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Objective: Because there is no reliable method on admission to predict whether a patient will require neurosurgical intervention in the future, the general approach remains to treat each patient with mild traumatic brain injury (mTBI) and subdural hematoma (SDH) as if they will require such an intervention. Consequently, there is a growing population of patients with mTBI and SDH that is overtriaged despite having a low probability of needing neurosurgical intervention. This study aimed to train and validate a predictive rule-out tool for neurosurgical intervention in patients with mTBI and SDH., Methods: This was a retrospective cohort study of all trauma patients admitted to six level I trauma centers in three states. Patients were included if they met the following criteria: admitted between 2016 and 2020, ≥ 18 years of age, ICD-10 diagnosis of isolated SDH, initial head imaging available, initial Glasgow Coma Scale score of 13-15, and arrived within 48 hours of injury. Exclusion criteria included skull fracture, intracranial hemorrhage other than an SDH, and no neurosurgical consultation. Prediction variables included 34 demographic, clinical, and radiographic variables. The study outcome was neurosurgical intervention within 48 hours of hospital admission. Seventy-five percent of the data were used for training, and 25% for testing. Multivariable logistic regression with fivefold cross-validation was used on the training set to identify covariates with the highest specificity while holding sensitivity at 100%. Results were validated on the testing set., Results: In total, 1000 patients were in the training set and 333 in the testing set. The overall neurosurgical intervention rate was 8.8%. For the fivefold cross-validation process, three variables were selected that maximized specificity while holding sensitivity at 100%: maximum hematoma thickness, initial Glasgow Coma Scale score, and preinjury antithrombotic use (sensitivity 100%, specificity 56%, area under the receiver operating characteristic curve 0.94). With a cutoff probability of neurosurgical intervention set at 1.88%, the final model was validated to predict neurosurgical intervention with a sensitivity of 100% (95% CI 88.4%-100%) and specificity of 55.1% (95% CI 49.3%-60.8%)., Conclusions: In this study, the largest of its kind to date, the authors successfully developed and validated a new tool for ruling out the necessity of neurosurgical intervention in patients with mTBI and isolated SDH. By successfully identifying more than half of patients who are unlikely to require neurosurgery within the first 2 days of admission, this tool can be used to improve treatment efficiency and provide patients and clinicians with valuable prognostic information.

PDE11A4 is a target of interest for the treatment of age-related memory disorders. A previous report from our laboratories described an amide series of potent, selective PDE11A4 inhibitors that was metabolically unstable. Investigation of heterocyclic amide isosteres for the labile amide moiety revealed distinct structure-activity relationships and identified several compounds with potency comparable to the amide series. This manuscript describes the characterization of structure-activity and structure-property relationships in this set, leading to the identification of an orally bioavailable, brain-penetrant, selective and potent PDE11A4 inhibitor. Target engagement experiments demonstrated PDE11A4 inhibition in the hypothalamus of mice that was absent in PDE11A4 knock out animals.

Background: Out-of-hospital cardiac arrest (OHCA) is a prevalent condition with high mortality and poor outcomes even in settings where extensive emergency care resources are available. Interventions to address OHCA have had limited success, with survival rates below 10% in national samples of high-income countries. In resource-limited settings, where scarcity requires careful priority setting, more data is needed to determine the optimal allocation of resources., Objective: To establish the cost-effectiveness of OHCA care and assess the affordability of interventions across income settings., Methods: The authors conducted a systematic review of economic evaluations on interventions to address OHCA. Six databases (PubMed, EMBASE, Global Health, Cochrane, Global Index Medicus, and Tuft's Cost-Effectiveness Registry) were searched in September 2023. Included studies were (1) economic evaluations (beyond a simple costing exercise); and (2) assessed an intervention in the chain of survival for OHCA. Article quality was assessed using the CHEERs checklist and data summarised. Findings were reported by major themes identified by the reviewers. Based upon the results of the cost-effectiveness analyses we then conduct an analysis for the progressive realization of the OHCA chain of survival from the perspective of decision-makers facing resource constraints., Results: Four hundred and sixty-eight unique articles were screened, and 46 articles were included for final data abstraction. Studies predominantly used a healthcare sector perspective, modeled for all patients experiencing non-traumatic cardiac OHCA, were based in the US, and presented results in US Dollars. No studies reported results or used model inputs from low-income settings. Progressive realization of the chain of survival could likely begin with investments in termination of resuscitation protocols, professional prehospital defibrillator use, and CPR training followed by the distribution of AEDs in high-density public locations. Finally, other interventions such as indiscriminate defibrillator placement or adrenaline use, would be the lowest priority for early investment., Conclusion: Our review found no high-quality evidence on the cost-effectiveness of treating OHCA in low-resource settings. Existing evidence can be utilized to develop a roadmap for the development of a cost-effective approach to OHCA care, however further economic evaluations using context-specific data are crucial to accurately inform prioritization of scarce resources within emergency care in these settings., (© 2024. The Author(s).)

The heterocyclic 2-Aminothiazoles scaffolds are used in a wide range of therapeutic applications against various diseases for its antioxidant, anti-inflammatory, antimicrobial and anticancer actions. In the present study, we synthesized novel aniline aromatic ring-substituted 2-Aminothiazole derivatives. Molecular docking was performed using Glide module of the Schrödinger Suite to fit compounds JG-49, JG-62, and KBA-18 against the Nicotinamide phosphoribosyl transferase (Nampt) enzyme, an intracellular regulator of Nicotinamide adenine dinucleotide (NAD) redox cofactor involved in energy metabolism and epigenetics and are implicated in aging and metabolic diseases. The three compounds viz. JG-49, JG-62, and KBA-18 showed an increase in Nampt enzymatic activity in vitro. All three substituted derivatives of 2-Aminothiazole showed no cytotoxicity with the mouse C2C12 myoblasts cultures assessed with the MTT cell viability assay. Moreover, the wound closure of the mouse C2C12 myoblasts in vitro displayed no significant difference between the treatment groups of the 2-Aminothiazole derivatives compared with the control naïve and DMSO treated myoblasts cultures, except for the 2-Aminothiazole substituted derivatives JG-62 and KBA-18, which showed a significant increase in the wound closure compared with the control cells at different concentrations. Taken together, we demonstrated that 2-Aminothiazole substituted derivatives provide enhanced Nampt activity, wound closure, and no cytotoxic effects in vitro. Further studies will allow to improve the substitution of 2-Aminothiazole derivatives and test their potential therapeutic applications.

Patients with heart failure with reduced ejection fraction (HFrEF) are at risk for chronic kidney disease (CKD). Elevated levels of circulating biomarkers soluble urokinase plasminogen activator receptor (suPAR), galectin-3, soluble suppression of tumorigenicity 2 (ST2), and N-terminal prohormone B-type natriuretic peptide (NT-proBNP) are associated with CKD progression and mortality. The predictive value of these biomarkers in a population with HFrEF and kidney disease is relatively unknown. We sought to determine whether these biomarkers were associated with longitudinal trajectory of estimated glomerular filtration rate (eGFR) in HFrEF and assess their association with mortality using a joint model to account for competing risks of ventricular assist device (VAD) implantation and heart transplantation. We included participants from the Registry Evaluation of Vital Information for Ventricular Assist Devices in Ambulatory Life with repeated eGFR measures over 2 years. Of 309 participants, mean age was 59 years, median eGFR 60 ml/min/1.73 m 2 , 45 participants died, 33 received VAD, and 25 received orthotopic heart transplantation. Higher baseline serum standardized suPAR (β coefficient = -0.36 √(ml/min/1.73 m 2 ), 95% confidence interval (-0.48 to -0.24), p < 0.001), standardized galectin-3 (-0.14 √(ml/min/1.73 m 2 ) (-0.27 to -0.02), p = 0.02), and log NT-proBNP (-0.23 √(ml/min/1.73 m 2 ) (-0.31 to -0.15), p < 0.001) were associated with eGFR decline. ST2 and log NT-proBNP were associated with mortality. Higher baseline suPAR, galectin-3, and NT-proBNP are associated with eGFR decline in patients with HFrEF. Only ST2 and NT-proBNP are associated with greater mortality after controlling for other factors including change in eGFR. These biomarkers may provide prognostic value for kidney disease progression in HFrEF and inform candidacy for advanced heart failure therapies., Competing Interests: Declaration of conflicting interestsThe author(s) declared the following potential conflicts of interest with respect to the research, authorship, and/or publication of this article: J. Grodin receives fees for scientific consulting from Pfizer, Eidos/BridgeBio, Astra-Zeneca, and Sarepta.

