bluuebunny/crossref_metadata_2025 huggingface dataset:
COVID-19-related retinal microvasculopathy and systemic implications in patients with severe disease: results from the Methuselah study
Authors: Castellino Niccolò , Longo Antonio , Russo Andrea , Bonfiglio Vincenza , Fallico Matteo , Toro Mario Damiano , Cappellani Francesco , Grillo Marco , Gaudio Agostino , Lo Cicero Lorenzo , Sessa Concetto , Colaci Michele , Malatino Lorenzo , Castellino Pietro , Avitabile Teresio , Zanoli Luca
Published: January 2024

Objectives

To assess the reversibility of retinal microvascular changes in the long term and to investigate the potential links with other vascular diseases of COVID-19.

Methods

We designed a prospective multicenter observational study. Patients were enrolled from the Methuselah study cohort. Retinal vascular function was studied in these patients using optical coherence tomography angiography (OCTA); aortic stiffness was measured using aortic pulse wave velocity. These examinations were performed 1 (Visit 1) and 12 (Visit 2) months after the hospital discharge for severe COVID-19. A control subject group matched for age and sex was included to define normal values.

Results

A total of 28 control subjects (56 eyes) and 25 patients (50 eyes) completed the scheduled OCTA assessment; 18 patients (36 eyes) also completed the macrovascular examination. Compared to controls, the vessel density of the superficial capillary plexus (SCP) was reduced, whereas the foveal avascular zone area was enlarged at Visit 1 (p = 0.016 and < 0.001, respectively) and was not modified after the 12-month follow-up in COVID-19 patients (p = 0.011 and 0.001, respectively). Higher inflammation and lower renal function during hospitalization were linked to higher aortic stiffness and reduced vessel density of the SCP 1 month after the acute phase of COVID-19. A slower recovery of aortic dysfunction was linked to worse retinal vascular outcomes at Visit 2.

Conclusion

Retinal vascular alterations were not reversible 12 months after COVID-19 and were linked to inflammation and renal dysfunction during hospitalization as well as to aortic stiffness measured during follow-up.
ACUM, an easily underdiagnosed cause of dysmenorrhea—A case report
Authors: Hu Qicai , Guo Chunlei , Chen Qing , Zhang Wei , Wang Huifang , Wei Weixia
Published: January 2024

This report described three cases with long-term severe dysmenorrhea, and these cases were referred to our department for medical help. The diagnosis of accessory cavitated uterine malformation (ACUM) was considered based on symptoms and ultrasound/MRI findings. Moreover, a combined approach involving hysteroscopic surgery and laparoscopic surgery was undertaken, and no complications occurred during surgery and in the post-operative period. It is important to consider ACUM in patients with severe dysmenorrhea that does not respond to medical management. Surgery is the most effective treatment for this anomaly.
In vitro evaluation of the immunomodulatory and wakame assimilation properties of Lactiplantibacillus plantarum strains from swine milk
Authors: Ohgi Ryusuke , Saha Sudeb , Zhou Binghui , Sakuma Taiga , Sakurai Mitsuki , Nakano Yuhka , Namai Fu , Ikeda-Ohtsubo Wakako , Suda Yoshihito , Nishiyama Keita , Villena Julio , Kitazawa Haruki
Published: January 2024

The emergence and spread of antibiotic resistance threat forced to explore alternative strategies for improving the resistance to pathogens in livestock production. Probiotic lactic acid bacteria represent an alternative for this objective. In this study, seven Lactiplantibacillus plantarum strains from porcine colostrum and milk were isolated, identified and characterized in terms of their abilities to modulate immunity in porcine intestinal epithelial (PIE) cells. Then, two potential immunoregulatory strains were studied in terms of their ability to utilize and grow in wakame (Undaria pinnafida). Isolates were identified by 16S rRNA gene and evaluated by studying their interaction with PIE cells. The expressions of peptidoglycan recognition proteins (PGRPs), nucleotide-binding oligomerization domain (NODs), host defense peptides (pBD), and type I interferons (IFNs) were evaluated by RT-qPCR. The strain 4M4417 showed a remarkable capacity to differentially regulate the expression of PGRP1, PGRP3, NOD1, NOD2, and pBD1 in PIE cells. On the other hand, the strain 4M4326 was the most efficient to improve the expression of IFN-α and IFN-β in PIE cells challenged with poly (I:C). Both L. plantarum 4M4326 and 4M4417 were characterized in terms of their ability to utilize wakame. Results demonstrated that both strains efficiently grew in wakame-based broth. Our results suggest that L. planatrum 4M4326 and 4M4417 are interesting candidates to develop immunomodulatory feeds based on wakame utilization. These new immunosynbiotic feeds could help to reduce severity of intestinal infections and improve immune health status in pigs.
Biodiversity of network modules drives ecosystem functioning in biochar-amended paddy soil
Authors: Xiao Yu , Zhou Guixiang , Qiu Xiuwen , Liu Fangming , Chen Lin , Zhang Jiabao
Published: January 2024

Introduction

Soil microbes are central in governing soil multifunctionality and driving ecological processes. Despite biochar application has been reported to enhance soil biodiversity, its impacts on soil multifunctionality and the relationships between soil taxonomic biodiversity and ecosystem functioning remain controversial in paddy soil.

