A Practical Dosing Algorithm for Deep Neuromuscular Blockade During Total Intravenous Anesthesia: ROCURITHM.

BACKGROUND: The number of trials investigating the effects of deep neuromuscular blockade (NMB) on surgical conditions and patient outcomes is steadily increasing. Consensus on which surgical procedures benefit from deep NMB (a post tetanic count of 1-2) and how to implement it has not been reached. The ESAIC does not advise routine application but recommends use of deep NMB to improve surgical conditions on indication. This study investigates the optimal dosing strategy to reach and maintain adequate deep NMB during total intravenous anesthesia. METHODS: Data from three trials investigating deep NMB during laparoscopic surgery with TIVA (n=424) was pooled to analyze the required rocuronium dose, when to start continuous infusion and how to adjust. The resulting algorithm was validated (n=32) and compared to the success rate in ongoing studies where the algorithm was not used (n=180). RESULTS: The mean rocuronium dose based on actual bodyweight for PTC 1-2 was 1.0 ± 0.27 mg.kg -1.h -1 in the trials where mean duration of surgery was ±2 hours (116 minutes). An induction dose of 0.6 mg.kg -1 lead to a PTC of 1-5 in a quarter of patients after a mean of 11 minutes. The remaining patients were equally divided over too shallow (additional bolus and direct start of continuous infusion) or too deep; a ±15-minute wait after PTC 0 for return of PTC to ≥1. Using the proposed algorithm, a mean 76% of all 5-minute measurements throughout surgery were on target PTC 1-2 in the validation cohort. The algorithm performed significantly better than anesthesiology residents without the algorithm, even after a learning curve from 0-20 patients (42% on target, P≤.001, Cohen's d=1.4 [95% CI 0.9, 1.8]) to 81-100 patients (61% on target, P≤.05, Cohen's d=0.7 [95% CI 0.1, 1.2]). CONCLUSIONS: We propose a dosing algorithm for deep NMB with rocuronium in patients receiving TIVA.

Buccal Mesenchymal Stromal Cells as a Source of Osseointegration of Titanium Implants.

We studied the interaction of human buccal mesenchymal stem cells (MSCs) and osteoblasts differentiated from them with the surface of titanium samples. MSCs were isolated by enzymatic method from buccal fat pads. The obtained cell culture was presented by MSCs, which was confirmed by flow cytometry and differentiation into adipocytes and osteoblasts. Culturing of buccal MSCs on titanium samples was accompanied by an increase in the number of cells for 15 days and the formation of a developed network of F-actin fibers in the cells. The viability of buccal MSCs decreased by 8 days, but was restored by 15 days. Culturing of osteoblasts obtained as a result of buccal MSC differentiation on the surface of titanium samples was accompanied by a decrease in their viability and proliferation. Thus, MSCs from buccal fat pads can be used to coat implants to improve osseointegration during bone reconstruction in craniofacial surgery and dentistry. To improve the integration of osteoblasts, modification of the surface of titanium samples is required.

Tuning the double lipidation of salmon calcitonin to introduce a pore-like membrane translocation mechanism.

A widespread strategy to increase the transport of therapeutic peptides across cellular membranes has been to attach lipid moieties to the peptide backbone (lipidation) to enhance their intrinsic membrane interaction. Efforts in vitro and in vivo investigating the correlation between lipidation characteristics and peptide membrane translocation efficiency have traditionally relied on end-point read-out assays and trial-and-error-based optimization strategies. Consequently, the molecular details of how therapeutic peptide lipidation affects it's membrane permeation and translocation mechanisms remain unresolved. Here we employed salmon calcitonin as a model therapeutic peptide and synthesized nine double lipidated analogs with varying lipid chain lengths. We used single giant unilamellar vesicle (GUV) calcein influx time-lapse fluorescence microscopy to determine how tuning the lipidation length can lead to an All-or-None GUV filling mechanism, indicative of a peptide mediated pore formation. Finally, we used a GUVs-containing-inner-GUVs assay to demonstrate that only peptide analogs capable of inducing pore formation show efficient membrane translocation. Our data provided the first mechanistic details on how therapeutic peptide lipidation affects their membrane perturbation mechanism and demonstrated that fine-tuning lipidation parameters could induce an intrinsic pore-forming capability. These insights and the microscopy based workflow introduced for investigating structure-function relations could be pivotal for optimizing future peptide design strategies.

