bluuebunny/crossref_metadata_2025 huggingface dataset:
Involving trained community health mediators in COVID-19 prevention measures. A process evaluation from Bremen, Germany
Authors: Brand Tilman , Gerstmann Marieke , Samkange-Zeeb Florence , Zeeb Hajo
Published: October 2023

Objective

The objective was to assess the feasibility of incorporating trained community health mediators in COVID-19 prevention in a multicultural and disadvantaged setting in Bremen, Germany. Specifically, we aimed to develop and implement measures corresponding to the needs of the residents and to analyse the role of digital communication tools and sustainability factors of the health mediator approach.

Methods

A comprehensive process evaluation using 41 qualitative interviews with residents, mediator short surveys and group discussions, work documentation sheets, and a stakeholder workshop was carried out.

Results

Uncertainties due to changing regulations, a lack of trust and fear of potential side effects were major themes identified in the needs assessment. The eight mediators documented more than 1,600 contacts. Digital communication via Facebook was a useful tool, but personal contacts remained crucial for communicating with residents. The participatory approach, multilingualism and the flexibility to react to dynamic situations were identified as relevant factors for the success and sustainability of the health mediator approach.

Conclusion

Multilingual health mediators can facilitate contact with and dissemination of health information to different communities and also can play an important role in pandemic preparedness.
Petrogenesis and geological implications of the qiyishan triassic granitoids in east Beishan orogen, inner Mongolia, NW China: evidence from geochronology, geochemistry and Nd-Hf isotopes
Authors: Liu Ruiqin , Chen Chao , Lv Xinbiao , Zhang Zhongcheng , Ruan Banxiao , Zhang Shanming , Hu Erhong
Published: October 2023

The Qiyishan deposit is a large-scale Rb polymetallic deposit in the Beishan orogen. However, there remain debates regarding its metallogenic age and tectonic setting. In addition, studies of Triassic tectono-magmatic events in the Beishan orogen are still insufficient, and conducting genesis studies on the Qiyishan Triassic granitoids will help to enhance the understanding of Triassic magmatism and tectonic evolution in the Beishan orogen. In this contribution, we report new data for the ore-forming granitoids of Qiyishan deposit, including zircon U-Pb ages, major and trace element concentrations and Nd-Hf isotope compositions to define the ages and genesis of the Qiyishan granitoids and discuss their origin and geodynamic implications. Zircon U-Pb dating of the Qiyishan ore-forming granitoids yielded three ages of 217.5 ± 1.3 Ma, 217.2 ±0.8 Ma, and 207.5 ± 2.0 Ma, respectively. The age of Rb mineralization can be constrained to 207.5± 2.0 Ma, while the age of W-Sn-Mo mineralization is considered to be slightly younger than approximately 217 Ma. The Characteristics of major and trace elements of the rock samples indicate that the Qiyishan granites can be classified to highly fractionated I-type granite, and characterised by a transition to A-type like granite to some extent. The granites were not only affected by fractional crystallisation, but also underwent magmatic-hydrothermal interaction. The zircon εHf(t) values of the Qiyishan granitoids ranged from 3.28 to 16.07 and the Hf model age (TDMc) ranged from 0.216 to 1.042 Ga, revealing that the Qiyishan granitoids originated from the partial melting of both mantle and crustal sources. εNd(t) values ranged from −0.52 to −0.25, with Nd model ages of 0.998 Ga to 1.007 Ga. These results indicate that the granitoids originated from the mantle-derived magmas intruding into the lower crust within an intracontinental extensional environment. Combining the previous studies of Triassic granites in the Beishan orogen and this work, the Triassic granites exhibit a transition from I-type to A-type along the northeast direction, indicating a decrease in the contribution of ancient crustal to the magma source. We propose that the Qiyishan granitoids formed in a transitional tectonic environment, signifying the shift from post-orogenic to intracontinental extensional settings in beishan orogen during late Triassic.
BAM15 as a mitochondrial uncoupler: a promising therapeutic agent for diverse diseases
Authors: Xiong Guoji , Zhang Kexin , Ma Yujie , Song Yixin , Zhang Wenqiang , Qi Tongbing , Qiu Hongyan , Shi Junfeng , Kan Chengxia , Zhang Jingwen , Sun Xiaodong
Published: October 2023

Subcellular organelles dysfunction is implicated in various diseases, including metabolic diseases, neurodegenerative diseases, cancer, and cardiovascular diseases. BAM15, a selective mitochondrial uncoupler, has emerged as a promising therapeutic agent due to its ability to enhance mitochondrial respiration and metabolic flexibility. By disrupting the coupling between electron transport and ATP synthesis, BAM15 dissipates the proton gradient, leading to increased mitochondrial respiration and energy expenditure. This review provides a comprehensive overview of BAM15, including its mechanism of action and potential therapeutic applications in diverse disease contexts. BAM15 has shown promise in obesity by increasing energy expenditure and reducing fat accumulation. In diabetes, it improves glycemic control and reverses insulin resistance. Additionally, BAM15 has potential in non-alcoholic fatty liver disease, sepsis, and cardiovascular diseases by mitigating oxidative stress, modulating inflammatory responses, and promoting cardioprotection. The safety profile of BAM15 is encouraging, with minimal adverse effects and remarkable tolerability. However, challenges such as its high lipophilicity and the need for alternative delivery methods need to be addressed. Further research is necessary to fully understand the therapeutic potential of BAM15 and optimize its application in clinical settings.
Pathological mechanisms of type 1 diabetes in children: investigation of the exosomal protein expression profile
Authors: Bai Baoling , Gao Kang , Zhang Kexin , Liu Lingyun , Chen Xiaobo , Zhang Qin
Published: October 2023

