Maximal Analgesic Effect Attained by the Use of Objective Neurophysiological Measurements With Closed-Loop Spinal Cord Stimulation.

OBJECTIVES: Spinal cord stimulation (SCS) has been challenged by the lack of neurophysiologic data to guide therapy optimization. Current SCS programming by trial-and-error results in suboptimal and variable therapeutic effects. A novel system with a physiologic closed-loop feedback mechanism using evoked-compound action potentials enables the optimization of physiologic neural dose by consistently and accurately activating spinal cord fibers. We aimed to identify neurophysiologic dose metrics and their ranges that resulted in clinically meaningful treatment responses. MATERIALS AND METHODS: Subjects from 3 clinical studies (n = 180) with baseline back and leg pain ≥60 mm visual analog scale and physical function in the severe to crippled category were included. Maximal analgesic effect (MAE) was operationally defined as the greatest percent reduction in pain intensity or as the greatest cumulative responder score (minimal clinically important differences [MCIDs]) obtained within the first 3 months of SCS implant. The physiologic metrics that produced the MAE were analyzed. RESULTS: We showed that a neural dose regimen with a high neural dose accuracy of 2.8µV and dose ratio of 1.4 resulted in a profound clinical benefit to chronic pain patients (MAE of 79 ± 1% for pain reduction and 12.5 ± 0.4 MCIDs). No differences were observed for MAE or neurophysiological dose metrics between the trial phase and post-implant MAE visit. CONCLUSION: For the first time, an evidence-based neural dose regimen is available for a neurostimulation intervention as a starting point to enable optimization of clinical benefit, monitoring of adherence, and management of the therapy.

Engineering Ethanologenicity into the Extremely Thermophilic Bacterium Anaerocellum (f. Caldicellulosiriuptor) bescii.

The anaerobic bacterium Anaerocellum (f. Caldicellulosiruptor) bescii natively ferments the carbohydrate content of plant biomass (including microcrystalline cellulose) into predominantly acetate, H2, and CO2, and smaller amounts of lactate, alanine and valine. While this extreme thermophile (growth Topt 78°C) is not natively ethanologenic, it has been previously metabolically engineered with this property, albeit initially yielding low solvent titers (∼ 15 mM). Herein we report significant progress on improving ethanologenicity in A. bescii, such that titers above 130 mM have now been achieved, while concomitantly improving selectivity by minimizing acetate formation. Metabolic engineering progress has benefited from improved molecular genetic tools and better understanding of A. bescii growth physiology. Heterologous expression of a mutated thermophilic alcohol dehydrogenase (AdhE) modified for co-factor requirement, coupled with bioreactor operation strategies related to pH control, have been key to enhanced ethanol generation and fermentation product specificity. Insights gained from metabolic modeling of A. bescii set the stage for its further improvement as a metabolic engineering platform.

Do tobacco regulatory and economic factors influence smoking cessation outcomes? A post-hoc analysis of the multinational EAGLES randomised controlled trial.

INTRODUCTION: We previously reported global regional differences in smoking cessation outcomes, with smokers of US origin having lower quit rates than smokers from some other countries. This post-hoc analysis examined global regional differences in individual-level and country-level epidemiological, economic and tobacco regulatory factors that may affect cessation outcomes. METHODS: EAGLES (Evaluating Adverse Events in a Global Smoking Cessation Study) was a randomised controlled trial that evaluated first-line cessation medications and placebo in 8144 smokers with and without psychiatric disorders from 16 countries across seven regions. Generalised linear and stepwise logistic regression models that considered pharmacotherapy treatment, psychiatric diagnoses, traditional individual-level predictors (eg, demographic and smoking characteristics) and country-specific smoking prevalence rates, gross domestic product (GDP) per capita, relative cigarette cost and WHO-derived MPOWER scores were used to predict 7-day point prevalence abstinence at the end of treatment. RESULTS: In addition to several traditional predictors, three of four country-level variables predicted short-term abstinence: GDP (0.54 (95% CI 0.47, 0.63)), cigarette relative income price (0.62 (95% CI 0.53, 0.72)) and MPOWER score (1.03 (95% CI 1.01, 1.06)). Quit rates varied across regions (22.0% in Australasia to 55.9% in Mexico). With northern North America (USA and Canada) as the referent, the likelihood of achieving short-term abstinence was significantly higher in Western Europe (OR 1.4 (95% CI 1.14, 1.61)), but significantly lower in Eastern Europe (0.39 (95% CI 0.22, 0.69)) and South America (0.17 (95% CI 0.08, 0.35)). CONCLUSIONS: Increased tobacco regulation was associated with enhanced quitting among participants in the EAGLES trial. Paradoxically, lower GDP, and more affordable cigarette pricing relative to a country's GDP, were also associated with higher odds of quitting. Geographical region was also a significant independent predictor. TRIAL REGISTRATION NUMBER: ClinicalTrials.gov, NCT01456936.