Methods

Herein, we characterized the biodiversity information on soil communities, including bacteria, fungi, protists, and nematodes, and tested their effects on twelve ecosystem metrics (including functions related to enzyme activities, nutrient provisioning, and element cycling) in biochar-amended paddy soil.

Results

The biochar amendment augmented soil multifunctionality by 20.1 and 35.7% in the early stage, while the effects were diminished in the late stage. Moreover, the soil microbial diversity and core modules were significantly correlated with soil multifunctionality.

Discussion

Our analysis revealed that not just soil microbial diversity, but specifically the biodiversity within the identified microbial modules, had a more pronounced impact on ecosystem functions. These modules, comprising diverse microbial taxa, especially protists, played key roles in driving ecosystem functioning in biochar-amended paddy soils. This highlights the importance of understanding the structure and interactions within microbial communities to fully comprehend the impact of biochar on soil ecosystem functioning in the agricultural ecosystem.
The association between closed-eye unipedal standing and the risk of cognitive impairment in the elderly: a 7-year community-based cohort study in Wuhan, China
Authors: Wang Shiwei , Guo Peng , Huang Chengjing , Zhang Yuqian , Xiang Bing , Zeng Jing , Zhou Feng , Xie Xinyan , Guo Yan , Yang Mei
Published: January 2024

Objectives

The prevention of cognitive impairment in the elderly is one of the public health priority areas. However, the relationship between closed-eye unipedal standing and cognitive impairment remains unclear.

Methods

This study was conducted on a group of elderly individuals from a community, using a prospective cohort study design. Participants were monitored for 7 years and were diagnosed with new-onset cognitive impairment. Logistic regression models and restricted cubic spline (RCS) were used to investigate the relationship between closed-eye unipedal standing and cognitive impairment. Stratified analysis by baseline characteristics were also performed.

Results

At baseline, 1,652 people aged 65 years or older were enrolled. Ultimately, 880 participants completed the follow-up and 155 (17.61%) of them satisfied the diagnostic criteria for cognitive impairment at follow-up. Compared to the closed-eye unipedal standing low group as the reference, the middle (OR = 0.601, 95% CI: 0.396–0.911) and high (OR = 0.508, 95% CI: 0.329–0.785) groups had significantly lower cognitive impairment risks. RCS analysis indicated a linear relationship (Pnon − linear = 0.177), with a reduced risk of developing cognitive impairment when the duration of closed-eye unipedal standing was exceeded ~2.920 s. Stratified analysis showed that for female, aged 70 years or younger, with 3 or more years of education, without lack of exercise and without falls within 1 year subgroup, the elderly in the high group of closed-eye unipedal standing had significantly reduced cognitive impairment risks.

Conclusion

Among the elderly population, closed-eye unipedal standing duration was linearly and negatively associated with the cognitive impairment risk. The closed-eye unipedal standing duration might be a predictive index for cognitive impairment in the elderly.
Radiation-induced glymphatic dysfunction in patients with nasopharyngeal carcinoma: a study using diffusion tensor image analysis along the perivascular space
Authors: Zheng Xingyou , Peng Jianchun , Zhao Qing , Li Li , Gao Jian-ming , Zhou Keyang , Tan Bei , Deng Lingling , Zhang Youming
Published: January 2024

Radiation encephalopathy (RE) refers to radiation-induced brain necrosis and is a life-threatening complication in patients with nasopharyngeal carcinoma (NPC) after radiotherapy (RT), and radiation-induced pre-symptomatic glymphatic alterations have not yet been investigated. We used diffusion tensor image analysis along the perivascular space (DTI-ALPS) index to examine the pre-symptomatic glymphatic alterations in NPC patients following RT. A total of 109 patients with NPC consisted of Pre-RT (n = 35) and Post-RT (n = 74) cohorts were included. The post-RT NPC patients, with normal-appearing brain structure at the time of MRI, were further divided into Post-RT-RE- (n = 58) and Post-RT-RE+ (n = 16) subgroups based on the detection of RE in follow-up. We observed lower DTI-ALPS left index, DTI-ALPS right index and DTI-ALPS whole brain index in post-RT patients than that in pre-RT patients (p < 0.05). We further found that post-RT-RE+ patients demonstrated significantly lower DTI-ALPS right (p = 0.013), DTI-ALPS whole brain (p = 0.011) and marginally lower DTI-ALPS left (p = 0.07) than Post-RT non-RE patients. Significant negative correlations were observed between the maximum dosage of radiation-treatment (MDRT) and DTI-ALPS left index (p = 0.003) as well as DTI-ALPS whole brain index (p = 0.004). Receiver operating characteristic (ROC) curve analysis showed that DTI-ALPS whole brain index exhibited good performance (AUC = 0.706) in identifying patients more likely developing RE. We concluded that glympathic function was impaired in NPC patients following RT and DTI-ALPS index may serve as a novel imaging biomarker for diagnosis of RE.
Fluid biomarkers in cerebral amyloid angiopathy
Authors: Savar Seyed Mehrdad , Ma Bin , Hone Eugene , Jahan Farzana , Markovic Shaun , Pedrini Steve , Shemehsavar Soudabeh , Easwaran Vandhana , Taddei Kevin , Gardener Samantha , Chhatwal Jasmeer P. , van Etten Ellis S. , van Osch Matthias J. P. , Clarke Daniel , Gnjec Anastazija , van Buchem Mark A. , Wermer Marieke J. H. , Hankey Graeme J. , Greenberg Steven M. , Martins Ralph N. , Sohrabi Hamid R.
Published: January 2024