Introduction

Type 1 diabetes (T1D) is a serious autoimmune disease with high morbidity and mortality. Early diagnosis and treatment remain unsatisfactory. While the potential for development of T1D biomarkers in circulating exosomes has attracted interest, progress has been limited. This study endeavors to explore the molecular dynamics of plasma exosome proteins in pediatric T1D patients and potential mechanisms correlated with T1D progression

Methods

Liquid chromatography-tandem mass spectrometry with tandem mass tag (TMT)6 labeling was used to quantify exosomal protein expression profiles in 12 healthy controls and 24 T1D patients stratified by age (≤ 6 years old and > 6 years old) and glycated hemoglobin (HbA1c) levels (> 7% or > 7%). Integrated bioinformatics analysis was employed to decipher the functions of differentially expressed proteins, and Western blotting was used for validation of selected proteins' expression levels.

Results

We identified 1035 differentially expressed proteins (fold change > 1.3) between the T1D patients and healthy controls: 558 in those ≤ 6-year-old and 588 in those > 6-year-old. In those who reached an HbA1c level < 7% following 3 or more months of insulin therapy, the expression levels of most altered proteins in both T1D age groups returned to levels comparable to those in the healthy control group. Bioinformatics analysis revealed that differentially expressed exosome proteins are primarily related to immune function, hemostasis, cellular stress responses, and matrix organization. Western blotting confirmed the alterations in RAB40A, SEMA6D, COL6A5, and TTR proteins.

Discussion

This study delivers valuable insights into the fundamental molecular mechanisms contributing to T1D pathology. Moreover, it proposes potential therapeutic targets for improved T1D management.
Early short-term effects on catecholamine levels and pituitary function in patients with pheochromocytoma or paraganglioma treated with [177Lu]Lu-DOTA-TATE therapy
Authors: Gubbi Sriram , Al-Jundi Mohammad , Auh Sungyoung , Jha Abhishek , Zou Joy , Shamis Inna , Meuter Leah , Knue Marianne , Turkbey Baris , Lindenberg Liza , Mena Esther , Carrasquillo Jorge A. , Teng Yating , Pacak Karel , Klubo-Gwiezdzinska Joanna , Del Rivero Jaydira , Lin Frank I.
Published: October 2023

Purpose

While there are reports of treatment-related endocrine disruptions and catecholamine surges in pheochromocytoma/paraganglioma (PPGL) patients treated with [177Lu]Lu-DOTA-TATE therapy, the spectrum of these abnormalities in the immediate post-treatment period (within 48 hours) has not been previously evaluated and is likely underestimated.

Methods

The study population included patients (≥18 years) enrolled in a phase 2 trial for treatment of somatostatin receptor (SSTR)-2+ inoperable/metastatic pheochromocytoma/paraganglioma with [177Lu]Lu-DOTA-TATE (7.4 GBq per cycle for 1 – 4 cycles). Hormonal measurements [adrenocorticotropic hormone (ACTH), cortisol, thyroid stimulating hormone (TSH), free thyroxine (FT4), follicle stimulating hormone (FSH), luteinizing hormone (LH), testosterone, estradiol, growth hormone, prolactin], catecholamines, and metanephrines were obtained on days-1, 2, 3, 30, and 60 per cycle as per trial protocol, and were retrospectively analyzed.

Results

Among the 27 patients (age: 54 ± 12.7 years, 48.1% females) who underwent hormonal evaluation, hypoprolactinemia (14.1%), elevated FSH (13.1%), and elevated LH (12.5%) were the most frequent hormonal abnormalities across all 4 cycles combined. On longitudinal follow-up, significant reductions were noted in i. ACTH without corresponding changes in cortisol, ii. TSH, and FT4, and iii. prolactin at or before day-30 of [177Lu]Lu-DOTA-TATE. No significant changes were observed in the gonadotropic axis and GH levels. Levels of all hormones on day-60 were not significantly different from day-1 values, suggesting the transient nature of these changes. However, two patients developed clinical, persistent endocrinopathies (primary hypothyroidism: n=1 male; early menopause: n=1 female). Compared to day-1, a significant % increase in norepinephrine, dopamine, and normetanephrine levels were noted at 24 hours following [177Lu]Lu-DOTA-TATE dose and peaked within 48 hours.

Conclusions

[177Lu]Lu-DOTA-TATE therapy is associated with alterations in endocrine function likely from radiation exposure to SSTR2+ endocrine tissues. However, these changes may sometimes manifest as clinically significant endocrinopathies. It is therefore important to periodically assess endocrine function during [177Lu]Lu-DOTA-TATE therapy, especially among symptomatic patients.

Clinical trial registration

https://clinicaltrials.gov/ct2/show/NCT03206060?term=NCT03206060&draw=2&rank=1, identifier NCT03206060.
Cytometry profiling of ex vivo recall responses to Coxiella burnetii in previously naturally exposed individuals reveals long-term changes in both adaptive and innate immune cellular compartments
Authors: Raju Paul Susan , Scholzen Anja , Reeves Patrick M. , Shepard Robert , Hess Joshua M. , Dzeng Richard K. , Korek Skylar , Garritsen Anja , Poznansky Mark C. , Sluder Ann E.
Published: October 2023

Introduction

Q fever, caused by the intracellular bacterium Coxiella burnetii, is considered an occupational and biodefense hazard and can result in debilitating long-term complications. While natural infection and vaccination induce humoral and cellular immune responses, the exact nature of cellular immune responses to C. burnetii is incompletely understood. The current study seeks to investigate more deeply the nature of long-term cellular recall responses in naturally exposed individuals by both cytokine release assessment and cytometry profiling.

