Quality of life and survivorship in patients with low-grade ovarian cancer.

OBJECTIVE: High-grade (HGOC) and low-grade ovarian carcinoma (LGOC) are distinct malignancies with different biological features, treatment paradigms, and life expectancies. However, differences in quality of life (QOL), sleep, and depressive symptoms have not been examined by grade, and neither have inflammatory profiles associated with these symptoms. We aim to characterize QOL and biomarkers by OC grade. METHODS: Participants included patients with HGOC (N = 578) or LGOC (N = 85). Participants completed baseline assessments of psychosocial factors prior to primary surgery or neoadjuvant chemotherapy and contributed saliva for cortisol and blood for interleukin-6 (IL-6) quantification. Samples were collected intraoperatively to quantify tumor cortisol. General linear models were used to examine differences in biological and psychological variables by grade. RESULTS: At baseline, patients with LGOC reported less depression (p = 0.018) and sleep disturbances (p = 0.014), but no significant difference in depressive mood (p = 0.11) or QOL (p = 0.51) compared to patients with HGOC, adjusting for age and disease stage. There were trends towards lower tumor cortisol levels (p = 0.078) in LGOC compared to HGOC. One-year post-diagnosis, we found a significant improvement in QOL and fatigue, and a decrease in vegetative depression and IL-6 levels irrespective of grade. CONCLUSIONS: We present the first characterization of psychosocial experiences of patients with LGOC. Despite having a better disease prognosis, patients with LGOC were just as likely to have mood disturbances as those with HGOC. There was a trend towards differences in tumor cortisol by grade. Our findings highlight the need to address well-being in patients with both low- and high-grade ovarian malignancies.

Natural history of spontaneous pancreatic portal vein fistulae: A systematic review of the literature.

BACKGROUND: Spontaneous pancreatic portal vein fistula (PPVF) - a rare complication of pancreatic inflammation - varies widely in presentation and means of diagnosis but has been previously associated with bleeding complications and mortality. A systematic review of published literature was performed to assess the frequency of outcomes. METHODS: A search of electronic databases (PubMed, Ovid MEDLINE, Scopus, EMBASE, gray literature) resulted in 1667 relevant unique manuscripts; 52 met inclusion criteria. RESULTS: A total of 74 unique (male n = 47, 63.5 %) patients were included. Mean age was 53.5 (±11.9) years. History of alcohol use was reported in 55 (74.3 %). Underlying chronic pancreatitis (CP) was present in 49 (66.2 %). In cases where presenting symptoms were reported (n = 57, 77.4 %), the most frequent were abdominal pain (63.5 %), weight loss (14.9 %), rash (12.2 %), nausea/vomiting (12.2 %), and polyarthritis (9.5 %). Computed tomography was the most common imaging modality used to confirm the diagnosis (n = 20, 27.0 %), followed by magnetic resonance cholangiopancreatography (n = 14, 18.9 %). Portal vein thrombosis was reported in 57 (77.0 %), and bleeding events (luminal, variceal, or intra-pseudocyst) were reported in 13(17.6 %) patients. Younger age was associated with higher risk of bleeding events. Mortality was reported in 12 (16.2 %) patients at any time during follow up. Older age and polyarthritis at presentation were associated with mortality. CONCLUSIONS: PPVF is a rare and potentially fatal condition, though rates of bleeding complication and death were relatively low in this population. High-quality observational studies are needed to better understand the pathophysiology and natural history of this diagnosis.

Mitochondrial Ca 2+ controls pancreatic cancer growth and metastasis by regulating epithelial cell plasticity.

Endoplasmic reticulum to mitochondria Ca 2+ transfer is important for cancer cell survival, but the role of mitochondrial Ca 2+ uptake through the mitochondrial Ca 2+ uniporter (MCU) in pancreatic adenocarcinoma (PDAC) is poorly understood. Here, we show that increased MCU expression is associated with malignancy and poorer outcomes in PDAC patients. In isogenic murine PDAC models, Mcu deletion ( Mcu KO ) ablated mitochondrial Ca 2+ uptake, which reduced proliferation and inhibited self-renewal. Orthotopic implantation of MCU-null tumor cells reduced primary tumor growth and metastasis. Mcu deletion reduced the cellular plasticity of tumor cells by inhibiting epithelial-to-mesenchymal transition (EMT), which contributes to metastatic competency in PDAC. Mechanistically, the loss of mitochondrial Ca 2+ uptake reduced expression of the key EMT transcription factor Snail and secretion of the EMT-inducing ligand TGFß. Snail re-expression and TGFß treatment rescued deficits in Mcu KO cells and restored their metastatic ability. Thus, MCU may present a therapeutic target in PDAC to limit cancer-cell-induced EMT and metastasis.