Cerebral amyloid angiopathy (CAA) is a type of cerebrovascular disorder characterised by the accumulation of amyloid within the leptomeninges and small/medium-sized cerebral blood vessels. Typically, cerebral haemorrhages are one of the first clinical manifestations of CAA, posing a considerable challenge to the timely diagnosis of CAA as the bleedings only occur during the later disease stages. Fluid biomarkers may change prior to imaging biomarkers, and therefore, they could be the future of CAA diagnosis. Additionally, they can be used as primary outcome markers in prospective clinical trials. Among fluid biomarkers, blood-based biomarkers offer a distinct advantage over cerebrospinal fluid biomarkers as they do not require a procedure as invasive as a lumbar puncture. This article aimed to provide an overview of the present clinical data concerning fluid biomarkers associated with CAA and point out the direction of future studies. Among all the biomarkers discussed, amyloid β, neurofilament light chain, matrix metalloproteinases, complement 3, uric acid, and lactadherin demonstrated the most promising evidence. However, the field of fluid biomarkers for CAA is an under-researched area, and in most cases, there are only one or two studies on each of the biomarkers mentioned in this review. Additionally, a small sample size is a common limitation of the discussed studies. Hence, it is hard to reach a solid conclusion on the clinical significance of each biomarker at different stages of the disease or in various subpopulations of CAA. In order to overcome this issue, larger longitudinal and multicentered studies are needed.
IMiD/CELMoD-induced growth suppression of adult T-cell leukemia/lymphoma cells via cereblon through downregulation of target proteins and their downstream effectors
Authors: Wang Yu , Shimosaki Shunsuke , Ikebe Emi , Iha Hidekatsu , Yamamoto Jun-ichi , Fife Nichole , Ichikawa Tomonaga , Hori Mitsuo , Ogata Masao , Tsukamoto Yoshiyuki , Hijiya Naoki , Moriyama Masatsugu , Hagiwara Shotaro , Kusano Shuichi , Saito Masumichi , Ahmed Kamruddin , Nishizono Akira , Handa Hiroshi , Morishita Kazuhiro
Published: January 2024

Adult T-cell leukemia/lymphoma (ATL) is an aggressive T-cell neoplasia associated with human T-cell leukemia virus type 1 (HTLV-1) infection and has an extremely poor prognosis. Lenalidomide (LEN; a second-generation immunomodulatory drug [IMiD]) has been employed as an additional therapeutic option for ATL since 2017, but its mechanism of action has not been fully proven, and recent studies reported emerging concerns about the development of second primary malignancies in patients treated with long-term IMiD therapy. Our purpose in this study was to elucidate the IMiD-mediated anti-ATL mechanisms. Thirteen ATL-related cell lines were divided into LEN-sensitive or LEN-resistant groups. CRBN knockdown (KD) led to a loss of LEN efficacy and IKZF2-KD-induced LEN efficacy in resistant cells. DNA microarray analysis demonstrated distinct transcriptional alteration after LEN treatment between LEN-sensitive and LEN-resistant ATL cell lines. Oral treatment of LEN for ATL cell-transplanted severe combined immunodeficiency (SCID) mice also indicated clear suppressive effects on tumor growth. Finally, a novel cereblon modulator (CELMoD), iberdomide (IBE), exhibited a broader and deeper spectrum of growth suppression to ATL cells with efficient IKZF2 degradation, which was not observed in other IMiD treatments. Based on these findings, our study strongly supports the novel therapeutic advantages of IBE against aggressive and relapsed ATL.
Development and evaluation of INT2GRATE: a platform for comprehensive assessment of the role of germline variants informed by tumor signature profile in Lynch syndrome
Authors: Isidro Raymond A. , Chittenden Anu , Walker McKenzie , Schwartz Alison , Koeller Diane R. , Hayes Connor P. , Unal Busra , Manam Monica Devi , Buehler Ryan M. , Manning Danielle K. , Sholl Lynette M. , Redston Mark S. , Yurgelun Matthew B. , Rana Huma Q. , Garber Judy E. , Ghazani Arezou A.
Published: January 2024

