In vitro Bactericidal Activities of Combination Antibiotic Therapies Against Carbapenem-Resistant Klebsiella pneumoniae With Different Carbapenemases and Sequence Types

Carbapenem-resistant Klebsiella pneumoniae (CRKP) is becoming increasingly problematic due to the limited effectiveness of new antimicrobials or other factors such as treatment cost. Thus, combination therapy remains a suitable treatment option. We aimed to evaluate the in vitro bactericidal activity of various antibiotic combinations against CRKP with different carbapenemase genotypes and sequence types (STs). Thirty-seven CRKP with various STs and carbapenemases were exposed to 11 antibiotic combinations (polymyxin B or tigecycline in combination with β-lactams including aztreonam, cefepime, piperacillin/tazobactam, doripenem, meropenem, and polymyxin B with tigecycline) in static time-kill studies (TKS) using clinically achievable concentrations. Out of the 407 isolate-combination pairs, only 146 (35.8%) were bactericidal (≥3 log10CFU/mL decrease from initial inoculum). Polymyxin B in combination with doripenem, meropenem, or cefepime was the most active, each demonstrating bactericidal activity in 27, 24, and 24 out of 37 isolates, respectively. Tigecycline in combination with β-lactams was rarely bactericidal. Aside from the lower frequency of bactericidal activity in the dual-carbapenemase producers, there was no apparent difference in combination activity among the strains with other carbapenemase types. In addition, bactericidal combinations were varied even in strains with similar STs, carbapenemases, and other genomic characteristics. Our findings demonstrate that the bactericidal activity of antibiotic combinations is highly strain-specific likely owing to the complex interplay of carbapenem-resistance mechanisms, i.e., carbapenemase genotype alone cannot predict in vitro bactericidal activity. The availability of WGS information can help rationalize the activity of certain combinations. Further studies should explore the use of genomic markers with phenotypic information to predict combination activity.

Extremely Southward Migration of the Antarctic Circumpolar Current During the Last Interglacial

The Antarctic Circumpolar Current (ACC) acts as a critical component to regulate the global thermohaline circulation and climate. However, active debate remains about the relative strength of ACC during current/past warm periods and underlying driving mechanisms. Here, we present sortable silt mean grain size records from the Scotia Sea to infer the ACC strength over the past 160 ka. The 22-ka cycles of sortable silt mean grain size suggest that the precession-driven contraction/expansion of Subtropical Jet dominates the migration of ACC fronts, and thus ACC speed and potential Atlantic Meridional Overturning Circulation stability. We find that the bottom flow speed during MIS 5e was over three times faster than the Holocene, with no apparent difference in ACC speed between the Holocene and the Last Glacial Maximum. We suggest that a southward shift of oceanic fronts of ~5° could cause the additional speed-up of ACC during MIS 5e. This could induce warmer water flowing in the ACC to approach and melt the Antarctica continental ice shelves, with corresponding effects on global sea level and the global climate.

Pet Ownership and Multiple Sclerosis during COVID-19

Background: Multiple sclerosis (MS) is associated with lower quality of life, reduced social participation, and decreased self-efficacy. The COVID-19 pandemic has had documented effects on the health and wellbeing of people with and without MS. Previous research has demonstrated the positive impact pets can have for people living with long-term conditions. Objectives: To explore the rates of pet ownership and pet attachment in people living with MS and pet ownership associations with quality of life, satisfaction with social roles, and self-efficacy scores; and to explore the effects of the COVID-19 outbreak on people’s perceived relationships with their pets. Materials and Methods: A postal questionnaire was distributed to members of a local MS Register and a control group of people without MS. The questionnaire assessed quality of life, satisfaction with social roles, self-efficacy, the perceived roles of pets, and pet-related concerns experienced during the COVID-19 pandemic. Results: No apparent difference in attachment to pets was found between the patient and control groups. Pet ownership and level of attachment were not associated with differences in quality of life or self-efficacy scores in people living with MS. Using multiple regression analysis, pet ownership was associated with a decrease in satisfaction with participation in social roles, but with the estimated effect being small compared to having a diagnosis of MS or being unemployed. Most participants reported that pets had positive roles during the pandemic, and the most reported pet-related concern was access to veterinary treatment. Conclusion: Pet owners both with and without MS reported subjective benefits to their wellbeing from pet ownership during COVID-19, although analysis suggested that pet ownership was associated with a reduction in satisfaction with social roles. The study had several limitations and suggestions are made for future work.