Background: For bloodstream infections (BSI), treatment and research have focused on short term mortality. The objective of this study was to describe the 1-year mortality and morbidity in survivors of bloodstream infection when compared to patients with negative blood cultures., Methods: We conducted a population-based retrospective cohort study using Ontario administrative databases. Patients were included if they had a blood culture taken from January 1, 2014, to December 31, 2021, and survived past 30 days from blood culture collection. They were followed for the subsequent year. Outcomes were compared among patients with BSI and those without BSI, including all-cause mortality, stroke, myocardial infarction (MI), congestive heart failure (CHF) exacerbation, new start dialysis and admission to a long-term care (LTC) facility. Prognostic factors were balanced using overlap weighting of propensity scores, and a survival or competing risk model was used to describe time-to-event., Results: Of 981,341 patients undergoing blood culture testing, 99,080 (10.1%) patients had a BSI and 882,261 (89.9%) patients did not. Outcomes were all more common among those with BSI as compared to those without BSI, including all-cause mortality (16,764 [16.9%] vs. 84,480 [9.6%]), stroke (1016 [1.0%] vs. 4680 [0.5%]), MI (1043 [1.1%] vs. 4547 [0.5%]), CHF exacerbation (2643 [2.7%] vs. 13,200 [1.5%]), new start dialysis (1703 [1.7%] vs. 2749 [0.3%]), and LTC admission (4231 [4.3%] vs. 13,016 [1.5%]). BSI had an adjusted hazard ratio of 1.10 (95% CI 1.08-1.12, P < 0.0001) for mortality, subdistribution hazard ratio (sHR) of 1.27 (95% CI 1.19-1.37, P < 0.0001) for stroke, sHR of 1.18 (95% CI 1.10-1.26, P < 0.0001) for MI, sHR of 1.05 (95% CI 1.01-1.10, P = 0.0176) for CHF exacerbation, sHR of 3.42 (95% CI 3.21-3.64, P < 0.0001) for new start dialysis and sHR of 1.87 (95% CI 1.80-1.94, P < 0.0001) for LTC admission., Conclusion: BSI survivors have substantial long-term mortality and morbidity including stroke, MI, new start dialysis and functional decline leading to LTC admission., Competing Interests: Declaration of Competing Interest The authors have no conflict of interest to disclose., (Copyright © 2024 The Author(s). Published by Elsevier Ltd.. All rights reserved.)

Context: The COVID-19 pandemic exposed governmental public health's outdated information technology and insufficient data science and informatics workforce capacity. The Centers for Disease Control and Prevention's Public Health Informatics Fellowship Program (PHIFP) is well positioned to strengthen public health data science and informatics workforce capacity., Program: Established in 1996, PHIFP is a 2-year, full-time, on-the-job training program. PHIFP includes a didactic curriculum, applied learning through informatics projects completed at the assigned host site, short-term technical assistance projects, and a final capstone project., Evaluation: Fellows have learned from and bolstered host site informatics capacity through the development or enhancement of information systems, evaluations, data integration, data visualization, and analysis. Among recent graduates, 54% are employed at Centers for Disease Control and Prevention and 16% are employed at other public health organizations, including local health departments., Discussion: Fellowships such as PHIFP, which recruit and train promising scientists in public health informatics, are important components of efforts to strengthen public health workforce capacity., Competing Interests: The authors declare that they have no conflicts of interests to disclose., (Copyright © 2024 Wolters Kluwer Health, Inc. All rights reserved.)

Lasso peptides are a diverse class of naturally occurring, highly stable molecules kinetically trapped in a distinctive [1]rotaxane conformation. How the ATP-dependent lasso cyclase constrains a relatively unstructured substrate peptide into a low entropy product has remained a mystery owing to poor enzyme stability and activity in vitro. In this study, we combined substrate tolerance data with structural predictions, bioinformatic analysis, molecular dynamics simulations and mutational scanning to construct a model for the three-dimensional orientation of the substrate peptide in the lasso cyclase active site. Predicted peptide cyclase molecular contacts were validated by rationally engineering multiple, phylogenetically diverse lasso cyclases to accept substrates rejected by the wild-type enzymes. Finally, we demonstrate the utility of lasso cyclase engineering by robustly producing previously inaccessible variants that tightly bind to integrin αvβ8, which is a primary activator of transforming growth factor β and, thus, an important anti-cancer target., (© 2024. The Author(s), under exclusive licence to Springer Nature America, Inc.)

The objectives of this study were to validate diagnostic tests to detect polymorphonuclear cells (PMNs) in bull semen, and to determine the prevalence of leucospermia in beef bulls with varying semen quality. We hypothesized that all tests have comparable diagnostic value, and that leucospermia is more prevalent in unsatisfactory breeders in association with poor semen quality. For the analytical validation, one ejaculate was obtained from five bulls. Aliquots of 50 × 10 6 purified sperm were incubated in triplicate with six concentrations of purified bovine PMNs: 1) no PMNs, 2) 0.25 × 10 6 PMN/ml, 3) 0.5 × 10 6 PMN/ml, 4) 2.5 × 10 6 PMN/ml, 5) 5 × 10 6 PMN/ml, 6) 10 × 10 6 PMN/ml. The PMNs were quantified using a hemacytometer, cytology, a leucocyte esterase dipstick test (LEDT), a peroxidase test, and CD45 immunolabeling. The number of leucocytes detected with the LEDT differed among treatments (P < 0.0001). The quantitative tests detected differences with the control treatment at a PMN concentration of ≥2.5 × 10 6 PMN/ml (P < 0.0001). Sperm motion parameters after 4 h of incubation at 38 °C were lower in samples with ≥5 × 10 6 PMN/ml (P < 0.05). For the clinical validation, semen samples from 305 beef bulls were evaluated. Unsatisfactory breeders (n = 83) had more CD45-positive cells (P = 0.016) and positive LEDT results (P = 0.008) than satisfactory breeders (n = 222). With CD45 immunostaining as the gold standard, the hemacytometer count had the highest clinical sensitivity (64.3 %) but the lowest specificity (73.3 %). A higher specificity was obtained with the peroxidase test (95.1 %) or semen cytology (98.8 %). In conclusion, the presence of ≥5 × 10 6 PMN/ml was associated with decreased semen quality in beef bulls. The hemacytometer count was the most sensitive bull-side test. But due to the low specificity, positive hemacytometer counts should be confirmed with the identification of peroxidase-positive cells or morphological identification of leucocytes on semen cytology. The CD45 immunostaining is the gold standard for the diagnosis of leucospermia in bulls., (Copyright © 2024. Published by Elsevier Inc.)

With a foundation built upon initial work from the 1980s demonstrating graft viability in cerebral ischemia, stem cell transplantation has shown immense promise in promoting survival, enhancing neuroprotection and inducing neuroregeneration, while mitigating both histological and behavioral deficits that frequently accompany ischemic stroke. These findings have led to a number of clinical trials that have thoroughly supported a strong safety profile for stem cell therapy in patients but have generated variable efficacy. As preclinical evidence continues to expand through the investigation of new cell lines and optimization of stem cell delivery, it remains critical for translational models to adhere to the protocols established through basic scientific research. With the recent shift in approach towards utilization of stem cells as a conjunctive therapy alongside standard thrombolytic treatments, key issues including timing, route of administration, and stem cell type must each be appropriately translated from the laboratory in order to resolve the question of stem cell efficacy for cerebral ischemia that ultimately will enhance therapeutics for stroke patients towards improving quality of life., Competing Interests: Declaration of conflicting interestsThe author(s) declared the following potential conflicts of interest with respect to the research, authorship, and/or publication of this article: CVB is a JCBFM editorial board member. Additionally, CVB receives royalties and owns patents in stem cell therapy for brain disorders.

There is a surprisingly strong effect on color appearance when low levels of luminance contrast are added to visual targets in which only S-cones are modulated. This phenomenon can be studied with checkerboard patterns composed of alternating S-cone-modulated checks and gray checks. + S checks look purple when surrounded by slightly brighter gray checks but look highly desaturated (lavender, almost white) when surrounded by darker gray checks. -S checks change in hue with luminance contrast; they look yellow when surrounded by darker gray checks but are greener when surrounded by lighter checks. Psychophysical paired comparisons confirm these perceptions. Furthermore, visual evoked potentials (VEPs) recorded from human posterior cortex indicate that signals evoked by low luminance contrast interact nonlinearly with S-cone-evoked signals in early cortical color processing. Our new psychophysics and electrophysiology results prove that human perception of color appearance is not based on neural computations within a separate, isolated color system. Rather, signals evoked by color contrast and luminance contrast interact to produce the colors we see., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier Ltd. All rights reserved.)

Objective: The objective was to identify demographic, clinical, and radiographic risk factors for neurosurgical intervention within 48 hours of admission in patients with mild traumatic brain injury and isolated subdural hematoma., Methods: The authors conducted a multicenter retrospective cohort study of all trauma patients admitted to 6 level I/II trauma centers who met the following criteria: admitted between January 1, 2016, and December 31, 2020, age ≥ 18 years, ICD-10 diagnosis code for isolated subdural hematoma, available initial head imaging, initial Glasgow Coma Scale score of 13-15, and arrival at the hospital within 48 hours of injury. Patients were excluded for skull fracture, non-subdural hematoma, and absence of neurosurgical consultation. The study outcome was neurosurgical intervention within 48 hours of hospital admission. Multivariable logistic regression with backward selection examined 30 demographic, clinical, and radiographic risk factors for neurosurgery., Results: In total, 1333 patients were included, of whom 117 (8.8%) received a neurosurgical intervention. When only demographic and clinical variables were considered, sex, mechanism of injury, and hours from injury to initial head imaging were significant covariates (area under the receiver operating characteristic curve [AUROC] [95% CI] 0.70 [0.65-0.75]). When only radiographic risk factors were considered, only maximum hemorrhage thickness (in mm) and midline shift (in mm) were independent risk factors for the outcome (AUROC 0.95 [0.92-0.97]). When all demographic, clinical, and radiographic variables were considered together, advanced directive, Injury Severity Score, midline shift, and maximum hemorrhage thickness were identified as significant risk factors for neurosurgical intervention within 48 hours of hospital admission (AUROC 0.95 [0.94-0.97])., Conclusions: In the setting of mild traumatic brain injury with isolated subdural hematoma, radiographic risk factors were shown to be stronger than demographic and clinical variables in understanding future risk of neurosurgical intervention. These final radiographic risk factors should be considered in the creation of future prediction models and used to increase the efficiency of existing management guidelines.

