A phase I clinical trial and molecular correlative studies were conducted to evaluate preclinical evidence for combinatorial activity of the proteasome inhibitor bortezomib, the epidermal growth ...factor receptor (EGFR) inhibitor cetuximab, and radiation therapy.
Patients with radiotherapy-naive stage IV or recurrent squamous cell carcinoma of the head and neck (SCCHN) were studied. Escalating doses of bortezomib (0.7, 1.0, and 1.3 mg/m²) were given intravenously twice weekly on days 1, 4, 8, and 11, every 21 days, with weekly cetuximab beginning 1 week prior and concurrently with intensity-modulated radiotherapy, delivered in 2 Gy fractions to 70 to 74 Gy. Molecular effects were examined in serial serum and SCCHN tumor specimens and the cell line UMSCC-1.
Seven patients were accrued before the study was terminated when five of six previously untreated patients with favorable prognosis oropharyngeal SCCHN progressed within 1 year (progression-free survival = 4.8 months; 95% CI, 2.6-6.9). Three patients each received bortezomib 0.7 or 1.0 mg/m², without dose-limiting toxicities; one patient treated at 1.3 mg/m² was taken off study due to recurring cetuximab infusion reaction and progressive disease (PD). Expected grade 3 toxicities included radiation mucositis (n = 4), dermatitis (n = 4), and rash (n = 1). SCCHN-related cytokines increased in serial serum specimens of patients developing PD (P = 0.029). Bortezomib antagonized cetuximab- and radiation-induced cytotoxicity, degradation of EGFR, and enhanced prosurvival signal pathway activation in SCCHN tumor biopsies and UMSCC-1.
Combining bortezomib with cetuximab and radiation therapy showed unexpected early progression, evidence for EGFR stabilization, increased prosurvival signaling, and SCCHN cytokine expression, warranting avoidance of this combination.
Background
Biologic treatments impose a large financial burden on healthcare payers. Subcutaneous formulations of trastuzumab and rituximab offer administration cost savings relative to the ...intravenous products through reduced preparation and infusion times. However, intravenous biosimilars have the potential to offset administration costs through lower drug costs.
Objective
The objective was to develop a budget impact model (BIM) from a payer’s perspective for the EU-5 countries (UK, France, Germany, Spain, Italy) to demonstrate the economic impact of using intravenous trastuzumab and rituximab biosimilars.
Methods
An incidence-based BIM was developed to estimate the net budget impact utilising epidemiology data from the literature, market research data on the use of relevant treatments in all approved indications, and corresponding costs. The budget impact was estimated for 5 years following introduction of the biosimilars.
Results
Analysis using the base-case results indicated that adoption of the biosimilars trastuzumab and rituximab would result in net cost savings. At year 5, the net budget saving ranged from €4.05 million to 303.86 million for rituximab and from €19 million to 172 million for trastuzumab. The cost saving could potentially extend treatment to 291–15,671 more patients with rituximab and 622–3688 more patients with trastuzumab.
Conclusion
This budget impact analysis emphasised that increased use of intravenous rituximab and trastuzumab biosimilars may result in cost savings from the payer’s perspective across the EU-5 countries.
Under the urban architecture paradigm for urban regeneration, the scope for research related to historical assets has broadened. Historical assets consist of private and public goods. The management ...responsibility of managing private goods is allocated to individuals, which has complicated the relationships among stakeholders and led to dissipation of assets and conflicts. To address this issue, this study focuses on community involvement in the conservation management of Kanazawa machiya, a Japanese traditional architecture style. This study was conducted in three phases. The first phase involved classification of the types of conservation management activities and the local actors related to Kanazawa machiya. In the second phase, the relationship between different stakeholders and the characteristics of conservation management activities were investigated using the DEMATEL method. Finally, it drew on the Power-Interest Grid to examine stakeholders′ performance capability. The case study of Kanazawa machiya indicates that the building-up of the conservation management system involves the local actors and development of their activities. It also shows an incremental shift away from a government-led system to one based on government-citizen cooperation. This study demonstrates the necessity of community involvement and civic activities for the conservation management of historical assets.
INTRODUCTION:
Depression is a common complication of pregnancy, but research is limited regarding its effect antepartum. This study assessed the relationship between maternal depressive symptoms and ...prenatal care utilization.
METHODS:
This retrospective cohort includes pregnant women who completed first- or second-trimester depression screening using the Edinburgh Postnatal Depression Scale (EPDS) between 2020 and 2021. Patient and pregnancy-related characteristics were compared between women who screened positive versus negative for depression. Multivariate logistic regression models were used to estimate odds of completing prenatal care milestones. The IRB approved a consent waiver.
