Adjuvants restore colistin sensitivity in mouse models of highly colistin-resistant isolates, limiting bacterial proliferation and dissemination.

Antimicrobial resistance (AMR) has led to a marked reduction in the effectiveness of many antibiotics, representing a substantial and escalating concern for global health. Particularly alarming is resistance in Gram-negative bacteria due to the scarcity of therapeutic options for treating infections caused by these pathogens. This challenge is further compounded by the rising incidence of resistance to colistin, an antibiotic traditionally considered a last resort for the treatment of multi-drug resistant (MDR) Gram-negative bacterial infections. In this study, we demonstrate that adjuvants restore colistin sensitivity in vivo. We previously reported that the salicylanilide kinase inhibitor IMD-0354, which was originally developed to inhibit the human kinase IKKß in the NFκB pathway, is a potent colistin adjuvant. Subsequent analog synthesis using an amide isostere approach led to the creation of a series of novel benzimidazole compounds with enhanced colistin adjuvant activity. Herein, we demonstrate that both IMD-0354 and a lead benzimidazole effectively restore colistin susceptibility in mouse models of highly colistin-resistant Klebsiella pneumoniae and Acinetobacter baumannii-induced peritonitis. These novel adjuvants show low toxicity in vivo, significantly reduce bacterial load, and prevent dissemination that could otherwise result in systemic infection.

Different aspects of failing to recover from proactive semantic interference predicts rate of progression from amnestic mild cognitive impairment to dementia.

Introduction: This study investigated the role of proactive semantic interference (frPSI) in predicting the progression of amnestic Mild Cognitive Impairment (aMCI) to dementia, taking into account various cognitive and biological factors. Methods: The research involved 89 older adults with aMCI who underwent baseline assessments, including amyloid PET and MRI scans, and were followed longitudinally over a period ranging from 12 to 55 months (average 26.05 months). Results: The findings revealed that more than 30% of the participants diagnosed with aMCI progressed to dementia during the observation period. Using Cox Proportional Hazards modeling and adjusting for demographic factors, global cognitive function, hippocampal volume, and amyloid positivity, two distinct aspects of frPSI were identified as significant predictors of a faster decline to dementia. These aspects were fewer correct responses on a frPSI trial and a higher number of semantic intrusion errors on the same trial, with 29.5% and 31.6 % increases in the likelihood of more rapid progression to dementia, respectively. Discussion: These findings after adjustment for demographic and biological markers of Alzheimer's Disease, suggest that assessing frPSI may offer valuable insights into the risk of dementia progression in individuals with aMCI.

Torsades de Pointes With a Normal Magnesium Level in the Setting of Short Bowel Syndrome.

Torsades de pointes (TdP) is a potentially fatal arrhythmia, typically presenting with a congenital or acquired etiology. Low serum magnesium level is a known cause leading to this arrhythmia. However, it has been found that even in the setting of a normal serum magnesium level and with no other foreseeable etiology, TdP may still occur, especially in those with chronic electrolyte deficiencies. TdP may be treated in a number of ways, including IV magnesium sulfate or defibrillation if the patient becomes unresponsive and hemodynamically unstable. In some cases, atrial overdrive is required with the use of isoproterenol. A final decision, however, would necessitate asking if the patient can be sent home on medical management to prevent recurrence of the arrhythmia or require placement of a permanent pacemaker. Here, we describe a patient developing recurrent TdP despite normal serum magnesium level in the setting of short bowel syndrome.

The relationship of semantic intrusions to different etiological subtypes of MCI and cognitively healthy older adults.