Objectives: This analysis aims to better reflect the value of new antibiotic treatment strategies, thereby informing clinical antibiotic use, antimicrobial reimbursement and/or hospital formulary decision-making in China., Design: We adapted a published and validated dynamic disease transmission and cost-effectiveness model to evaluate the clinical and economic outcomes of introducing a new antibiotic, ceftazidime/avibactam (CAZ-AVI) for treating resistant infections in Zhejiang province, China. Outcomes were assessed over a 10-year infectious period and an annual discount rate of 5%. Costs were extracted from the hospital's Health Information System (HIS) and obtained after data cleaning, aggregation and discounting., Setting: The Chinese healthcare system perspective., Participants: 10 905 patients in a Chinese tier-3 hospital from 2018 to 2021 with any of the three common infections (complicated intra-abdominal infection (cIAI), hospital-acquired/ventilator-associated pneumonia (HAP/VAP) and infections with limited treatment options (LTO)) caused by three common resistant pathogens ( Escherichia coli, Klebsiella spp. and Pseudomonas aeruginosa )., Interventions: (1) Current treatment strategy (piperacillin-tazobactam (pip/taz) and meropenem); (2) CAZ-AVI at the third line; (3) CAZ-AVI at the second line; (4) CAZ-AVI at the first line; (5) CAZ/AVI first line, two lines diversified (i.e., equal pip/taz and CAZ-AVI at the first line; meropenem at the last line) and (6) CAZ/AVI first line, all-lines diversified., Primary Outcome Measures: Quality-adjusted life years (QALYs) lost, hospitalisation costs and incremental net monetary benefit (INMB) were used to assess cost-effectiveness., Results: Over 10 years, the introduction of CAZ-AVI to the current treatment strategy led to lower hospitalisation costs and more QALYs across all five treatment strategies, with between 68 284 and 78 571 QALYs gained whilst saving up to US$236.37 for each additional QALY gained. The INMB of introducing CAZ-AVI is estimated up to US$3 550 811 878., Conclusions: Introducing CAZ-AVI had a positive impact on clinical and economic outcomes for treating antimicrobial resistance, and diversifying the antibiotics use early in the treatment might yield the best benefits., Competing Interests: Competing interests: YC, PD and AA-T are employees of Pfizer. JG is an employee of Health Economics and Outcomes Research Ltd.; Health Economics and Outcomes Research Ltd. received fees from Pfizer in relation to this study. HD and XZ are paid consultants to Pfizer from Zhejiang University and Shandong University, respectively., (© Author(s) (or their employer(s)) 2024. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Background: The effect of a liberal transfusion strategy as compared with a restrictive strategy on outcomes in critically ill patients with traumatic brain injury is unclear., Methods: We randomly assigned adults with moderate or severe traumatic brain injury and anemia to receive transfusion of red cells according to a liberal strategy (transfusions initiated at a hemoglobin level of ≤10 g per deciliter) or a restrictive strategy (transfusions initiated at ≤7 g per deciliter). The primary outcome was an unfavorable outcome as assessed by the score on the Glasgow Outcome Scale-Extended at 6 months, which we categorized with the use of a sliding dichotomy that was based on the prognosis of each patient at baseline. Secondary outcomes included mortality, functional independence, quality of life, and depression at 6 months., Results: A total of 742 patients underwent randomization, with 371 assigned to each group. The analysis of the primary outcome included 722 patients. The median hemoglobin level in the intensive care unit was 10.8 g per deciliter in the group assigned to the liberal strategy and 8.8 g per deciliter in the group assigned to the restrictive strategy. An unfavorable outcome occurred in 249 of 364 patients (68.4%) in the liberal-strategy group and in 263 of 358 (73.5%) in the restrictive-strategy group (adjusted absolute difference, restrictive strategy vs. liberal strategy, 5.4 percentage points; 95% confidence interval, -2.9 to 13.7). Among survivors, a liberal strategy was associated with higher scores on some but not all the scales assessing functional independence and quality of life. No association was observed between the transfusion strategy and mortality or depression. Venous thromboembolic events occurred in 8.4% of the patients in each group, and acute respiratory distress syndrome occurred in 3.3% and 0.8% of patients in the liberal-strategy and restrictive-strategy groups, respectively., Conclusions: In critically ill patients with traumatic brain injury and anemia, a liberal transfusion strategy did not reduce the risk of an unfavorable neurologic outcome at 6 months. (Funded by the Canadian Institutes of Health Research and others; HEMOTION ClinicalTrials.gov number, NCT03260478.)., (Copyright © 2024 Massachusetts Medical Society.)

Premise: Reticulate evolution, often accompanied by polyploidy, is prevalent in plants, and particularly in the ferns. Resolving the resulting non-bifurcating histories remains a major challenge for plant phylogenetics. Here, we present a phylogenomic investigation into the complex evolutionary history of the vining ferns, Lygodium (Lygodiaceae, Schizaeales)., Methods: Using a targeted enrichment approach with the GoFlag 408 flagellate land plant probe set, we generated large nuclear and plastid sequence datasets for nearly all taxa in the genus and constructed the most comprehensive phylogeny of the family to date using concatenated maximum likelihood and coalescence approaches. We integrated this phylogeny with cytological and spore data to explore karyotype evolution and generate hypotheses about the origins of putative polyploids and hybrids., Results: Our data and analyses support the origins of several putative allopolyploids (e.g., L. cubense, L. heterodoxum) and hybrids (e.g., L. ×fayae) and also highlight the potential prevalence of autopolyploidy in this clade (e.g., L. articulatum, L. flexuosum, and L. longifolium)., Conclusions: Our robust phylogenetic framework provides valuable insights into dynamic reticulate evolution in this clade and demonstrates the utility of target-capture data for resolving these complex relationships., (© 2024 The Author(s). American Journal of Botany published by Wiley Periodicals LLC on behalf of Botanical Society of America.)

This study investigated relations between a measure of early-stage visual function and self-reported visual anomalies in individuals at clinical high risk for psychosis (CHR-P). Eleven individuals at CHR identified via the Structured Interview for Psychosis-Risk Syndromes (SIPS) were recruited from a CHR-P research program in NYC. The sample was ~36% female, ranging from 16 to 33 years old ( M = 23.90, SD = 6.14). Participants completed a contrast sensitivity task on an iPad with five spatial frequencies (0.41-13 cycles/degree) and completed the self-report Audio-Visual Abnormalities Questionnaire. Higher contrast sensitivity (better performance) to low spatial frequencies was associated with higher perceptual ( r = 0.616, p = 0.044) and visual disturbances ( r = 0.667, p = 0.025); lower contrast sensitivity to a middle spatial frequency was also associated with higher perceptual ( r = -0.604, p = 0.049) and visual disturbances ( r = -0.606, p = 0.048). This relation between the questionnaire and contrast sensitivity to low spatial frequency may be indicative of a reduction in lateral inhibition and "flooding" of environmental stimuli. The association with middle spatial frequencies, which play a critical role in face processing, may result in a range of perceptual abnormalities. These findings demonstrate that self-reported perceptual anomalies occur in these individuals and are linked to performance on a measure of early visual processing.

Objective: To explore consultation patterns, management practices, and costs of foot, ankle, and leg problems in Australian primary care., Study Design: We analyzed data from the Bettering the Evaluation and Care of Health program, April 2000 to March 2016. Foot, ankle, and leg problems were identified using the International Classification of Primary Care, Version 2 PLUS terminology. Data were summarized using descriptive statistics examining general practitioner (GP) and patient characteristics associated with a foot, ankle, or leg problem being managed. Cost to government was estimated by extracting fees for GP consultations, diagnostic imaging, and pathology services from the Medicare Benefits Schedule (MBS) database. Costs for prescription-only medicines were extracted from the Pharmaceutical Benefits Schedule and for nonprescribed medications, large banner discount pharmacy prices were used., Results: GPs recorded 1,568,100 patient encounters, at which 50,877 foot, ankle, or leg problems were managed at a rate of 3.24 (95% confidence intervals [CIs] 3.21-3.28) per 100 encounters. The management rate of foot, ankle, or leg problems was higher for certain patient characteristics (older, having a health care card, socioeconomically disadvantaged, non-Indigenous, and being English speaking) and GP characteristics (male sex, older age, and Australian graduate). The most frequently used management practice was the use of medications. The average cost (Australian dollars) per encounter was A$52, with the total annual cost estimated at A$256m., Conclusions: Foot, ankle, and leg problems are frequently managed by GPs, and the costs associated with their management represent a substantial economic impact in Australian primary care., (© The Author(s) 2022. Published by Oxford University Press.)