Factors associated with fall risk increasing drug use in older black and white men and women: the Health ABC Study.

BACKGROUND: Most older adults use medications that may increase falls, often defined as fall risk increasing drugs or "FRIDs". Two definitions for FRIDs, the Centers for Disease Control and Prevention's (CDC) Stopping Elderly Accidents, Deaths & Injuries (STEADI-Rx) and Swedish National Board of Health and Welfare (SNBHW) definitions, are widely accepted, though include different FRIDs in their definitions. Whether factors associated with FRID use in older adults differ by definition is unknown. METHODS: We hypothesized that factors for FRID use will vary by FRID definition in 1,352 community-dwelling older Black and White adults with medication information in the Health, Aging and Body Composition Study (Health ABC; 2007-08 clinic visit; 83.4 ± 2.8 years; 54.1% women; 65.1% White). Multivariable logistic regression and multivariable negative binomial regression, progressively entering groups of covariates (demographics, lifestyle/behavior factors, and multimorbidity), modeled FRID use (yes/no) and count. RESULTS: Of 87.0% participants using SNBHW FRIDs, 82.9% used cardiac medications, with lower use of all other FRIDs (range:1.1-12.4%). Of 86.6% participants using STEADI-Rx FRIDs, 80.5% used cardiac medications, with lower use of all other FRIDs (range:1.1-16.1%). Participants with FRID use by either definition were more likely to have chronic health conditions, a hospitalization in the prior year, higher non-FRIDs medication counts, higher Center for Epidemiologic Studies Depression Scale (CES-D) scores, and less physical activity (all p < 0.05). Participants with STEADI-Rx FRID use had poorer vision and higher Modified Mini-Mental State (3MS) scores. In multivariable logistic regression for SNBHW use, hypertension, body mass index (BMI), 3MS scores, and non-FRID count were positively associated with FRID use and poorer vision and Digit Symbol Substitution Test (DSST) scores were negatively associated. In addition to SNBHW factors, higher CES-D scores were associated with STEADI-Rx FRID use. In multivariable negative binomial regression, hypertension, higher BMI, CES-D scores, and non-FRID count were associated with higher FRID count and sleep problems with lower FRID count for both definitions. Higher 3MS and lower DSST scores were associated with higher STEADI-Rx FRID count. Women had lower SNBHW FRID count after adjustments. CONCLUSIONS: Risk factors for FRID use in older adults differ slightly by STEADI-Rx and SNBHW FRIDs definition, but are largely similar.

Improved technical outcomes with converting thrombectomy techniques after failed first pass recanalization.

BACKGROUND: A higher number of recanalization attempts reduces the efficacy of endovascular thrombectomy (EVT) for acute ischemic stroke secondary to large vessel occlusion (LVO). We assessed the impact of switching EVT techniques after a failed first pass on procedural and clinical outcomes. METHODS: This multicenter international study, conducted between January 2013 and December 2022, included patients undergoing EVT for anterior circulation LVO (internal carotid artery or M1 segments) with failed first pass recanalization. Propensity score matching identified a 1:1 matched cohort of patients in whom EVT technique was changed after a failed first pass and those with the same technique repeated. The primary outcome was successful recanalization at second attempt defined as Thrombolysis in Cerebral Ischemia (TICI) score of 2B or higher. Secondary outcomes were 90-day modified Rankin Score (mRS) and postprocedural hemorrhage. RESULTS: Among 2167 patients, converting to an alternative technique after a failed first pass was associated with higher odds of successful recanalization (adjusted OR (aOR)=1.5, p=0.041), and higher odds of mRS 0-2 at 90 days (aOR=1.6, p=0.005) without additional risk of symptomatic hemorrhage (p=0.379). Using a propensity score matched cohort of 490 patients, technique conversion at second attempt increased odds of successful recanalization at second attempt (aOR=1.32, p=0.006) and 90-day mRS 0-2 (aOR=1.38, p=0.008). CONCLUSIONS: Early conversion to an alternative EVT technique after a failed first pass recanalization in patients with AIS is associated with better technical success and clinical outcomes.

