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Heterogenous biofilm mass-transport model replicates periphery sequestration of antibiotics in <i>Pseudomonas aeruginosa</i> PAO1 microcolonies
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A model for antibiotic accumulation in bacterial biofilm microcolonies utilizing heterogenous porosity and attachment site profiles replicated the periphery sequestration reported in prior experimental studies on
Pseudomonas aeruginosa PAO1
biofilm cell clusters. These
P. aeruginosa
cell clusters are in vitro models of the chronic
P. aeruginosa
infections in cystic fibrosis patients which display recalcitrance to antibiotic treatments, leading to exacerbated morbidity and mortality. This resistance has been partially attributed to periphery sequestration, where antibiotics fail to penetrate biofilm cell clusters. The physical phenomena driving this periphery sequestration have not been definitively established. This paper introduces mathematical models to account for two proposed physical phenomena driving periphery sequestration: biofilm matrix attachment and volume-exclusion due to variable biofilm porosity. An antibiotic accumulation model which incorporated these phenomena better fit observed periphery sequestration data compared to previous models.
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The Colors of My Skin: The Making of Black German Identity
No full textTo those belonging to the majority white culture in Germany, the concept of someone being both Black and German can seem a contradiction in terms. Due to the way German citizenship laws have historically been tied to blood, and German blood associated with whiteness, Black Germans have always had a hard time being recognized as full-fledged German citizens despite having a German birthplace, citizenship, and socialization. Specifically, this misrecognition as foreigners, i.e., as non-Germans, leads to Black Germans being discriminated
against, underrepresented, misrepresented, systematically excluded, and simply ignored in the country they call home. Devoting each chapter to examples of a particular literary genre such as life writing, poems, a play, and a novel, this dissertation explores the ways Black German authors push back against the exclusionary tendencies and practices that they face in the majority culture, fight for equality and recognition of their history and presence and define themselves on their own terms as both Black and German. In my analysis, I use the analytical term melodrama, or the family melodrama in particular which I define as an expressive mode that looks at how racial tensions are expressed in the domestic space. Family melodrama is also a useful analytic tool as it portrays clear moral categories of good vs. evil and focuses on a central character who has been victimized in some way. I demonstrate how employing melodrama allows Black German authors not only to critique racism but also evoke sympathy as well as offer hope for a minority group such as themselves
Individual differences in postoperative recovery trajectories for adult symptomatic lumbar scoliosis
No full textClinical and radiographic presentation and treatment of patients with cervical deformity secondary to thoracolumbar proximal junctional kyphosis are distinct despite achieving similar outcomes: Analysis of 123 prospective CD cases.
No full textCD development secondary to PJK was recently documented in adult spinal deformity patients after surgical correction for thoracolumbar ASD. This study analyzes surgical management of patients with CD secondary to proximal junctional kyphosis (PJK) versus patients with primary CD. Retrospective review of multicenter cervical deformity (CD) database. CD defined as at least one of the following: C2-C7 coronal Cobb > 10°, cervical lordosis (CL) > 10°, cervical sagittal vertical axis (cSVA) > 4cm, CBVA > 25°. Patients were grouped into those with PJK (UIV +2 0.05). PJK patients experienced higher rates of complications 30 and 90 days post-operatively (23.1% vs. 5.2%, p = 0.004; 30.8% vs. 19.6%, p = 0.026), and more instrumentation failure 30 days postoperatively (7.8% vs. 1.0%, p = 0.004). Patients with cervical deformity secondary to PJK had worse baseline CD, despite no differences in HRQL or demographics. Surgical correction of CD associated with PJK required more invasive surgery and had higher complication rates than non-PJK patients, despite achieving similar clinical outcomes
The Regulation of Effort Exertion by the Nucleus Accumbens Core
No full text The nucleus accumbens core is believed to play an important role in regulating effort exertion. Effort can be explained as the energetic costs of an action relative to its long-term benefits. Using fixed-ratio schedules of reinforcement, different effort requirements can be imposed upon mice, as the cost per benefit is determined by these press-per-pellet ratios. Fixed-ratio schedules have long been used to study effort, and manipulations that impact more effortful behaviors to a greater extent have consistently been interpreted as demonstrating a decrease in the willingness to exert effort. For decades, in numerous studies, these effects have been consistently observed following manipulations that disrupt a specific region of the brain, the nucleus accumbens. In the accumbens there are two main types of neurons, the direct and indirect pathway neurons, that play different roles in behavior and project to different downstream structures. The accumbens has also traditionally been divided into two subregions, the core and the shell. Much of what is known about these circuits comes from work where the researchers inject drugs into the accumbens, but newer research methods have become far more precise. Optogenetic techniques, with improved temporal resolution, spatial resolution, and cell-type specificity, have become extremely useful tools across many areas of neurobiology; but optogenetics has yet to be applied specifically to questions regarding the regulation of effort. Here these questions have been addressed by combining optogenetics (activation or inhibition of direct or indirect pathway neurons in the core or shell) with various fixed-ratio procedures used to enforce distinct effort requirements. Pressing reductions elicited by activation of direct pathway neurons in the core were significant, but demonstrated no relationship with effort requirement. In contrast, effort-dependent pressing reductions were caused by activation of core indirect pathway neurons. Furthermore, this indirect effect was not caused by motor impairments or differences in appetite, because port-entry rates were maintained during these same sessions, regardless of ratio schedule. Although the direct pathway effect was effort-independent, activating these neurons in the core was also found to elicit persistent gnawing, upon inedible objects in the animals’ surroundings. In addition, significant increases in pressing were caused by inhibition of indirect pathway neurons in the core, and solely for the high-effort sessions. Lastly, optogenetic activation of indirect pathway neurons was found to elicit no behavioral effect when administered in the shell.
