Tracking and modeling the movement of Queensland fruit flies, Bactrocera tryoni, using harmonic radar in papaya fields.

Determining movement parameters for pest insects such as tephritid fruit flies is critical to developing models which can be used to increase the effectiveness of surveillance and control strategies. In this study, harmonic radar was used to track wild-caught male Queensland fruit flies (Qflies), Bactrocera tryoni, in papaya fields. Experiment 1 continuously tracked single flies which were prodded to induce movement. Qfly movements from this experiment showed greater mean squared displacement than predicted by both a simple random walk (RW) or a correlated random walk (CRW) model, suggesting that movement parameters derived from the entire data set do not adequately describe the movement of individual Qfly at all spatial scales or for all behavioral states. This conclusion is supported by both fractal and hidden Markov model (HMM) analysis. Lower fractal dimensions (straighter movement paths) were observed at larger spatial scales (> 2.5 m) suggesting that Qflies have qualitatively distinct movement at different scales. Further, a two-state HMM fit the observed movement data better than the CRW or RW models. Experiment 2 identified individual landing locations, twice a day, for groups of released Qflies, demonstrating that flies could be tracked over longer periods of time.

Comparative Analysis of Upper Limb Impairment Rating Processes in the AMA Guides Sixth Edition 2024 vs 2008: Impact on Stakeholders.

OBJECTIVE: To evaluate how upper limb impairment ratings are affected by updates to the AMA Guides to the Evaluation of Permanent Impairment (AMA Guides) Sixth Edition 2024 compared with the AMA Guides Sixth Edition 2008, and to investigate potential correlations with judicial, legislative, and economic factors. METHODS: Two expert evaluators reviewed 31 upper limb clinical vignettes from the 2008 and 2024 versions. The impairment ratings for each version were compared. RESULTS: After following the impairment ratings steps in each version, the results for 2024 showed no significant differences when compared with the impairment ratings generated using 2008 methods (Cohen's Kappa = 1.00). CONCLUSIONS: The updated AMA Guides Sixth Edition 2024 with improved, transparent processes and enhanced diagnosis-based impairment tables provides efficiency while retaining the accuracy, validity, and reliability of past versions of the AMA Guides.

An endothelial SOX18-mevalonate pathway axis enables repurposing of statins for infantile hemangioma.

Infantile hemangioma (IH) is the most common tumor in children and a paradigm for pathological vasculogenesis, angiogenesis and regression. Propranolol is the mainstay of treatment for IH. It inhibits hemangioma vessel formation via a ß-adrenergic receptor independent off-target effect of its R(+) enantiomer on the endothelial specific transcription factor sex-determining region Y (SRY) box transcription factor 18 (SOX18). Transcriptomic profiling of patient-derived hemangioma stem cells uncovered the mevalonate pathway (MVP) as a target of R(+) propranolol. Loss of SOX18 function confirmed R(+) propranolol mode of action on the MVP. Functional validation in preclinical IH models revealed that statins - targeting the MVP - are potent inhibitors of hemangioma vessel formation. We propose a novel SOX18-MVP-axis as a central regulator of IH pathogenesis and suggest statin repurposing to treat IH. Our findings reveal novel pleiotropic effects of beta-blockers and statins acting on the SOX18-MVP axis to disable an endothelial specific program in IH, which may impact other scenarios involving pathological vasculogenesis and angiogenesis.

Differing planes of nutrition alter serum and histotroph amino acid composition in nonpregnant, multiparous beef cows on day three of the estrous cycle.