Methods for Neuroscience Drug Development: Guidance on Standardization of the Process for Defining Clinical Outcome Strategies in Clinical Trials.

Neurosciences clinical trials continue to have notoriously high failure rates. Appropriate outcomes selection in early clinical trials is key to maximizing the likelihood of identifying new treatments in psychiatry and neurology. The field lacks good standards for designing outcome strategies, therefore The Outcomes Research Group was formed to develop and promote good practices in outcome selection. This article describes the first published guidance on the standardization of the process for clinical outcomes in neuroscience. A minimal step process is defined starting as early as possible, covering key activities for evidence generation in support of content validity, patient-centricity, validity requirements and considerations for regulatory acceptance. Feedback from expert members is provided, regarding the risks of shortening the process and examples supporting the recommended process are summarized. This methodology is now available to researchers in industry, academia or clinics aiming to implement consensus-based standard practices for clinical outcome selection, contributing to maximizing the efficiency of clinical research.

Impact of gene expression profiling on diagnosis and survival after metastasis in patients with uveal melanoma.

Surveillance frequency for metastasis is guided by gene expression profiling (GEP). This study evaluated the effect of GEP on time to diagnosis of metastasis, subsequent treatment and survival. A retrospective study was conducted of 110 uveal melanoma patients with GEP (DecisionDx-UM, Castle Biosciences, Friendswood, Texas, USA) and 110 American Joint Committee on Cancer-matched controls. Surveillance testing and treatment for metastasis were compared between the two groups and by GEP class. Rates of metastasis, overall survival and melanoma-related mortality were calculated using Kaplan-Meier estimates. Baseline characteristics and follow-up time were balanced in the two groups. Patients' GEP classification was 1A in 41%, 1B in 25.5% and 2 in 33.6%. Metastasis was diagnosed in 26.4% (n = 29) in the GEP group and 23.6% (n = 26) in the no GEP group (P = 0.75). Median time to metastasis was 30.5 and 22.3 months in the GEP and no GEP groups, respectively (P = 0.44). Median months to metastasis were 34.7, 75.8 and 26.1 in class 1A, 1B and 2 patients, respectively (P = 0.28). Disease-specific 5-year survival rates were 89.4% [95% confidence interval (CI): 81.0-94.2%] and 84.1% (95% CI: 74.9-90.1%) in the GEP and no GEP groups respectively (P = 0.49). Median time to death from metastasis was 10.1 months in the GEP group and 8.5 months in the no GEP group (P = 0.40). There were no significant differences in time to metastasis diagnosis and survival outcomes in patients with and without GEP. To realize the full benefit of GEP, more sensitive techniques for detection of metastasis and adjuvant therapies are required.

In vivo calcium imaging shows that satellite glial cells have increased activity in painful states.

Satellite glial cells are important for proper neuronal function of primary sensory neurons for which they provide homeostatic support. Most research on satellite glial cell function has been performed with in vitro studies, but recent advances in calcium imaging and transgenic mouse models have enabled this first in vivo study of single-cell satellite glial cell function in mouse models of inflammation and neuropathic pain. We found that in naïve conditions, satellite glial cells do not respond in a time-locked fashion to neuronal firing. In painful inflammatory and neuropathic states, we detected time-locked signals in a subset of satellite glial cells, but only with suprathreshold stimulation of the sciatic nerve. Surprisingly, therefore, we conclude that most calcium signals in satellite glial cells seem to develop at arbitrary intervals not directly linked to neuronal activity patterns. More in line with expectations, our experiments also revealed that the number of active satellite glial cells was increased under conditions of inflammation or nerve injury. This could reflect the increased requirement for homeostatic support across dorsal root ganglion neuron populations, which are more active during such painful states.