AcrIF11 is a potent CRISPR-specific ADP-ribosyltransferase encoded by phage and plasmid.

Phage-encoded anti-CRISPR (Acr) proteins inhibit CRISPR-Cas systems to allow phage replication and lysogeny maintenance. Most of the Acrs characterized to date are stable stoichiometric inhibitors, and while enzymatic Acrs have been characterized biochemically, little is known about their potency, specificity, and reversibility. Here, we examine AcrIF11, a widespread phage and plasmid-encoded ADP-ribosyltransferase (ART) that inhibits the Type I-F CRISPR-Cas system. We present an NMR structure of an AcrIF11 homolog that reveals chemical shift perturbations consistent with NAD (cofactor) binding. In experiments that model both lytic phage replication and MGE/lysogen stability under high targeting pressure, AcrIF11 is a highly potent CRISPR-Cas inhibitor and more robust to Cas protein level fluctuations than stoichiometric inhibitors. Furthermore, we demonstrate that AcrIF11 is remarkably specific, predominantly ADP-ribosylating Csy1 when expressed in P. aeruginosa. Given the reversible nature of ADP-ribosylation, we hypothesized that ADPr eraser enzymes (macrodomains) could remove ADPr from Csy1, a potential limitation of PTM-based CRISPR inhibition. We demonstrate that diverse macrodomains can indeed remove the modification from Csy1 in P. aeruginosa lysate. Together, these experiments connect the in vitro observations of AcrIF11's enzymatic activity to its potent and specific effects in vivo, clarifying the advantages and drawbacks of enzymatic Acrs in the evolutionary arms race between phages and bacteria.

Hydrolyzed collagen supplementation prior to resistance exercise augments collagen synthesis in a dose-response manner in resistance-trained, middle-aged men.

BACKGROUND: Resistance exercise (RE) increases collagen synthesis in young and older men, while hydrolyzed collagen (HC) ingestion improves this response to RE in a dose-response manner in young men. However, the collagen synthesis response to RE with and without HC in middle-aged men is unknown. METHODS: Eight resistance-trained men (age: 49±8 years; height: 1.78±0.02m; mass: 90±4kg) took part in this double-blind, crossover design study, and undertook 4×10 repetitions of lower-limb RE at maximum load, after consuming 0g, 15g, or 30g vitamin C-enriched HC. We analyzed venous blood samples for N-terminal propeptide of type 1 pro-collagen (PINP), ß-isomerized C-terminal telopeptide of type 1 collagen (ß-CTx) and 18 collagen amino acids throughout all three interventions. RESULTS: The serum PINP concentration×time area-under-the-curve (AUC) was higher following 30g (169±28 µg/mL×h) than 15g (134±23 µg/mL×h, P<0.05) HC ingestion, and both 15g and 30g were higher than 0g HC (96±23 µg/mL×h, P<0.05). RE with 0g HC showed no change in serum PINP concentration. The AUCs for glycine, proline, hydroxyproline, alanine, arginine, lysine, serine, leucine, valine and isoleucine were greater with 30g than 15g and 0g HC ingestion (P<0.05), and greater with 15g than 0g HC ingestion (P<0.05). Plasma ß-CTx concentration decreased after RE independently of HC dose. CONCLUSIONS: Our study suggests connective tissue anabolic resistance to RE in middle-aged men but ingesting 15g HC rescues the collagen synthesis response, and 30g augments that response further. This dose-response is associated with the increased bioavailability of collagen amino acids in the blood, which stimulate collagen synthesis.

Efficacy and safety of rozanolixizumab in patients with muscle-specific tyrosine kinase autoantibody-positive generalised myasthenia gravis: a subgroup analysis of the randomised, double-blind, placebo-controlled, adaptive phase III MycarinG study.