Assessment of change in antimicrobial susceptibility pattern of bacteria causing orthopaedic infections by sequential sampling: A prospective cohort study.

Background: Management of Orthopaedic wound infections often depend on isolation of bacteria species (spp.) and its subsequent antimicrobial susceptibility testing (AST). However, the susceptibility to antibiotics may change over time in the same bacterial spp. particularly after initiation of antibiotic therapy. Repeating AST through sequential sampling can be used for the early detection of changes in antimicrobial susceptibility pattern. However, the recommendations about the optimal frequency of repeat AST for same bacterial spp. isolates from same patient to detect the changes in susceptibility patterns are still not established. Furthermore, no prospective research is available to address the crucial issue. Thus, we aimed this study to evaluate the need of repeat AST through sequential samples from the same site. Methods: AST was performed on same bacterial spp. isolates from three sequential samples using Kirby-Bauer disc diffusion method. Considering day 1 as control/baseline, changes in antimicrobial susceptibility pattern was interpreted on two sequential instances (on day 3 and day5). Changes were categorized into favorable & unfavorable and major & minor change categories. Results: The overall change in antimicrobial susceptibility pattern was 28 % on instance 1(on day3) and 36.1 % at instance 2 (on day 5). Susceptible to resistance phenotypic change was 14.9 % at instance 1 and 9.2 % at instance 2.A higher percentage change per case in antimicrobial susceptibility pattern was observed at instance 2. Predominant changes were towards the direction of favorable antimicrobial susceptibility pattern. Conclusion: The risk of change in antimicrobial susceptibility potential was over 10 % at both the instances. Furthermore, it was higher at instance 2 i.e., at day5, therefore a repeat sequential antimicrobial susceptibility testing would be recommended at later instance.

Effectiveness of Ultrasonography- and Fluoroscopy-Guided Caudal Epidural Injections in the Management of Chronic Lumbar Disc Disease: A Retrospective Comparative Study.

INTRODUCTION: Lumbar disc disease is one of the common causes of lower back pain caused by a change in the structure of the normal disc. Most of the time, disc disease happens as a result of aging and the normal breakdown that occurs within the disc. Caudal epidural steroid injections are the popular treatment for patients with chronic low back pain that does not respond to conservative management. METHOD: A retrospective survey was administered to 160 patients who had received caudal epidural injections for chronic low back pain in the past, but only 74 patients who completed the scheduled follow-ups were included in the study. They were divided into two groups based on the imaging modality used for guiding the caudal epidural steroid injections, either ultrasonography or fluoroscopy, and then assessed for improvement in pain on the Numeric Rating Scale (NRS), for functional improvement on the Oswestry Disability Index (ODI), and for satisfaction on the North American Spine Society Patient Satisfaction Scale (SSPSS). RESULTS: Mean NRS pain scores improved significantly from baseline at 6.78 and 7.00 in the fluoroscopy and ultrasound groups, respectively, to 2.03 and 2.16 at 12 weeks post-procedure. The difference between the groups was not statistically significant (p > 0.05). The Oswestry Disability Index was completed at baseline and after 12 weeks of follow-up for both groups, and there was no significant difference between the two groups; the fluoroscopy group's mean Oswestry Disability Index scores were 52.4 at baseline and 35.6 at 12 weeks, whereas the scores for the ultrasound group were 50.3 at baseline and 37.9 at 12 weeks. Conversely, patient satisfaction as assessed using the SSPSS rose in both groups up to 12 weeks (p > 0.05). CONCLUSION: The ultrasound- and fluoroscopy-guided caudal epidural steroid injections proved equally effective in easing the pain, disability, and satisfaction levels of patients with chronic lower back pain.

