house officers, registrars, and consultants, were included in this study. RESULTS: All participants were able to complete the assessment, with a mean time to complete separate patient vignettes of 59.35 (SD 10.35) seconds. The mean system usability scale score was 91.94 (SD 8.54), which corresponds to a qualitative rating of "excellent." The clinicians found the app intuitive and easy to use, with the majority describing its predictions as a useful adjunct to their clinical practice. The main concern was related to the use of the app in isolation rather than in conjunction with other clinical parameters. However, most clinicians speculated that the app could positively reinforce or validate their clinical decision-making. CONCLUSIONS: Translating artificial intelligence technologies into the clinical setting remains an important but challenging task. We demonstrate the effectiveness, efficiency, and system usability of a web-based app designed to predict the outcomes of patients with COVID-19 from an ANN.

Tissue-specific modulation of gene expression in response to lowered insulin signalling in Drosophila.

Reduced activity of the insulin/IGF signalling network increases health during ageing in multiple species. Diverse and tissue-specific mechanisms drive the health improvement. Here, we performed tissue-specific transcriptional and proteomic profiling of long-lived Drosophila dilp2-3,5 mutants, and identified tissue-specific regulation of >3600 transcripts and >3700 proteins. Most expression changes were regulated post-transcriptionally in the fat body, and only in mutants infected with the endosymbiotic bacteria, Wolbachia pipientis, which increases their lifespan. Bioinformatic analysis identified reduced co-translational ER targeting of secreted and membrane-associated proteins and increased DNA damage/repair response proteins. Accordingly, age-related DNA damage and genome instability were lower in fat body of the mutant, and overexpression of a minichromosome maintenance protein subunit extended lifespan. Proteins involved in carbohydrate metabolism showed altered expression in the mutant intestine, and gut-specific overexpression of a lysosomal mannosidase increased autophagy, gut homeostasis, and lifespan. These processes are candidates for combatting ageing-related decline in other organisms.

Use of micro-CT to determine tracheobronchial airway geometries in three strains of mice used in inhalation toxicology as disease models.

Aerosol dosimetry estimates for mouse strains used as models for human disease are not available, primarily because of the lack of tracheobronchial airway morphometry data. By using micro-CT scans of in-situ prepared lung casts, tracheobronchial airway morphometry for four strains of mice were obtained: Balb/c, AJ, C57BL/6, and Apoe-/- . The automated tracheobronchial airway morphometry algorithms for airway length and diameter were successfully verified against previously published manual and automated tracheobronchial airway morphometry data derived from two identical in-situ Balb/c mouse lung casts. There was also excellent agreement in tracheobronchial airway length and diameter between the automated and manual airway data for the AJ, C57BL/6, and Apoe-/- mice. Differences in branch angle measurements were partially due to the differences in definition between the automated algorithms and manual morphometry techniques. Unlike the manual airway morphometry techniques, the automated algorithms were able to provide a value for inclination to gravity for each airway. Inclusion of an inclination to gravity angle for each airway along with airway length, diameter, and branch angle make the current automated tracheobronchial airway data suitable for use in dosimetry programs that can provide dosimetry estimates for inhaled material. The significant differences in upper tracheobronchial airways between Balb/c mice and between C57BL/6 and Apoe-/- mice highlight the need for mouse strain-specific aerosol dosimetry estimates.

Optical costs and benefits of disorder in biological photonic crystals.

Photonic structures in ordered, quasi-ordered or disordered forms have evolved across many different animal and plant systems. They can produce complex and often functional optical responses through coherent and incoherent scattering processes, often too, in combination with broadband or narrowband absorbing pigmentation. Interestingly, these systems appear highly tolerant of faults in their photonic structures, with imperfections in their structural order appearing not to impact, discernibly, the systems' optical signatures. The extent to which any such biological system deviates from presenting perfect structural order can dictate the optical properties of that system and, thereby, the optical properties that system delivers. However, the nature and extent of the optical costs and benefits of imperfect order in biological systems demands further elucidation. Here, we identify the extent to which biological photonic systems are tolerant of defects and imperfections. Certainly, it is clear that often significant inherent variations in the photonic structures of these systems, for instance a relatively broad distribution of lattice constants, can consistently produce what appear to be effective visual appearances and optical performances. In this article, we review previously investigated biological photonic systems that present ordered, quasi-ordered or disordered structures. We discuss the form and nature of the optical behaviour of these structures, focusing particularly on the associated optical costs and benefits surrounding the extent to which their structures deviate from what might be considered ideal systems. Then, through detailed analyses of some well-known 1D and 2D structurally coloured systems, we analyse one of the common manifestations of imperfect order, namely, the extent and nature of positional disorder in the systems' spatial distribution of layers and scattering centres. We use these findings to inform optical modelling that presents a quantitative and qualitative description of the optical costs and benefits of such positional disorder among ordered and quasi-ordered 1D and 2D photonic systems. As deviation from perfectly ordered structures invariably limits the performance of technology-oriented synthetic photonic processes, we suggest that the use of bio-inspired fault tolerance principles would add value to applied photonic technologies.