1083. Phase 1b Results of Pharmacokinetics, Pharmacodynamics, and Safety for LBP-EC01, a CRISPR-Cas3 Enhanced Bacteriophage Cocktail Targeting Escherichia coli that Cause Urinary Tract Infections

Background LBP-EC01 is the first CRISPR-engineered bacteriophage product to successfully complete Phase 1b testing in a clinical program designed to address infections caused by E. coli initially targeting urinary tract infections (UTIs). Thirty-six subjects were enrolled in this randomized, double blind study to assess the safety, tolerability, pharmacokinetics and pharmacodynamics of LBP-EC01 in patients with lower urinary tract colonization caused by E. coli. Methods Results No drug-related Treatment Emergent Adverse Events (TEAEs) were observed. All nondrug related TEAEs were Grade 2 or below and there were no tolerability signals associated with LBP-EC01.A modified ITT (mITT) population was defined to assess PK in subjects treated with LBP-EC01 (n=17). Subjects were removed from the PK analysis who had missing or insufficient colonization at baseline (n=3), were exposed to antibiotics during screening or study conduct (n=3) or exhibited a non-drug related SAE (n=1). Of these subjects, 12 were found to be sensitive to LBP-EC01 and of these, 10 (83%) showed phage amplification. A PD analysis compared the mITT populations of LBP-EC01 vs. placebo (n=6) and showed that the LBP-EC01 arm had a decrease in E. coli that was greatest within 24 hours of initial treatment and remained below baseline across the entire treatment period. The placebo arm showed increased levels of E. coli and higher variability over the treatment period. An average difference of 2-3 log (100x to 1,000x) existed in urine E. coli concentration (CFU/mL) between the LBP-EC01 and placebo arms across the duration of the treatment period. Conclusion LBP-EC01 has proved to be safe and well-tolerated in this Phase 1b study of subjects colonized by E. coli. In addition, phage amplification was observed in patients with E. coli isolates sensitive to LBP-EC01, demonstrating a clear proof of mechanism. Finally, the apparent difference in PD effect between LBP-EC01 and placebo which was irrespective of MDR status, provides promise that LBP-EC01 may someday be an excellent option for patients suffering from UTIs caused by E. coli, especially in strains that are resistant to conventional antibiotics. Disclosures Dave ousterout, PhD, InceptorBio (Advisor or Review Panel member, Shareholder)Locus Biosciences (Employee, Shareholder)

Blood Neurofilament Light Chain in Parkinson’s Disease: Comparability between Parkinson’s Progression Markers Initiative (PPMI) and Asian Cohorts

