Likelihood-based interactive local docking into cryo-EM maps in ChimeraX.

The interpretation of cryo-EM maps often includes the docking of known or predicted structures of the components, which is particularly useful when the map resolution is worse than 4 Å. Although it can be effective to search the entire map to find the best placement of a component, the process can be slow when the maps are large. However, frequently there is a well-founded hypothesis about where particular components are located. In such cases, a local search using a map subvolume will be much faster because the search volume is smaller, and more sensitive because optimizing the search volume for the rotation-search step enhances the signal to noise. A Fourier-space likelihood-based local search approach, based on the previously published em_placement software, has been implemented in the new emplace_local program. Tests confirm that the local search approach enhances the speed and sensitivity of the computations. An interactive graphical interface in the ChimeraX molecular-graphics program provides a convenient way to set up and evaluate docking calculations, particularly in defining the part of the map into which the components should be placed.

Total mesorectal excision after rectal-sparing approach in locally advanced rectal cancer patients after neoadjuvant treatment: a high volume center experience.

Background: In patient with a complete or near-complete clinical response after neoadjuvant treatment for locally advanced rectal cancer, the organ-sparing approach [watch & wait (W&W) or local excision (LE)] is a possible alternative to major rectal resection. Although, in case of local recurrence or regrowth, after these treatments, a total mesorectal excision (TME) can be operated. Method: In this retrospective study, we selected 120 patients with locally advanced rectal cancer (LARC) who had a complete or near-complete clinical response after neoadjuvant treatment, from June 2011 to June 2021. Among them, 41 patients were managed by W&W approach, whereas 79 patients were managed by LE. Twenty-three patients underwent salvage TME for an unfavorable histology after LE (11 patients) or a local recurrence/regrowth (seven patients in LE group - five patients in W&W group), with a median follow-up of 42 months. Results: Following salvage TME, no patients died within 30 days; serious adverse events occurred in four patients; 8 (34.8%) patients had a definitive stoma; 8 (34.8%) patients undergone to major surgery for unfavorable histology after LE - a complete response was confirmed. Conclusion: Notably active surveillance after rectal sparing allows prompt identifying signs of regrowth or relapse leading to a radical TME. Rectal sparing is a possible strategy for LARC patients although an active surveillance is necessary.

Biochemical Changes in Adult Male Gamers During Prolonged Gaming: Pilot Study.

BACKGROUND: Gaming has become an integrated part of life for children and adults worldwide. Previous studies on the impact of gaming on biochemical parameters have primarily addressed the acute effects of gaming. The literature is limited, and the study designs are very diverse. The parameters that have been investigated most thoroughly are blood glucose and cortisol. OBJECTIVE: This exploratory study is the first to investigate the effects of long gaming sessions on the biochemical parameters of healthy male adults. The extensive testing allowed us to observe short-term changes (within 6 hours), long-term changes during the duration of the gaming sessions, and follow-up after 1 week to determine whether any changes were longer lasting. METHODS: In total, 9 experienced gamers completed 2 back-to-back 18-hour gaming sessions interspersed with a 6-hour rest period. All participants adhered to a structured sleep pattern due to daytime employment or attending university. Blood, saliva, and urine samples were collected from the participants every 6 hours. Linear mixed-effect models were used to analyze the repeated-measures data accumulated during the study. A total of 51 biochemical parameters were investigated. RESULTS: In total, 12 of the 51 biochemical parameters significantly changed during the study: alkaline phosphatase, aspartate aminotransferase, bilirubin, chloride, creatinine, glucose, hemoglobin, immature reticulocyte fraction, lactate, methemoglobin, sodium, and thrombocytes. All changes were within the normal range. The mean glucose level of the participants was 4.39 (SD 0.07) mmol/L at baseline, which increased significantly by 0.24 (SD 0.07) mmol/L per 6 hours during the first period and by 0.38 (SD 0.07) mmol/L per 6 hours in the second period (P<.001). The glucose levels during the second session increased even though the participants had little energy intake. Cortisol levels did not change significantly, although the cortisol pattern deviated from the typical circadian rhythm. During both gaming sessions, we observed increasing cortisol levels from 6 AM until noon. The participants were relatively dehydrated at the start of the study. The patients were asked to fast before the first blood sampling. Within the first 6 hours of the study, the participants rehydrated, followed by relative dehydration during the remainder of the study. This pattern was identified using the following parameters: albumin, creatinine, hemoglobin, erythrocytes, potassium, and platelets. CONCLUSIONS: This study is the first of its kind, and many of the analyses in the study yielded novel results. The study was designed to emulate the behavior of gamers during the weekend and other long gaming sessions. At this point, we are not able to determine the difference between the effects of gaming and behavior during gaming. Regardless, the results of this study suggest that healthy gamers can partake in long gaming sessions, with ample amounts of unhealthy foods and little rest, without acute impacts on health.

