Total Dose Research Articles

The Impact of a Twice-daily Versus Once-daily Proton Pump Inhibitor Dosing Regimen on Laryngopharyngeal Reflux Symptoms: A Prospective Randomized Controlled Trial.

Proton pump inhibitors (PPIs) play a crucial role in managing laryngopharyngeal reflux (LPR), but the optimal dosing regimen remains unclear. We aim to compare the effectiveness of the same total PPI dose administered twice daily versus once daily in LPR patients. We conducted a prospective randomized controlled trial at a tertiary referral hospital, enrolling a total of 132 patients aged 19 to 79 with LPR. These patients were randomly assigned to receive either a 10 mg twice daily (BID) or a 20 mg once daily (QD) dose of ilaprazole for 12 weeks. The Reflux Symptom Index (RSI) and Reflux Finding Score (RFS) were assessed at 8 weeks and 16 weeks. The primary endpoint was the RSI response, defined as a reduction of 50% or more in the total RSI score from baseline. We also analyzed the efficacy of the dosing regimens and the impact of dosing and duration on treatment outcomes. The BID group did not display a higher response rate for RSI than the QD group. The changes in total RSI scores at the 8-week and 16- week visits showed no significant differences between the 2 groups. Total RFS alterations were also comparable between both groups. Each dosing regimen demonstrated significant decreases in RSI and RFS. Both BID and QD PPI dosing regimens improved subjective symptom scores and objective laryngoscopic findings. There was no significant difference in RSI improvement between the 2 dosing regimens, indicating that either dosing regimen could be considered a viable treatment option.

Altered states of consciousness in Danish healthy volunteers and recreational users of psilocybin and the possible impact of setting and intention: Danish validation of the five-dimensional altered states of consciousness questionnaire.

Psychedelic substances reliably induce marked altered states of consciousness (ASC), which may be important for lasting effects and clinical outcomes of psychedelic intervention. Several instruments are available to measure the acute psychedelic experience, of which the Five Dimensional Altered States of Consciousness Questionnaire (5D-ASC) is commonly used. The questionnaire can be scored and analyzed as having five dimensions or 11 subscales, but the two have not been evaluated with comparable factor analysis methods. The Danish translation of the 5D-ASC was completed by one sample of healthy volunteers receiving psilocybin in a laboratory setting (N = 47) and one sample of recreative users5D-ASC of psychedelics (N = 550), who reported retrospectively through an online survey based on their most recent experience with psilocybin. We calculated internal consistency measures of Cronbach's alpha and McDonald's omega, conducted a confirmatory factor analysis of the previously suggested factor structures, and tested for possible associations between the 5D-ASC total scores and dose, setting, and intention. For the 11 subscales, we reported omega-sem (composite reliability) using the parameters of the fitted confirmatory factor analyses model. Confirmatory factor analysis showed that the 11 subscales had a good fit to data and showed a better fit compared to the originally proposed five-dimensional solution and good internal consistencies. We further found that the 5D-ASC total scores correlated positively with the dose in the recreative sample. We found no correlations between 5D-ASC total scores and intention or setting. We find the Danish 5D-ASC to be a valid tool for measuring ASC among Danish-speaking individuals.

A Whole-Transcriptomic Analysis of Canine Oral Melanoma: A Chance to Disclose the Radiotherapy Effect and Outcome-Associated Gene Signature.

Oral melanoma (OM) is the most common malignant oral tumour among dogs and shares similarities with human mucosal melanoma (HMM), validating the role of canine species as an immunocompetent model for cancer research. In both humans and dogs, the prognosis is poor and radiotherapy (RT) represents a cornerstone in the management of this tumour, either as an adjuvant or a palliative treatment. In this study, by means of RNA-seq, the effect of RT weekly fractionated in 9 Gray (Gy), up to a total dose of 36 Gy (4 weeks), was evaluated in eight dogs affected by OM. Furthermore, possible transcriptomic differences in blood and biopsies that might be associated with a longer overall survival (OS) were investigated. The immune response, glycosylation, cell adhesion, and cell cycle were the most affected pathways by RT, while tumour microenvironment (TME) composition and canonical and non-canonical WNT pathways appeared to be modulated in association with OS. Taking these results as a whole, this study improved our understanding of the local and systemic effect of RT, reinforcing the pivotal role of anti-tumour immunity in the control of canine oral melanoma (COM).

Acute Kidney Injury in Relation to Nephrotoxic Medication Use Among Critically Ill Children in the Paediatric Intensive Care Unit.

