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Journal of Affective Disorders Jun 2024Cariprazine has emerged as a promising augmenting treatment agent for unipolar depression and as a monotherapy option for bipolar depression. We evaluated cariprazine's...
BACKGROUND
Cariprazine has emerged as a promising augmenting treatment agent for unipolar depression and as a monotherapy option for bipolar depression. We evaluated cariprazine's efficacy in treating acute major depressive episodes in individuals with major depressive disorder (MDD) or bipolar disorder.
METHODS
A systematic review was conducted on MEDLINE, Embase, PyscInfo, Scopus and Web of Science, ClinicalTrials.gov and ScanMedicine. Study quality was assessed using the RoB 2 tool. Pairwise and dose-response meta-analyses were conducted with RStudio. Evidence quality was assessed with GRADE.
RESULTS
Nine RCTs meeting inclusion criteria encompassed 4877 participants. Cariprazine, compared to placebo, significantly reduced the MADRS score (MD = -1.49, 95 % CI: -2.22 to -0.76) and demonstrated significantly higher response (RR = 1.21, 95 % CI: 1.12 to 1.30) and remission (RR = 1.19, 95 % CI: 1.06 to 1.34) rates. Subgroup analysis unveiled statistically significant reductions in MADRS score in MDD (MD = -1.15, 95 % CI: -2.04 to -0.26) and bipolar I disorder (BDI) (MD = -2.53, 95 % CI: -3.61 to -1.45), higher response rates for both MDD (RR = 1.19, 95 % CI: 1.08 to 1.31) and BDI (RR = 1.27, 95 % CI: 1.10 to 1.46), and higher remission rates only for BDI (RR = 1.41, 95 % CI: 1.24 to 1.60). A higher rate of treatment discontinuation due to adverse events was observed.
LIMITATIONS
Reliance solely on RCTs limits generalisability; strict criteria might not reflect real-world diversity.
CONCLUSIONS
Cariprazine demonstrates efficacy in treating major depressive episodes, although variations exist between MDD and BDI and tolerability may be an issue.
PubMed: 38942207
DOI: 10.1016/j.jad.2024.06.099 -
Radiotherapy and Oncology : Journal of... Jun 2024To investigate quality assurance (QA) techniques for in vivo dosimetry and establish its routine uses for proton FLASH small animal experiments with a saturated monitor...
PURPOSE
To investigate quality assurance (QA) techniques for in vivo dosimetry and establish its routine uses for proton FLASH small animal experiments with a saturated monitor chamber.
METHODS AND MATERIALS
227 mice were irradiated at FLASH or conventional (CONV) dose rates with a 250 MeV FLASH-capable proton beamline using pencil beam scanning to characterize the proton FLASH effect on abdominal irradiation and examining various endpoints. A 2D strip ionization chamber array (SICA) detector was positioned upstream of collimation and used for in vivo dose monitoring during irradiation. Before each irradiation series, SICA signal was correlated with the isocenter dose at each delivered dose rate. Dose, dose rate, and 2D dose distribution for each mouse were monitored with the SICA detector.
RESULTS
Calibration curves between the upstream SICA detector signal and the delivered dose at isocenter had good linearity with minimal R values of 0.991 (FLASH) and 0.985 (CONV), and slopes were consistent for each modality. After reassigning mice, standard deviations were less than 1.85 % (FLASH) and 0.83 % (CONV) for all dose levels, with no individual subject dose falling outside a ± 3.6 % range of the designated dose. FLASH fields had a field-averaged dose rate of 79.0 ± 0.8 Gy/s and mean local average dose rate of 160.6 ± 3.0 Gy/s. In vivo dosimetry allowed for the accurate detection of variation between the delivered and the planned dose.
CONCLUSION
In vivo dosimetry benefits FLASH experiments through enabling real-time dose and dose rate monitoring allowing mouse cohort regrouping when beam fluctuation causes delivered dose to vary from planned dose.
PubMed: 38942121
DOI: 10.1016/j.radonc.2024.110404 -
Medical Physics Jun 2024An ultra-high dose rate (UHDR) electron accelerator for FLASH radiotherapy (RT) produces very intense bremsstrahlung by the interaction of the electron beam with objects...