Background: Muscle-specific tyrosine kinase (MuSK) autoantibody-positive (Ab+) generalised myasthenia gravis (gMG) is a rare and frequently severe subtype of gMG. Objectives: To assess the efficacy and safety of rozanolixizumab in the subgroup of patients with MuSK Ab+ gMG in the MycarinG study. Design: A randomised, double-blind, placebo-controlled phase III study. Methods: Patients with acetylcholine receptor (AChR) Ab+ or MuSK Ab+ gMG (aged ⩾18 years, Myasthenia Gravis Foundation of America Disease Class II-IVa, Myasthenia Gravis Activities of Daily Living [MG-|ADL] score ⩾3.0 [non-ocular symptoms], Quantitative Myasthenia Gravis score ⩾11.0) were randomly assigned (1:1:1) to receive once-weekly subcutaneous infusions of rozanolixizumab 7 mg/kg, rozanolixizumab 10 mg/kg or placebo for 6 weeks, followed by an 8-week observation period. Randomisation was stratified by AChR and MuSK autoantibody status. The primary study endpoint was change from baseline to Day 43 in MG-ADL score. Treatment-emergent adverse events (TEAEs) were also assessed. Results: Overall, 200 patients were randomised, of whom 21 had MuSK Ab+ gMG and received rozanolixizumab 7 mg/kg (n = 5), 10 mg/kg (n = 8) or placebo (n = 8). In patients with MuSK Ab+ gMG, reductions from baseline to Day 43 in MG-ADL scores were observed: rozanolixizumab 7 mg/kg least squares mean (LSM) change (standard error), -7.28 (1.94); 10 mg/kg, -4.16 (1.78); and placebo, 2.28 (1.95). Rozanolixizumab 7 mg/kg LSM difference from placebo was -9.56 (97.5% confidence interval: -15.25, -3.87); 10 mg/kg, -6.45 (-11.03, -1.86). TEAEs were experienced by four (80.0%), five (62.5%) and three (37.5%) patients with MuSK Ab+ gMG receiving rozanolixizumab 7 mg/kg, 10 mg/kg and placebo, respectively. No patients experienced serious TEAEs. No deaths occurred. Conclusion: This subgroup analysis of adult patients with MuSK Ab+ gMG enrolled in the MycarinG study supports the use of rozanolixizumab as an effective treatment option for patients with gMG who have MuSK autoantibodies. Trial registration: ClinicalTrials.gov: NCT03971422 (https://clinicaltrials.gov/study/NCT03971422); EU Clinical Trials Register: EudraCT 2019-000968-18 (https://www.clinicaltrials|register.eu/ctr-search/trial/2019-000968-18/GB).

Rozanolixizumab improved symptoms in people with anti-muscle-specific tyrosine kinase antibody-positive generalised myasthenia gravis in the MycarinG clinical study Myasthenia gravis is a rare, chronic autoimmune disease affecting the communication between nerves and muscles. People with the disease experience fluctuating muscle weakness and fatigue, leading to problems with mobility, speaking, swallowing and breathing. The disease is called generalised when muscles other than those that move the eyes and eyelids are affected. It is caused by antibodies that attack a person's own cells. Most people with the disease have antibodies against acetylcholine receptors (AChRs). However, some have antibodies against the muscle-specific tyrosine kinase (MuSK) protein and can experience more severe symptoms compared with people who have anti-AChR antibodies. Standard treatments for myasthenia gravis do not always work for people with anti-MuSK antibodies. The MycarinG study looked at whether rozanolixizumab was better than a placebo at treating the symptoms of adults with generalised myasthenia gravis and anti-AChR or anti-MuSK antibodies. Assessments measured disease severity and myasthenia gravis symptoms, such as physical fatigue, and how they affected daily activities. The study also looked at whether people receiving rozanolixizumab had any side effects. Here, we look at the group of people with anti-MuSK antibodies who took part in the MycarinG study. In total, 21 of the 200 people in the study had anti-MuSK antibodies. The symptoms of myasthenia gravis improved more in people with anti-MuSK antibodies who received rozanolixizumab than in those who received placebo. Common side effects with rozanolixizumab included headache, diarrhoea and feeling sick. No serious side effects were seen, and no patients died. The results show that rozanolixizumab is an effective treatment for people with generalised myasthenia gravis who have anti-MuSK antibodies. The results in this group of people are consistent with those seen in all people who took part in the study (with either antibody type).