INTRODUCTION: There is increasing evidence that susceptibility to proactive semantic interference (PSI) and the failure to recover from PSI (frPSI) as evidenced by intrusion errors may be early cognitive markers of both preclinical and prodromal Alzheimer's disease (AD). METHODS: One hundred forty-five participants were administered extensive clinical and neuropsychological evaluations including the Loewenstein-Acevedo Scales for Semantic Interference and Learning (LASSI-L), a sensitive cognitive stress test measuring PSI and frPSI. Participants also underwent structural magnetic resonance imaging (MRI) and amyloid positron emission tomography/computed tomography (PET/CT) imaging. RESULTS: PSI and frPSI errors were much more prevalent in the mild cognitive impairment (MCI)-AD (amyloid positive) group than the other diagnostic groups. The number of intrusion errors observed across the other MCI groups without amyloid pathology and those with normal cognition were comparable. DISCUSSION: Semantic intrusion errors on the LASSI-L occur much less frequently in persons who have different types of non-AD-related MCI and may be used as an early cognitive marker of prodromal AD.

Eukaryotic phosphatase inhibitors enhance colistin efficacy in gram-negative bacteria.

The mounting threat of multi-drug-resistant (MDR) bacteria places a tremendous strain on the antimicrobial clinical arsenal, forcing physicians to revert to near-obsolete antibiotics to treat otherwise intractable infections. Antibiotic adjuvant therapy has emerged as a viable alternative to the development of novel antimicrobial agents. This method uses combinations of an existing antibiotic and a non-antimicrobial small molecule, where the combination either breaks drug resistance or further potentiates antibiotic activity. Through a high-content screen of eukaryotic kinase inhibitors, our group previously identified two highly potent adjuvants that synergize with colistin, a cyclic, polycationic antimicrobial peptide that serves as a drug of last resort for the treatment of MDR Gram-negative bacterial infections. Cell signaling proteins implicated in colistin resistance mechanisms display both kinase and phosphatase activities. Herein, we explore the potential for eukaryotic phosphatase inhibitors to be repurposed as colistin adjuvants. From a panel of 48 unique structures, we discovered that the natural product kuwanon G breaks colistin resistance, while the non-antimicrobial macrolide ascomycin potentiates colistin in polymyxin-susceptible bacteria.

Structure-Function Studies on IMD-0354 Identifies Highly Active Colistin Adjuvants.

Infections caused by multidrug-resistant (MDR) bacteria, particularly Gram-negative bacteria, are an escalating global health threat. Often clinicians are forced to administer the last-resort antibiotic colistin; however, colistin resistance is becoming increasingly prevalent, giving rise to the potential for a situation in which there are no treatment options for MDR Gram-negative infections. The development of adjuvants that circumvent bacterial resistance mechanisms is a promising orthogonal approach to the development of new antibiotics. We recently disclosed that the known IKK-ß inhibitor IMD-0354 potently suppresses colistin resistance in several Gram-negative strains. In this study, we explore the structure-activity relationship (SAR) between the IMD-0354 scaffold and colistin resistance suppression, and identify several compounds with more potent activity than the parent against highly colistin-resistant strains of Acinetobacter baumannii and Klebsiella pneumoniae.

Repurposing Eukaryotic Kinase Inhibitors as Colistin Adjuvants in Gram-Negative Bacteria.

Kinase inhibitors comprise a diverse cohort of chemical scaffolds that are active in multiple biological systems. Currently, thousands of eukaryotic kinase inhibitors are commercially available, have well-characterized targets, and often carry pharmaceutically favorable toxicity profiles. Recently, our group disclosed that derivatives of the natural product meridianin D, a known inhibitor of eukaryotic kinases, modulated behaviors of both Gram-positive and Gram-negative bacteria. Herein, we expand our exploration of kinase inhibitors in Gram-negative bacilli utilizing three commercially available kinase inhibitor libraries and, ultimately, identify two chemical structures that potentiate colistin (polymyxin E) in multiple strains. We report IMD-0354, an inhibitor of IKK-ß, as a markedly effective adjuvant in colistin-resistant bacteria and also describe AR-12 (OSU-03012), an inhibitor of pyruvate dehydrogenase kinase-1 (PDK-1), as a potentiator in colistin-sensitive strains. This report comprises the first description of the novel cross-reactivity of these molecules.

Second-Generation Tryptamine Derivatives Potently Sensitize Colistin Resistant Bacteria to Colistin.

