Human Rotator Cuff Tears Reveal an Age-Dependent Increase in Markers of Cellular Senescence and Selective Removal of Senescent Cells With Dasatinib + Quercetin Increases Genetic Expression of COL1A1 In Vitro.

PURPOSE: To quantify cellular senescence in supraspinatus tendon and subacromial bursa of humans with rotator cuff tears and to investigate the in vitro efficacy of the senolytic dasatinib + quercetin (D+Q) to eliminate senescent cells and alter tenogenic differentiation. METHODS: Tissue was harvested from 41 patients (mean age, 62 years) undergoing arthroscopic rotator cuff repairs. In part 1 (n = 35), senescence was quantified using immunohistochemistry and gene expression for senescent cell markers (p16 and p21) and the senescence-associated secretory phenotype (SASP) (interleukin [IL] 6, IL-8, matrix metalloproteinase [MMP] 3, monocyte chemoattractant protein [MCP] 1). Senescence was compared between patients <60 and ≥60 years old. In part 2 (n = 6) , an in vitro model of rotator cuff tears was treated with D+Q or control. D+Q, a chemotherapeutic and plant flavanol, respectively, kill senescent cells. Gene expression analysis assessed the ability of D+Q to kill senescent cells and alter markers of tenogenic differentiation. RESULTS: Part 1 revealed an age-dependent significant increase in the relative expression of p21, IL-6, and IL-8 in tendon and p21, p16, IL-6, IL-8, and MMP-3 in bursa (P < .05). A significant increase was seen in immunohistochemical staining of bursa p21 (P = .028). In part 2, D+Q significantly decreased expression of p21, IL-6, and IL-8 in tendon and p21 and IL-8 in bursa (P < .05). Enzyme-linked immunosorbent assay analysis showed decreased release of the SASP (IL-6, MMP-3, MCP-1; P = .002, P = .024, P < .001, respectively). Tendon (P = .022) and bursa (P = .027) treated with D+Q increased the expression of COL1A1. CONCLUSIONS: While there was an age-dependent increase in markers of cellular senescence, this relationship was not consistently seen across all markers and tissues. Dasatinib + quercetin had moderate efficacy in decreasing senescence in these tissues and increasing COL1A1 expression. CLINICAL RELEVANCE: This study reveals that cellular senescence may be a therapeutic target to alter the biological aging of rotator cuffs and identifies D+Q as a potential therapy.

Total synthesis and antibacterial evaluation of Empetroxepins A and B and related analogs.

Empetroxepins A and B, which are 10,11-dihydrodibenz[b,f]oxepins produced by the Black Crowberry (Empetrum nigrum), displayed weak anti-tubercular activity upon isolation, but have not been explored for antibiotic activity despite their molecular similarity to other phenolic antibacterial natural products. Herein we detail the first total synthesis of Empetroxepins A and B via a selective demethylation strategy and antibacterial structure activity relationship (SAR) study of the natural products and related analogs. Empetroxepin A was found to be weakly active against susceptible strains of Staphylococcus aureus (SA) and Bacillus subtilis (BS) with a minimum inhibitory concentration (MIC) of 256 µg/mL against both bacteria, whereas Empetroxepin B was found to be weakly active against only BS (MIC = 256 µg/mL). Neither natural product was active against Escherichia coli (EC). Antibiotic activity was improved through derivatization of the 10,11-dihydrodibenz[b,f]oxepin core with the best compound of the SAR series, 9-chloro-10,11-dihydrodibenzo[b,f]oxepine-2,3,4-triol, having MICs of 8 µg/mL, 16 µg/mL, and 256 µg/mL against SA, BS, and EC respectively.

Helical Molecular Springs with Varying Spring Constants.

We report a general synthetic route toward helical ladder polymers with varying spring constants, built with chirality-assisted synthesis (CAS). Under tension and compression, these shape-persistent structures do not unfold, but rather stretch and compress akin classical Hookean springs. Our synthesis is adaptable to helices with different pitch and diameter, which allowed us to investigate how molecular flexibility in solution depends on the exact geometry of the ladder polymers. Specifically, we showed with molecular dynamic simulations and by measuring the longitudinal 1 H NMR relaxation times (T1 ) for our polymers at different Larmor frequencies, that increasing the helix diameter leads to increased flexibility. Our results present initial design rules for tuning the mechanical properties of intrinsically helical ladder polymers in solution, which will help inspire a new class of robust, spring-like molecular materials with varying mechanical properties.

