Prognosis for local radical treatment in patients with esophageal squamous cell carcinoma with low-risk oligometastatic recurrence after curative resection: a retrospective cohort study.

Background: Patients with esophageal carcinoma (EC) with recurrent disease have a poor prognosis. A limited numbers of metastases, safely treatable with curative intent, diagnosed after curative esophagectomy may be defined as oligometastatic recurrence (OLR). However, the appropriate number of metastases and metastatic organs involved remains incompletely characterized. And the role of local therapy in OLR after radical esophagectomy remains unknown. Therefore, this study aimed to more accurately define low-risk OLR in patients with esophageal squamous cell carcinoma (ESCC) treated with radical resection and investigate the role of chemotherapy combined with local treatment (CCLT) in these patients. Methods: A total of 83 sequential patients with ESCC who underwent radical esophagectomy, with an Eastern Cooperative Oncology Group (ECOG) performance status ≤2, with ability to tolerate chemotherapy (CT) and local treatment, and with newly diagnosed recurrence between January 2010 and May 2019 in our hospital were recruited. Overall survival (OS) curves after recurrence were analyzed using the Kaplan-Meier method, and a log-rank test was used to assess the OS differences. Cox proportional hazards regression analysis was performed to identify independent factors associated with 2-year OS. Regular follow-up examinations were assessed by thoracic and upper abdominal computed tomography (CT) scanning every 3 months in the first year, every 6 months over the next 2 years, and yearly thereafter. Results: Of the 83 patients with ESCC (71 males and 12 females), the median age was 56 years (range, 37-79 years). Thirty-five patients with ESCC with ≤5 metastases safely treatable with curative intent located in a single organ had a favorable OS compared to 48 patients with metastases located in 2-3 organs with or without regional recurrence and/or regional lymph node (LN) metastases. In our study, low-risk OLR was defined as the presence of ≤5 metastases safely treatable with curative intent in a single organ and was compared to patients with 2-3 organs involved. The 2-year OS of patients with low-risk OLR with liver oligometastases was significantly worse than survival in patients with lung oligometastases (0% vs. 61.1%, P=0.009). Patients with ESCC in the low-risk OLR group treated with CCLT had a better 2-year OS after recurrence than those who received CT alone (66.7% vs. 30.4%, P=0.003). The multivariable Cox regression model identified treatment method [hazard ratio (HR) 3.920, P=0.02] as an independent factor affecting OS after recurrence for low-risk OLR. Conclusions: Low-risk OLR was defined as ≤5 metastases safely treatable with curative intent in a single organ. Patients with ESCC with low-risk OLR after curative resection treated with CCLT have a favorable OS compared to those treated with CT alone. CCLT is a promising treatment option for patients with ESCC and low-risk OLR.

Molecular subtype and risk of local recurrence after nipple­sparing mastectomy for breast cancer.

The present study aimed to investigate whether local recurrence (LR) after nipple-sparing mastectomy (NSM) and reconstruction was associated with i) Ki67 values and molecular subtypes of the initial lesions, and ii) the size of the initial tumor and the size of the implant. A total of 156 patients with breast cancer with a mean age of 51.58 years (age range, 26-75 years) who underwent NSM with primary implant breast reconstruction were analyzed. After surgery, the mean follow-up time was 59.26 months (range, 17-85 months). Molecular subtypes, Ki67 values, estrogen receptor (ER), progesterone receptor (PR) and human epidermal growth factor receptor 2 (HER2) status were recorded for each patient. Additionally, information regarding the size of the implant and the initial tumor size were collected. The information was used to assess LR. For univariate analyses of risk factors, χ2 test, Fisher's exact test, Mann-Whitney U test and Student's t-test for independent samples were used. For multivariate analyses, a Cox proportional-hazards model was used. NSM was the primary treatment for breast cancer in 34/156 patients (21.8%), while 122/156 (78.2%) of patients received neoadjuvant chemotherapy followed by surgery. Luminal B was the most frequent molecular subtype, detected in 82/156 patients (52.6%), whereas the luminal A subtype was detected in 37 patients (23.7%) and the HER2-enriched subtype was detected in 17/156 patients (10.9%). Ki67 expression was low in 13/156 patients (8.3%), while medium expression was detected in 78/156 patients (50.0%) and high expression was present in 58/156 patients (37.2%). LR was noted in 17/156 patients (10.9%). As determined by univariate analysis, lower ER (P=0.010) and PR (P=0.008) expression were indicated to be significant risk factors for LR. In conclusion, in the present patient cohort, low ER and PR expression were risk factors for LR of breast cancer, whereas Ki67 status and molecular subtype were not statistically significant risk factors for LR. Additionally, the size of the initial tumor and the size of the implant were not risk factors for LR. These findings are consistent with the current literature, and should be utilized when discussing treatment options and potential clinical outcomes with patients prior to surgical management.

