High Dose Research Articles

Quality Indicators for Pain in Adults: A Review of Performance Measures by the American College of Physicians.

Pain is a debilitating symptom generally caused by injuries or various conditions. It can be acute, subacute, or chronic and can have a significant impact on a patient's quality of life. The goal of managing pain is to relieve or reduce suffering and improve patient functioning. Several performance measures that address the treatment of pain are used in payment, public reporting, or accountability programs. The American College of Physicians (ACP) embraces performance measurement as a means to improve quality of care. ACP believes that a performance measure must be methodologically sound and evidence-based to be considered for inclusion in payment, accountability, or reporting programs. However, a plethora of performance measures that provide minimal or no value to patient care have inundated physicians, practices, and systems with the burden of collecting and reporting data. ACP's Performance Measurement Committee (PMC) reviews performance measures using a validated process to recognize high-quality performance measures, address gaps and areas for improvement in performance measures, and help reduce reporting burden. There is a need for a higher standard for a performance measure when reputation and reimbursement are on the line. This paper aims to present a review of current performance measures for pain to inform physicians, payers, and policymakers in their selection and use of performance measures. The PMC reviewed 6 performance measures for pain relevant to internal medicine physicians, of which 3 were considered valid at their intended levels of attribution ("Use of Imaging for Low Back Pain," "Use of Opioids at High Dosage in Persons Without Cancer," and "Use of Opioids From Multiple Providers in Persons Without Cancer"). This paper also proposes a performance measure concept to address a quality-of-care gap based on the current clinical guideline from ACP and the American Academy of Family Physicians, "Nonpharmacologic and Pharmacologic Management of Acute Pain From Non-low Back, Musculoskeletal Injuries in Adults."

Transgenic expression of human cytochrome P450 2E1 in C. elegans and rat PC-12 cells sensitizes to ethanol-induced locomotor and mitochondrial effects

Chronic alcohol (ethanol) use is increasing in the United States and has been linked to numerous health issues in multiple organ systems including neurological dysfunction and diseases. Ethanol toxicity is mainly driven by the metabolite acetaldehyde, which is generated through three pathways: alcohol dehydrogenase (ADH2), catalase (CAT), and cytochrome P450 2E1 (CYP2E1). ADH2, while the main ethanol clearance pathway in the liver, is not expressed in the mammalian brain, resulting in CAT and CYP2E1 driving local metabolism of ethanol in the central nervous system. CYP2E1 is known to generate reactive metabolites and reactive oxygen species and localizes to the mitochondria (mtCYP2E1) and endoplasmic reticulum (erCYP2E1). We sought to understand the consequences of mtCYP2E1 and erCYP2E1 in the nervous system during acute ethanol exposure. To answer this question, we generated transgenic Caenorhabditis elegans roundworms expressing human CYP2E1 in the mitochondria, endoplasmic reticulum, or both and exposed them to ethanol. We found that at lower concentrations, wild-type and mtCYP2E1-expressing worms had a small but significant inhibition of locomotion, whereas the erCYP2E1-expressing worms showed protection from this inhibition. At higher doses, all strains had reduced locomotion, but the erCYP2E1-expressing worms recovered faster than wild-type controls. CYP2E1 expression, regardless of organellar targeting, reduced mitochondrial respiration in response to ethanol. Similarly, transgenic expression of CYP2E1 in either organelle in PC-12 rat neuronal cell lines sensitized them to ethanol-induced cell death. Together, these findings suggest that subcellular localization of CYP2E1 impacts behavioral effects of ethanol and should be further studied in the mammalian central nervous system.

Pharmacokinetics and pharmacodynamics of the factor XIa-inhibiting antibody osocimab in healthy male East Asian volunteers: Results from two phase 1 studies.