Endometrial-derived uterine histotroph is a critical component of nutrient supply to a growing conceptus throughout gestation; however, the effect of nutritional plane on histotroph nutrient composition remains unknown in multiparous cows. We hypothesized that differing planes of nutrition would alter histotroph and serum nutrient composition in beef cattle. Thus, we evaluated serum and histotroph amino acid and glucose composition, and serum non-esterified fatty acids (NEFA) and blood urea nitrogen (BUN) in cows individually fed to maintain body weight (0 kd/d, n = 9; CON) compared with those losing moderate body weight (-0.7 kg/d, n = 9; NEG). After 49 d of differing nutritional planes, cows were subjected to the 7-d CoSynch + CIDR estrus synchronization protocol and then slaughtered on d 62. Blood serum (d 0 and 62) and uterine histotroph [d 62; from uterine horns ipsilateral and contralateral to the corpus luteum (CL)] were collected and analyzed for concentrations of amino acids, glucose, and NEFA. Performance characteristics, body composition via ultrasound (d 0 and 62), and carcass characteristics were collected. Body condition score, change in body weight, average daily gain (ADG), dry matter intake (DMI), and gain:feed (G:F) were decreased (P ≤ 0.05) in NEG vs. CON cows. There were no differences in body composition or carcass characteristics, except an increase (P ≤ 0.05) in dressing percentage in NEG cows due to differences in gut fill, consistent with study design. Serum NEFA increased (P ≤ 0.05) in the NEG group, but there were no differences between NEG vs. CON in glucose or BUN. Serum histidine increased (P ≤ 0.05) and alanine, isoleucine and tryptophan decreased (P ≤ 0.05) in NEG vs. CON cows. Compared with that of the uterine horn ipsilateral to the CL, histotroph from the uterine horn contralateral to the CL had increased (P ≤ 0.05) isoleucine, asparagine, and proline concentrations in NEG cows, and decreased (P ≤ 0.05) tryptophan as a proportion of essential and total amino acids. There were no differences in glucose concentrations of histotroph contralateral or ipsilateral to the CL. Cow nutritional plane does alter serum and histotroph amino acid composition, although the presence of an embryo may be necessary to fully elucidate these changes. Differences in serum and histotroph tryptophan should be given consideration in future studies due to its importance as an essential amino acid in protein synthesis and bioactive affects.

One-carbon metabolite supplementation increases vitamin B12, folate, and methionine cycle metabolites in beef heifers and fetuses in an energy dependent manner at day 63 of gestation.

One-carbon metabolites (OCM) are metabolites and cofactors which include folate, vitamin B12, methionine, and choline that support methylation reactions. The objectives of this study were to investigate the effects of moderate changes in maternal body weight gain in combination with OCM supplementation during the first 63 days of gestation in beef cattle on (1) B12 and folate concentrations in maternal serum (2) folate cycle intermediates in maternal and fetal liver, allantoic fluid (ALF), and amniotic fluid (AMF) and (3) metabolites involved in one-carbon metabolism and related metabolic pathways in maternal and fetal liver. Heifers were either intake restricted (RES) and fed to lose 0.23 kg/d, or fed to gain 0.60 kg/d (CON). Supplemented (+OCM) heifers were given B12 and folate injections weekly and fed rumen protected methionine and choline daily, while non-supplemented (-OCM) heifers were given weekly saline injections. These two treatments were combined in a 2 × 2 factorial arrangement resulting in four treatments: CON-OCM, CON+OCM, RES-OCM, and RES+OCM. Samples of maternal serum, maternal and fetal liver, ALF, and AMF were collected at slaughter on day 63 of gestation. Restricted maternal nutrition most notably increased (P ≤ 0.05) the concentration of: vitamin B12 in maternal serum, 5,10-methylenetetrahydrofolate and 5,10-methenyltetrahydrofolate in maternal liver, and of cystathionine in fetal liver; conversely, maternal restriction decreased (P = 0.05) 5,10-methylenetetrahydrofolate concentration in fetal liver. Supplementing OCM increased (P ≤ 0.05) the concentrations of: maternal serum B12, folate and folate intermediates, ALF and AMF 5-methyltetrahydrofolate concentration, and altered (P ≤ 0.02) other maternal liver intermediates including S-adenosylmethionine, dimethylglycine, cystathionine Glutathione reduced, glutathione oxidized, taurine, serine, sarcosine, and pyridoxine. These data demonstrate that OCM supplementation was effective at increasing maternal OCM status. Furthermore, these data are similar to previously published literature where restricted maternal nutrition also affected maternal OCM status. Altering OCM status in both the dam and fetus could impact fetal developmental outcomes and production efficiencies. Lastly, these data demonstrate that fetal metabolite abundance is highly regulated, although the changes required to maintain homeostasis may program altered metabolism postnatally.

Ultracongruent Versus Posterior-Stabilized Polyethylene: No Difference in Anterior Knee Pain but Decreased Noise Generation.