Sustained delivery of celecoxib from nanoparticles embedded in hydrogel injected into the biopsy cavity to prevent biopsy-induced breast cancer metastasis.

PURPOSE: We have previously reported that protracted Cyclooxygenase-2 (COX-2) activity in bone marrow-derived cells (BMDCs) infiltrating into biopsy wounds adjacent to the biopsy cavity of breast tumors in mice promotes M2-shift of macrophages and pro-metastatic changes in cancer cells, effects which were suppressed by oral administration of COX-2 inhibitors. Thus, local control of COX-2 activity in the biopsy wound may mitigate biopsy-induced pro-metastatic changes. METHODS: A combinatorial delivery system-thermosensitive biodegradable poly(lactic acid) hydrogel (PLA-gel) incorporating celecoxib-encapsulated poly(lactic-co-glycolic acid) nanoparticles (Cx-NP/PLA-gel)-was injected into the biopsy cavity of Py230 murine breast tumors to achieve local control of COX-2 activity in the wound stroma. RESULTS: A single intra-biopsy cavity injection of PLA-gel loaded with rhodamine-encapsulated nanoparticles (NPs) showed sustained local delivery of rhodamine preferentially to infiltrating BMDCs with minimal to no rhodamine uptake by the reticuloendothelial organs in mice. Moreover, significant reductions in M2-like macrophage density, cancer cell epithelial-to-mesenchymal transition, and blood vessel density were observed in response to a single intra-biopsy cavity injection of Cx-NP/PLA-gel compared to PLA-gel loaded with NPs containing no payload. Accordingly, intra-biopsy cavity injection of Cx-NP/PLA-gel led to significantly fewer metastatic cells in the lungs than control-treated mice. CONCLUSION: This study provides evidence for the feasibility of sustained, local delivery of payload preferential to BMDCs in the wound stroma adjacent to the biopsy cavity using a combinatorial delivery system to reduce localized inflammation and effectively mitigate breast cancer cell dissemination.

Mucosa-penetrating liposomes for esophageal local drug delivery.

Local drug delivery to the esophagus is hampered by rapid transit time and poor permeability of the mucosa. If some strategies aimed to improve the residence time have been proposed, non-invasive approaches to increase the drug penetration in the mucosa have not been described so far. Herein, we designed mucosa-penetrating liposomes to favor the penetration and retention of curcumin (CURC) in the esophagus. A novel mucosa penetrating peptide (MPP), SLENKGP, was selected by Phage Display and conjugated to pegylated liposomes at different PEG and MPP's surface densities. Pegylation assured a long residence time of liposomes (at least 30 min) in the esophagus in vivo, but it did not favor the penetration of CURC in the mucosa. MPP-decorated liposomes instead delivered a significant higher amount of CURC in the mucosa compared to naked pegylated liposomes. Confocal microscopy studies showed that naked pegylated liposomes remain confined in the superficial layers of the mucosa whereas MPP-decorated liposomes penetrate the whole epithelium. In vitro, MPP reduced the interaction of PEG with mucin, meanwhile favoring the paracellular penetration of liposomes across epithelial cell multilayers. In conclusion, pegylated liposomes represent a valid approach to target the esophagus and the surface functionalization with MPP enhances their penetration in the mucosa.

Evaluation of the Effect of Benzydamine Hydrochloride on the Intensity of Gag Reflex: A Randomized Single-Blind Clinical Trial.