Concise Review: Mesenchymal Stem Cells Derived from Human Pluripotent Cells, an Unlimited and Quality-Controllable Source for Therapeutic Applications.

Despite the long discrepancy over their definition, heterogeneity, and functions, mesenchymal stem cells (MSCs) have proved to be a key player in tissue repair and homeostasis. Generally, somatic tissue-derived MSCs (st-MSCs) are subject to quality variations related to donated samples and biosafety concern for transmission of potential pathogens from the donors. In contrast, human pluripotent stem cells (hPSCs) are unlimited in supply, clear in the biological background, and convenient for quality control, genetic modification, and scale-up production. We, and others, have shown that hPSCs can differentiate in two dimensions or three dimensions to MSCs (ps-MSCs) via embryonic (mesoderm and neural crest) or extraembryonic (trophoblast) cell types under serum-containing or xeno-free and defined conditions. Compared to st-MSCs, ps-MSCs appear less mature, proliferate faster, express lower levels of inflammatory cytokines, and respond less to traditional protocols for st-MSC differentiation to other cell types, especially adipocytes. Nevertheless, ps-MSCs are capable of immune modulation and treatment of an increasing number of animal disease models via mitochondria transfer, paracrine, exosomes, and direct differentiation, and can be potentially used as a universal and endless therapy for clinical application. This review summarizes the progress on ps-MSCs and discusses perspectives and challenges for their potential translation to the clinic. Stem Cells 2019;37:572-581.

Prevalence, Risk Factors, and Clinical Consequences of Recurrent Activation of a Rapid Response Team: A Multicenter Observational Study.

INTRODUCTION: Rapid response teams (RRTs) are groups of health-care providers, implemented by hospitals to respond to distressed hospitalized patients on the hospital wards. Patients assessed by the RRT for deterioration may be admitted to the intensive care unit (ICU) or may be triaged to remain on the wards, putting them at risk of recurrent deterioration and repeat RRT activation. Previous studies evaluating outcomes of patients with recurrent deterioration and multiple RRT activations have produced conflicting results. METHODS: We used a prospectively collected multicenter registry from 2 hospitals within a single tertiary-level hospital system between 2012 and 2016. Comparisons were made between patients with a single RRT activation and those with multiple RRT activations over the course of their admission. Primary outcome was in-hospital mortality, which was analyzed using multivariable logistic regression. RESULTS: A total of 5995 patients who had any RRT activation were analyzed. Of that, 1183 (19.7%) patients had recurrent deterioration and multiple RRT activations during their admission. Risk factors for recurrent deterioration included admission from a home setting (as opposed to a long-term care facility), RRT activation during nighttime hours, and delay (>1 hour) to RRT activation. Recurrent deterioration was associated with increased odds of mortality (adjusted odds ratio [OR]: 1.44 [1.28-1.64], P = <.001). Increasing number of RRT activations were associated with increasing risk of mortality. Patients with recurrent deterioration had prolonged median hospital length of stay (21.0 days vs 12.0 days, P < .001), while patients with only a single activation were more likely to be admitted to the ICU (adjusted OR: 2.30 [1.96-2.70], P < .001). CONCLUSIONS: Recurrent deteriorations leading to RRT activations among hospitalized patients are associated with increased odds of mortality and prolonged hospital length of stay. This work identifies a group of patients who warrant closer attention to help reduce adverse outcomes.

Outcomes of Older Hospitalized Patients Requiring Rapid Response Team Activation for Acute Deterioration.