Background: Critically ill children are vulnerable to acute kidney injury (AKI) and are often exposed to nephrotoxic medications. Objectives: We aimed to investigate the association between nephrotoxic medications and the risk of AKI in critically ill children admitted to our paediatric intensive care unit (PICU). Methods: Patients aged > 1 month to ≤18 years old were prospectively recruited from 6/2020 to 6/2021. The medication records from 14 days prior to PICU admission to PICU discharge were reviewed. Medication-exposure intensity was defined as the number of concomitant nephrotoxic medications. The relative risk (RR) of nephrotoxic medication exposure indices and other potential predictors for AKI development were determined. Results: Altogether 253 episodes of admissions (median [IQR] age of 4.9 [9.6] years) were enrolled. The AKI incidence was 41.9% and 69.2% of the patients were exposed to ≥1 of the 47 nephrotoxic medications. The total nephrotoxic medication dose (RR: 1.01 [1.00, 1.02]) and medication-exposure intensity (RR: 1.381 [1.101, 1.732]) were significantly associated with AKI development. The risk of AKI increased when the medication-exposure intensity was ≥4 (RR: 3.687 (1.320, 10.301)). During their PICU stay, children with AKI received a higher number (P < .01), total dose (P < .01) and medication exposure intensity (P < .01) of nephrotoxic medications. Children with AKI who received nephrotoxic medications were more likely to have a persistently higher peak-to-baseline ratio (P = .046). Conclusion: Nephrotoxic medication exposure significantly increased the risk of AKI development among critically ill children. The use of nephrotoxic medications among critically ill children at risk for AKI should be monitored frequently.

The association between exosomal proteins and the efficacy of thermoradiochemotherapy in overweight/obese rectal cancer patients: a pilot prospective cohort study

Background: Overweight and especially obesity are associated with the risk of the development and progression of colorectal cancer. It can be assumed that there are multifaceted interactions between the tumor and adipose tissue during anti-tumor treatment. Cancer cells secrete exosomes, extracellular vesicles affecting the microenvironment of the tumor and promoting its progression or regression. The presence of transcription/translation/folding factors (heat shock proteins (HSPs), matrix metalloproteinases (MMPs) and their tissue inhibitors (TIMPs) in exosomes secreted by irradiated cells and cells exposed to hyperthermia, indicates the cell adaptation to the thermal and radiation stress. Aim: To analyze the MMPs, TIMP1, and HSPs on CD9-positive (CD9+) exosomes, as well as on exosomes of adipocytic origin (FABP4+) in rectal cancer patients with overweight/obesity under thermoradiochemotherapy (TRCT) and their association with the immediate treatment efficacy. Methods: Since 2021, 20 patients (of those 8 men; median age 59.0 [52.0; 63.0] years, median body mass index 29.6 [28.5; 33.1] kg/m2) with morphologically verified rectal cancer (T3-4N0M0 and T3-4N1M0, differentiation grade G1–G3) have been participating in the study. They were treated with TRCT: external gamma therapy (2 Gy, 1 fraction/day, 5 days/week, total focal dose 54 Gy), chemotherapy with capecitabine (825 mg/m2 twice daily) combined with local hyperthermia (42–44 °C, 60 min, 3 times/week, 10 sessions). The TRCT efficacy was assessed by RECIST 1.1 and ESGAR criteria. Blood samples for exosomes were taken from the patients at baseline (point 1), in the middle of the treatment course (point 2), at 6 to 10 weeks after the end of TRCT (point 3), and at 6 months after point 1 (point 4). Small extracellular vesicles were isolated from plasma by ultrafiltration with double ultracentrifugation. The isolated exosomes were characterized by transmission electronic microscopy, flow cytometry and nanoparticle trajectory analysis (NTA). Results: TRCT resulted in complete tumor regression in 13/20 of the rectal cancer patients and partial regression or stabilization in 7/20. Four subpopulations of CD9+ and FABP4+ exosomes associated with the TRCT efficacy were identified (CD9+MMP2+, СD9+MMP2+9+TIMP1+, СD9+MMP2+9+TIMP1-, and FABP4+MMP2+9-TIMP1+). Compared to the CD9+ exosomes, the adipocytic vesicles had higher MMP2 expression (p = 0.026); however, the adipocyte vesicles subpopulation were virtually free of vesicles with combined MMP2 and MMP9 gelatinase expression. The HSPs expression by circulating exosomes at various TRCT steps was associated neither with direct treatment efficacy nor with the vesicle type. Conclusion: The expression of MMPs and TIMP1 on CD9+ and FABP4+ exosomes is associated with TRCT efficacy. In the future, vesicular markers could be used to build prognostic models, to identify patient groups with an unfavorable prognosis, and to personalize treatment and follow-up.

Surfactant system of the lungs in antiphospholipid syndrome under the conditions of administration of the immunosuppressive agent FTY-720