The pharmacokinetics, pharmacodynamics, immunogenicity, and safety of osocimab single doses in healthy Chinese and Japanese volunteers over 149 days were evaluated. Two phase 1 single-blinded, placebo-controlled studies with 27 Japanese and 50 Chinese participants were conducted. Osocimab was investigated with IV doses of 0.3, 1.25, and 2.5 mg/kg (Chinese study) and 0.3, 1.25, and 5.0 mg/kg (Japanese study), as well as SC doses of 3.0 and 6.0 mg/kg (Chinese study) and 6.0 mg/kg (Japanese study). The maximum plasma concentration was reached 1-3 h and 4-6 days after IV and SC administration, respectively. Osocimab exhibited a deviation from dose-proportional pharmacokinetics for AUC but not Cmax; higher doses had higher apparent clearance and disproportionately lower total exposure. A slightly lower exposure was observed in Japanese compared with Chinese volunteers after IV administration; conversely, relatively higher exposure in Japanese volunteers with SC dosing was identified. Osocimab was associated with a dose-dependent increase in activated partial thromboplastin time (aPTT). Maximal aPTT prolongations were observed 1-4 h and 2-6 days after IV and SC administration, respectively. Anti-drug antibodies of low titer were detected in 1/9 (11.1%) Japanese volunteers administered placebo and 26/40 (65.0%) Chinese volunteers administered osocimab. Adverse events were reported in 8/18 (44.4%) Japanese and 28/40 (70.0%) Chinese volunteers who received osocimab, as well as in 1/9 (11.1%) Japanese and 6/10 (60.0%) Chinese volunteers who received placebo. In conclusion, data did not suggest a clear dose-proportionality for osocimab within the investigated dose range. The effect of osocimab on aPTT was expected per its mechanism of action. Osocimab was generally well tolerated.

Oral toxicity of the acetone extract of Coffea arabica var. Oro Azteca leaves in CD-1 mice

The investigation of coffee leaves as a source of bioactive principles represents a relatively unexplored area of research. The study assesses the potential adverse effects of an aqueous acetone extract derived from Coffea arabica var. Oro Azteca leaves. The phenolic composition of the extract was identified and quantified by UPLC-MS/MS, and its acute and repeated-dose effects were evaluated in six-week-old CD-1 mice (n = 11 for acute evaluation and n = 20 female and n = 20 male for repeated-dose evaluation). The extract demonstrated no significant toxicity, maintaining consistent body weight and exhibiting a hepatoprotective effect by reducing ALT levels at a dose of 500 mg/kg. Some hyperactivity was observed at the highest doses, but overall, the extract enhanced the immune response and showed no histological alterations, except for mild inflammation in certain organs. The extract, which contains abundant quinic acid, chlorogenic acid, epicatechin, procyanidin B2, and mangiferin, has been deemed safe for consumption.

Influence of fly ash and granulated blast furnace slag on autogenous shrinkage and drying shrinkage of cement-based materials mixed with alkali accelerator and alkali-free accelerator

Shotcrete shrinkage and cracking are getting more threatening due to its high content of cementitious materials, small aggregate particle size and a large amount of accelerator, which poses a great threat to the construction safety of engineering structures. This paper studies the volume stability of cement mortar with different contents of fly ash (FA) and granulated blast furnace slag (GBFS) (10%/20%/30%) under the condition that the dosage of alkali liquid accelerator is 4% and that of the alkali-free liquid accelerator is 7%. This work is designed to provide a guidance for the basic research and practical application. By comparing the autogenous shrinkage, drying shrinkage, mass loss caused by drying condition, and internal humidity change of drying condition of cement mortar within 180 days of age. Combined with MIP analysis, XRD hydration product analysis, and SEM hydration product morphology analysis, the results show that both fly ash and granulated blast furnace slag can reduce the autogenous shrinkage and drying shrinkage of cement mortar mixed with accelerator to a certain extent, and the shrinkage reduction effect of FA is more prominent. The reduction effect of GBFS is more obvious at high dosages. Adding FA and high content of GBFS can increase the mass loss of cement mortar under drying shrinkage conditions. The high content of mineral admixtures will exacerbate the rate of decrease in the internal humidity of the cement mortar. The reasons for the reduction of autogenous shrinkage and drying shrinkage of cement mortar mixed with accelerators due to the addition of FA and GBFS are: the early activity of the two mineral admixtures is low, and the hydration process is slow. And the reduction of pore size with the range of 5-50nm leads to the reduction of capillary tensile stress and the weakening of the driving force for shrinkage deformation. Among them, the shrinkage reduction effect of fly ash is more pronounced. Therefore, mineral admixture can be used to replace a certain amount of cement in actual shotcrete construction, so as to increase the volume stability of shotcrete.