BACKGROUND: Noise generation and anterior knee pain can occur after primary total knee arthroplasty (TKA) and may affect patient satisfaction. Polyethylene design in cruciate-sacrificing implants could be a variable influencing these complications. The purpose of this study was to analyze the effect of polyethylene design on noise generation and anterior knee pain. METHODS: We prospectively reviewed a cohort of patients who underwent primary TKA between 2014 and 2022 by a single surgeon using either a posterior-stabilized (PS) or ultracongruent (UC) polyethylene of the same implant design. The primary outcomes were measured through a noise generation questionnaire and the Knee Injury and Osteoarthritis Outcome Score-Patellofemoral score. RESULTS: A total of 409 TKA procedures were included, 153 (37.4%) PS and 256 (62.6%) UC. No difference was noted in the Knee Injury and Osteoarthritis Outcome Score-Patellofemoral score between PS and UC designs (71.7 ± 26 versus 74.2 ± 23.2, P = 0.313). A higher percentage of patients in the PS cohort reported hearing (32.7% versus 22.3%, P = 0.020) or feeling noise (28.8 versus 20.3, P = 0.051) coming from their implant. No notable difference was observed in noise-related satisfaction rates. Independent risk factors of noise generation were age (OR, 0.96; P = 0.006) and PS polyethylene (OR, 1.61; P = 0.043). Noise generation was associated with decreased patient-reported outcome measure scores (P < 0.001). CONCLUSION: While there was no difference in anterior knee pain between PS and UC polyethylene designs, PS inserts exhibit higher rates of noise generation compared with UC. Noise generation had comparable satisfaction but was associated with decreased patient-reported outcome measure scores.

Effectiveness of dexmedetomidine on patient-centred outcomes in surgical patients: a systematic review and Bayesian meta-analysis.

BACKGROUND: Dexmedetomidine is increasingly used for surgical patients requiring general anaesthesia. However, its effectiveness on patient-centred outcomes remains uncertain. Our main objective was to evaluate the patient-centred effectiveness of intraoperative dexmedetomidine for adult patients requiring surgery under general anaesthesia. METHODS: We conducted a systematic search of MEDLINE, Embase, CENTRAL, Web of Science, and CINAHL from inception to October 2023. Randomised controlled trials (RCTs) comparing intraoperative use of dexmedetomidine with placebo, opioid, or usual care in adult patients requiring surgery under general anaesthesia were included. Study selection, data extraction, and risk of bias assessment were performed by two reviewers independently. We synthesised data using a random-effects Bayesian regression framework to derive effect estimates and the probability of a clinically important effect. For continuous outcomes, we pooled instruments with similar constructs using standardised mean differences (SMDs) and converted SMDs and credible intervals (CrIs) to their original scale when appropriate. We assessed the certainty of evidence using the Grading of Recommendations Assessment, Development and Evaluation (GRADE) methodology. Our primary outcome was quality of recovery after surgery. To guide interpretation on the original scale, the Quality of Recovery-15 (QoR-15) instrument was used (range 0-150 points, minimally important difference [MID] of 6 points). RESULTS: We identified 49,069 citations, from which 44 RCTs involving 5904 participants were eligible. Intraoperative dexmedetomidine administration was associated with improvement in postoperative QoR-15 (mean difference 9, 95% CrI 4-14, n=21 RCTs, moderate certainty of evidence). We found 99% probability of any benefit and 88% probability of achieving the MID. There was a reduction in chronic pain incidence (odds ratio [OR] 0.42, 95% CrI 0.19-0.79, n=7 RCTs, low certainty of evidence). There was also increased risk of clinically significant hypotension (OR 1.98, 95% CrI 0.84-3.92, posterior probability of harm 94%, n=8 RCTs) and clinically significant bradycardia (OR 1.74, 95% CrI 0.93-3.34, posterior probability of harm 95%, n=10 RCTs), with very low certainty of evidence for both. There was limited evidence to inform other secondary patient-centred outcomes. CONCLUSIONS: Compared with placebo or standard of care, intraoperative dexmedetomidine likely results in meaningful improvement in the quality of recovery and chronic pain after surgery. However, it might increase clinically important bradycardia and hypotension. SYSTEMATIC REVIEW PROTOCOL: PROSPERO (CRD42023439896).

The Society for Cardiovascular Magnetic Resonance Registry at 150,000.