An Insulin-Sensitive Circular RNA that Regulates Lifespan in Drosophila.

Circular RNAs (circRNAs) are abundant and accumulate with age in neurons of diverse species. However, only few circRNAs have been functionally characterized, and their role during aging has not been addressed. Here, we use transcriptome profiling during aging and find that accumulation of circRNAs is slowed down in long-lived insulin mutant flies. Next, we characterize the in vivo function of a circRNA generated by the sulfateless gene (circSfl), which is consistently upregulated, particularly in the brain and muscle, of diverse long-lived insulin mutants. Strikingly, lifespan extension of insulin mutants is dependent on circSfl, and overexpression of circSfl alone is sufficient to extend the lifespan. Moreover, circSfl is translated into a protein that shares the N terminus and potentially some functions with the full-length Sfl protein encoded by the host gene. Our study demonstrates that insulin signaling affects global circRNA accumulation and reveals an important role of circSfl during aging in vivo.

Non-typhoidal salmonellosis presenting as acute calculus cholecystitis.

Non-typhoidal Salmonella spp.are Gram-negative bacilli, which typically cause a clinical picture of gastroenteritis and, less commonly, patients may become a chronic carrier of the pathogen within their gallbladder. We describe a rare clinical presentation of a non-typhoidal Salmonella spp. infection as acute calculus cholecystitis in an adult patient. Salmonella enterica subsp. Salamae (ST P4271) was grown from cholecystostomy fluid, and the patient subsequently underwent a laparoscopic cholecystectomy that demonstrated a necrotic gallbladder fundus. We advise that microbiological sampling of bile is essential, especially in the context of foreign travel, to detect unusual pathogens as in this case or common pathogens that may have unusual antimicrobial resistance. Given the necrotic gallbladder as in this case, we also advise that early cholecystectomy should be strongly considered in these patients.

Towards Estimating the Uncertainty Associated with Three-Dimensional Geometry Reconstructed from Medical Image Data.

Patient-specific computational modeling is increasingly used to assist with visualization, planning, and execution of medical treatments. This trend is placing more reliance on medical imaging to provide accurate representations of anatomical structures. Digital image analysis is used to extract anatomical data for use in clinical assessment/planning. However, the presence of image artifacts, whether due to interactions between the physical object and the scanning modality or the scanning process, can degrade image accuracy. The process of extracting anatomical structures from the medical images introduces additional sources of variability, e.g., when thresholding or when eroding along apparent edges of biological structures. An estimate of the uncertainty associated with extracting anatomical data from medical images would therefore assist with assessing the reliability of patient-specific treatment plans. To this end, two image datasets were developed and analyzed using standard image analysis procedures. The first dataset was developed by performing a "virtual voxelization" of a CAD model of a sphere, representing the idealized scenario of no error in the image acquisition and reconstruction algorithms (i.e., a perfect scan). The second dataset was acquired by scanning three spherical balls using a laboratory-grade CT scanner. For the idealized sphere, the error in sphere diameter was less than or equal to 2% if 5 or more voxels were present across the diameter. The measurement error degraded to approximately 4% for a similar degree of voxelization of the physical phantom. The adaptation of established thresholding procedures to improve segmentation accuracy was also investigated.

Closed-Loop Control for Precision Antimicrobial Delivery: An In Silico Proof-of-Concept.