Hybrid algorithms for SAR matrix compression and the impact of post-processing on SAR calculation complexity.

PURPOSE: This study proposes faster virtual observation point (VOP) compression as well as post-processing algorithms for specific absorption rate (SAR) matrix compression. Furthermore, it shows the relation between the number of channels and the computational burden for VOP-based SAR calculation. METHODS: The proposed new algorithms combine the respective benefits of two different criteria for determining upper boundedness of SAR matrices by the VOPs. Comparisons of the old and new algorithms are performed for head coil arrays with various channel counts. The new post-processing algorithm is used to post-process the VOP sets of nine arrays, and the number of VOPs for a fixed median relative overestimation is compared. RESULTS: The new algorithms are faster than the old algorithms by a factor of two to more than 10. The compression efficiency (number of VOPs relative to initial number of SAR matrices) is identical. For a fixed median relative overestimation, the number of VOPs increases logarithmically with the number of RF coil channels when post-processing is applied. CONCLUSION: The new algorithms are much faster than previous algorithms. Post-processing is very beneficial for online SAR supervision of MRI systems with high channel counts, since for a given number of VOPs the relative SAR overestimation can be lowered.

Addressing human factors in the recognition and management of local anaesthetic systemic toxicity.

In the perioperative environment, local anaesthetics are commonly administered to patients to provide analgesia and anaesthesia for a large range of surgical procedures. Although rare, their use can result in systemic toxicity, which is a life-threatening complication, underscoring the importance of early recognition and prompt management to mitigate patient risks. This article evaluates the impact of human factors and other aspects such as insufficient monitoring, errors in drug administration and poor adherence to safety protocols on the development and management of local anaesthetic systemic toxicity and provides practical considerations to minimise its occurrence.

Local adaptation, recombination, and the fate of neopolyploids.

Polyploidy is widely recognized as an important speciation mechanism because it isolates tetraploids from their diploid progenitors. Polyploidy also provides new genetic material that may facilitate adaptive evolution. However, new mutations are more likely to arise after a neopolyploid already has successfully invaded a population. Thus, the role of adaptive forces in establishing a polyploid remains unclear. One solution to this apparent paradox may lie in the capacity of polyploids to suppress recombination among preexisting locally adapted alleles. The local adaptation mechanism requires that spatially heterogeneous selection acts on multiple loci and that gene flow introduces maladapted alleles to the population where the polyploid forms. The mechanism requires neither strong genetic drift nor any intrinsic benefit of genome doubling and can accommodate any mode of gene action. A unique prediction of the mechanism is that adaptive alleles should predate polyploidization, a pattern consistent with observations from a few well-studied polyploids. The mechanism is also consistent with the coexistence of both diploid and tetraploid cytotypes, fitness heterogeneity among independently derived polyploids, and the prevalence of outcrossing among older polyploids. The local adaptation mechanism also makes novel predictions about circumstances favoring polyploid invasions that can be tested using molecular genetic or comparative approaches.

Comparison of 2% lidocaine infiltration and eutectic mixture of local anesthetics cream application before spinal needle insertion for pain reduction and assessment of maternal satisfaction levels in women undergoing cesarean section at a tertiary care se.