BACKGROUND: Cardiovascular magnetic resonance (CMR) is increasingly utilized to evaluate expanding cardiovascular conditions. The Society for Cardiovascular Magnetic Resonance (SCMR) Registry is a central repository for real-world clinical data to support cardiovascular research, including those relating to outcomes, quality improvement, and machine learning. The SCMR Registry is built on a regulatory-compliant, cloud-based infrastructure that houses searchable content and Digital Imaging and Communications in Medicine images. The goal of this study is to summarize the status of the SCMR Registry at 150,000 exams. METHODS: The processes for data security, data submission, and research access are outlined. We interrogated the Registry and presented a summary of its contents. RESULTS: Data were compiled from 154,458 CMR scans across 20 United States sites, containing 299,622,066 total images (∼100 terabytes of storage). Across reported values, the human subjects had an average age of 58 years (range 1 month to >90 years old), were 44% (63,070/145,275) female, 72% (69,766/98,008) Caucasian, and had a mortality rate of 8% (9,962/132,979). The most common indication was cardiomyopathy (35,369/131,581, 27%), and most frequently used current procedural terminology code was 75561 (57,195/162,901, 35%). Macrocyclic gadolinium-based contrast agents represented 89% (83,089/93,884) of contrast utilization after 2015. Short-axis cines were performed in 99% (76,859/77,871) of tagged scans, short-axis late gadolinium enhancement (LGE) in 66% (51,591/77,871), and stress perfusion sequences in 30% (23,241/77,871). Mortality data demonstrated increased mortality in patients with left ventricular ejection fraction <35%, the presence of wall motion abnormalities, stress perfusion defects, and infarct LGE, compared to those without these markers. There were 456,678 patient-years of all-cause mortality follow-up, with a median follow-up time of 3.6 years. CONCLUSION: The vision of the SCMR Registry is to promote evidence-based utilization of CMR through a collaborative effort by providing a web mechanism for centers to securely upload de-identified data and images for research, education, and quality control. The Registry quantifies changing practice over time and supports large-scale real-world multicenter observational studies of prognostic utility.

Dynamic Transcriptional Programs During Single NK Cell Killing: Connecting Form to Function in Cellular Immunotherapy.

Introduction: Natural killer (NK) cell-based therapies are a promising new method for treating indolent cancer, however engineering new therapies is complex and progress towards therapy for solid tumors is slow. New methods for determining the underlying intracellular signaling driving the killing phenotype would significantly improve this progress. Methods: We combined single-cell RNA sequencing with live cell imaging of a model system of NK cell killing to correlate transcriptomic data with functional output. A model of NK cell activity, the NK-92 cell line killing of HeLa cervical cancer cells, was used for these studies. NK cell killing activity was observed by microscopy during co-culture with target HeLa cells and killing activity subsequently manually mapped based on NK cell location and Annexin V expression. NK cells from this culture system were profiled by single-cell RNA sequencing using the 10× Genomics platform, and transcription factor activity inferred using the Viper and DoRothEA R packages. Luminescent microscopy of reporter constructs in the NK cells was then used to correlate activity of inferred transcriptional activity with killing activity. Results: NK cells had heterogeneous killing activity during 10 h of culture with target HeLa cells. Analysis of the single cell sequencing data identified Nuclear Factor Kappa B (NF-κB), Signal Transducer and Activator of Transcription 1 (STAT1) and MYC activity as potential drivers of NK cell functional phenotype in our model system. Live cell imaging of the transcription factor activity found NF-κB activity was significantly correlated with past killing activity. No correlation was observed between STAT1 or MYC activity and NK cell killing. Conclusions: Combining luminescent microscopy of transcription factor activity with single-cell RNA sequencing is an effective means of assigning functional phenotypes to inferred transcriptomics data. Supplementary Information: The online version contains supplementary material available at 10.1007/s12195-024-00812-3.

Cross-sectional and longitudinal changes in mind-wandering in older adulthood.

Age-related declines in the frequency of mind-wandering are well established. Theories of mind-wandering have attempted to explain why this decline occurs, but no one theory firmly predicts such changes. One problem with these theoretical views, and the studies that have grown out of them, is their reliance on cross-sectional methods, which do not account for within-person changes over time in mind-wandering, and it is well-documented that cross-sectional and longitudinal changes in some cognitive domains do not align. We present a novel analysis of longitudinal change in subjective and objective indicators of mind-wandering during a sustained attention task. Cognitively normal adults (N = 277, age range 42-94) completed a sustained attention task with thought probes to measure mind-wandering repeatedly over several years. Linear mixed effect models revealed baseline differences in subjective mind-wandering reports among middle-aged and older adults. However, longitudinally, middle-aged participants showed a significant increase in subjective mind-wandering, whereas older participants showed no change. Changes in mind-wandering could not be explained by attentional control ability or contemporaneous estimates of interest and perceived difficulty, but they were explained by baseline levels of conscientiousness. Objective measures of mind-wandering did not show these same patterns and were largely only associated with participants perceived difficulty. Our results build on previous cross-sectional research and suggest that incorporating longitudinal analyses into theories of ageing and mind-wandering and mind-wandering more broadly is important for refining these theories. (PsycInfo Database Record (c) 2024 APA, all rights reserved).