Methods

Individuals exposed during the 2007-2010 Dutch Q fever outbreak were grouped in 2015, based on a C. burnetii-specific IFNγ release assay (IGRA), serological status, and self-reported clinical symptoms during initial infection, into asymptomatic IGRA-negative/seronegative controls, and three IGRA-positive groups (seronegative/asymptomatic; seropositive/asymptomatic and seropositive/symptomatic). Recall responses following in vitro re-stimulation with heat-inactivated C. burnetii in whole blood, were assessed in 2016/2017 by cytokine release assays (n=55) and flow cytometry (n=36), and in blood mononuclear cells by mass cytometry (n=36).

Results

Cytokine release analysis showed significantly elevated IL-2 responses in all seropositive individuals and elevated IL-1β responses in those recovered from symptomatic infection. Comparative flow cytometry analysis revealed significantly increased IFNγ, TNFα and IL-2 recall responses by CD4 T cells and higher IL-6 production by monocytes from symptomatic, IGRA-positive/seropositive individuals compared to controls. Mass cytometry profiling and unsupervised clustering analysis confirmed recall responses in seropositive individuals by two activated CD4 T cell subsets, one characterized by a strong Th1 cytokine profile (IFNγ+IL-2+TNFα+), and identified C. burnetii-specific activation of CD8 T cells in all IGRA-positive groups. Remarkably, increased C. burnetii-specific responses in IGRA-positive individuals were also observed in three innate cell subpopulations: one characterized by an IFNγ+IL-2+TNFα+ Th1 cytokine profile and lack of canonical marker expression, and two IL-1β-, IL-6- and IL-8-producing CD14+ monocyte subsets that could be the drivers of elevated secretion of innate cytokines in pre-exposed individuals.

Discussion

These data highlight that there are long-term increased responses to C. burnetii in both adaptive and innate cellular compartments, the latter being indicative of trained immunity. These findings warrant future studies into the protective role of these innate responses and may inform future Q fever vaccine design.
Case Report: Overcoming challenges in pancreatic cancer with liver metastases: a personalized therapeutic odyssey of TACE, ablation, and immunotherapy
Authors: Zhu Ying , Ning Zhouyu , Meng Zhiqiang
Published: October 2023

Pancreatic cancer represents a malignant neoplasm originating from pancreatic cells. The optimal approach to cancer treatment remains uncertain, lacking a definitive consensus. Here, we present a compelling case of a 49-year-old female with pancreatic head cancer with liver metastases, as identified by CT and confirmed by biopsy. PET-CT indicated widespread metastatic involvement. TACE therapy with gemcitabine and cisplatin was initiated, yielding a stable disease response. The patient’s high PD-L1 expression prompted TACE-PD-1 monoclonal antibody combination therapy. Subsequent treatments, including ablation, sustained PD-1 immunotherapy, and consolidation TACE, culminated in a complete response, as evidenced by imaging and tumor marker dynamics. Our case underscores the potential of multifaceted strategies in managing aggressive pancreatic cancer.
Sea surface skin temperature retrieval from HY-1D COCTS observations
Authors: Li Zhuomin , Guan Lei , Chen Rui
Published: October 2023

The Haiyang-1D (HY-1D) satellite is an operational satellite for observing the ocean and was launched on 11 June 2020. The Chinese Ocean Color and Temperature Scanner (COCTS) is on board the HY-1D satellite and the 11 μm and 12 μm channel data can be used for sea surface temperature (SST) retrieval. This paper uses the COCTS 11 μm and 12 μm channel brightness temperatures (BTs) for skin SST retrieval based on atmospheric radiative transfer modeling. Representative atmospheric profiles are selected from the global ERA5 atmospheric profiles, and the 11 μm and 12 μm channel BTs are simulated using MODerate resolution atmospheric TRANsmission (MODTRAN) with the selected profiles. The skin SST retrieval algorithm is determined for each latitude band based on the simulated BT and ERA5 sea surface skin temperature. Cloud detection is performed using the visible channel data, 11 μm and 12 μm channel BT, retrieved COCTS SST, and the reference SST. The retrieved COCTS skin SST is validated with the in situ SST and the Visible Infrared Imaging Radiometer Suites (VIIRS) SST. The global COCTS SST from May to July 2021 was retrieved and evaluated. The time window is 1 h, and the spatial window is 0.01°×0.01°. The bias of COCTS SST and in situ SST is -0.11°C, the standard deviation is 0.54°C, the median is -0.08°C, and the robust standard deviation is 0.47°C. The bias of COCTS SST and VIIRS SST is 0.03°C, the standard deviation is 0.53°C, the median is 0.06°C, and the robust standard deviation is 0.49°C. The results demonstrate that the algorithm performs well for the global coverage.
Acute abdominal pain as the first symptom of Chlamydia psittaci pneumonia complicated by acute pancreatitis: a case report
Authors: Fang Changquan , Xie Yanjun , Mai Hui , Xu Limin
Published: October 2023

Background

Chlamydia psittaci infections primarily cause damage to the lungs but may also affect the cardiovascular system, gastrointestinal tract, liver, kidney, and brain, resulting in a variety of extrapulmonary complications. However, reports regarding C. psittaci infection-associated pancreatitis are rare. In this report, a patient with C. psittaci pneumonia complicated by acute pancreatitis is presented.