The presence of variants of uncertain significance (VUS) in DNA mismatch repair (MMR) genes leads to uncertainty in the clinical management of patients being evaluated for Lynch syndrome (LS). Currently, there is no platform to systematically use tumor-derived evidence alongside germline data for the assessment of VUS in relation to LS. We developed INT2GRATE (INTegrated INTerpretation of GeRmline And Tumor gEnomes) to leverage information from the tumor genome to inform the potential role of constitutional VUS in MMR genes. INT2GRATE platform has two components: a comprehensive evidence-based decision tree that integrates well-established clinico-genomic data from both the tumor and constitutional genomes to help inform the potential relevance of germline VUS in LS; and a web-based user interface (UI). With the INT2GRATE decision tree operating in the backend, INT2GRATE UI enables the front-end collection of comprehensive clinical genetics and tumor-derived evidence for each VUS to facilitate INT2GRATE assessment and data sharing in the publicly accessible ClinVar database. The performance of the INT2GRATE decision tree was assessed by qualitative retrospective analysis of genomic data from 5057 cancer patients with MMR alterations which included 52 positive control cases. Of 52 positive control cases with LS and pathogenic MMR alterations, 23 had all the testing parameters for the evaluation by INT2GRATE. All these variants were correctly categorized as INT2GRATE POSITIVE. The stringent INT2GRATE decision tree flagged 29 of positive cases by identifying the absence or unusual presentation of specific evidence, highlighting the conservative INT2GRATE logic in favor of a higher degree of confidence in the results. The remaining 99% of cases were correctly categorized as INCONCLUSIVE due to the absence of LS criteria and ≥1 tumor parameters. INT2GRATE is an effective platform for clinical and genetics professionals to collect and assess clinical genetics and complimentary tumor-derived information for each germline VUS in suspected LS patients. Furthermore, INT2GRATE enables the collation of integrated tumor-derived evidence relevant to germline VUS in LS, and sharing them with a large community, a practice that is needed in precision oncology.
Current and future on definitive concurrent chemoradiotherapy for inoperable locally advanced esophageal squamous cell carcinoma
Authors: Xie Renxian , Cai Qingxin , Chen Tong , Huang Hongxin , Chen Chuangzhen
Published: January 2024

Esophageal squamous cell carcinoma (ESCC) is an aggressive and fatal disease that is usually diagnosed when the chances for surgical intervention has been missed. Definitive concurrent chemoradiotherapy (dCRT) is the first choice of treatment for inoperable locally advanced esophageal squamous cell carcinoma (LA-ESCC). Nevertheless, the local recurrence rate for esophageal cancer patients undergoing dCRT remains high at 40-60%, with a 5-year overall survival rate of solely 10-30%. Immunotherapy in combination with dCRT is a promising treatment for inoperable LA-ESCC, for that improved long-term survival is expected. The present review provides a comprehensive overview of the evolutionary trajectory of dCRT for LA-ESCC, delineates notable relevant clinical studies, addresses unresolved concerns regarding the combination of dCRT with immunotherapy, and highlights promising directions for future research. When dCRT is combined with immunotherapy, the following aspects should be carefully explored in the future studies, including the optimal irradiation dose, segmentation scheme, radiotherapy technique, timing, sequence and duration of radiotherapy, and the selection of chemotherapeutic and immunologic drugs. In addition, further investigations on the mechanisms of how dCRT combined with immunotherapy exerts synergistic anti-tumor effects and molecular biomarkers ensuring precise screening of ESCC patients are needed.
Impact of the response to platinum-based chemotherapy on the second-line immune checkpoint inhibitor monotherapy in non-small cell lung cancer with PD-L1 expression ≤49%: a multicenter retrospective study
Authors: Yoshimura Akihiro , Takeda Takayuki , Kataoka Nobutaka , Tanimura Keiko , Fukui Mototaka , Chihara Yusuke , Takei Shota , Kawachi Hayato , Nakanishi Kentaro , Yamanaka Yuta , Tamiya Nobuyo , Honda Ryoichi , Okura Naoko , Yamada Takahiro , Uryu Kiyoaki , Murai Junji , Shiotsu Shinsuke , Yoshioka Hiroshige , Yamada Tadaaki , Kurata Takayasu , Takayama Koichi
Published: January 2024

Introduction

The efficacy of second-line immune checkpoint inhibitor (ICI) therapy is limited in non-small cell lung cancer (NSCLC) patients with ≤ 49% PD-L1 expression. Although chemoimmunotherapy is a promising strategy, platinum-based chemotherapy followed by ICI monotherapy is often used to avoid synergistic adverse events. However, predictors of the efficacy of ICI monotherapy after platinum-based chemotherapy in NSCLC with ≤ 49% PD-L1 expression remain scarce.

Methods

This multicenter retrospective study evaluated 54 advanced or recurrent NSCLC patients with ≤ 49% PD-L1 expression who were treated with second-line ICI monotherapy following disease progression on first-line platinum-based chemotherapy at nine hospitals in Japan. The impact of response to platinum-based chemotherapy on the efficacy of subsequent ICI monotherapy was investigated.

