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Neuromodulation : Journal of the... Jul 2024This study analyzes the stimulation parameters implemented during two successful trials that used non-invasive transcutaneous spinal cord stimulation (tSCS) to...
OBJECTIVES
This study analyzes the stimulation parameters implemented during two successful trials that used non-invasive transcutaneous spinal cord stimulation (tSCS) to effectively improve upper extremity function after chronic spinal cord injury (SCI). It proposes a framework to guide stimulation programming decisions for the successful translation of these techniques into the clinic.
MATERIALS AND METHODS
Programming data from 60 participants who completed the Up-LIFT trial and from 17 participants who subsequently completed the LIFT Home trial were analyzed. All observations of stimulation amplitudes, frequencies, waveforms, and electrode configurations were examined. The incidence of adverse events and relatedness to stimulation parameters is reported. A comparison of parameter usage across the American Spinal Injury Association Impairment Scale (AIS) subgroups was conducted to evaluate stimulation strategies across participants with varying degrees of sensorimotor preservation.
RESULTS
Active (cathodal) electrodes were typically placed between the C3/C4 and C6/C7 spinous processes. Most sessions featured return (anodal) electrodes positioned bilaterally over the anterior superior iliac spine, although clavicular placement was frequently used by 12 participants. Stimulation was delivered with a 10-kHz carrier frequency and typically a 30-Hz burst frequency. Biphasic waveforms were used in 83% of sessions. Average stimulation amplitudes were higher for biphasic waveforms. The AIS B subgroup required significantly higher amplitudes than did the AIS C and D subgroups. Device-related adverse events were infrequent, and not correlated with specific waveforms or amplitudes. Within the home setting, participants maintained their current amplitudes within 1% of the preset values. The suggested stimulation programming framework dictates the following hierarchical order of parameter adjustments: current amplitude, waveform type, active/return electrode positioning, and burst frequency, guided by clinical observations as required.
CONCLUSIONS
This analysis summarizes effective stimulation parameters from the trials and provides a decision-making framework for clinical implementation of tSCS for upper extremity functional restoration after SCI. The parameters are aligned with existing literature and proved safe and well tolerated by participants.
PubMed: 38958629
DOI: 10.1016/j.neurom.2024.05.005 -
Journal of Chemical Theory and... Jul 2024Self-splicing ribozymes are small ribonucleic acid (RNA) enzymes that catalyze their own cleavage through a transphosphoesterification reaction. While this process is...
Self-splicing ribozymes are small ribonucleic acid (RNA) enzymes that catalyze their own cleavage through a transphosphoesterification reaction. While this process is involved in some specific steps of viral RNA replication and splicing, it is also of importance in the context of the (putative) first autocatalytic RNA-based systems that could have preceded the emergence of modern life. The uncatalyzed phosphoester bond formation is thermodynamically very unfavorable, and many experimental studies have focused on understanding the molecular features of catalysis in these ribozymes. However, chemical reaction paths are short-lived and not easily characterized by experimental approaches, so molecular simulation approaches appear as an ideal tool to unveil the molecular details of the reaction. Here, we focus on the model hairpin ribozyme. We show that identifying a relevant initial conformation for reactivity studies, which is frequently overlooked in mixed quantum-classical studies that predominantly concentrate on the chemical reaction itself, can be highly challenging. These challenges stem from limitations in both available experimental structures (which are chemically altered to prevent self-cleavage) and the accuracy of force fields, together with the necessity for comprehensive sampling. We show that molecular dynamics simulations, combined with extensive conformational phase space exploration with Hamiltonian replica-exchange simulations, enable us to characterize the relevant conformational basins of the minimal hairpin ribozyme in the ligated state prior to self-cleavage. We find that what is usually considered a canonical reactive conformation with active site geometries and hydrogen-bond patterns that are optimal for the addition-elimination reaction with general acid/general base catalysis is metastable and only marginally populated. The thermodynamically stable conformation appears to be consistent with the expectations of a mechanism that does not require the direct participation of ribozyme residues in the reaction. While these observations may suffer from forcefield inaccuracies, all investigated forcefields lead to the same conclusions upon proper sampling, contrasting with previous investigations on shorter timescales suggesting that at least one reparametrization of the Amber99 forcefield allowed to stabilize aligned active site conformations. Our study demonstrates that identifying the most pertinent reactant state conformation holds equal importance alongside the accurate determination of the thermodynamics and kinetics of the chemical steps of the reaction.