Case description

The patient presented with acute upper abdominal pain and developed severe pyrexia and dyspnoea one day later. A chest computed tomography image revealed patchy consolidation in the left lung. The disease progressed rapidly, and the patient exhibited liver and kidney damage and type 1 respiratory failure within a short period of time. Metagenomic next-generation sequencing of alveolar lavage fluid revealed the presence of C. psittaci. The patient was administered doxycycline and moxifloxacin, after which the patient’s abdominal pain and lung infection significantly resolved.

Conclusion

This case report demonstrates that extrapulmonary C. psittaci infections due to secondary acute pancreatitis can manifest as abdominal pain, although the exact mechanisms of C. psittaci caused by acute pancreatitis remain unclear. Timely diagnoses and treatments of such infections are necessary to achieve favorable clinical outcomes.
Application of multi-functional lactic acid bacteria strains in a pilot scale feta cheese production
Authors: Kamarinou Christina S. , Papadopoulou Olga S. , Doulgeraki Agapi I. , Tassou Chrysoula C. , Galanis Alex , Chorianopoulos Nikos G. , Argyri Anthoula A.
Published: October 2023

Feta cheese is the most recognized Greek Protected Designation of Origin (PDO) product in the world. The addition of selected autochthonous lactic acid bacteria (LAB) strains to cheese milk as adjunct cultures is gaining more attention, since they can impact the nutritional, technological and sensory properties of cheeses, as well as improve the safety of the product. The aim of this study was to produce Feta cheese with enhanced quality and safety, and distinctive organoleptic characteristics by applying autochthonous lactic acid bacteria (LAB) with multi-functional properties as adjunct cultures. Feta cheeses were produced with the commercial lactococcal starter culture and the addition of 9 LAB strains (Lactococcus lactis SMX2 and SMX16, Levilactobacillus brevis SRX20, Lacticaseibacillus paracasei SRX10, Lactiplantibacillus plantarum FRX20 and FB1, Leuconostoc mesenteroides FMX3, FMX11, and FRX4, isolated from artisanal Greek cheeses) in different combinations to produce 13 cheese trials (12 Feta trials with the adjunct LAB isolates and the control trial). In addition, Feta cheese manufactured with FMX3 and SMX2 and control Feta cheese were artificially inoculated (4 log CFU/g) with Listeria monocytogenes (a cocktail of 4 acid or non-acid adapted strains). Cheese samples were monitored by microbiological and physicochemical analyses during ripening, and microbiological, physicochemical, molecular and sensory analyses during storage at 4°C. The results showed that after manufacture, the LAB population was ca. 9.0 log CFU/g at all samples, whereas during storage, their population declined to 6.5–7.0 log CFU/g. In the Listeria inoculated samples, Listeria was absent after 60 days (end of ripening) and after 90 days in the adjunct culture, and in the control trials, respectively. Moreover, the addition of selected strains, especially Lcb. paracasei SRX10, led to cheeses with desirable and distinctive organoleptic characteristics. Furthermore, randomly amplified polymorphic PCR (RAPD-PCR) molecular analysis confirmed that the multi-functional LAB strains were viable by the end of storage. Overall, the results of this study are promising for the use of autochthonous strains in various combinations with the commercial starter culture to satisfy industry requirements and consumer demands for traditional and high added value fermented products.
Multiple ossified intracranial and spinal meningiomas: a rare case report and literature review
Authors: Wang Jian , Zhang Anbang , Wang Boya , Yuan Jingmeng , Zhu Junchi , Li Mengjiao , Liu Henli , Cheng Lijuan , Kong Ping
Published: October 2023

Ossified intracranial meningiomas (OIM) and ossified spinal meningiomas (OSM) are rare neoplasms of mesenchymal origin that predominantly manifest in the spinal cord and infrequently in the cranial region, accounting for ~0. 7–5.5% of all meningiomas. It is extremely rare to have multiple intracranial and spinal lesions accompanied by ossification. Herein, we report this rare case for the first time. A 34-year-old woman presented with paresthesia and limb weakness in the right lower limb and gradually worsened. Approximately half a year later, she could only walk with crutches. Magnetic resonance imaging of the brain and spinal cord showed multiple meningiomas, and histopathological examination confirmed multiple OIM and OSM (WHO grade 1). Multiple OIM and OSM are extremely rare with diverse imaging features, and it is easily confused with other tumors. Histopathological examination is the final diagnostic method.
Case report: An OSAS patient with comorbid RLS/PLMS – a closer look at the causes of PAP intolerance
Authors: Dirks Christina A. H. , Bachmann Cornelius G.
Published: October 2023

Since 2017, hypoglossal nerve stimulation has been included in the S3-guidelines on restorative sleep/sleep disorders as an alternative treatment for patients with obstructive sleep related breathing disorders who cannot tolerate conventional PAP-therapy. Under certain conditions, some of these patients have the option to have a tongue pacemaker implanted during a surgical procedure to regain a restful night’s sleep. However, in some cases it does not solve the problem. In this case report, we present a patient who continued to have restless sleep despite implantation of a hypoglossus nerve stimulator. We provide a closer look at the underlying causes of PAP intolerance and emphasize the importance of a combined pneumological and neurological approach to sleep medicine in sleep-specific therapy evaluation.
A cohort study on anxiety and perceived recovery 3 and 12 months after mild to moderate stroke
Authors: Nelsone Linda , Rafsten Lena , Abzhandadze Tamar , Sunnerhagen Katharina S.
Published: October 2023

Background

Anxiety is a common complication of stroke, affecting one in every three stroke survivors. Stroke recovery is a dynamic process, with most recovery occurring within the first 3 months. However, how anxiety affects this dynamic remains unknown. Therefore, this study aimed to investigate how anxiety affects perceived recovery at 3 and 12 months after stroke. Additionally we also examined the change in perceived stroke recovery from 3 to 12 months and its relationship with anxiety.

