bluuebunny/crossref_metadata_2025 huggingface dataset:
Iron affects localization of Ght5 in fission yeast
Authors: Akyüz Sevim Nur , Kina Umit Yasar , Aly Ahmed S I , Palabiyik Bedia
Published: April 2023

Iron is an essential cofactor for eukaryotic cells, as well as a toxic metal under certain conditions. On the other hand, glucose is the preferred energy and carbon source by most organisms and is an important signaling molecule in the regulation of biological processes. In Schizosaccharomyces pombe, the Ght5 hexose transporter, known as a high affinity glucose transporter, is required for cell proliferation in low glucose concentrations. Herein, we aimed to investigate the effects of iron stress on the Ght5 hexose transporter under glucose repression and derepression conditions. The effect of iron stress on the expression profile of the ght5 gene was analyzed by RT-qPCR and western blot. The localization of the Ght5-mNeonGreen fusion protein examined with confocal microscopy. Our results revealed that iron stress had an inhibitory effect on ght5 expression, and it altered Ght5 localization on the cell surface, causing it to accumulate in the cytoplasm.
Low-cost culture media designed for biomass production of beneficial lactic acid bacteria for their inclusion in a formula to treat bovine reproductive infections
Authors: Miranda Maria Hortencia , Nader-Macías María Elena Fátima
Published: April 2023

As a first step for the use of probiotics in a formula for cattle, it is required to have available low-cost culture medium(s) and efficient production conditions for the growth of probiotic bacteria and high production of cell biomass. De Man–Rogosa–Sharpe medium, used frequently for lactic acid bacteria (LAB) contains adequate ingredients for their growth but is very expensive for industrial application. The nutrients required for LAB growth are strain-dependent. In this work, traditional culture media were evaluated omitting and/or modifying ingredients in their composition, as carbon or nitrogen source, on the basis of their low-cost industrial waste, to select those supporting the most efficient growth. The results showed that the formulation of culture media containing fructose (0.5%) and molasses (1.0%) was better for the growth and production of cell biomass for all the strains assayed, except Lactobacillus gasseri CRL1421 growing in 1.5% corn syrup. FM902 yeast extract at concentrations between 1.5% and 2.5% was the most adequate for most of the strains. The LAB grown in the designed media maintained the beneficial properties for which they selected. The use of the culture media designed to produce biomass decrease production costs, which is an important step for the feasible industrial production of probiotic pharmaceuticals.
A review of inverse data envelopment analysis: origins, development and future directions
Authors: Emrouznejad Ali , Amin Gholam R , Ghiyasi Mojtaba , Michali Maria
Published: April 2023

Data envelopment analysis (DEA) is a widely used mathematical programming approach for assessing the efficiency of decision-making units (DMUs) in various sectors. Inverse DEA is a post-DEA sensitivity analysis approach developed initially for solving resource allocation. The main objective of inverse DEA is to determine the optimal quantity of inputs and/or outputs for each DMU under input and/or output perturbation (s), which would allow them to reach a given efficiency target. Since the early 2000s, inverse DEA has been extended theoretically and applied successfully in different areas including banking, energy, education, sustainability and supply chain management. In recent years, research has demonstrated the potential of inverse DEA for solving novel inverse problems, such as estimating merger gains, minimizing production pollution, optimizing business partnerships and more. This paper provides a comprehensive survey of the latest theoretical and practical advancements in inverse DEA while also highlighting potential areas for future research and development in this field. One such area is exploring the use of heuristic algorithms and optimization techniques in conjunction with inverse DEA models to address issues of infeasibility and nonlinearity. Moreover, applying inverse DEA to new sectors such as healthcare, agriculture and environmental and climate change issues holds great promise for future research. Overall, this paper sets the stage for further advancements in this promising approach.
The US Intelligence Community, Global Security, and AI: From Secret Intelligence to Smart Spying
Authors: Moran Christopher R , Burton Joe , Christou George
Published: April 2023

This article examines the ways in which the US intelligence community is leveraging the power of artificial intelligence (AI) for national security purposes. Drawing on declassified intelligence records, it contends that this community has been fascinated by AI for decades. This is important to acknowledge because this historical context has shaped contemporary projects and thinking within the community. It has given the United States a first-mover advantage, establishing precedents that other global actors need to comply with, negotiate or resist. The article advances three arguments. One, the community has long recognized that it needs to collaborate with the tech sector on AI. However, these relationships bring certain challenges since the sector is a curious compound of ideologies and interests. Two, while the community was initially attracted to the data processing advantages of AI to help human analysts to overcome “data smog,” today it has broadened its focus to consider how AI can improve all stages of the intelligence cycle. Three, while many voices feverishly herald the transformative potential of AI in the global security environment, we argue instead that US agencies will not be able to exploit the full potential of AI, and thus talk of an intelligence revolution is premature. This is because of national and international rules on data collection and retention but also because of cultural tensions within the global AI ecosystem. The discussion will appeal to scholars and practitioners interested in the impact of emerging technologies on national security processes and decision-making and, more broadly, global security.
Anaplasmosis-Induced Hemophagocytic Lymphohistiocytosis: A Case Report and Review of the Literature
Authors: Scribner Jacob , Wu Benita , Lamyaithong Andre , Arcega Victor , Villanueva Daphne-Dominique
Published: April 2023