Enhanced Surgical Techniques in Orthopedics: A Comprehensive Guide for Surgeons Based on Modification of the McFarland and Osborne Approach to the Hip.

INTRODUCTION: The implementation of various approaches in hip arthroplasties introduces distinct advantages and complications. Notably, widely adopted methods such as the posterior approach have been linked to elevated rates of posterior hip dislocations and iatrogenic sciatic nerve injuries, while the lateral approach has been associated with superior gluteal nerve injuries. In this study, we propose a refined modification of the McFarland and Osborne approach, aiming to amalgamate the most favorable aspects of prior modifications of the lateral approach to the hip. Additionally, our contribution extends to providing a comprehensive stepwise guide for the exposure and closure processes in cases of bipolar hemiarthroplasty or total hip replacement. This modification not only offers potential advantages to seasoned orthopedic surgeons but also serves as a valuable resource for young Turks venturing into hip surgeries. MATERIAL AND METHODS: 14 patients with femoral neck fractures underwent surgery using the modified McFarland and Osborne approach and were followed up for a period of six months. The functional outcome was analyzed by the Modified Mobility and Aids Scoring Matrix. RESULTS: Seven of the 14 patients attained pre-injury status with respect to the Mobility and Aids scoring matrix. six patients had a fall of 1, and one patient had a fall of 2, as compared to pre-injury status. CONCLUSION: Our research suggests that this method serves as a superior alternative to conventional approaches, demonstrating notable advantages in terms of dissection difficulty, reduced risk to neurovascular structures, and minimized post-operative hip dislocations. Additionally, it exhibits a favorable outcome, enabling a return to pre-injury levels of activity.

Mdm2 requires Sprouty4 to regulate focal adhesion formation and metastasis independent of p53.

Although the E3 ligase Mdm2 and its homologue and binding partner MdmX are the major regulators of the p53 tumor suppressor protein, it is now evident that Mdm2 and MdmX have multiple functions that do not involve p53. As one example, it is known that Mdm2 can regulate cell migration, although mechanistic insight into this function is still lacking. Here we show in cells lacking p53 expression that knockdown of Mdm2 or MdmX, as well as pharmacological inhibition of the Mdm2/MdmX complex, not only reduces cell migration and invasion, but also impairs cell spreading and focal adhesion formation. In addition, Mdm2 knockdown decreases metastasis in vivo. Interestingly, Mdm2 downregulates the expression of Sprouty4, which is required for the Mdm2 mediated effects on cell migration, focal adhesion formation and metastasis. Further, our findings indicate that Mdm2 dampening of Sprouty4 is a prerequisite for maintaining RhoA levels in the cancer cells that we have studied. Taken together we describe a molecular mechanism whereby the Mdm2/MdmX complex through Sprouty4 regulates cellular processes leading to increase metastatic capability independently of p53.

Full maturation of in vitro Plasmodium falciparum oocysts using the AlgiMatrix 3D culture system.

BACKGROUND: Plasmodium falciparum oocysts undergo growth and maturation in a unique setting within the mosquito midgut, firmly situated between the epithelium and the basal lamina. This location exposes them to specific nutrient exchange and metabolic processes while in direct contact with the mosquito haemolymph. The limited availability of in vitro culture systems for growth of the various P. falciparum mosquito stages hampers study of their biology and impedes progress in combatting malaria. METHODS: An artificial in vitro environment was established to mimic this distinctive setting, transitioning from a 2D culture system to a 3D model capable of generating fully mature oocysts that give rise to in vitro sporozoites. RESULTS: A two-dimensional (2D) chamber slide was employed along with an extracellular matrix composed of type IV collagen, entactin, and gamma laminin. This matrix facilitated development of the optimal medium composition for cultivating mature P. falciparum oocysts in vitro. However, the limitations of this 2D culture system in replicating the in vivo oocyst environment prompted a refinement of the approach by optimizing a three-dimensional (3D) alginate matrix culture system. This new system offered improved attachment, structural support, and nutrient exchange for the developing oocysts, leading to their maturation and the generation of sporozoites. CONCLUSIONS: This technique enables the in vitro growth of P. falciparum oocysts and sporozoites.

Microneedle-Mediated Delivery of siRNA Via Liposomal-Based Transfection for Inner Ear Gene Therapy.