Antiphospholipid syndrome (APS) is a thrombophilic disease in the pathogenesis of which the leading role belongs to antibodies reacting with antigenic determinants of phospholipids. APS is a systemic autoimmune pathology that involves many organs and systems in the pathological process, including the respiratory system. Given the fact that the lung surfactant is mainly represented by phospholipids, it can be presented that the surfactant is damaged and its functioning is impaired in APS. The results of our experiments showed that in antiphospholipid syndrome, there was a decline in the functional activity of the surfactant and a change in its biochemical composition. The introduction of FTY-720 normalized the parameters of the lung surfactant system, which were changed during the modeling of antiphospholipid syndrome. The work shows the effectiveness of the therapy of this autoimmune pathology with immunosuppressor FTY-720, which is a structural analogue of endogenous sphingosine. The effect of the drug is based on the modulation of sphingosine-1 phosphate receptors of lymphocytes. The main effect of the immunosuppressor FTY-720 as a result of receptor interaction is a decrease in the number of circulating lymphocytes. The research involved 85 white random bred male rats: Group 1 (APS modeling) consisted of 30 rats who were intravenously injected with cardiolipin antigen at a total dose of 0.2-0.4 mg per rat every other day for three weeks; Group 2 (control) consisted of 25 rats who were injected with 0.9% NaCl solution according to the same scheme; and Group 3 including 30 rats in which APS was combined with the administration of the immunosuppressive agent FTY-720 (intraperitoneally 1 mg/kg of animal weight). Three weeks later, there was an operation conducted with the purpose of extraction of the bronchopulmonary complex. After extraction of the bronchopulmonary complex, its triple lavage was carried out with 0.9% NaCl solution. The material of the experimental study was a lavage liquid, in which the biophysical and biochemical parameters of the surfactant were studied. Langmuir–Blodgett method was used to identify static, minimal and maximal surface tension. These figures were used to identify integrative indicator reflecting surfactant characteristics – the Clements stability index. The fractional composition of surfactant phospholipids was determined by thin-layer chromatography. The results of our experiments showed that in antiphospholipid syndrome, there was a decline in the functional activity of the surfactant and a change in its biochemical composition. The introduction of FTY-720 normalized the parameters of the lung surfactant system, which were changed during the modeling of antiphospholipid syndrome.

A phase I/II study of nanoliposomal irinotecan and carboplatin in patients with advanced or metastatic, poorly differentiated gastroenteropancreatic neuroendocrine carcinoma characterized by tissue and liquid next-generation sequencing.

52 Background: For locally advanced or metastatic gastroenteropancreatic neuroendocrine carcinomas (GEP-NECs), standard chemotherapy typically incorporates etoposide or irinotecan plus platinum agents. Herein, we initiate a phase I/II trial to apply Nal-IRI in combination with carboplatin as the 1st line treatment in patients with GEP-NECs to define the dose-limiting toxicity (DLT) and recommended phase II dose (RP2D). Methods: In the phase I part, traditional 3+3 design was applied. Enrolled patients would receive escalating dose of 60 (level -1), 80 (starting dose, level 0) or 100 (level 1) mg/m2 salt-form nal-IRI plus carboplatin AUC=4 with maximum total dose of 600 mg on D1, every 21 days as a cycle. DLTs were evaluated during the first one cycle of treatment with tumor assessment every 6 weeks. Prophylaxis G-CSF was not allowed in the first cycle Paired testing of tissue (TBx) and liquid biopsy (LBx) was done by Illumina TSO500 platform before treatment. The second LBx would be repeated for confirmed partial responders when progression. Results: Totally 6 GEP-NEC patients with primary sites of colon in three, and each one in esophagus, ampulla of Vater and pancreas were enrolled to level 0. One patient had DLT of grade 4 neutropenia lasting for 3 days even under salvage G-CSF. Treatment-related adverse events showed grade 3/4 neutropenia (33.4%), grade 2 anemia (16.7%), grade 3 fatigue (16.7%), and grade 2 skin rash (16.7%). Four patients achieved confirmed partial response and 2 patients got stable disease, with the objective response rate of 66.7% (95% confidence interval: 22%-96%). After the data and safety monitoring board meeting, level 0 was decided as RP2D but not escalation to level 1 because of acceptable toxicity profiles and promising efficacies. Comprehensive genomic profiling showed that driver mutations were identified in three cases including two harboring BRAFV600E mutation and one with KRASG12D mutation. The other three cases lacking driver mutation showed frequent copy number alteration including 1 with MDM2 amplification (copy number 27) and a wild-type TP53. Homologous recombination deficiency (HRD), as determined by GIS score, was identified in a colon GEP-NEC who remained to be HRD-positive at progression but a higher TMB (from 4.7 to 10.2 Muts/Mb) and a higher BRAFV600E mutation allele frequency (from 24.1% to 43.6%) in tumor tissue, compared to the baseline profiling. Conclusions: Based on current data, the RP2D is 80 mg/m2 of nal-IRI (salt-form) and carboplatin of AUC=4, every 3 weeks. The extension phase II study in GEP-NEC is ongoing. Clinical trial information: NCT05385861 .

Intratumoral Chemotherapy: The Effects of Drug Concentration and Dose Apportioning on Tumor Cell Injury.