The effect of Fenugreek seed dry extract supplement on glycemic indices, lipid profile, and prooxidant-antioxidant balance in patients with type 2 diabetes: A double-blind randomized clinical trial.

This study aims to determine the effects of fenugreek seed dry extract (FDE) on the glycemic indices, lipid profile, and prooxidant-antioxidant balance (PAB) in patients with type 2 diabetes (T2D). A double-blind randomized clinical trial was carried out on 54 individuals with T2D. Participants were randomly assigned to a FDE group (received 3 tablets containing 335 mg of FDE daily for 8 weeks) or a placebo group (received tablets containing microcrystalline cellulose). Anthropometric indices, physical activity, diet, fasting blood sugar (FBS), serum insulin, Homeostatic Model Assessment for Insulin Resistance (HOMA-IR), triglyceride (TG), total cholesterol (TC), low-density lipoprotein-cholesterol (LDL-C), high-density lipoprotein (HDL-C), and PAB were assessed. An eight-week intake of 3 tablets containing 335 mg of FDE decreased serum insulin (P=0.016, P<0.001), HOMA-IR (P=0.009, P<0.001), TG (P<0.001, P=0.001), and PAB (P<0.001, P<0.001) compared to the baseline, in both placebo and intervention groups respectively. TC decreased significantly compared to the baseline in the placebo group (P=0.028), while HDL-C increased in the FDE group compared to the baseline (P<0.001) and placebo group (P=0.014). In the present study even though changes of parameters were more in intervention group compared to the control group, we did not observe any significant differences between studied groups except for HDL-C. However, the effects might become apparent with a higher dosage, longer study duration, or a larger sample size compared to the placebo group. Further clinical trials are needed in this regard.

AMPK-Mediated Hypolipidemic Effects of a Salvia miltiorrhiza and Paeonia lactiflora Mixed Extract on High-Fat Diet-Induced Liver Triglyceride Accumulation: An In Vivo and In Vitro Study.

This study investigates the hypolipidemic effects of a mixed extract of Salvia miltiorrhiza and Paeonia lactiflora (USCP119) in HFD-fed hamsters and in vitro cellular models. Over an 8-week period, HFD-fed hamsters were assigned to one of six groups: normal diet, HFD control, HFD with 50 mg/kg USCP119, HFD with 100 mg/kg USCP119, HFD with 50 mg/kg USCP119 twice daily (BID), and HFD with omega-3 fatty acids. Key outcomes assessed included body weight, serum triglycerides (TG), total cholesterol (TC), liver weight, hepatic TG levels, and epididymal fat. In cellular models, the impact of USCP119 on lipid accumulation and adipogenic markers was evaluated. USCP119 treatment at 50 mg/kg BID resulted in the lowest weight gain (15.5%) and the most significant reductions in serum TG and hepatic TG levels compared to the HFD control. The 100 mg/kg dose also led to substantial reductions in serum TG and TC levels and notable decreases in low-density lipoprotein cholesterol. USCP119 at 50 mg/kg once daily reduced TG and TC levels but was less effective than the higher doses. In cellular models, USCP119 was non-toxic up to 400 µg/mL and effectively reduced lipid accumulation, modulated adipogenic markers, and enhanced AMPK signaling, improving lipid metabolism and insulin sensitivity. All USCP119 treatments demonstrated effectiveness in managing hyperlipidemia and related metabolic disorders, with variations in impact depending on the dosage. The ability of USCP119 to reduce fat accumulation, improve lipid profiles, and enhance insulin sensitivity highlights its potential as a valuable dietary supplement for addressing high-fat diet-induced hyperlipidemia and metabolic disturbances.