Background: This study aimed to compare two analgesic pretreatment techniques for assessing pain reduction before spinal needle insertion and the subsequent patient satisfaction levels in pregnant women undergoing cesarean sections. Methods: Sixty pregnant women scheduled for elective cesarean section under spinal anesthesia were randomly assigned to two groups. The Lidocaine group received local skin infiltration with 2% lidocaine pretreatment before spinal needle introducer insertion, whereas the eutectic mixture of local anesthetics (EMLA) group received EMLA (lidocaine 2.5% and prilocaine 2.5%) cream pretreatment for at least 30 min before spinal needle introducer insertion. Subjective and objective pain scores, procedure duration, number of attempts, maternal satisfaction, and decisions regarding future numbing procedures and regional anesthesia were assessed. Results: The demographic characteristics of the patients were similar between groups. The mean visual analogue scale (VAS) pain score was significantly lower in the EMLA group compared to the lidocaine group (1.2 ± 1.1 vs. 2.8 ± 1.7, estimated difference 1.6; 95% confidence interval [CI], 0.8-2.3; P < 0.05). Additionally, the objective pain score was significantly lower in the EMLA group (P < 0.05). The duration of spinal block placement was significantly longer in the lidocaine group than in the EMLA group (estimated difference, 0.74; 95% CI, 0.50-1.00; P < 0.05). The number of attempts to perform the spinal block placement was similar in both groups. However, women in the EMLA group expressed greater overall satisfaction than those in the lidocaine group (76.7% vs. 20%, P < 0.05). Conclusions: Analgesic pretreatment with EMLA cream is superior to local skin infiltration with lidocaine in pregnant patients undergoing elective cesarean section under spinal anesthesia.

Frequency of and risk factors associated with local recurrence after spinal stereotactic body radiation therapy without surgery.

PURPOSE: This study aimed to identify factors associated with local recurrence after spinal stereotactic body radiation therapy (SBRT), focusing on patient movement during treatment and tumor characteristics. METHODS: A total of 48 patients who underwent spinal SBRT alone without surgery from August 2017 to October 2022 were evaluated. Logistic regression analysis was conducted to identify factors associated with local recurrence, including patient movement and tumor characteristics such as soft tissue involvement and tumor volume. Patient movement during treatment was measured using cone beam computed tomography before and after irradiation. RESULTS: Among the included cases, 68.7% and 42.6% had soft tissue involvement and movement exceeding 1 mm, respectively. The median follow-up duration for local recurrence was 11.6 (range: 0.7-44.9) months, whereas the median duration to local recurrence was 6.3 months. Within 12 months, 29.3% of the patients experienced local recurrence, among whom 43.9% moved ≥ 1 mm during treatment, whereas 15.8% did not move. Univariable analysis found that both soft tissue involvement (OR = 10.3, 1.21-87.9; p = 0.033) and patient movement ≥ 1 mm (OR = 5.75, 1.45-22.8; p = 0.013) were associated with local recurrence. Multivariable analysis identified patient movement as an independent prognostic factor for local recurrence (OR = 5.15, 1.06-25.0; p = 0.042). CONCLUSION: Our results suggest that patient movement during spinal SBRT was associated with local recurrence, emphasizing the need for better immobilization techniques and shorter delivery times to improve tumor control.

Network resonance and the auditory steady state response.

The auditory steady state response (ASSR) arises when periodic sounds evoke stable responses in auditory networks that reflect the acoustic characteristics of the stimuli, such as the amplitude of the sound envelope. Larger for some stimulus rates than others, the ASSR in the human electroencephalogram (EEG) is notably maximal for sounds modulated in amplitude at 40 Hz. To investigate the local circuit underpinnings of the large ASSR to 40 Hz amplitude-modulated (AM) sounds, we acquired skull EEG and local field potential (LFP) recordings from primary auditory cortex (A1) in the rat during the presentation of 20, 30, 40, 50, and 80 Hz AM tones. 40 Hz AM tones elicited the largest ASSR from the EEG acquired above auditory cortex and the LFP acquired from each cortical layer in A1. The large ASSR in the EEG to 40 Hz AM tones was not due to larger instantaneous amplitude of the signals or to greater phase alignment of the LFP across the cortical layers. Instead, it resulted from decreased latency variability (or enhanced temporal consistency) of the 40 Hz response. Statistical models indicate the EEG signal was best predicted by LFPs in either the most superficial or deep cortical layers, suggesting deep layer coordinators of the ASSR. Overall, our results indicate that the recruitment of non-uniform but more temporally consistent responses across A1 layers underlie the larger ASSR to amplitude-modulated tones at 40 Hz.

Deep brain stimulation of the subthalamic nucleus under general anesthesia versus local anesthesia in the treatment of Parkinson's disease: a meta-analysis of randomized clinical trials.

