Search

IMPORTANCE: Individuals who are incarcerated represent a vulnerable group due to concerns about their ability to provide voluntary and informed consent, and there are considerable legal protections regarding their participation in medical research. Little is known about the quality of surgical care received by this population. OBJECTIVE: To evaluate perioperative surgical care provided to patients who are incarcerated within the Texas Department of Criminal Justice (TDCJ) and compare their outcomes with that of the general nonincarcerated population. DESIGN, SETTING, AND PARTICIPANTS: This cohort study analyzed data from patients who were incarcerated within the TDCJ and underwent general or vascular surgery at the University of Texas Medical Branch (UTMB) from 2012 to 2021. Case-specific outcomes for a subset of these patients and for patients in the general academic medical center population were obtained from the American College of Surgeons National Quality Improvement Program (ACS-NSQIP) and compared. Additional quality metrics (mortality index, length of stay index, and excess hospital days) from the Vizient Clinical Data Base were analyzed for patients in the incarcerated and nonincarcerated groups who underwent surgery at UTMB in 2020 and 2021 to provide additional recent data. Patient-specific demographics, including age, sex, and comorbidities were not available for analysis within this data set. MAIN OUTCOME AND MEASURES: Perioperative outcomes (30-day morbidity, mortality, and readmission rates) were compared between the incarcerated and nonincarcerated groups using the Fisher exact test. RESULTS: The sample included data from 6675 patients who were incarcerated and underwent general or vascular surgery at UTMB from 2012 to 2021. The ACS-NSQIP included data (2012-2021) for 2304 patients who were incarcerated and 602 patients who were not and showed that outcomes were comparable between the TDCJ population and that of the general population treated at the academic medical center with regard to 30-day readmission (6.60% vs 5.65%) and mortality (0.91% vs 1.16%). However, 30-day morbidity was significantly higher in the TDCJ population (8.25% vs 5.48%, P = .01). The 2020 and 2021 data from the Vizient Clinical Data Base included 629 patients who were incarcerated and 2614 who were not and showed that the incarcerated and nonincarcerated populations did not differ with regard to 30-day readmission (12.52% vs 11.30%) or morbidity (1.91% vs 2.60%). Although the unadjusted mortality rate was significantly lower in the TDCJ population (1.27% vs 2.68%, P = .04), mortality indexes, which account for case mix index, were similar between the 2 populations (1.17 vs 1.12). CONCLUSIONS AND RELEVANCE: Findings of this cohort study suggest that patients who are incarcerated have equivalent rates of mortality and readmission compared with a general academic medical center population. Future studies that focus on elucidating the potential factors associated with perioperative morbidity and exploring long-term surgical outcomes in the incarcerated population are warranted.

A massacre of Aztec leaders prompted a revolt in Tenochtitlán (depicted at bottom), forcing Cortés into a costly withdrawal on June 30, 1520, recorded by the Spanish as La Noche Triste ("The Night of Sorrows"). Features For the sick, half-starved inhabitants of Tenochtitlán, island capital of the beleaguered Aztec empire, the new year of 1521 offered only severe hardship and continued bloodshed. On November 8, with 2,000 Tlaxcalan warriors, porters, guides and cooks added to the Spanish ranks (the Totonacs had returned home), Cortés boldly marched into Tenochtitlán, where Montezuma extended the Spaniards a diplomatic if wary welcome. Hernán Cortés Charles V Xicotencatl the Elder Montezuma II Despite the Spaniards' advantages in arms and armor, Cortés small landing force was no match for superior Aztec forces. [Extracted from the article]