Intraperitoneal daptomycin dosing for peritonitis may be inadequate: a Monte Carlo simulation approach to optimize dosing and outcomes

A two-compartmental mathematical pharmacokinetic model with first-order elimination of patients receiving CAPD of 4 exchanges for 6 h with 2 L of dialysate used in each cycle was developed to predict daptomycin disposition in 120 h of therapy. The pharmacodynamic target was plasma AUC/MIC equal to or greater than 666. The dose that achieved at least 90% of the probability of target attainment was defined as an optimal dose. Administering intraperitoneal 300 mg daily for 1 exchange daily regimen would be sufficient to treat peritonitis with S. aureus infection with MICs of 0.25 mg/L in patients undergoing CAPD. A higher dosage may be required for infections with a higher minimum inhibitory concentration. Pharmacodynamic targets and MICs significantly contributed to daptomycin doses in this setting. Clinical validation of our recommendations is recommended.

An Assessment of Hepatoprotective Activity of Glycyrrhiza glabra Root Extract against Hepatic Injured Rodent Model

Hepatotoxicity, or liver damage, is caused by hepatotoxins, which can originate from chemicals, dietary supplements, prescription drugs, and medicinal plants. Nowadays, medicinal and aromatic plants are excellent resources for creating novel drugs and curing both psychological and physical illnesses. Given this, licorice, a perennial herb, rich in properties of potential health advantages have been investigated with CCl4 induced hepatic injury on the rodent model to assess its hepatoprotective potential. The study results demonstrated an altered hepatic condition with reduced CCl4 concentration in the liver. The study results show a significant (p&lt;0.05) decrease only at high dosages in SGPT, creatinine level, and total body cholesterol whereas, for low and medium doses, non-significant alleviations were noticed in a dose-dependent manner when compared with the negative control group. Besides, SGOT, urea, LDL, and triglyceride levels were observed with a dose-dependent and non-significant decrease compared to the negative control group. Consequently, more research is required to properly use licorice (Glycyrrhiza glabra) as a less hazardous and more effective substitute for synthetic medications in the field of hepatotoxic therapy, given that it has been found to have potential hepatoprotective properties against hepatotoxicity in this study.

Novel Drug Delivery Systems: An effective platform for Enhanced Therapy

Modern developments in drug pharmacokinetic and Pharmacodynamics behavior make developing the optimal drug delivery method more rational. It is already clear that future success in medication delivery research will mostly come from interdisciplinary collaborations. Pharmaceutical businesses stand to gain enormous commercial potential and advance human disease treatment by employing better drug delivery methods to make therapeutic agents safer and more effective. It is already apparent that multidisciplinary efforts will mostly be responsible for future success in drug delivery research. Any therapeutic agent that can be made safer and more effective while using an enhanced drug delivery method represents a step forward in the treatment of human diseases as well as significant marketing potential for pharmaceutical companies. The best drug delivery systems, based on the etiology and physiological requirements of the body, deliver a predefined dose of medication to the intended site at the appropriate time and place. The speed at which a medication reaches its intended location cannot be controlled by conventional pharmaceutical dosage forms. Novel drug delivery systems (NDDS) are carriers that maintain the drug concentration in the therapeutic range for longer periods of time and may also deliver the content to the targeted site if desired and as needed, because higher doses often cause serious side effects during treatment. Because of this, therapeutic dosages for drug dispersion in non-target tissue and bodily fluids may be far higher than those needed in target cells.

Bisphenol H exposure disrupts Leydig cell function in adult rats via oxidative stress-mediated m6A modifications: Implications for reproductive toxicity

