We conducted a pediatric phase I trial of the vascular endothelial growth factor (VEGF)-neutralizing antibody bevacizumab (BV). Primary aims included estimating the maximum-tolerated dose (MTD) and ...determining the dose-limiting toxicities (DLTs), pharmacokinetics, and biologic effects of BV in children with cancer.
BV (5, 10, 15 mg/kg) was administered intravenously every 2 weeks in 28-day courses to children with refractory solid tumors.
Twenty-one patients enrolled, 20 (median age, 13 years) were eligible, and 18 completed one course and were fully assessable for toxicity. A total of 67 courses were administered (median, three courses per patient; range, one to 16 courses). Treatment was well tolerated with no DLTs observed. Non-DLTs included infusional reaction, rash, mucositis, proteinuria, and lymphopenia. Increases in systolic and diastolic blood pressure not meeting Common Terminology Criteria for Adverse Events (CTCAEv3) pediatric-specific criteria for hypertension were observed. There was no hemorrhage or thrombosis. Growth perturbation was not detected in a limited sample over the first course. The serum exposure to BV as measured by area under the concentration-time curve (AUC) seemed to increase in proportion to dose. The median clearance of BV was 4.1 mL/d/kg (range, 3.1 to 15.5 mL/d/kg), and the median half-life was 11.8 days (range, 4.4 to 14.6 days). No objective responses were observed. Exploratory analyses on circulating endothelial mobilization and viability are consistent with the available adult data.
BV is well tolerated in children. Phase II pediatric studies of BV in combination with chemotherapy in dosing schedules similar to adults are planned.
Accurate assessment of apple fruit maturity at harvest is required since fruit harvested too early or too late are susceptible to physiological disorders or excessive softening during subsequent ...storage. Biological markers of early fruit maturity allow forecasting of optimal harvest time, contributing significant industry value through more accurate management of harvest logistics. This study investigated the changes in cortex of apple (Malus x domestica ‘Royal Gala’) fruit at four harvests: very early (H1), early (H2), commercial (H3) and late (H4), using a combination of transcriptomics, metabolomics, hormone abundances and enzyme activity profiles. Harvest times were discriminated based on several sets of variates, showing that metabolism was very active within this short time period. Good discrimination between H1 and H2 and between H2 and H3 was observed in the declining abundance of a range of photosystem transcripts and the increasing abundance of early ripening markers. Degradation of the photosynthetic apparatus was correlated with ethylene production. Multi-omics analysis using mixOmics identified groups of variates whose abundance declined or increased during the harvest period, and strong correlations between components of different pathways were evident. We identify a suite of biomarkers, including Chl a/b binding protein of LHCII, Xyloglucan glycosyltransferase 5, PG1, ACO1, internal ethylene concentration and starch pattern index, for orchardists to accurately predict harvest time several weeks in advance, thus providing time to mobilise the necessary logistical resources.
•Apple fruit maturity around the harvest period was assessed using multi-omics.•MixOmics and DIABLO was used to identify biomarkers of apple fruit maturity.•CAB of LHCII, XyGT5, PG1, ACO1, IEC and SPI were identified as best biomarkers.•These biomarkers can be deployed to predict harvest time several weeks in advance.•Advance notice of optimal harvest provides time to mobilise logistical resources.
Accurate determination of kiwifruit maturity in the first half of the harvest window is crucial in predicting storage risk, since early-harvested fruit are more susceptible to disorders and rots ...during extended cold storage. Maturity estimations are usually based on soluble solids content (SSC), but SSC alone is unreliable at early harvest times, necessitating the need for more precise markers. To address this, we performed multi-omics on harvested, yellow-fleshed kiwifruit at four chronological ages based on days after anthesis, namely early harvest (H1), early-mid (H2), late-mid (H3) and late harvest (H4), across two seasons from the same orchard. Analysis of phenotype, transcriptome, metabolome, proteome, hormone concentrations and enzyme activity profiles identified discriminating features within the datasets that separated harvest times, particularly in the first half of the harvest window. Strong seasonal variability was observed. The most reliable variates for maturity estimation were found in the transcriptome, and two transcripts with sharply decreasing abundance during early harvest (Aquaporin TIP4-1 and MYB10) and three transcripts with sharply increasing abundance during later harvest (β-Amylase 3.2, Pectinesterase inhibitor protein and α-Terpineol synthase) with relative seasonal stability were identified. In a different season we used these five potential biomarkers in combination with SSC as a predictive tool. This allowed precise assessment of the maturity stage of fruit in the first half of the harvest window from 12 orchards in four geographical regions, and accurate prediction of their storage outcome.