Type 2 diabetes mellitus (T2D), a major cause of worldwide morbidity and mortality, is characterized by dysfunction of insulin-producing pancreatic islet β cells1,2. T2D genome-wide association studies (GWAS) have identified hundreds of signals in non-coding and β cell regulatory genomic regions, but deciphering their biological mechanisms remains challenging3–5. Here, to identify early disease-driving events, we performed traditional and multiplexed pancreatic tissue imaging, sorted-islet cell transcriptomics and islet functional analysis of early-stage T2D and control donors. By integrating diverse modalities, we show that early-stage T2D is characterized by β cell-intrinsic defects that can be proportioned into gene regulatory modules with enrichment in signals of genetic risk. After identifying the β cell hub gene and transcription factor RFX6within one such module, we demonstrated multiple layers of genetic risk that converge on an RFX6-mediated network to reduce insulin secretion by β cells. RFX6perturbation in primary human islet cells alters β cell chromatin architecture at regions enriched for T2D GWAS signals, and population-scale genetic analyses causally link genetically predicted reduced RFX6expression with increased T2D risk. Understanding the molecular mechanisms of complex, systemic diseases necessitates integration of signals from multiple molecules, cells, organs and individuals, and thus we anticipate that this approach will be a useful template to identify and validate key regulatory networks and master hub genes for other diseases or traits using GWAS data.

IMPORTANCE: There remains an unmet need to improve clinical outcomes in patients with recurrent or metastatic squamous cell carcinoma of the head and neck (R/M SCCHN). OBJECTIVE: To evaluate clinical benefit of first-line nivolumab plus ipilimumab vs nivolumab alone in patients with R/M SCCHN. DESIGN, SETTING, AND PARTICIPANTS: The CheckMate 714, double-blind, phase 2 randomized clinical trial was conducted at 83 sites in 21 countries between October 20, 2016, and January 23, 2019. Eligible participants were aged 18 years or older and had platinum-refractory or platinum-eligible R/M SCCHN and no prior systemic therapy for R/M disease. Data were analyzed from October 20, 2016 (first patient, first visit), to March 8, 2019 (primary database lock), and April 6, 2020 (overall survival database lock). INTERVENTIONS: Patients were randomized 2:1 to receive nivolumab (3 mg/kg intravenously [IV] every 2 weeks) plus ipilimumab (1 mg/kg IV every 6 weeks) or nivolumab (3 mg/kg IV every 2 weeks) plus placebo for up to 2 years or until disease progression, unacceptable toxic effects, or consent withdrawal. MAIN OUTCOMES AND MEASURES: The primary end points were objective response rate (ORR) and duration of response between treatment arms by blinded independent central review in the population with platinum-refractory R/M SCCHN. Exploratory end points included safety. RESULTS: Of 425 included patients, 241 (56.7%; median age, 59 [range, 24-82] years; 194 males [80.5%]) had platinum-refractory disease (nivolumab plus ipilimumab, n = 159; nivolumab, n = 82) and 184 (43.3%; median age, 62 [range, 33-88] years; 152 males [82.6%]) had platinum-eligible disease (nivolumab plus ipilimumab, n = 123; nivolumab, n = 61). At primary database lock, the ORR in the population with platinum-refractory disease was 13.2% (95% CI, 8.4%-19.5%) with nivolumab plus ipilimumab vs 18.3% (95% CI, 10.6%-28.4%) with nivolumab (odds ratio [OR], 0.68; 95.5% CI, 0.33-1.43; P = .29). Median duration of response for nivolumab plus ipilimumab was not reached (NR) (95% CI, 11.0 months to NR) vs 11.1 months (95% CI, 4.1 months to NR) for nivolumab. In the population with platinum-eligible disease, the ORR was 20.3% (95% CI, 13.6%-28.5%) with nivolumab plus ipilimumab vs 29.5% (95% CI, 18.5%-42.6%) with nivolumab. The rates of grade 3 or 4 treatment-related adverse events with nivolumab plus ipilimumab vs nivolumab were 15.8% (25 of 158) vs 14.6% (12 of 82) in the population with platinum-refractory disease and 24.6% (30 of 122) vs 13.1% (8 of 61) in the population with platinum-eligible disease. CONCLUSIONS AND RELEVANCE: The CheckMate 714 randomized clinical trial did not meet its primary end point of ORR benefit with first-line nivolumab plus ipilimumab vs nivolumab alone in platinum-refractory R/M SCCHN. Nivolumab plus ipilimumab was associated with an acceptable safety profile. Research to identify patient subpopulations in R/M SCCHN that would benefit from nivolumab plus ipilimumab over nivolumab monotherapy is warranted. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT02823574