The role of surgical tissue injury and intraoperative sympathetic activation in postoperative immunosuppression after breast-conserving surgery versus mastectomy: a prospective observational study.

BACKGROUND: Breast cancer is the second most common cause of death from cancer in women worldwide. Counterintuitively, large population-based retrospective trials report better survival after breast-conserving surgery (BCS) compared to mastectomy, corrected for tumour- and patient variables. More extensive surgical tissue injury and activation of the sympathetic nervous system by nociceptive stimuli are associated with immune suppression. We hypothesized that mastectomy causes a higher expression of plasma damage associated molecular patterns (DAMPs) and more intraoperative sympathetic activation which induce postoperative immune dysregulation. Immune suppression can lead to postoperative complications and affect tumour-free survival. METHODS: In this prospective observational study, plasma DAMPs (HMGB1, HSP70, S100A8/A9 and S100A12), intraoperative sympathetic activation (Nociception Level (NOL) index from 0 to 100), and postoperative immune function (plasma cytokine concentrations and ex vivo cytokine production capacity) were compared in patients undergoing elective BCS (n = 20) versus mastectomy (n = 20). RESULTS: Ex vivo cytokine production capacity of TNF, IL-6 and IL-1ß was nearly absent in both groups one hour after surgery. Levels appeared recovered on postoperative day 3 (POD3), with significantly higher ex vivo production capacity of IL-1ß after BCS (p = .041) compared to mastectomy. Plasma concentration of IL-6 was higher one hour after mastectomy (p = .045). Concentrations of plasma alarmins S100A8/A9 and S100A12 were significantly higher on POD3 after mastectomy (p = .003 and p = .041, respectively). Regression analysis showed a significantly lower percentage of NOL measurements ≤ 8 (absence of nociception) during mastectomy when corrected for norepinephrine equivalents (36% versus 45% respectively, p = .038). Percentage of NOL measurements ≤ 8 of all patients correlated with ex vivo cytokine production capacity of IL-1ß and TNF on POD3 (r = .408; p = .011 and r = .500; p = .001, respectively). CONCLUSIONS: This pilot study revealed substantial early postoperative immune suppression after BCS and mastectomy that appears to recover in the following days. Differences between BCS and mastectomy in release of DAMPs and intraoperative sympathetic activation could affect postoperative immune homeostasis and thereby contribute to the better survival reported after BCS in previous large population-based retrospective trials. These results endorse further exploration of (1) S100 alarmins as potential therapeutic targets in breast cancer surgery and (2) suppression of intraoperative sympathetic activation to substantiate the observed association with postoperative immune dysregulation.

Exotic Dark Matter Search with the Majorana Demonstrator.

With excellent energy resolution and ultralow-level radiogenic backgrounds, the high-purity germanium detectors in the Majorana Demonstrator enable searches for several classes of exotic dark matter (DM) models. In this work, we report new experimental limits on keV-scale sterile neutrino DM via the transition magnetic moment from conversion to active neutrinos ν_{s}→ν_{a}. We report new limits on fermionic dark matter absorption (χ+A→ν+A) and sub-GeV DM-nucleus 3→2 scattering (χ+χ+A→ϕ+A), and new exclusion limits for bosonic dark matter (axionlike particles and dark photons). These searches utilize the (1-100)-keV low-energy region of a 37.5-kg y exposure collected by the Demonstrator between May 2016 and November 2019 using a set of ^{76}Ge-enriched detectors whose surface exposure time was carefully controlled, resulting in extremely low levels of cosmogenic activation.

Underneath Images and Robots, Looking Deeper into the Pneumoperitoneum: A Narrative Review.