Antibiotic resistance has significantly increased since the beginning of the 21st century. Currently, the polymyxin colistin is typically viewed as the antibiotic of last resort for the treatment of multidrug resistant Gram-negative bacterial infections. However, increased colistin usage has resulted in colistin-resistant bacterial isolates becoming more common. The recent dissemination of plasmid-borne colistin resistance genes (mcr 1-8) into the human pathogen pool is further threatening to render colistin therapy ineffective. New methods to combat antibiotic resistant pathogens are needed. Herein, the utilization of a colistin-adjuvant combination that is effective against colistin-resistant bacteria is described. At 5 µM, the lead adjuvant, which is nontoxic to the bacteria alone, increases colistin efficacy 32-fold against bacteria containing the mcr-1 gene and effects a 1024-fold increase in colistin efficacy against bacteria harboring chromosomally encoded colistin resistance determinants; these combinations lower the colistin minimum inhibitory concentration (MIC) to or below clinical breakpoint levels (≤2 µg/mL).

Types of errors on a semantic interference task in mild cognitive impairment and dementia.

OBJECTIVE: This research aimed to determine whether qualitative analysis of different types of intrusion errors on a verbal cognitive task was useful in detecting subtle cognitive impairment in preclinical stages prior to the progression to dementia. METHOD: Different types of semantic intrusions on the Loewenstein-Acevedo Scales of Semantic Interference and Learning (LASSI-L) were compared across 160 individuals diagnosed as cognitively normal (CN), amnestic Mild Cognitive Impairment (aMCI), and dementia. The sample included Hispanics and non-Hispanic European Americans. RESULTS: Across diagnostic groups, the most common type of intrusion error was actual targets presented from a competing word list under conditions eliciting proactive semantic interference (PSI), and retroactive semantic interference (RSI), followed by intrusions that represented one of three overlapping semantic categories but none of the targets from List A or B. Nonsemantic intrusions rarely occurred. These competing list intrusions (CLI) and semantically related intrusions (SRI) differentiated between aMCI and CN participants. Further, these intrusion error were related to brain amyloid load, indicating their importance as potential primary markers of AD-related neurodegeneration. Ethnicity effects were not seen across the types of intrusion errors. CONCLUSIONS: Two types of intrusion errors (CLI and SRI) showed differences between the CN and aMCI group, with the aMCI group evidencing a higher rate of these intrusion errors compared with the CN group. These results support previous literature about the LASSI-L's sensitivity at the earliest stages of abnormal aging. (PsycINFO Database Record (c) 2019 APA, all rights reserved).

Tryptamine derivatives disarm colistin resistance in polymyxin-resistant gram-negative bacteria.

The last three decades have seen a dwindling number of novel antibiotic classes approved for clinical use and a concurrent increase in levels of antibiotic resistance, necessitating alternative methods to combat the rise of multi-drug resistant bacteria. A promising strategy employs antibiotic adjuvants, non-toxic molecules that disarm antibiotic resistance. When co-dosed with antibiotics, these compounds restore antibiotic efficacy in drug-resistant strains. Herein we identify derivatives of tryptamine, a ubiquitous biochemical scaffold containing an indole ring system, capable of disarming colistin resistance in the Gram-negative bacterial pathogens Acinetobacter baumannii, Klebsiella pneumoniae, and Escherichia coli while having no inherent bacterial toxicity. Resistance was overcome in strains carrying endogenous chromosomally-encoded colistin resistance machinery, as well as resistance conferred by the mobile colistin resistance-1 (mcr-1) plasmid-borne gene. These compounds restore a colistin minimum inhibitory concentration (MIC) below the Clinical & Laboratory Sciences Institute (CLSI) breakpoint in all resistant strains.

Effects of Bilingualism on Verbal and Nonverbal Memory Measures in Mild Cognitive Impairment.