Bisphenol H (BPH) has emerged as a potential alternative to bisphenol A (BPA), which has been curtailed for use due to concerns over its reproductive and endocrine toxicity. This study investigates whether BPH exerts antiandrogenic effects by impairing Leydig cell function, a critical component in testosterone production. We administered orally BPH to adult male rats at doses of 0, 1, 10, and 100 mg/kg/day for 7 days. Notably, BPH treatment resulted in a dose-dependent reduction in testicular testosterone levels, with significant decreases observed at ≥ 1 mg/kg/day. Additionally, BPH affected the expression of key genes involved in steroidogenesis and cholesterol metabolism, including Nr5a1, Nr3c4, Lhcgr, Scarb1, and Star, at higher doses (10 and/or 100 mg/kg/day). The study also revealed alterations in antioxidant gene expression (Sod2 and Cat) and modulation of m6A-related genes (Ythdf1–3 and Foxo3) and their proteins. Through MeRIP-qPCR analysis, we identified increased m6A modifications in Scarb1 and Star genes following BPH exposure. In vitro experiments with primary Leydig cells confirmed that BPH enhanced oxidative stress and diminished testosterone production, which were partially mitigated by antioxidant vitamin E supplementation and Ythdf3 knockdown. Meanwhile, simultaneous administration of BPH and vitamin E to primary Leydig cells partially counteracted BPH-induced alterations in the Ythdf3 expression. Our findings underscore a novel mechanism by which BPH disrupts Leydig cell function through the oxidative stress-m6A modification-autophagy pathway, raising concerns about its potential reproductive toxicity.

The glucocorticoid dose-mortality nexus in pneumonia patients: unveiling the threshold effect.

The impact of glucocorticoid use on mortality risk in pneumonia patients remains unclear. This study aimed to investigate the relationship between the accumulated dose of glucocorticoids (ADG) and secondary pneumonia mortality risk among patients receiving oral or intravenous glucocorticoids. Data from the DRYAD database were analyzed, covering pneumonia patients from six academic hospitals over a 5-year period who had been administered oral or intravenous glucocorticoids. Piecewise linear regression and multivariate regression analysis were utilized to assess the association between ADG and mortality risk in pneumonia patients, while adjusting for potential confounders. Among the 628 pneumonia patients included, the 30-day mortality rate was 23.1% and the 90-day mortality rate was 26.4%. In the high-dose glucocorticoid group (≥24mg/day of methylprednisolone or an equivalent glucocorticoid within 30 days before admission), the 30-day and 90-day mortality rates were 31.2% and 35.9%, respectively. Piecewise linear regression analysis demonstrated a non-linear relationship between ADG and mortality risk in pneumonia patients. Multivariate regression analysis revealed a significantly lower mortality risk in patients receiving an ADG of 20-39g methylprednisolone compared to those receiving lower (<20g) or higher doses (≥40g), after adjusting for potential confounding factors. Additionally, in the high-dose glucocorticoid group, surpassing the inflection point of 20g of methylprednisolone raised the 30-day and 90-day mortality risks (adjusted odds ratio, 95% confidence interval: 1.16, 1.03-1.30 and 1.23, 1.07-1.42, respectively). Notably, this threshold effect was observed exclusively in male patients. This study provides evidence supporting a potential threshold effect between ADG and mortality risk in oral or intravenous glucocorticoid users with secondary pneumonia. Specifically, male patients receiving high-dose glucocorticoids should undergo close monitoring when the ADG of methylprednisolone exceeds 20g, as it may be associated with an elevated risk of mortality.

Bovine lactoferrin alleviates aflatoxin B1 induced hepatic and renal injury in broilers by mediating Nrf2 signaling pathway

Aflatoxin B1 (AFB1) a mycotoxin found in chicken feed that possess a global hazard to poultry health. However different potent compounds like bovine lactoferrin (bLF) may prove to be protective effects against AFB1. This study aims to explore the protective effect of bLF against AFB1-induced injury in the liver and kidney in broiler. For this purpose, 600 broilers chicks were randomly alienated into five groups (n=120 each): negative control; positive control (3mg/kg AFB1), and bLF high, medium, and low dosage groups (600 mg/kg, 300 mg/kg, and 150 mg/kg, respectively). The results highlight that AFB1 toxicity in birds exhibited low feed intake, reduction in weight gain, and a decrease in FCR while, bLF regulated these adverse effects. Meanwhile, AFB1 group showed higher levels of alanine transaminase (ALT) and aspartate aminotransferase (AST) and lower levels of superoxide dismutase (SOD) and glutathione (GSHpx) in liver, while urea and creatinine were decline in kidney. Supplementation with bLF effectively controlled these biomarkers and control the negative effects of toxicity. Furthermore, hematoxylin and eosin (H&E) staining exhibited normal morphological structures within liver and kidney in the bLF treated groups, while degenerative changes were observed in AFB1 group. Similarly, bLF, decreased oxidative stress and thus prevented apoptosis in the liver and kidney cells of the birds. Whereas, mRNA level of mitochondrial apoptosis related gene including Bcl-2 (Bak and Bax), caspase-3 and caspase-9 was upregulated, while bcl2 gene were downregulated in AFB1 group. Dietary supplementation of bLF effectively normalizes the expression of these genes. AFB1 exposed birds shown to decrease gene expression level of the crucial component of Nrf2 pathway, responsible to regulate antioxidant defense. Interestingly, bLF reverse these detrimental effects of and restore the normal expression levels of Nrf2 pathway. Conclusively, our findings demonstrate that bLF mitigates the detrimental effects of AFB1, besides regulation of the apoptosis-related genes via mitochondrial pathways. These findings validate that the bLF (600 mg/kg) could be used as protective agent against AFB1-induced liver and kidney damage.

