Actual Cost of Extracorporeal Cardiopulmonary Resuscitation: A Time-Driven Activity-Based Costing Study.

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.

Expanding the landscape of oncogenic drivers and treatment options in acral and mucosal melanomas by targeted genomic profiling.

Despite advancements in treating cutaneous melanoma, patients with acral and mucosal (A/M) melanomas still have limited therapeutic options and poor prognoses. We analyzed 156 melanomas (101 cutaneous, 28 acral, and 27 mucosal) using the Foundation One cancer-gene specific clinical testing platform and identified new, potentially targetable genomic alterations (GAs) in specific anatomic sites of A/M melanomas. Using novel pre-clinical models of A/M melanoma, we demonstrate that several GAs and corresponding oncogenic pathways associated with cutaneous melanomas are similarly targetable in A/M melanomas. Other alterations, including MYC and CRKL amplifications, were unique to A/M melanomas and susceptible to indirect targeting using the BRD4 inhibitor JQ1 or Src/ABL inhibitor dasatinib, respectively. We further identified new, actionable A/M-specific alterations, including an inactivating NF2 fusion in a mucosal melanoma responsive to dasatinib in vivo. Our study highlights new molecular differences between cutaneous and A/M melanomas, and across different anatomic sites within A/M, which may change clinical testing and treatment paradigms for these rare melanomas.

Population density and vegetation resources influence demography in a hibernating herbivorous mammal.

Demography of herbivorous mammal populations may be affected by changes in predation, population density, harvesting, and climate. Whereas numerous studies have focused on the effect of single environmental variables on individual demographic processes, attempts to integrate the consequences of several environmental variables on numerous functional traits and demographic rates are rare. Over a 32-year period, we examined how forage availability (vegetation assessed through NDVI) and population density affected the functional traits and demographic rates of a population of Columbian ground squirrels (Urocitellus columbianus), a herbivorous hibernating rodent. We focused on mean population phenology, body mass, breeding success, and survival. We found a negative effect of population density on demographic rates, including on breeding success and pup and adult survival to the next year. We found diverging effects of vegetation phenology on demographic rates: positive effects of a later start of the growing season on adult and yearling female survival, and juvenile survival, but no clear effect on male survival. Interestingly, neither population density nor vegetation affected population phenology or body condition in the following year. Vegetative growth rate had a positive influence on female mass gain (somatic investment) over a season, but both vegetative growth rate and biomass, surprisingly, had negative effects on the survival of young through their first hibernation. Thus, ground squirrels appeared to benefit more from later timing of vegetation than increases in vegetative biomass per se. Our study provides evidence for complex ecological effects of vegetation and population density on functional traits and demographic rates of small mammal populations.

Automated magnetic resonance imaging-based grading of the lumbar intervertebral disc and facet joints.

Background: Degeneration of both intervertebral discs (IVDs) and facet joints in the lumbar spine has been associated with low back pain, but whether and how IVD/joint degeneration contributes to pain remains an open question. Joint degeneration can be identified by pairing T1 and T2 magnetic resonance imaging (MRI) with analysis techniques such as Pfirrmann grades (IVD degeneration) and Fujiwara scores (facet degeneration). However, these grades are subjective, prompting the need to develop an automated technique to enhance inter-rater reliability. This study introduces an automated convolutional neural network (CNN) technique trained on clinical MRI images of IVD and facet joints obtained from public-access Lumbar Spine MRI Dataset. The primary goal of the automated system is to classify health of lumbar discs and facet joints according to Pfirrmann and Fujiwara grading systems and to enhance inter-rater reliability associated with these grading systems. Methods: Performance of the CNN on both the Pfirrmann and Fujiwara scales was measured by comparing the percent agreement, Pearson's correlation and Fleiss kappa value for results from the classifier to the grades assigned by an expert grader. Results: The CNN demonstrates comparable performance to human graders for both Pfirrmann and Fujiwara grading systems, but with larger errors in Fujiwara grading. The CNN improves the reliability of the Pfirrmann system, aligning with previous findings for IVD assessment. Conclusion: The study highlights the potential of using deep learning in classifying the IVD and facet joint health, and due to the high variability in the Fujiwara scoring system, highlights the need for improved imaging and scoring techniques to evaluate facet joint health. All codes required to use the automatic grading routines described herein are available in the Data Repository for University of Minnesota (DRUM).

Dopamine-mediated interactions between short- and long-term memory dynamics.