OBJECTIVES: Maintaining two active languages may increase cognitive and brain reserve among bilingual individuals. We explored whether such a neuroprotective effect was manifested in the performance of memory tests for participants with amnestic mild cognitive impairment (aMCI). METHODS: We compared 42 bilinguals to 25 monolinguals on verbal and nonverbal memory tests. We used: (a) the Loewenstein-Acevedo Scales for Semantic Interference and Learning (LASSI-L), a sensitive test that taps into proactive, retroactive, and recovery from proactive semantic interference (verbal memory), and (b) the Benson Figure delayed recall (nonverbal memory). A subsample had volumetric MRI scans. RESULTS: The bilingual group significantly outperformed the monolingual group on two LASSI-L cued recall measures (Cued A2 and Cued B2). A measure of maximum learning (Cued A2) showed a correlation with the volume of the left hippocampus in the bilingual group only. Cued B2 recall (sensitive to recovery from proactive semantic interference) was correlated with the volume of the hippocampus and the entorhinal cortex of both cerebral hemispheres in the bilingual group, as well as with the left and right hippocampus in the monolingual group. The memory advantage in bilinguals on these measures was associated with higher inhibitory control as measured by the Stroop Color-Word test. CONCLUSIONS: Our results demonstrated a superior performance of aMCI bilinguals over aMCI monolinguals on selected verbal memory tasks. This advantage was not observed in nonverbal memory. Superior memory performance of bilinguals over monolinguals suggests that bilinguals develop a different and perhaps more efficient semantic association system that influences verbal recall. (JINS, 2019, 25, 15-28).

Utilizing semantic intrusions to identify amyloid positivity in mild cognitive impairment.

OBJECTIVE: Semantic intrusion (SI) errors may highlight specific breakdowns in memory associated with preclinical Alzheimer disease (AD); however, there have been no investigations to determine whether SI errors occur with greater frequency in persons with amnestic mild cognitive impairment (aMCI) confirmed as amyloid positive (Amy+) vs those who have clinical symptoms of aMCI-AD with negative amyloid scans (suspected non-AD pathology [SNAP]) or persons who are diagnosed with other brain disorders affecting cognition. METHODS: Eighty-eight participants with aMCI underwent brain amyloid PET and MRI scans and were classified as early AD (Amy+), SNAP (Amy-), or other neurological/psychiatric diagnosis (Amy-). We focused on SI on the Loewenstein-Acevedo Scales for Semantic Interference and Learning (LASSI-L) targeting proactive semantic interference (PSI; old semantic learning interferes with new semantic learning), failure to recover from PSI after an additional learning trial (frPSI), and retroactive semantic interference (new semantic learning interferes with memory for old semantic learning). RESULTS: SIs on measures of PSI and frPSI distinguished between Amy+ AD and SNAP and other non-AD cases. PSI and frPSI intrusions evidenced moderately high associations with reduced volumes in the entorhinal cortex, superior temporal regions, and supramarginal gyrus. No such associations were observed in cases with SNAP. CONCLUSIONS: SIs on the LASSI-L related to PSI and frPSI uniquely differentiated Amy+ and Amy- participants with aMCI and likely reflect deficits with inhibition and source memory in preclinical AD not captured by traditional cognitive measures. This may represent a specific, noninvasive test successful at distinguishing cases with true AD from those with SNAP.

Meridianin D Analogues Display Antibiofilm Activity against MRSA and Increase Colistin Efficacy in Gram-Negative Bacteria.

In the last 30 years, development of new classes of antibiotics has slowed, increasing the necessity for new options to treat multidrug resistant bacterial infections. Development of antibiotic adjuvants that increase the effectiveness of currently available antibiotics is a promising alternative approach to classical antibiotic development. Reports of the ability of the natural product meridianin D to modulate bacterial behavior have been rare. Herein, we describe the ability of meridianin D to inhibit biofilm formation of methicillin-resistant Staphylococcus aureus (MRSA) and to increase the potency of colistin against colistin-resistant and sensitive Gram-negative bacteria. Analogues were identified that are capable of inhibiting and dispersing MRSA biofilms and lowering the colistin MIC to below the CLSI breakpoint against Acinetobacter baumannii, Klebsiella pneumoniae, and Escherichia coli.