Deep brain stimulation (DBS) stands as the preferred treatment for Parkinson's disease (PD) patients manifesting refractory motor symptoms or when medication side effects outweigh the benefits. Though traditionally administered under local anesthesia coupled with sedation (LA + S), recent evidence hints at comparable outcomes under general anesthesia (GA). This systematic review and meta-analysis aimed to scrutinize post-surgical outcomes in randomized PD patients undergoing DBS surgery while GA versus LA + S. We searched PubMed, Cochrane, and Embase databases following PRISMA guidelines. We included randomized studies directly comparing DBS surgery under GA versus LA + S, delineating clinical outcomes. Safety outcomes assessed disparities in infection and hemorrhage risk. Mean differences (MD) and Risk Differences (RD) with 95% Confidence Intervals (CI) were utilized to evaluate outcomes, under a random-effects model. Heterogeneity was evaluated through I² statistics, and in studies exhibiting high heterogeneity, exclusion analysis was performed. Evaluated outcomes encompassed motor improvement, complications, behavioral and mood effects gauged by the Unified Parkinson's Disease Rating Scale (UPDRS), Parkinson's Disease Questionnaire 39 (PDQ39), and daily levodopa equivalent dose (LEDD). A total of 3 studies, encompassing 203 patients, were reviewed. At a 6-month follow-up, in patients undergoing GA during surgery, there was no statistically significant difference compared to the LA + S group in terms of UPDRS III ON (MD 0.19; 95% CI -2.21 to 2.59; p = 0.88; I²=0%), UPDRS III OFF (MD 0.58; 95% CI -4.30 to 5.45; p = 0.21; I²=0%), UPDRS IV ON ( (MD 0.98; 95% CI -0.95 to 2.92; p = 0.32; I²=23%), PDQ39 (MD -1.27; 95% CI -6.31 to 3.77; p = 0.62; I²=0%), and LEDD (MD -1.99; 95% CI -77.88 to 73.90; p = 0.96; I²=32%). There was no statistically significant difference between groups in terms of infection (RD 0.02; 95% CI -0.02 to 0.05; p = 0.377; I²=0%) or hemorrhage (RD 0.04; 95% CI -0.03 to 0.11; p = 0.215; I²=0%). Our findings suggest, based on short-term follow-up, that GA is not inferior to LA + S in terms of benefits for the selected outcomes. However, further studies are needed to determine whether there are significant long-term clinical differences between these groups.

The Method of Everything vs. Experimenter Bias of Loophole-Free Bell Experiments.

Experimenter bias compromises the integrity and advancement of science, especially when awarded as such. For example, the 2022 Nobel Prize in Physics awarded for the loophole-free experiments that tested physicist John S. Bell's inequality theorem. These experiments employed the logic of conducting local experiments to obtain local evidence that contradicted local realistic theories of nature, thereby validating quantum mechanics as a fundamental non-local theory. However, there was one loophole that was wittingly not tested by the Nobel laureates. The notable exception was Bell's "super-deterministic" loophole, which was validated (2000) (2001) (2002) (2003) (2004) (2005) (2006) (2007) (2008) (2009) (2010) (2011) (2012) non-locally, thus compromising the subsequent Nobel Prize. More importantly, the discovery of two mutually exclusive and jointly exhaustive non-local hidden variables revealed why local scientific methods obtain false-positive and false-negative results. With knowledge of this fundamental omission, the inclusion of the non-local hidden variables in the local methods used in science can then advance it to be a complete study of nature.

Health risk assessment by consumption of commercial biota contaminated with heavy metals in Tampamachoco coastal lagoon, Gulf of Mexico.

Metal pollution is a significant environmental and health problem in aquatic ecosystems worldwide, particularly in coastal systems impacted by emissions from thermoelectric plants, as is the case of the Tampamachoco lagoon. To evaluate the seasonal contamination levels of Cd, Pb, Cr, and Cu in species of commercial interest in the Tampamachoco lagoon and estimate the health risk associated with their consumption, a total of 180 fish, 90 oysters (Crassostrea virginica), 27 crabs (Callinectes sapidus), and 24 shrimp (Litopenaeus setiferus) were sampled. Metal concentrations in the species analyzed were Cu > Pb > Cr > Cd. According to the Target Hazard Quotient and the health risk index, consumption of the marine species examined should be considered safe for human health, as both values are <1. However, Carcinogenic risk values for Pb and Cr indicated that consumers may be at risk of cancer (10-3), due to exposure from the thermoelectric emissions.