In Vivo Intra-Articular Antibiotic Concentrations at 24 Hours After TKA Fall Below the Minimum Inhibitory Concentration for Most Bacteria: A Randomized Study of Commercially Available Bone Cement.

BACKGROUND: The use of antibiotic-loaded bone cement (ALBC) to help reduce the risk of infection after primary total knee arthroplasty (TKA) is controversial. There is a paucity of in vivo data on the elution characteristics of ALBC. We aimed to determine whether the antibiotic concentrations of 2 commercially available ALBCs met the minimum inhibitory concentration (MIC) and minimum biofilm eradication concentration (MBEC) for common infecting organisms. METHODS: Forty-five patients undergoing TKA were randomized to receive 1 of the following: bone cement without antibiotic (the negative control; n = 5), a commercially available formulation containing 1 g of tobramycin (n = 20), or a commercially available formulation containing 0.5 g of gentamicin (n = 20). Intra-articular drains were placed, and fluid was collected at 4 and 24 hours postoperatively. An automated immunoassay measuring antibiotic concentration was performed, and the results were compared against published MIC and MBEC thresholds. RESULTS: The ALBC treatment groups were predominantly of White (65%) or Black (32.5%) race and were 57.5% female and 42.4% male. The mean age (and standard deviation) was 72.6 ± 7.2 years in the gentamicin group and 67.6 ± 7.4 years in the tobramycin group. The mean antibiotic concentration in the tobramycin group was 55.1 ± 37.7 µg/mL at 4 hours and 19.5 ± 13.0 µg/mL at 24 hours, and the mean concentration in the gentamicin group was 38.4 ± 25.4 µg/mL at 4 hours and 17.7 ± 15.4 µg/mL at 24 hours. Time and antibiotic concentration had a negative linear correlation coefficient (r = -0.501). Most of the reference MIC levels were reached at 4 hours. However, at 24 hours, a considerable percentage of patients had concentrations below the MIC for many common pathogens, including Staphylococcus epidermidis (gentamicin: 65% to 100% of patients; tobramycin: 50% to 85%), methicillin-sensitive Staphylococcus aureus (gentamicin: 5% to 90%; tobramycin: 5% to 50%), methicillin-resistant S. aureus (gentamicin: 5% to 65%; tobramycin: 50%), Streptococcus species (gentamicin: 10% to 100%), and Cutibacterium acnes (gentamicin: 10% to 65%; tobramycin: 100%). The aforementioned ranges reflect variation in the MIC among different strains of each organism. Gentamicin concentrations reached MBEC threshold values at 4 hours only for the least virulent strains of S. aureus and Escherichia coli. Tobramycin concentrations did not reach the MBEC threshold for any of the bacteria at either time point. CONCLUSIONS: The elution of antibiotics from commercially available ALBC decreased rapidly following TKA, and only at 4 hours postoperatively did the mean antibiotic concentrations exceed the MIC for most of the pathogens. Use of commercially available ALBC may not provide substantial antimicrobial coverage following TKA. LEVEL OF EVIDENCE: Therapeutic Level I. See Instructions for Authors for a complete description of levels of evidence.

Energetic demands regulate sleep-wake rhythm circuit development.

Sleep and feeding patterns lack strong daily rhythms during early life. As diurnal animals mature, feeding is consolidated to the day and sleep to the night. In Drosophila, circadian sleep patterns are initiated with formation of a circuit connecting the central clock to arousal output neurons; emergence of circadian sleep also enables long-term memory (LTM). However, the cues that trigger the development of this clock-arousal circuit are unknown. Here, we identify a role for nutritional status in driving sleep-wake rhythm development in Drosophila larvae. We find that in the 2nd instar larval period (L2), sleep and feeding are spread across the day; these behaviors become organized into daily patterns by the 3rd instar larval stage (L3). Forcing mature (L3) animals to adopt immature (L2) feeding strategies disrupts sleep-wake rhythms and the ability to exhibit LTM. In addition, the development of the clock (DN1a)-arousal (Dh44) circuit itself is influenced by the larval nutritional environment. Finally, we demonstrate that larval arousal Dh44 neurons act through glucose metabolic genes to drive onset of daily sleep-wake rhythms. Together, our data suggest that changes to energetic demands in developing organisms trigger the formation of sleep-circadian circuits and behaviors.