Laparoscopy offers numerous advantages over open procedures, minimizing trauma, reducing pain, accelerating recovery, and shortening hospital stays. Despite other technical advancements, pneumoperitoneum insufflation has received little attention, barely evolving since its inception. We explore the impact of pneumoperitoneum on patient outcomes and advocate for a minimally invasive approach that prioritizes peritoneal homeostasis. The nonlinear relationship between intra-abdominal pressure (IAP) and intra-abdominal volume (IAV) is discussed, emphasizing IAP titration to balance physiological effects and surgical workspace. Maintaining IAP below 10 mmHg is generally recommended, but factors such as patient positioning and surgical complexity must be considered. The depth of neuromuscular blockade (NMB) is explored as another variable affecting laparoscopic conditions. While deep NMB appears favorable for surgical stillness, achieving a balance between IAP and NMB depth is crucial. Temperature and humidity management during pneumoperitoneum are crucial for patient safety and optical field quality. Despite the debate over the significance of temperature drop, humidification and the warming of insufflated gas offer benefits in peritoneal homeostasis and visual clarity. In conclusion, there is potential for a paradigm shift in pneumoperitoneum management, with dynamic IAP adjustments and careful control of insufflated gas temperature and humidity to preserve peritoneal homeostasis and improve patient outcomes in minimally invasive surgery.

Deep neuromuscular blockade in adults undergoing an abdominal laparoscopic procedure.

BACKGROUND: Laparoscopic surgery is the preferred option for many procedures. To properly perform laparoscopic surgery, it is essential that sudden movements and abdominal contractions in patients are prevented, as it limits the surgeon's view. There has been a growing interest in the potential beneficial effect of deep neuromuscular blockade (NMB) in laparoscopic surgery. Deep NMB improves the surgical field by preventing abdominal contractions, and it is thought to decrease postoperative pain. However, it is uncertain if deep NMB improves intraoperative safety and thereby improves clinical outcomes. OBJECTIVES: To evaluate the benefits and harms of deep neuromuscular blockade versus no, shallow, or moderate neuromuscular blockade during laparoscopic intra- or transperitoneal procedures in adults. SEARCH METHODS: We used standard, extensive Cochrane search methods. The latest search date was 31 July 2023. SELECTION CRITERIA: We included randomised clinical trials (irrespective of language, blinding, or publication status) in adults undergoing laparoscopic intra- or transperitoneal procedures comparing deep NMB to moderate, shallow, or no NMB. We excluded trials that did not report any of the primary or secondary outcomes of our review. DATA COLLECTION AND ANALYSIS: We used standard Cochrane methods. Our primary outcomes were 1. all-cause mortality, 2. health-related quality of life, and 3. proportion of participants with serious adverse events. Our secondary outcomes were 4. proportion of participants with non-serious adverse events, 5. readmissions within three months, 6. short-term pain scores, 7. measurements of postoperative recovery, and 8. operating time. We used GRADE to assess the certainty of evidence for each outcome. MAIN RESULTS: We included 42 randomised clinical trials with 3898 participants. Most trials included participants undergoing intraperitoneal oncological resection surgery. We present the Peto fixed-effect model for most dichotomous outcomes as only sparse events were reported. Comparison 1: deep versus moderate NMB Thirty-eight trials compared deep versus moderate NMB. Deep NMB may have no effect on mortality, but the evidence is very uncertain (Peto odds ratio (OR) 7.22, 95% confidence interval (CI) 0.45 to 115.43; 12 trials, 1390 participants; very low-certainty evidence). Deep NMB likely results in little to no difference in health-related quality of life up to four days postoperative (mean difference (MD) 4.53 favouring deep NMB on the Quality of Recovery-40 score, 95% CI 0.96 to 8.09; 5 trials, 440 participants; moderate-certainty evidence; mean difference lower than the mean clinically important difference of 10 points). The evidence is very uncertain about the effect of deep NMB on intraoperatively serious adverse events (deep NMB 38/1150 versus moderate NMB 38/1076; Peto OR 0.95, 95% CI 0.59 to 1.52; 21 trials, 2231 participants; very low-certainty evidence), short-term serious adverse events (up to 60 days) (deep NMB 37/912 versus moderate NMB 42/852; Peto OR 0.90, 95% CI 0.56 to 1.42; 16 trials, 1764 participants; very low-certainty evidence), and short-term non-serious adverse events (Peto OR 0.94, 95% CI 0.65 to 1.35; 11 trials, 1232 participants; very low-certainty evidence). Deep NMB likely does not alter the duration of surgery (MD -0.51 minutes, 95% CI -3.35 to 2.32; 34 trials, 3143 participants; moderate-certainty evidence). The evidence is uncertain if deep NMB alters the length of hospital stay (MD -0.22 days, 95% CI -0.49 to 0.06; 19 trials, 2084 participants; low-certainty evidence) or pain scores one hour after surgery (MD -0.31 points on the numeric rating scale, 95% CI -0.59 to -0.03; 22 trials, 1823 participants; very low-certainty evidence; mean clinically important difference 1 point) and 24 hours after surgery (MD -0.60 points on the numeric rating scale, 95% CI -1.05 to -0.15; 16 trials, 1404 participants; very low-certainty evidence; mean clinically important difference 1 point). Comparison 2: deep versus shallow NMB Three trials compared deep versus shallow NMB. The trials did not report on mortality and health-related quality of life. The evidence is very uncertain about the effect of deep NMB compared to shallow NMB on the proportion of serious adverse events (RR 1.66, 95% CI 0.50 to 5.57; 2 trials, 158 participants; very low-certainty evidence). Comparison 3: deep versus no NMB One trial compared deep versus no NMB. There was no mortality in this trial, and health-related quality of life was not reported. The proportion of serious adverse events was 0/25 in the deep NMB group and 1/25 in the no NMB group. AUTHORS' CONCLUSIONS: There was insufficient evidence to draw conclusions about the effects of deep NMB compared to moderate NMB on all-cause mortality and serious adverse events. Deep NMB likely results in little to no difference in health-related quality of life and duration of surgery compared to moderate NMB, and it may have no effect on the length of hospital stay. Due to the very low-certainty evidence, we do not know what the effect is of deep NMB on non-serious adverse events, pain scores, or readmission rates. Randomised clinical trials with adequate reporting of all adverse events would reduce the current uncertainties. Due to the low number of identified trials and the very low certainty of evidence, we do not know what the effect of deep NMB on serious adverse events is compared to shallow NMB and no NMB. We found no trials evaluating mortality and health-related quality of life.