The addition of intravenous (i.v.) chemotherapy to i.v. immunotherapy for patients with lung cancer results in improved overall survival but is limited by synergistic side effects and an unknown, highly variable final cytotoxic dose within the tumor. The synergy between i.v. chemo- and immunotherapies is hypothesized to occur as a result of cell injury caused by chemotherapy, a mechanism demonstrated to drive antigen presentation within the tumor microenvironment. Intratumoral delivery of chemotherapy may thus be optimized to maximize tumor cell injury. To assess the balance between the damage versus the death of tumor cells, we developed a computational model of intratumoral dynamics within a lung cancer tumor for three different chemotherapy agents following direct injection as a function of location and number of injection sites. We based the model on the morphology of a lung tumor obtained from a thoracic CT scan. We found no meaningful difference in the extent of tumor cell damage between a centrally injected versus peripherally injected agent, but there were significant differences between a single injection versus when the total dose was apportioned between multiple injection sites. Importantly, we also found that the standard chemotherapeutic concentrations used for intravenous administration were effective at causing cell death but were too high to generate significant cell injury. This suggests that to induce maximal tumor cell injury, the optimal concentration should be several orders of magnitude lower than those typically used for intravenous therapy.

Feasibility of Remotely Controlled Capsule to Enable Directionality and Higher Dose Rates for Conventional Low Dose Rate Brachytherapy Using Topas

With low dose radiation (LDR) brachytherapy, thus far, only low dose rates could be used with low energy level radiation sources at 30 keV or less due to the risk of radiation to healthy cells, tissue, and organs. The radiation seeds are placed in the location of the tumor and is left in the body for the total dose to be continuously administered throughout the decay period of the radiation seed. However, the amount of time to deliver the total dose can take up to several months depending on the type of radiation source, tumor size and location, due to the low dose rate of <2 Gy/hr. In contrast, high dose radiation (HDR) is defined as a dose delivered at a rate >12 Gy/hr, although usually much higher, often in excess of 1 Gy/min, with a higher energy radiation source close to 0.5 MeV.For the first time, a remotely controllable, implanted radiation capsule is introduced, to enable a very high dose rate of 10 Gy/min for 30 keV I-125 radiation source. Until now, this combination of low energy and high dose rate for implanted radiation seeds for LDR was not possible due to the risk of radiation. The implantable capsule is designed to control this risk of radiation by remotely controlling the opening of the capsule hole. In the open case, the high dose rate of I-125 is delivered for a duration of 1 minute and then closed to stop emission.For feasibility, a simulation study was conducted using TOPAS for Monte Carlo simulation of radiotherapy. In the top right figures, a cylindrical capsule of height 6 mm, diameter 3 mm, and wall thickness 0.9 mm is designed using gold to contain the radiation and prevent leakage radiation. An opening of 30 degrees was made in the middle of the capsule wall where the radiation was to be emitted. For the radiation source, a 30 keV I-125 was used with a specific activity of 6.42 x 1014 Bq/gram. With a wall thickness of 0.9 mm, calculations showed that 4.4 micrograms of I-125 was needed to increase the source activity for 1.454 x 1020 Bq per second for a high dose rate of 10 Gy/min.The yellow and red colors in the capsule are both gold with wall thickness of 0.9 mm. The red portion of the cylinder is where the 30 degree opening was defined. The green lines show the paths of the radiation particles.TOPAS simulation results successfully show that the capsule contains the radiation and the only direction of radiation is through the defined opening in the capsule. The bottom three graphs show the x, y, and z plane cuts showing a directional radiation beam that drops in intensity, from a range of 1.0 to 0, over distance and slightly widens over distance.To control the opening and closing of the hole in the radiation capsule, an inner cylinder and outer cylinder is used, where the inner cylinder can move up and down. A permanent magnet is attached to the bottom of the inner cylinder and an electromagnet is attached to the base at the bottom of the capsule. An implantable inductive coil receives an AC current from the external inductive coil, which is rectified using a diode and capacitor circuit. This DC current powers the electromagnet, which repels the inner cylinder, moving it up to align the windows of the inner and outer cylinders. This alignment opens the hole and radiation is emitted towards the target tumor. After the dose is delivered, the current is turned off, which turns off the electromagnet. With no repelling force from the electromagnet, the permanent magnet reattaches itself to the base, and the inner cylinder slides down and the windows are no longer aligned. This blocks the radiation from being emitted. The dimensions of the capsule and the windows depend on the radiation source and tumor size. Micromachining and micro 3D printing techniques can be applied for fabrication of the device.In conclusion, a feasibility study using TOPAS demonstrated that a 0.9 mm gold wall with a hole can contain a very high source activity of I-125 radiation for a very high dose rate of 10 Gy/min and emit a directional beam through the hole. A remotely controllable capsule can enable a high dose rate with LDR brachytherapy that combines the advantages of LDR and HDR, which is minimum radiation risk and minimum treatment time, simultaneously. Potential applications for this is intracavitary cancer treatment such as esophageal or cervical cancer. Figure 1

Daily Sedation Interruption vs Continuous Sedation in Pediatric Patients Receiving Mechanical Ventilation