In dynamic environments, animals make behavioral decisions based on the innate valences of sensory cues and information learnt about these cues across multiple timescales1-3. However, it remains unclear how the innate valence of a sensory stimulus affects acquisition of learnt valence information and subsequent memory dynamics. Here we show that in the Drosophila brain, interconnected short- and long-term memory units of the mushroom body jointly regulate memory via dopamine signals that encode innate and learnt sensory valences. Through time-lapse, in vivo voltage-imaging studies of neural spiking in >500 flies undergoing olfactory associative conditioning, we found that protocerebral posterior lateral 1 dopamine neurons (PPL1-DANs)4 heterogeneously and bi-directionally encode innate and learnt valences of punishment, reward, and odor cues. During learning, these valence signals regulate memory storage and extinction in mushroom body output neurons (MBONs)5. In initial conditioning bouts, PPL1-γ1pedc and PPL1-γ2α'1 neurons control short-term memory formation, which weakens inhibitory feedback from MBON-γ1pedc>α/ß to PPL1-α'2α2 and PPL1-α3. During further conditioning, this diminished feedback allows these two PPL1-DANs to encode the net innate plus learnt valence of the conditioned odor cue, which gates long-term memory formation. A computational model constrained by the fly connectome6,7 and our spiking data explains how dopamine signals mediate the circuit interactions between short- and long-term memory traces, yielding predictions that our experiments confirm. Overall, the mushroom body achieves flexible learning via the integration of innate and learnt valences within parallel learning units sharing feedback interconnections. This hybrid physiologic-anatomic mechanism may be a general means by which dopamine regulates memory dynamics in other species and brain structures, including the vertebrate basal ganglia.

Batter's Shoulder: Diagnosis, Management, and Outcomes.

Batter's shoulder is characterized by posterior shoulder instability in the lead (front) shoulder of a batting athlete. This most commonly occurs as a discrete event, particularly a swing and miss at an outside pitch, which leads to an episode of shoulder subluxation. A thorough history and physical examination is key to diagnosis, with patients feeling pain and instability of the lead shoulder when attempting the baseball swing or during pushing-type activities, as well as positive posterior labral signs in tests such as the Kim, jerk, and modified dynamic labral shear tests. Magnetic resonance imaging can confirm the diagnosis of posterior labral tear and may show concomitant pathologies such as a reverse Hill-Sachs lesion. Nonsurgical treatment is directed at rotator cuff and scapular strengthening; however, arthroscopic posterior labral repair is often required for definitive stabilization. Overall, this is a relatively rare diagnosis, but outcomes of surgical repair are favorable with high satisfaction and rates of return to competition.

Stability-Enhanced Cisplatin Gold Nanoparticles As Therapeutic Anticancer Agents.

Using dendron chemistry, we developed stability enhanced, carboxylate surface modified (negatively charged dendron) AuNPs (Au-NCD). Since the carboxylate surface of Au-NCD is optimal for complexation with cisplatin (Pt) moieties, we further synthesized Pt loaded Au-NCD (Au-NCD/Pt) to serve as potential therapeutic anticancer agents. The size distribution, zeta potential and surface plasmon resonance of both Au-NCDs and Au-NCD/Pt were characterized via dynamic light scattering, scanning transmission electron microscopy and ultraviolet-visible spectrophotometry. Surface chemistry, Pt uptake, and Pt release were evaluated using inductively coupled plasma-mass spectrometry and X-ray photoelectron spectroscopy. Colloidal stability in physiological media over a wide pH range (1 to 13) and shelf-life stability (up to 6 months) were also assessed. Finally, the cytotoxicity of both Au-NCD and Au-NCD/Pt to Chinese hamster ovary cells (CHO K1; as a normal cell line) and to human lung epithelial cells (A549; as a cancer cell line) were evaluated. The results of these physicochemical and functional cytotoxicity studies with Au-NCD/Pt demonstrated that the particles exhibited superlative colloidal stability, cisplatin uptake and in vitro anticancer activity despite low amounts of Pt release from the conjugate.

Exploratory assessment of the effect of systemic administration of soluble glycoprotein 130 on cognitive performance and chemokine levels in a mouse model of experimental traumatic brain injury.