Elevated blood neurofilament light chain (NfL), which indicates the loss of neuronal integrity, is increasingly implicated as a diagnostic and outcome-predicting biomarker for neurological diseases. However, its diagnostic implication for Parkinson’s disease (PD) remains unclear, with conflicting data reported by several studies. This may result from the demographic heterogeneity of the studied cohorts. The present study investigated the comparability of blood NfL between a domestic, single-centered PD cohort from Shuang Ho Hospital (SHH) in Taiwan, with the large international, multi-center cohort, Parkinson’s Progression Markers Initiative (PPMI). In the SHH PD cohort, with 61 people with PD (PwP) and 25 healthy non-PD controls, plasma NfL unexpectedly was significantly higher in the control group than PwP (14.42 ± 13.84 vs. 9.39 ± 6.91 pg/mL, p = 0.05). Interestingly, subgroup analysis revealed a non-significant difference of plasma NfL levels in male PwP compared with controls (8.58 ± 6.21 vs. 7.25 ± 4.43 pg/mL, p =0.575), whereas NfL levels were significantly lower in the female PwP group than in their healthy control peers (10.29 ± 7.62 vs. 17.79 ± 15.52 pg/mL, p = 0.033). Comparative analysis of the SHH and PPMI cohorts revealed a comparable gender-stratified distribution of blood NfL based on approximate theoretical quantiles. After adjusting for age and gender, no apparent difference in NfL value distribution was observed between the SHH and PPMI cohorts’ control or PD groups. Significant downregulation of blood NfL levels were positively correlated with a reduced probability of having a PD diagnosis in both cohorts. These results demonstrated that the adjustment for demographic background enhances comparability between cohorts, and may be required to eliminate covariate/confounder-associated conflict in blood NfL results between different PD studies. This experience may be beneficial to other researchers around the world who are saddled with limited study participants, especially as data from small cohort sizes are often at greater risk of being skewed by specific variables.

A Gauge Theory for the Weak and Electromagnetic Interactions

In this chapter we develop the Glashow–Weinberg–Salam theory of electromagnetic and weak interactions based on the gauge group SU(2) × U(1). We show that the apparent difference in strength between the two interactions is due to the Brout–Englert–Higgs phenomenon which results in heavy intermediate vector bosons. The model is presented first for the leptons, and then we argue that the extension to hadrons requires the introduction of a fourth quark. We show that the GIM mechanism guarantees the natural suppression of strangeness changing neutral currents. In the same spirit, the need to introduce a natural source of CP-violation leads to a six quark model with the Cabibbo–Kobayashi–Maskawa mass matrix.

Buckling Pattern Transition Of Periodic Porous Elastomers Induced By Proportional Loading Conditions

This paper focuses on the buckling instabilities of periodic porous elastomers under combined multiaxial loading. A numerical model based on the periodic boundary condition (PBC) for the 2D representative volume element (RVE) is proposed, in which two proportional loading parameters are employed to control the complex stressing state applied to the RVE model. A homogenization-based orthogonal transformation matrix is established by satisfying the equality of the total work rate to realize a proportional multiaxial loading on the RVE. First, the transition behavior of buckling patterns of periodic porous structures is revealed through instability analysis for the RVE consisting of [Formula: see text] primitive cells with circular holes subjected to different proportional loading conditions. Simulation results show that the first-order buckling mode of RVE may change suddenly from a uniaxial shearing buckling pattern to a biaxial rotating buckling pattern at a critical loading proportion. Then the influences of the number of primitive cells in the enlarged RVE on the buckling behavior are discussed. When the number of primitive cells in any enlarging direction is odd, the points of buckling pattern transition of the enlarged RVEs vary significantly with the number of cells in RVE. When the number of primitive cells is even in both enlarging directions, there is no apparent difference for the critical buckling stresses of the enlarged RVEs.

Angiotensin–Converting Enzyme (ACE) 1 Gene Polymorphism and Phenotypic Expression of COVID-19 Symptoms