Cases of anaplasmosis have increased steadily and are appearing in states where it is less common. While symptoms are usually mild, in rare cases it can cause hemophagocytic lymphohistiocytosis. Here, we present a case of polymerase chain reaction–confirmed Anaplasma phagocytophilum with morulae on peripheral blood smear associated with biopsy-proven hemophagocytic lymphohistiocytosis.
Lipid transport protein ORP2A promotes glucose signaling by facilitating RGS1 degradation
Authors: Yu Qian , Zou Wenjiao , Liu Kui , Sun Jialu , Chao Yanru , Sun Mengyao , Zhang Qianqian , Wang Xiaodong , Wang Xiaofei , Ge Lei
Published: April 2023

Heterotrimeric GTP-binding proteins (G proteins) are a group of regulators essential for signal transmission into cells. Regulator of G protein signaling 1 (AtRGS1) possesses intrinsic GTPase-accelerating protein (GAP) activity and could suppress G protein and glucose signal transduction in Arabidopsis (Arabidopsis thaliana). However, how AtRGS1 activity is regulated is poorly understood. Here, we identified a knockout mutant of oxysterol binding protein-related protein 2A, orp2a-1, which exhibits similar phenotypes to the arabidopsis g-protein beta 1-2 (agb1-2) mutant. Transgenic lines overexpressing ORP2A displayed short hypocotyls, a hypersensitive response to sugar, and lower intracellular AtRGS1 levels than the control. Consistently, ORP2A interacted with AtRGS1 in vitro and in vivo. Tissue-specific expression of 2 ORP2A alternative splicing isoforms implied functions in controlling organ size and shape. Bioinformatic data and phenotypes of orp2a-1, agb1-2, and the orp2a-1 agb1-2 double mutant revealed the genetic interactions between ORP2A and Gβ in the regulation of G protein signaling and sugar response. Both alternative protein isoforms of ORP2A localized in the endoplasmic reticulum (ER), plasma membrane (PM), and ER–PM contact sites and interacted with vesicle-associated membrane protein-associated protein 27-1 (VAP27-1) in vivo and in vitro through their two phenylalanines in an acidic track-like motif. ORP2A also displayed differential phosphatidyl phosphoinositide binding activity mediated by the pleckstrin homology domain in vitro. Taken together, the Arabidopsis membrane protein ORP2A interacts with AtRGS1 and VAP27-1 to positively regulate G protein and sugar signaling by facilitating AtRGS1 degradation.
Interplay between NIN-LIKE PROTEINs 6 and 7 in nitrate signaling
Authors: Cheng Yu-Hsuan , Durand Mickael , Brehaut Virginie , Hsu Fu-Chiun , Kelemen Zsolt , Texier Yves , Krapp Anne , Tsay Yi-Fang
Published: April 2023

NLP7 (NIN-LIKE-PROTEIN 7) is the major transcriptional factor responsible for the primary nitrate response (PNR), but the role of its homolog, NLP6, in nitrogen signaling and the interplay between NLP6 and NLP7 remain to be elucidated. In this study, we show that, like NLP7, nuclear localization of NLP6 via a nuclear retention mechanism is nitrate dependent, but nucleocytosolic shuttling of both NLP6 and NLP7 is independent of each other. Compared with single mutants, the nlp6nlp7 double mutant displays a synergistic growth retardation phenotype in response to nitrate. The transcriptome analysis of the PNR showed that NLP6 and NLP7 govern ∼50% of nitrate-induced genes, with cluster analysis highlighting 2 distinct patterns. In the A1 cluster, NLP7 plays the major role, whereas in the A2 cluster, NLP6 and NLP7 are partially functionally redundant. Interestingly, comparing the growth phenotype and PNR under high- and low-nitrate conditions demonstrated that NLP6 and NLP7 exert a more dominant role in the response to high nitrate. Apart from nitrate signaling, NLP6 and NLP7 also participated in high ammonium conditions. Growth phenotypes and transcriptome data revealed that NLP6 and NLP7 are completely functionally redundant and may act as repressors in response to ammonium. Other NLP family members also participated in the PNR, with NLP2 and NLP7 acting as broader regulators and NLP4, -5, -6, and -8 regulating PNR in a gene-dependent manner. Thus, our findings indicate that multiple modes of interplay exist between NLP6 and NLP7 that differ depending on nitrogen sources and gene clusters.
“Sentinel or accomplice”: gut microbiota and microglia crosstalk in disorders of gut–brain interaction
Authors: Zheng Haonan , Zhang Cunzheng , Zhang Jindong , Duan Liping
Published: April 2023

Abnormal brain–gut interaction is considered the core pathological mechanism behind the disorders of gut–brain interaction (DGBI), in which the intestinal microbiota plays an important role. Microglia are the “sentinels” of the central nervous system (CNS), which participate in tissue damage caused by traumatic brain injury, resist central infection and participate in neurogenesis, and are involved in the occurrence of various neurological diseases. With in-depth research on DGBI, we could find an interaction between the intestinal microbiota and microglia and that they are jointly involved in the occurrence of DGBI, especially in individuals with comorbidities of mental disorders, such as irritable bowel syndrome (IBS). This bidirectional regulation of microbiota and microglia provides a new direction for the treatment of DGBI. In this review, we focus on the role and underlying mechanism of the interaction between gut microbiota and microglia in DGBI, especially IBS, and the corresponding clinical application prospects and highlight its potential to treat DGBI in individuals with psychiatric comorbidities.
Reduction in the propensity of rapid eye movement sleep and phasic-to-tonic ratio in patients with refractory epilepsy
Authors: Yeh Wei-Chih , Li Ying-Sheng , Hsu Chung-Yao
Published: April 2023

Study Objectives

Patients with epilepsy exhibit disturbed sleep architecture and shorter rapid eye movement (REM) sleep compared with healthy controls. REM sleep consists of two microstates, phasic and tonic REM. Studies suggest that epileptic activity is suppressed in phasic but not in tonic REM. However, changes in the REM microstructure in patients with epilepsy are still unknown. Therefore, this study evaluated the differences in REM microstructure between patients with refractory and medically controlled epilepsy.