•Early-season kiwifruit are more susceptible to storage disorders and rots.•Measuring SSC alone often gives insufficient information about maturity.•MixOmics was used to identify at-harvest biomarkers of fruit maturity.•TIP4-1, MYB10, β-Amylase 3.2 and PMEi were identified as best biomarkers.•Application of these biomarkers may assist in predicting storage performance.
Summary
The first uterus transplantation was performed in 2000. As key milestones are reached (long‐lasting graft survival in 2011, and first birth from a transplanted womb in 2014), the ethical ...debate around uterus transplant evolves. We performed a systematic review of articles on uterus transplantation. Ethical themes were extracted and categorized according to four bioethical principles. Papers were divided into time periods separated by key events in uterus transplant history: Phase I (first technical achievement, 2002–2011), Phase II (clinical achievement, 2012–2014), and Phase III (after the first childbirth, 2015–2018). Eighty‐one articles were included. The majority of ethics papers were published in Phase III (65%, P < 0.0001), that is after the first birth. Eighty percent of papers discussed nonmaleficence making it the most discussed principle. The first birth acted as a pivotal point: nonmaleficence was discussed by a lower proportion of articles (P = 0.0073), as was beneficence (P = 0.0309). However, discussion of justice increased to become the most discussed principle of the time period (P = 0.0085). The ethical debate surrounding uterus transplantation has evolved around landmark events that signify scientific progress. As safety and efficacy become evident, the focus of ethical debate shifts from clinical equipoise to socioeconomic challenges and equitable access to uterus transplantation.
When first conceived, antiangiogenic therapy for cancer offered the possibility of universal efficacy, low toxicity, and little possibility of resistance. Blockade of the vascular endothelial growth ...factor (VEGF) pathway has yielded the most promising results both in animal models and in patients. However, resistance to VEGF blockade has been found even when given in combination with chemotherapy or other antiangiogenic agents. This resistance is associated with remodeled vasculature and with increased expression of angiogenic factors, such as PDGF-B and angiopoietin-1, which may contribute to vessel stabilization. Future efforts must be directed towards the identification of factors associated with vascular remodeling in order to improve the efficacy of antiangiogenic therapy.
Le Fort-based, maxillofacial allotransplantation is a reconstructive alternative gaining clinical acceptance. However, the vast majority of single-jaw transplant recipients demonstrate ...less-than-ideal skeletal and dental relationships, with suboptimal aesthetic harmony. The purpose of this study was to investigate reproducible cephalometric landmarks in a large-animal model, where refinement of computer-assisted planning, intraoperative navigational guidance, translational bone osteotomies, and comparative surgical techniques could be performed.
Cephalometric landmarks that could be translated into the human craniomaxillofacial skeleton, and that would remain reliable following maxillofacial osteotomies with midfacial alloflap inset, were sought on six miniature swine. Le Fort I- and Le Fort III-based alloflaps were harvested in swine with osteotomies, and all alloflaps were either autoreplanted or transplanted. Cephalometric analyses were performed on lateral cephalograms preoperatively and postoperatively. Critical cephalometric data sets were identified with the assistance of surgical planning and virtual prediction software and evaluated for reliability and translational predictability.
Several pertinent landmarks and human analogues were identified, including pronasale, zygion, parietale, gonion, gnathion, lower incisor base, and alveolare. Parietale-pronasale-alveolare and parietale-pronasale-lower incisor base were found to be reliable correlates of sellion-nasion-A point angle and sellion-nasion-B point angle measurements in humans, respectively.
There is a set of reliable cephalometric landmarks and measurement angles pertinent for use within a translational large-animal model. These craniomaxillofacial landmarks will enable development of novel navigational software technology, improve cutting guide designs, and facilitate exploration of new avenues for investigation and collaboration.
Transgender women (TW) experience significant inequities in healthcare access and health disparities compared to cisgender populations. Access to non-transition related healthcare is understudied ...among TW. We aimed to assess the association between access to care and gender minority stress and resilience factors among TW living with and without HIV in eastern and southern United States.