Statement of the Problem: Gag reflex is among the most common problems during dental and endoscopic procedures. Benzydamine hydrochloride is a non-steroidal anti-inflammatory medication and a local anesthetic that might be useful in reducing the gag reflex. Purpose: This study aimed to evaluate the effects of benzydamine hydrochloride mouthwash on the intensity of the gag reflex. Materials and Method: In this randomized clinical trial study, 30 participants aged 21-26 with a gag trigger point index (GTPI) higher than 2 were divided into 2 groups. In the case group, 15 ml of 0.15% benzydamine hydrochloride mouthwash was gargled for 1 minute, and after 10 minutes GTPI test was conducted. In the control group, 4 puffs of 10% lidocaine spray were applied to the mucosa of the targeted area, and after 5 minutes, GTPI was measured. Participants were asked about the taste and smell of the medications. Results: GTPI was significantly reduced in both groups. In the lidocaine group, the GTPI score changed from 4.47 to 2.00 (p< 0.001), and that for the benzydamine group was 4.20 to 1.47 (p< 0.001). The variance rate of the gag reflex was -2.73 and -2.47 in the benzydamine group and lidocaine group, respectively. However, this reduction was not statistically significant between the two groups. Moreover, benzydamine mouthwash has a significantly better taste and smell than lidocaine (p= 0.001). Conclusion: The results of this study showed that benzydamine mouthwash could be used quite effectively in reducing the gag reflex.

Adaptive capacity to reduce disaster risks in informal settlements.

The eMalahleni Local Municipality (eLM) in Mpumalanga province, South Africa, has a number of informal settlements because of the influx of people seeking employment in the municipal area. These informal settlements are exposed to a number of hazards, including underground fires, air and water pollution, sinkholes, abandoned mining areas and acid mining drainage. South Africa's National Development Plan (NDP) incorporates the United Nation's Sustainable Development Goals, which are intended to upgrade informal settlements on suitable land. The Department of Human Settlement recognised the gap in the policy because upgrading only included physical structures and did not include adaptive capacity for communities to create resilience to withstand disasters. The researcher used a case study research design for the inquiry intended to recommend adaptive capacity and reduce disaster risks in informal settlements in the eLM. Purposive sampling was used to select 25 participants from eLM, provincial government departments and informal settlements. The data were analysed using thematic analysis based on the study's conceptual framework. The research findings revealed that the government has not done much to involve vulnerable communities during the development of policies to reduce disaster risks within informal settlements. In particular, the failure of the government to promote and reinforce public participation in disaster risk reduction programmes leaves the vulnerable communities defenceless. Contribution: This study strengthens the intergovernmental structures and public participation to reduce disaster risks in communities. This study discourages a silos mentality and encourages coordination between government departments to identify root causes by applying the pressure and release model for effective disaster risk reduction.

Treatment escalation and de-escalation of de-novo metastatic castration-sensitive prostate cancer.

Androgen receptor signaling inhibitors combined with androgen deprivation therapy have become the standard of care for metastatic castration-sensitive prostate cancer (mCSPC), regardless of tumor volume or risk. However, survival of approximately one-third of these patients has not improved, necessitating further treatment escalation. On the other hand, for patients with oligometastatic mCSPC, there is an emerging role for local radiation therapy. Although data remain scarce, it is expected that treatment of both primary tumor as well as metastasis-directed therapy may improve survival outcomes. In these patients, systemic therapy may be de-escalated to intermittent therapy. However, precise risk stratification is necessary for risk-based treatment escalation or de-escalation. In addition to risk stratification based on clinical parameters, research has been conducted to incorporate genomic and/or transcriptomic data into risk stratification. In future, an integrated risk model is expected to precisely stratify patients and guide treatment strategies. Here, we first review the transition of the standard treatment for mCSPC over the last decade and further discuss the newest concept of escalating or de-escalating treatment using a multi-modal approach based on the currently available literature.

Anterior thalamic nucleus local field potentials during focal temporal lobe epileptic seizures.