HYPOTHESIS: Microneedle-mediated intracochlear injection of siRNA-Lipofectamine through the round window membrane (RWM) can be used to transfect cells within the cochlea. BACKGROUND: Our laboratory has developed 100-µm diameter hollow microneedles for intracochlear injection through the guinea pig RWM. In this study, we test the feasibility of microneedle-mediated injection of siRNA and Lipofectamine, a commonly used reagent with known cellular toxicity, through the RWM for cochlear transfection. METHODS: Fluorescently labeled scramble siRNA was diluted into Lipofectamine RNAiMax and OptiMEM. One microliter of 5 µM siRNA was injected through the RWM of Hartley guinea pigs at a rate of 1 µl/min (n = 22). In a control group, 1.0 µl of Lipofectamine, with no siRNA, was diluted into OptiMEM and injected in a similar fashion (n = 5). Hearing tests were performed before and either at 24 hours, 48 hours, or 5 days after injection. Afterward, animals were euthanized, and cochleae were harvested for imaging. Control cochleae were processed in parallel to untreated guinea pigs. RESULTS: Fluorescence, indicating successful transfection, was observed within the basal and middle turns of the cochlea with limited distribution in the apex at 24 and 48 hours. Signal was most intense in the organ of Corti, spiral ligament, and spiral ganglion. Little to no fluorescence was observed at 5 days post-injection. No significant changes in auditory brainstem response (ABR) were noted post-perforation at 5 days, suggesting that siRNA-Lipofectamine at low doses does not cause cochlear toxicity. CONCLUSIONS: Small volumes of siRNA and Lipofectamine can be effectively delivered to cochlear structures using microneedles, paving the way for atraumatic cochlear gene therapy.

Speech Quality Perception in Unilateral Cochlear Implant Users With Single-Sided Deafness.

OBJECTIVE: Cochlear implant (CI) users frequently complain about speech quality perception (SQP). In patients undergoing cochlear implantation for single-sided deafness, there is concern that poor SQP from the implanted ear will negatively impact binaural (CI + normal hearing [NH]) SQP. In this study, we investigate if binaural SQP is measurably different than unimplanted NH alone. STUDY DESIGN: Cross-sectional study. SETTING: Tertiary care center. METHODS: Fifteen unilateral CI users with NH in the contralateral ear completed the validated Columbia Speech Quality Instrument. This instrument consists of 9 audio clips rated across 14 specific speech qualities using a 10-point visual analog scale. SQP was assessed in 3 conditions: CI only, NH only, and CI + NH. RESULTS: Median speech quality scores were worse in the CI only condition compared to the NH only (50.0 vs 72.6, P = .0003) and binaural (50.0 vs 71.0, P = .007) conditions. Median speech quality scores were not significantly different between the NH only and binaural conditions (72.6 vs 71, P = .8). Compared to NH, CI speech quality sounded less clear, less natural, and more mechanical. CONCLUSION: Compared to NH, SQP is poorer with a CI alone. However, in contrast to expectation, there is no significant difference between NH and binaural SQP. This suggests poorer CI speech perception does not negatively impact binaural SQP in patients undergoing cochlear implantation for single-sided deafness.

Pembrolizumab plus chemotherapy in frontline treatment of advanced ovarian cancer: Clinical and translational results from a phase 2 trial.

BACKGROUND: The efficacy and feasibility of pembrolizumab combined with chemotherapy in frontline management of advanced high-grade epithelial ovarian cancer (EOC) is unknown. Additionally, modification of the tumor microenvironment following neoadjuvant therapy is not well understood. METHODS: In this single-arm phase 2 trial (this study was registered at ClinicalTrials.gov: NCT02520154), eligible patients received up to 4 cycles of neoadjuvant chemotherapy followed by interval cytoreduction, 3 cycles of adjuvant intravenous carboplatin/weekly paclitaxel/pembrolizumab, and finally maintenance pembrolizumab until progression or toxicity (maximum 20 cycles). The primary endpoint was progression-free survival (PFS). Secondary endpoints included feasibility, toxicity, and overall survival (OS). PD-L1 staining, multiplex immunofluorescence staining, RNA sequencing, reverse-phase protein array analyses were performed on pre- and post-chemotherapy samples. FINDINGS: Thirty-one eligible patients were enrolled. Median PFS and OS was 14.88 (95% CI 12.39-23.00) and 57.43 months (95% CI 30.88-not reached), respectively. Among those with PD-L1 combined positive score (CPS) ≥10, the median PFS and OS were not reached compared to those with CPS <10 (10.50 and 30.90 months, respectively). Feasibility was met, with all patients completing their planned adjuvant cycles. Treatment discontinuation due to immune-related toxicity occurred in 6 patients (20%). Chemotherapy resulted in an infiltration of anti-tumor immune cells in the tumor microenvironment. Samples of patients with the best PFS demonstrated increased expression of NF-κB, TGF-ß, and ß-catenin signaling. CONCLUSIONS: Pembrolizumab with chemotherapy was feasible and resulted in PFS within the historical range for this EOC population. Patients with CPS ≥10 may benefit more from this regimen, and future studies should investigate this potential biomarker. FUNDING: This investigator-initiated trial was funded by Merck.