Results

The response to first-line platinum-based chemotherapy was divided into two groups: the non-progressive disease (PD) group, which included patients who did not experience disease progression after four cycles of chemotherapy, and the PD group, which included patients who showed initial PD or could not maintain disease control during the four cycles of chemotherapy and switched to second-line ICI monotherapy. Among the 54 patients, 32 and 22 were classified into the non-PD and PD groups, respectively. The non-PD group showed better response rates (p = 0.038) and longer overall survival (OS) with ICI monotherapy (p = 0.023) than the PD group. Multivariate analysis identified that maintaining a non-PD status after four cycles of chemotherapy was an independent prognostic factor for ICI monotherapy (p = 0.046). Moreover, patients with a modified Glasgow Prognostic Score (mGPS) of 0 showed a tendency for longer OS with ICI monotherapy (p = 0.079), and there was a significant correlation between maintaining non-PD after four cycles of chemotherapy and an mGPS of 0 (p = 0.045).

Conclusion

Maintaining a non-PD status after four cycles of platinum-based chemotherapy was a predictor of OS after second-line ICI monotherapy. These findings will help physicians select the most suitable treatment option for NSCLC patients who were treated with platinum-based chemotherapy and switched to second-line treatment. Those who experienced early PD during platinum-based chemotherapy should not be treated with ICI monotherapy in the second-line setting.
Cancer-associated financial burden in German head and neck cancer patients
Authors: Rast Jonas , Zebralla Veit , Dietz Andreas , Wichmann Gunnar , Wiegand Susanne
Published: January 2024

Background

The financial toxicity of cancer causes higher morbidity and mortality. As the financial burden due to head and neck cancer (HNC) in European healthcare systems with legally established compulsory health insurance is still poorly understood, we set up an investigation to assess the financial impact of HNC.

Methods

Between August 2022 and March 2023, HNC consecutive patients (n = 209) attending the cancer aftercare program of a university hospital in an outpatient setting were surveyed utilizing self-administered questionnaires about their socioeconomic situation, income loss, and out-of-pocket payments (OOPPs).

Results

The majority of HNC patients (n = 119, 59.5%) reported significant financial burden as a consequence of OOPP (n = 100, 50.0%) and/or income loss (n = 51, 25.5%). HNC patients reporting financial burden due to OOPP had on average 1,716 € per year costs related to their disease, whereas patients reporting an income loss had a mean monthly income loss of 620.53 €. Advanced UICC (7th edition, 2017) stage, T3 or T4 category, and larynx/hypopharynx cancer are significant predictors of financial burden.

Conclusion

HNC survivors suffer from significant financial burden after HNC treatment, even in Germany with a healthcare system with statutory health insurance. The findings from this study offer valuable insights for healthcare professionals and policymakers, helping them acknowledge the economic impact of HNC.
Effective treatment of advanced lung adenocarcinoma with paraneoplastic leukemoid reaction with Lorlatinib: a case report
Authors: Niu Ruiqi , Zhang Yiruo , Pang Jingdan , Zhou Qing , Lei Yu , Du Yingying
Published: January 2024

Background

Lorlatinib is a new generation ALK kinase inhibitor. We describe a 52-year-old patient with ALK-positive advanced lung adenocarcinoma who achieved remission after multi-line therapy combined with paraneoplastic leukemoid reaction treated with Lorlatinib.

Case report

A 52-year-old male patient was diagnosed with stage IV right lung adenocarcinoma, ALK: (+), previously received oral Crizotinib and Alectinib. Blood routine showed white blood cells abnormally elevated after disease progression, and maximum white blood cell count was 179.14×10^9/L. The patient was enrolled in study entitled “a phase II, multicenter, open-label, dual-cohort study to evaluate the efficacy and safety of LORLATINIB monotherapy in ALK inhibitor-treated locally advanced or metastatic ALK-positive non-small cell lung cancer patients in China”. With oral Lorlatinib, the white blood cell count decreased from 179.14×10^9/L to normal after two weeks of administration. PFS was 4.5 months. When follow up imaging showed lesions progression, the white blood cell count increased again, diagnosing a paraneoplastic leukemic reaction. OS was 5.2 months.

Conclusion

In this case, fourth-line Lorlatinib treatment is effiective in ALK-positive advanced patient with paraneoplastic leukemoid reaction. ClinicalTrials.gov Identifier: NCT03909971
Diagnostic validity of p16, E-cadherin, cyclin D1, p53, and HPV E6/E7 mRNA in CIN 3-like squamous cell carcinoma of the cervix
Authors: Xing Zhao , Danhua Shen , Xiaobo Zhang
Published: January 2024

Objective

Cervical intraepithelial neoplasia grade 3 (CIN 3)-like SCC is a recently identified deceptive growth pattern that closely mimics endocervical crypt involvement by CIN 3. As CIN 3-like SCC is indistinguishable from endocervical crypt involvement by CIN 3, it poses a significant challenge for pathologists.

Method

We examined 23 cases of CIN 3-like SCC, 6 of which also had concomitant conventional invasive SCC, and 9 cases of endocervical crypt involvement by CIN 3 as a control group. Immunohistochemistry was used to investigate the expression of p16, E-cadherin, cyclin D1, and p53, and the expression of human papillomavirus (HPV) E6/E7 mRNA, the key virus carcinogen of HPV, was detected. The clinicopathological, immunohistochemical, and molecular characteristics of endocervical crypt involvement by CIN 3, CIN 3-like SCC, and the concomitant conventional invasive SCC element were examined.