The effectiveness of daily sedation interruption (DSI, defined as temporary interruption of sedation) has yet to be demonstrated in critically ill pediatric patients. To compare the clinical outcomes of DSI vs continuous intravenous (IV) sedation in patients receiving invasive mechanical ventilation (MV) support in the pediatric intensive care unit (PICU). A systematic search for studies was conducted using predefined keywords and Medical Subject Headings in 5 major databases (PubMed, Embase, Web of Science, CINAHL [Cumulated Index to Nursing and Allied Health Literature], and Cochrane Central Register of Controlled Trials) from database inception to October 31, 2023. Retrospective and prospective observational studies, randomized clinical trials (RCTs), and systematic reviews were assessed for inclusion. Studies were eligible if they compared DSI to continuous IV sedation in patients aged 18 years or younger requiring MV in the PICU. Study characteristics, including the types of sedation, sedation protocols, and clinical outcomes, were extracted. The Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) reporting guideline was followed. A random-effects model was used to pool results from articles for the meta-analysis. The primary outcomes of interest were duration of MV and length of PICU stay. Secondary outcomes included total sedative dose requirement, adverse events (eg, complications associated with MV, withdrawal, and delirium), and mortality. A total of 6 RCTs with 2810 pediatric patients (1569 males [55.8%]; mean age, 26.5 [95% CI, 15.0-37.9] months) were included in the final analysis; patients had a mean PRISM (Pediatric Risk of Mortality) score of 13.68 (95% CI, 10.75-16.61). Compared with continuous IV sedation, DSI was associated with a reduction in length of PICU stay (5 studies, n = 2770; mean difference [MD], -1.45 [95% CI, -2.75 to -0.15] days; P = .03]. There was no difference in MV duration (5 studies, n = 2750; MD, -0.93 [95% CI, -1.89 to 0.04] days; P = .06), total doses of midazolam (3 studies, n = 191; MD, -1.66 [95% CI, -3.95 to 0.63] mg/kg) and morphine used (2 studies, n = 189; MD, -2.63 [95% CI, -7.01 to 1.75] mg/kg), or adverse events (risk ratio [RR], 1.03 [95% CI, 0.74-1.42]; P = .88). There was no difference in mortality between patients exposed vs not exposed to DSI (RR, 0.89 [95% CI, 0.55-1.46]; P = .65). This systematic review and meta-analysis found that use of DSI in pediatric patients was associated with reduced length of PICU stay with no increase in adverse events. Further research is needed to ascertain whether this strategy is associated with improved neurodevelopmental outcomes in PICU survivors.

A Randomized Trial Comparing Concurrent versus Sequential Radiation and Endocrine Therapy in Early-Stage, Hormone-Responsive Breast Cancer.

Concerns exist regarding increased toxicities, including endocrine therapy toxicity, with concurrent radiation and endocrine therapy in early breast cancer (EBC). We present a pragmatic, randomized trial comparing concurrent versus sequential endocrine and radiotherapy in hormone-responsive EBC. In this multicenter trial, patients were randomized to receive adjuvant endocrine therapy concurrent with, or sequential to, radiotherapy. The primary outcome was change in endocrine therapy toxicity from baseline to 3 months post radiotherapy using the Functional Assessment of Cancer Therapy-Endocrine Symptom (FACT-ES) score. From September 2019 to January 2021, 133 patients were randomized to concurrent endocrine and radiotherapy, and 127 to sequential treatment. Most patients were post-menopausal (72.7%, 189/260) with stage 1 disease (65.8%, 171/260). Tamoxifen was the endocrine therapy of choice for 69.6% (181/260) of patients, and an aromatase inhibitor for the remainder. The median total radiation dose and fractions were 40.1 Gray (range 26-50) and 15 fractions (range 5-25), respectively. For the primary outcome of change in endocrine therapy toxicity per FACT-ES scores from baseline to 3 months post radiotherapy, no significant difference was found between the groups (median [range] = -4.9 (-82, 38.8) for concurrent and -5.1 (-42, 40) for sequential, p = 0.87). This is the first trial to investigate the impact of concurrent versus sequential adjuvant endocrine and radiotherapy on endocrine therapy-related toxicities. The findings provide further support to allow the optimal timing of radiation and endocrine therapy to be tailored for the individual patient.

Influence of γ‐irradiation dose on the mechanical and tribological properties of fluoroelastomer

AbstractFluoroelastomer (FKM) undergo various degrees of degradation in a gamma‐irradiated environment, leading to changes in their mechanical and tribological properties. In this paper, changes in the properties of FKM were investigated for six different doses. Fourier transform infrared‐atomic absorption spectroscopy (FTIR‐ATR) results show that FKM samples undergo dehydrofluorination and oxidation reactions during irradiation, resulting in the formation of C=C, C=O, and ‐OH functional groups. The results of the swelling test showed that the degree of cross‐linking of the FKM specimens increased with increasing irradiation dose. Mechanical test results show that the fracture mechanism of FKM specimens gradually evolves from ductile fracture to brittle fracture with the increase of irradiation dose. Its tensile strength reaches its maximum at an irradiation dose of 1000 kGy, and the modulus of elasticity becomes larger with increasing irradiation dose. The results of wear tests show that the average coefficient of friction of FKM specimens first decreases, reaches a minimum at 500 kGy, and then gradually increases. The amount of wear increases with increasing irradiation dose. The wear mechanism of FKM specimens is abrasive wear at 0–500 kGy, adhesive wear at 1000 and 2000 kGy, and fatigue wear at 3000 kGy.Highlights FKM was irradiated by gamma‐ray with a total dose of 3000 kGy. Dehydrofluorination and oxidation reactions occur during irradiation. Increased cross‐linking leads to changes in mechanical properties. The wear mechanism of FKM with different doses has been investigated.