Tart cherries have low glycemic index, antioxidant and anti-inflammatory properties, and therefore may benefit performance and recovery from exercise. We determined the effects of consuming tart cherry juice versus a high-glycemic index sports drink on cycling performance, substrate oxidation, and recovery of low-frequency fatigue. Using a randomized, counter-balanced cross-over design, with one-month washout, 12 recreational cyclists (8 males and 4 females; 35±16y; VO2peak 38.2±7.4 ml/kg/min) consumed cherry juice or sports drink twice a day (300mL/d) for 4d before and 2d after exercise. On the exercise day, beverages (providing 1g/kg carbohydrate) were consumed 45min before 90min of cycling at 65%VO2peak, followed by a 10km time trial. Blood glucose, lactate, carbohydrate and fat oxidation, respiratory exchange ratio (RER), O2 cost of cycling, and rating of perceived exertion (RPE) were measured during the initial 90min of cycling. Muscle soreness, maximal voluntary contraction (MVC) and low-frequency fatigue were determined at baseline and after the time trial on the exercise day, and 30min after beverage consumption 24 and 48h later. There were no differences for time trial performance (17±3min cherry juice vs. 17±2min sports drink, p = 0.27) or any other measures between drink conditions. There were time main effects (p<0.05) for isometric MVC (decreasing) and low-frequency fatigue (increasing; i.e. decreased force at low relative to high stimulation frequencies), changing significantly from baseline to post-exercise and then returning to baseline at 24h post-exercise. Tart cherry juice was not effective for improving performance, substrate oxidation during exercise, and recovery from exercise, compared to a high-glycemic index sports drink., Competing Interests: The authors have declared that no competing interests exist., (Copyright: © 2024 Gao et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

Delirium is a heterogeneous syndrome characterized by an acute change in level of consciousness that is associated with inattention and disorganized thinking. Delirium affects most critically ill patients and is associated with poor patient-oriented outcomes such as increased mortality, longer ICU and hospital length of stay, and worse long-term cognitive outcomes. The concept of delirium and its subtypes has existed since nearly the beginning of recorded medical literature, yet robust therapies have yet to be identified. Analogous to other critical illness syndromes, we suspect the lack of identified therapies stems from patient heterogeneity and prior subtyping efforts that do not capture the underlying etiology of delirium. The time has come to leverage machine learning approaches, such as supervised and unsupervised clustering, to identify clinical and pathophysiological distinct clusters of delirium that will likely respond differently to various interventions. We use sedation in the ICU as an example of how precision therapies can be applied to critically ill patients, highlighting the fact that while for some patients a sedative drug may cause delirium, in another cohort sedation is the specific treatment. Finally, we conclude with a proposition to move away from the term delirium, and rather focus on the treatable traits that may allow precision therapies to be tested., Competing Interests: Dr. Prendergast received funding from McGraw-Hill; he received support for article research from the National Institutes of Health; he disclosed off-label use of antipsychotic agents to treat delirium. Dr. Boyd’s institution received funding from the Canadian Institute of Health Research; he received funding from Ontario Health-Trillium Gift of Life Network. Dr. Potter has disclosed that she does not have any potential conflicts of interest., (Copyright © 2024 by the Society of Critical Care Medicine and Wolters Kluwer Health, Inc. All Rights Reserved.)

Background: General practitioners (GPs) make numerous care decisions throughout their workdays. Extended periods of decision making can result in decision fatigue, a gradual shift toward decisions that are less cognitively effortful. This study examines whether observed patterns in GPs' prescribing decisions are consistent with the decision fatigue phenomenon. We hypothesized that the likelihood of prescribing frequently overprescribed medications (antibiotics, benzodiazepines, opioids; less effortful to prescribe) will increase and the likelihood of prescribing frequently underprescribed medications (statins, osteoporosis medications; more effortful to prescribe) will decrease over the workday., Methods: This study used nationally representative primary care data on GP-patient encounters from the Bettering the Evaluation and Care of Health program from Australia. The association between prescribing decisions and order of patient encounters over a GP's workday was assessed with generalized linear mixed models accounting for clustering and adjusting for patient, provider, and encounter characteristics., Results: Among 262,456 encounters recorded by 2,909 GPs, the odds of prescribing antibiotics significantly increased by 8.7% with 15 additional patient encounters (odds ratio [OR] = 1.087; confidence interval [CI] = 1.059-1.116). The odds of prescribing decreased significantly with 15 additional patient encounters by 6.3% for benzodiazepines (OR = 0.937; CI = 0.893-0.983), 21.9% for statins (OR = 0.791; CI = 0.753-0.831), and 25.0% for osteoporosis medications (OR = 0.750; CI = 0.690-0.814). No significant effects were observed for opioids. All findings were replicated in confirmatory analyses except the effect of benzodiazepines., Conclusions: GPs were increasingly likely to prescribe antibiotics and were less likely to prescribe statins and osteoporosis medications as the workday wore on, which was consistent with decision fatigue. There was no convincing evidence of decision fatigue effects in the prescribing of opioids or benzodiazepines. These findings establish decision fatigue as a promising target for optimizing prescribing behavior., Highlights: We found that as general practitioners progress through their workday, they become more likely to prescribe antibiotics that are reportedly overprescribed and less likely to prescribe statins and osteoporosis medications that are reportedly underprescribed.This change in decision making over time is consistent with the decision fatigue phenomenon. Decision fatigue occurs when we make many decisions without taking a rest break. As we make those decisions, we become gradually more likely to make decisions that are less difficult.The findings of this study show that decision fatigue is a possible target for improving guideline-compliant prescribing of pharmacologic medications., Competing Interests: The authors declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article. The authors disclosed receipt of the following financial support for the research, authorship, and/or publication of this article: Financial support for this study was provided by a Small Research Grant from the Royal Society of Edinburgh (grant ID: 2156). The funding agreement ensured that authors’ independence in designing the study, interpreting the data, writing, and publishing the report. The BEACH project itself was funded through arm’s length research agreements with the following organizations: Abbott Australasia; AbbVie; AstraZeneca (Australia); Australian Government Department of Health; Australian Government Department of Veterans’ Affairs; Aventis Pharma; Bayer Australia; bioCSL (Australia); GlaxoSmithKline Australia; Janssen-Cilag; Merck, Sharp and Dohme (Australia); National Prescribing Service; Novartis Pharmaceuticals Australia; Pfizer Australia; Roche Product; Sanofi-Aventis Australia; Wyeth Australia.

Introduction: Evidence indicates that retraumatization has a detrimental effect for those women who are accessing perinatal services. One in five women worldwide has a history of childhood adversity. Between 18% and 34% of women experience trauma, which is a well-known risk factor for the onset of chronic mental health disorders. There is a lack of evidence on women's experiences on retraumatization in perinatal care settings and how to prevent retraumatization from occurring. The purpose of this study was to conduct an integrative review on women experiences of retraumatization to determine preventive measures within perinatal services., Methods: This integrative review followed Whittemore and Knafl's 5-stage framework as it allows for the inclusion and integration of diverse research methodologies into an overall synthesis of the evidence. A systematic search of 5 databases was conducted (Web of Science, MEDLINE, CINAHL, ASSIA, and PsychINFO) with no date, language, or geographical limits set due to the paucity of research published in this subject area. This review was conducted and reported according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines., Results: Fifteen studies met the inclusion criteria and were included in the thematic synthesis. The review identified that participants across the studies had a history of child sexual abuse, sexual abuse, and rape. Three main themes plus subthemes were identified: (1) activating (subthemes: positions in labor, intimate procedures, communications with health care professionals, loss of control); (2) outcomes (subtheme: emotional responses); and (3) interventions reducing or preventing retraumatization (subthemes: role of the health care professional, screening for abuse and history of trauma)., Discussion: Our findings demonstrate that women are experiencing retraumatization in perinatal services, and there is evidence of formalized approaches being applied in clinical settings to prevent retraumatization from occurring. This study is the first to examine the factors that contribute to retraumatization in perinatal services and make recommendations to reduce the harmful practices in place in perinatal care settings., (© 2024 The Author(s). Journal of Midwifery & Women's Health published by Wiley Periodicals LLC on behalf of American College of Nurse Midwives (ACNM).)

Objective: The nomenclature characterizing posterior fossa (PF) extraventricular (EV) CSF collections in radiological reports can be quite variable, leading to uncertainty about the subsequent clinical course that may result in multiple follow-up imaging studies that may not be needed and occasionally to operative intervention that is not warranted. The important factor is the mass effect of the PF EV CSF collection on adjacent structures, the presence of hydrocephalus, and the likelihood of the CSF collection increasing in size over time., Methods: The authors respectively reviewed the imaging database at Children's Hospital Los Angeles to identify all radiological reports from 2000 to 2015 indicating the presence of an EV CSF collection in the PF that was characterized as containing an arachnoid cyst, being cystic, or being an abnormal CSF collection., Results: Of the 332 reports in 65 patients, the PF EV CSF collection was described as an arachnoid cyst or cystic in 306 with 20 different terms being used. In those patients who underwent multiple imaging studies, the PF EV CSF collection was often described differently in each report. Of this group, 47 (72%) patients did not undergo PF surgery. Eighteen (28%) patients did undergo PF surgery, of whom 14 had both hydrocephalus and brainstem displacement, 2 had brainstem displacement but no hydrocephalus, and 2 had neither brainstem displacement nor hydrocephalus and in retrospect did not benefit from PF surgery., Conclusions: The terminology in radiology reports describing EV PF CSF collections is variable, is inconsistent, and does not correlate well with clinical management or the need for PF surgery. Significant brainstem displacement and hydrocephalus in the presence of EV PF CSF collection is highly correlated with the need for PF surgery. The incidence of a PF EV CSF collection increasing to become symptomatic becomes more remote the older the patient is at the time of diagnosis as compared with those that occur mainly in infancy. There are true EV CSF cysts in the PF, but the ones that are of consequence are those that exert pressure on the brainstem, obstruct CSF flow, or both. Calling any increased amount of CSF in the PF a "cyst" or "cystic" can cause uncertainty, leading to one or more subsequent imaging studies or, in rare cases, unwarranted operative intervention.