Repetitive physical exercise induces physiological adaptations in skeletal muscle that improves exercise performance and is effective for the prevention and treatment of several diseases. Genetic evidence indicates that the orphan nuclear receptors estrogen receptor-related receptors (ERRs) play an important role in skeletal muscle exercise capacity. Three ERR subtypes exist (ERRα, β, and γ), and although ERRβ/γ agonists have been designed, there have been significant difficulties in designing compounds with ERRα agonist activity. Additionally, there are limited synthetic agonists that can be used to target ERRs in vivo. Here, we report the identification of a synthetic ERR pan agonist, SLU-PP-332, that targets all three ERRs but has the highest potency for ERRα. Additionally, SLU-PP-332 has sufficient pharmacokinetic properties to be used as an in vivochemical tool. SLU-PP-332 increases mitochondrial function and cellular respiration in a skeletal muscle cell line. When administered to mice, SLU-PP-332 increased the type IIa oxidative skeletal muscle fibers and enhanced exercise endurance. We also observed that SLU-PP-332 induced an ERRα-specific acute aerobic exercise genetic program, and the ERRα activation was critical for enhancing exercise endurance in mice. These data indicate the feasibility of targeting ERRα for the development of compounds that act as exercise mimetics that may be effective in the treatment of numerous metabolic disorders and to improve muscle function in the aging.

The NR superfamily comprises 48 transcription factors in humans that control a plethora of gene network programs involved in a wide range of physiologic processes. This review will summarize and discuss recent progress in NR biology and drug development derived from integrating various approaches, including biophysical techniques, structural studies, and translational investigation. We also highlight how defective NR signaling results in various diseases and disorders and how NRs can be targeted for therapeutic intervention via modulation via binding to synthetic lipophilic ligands. Furthermore, we also review recent studies that improved our understanding of NR structure and signaling.Significance StatementNuclear receptors (NRs) are ligand-regulated transcription factors that are critical regulators of myriad physiological processes. NRs serve as receptors for an array of drugs, and in this review, we provide an update on recent research into the roles of these drug targets.

In keeping with the medieval tradition of warrior kings leading their armies into battle, King Edward I of England spent most of his long and turbulent reign (1272-1307) in almost constant campaigning, be it in Wales, Scotland, continental Europe or the Holy Land. Having driven off the Scottish cavalry, ridden down Wallace's archers and riddled his pikemen with arrows, Edward brought his entire army to bear and prevailed. Edward's high-handed efforts to strip Scotland of its national identity provoked further unrest Longshanks' "9/11" fell on Sept. 11, 1297, when Scottish pikemen defeated an English army at a bridge across the River Forth in Stirling, Scotland. Edward's smile on the face of a circa 1280 English coin belies the ruthless nature for which "Longshanks" became known. [Extracted from the article]