Result

CIN 3-like SCC exhibited a characteristic morphology similar to endocervical crypt involvement by CIN 3, with pushing borders invading into the wall of the cervix, often to a significant depth in most cases. Immunophenotypic features of E-cadherin, p16, cyclin D1, and p53 differed between CIN 3-like SCC and conventional invasive SCC, both in staining intensity and region. E6/E7 mRNA expression was higher in CIN 3-like SCC than in endocervical crypt involvement by CIN 3 (P < 0.05).

Conclusion

CIN 3-like SCC is the type of cancer, presenting numerous challenges and potential for confusion as it mimics the phenotypes of endocervical crypt involvement by CIN 3.
Magnitude and its associated factors of neonatal jaundice among neonates admitted to the neonatal intensive care unit of Dessie Town public hospitals, Amhara region, Ethiopia, 2020: a multicenter cross-sectional study
Authors: Tessema Mohammed , Mekonnen Hussen , Alemu Tsion , Godie Yohannes , Teklehaimanot Wegayehu Zeneb , Mengstie Leweyehu Alemaw
Published: January 2024

Background

Neonatal jaundice is a prevalent illness affecting approximately 60%–80% of newborns. In severe cases, it can result in severe neurological distress. Approximately 1.1 million neonates are affected annually on a global scale, with the vast majority living in sub-Saharan Africa and southern Asia. It is common in newborns in the first week of life. This study aims to assess the magnitude and determinants of jaundice in newborns admitted to the neonatal intensive care unit (NICU) of public hospitals in the city of Dessie in northern Ethiopia.

Methods

An institutional cross-sectional study was conducted at the NICU at Dessie town public hospitals from 30 March to 30 April 2020. A systematic random sampling procedure was used to select the study participants. Data were collected through face-to-face interviews with mothers using a structured questionnaire and by reviewing neonatal medical records using a checklist. Binary logistic regression analysis was used to identify the determinants of neonatal jaundice. A significance level of less than 0.05 was used to declare the statistical significance in the final model.

Results

A total of 218 neonates with their mothers were included in the study. The prevalence rate of neonatal jaundice was found to be 28.4%. The major associated factors for neonatal jaundice were sepsis [adjusted odds ratio (AOR): 10.13, 95% confidence interval (CI) = 2.36, 43.56], preterm < 37 weeks (AOR: 6.03, 95% CI = 1.41, 25.79) low APGAR score < 7 (AOR: 7.34, 95% CI = 1.34, 39.65), ABO incompatibility (AOR: 24.55 95% CI = 1.58, 68.83), prolonged labor (AOR 9.03, 95% CI = 1.67, 48.33), and Rh incompatibility (AOR = 30.40, 95% CI = 2.01, 66.20).

Conclusion

The magnitude of neonatal jaundice among neonates was determined to be high. Therefore, both maternal and neonatal factors contributed significantly to the management of neonatal jaundice and also influenced the use of phototherapy treatment. Proper consideration of these factors is crucial for the prevention and treatment of neonatal jaundice.
Potential for a cerebellar role in moderate-late preterm associated behavioural disorders
Authors: Pavy Carlton L. , Shaw Julia C. , Moloney Roisin A. , Palliser Hannah K. , Hirst Jonathon J.
Published: January 2024

Preterm birth is known to cause impaired cerebellar development, and this is associated with the development of neurobehavioral disorders. This review aims to identify the mechanisms through which preterm birth impairs cerebellar development and consequently, increases the risk of developing neurobehavioral disorders. The severity of these disorders is directly related to the degree of prematurity, but it is also evident that even late preterm births are at significantly increased risk of developing serious neurobehavioral disorders. Preterm birth is associated with hypoxic events and increased glutamatergic tone within the neonatal brain which contribute to excitotoxic damage. The cerebellum is a dense glutamatergic region which undergoes relatively late neurodevelopment up to and beyond birth. Evidence indicates that the cerebellum forms reciprocal connections to regions important in behaviour regulation such as the limbic system and frontal cortex. Studies using fMRI (functional magnetic resonance Imaging), BOLD (blood oxygen level dependent) response and morphology studies in humans show the cerebellum is often involved in disorders such as attention deficit hyperactivity disorder (ADHD) and anxiety. The vulnerability of the cerebellum to preterm birth insult and its connections to behaviour associated brain regions implicates it in the development of neurobehavioral disorders. Protection against preterm associated insults on the cerebellum may provide a novel avenue through which ADHD and anxiety can be reduced in children born preterm.
Exploration of biomarkers for efficacy evaluation of traditional Chinese medicine syndromes of acute exacerbation of chronic obstructive pulmonary disease based on metabolomics
Authors: Hailong Zhang , Yimei Si , Yan Du , Xinguang Liu , Jiansheng Li
Published: January 2024

Background: Traditional Chinese medicine (TCM) is effective for the treatment of acute exacerbation of chronic obstructive pulmonary disease (AECOPD); however, there is no objective index for the evaluation of TCM syndrome efficacy. This study aimed to screen biomarkers related to the efficacy of TCM syndrome using metabolomics.