Although our understanding of herpes simplex virus type 1 (HSV-1) biology has been considerably enhanced, developing therapeutic strategies to eliminate HSV-1 in latently infected individuals remains a public health concern. Current antiviral drugs used for the treatment of HSV-1 complications are not specific and do not address latent infection. We recently developed a CRISPR-Cas9-based gene editing platform to specifically target the HSV-1 genome. In this study, we further used 2D Vero cell culture and 3D human induced pluripotent stem cell-derived cerebral organoid (CO) models to assess the effectiveness of our editing constructs targeting viral ICP0 or ICP27 genes. We found that targeting the ICP0 or ICP27 genes with AAV2-CRISPR-Cas9 vectors in Vero cells drastically suppressed HSV-1 replication. In addition, we productively infected COs with HSV-1, characterized the viral replication kinetics, and established a viral latency model. Finally, we discovered that ICP0- or ICP27-targeting AAV2-CRISPR-Cas9 vector significantly reduced viral rebound in the COs that were latently infected with HSV-1. In summary, our results suggest that CRISPR-Cas9 gene editing of HSV-1 is an efficient therapeutic approach to eliminate the latent viral reservoir and treat HSV-1-associated complications., Competing Interests: G.-X.R. and J.G. are employees of Excision BioTherapeutics. K.K. is named inventor on patents that cover the viral gene editing technology that is the subject of this article. K.K. is a co-founder, board member, scientific advisor, and holds equity in Excision BioTherapeutics, a biotech start-up that has licensed the viral gene editing technology from Temple University for commercial development and clinical trials., (© 2024 The Author(s).)

Objective: To understand if autoantibodies account for racial variation in disease severity, we compared autoantibody distribution and associated phenotype between self-identified black and white systemic sclerosis (SSc) patients., Methods: 803 black and 2178 white SSc patients had systematic testing for autoantibodies using Euroimmun (centromere (ACA), RNA-polymerase III (POLR3), Scl70, PM/Scl, NOR90, Th/To, Ku, U3RNP and Ro52) and commercial ELISA (U1RNP). In this observational study, logistic regression was performed to assess the association between self-identified race and outcomes, adjusting for autoantibodies. To estimate whether the effect of race was mediated by autoantibody status, race coefficients from multivariate models including and excluding autoantibodies were compared., Results: Anti-Scl70, anti-U1RNP, anti-U3RNP, anti-Th/To, anti-Ku and anti-NOR90 were more common in the black cohort than in the white cohort, which was enriched for ACA, anti-POLR3 and anti-PM/Scl. Black individuals had a higher prevalence of severe Raynaud's, skin, lung, gastrointestinal and renal disease whereas white individuals had a higher prevalence of severe heart and muscle disease. Adjusting for autoantibodies decreased the effect of race on outcome for telangiectasias, forced vital capacity <70%, pulmonary hypertension and severe lung, heart, muscle and gastrointestinal disease by 11%-44% and increased the association between race and renal crisis and severe kidney disease by 37%-52%., Conclusions: This study is the largest systematic analysis of autoantibody responses in a geographically diverse population of black SSc patients. Black and white individuals with SSc have distinct autoantibody profiles. Autoantibodies explain only a fraction of the effect of race on clinical outcomes, suggesting other factors contribute to disparate outcomes between these groups., Competing Interests: Competing interests: RD received consulting fees from CSL Behring and Astra-Zeneca. LAS received grant funding from Horizon Pharmaceuticals, aTyr Pharmaceuticals and Kinevant Pharmaceuticals and honoraria from Janssen Pharmaceuticals. She served on the data safety monitoring board for Argenx Pharmaceuticals. LC received grant funding from Boehringer Ingelheim and consulting fees from Kyverna, Eicos Sciences, Genentech, IgM Biosciences, Lilly. She participated in an advisory capacity for Mitsubishi Tanabe and Janssen. FB received honoraria from Janssen. RMS received grant funding from Boehringer Ingelheim, Merck and Amgen; he is the CEO of FibroBiologics. JV received consulting fees from TeneoBio, and Conquest; he serves on the data safety monitoring board for Conquest. MDM received grant funding from Prometheus Biosciences, Mitsubishi Tanabe, Boehringer Ingelheiem, Eicos, Corbus and Horizon Pharmaceuticals. She received consulting fees from Cabaletta Pharmaceuticals; she served on the advisory board for Mitsubishi Tanabe and Eicos Sciences. AS has grant support from Kadmon, Arena Pharmaceuticals, Medpace and Eicos Sciences., (© Author(s) (or their employer(s)) 2024. No commercial re-use. See rights and permissions. Published by BMJ on behalf of EULAR.)

Selective internal radiation therapy (SIRT) is a novel intervention for both primary and metastatic malignant liver lesions. Adrenocortical carcinoma (ACC) is rare with limited treatment options; evidence for SIRT in ACC liver metastases consists of case reports only. Selective internal radiation therapy (SIRT) was employed to treat recurrent liver metastases in a 49-year-old gentleman with ACC, who previously underwent a left-sided hepatectomy. The patient opted for SIRT after reviewing the literature regarding mitotane chemotherapy and its toxicities. Selective internal radiation therapy (SIRT) provided several months of progression-free survival (PFS), with no toxicity and an excellent radiological response. The patient re-presented 12 years after the initial diagnosis with skeletal metastases and sadly died in September 2022. Substantial unmet need exists for effective treatments in ACC, with 75% of patients presenting with incurable disease. Developing widespread disease, SIRT offered 2 years' PFS in our patient; this was well tolerated with minimal residual liver impairment. Its use in ACC liver-limited disease warrants investigation., Significance Statement: Adrenocortical carcinoma (ACC) is a rare and aggressive tumour with limited treatments. Once metastatic disease develops, existing standard-of-care treatments offer a dismal overall survival, alongside marked toxicities. Selective internal radiation therapy (SIRT) may represent a new intervention in the treatment paradigm for liver-limited, metastatic ACC. Here, we present the case of a patient treated with multiple rounds of SIRT for relapsed, liver-limited ACC, prolonging survival by several years. Recurrent SIRT led to maintained liver function and no toxicities. Little evidence outlines its use in ACC but further study is certainly warranted to ascertain the value of SIRT, considering the limited treatment landscape that currently exists., Competing Interests: The authors declare that there is no conflict of interest that could be perceived as prejudicing the impartiality of the study reported., (© NHS Lothian.)

The prevalence of anatomical-based subtypes of feline congenital extrahepatic portosystemic shunts (EHPSS) has not been completely elucidated. The goal of this study was to use CT angiography to create an anatomical-based nomenclature system for feline congenital EHPSS. Additionally, subjective portal perfusion scores were generated to determine if intrinsic portal vein development was associated with different shunt conformations or patient age at the time of CT. The SVSTS and VIRIES list services were used to recruit cases. Data collected included patient DOB, gender, breed, weight, CT date, and reported diagnosis. Shunts were classified based upon (1) the shunt portal vessel(s) of origin, (2) the shunt systemic vessel(s) of insertion, and (3) any substantial portal vessels contributing to the shunt. Additionally, hepatic portal perfusion was subjectively scored between 1 (poor/none) and 5 (good/normal) based on the caliber of the intrahepatic PVs. A total of 264 CT scans were submitted from 29 institutions. Due to exclusion criteria, 33 (13%) were removed, leaving 231 CT scans to be included. Twenty-five different EHPSS anatomies were identified with five classifications accounting for 78% of all shunts (LGP [53%], LGC-post [11%], LCG [7%], LGC-pre [4%], and PC [4%]). Shunt origin involved the left gastric vein in 75% of the described classifications. Significant differences were identified among the five most common shunt types with respect to age at the time of CT scan (P = .002), breed (P < .001), and subjective portal perfusion score (P < .001). This refined anatomical classification system for feline EHPSS may enable improved understanding, treatment comparisons, and outcome prediction for cats with these anomalies., (© 2024 American College of Veterinary Radiology.)

Purpose: Frailty is common in critically ill patients but the timing and optimal method of frailty ascertainment, trajectory and relationship with care processes remain uncertain. We sought to elucidate the trajectory and care processes of frailty in critically ill patients as measured by the Clinical Frailty Scale (CFS) and Frailty Index (FI)., Methods: This is a multi-centre prospective cohort study enrolling patients ≥ 50 years old receiving life support > 24 h. Frailty severity was assessed with a CFS, and a FI based on the elements of a comprehensive geriatric assessment (CGA) at intensive care unit (ICU) admission, hospital discharge and 6 months. For the primary outcome of frailty prevalence, it was a priori dichotomously defined as a CFS ≥ 5 or FI ≥ 0.2. Processes of care, adverse events were collected during ICU and ward stays while outcomes were determined for ICU, hospital, and 6 months., Results: In 687 patients, whose age (mean ± standard deviation) was 68.8 ± 9.2 years, frailty prevalence was higher when measured with the FI (CFS, FI %): ICU admission (29.8, 44.8), hospital discharge (54.6, 67.9), 6 months (34.1, 42.6). Compared to ICU admission, aggregate frailty severity increased to hospital discharge but improved by 6 months; individually, CFS and FI were higher in 45.3% and 50.6% patients, respectively at 6 months. Compared to hospital discharge, 18.7% (CFS) and 20% (FI) were higher at 6 months. Mortality was higher in frail patients. Processes of care and adverse events were similar except for worse ICU/ward mobility and more frequent delirium in frail patients., Conclusions: Frailty severity was dynamic, can be measured during recovery from critical illness using the CFS and FI which were both associated with worse outcomes. Although the CFS is a global measure, a CGA FI based may have advantages of being able to measure frailty levels, identify deficits, and potential targets for intervention., (© 2024. The Author(s).)