A pilot study to evaluate the combination of surgery and brachytherapy for local tumor control in young children with perianal rhabdomyosarcoma

BackgroundPerianal rhabdomyosarcoma ((P)RMS) are rare and have a poor prognosis. Data in young children are limited and local therapy is not well defined. Combined brachytherapy and surgery is routinely being used for RMS at other sites in children as it provides good oncologic outcomes and allows for organ-sparing surgery. The objective of this study was to evaluate this combination treatment for local tumor control and organ-sparing surgery in young children with (P)RMS. MethodsA retrospective review of the medical records of all children who underwent surgery and brachytherapy for (P)RMS at our institution since 2009 was conducted. ResultsSurgery for (P)RMS was performed in 6 patients at a median age of 19 months (range 8–50). Embryonal RMS was diagnosed in 4 patients and alveolar RMS in 2 patients, of which 1 patient had FOXO1 fusion-positive RMS. All patients underwent postoperative high-dose rate (HDR) brachytherapy. Organ-preserving surgery was achieved in 5 of 6 patients (83 %). In 1 patient, the entire sphincter was infiltrated, making organ-preserving resection impossible. 5 of 6 patients (83 %) exhibited an event-free and overall survival at a median follow-up of 26 months (range 8–107). One patient died due to locoregional recurrence. Complications were urethral leakage in 1 patient followed by urethral stenosis and delayed wound healing and vaginal stenosis in another patient. No patient reported fecal incontinence. ConclusionsCombined treatment with surgery and HDR brachytherapy is feasible in very young children with (P)RMS and leads to a favorable oncologic outcome. Preliminary data show a good functional preservation.

Year-Long Cannabis Use for Medical Symptoms and Brain Activation During Cognitive Processes

Cannabis is increasingly being used to treat medical symptoms, but the effects on brain function in those using cannabis for these symptoms are not known. To test whether 1 year of cannabis use for medical symptoms after obtaining a medical cannabis card was associated with increased brain activation during working memory, reward, and inhibitory control tasks, areas of cognition affected by cannabis. This cohort study was conducted from July 2017 to July 2020 among participants from the greater Boston area who were recruited as part of a clinical trial of individuals seeking medical cannabis cards for anxiety, depression, pain, or insomnia symptoms. Participants were aged between 18 and 65 years. Exclusion criteria were daily cannabis use and cannabis use disorder at baseline. Data analysis was conducted from August 2021 to April 2024. Outcomes were whole brain functional activation during tasks involving working memory, reward, and inhibitory control at baseline and after 1 year of medical cannabis card ownership. Imaging was collected from participants before and 1 year after obtaining medical cannabis cards, with 57 participants at baseline (38 female [66.7%]; 6 [10.5%] Black and 45 [78.9%] White participants; 1 [1.8%] Hispanic participant; median [IQR] age, 34.0 [24.0-51.0] years) and 54 participants at 1 year (37 female [68.5%]; 4 [7.4%] Black and 48 [88.9%] White participants; 1 [1.9%] Hispanic participant, median [IQR] age, 36.5 [25.0-51.0] years). Imaging was also collected in 32 healthy control participants at baseline (22 female [68.8%]; 2 [6.2%] Black and 27 [84.4%] White participants; 3 [9.4%] Hispanic participants; median [IQR] age, 33.0 [24.8-38.2] years). In all groups and at both time points, functional imaging revealed canonical activations of the probed cognitive processes. No statistically significant difference in brain activation between the 2 time points (baseline and 1 year) in those with medical cannabis cards and no associations between changes in cannabis use frequency and brain activation after 1 year were found. In this cohort study of adults obtaining medical cannabis cards for medical symptoms, no significant association between brain activation in the areas of cognition of working memory, reward, and inhibitory control and 1 year of cannabis use was observed. The results warrant further studies that probe the association of cannabis at higher doses, with greater frequency, in younger age groups, and with larger, more diverse cohorts.

