Prospective randomized pilot study of a novel patient-centered pathology report for colorectal polyps.

Objective: US patients have increased access to their medical records, yet the information is not always understandable. To improve patient understanding, we tested a patient-centered pathology report (PCPR) containing results for recent colon cancer screening or surveillance colonoscopy. Methods: A pilot randomized trial assessed the impact of addition of the PCPR to a standard pathology report on knowledge accuracy, decisional self-efficacy and control, and therapeutic alliance. Results: 55 participants were enrolled; 20 participants in the intervention group and 24 controls completed follow-up. There was no significant difference in polyp knowledge between groups at baseline or 30-days, with similar confidence in understanding their diagnoses, decisional self-efficacy, and therapeutic alliance. Most participants receiving a PCPR felt that it helped them understand their diagnosis better and should always be provided with the standard pathology report. Conclusion: Although patient attitudes toward the PCPR were positive, receiving it did not significantly improve knowledge accuracy or measures of self-efficacy. Further iterations should be explored to communicate key knowledge about colorectal polyp results. Innovation: A stakeholder-driven approach to PCPR development facilitated construction of a personalized document that has potential to increase patient's understanding for their results and needed follow-up.

Pseudomonas aeruginosa kills Staphylococcus aureus in a polyphosphate-dependent manner.

Due to their frequent coexistence in many polymicrobial infections, including in patients with burn or chronic wounds or cystic fibrosis, recent studies have started to investigate the mechanistic details of the interaction between the opportunistic pathogens Pseudomonas aeruginosa and Staphylococcus aureus. P. aeruginosa rapidly outcompetes S. aureus under in vitro co-cultivation conditions, which is mediated by several of P. aeruginosa's virulence factors. Here, we report that polyphosphate (polyP), an efficient stress defense system and virulence factor in P. aeruginosa, plays a role for the pathogen's ability to inhibit and kill S. aureus in a contact-independent manner. We show that P. aeruginosa cells characterized by low polyP level are less detrimental to S. aureus growth and survival while the gram-positive pathogen is significantly more compromised by the presence of P. aeruginosa cells that produce high level of polyP. We show that the polyP-dependent phenotype could be a direct effect by the biopolymer, as polyP is present in the spent media and causes significant damage to the S. aureus cell envelope. However, more likely is that polyP's effects are indirect through the regulation of one of P. aeruginosa's virulence factors, pyocyanin. We show that pyocyanin production in P. aeruginosa occurs polyP-dependent and harms S. aureus through membrane damage and the generation of reactive oxygen species, resulting in increased expression of antioxidant enzymes. In summary, our study adds a new component to the list of biomolecules that the gram-negative pathogen P. aeruginosa generates to compete with S. aureus for resources.

Expression of RcrB confers resistance to hypochlorous acid in uropathogenic Escherichia coli.

To eradicate bacterial pathogens, neutrophils are recruited to the sites of infection, where they engulf and kill microbes through the production of reactive oxygen and chlorine species (ROS/RCS). The most prominent RCS is the antimicrobial oxidant hypochlorous acid (HOCl), which rapidly reacts with various amino acid side chains, including those containing sulfur and primary/tertiary amines, causing significant macromolecular damage. Pathogens like uropathogenic Escherichia coli (UPEC), the primary causative agent of urinary tract infections, have developed sophisticated defense systems to protect themselves from HOCl. We recently identified the RcrR regulon as a novel HOCl defense strategy in UPEC. Expression of the rcrARB operon is controlled by the HOCl-sensing transcriptional repressor RcrR, which is oxidatively inactivated by HOCl resulting in the expression of its target genes, including rcrB. The rcrB gene encodes a hypothetical membrane protein, deletion of which substantially increases UPEC's susceptibility to HOCl. However, the mechanism behind protection by RcrB is unclear. In this study, we investigated whether (i) its mode of action requires additional help, (ii) rcrARB expression is induced by physiologically relevant oxidants other than HOCl, and (iii) expression of this defense system is limited to specific media and/or cultivation conditions. We provide evidence that RcrB expression is sufficient to protect E. coli from HOCl. Furthermore, RcrB expression is induced by and protects from several RCS but not from ROS. RcrB plays a protective role for RCS-stressed planktonic cells under various growth and cultivation conditions but appears to be irrelevant for UPEC's biofilm formation. IMPORTANCE Bacterial infections pose an increasing threat to human health, exacerbating the demand for alternative treatments. Uropathogenic Escherichia coli (UPEC), the most common etiological agent of urinary tract infections (UTIs), are confronted by neutrophilic attacks in the bladder, and must therefore be equipped with powerful defense systems to fend off the toxic effects of reactive chlorine species. How UPEC deal with the negative consequences of the oxidative burst in the neutrophil phagosome remains unclear. Our study sheds light on the requirements for the expression and protective effects of RcrB, which we recently identified as UPEC's most potent defense system toward hypochlorous acid (HOCl) stress and phagocytosis. Thus, this novel HOCl stress defense system could potentially serve as an attractive drug target to increase the body's own capacity to fight UTIs.