Perioperative outcomes of laparoscopic low anterior resection using ArtiSential® versus robotic approach in patients with rectal cancer: a propensity score matching analysis.

BACKGROUND: Total mesorectal excision using conventional straight fixed devices may be technically difficult because of the narrow and concave pelvis. Several laparoscopic articulating tools have been introduced as an alternative to robotic systems. The aim of this study was to compare perioperative outcomes between laparoscopic low anterior resection using ArtiSential® and robot-assisted surgery for rectal cancer. METHODS: This retrospective study included 682 patients who underwent laparoscopic or robotic low anterior resection  for rectal cancer from September 2018 to December 2021. Among them, 82 underwent laparoscopic surgery using ArtiSential® (group A) and 201 underwent robotic surgery (group B). A total of 73 [group A; 66.37 ± 11.62; group B 65.79 ± 11.34] patients were selected for each group using a propensity score matching analysis. RESULTS: There was no significant difference in the baseline characteristics between group A and B. Mean operative time was longer in group B than A (163.5 ± 61.9 vs 250.1 ± 77.6 min, p < 0.001). Mean length of hospital stay was not significantly different between the two groups (6.2 ± 4.7 vs 6.7 ± 6.1 days, p = 0.617). Postoperative complications, reoperation, and readmission within 30 days after surgery were similar between the two groups. Pathological findings revealed that the circumferential resection margins were above 10 mm in both groups (11.00 ± 7.47 vs 10.17 ± 6.25 mm, p = 0.960). At least 12 lymph nodes were sufficiently harvested, with no significant difference in the number harvested between the groups (20.5 ± 9.9 vs 19.7 ± 7.3, p = 0.753). CONCLUSIONS: Laparoscopic low anterior resection using ArtiSential® can achieve acceptable clinical and oncologic outcomes. ArtiSential®, a multi-joint and articulating device, may serve a feasible alternative approach to robotic surgery in rectal cancer.