PubMed: 38958594
DOI: 10.1021/acs.jctc.4c00294 -
Environmental Science & Technology Jul 2024As the number of coastal nuclear facilities rapidly increases and the wastewater from the Fukushima Nuclear Plant has been discharged into the Pacific Ocean, the nuclear...
As the number of coastal nuclear facilities rapidly increases and the wastewater from the Fukushima Nuclear Plant has been discharged into the Pacific Ocean, the nuclear environmental safety of China's marginal seas is gaining increased attention along with the heightened potential risk of nuclear accidents. However, insufficient work limits our understanding of the impact of human nuclear activities on the Yellow Sea (YS) and the assessment of their environmental process. This study first reports the I and I records of posthuman nuclear activities in the two YS sediments. Source identification of anthropogenic I reveals that, in addition to the gaseous I release and re-emission of oceanic I discharged from the European Nuclear Fuel Reprocessing Plants (NFRPs), the Chinese nuclear weapons testing fallout along with the global fallout is an additional I input for the continental shelf of the YS. The I/I atomic ratios in the North YS (NYS) sediment are significantly higher than those in the other adjacent coastal areas, attributed to the significant riverine input of particulate I by the Yellow River. Furthermore, we found a remarkable I latitudinal disparity in the sediments than those in the seawaters in the various China seas, revealing that sediments in China's marginal seas already received a huge anthropogenic I from terrigenous sources via rivers and thus became a significant sink of anthropogenic I. This study broadens an insight into the potential impacts of terrigenous anthropogenic pollution on the Chinese coastal marine radioactive ecosystem.
PubMed: 38958591
DOI: 10.1021/acs.est.4c02123 -
Journal of Chemical Information and... Jul 2024One of the most challenging tasks in modern medicine is to find novel efficient cancer therapeutic methods with minimal side effects. The recent discovery of several...
One of the most challenging tasks in modern medicine is to find novel efficient cancer therapeutic methods with minimal side effects. The recent discovery of several classes of organic molecules known as "molecular jackhammers" is a promising development in this direction. It is known that these molecules can directly target and eliminate cancer cells with no impact on healthy tissues. However, the underlying microscopic picture remains poorly understood. We present a study that utilizes theoretical analysis together with experimental measurements to clarify the microscopic aspects of jackhammers' anticancer activities. Our physical-chemical approach combines statistical analysis with chemoinformatics methods to design and optimize molecular jackhammers. By correlating specific physical-chemical properties of these molecules with their abilities to kill cancer cells, several important structural features are identified and discussed. Although our theoretical analysis enhances understanding of the molecular interactions of jackhammers, it also highlights the need for further research to comprehensively elucidate their mechanisms and to develop a robust physical-chemical framework for the rational design of targeted anticancer drugs.
PubMed: 38958581
DOI: 10.1021/acs.jcim.4c00806 -
American Journal of Physical Medicine &... Jul 2024The aim of this study was to determine whether patients treated with platelet-poor plasma (PPP) after an acute thigh muscle injury would have a faster return to activity...
OBJECTIVE
The aim of this study was to determine whether patients treated with platelet-poor plasma (PPP) after an acute thigh muscle injury would have a faster return to activity compared to patients treated with platelet-rich plasma (PRP).
DESIGN
This quasi-experimental study included 100 patients (ages 16-45) with an acute thigh muscle injury diagnosed by sports ultrasound and treated with either PRP or PPP followed by a course of structured rehabilitation. The primary outcome was the number of days until unrestricted participation in sport, while the secondary outcome was the rate of recurrent injury within 12 months.
RESULT
The time until full, unrestricted participation in sport was significantly lower in the PPP group compared to the PRP group for all injury grades, with patients in the PPP group on average returning to unrestricted participation in sport 22.89 days more quickly than the PRP group (p < 0.001). Additionally, no significant difference in recurrent injury up to 12 months post-procedure was seen between groups (p = 0.967).
CONCLUSIONS
PPP resulted in faster return to sport than PRP for acute thigh muscle injuries with a non-inferior injury recurrence rate. These findings suggest that future high level studies comparing PPP and PRP for the treatment of thigh muscle injuries should be considered.
PubMed: 38958567
DOI: 10.1097/PHM.0000000000002591 -
Advanced Science (Weinheim,... Jul 2024Increasing evidence suggests the role of reactive oxygen and nitrogen species (RONS) in regulating antitumor immune effects and immunosuppression. RONS modify...