OBJECTIVE: Inappropriate dosing of patients with antibiotics is a driver of antimicrobial resistance, toxicity, and poor outcomes of therapy. In this paper, we investigate, in silico, the hypothesis that the use of a closed-loop control system could improve the attainment of pharmacokinetic-pharmacodynamic targets for antimicrobial therapy, where wide variations in target attainment have been reported. This includes patients in critical care, patients with renal disease, and patients with obesity. METHODS: The presented in silico study focuses on vancomycin delivery, a first line therapy for Methicillin-resistant Staphylococcus aureus (MRSA) that has serious side effects, including nephrotoxicity. For this purpose, an in silico platform for the simulation of pharmacokinetics of vancomycin agents was developed including 24 virtual noncritically ill-adult subjects obtained from routinely collected data from two prospective audits of vancomycin therapy. Intraday variability on renal clearance, sensor error, and infusion constraints were taken into account. Proportional integral derivative (PID) controller was chosen because of its simplicity of implementation and satisfactory performance. RESULTS: Even though significant intraday variability and sensor error were considered in the simulations, by assuming a minimum inhibitory concentration of 1 mg/l for MRSA, the proposed controller was able to reach the well-established therapeutic target of 24-h area under curve to minimum inhibitory concentration ratio equal to 400 $\text{mg} \cdot \text{h}\text{/}\text{l}$ for all the studied subjects, while staying significantly below toxic levels. CONCLUSION: A PID controller has the potential to precisely deliver a vancomycin therapy in a noncritically ill-adult population. SIGNIFICANCE: Closed-loop control for precision Vancomycin delivery can potentially reduce toxicity and poor therapeutic outcomes, as well as reduce antimicrobial resistance.

Obtaining antibiotics online from within the UK: a cross-sectional study.

Background: Improved antibiotic stewardship (AS) and reduced prescribing in primary care, with a parallel increase in personal internet use, could lead citizens to obtain antibiotics from alternative sources online. Objectives: A cross-sectional analysis was performed to: (i) determine the quality and legality of online pharmacies selling antibiotics to the UK public; (ii) describe processes for obtaining antibiotics online from within the UK; and (iii) identify resulting AS and patient safety issues. Methods: Searches were conducted for 'buy antibiotics online' using Google and Yahoo. For each search engine, data from the first 10 web sites with unique URL addresses were reviewed. Analysis was conducted on evidence of appropriate pharmacy registration, prescription requirement, whether antibiotic choice was 'prescriber-driven' or 'consumer-driven', and whether specific information was required (allergies, comorbidities, pregnancy) or given (adverse effects) prior to purchase. Results: Twenty unique URL addresses were analysed in detail. Online pharmacies evidencing their location in the UK ( n = 5; 25%) required a prescription before antibiotic purchase, and were appropriately registered. Online pharmacies unclear about the location they were operating from ( n = 10; 50%) had variable prescription requirements, and no evidence of appropriate registration. Nine (45%) online pharmacies did not require a prescription prior to purchase. For 16 (80%) online pharmacies, decisions were initially consumer-driven for antibiotic choice, dose and quantity. Conclusions: Wide variation exists among online pharmacies in relation to antibiotic practices, highlighting considerable patient safety and AS issues. Improved education, legislation, regulation and new best practice stewardship guidelines are urgently needed for online antibiotic suppliers.

Mapping the decision pathways of acute infection management in secondary care among UK medical physicians: a qualitative study.

BACKGROUND: The inappropriate use of antimicrobials drives antimicrobial resistance. We conducted a study to map physician decision-making processes for acute infection management in secondary care to identify potential targets for quality improvement interventions. METHODS: Physicians newly qualified to consultant level participated in semi-structured interviews. Interviews were audio recorded and transcribed verbatim for analysis using NVIVO11.0 software. Grounded theory methodology was applied. Analytical categories were created using constant comparison approach to the data and participants were recruited to the study until thematic saturation was reached. RESULTS: Twenty physicians were interviewed. The decision pathway for the management of acute infections follows a Bayesian-like step-wise approach, with information processed and systematically added to prior assumptions to guide management. The main emerging themes identified as determinants of the decision-making of individual physicians were (1) perceptions of providing 'optimal' care for the patient with infection by providing rapid and often intravenous therapy; (2) perceptions that stopping/de-escalating therapy was a senior doctor decision with junior trainees not expected to contribute; and (3) expectation of interactions with local guidelines and microbiology service advice. Feedback on review of junior doctor prescribing decisions was often lacking, causing frustration and confusion on appropriate practice within this cohort. CONCLUSION: Interventions to improve infection management must incorporate mechanisms to promote distribution of responsibility for decisions made. The disparity between expectations of prescribers to start but not review/stop therapy must be urgently addressed with mechanisms to improve communication and feedback to junior prescribers to facilitate their continued development as prudent antimicrobial prescribers.