Individual curved-needle interstitial template created using three-dimensional printing for brachytherapy for distal parauterine tumor recurrence.

Achieving a clinically acceptable dose distribution with commercial vaginal applicators for brachytherapy of recurrent parauterine tumors is challenging. However, the application of three-dimensional (3D) printing technology in brachytherapy has been widely acknowledged and can improve clinical treatment outcomes. This study aimed to introduce an individual curved-needle interstitial template (ICIT) created using 3D printing technology for high-dose-rate (HDR) brachytherapy with interstitial treatment to provide a clinically feasible approach to distal parauterine and vaginal cuff tumors. The entire workflow, including the design, optimization, and application, is presented. Ten patients with pelvic cancer recurrence were examined at our center. The vaginal topography was filled with gauze strips soaked in developer solution, and images were obtained using computed tomography (CT) and magnetic resonance imaging (MRI). Curved needle paths were designed, and ICITs were 3D-printed according to the high-risk clinical target volume (HRCTV) and vaginal filling model. The dose and volume histogram parameters of the HRCTV (V100, V200, D90, and D98) and organs at risk (OARs) (D2cc) were recorded. All patients completed interstitial brachytherapy treatment with the 3D-printed ICIT. One patient experienced vaginal cuff tumor recurrence, and nine patients experienced parametrial tumor recurrence (four on the left and five on the right). We used two to five interstitial needles, and the maximum angle of the curved needle was 40°. No source obstruction events occurred during treatment of these 10 patients. The doses delivered to the targets and OARs of all patients were within the dose limits and based on clinical experience at our center. The ICIT is a treatment option for patients with distal parauterine tumor recurrence. This method addresses the limitations of vaginal intracavitary and standard interstitial applicators. The ICIT has the advantages of biocompatibility, personalization, and magnetic resonance imaging compatibility.

The modulation of social and non-social behavior by arginine vasotocin in the common waxbill, Estrilda astrild

The influence of the neuropeptide arginine vasotocin (AVT) has been demonstrated across various species, on an ample range of behaviors, yet the results appear to be highly species-specific. In this study, we aimed to test how AVT influences both social and non-social behaviors in the common waxbill Estrilda astrild, a highly social estrildid finch. Through a within-subject design study, we experimentally manipulated AVT pathways through muscular injections of both an agonist and an antagonist of AVT at different dosages, and performed competition over food tests to assess behavioral changes. Our observations reveal a decrease in birds' movements with both low and high dosages of AVT. Additionally, the higher AVT dosage led to a significant decrease in birds' feeding, aggressive behavior, and allopreening. Conversely, the lower AVT dosage increased the duration of allopreening, which is a proxy for affiliation. The use of Manning Compound, a V1a antagonist, did not produce any changes in behavior, however, the absence of affinity studies for this compound in birds makes it difficult to interpret these results. It is plausible that in common waxbills, AVT V1b or V1a receptors may be involved in regulating movement, feeding, aggressive behavior, and allopreening, rather than V2 AVT receptors.