Like most young animals, babies must obtain enough nutrients and energy to grow, yet they also need to rest for their brains to mature properly. As many exhausted new parents know first-hand, balancing these conflicting needs results in frequent, rapid switches between eating and sleeping. Eventually, new-borns' internal biological clock system, which is aligned with the 24-hour light cycle, becomes fully operational. Exactly how this then translates into allowing them to stay alert during the day and be sleepy at night is still unclear. Like humans, the larvae of fruit flies first sleep haphazardly before developing a circadian pattern whereby they sleep at night and eat during the day. This shift occurs when a group of nerve cells called DN1a, whose job is to 'keep time', connects with Dh44, a subset of neurons which, when active, promote wakefulness. The trigger for these changes, however, has remained elusive. In response, Poe et al. hypothesized that feeding behaviour and nutrient availability coordinated the emergence of sleep rhythms in fruit flies. Forcing fruit fly larvae to keep feeding in an 'immature' pattern ­ by either genetic manipulations or reducing the sugar content of their food ­ not only prevented them from developing 'mature' sleeping rhythms but also resulted in memory problems. These experiments also showed that the DN1a-Dh44 connection depends on nutrient availability, as it did not form in larvae raised on the low-sugar food. Further genetic experiments showed that the Dh44 cells themselves act like nutrient sensors during the emergence of sleeping patterns. These results shed new light on the factors triggering sleep rhythm development. Poe et al. hope that the understanding gained can be extended to humans and eventually help manage nervous system disorders and health problems associated with disrupted sleep during early life.

The impact of Library Size and Scale of Testing on Virtual Screening.

Virtual libraries for ligand discovery have recently increased 10,000-fold, and this is thought to have improved hit rates and potencies from library docking. This idea has not, however, been experimentally tested in direct comparisons of larger-vs-smaller libraries. Meanwhile, though libraries have exploded, the scale of experimental testing has little changed, with often only dozens of high-ranked molecules investigated, making interpretation of hit rates and affinities uncertain. Accordingly, we docked a 1.7 billion molecule virtual library against the model enzyme AmpC ß-lactamase, testing 1,521 new molecules and comparing the results to the same screen with a library of 99 million molecules, where only 44 molecules were tested. Encouragingly, the larger screen outperformed the smaller one: hit rates improved by two-fold, more new scaffolds were discovered, and potency improved. Overall, 50-fold more inhibitors were found, supporting the idea that there are many more compounds to be discovered than are being tested. With so many compounds evaluated, we could ask how the results vary with number tested, sampling smaller sets at random from the 1521. Hit rates and affinities were highly variable when we only sampled dozens of molecules, and it was only when we included several hundred molecules that results converged. As docking scores improved, so too did the likelihood of a molecule binding; hit rates improved steadily with docking score, as did affinities. This also appeared true on reanalysis of large-scale results against the σ2 and dopamine D4 receptors. It may be that as the scale of both the virtual libraries and their testing grows, not only are better ligands found but so too does our ability to rank them.

Evaluation of a Comprehensive Algorithm for PICU Patients With New Fever or Instability: Association of Clinical Decision Support With Testing Practices.