Many steps of RNA processing occur during transcription by RNA polymerases. Co-transcriptional activities are deemed commonplace in prokaryotes, in which the lack of membrane barriers allows mixing of all gene expression steps, from transcription to translation. In the past decade, an extraordinary level of coordination between transcription and RNA processing has emerged in eukaryotes. In this Review, we discuss recent developments in our understanding of co-transcriptional gene regulation in both eukaryotes and prokaryotes, comparing methodologies and mechanisms, and highlight striking parallels in how RNA polymerases interact with the machineries that act on nascent RNA. The development of RNA sequencing and imaging techniques that detect transient transcription and RNA processing intermediates has facilitated discoveries of transcription coordination with splicing, 3'-end cleavage and dynamic RNA folding and revealed physical contacts between processing machineries and RNA polymerases. Such studies indicate that intron retention in a given nascent transcript can prevent 3'-end cleavage and cause transcriptional readthrough, which is a hallmark of eukaryotic cellular stress responses. We also discuss how coordination between nascent RNA biogenesis and transcription drives fundamental aspects of gene expression in both prokaryotes and eukaryotes., (© 2024. Springer Nature Limited.)

Background: Out-of-hospital cardiac arrest (OHCA) is a prevalent condition with high mortality and poor outcomes even in settings where extensive emergency care resources are available. Interventions to address OHCA have had limited success, with survival rates below 10% in national samples of high-income countries. In resource-limited settings, where scarcity requires careful priority setting, more data is needed to determine the optimal allocation of resources., Objective: To establish the cost-effectiveness of OHCA care and assess the affordability of interventions across income settings., Methods: The authors conducted a systematic review of economic evaluations on interventions to address OHCA. Included studies were (1) economic evaluations (beyond a simple costing exercise); and (2) assessed an intervention in the chain of survival for OHCA. Article quality was assessed using the CHEERs checklist and data summarised. Findings were reported by major themes identified by the reviewers. Based upon the results of the cost-effectiveness analyses we then conduct an analysis for the progressive realization of the OHCA chain of survival from the perspective of decision-makers facing resource constraints., Results: 468 unique articles were screened, and 46 articles were included for final data abstraction. Studies predominantly used a healthcare sector perspective, modeled for all patients experiencing non-traumatic cardiac OHCA, were based in the US, and presented results in US Dollars. No studies reported results or used model inputs from low-income settings. Progressive realization of the chain of survival could likely begin with investments in TOR protocols, professional prehospital defibrillator use, and CPR training followed by distribution of AEDs in high-density public locations. Finally, other interventions such as indiscriminate defibrillator placement or adrenaline use, would be the lowest priority for early investment., Conclusion: Our review found no high-quality evidence on the cost-effectiveness of treating OHCA in low-resource settings. Existing evidence can be utilized to develop a roadmap for the development of a cost-effective approach to OHCA care, however further economic evaluations using context-specific data are crucial to accurately inform prioritization of scarce resources within emergency care in these settings., Competing Interests: Competing interests: The authors declare that they have no competing interests

Background: The goal of antibiotic stewardship programs (ASPs) is to ensure that patients receive effective therapy while minimizing adverse events. To overcome barriers commonly faced in implementing successful ASPs, the Agency for Healthcare Research and Quality (AHRQ) established a multifaceted, nationwide Safety Program for Improving Antibiotic Use in 2018. This report summarizes the lessons learned from the implementation of this initiative based on structured interviews of personnel from participating sites., Methods: At the completion of the one-year initiative, semistructured exit interviews were conducted with site leaders at 151 of the 402 hospitals that participated. These interviews consisted of open-ended questions about the perceived effectiveness of components of the Safety Program. Qualitative analyses incorporated both deductive coding themes (based on existing literature) and an iteratively developed inductive coding framework (based on salient themes that emerged from a subset of interviews)., Results: Several components of the Safety Program were identified as effective in expanding local stewardship activities, including techniques and strategies to implement sustainable ASPs, access to Implementation Advisors to keep sites engaged, provision of local benchmarked antibiotic use data to compare to similar hospitals, and Safety Program materials such as the antibiotic time-out tool to integrate stewardship techniques into daily work flows. The biggest challenges to greater effectiveness were suboptimal frontline staff engagement and difficulty changing antibiotic prescribing culture. Some approaches used to overcome these barriers (peer-to-peer communication and education through team huddles, identifying physician champions, informal rounds to enhance collegiality and buy-in, and engagement of hospital leadership) were identified., Conclusion: Lessons learned from the Safety Program can be applied by other teams looking to promote an effective ASP at their hospital or system. The themes that emerged in this study likely also have relevance across a wide range of large-scale quality improvement initiatives., (Copyright © 2024 The Joint Commission. All rights reserved.)

Introduction: Musculoskeletal pain and opioid misuse frequently co-occur., Review of the Literature: The US Preventive Services Task Force calls for all health care providers to be trained to screen for misuse and/or opioid use disorder. The purpose of this study was to develop and implement an opioid misuse training program that could be used by physical therapists., Subjects: Thirteen practicing physical therapists were invited to participate in a curriculum development project., Methods: Using the Curriculum Framework, a collaborative learning approach was used to develop an opioid misuse training program and training manual for physical therapists. Four training sessions were provided virtually every 2 weeks. Topics included an introduction to the opioid crisis, screening, assessing, and communicating with patients and with the health care team about opioid misuse. Each didactic session was followed by a participant feedback session where participants provided recommendations on improving the training content and their impressions on the barriers and facilitators to incorporating the training into practice. A companion training manual was created and sent to participants for comment. Participants were asked over email to describe whether and how they incorporated training materials into clinical practice during the training curriculum., Results: All participants attended sessions 1-3. Twelve (92.3%) attended the fourth session. Based on the participants' feedback, training sessions were edited, and a companion training manual was finalized and distributed to each participant. After the fourth session, 9 participants (69.2%) reported using what they learned in the training. During the participant feedback sessions, participants regarded the training as important. Some participants expressed barriers to discussing opioids with patients and concerns about whether the training was within physical therapists' scope of practice., Discussion and Conclusion: An iteratively developed training program for physical therapists to address opioid misuse was acceptable, feasible, and provided immediate practice change by most participants., (Copyright © 2024 Academy of Physical Therapy Education, APTA.)

Accurately reconstructing the reticulate histories of polyploids remains a central challenge for understanding plant evolution. Although phylogenetic networks can provide insights into relationships among polyploid lineages, inferring networks may be hindered by the complexities of homology determination in polyploid taxa. We use simulations to show that phasing alleles from allopolyploid individuals can improve phylogenetic network inference under the multispecies coalescent by obtaining the true network with fewer loci compared to haplotype consensus sequences or sequences with heterozygous bases represented as ambiguity codes. Phased allelic data can also improve divergence time estimates for networks, which is helpful for evaluating allopolyploid speciation hypotheses and proposing mechanisms of speciation. To achieve these outcomes in empirical data, we present a novel pipeline that leverages a recently developed phasing algorithm to reliably phase alleles from polyploids. This pipeline is especially appropriate for target enrichment data, where depth of coverage is typically high enough to phase entire loci. We provide an empirical example in the North American Dryopteris fern complex that demonstrates insights from phased data as well as the challenges of network inference. We establish that our pipeline (PATÉ: Phased Alleles from Target Enrichment data) is capable of recovering a high proportion of phased loci from both diploids and polyploids. These data may improve network estimates compared to using haplotype consensus assemblies by accurately inferring the direction of gene flow, but statistical non-identifiability of phylogenetic networks poses a barrier to inferring the evolutionary history of reticulate complexes., (© The Author(s) 2024. Published by Oxford University Press, on behalf of the Society of Systematic Biologists. All rights reserved. For commercial re-use, please contact reprints@oup.com for reprints and translation rights for reprints. All other permissions can be obtained through our RightsLink service via the Permissions link on the article page on our site—for further information please contact journals.permissions@oup.com.)

High angular resolution imaging is an increasingly important capability in contemporary astrophysics. Of particular relevance to emerging fields such as the characterization of exoplanetary systems, imaging at the required spatial scales and contrast levels results in forbidding challenges in the correction of atmospheric phase errors, which in turn drives demanding requirements for precise wavefront sensing. Asgard is the next-generation instrument suite at the European Southern Observatory's Very Large Telescope Interferometer (VLTI), targeting advances in sensitivity, spectral resolution, and nulling interferometry. In this paper, we describe the requirements and designs of three core modules: Heimdallr, a beam combiner for fringe tracking, low order wavefront correction, and visibility science; Baldr, a Zernike wavefront sensor to correct high order atmospheric aberrations; and Solarstein, an alignment and calibration unit. In addition, we draw generalizable insights for designing such system and discuss integration plans.

Anticancer nucleosides are effective against solid tumors and hematologic malignancies, but typically are prone to nucleoside metabolism resistance mechanisms. Using a nucleoside-specific multiplexed high-throughput screening approach, we discovered 4'-ethynyl-2'-deoxycytidine (EdC) as a third-generation anticancer nucleoside prodrug with preferential activity against diffuse large B-cell lymphoma (DLBCL) and acute lymphoblastic leukemia (ALL). EdC requires deoxycytidine kinase (DCK) phosphorylation for its activity and induces replication fork arrest and accumulation of cells in S-phase, indicating it acts as a chain terminator. A 2.1Å cocrystal structure of DCK bound to EdC and UDP reveals how the rigid 4'-alkyne of EdC fits within the active site of DCK. Remarkably, EdC was resistant to cytidine deamination and SAMHD1 metabolism mechanisms and exhibited higher potency against ALL compared with FDA-approved nelarabine. Finally, EdC was highly effective against DLBCL tumors and B-ALL in vivo. These data characterize EdC as a preclinical nucleoside prodrug candidate for DLBCL and ALL., (©2023 American Association for Cancer Research.)