This study was a cross-sectional analysis of baseline data drawn from a cohort of 1613 adult TW from the LITE Study. The cohort permitted participation through two modes: a site-based, technology-enhanced mode and an exclusively online (remote) mode. Exploratory and confirmatory factor analyses determined measurement models for gender minority stress, resilience, and healthcare access. Structural equation modeling was used to assess the relationships between these constructs. Models were evaluated within the overall sample and separately by mode and HIV status.
Higher levels of gender minority stress, as measured by anticipated discrimination and non-affirmation were associated with decreased access to healthcare. Among TW living with HIV, higher levels of anticipated discrimination, non-affirmation, and social support were associated with decreased healthcare access. Among TW living without HIV in the site-based mode, resilience was positively associated with positive healthcare experiences and inversely associated with barriers to healthcare access. Among TW living without HIV in the online mode, anticipated discrimination was associated with barriers to healthcare access; resilience was positively associated with positive healthcare experiences and inversely associated with barriers to healthcare access.
Gender minority stress was associated with increased barriers to healthcare access among TW in the US, regardless of HIV status. Resilience factors did not mediate this effect. Interventions aiming to increase healthcare access among TW can be aided by efforts to mitigate drivers of gender minority stress and improve patient experiences in healthcare facilities.
The COVID-19 pandemic has exacted a physical and mental health toll on health care and hospital workers (HHWs). To provide COVID-19 care, HHWs expected health care institutions to support equipment ...and resources, ensure safety for patients and providers, and advocate for employees' needs. Failure to do these acts has been defined as institutional betrayal. Using a mixed-methods approach, this study aimed to explore the experience of institutional betrayal in HHWs serving COVID-19 patients and the associations between self-reported institutional betrayal and both burnout and career choice regret. Between July 2020 and January 2021, HHWs working in an urban U.S. health care system participated in an online survey (n = 1,189) and semistructured interview (n = 67). Among 1,075 quantitative participants, 57.8% endorsed institutional betrayal. Qualitative participants described frustration when the institution did not prioritize their safety while reporting they perceived receiving inadequate compensation from the system and felt that leadership did not sufficiently respond to their needs. Participants who endorsed prolonged breaches of trust reported more burnout and stronger intent to quit their job. Quantitatively, institutional betrayal endorsement was associated with 3-fold higher odds of burnout, aOR = 2.94, 95% CI 2.22, 3.89, and 4-fold higher odds of career choice regret, aOR = 4.31, 95% CI 3.15, 5.89, compared to no endorsement. Developing strategies to prevent, address, and repair institutional betrayal in HHWs may be critical to prevent and reduce burnout and increase motivation to work during and after public health emergencies.
Abstract
Background
The objective of this study was to determine the safety, tolerability, and distribution of MTX110 (aqueous panobinostat) delivered by convection-enhanced delivery (CED) in ...patients with newly diagnosed diffuse intrinsic pontine glioma (DIPG) who completed focal radiation therapy (RT).
Methods
Patients with DIPG (2–21 years) were enrolled after RT. CED of MTX110 combined with gadoteridol was completed across 7 dose levels (DL) (30–90 µM; volumes ranging from 3 mL to 2 consecutive doses of 6 mL). An accelerated dose escalation design was used. Distribution of infusate was monitored with real-time MR imaging. Repeat CED was performed every 4–8 weeks. Quality-of-life (QoL) assessments were obtained at baseline, every 3 months on therapy, and end of therapy.
Results
Between May 2018 and March 2020, 7 patients who received a total of 48 CED infusions, were enrolled (median age 8 years, range 5–21). Three patients experienced dose-limited toxicities. Four grade 3 treatment-related adverse events were observed. Most toxicities were transient new or worsening neurologic function. Median overall survival (OS) was 26.1 months (95% confidence interval: 14.8–not reached). Progression-free survival was 4–14 months (median, 7). Cumulative percentage of tumor coverage for combined CED infusions per patient ranged from 35.6% to 81.0%. Increased CED infusions were negatively associated with self-reported QoL assessments.
Conclusion
Repeat CED of MTX110 with real-time imaging with gadoteridol is tolerable for patients with DIPG. Median OS of 26.1 months compares favorably with historical data for children with DIPG. The results support further investigation of this strategy in a larger cohort.
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