Expression of RcrB confers resistance to hypochlorous acid in uropathogenic Escherichia coli.

To eradicate bacterial pathogens, neutrophils are recruited to the sites of infection, where they engulf and kill microbes through the production of reactive oxygen and chlorine species (ROS/RCS). The most prominent RCS is antimicrobial oxidant hypochlorous acid (HOCl), which rapidly reacts with various amino acids side chains, including those containing sulfur and primary/tertiary amines, causing significant macromolecular damage. Pathogens like uropathogenic Escherichia coli (UPEC), the primary causative agent of urinary tract infections (UTIs), have developed sophisticated defense systems to protect themselves from HOCl. We recently identified the RcrR regulon as a novel HOCl defense strategy in UPEC. The regulon is controlled by the HOCl-sensing transcriptional repressor RcrR, which is oxidatively inactivated by HOCl resulting in the expression of its target genes, including rcrB . rcrB encodes the putative membrane protein RcrB, deletion of which substantially increases UPEC's susceptibility to HOCl. However, many questions regarding RcrB's role remain open including whether (i) the protein's mode of action requires additional help, (ii) rcrARB expression is induced by physiologically relevant oxidants other than HOCl, and (iii) expression of this defense system is limited to specific media and/or cultivation conditions. Here, we provide evidence that RcrB expression is sufficient to E. coli 's protection from HOCl and induced by and protects from several RCS but not from ROS. RcrB plays a protective role for RCS-stressed planktonic cells under various growth and cultivation conditions but appears to be irrelevant for UPEC's biofilm formation. IMPORTANCE: Bacterial infections pose an increasing threat to human health exacerbating the demand for alternative treatment options. UPEC, the most common etiological agent of urinary tract infections (UTIs), are confronted by neutrophilic attacks in the bladder, and must therefore be well equipped with powerful defense systems to fend off the toxic effects of RCS. How UPEC deal with the negative consequences of the oxidative burst in the neutrophil phagosome remains unclear. Our study sheds light on the requirements for the expression and protective effects of RcrB, which we recently identified as UPEC's most potent defense system towards HOCl-stress and phagocytosis. Thus, this novel HOCl-stress defense system could potentially serve as an attractive drug target to increase the body's own capacity to fight UTIs.

Synthesis of spirooxindoles via formal acetylene insertion into a common palladacycle intermediate.

A palladium-catalyzed spirocyclization reaction is reported, which is proposed to arise via insertion of an oxabicycle into a palladacycle, formed from carbocyclization and a C-H functionalization sequence. Mechanistic studies suggest the insertion is diastereoselective and a post-catalytic retro-Diels-Alder step furnishes an alkene, wherein the oxibicycle has served as an acetylene surrogate. Aryl iodides and carbamoyl chlorides were compatible as starting materials under the same reaction conditions, enabling the convergent and complementary synthesis of spirooxindoles, as well as other azacycles. These spirooxindoles allowed further transformations that were previously unaccessible.

The Epidermal Microbiome Within an Aggregation of Leopard Sharks (Triakis semifasciata) Has Taxonomic Flexibility with Gene Functional Stability Across Three Time-points.

The epidermis of Chondrichthyan fishes consists of dermal denticles with production of minimal but protein-rich mucus that collectively, influence the attachment and biofilm development of microbes, facilitating a unique epidermal microbiome. Here, we use metagenomics to provide the taxonomic and functional characterization of the epidermal microbiome of the Triakis semifasciata (leopard shark) at three time-points collected across 4 years to identify links between microbial groups and host metabolism. Our aims include (1) describing the variation of microbiome taxa over time and identifying recurrent microbiome members (present across all time-points); (2) investigating the relationship between the recurrent and flexible taxa (those which are not found consistently across time-points); (3) describing the functional compositions of the microbiome which may suggest links with the host metabolism; and (4) identifying whether metabolic processes are shared across microbial genera or are unique to specific taxa. Microbial members of the microbiome showed high similarity between all individuals (Bray-Curtis similarity index = 82.7, where 0 = no overlap, 100 = total overlap) with the relative abundance of those members varying across sampling time-points, suggesting flexibility of taxa in the microbiome. One hundred and eighty-eight genera were identified as recurrent, including Pseudomonas, Erythrobacter, Alcanivorax, Marinobacter, and Sphingopxis being consistently abundant across time-points, while Limnobacter and Xyella exhibited switching patterns with high relative abundance in 2013, Sphingobium and Sphingomona in 2015, and Altermonas, Leeuwenhoekiella, Gramella, and Maribacter in 2017. Of the 188 genera identified as recurrent, the top 19 relatively abundant genera formed three recurrent groups. The microbiome also displayed high functional similarity between individuals (Bray-Curtis similarity index = 97.6) with gene function composition remaining consistent across all time-points. These results show that while the presence of microbial genera exhibits consistency across time-points, their abundances do fluctuate. Microbial functions however remain stable across time-points; thus, we suggest the leopard shark microbiomes exhibit functional redundancy. We show coexistence of microbes hosted in elasmobranch microbiomes that encode genes involved in utilizing nitrogen, but not fixing nitrogen, degrading urea, and resistant to heavy metal.