OBJECTIVES: Rapid response teams are groups of healthcare providers that have been implemented by many hospitals to respond to acutely deteriorating patients admitted to the hospital wards. Hospitalized older patients are at particular risk of deterioration. We sought to examine outcomes of older patients requiring rapid response team activation. DESIGN: Analysis of a prospectively collected registry. SETTING: Two hospitals within a single tertiary care level hospital system between 2012 and 2016. PATIENTS: Five-thousand nine-hundred ninety-five patients were analyzed. Comparisons were made between older patients (defined as ≥ 75 yr old) and younger patients. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: All patient information, outcomes, and rapid response team activation information were gathered at the time of rapid response team activation and assessment. The primary outcome was in-hospital mortality, analyzed using multivariate logistic regression. Two-thousand three-hundred nine were older patients (38.5%). Of these, 835 (36.2%) died in-hospital, compared with 998 younger patients (27.1%) (adjusted odds ratio, 1.83 [1.54-2.18]; p < 0.001). Among patients admitted from home, surviving older patients were more likely to be discharged to a long-term care facility (adjusted odds ratio, 2.38 [95% CI, 1.89-3.33]; p < 0.001). Older patients were more likely to have prolonged delay to rapid response team activation (adjusted odds ratio, 1.79 [1.59-2.94]; p < 0.001). Among patients with goals of care allowing for ICU admission, older patients were less likely to be admitted to the ICU (adjusted odds ratio, 0.66 [0.36-0.79]), and less likely to have rapid response team activation during daytime hours (adjusted odds ratio, 0.73 [0.62-0.98]; p < 0.001). CONCLUSIONS: Older patients with in-hospital deterioration requiring rapid response team activation had increased odds of death and long-term care disposition. Rapid response team activation for older patients was more likely to be delayed, and occur during nighttime hours. These findings highlight the worse outcomes seen among older patients with in-hospital deterioration, identifying areas for future quality improvement.

Summative Usability Evaluation of the SCTE-AI Device: A Novel Prefilled Autoinjector for Subcutaneous Testosterone Administration.

BACKGROUND: The subcutaneous testosterone enanthate (TE) autoinjector (SCTE-AI) is a single-use, pre-filled, disposable autoinjector intended for testosterone (T) self-administration in adult males with T deficiency. AIM: To evaluate the usability of the market configuration of the SCTE-AI, including packaging and instructions for use (IFU), in order to identify and mitigate any preventable patterns of use errors that could result in harm. METHODS: 4 groups of participants (injection-naïve or injection-experienced patients or caregivers) were randomized to 1 of 3 doses (50, 75, and 100 mg) of TE and either trained (ie, reviewed the IFU and shown how to properly inject) or not trained (only given the IFU). After simulated at-home use, participants were asked questions regarding the comprehensibility of the IFU and the intuitiveness/usability of the device. All tasks were measured as success, use error, or close call (participant initiated an error but recovered in time). MAIN OUTCOME MEASURE: Usability (success rates, errors, and close calls) of the drug/device combination by adult males with T deficiency or their caregivers. RESULTS: 65 patients received 1 dose of TE, and 59 patients received 2 doses. Overall, 99 of 123 (80.5%) attempted injections resulted in administration of 1 full dose. Injection success rates were high and comparable among the various user groups. The most common use error (21 of 24) was due to not holding the autoinjector on the abdomen long enough (at least 8 seconds). Few critical drug delivery and safety errors or close calls were observed. No unmitigated use errors by patients or caregivers were apparent that could result in harm or have a negative impact on treatment. SCTE-AI was well tolerated. CLINICAL IMPLICATIONS: The SCTE-AI development process resulted in a subcutaneous, TE autoinjection device that is intuitive to use, with clear labeling and packaging and an easy-to-understand IFU, providing an option for T-deficient adult males to self-inject subcutaneously at home. STRENGTH & LIMITATIONS: The strengths of the study include use of a patient-ready drug/device combination for self-administration and inclusion of both injection-naïve and injection-experienced patients and caregivers. The main limitation of the study is the presence of observers/cameras that may have distracted or created performance anxiety, potentially contributing to errors. CONCLUSION: Results of this usability validation study indicate that the SCTE-AI device is safe and intuitive to use, with a low potential for harm and is associated with a high rate of injection success, regardless of prior training or experience. Arora S, Moclair B, Murphy K, et al. Summative Usability Evaluation of the SCTE-AI Device: A Novel Prefilled Autoinjector for Subcutaneous Testosterone Administration. J Sex Med 2018;15:1707-1715.