Methods

In this longitudinal study patients with stroke were enrolled at Sahlgrenska University Hospital, Gothenburg, Sweden. The Hospital Anxiety and Depression Scale was used to assess anxiety, and the Stroke Impact Scale was used to assess perceived recovery 3 and 12 months after the stroke. The difference in perceived stroke recovery between the anxiety and no-anxiety groups at 3 and 12 months was analyzed. Changes in perceived stroke recovery were calculated and trichotomized from 3 to 12 months based on clinically significant positive changes (+10 points or more), clinically important negative changes (−10 points or less), or no changes (±9). At 3 and 12 months after the stroke, negative and positive recovery was compared to no change in recovery regarding anxiety scores.

Results

This study included 99 patients (44.4% female, median age, 77 years). At 3 and 12 months after the stroke, the median recovery score was 80 out of 100. At 3- and 12-months 17.6 and 15.7% of the patients experienced anxiety, respectively. At both time points, there was a significant association between anxiety and lower perceived stroke recovery (at 3 months: p < 0.001; and 12 months p = 0.002). Among participants with anxiety at 3 or 12 months after stroke, a positive change in recovery from 3 to 12 months was identified (3 months, p = 0.004 and 12 months, p = 0.0014).

Conclusion

Anxiety symptoms following a stroke are associated with lower levels of perceived stroke recovery for at least 1 year after the stroke. Identifying patients with anxiety early after stroke may be beneficial for identifying those at risk of lower recovery.

Clinical trial registration:ClinicalTrials.gov, identifier [NCT01622205]. Registered on June 19, 2012 (retrospectively registered).
Planned drug holidays during treatment with lenvatinib for radioiodine-refractory differentiated thyroid cancer: a retrospective study
Authors: Matsuyama Chihiro , Enokida Tomohiro , Ueda Yuri , Suzuki Shinya , Fujisawa Takao , Ito Kazue , Okano Susumu , Tahara Makoto
Published: October 2023

Background

In the phase 3 SELECT study, lenvatinib significantly improved prognostic outcomes vs. placebo in patients with radioiodine-refractory differentiated thyroid cancer (RR-DTC). However, toxicity of lenvatinib is sometimes considerable and requires frequent dose interruptions and modifications. Recently, planned drug holidays have been proposed as a means of avoiding severe adverse events (AEs).

Methods

We retrospectively reviewed medical records to compare the efficacy and safety of lenvatinib in RR-DTC patients who underwent planned drug holidays (planned holiday group) vs. those who received conventional daily oral administration (daily group).

Results

The subjects were 25 patients in the planned holiday group and 21 in the daily group. Median age was 73 years (range 43-84) and 62 years (range 42-75), and histologic subtype of papillary/follicular was 21/4 cases and 15/6 cases, respectively. Time to treatment failure (TTF) and overall survival (OS) were significantly longer in the planned holiday group than the daily group (not reached [NR] vs. 14.9 months, hazard ratio [HR] 0.25, 95% confidence interval [Cl] 0.11-0.58, p<0.001; NR vs. 26.6 months, HR 0.20, 95% CI 0.073-0.58, p=0.001, respectively). Median progression-free survival (PFS) was NR in the planned holiday group vs. 15.1 months in the daily group (HR 0.31, 95% CI 0.14-0.68, p=0.002). Duration of the period with lenvatinib dose ≥10 mg was significantly longer in the planned holiday group (NR vs. 6.5 months, HR 0.22, 95% CI 0.10-0.49, p<0.001), and the frequency of drug interruption due to intolerable AEs was lower (68.0% vs. 95.2%, p=0.027).

Conclusion

Planned drug holidays for lenvatinib demonstrated significantly longer PFS, TTF, and OS than daily oral administration, and less intolerable toxicity leading to further unplanned treatment interruption. These benefits were apparently associated with a more extended period of lenvatinib administration at ≥10 mg. These findings might contribute to a favorable patient prognosis and safer toxicity profile.
Tumor microenvironment-induced tumor cell plasticity: relationship with hypoxic stress and impact on tumor resistance
Authors: Zaarour RF. , Ribeiro M. , Azzarone B. , Kapoor S. , Chouaib S.
Published: October 2023