Semantic Intrusions and Failure to Recover From Semantic Interference in Mild Cognitive Impairment: Relationship to Amyloid and Cortical Thickness.

BACKGROUND: Accumulating evidence indicates that the failure to recover from the effects of proactive semantic interference [frPSI] represents an early cognitive manifestation of preclinical Alzheimer's disease. A limitation of this novel paradigm has been a singular focus on the number of targets correctly recalled, without examining co-occurring semantic intrusions [SI] that may highlight specific breakdowns in memory. OBJECTIVES: We focused on SI and their relationship to amyloid load and regional cortical thickness among persons with amnestic mild cognitive impairment (aMCI). METHODS: Thirty-three elders diagnosed with aMCI underwent F-18 florbetaben amyloid PET scanning with MRI scans of the brain. We measured the correlation of SI elicited on cued recall trials of the Loewenstein-Acevedo Scales for Semantic Interference and Learning [LASSI-L] with mean cortical amyloid load and regional cortical thickness in AD prone regions. RESULTS: SI on measures sensitive to frPSI was related to greater total amyloid load and lower overall cortical thickness [CTh]. In particular, SI were highly associated with reduced CTh in the left entorhinal cortex [r=-.71; p<.001] and left medial orbital frontal lobe [r=-.64; p<.001]; together accounting for 66% of the explained variability in regression models. CONCLUSION: Semantic intrusions on measures susceptible to frPSI related to greater brain amyloid load and lower cortical thickness. These findings further support the hypothesis that frPSI, as expressed by the percentage of intrusions, may be a cognitive marker of initial neurodegeneration and may serve as an early and distinguishing test for preclinical AD that may be used in primary care or clinical trial settings.

Small molecule adjuvants that suppress both chromosomal and mcr-1 encoded colistin-resistance and amplify colistin efficacy in polymyxin-susceptible bacteria.

Bacterial resistance to polymyxin antibiotics has taken on a new and more menacing form. Common are genomically-encoded resistance mechanisms to polymyxins, specifically colistin (polymyxin E), however, the plasmid-borne mobile colistin resistance-1 (mcr-1) gene has recently been identified and poses a new threat to global public health. Within six months of initial identification in Chinese swine in November 2015, the first human clinical isolation in the US was reported (Apr. 2016). Herein we report successful reversion of mcr-1-driven colistin resistance in Acinetobacter baumannii, Klebsiella pneumoniae, and Escherichia coli with adjuvants we previously reported as modulators of chromosomally-encoded colistin resistance. Further screening of our in-house library of nitrogen-dense heterocycles has identified additional chemical scaffolds that actively attenuate colistin resistance. Ultimately, we present a diverse cohort of adjuvants that both sensitize colistin-resistant and colistin-susceptible bacteria to this antibiotic, thus providing a potential avenue to both reduce colistin dosage and toxicity, and overcome colistin resistance.

Laparoscopic repair of paraesophageal hernias.

BACKGROUND AND OBJECTIVES: Laparoscopy has quickly become the standard surgical approach to repair paraesophageal hernias. Although many centers routinely perform this procedure, relatively high recurrence rates have led many surgeons to question this approach. We sought to evaluate outcomes in our cohort of patients with an emphasis on recurrence rates and symptom improvement and their correlation with true radiologic recurrence seen on contrast imaging. METHODS: We retrospectively identified 126 consecutive patients who underwent laparoscopic repair of a large paraesophageal hernia between 2000 and 2010. Clinical outcomes were reviewed, and data were collected regarding operative details, perioperative and postoperative complications, symptoms, and follow-up imaging. Radiologic evidence of any size hiatal hernia was considered to indicate a recurrence. RESULTS: There were 95 female and 31 male patients with a mean age (±standard deviation) of 71±14 years. Laparoscopic repair was completed successfully in 120 of 126 patients, with 6 operations converted to open procedures. Crural reinforcement with mesh was performed in 79% of patients, and 11% underwent a Collis gastroplasty. Fundoplications were performed in 90% of patients: Nissen (112), Dor (1), and Toupet (1). Radiographic surveillance, obtained at a mean time interval of 23 months postoperatively, was available in 89 of 126 patients (71%). Radiographic evidence of a recurrence was present in 19 patients (21%). Reoperation was necessary in 6 patients (5%): 5 for symptomatic recurrence (4%) and 1 for dysphagia (1%). The median length of stay was 4 days. CONCLUSION: Laparoscopic paraesophageal hernia repair results in an excellent outcome with a short length of stay when performed at an experienced center. Radiologic recurrence is observed relatively frequently with routine surveillance; however, many of these recurrences are small, and few patients require correction of the recurrence. Furthermore, these small recurrent hernias are often asymptomatic and do not seem to be associated with the same risk of severe complications developing as the initial paraesophageal hernia.