Analysis of Lithium Aging Using Machine Learning-Enhanced Spectroscopy Techniques.

Lithium compounds such as lithium hydride (LiH) and lithium hydroxide (LiOH) have a wide range of industrial applications, but are highly reactive in environments with H2O and CO2. These reactions lead to the ingrowth of secondary lithium compounds, which can alter the homogeneity and affect the application of particular lithium chemicals. This study performed an exploratory analysis of different lithium compounds using laser-induced breakdown spectroscopy (LIBS) and Raman spectroscopy. Machine learning models are trained on the recorded spectral data to discriminate emission features that differ between LiH, LiOH, and Li2CO3 to perform high-fidelity classification. Support vector machine classifiers yield perfect prediction accuracy between the three compounds with optimal training time. Multivariate methods are then used to produce regression models quantifying the ingrowth of LiOH in LiH. Performing a mid-level data fusion of selected LIBS and Raman features with partial least-squares regression produces the superlative model with a root mean square error of 2.5 wt% and a detection limit of 6.3 wt%.

Pregnancy-Induced Hypertension Pathophysiology and Contemporary Management Strategies: A Narrative Review.

In the case of PIH, the history is the story of gradually developing awareness and the gradual formation of requisite knowledge. The development of the sphygmomanometer, or blood pressure cuff, in the late 1700s, provided the basis for modern systematic blood pressure reporting for Gravid patients. In the following years and over a few decades, the relationship between high blood pressure and these complications, such as preeclampsia and eclampsia, became clearer. The hypertensive disease was categorized by the American Committee on Maternal Welfare in 1952, which included PIH, chronic hypertension, and preeclampsia. Today, attention is being paid to the identification of such factors, the search for ways to enhance the treatment of diseases, methods for their diagnosis, and the enhancement of pregnancy outcomes. Pregnancy can cause high blood pressure in two of the following ways: preeclampsia and gestational hypertension. These conditions are both part of something called pregnancy-induced hypertension (PIH). In the world, most problems for moms and babies during pregnancy come from PIH. To help both mom and baby, we need to know a lot about what causes it, how to manage it, and how to watch the baby carefully. Aspects like immune responses, the environment, and genes all mix to cause PIH. They make the placenta not work right. When the cells that help the placenta grow don't do their job well, when blood vessels are stiff, when there's too much stress on the body, or when there's not a good balance of chemicals that help build blood vessels, things can get bad. Blood vessels all over the body squeeze tight, blood flow goes down, and blood pressure goes up. That can make a lot of organs stop working right and stop the baby from healthy growth. Various studies concluded that PIH severely limits the blood flow to the placenta and thus contributes to reduced fetal growth. It showed that compared to other hospitals, women who experience PIH are more likely to give birth early before the baby is ready, that is, before 37 weeks, and may cause further health complications to the baby. This normally makes the offspring have low birth weight and exposes them to many complications in infancy and the future in case they are born to mothers with PIH. In severe cases, PIH may lead to the death of the infant either by stillbirth or immediately after birth. The researchers have noted several predisposing factors to PIH, which include histories of elevated blood pressure, diabetes, being overweight or obese, and having a family history of PIH. Educating women about the presence of PIH and its causes can help them consult health facilities early, thus helping leaders in achieving better pregnancy results.