Objective: To analyze the local field potentials (LFPs) in patients with focal drug-resistant epilepsy (DRE) from the anterior nucleus of the thalamus (ANT) during inter-ictal state and seizure state. Method: ANT stereotactic EEG (SEEG) recordings were studied in four patients with focal temporal lobe epilepsy. SEEG data was classified as inter-ictal and ictal state and sub-categorized into electrographic (ESz), focal aware seizure (FAS), focal with impaired awareness (FIA), or focal to bilateral tonic-clonic seizure (FBTC). LFP was analyzed at 4 Hz, 8 Hz, 16 Hz, 32 Hz, high gamma (100 Hz), and ripples (200 Hz) using spectrogram analysis and a statistical comparison of normalized power spectral density (PSD) averaged during seizures versus pre-ictal baseline segments. Result: The LFP recordings were analyzed for 162 seizures (127 ESz, 23 FAS, 6 FIA, and 6 FBTC). Based on time-frequency data (spectrogram), a broad band of activity, occurring between 2 and 6 Hz and centered at 4 Hz, and thin-band activity occurring specifically at 8 Hz on the frequency spectrogram were observed during the inter-ictal state. Statistically significant changes in LFP-PSD were seen for FAS, FIA, and FBTC. We observed a significant gain in LFP at the lower frequency band during FAS at 4 Hz, FIA, and FBTC at 4, 8, and 16 Hz while also observing increases at higher frequencies during FBTC at 100 and 200 Hz and a decrease during FAS seizures at 32 Hz. In contrast, no significant change in LFP power was seen for electrographic seizures. Interpretation: Our observations from a limited dataset indicate that all clinical seizure types, but not electrographic seizures, caused a change in ANT-LFP based on the magnitude of the associated power spectral density (PSD). Future work will be needed to validate the use of ANT-LFP at these frequencies as accurate measurements of seizure occurrence and severity. This work represents a first step toward understanding ANT thalamic LFP patterns during focal seizures and developing adaptive DBS strategies.

Acute Pain Management in a Multi-site Trauma Patient.

Pain management is often difficult in the setting of multi-site trauma such as that caused by motor vehicle accidents (MVA), which is especially compounded in the setting of polysubstance abuse. This often results in patients with poor pain tolerance requiring escalating doses of opioid therapy, which creates a vicious cycle. The use of peripheral nerve blocks (PNB) has been shown to decrease overall opioid consumption and can be used effectively to manage postoperative pain in this patient population. Our case report aims to highlight the importance of PNBs as part of a multimodal approach to pain management in patients with polytrauma in the setting of polysubstance abuse.

Tongue orthotopic xenografts to study fusion-negative rhabdomyosarcoma invasion and metastasis in live animals.

PAX3/7 fusion-negative rhabdomyosarcoma (FN-RMS) is a childhood mesodermal lineage malignancy with a poor prognosis for metastatic or relapsed cases. Limited understanding of advanced FN-RMS is partially attributed to the absence of sequential invasion and dissemination events and the challenge in studying cell behavior, using, for example, non-invasive intravital microscopy (IVM), in currently used xenograft models. Here, we developed an orthotopic tongue xenograft model of FN-RMS to study cell behavior and the molecular basis of invasion and metastasis using IVM. FN-RMS cells are retained in the tongue and invade locally into muscle mysial spaces and vascular lumen, with evidence of hematogenous dissemination to the lungs and lymphatic dissemination to lymph nodes. Using IVM of tongue xenografts reveals shifts in cellular phenotype, migration to blood and lymphatic vessels, and lymphatic intravasation. Insight from this model into tumor invasion and metastasis at the tissue, cellular, and subcellular level can guide new therapeutic avenues for advanced FN-RMS.

Impact of Targeted Systemic Therapy and Radiotherapy on Patients Undergoing Spine Surgery for Metastatic Renal Cell Carcinoma.