Since the 1940s, patch tests in healthy volunteers (Human Predictive Patch Tests, HPPTs) have been used to identify chemicals that cause skin sensitization in humans. Recently, we reported the results of a major curation effort to support the development of OECD Guideline 497 on Defined Approaches (DAs) for skin sensitization (OECD in Guideline No. 497: Defined Approaches on Skin Sensitisation, 2021a. https://doi.org/10.1787/b92879a4-en ). In the course of this work, we compiled and published a database of 2277 HPPT results for 1366 unique test substances (Strickland et al. in Arch Toxicol 97:2825-2837, 2023. https://doi.org/10.1007/s00204-023-03530-3 ). Here we report a detailed analysis of the value of HPPT data for classification of chemicals as skin sensitizers under the United Nations' Globally Harmonized System of Classification and Labelling of Chemicals (GHS). As a result, we propose the dose per skin area (DSA) used for classification by the GHS to be replaced by or complemented with a dose descriptor that may better reflect sensitization incidence [e.g., the DSA causing induction of sensitization in one individual (DSA1+) or the DSA leading to an incidence of induction in 5% of the tested individuals (DSA05)]. We also propose standardized concepts and workflows for assessing individual HPPT results, for integrating multiple HPPT results and for using them in concert with Local Lymph Node Assay (LLNA) data in a weight of evidence (WoE) assessment. Overall, our findings show that HPPT results are often not sufficient for deriving unambiguous classifications on their own. However, where they are, the resulting classifications are reliable and reproducible and can be integrated well with those from other skin sensitization data, such as the LLNA., (© 2024. This is a U.S. Government work and not under copyright protection in the US; foreign copyright protection may apply.)

Purpose: To use the hepatocyte-specific gadolinium-based contrast agent gadoxetate combined with hyperpolarized (HP) [1- 13 C]pyruvate MRI to selectively suppress metabolic signals from normal hepatocytes while preserving the signals arising from tumors., Methods: Simulations were performed to determine the expected changes in HP 13 C MR signal in liver and tumor under the influence of gadoxetate. CC531 colon cancer cells were implanted into the livers of five Wag/Rij rats. Liver and tumor metabolism were imaged at 3 T using HP [1- 13 C] pyruvate chemical shift imaging before and 15 min after injection of gadoxetate. Area under the curve for pyruvate and lactate were measured from voxels containing at least 75% of normal-appearing liver or tumor., Results: Numerical simulations predicted a 36% decrease in lactate-to-pyruvate (L/P) ratio in liver and 16% decrease in tumor. In vivo, baseline L/P ratio was 0.44 ± 0.25 in tumors versus 0.21 ± 0.08 in liver (p = 0.09). Following administration of gadoxetate, mean L/P ratio decreased by an average of 0.11 ± 0.06 (p < 0.01) in normal-appearing liver. In tumors, mean L/P ratio post-gadoxetate did not show a statistically significant change from baseline. Compared to baseline levels, the relative decrease in L/P ratio was significantly greater in liver than in tumors (-0.52 ± 0.16 vs. -0.19 ± 0.25, p < 0.05)., Conclusions: The intracellular hepatobiliary contrast agent showed a greater effect suppressing HP 13 C MRI metabolic signals (through T 1 shortening) in normal-appearing liver when compared to tumors. The combined use of HP MRI with selective gadolinium contrast agents may allow more selective imaging in HP 13 C MRI., (© 2024 The Authors. Magnetic Resonance in Medicine published by Wiley Periodicals LLC on behalf of International Society for Magnetic Resonance in Medicine.)

Objective: To conduct feasibility and cost analysis of portable MRI implementation in a remote setting where MRI access is otherwise unavailable., Methods: Portable MRI (ultra-low field, 0.064T) was installed in Weeneebayko General Hospital, Moose Factory, Ontario. Adult patients, presenting with any indication for neuroimaging, were eligible for study inclusion. Scanning period was from November 14, 2021, to September 6, 2022. Images were sent via a secure PACS network for Neuroradiologist interpretation, available 24/7. Clinical indications, image quality, and report turnaround time were recorded. A cost analysis was conducted from a healthcare system's perspective in 2022 Canadian dollars, comparing cost of portable MRI implementation to transporting patients to a center with fixed MRI., Results: Portable MRI was successfully implemented in a remote Canadian location. Twenty-five patients received a portable MRI scan. All studies were of diagnostic quality. No clinically significant pathologies were identified on any of the studies. However, based on clinical presentation and limitations of portable MRI resolution, it is estimated that 11 (44%) of patients would require transfer to a center with fixed MRI for further imaging workup. Cost savings were $854,841 based on 50 patients receiving portable MRI over 1 year. Five-year budget impact analysis showed nearly $8 million dollars saved., Conclusions: Portable MRI implementation in a remote setting is feasible, with significant cost savings compared to fixed MRI. This study may serve as a model to democratize MRI access, offer timely care and improved triaging in remote areas where conventional MRI is unavailable.

In this study, we demonstrate the safety and utility of CRISPR-Cas9 gene editing technology for in vivo editing of proviral DNA in ART-treated, virally controlled simian immunodeficiency virus (SIV) infected rhesus macaques, an established model for HIV infection. EBT-001 is an AAV9-based vector delivering SaCas9 and dual guide RNAs designed to target multiple regions of the SIV genome: the viral LTRs, and the Gag gene. The results presented here demonstrate that a single IV inoculation of EBT-001 at each of 3 dose levels (1.4 × 10 12 , 1.4 × 10 13 and 1.4 × 10 14 genome copies/kg) resulted in broad and functional biodistribution of AAV9-EBT-001 to known tissue reservoirs of SIV. No off-target effects or abnormal pathology were observed, and animals returned to their normal body weight after receiving EBT-001. Importantly, the macaques that received the 2 highest doses of EBT-001 showed improved absolute lymphocyte counts as compared to antiretroviral-treated controls. Taken together, these results demonstrate safety, biodistribution, and in vivo proviral DNA editing following IV administration of EBT-001, supporting the further development of CRISPR-based gene editing as a potential therapeutic approach for HIV in humans., (© 2023. The Author(s).)

Introduction: In toxicology, steps are being taken towards more mechanism-focused and human relevant approaches to risk assessment, requiring new approaches and methods. Additionally, there is increasing emphasis by regulators on risk assessment of immunotoxicity. Methods: Here we present data from a peripheral blood mononuclear cell (PBMC) system whereby a varied set of stimuli, including those against the TCR and Toll-like receptors, enable readouts of cytokine and prostaglandin E2 (PGE2) production with monocyte, T cell and B cell viability, proliferation, and associated activation markers. In addition to results on the impact of the stimuli used, initial profiling data for a case study chemical, curcumin, is presented, illustrating how the system can be used to generate information on the impact of exogenous materials on three major constituent immune cell subsets for use in risk assessment and to direct follow-on studies. Results: The different stimuli drove distinct responses, not only in relation to the "quantity" of the response but also the "quality". Curcumin had a limited impact on the B cell parameters measured, with the stimuli used, and it was noted that in contrast to T cells where there was either no impact or a reduction in viability and proliferation with increasing concentration, for B cells there was a small but significant increase in both measurements at curcumin concentrations below 20 µM. Similarly, whilst expression of activation markers by T cells was reduced by the highest concentration of curcumin, they were increased in B cells. Curcumin only impacted the viability of stimulated monocytes at the highest concentration and had differential impact on different activation markers. Levels of all cytokines and PGE2 were reduced at higher concentrations. Discussion: Although the platform has certain limitations, it nevertheless enables assessment of healthy baseline monocyte, T-, and B-cell responses, and scrutiny of the impact of different stimuli to detect potential immune suppression or enhancement from exogenous materials. In the case of curcumin, a pattern of responses indicative of immune suppressive / anti-inflammatory effects was detected. It is an accessible, highly modifiable system that can be used to screen materials and guide further studies, providing a holistic, integrated picture of effects., Competing Interests: Authors SC, RR, and DS were employed by the Safety and Environmental Assurance Centre (SEAC), Unilever, Colworth Science Park. Authors FS, LH, NB, OQ, and JG were employed by Celentyx Ltd., (Copyright © 2024 Cochrane, Rajagopal, Sheffield, Stewart, Hathaway, Barnes, Qureshi and Gordon.)

Pyrolysis-based waste-to-bioenergy development has the potential to resolve some of the major challenges facing rural communities in India such as poor electrification, household air pollution, and farmland degradation and contamination. Existing understanding and analysis of the economic feasibility and environmental impact of bioenergy deployment in rural areas is limited by parameter uncertainties, and relevant business model innovation following economic evaluation is even scarcer. This paper uses findings from a new field survey of 1200 rural households to estimate the economic feasibility and environmental impact of a pyrolysis-based bioenergy trigeneration development that was designed to tackle these challenges. Based on the survey results, probability distributions were constructed and used to supply input parameters for cost-benefit analysis and life cycle assessment. Monte Carlo simulation was applied to characterise the uncertainties of economic feasibility and environmental impact accounting. It was shown that the global warming potential of the development was 350 kg of CO 2 -eq per capita per annum. Also, the survey identified a significant mismatch between feedstock prices considered in the literature and prices asked for by the surveyed villagers. The results of the cost-benefit analysis and life cycle assessment were then applied to propose two novel business models inspired by the Business Model Canvas, which had the potential to achieve up to 90 % economic profitability and result in a benefit-cost ratio of 1.35-1.75. This is the first study achieving combined environmental and economic analysis and business model innovation for rural bioenergy production in developing countries., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Authors. Published by Elsevier B.V. All rights reserved.)