Impact of nighttime Rapid Response Team activation on outcomes of hospitalized patients with acute deterioration.

BACKGROUND: Rapid Response Teams (RRTs) are groups of healthcare providers that are used by many hospitals to respond to acutely deteriorating patients admitted to the wards. We sought to identify outcomes of patients assessed by RRTs outside standard working hours. METHODS: We used a prospectively collected registry from two hospitals within a single tertiary care-level hospital system between May 1, 2012, and May 31, 2016. Patient information, outcomes, and RRT activation information were stored in the hospital data warehouse. Comparisons were made between RRT activation during daytime hours (0800-1659) and nighttime hours (1700-0759). The primary outcome was in-hospital mortality, analyzed using a multivariable logistic regression model. RESULTS: A total of 6023 RRT activations on discrete patients were analyzed, 3367 (55.9%) of which occurred during nighttime hours. Nighttime RRT activation was associated with increased odds of mortality, as compared with daytime RRT activation (adjusted OR 1.34, 95% CI 1.26-1.40, P = 0.02). The time periods associated with the highest odds of mortality were 0600-0700 (adjusted OR 1.30, 95% CI 1.09-1.61) and 2300-2400 (adjusted OR 1.34, 95% CI 1.01-1.56). Daytime RRT activation was associated with increased odds of intensive care unit admission (adjusted OR 1.40, 95% CI 1.31-1.50, P = 0.02). Time from onset of concerning symptoms to RRT activation was shorter among patients assessed during daytime hours (P < 0.001). CONCLUSIONS: Acutely deteriorating ward patients assessed by an RRT at nighttime had a higher risk of in-hospital mortality. This work identifies important shortcomings in health service provision and quality of care outside daytime hours, highlighting an opportunity for quality improvement.

Discovery of periplasmic solute binding proteins with specificity for ketone bodies: ß-hydroxybutyrate binding proteins.

Polyhydroxyalkanoates are a class of biodegradable, thermoplastic polymers which represent a major carbon source for various bacteria. Proteins which mediate the translocation of polyhydroxyalkanoate breakdown products, such as ß-hydroxybutyrate (BHB)-a ketone body which in humans serves as an important biomarker, have not been well characterized. In our investigation to screen a solute-binding protein (SBP) which can act as a suitable recognition element for BHB, we uncovered insights at the intersection of bacterial metabolism and diagnostics. Herein, we identify SBPs associated with putative ATP-binding cassette transporters that specifically recognize BHB, with the potential to serve as recognition elements for continuous quantification of this analyte. Through bioinformatic analysis, we identified candidate SBPs from known metabolizers of polyhydroxybutyrate-including proteins from Cupriavidus necator, Ensifer meliloti, Paucimonas lemoignei, and Thermus thermophilus. After recombinant expression in Escherichia coli, we demonstrated with intrinsic tryptophan fluorescence spectroscopy that four candidate proteins interacted with BHB, ranging from nanomolar to micromolar affinity. Tt.2, an intrinsically thermostable protein from Thermus thermophilus, was observed to have the tightest binding and specificity for BHB, which was confirmed by isothermal calorimetry. Structural analyses facilitated by AlphaFold2, along with molecular docking and dynamics simulations, were used to hypothesize key residues in the binding pocket and to model the conformational dynamics of substrate unbinding. Overall, this study provides strong evidence identifying the cognate ligands of SBPs which we hypothesize to be involved in prokaryotic cellular translocation of polyhydroxyalkanoate breakdown products, while highlighting these proteins' promising biotechnological application.

Identification of function for CD44 intracytoplasmic domain (CD44-ICD): modulation of matrix metalloproteinase 9 (MMP-9) transcription via novel promoter response element.