OBJECTIVES: Previously, we implemented a comprehensive decision support tool, a "New Fever Algorithm," to support the evaluation of PICU patients with new fever or instability. This tool was associated with a decline in culture rates without safety concerns. We assessed the impact of the algorithm on testing practices by identifying the proportion of cultures pre- vs. post-implementation that were discordant with algorithm guidance and may have been avoidable. DESIGN: Retrospective evaluation 12 months pre- vs. post-quality improvement intervention. SETTING: Single-center academic PICU and pediatric cardiac ICU. SUBJECTS: All admitted patients. INTERVENTIONS: Implementing the "New Fever Algorithm" in July 2020. MEASUREMENTS AND MAIN RESULTS: Patient medical records were reviewed to categorize indications for all blood, respiratory, and urine cultures. Among cultures obtained for new fever or new clinical instability, we assessed specific testing patterns that were discordant from the algorithm's guidance such as blood cultures obtained without documented concern for sepsis without initiation of antibiotics, respiratory cultures without respiratory symptoms, urine cultures without a urinalysis or pyuria, and pan-cultures (concurrent blood, respiratory, and urine cultures). Among 2827 cultures, 1950 (69%) were obtained for new fever or instability. The proportion of peripheral blood cultures obtained without clinical concern for sepsis declined from 18.6% to 10.4% (p < 0.0007). Respiratory cultures without respiratory symptoms declined from 41.5% to 27.4% (p = 0.01). Urine cultures without a urinalysis did not decline (from 27.6% to 25.1%). Urine cultures without pyuria declined from 83.0% to 73.7% (p = 0.04). Pan-cultures declined from 22.4% to 10.6% (p < 0.0001). Overall, algorithm-discordant testing declined from 39% to 30% (p < 0.0001). CONCLUSIONS: The majority of cultures obtained were for new fever or instability and introduction of the "New Fever Algorithm" was associated with reductions in algorithm-discordant testing practices and pan-cultures. There remain opportunities for improvement and additional strategies are warranted to optimize testing practices for in this complex patient population.

Safe(r)-by-design principles in the thermoplastics industry: guidance on release assessment during manufacture of nano-enabled products.

Background: The application of nanomaterials (NMs) and nano-enabled products (NEPs) across many industries has been extensive and is still expanding decades after first being identified as an emerging technology. Additive manufacturing has been greatly impacted and has seen the benefits of integrating NMs within products. With the expansion of nanotechnology, there has been a need to develop more adaptive and responsive methods to ascertain risks and ensure technology is developed safely. The Safe(r)-by-Design (SbD) concept can be used to establish safe parameters and minimise risks during the materials' lifecycle, including the early stages of the supply chain. Exposure monitoring has advanced in recent years with the creation of standardised protocols for occupational exposure assessment of nano-objects and their aggregates and agglomerates (NOAA). Methods: To aid in the development of an online SbD-supporting platform by the EU-funded project SAbyNA, we adopt a Europe Standard for monitoring release of NOAA to identify if a greater release of NOAA is associated with incorporation of NMs within NEPs compared to a polymer matrix alone. Case studies included filaments of polypropylene (PP) with nano-Ag or polycarbonate (PC) with single-walled carbon nanotubes (SWCNTs). NMs were received in masterbatch, and therefore previously modified to align with SbD interventions. Results were collected in line with European Standard recommendations: monitoring particle concentrations using direct reading instruments (DRI), sampling for offline chemical and morphological analysis, and collecting contextual information. Results and discussion: Based on the criteria described in the European standard (BS EN 17058), data from both case studies identified that inhalation exposure relating to NM was "unlikely". Despite this, during the production of the SWCNT-PC filaments, some noteworthy observations were made, including several DRI activity measurements shown to be higher than background levels, and material morphologically similar to the reference SWCNT/polymeric masterbatch observed in offline analysis. The data collected during this campaign were used to discuss choices available for data interpretation and decision-making in the European Standard for monitoring release of NOAA and also to facilitate the development of SAbyNA's user-friendly industry platform for the SbD of NMs and NEPs.

Association Between Traumatic Brain Injury and Cognitive Decline Among Middle-to-Older Aged Men in the Vietnam Era Twin Study of Aging.

Traumatic brain injury (TBI) is associated with increased risk of dementia. However, whether TBI is associated with greater cognitive decline over time in specific cognitive domains among older adults is not well understood. This prospective cohort study used data from 1476 male Vietnam Era Twin Study of Aging participants (average age at study entry = 57.9 years, range = 51-71 years; 97.6% non-Hispanic; 92.5% White) collected from 2003 to 2019, who had complete information on prior TBI. Participants completed a comprehensive neuropsychological assessment at up to three visits over up to a 12-year follow-up period during which they also self-reported their history of TBI. Multivariable, linear mixed-effects models were used to assess associations between TBI and cognitive performance trajectories. Effect measure modification by apolipoprotein E (APOE) epsilon 4 (ε4) genotype status was assessed in a subset of participants. Thirty-one percent of participants reported a history of TBI; 29.4% were APOE ε4 carriers. There were no statistically significant associations of TBI with decline in episodic memory, executive function, or processing speed among participants overall. In models stratified by APOE ε4 carrier status, TBI was associated with a larger magnitude of decline in executive function for APOE ε4 carriers (ß = -0.0181; 95% confidence interval [CI] -0.0335, -0.0027) compared to noncarriers (ß = -0.0031; 95% CI -0.0128, 0.0067; P Interaction = 0.03). In sensitivity analyses, TBI earlier in life (before military induction, average age = 20 years) was associated with faster declines in executive function compared to no TBI, irrespective of APOE ε4 status. In this sample of middle-to-older aged men, TBI was associated with faster declines in executive function among APOE ε4 carriers and among those who reported TBI in early life. These findings support the importance of a life course perspective when considering factors that may influence cognitive health in aging.