Transcarotid TAVR for Severe Bicuspid Aortic Stenosis With Virtually Atretic Coarctation of the Thoracic Aorta.

Transcatheter aortic valve replacement by alternate access sites allows for treatment of patients with unfavorable anatomy for a transfemoral approach. To our knowledge, we present the first reported case of successful transcatheter aortic valve replacement via the transcarotid approach in a 65-year-old man with a symptomatic severe bicuspid aortic valve stenosis and virtually atretic coarctation of the thoracic aorta.

Fabrication of Aluminum Foil Integrated Pegylated Gold Nanoparticle Surface-Enhanced Raman Scattering Substrate for the Detection and Classification of Uropathogenic Bacteria.

Rapid detection and classification of pathogenic microbes for food hygiene, healthcare, environmental contamination, and chemical and biological exposures remain a major challenge due to nonavailability of fast and accurate detection methods. The delay in clinical diagnosis of the most frequent bacterial infections, particularly urinary tract infections (UTIs), which affect about half of the population at least once in their lifetime, can be fatal if not detected and treated appropriately. In this work, we have fabricated aluminum (Al) foil integrated pegylated gold nanoparticles (AuNPs) as a potential surface-enhanced Raman scattering (SERS) substrate, which is used for the detection and classification of uropathogens, namely, E. coli, S. aureus, and P. aeruginosa directly from the culture without any pretreatment. The substrate is first drop cast with bacterial pellets and then pegylated AuNPs, and the interaction of two on Al foil base gives identifiable characteristic Raman peaks with good reproducibility. With the use of chemometric methods such as principal component analysis (PCA), the Al foil-based SERS substrate offers a quick, effective detection and classification of three strains of UTI bacteria with the least bacterial concentration (105 cells mL-1) necessary for clinical diagnosis. In addition, this substrate was able to detect E. coli positive clinical samples by giving SERS fingerprint information directly from centrifuged urine samples within minutes. The stability of pegylated AuNPs provides for its application at the point of care with rapid and easy detection of uropathogens as well as the possibility of advancement in healthcare applications.

Dysembryoplastic Neuroepithelial Tumor: A Case Report of A Benign Intracranial Lesion Masquerading as Seizure Disorder.

The uncommon, benign dysembryoplastic neuroepithelial tumor (DNET, WHO grade 1) is frequently linked to epilepsy. It is a glioneuronal neoplasm in the cerebral cortex of children or young adults defined by the presence of a pathognomonic glioneuronal element that may be linked to glial nodules and activating mutations of fibroblast growth factor receptor 1 (FGFR1) (CNS WHO grade 1 according to WHO classification of CNS and pituitary tumors, 2021 ). The cerebral cortex is primarily affected. The most frequent areas are the temporal lobe, particularly the medial lobe, frontal lobe, and other cortex. This study reports the instance of a 31-year-old male who had a history of seizures for the past 20 years and complained of a sudden headache and vomiting at the hospital. MRI revealed a cortical-based lesion in the left posterior temporo-occipital region. A biopsy sample was sent for histopathological examination. DNETs are usually benign, non-recurring lesions and rarely can be a malignant transformation. Although they are frequently stable tumors, surgical excision seldom results in recurrence.

Interhospital variability in hospital admissions for patients with low-risk syncope presenting to the emergency department.

Background: Guidelines and risk scores have sought to standardize the management of syncope in the emergency department (ED), but variation in practice remains. Objective: The purpose of this study was to explore factors associated with admission for patients presenting to the ED with low-risk syncope. Methods: Our study population included adult patients in the Nationwide Emergency Department Sample between 2006 and 2019 who presented to an ED with a primary diagnosis of syncope. Multivariable hierarchical logistic regression analyses determined the association of patient or hospital factors with admission. Reference effect measures methodology assessed the relative contributions of patient, hospital, and unmeasured hospital factors. Results: Of the 3,206,739 qualifying encounters during the study period, 804,398 (25.1%) met low-risk criteria. Of these patients, 20,260 were admitted to the hospital (2.5%). Factors associated with increased odds of admission included increasing age and weekend presentation to the hospital, while female sex, lack of medical insurance, hospital region, teaching status, and higher ED volume decile were associated with lower odds of admission. Reference effect measures methodology demonstrated that unmeasured site variability contributed the widest range of odds for admission (odds ratio [OR] 5th percentile vs 95th percentile 0.23-4.38) compared with the composite patient (OR 0.33-3.68) or hospital (OR 0.65-1.30) factors. Conclusion: Admission patterns for low-risk syncope varies widely across institutions. Unmeasured site variation contributes significantly to the variability in admission rates, suggesting which hospital a patient presents to plays a disproportionate role in admission decisions. Further guidance to reduce practice variation in syncope care in the ED is needed.