The role of tumor interaction with stromal components during carcinogenesis is crucial for the design of efficient cancer treatment approaches. It is widely admitted that tumor hypoxic stress is associated with tumor aggressiveness and thus impacts susceptibility and resistance to different types of treatments. Notable biological processes that hypoxia functions in include its regulation of tumor heterogeneity and plasticity. While hypoxia has been reported as a major player in tumor survival and dissemination regulation, the significance of hypoxia inducible factors in cancer stem cell development remains poorly understood. Several reports indicate that the emergence of cancer stem cells in addition to their phenotype and function within a hypoxic tumor microenvironment impacts cancer progression. In this respect, evidence showed that cancer stem cells are key elements of intratumoral heterogeneity and more importantly are responsible for tumor relapse and escape to treatments. This paper briefly reviews our current knowledge of the interaction between tumor hypoxic stress and its role in stemness acquisition and maintenance. Our review extensively covers the influence of hypoxia on the formation and maintenance of cancer stem cells and discusses the potential of targeting hypoxia-induced alterations in the expression and function of the so far known stem cell markers in cancer therapy approaches. We believe that a better and integrated understanding of the effect of hypoxia on stemness during carcinogenesis might lead to new strategies for exploiting hypoxia-associated pathways and their targeting in the clinical setting in order to overcome resistance mechanisms. More importantly, at the present time, efforts are oriented towards the design of innovative therapeutical approaches that specifically target cancer stem cells.
Trajectory generation based on power for urban air mobility
Authors: Paielli Russell A.
Published: October 2023

A method of generating trajectories based on power is proposed for Urban Air Taxis. The method is simpler and more direct than traditional methods because it does not require a detailed aircraft model or a flight control model. Instead, it allows the user to specify the route, the static longitudinal profile (altitude as a function of distance), and a power model to determine the progress in time along that profile. The power model can be determined from a recorded or simulated trajectory of the same aircraft type. This capability allows a trajectory to be generated or reshaped to avoid conflicts while preserving the basic performance characteristics. Net or excess power is defined as the rate of change of mechanical (kinetic and potential) energy, and it is modeled as a function of airspeed. The time steps between discrete points in space along the trajectory are used to yield a specified power as a function of airspeed, and they are determined by solving a cubic polynomial at each point. An elliptical profile is used to generate an example trajectory. The dependence of trip flight time on various parameters is analyzed and plotted.
Role of mu opioid receptor (MOR) agonist efficacy as a determinant of opioid antinociception in a novel assay of pain-depressed behavior in female and male mice
Authors: Negus S. Stevens , Akbarali Hamid I. , Kang Minho , Lee Young K. , Marsh Samuel A. , Santos Edna J. , Zhang Yan
Published: October 2023

Introduction

Intermediate efficacy mu opioid receptor (MOR) agonists have potential to retain analgesic effectiveness while improving safety, but the optimal MOR efficacy for effective and safe opioid analgesia is unknown. Preclinical assays of pain-depressed behavior can assess effects of opioids and other candidate analgesics on pain-related behavioral depression, which is a common manifestation of clinically relevant pain and target of pain treatment. Accordingly, the present study goal was to validate a novel assay of pain-depressed locomotor behavior in mice and evaluate the role of MOR efficacy as a determinant of opioid analgesic effects and related safety measures.

Methods

Male and female ICR mice were tested in a locomotor chamber consisting of 2 compartments connected by a doorway that contained a 1-inch-tall barrier. Dependent measures during 15-min behavioral sessions included crosses between compartments (which required vertical activity to surmount the barrier) and total movement counts (which required horizontal activity to break photobeams in each compartment).

Results and Discussion

Intraperitoneal injection of lactic acid (IP acid) produced a concentration- and time-dependent depression of both endpoints. Optimal blockade of IP acid-induced behavioral depression with minimal motor impairment was achieved with intermediate-efficacy MOR treatments that also produced less gastrointestinal-transit inhibition and respiratory depression than the high-efficacy MOR agonist fentanyl. Sex differences in treatment effects were rare. Overall, these findings validate a novel procedure for evaluating opioids and other candidate analgesic effects on pain-related behavioral depression in mice and support continued research with intermediate-efficacy MOR agonists as a strategy to retain opioid analgesic effectiveness with improved safety.
Neonatal cholestasis as the onset symptom of McCune–Albright syndrome: case reports and a literature review
Authors: Fang Weiyuan , Zhang Yanhui , Chen Lian , Xie Xinbao
Published: October 2023

Aim

This study aimed to summarize and show the characteristics and evolutionary process of neonatal cholestasis caused by McCune–Albright syndrome (MAS), as neonatal cholestasis may be the initial manifestation of MAS before other classic clinical features appear.

Methods

The clinical characteristics, treatment methods, and outcomes of three neonatal cholestasis cases caused by MAS in our center were retrospectively studied. In addition, all the reported cases of MAS combined with cholestasis were reviewed and summarized to show the cholestatic features in them.

Results

We have confirmed three MAS cases in our center, presenting onset symptoms of jaundice, pale stool, and neonatal cholestasis soon after birth. The cholestasis subsided spontaneously at around the sixth month. The literature review showed that the levels of total bilirubin, conjugated bilirubin, ALT, AST, and GGT in neonatal MAS cholestasis cases were 207 μmol/L (range 65–445 μmol/L), 162 μmol/L (range 46–412 μmol/L), 821 U/L (range 85–3,597 U/L), 532 U/L (range 127–3,633 U/L), and 244 U/L (range 79–3,800 U/L), respectively. Liver histology showed canalicular and hepatocellular cholestasis, giant hepatic cell transformation, and bile paucity. Extrahepatic manifestations such as café-au-lait pigmented skin lesions, Cushing's syndrome, hyperthyroidism, renal tubular dysfunction, and skeletal abnormalities could occur simultaneously when jaundice occurred. GNAS mutations had a high positive rate (83.3%–100%) in liver tissue with cholestasis. Neonatal cholestasis caused by MAS could be self-resolved, but hepatic lesions persist and have malignant potential.