An Assessment of Hepato-protective Activity of Hygrophila auriculata Root Extract against Hepatic Injured Rodent Model

Liver is a crucial organ that is susceptible to several hepatotoxins causing hepato-toxicities. These days, medicinal plants have been considered to be more promising compared with the conventionally utilized medications for hepatic treatments. In light of the dire circumstances affecting worldwide currently, Hygrophila auriculata is a vital plant with an abundance of health advantages and hepatoprotective properties. In this experiment, carbon tetrachloride (CCl4) was utilized to cause hepatotoxicity in rats and this plant's anti-hepatotoxic activity was evaluated through assessing the outcomes of several parameters (Liver functioning tests, kidney functioning tests and lipid profiles). Subsequent research revealed that the plant may, to varying degrees and in a dependent way, successfully restore the disrupted pathological state to healthy status. To interpret statistical analysis, the "One-way Anova test" was conducted using the SPSS 16 software. In the case of SGPT, the medium and high dose produced statistically significant (p&lt;0.05) outcomes as compared to the negative control group and for SGOT decrease in all three groups were non-significant (p&gt;0.05). Then for creatinine levels, the outcome for medium, and high dosages were statistically significant (p&lt;0.05) whereas in case of urea level only the high dose imparted significant (p&lt;0.05) decrease. However, none of the dosages for total cholesterol and triglyceride level produced statistically significant (p&lt;0.05) effects. Only in the medium and high doses, HDL levels improved statistically significantly (p&lt;0.05) whereas only the high dosages reduced reduce the LDL quantity in the blood significantly (p&lt;0.05). As a result, Hygrophila auriculata is thought to possess a significant capacity for liver protection and may serve as a more secure and effective substitute for the commercially available synthetic medication, silymarin. To sum up, additional research is required in the future before this appealing plant could get utilized in the arena of hepatotoxic treatments.

Computer-aided nanodrug discovery: recent progress and future prospects.

Nanodrugs, which utilise nanomaterials in disease prevention and therapy, have attracted considerable interest since their initial conceptualisation in the 1990s. Substantial efforts have been made to develop nanodrugs for overcoming the limitations of conventional drugs, such as low targeting efficacy, high dosage and toxicity, and potential drug resistance. Despite the significant progress that has been made in nanodrug discovery, the precise design or screening of nanomaterials with desired biomedical functions prior to experimentation remains a significant challenge. This is particularly the case with regard to personalised precision nanodrugs, which require the simultaneous optimisation of the structures, compositions, and surface functionalities of nanodrugs. The development of powerful computer clusters and algorithms has made it possible to overcome this challenge through in silico methods, which provide a comprehensive understanding of the medical functions of nanodrugs in relation to their physicochemical properties. In addition, machine learning techniques have been widely employed in nanodrug research, significantly accelerating the understanding of bio-nano interactions and the development of nanodrugs. This review will present a summary of the computational advances in nanodrug discovery, focusing on the understanding of how the key interfacial interactions, namely, surface adsorption, supramolecular recognition, surface catalysis, and chemical conversion, affect the therapeutic efficacy of nanodrugs. Furthermore, this review will discuss the challenges and opportunities in computer-aided nanodrug discovery, with particular emphasis on the integrated "computation + machine learning + experimentation" strategy that can potentially accelerate the discovery of precision nanodrugs.

In total knee arthroplasty surgeries, what is the effective dose of intra-articular tranexamic acid?

The aim of our study was to evaluate the effect of different doses of intra-articular (IA) tranexamic acid (TXA) on blood loss in total knee arthroplasty surgeries and compare it to the control group. A total of 160 patients who underwent unilateral total knee arthroplasty surgery at Edirne State Hospital between 2016 and 2020 were divided into four groups. The estimated blood loss and amount of blood loss from drainage, as well as transfusion rates, were compared between the groups based on surgical pre- and post-operative blood parameters to evaluate the dose effectiveness. In our study, all TXA groups significantly reduced the estimated blood loss and amount of blood loss from drainage compared to the control group. No statistically significant difference was found between the control group and the group receiving 1 g of TXA in terms of transfusion rates (p = 0.062), and no statistically significant difference was found between the groups receiving 2 g and 3 g of TXA. The use of 2 g of IA TXA is an effective dose for controlling blood loss in total knee arthroplasty surgeries. Lower doses do not have a significant effect on transfusion rates, whereas higher doses do not significantly increase effectiveness.