Heavy alcohol use, including binge drinking, is associated with high morbidity and mortality among men who have sex with men (MSM). Self‐reported alcohol measures may lead to inaccurate estimates due to recall and social desirability biases. Objective alcohol biomarkers like phosphatidylethanol (PEth) can be used to corroborate self‐report and could help to inform treatment approaches and research strategies for alcohol using MSM. From 2015 to 2020, alcohol using MSM ≥18 years were enrolled in a randomized controlled trial evaluating the efficacy of naltrexone in reducing binge drinking. Using this trial's baseline data, we applied multivariable logistic regression to identify the correlates of high PEth levels (i.e., ≥87 ng/ml) and concordance between PEth levels and self‐reported heavy drinking. Of 118 MSM, 64% had PEth levels ≥87 ng/ml and 72% had PEth levels that were concordant with self‐reported heavy alcohol use. Factors significantly associated in separate models with elevated PEth levels were income ≥$60,000 (adjusted odds ratio [aOR] = 4.09; 95% CI = 1.13 to 14.82), being employed (aOR = 4.04; 95% CI = 1.45 to 11.32), episodic cannabis use (aOR = 4.63; 95% CI = 1.27 to 16.92), and any alcohol/substance use prior to or during anal intercourse (aOR = 2.52; 95% CI = 1.08 to 5.90). Living with HIV was associated with significantly lower odds of elevated PEth levels (aOR = 0.23; 95% CI = 0.09 to 0.61). Factors associated with significantly higher concordance between PEth levels and self‐reported heavy alcohol use included at least weekly use of poppers (aOR = 6.41; 95% CI = 1.27 to 32.28) and polysubstance use (aOR = 2.53; 95% CI = 1.02 to 6.27). Living with HIV was associated with lower odds of concordance (aOR = 0.36; 95% CI = 0.14 to 0.97). PEth may enhance the detection of heavy drinking among MSM, including the identification of subpopulations that may benefit from targeted alcohol reduction interventions. However, PEth values for MSM living with HIV showed modest concordance with self‐reported alcohol use and may need to be supplemented with additional biomarkers or evaluated against a different cutoff. Binge drinking contributes significantly to morbidity among men who have sex with men (MSM). Phosphatidylethanol (PEth) is a promising biomarker to objectively identify drinking thresholds. Among binge‐drinking MSM, high PEth levels (≥87 ng/ml) were associated with high income, marijuana use, being employed, alcohol/substance use before sex, and living without HIV. People living with HIV (PLWH) had lower odds of concordant self‐report and PEth levels. Our findings support PEth as a reliable tool to identify heavy drinking and corroborate evidence of reduced PEth sensitivity for PLWH.

Biliary leaks are challenging complications associated with an array of surgical and percutaneous interventions, and effective management by a multidisciplinary team includes advanced treatments to limit morbidity and mortality.

This review is a summary of the most up-to-date knowledge regarding assessment of atmospheric deposition of reactive nitrogen (Nr) pollutants across complex terrain in the UK. Progress in the understanding of the mechanisms and quantification of Nrdeposition in areas of complex topography is slow, as no concerted attempts to measure the components of Nrin complex terrain have been made in the last decade. This is likely due to the inherent complexity of the atmospheric processes and chemical interactions which contribute to deposition in these areas. More than 300 studies have been reviewed, and we have consulted with a panel of international experts which we assembled for that purpose. We report here on key findings and knowledge gaps identified regarding measurement and modelling techniques used to quantify deposition of Nracross complex terrain in the UK, which depending on definition, may represent up to 60% of land coverage across Great Britain. The large body of peer reviewed papers, reports and other items reviewed in this study has highlighted both the strengths and weaknesses in the tools available to scientists, regulators and policy makers. This review highlights that there is no coherent global research effort to constrain the uncertainties in Nrdeposition over complex terrain, despite the clearly identified risk of N deposition to ecosystems and water quality. All evidence identified that enhanced Nrdeposition across complex terrain occurs, and magnitude of the enhancement is not known; however, there are major uncertainties particularly in the differences between modelled and measured wet deposition in complex terrain and representing accurate surface interactions in models. Using simplified estimates for Nrdeposition, based on current understanding of current measurement and model approaches, an enhancement across UK complex terrain in the range of a factor of 1.4–2.5 (i.e.40–150% larger than current estimates) is likely over complex upland terrain. If at the upper limits of this, then significantly more ecosystems in the UK would be at a direct risk of degradation, and the potential for long-term non-remediable water quality issues increased.