CD44 is a multifunctional cell receptor that conveys a cancer phenotype, regulates macrophage inflammatory gene expression and vascular gene activation in proatherogenic environments, and is also a marker of many cancer stem cells. CD44 undergoes sequential proteolytic cleavages that produce an intracytoplasmic domain called CD44-ICD. However, the role of CD44-ICD in cell function is unknown. We take a major step toward the elucidation of the CD44-ICD function by using a CD44-ICD-specific antibody, a modification of a ChIP assay to detect small molecules, and extensive computational analysis. We show that CD44-ICD translocates into the nucleus, where it then binds to a novel DNA consensus sequence in the promoter region of the MMP-9 gene to regulate its expression. We also show that the expression of many other genes that contain this novel response element in their promoters is up- or down-regulated by CD44-ICD. Furthermore, hypoxia-inducible factor-1α (Hif1α)-responsive genes also have the CD44-ICD consensus sequence and respond to CD44-ICD induction under normoxic conditions and therefore independent of Hif1α expression. Additionally, CD44-ICD early responsive genes encode for critical enzymes in the glycolytic pathway, revealing how CD44 could be a gatekeeper of the Warburg effect (aerobic glycolysis) in cancer cells and possibly cancer stem cells. The link of CD44 to metabolism is novel and opens a new area of research not previously considered, particularly in the study of obesity and cancer. In summary, our results finally give a function to the CD44-ICD and will accelerate the study of the regulation of many CD44-dependent genes.

Associations Between Trait Boredom and Frequency of Cannabis, Alcohol, and Tobacco Use in College Students.

Objective: Boredom is a common emotion associated with substance use in college students - a group already at risk for substance misuse. The purpose of this study is to understand how two types of trait boredom (susceptibility and proneness) in college students are associated with frequency of cannabis, alcohol, and tobacco use. Method: Data were collected from an online survey completed by a sample of undergraduate students (N = 414, Mage = 19.55, 84.5% female; 64.3% White) enrolled at a large public university in the northwest. Multivariate logistic regression was used to evaluate the association between trait boredom and frequency of cannabis, alcohol, and tobacco use after controlling for age, sex, and race. Results: Boredom susceptibility was a significant predictor of annual, monthly, and weekly cannabis and alcohol use, but only annual and monthly tobacco use. Boredom proneness was only a significant predictor for monthly alcohol use. Conclusions: Findings were generally consistent across types of substances and frequency of use for boredom susceptibility, indicating students higher in susceptibility, rather than proneness, are a subgroup to target prevention interventions to alleviate boredom and subsequent maladaptive coping mechanisms.

The use of machine learning for predicting candidates for outpatient spine surgery: a review.

While spine surgery has historically been performed in the inpatient setting, in recent years there has been growing interest in performing certain cervical and lumbar spine procedures on an outpatient basis. While conducting these procedures in the outpatient setting may be preferable for both the surgeon and the patient, appropriate patient selection is crucial. The employment of machine learning techniques for data analysis and outcome prediction has grown in recent years within spine surgery literature. Machine learning is a form of statistics often applied to large datasets that creates predictive models, with minimal to no human intervention, that can be applied to previously unseen data. Machine learning techniques may outperform traditional logistic regression with regards to predictive accuracy when analyzing complex datasets. Researchers have applied machine learning to develop algorithms to aid in patient selection for spinal surgery and to predict postoperative outcomes. Furthermore, there has been increasing interest in using machine learning to assist in the selection of patients who may be appropriate candidates for outpatient cervical and lumbar spine surgery. The goal of this review is to discuss the current literature utilizing machine learning to predict appropriate patients for cervical and lumbar spine surgery, candidates for outpatient spine surgery, and outcomes following these procedures.

Prevalence and antibiotic resistance of Staphylococcus aureus associated with a college-aged cohort: life-style factors that contribute to nasal carriage.