Uncontrolled neuroinflammation mediates traumatic brain injury (TBI) pathology and impairs recovery. Interleukin-6 (IL-6), a pleiotropic inflammatory regulator, is associated with poor clinical TBI outcomes. IL-6 operates via classical-signaling through membrane-bound IL-6 receptor (IL-6R) and trans-signaling through soluble IL-6 receptor (s)IL-6R. IL-6 trans-signaling specifically contributes to neuropathology, making it a potential precision therapeutic TBI target. Soluble glycoprotein 130 (sgp130) prevents IL-6 trans-signaling, sparing classical signaling, thus is a possible treatment. Mice received either controlled cortical impact (CCI) (6.0 ± 0.2 m/s; 2 mm; 50-60ms) or sham procedures. Vehicle (VEH) or sgp130-Fc was subcutaneously administered to sham (VEH or 1 µg) and CCI (VEH, 0.25 µg or 1 µg) mice on days 1, 4, 7, 10 and 13 post-surgery to assess effects on cognition [Morris Water Maze (MWM)] and ipsilateral hemisphere IL-6 related biomarkers (day 21 post-surgery). CCI + sgp130-Fc groups (0.25 µg and 1 µg) were combined for analysis given similar behavior/biomarker outcomes. CCI + VEH mice had longer latencies and path lengths to the platform and increased peripheral zone time versus Sham + VEH and Sham + sgp130-Fc mice, suggesting injury-induced impairments in learning and anxiety. CCI + sgp130-Fc mice had shorter platform latencies and path lengths and had decreased peripheral zone time, indicating a therapeutic benefit of sgp130-Fc after injury on learning and anxiety. Interestingly, Sham + sgp130-Fc mice had shorter platform latencies, path lengths and peripheral zone times than Sham + VEH mice, suggesting a beneficial effect of sgp130-Fc, independent of injury. CCI + VEH mice had increased brain IL-6 and decreased sgp130 levels versus Sham + VEH and Sham + sgp130-Fc mice. There was no treatment effect on IL-6, sIL6-R or sgp130 in Sham + VEH versus Sham + sgp130-Fc mice. There was also no treatment effect on IL-6 in CCI + VEH versus CCI + sgp130-Fc mice. However, CCI + sgp130-Fc mice had increased sIL-6R and sgp130 versus CCI + VEH mice, demonstrating sgp130-Fc treatment effects on brain biomarkers. Inflammatory chemokines (MIP-1ß, IP-10, MIG) were increased in CCI + VEH mice versus Sham + VEH and Sham + sgp130-Fc mice. However, CCI + sgp130-Fc mice had decreased chemokine levels versus CCI + VEH mice. IL-6 positively correlated, while sgp130 negatively correlated, with chemokine levels. Overall, we found that systemic sgp130-Fc treatment after CCI improved learning, decreased anxiety and reduced CCI-induced brain chemokines. Future studies will explore sex-specific dosing and treatment mechanisms for sgp130-Fc therapy.

Automatic Forward Model Parameterization with Bayesian Inference of Conformational Populations.

To quantify how well theoretical predictions of structural ensembles agree with experimental measurements, we depend on the accuracy of forward models. These models are computational frameworks that generate observable quantities from molecular configurations based on empirical relationships linking specific molecular properties to experimental measurements. Bayesian Inference of Conformational Populations (BICePs) is a reweighting algorithm that reconciles simulated ensembles with ensemble-averaged experimental observations, even when such observations are sparse and/or noisy. This is achieved by sampling the posterior distribution of conformational populations under experimental restraints as well as sampling the posterior distribution of uncertainties due to random and systematic error. In this study, we enhance the algorithm for the refinement of empirical forward model (FM) parameters. We introduce and evaluate two novel methods for optimizing FM parameters. The first method treats FM parameters as nuisance parameters, integrating over them in the full posterior distribution. The second method employs variational minimization of a quantity called the BICePs score that reports the free energy of "turning on" the experimental restraints. This technique, coupled with improved likelihood functions for handling experimental outliers, facilitates force field validation and optimization, as illustrated in recent studies (Raddi et al. 2023, 2024). Using this approach, we refine parameters that modulate the Karplus relation, crucial for accurate predictions of J -coupling constants based on dihedral angles ( ϕ ) between interacting nuclei. We validate this approach first with a toy model system, and then for human ubiquitin, predicting six sets of Karplus parameters for J H N H α 3 , J H α C ' 3 , J H N C ß 3 , J H N C ' 3 , J C ' C ß 3 , J C ' C ' 3 . This approach, which does not rely on any predetermined parameterization, enhances predictive accuracy and can be used for many applications.

Occupational Contact Dermatitis in Construction Workers: A Retrospective Analysis of the North American Contact Dermatitis Group Data, 2001-2020.