The renin–angiotensin–aldosterone system (RAAS) appears to play an important role in SARS-CoV-2 infection. Polymorphisms within the genes that control this enzymatic system are candidates for elucidating the pathogenesis of COVID-19, since COVID-19 is not only a pulmonary disease but also affects many organs and systems throughout the body in multiple ways. Most striking is the fact that ACE2, one of the major components of the RAAS, is a prerequisite for SARS-COV-2 infection. Recently, we and other groups reported an association between a polymorphism of the ACE1 gene (a homolog of ACE2) and the phenotypic expression of COVID-19, particularly in its severity. The ethnic difference in ACE1 insertion (I)/deletion (D) polymorphism seems to explain the apparent difference in mortality between the West and East Asia. The purpose of this review was to further evaluate the evidence linking ACE1 polymorphisms to COVID-19. We searched the Medline database (2019–2021) for reference citations of relevant articles and selected studies on the clinical outcome of COVID-19 related to ACE1 I/D polymorphism. Although the numbers of patients are not large enough yet, most available evidence supports the notion that the DD genotype adversely influences COVID-19 symptoms. Surprisingly, small studies conducted in several countries yielded opposite results, suggesting that the ACE1 II genotype is a risk factor. This contradictory result may be the case in certain geographic areas, especially in subgroups of patients. It may also be due to interactions with other genes or to yet unexplained biochemical mechanisms. According to our hypothesis, such candidates are genes that are functionally involved in the pathophysiology of COVID-19, can act in concert with the ACE1 DD genotype, and that show differences in their frequency between the West and East Asia. For this, we conducted research focusing on Alu-related genes. The current study on the ACE1 genotype will provide potentially new clues to the pathogenesis, treatment, and diagnosis of SARS-CoV-2 infections.

Neural activation in photosensitive brain regions of Atlantic salmon (Salmo salar) after light stimulation

Photoreceptive inputs to the teleost brain are perceived as image of the visual world and as photo-modulation of neuroendocrine and neuronal signals. The retina and pineal organ are major receptive organs with projections to various parts of the brain, but in the past decades deep brain photoreceptors have emerged as candidates for photoreceptive inputs, either independent or in combination with projections from light sensory organs. This study aimed to test the effects of narrow bandwidth light using light-emitting diodes technology on brain neural activity through putative opsin stimulation in Atlantic salmon. The expression of c-fos, a known marker of neural activity, was compared in situ between dark-adapted salmon parr and following light stimulation with different wavelengths. c-fos expression increased with duration of light stimulation and the strongest signal was obtained in fish exposed to light for 120 minutes. Distinct and specific brain regions were activated following dark to light stimulation, such as the habenula, suprachiasmatic nucleus, thalamus, and hypothalamus. The c-fos expression was overlapping with photoreceptors expressing melanopsin and/or vertebrate ancient opsin, suggesting a potential direct activation by light. Interestingly in the habenula, a distinct ring of vertebrate ancient opsin and melanopsin expressing cells is overlapping with c-fos expression after neural activation. Salmon exposed to different spectra had neural activation in similar brain regions. The most apparent difference was melanopsin expression in the lateral cells of the lateral tuberal nuclus in the hypothalamus, which appeared to be specifically activated by red light. Light-stimulated neuronal activity in the deep brain was limited to subpopulations of neurons, mainly in regions with neuronal modulation activity, retinal and pineal innervations and known presence of nonvisual photoreceptors. The overlapping expression patterns of c-fos and nonvisual opsins support direct light stimulation of deep brain photoreceptors and the importance of these systems in light induced brain activity.

Bayesian inference with incomplete knowledge explains perceptual confidence and its deviations from accuracy

In perceptual decisions, subjects infer hidden states of the environment based on noisy sensory information. Here we show that both choice and its associated confidence are explained by a Bayesian framework based on partially observable Markov decision processes (POMDPs). We test our model on monkeys performing a direction-discrimination task with post-decision wagering, demonstrating that the model explains objective accuracy and predicts subjective confidence. Further, we show that the model replicates well-known discrepancies of confidence and accuracy, including the hard-easy effect, opposing effects of stimulus variability on confidence and accuracy, dependence of confidence ratings on simultaneous or sequential reports of choice and confidence, apparent difference between choice and confidence sensitivity, and seemingly disproportionate influence of choice-congruent evidence on confidence. These effects may not be signatures of sub-optimal inference or discrepant computational processes for choice and confidence. Rather, they arise in Bayesian inference with incomplete knowledge of the environment.