Increasing evidence suggests the role of reactive oxygen and nitrogen species (RONS) in regulating antitumor immune effects and immunosuppression. RONS modify biomolecules and induce oxidative post-translational modifications (oxPTM) on proteins that can alarm phagocytes. However, it is unclear if and how protein oxidation by technical means could be a strategy to foster antitumor immunity and therapy. To this end, cold gas plasma technology producing various RONS simultaneously to oxidize the two melanoma-associated antigens MART and PMEL is utilized. Cold plasma-oxidized MART (oxMART) and PMEL (oxPMEL) are heavily decorated with oxPTMs as determined by mass spectrometry. Immunization with oxidized MART or PMEL vaccines prior to challenge with viable melanoma cells correlated with significant changes in cytokine secretion and altered T-cell differentiation of tumor-infiltrated leukocytes (TILs). oxMART promoted the activity of cytotoxic central memory T-cells, while oxPMEL led to increased proliferation of cytotoxic effector T-cells. Similar T-cell results are observed after incubating splenocytes of tumor-bearing mice with B16F10 melanoma cells. This study, for the first time, provides evidence of the importance of oxidative modifications of two melanoma-associated antigens in eliciting anticancer immunity.
PubMed: 38958560
DOI: 10.1002/advs.202404131 -
Advanced Science (Weinheim,... Jul 2024The androgen receptor (AR) is an attractive target for treating prostate cancer, considering its role in the development and progression of localized and metastatic...
The androgen receptor (AR) is an attractive target for treating prostate cancer, considering its role in the development and progression of localized and metastatic prostate cancer. The high global mortality burden of prostate cancer, despite medical treatments such as androgen deprivation or AR antagonist therapy, highlights the need to explore alternative strategies. One strategy involves the use of heterobifunctional degraders, also known as proteolysis-targeting chimeras, which are novel small-molecule therapeutics that inhibit amplified or mutated targets. Here, the study reports a novel cereblon-based AR degrader, UBX-390, and demonstrates its superior activity over established AR degraders, such as ARV-110 or ARCC-4, in prostate cancer cells under short- and long-term treatment conditions. UBX-390 suppresses chromatin binding and gene expression of AR and demonstrates substantial efficacy in the degradation of AR mutants in patients with treatment-resistant prostate cancer. UBX-390 is presented as an optimized AR degrader with remarkable potential for treating castration-resistant prostate cancer.
PubMed: 38958553
DOI: 10.1002/advs.202400398 -
Nanoscale Jul 2024The nanoscale form of the Chevrel phase, MoS, is demonstrated to be a highly efficient zinc-free anode in aqueous zinc ion hybrid supercapacitors (ZIHSCs). The unique...
The nanoscale form of the Chevrel phase, MoS, is demonstrated to be a highly efficient zinc-free anode in aqueous zinc ion hybrid supercapacitors (ZIHSCs). The unique morphological characteristics of the material when its dimensions approach the nanoscale result in fast zinc intercalation kinetics that surpass the ion transport rate reported for some of the most promising materials, such as TiS and TiSe. Raman spectroscopy, post-mortem X-ray diffraction, Hard X-ray photoelectron spectroscopy, and density functional theory (DFT) calculations were combined to understand the overall mechanism of the zinc ion (de)intercalation process. The previously unknown formation of the sulfur-deficient ZnMoS (ZnMoS) phase is identified, leading to a re-evaluation of the mechanism of the (de)intercalation process. A full cell comprised of an activated carbon (YEC-8A) positive electrode delivers a cell capacity of 38 mA h g and an energy density of 43.8 W h kg at a specific current density of 0.2 A g. The excellent cycling stability of the device is demonstrated for up to 8000 cycles at 3 A g with a coulombic efficiency close to 100%. Post-mortem microscopic studies reveal the absence of dendrite formation at the nanosized MoS anode, in stark contrast to the state-of-the-art zinc electrode.
PubMed: 38958552
DOI: 10.1039/d4nr01238k -
Critical Care Explorations Jul 2024To determine the actual cost and drivers of the cost of an extracorporeal cardiopulmonary resuscitation (E-CPR) care cycle.
OBJECTIVES
To determine the actual cost and drivers of the cost of an extracorporeal cardiopulmonary resuscitation (E-CPR) care cycle.