Methods

This retrospective case–control study included patients with refractory and medically controlled epilepsy. Sleep parameters of the patients were recorded by standard polysomnography. In addition, the microstructures of sleep and REM sleep were compared between the two epilepsy groups.

Results

Forty-two patients with refractory epilepsy and 106 with medically controlled epilepsy were evaluated. The refractory group showed significantly decreased REM sleep (p = 0.0062), particularly in the first and second sleep cycles (p = 0.0028 and 0.00482, respectively), as well as longer REM latency (p = 0.0056). Eighteen and 28 subjects in the refractory and medically controlled epilepsy groups, respectively, with comparable REM sleep percentages, underwent REM microstructure examination. Phasic REM sleep was significantly lower in the refractory group (4.5% ± 2.1% vs. 8.0% ± 4.1%; p = 0.002). In addition, the phasic-to-tonic ratio was significantly decreased (4.8 ± 2.3 vs. 8.9 ± 4.9; p = 0.002) and negatively associated with refractory epilepsy (coefficient = −0.308, p = 0.0079).

Conclusion

Patients with refractory epilepsy exhibited REM sleep disturbance at both macro and microstructure levels.
Sleep behavior traits and associations with opioid-related adverse events: a cohort study
Authors: Chen Rudy W , Ulsa Ma Cherrysse , Li Peng , Gao Chenlu , Zheng Xi , Xu Jiawei , Luo Yong , Shen Shiqian , Lane Jacqueline , Scheer Frank A J L , Hu Kun , Gao Lei
Published: April 2023

Study Objectives

Opioid-related adverse events (OAEs), including opioid use disorders, overdose, and death, are serious public health concerns. OAEs are often associated with disrupted sleep, but the long-term relationship between poor sleep and subsequent OAE risk remains unknown. This study investigates whether sleep behavior traits are associated with incident OAEs in a large population cohort.

Methods

444 039 participants (mean age ± SD 57 ± 8 years) from the UK Biobank reported their sleep behavior traits (sleep duration, daytime sleepiness, insomnia-like complaints, napping, and chronotype) between 2006 and 2010. The frequency/severity of these traits determined a poor sleep behavior impacts score (0–9). Incident OAEs were obtained from hospitalization records during 12-year median follow-up. Cox proportional hazards models examined the association between sleep and OAEs.

Results

Short and long sleep duration, frequent daytime sleepiness, insomnia symptoms, and napping, but not chronotype, were associated with increased OAE risk in fully adjusted models. Compared to the minimal poor sleep behavior impacts group (scores of 0–1), the moderate (4–5) and significant (6–9) groups had hazard ratios of 1.47 (95% confidence interval [1.27, 1.71]), p < 0.001, and 2.19 ([1.82, 2.64], p < 0.001), respectively. The latter risk magnitude is greater than the risk associated with preexisting psychiatric illness or sedative-hypnotic medication use. In participants with moderate/significant poor sleep impacts (vs. minimal), subgroup analysis revealed that age <65 years was associated with a higher OAE risk than in those ≥65 years.

Conclusions

Certain sleep behavior traits and overall poor sleep impacts are associated with an increased risk for opioid-related adverse events.
Manganese relative oral bioavailability in electric arc furnace steel slag is influenced by high iron content and low bioaccessibility
Authors: Proctor Deborah M , Vivanco Stephanie N , Blanchette Alexander D
Published: April 2023

Electric arc furnace (EAF) slag is a rock-like aggregate produced with carbon steel and used for construction, including residential ground cover. It is enriched with manganese (Mn) and other metals, including iron (Fe), but because metals are bound in mineral matrices, in vitro bioaccessibility (BA) is limited. We conducted a relative bioavailability (RBA) study using F344 rats to assess Mn RBA from EAF slag ingestion, compared with Mn in diet. Mn and Fe were measured in liver, and Mn in lung and striatum, the target tissue of the brain. Mn levels in each tissue were fit by dose-to-tissue concentration (D-TC) curves. The D-TC relationship was the most highly significant for the linear model using liver Mn, and the RBA was 48%. The D-TC relationship in lung showed a positive slope for chow, but that for EAF slag was slightly negative, and the RBA was 14%. In comparison, the striatum D-TC remained relatively constant, supporting that homeostasis was maintained. Increased Fe was observed in the liver of EAF slag-dosed groups, suggesting that Mn absorption was inhibited by the high Fe content of slag. Lung and striatum D-TC curves demonstrated that systemic delivery of Mn from EAF slag ingestion is limited and support an RBA of 14% for risk assessment. Although Mn levels in slag are elevated compared with health-based screening guidelines, this study supports that incidental ingestion of Mn in EAF slag is unlikely to pose a neurotoxicity hazard due to homeostatic controls, low BA, and high Fe content.
Biomechanical Analysis of Combined Medial Calcar and Lateral Locked Plating Versus Isolated Lateral Locked Plating of Proximal Humerus Fractures
Authors: Kotler Joshua A. , Zuppke Julia N. , Abraham Vivek M. , Sanville Jennifer A. , Nabet Austin C. , Carofino Bradley , Gardner Michael J. , Smith Christopher S.
Published: April 2023

Objective:

Medial calcar buttress plating combined with lateral locked plating is biomechanically tested against isolated lateral locked plating in synthetic humeri models for the treatment of proximal humerus fractures.