An electron transfer series of octahedral chromium complexes containing a redox non-innocent α-diimine ligand.

An electron-transfer series of octahedral α-diimine complexes [((H)L(Cy))3Cr](n+)(BARF)n (n = 2, 1, 0) has been synthesized and crystallographically characterized. Cyclic voltammetry indicated additional formation of [((H)L(Cy))3Cr](3+). The molecular structures suggested that all redox processes were ligand-based. Magnetic moments were consistent with spin ground states of S = 0 for [(H)L(Cy)3Cr](0), S = 1/2 for [(H)L(Cy)3Cr](+1), and S = 1 for [(H)L(Cy)3Cr](+2). The experimental data is consistent with chromium maintaining the +III oxidation state throughout, while being coordinated by varying numbers of neutral diimines ((H)L(Cy)) and diimine radical anions ((H)L(Cy)˙(-)).

Sharing knowledge, saving time: an online toolbox to aid junior doctors.

Junior doctors are too often frustrated by not being able to quickly find information for how to make referrals, book investigations and contact other professionals at hospital. To make matters worse, much of the knowledge gained by doctors throughout the year is lost during the August rotation. There is an unmet need for retaining such knowledge, in order to facilitate a smoother and safer handover. We set up the "Doctors Directory" at our trust; a website run by junior doctors, providing specific, up-to-date information relevant to other junior doctors within the trust. Whilst providing day-to-day information, it also contains a "survival guide" for each hospital firm. We surveyed junior doctors before and after the implementation of this site. 81% of FY1s surveyed have used the site. Of the doctors that had used the site, 94% found it helpful with a mean self reported time saving of 39 minutes a day. Whilst still in its infancy, the site now has mobile access, and has an average of 60 hits a day. Quality improvement projects such as this are readily scalable to other hospitals and have enabled junior doctors to waste less time finding how to do jobs and more time actually getting them done.

Time-calibrated phylogeny of the woody Australian genus Hakea (Proteaceae) supports multiple origins of insect-pollination among bird-pollinated ancestors.

PREMISE OF THE STUDY: A past study based on morphological data alone showed that the means by which plants of the Australian genus Hakea reduce florivory is related to the evolution of bird pollination. For example, bird pollination was shown to have arisen only in insect-pollinated lineages that already produced greater amounts of floral cyanide, a feature that reduces florivory. We examine a central conclusion of that study, and a common assumption in the literature, that bird pollination arose in insect-pollinated lineages, rather than the reverse. METHODS: We combined morphological and DNA data to infer the phylogeny and age of the Australian genus Hakea, using 9.2 kilobases of plastid and nuclear DNA and 46 morphological characters from a taxonomically even sampling of 55 of the 149 species. KEY RESULTS: Hakea is rooted confidently in a position that has not been suggested before. The phylogeny implies that bird pollination is primitive in Hakea and that multiple shifts to insect pollination have occurred. The unexpectedly young age of Hakea (a crown age of ca. 10 Ma) makes it coincident with its primary bird pollinators (honeyeaters) throughout its history. CONCLUSIONS: Our study demonstrates that Hakea is an exception to the more commonly described shift from insect to bird pollination. However, we note that only one previous phylogenetic study involved Australian plants and their honeyeater pollinators and that our finding might prove to be more common on that continent.