PERSPECTIVE
A time-driven activity-based costing study conducted from a healthcare provider perspective.
SETTING
A quaternary care ICU providing around-the-clock E-CPR service for out-of-hospital cardiac arrest (OHCA) and in-hospital cardiac arrest (IHCA) in Australia.
METHODS
The E-CPR care cycle was defined as the time from initiating E-CPR to hospital discharge or death of the patient. Detailed process maps with discrete steps and probabilistic decision nodes accounting for the complex trajectories of E-CPR patients were developed. Data about clinical and nonclinical resources and timing of activities was collected multiple times for each process . Total direct costs were calculated using the time estimates and unit costs per resource for all clinical and nonclinical resources. The total direct costs were combined with indirect costs to obtain the total cost of E-CPR.
RESULTS
From 10 E-CPR care cycles observed during the study period, a minimum of 3 observations were obtained per process. The E-CPR care cycle's mean (95% CI) cost was $75,014 ($66,209-83,222). Initiation of extracorporeal membrane oxygenation (ECMO) and ECMO management constituted 18% of costs. The ICU management (35%) and surgical costs (20%) were the primary cost determinants. IHCA had a higher mean (95% CI) cost than OHCA ($87,940 [75,372-100,570] vs. 62,595 [53,994-71,890], p < 0.01), mainly because of the increased survival and ICU length of stay of patients with IHCA. The mean cost for each E-CPR survivor was $129,503 ($112,422-147,224).
CONCLUSIONS
Significant costs are associated with E-CPR for refractory cardiac arrest. The cost of E-CPR for IHCA was higher compared with the cost of E-CPR for OHCA. The major determinants of the E-CPR costs were ICU and surgical costs. These data can inform the cost-effectiveness analysis of E-CPR in the future.
Topics: Humans; Cardiopulmonary Resuscitation; Extracorporeal Membrane Oxygenation; Out-of-Hospital Cardiac Arrest; Australia; Intensive Care Units; Time Factors; Male; Female; Middle Aged; Heart Arrest; Health Care Costs; Costs and Cost Analysis
PubMed: 38958545
DOI: 10.1097/CCE.0000000000001121 -
Journal of the American Geriatrics... Jul 2024Ageism is a major but oft-overlooked social determinant of health. In fact, it is widely accepted among scholars that ageism is one of the least acknowledged forms of...
BACKGROUND
Ageism is a major but oft-overlooked social determinant of health. In fact, it is widely accepted among scholars that ageism is one of the least acknowledged forms of inequality, although few empirical attempts have been made to substantiate this claim. This is the first study that quantifies the amount of discourse dedicated to ageism, sexism, and racism on Twitter. Specifically, we rely on the usage of hashtags as a proxy for the frequency of discussions surrounding each form of inequality over a 15-year period from 2007 to 2022. We also identify key events that triggered spikes in Twitter activity for each form of inequality.
METHODS
Hashtags related to racism and sexism were extracted from past scholarship. We also employed a snowball sampling method whereby we queried the hashtags using Twitter's search function to identify other hashtags. As limited research has been conducted on ageism-related hashtags, we queried hashtags utilized by advocacy groups and adopted a snowball sampling method to compile other relevant hashtags. Tweets collected (N = 154,353,047) spanned 15 years, from August 23, 2007 to December 31, 2022.
RESULTS
From 2007 to 2022, racism-related hashtags were used the most, followed by sexism-related hashtags and ageism-related hashtags. Racism-related hashtags (N = 99,250,348) were mentioned about 60 times more than ageism-related hashtags (N = 1,648,926). Sexism-related hashtags (N = 38,933,113) were mentioned 24 times more than ageism-related hashtags. The increasing linear trend of tweets associated with ageism (p < 0.001), sexism (p < 0.05), and racism (p < 0.05) reached significance. Incidents of racism and sexism often generated widespread public outrage. Conversely, instances of ageism rarely caused spikes in social media activity. Rather, these spikes were mainly observed during events such as the release of a report on ageism, a conference related to aging, or observances such as International Day of Older Persons.
CONCLUSION
There is a need to hasten moves to raise awareness of ageism. To ensure that discussions on ageism are not confined to academic and policy circles, advocacy campaigns could be held to educate the public on the issue and its negative concomitants.
PubMed: 38958541
DOI: 10.1111/jgs.19047