Methods: We recruited AECOPD patients with phlegm-heat congesting lung (PH)/phlegm-damp amassing lung (PD) syndrome and treated them with Chinese herbal medicine (Qingre Huatan or Zaoshi Huatan granules) in addition to conventional medicine for 7 days. Data on clinical symptoms and sign scores, modified British Medical Research Council (mMRC), COPD assessment test (CAT), and inflammation indicators, including white blood cell (WBC) count, percentage of neutrophil count (NEU%), and C-reactive protein (CRP), were collected before and after treatment to evaluate the therapeutic effect. Serum samples were collected before and after treatment for metabolomic analysis to screen differential metabolites.

Results: A total of 69 patients with AECOPD were enrolled, including 41 and 28 patients in the PH and PD groups, respectively. The clinical symptoms and sign scores, CAT, mMRC, NEU%, and CRP levels after treatment were lower than those before treatment in both groups (p < 0.05). Serum metabolomics analysis showed that there were 13 differential metabolites in the PH group and 16 differential metabolites in the PD group before and after treatment (p < 0.05, variable importance projection (VIP) ≥ 1.00). In the PH group, lysophosphatidylcholine (LPC) (16:0), LPC (17:1), LPC (18:3), LPC (18:2), and LPC (17:0) negatively correlated with clinical symptoms and sign scores (p < 0.05); LPC (16:0), LPC (17:1), LPC (16:1), and LPC (17:0) negatively correlated with WBC (p < 0.05) and NEU% (p < 0.05); and LPC (16:0) negatively correlated with CRP levels. In the PD group, L-phenylalanine positively correlated with CRP levels (p < 0.05), and 2-methylbutyroylcarnitine positively correlated with clinical symptoms and sign (p < 0.05) and CAT scores (p < 0.05). DL-carnitine positively correlated with clinical symptoms and sign scores (p < 0.05).

Conclusion: Serum metabolites may be potential indicators to objectively evaluate the efficacy of TCM syndromes; however, further large controlled trials are required to verify these findings.
Pharmacokinetics, pharmacodynamics and safety of 15 mg-tolvaptan administered orally for 7 consecutive days to Chinese patients with child-Pugh B cirrhosis
Authors: Liu Hongzhong , Wang Yongfeng , Liu Tao , Chen Yingxuan , Zheng Xin , Liu Ming , Zhao Qian , Zeng Minde , Jiang Ji , Mao Yimin , Hu Pei
Published: January 2024

Background: Tolvaptan, a selective vasopressin V2-receptor antagonist, can elicit a diuretic effect without significant electrolyte loss. The aims were to evaluate multiple-dose pharmacokinetics, pharmacodynamics and safety of daily administration of 15 mg tolvaptan in Chinese adult patients with confirmed Child-Pugh Class B cirrhosis accompanied by ascites.

Methods: This was an open-label, single-center, single- and multiple-dose study. All patients received a daily 15 mg dose of tolvaptan for 7 consecutive days. The plasma concentrations of tolvaptan and its two metabolites (DM-4103, DM-4107) were measured using high-performance liquid chromatography with tandem mass spectrometry (HPLC-MS/MS). In addition, various pharmacokinetics parameters were calculated. The pharmacodynamic outcomes evaluated changes in serum sodium and potassium concentrations, daily urine volume, daily water consumption, fluid balance and body weight. Safety profiles, including the incidence of treatment-emergent adverse events (TEAEs), were carefully recorded.

Results: Eleven patients with Child-Pugh B cirrhosis were eventually enrolled in the study. Plasma concentrations of tolvaptan and DM-4107 reached steady-states after 7 days of consecutive oral administration. No accumulation of tolvaptan or DM-4107 was found, but DM-4103 accumulated 18.2-fold after multiple-dosing. The daily urine volume and daily water consumption were statistically significantly increased after administration of tolvaptan from Day 1 to Day 7 (all p < 0.05), accompanied by an increased serum sodium concentration. Of 11 patients, 9 (81.8%) reported 20 TEAEs, with the majority being mild to moderate in severity. The most commonly occurring TEAEs were thirst (45.5%), pollakiuria (36.4%) and dry mouth (27.3%).

Conclusion: Tolvaptan at a daily dose of 15 mg had a diuretic effect but did not increase serum sodium excretion or lead to tolvaptan accumulation. It is therefore can be safely used for short-term treatment of Chinese adult patients with confirmed Child-Pugh B cirrhosis.