RESULTS:
Of 718 women who completed the EPDS in early pregnancy, 85 (12%) screened positive for depression. A greater proportion of these women were younger (
P
=.034), unpartnered (
P
=.005), publicly insured (
P
=.013), had a history of substance use (
P
<.0001) or prior psychiatric diagnosis (
P
<.0001), and started prenatal care later (
P
=.002) than those who screened negative. Although there were no significant differences in total routine prenatal care visits (
P
=.123), the adjusted odds of completing third-trimester milestones including glucose tolerance testing (odds ratio OR 95% CI 0.596 0.364–0.975) and group B streptococcus testing (OR 95% CI 0.559 0.330–0.947) were lower among women who screened positive for depression. In addition, higher EPDS scores were positively correlated with number of labor and delivery triage visits (
r
=0.103,
P
=.006).
CONCLUSION:
Women who screen positive for depression during pregnancy are a socially vulnerable group at risk of starting prenatal care late, missing major milestones, and overusing nonroutine medical services. Early mental health screening and intervention in pregnancy may help improve prenatal outcomes.
Intubation has been associated with laryngeal injury that often resolves spontaneously without complication. We present a case of a child intubated for less than 48 hours, who presented with ...dysphonia and intermittent dyspnea two months after intubation due to epiglottic and vocal process granulomas. This is unusual in that multiple granulomas were found in the posterior glottis and supraglottis after short-term intubation. Our objective was to determine if there are risk factors for developing persistent post-intubation sequelae, including the delayed presentation and unusual location of post-intubation granulomas in our case.
Case report and systematic literature review.
Pubmed database, which is inclusive of MEDLINE, was used to perform a literature review with the search terms ((pediatric OR children OR neonatal OR infant) AND (laryngeal OR supraglottic) AND intubation AND (granuloma OR injury OR complication)). Only English language results were reviewed. Titles and abstracts from 379 results were reviewed. Full text was reviewed from all original studies which included human pediatric subjects and endoscopic examinations after endotracheal intubation.
In our case, laryngeal granuloma size reduced significantly after starting anti-reflux medications. The remainder was removed with laryngeal microdebrider with no recurrence at 3 weeks and 2.5 years post-operatively. Overall, 28 of the 379 studies reviewed identified evidence of laryngeal trauma due to intubation, however only 6 studies documented any type of supraglottic injury. Risk factors identified for developing post-intubation sequelae included intubation duration greater than 24 h; trauma to the larynx via various mechanisms including traumatic intubation, need for reintubation and tube changes, and increased movement while intubated; and presence of respiratory tract infection during intubation.
Trauma to the larynx during intubation should be avoided to minimize post-intubation injury in pediatric patients, by using appropriate intubation protocols, endotracheal tube size, and adequate sedation.
•A child rights education-program application enhanced children’s awareness of their four major rights.•The most important rights that Bangladesh children valued were general and development ...rights.•Considering children’s socio-cultural context within an educational approach is essential in official development assistance (ODA).
This study conducted a child rights education program for elementary school children in Bangladesh through official development assistance (ODA) and examined its effectiveness. The program’s contents focused on four major child rights and educated 842 elementary school children between 10 and 15 in Bangladesh. Elementary school teachers taught the program using tablets. The research, first, examined the program’s overall effect and, second, analyzed whether the children’s perception of child rights developed. Pre-and-post questionnaires about child rights recognition investigated whether children’s perceptions of their rights advanced. The results showed that the child rights education program in Bangladesh had an overall educational effect. Additionally, it confirmed that children’s perceptions of their four major rights increased significantly after participating in the program. The results led to two conclusions. First, the nation should expand the child rights education program and operate it qualitatively and quantitatively to support children around the world to lead healthy and happy lives. Second, it is vital to approach children’s socio-cultural contexts when operating educational programs for them through ODA.
Abstract Background and Aims Considering the natural decline of GFR with renal senescence, an age-adjusted estimated glomerular filtration rate (eGFR)-based chronic kidney disease (CKD) definition ...was recently proposed, which has been supported by that mortality risks start to increase at GFR <45 mL/min/1.73 m2 in older adults (≥65 years). However, the eGFR threshold for mortality and kidney outcomes in older patients with diabetes was less understood. We aimed to evaluate eGFR levels that raise the risk of mortality or end-stage kidney disease (ESKD) in older patients with diabetes. Method Older adult patients (≥65 years) with type 2 diabetes who visited our outpatient diabetes center during 2009 were retrospectively identified and followed up until 2017. Patients were categorized into four groups per their CKD-EPI equation-based eGFR: ≥60, 45–59, 30–44, and 15–29 mL/min/1.73 m2. Cox proportional hazard analysis for all-cause mortality and competing-risk analysis for ESKD (with a competing event of pre-ESKD death) were performed. Results Among 3,065 patients, 19%, 8%, and 2% of patients had eGFR 45–59, 30–44, and 15–29 mL/min/1.73 m2 at baseline, respectively. After adjusting various clinical covariates, including blood pressure, diabetes duration, urine albumin/creatinine ratio, HbA1c, serum cholesterol levels, and major comorbidities, patients with eGFR 30–44 and 15–29 mL/min/1.73 m2 had 1.51-fold (95% confidence interval CI 1.17–1.95, P < 0.001) and 2.66-fold (95% CI 1.87–3.79, P < 0.001) higher risks of mortality, respectively, whereas patients with eGFR 45–59 mL/min/1.73 m2 had a comparable risk (1.18, 95% CI 0.96–1.45, P = 0.127) to those with eGFR ≥60 mL/min/1.73 m2. Substitution hazard ratios for ESKD were 2.29 (95% CI 1.41–3.71, P = 0.001), 5.25 (95% CI 3.27–8.41, P < 0.001), and 16.74 (95% CI 9.73–28.80, P < 0.001) in patients with eGFR 45–59, 30–44, 15–29 mL/min/1.73 m2, respectively. In a subgroup of patients 75 or older (n = 800), patients with eGFR 45–59 mL/min/1.73 m2 exhibited comparable risks for both ESKD and mortality. Conclusion Reduced eGFR < 60 mL/min/1.73 m2 predicted an increased risk of ESKD in older patients with diabetes, suggesting that the current traditional eGFR threshold appears feasible. Thus, some high-risk individuals may be missed if age-adapted eGFR criteria with a lower eGFR threshold than 60 mL/min/1.73 m2 are universally applied for older adults ≥65 years.