Transparent Perovskite Wafers via Nanocrystals Ordered Coalescence Toward Sensitive and Stable X‐Ray Detection and Imaging

AbstractMetal halide perovskite wafers have shown significant potential in large‐area X‐ray detection and imaging. However, a distinct difference in optical transparency between state‐of‐the‐art perovskite wafers and single crystals indicates the inferior crystal quality of perovskite wafers, which limits the performance and stability of wafer‐based X‐ray detectors. Here, nano‐sized MAPbBr3 powders are utilized to fabricate dense perovskite wafers by low‐temperature hot‐pressing with high transparency above 60% within the 552–800 nm wavelength range. Adjacent nanocrystals assemble following the ordered coalescence mechanism, resulting in the exclusion of nanoscopic pores and crystallographic reorientation. The transparent MAPbBr3 wafer‐based detectors achieve an impressively high X‐ray sensitivity of 1.14 × 105 µC Gyair−1 cm−2 and a low detection limit of 149 nGyair s−1, which is superior to opaque MAPbBr3 wafer detectors (5.64 × 104 µC Gyair−1 cm−2 and 316.7 nGyair s−1) and comparable to MAPbBr3 single‐crystal detectors. Moreover, the detectors demonstrate high uniformity and outstanding stability under continuous X‐ray irradiation of a total dose of up to 5.9 Gyair, equaling to 29 500 times posteroanterior chest examinations. The high sensitivity and low detection limit of the detectors lead to clear X‐ray imaging performance.

A comparative evaluation of 0.25% bupivacaine and 0.25% levobupivacaine in peritubal infiltration in percutaneous nephrolithotomy

Background: Percutaneous nephrolithotomy (PCNL) is a routine endourologic procedure in patients with renal calculi. Although it is less painful than open surgery, pain around the nephrostomy tube is a clinical problem; therefore, good post-operative analgesia is required to alleviate pain. Peritubal infiltration can be one of the choices to alleviate pain around the nephrostomy tube. Aims and Objectives: The aim of this study was to evaluate the efficacy of peritubal infiltration of local anesthetics for post-operative pain following PCNL. Materials and Methods: A total of 60 patients with American Society of Anesthesiologists Grade I/II scheduled for elective PCNL surgeries were randomly allocated into two groups. Group L received levobupivacaine 0.25% (30 mL) and Group B received bupivacaine 0.25% (30 mL). The duration of rescue analgesia, total dose of tramadol consumption in 24 h, hemodynamic parameters, and adverse events during the post-operative period were noted. Results: The mean duration of rescue analgesia in Group L was 274.50±24.89 min and in Group B was 275.33±23.04 min which was not significant (P&gt;0.05). Conclusion: Peritubal infiltration of 0.25% levobupivacaine and 0.25% bupivacaine is efficient in alleviating post-operative pain after PCNL. Both drugs can be used for infiltration around nephrostomy tubes in PCNL surgeries safely and are associated with minimal side effects.

Clinical Outcomes of Proton Beam Therapy for Unresectable Locally Advanced Pancreatic Cancer: A Single-Center Retrospective Study

PurposeWe retrospectively researched the treatment outcome of proton beam therapy (PBT) and assessed its efficacy for inoperable locally advanced pancreatic cancer (LAPC) at our institution. Materials and MethodsFifty-four patients (28 males and 26 females, median age 67 years of ranges from 40 to 88 years were diagnosed with unresectable stage III LAPC and administered PBT from April 2009 to March 2020. Either patients who could not complete PBT, or had new distant metastases during the treatment, or did not have enough follow-up time were excluded from this study. All patients were clinically staged based on the International Union of Cancer TNM staging system (UICC 8th edition) using CT, MRI, and PET, and were diagnosed as stage III (histologic type: eighteen adenocarcinoma patients, thirty-six clinically diagnosed patients). PBT was performed using the passive method, with a median total dose of 67.5 GyE (range: 50-77 GyE/25-35 fractions). Chemotherapy was used in combination during PBT in forty-six patients (85.2%). Overall survival (OS), local progression-free survival (LPFS), progression-free survival (PFS), and median overall survival time (MST) were analyzed by Kaplan-Meier and log-rank tests. Univariate and multivariate analyses were performed for the following factors: maximum standardized uptake value (SUVmax), ECOG-performance status (PS), tumor site, total irradiation dose, concurrent chemotherapy, and primary tumor site. Cutoff values for SUVmax and tumor diameter were estimated using receiver operating characteristic (ROC) curves and area under the curve (AUC) based on OS. Multivariate analysis was evaluated using the Cox proportional hazards models. Adverse events were evaluated using CTCAE ver. 5.0. ResultsThe median observation period was 17.4 months of ranges from 4.0 to 89.7 months. The median tumor diameter was 36.5 mm of ranges from 15 to 90 mm, the median SUVmax was 5.85 (range: 2.1-27.6), and their cutoff values were estimated to 37 mm and 4.8 mm, respectively. 1-, 2-year OS were 77.8%, 35.2% with MST 18.2 months, respectively and only one patient survived more than 5 years. 12 patients (22.2%) developed local recurrence, and 1-, 2-year LPFS rate were 89.7% and 74.5%, respectively; PFS at 1-year was 58.8%. PS score, Tumor site and irradiation dose were the prognostic factor related to OS that showed a significant difference. On the other hand, there was a significant difference in factors involved in LPFS, 96.7%/77.9% in the first year and 86.6%/54.4% in the second year in the groups with tumor dose ≥67.5 GyE and <67.5 GyE, respectively (p = 0.015). Treatment-related acute toxicities were neutropenia (Grade1/2/3:3.7%/11.1%/31.5%), leukopenia (Grade 1/2/3:1.8%/7.4%/20.4%), and thrombocytopenia (Grade 1/2:1.8%/7.4%), while the late effects including peptic ulcer were captured only grade2+. The late adverse events of Grade 3 or higher were not observed. ConclusionsPBT achieving 67.5 Gy combined with standard chemotherapy showed the excellent local control for unresectable LAPC. Total irradiation dose, Tumor site and PS score at an initial diagnosis could be important prognostic factors. In this study, the dose-effect relationship was found so an increase in dose should be considered to improve prognosis.