These findings suggest that the willingness of animals to exert effort is being determined by the output of the indirect pathway projections from the core; and that these cells play this role somewhat exclusively, as the direct pathway is not regulating effort, and neither is the shell. But, indirect pathway neurons in the core determine willingness to exert effort on a moment-to-moment timescale, and this effort regulation process is bidirectional in nature, as demonstrated via bidirectional optogenetics. High output in these cells reduces the willingness to exert effort, whereas low output is associated with a greater willingness. These findings are novel, particularly the timescale of this effect, but in general they are in agreement with a large body of previous work. They also suggest that the two pathways and the two accumbal subregions play distinct roles in motivated behavior, and interestingly, core direct pathway activation can cause gnawing.
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Single-shot Ad26 vaccine protects against SARS-CoV-2 in rhesus macaques.
No full textA safe and effective vaccine for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) may be required to end the coronavirus disease 2019 (COVID-19) pandemic1-8. For global deployment and pandemic control, a vaccine that requires only a single immunization would be optimal. Here we show the immunogenicity and protective efficacy of a single dose of adenovirus serotype 26 (Ad26) vector-based vaccines expressing the SARS-CoV-2 spike (S) protein in non-human primates. Fifty-two rhesus macaques (Macaca mulatta) were immunized with Ad26 vectors that encoded S variants or sham control, and then challenged with SARS-CoV-2 by the intranasal and intratracheal routes9,10. The optimal Ad26 vaccine induced robust neutralizing antibody responses and provided complete or near-complete protection in bronchoalveolar lavage and nasal swabs after SARS-CoV-2 challenge. Titres of vaccine-elicited neutralizing antibodies correlated with protective efficacy, suggesting an immune correlate of protection. These data demonstrate robust single-shot vaccine protection against SARS-CoV-2 in non-human primates. The optimal Ad26 vector-based vaccine for SARS-CoV-2, termed Ad26.COV2.S, is currently being evaluated in clinical trials
Efficient and Collaborative Methods for Distributed Machine Learning
No full textIn recent years, there has been a significant expansion in the scale and complexity of neural networks. This has resulted in significant demand for data, computation, and energy resources. In this light, it is crucial to enhance and optimize the efficiency of these ML models and algorithms. Additionally, the rise in computational capabilities of modern devices has prompted a shift towards distributed systems that enable localized data storage and model training. While this evolution promises substantial potential, it introduces a series of challenges. Such challenges encompass addressing the heterogeneity across systems, data, models, and supervision, balancing the trade-off among communication, computation, and performance, as well as building a community of shared interest to encourage collaboration in the emerging era of Artificial General Intelligence (AGI). In this dissertation, we contribute to the establishment of a theoretically justified, methodologically comprehensive, and universally applicable Efficient and Collaborative Distributed Machine Learning framework. Specifically, in Part I, we contribute to methodologies for Efficient Machine Learning including for both learning and inference. In this direction, we propose a parameter-efficient model, namely Restricted Recurrent Neural Networks (RRNN), that leverage the recurrent structures of RNNs using weight sharing in order to improve learning efficiency. We also introduce an optimal measure of vector sparsity named the PQ Index (PQI), and postulate a hypothesis connecting this sparsity measure and compressibility of neural networks. Based on this, we propose a Sparsity-informed Adaptive Pruning (SAP) algorithm. This algorithm adaptively determines the pruning ratio to enhance inference efficiency. In Part II, we address both efficiency and collaboration in Distributed Machine Learning. We introduce Distributed Recurrent Autoencoders for Scalable Image Compression (DRASIC), a data-driven Distributed Source Coding framework that can compress heterogeneous data in a scalable and distributed manner. We then propose Heterogeneous Federated Learning (HeteroFL), demonstrating the feasibility of training localized heterogeneous models to create a global inference model. Subsequently, we propose a new Federated Learning (FL) framework, namely SemiFL, to tackle Semi-Supervised Federated Learning (SSFL) for clients with unlabeled