BACKGROUND
An ultra-high dose rate (UHDR) electron accelerator for FLASH radiotherapy (RT) produces very intense bremsstrahlung by the interaction of the electron beam with objects both inside and outside of the accelerator. The bremsstrahlung dose per pulse is typically 1-2 orders of magnitude larger than that of conventional RT x-ray treatment of the same energy, and for electron energies above 10 MeV, the bremsstrahlung produces substantially more induced radioactivity outside the accelerator than for conventional RT. Therefore, a thorough radiation safety assessment is mandatory prior to the operation of a UHDR electron accelerator.
PURPOSE
To evaluate the radiation safety of a prototype FLASH-enabled Varian TrueBeam accelerator and to develop a general framework for assessment of all key radiation safety properties of a UHDR electron accelerator for FLASH RT.
METHODS
Production of bremsstrahlung and induced radioactivity by a UHDR electron accelerator is modeled by various analytical methods. The analytical modeling is compared with National Institute of Standards and Technology (NIST) bremsstrahlung yield data as well as measurements of primary bremsstrahlung outside the bunker and induced radioactivity of irradiated thick targets for a FLASH-enabled 16 MeV Varian TrueBeam electron accelerator. In addition, the analytical modeling is complemented by measurements of secondary bremsstrahlung inside/outside the bunker and neutrons at the maze entrance.
RESULTS
Calculated bremsstrahlung yields deviate maximum 8.5% from NIST data, and all measurements of primary bremsstrahlung and induced radioactivity agree with calculations, validating the analytical tools. In addition, it is found that scattering foil bremsstrahlung dominates primary bremsstrahlung and the main source of secondary bremsstrahlung is the irradiated object outside the accelerator. It follows that primary and secondary bremsstrahlung outside the bunker can be calculated using the same simple formalism as that used for conventional RT. Measured primary bremsstrahlung tenth-value layers for concrete of the simple formalism are in good agreement with NCRP and IAEA data, while measured secondary bremsstrahlung tenth-value layers for concrete are considerably lower than NCRP and IAEA data. All calculations and measurements form a general framework for assessment of all key radiation safety properties of a UHDR electron accelerator.
CONCLUSIONS
The FLASH-enabled Varian TrueBeam accelerator is safe for normal operation (max. 99 pulses per irradiation) in a bunker designed for at least 15 MV conventional x-ray treatment unless the UHDR workload is much larger than the x-ray workload. A similar finding applies to other UHDR electron accelerators. However, during beam tuning, radiation survey, or other tests with extended irradiation time, the UHDR workload may become very large, necessitating the implementation of additional safety measures.
PubMed: 38941539
DOI: 10.1002/mp.17245 -
European Journal of Pediatrics Jun 2024The purpose of this study is to evaluate the efficacy and safety of belimumab combined with the standard regimen in treating children with active lupus nephritis. This...
UNLABELLED
The purpose of this study is to evaluate the efficacy and safety of belimumab combined with the standard regimen in treating children with active lupus nephritis. This single-center, retrospective cohort study used clinical data of children with newly active lupus nephritis hospitalized in the Department of Nephrology between December 2004 and February 2023. Patients were divided into a belimumab or traditional treatment group according to whether or not they received belimumab. Renal remission and recurrence rates and glucocorticoid dose were compared between groups. Forty-seven children (median age 11 years) were enrolled, including 30 and 17 children in the traditional treatment and belimumab groups, respectively. The Systemic Lupus Erythematosus Disease Activity Index-2000 (SLEDAI-2000) score of children in the belimumab group (23.59 ± 7.78) was higher than that in the traditional treatment group (19.13 ± 6.10) (P = 0.035). The two groups showed no significant difference in the frequency of pyuria, gross hematuria, and the levels of 24-h proteinuria and estimated glomerular filtration rate. The complement C3/C4 in the belimumab group recovered faster than that in the traditional treatment group (P < 0.05). There were no between-group differences in the complete renal remission rate at 6 or 12 months (P = 0.442, P = 0.759). There were no between-group differences in 1-year recurrence rate (P = 0.303). Furthermore, 6 and 12 months after treatment, glucocorticoid doses were lower in the belimumab than the traditional treatment group (17.87 ± 6.96 mg/d vs. 27.33 ± 8.40 mg/d, P = 0.000; 10.00 (5.3) mg/d vs. 13.75 (10.0) mg/d, P = 0.007), respectively.