Objective: Congenital anomalies of the atlanto-occipital articulation may be present in patients with Chiari malformation type I (CM-I). However, it is unclear how these anomalies affect the biomechanical stability of the craniovertebral junction (CVJ) and whether they are associated with an increased incidence of occipitocervical fusion (OCF) following posterior fossa decompression (PFD). The objective of this study was to determine the prevalence of condylar hypoplasia and atlas anomalies in children with CM-I and syringomyelia. The authors also investigated the predictive contribution of these anomalies to the occurrence of OCF following PFD (PFD+OCF)., Methods: The authors analyzed the prevalence of condylar hypoplasia and atlas arch anomalies for patients in the Park-Reeves Syringomyelia Research Consortium database who underwent PFD+OCF. Condylar hypoplasia was defined by an atlanto-occipital joint axis angle (AOJAA) ≥ 130°. Atlas assimilation and arch anomalies were identified on presurgical radiographic imaging. This PFD+OCF cohort was compared with a control cohort of patients who underwent PFD alone. The control group was matched to the PFD+OCF cohort according to age, sex, and duration of symptoms at a 2:1 ratio., Results: Clinical features and radiographic atlanto-occipital joint parameters were compared between 19 patients in the PFD+OCF cohort and 38 patients in the PFD-only cohort. Demographic data were not significantly different between cohorts (p > 0.05). The mean AOJAA was significantly higher in the PFD+OCF group than in the PFD group (144° ± 12° vs 127° ± 6°, p < 0.0001). In the PFD+OCF group, atlas assimilation and atlas arch anomalies were identified in 10 (53%) and 5 (26%) patients, respectively. These anomalies were absent (n = 0) in the PFD group (p < 0.001). Multivariate regression analysis identified the following 3 CVJ radiographic variables that were predictive of OCF occurrence after PFD: AOJAA ≥ 130° (p = 0.01), clivoaxial angle < 125° (p = 0.02), and occipital condyle-C2 sagittal vertical alignment (C-C2SVA) ≥ 5 mm (p = 0.01). A predictive model based on these 3 factors accurately predicted OCF following PFD (C-statistic 0.95)., Conclusions: The authors' results indicate that the occipital condyle-atlas joint complex might affect the biomechanical integrity of the CVJ in children with CM-I and syringomyelia. They describe the role of the AOJAA metric as an independent predictive factor for occurrence of OCF following PFD. Preoperative identification of these skeletal abnormalities may be used to guide surgical planning and treatment of patients with complex CM-I and coexistent osseous pathology.

The DNA damage response (DDR) protein DNA Polymerase θ (Polθ) is synthetic lethal with homologous recombination (HR) factors and is therefore a promising drug target in BRCA1/2 mutant cancers. We discover an allosteric Polθ inhibitor (Polθi) class with 4-6 nM IC 50 that selectively kills HR-deficient cells and acts synergistically with PARP inhibitors (PARPi) in multiple genetic backgrounds. X-ray crystallography and biochemistry reveal that Polθi selectively inhibits Polθ polymerase (Polθ-pol) in the closed conformation on B-form DNA/DNA via an induced fit mechanism. In contrast, Polθi fails to inhibit Polθ-pol catalytic activity on A-form DNA/RNA in which the enzyme binds in the open configuration. Remarkably, Polθi binding to the Polθ-pol:DNA/DNA closed complex traps the polymerase on DNA for more than forty minutes which elucidates the inhibitory mechanism of action. These data reveal a unique small-molecule DNA polymerase:DNA trapping mechanism that induces synthetic lethality in HR-deficient cells and potentiates the activity of PARPi., (© 2024. The Author(s).)

Study Question: What are parents' perceptions of their relationships with and the psychosocial adjustments of their children who are born via embryo donation?, Summary Answer: Families created through embryo donation have well-adjusted parent-child relationships and reassuring child psychosocial outcomes., What Is Known Already: Embryo donation is an effective and growing form of third-party reproduction, but there is limited research in this field. Prior studies suggest that families created through gamete donation function well regarding parent-child relationship quality and child behavioral and socioemotional adjustment., Study Design, Size, Duration: This is a cross-sectional survey study with 187 total participants., Participants/materials, Setting, Methods: Parents of children born via embryo donation were recruited nationally by contacting all embryo donation programs registered with the Society for Assisted Reproductive Technology Clinic Outcome Reporting System (SART CORS) as well as medically directed embryo donation or 'embryo adoption' centers. Participants completed three online Qualtrics questionnaires. The first was a survey including 33 questions on demographics, the procurement process, and self-reported obstetric outcomes. Participants also completed two standardized measures assessing children's behavior and parents' adjustment to parenthood: the Strengths and Difficulties Questionnaire (SDQ) and the Parental Acceptance-Rejection Questionnaire (PARQ). Scoring of the SDQ and PARQ was totaled and compared to standardized values (SDQ) or previously published results on other forms of gamete donation (PARQ), such as oocyte donation and sperm donation., Main Results and the Role of Chance: On the SDQ (n = 46), the average total difficulties scores by age were: 8.2 ± 0.98 for ages 2-4, 7.6 ± 0.93 for ages 5-10, and 3.5 ± 0.77 for ages 11-17; this is compared to the normal reported range of 0-13, which indicates that clinically significant psychosocial problems are unlikely. Across all ages and individual categories (emotional symptoms, conduct problem, hyperactivity, peer problem, prosocial), scores on the SDQ were within the normal ranges. The average PARQ score (n = 70) for all respondents was 27.5 ± 1.18 (range: 24-96), suggesting perceived parental acceptance., Limitations, Reasons for Caution: Because this study was cross-sectional, it could not capture familial relationships over time. This survey-based study design allows for potential selection bias (parents of well-adjusted children may be more likely to participate). Additionally, the overall sample size is relatively small; however, it remains one of the largest published to date. Another significant limitation to this study is the lack of generalizability: most participants were recruited from private, faith-based, embryo donation programs who are demographically similar., Wider Implications of the Findings: Though embryo donation is an established form of third-party reproduction, it is significantly less robustly studied compared to other forms of gamete donation (oocyte or sperm donation). This study provides a larger data set with a more expanded age range of children compared to the limited number of previously published studies. Furthermore, these findings indicate a high parental disclosure rate with respect to the use of embryo donation which contrasts previous findings., Study Funding/competing Interest(s): No external funding source was utilized for the completion of this study. No conflicts are disclosed., Trial Registration Number: N/A., (© The Author(s) 2024. Published by Oxford University Press on behalf of European Society of Human Reproduction and Embryology. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

Purpose: We evaluated the properties and activity of AZD9574, a blood-brain barrier (BBB) penetrant selective inhibitor of PARP1, and assessed its efficacy and safety alone and in combination with temozolomide (TMZ) in preclinical models., Experimental Design: AZD9574 was interrogated in vitro for selectivity, PARylation inhibition, PARP-DNA trapping, the ability to cross the BBB, and the potential to inhibit cancer cell proliferation. In vivo efficacy was determined using subcutaneous as well as intracranial mouse xenograft models. Mouse, rat, and monkey were used to assess AZD9574 BBB penetration and rat models were used to evaluate potential hematotoxicity for AZD9574 monotherapy and the TMZ combination., Results: AZD9574 demonstrated PARP1-selectivity in fluorescence anisotropy, PARylation, and PARP-DNA trapping assays and in vivo experiments demonstrated BBB penetration. AZD9574 showed potent single agent efficacy in preclinical models with homologous recombination repair deficiency in vitro and in vivo. In an O6-methylguanine-DNA methyltransferase (MGMT)-methylated orthotopic glioma model, AZD9574 in combination with TMZ was superior in extending the survival of tumor-bearing mice compared with TMZ alone., Conclusions: The combination of three key features-PARP1 selectivity, PARP1 trapping profile, and high central nervous system penetration in a single molecule-supports the development of AZD9574 as the best-in-class PARP inhibitor for the treatment of primary and secondary brain tumors. As documented by in vitro and in vivo studies, AZD9574 shows robust anticancer efficacy as a single agent as well as in combination with TMZ. AZD9574 is currently in a phase I trial (NCT05417594). See related commentary by Lynce and Lin, p. 1217., (©2023 American Association for Cancer Research.)

Controlling malaria requires new drugs against Plasmodium falciparum . The P. falciparum cGMP-dependent protein kinase (PfPKG) is a validated target whose inhibitors could block multiple steps of the parasite's life cycle. We defined the structure-activity relationship (SAR) of a pyrrole series for PfPKG inhibition. Key pharmacophores were modified to enable full exploration of chemical diversity and to gain knowledge about an ideal core scaffold. In vitro potency against recombinant PfPKG and human PKG were used to determine compound selectivity for the parasite enzyme. P. berghei sporozoites and P. falciparum asexual blood stages were used to assay multistage antiparasitic activity. Cellular specificity of compounds was evaluated using transgenic parasites expressing PfPKG carrying a substituted "gatekeeper" residue. The structure of PfPKG bound to an inhibitor was solved, and modeling using this structure together with computational tools was utilized to understand SAR and establish a rational strategy for subsequent lead optimization.