Background: Construction workers (CWs) are at risk for occupational contact dermatitis (CD) owing to workplace exposures. Objective: Determine the prevalence of occupational allergic CD and characterize common occupational allergens in CWs referred for patch testing in the United States and Canada. Methods: Retrospective cross-sectional analysis of patients patch tested by the North American Contact Dermatitis Group from 2001 to 2020. Results: Of 47,843 patch-tested patients, 681 (1.4%) were CWs. Compared with non-CWs, CWs were more likely to be male (91.0% vs 30.9%) have occupational skin disease (36.9% vs 11.4%) and have hand involvement (37.2% vs 22.5%) (all P < 0.0001). Of 681 CWs, 60.1% (411) had clinically relevant positive patch test reactions, and nearly 1/3 of CWs (128) had occupationally relevant reactions. Most common occupationally relevant allergens were potassium dichromate 0.25% pet. (30.5%, 39/128), bisphenol A epoxy resin 1% pet. (28.1%, 36/128), carba mix 3% pet. (14.8%, 19/128), cobalt (ii) chloride hexahydrate 1% pet. (14.1%, 18/128), and thiuram mix 1% pet. (14.1%, 18/128). Top sources of occupationally relevant allergens were cement/concrete/mortar (20.4%, 46/225), gloves (15.1%, 34/225), and coatings (paint/lacquer/shellac/varnish/stains) (9.8%, 22/225). Conclusions: Occupational CD in North American CWs is common. In this group, frequently identified etiological sources of occupational allergic CD included metals, epoxy resin, and rubber.

PLA2G15 is a Lysosomal BMP Hydrolase with Ester Position Specificity and its Targeting Ameliorates Lysosomal Disease.

Lysosomes catabolize lipids and other biological molecules, a function essential for cellular and organismal homeostasis. Key to lipid catabolism in the lysosome is bis(monoacylglycero)phosphate (BMP), a major lipid constituent of intralysosomal vesicles (ILVs) and a stimulator of lipid-degrading enzymes. BMP levels are altered in a broad spectrum of human conditions, including neurodegenerative diseases. Although BMP synthase was recently discovered, it has long been thought that BMP's unique stereochemistry confers resistance to acid phospholipases, a requirement for its role in the lysosome. Here, we demonstrate that PLA2G15, a major lysosomal phospholipase, efficiently hydrolyzes BMP with primary esters regardless of stereochemistry. Interestingly, we discover that BMP's unique esterification position is what confers resistance to hydrolysis. Purified PLA2G15 catabolizes most BMP species derived from cell and tissue lysosomes under acidic conditions. Furthermore, PLA2G15 catalytic activity against synthesized BMP stereoisomers with primary esters was comparable to its canonical substrates. Conversely, BMP with secondary esters is intrinsically stable in vitro and requires acyl migration for hydrolysis in lysosomes. Consistent with our biochemical data, PLA2G15-deficient tissues and cells accumulate multiple BMP species, a phenotype reversible by supplementing wildtype PLA2G15 but not its catalytically dead mutant. Increasing BMP levels by targeting PLA2G15 reverses the cholesterol accumulation phenotype in Niemann Pick Disease Type C (NPC1) patient fibroblasts and significantly ameliorate disease pathologies in NPC1-deficient mice leading to extended lifespan. Our findings establish the rules that govern the stability of BMP in the lysosome and identify PLA2G15 as a lysosomal BMP hydrolase and as a potential target for modulating BMP levels for therapeutic intervention.

Sexual behavior among emerging adults in Africa: a systematic review and meta-analysis.

BACKGROUND: Estimates on sexual behavior (SB) among emerging adults (EmA) is varied in literature, which presents a challenge when designing targeted interventions. We aimed to summarize literature on prevalence and risk factors of SB among EmA in Africa. METHODS: A search for studies published in PubMed, Embase and Psych Info by March 2023 was done. Studies involving EmA (18-25 years), conducted in Africa and reporting one or more of seven SB were reviewed. Pooled prevalence estimates were summarized using forest plots. Heterogeneity in SB was explored. Risk factors were synthesized using a modified socio-ecological model. RESULTS: Overall, 143 studies were analyzed. Non-condom use had the highest pooled prevalence (47% [95% CI: 42-51]), followed by study-defined SB (37% [95% CI: 25-50]) and concurrency (37% [95% CI: 21-54]), multiple sex partners (31% [95% CI: 25-37]), younger age at sexual debut (26% [95% CI: 20-32]), age disparate relationships (24% [95% CI: 17-32]) and transactional sex (19% [95% CI: 13-26]). Heterogeneity was partially explained by sex, with female participants having higher pooled prevalence estimates compared to their male counterparts. In four of the seven outcomes, alcohol/drug use was the most common risk factor. CONCLUSIONS: SB was common among EmA and differentially higher in emerging female adults. Non-condom use had the highest pooled prevalence, which may contribute to the transmission of HIV and other sexually transmitted infections (STIs). Interventions targeting emerging female adults and alcohol/drug use may reduce SB, which may in-turn mitigate transmission of HIV and other STIs among EmA in Africa.