CONCLUSION
With an equivalent renal remission rate, belimumab combined with the standard traditional regimen might promote the tapering of glucocorticoids, and the incidence of adverse events is low.
WHAT IS KNOWN
• Belimumab is documented as an adjunctive treatment with systemic lupus erythematosus (c-SLE) LN with efficacy. • Due to the paucity of studies, its effects and side effects in children with LN remain unclear.
WHAT IS NEW
• This single-center, retrospective cohort study evaluated the efficacy and safety of belimumab combined with the standard regimen in treating children with proliferative LN. • Belimumab combined with the standard traditional treatment might promote the tapering of glucocorticoids, while exhibiting a low occurrence of adverse events.
PubMed: 38940925
DOI: 10.1007/s00431-024-05662-9 -
Clinical Cancer Research : An Official... Jun 2024Recurrent small cell lung cancer (SCLC) has few effective treatments. The EZH2-SLFN11 pathway is a driver of acquired chemoresistance that may be targeted.
PURPOSE
Recurrent small cell lung cancer (SCLC) has few effective treatments. The EZH2-SLFN11 pathway is a driver of acquired chemoresistance that may be targeted.
PATIENTS AND METHODS
This phase I/II trial investigated valemetostat, an EZH1/2 inhibitor, with fixed-dose irinotecan in patients with recurrent SCLC. Phase I primary objectives were to assess safety and a recommended phase II dose (RP2D). The phase II primary objective was to determine overall response rate (ORR), with secondary objectives of duration of response (DoR), progression-free survival (PFS) and overall survival (OS). Immunohistochemistry of pre- and on-treatment tumor biopsies and pharmacokinetics analysis were performed.
RESULTS
Twenty-two patients enrolled (phase I, n=12; phase II n=10); one withdrew consent prior to treatment. Three dose-limiting toxicities (DLTs) in dose-escalation resulted in valemetostat 100 mg orally daily selected as RP2D. Among 21 toxicity-evaluable patients, the most frequent (≥20%) treatment-related adverse events were diarrhea, fatigue, nausea, and rash; 3 patients discontinued treatment for toxicity. In phase II, 3/10 patients experienced DLTs triggering a stopping rule. The ORR was 4/19 (21%, 95% CI 6 to 46%). The median DoR, PFS and OS were 4.6 mo, 2.2 mo (95% CI 1.3 to 7.6 mo) and 6.6 mo (95% CI 4.3 to not reached). SLFN11, EZH2 and SCLC subtyping markers did not correlate with response. MHC-I protein expression increased in 4/4 patients with paired biopsies, including 3/3 responders; two responders demonstrated subtype switching on treatment.
CONCLUSIONS
Valemetostat and irinotecan was not tolerated but demonstrated efficacy in recurrent SCLC. Valemetostat may warrant further investigation in SCLC.
PubMed: 38940666
DOI: 10.1158/1078-0432.CCR-23-3383 -
International Journal of Molecular... Aug 2024Osteosarcoma (OS) is a highly malignant primary bone neoplasm that is the leading cause of cancer‑associated death in young people. GNE‑477 belongs to the second...
Osteosarcoma (OS) is a highly malignant primary bone neoplasm that is the leading cause of cancer‑associated death in young people. GNE‑477 belongs to the second generation of mTOR inhibitors and possesses promising potential in the treatment of OS but dose tolerance and drug toxicity limit its development and utilization. The present study aimed to prepare a novel HO stimulus‑responsive dodecanoic acid (DA)‑phenylborate ester‑dextran (DA‑B‑DEX) polymeric micelle delivery system for GNE‑477 and evaluate its efficacy. The polymer micelles were characterized by morphology, size and critical micelle concentration. The GNE‑477 loaded DA‑B‑DEX (GNE‑477@DBD) tumor‑targeting drug delivery system was established and the release of GNE‑477 was measured. The cellular uptake of GNE‑477@DBD by three OS cell lines (MG‑63, U2OS and 143B cells) was analyzed utilizing a fluorescent tracer technique. The hydroxylated DA‑B was successfully grafted onto dextran at a grafting rate of 3%, suitable for forming amphiphilic micelles. Following exposure to HO, the DA‑B‑DEX micelles ruptured and released the drug rapidly, leading to increased uptake of GNE‑477@DBD by cells with sustained release of GNE‑477. The experiments, including MTT assay, flow cytometry, western blotting and RT‑qPCR, demonstrated that GNE‑477@DBD inhibited tumor cell viability, arrested cell cycle in G1 phase, induced apoptosis and blocked the PI3K/Akt/mTOR cascade response. , through the observation of mice tumor growth and the results of H&E staining, the GNE‑477@DBD group exhibited more positive therapeutic outcomes than the free drug group with almost no adverse effects on other organs. In conclusion, HO‑responsive DA‑B‑DEX presents a promising delivery system for hydrophobic anti‑tumor drugs for OS therapy.