Methods:

Proximal humerus fractures (OTA/AO type 11-A2.1) were manufactured in 10 pairs of Sawbones humeri models (Sawbones, Pacific Research Laboratories, Vashon Island, WA). Specimen were randomly assigned and instrumented with either medial calcar buttress plating combined with lateral locked plating (CP) or isolated lateral locked plating (LP). Nondestructive torsional and axial load tests were performed to evaluate construct stiffness. Large-cycle axial tests were conducted followed by destructive ramp-to-failure tests. Cyclic stiffness was compared in both nondestructive and ultimate failure loads. Failure displacement was recorded and compared between groups.

Results:

The addition of medial calcar buttress plating to lateral locked plating constructs significantly increased the axial (P < 0.01) and torsional (P < 0.01) stiffness of the construct compared with isolated lateral locked plating by 95.56% and 37.46%, respectively. All models demonstrated greater axial stiffness (P < 0.01) after 5000 cycles of axial compression, not dependent on the fixation method. During destructive testing, the CP construct withstood 45.35% larger load (P < 0.01) and congruently exhibited 58% less humeral head displacement (P = 0.02) before failure when compared with the LP construct.

Conclusion:

This study demonstrates the biomechanical superiority of medial calcar buttress plating when combined with lateral locked plating as compared with isolated lateral locked plating of OTA/AO type 11-A2.1 proximal humerus in synthetic humeri models.
Characteristics of Scientific Success in Phase 1 Pediatric Oncology Clinical Trials: Establishing a Need for Integrated Patient-Reported Outcomes Even in Early Phase Trials
Authors: Keim-Malpass Jessica , Blair Lisa , Doede Aubrey , Chu Crystal , Graham Connor , Petersen William C.
Published: April 2023

Background:

Pediatric clinical trials are particularly vulnerable to challenges in participant accrual, making them more likely to encounter early termination.

Objective:

To describe clinical trial characteristics of phase 1 pediatric oncology clinical trials registered in ClinicalTrials.gov through 2017.

Method:

We identified a retrospective cohort and abstracted key clinical trial characteristics from this data source. We calculated a bivariate logistic regression to explore factors related to early trial termination.

Results:

Over 1400 phase 1 trials were included in this analysis. Only 3.2% of trials included any type of patient-reported outcome (PRO) as a secondary outcome and 21.6% of phase 1 trials did not meet scientific success due to early termination. National Institutes of Health (NIH)-funded phase 1 trials had the lowest percentage of early termination.

Conclusions:

Phase 1 clinical trials for pediatric patients with cancer are at risk of early termination due to lack of enrollment. A deeper understanding of clinical trial design elements, characteristics, and eligibility determination may contribute to a higher proportion of trials meeting successful enrollment.

Implications for Practice:

Oncology nurses and nurse scientists uniquely contribute to an understanding of family-centered approaches and should take an active role in trial design for pediatric cancers that could help capture meaningful PROs during a vulnerable clinical trajectory.

What Is Foundational:

Very little attention has been given to understanding characteristics of phase 1 clinical trials for pediatric cancers that may impact the state of the science and care delivery for patients with advanced pediatric cancer diagnoses.
Effects of Auricular Acupressure on Symptom Burden and Quality of Life in Patients With Advanced Lung Cancer Treated With Immunotherapy Based on the Midnight-noon Ebb-flow Theory: A Randomized Controlled Trial
Authors: Lin Yuting , Wang Yali , Yan Rong , Li Zhen , Ding Min , Meng Xiangmin , Yu Weiwei
Published: April 2023

Background:

The burden of immunotherapy-induced symptoms is prevalent in patients with advanced lung cancer and may impact their quality of life (QOL).

Objective:

To investigate the effect of auricular acupressure, based on the theory of midnight-noon ebb-flow, and using a randomized controlled trial, on alleviating symptoms burden and QOL in patients with advanced lung cancer during 3 cycles of immunotherapy treatment.

Methods:

Patients with advanced lung cancer who received immunotherapy were recruited. The control group (n = 60) was treated with standard clinical treatment and nursing care, and the intervention group (n = 60) was treated with 3 cycles of auricular acupressure under the guidance of midnight-noon ebb-flow theory. Patients’ symptoms and QOL were compared before and after the intervention of 3 cycles.

Results:

At 2 cycles after the intervention for symptoms burden and QOL, there were statistically significant differences between the control group and the intervention group (P < .05), but no statistically significant difference between the two groups after 3 cycles.

Conclusion:

Auricular acupressure based on the theory of midnight-noon ebb-flow can alleviate the specific symptom burden of immunotherapy patients with advanced lung cancer and improve their QOL.

Implications for Practice:

The special Traditional Chinese Medicine (TCM) nursing technology of auricular acupressure combined with TCM time treatment is beneficial and safe.