Mechanism and rational combinations with GP-2250, a novel oxathiazine derivative, in ovarian cancer.

BACKGROUND: GP-2250, a novel analog of taurultam (TRLT), has emerged as a potent anti-neoplastic drug; however, the mechanisms underlying its effects are not well understood. Here, we investigated the mechanism of action and the biological effects of GP-2250 using in vitro and in vivo models. METHODS: We carried out a series of in vitro (MTT assay, Annexin V/PI assay, colony formation assay, reverse-phase protein array [RPPA], and HRLC/IC analysis) to determine the biological activity of GP-2250 and investigate the mechanism of action. In vivo experiments were carried out to determine the therapeutic efficacy of GP-2250 alone and in combination with standard-of-care drugs (e.g., paclitaxel, cisplatin, topotecan, and poly ADP-ribose polymerase [PARP] inhibitors). RESULTS: We investigated the cytotoxic effect of GP-2250 in 10 ovarian cancer cell lines and found GP-2250 combined with a PARP inhibitor had the greatest synergy. RPPA revealed that GP-2250 inhibited hypoxia-inducible factor-1α, AKT, and mammalian target of rapamycin (mTOR) activation and expression. High-resolution mass spectrometry revealed that hexokinase2 activity and protein expression were significantly reduced by GP-2250 exposure. Furthermore, GP-2250 reduced glycolysis and ATP synthesis in cancer cells. An in vivo pharmacodynamic experiment using the OVCAR8 mouse model demonstrated that 500 mg/kg GP-2250 was effective in downregulating AKT and mTOR activation and expression. In the in vivo therapy experiment using an orthotopic mouse model, a combination of GP-2250 with either PARP inhibitors or bevacizumab showed a significant reduction of tumor weights and nodules compared to those treated with a vehicle, control IgG groups, or monotherapy groups. CONCLUSIONS: Taken together, our data indicate that GP-2250 exerts profound effects on tumor metabolism and, in combination with PARP inhibitors or bevacizumab, showed promising anti-tumor efficacy. These findings could have implications for the clinical development of GP-2250.

Effectiveness of Botulinum Toxin Injection With Casting in Children With Spastic Cerebral Palsy: A Randomized Controlled Trial.

BACKGROUND: The most common form of movement disorder presented in children with cerebral palsy is spasticity, and dynamic equinus is the most common spastic ankle deformity. Botulinum toxin (BT) injection is now an established first-line treatment for focal spasticity. AIM: To assess the effects of BT injection with casting in the treatment of dynamic equinus in children diagnosed with cerebral palsy with spastic diplegia. SETTING AND DESIGN: A prospective randomized controlled trial was conducted among patients aged 2-12 years with cerebral palsy and spastic diplegia, attending the general outpatient department and admitted to the indoor facility of the Department of Physical Medicine and Rehabilitation and the Department of Pediatric Orthopedics at King George's Medical University, Lucknow. MATERIAL AND METHODS: Two groups of 19 patients each were formed. Group A received BT injection with casting, whereas in group B, only a cast was applied. Outcome measures including spasticity by Modified Ashworth Scale (MAS), Modified Tardieu Scale (MTS), range of motion (ROM), passive ankle dorsiflexion, and Gross Motor Function Measure (GMFM-66) (dimensions D and E) were assessed before and after the intervention. RESULTS: The participants in groups A and B were age-matched. A statistically significant difference was seen within group A and group B for MAS, passive ROM-dorsiflexion (PROM-DF), and passive ROM-plantarflexion (PROM-PF) at various follow-ups. In the 3rd week, MAS in each group was statistically insignificant (p-value> 0.05). CONCLUSION: There was a significant improvement in tone and a significant increase in the passive range of motion in both groups.