Topics: Animals; Humans; Micelles; Osteosarcoma; Hydrogen Peroxide; Cell Line, Tumor; Dextrans; Mice; Lauric Acids; Apoptosis; Polymers; Xenograft Model Antitumor Assays; Bone Neoplasms; Mice, Nude; Antineoplastic Agents; Mice, Inbred BALB C; Male; TOR Serine-Threonine Kinases
PubMed: 38940336
DOI: 10.3892/ijmm.2024.5393 -
Annals of Agricultural and... Jun 2024Ultraviolet light in the UV-C band is known as germicidal radiation and was widely used for both sterilization of the equipment and creation of a sterile environment....
INTRODUCTION AND OBJECTIVE
Ultraviolet light in the UV-C band is known as germicidal radiation and was widely used for both sterilization of the equipment and creation of a sterile environment. The aim of the study is to assess the effectiveness of inactivation of microorganisms deposited on surfaces with various textures by UV-C radiation disinfection devices.
MATERIAL AND METHODS
Five microorganisms (3 bacteria, virus, and fungus) deposited on metal, plastic, and glass surfaces with smooth and rough textures were irradiated with UV-C light emitted by low-pressure mercury lamp and ultraviolet emitting diodes (LEDs), from a distance of 0.5 m, 1 m, and 1.5 m to check their survivability after 20-minute exposure.
RESULTS AND CONCLUSIONS
Both tested UV-C sources were effective in inactivation of microorganisms; however, LED emitter was more efficient in this respect than the mercury lamp. The survival rate of microorganisms depended on the UV-C dose, conditioned by the distance from UV-C source being the highest at 0.5 m and the lowest at 1.5 m. For the tested microorganisms, the highest survival rate after UV-C irradiation was usually visible on glass and plastic surfaces. This observation should be considered in all environments where the type of material (from which the elements of technical equipment are manufactured and may be contaminated by specific activities) is important for maintaining the proper level of hygiene and avoiding the unwanted and uncontrolled spread of microbiological pollution.
Topics: Ultraviolet Rays; Disinfection; Fungi; Bacteria; Viruses; Surface Properties; Microbial Viability; Plastics; Glass
PubMed: 38940114
DOI: 10.26444/aaem/189695 -
Acta Medica Philippina 2024This study aims to report the incidence and characteristics of breakthrough infections among medical students in the first Philippine private medical school that resumed...
OBJECTIVE
This study aims to report the incidence and characteristics of breakthrough infections among medical students in the first Philippine private medical school that resumed limited face-to-face classes and clinical rotations from July to December 2021.
METHODS
This is a descriptive study using secondary worksheet from multiple-source records review of breakthrough infections among medical students from July to December 2021.
RESULTS
Among the 837 vaccinated medical students, 23 (2.7%) experienced COVID-19 breakthrough infections. Of these, 9 were male and 14 were female. Four were asymptomatic and 19 were symptomatic. Of the 19 symptomatic, 18 had mild and 1 had severe disease. Mild infections presented with upper respiratory tract symptoms. Duration of symptoms ranged from 4 to 27 days with an average of 10 days. Timing of breakthrough infections ranged from 35 to 212 days after the second dose of COVID-19 vaccine with a mean of 86 days. Contact with confirmed cases was reported in 14 of 23 cases, 13 were from household members and none within the SLICE and CLARO programs.
CONCLUSION
Our study showed that even in the midst of the Delta surge, low breakthrough infection rate with mostly mildly symptomatic cases and no case transmissions within the SLICE and CLARO programs are possible with vaccination, regular health surveillance, and strict adherence to minimum health protocols.
PubMed: 38939856
DOI: 10.47895/amp.vi0.6523 -
Very Elderly Patients With Atrial Fibrillation Treated With Edoxaban: Impact of Frailty on Outcomes.JACC. Advances Sep 2023Age and frailty are associated with underuse of anticoagulation in elderly patients with atrial fibrillation (AF).