Effect of dapagliflozin on readmission and loop diuretics use in patients with acute heart failure: a retrospective propensity score-matched cohort study

BackgroundThe efficacy of dapagliflozin in patients with acute heart failure remains unclear.ObjectiveTo investigate the impact of dapagliflozin (DAPA) on loop diuretics use and 90-day readmission in patients with acute heart failure.MethodsIn a retrospective cohort study, patients diagnosed with acute heart failure or chronic heart failure with acute exacerbation admitted to Fuyang People’s Hospital from January 2021 to April 2023, this study used DAPA (at a dose of 10 mg once daily) in combination with standard treatment. The patients were divided into DAPA group and DAPA-Free group based on whether they used DAPA in acute heart failure. To minimize the influence of confounding factors and ensure comparability between groups, we used propensity score matching (PSM).ResultsA total of 399 patients were included, with 206 patients (51.63%) in the DAPA group and 193 patients (48.37%) in the DAPA-Free group. PSM produced 160 pairs. After PSM, there were no statistically significant differences between the DAPA and DAPA-Free groups in terms of readmission of all causes (16.88% vs. 18.12%, OR 0.9141, 95% CI 0.5385–1.552, log rank P = 0.739) or readmission for heart failure (11.88% vs. 15.0%, OR 0.9077, 95% CI 0.4441–1.469, log rank P = 0.484) after 90-day follow-up. Patients in the DAPA group had a lower mean daily dose of intravenous loop diuretics compared to the DAPA-Free group (20 mg/d vs. 30.00 mg/d, P<0.001), lower total loop diuretic dose during hospitalization (106.06 ± 31.23 mg vs. 144.50 ± 45.39 mg, P = 0.038) and a decreased number of diuretic types used (11.88% vs. 23.12%, P = 0.008).ConclusionsDAPA reduced the dose of intravenous loop diuretics. However, it did not improve all-cause readmission for 90 days or readmission for heart failure after discharge.

Assessing radon hazard in drinking water: A comprehensive approach integrating deterministic and probabilistic methods with water consumption routines

The research aimed to determine the spatiotemporal distribution patterns of radon activity concentrations in tap water of Yerevan city and assess radon-associated hazards using both deterministic and probabilistic approaches. This was accomplished by integrating one-year monitoring data of radon in water with water consumption habits among adult population clusters, which were identified through food frequency questionnaire in Yerevan.The study findings indicated variations in radon activity levels across administrative districts. The highest average activity concentrations were detected in Davtashen (7.07 Bq/L), while the lowest average was observed in Kanaker-Zeytun (1.57 Bq/L). The overall pattern of spatiotemporal variation during monitoring period revealed higher prevalence of radon in water in the northern and western parts of the city compared to the east and south, indicating different sources of drinking water. The radon-associated hazard assessment from water, using a deterministic approach (e.g., inhalation, ingestion, radon dissolution in blood, total effective dose), revealed values below the individual dose criterion (IDC) of 0.1 mSv/y. Monte Carlo simulation revealed a probability of exceeding IDC in specific water consumption-based groups. Residents of Yerevan who drink more than 3 L water daily with the highest observed activity concentration of 11.4 Bq/L, have an 86.26 % chance of exceeding IDC. Residents consuming 2.1 L water daily have a 7.02 % chance of exceeding IDC.The study highlights the importance of applied principles and methodologies for radon monitoring, particularly considering actual water consumption data and different risk assessment approaches. Considering the worst-case scenario results, it is recommended to keep tap water consumption up to 3 L per day, keeping the tap open longer to reduce radon levels. It also emphasizes the need for continued monitoring, given the variations in radon activity. The study provides valuable insights into radon exposure assessment, mitigation, and action plans in terms of water safety and public health.