Complications and technical success on upper limb vascular access for endovascular repair of complex abdominal and thoraco-abdominal aortic aneurysms: a systematic review and meta-analysis.

PURPOSE: This study aims to assess the efficacy and complications associated with upper limb catheterization during complex aneurysm endovascular surgery repair. METHODS: A systematic review was conducted following PRISMA guidelines, involving a search across PubMed, Cochrane CENTRAL, and Web of Science. Primary endpoint was represented by 30-day stroke. Secondary endpoints were target vessels technical success, 30-day mortality, local access-related complications. Meta-analyses were performed using a random-effects model. RESULTS: Sixteen observational studies encompassing 4,137 patients were included. The 30-day stroke incidence for upper limb access was 1.4% (95% CI 1.0%-1.8%), slightly higher than lower limb, despite not statistically significant. Mortality varied between 0-6.8%, and local access-related complications occurred in 3.2% (95% CI 1.9%-4.4%). Technical success in target vessel catheterization was 99.2% (95% CI 98.4%-100.0%). CONCLUSION: This systematic review and meta-analysis demonstrate the safety and efficacy of upper limb access for f/b-EVAR, with low stroke risk, mortality rates, and minimal local complications. Despite the risk of bias, the findings suggest that upper limb access may be beneficial, especially in bailout situations when femoral access fails, offering valuable insights for clinical decision-making.

Pharmacokinetic study of local and systemic gentamicin concentrations after subcutaneous implantation of a gentamicin-impregnated collagen sponge in dogs.

This study evaluated the pharmacokinetics of commercial gentamicin-impregnated collagen sponges (GICS) applied subcutaneously in dogs. In six healthy beagles, an 11 ×6cm subcutaneous pocket was created, a folded 10×10cm GICS was inserted, and saline was injected to mimic a seroma. Wound fluid samples were aspirated, and the gentamicin concentration was determined. Simultaneously, blood samples were collected to evaluate the corresponding systemic gentamicin concentration. All samples were collected before and 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, 18, 24, 36, 48, 72, 96, 120, and 168hours after GICS placement. The local Cmax of gentamicin was reached after 0.5hours (range, 0.5-1.0hours) post-implantation in 5/6 dogs at a median concentration of 2053.3µg/mL (range, 918.0-2791.9µg/mL). Whitin 24hours, the local concentration dropped below the MIC for Staphylococcus sp. (4µg/mL) in 5/6 dogs. Plasma Cmax was achieved at a median of 1.2hours post-implantation (range, 1.0-2.0hours) and reached a median concentration of 10.3µg/mL (range, 8.8-18.03µg/mL). After 6hours, the gentamicin concentration in the plasma was below 4µg/mL in all dogs. The GICS provided a high local concentration of gentamicin in a short time with a local Cmax:MIC ratio of 513:1, largely sufficient to eliminate susceptible bacteria, including methicillin-resistant Staphylococcus pseudintermedius (MRSP) and Pseudomonas sp., in a clinical setting. The repeated administration of saline in the present study seemed to have induced a quicker gentamicin release from the GICS than described in previous studies that typically dealt with "drier" wounds.

Combined Chemotherapy and Immunotherapy Induction for Screening of Patients with Cervical Esophageal Carcinoma for Subsequent Local Treatment: A New Treatment Paradigm.