This review focuses on the human pancreatic islet—including its structure, cell composition, development, function, and dysfunction. After providing a historical timeline of key discoveries about human islets over the past century, we describe new research approaches and technologies that are being used to study human islets and how these are providing insight into human islet physiology and pathophysiology. We also describe changes or adaptations in human islets in response to physiologic challenges such as pregnancy, aging, and insulin resistance and discuss islet changes in human diabetes of many forms. We outline current and future interventions being developed to protect, restore, or replace human islets. The review also highlights unresolved questions about human islets and proposes areas where additional research on human islets is needed.Graphical Abstract

Junipers (Juniperusspp.) are woody invasive plants that have caused encroachment problems in the U.S. western rangeland, decreasing forage productivity and biodiversity. A potential solution to this issue is the use of goats in target grazing programs. Selecting goats for juniper consumption is of great interest to rangeland farmers. Therefore, our main objectives were to 1) estimate genetic parameters, including heritability and repeatability, for juniper consumption in Angora (ANG) and Boer x Spanish (BxS) composite population of goats grazing on West Texas rangelands (USA); and, 2) perform a genome-wide association study (GWAS) to identify candidate genes associated with juniper consumption. Fecal samples were collected multiple times between 2008 and 2017 and analyzed using near-infrared reflectance spectroscopy (NIRS) to estimate the percentage of juniper in the diet of goats, using calibration equations previously developed in controlled studies. We analyzed a dataset comprising 2,327 records from 459 ANG and 8,714 records from 1,996 BxS. The pedigree file included 1,601 and 2,426 ANG and BxS goats, respectively. Genomic information for 50,957 single nucleotide polymorphisms (SNP) from 93 ANG and 238 BxS goats was included in the analyses. Sampling date and sex were fitted as categorical fixed effects and age as a linear covariate in the statistical models. Animal direct additive genetic and permanent environment were considered as random effects. Genetic parameters were calculated based on the Restricted Maximum Likelihood method under the single-step genomic BLUP procedure implemented in the BLUPf90+ family of programs. We used de-regressed estimated breeding values and whole-genome sequence data for the GWAS analyses with 8 million SNP for the ANG and 5.3 million SNP for the BxS. The software GCTA was employed for these analyses. Juniper percentage in their diets varied across the years and ranged from 2.14% (± 7.51%) to 14.6% (± 11.0%) for ANG and from 10.5% (± 14.7) to 33.8% (± 18.1) for the BxS population. The heritability estimate for juniper consumption was 0.19 (± 0.038) for ANG and 0.28 (± 0.022) for BxS, indicating that juniper consumption can be increased through selection. The repeatability values were 0.21 for ANG and 0.37 for BxS. The GWAS revealed 1,257 significant SNP located within or close to 220 genes in ANG, and 878 SNP related to 159 genes in BxS, suggesting their association with juniper consumption. These findings suggest that juniper consumption is under genetic control and has a polygenic inheritance pattern influenced by multiple genes of small effect. The heritability and repeatability estimates indicate that genetic improvement of juniper consumption is feasible in both goat populations.

To retrospectively assess the outcomes of Inferior Vena Cava (IVC) filters placed in critically ill patients in the ICU at bedside using digital radiograph (DR) guidance with previous cross-sectional imaging for planning, compared to IVC filters placed by conventional fluoroscopy (CF).

Decellularized adipose tissue (DAT) scaffolds represent a promising cell-instructive platform for soft tissue engineering. While recent work has highlighted that mesenchymal stromal cells, including adipose-derived stromal cells (ASCs), can be combined with decellularized scaffolds to augment tissue regeneration, the mechanisms involved require further study. The objective of this work was to probe the roles of syngeneic donor ASCs and host-derived macrophages in tissue remodeling of DAT scaffolds within an immunocompetent mouse model. Dual transgenic reporter mouse strains were employed to track and characterize the donor ASCs and host macrophages within the DAT implants. More specifically, ASCs isolated from dsRed mice were seeded on DAT scaffolds, and the seeded and unseeded control scaffolds were implanted subcutaneously into MacGreen transgenic mice for up to 8 weeks. ASC seeding was shown to augment cell infiltration into the DAT implants at 8 weeks, and this was linked to significantly enhanced angiogenesis relative to the unseeded controls. Immunohistochemical staining demonstrated long-term retention of the syngeneic donor ASCs over the duration of the 8-week study, providing evidence that the DAT scaffolds are a cell-supportive delivery platform. Notably, newly formed adipocytes within the DAT implants were not dsRed+, indicating that the donor ASCs supported fat formation through indirect mechanisms. Immunohistochemical tracking of host macrophages through costaining for enhanced green fluorescent protein with the macrophage marker Iba1 revealed that ASC seeding significantly increased the number of infiltrating macrophages within the DAT implants at 3 weeks, while the fraction of macrophages relative to the total cellular infiltrate was similar between the groups at 1, 3, and 8 weeks. Consistent with the tissue remodeling response that was observed, western blotting demonstrated that there was significantly augmented expression of CD163 and CD206, markers of constructive M2-like macrophages, within the ASC-seeded DAT implants. Overall, our results demonstrate that exogenous ASCs enhance tissue regeneration within DAT scaffolds indirectly through multimodal mechanisms that include host cell recruitment and immunomodulation. These data provide further evidence to support the use of decellularized scaffolds as a delivery platform for ASCs in tissue engineering.