Cardiopulmonary resuscitation employing only abdominal compressions in infants after cardiac surgery: A secondary sub-analysis of the ICU-RESUS study.

Importance: Patients with underlying cardiac disease form a considerable proportion of pediatric patients who experience in-hospital cardiac arrest. In pediatric patients after cardiac surgery, CPR with abdominal compressions alone (AC-CPR) may provide an alternative to standard chest compression CPR (S-CPR) with additional procedural and physiologic advantages. Objective: Quantitatively describe hemodynamics during cardiopulmonary resuscitation (CPR) and outcomes of infants who received only abdominal compressions (AC-CPR). Design: This is a sub-group analysis of the prospective, observational cohort from the ICU-RESUS trial NCT028374497. Setting & Patients: A single site quaternary care pediatric cardiothoracic intensive care unit enrolled in the ICU-RESUS trial. Patients less than 1 year of age with congenital heart disease who required compressions during cardiac arrest. Interventions: Use of AC-CPR during cardiac arrest resuscitation. Measurements and Main Results: Invasive arterial line waveforms during CPR were analyzed for 11 patients (10 surgical cardiac and 1 medical cardiac). Median weight was 3.3 kg [IQR 3.0, 4.0]; and median duration of CPR was 5.0 [3.0, 20.0] minutes. Systolic (median 57 [IQR 48, 65] mmHg) and diastolic (median 32 [IQR 24, 43] mmHg) blood pressures were achieved with a median rate of 114 [IQR 100, 124] compressions per minute. Return of spontaneous circulation was obtained in 9 of 11 (82%) patients; 2 patients (18%) were cannulated for extracorporeal cardiopulmonary resuscitation (ECPR) and 6 (55%) survived to hospital discharge with favorable neurologic outcome. Conclusions: AC-CPR may offer an alternative method to maintain perfusion for infants who experience cardiac arrest. This may have particular benefit in pediatric patients after cardiac surgery for whom external chest compressions may be harmful due to anatomic and physiologic considerations.

Middle Meningeal Artery Embolization for Chronic Subdural Hematoma Using N-Butyl Cyanoacrylate With a D5W Push Technique: A Multicentric North American Study of 269 Patients.

BACKGROUND AND OBJECTIVES: As the aging population increases, the incidence of chronic subdural hematomas (cSDHs) is expected to rise. Surgical evacuation, though effective, sees up to 30% recurrence. Middle meningeal artery (MMA) embolization, particularly with n-butyl cyanoacrylate (n-BCA) glue diluted in D5W for distal penetration, has shown promise in reducing recurrences. Limited reports have investigated the safety and technical feasibility of n-BCA as a primary liquid embolic agent using the D5W push technique in cSDH. This series is the largest in the literature investigating the outcomes of this technique in cSDH. METHODS: A multicenter retrospective database analysis was conducted on consecutive patients who underwent MMA embolization using n-BCA embolisate. Data collected included patient demographics, procedural information, angiographic data, and periprocedural complications. RESULTS: The study included 269 patients with a median age of 76 years. Nearly half of the patients had previous surgeries, and 93 underwent contralateral embolization for bilateral cSDH. Successful MMA embolization with effective distal penetration was achieved in all cases. The complication rate was 2.2%. Significant improvements were noted at a 60-day follow-up, with a median reduction in cSDH diameter of 40.6% (P < .001) and 53% of patients showing neurological improvement. No recurrent cSDH or need for retreatment was observed in patients who underwent follow-up. CONCLUSION: MMA embolization using n-BCA with the D5W push technique is safe and technically feasible. It can be used adjunctively or as an alternative to surgery in patients with cSDH, resulting in decreased recurrence, high technical success, improved distal penetration, and low complication rates.

Computationally Driven Discovery of a BCR-ABL1 Kinase Inhibitor with Activity in Multidrug-Resistant Chronic Myeloid Leukemia.