BACKGROUND
Age and frailty are associated with underuse of anticoagulation in elderly patients with atrial fibrillation (AF).
OBJECTIVES
This study aimed at assessing major clinical outcomes in very elderly patients with AF treated with recommended dose edoxaban and look for a possible relation with frailty measured by a validated score.
METHODS
This prospective multicenter cohort study enrolled consecutive very elderly (age ≥80 years) anticoagulation-naïve patients starting recommended doses of edoxaban. Upon entry into the study, patients were categorized into nonfrail, prefrail and frail with the SHARE-FI (Survey of Health, Ageing, and Retirement in Europe-Frailty Index) score. The primary outcome was a composite incidence of stroke/systemic embolism, major bleeding, clinically relevant nonmajor bleeding, and death between frail and fitter patients over 2 years follow-up. Secondary outcomes were frailty-related incidence of the individual components part of the composite outcome.
RESULTS
Of the 180 screened patients, 176 were enrolled in the study. Of these, 58 (32.9%) were frail, 35 (19.8%) prefrail, and 83 (47.2%) nonfrail. The composite outcome occurred in 49 patients (18.9% per patient-year). No difference in the primary endpoint between frail and fitter patients (incidence rate ratio: 1.2; 95% CI: 0.6-2.2) was observed. On multivariable analysis, anemia was significantly related to the primary outcome (HR: 3.6; 95% CI: 1.8-7.3; < 0.001), while frailty was not (frail vs nonfrail HR: 0.9; 95% CI: 0.5-1.8). No difference across frailty categories of the individual components of composite events was observed, except for death.
CONCLUSIONS
Anticoagulation with recommended dose edoxaban is feasible in very elderly patients with AF even if frail. (ESCAPE [Edoxaban and Frailty in Senior Individuals]; NCT03524924).
PubMed: 38939480
DOI: 10.1016/j.jacadv.2023.100569 -
JACC. Advances Mar 2024Patients with likely pathogenic/pathogenic desmoplakin () variants are poorly characterized. Some of them meet diagnostic criteria for arrhythmogenic right ventricular...
BACKGROUND
Patients with likely pathogenic/pathogenic desmoplakin () variants are poorly characterized. Some of them meet diagnostic criteria for arrhythmogenic right ventricular cardiomyopathy (ARVC), but it is unclear how risk stratification strategies for ARVC perform in this setting.
OBJECTIVES
The purpose of this study was to characterize arrhythmic outcomes and to test the performance of the recently validated ARVC risk calculator in patients with likely pathogenic/pathogenic variants fulfilling definite 2010 ARVC Task Force Criteria (-TFC+).
METHODS
-TFC+ patients were enrolled from 20 institutions across 3 continents. Ventricular arrhythmias (VA), defined as a composite of sustained ventricular tachycardia (VT), appropriate implantable cardioverter defibrillator therapies, and ventricular fibrillation/sudden cardiac death events in follow-up, were reported as the primary outcome. We tested the performance of the ARVC risk calculator for VA prediction, reporting c-statistics.
RESULTS
Among 252 -TFC+ patients (age 39.6 ± 16.9 years, 35.3% male), 94 (37.3%) experienced VA over 44.5 [IQR: 19.6-78.3] months. Patients with left ventricle involvement (n = 194) were at higher VA risk (log-rank = 0.0239). History of nonsustained VT (aHR 2.097; = 0.004) showed the strongest association with VA occurrence during the first 5-year follow-up. Neither age ( = 0.723) nor male sex ( = 0.200) was associated with VAs at follow-up. In 204 patients without VA at diagnosis, incident VA rate was high (32.8%; 7.37%/y). The ARVC risk calculator performed poorly overall (c-statistic 0.604 [0.594-0.614]) and very poorly in patients with left ventricular disease (c-statistic 0.558 [0.556-0.560]).
CONCLUSIONS
-TFC+ patients are at substantial risk for VAs. The ARVC risk calculator performs poorly in -TFC+ patients suggesting need for a gene-specific risk algorithm. Meanwhile, -TFC+ patients with nonsustained VT should be considered as high-risk.
PubMed: 38938828
DOI: 10.1016/j.jacadv.2024.100832