Excess nitrogen and phosphorus (“nutrients”) loadings continue to affect ecosystem function and human health across the U.S. Our ability to connect atmospheric inputs of nutrients to aquatic end points remains limited due to uncoupled air and water quality monitoring. Where connections exist, the information provides insights about source apportionment, trends, risk to sensitive ecosystems, and efficacy of pollution reduction efforts. We examine several issues driving the need for better integrated monitoring, including: coastal eutrophication, urban hotspots of deposition, a shift from oxidized to reduced nitrogen deposition, and the disappearance of pristine lakes. Successful coordination requires consistent data reporting; collocating deposition and water quality monitoring; improving phosphorus deposition measurements; and filling coverage gaps in urban corridors, agricultural areas, undeveloped watersheds, and coastal zones.

Patients undergoing evaluation for solid organ transplantation (SOT) often have a history of malignancy. Although the cancer has been treated in these patients, the benefits of transplantation need to be balanced against the risk of tumor recurrence, especially in the setting of immunosuppression. Prior guidelines of when to transplant patients with a prior treated malignancy do not take in to account current staging, disease biology, or advances in cancer treatments. To develop contemporary recommendations, the American Society of Transplantation held a consensus workshop to perform a comprehensive review of current literature regarding cancer therapies, cancer stage‐specific prognosis, the kinetics of cancer recurrence, and the limited data on the effects of immunosuppression on cancer‐specific outcomes. This document contains prognosis based on contemporary treatment and transplant recommendations for breast, colorectal, anal, urological, gynecological, and nonsmall cell lung cancers. This conference and consensus documents aim to provide recommendations to assist in the evaluation of patients for SOT given a history of a pretransplant malignancy. This article presents consensus expert opinion transplant recommendations for patients with a prior breast, colorectal, anal, urological, gynecological, or non‐small cell lung cancer. See the companion review on page 475and an editorial from Hart and Engels on page 447.

Patients undergoing evaluation for solid organ transplantation (SOT) frequently have a history of malignancy. Only patients with treated cancer are considered for SOT but the benefits of transplantation need to be balanced against the risk of tumor recurrence, taking into consideration the potential effects of immunosuppression. Prior guidelines on timing to transplant in patients with a prior treated malignancy do not account for current staging, disease biology, or advances in cancer treatments. To update these recommendations, the American Society of Transplantation (AST) facilitated a consensus workshop to comprehensively review contemporary literature regarding cancer therapies, cancer stage specific prognosis, the kinetics of cancer recurrence, as well as the limited data on the effects of immunosuppression on cancer‐specific outcomes. This document contains prognosis, treatment, and transplant recommendations for melanoma and hematological malignancies. Given the limited data regarding the risk of cancer recurrence in transplant recipients, the goal of the AST‐sponsored conference and the consensus documents produced are to provide expert opinion recommendations that help in the evaluation of patients with a history of a pretransplant malignancy for transplant candidacy. This article presents consensus expert opinion recommendations regarding the timing of transplantation for patients with a history of melanoma or hematological malignancies. The companion review is on page 460and an editorial from Hart and Engels is on page 447.