Conclusion

MAS can be one of the causes of neonatal cholestasis, which may be the first manifestation of the disease. Extrahepatic coexisting symptoms of MAS and liver histology can help to distinguish MAS from other etiology of cholestasis. Detecting GNAS mutations in liver tissue may shorten diagnostic time and is of particular interest in the partial and atypical forms of MAS with neonatal cholestasis. Neonatal cholestasis in children with MAS can self-resolve, but liver dysfunction and malignant lesions persist.
Red sacaca essential oil-loaded nanostructured lipid carriers optimized by factorial design: cytotoxicity and cellular reactive oxygen species levels
Authors: Chura Sofia Santos Donaire , Memória Kathelen Anne Sudo , Lopes Amanda Tibães , Pelissari Franciele Maria , Da Silveira João Vinícios Wirbitzki , Bezerra Jaqueline de Araújo , Chaves Francisco Celio Maia , Rodrigues Ana Paula , Faria Jerusa Araújo Quintão Arantes , Carneiro Guilherme
Published: October 2023

Amazonian flora includes several species with the potential to develop pharmaceutical and biotechnological products. The essential oils from Amazonian species possess some biological properties, such as antioxidant, antibacterial, and cytotoxic activities. The essential oil of red sacaca (RSO), Croton cajucara Benth., contains metabolites characterized by antioxidant and anti-inflammatory activities. Nanostructured lipid carriers (NLC) are an advantageous alternative for the effective delivery of drugs because they can solubilize lipophilic actives and reduce their cytotoxicity. This study aimed to optimize the synthesis of RSO-loaded nanostructured lipid carriers (NLC-RSO) using a 23 factorial design and investigate their antioxidant and cytotoxic effects. The red sacaca essential oil (RSO) metabolite profile was characterized using gas chromatography coupled with a mass spectrometer (GC-MS), identifying 33 metabolites, with linalool and 7-hydroxy-calamenene as the major ones, as reported in the literature. The optimized NLC-RSO formulation had a particle size less than 100 nm and a polydispersity index lower than 0.25. After characterizing NLC-RSO using Fourier-transform infrared spectroscopy, powder X-ray diffraction, zeta potential, moisture content, and wettability, in vitro cytotoxicity were performed in A549 and BEAS-2B cell lines using the resazurin metabolism assay. The data indicated a lower IC50 for RSO than for NLC-RSOs in both cell lines. Furthermore, low cytotoxicity of blank nanoparticles (blank NP) and medium chain triglycerides-loaded nanostructured lipid carriers (NLC-MCT) towards both pulmonary cell lines was noted. At a concentration of 50–100 μg/mL, free RSO exhibited higher cytotoxicity than NLC-RSO, demonstrating the protective effect of this lipid carrier in reducing cytotoxicity during metabolite delivery. Similarly, free RSO showed higher 2,2-diphenyl-1-picrylhydrazyl (DPPH) radical scavenging than NLC-RSO, also indicating this protective effect. The 2′,7′-dichlorofluorescein diacetate (DCFH-DA) intracellular reactive oxygen species (ROS) level assay did not show differences between the treatments at higher but non-cytotoxic dosages. Taken together, our results suggest that NLC-RSOs are potential RSO delivery systems for applications related to cancer treatment.
Cellular traits regulate fluorescence-based light-response phenotypes of coral photosymbionts living in-hospite
Authors: McQuagge Audrey , Pahl K. Blue , Wong Sophie , Melman Todd , Linn Laura , Lowry Sean , Hoadley Kenneth D.
Published: October 2023

Diversity across algal family Symbiodiniaceae contributes to the environmental resilience of certain coral species. Chlorophyll-a fluorescence measurements are frequently used to determine symbiont health and resilience, but more work is needed to refine these tools and establish how they relate to underlying cellular traits. We examined trait diversity in symbionts from the generas Cladocopium and Durusdinium, collected from 12 aquacultured coral species. Photophysiological metrics (ΦPSII, σPSII, ρ, τ1, τ2, antenna bed quenching, non-photochemical quenching, and qP) were assessed using a prototype multi-spectral fluorometer over a variable light protocol which yielded a total of 1,360 individual metrics. Photophysiological metrics were then used to establish four unique light-response phenotypic variants. Corals harboring C15 were predominantly found within a single light-response phenotype which clustered separately from all other coral fragments. The majority of Durusdinium dominated colonies also formed a separate light-response phenotype which it shared with a few C1 dominated corals. C15 and D1 symbionts appear to differ in which mechanisms they use to dissipate excess light energy. Spectrally dependent variability is also observed across light-response phenotypes that may relate to differences in photopigment utilization. Symbiont cell biochemical and structural traits (atomic C:N:P, cell size, chlorophyll-a, neutral lipid content) was also assessed within each sample and differ across light-response phenotypes, linking photophysiological metrics with underlying primary cellular traits. Strong correlations between first- and second-order traits, such as Quantum Yield and cellular N:P content, or light dissipation pathways (qP and NPQ) and C:P underline differences across symbiont types and may also provide a means for using fluorescence-based metrics as biomarkers for certain primary-cellular traits.
Quality control of Ganoderma lucidum by using C, H, O, and N stable isotopes and C and N contents for geographical traceability
Authors: Zhang Ying , Jiang Kunxia , Chen Sisi , Wang Lina , Zhang Xun , Xu Wen , Yam Mun Fei , Wu Changhui , Xu Wei , Lin Yu
Published: October 2023

Rationale

Ganoderma lucidum (G. lucidum) is a popular medicinal fungus that has been used in traditional medicine for decades, with its provenance influencing its medicinal and commercial worth. The amount of active ingredients and the price of G. lucidum from different origins vary significantly; hence, fraudulent labeling is common. Reliable techniques for G. lucidum geographic verification are urgently required to safeguard the interests of consumers, producers, and honest dealers. A stable isotope is widely acknowledged as a useful traceability technique and could be developed to confirm the geographical origin of G. lucidum.