Redox-Mediated Inactivation of the Transcriptional Repressor RcrR is Responsible for Uropathogenic Escherichia coli's Increased Resistance to Reactive Chlorine Species.

The ability to overcome stressful environments is critical for pathogen survival in the host. One challenge for bacteria is the exposure to reactive chlorine species (RCS), which are generated by innate immune cells as a critical part of the oxidative burst. Hypochlorous acid (HOCl) is the most potent antimicrobial RCS and is associated with extensive macromolecular damage in the phagocytized pathogen. However, bacteria have evolved defense strategies to alleviate the effects of HOCl-mediated damage. Among these are RCS-sensing transcriptional regulators that control the expression of HOCl-protective genes under non-stress and HOCl stress. Uropathogenic Escherichia coli (UPEC), the major causative agent of urinary tract infections (UTIs), is particularly exposed to infiltrating neutrophils during pathogenesis; however, their responses to and defenses from HOCl are still completely unexplored. Here, we present evidence that UPEC strains tolerate higher levels of HOCl and are better protected from neutrophil-mediated killing compared with other E. coli. Transcriptomic analysis of HOCl-stressed UPEC revealed the upregulation of an operon consisting of three genes, one of which encodes the transcriptional regulator RcrR. We identified RcrR as a HOCl-responsive transcriptional repressor, which, under non-stress conditions, is bound to the operator and represses the expression of its target genes. During HOCl exposure, however, the repressor forms reversible intermolecular disulfide bonds and dissociates from the DNA resulting in the derepression of the operon. Deletion of one of the target genes renders UPEC significantly more susceptible to HOCl and phagocytosis indicating that the HOCl-mediated induction of the regulon plays a major role for UPEC's HOCl resistance. IMPORTANCE How do pathogens deal with antimicrobial oxidants produced by the innate immune system during infection? Uropathogenic Escherichia coli (UPEC), the most common etiological agent of urinary tract infections (UTIs), is particularly exposed to infiltrating neutrophils and, therefore, must counter elevated levels of the antimicrobial oxidant HOCl to establish infection. Our study provides fundamentally new insights into a defense mechanism that enables UPEC to fend off the toxic effects of HOCl stress. Intriguingly, the defense system is predominantly found in UPEC and absent in noninvasive enteropathogenic E. coli. Our data suggest expression of the target gene rcrB is exclusively responsible for UPEC's increased HOCl tolerance in culture and contributes to UPEC's survival during phagocytosis. Thus, this novel HOCl stress defense system could potentially serve as an attractive drug target to increase the body's own capacity to fight UTIs.

Reversible C-C bond formation using palladium catalysis.

A widely appreciated principle is that all reactions are fundamentally reversible. Observing reversible transition metal-catalysed reactions, particularly those that include the cleavage of C-C bonds, is more challenging. The development of palladium- and nickel-catalysed carboiodination reactions afforded access to the cis and trans diastereomers of the iodo-dihydroisoquinolone products. Using these substrates, an extensive study investigating the reversibility of C-C bond formation using a simple palladium catalyst was undertaken. Herein we report a comprehensive investigation of reversible C-C bond formation using palladium catalysis employing diastereomeric neopentyl iodides as the starting point. It was shown that both diastereomers could be converted to a common product under identical catalytic conditions. A combination of experimental and computational studies were used to probe the operative mechanism. A variety of concepts key to understanding the process of reversible C-C bond formations were investigated, including the effect of electronic and steric parameters on the C-C bond-cleavage step.

Exercise prevents whole body type 2 diabetes risk factors better than estradiol replacement in rats.