Food safety assessment and 28-day toxicity study of the synbiotic medical food consortium SBD121.

The human gut microbiome plays a crucial role in immune function. The synbiotic consortium or Defined Microbial Assemblage™ (DMA™) Medical Food product, SBD121, consisting of probiotic microbes and prebiotic fibers was designed for the clinical dietary management of rheumatoid arthritis. A 28-day repeated administration study was performed to evaluate the oral toxicity of SBD121 in male and female rats (age/weight at study start: 60 days/156-264 g) administered levels of 0, 4.96 x 1010, 2.48 x 1011, or 4.96 x 1011 colony forming units (CFU)/kg-bw. No treatment related changes were observed in ophthalmological effects, mortality, morbidity, general health and clinical observations, urinalysis, hematology, serum chemistry, absolute or relative organ weights, gross necropsy, or histopathology. A significant decrease in body weight was reported in females in the low and high-concentration groups, which corresponded in part with a significant decrease in food consumption. Results of the functional observation battery indicated front grip strength was significantly greater in the high-concentration males compared to the controls; however, this effect was not considered adverse. Based on these findings, the administration of the Medical Food SBD121 to male and female rats has a no-observable adverse effect level (NOAEL) at the highest level tested of 4.96 x 1011 CFU/kg-bw.

Interventions for postburn pruritus.