Staphylococcus aureus is an opportunistic human pathogen that can frequently be found at various body locations, such as the upper respiratory tract, nostrils, skin, and perineum. S. aureus is responsible for causing a variety of conditions, which range from minor skin infections and food poisoning to life-threatening sepsis and endocarditis. Furthermore, S. aureus has developed resistance to numerous antimicrobial agents, which has made treatment of S. aureus infections difficult. In the present study, we examined lifestyle factors that could increase the likelihood of S. aureus carriage, the overall prevalence of S. aureus, as well as assessed the antibiotic resistance profiles of the S. aureus isolates among a population of college students. Five hundred nasal samples were collected and analyzed via selective growth media, coagulase and protein A testing, as well as polymerase chain reaction and DNA sequencing. One hundred four out of the 500 samples collected (21%) were identified as containing S. aureus. The S. aureus isolates were resistant to penicillin (74%), azithromycin (34%), cefoxitin (5%), ciprofloxacin (5%), tetracycline (4%), and trimethoprim (1%), but sensitive to gentamicin and rifampin. Lastly, we identified several lifestyle factors (i.e., pet exposure, time spent at the university recreational facility, musical instrument usage, and tobacco usage) positively correlated with S. aureus nasal colonization.

Design and evaluation of poly-nitrogenous adjuvants capable of potentiating antibiotics in Gram-negative bacteria.

Antibiotic resistance has been a growing public health crisis since the 1980s. Therefore, it is essential not only to continue to develop novel antibiotics but also to develop new methods for overcoming resistance mechanisms in pathogenic bacteria so antibiotics can be reactivated towards these resistant strains. One common cause of antibiotic resistance in Gram-negative bacteria is reduced permeability of the tightly packed, negatively charged lipopolysaccharide outer membrane (OM), which dramatically reduces or even prevents antibiotic accumulation within the cell. Adjuvants that promote passive diffusion through the OM, including phenylalanine-arginine-ß-naphthylamide, tobramycin, and pentamidine, have proven useful in potentiating antibiotics against Gram-negative bacteria. Structural evaluation of these adjuvants, which all include multiple nitrogenous groups, indicates that the entry rules developed for improving antibiotic accumulation in Escherichia coli (EC), could also be used to guide adjuvant development. To this end, a series of structurally simple poly-nitrogenous diphenylsuccinamide compounds have been prepared and evaluated for their ability to potentiate a panel of classic antibiotics in wild-type EC and Pseudomonas aeruginosa (PA). Modest adjuvant activity was observed for all compounds surveyed when co-administered with known antibiotics to inhibit either wild-type EC or PA, and all were able to accumulate in both EC and PA.

Abdominal Wall Thickness is a Predictor for Surgical Site Infections in Patients Undergoing Colorectal Operations.

BACKGROUND: Surgical site infections (SSIs) are an established complication following colorectal operations, with rates up to 30% reported in the literature. Obesity is a known risk factor for SSI; however, body mass index (BMI), body fat percentage, waist-hip ratio, or abdominal circumference are imperfect measures. The purpose of our study was to determine whether abdominal wall thickness (AWT) is predictive of SSI. METHODS: We queried our American College of Surgeons National Surgical Quality Improvement Project (ACS-NSQIP) database for patients (age ≥18 years) undergoing a colectomy at the University of Kentucky (UK) from January 1, 2013 to December 31, 2018. The exclusion criteria included patients with open abdomens or the lack of preoperative computed tomography (CT) within 3 months of their operation. AWT was measured at the level of the anterior superior iliac spine (ASIS) on abdominal CT. SSI was defined by superficial SSI, deep SSI, and wound dehiscence. RESULTS: Of 1261 patients enrolled, 52.2% were female, with an average age of 57.4 years. More patients had laparoscopic operations (51%), and the median length of stay was 7 days. Our study demonstrated an SSI rate of 9.4% and a 30-day readmission rate of 11%. The overall mean AWT was 2.6 cm (range .1-13.1), and patients with the highest AWT quintile were more likely to develop an SSI than the lowest quintile (12% vs. 5%). After controlling for risk factors and confounders, the odds of an SSI were 3.6 times higher for patients with the highest AWT than patients with the lowest AWT. CONCLUSIONS: Among colorectal surgery patients, AWT is an independent risk factor predictive for SSI.

Analysis of Patient Factors Affecting In Vitro Characteristics of Subacromial Bursal Connective Tissue Progenitor Cells during Rotator Cuff Repair.