Foundational:

The QOL of patients can be improved by nursing technology with TCM, which may be best used as a part of clinical work.
Treatment of intermediate-risk prostate cancer with active surveillance in the routine care—Long-term outcomes of a prospective noninterventional study (HAROW)
Authors: Weissbach Lothar , Schwarte Andreas , Boedefeld Edith A. , Herden Jan
Published: April 2023

Background

We report here the long-term outcomes of patients with intermediate-risk prostate cancer (PCa) treated with active surveillance (AS) in a daily routine setting.

Material and methods

HAROW (2008–2013) was a noninterventional, health service research study investigating the management of localized PCa in a community setting. A substantial proportion of the study centers were office-based urologists. A follow-up examination of all intermediate-risk patients with AS was conducted. Overall, cancer-specific, metastasis-free, and treatment-free survival rates, as well as reasons for discontinuation, were determined and discussed.

Results

Of the 2957 patients enrolled, 52 with intermediate-risk PCa were managed with AS and were available for evaluation. The median follow-up was 6.8 years (interquartile range, 3.4–8.6 years). Seven patients (13.5%) died of causes unrelated to PCa, of whom 4 were under AS or under watchful waiting. Two patients (3.8%) developed metastasis. The estimated 8-year overall, cancer-specific, metastasis-free, and treatment-free survival rates were 85% (95% confidence interval [CI], 72%–96%), 100%, 93% (95% CI, 82%–100%), and 31% (95% CI, 17%–45%), respectively. On multivariable analysis, prostate-specific antigen density of ≥0.2 ng/mL2 was significantly predictive of receiving invasive treatment (hazard ratio, 3.29; p = 0.006). Reasons for discontinuation were more often due to patient's or physician's concerns (36%) than due to observed clinical progression.

Conclusions

Although survival outcome data for intermediate-risk patients managed with AS in real-life health care conditions were promising, rates of discontinuation were high, and discontinuation was often a patient's decision, even when the signs of disease progression were absent. This might be an indication of higher levels of mental burden and anxiety in this specific subgroup of patients, which should be considered when making treatment decisions. From a psychological perspective, not all intermediate-risk patients are optimal candidates for AS.
Family Perspectives on In-Home Multimodal Longitudinal Data Collection for Children Who Function Across the Developmental Spectrum
Authors: Boerner Katelynn E. , Pearl-Dowler Leora , Holsti Liisa , Wharton Marie-Noelle , Siden Harold , Oberlander Tim F.
Published: April 2023

Objective:

Quality child health research requires multimodal, multi-informant, longitudinal tools for data collection to ensure a holistic description of real-world health, function, and well-being. Although advances have been made, the design of these tools has not typically included community input from families with children whose function spans the developmental spectrum.

Methods:

We conducted 24 interviews to understand how children, youth, and their families think about in-home longitudinal data collection. We used examples of smartphone-based Ecological Momentary Assessment of everyday experiences, activity monitoring with an accelerometer, and salivary stress biomarker sampling to help elicit responses. The children and youth who were included had a range of conditions and experiences, including complex pain, autism spectrum disorder, cerebral palsy, and severe neurologic impairments. Data were analyzed using reflexive thematic analysis and descriptive statistics of quantifiable results.

Results:

Families described (1) the importance of flexibility and customization within the data collection process, (2) the opportunity for a reciprocal relationship with the research team; families inform the research priorities and the development of the protocol and also benefit from data being fed back to them, and (3) the possibility that this research approach would increase equity by offering accessible participation opportunities for families who might otherwise not be represented. Most families expressed interest in participating in in-home research opportunities, would find most methods discussed acceptable, and cited 2 weeks of data collection as feasible.

Conclusion:

Families described diverse areas of complexity that necessitate thoughtful adaptations to traditional research designs. There was considerable interest from families in active engagement in this process, particularly if they could benefit from data sharing. This feedback is being incorporated into pilot demonstration projects to iteratively codesign an accessible research platform.
An Optimized LC-MS/MS Method for Quantification of Sunitinib and N-Desethyl Sunitinib in Human Plasma and Its Application for Therapeutic Drug Monitoring
Authors: Li Qiaoqiao , Tang Tiantian , Zhang Min , Li Lixian , Chen Wanyi
Published: April 2023

Background:

Sunitinib (SUN) malate is an oral, multitargeted, tyrosine kinase inhibitor approved for the treatment of metastatic renal cell carcinoma, imatinib-resistant or imatinib-intolerant gastrointestinal stromal tumors, and pancreatic neuroendocrine tumors. SUN has a narrow therapeutic window and high variability in interpatient pharmacokinetic parameters. Clinical detection methods for SUN and N-desethyl SUN limit the application of SUN to therapeutic drug monitoring. All published methods for quantifying SUN in human plasma require strict light protection to avoid light-induced isomerism or the use of additional quantitative software. To avoid these difficult processes in clinical routines, the authors propose a novel method that merges the peaks of the E-isomer and Z-isomer of SUN or N-desethyl SUN into a single peak.

Methods:

The E-isomer and Z-isomer peaks of SUN or N-desethyl SUN were merged into a single peak by optimizing the mobile phases to decrease the resolution of the isomers. A suitable chromatographic column was selected to obtain a good peak shape. Thereafter, the conventional and single-peak methods (SPM) were simultaneously validated and compared according to the guidelines published by the Food and Drug Administration in 2018 and the Chinese Pharmacopoeia in 2020.