BACKGROUND: Postburn pruritus (itch) is a common and distressing symptom experienced on healing or healed burn or donor site wounds. Topical, systemic, and physical treatments are available to control postburn pruritus; however, it remains unclear how effective these are. OBJECTIVES: To assess the effects of interventions for treating postburn pruritus in any care setting. SEARCH METHODS: In September 2022, we searched the Cochrane Wounds Specialised Register, the Cochrane Central Register of Controlled Trials (CENTRAL), Ovid MEDLINE (including In-Process & Other Non-Indexed Citations), Ovid Embase, and EBSCO CINAHL Plus. We also searched clinical trials registries and scanned references of relevant publications to identify eligible trials. There were no restrictions with respect to language, publication date, or study setting. SELECTION CRITERIA: Randomised controlled trials (RCTs) that enrolled people with postburn pruritus to compare an intervention for postburn pruritus with any other intervention, placebo or sham intervention, or no intervention. DATA COLLECTION AND ANALYSIS: We used the standard methodological procedures expected by Cochrane. We used GRADE to assess the certainty of the evidence. MAIN RESULTS: We included 25 RCTs assessing 21 interventions with 1166 randomised participants. These 21 interventions can be grouped into six categories: neuromodulatory agents (such as doxepin, gabapentin, pregabalin, ondansetron), topical therapies (such as CQ-01 hydrogel, silicone gel, enalapril ointment, Provase moisturiser, beeswax and herbal oil cream), physical modalities (such as massage therapy, therapeutic touch, extracorporeal shock wave therapy, enhanced education about silicone gel sheeting), laser scar revision (pulsed dye laser, pulsed high-intensity laser, fractional CO2 laser), electrical stimulation (transcutaneous electrical nerve stimulation, transcranial direct current stimulation), and other therapies (cetirizine/cimetidine combination, lemon balm tea). Most RCTs were conducted at academic hospitals and were at a high risk of performance, attrition, and detection bias. While 24 out of 25 included studies reported change in burn-related pruritus, secondary outcomes such as cost-effectiveness, pain, patient perception, wound healing, and participant health-related quality of life were not reported or were reported incompletely. Neuromodulatory agents versus antihistamines or placebo There is low-certainty evidence that doxepin cream may reduce burn-related pruritus compared with oral antihistamine (mean difference (MD) -2.60 on a 0 to 10 visual analogue scale (VAS), 95% confidence interval (CI) -3.79 to -1.42; 2 studies, 49 participants). A change of 2 points represents a minimal clinically important difference (MCID). Due to very low-certainty evidence, it is uncertain whether doxepin cream impacts the incidence of somnolence as an adverse event compared to oral antihistamine (risk ratio (RR) 0.64, 95% CI 0.32 to 1.25; 1 study, 24 participants). No data were reported on pain in the included study. There is low-certainty evidence that gabapentin may reduce burn-related pruritus compared with cetirizine (MD -2.40 VAS, 95% CI -4.14 to -0.66; 1 study, 40 participants). A change of 2 points represents a MCID. There is low-certainty evidence that gabapentin reduces the incidence of somnolence compared to cetirizine (RR 0.02, 95% CI 0.00 to 0.38; 1 study, 40 participants). No data were reported on pain in the included study. There is low-certainty evidence that pregabalin may result in a reduction in burn-related pruritus intensity compared with cetirizine with pheniramine maleate (MD -0.80 VAS, 95% CI -1.24 to -0.36; 1 study, 40 participants). A change of 2 points represents a MCID. There is low-certainty evidence that pregabalin reduces the incidence of somnolence compared to cetirizine (RR 0.04, 95% CI 0.00 to 0.69; 1 study, 40 participants). No data were reported on pain in the included study. There is moderate-certainty evidence that ondansetron probably results in a reduction in burn-related pruritus intensity compared with diphenhydramine (MD -0.76 on a 0 to 10 numeric analogue scale (NAS), 95% CI -1.50 to -0.02; 1 study, 38 participants). A change of 2 points represents a MCID. No data were reported on pain and adverse events in the included study. Topical therapies versus relevant comparators There is moderate-certainty evidence that enalapril ointment probably decreases mean burn-related pruritus compared with placebo control (MD -0.70 on a 0 to 4 scoring table for itching, 95% CI -1.04 to -0.36; 1 study, 60 participants). No data were reported on pain and adverse events in the included study. Physical modalities versus relevant comparators Compared with standard care, there is low-certainty evidence that massage may reduce burn-related pruritus (standardised mean difference (SMD) -0.86, 95% CI -1.45 to -0.27; 2 studies, 166 participants) and pain (SMD -1.32, 95% CI -1.66 to -0.98). These SMDs equate to a 4.60-point reduction in pruritus and a 3.74-point reduction in pain on a 10-point VAS. A change of 2 VAS points in itch represents a MCID. No data were reported on adverse events in the included studies. There is low-certainty evidence that extracorporeal shock wave therapy (ESWT) may reduce burn-related pruritus compared with sham stimulation (SMD -1.20, 95% CI -1.65 to -0.75; 2 studies, 91 participants). This equates to a 5.93-point reduction in pruritus on a 22-point 12-item Pruritus Severity Scale. There is low-certainty evidence that ESWT may reduce pain compared with sham stimulation (MD 2.96 on a 0 to 25 pressure pain threshold (PPT), 95% CI 1.76 to 4.16; 1 study, 45 participants). No data were reported on adverse events in the included studies. Laser scar revision versus untreated or placebo controls There is moderate-certainty evidence that pulsed high-intensity laser probably results in a reduction in burn-related pruritus intensity compared with placebo laser (MD -0.51 on a 0 to 1 Itch Severity Scale (ISS), 95% CI -0.64 to -0.38; 1 study, 49 participants). There is moderate-certainty evidence that pulsed high-intensity laser probably reduces pain compared with placebo laser (MD -3.23 VAS, 95% CI -5.41 to -1.05; 1 study, 49 participants). No data were reported on adverse events in the included studies. AUTHORS' CONCLUSIONS: There is moderate to low-certainty evidence on the effects of 21 interventions. Most studies were small and at a high risk of bias related to blinding and incomplete outcome data. Where there is moderate-certainty evidence, practitioners should consider the applicability of the evidence for their patients.

Impaired longitudinal systolic-diastolic coupling and cardiac response to exercise in patients with hypertrophic cardiomyopathy.