The permeability glycoprotein, encoded by the ABCB1 gene, is widely implicated in multidrug resistance (MDR), as it has been shown to reduce the intracellular concentration of most small molecule therapeutics, including the majority of the breakpoint cluster region Abelson proto-oncogene 1 (BCR-ABL1) kinase inhibitors used in the treatment of Philadelphia chromosome positive (Ph+) leukemias. With this in mind, we describe an integrated theoretical and experimental approach to shed light on substituent effects in the pendant anilino moiety of 4-anilinoquinazolines and 4-anilinoquinoline-3-carbonitrile-based kinase inhibitors and their influence on P-gp-mediated efflux. This analysis culminated in the identification of a hydroxylamine-bearing, dual cSRC/BCR-ABL1 kinase inhibitor 16a that exhibits a marked reduction in P-gp-mediated efflux ratio and potent activity in a Ph+ patient-derived cell line (K562) and an MDR-Ph+ patient-derived cell line (K562/Dox) overexpressing P-gp. Overall, we demonstrate that the P-gp-mediated efflux ratio can be minimized by computationally driven optimization of the molecular dipole and/or cpKa without recourse to intramolecular hydrogen bonds.

Cuprophilic Interactions in Polymeric [Cu10O2(Mes)6]n.

The properties of cuprophilic compounds and the underlying fundamental principles responsible for the Cu(I)···Cu(I) interactions have been the subject of intense research as their diverse structural and physical attributes are being explored. In this light, we performed a new study of the compound [Cu10O2(Mes)6] reported by Haakansson et al. using state of the art experimental and theoretical analysis techniques. Doing this, we found the compound to be a polymer in the solid state, best written as [Cu10O2(Mes)6]n, with unsupported Cu(I)···Cu(I) contacts linking the monomers (2.776 Å). The monomeric unit also exhibits various cuprophilic contacts bridged by mesityl and/or oxo ligands. The compound was analyzed in its solid state, revealing luminescent properties resulting from two distinct fluorescent emissions, as well as in solution, in which its polymeric structure reversibly decomposes. A quantum theory of atoms in molecules (QTAIM) analysis based on density functional theory (DFT) calculations allows to characterize the various Cu(I)···Cu(I) contacts, in which only a few, and not necessarily the shortest, are associated with a bond critical point. Additionally, an energy decomposition analysis of the bonding between monomers indicates that it is dominated by dispersion forces in which the ligands play a dominant role, resulting in bonding energies significantly larger than found in previous DFT investigations based on less bulky models.

Structure and inhibition mechanisms of Mycobacterium tuberculosis essential transporter efflux protein A.

A broad chemical genetics screen in Mycobacterium tuberculosis (Mtb) to identify inhibitors of established or previously untapped targets for therapeutic development yielded compounds (BRD-8000.3 and BRD-9327) that inhibit the essential efflux pump EfpA. To understand the mechanisms of inhibition by these compounds, we determined the structures of EfpA with inhibitors bound at 2.7 - 3.4 Å resolution. Our structures reveal different mechanisms of inhibition for the two inhibitors. BRD-8000.3 binds in a tunnel making contact with the lipid bilayer and extending toward the central cavity to displace the fatty acid chain of a lipid molecule bound in the apo structure, suggesting its blocking of an access route for a natural lipidic substrate, in contrast to its uncompetitive mechanism for the small molecule substrate ethidium bromide which likely enters through an alternative tunnel. Meanwhile, BRD-9327 binds in the outer vestibule without complete blockade of the substrate path to the outside, suggesting its possible inhibition of the dynamical motion necessary for "alternate access" to the two different sides of the membrane, as is characteristic of major facilitator superfamily (MFS) transporters. Both inhibitors may have a role in inhibiting the "alternate access" mechanism that could account for the uncompetitive nature of their efflux of some substrates. Our results explain the basis of the synergy of these inhibitors and their potential for combination in a multi drug strategy for anti-tuberculosis therapy. They also potentially point to a possible function for this essential efflux pump as a lipid transporter. The structures provide a foundation for rational modification of these inhibitors to increase potency.

The Polyanalgesic Consensus Conference (PACC)®: Updates on Clinical Pharmacology and Comorbidity Management in Intrathecal Drug Delivery for Cancer Pain.