BACKGROUND: In patients undergoing spine surgery for renal cell carcinoma (RCC), we sought to: (1) describe patterns of postoperative targeted systemic therapy and radiotherapy (RT), (2) compare perioperative outcomes among those treated with targeted systemic therapy to those without, and (3) evaluate the impact of targeted systemic therapy and/or RT on overall survival (OS) and local recurrence (LR). METHODS: A single-institution, retrospective cohort study of patients undergoing spine surgery for metastatic RCC from 2010 to 2021 was undertaken. Treatment groups were RT alone, targeted systemic therapy alone, dual therapy consisting of RT and targeted systemic therapy, and neither therapy. Multivariable Cox regression controlled for age, race, sex, insurance, and preoperative targeted systemic therapy. RESULTS: Forty-nine patients underwent spine surgery for RCC. Postoperatively, 4 patients (8%) received RT alone, 19 (38.8%) targeted systemic therapy alone, 12 (24.5%) dual therapy, and 13 (28.6%) neither. All groups were similar in demographics, preoperative Karnofsky Performance Score (P = 0.372), tumor size (P = 0.413), readmissions (P = 0.884), complications (P = 0.272), Karnofsky Performance Score (P = 0.466), and Modified McCormick Scale (P = 0.980) at last follow-up. Higher 1-year survival was found in dual therapy (83.3%) compared with other therapies. OS was significantly longer in patients with dual therapy compared with other therapies (log-rank; P = 0.010). Multivariate Cox regression (HR = 0.08, 95% CI = 0.02-0.31, P < 0.001) showed longer OS in dual therapy compared with other therapies. Seven patients (14.3%) experienced LR, and a similar time to LR was found between groups (log-rank; P = 0.190). CONCLUSION: In patients undergoing metastatic spine surgery for RCC, postoperative dual therapy demonstrated significantly higher 1-year survival and OS compared with other therapies. CLINICAL RELEVANCE: Multidisciplinary management of metastatic RCC is necessary to ensure timely implementation of targeted systemic therapy and RT to improve outcomes.

Nomogram for Predicting Emergent Conversion to General Anaesthesia in Stroke Patients During Thrombectomy.

RATIONALE AND OBJECTIVES: The aim of this study was to develop and validate a nomogram for predicting emergent conversion to general anaesthesia (GA) in stroke patients during thrombectomy. METHODS: In this retrospective study, 458 patients (320 and 138 were randomised into the training and validation cohorts) were enroled. Univariable and multivariable logistic regression analyses were employed to identify risk factors for emergent conversion to GA. Subsequently, a nomogram was constructed based on the identified risk factors. The discriminative ability, calibration, and clinical utility of the nomogram were assessed in both the training and validation cohorts using receiver operating characteristic (ROC) curve analysis, Hosmer-Lemeshow test, and decision curve analysis (DCA). RESULTS: The emergent conversion to GA occurred in 56 cases (12.2%). In the training cohort, four independent predictors of emergent conversion to GA were identified and incorporated into the nomogram: core infarct volume > 70 mL, severe aphasia, severe cerebral vessel tortuosity, and vertebrobasilar occlusion. The ROC curves illustrated area under curve values of 0.931 (95% CI: 0.863-0.998) and 0.893 (95% CI: 0.852-0.935) for the training and validation cohorts, respectively. Hosmer-Lemeshow testing resulted in average absolute errors of 0.028 and 0.031 for the two cohorts. DCA demonstrated the nomogram's exceptional utility and accuracy across a majority of threshold probabilities. CONCLUSION: The constructed nomogram displayed promising predictive accuracy for emergent conversion to GA in stroke patients during thrombectomy, thereby providing potential assistance for clinical decision-making.

A method for the synchronization of inertial sensor signals and local field potentials from deep brain stimulation systems.

OBJECTIVE: Recent innovative neurostimulators allow recording local field potentials (LFPs) while performing motor tasks monitored by wearable sensors. Inertial sensors can provide quantitative measures of motor impairment in people with subthalamic nucleus deep brain stimulation. To the best of our knowledge, there is no validated method to synchronize inertial sensors and neurostimulators without an additional device. This study aims to define a new synchronization method to analyze disease-related brain activity patterns during specific motor tasks and evaluate how LFPs are affected by stimulation and medication. Approach: Twelve male subjects treated with subthalamic nucleus deep brain stimulation were recruited to perform motor tasks in four different medication and stimulation conditions. In each condition, a synchronization protocol was performed consisting of taps on the implanted device, which produces artifacts in the LFPs that an inertial sensor can simultaneously record. Main results: In 64% of the recruited subjects, induced artifacts were detected at least once. Among those subjects, 83% of the recordings could be correctly synchronized offline. The remaining recordings were synchronized by video analysis. Significance: The proposed synchronization method does not require an external system and can be easily integrated into clinical practice. The procedure is simple and can be carried out in a short time. A proper and simple synchronization will also be useful to analyze subthalamic neural activity in the presence of specific events (e.g., freezing of gait events) to identify predictive biomarkers. .

Survival outcomes and failure patterns for oropharyngeal cancers treated with simultaneous integrated boost in intensity modulated radiotherapy (SIB-IMRT) and concurrent chemotherapy.