BACKGROUND: In patients with hypertrophic cardiomyopathy (HCM), impaired augmentation of stroke volume and diastolic dysfunction contribute to exercise intolerance. Systolic-diastolic (S-D) coupling characterizes how systolic contraction of the left ventricle (LV) primes efficient elastic recoil during early diastole. Impaired S-D coupling may contribute to the impaired cardiac response to exercise in patients with HCM. METHODS: Patients with HCM (n = 25, age = 47 ± 9 years) and healthy adults (n = 115, age = 49 ± 10 years) underwent a cardiopulmonary exercise testing (CPET) and echocardiogram. S-D coupling was defined as the ratio of LV longitudinal excursion of the mitral annulus during early diastole (EDexc) and systole (Sexc) and compared between groups. Peak oxygen uptake (peak V̇O2) (Douglas bags), cardiac index (C2H2 rebreathe), and stroke volume index (SVi) were assessed during CPET. Linear regression was performed between S-D coupling and peak V̇O2, peak cardiac index, and peak SVi. RESULTS: S-D coupling was lower in HCM (Controls: 0.63 ± 0.08, HCM: 0.56 ± 0.10, p < 0.001). Peak V̇O2 and stroke volume reserve were lower in patients with HCM (Peak VO2 Controls: 28.5 ± 5.5, HCM: 23.7 ± 7.2 mL/kg/min, p < 0.001, SV reserve: Controls 39 ± 16, HCM 30 ± 18 mL, p = 0.008). In patients with HCM, S-D coupling was associated with peak V̇O2 (r = 0.47, p = 0.018), peak cardiac index (r = 0.60, p = 0.002), and peak SVi (r = 0.63, p < 0.001). CONCLUSION: Systolic-diastolic coupling was impaired in patients with HCM and was associated with fitness and the cardiac response to exercise. Inefficient S-D coupling may link insufficient stroke volume generation, diastolic dysfunction, and exercise intolerance in HCM.

Expertise in surgical neuro-oncology. Results of a survey by the EANS neuro-oncology section.

Introduction: Technical advances and the increasing role of interdisciplinary decision-making may warrant formal definitions of expertise in surgical neuro-oncology. Research question: The EANS Neuro-oncology Section felt that a survey detailing the European neurosurgical perspective on the concept of expertise in surgical neuro-oncology might be helpful. Material and methods: The EANS Neuro-oncology Section panel developed an online survey asking questions regarding criteria for expertise in neuro-oncological surgery and sent it to all individual EANS members. Results: Our questionnaire was completed by 251 respondents (consultants: 80.1%) from 42 countries. 67.7% would accept a lifetime caseload of >200 cases and 86.7% an annual caseload of >50 as evidence of neuro-oncological surgical expertise. A majority felt that surgeons who do not treat children (56.2%), do not have experience with spinal fusion (78.1%) or peripheral nerve tumors (71.7%) may still be considered experts. Majorities believed that expertise requires the use of skull-base approaches (85.8%), intraoperative monitoring (83.4%), awake craniotomies (77.3%), and neuro-endoscopy (75.5%) as well as continuing education of at least 1/year (100.0%), a research background (80.0%) and teaching activities (78.7%), and formal interdisciplinary collaborations (e.g., tumor board: 93.0%). Academic vs. non-academic affiliation, career position, years of neurosurgical experience, country of practice, and primary clinical interest had a minor influence on the respondents' opinions. Discussion and conclusion: Opinions among neurosurgeons regarding the characteristics and features of expertise in neuro-oncology vary surprisingly little. Large majorities favoring certain thresholds and qualitative criteria suggest a consensus definition might be possible.

A pilot dose-finding study of Terazosin in humans.

Background: Parkinson's disease (PD) is a prevalent neurodegenerative disorder where progressive neuron loss is driven by impaired brain bioenergetics, particularly mitochondrial dysfunction and disrupted cellular respiration. Terazosin (TZ), an α-1 adrenergic receptor antagonist with a known efficacy in treating benign prostatic hypertrophy and hypertension, has shown potential in addressing energy metabolism deficits associated with PD due to its action on phosphoglycerate kinase 1 (PGK1). This study aimed to investigate the safety, tolerability, bioenergetic target engagement, and optimal dose of TZ in neurologically healthy subjects. Methods: Eighteen healthy men and women (60 - 85 years old) were stratified into two cohorts based on maximum TZ dosages (5 mg and 10 mg daily). Methods included plasma and cerebrospinal fluid TZ concentration measurements, whole blood ATP levels, 31 Phosphorous magnetic resonance spectroscopy for brain ATP levels, 18 F-FDG PET imaging for cerebral metabolic activity, and plasma metabolomics. Results: Our results indicated that a 5 mg/day dose of TZ significantly increased whole blood ATP levels and reduced global cerebral 18 F-FDG PET uptake without significant side effects or orthostatic hypotension. These effects were consistent across sexes. Higher doses did not result in additional benefits and showed a potential biphasic dose-response. Conclusions: TZ at a dosage of 5 mg/day engages its metabolic targets effectively in both sexes without inducing significant adverse effects and provides a promising therapeutic avenue for mitigating energetic deficiencies. Further investigation via clinical trials to validate TZ's efficacy and safety in neurodegenerative (i.e., PD) contexts is warranted.