INTRODUCTION: The International Neuromodulation Society convened a multispecialty group of physicians based on expertise with international representation to establish evidence-based guidance on using intrathecal drug delivery in chronic pain treatment. This Polyanalgesic Consensus Conference (PACC)® project's scope is to provide evidence-based guidance for clinical pharmacology and best practices for intrathecal drug delivery for cancer pain. MATERIALS AND METHODS: Authors were chosen on the basis of their clinical expertise, familiarity with the peer-reviewed literature, research productivity, and contributions to the neuromodulation literature. Section leaders supervised literature searches using Medline, EMBASE, Cochrane CENTRAL, BioMed Central, Web of Science, Google Scholar, PubMed, Current Contents Connect, Meeting Abstracts, and Scopus from 2017 (when the PACC last published guidelines) to the present. Identified studies were graded using the United States Preventive Services Task Force criteria for evidence and certainty of net benefit. Recommendations were based on the strength of evidence, and when evidence was scant, recommendations were based on expert consensus. RESULTS: The PACC evaluated the published literature and established evidence- and consensus-based expert opinion recommendations to guide best practices in treating cancer pain. Additional guidance will occur as new evidence is developed in future iterations of this process. CONCLUSIONS: The PACC recommends best practices regarding the use of intrathecal drug delivery in cancer pain, with an emphasis on managing the unique disease and patient characteristics encountered in oncology. These evidence- and consensus-based expert opinion recommendations should be used as a guide to assist decision-making when clinically appropriate.

Multisensory approach in Mental Imagery: ALE meta-analyses comparing Motor, Visual and Auditory Imagery.

Mental Imagery is a topic of longstanding and widespread scientific interest. Individual studies have typically focused on a single modality (e.g. Motor, Visual, Auditory) of Mental Imagery. Relatively little work has considered directly comparing and contrasting the brain networks associated with these different modalities of Imagery. The present study integrates data from 439 neuroimaging experiments to identify both modality-specific and shared neural networks involved in Mental Imagery. Comparing the networks involved in Motor, Visual, and Auditory Imagery identified a pattern whereby each form of Imagery preferentially recruited 'higher level' associative brain regions involved in the associated 'real' experience. Results also indicate significant overlap in a left-lateralized network including the pre-supplementary motor area, ventral premotor cortex and inferior parietal lobule. This pattern of results supports the existence of a 'core' network that supports the attentional, spatial, and decision-making demands of Mental Imagery. Together these results offer new insights into the brain networks underlying human imagination.

Comparative study of ten machine learning algorithms for short-term forecasting in gas warning systems.

This research aims to explore more efficient machine learning (ML) algorithms with better performance for short-term forecasting. Up-to-date literature shows a lack of research on selecting practical ML algorithms for short-term forecasting in real-time industrial applications. This research uses a quantitative and qualitative mixed method combining two rounds of literature reviews, a case study, and a comparative analysis. Ten widely used ML algorithms are selected to conduct a comparative study of gas warning systems in a case study mine. We propose a new assessment visualization tool: a 2D space-based quadrant diagram can be used to visually map prediction error assessment and predictive performance assessment for tested algorithms. Overall, this visualization tool indicates that LR, RF, and SVM are more efficient ML algorithms with overall prediction performance for short-term forecasting. This research indicates ten tested algorithms can be visually mapped onto optimal (LR, RF, and SVM), efficient (ARIMA), suboptimal (BP-SOG, KNN, and Perceptron), and inefficient algorithms (RNN, BP_Resilient, and LSTM). The case study finds results that differ from previous studies regarding the ML efficiency of ARIMA, KNN, LR, LSTM, and SVM. This study finds different views on the prediction performance of a few paired algorithms compared with previous studies, including RF and LR, SVM and RF, KNN and ARIMA, KNN and SVM, RNN and ARIMA, and LSTM and SVM. This study also suggests that ARIMA, KNN, LR, and LSTM should be investigated further with additional prediction error assessments. Overall, no single algorithm can fit all applications. This study raises 20 valuable questions for further research.

Inspiratory Muscle Training for Lung Transplant Candidates and Recipients.