Evaluating the Impact of Operative Team Familiarity on Cardiac Surgery Outcomes: A Retrospective Cohort Study of Medicare Beneficiaries.

OBJECTIVE: To associate surgeon-anesthesiologist team familiarity (TF) with cardiac surgery outcomes. BACKGROUND: TF, a measure of repeated team member collaborations, has been associated with improved operative efficiency; however, examination of its relationship to clinical outcomes has been limited. METHODS: This retrospective cohort study included Medicare beneficiaries undergoing coronary artery bypass grafting (CABG), surgical aortic valve replacement (SAVR), or both (CABG+SAVR) between January 1, 2017, and September 30, 2018. TF was defined as the number of shared procedures between the cardiac surgeon and anesthesiologist within 6 months of each operation. Primary outcomes were 30- and 90-day mortality, composite morbidity, and 30-day mortality or composite morbidity, assessed before and after risk adjustment using multivariable logistic regression. RESULTS: The cohort included 113,020 patients (84,397 CABG; 15,939 SAVR; 12,684 CABG+SAVR). Surgeon-anesthesiologist dyads in the highest [31631 patients, TF median (interquartile range)=8 (6, 11)] and lowest [44,307 patients, TF=0 (0, 1)] TF terciles were termed familiar and unfamiliar, respectively. The rates of observed outcomes were lower among familiar versus unfamiliar teams: 30-day mortality (2.8% vs 3.1%, P =0.001), 90-day mortality (4.2% vs 4.5%, P =0.023), composite morbidity (57.4% vs 60.6%, P <0.001), and 30-day mortality or composite morbidity (57.9% vs 61.1%, P <0.001). Familiar teams had lower overall risk-adjusted odds of 30-day mortality or composite morbidity [adjusted odds ratio (aOR) 0.894 (0.868, 0.922), P <0.001], and for SAVR significantly lower 30-day mortality [aOR 0.724 (0.547, 0.959), P =0.024], 90-day mortality [aOR 0.779 (0.620, 0.978), P =0.031], and 30-day mortality or composite morbidity [aOR 0.856 (0.791, 0.927), P <0.001]. CONCLUSIONS: Given its relationship with improved 30-day cardiac surgical outcomes, increasing TF should be considered among strategies to advance patient outcomes.

Assessing spontaneous sensory neuron activity using in vivo calcium imaging.

ABSTRACT: Heightened spontaneous activity in sensory neurons is often reported in individuals living with chronic pain. It is possible to study this activity in rodents using electrophysiology, but these experiments require great skill and can be prone to bias. Here, we have examined whether in vivo calcium imaging with GCaMP6s can be used as an alternative approach. We show that spontaneously active calcium transients can be visualised in the fourth lumbar dorsal root ganglion (L4 DRG) through in vivo imaging in a mouse model of inflammatory pain. Application of lidocaine to the nerve, between the inflamed site and the DRG, silenced spontaneous firing and revealed the true baseline level of calcium for spontaneously active neurons. We used these data to train a machine learning algorithm to predict when a neuron is spontaneously active. We show that our algorithm is accurate in 2 different models of pain: intraplantar complete Freund adjuvant and antigen-induced arthritis, with accuracies of 90.0% ±1.2 and 85.9% ±2.1, respectively, assessed against visual inspection by an experienced observer. The algorithm can also detect neuronal activity in imaging experiments generated in a different laboratory using a different microscope configuration (accuracy = 94.0% ±2.2). We conclude that in vivo calcium imaging can be used to assess spontaneous activity in sensory neurons and provide a Google Colaboratory Notebook to allow anyone easy access to our novel analysis tool, for the assessment of spontaneous neuronal activity in their own imaging setups.

Five Year Results of Endovascular versus Medical Therapy in Acute Type B Aortic Intramural Haematoma: Meta-Analysis of Reconstructed Time to Event Data.