National Cancer Database analysis of radiation therapy consolidation modality and dose for inoperable endometrial cancer

We utilized the National Cancer Database (NCDB) to evaluate trends and assess outcomes in radiation therapy (RT) boost modality and total dose among medically inoperable endometrial cancer (EC) patients with locoregional disease. Patients with International Federation of Gynecology and Obstetrics (FIGO) stage I - IIIC2 inoperable EC treated with RT ± chemotherapy were analyzed. Practice patterns compared external beam RT (EBRT) versus high-dose-rate brachytherapy (BT) boost and total RT dose (palliative: ≤3000 cGy, definitive low dose [DLD]: 4500 - 6249 cGy, definitive high dose [DHD]: ≥6250 cGy) over time. Kaplan-Meier method evaluated overall survival (OS) and Cox proportional hazard modeling assessed variables associated with OS. NCDB included 1755 total cases, of which 1209 received a radiotherapy boost. From 2004 to 2019, boost modality rates differed with increasing utilization of BT consolidation and a decreasing rate of palliation. Predictors of a palliative dose were stage III disease, Black race, N2 disease, and poorly or undifferentiated grade. Multivariable analysis found BT boost was associated with lower mortality compared to EBRT (HR: 0.81, CI: 0.68-0.97; p = 0.019). Mortality rates were higher for palliation versus DHD. Additional factors associated with inferior survival were increasing age, worse Charlson-Deyo score, higher T stage, higher N stage, and moderately, poorly, or undifferentiated grade. Utilization of BT boost for locoregionally confined, medically inoperable EC has increased since 2004. Brachytherapy consolidation remains an effective RT modality for medically inoperable EC, associated with lower mortality compared to EBRT consolidation.

Melphalan Dose in Combination With Fludarabine Affects Gastrointestinal Toxicity and Graft-Versus-Host Disease After Allogeneic Transplantation in Acute Myeloid Leukemia and Myelodysplastic Syndromes

Fludarabine (Flu) and melphalan (Mel) reduced-intensity conditioning is frequently used for allogenic hematopoietic cell transplant (allo-HCT) in patients with acute myeloid leukemia (AML) and myelodysplastic syndromes (MDS). However, there is limited evidence on the impact of Mel dosing on toxicities and clinical outcomes of allo-HCT. We retrospectively compared 8/8 HLA-matched donor allo-HCT outcomes of 345 patients with AML or MDS receiving total Mel dose of 100 mg/m2 (Mel-100, n = 62) versus 140 mg/m2 (Mel-140, n = 283) in combination with Flu. Median age at allo-HCT was 66 years and median follow-up was 36.5 months. For Mel-100 versus Mel-140 groups, any grade gastrointestinal (GI) toxicity rates were 40.3% versus 67.8% (P < .001), day 100 grade II to IV acute graft-versus-host disease (GVHD) rates were 21.0% versus 43.1% (P = .001) and 2-year chronic GVHD rates were 17.4% versus 27.1% (P = .033). In multivariable analysis, Mel-140 resulted in higher risks of GI toxicity (HR = 1.83, P = .013), grade II to IV acute GVHD (HR=2.35, P = .003), and moderate/severe chronic GVHD (HR = 3.13, P = .007). Total Mel dose had no independent impact on oral mucositis, nonrelapse mortality, relapse, relapse-free survival, and overall survival. While independent validation of our observation is warranted, our findings support using Mel-100 in combination with Flu to minimize allo-HCT toxicities and morbidities related to GVHD.

Retrospective review of surgeon administered transversus abdominis plane blocks at emergency caesarean.

Effective analgesics with minimal side effects are imperative for patient and neonate wellbeing postpartum. Post-caesarean section ultrasound-guided transversus abdominis plane (TAP) blocks have proven safety and efficacy. Surgical TAP blocks appear effective and require little time and equipment. No previous examination of surgical TAP blocks in patients having undergone emergency caesarean section has been undertaken. To investigate surgical TAP block and multimodal analgesic use during emergency caesarean section, the effect on surgical time, post-operative analgesia use, and admission length. We performed a retrospective review of 250 patients who underwent emergency caesarean in 2022. Surgical TAP blocks were performed with 20 mL of 0.375% ropivacaine either side. Primary outcomes included surgical time, length of admission, time to first request of rescue opiate, opiate use in first post-operative 24 h, total dose used during admission, and opiates prescribed on discharge. Ninety-six patients received surgical TAP blocks, and 154 did not. There were no statistically significant differences in the primary outcomes. Subgroup analyses were performed in patients who did not receive intrathecal morphine, body mass index over 30 kg/m2, for patients whom this was their first caesarean, and for TAP blocks versus local infiltration to the wound. There were no significant differences in the primary outcomes in these subgroups. Surgical TAP blocks did not prolong surgical time or decrease post-operative analgesia use or admission length in patients having undergone emergency caesarean. Patient-tailored multimodal analgesia is encouraged, although more research is needed.