BACKGROUND: Intensity modulated radiotherapy (IMRT) has become a standard radiotherapy treatment delivery option owing to the advantages it offers in terms of target coverage and organ sparing. Furthermore, the ability to introduce different fractionation for different targets lets us deliver higher doses to the high-risk areas and lower doses to the elective volumes at the same sitting, referred to as simultaneous integrated boost (SIB). In the current study, we intended to retrospectively analyze the clinical outcomes and patterns of the failure of oropharyngeal cancers treated with SIB-IMRT and concurrent chemotherapy at our centre and analyze the factors contributing to poorer outcomes. MATERIAL AND METHODS: Data of oropharyngeal cancer patients treated with SIB-IMRT and concurrent chemotherapy were retrieved from the institutional database. Patient demographic details, histopathological features, staging, treatment details, failure patterns and outcomes were documented. All potential factors were evaluated for outcomes. Radiation was delivered by using the SIB-IMRT technique. High-risk planning target volume (PTV) received 66 Gy in 2.2 Gy/fraction, intermediate and low-risk PTV received 60 Gy and 54 Gy, respectively. Primary endpoint was to assess local control (LC), regional control (RC) and loco-regional control (LRC) rates and secondary end point was to evaluate the survival outcomes - overall survival (OS) and cancer-specific mortality. All survival analyzes were performed using the Kaplan-Meier method. RESULTS: A total of 169 cases were included in the final analysis. The median age was 55 years (range 20-78) with 95.3% males. The base of tongue was the most common primary site. Around 54% cases were node negative with 38% patients having stage IV disease. The local control rates for N0 vs. N+ cases were 74.1 vs. 62.3% (P = 0.046), respectively. Similarly, the 4-year RC rates for N0 vs. N+ cases were 94.4 vs. 83.5% (P = 0.024), respectively. On multivariate analysis, only 4-year RC rates showed significant difference between the two (P = 0.039). No differences were found between T stages in LRC and OS. The 4-year LRC rates for stages 1, 2 vs. 3, 4 were non-significant (69.2 vs. 66.3%; P = 0.178). The 4-year OS rate was 81.3%. The 4-year LC and LRC rates were 67.8 and 89.5%, respectively. There were 54 local and 17 regional failures. The median time to failure was 13 months (range 3.6-82.9). CONCLUSION: SIB-IMRT provides comparable outcomes for oropharyngeal cancers. OS and loco-regional recurrences were significantly worse for nodal positive disease.

Comparative efficacy of topical lidocaine, tetracaine, and articaine for post-tonsillectomy pain management in children: a prospective, placebo-controlled study.

BACKGROUND: The most important problem in tonsillectomy is pain in the early postoperative period. OBJECTIVE: We purposed to compare the effects of lidocaine, tetracaine, and articaine application to the peritonsillar bed on post-tonsillectomy pain in children. METHODS: The prospective, placebo-controlled study included 80 patients, ages 3-14, who were scheduled for elective tonsillectomy. Patients were randomly divided into four groups. Group 1 received 0.9% NaCl; group 2 received 2% lidocaine; group 3 received 2% tetracaine; and group 4 received 4% articaine to the tonsillary bed for 5 min just after the operation. All patients were evaluated in terms of pain and pain-related adverse events in the postoperative 24 h. RESULTS: All groups that used local anesthetics had significantly lower pain levels than the control group in the first eight hours (p < .001). Furthermore, the articaine group had a lower pain score than the tetracaine group at the eighth hour (p < .05). The articaine group had a lower pain score at the 16th hour than both the control and tetracaine groups (p < .05). There was no significant difference between the groups at the 24th hour (p > .05). CONCLUSION AND SIGNIFICANCE: We recommend the immediate application of topical articaine to the tonsillar bed following the procedure to enhance postoperative pain management.

Mutation Screening of Dictyostelium Restriction Enzyme-Mediated Integration (REMI) Libraries.

Identifying the mechanisms of action of existing and novel drugs is essential for the development of new compounds for therapeutic and commercial use. Here we provide a technique to identify these mechanisms through isolating mutant cell lines that show resistance to drug-induced phenotypes using Dictyostelium discoideum REMI libraries. This approach provides a robust and rapid chemical-genetic screening technique that enables an unbiased approach to identify proteins and molecular pathways that control drug sensitivity. Mutations that result in drug resistance often occur in target proteins thus identifying the specific protein targets for drugs and bioactive natural products. Following the identification of a list of putative molecular targets user selected compound targets can be analyzed to confirm and validate direct inhibitory effects.