OBJECTIVE: To evaluate outcomes in the follow up of thoracic endovascular aortic repair (TEVAR) vs. medical therapy in patients with acute type B aortic intramural haematoma (IMH). DATA SOURCES: The following sources were searched for articles meeting the inclusion criteria and published by July 2023: PubMed/MEDLINE, EMBASE, CENTRAL/CCTR (Cochrane Controlled Trials Register). REVIEW METHODS: This systematic review with pooled meta-analysis of time to event data followed the Preferred Reporting Items for Systematic Reviews and Meta-analyses (PRISMA) reporting guidelines, and its protocol was registered on the public platform PROSPERO (CRD42023456222). The following were analysed: overall survival (all cause mortality), aortic related mortality, and restricted mean survival time. Certainty of evidence was evaluated through the Grading of Recommendations, Assessment, Development, and Evaluations (GRADE) tool. RESULTS: Eight studies met the eligibility criteria, including 1 015 patients (440 in the TEVAR group and 575 in the medical therapy group). All studies were observational, and the pooled cohort had a median follow up of 5.1 years. Compared with patients who received medical therapy alone, those who underwent TEVAR had a statistically significantly lower risk of all cause death (HR 0.44, 95% CI 0.30 - 0.65; p < .001; GRADE certainty: low), lower risk of aortic related death (HR 0.04, 95% CI 0.01 - 0.31; p = .002; GRADE certainty: low) and lifetime gain (restricted mean survival time was overall 201 days longer with TEVAR; p < .001). CONCLUSION: Thoracic endovascular aortic repair may be associated with lower risk of all cause and aortic related death compared with medical therapy in patients with acute type B IMH; however, the underlying data are not strong enough to draw robust clinical conclusions. Randomised controlled trials with large sample sizes and longer follow up are warranted to elucidate this question.

Studying the Proliferative Activity of Human Corneal Stromal Cell Populations.

The proliferative activity of populations of stromal cells (fibroblasts) obtained from human corneal lenticles under conditions of their differentiation into keratocytes was studied. It was shown that during differentiation, the number of dividing fibroblasts and the frequency of divisions, and motor activity of these cells (speed of movement along the cell trajectory and the length of the trajectory) sharply decreased. These findings indicate a decrease in the proliferative activity of fibroblasts under conditions of their differentiation and transformation into keratocytes. A period of 17 days is sufficient for differentiation of corneal fibroblasts into keratocytes.

Metformin activates AMPK and mTOR to Inhibit RANKL-stimulated osteoclast formation.

OBJECTIVE: Metformin is a medication used to treat type 2 diabetes by inhibiting hepatic glucose production through adenosine monophosphate-activated protein kinase (AMPK) activation. Autophagy is closely related to the homeostasis and stress mechanisms of the body. In recent years, much research has arisen on therapeutic methods utilizing autophagy mechanisms to treat diagnoses such as metabolic diseases, tumors, and Alzheimer's disease. This study thus aimed to investigate the effects of metformin treatment on the differentiation of osteoclasts and changes in AMPK mechanisms, which play an important role in regulating energy homeostasis, and mTOR, a highly conserved kinase that regulates autophagy. MATERIALS AND METHODS: Experimentation, including 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay, tartrate-resistant acid phosphate (TRAP) staining, pit formation assay, immunofluorescence, western blotting, and real-time polymerase chain reaction (PCR) was performed to investigate the effects of metformin on osteoclast differentiation. Additionally, to investigate its association with AMPK and pathways, the AMPK inhibitor compound C and mammalian targets of rapamycin (mTOR) activator leucine were used to examine the expression of osteoclast- or autophagy-related proteins, genes, and TRAP-positive cells. RESULTS: Metformin showed no cytotoxic effects on mouse osteoblastic cell lines (MC3T3-E1) and murine macrophage cell lines (RAW264.7) but did inhibit osteoclast differentiation. Furthermore, metformin was found to inhibit osteoclast differentiation through AMPK activation and mTOR inhibition. In turn, AMPK inhibition using compound C promoted osteoclast differentiation, and mTOR activation using leucine inhibited autophagy and osteoclast differentiation. CONCLUSIONS: Metformin activates the AMPK pathway while functioning as an activator of mTOR, thereby leading to the inhibition of autophagy and osteoclast differentiation.