The absence of estrogens in postmenopausal women is linked to an increased risk of type 2 diabetes (T2D) and estradiol replacement can decrease this risk. Notably, exercise can also treat and prevent T2D. This study seeks to understand the molecular mechanisms by which estradiol and exercise induce their beneficial effects via assessing whole body and cellular changes. Female Wistar rats were ovariectomized and fed a high-fat diet for 10 wk and divided into the following four experimental groups: 1) no treatment (control), 2) exercise (Ex), 3) estradiol replacement, and 4) Ex + estradiol. Both Ex and estradiol decreased the total body weight gain. However, only exercise effectively reduced the white adipose tissue (WAT) weight gain, food intake, blood glucose levels, and serum insulin levels. At the molecular level, exercise increased the noninsulin-stimulated pAkt levels in the WAT. In the liver, estradiol increased the protein expression of acetyl-CoA carboxylase (ACC) and fatty acid synthase (FAS) and estradiol decreased the hepatic protein expression of lipoprotein lipase (LPL). In the WAT, estradiol and exercise increased the protein expression of adipose triglyceride lipase (ATGL). Exercise provides better protection against T2D when considering whole body measurements, which may be due to increased noninsulin-stimulated pAkt in the WAT. However, at the cellular level, several molecular changes in fat metabolism and fat storage occurred in the liver and WAT with estradiol treatment.NEW & NOTEWORTHY Exercise provides better protection than estradiol against type 2 diabetes when considering whole body measurements including adipose tissue weight, blood glucose levels, and serum insulin levels, which may be due to increased noninsulin-stimulated pAkt in the adipose tissue. However, at the cellular level, several molecular changes in fat metabolism and fat storage occurred in the liver and adipose tissue with estradiol treatment.

Feeding and thermal conditioning enhance coral temperature tolerance in juvenile Pocillopora acuta.

Scleractinian corals form the foundation of coral reefs by acquiring autotrophic nutrition from photosynthetic endosymbionts (Symbiodiniaceae) and use feeding to obtain additional nutrition, especially when the symbiosis is compromised (i.e. bleaching). Juvenile corals are vulnerable to stress due to low energetic reserves and high demand for growth, which is compounded when additional stressors occur. Therefore, conditions that favour energy acquisition and storage may enhance survival under stressful conditions. To investigate the influence of feeding on thermal tolerance, we exposed Pocillopora acuta juveniles to temperature (ambient, 27.4°C versus cool, 25.9°C) and feeding treatments (fed versus unfed) for 30 days post-settlement and monitored growth and physiology, followed by tracking survival under thermal stress. Feeding increased growth and resulted in thicker tissues and elevated symbiont fluorescence. Under high-temperature stress (31-60 days post-settlement; ca 30.1°C), corals that were fed and previously exposed to cool temperature had 33% higher survival than other treatment groups. These corals demonstrated reduced symbiont fluorescence, which may have provided protective effects under thermal stress. These results highlight that the impacts of feeding on coral physiology and stress tolerance are dependent on temperature and as oceans continue to warm, early life stages may experience shifts in feeding strategies to survive.

Evaluating frailty in Medicaid Home and Community-based Services clients: a feasibility and comparison study between the SHARE-FI and SPPB.

BACKGROUND: Frailty assessment most commonly occurs within health care settings by health care providers. Implementing frailty assessment within non-medical settings that provide comprehensive social services for older adults may be an opportunity for population-based frailty screening and care. One such non-medical setting in which older adults receive care is Medicaid Home and Community-based Services (HCBS). Determining the feasibility of frailty screening within this non-medical setting is the first step towards population-based frailty assessment and care. The aims of this study were to (1) determine the feasibility of evaluating frailty using two different approaches (the Survey of Health Among Retired Europeans-Frailty Instrument (SHARE-FI) and Short Physical Performance Battery (SPPB)) among HCBS clients, (2) determine the agreement between the methods, and (3) explore specific frailty deficits on these measures to provide detailed knowledge on HCBS client impairments. METHODS: This cross-sectional study occurred in HCBS client homes throughout the Chicagoland area. A research assistant with no health care provider training conducted all frailty assessments. We used the freely available SHARE-FI calculator to generate both a categorical and continuous frailty score. We used the SPPB to capture both a categorical score with frailty categories assigned as 0-6 (frail), 7-9 (pre-frail), and 10-12 (non-frail) and continuous score. We evaluated feasibility via domains of acceptability, implementation, adaptation, and practicality. We used Cohen's kappa and Spearman's correlation to determine agreement between frailty tools. RESULTS: We enrolled n = 139 HCBS clients. Frailty assessment was feasibility via both the SHARE-FI and SPPB. The SHARE-FI was more practical given the fewer training needs, shorter administration time, and reduced equipment needs. There was a statically significant fair agreement between SHARE-FI and SPPB categorical scores with stronger agreement between SHARE-FI and SPPB continuous scores (r = - 0.448, p < .005; 95% CI, - 0.571, - 0.305). Among the five frailty criteria on the SHARE-FI, a pattern emerged of the highest frequency of positive responses to each criterion among frail clients followed by pre-frail and then non-frail. CONCLUSIONS: Frailty assessment is feasible within HCBS settings conducted by a non-medical provider. Using continuous frailty scores provides stronger agreement between measures compared with categorical scores. Frailty can be feasibly measured in a non-medical setting providing initial evidence for a mechanism for population screening and care for frailty in HCBS.