Comparable results in total knee arthroplasty using the ROSA knee system versus the conventional technique: A retrospective propensity-matched cohort study.

PURPOSE: Robotic-assisted total knee arthroplasty (RA-TKA) is an increasingly popular alternative that may increase the accuracy of conventional TKA techniques. This study aims to evaluate RA-TKA accuracy and compare its radiographic and clinical outcomes to conventional TKA (cTKA). METHODS: A retrospective examination of patients with bi- or tricompartmental knee osteoarthritis who underwent RA-TKA (RObotic Surgical Assistant system) or cTKA and were prospectively documented in the TKA registry. Accuracy was assessed using standardized radiographic implant position evaluations, namely femoral and tibial coronal angles and femoral and tibial sagittal angles. Baseline demographics, surgery details and 6- and 12-month post-TKA patient-reported outcomes (PROMs; e.g., Oxford Knee Score [OKS] and Core Outcome Measures Index) were compared between RA-TKA and propensity score-matched cTKA patients. RESULTS: Overall correlation between preset and 6-week postoperative angle measurements for RA-TKA was low with significant differences noted only for mean tibial sagittal angles (84.6° [RA-TKA] vs. 82.3° [cTKA]) (p < 0.001). The study groups were demographically similar, although RA-TKA patients had slightly longer operative times and higher blood loss but shorter inpatient stays. There were sustainable improvements in all PROMs already at 6 months, yet RA-TKA patients had significantly higher OKS values over their conventional counterparts at this time point. CONCLUSION: Radiological and clinical outcomes were comparable between RA-TKA and cTKA. The robotic-assisted system demonstrated higher accuracy in the coronal than sagittal plane and RA-TKA patients achieved better short-term outcomes for pain and disability. While both methods are similar in the hands of a skilled surgeon, long-term studies are necessary to establish clear method superiority. LEVEL OF EVIDENCE: Therapeutic, Level III.

Structural Changes in Brain White Matter Tracts Associated With Overactive Bladder Revealed by Diffusion Tensor Magnetic Resonance Imaging: Findings From a Symptoms of Lower Urinary Tract Dysfunction Research Network Cross-Sectional Case-Control Study.

PURPOSE: Our objective was to investigate structural changes in brain white matter tracts using diffusion tensor imaging (DTI) in patients with overactive bladder (OAB). MATERIALS AND METHODS: Treatment-seeking OAB patients and matched controls enrolled in the cross-sectional case-control LURN (Symptoms of Lower Urinary Tract Dysfunction Research Network) Neuroimaging Study received a brain DTI scan. Microstructural integrity of brain white matter was assessed using fractional anisotropy (FA) and mean diffusivity. OAB and urgency urinary incontinence (UUI) symptoms were assessed using the OAB Questionnaire Short-Form and International Consultation on Incontinence Questionnaire-Urinary Incontinence. The Lower Urinary Tract Symptoms Tool UUI questions and responses were correlated with FA values. RESULTS: Among 221 participants with evaluable DTI data, 146 had OAB (66 urinary urgency-only without UUI, 80 with UUI); 75 were controls. Compared with controls, participants with OAB showed decreased FA and increased mean diffusivity, representing greater microstructural abnormalities of brain white matter tracts among OAB participants. These abnormalities occurred in the corpus callosum, bilateral anterior thalamic radiation and superior longitudinal fasciculus tracts, and bilateral insula and parahippocampal region. Among participants with OAB, higher OAB Questionnaire Short-Form scores were associated with decreased FA in the left inferior fronto-occipital fasciculus, P < .0001. DTI differences between OAB and controls were driven by the urinary urgency-only (OAB-dry) but not the UUI (OAB-wet) subgroup. CONCLUSIONS: Abnormalities in microstructural integrity in specific brain white matter tracts were more frequent in OAB patients. More severe OAB symptoms were correlated with greater degree of microstructural abnormalities in brain white matter tracts in patients with OAB. TRIAL REGISTRATION: ClinicalTrials.gov: NCT02485808.