Results:

The verification results showed that the SPM was superior to the conventional method in the matrix effect and met the requirements for biological sample analysis. SPM was then applied to detect the total steady-state concentration of SUN and N-desethyl SUN in tumor patients who received SUN malate.

Conclusions:

The established SPM makes the detection of SUN and N-desethyl SUN easier and faster without light protection or extra quantitative software, making it more appropriate for routine clinical use. The clinical application results showed that 12 patients took 37.5 mg per day, with a median total trough steady-state concentration of 75.0 ng/mL.
Simultaneous Determination of Rifamycin Antibiotics and Their Active Metabolites in Human Plasma Using UHPLC-MS/MS to Evaluate Their Impact on Target Peak Concentrations: A Short Communication
Authors: Wu Ling-jie , Ye Zhen-jie , Zhang Xiao-ying , Zhang Xiao-long , Zheng Ai-xian , Liu Xiao-long , Yu Xiao-ling
Published: April 2023

Background:

Standard and proper antituberculosis (anti-TB) treatment is essential for patients with TB, and rifamycin antibiotics are key components of anti-TB therapy. Therapeutic drug monitoring (TDM) of rifamycin antibiotics can shorten the time to response and complete treatment of TB. Notably, antimicrobial activities of the major active metabolites of rifamycin are similar to those of their parent compounds. Thus, a rapid and simple assay was developed for simultaneous determination of rifamycin antibiotics and their major active metabolites in plasma to evaluate their impact on target peak concentrations. Here, the authors have developed and validated a method for simultaneous determination of rifamycin antibiotics and their active metabolites in human plasma using ultrahigh-performance liquid chromatography tandem mass spectrometry.

Methods:

Analytical validation of the assay was performed in accordance with the bioanalytical method validation guidance for industry described by the US Food and Drug Administration and the guidelines for bioanalytical method validation described by the European Medicines Agency.

Results:

The drug concentration quantification method for rifamycin antibiotics, including rifampicin, rifabutin, and rifapentine, and their major active metabolites was validated. Significant differences in the proportions of active metabolites in rifamycin antibiotics may affect the redefinition of their effective concentration ranges in the plasma. The method developed herein is expected to redefine the ranges of “true” effective concentrations of rifamycin antibiotics (including parent compounds and their active metabolites).

Conclusions:

The validated method can be successfully applied for high-throughput analysis of rifamycin antibiotics and their active metabolites for TDM in patients receiving anti-TB treatment regimens containing these antibiotics. Proportions of active metabolites in rifamycin antibiotics markedly varied among individuals. Depending on the clinical indications of patients, the therapeutic ranges for rifamycin antibiotics may be redefined.
A multiplexed barcode approach to simultaneously evaluate gene delivery by adeno-associated virus capsid variants in nonhuman primates
Authors: Stone Daniel , Meumann Nadja , Kuhlmann Anne-Sophie , Peterson Christopher W. , Xie Hong , Roychoudhury Pavitra , Loprieno Michelle A. , Vu Xuan-Khang , Strongin Daniel E. , Kenkel Elizabeth J. , Haick Anoria , Stensland Laurence , Obenza Willimark M. , Parrott Jacob , Nelson Veronica , Murnane Robert D. , Huang Meei-Li , Aubert Martine , Kiem Hans-Peter , Büning Hildegard , Jerome Keith R.
Published: April 2023

Background and Aims:

Adeno-associated virus (AAV) vectors are widely used to deliver therapeutic transgenes to distinct tissues, including the liver. Vectors based on naturally occurring AAV serotypes as well as vectors using engineered capsids have shown variations in tissue tropism and level of transduction between different mouse models. Moreover, results obtained in rodents frequently lack translatability into large animal studies. In light of the increasing interest in AAV vectors for human gene therapy, an increasing number of studies are being performed in nonhuman primates. To keep animal numbers to a minimum and thus optimize the process of AAV capsid selection, we developed a multiplex barcoding approach to simultaneously evaluate the in vivo vector performance for a set of serotypes and capsid-engineered AAV vectors across multiple organs.

Approach and Results:

Vector biodistribution and transgene expression were assessed by quantitative PCR, quantitative reverse transcription PCR, vector DNA amplicon Illumina sequencing and vRNAseq in male and female rhesus macaques simultaneously dosed with a mixture of barcoded naturally occurring or engineered AAV vectors encoding the same transgene. As expected, our findings show animal-to-animal variation in both the biodistribution and tissue transduction pattern, which was partly influenced by each animal’s distinctive serological status.

Conclusions:

This method offers a robust approach to AAV vector optimization that can be used to identify and validate AAV vectors for gene delivery to potentially any anatomical site or cell type.
Comparison of Finger, Hand, and Wrist Injuries in the US Air Force to US Workers
Authors: Gwilliam Melody , Hendricks Scott , Socias-Morales Christina , Burnham Bruce , Gomes Harold , Reichard Audrey , Stallings Heidi
Published: April 2023

Objective

Fingers, hands, and wrists (FHW) are the most frequently injured body parts in work-related injuries. This study described and compared FHW injuries among enlisted, officer, and civilian US Air Force (USAF) personnel to those in the US workforce.