Dopamine Release Dynamics in the Nucleus Accumbens Are Modulated by the Timing of Electrical Stimulation Pulses When Applied to the Medial Forebrain Bundle and Medial Prefrontal Cortex.

Electrical brain stimulation has been used in vivo and in vitro to investigate neural circuitry. Historically, stimulation parameters such as amplitude, frequency, and pulse width were varied to investigate their effects on neurotransmitter release and behavior. These experiments have traditionally employed fixed-frequency stimulation patterns, but it has previously been found that neurons are more precisely tuned to variable input. Introducing variability into the interpulse interval of stimulation pulses will inform on how dopaminergic release can be modulated by variability in pulse timing. Here, dopaminergic release in rats is monitored in the nucleus accumbens (NAc), a key dopaminergic center which plays a role in learning and motivation, by fast-scan cyclic voltammetry. Dopaminergic release in the NAc could also be modulated by stimulation region due to differences in connectivity. We targeted two regions for stimulation─the medial forebrain bundle (MFB) and the medial prefrontal cortex (mPFC)─due to their involvement in reward processing and projections to the NAc. Our goal is to investigate how variable interpulse interval stimulation patterns delivered to these regions affect the time course of dopamine release in the NAc. We found that stimulating the MFB with these variable stimulation patterns saw a highly responsive, frequency-driven dopaminergic response. In contrast, variable stimulation patterns applied to the mPFC were not as sensitive to the variable frequency changes. This work will help inform on how stimulation patterns can be tuned specifically to the stimulation region to improve the efficiency of electrical stimulation and control dopamine release.

Perioperative pain perception in patients undergoing dermatologic surgery with local anesthesia - A prospective observational study.

BACKGROUND: Dermatosurgical procedures are predominantly performed under local anesthesia, yet there are few studies on perioperative pain management for extensive or staged procedures under local anesthesia. The purpose of this study was to assess pain during dermatologic surgery, describe perioperative pain management, and identify factors that influence pain perception. PATIENTS AND METHODS: This prospective, monocentric study included inpatients undergoing dermatologic surgery under local anesthesia from April to December 2021. Preoperative demographic data, a pain questionnaire, and four psychometric questionnaires (PCS, LOT-R, SFQ, PHQ-9) were collected. Postoperative pain and analgesic use during the first 24 hours were recorded. RESULTS: A total of 120 patients (with a total of 191 interventions) were included in the study. Mean postoperative pain was reported to be very low (NRS < 2). Preoperative pain and expected postoperative pain were found to be predictive of postoperative pain. There was a strong correlation between catastrophizing and preoperative anxiety (r = 0.65) and a moderate correlation between depression and preoperative anxiety (r = 0.46). CONCLUSIONS: Dermatologic surgery under local anesthesia is generally considered painless. During preoperative counseling and assessment, attention should be paid to patients who fear surgery, report pain, or anticipate postoperative pain, as they have an increased risk of experiencing postoperative pain.

Investigations on the EPR g factors and local structures for the orthorhombic and tetragonal Cu2+ centers in Pb[Zr0.54Ti0.46]O3.

The defect models of the orthorhombical and tetragonal Cu2+ centers in Pb[Zr0.54Ti0.46]O3 are attributed to Cu2+ ions occupying the sixfold coordinated octahedral Ti4+ site with and without charge compensation, respectively. The electron paramagnetic resonance (EPR) g factors gi (i = x, y, z) of the Cu2+ centers in Pb[Zr0.54Ti0.46]O3 are theoretically studied by using the perturbation formulas of a 3d9 ion under orthorhombically and tetragonally elongated octahedra. Based on the calculation, the impurity off-center displacements are about 0.253 and 0.162 Å for the orthorhombical and tetragonal Cu2+ centers, respectively. Meanwhile, the planar Cu2+-O2- bonds are found to experience the relative variation ΔR (≈0.102 Å) along the a- and b-axes for the orthorhombical Cu2+ center due to the Jahn-Teller (JT) effect. The theoretical EPR g factors based on the above local structures agree well with the observed values.