Abstract Background and Aims Kidney immune cells and endothelial cells are involved in pathogenesis of kidney ischemia-reperfusion injury and potential therapeutic targets to improve kidney ...transplant outcomes. We hypothesized that dietary salt intake can change kidney immune cells and endothelial cells. Method C57BL/6 mice were treated with normal diet, low-salt diet, or high-salt diet. After 6 weeks of allocated diets, mice were euthanized, and their kidneys were collected. Leukocyte infiltration was assessed with CD45 immunohistochemistry. Lymphocytes were isolated from kidneys and were studied by flow cytometry. Human kidney transplant tissues obtained by a protocol biopsy at 2 weeks after kidney transplantation were stained with CD45, CD3, CD20, and CD31. Expression of each marker was quantified using an automated imaging analysis system and analyzed per donors’ pre-donation 24 h urine sodium levels. Induced pluripotent stem cell-derived endothelial cells (iPSC-ECs) from healthy individuals and end-stage kidney disease (ESKD) patients were treated with different sodium concentrations, and their proliferation was assessed. Results Kidneys from mice fed with high-salt diet had higher kidney leukocytes (CD45+) than those fed with normal diet (1.9 ± 0.3% vs 0.9 ± 0.1%, P = .043). Effector-memory CD4+ T cells (normal 44.2 ± 2.6%; low-salt 57.1 ± 3.5%, P = .020; high-salt 62.1 ± 2.5% of CD4+ T cells, P = .002) and mature B cells (70.0 ± 1.5%; 79.1 ± 1.4%, P = .001; 76.7 ± 1.6% of CD19+ cells, P = .015) increased by low-salt and high-salt diets, whereas naïve CD4+ T cells deceased (45.9 ± 2.1%; 32.7 ± 3.2%, P = .016; 27.8 ± 3.1% of CD4+ T cells, P = .001) in kidneys. Human kidney transplants from donors under low-salt diet showed lower total leukocytes (CD45+, 0.3 ± 0.1% vs 0.9 ± 0.3%, P = .019) with lower T and B cells (CD3+, 1.8 ± 0.2% vs 3.5 ± 0.4%, P<.001; CD20+, 0.8 ± 0.1% vs 2.1 ± 0.6%, P = .011) and higher capillary density (CD31+, 29.0 ± 2.2% vs 16.1 ± 1.8%, P = .009) compared to those from donors under high-salt diet. The proliferation of iPSC-ECs from healthy individuals and ESKD patients after hypoxia was reduced under higher sodium concentrations. Conclusion High-salt and low-salt diets affect kidney immune cell compositions and numbers as well as endothelial cells. Reconstitution of kidney microenvironment by modifying dietary salt intake could be a novel approach to improve kidney transplant outcomes.
A thermal-runaway model of lithium-ion battery is developed by devising a resistive heating that includes short circuit current and integrating it with existing electrochemical and exothermic ...reaction model of lithium-ion battery. With the developed model, a guideline for designing lithium-ion battery is suggested to delay onset of thermal-runaway. First and foremost, the simulation result obtained from developed mathematical model confirms that thermal-runaway is retarded when the area of heat transfer is augmented in the cells of same volume and capacity. Next, it is also demonstrated that, under the simulation condition in which the loading level of active materials is set as a design variable, if short circuit resistance is same, thermal-runaway occurs in a lithium-ion battery with high loading level whereas thermal-runaway do not occur when the loading level is low. Assuming the same area of electrical short, thermal-runaway occurs when cathode active material of 619 J/g is used, but thermal-runaway does not occur with the cathode active material of 429 J/g. If short circuit resistance is same, a cell of which the internal resistance equals 0.025 Ω drives itself into thermal-runaway, while cells with higher internal resistance, i.e. 0.03 Ω, do not.
•A thermal-runaway model is developed with electrochemical and reaction model.•A thermal-runaway model is quantitatively matched with the experimental results.•A guideline for designing is suggested to delay onset of thermal-runaway.•A short-circuit model is developed with short-circuit resistance and ohm's law.
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