Rural hospitals are closing at an increasing rate. From 2010 to 2014, 47 rural hospitals closed, affecting 1.5 million people. The presence of surgeons is critical to keeping these hospitals open; to provide initial trauma care, cancer screening, and care to populations that cannot easily travel; and to provide solid general surgery procedures to almost 60 million Americans. Actions to provide surgeons trained for rural practice include exposure of surgery to students in high school (and earlier), recruitment of rural students into medical school, rural rotations in medical school, rural tracts within surgical residencies, and programs to support and retain rural surgeons.

The estrogen related receptors (ERRs) are a subgroup of nuclear receptors that play a role in regulation of cellular metabolism. Prostate cancer (PCa) cells display altered metabolic signatures, such as the Warburg effect, and the ERRs have been implicated in driving this phenotype. Despite the lack of a known endogenous ligand, synthetic ligands that target the ERRs have been discovered. For example, the ERRα inverse agonist XCT790 modulates metabolic pathways in PCa cells, but it also functions as a mitochondrial uncoupler independent of targeting ERRα. Here, we describe a novel dual ERRα/γ inverse agonist, SLU-PP-1072, derived from the GSK4716 ERRγ agonist scaffold that is distinct from the XCT790 scaffold. SLU-PP-1072 alters PCa cell metabolism and gene expression, resulting in cell cycle dysregulation and increased apoptosis without acute mitochondrial uncoupling activity. Our data suggest that inhibition of ERRα/γ may be beneficial in treatment of PCa, and SLU-PP-1072 provides a unique chemical tool to evaluate the pharmacology of ERRα and ERRγ.

Drug discovery faces a crisis. The industry has used up the “obvious” space in which to find novel drugs for biomedical applications, and productivity is declining. One strategy to combat this is rational approaches to expand the search space without relying on chemical intuition, to avoid rediscovery of similar spaces. In this work, we present proof of concept of an approach to rationally identify a “chemical vocabulary” related to a specific drug activity of interest without employing known rules. We focus on the pressing concern of multidrug resistance in Pseudomonas aeruginosaby searching for submolecules that promote compound entry into this bacterium. By synergizing theory, computation, and experiment, we validate our approach, explain the molecular mechanism behind identified fragments promoting compound entry, and select candidate compounds from an external library that display good permeation ability.

Australia has unmet need for transplantation. We sought to assess the impact of cultural and linguistic diversity (CALD) on family consent and medical suitability for organ donation.

Targeted livestock grazing is a proven tool for manipulating rangeland vegetation, and current knowledge about targeted livestock grazing is extensive and expanding rapidly. Targeted grazing prescriptions optimize the timing, frequency, intensity, and selectivity of grazing (or browsing) in combinations that purposely exert grazing/browsing pressure on specific plant species or portions of the landscape. Targeted grazing differs from traditional grazing management in that the goal of targeted grazing is to apply defoliation or trampling to achieve specific vegetation management objectives, whereas the goal of traditional livestock grazing management is generally the production of livestock commodities. A shared aim of targeted livestock grazing and traditional grazing management is to sustain healthy soils, flora, fauna, and water resources that, in turn, can sustain natural ecological processes (e.g., nutrient cycle, water cycle, energy flow). Targeted grazing prescriptions integrate knowledge of plant ecology, livestock nutrition, and livestock foraging behavior. Livestock can be focused on target areas through fencing, herding, or supplement placement. Although practices can be developed to minimize the impact of toxins contained in target plants, the welfare of the animals used in targeted grazing must be a priority. Monitoring is needed to determine if targeted grazing is successful and to refine techniques to improve efficacy and efficiency. Examples of previous research studies and approaches are presented to highlight the ecological benefits that can be achieved when targeted grazing is applied properly. These cases include ways to suppress invasive plants and ways to enhance wildlife habitat and biodiversity. Future research should address the potential to select more adapted and effective livestock for targeted grazing and the associated animal welfare concerns with this practice. Targeted livestock grazing provides land managers a viable alternative to mechanical, chemical, and prescribed fire treatments to manipulate rangeland vegetation.