OBJECTIVES: Inspiratory muscle training is used in rehabilitation to exercise respiratory muscles in various conditions associated with limited ventilatory reserve. In this review, we investigated inspiratory muscle training in lung transplant candidates and recipients. MATERIALS AND METHODS: We searched 5 primary databases from inception through April 2024. Two key word entries, "lung transplantation" and "inspiratory muscle training," were matched using the Boolean operator AND. No filters were applied for document type, age, sex, publication date, language, and subject. RESULTS AND CONCLUSIONS: The searched databases returned 119 citations. Seven articles that considered 64 patients (47% female) were included in the final analysis, with 1 study involving a pediatric patient. Lung transplant recipients used a threshold trainer at 15% to 60% of maximal inspiratory pressure and mostly exercised twice daily for 10 to 15 minutes per session. Lung transplant candidates exercised at 30% to >50% of maximal inspiratory pressure twice daily, performing 30 to 60 inspirations or for 15 minutes. The highest inspiratory muscle strength was observed in a series of adult lung transplant recipients whose mean value improved by 31.8 ± 14.6 cmH2O versus baseline after treatment. To the same extent, the highest value of maximal inspiratory pressure was detected in a pediatric patient who scored 180 cmH2O after training. Overall, participants obtained improvements in lung function (forced expiratory volume in 1 second, forced vital capacity), functional performance, dyspnea intensity, and exercise tolerance. Inspiratory muscle training is easy to perform and can be done at home without specific supervision (in adults) before or after a lung transplant. Nevertheless, additional rigorous investigations should aim to replicate the positive effects reported in the present review.

Pre-pregnancy substance use and first trimester cardiovascular health among nulliparous pregnant people: The nuMoM2b Study.

BACKGROUND: Suboptimal pre-pregnancy health, including substance use and cardiovascular risk factors, is associated with higher risks of maternal-foetal morbidity and mortality. OBJECTIVE: To determine if pre-pregnancy substance use is associated with early pregnancy cardiovascular health (CVH). It is hypothesised that pre-pregnancy use of substances is associated with worse CVH in the first trimester of pregnancy. METHODS: This is a secondary analysis from the 2010-2015 United States nuMoM2b cohort (n = 9895). Pre-pregnancy alcohol, tobacco, marijuana, and illicit substance use were assessed through questionnaires. Latent class analysis categorised participants based on their 3-month pre-pregnancy or ever(*) substance use: (1) Illicit substances*, marijuana*, and alcohol use (n = 1234); (2) marijuana* and alcohol use (n = 2066); (3) tobacco and alcohol use (n = 636); and (4) alcohol only use (n = 3194). The referent group reported no pre-pregnancy substance use (n = 2765). First trimester CVH score from 0 (least healthy) to 100 (most healthy) was calculated using a modified American Heart Association Life's Essential 8 framework and included body mass index (BMI), blood pressure, blood glucose, non-HDL cholesterol, diet, sleep, and physical activity. Multiple linear regression evaluated the relationship between pre-pregnancy substance use classes and CVH scores. RESULTS: CVH score varied by class: No substance use (mean: 65, SD: ±1.3), illicit substances*, marijuana*, and alcohol use (68 ± 1.3), marijuana* and alcohol use (67 ± 1.3), tobacco and alcohol use (62 ± 1.4), and alcohol only use (67 ± 1.3). In adjusted models, those who used tobacco and alcohol compared to the no substance use class had a lower CVH score (-2.82); other classes had scores ranging from 1.81 to 2.44 points higher than the no substance use class. Individual CVH component scores followed similar patterns. CONCLUSIONS: All groups, but most markedly those who used tobacco and alcohol prior to pregnancy, began pregnancy with only moderate CVH and may benefit from CVH promotion efforts along with substance use treatment.

Source and propagation modelling scenarios for environmental impact assessment: Model verificationa).

Evaluation of possible effects of underwater sound on aquatic life requires quantification of the sound field. A marine sound source and propagation modelling workshop took place in June 2022, whose objectives were to facilitate the evaluation of source and propagation models and to identify relevant metrics for environmental impact assessment. The scope of the workshop included model verification (model-model comparison) and model validation (model-measurement comparison) for multiple sources, including airguns, a low-frequency multi-beam echo sounder, and a surface vessel. Several verification scenarios were specified for the workshop; these are described herein.