Group sequential design for time-to-event outcome with non-proportional hazards using the concept of relative time utilizing two different Weibull distributions.

A group sequential design allows investigators to sequentially monitor efficacy and safety as part of interim testing in phase III trials. Literature is well developed in the case of continuous and binary outcomes, however, in case of trials with a time-to-event outcome, popular methods of sample size calculation often assume proportional hazards. In situations where the proportional hazards assumption is inappropriate as indicated by historical data, these popular methods are very restrictive. In this paper, a novel simulation-based group sequential design is proposed for a two-arm randomized phase III clinical trial with a survival endpoint for the non-proportional hazards scenario. By assuming that the survival times for each treatment arm follow two different Weibull distributions, the proposed method utilizes the concept of Relative Time to calculate the efficacy and safety boundaries at selected interim testing points. The test statistic used to generate these boundaries is asymptotically normal, allowing p-value calculation at each boundary. Many design features specific to time-to-event data can be incorporated with ease. Additionally, the proposed method allows the flexibility of having the accelerated failure time model and the proportional hazards model as constrained special cases. Real life applications are discussed demonstrating the practicality of the proposed method.

Duplications and Retrogenes Are Numerous and Widespread in Modern Canine Genomic Assemblies.

Recent years have seen a dramatic increase in the number of canine genome assemblies available. Duplications are an important source of evolutionary novelty and are also prone to misassembly. We explored the duplication content of nine canine genome assemblies using both genome self-alignment and read-depth approaches. We find that 8.58% of the genome is duplicated in the canFam4 assembly, derived from the German Shepherd Dog Mischka, including 90.15% of unplaced contigs. Highlighting the continued difficulty in properly assembling duplications, less than half of read-depth and assembly alignment duplications overlap, but the mCanLor1.2 Greenland wolf assembly shows greater concordance. Further study shows the presence of multiple segments that have alignments to four or more duplicate copies. These high-recurrence duplications correspond to gene retrocopies. We identified 3,892 candidate retrocopies from 1,316 parental genes in the canFam4 assembly and find that ∼8.82% of duplicated base pairs involve a retrocopy, confirming this mechanism as a major driver of gene duplication in canines. Similar patterns are found across eight other recent canine genome assemblies, with metrics supporting a greater quality of the PacBio HiFi mCanLor1.2 assembly. Comparison between the wolf and other canine assemblies found that 92% of retrocopy insertions are shared between assemblies. By calculating the number of generations since genome divergence, we estimate that new retrocopy insertions appear, on average, in 1 out of 3,514 births. Our analyses illustrate the impact of retrogene formation on canine genomes and highlight the variable representation of duplicated sequences among recently completed canine assemblies.

Synthesis, Structures, and Magnetic Investigations of Nickel Phosphates: Ni2(PO4)(OH), Ni7(PO4)3(HPO4)(OH)3, and NaNiPO4 Including Potential Haldane Behavior.

Three novel nickel-phosphate structures are reported, Ni2(PO4)(OH) (I), Ni7(PO4)3(HPO4)(OH)3 (II), and NaNiPO4 (III). Each new system was prepared via a high-temperature hydrothermal synthesis at 600-650 °C. All three compounds are built of quasi-one-dimensional (quasi-1-D) Ni2+ containing chains with varying phosphate bridging modes and were characterized by single crystal X-ray diffraction and magnetic susceptibility. All three compounds display very different magnetic behavior. Anisotropic magnetic data is reported for Ni2(PO4)(OH) (I) exhibiting slow antiferromagnetic ordering in the high-temperature regime with substructures that begin to form below 32 K at different field strengths. These characteristics affirm I as being one of the few Haldane-like material candidates. The Ni7(PO4)3(HPO4)(OH)3 (II) material is a member of the unusual ellenbergerite structural family and displays complex inter- and intrachain magnetic interactions while NaNiPO4 (III) shows antiferromagnetic ordering near 18 K. This magnetic behavior is correlated with their structures.