Unsatisfactory failure rates following rotator cuff (RC) repair have led orthopaedic surgeons to explore biological augmentation of the healing enthesis. The subacromial bursa (SB) contains abundant connective tissue progenitor cells (CTPs) that may aid in this process. The purpose of the study was to investigate the influence of patient demographics and tear characteristics on the number of colony-forming units (CFUs) and nucleated cell count (NCC) of SB-derived CTPs. In this study, we harvested SB tissue over the supraspinatus tendon and muscle in 19 patients during arthroscopic RC repair. NCC of each sample was analyzed on the day of the procedure. After 14 days, CFUs were evaluated under a microscope. Spearman's rank correlation coefficient was then used to determine the relationship between CFUs or NCC and patient demographics or tear characteristics. The study found no significant correlation between patient demographics and the number of CFUs or NCC of CTPs derived from the SB (p > 0.05). The study did significantly observe that increased tear size was negatively correlated with the number of CFUs (p < 0.05). These results indicated that increased tear size, but not patient demographics, may influence the viability of CTPs and should be considered when augmenting RCrepairs with SB.

Advances in antibiotic drug discovery: reducing the barriers for antibiotic development.

Antibiotic drug discovery has been an essential field of research since the early 1900s, but the threat from infectious bacteria has only increased over the decades because of the emergence of widespread multidrug resistance. In this review, we discuss the recent advances in natural product, computational and medicinal chemistry that have reinvigorated the field of antibiotic drug discovery while giving perspective on how easily, both in cost and in expertise, these methods can be implemented by other researchers with the goal of increasing the number of scientists contributing to this public health crisis.

Size-selective Catalytic Polymer Acylation with a Molecular Tetrahedron.

Selective catalysis at the molecular level represents a cornerstone of chemical synthesis. However, it still remains an open question how to elevate tunable catalysis to larger length scales to functionalize whole polymer chains in a selective manner. We now report a hydrazone-linked tetrahedron with wide openings, which acts as a catalyst to size-selectively functionalize polydisperse polymer mixtures. Our experimental and computational evidence supports a dual role of the hydrazone-linked tetrahedron. To accelerate functionalization of the polymer substrates, the tetrahedron (i) unfolds the polymer substrates and/or breaks the polymer aggregates as well as (ii) enables target sites (amino groups) on the polymers to coordinate with catalytic units (triglyme) attached to the tetrahedron. With the tetrahedron as the catalyst, we find that the reactivity of the shorter polymers increases selectively. Our findings enable the possibility to engineer hydrolytically stable molecular polyhedra as organocatalysts for size-selective polymer modification.

Incorporating Laboratory Values Into a Machine Learning Model Improves In-Hospital Mortality Predictions After Rapid Response Team Call.

OBJECTIVES: Machine learning models have been used to predict mortality among patients requiring rapid response team activation. The goal of our study was to assess the impact of adding laboratory values into the model. DESIGN: A gradient boosted decision tree model was derived and internally validated to predict a primary outcome of in-hospital mortality. The base model was then augmented with laboratory values. SETTING: Two tertiary care hospitals within The Ottawa Hospital network. PATIENTS: Inpatients over the age of 18 years who experienced a rapid response team activation between January 1, 2015, and May 31, 2016. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: A total of 2,061 rapid response team activations occurred during the study period. The in-hospital mortality rate was 29.4%. Patients who died were older (median age, 72 vs 68 yr; p < 0.001), had a longer length of stay (length of stay) prior to rapid response team activation (4 vs 2 d; p < 0.001), and more often had respiratory distress (31% vs 22%; p < 0.001). Our base model without laboratory values performed with an area under the receiver operating curve of 0.71 (95% CI, 0.71-0.72). When the base model was augmented with laboratory values, the area under the receiver operating curve improved to 0.77 (95% CI, 0.77-0.78). Important mortality predictors in the base model were age, estimated ratio of Pao2 to Fio2 (calculated using oxygen saturation and estimated Fio2), length of stay prior to rapid response team activation, and systolic blood pressure. CONCLUSIONS: Machine learning models can identify rapid response team patients at a high risk of mortality and potentially supplement clinical decision making. Incorporating laboratory values into model development significantly improved predictive performance in this study.