Constraints on the Decay of

^{180m}Ta is a rare nuclear isomer whose decay has never been observed. Its remarkably long lifetime surpasses the half-lives of all other known ß and electron capture decays due to the large K-spin differences and small energy differences between the isomeric and lower-energy states. Detecting its decay presents a significant experimental challenge but could shed light on neutrino-induced nucleosynthesis mechanisms, the nature of dark matter, and K-spin violation. For this study, we repurposed the Majorana Demonstrator, an experimental search for the neutrinoless double-beta decay of ^{76}Ge using an array of high-purity germanium detectors, to search for the decay of ^{180m}Ta. More than 17 kg, the largest amount of tantalum metal ever used for such a search, was installed within the ultralow-background detector array. In this Letter, we present results from the first year of Ta data taking and provide an updated limit for the ^{180m}Ta half-life on the different decay channels. With new limits up to 1.5×10^{19} yr, we improved existing limits by 1-2 orders of magnitude which are the most sensitive searches for a single ß and electron capture decay ever achieved. Over all channels, the decay can be excluded for T_{1/2}<0.29×10^{18} yr.

Spiral-phase-objective for a compact spiral-phase-contrast microscopy.

Spiral-phase-contrast imaging, which utilizes a spiral phase optical element, has proven to be effective in enhancing various aspects of imaging, such as edge contrast and shadow imaging. Typically, the implementation of spiral-phase-contrast imaging requires the formation of a Fourier plane through a 4f optical configuration in addition to an existing optical microscope. In this study, we present what we believe to be a novel single spiral-phase-objective, integrating a spiral phase plate, which can be easily and simply applied to a standard microscope, such as a conventional objective. Using a new hybrid design approach that combines ray-tracing and field-tracing simulations, we theoretically realized a well-defined and high-quality vortex beam through the spiral-phase-objective. The spiral-phase-objective was designed to have conditions that are practically manufacturable while providing predictable performance. To evaluate its capabilities, we utilized the designed spiral-phase-objective to investigate isotropic spiral phase contrast and anisotropic shadow imaging through field-tracing simulations, and explored the variation of edge contrast caused by changes in the thickness of the imaging object.

[Control of hormonal rhinitis symptoms in patients with hypothyrosis: pathogenetic and clinical aspects]. / Kontrol' simptomov khronicheskogo rinita u patsientov s gipotireozom: patogeneticheskie i klinicheskie aspekty.

BACKGROUND: One of the poorly studied sections of the pathology of ENT organs is chronic rhinitis in patients with hypothyroidism, the pathogenesis of which has not been fully understood, the diagnosis causes significant difficulties, and there are no recommendations for treatment. Despite receiving replacement therapy with levothyroxine, the symptoms of rhinitis persist. OBJECTIVE: To study the effectiveness of the use of intranasal glucocorticosteroids in patients with chronic rhinitis and hypothyroidism. MATERIAL AND METHODS: Patients with chronic rhinitis and hypothyroidism used mometasone nasal spray 100 mcg 1 time per day for a course of treatment of 2 months (n=60). To assess the symptoms of rhinitis, a visual analog scale (0-10 points), endoscopic examination of ENT organs, anterior active rhinomanometry were used. Evaluation of mucociliary transport was used a saccharin test. The concentration of transforming growth factor (TGF-ß1) in nasal secretion and blood serum was studied by ELISA (Enzyme-Linked Immunosorbent Assay), the number of metabolites of NO - nitrites+nitrates (NOx) was recorded by colorimetric method. RESULTS: The use of mometasone nasal spray in patients with hypothyroidism helped to reduce complaints on a visual-analog scale (difficulty in nasal breathing, rhinorrhea) and improve nasal breathing according to anterior active rhinomanometry. The concentrations of TGF-ß1 and NOx in nasal secretions before mometasone treatment were higher than after treatment, which probably indicates the contribution of these substances to the formation of edematous hypertrophic changes from the nose in patients with hypothyroidism.