data. This method performs comparably with state-of-the-art centralized Semi-Supervised Learning (SSL), and fully supervised FL techniques. Finally, we propose Gradient Assisted Learning (GAL) in order to enable collaborations among multiple organizations without sharing data, models, and objective functions. This method significantly outperforms local learning baselines and achieves near-oracle performance. In Part III, we develop collaborative applications for building a community of shared interest. We apply SemiFL to Keyword Spotting (KWS), a technique widely used in virtual assistants. Numerical experiments demonstrate that one can train models from the scratch, or transfer from pre-trained models in order to leverage heterogeneous unlabeled on-device data, using only a small amount of labeled data from the server. Finally, we propose a Decentralized Multi-Target Cross-Domain Recommendation (DMTCDR) which enhances the recommendation performance of decentralized organizations without compromising data privacy or model confidentiality.</p
A Brief Screening and Assessment Tool for Opioid Use in Adults: Results from a Validation Study of the Tobacco, Alcohol, Prescription Medication, and Other Substances Tool.
No full textObjectivesThis secondary analysis evaluated opioid-specific validation results of the Tobacco, Alcohol, Prescription Medication, and Other Substances (TAPS) tool for screening in primary care.MethodsThis study is a secondary data analysis of the TAPS validation study. Performance of the TAPS tool for screening for unhealthy opioid use (with a score of 1+ for heroin and/or prescription opioids representing a positive screen) was evaluated. Discriminative ability was examined in comparison with reference standard measures across the spectrum of unhealthy opioid use: timeline follow-back with and without oral fluid testing identifying past-month use and the modified Composite International Diagnostic Interview for past-year problem use, opioid use disorder (OUD), and moderate-severe OUD.ResultsIn a sample of 2000 primary care patients, 114 screened positive for opioids on the TAPS tool. With a TAPS cutoff equal to 1+, the TAPS accurately identified past-month use, problem use, any OUD, and moderate-severe OUD (sensitivities = 68%-85%, specificities = 97%-98%, area under the curve = 0.80-0.91). When past-month use was expanded to include timeline follow-back with oral fluid testing, accuracy declined (52% sensitivity [95% confidence interval, 43%-60%], 98% specific [95% confidence interval, 97%-98%]).ConclusionsWhile further testing in a larger population sample may be warranted, given their brevity, simplicity, and accuracy when self-administered, the TAPS opioid items can be used in primary care settings for a spectrum of unhealthy opioid use; however, self-disclosure remains an issue in primary care settings
Glucosylsphingosine (Lyso-Gb<sub>1</sub>): An Informative Biomarker in the Clinical Monitoring of Patients with Gaucher Disease.
No full textHistorically, disease burden and treatment responses in patients with Gaucher disease (GD) was assessed by monitoring clinical data, laboratory, imaging, chitotriosidase (CHITO), and other biomarkers; however, these biomarkers lack specificity and CHITO is uninformative in patients heterozygous or homozygous for the CHIT1 c.1049_1072dup24 variant. Recently, glucosylsphingosine (lyso-Gb1), a sensitive and specific GD biomarker, has been recommended for patient monitoring. Furthermore, studies measuring lyso-Gb1 and CHITO in patients on long-term treatment with enzyme replacement therapy (ERT) and/or substrate reduction therapy (SRT) reported as group data show a reduction in both analytes, yet individualized patient data are generally unavailable. We describe seven patients on long-term treatment with longitudinal clinical data with monitoring based on current treatment guidelines. We present four patients who exhibit stable disease with normalized CHITO despite elevated lyso-Gb1. We present one patient who transitioned from ERT to SRT due to lack of a clinical response with life-threatening thrombocytopenia who responded with marked improvement in platelets, and normalized levels of both CHITO and lyso-Gb1. Finally, we present two ERT to SRT switch patients with stable disease on ERT who exhibited non-compliance on SRT, one with mirrored marked elevations of CHITO and lyso-Gb1; and another with normal CHITO and platelets, but increasing lyso-Gb1 levels and enlarged spleen. These clinical vignettes highlight the role of lyso-Gb1 as a sensitive biomarker in management of patients with GD, and its further value when CHITO is normal and thus uninformative. We highlight the personalized medicine approach needed to optimize treatment outcomes and recommendations for these patients