Methods

G. lucidum samples from various sources and in varying stages were identified by using δ13C, δD, δ18O, δ15N, C, and N contents combined with chemometric tools. Chemometric approaches, including PCA, OPLS-DA, PLS, and FLDA models, were applied to the obtained data. The established models were used to trace the origin of G. lucidum from various sources or track various stages of G. lucidum.

Results

In the stage model, the δ13C, δD, δ18O, δ15N, C, and N contents were considered meaningful variables to identify various stages of G. lucidum (bud development, growth, and maturing) using PCA and OPLS-DA and the findings were validated by the PLS model rather than by only four variables (δ13C, δD, δ18O, and δ15N). In the origin model, only four variables, namely δ13C, δD, δ18O, and δ15N, were used. PCA divided G. lucidum samples into four clusters: A (Zhejiang), B (Anhui), C (Jilin), and D (Fujian). The OPLS-DA model could be used to classify the origin of G. lucidum. The model was validated by other test samples (Pseudostellaria heterophylla), and the external test (G. lucidum) by PLS and FLDA models demonstrated external verification accuracy of up to 100%.

Conclusion

C, H, O, and N stable isotopes and C and N contents combined with chemometric techniques demonstrated considerable potential in the geographic authentication of G. lucidum, providing a promising method to identify stages of G. lucidum.
Pilot study of attentional retraining for postpartum smoking relapse
Authors: Forray Ariadna , Gunter-Riley R. Gwen , Maltz Caro , Waters Andrew J.
Published: October 2023

Introduction

Tobacco smoking is a leading cause of preventable death worldwide. The perinatal period provides a unique opportunity for intervention, as many smokers quit smoking during pregnancy but relapse postpartum. Novel relapse prevention interventions that reduce the burden of treatment attendance in this population are needed. Attentional retraining (AR) has been shown to reduce attentional biases toward smoking-related stimuli, a cognitive process implicated in smoking, AR has not been applied to perinatal smokers, and the effect of AR on craving and smoking is not clear. The goal of this study was to evaluate the delivery of AR for smoking cues in perinatal smokers utilizing a mobile intervention.

Methods

This pilot study utilized Ecological Momentary Assessment (EMA) methodology delivered on a mobile device to examine the relapse process and evaluate the utility of AR in former smokers attempting to remain abstinent postpartum. AR (or Control Training) was administered to abstinent smokers (N = 17) for up to 2 weeks both before and after delivery.

Results

All 17 participants completed the study. There was evidence that AR reduced attentional bias in the AR group (vs. Controls). There was no evidence that AR reduced craving. An exploratory analysis revealed that there was no evidence that AR reduced smoking during the study period.

Discussion

AR using EMA methodology via a mobile device is feasible in perinatal smokers. Further research using larger samples is required to evaluate the utility of mobile AR in reducing craving and smoking.
Development and evaluation of a tailored mHealth parenting program for multicultural families: a three-arm cluster randomized controlled trial
Authors: Son Hyunmi , Han Gyumin
Published: October 2023

Objective

Health management of children during early childhood requires substantial information. Multicultural families find it difficult to obtain and use parenting-relevant information for their young children. This study aimed to develop, implement, and evaluate a tailored Health parenting program and lay-health workers’ support to improve children’s health in multicultural families in Korea.

Methods

In this study, we employed the Analysis, Design, Development, Implementation, and Evaluation (ADDIE) model as the conceptual framework, guiding the creation of a tailored mHealth application supplemented by a lay-health worker support module. The efficacy of the program was assessed through an experimental three-arm cluster randomized controlled trial. A total of 101 participants were stratified into three distinct groups as follows: (1) Experimental Group A, which received the mHealth program alongside the lay-health worker support component; (2) Experimental Group B, exposed solely to the mHealth program; and (3) Control Group, devoid of any intervention. Within these groups, 101 marriage migrant women hailing from Vietnam, the Philippines, and China were incorporated, with each group comprising 33, 30, and 38 participants, respectively. The study’s primary endpoint encompassed a comprehensive assessment of health-promoting behaviors, proficiency in eHealth literacy, and the family strength.

Results

The analysis revealed noteworthy interactions among the three distinct groups over the course of time, with implications for health-promotion behaviors (p = 0.041), eHealth literacy (p = 0.037), and family strength (p = 0.044). Specifically, the experimental groups exhibited substantially elevated levels of the specified outcome variables when contrasted with the control group. Notably, the positive effects persisted even up to 12 weeks subsequent to the conclusion of the intervention, underscoring the program’s capacity to foster enduring improvements in the observed metrics.

Conclusion

This study highlights the benefits of offering contextually appropriate information to target groups constrained by challenges in information access, evaluation, and utilization. Notably, drawing from their positive experiences in this process, we underscore the importance of employing lay health workers. These workers play a crucial role in fostering and ensuring sustained behavioral changes.