Methods

All work-related, noncombat FHW injuries (≥1 lost workday) and demographics among USAF personnel and US workforce (2008–2018) were included. The USAF FHW injury rates were age adjusted to the US employment and compared by sex, source, event, and nature of the injuries.

Results

Finger, hand, and wrist injuries were significantly lower among the USAF personnel and among females. In both populations, FHW injuries from falls were higher and increased with age group among females. Males had higher overall FHW injuries from contact with objects and equipment.

Conclusions

Prevention efforts should focus on understanding risk factors and sharing successful prevention activities.
“Tool-in-lesion” Accuracy of Galaxy System—A Robotic Electromagnetic Navigation BroncHoscopy With Integrated Tool-in-lesion-Tomosynthesis Technology
Authors: Bhadra Krish , Rickman Otis B. , Mahajan Amit K. , Hogarth Douglas Kyle
Published: April 2023

Background:

The Galaxy System (Noah Medical) is a novel robotic endoluminal platform using electromagnetic navigation combined with integrated tomosynthesis technology and augmented fluoroscopy. It provides intraprocedural imaging to correct computerized tomography (CT) to body divergence and novel confirmation of tool-in-lesion (TIL). The primary aim of this study was to assess the TIL accuracy of the robotic bronchoscope with integrated digital tomosynthesis and augmented fluoroscopy.

Methods:

Four operators conducted the experiment using 4 pigs. Each physician performed between 4 and 6 nodule biopsies for 20 simulated lung nodules with purple dye and a radio pacifier. Using Galaxy’s “Tool-in-Lesion Tomography (TOMO+)” with augmented fluoroscopy, the physician navigated to the lung nodules, and a tool (needle) was placed into the lesion. TIL was defined by the needle in the lesion determined by cone-beam CT.

Results:

The lung nodule’s average size was 16.3 ± 0.97 mm and was predominantly in the lower lobes (65%). All 4 operators successfully navigated to all (100%) of the lesions in an average of 3 minutes and 39 seconds. The median number of tomosynthesis sweeps was 3 and augmented fluoroscopy was utilized in most cases (17/20 or 85%). TIL after the final TOMO sweep was 95% (19/20) and tool-touch-lesion was 5% (1/20). Biopsy yielding purple pigmentation was also 100% (20/20).

Conclusion:

The Galaxy System demonstrated successful digital TOMO confirmed TIL success in 95% (19/20) of lesions and tool-touch-lesion in 5% (1/20) as confirmed by cone-beam CT. Successful diagnostic yield was achieved in 100% (20/20) of lesions as confirmed by intralesional pigment acquisition.
Differences in Hearing, Balance, and Quality-of-Life Outcomes in Petroclival Versus Nonpetroclival Posterior Fossa Meningiomas
Authors: Gillard Danielle M. , Jiam Nicole T. , Morshed Ramin A. , Bhutada Abhishek S. , Crawford Ethan D. , Braunstein Steve W. , Sabes Jennifer Henderson , Theodosopoulos Philip V. , Cheung Steven W.
Published: April 2023

Objective

To compare hearing, tinnitus, balance, and quality-of-life treatment outcomes of petroclival meningioma and nonpetroclival cerebellopontine angle meningioma cohorts.

Study Design

A retrospective cohort study of 60 patients with posterior fossa meningiomas, 25 petroclival and 35 nonpetroclival, who were treated at a single tertiary care center between 2000 and 2020.

Intervention

A survey battery that included the Hearing Effort of the Tumor Ear, Speech and Spatial Qualities of Hearing, Tinnitus Functional Index, Dizziness Handicap Inventory (DHI), and Short Form Health Survey. Petroclival and nonpetroclival cohorts were matched for tumor size and demographic features.

Main Outcome Measures

Differences between groups in hearing, balance outcomes, and quality of life and patient factors that influence posttreatment quality of life.

Results

Petroclival meningioma patients reported poorer audiovestibular outcomes with a higher rate of deafness in the tumor ear (36.0% versus 8.6%, p = 0.032) and lower functional hearing by the Hearing Effort of the Tumor Ear, Speech and Spatial Qualities of Hearing (76.6 [6.1] versus 82.0 [4.4], p < 0.001). Current dizziness rate was higher (48.0% versus 23.5%, p = 0.05), with more severe dizziness by DHI (18.4 [4.8] versus 5.7 [2.2], p < 0.001). Both cohorts had similar high quality of life and low tinnitus severity indices. Quality-of-life Short Form Health Survey predictors were tumor size (p = 0.012) and DHI (p = 0.005) in multivariable analysis.

Conclusions

Hearing and dizziness treatment outcomes of petroclival meningioma are poorer relative to other posterior fossa meningiomas. Despite audiovestibular outcome distinctions, the overall posttreatment quality of life was high for both petroclival and nonpetroclival meningioma.
The Role of Telemedicine for Evaluation and Management of Dizzy Patients: A Systematic Review
Authors: Meinhardt Gerek , Perez Nicole , Sharrer Christine , Ratmeyer Paul , Van Maele Nicholas , Robinson Lauren , Adkins David , Schuh Marissa , Bush Matthew L.
Published: April 2023

Objectives

To conduct a scoping systematic review of the literature on the use of telemedicine to evaluate, diagnose, and manage patients with dizziness.

Data Sources

Web of Science, SCOPUS, and MEDLINE PubMed databases.