A unique self-organization of bacterial sub-communities creates iridescence in Cellulophaga lytica colony biofilms.

Iridescent color appearances are widespread in nature. They arise from the interaction of light with micron- and submicron-sized physical structures spatially arranged with periodic geometry and are usually associated with bright angle-dependent hues. Iridescence has been reported for many animals and marine organisms. However, iridescence has not been well studied in bacteria. Recently, we reported a brilliant "pointillistic" iridescence in colony biofilms of marine Flavobacteria that exhibit gliding motility. The mechanism of their iridescence is unknown. Here, using a multi-disciplinary approach, we show that the cause of iridescence is a unique periodicity of the cell population in the colony biofilm. Cells are arranged together to form hexagonal photonic crystals. Our model highlights a novel pattern of self-organization in a bacterial biofilm. "Pointillistic" bacterial iridescence can be considered a new light-dependent phenomenon for the field of microbiology.

Nuclear hormone receptor DHR96 mediates the resistance to xenobiotics but not the increased lifespan of insulin-mutant Drosophila.

Lifespan of laboratory animals can be increased by genetic, pharmacological, and dietary interventions. Increased expression of genes involved in xenobiotic metabolism, together with resistance to xenobiotics, are frequent correlates of lifespan extension in the nematode worm Caenorhabditis elegans, the fruit fly Drosophila, and mice. The Green Theory of Aging suggests that this association is causal, with the ability of cells to rid themselves of lipophilic toxins limiting normal lifespan. To test this idea, we experimentally increased resistance of Drosophila to the xenobiotic dichlordiphenyltrichlorethan (DDT), by artificial selection or by transgenic expression of a gene encoding a cytochrome P450. Although both interventions increased DDT resistance, neither increased lifespan. Furthermore, dietary restriction increased lifespan without increasing xenobiotic resistance, confirming that the two traits can be uncoupled. Reduced activity of the insulin/Igf signaling (IIS) pathway increases resistance to xenobiotics and extends lifespan in Drosophila, and can also increase longevity in C. elegans, mice, and possibly humans. We identified a nuclear hormone receptor, DHR96, as an essential mediator of the increased xenobiotic resistance of IIS mutant flies. However, the IIS mutants remained long-lived in the absence of DHR96 and the xenobiotic resistance that it conferred. Thus, in Drosophila IIS mutants, increased xenobiotic resistance and enhanced longevity are not causally connected. The frequent co-occurrence of the two traits may instead have evolved because, in nature, lowered IIS can signal the presence of pathogens. It will be important to determine whether enhanced xenobiotic metabolism is also a correlated, rather than a causal, trait in long-lived mice.

Use of poisons information resources and satisfaction with electronic products by Victorian emergency department staff.

OBJECTIVE: ED staff use a range of poisons information resources of varying type and quality. The present study aims to identify those resources utilised in the state of Victoria, Australia, and assess opinion of the most used electronic products. METHODS: A previously validated self-administered survey was conducted in 15 EDs, with 10 questionnaires sent to each. The survey was then repeated following the provision of a 4-month period of access to Toxinz™, an Internet poisons information product novel to the region. The study was conducted from December 2010 to August 2011. RESULTS: There were 117 (78%) and 48 (32%) responses received from the first and second surveys, respectively, a 55% overall response rate. No statistically significant differences in professional group, numbers of poisoned patients seen or resource type accessed were identified between studies. The electronic resource most used in the first survey was Poisindex® (48.68%) and Toxinz™ (64.1%) in the second. There were statistically significant (P < 0.01) improvements in satisfaction in 26 of 42 questions between surveys, and no decrements. Although the majority of responders possessed mobile devices, less than half used them for poisons information but would do so if a reputable product was available. CONCLUSION: The order of poisons information sources most utilised was: consultation with a colleague, in-house protocols and electronic resources. There was a significant difference in satisfaction with electronic poisons information resources and a movement away from existing sources when choice was provided. Interest in increased use of mobile solutions was identified.