BACKGROUND: Definitive chemoradiotherapy is recommended as the primary treatment for cervical esophageal carcinoma (CEC). However, local control rates remain unsatisfactory for some patients. Therefore, in this study, we introduced a new treatment paradigm for individuals with CEC, customizing the choice between subsequent local treatments based on their response to induction chemotherapy and immunotherapy. PATIENTS AND METHODS: Induction treatment comprised two to four cycles of chemotherapy combined with programmed cell death protein 1 (PD-1) inhibitors. Patients achieving complete response (CR) or near CR after induction treatment underwent definitive chemoradiotherapy (dCRT), while those not achieving CR or near CR underwent surgical resection. RESULTS: Among the 40 eligible patients, 14 (35.0%) achieved a CR or near CR after induction treatment. Of the ten patients achieving a CR or near CR, one developed an esophageal fistula after dCRT (10.0%). Among the eight non-CR or non-near CR patients receiving chemoradiotherapy, six developed esophageal fistula (75.0%). Among the 26 patients who did not achieve CR or near CR after induction treatment, the 1-year cancer specific survival (CSS) rates were 93.3% [95% confidence interval (CI) 0.815-1%] for the 18 patients in the surgery group, and 71.4% (95% CI 0.447-1%) for the 8 patients in the chemoradiotherapy group (p = 0.027). The overall laryngeal preservation rate was 85.0% (34/40), with a functional laryngeal preservation rate of 77.5% (31/40). CONCLUSION: The approach consisting of combined immunotherapy and chemotherapy successfully identified patients who were responding well to induction treatment and who were sensitive to radiotherapy, for chemoradiotherapy; thus, improving laryngeal preservation rates. In addition, it also identified patients with poor responses to induction treatment and radiotherapy, for timely surgery; hence, reducing radiotherapy complications and enhancing survival.

Clinical benefits of combining oral cytotoxic chemotherapeutic agents with radiotherapy in patients with T2N0 glottic squamous cell carcinoma based on the reports of the Head and Neck Cancer Registry of Japan.

BACKGROUND: T2N0 glottic squamous cell carcinoma (SCC) typically responds well to radiotherapy (RT); however, achieving local control remains challenging. In cases of RT failure, total laryngectomy may be necessary. Improved local control and preservation of the larynx directly enhances patients' quality of life. Our retrospective analysis using the Japan Head and Neck Cancer Registry (JHNCR) aimed to compare the clinical benefits of RT and chemoradiotherapy (CRT) in patients with T2N0 glottic SCC. METHODS: Using data from the JHNCR (2011-2015), we included 1,231 patients with T2N0 glottic SCC. Among them, 346 received curative RT and 425 underwent curative CRT. The CRT group was further divided into the oral CRT (Oral CRT, N=120) and intravenous CRT (DIV CRT, N=305) groups. This study assessed local control rate (LCR), progression-free survival (PFS), and overall survival (OS). A 1:1 propensity score-matching analysis was used to adjust for patient characteristics. RESULTS: After matching, 105 pairs compared RT with Oral CRT, and 224 pairs compared RT with DIV CRT. The variables were well-balanced in the matched populations. In the matched populations, the Oral CRT group had significantly better 5-year LCR and PFS than the RT group (LCR, 89.4 % vs. 80.6 %, P=0.043; and PFS, 85.5 % vs. 72.3 %, P=0.025, respectively), while the DIV RT group had significantly better 5-year PFS than the RT group (80.1 % vs. 68.6 %, P=0.026). CONCLUSIONS: The clinical benefits of better local and disease controls were observed when oral chemotherapy was added to RT in patients with T2N0 glottic SCC. Thus, the significance of adding oral chemotherapeutic agents to RT in the treatment of T2N0 glottic SCC requires further prospective investigation.

Spiking Laguerre Volterra networks - predicting neuronal activity from local field potentials.

OBJECTIVE: Understanding the generative mechanism between Local Field Potentials (LFP) and neuronal spiking activity is a crucial step for understanding information processing in the brain. Up to now, most approaches have relied on simply quantifying the coupling between LFP and spikes. However, very few have managed to predict the exact timing of spike occurrence based on LFP variations. APPROACH: Here, we fill this gap by proposing novel spiking Laguerre-Volterra Network (sLVN) models to describe the dynamic LFP-spike relationship. Compared to conventional artificial neural networks, the sLVNs are interpretable models that provide explainable features of the underlying dynamics. MAIN RESULTS: The proposed networks were applied on extracellular microelectrode recordings of Parkinson's Disease (PD) patients during Deep Brain Stimulation (DBS) surgery. Based on the predictability of the LFP-spike pairs, we detected three neuronal populations with unique signal characteristics and sLVN model features. SIGNIFICANCE: These clusters were indirectly associated with motor score improvement following DBS surgery, warranting further investigation into the potential of spiking activity predictability as an intraoperative biomarker for optimal DBS lead placement.