Study Selection

The inclusion criteria included the following: pertaining to telemedicine and the evaluation, diagnosis, treatment, or management of dizziness. Exclusion criteria included the following: single-case studies, meta-analyses, and literature and systematic reviews.

Data Extraction

Outcomes recorded for each article included the following: study type, patient population, telemedicine format, dizziness characteristics, level of evidence, and quality assessment.

Data Synthesis

The search returned 15,408 articles, and a team of four screened the articles for inclusion criteria status. A total of 9 articles met the inclusion criteria and were included for review. Of the nine articles, four were randomized clinical trials, three were prospective cohort studies, and two were qualitative studies. The telemedicine format was synchronous in three studies and asynchronous in six studies. Two of the studies involved acute dizziness only, four involved chronic dizziness only, one involved both acute and chronic dizziness, and two did not specify dizziness type. Six of the studies included the diagnosis of dizziness, two involved the evaluation of dizziness, and three involved treatment/management. Some of the reported benefits of telemedicine for dizziness patients included cost savings, convenience, high patient satisfaction, and improvement in dizziness symptoms. Limitations included access to telemedicine technology, Internet connectivity, and dizziness symptoms interfering with the telemedicine application.

Conclusions

Few studies investigate the evaluation, diagnosis, or management of dizziness using telemedicine. The lack of protocols and standards of care for telemedicine evaluation of dizzy patients creates some challenges in care delivery; however, these reviewed studies provide examples of the breadth of care that has been provided remotely.
The ongoing impact of COVID-19 on testing for and diagnoses of HIV and bacterial sexually transmitted infections in Oregon
Authors: Menza Timothy W. , Zlot Amy , Gonzalez-Pena Yuritzy , Capizzi Jeff , Bush Lea , Humphrey Sarah , Kapoor Hema , Moore Rebecca , Garai Jillian
Published: April 2023

Background

The COVID-19 pandemic has disrupted HIV and sexually transmitted infection (STI) testing accessibility. We sought to assess the longer-term impacts of COVID-19 on HIV and STI testing and diagnosis in Oregon.

Methods

First, we examined HIV, Neisseria gonorrhoeae (NG)/Chlamydia trachomatis (CT), and syphilis tests conducted at the Oregon State Public Health Laboratory (public sector) and a large commercial laboratory (private sector) and HIV, NG, CT, and primary and secondary (P&S) syphilis diagnoses in Oregon from 1/1/2019-12/31/2021. We compared monthly testing and diagnosis rates in five pre-specified time periods: pre-COVID-19 (1/2019-2/2020), stay-at-home order (3/2020-5/2020), reopening (6/2020-12/2020), vaccine availability (1/2021-6/2021), and Delta/early Omicron spread (7/2021-12/2021). Second, we calculated the number of HIV and STI diagnoses per test in the public and private sectors. Finally, we used seasonal autoregressive integrated moving average (SARIMA) models to predict expected HIV and STI diagnoses for comparison to those observed.

Results

Both public and private sector HIV and bacterial STI testing fell to nadirs in April 2020 with incomplete recovery to 2019 levels by the close of 2021. Compared to pre-COVID-19, public sector and private sector testing was significantly lower in all subsequent time periods. Compared to pre-COVID-19, P&S syphilis cases were 52%, 75%, and 124% greater in the reopening, vaccine availability, and Delta/early Omicron periods, respectively. From 3/2020-12/2021, we observed an excess of P&S syphilis cases (+37.1%; 95%CI: 22.2%, 52.1%) and a deficit in CT cases (-10.7%; 95%CI: -15.4%, -6.0%).

Conclusions

By 12/2021, HIV/STI testing had not recovered to pre-COVID-19 levels and HIV/STI continue to be underdiagnosed. Despite decreased testing, P&S syphilis cases have increased substantially.
Geosexual Archetype, Preventive Behaviors, and Sexually Transmitted Infections Among High-Risk Men Who Have Sex With Men
Authors: Dharma Christoffer , Guimond Tim , Salway Travis , Lachowsky Nathan J. , Card Kiffer G. , Gesink Dionne
Published: April 2023

Background

Social geography plays an important role in transmission of sexually transmitted infections (STIs) among men who have sex with men. Previous qualitative work had identified 7 “geosexual archetypes,” each with distinct travel patterns for sex and potentially important differences in STI rates. The objective of this article was to explore what could be learned about STI transmission by looking at STI prevention strategies (condom use and preexposure prophylaxis use) and prevalence of STIs among these geosexual archetypes.

Methods

We analyzed data from the Sex Now 2019 online survey in Canada. Men who have sex with men who reported 3 or more partners in the past 6 months were included in the analysis (n = 3649).

Results

The most common archetype was “geoflexible” (sex at home, partner's home, and other places; 35.6%), followed by “privates” (sex only at own/partner's home; 23.0%); the least common archetypes was “rover” (sex not at home or partner's place; 4.0%). There were significant variations in both STI prevention strategies and prevalence of bacterial STIs in the past year by geosexual archetype. In particular, among those who were HIV negative, those who reported a geoflexible archetype and used preexposure prophylaxis but did not use condoms consistently had a 52.6% prevalence of bacterial STIs, which was much higher compared with all other groups. Within other archetypes, those living with HIV had the highest prevalence of bacterial STIs.

Conclusions

Geosexual archetype together with participant's STI prevention strategies was a strong predictor of bacterial STI risk. Understanding how place is connected to bacterial STIs is key in prevention as individuals do not live in isolation.