Clinical Trial Registration:https://clinicaltrials.gov/search?term=NCT01359462, identifier NCT01359462.
Surgical procedure of intratympanic injection and inner ear pharmacokinetics simulation in domestic pigs
Authors: Moatti Adele , Connard Shannon , De Britto Novietta , Dunn William A. , Rastogi Srishti , Rai Mani , Schnabel Lauren V. , Ligler Frances S. , Hutson Kendall A. , Fitzpatrick Douglas C. , Salt Alec , Zdanski Carlton J. , Greenbaum Alon
Published: January 2024

Introduction: One major obstacle in validating drugs for the treatment or prevention of hearing loss is the limited data available on the distribution and concentration of drugs in the human inner ear. Although small animal models offer some insights into inner ear pharmacokinetics, their smaller organ size and different barrier (round window membrane) permeabilities compared to humans can complicate study interpretation. Therefore, developing a reliable large animal model for inner ear drug delivery is crucial. The inner and middle ear anatomy of domestic pigs closely resembles that of humans, making them promising candidates for studying inner ear pharmacokinetics. However, unlike humans, the anatomical orientation and tortuosity of the porcine external ear canal frustrates local drug delivery to the inner ear.

Methods: In this study, we developed a surgical technique to access the tympanic membrane of pigs. To assess hearing pre- and post-surgery, auditory brainstem responses to click and pure tones were measured. Additionally, we performed 3D segmentation of the porcine inner ear images and used this data to simulate the diffusion of dexamethasone within the inner ear through fluid simulation software (FluidSim).

Results: We have successfully delivered dexamethasone and dexamethasone sodium phosphate to the porcine inner ear via the intratympanic injection. The recorded auditory brainstem measurements revealed no adverse effects on hearing thresholds attributable to the surgery. We have also simulated the diffusion rates for dexamethasone and dexamethasone sodium phosphate into the porcine inner ear and confirmed the accuracy of the simulations using in-vivo data.

Discussion: We have developed and characterized a method for conducting pharmacokinetic studies of the inner ear using pigs. This animal model closely mirrors the size of the human cochlea and the thickness of its barriers. The diffusion time and drug concentrations we reported align closely with the limited data available from human studies. Therefore, we have demonstrated the potential of using pigs as a large animal model for studying inner ear pharmacokinetics.
Adherence to exercise after an acute coronary syndrome: a 6-month randomized controlled trial
Authors: Saarikoski Essi O. , Roiha Elina T. M. , Kiviniemi Antti M. , Cerdán-De-las-Heras Jose , Perkiömäki Juha , Kaikkonen Kari S. , Tulppo Mikko P.
Published: January 2024

Introduction: Exercise training with well-known health benefits is a key element in the self-management of coronary artery disease (CAD). Although current guidelines for patients with CAD recommend daily exercise training, most of the patients do not follow the guidelines. We tested the hypothesis that an exercise training program guided by a novel technology used at home will improve adherence to exercise training.

Methods: One to three weeks after percutaneous coronary intervention (PCI), acute coronary syndrome patients (n = 50) were randomized into traditional (age 65 ± 8 years) and novel technology-guided (age 60 ± 8 years) exercise rehabilitation groups. The novel technology included a tablet computer with a virtual autonomous physiotherapy agent (VAPA group) for every patient at home; it was used to guide exercise training time, volume, and intensity. Traditional rehabilitation was performed by exercise training prescriptions, phone calls, and diaries (control group). The duration of the rehabilitation program was 6 months for both groups. Exercise capacity and 24-h heart rate variability were measured at baseline and at the end of the program. Adherence to exercise was measured over 6 months as the percentage of realized training.

Results: None of the patients dropped out from the VAPA group, while three patients dropped out from the control group. Adherence to exercise was higher in the VAPA group than in the control group for resistance training (141% ± 56% vs. 50% ± 20%, p < 0.0001), and there were no differences between the groups for aerobic training (144% ± 45% vs. 119% ± 65%, p = 0.22). Exercise capacity increased in both the groups (time p < 0.001, time × group interaction p = ns). High-frequency power of R-R intervals (lnHF) increased in the VAPA group but remained unchanged in the control group (natural logarithm of lnHF power from 5.5 ± 0.7 to 5.8 ± 0.9 ms2 and from 5.3 ± 0.8 to 5.2 ± 0.7 ms2, respectively, time × group interaction p = 0.014).

Conclusion: Compared with the use of traditional methods, the use of novel technology at home results in better adherence to exercise, particularly in resistance training, in acute coronary syndrome patients. Second, the VAPA group showed improved cardiac vagal regulation, documented by increased vagally mediated R-R interval fluctuation, compared with the traditional training group (ClinicalTrials.gov identifier: NCT03704025).
Below or all the way to the peak? Oxygen uptake efficiency slope as the index of cardiorespiratory response to exercise—the NOODLE study
Authors: Kasiak Przemysław , Kowalski Tomasz , Rębiś Kinga , Klusiewicz Andrzej , Starczewski Michał , Ładyga Maria , Wiecha Szczepan , Barylski Marcin , Poliwczak Adam Rafał , Wierzbiński Piotr , Mamcarz Artur , Śliż Daniel
Published: January 2024

Background: The ratio of oxygen uptake (VO2) to minute ventilation (VE) is described as the oxygen uptake efficiency slope (OUES). OUES has been suggested as a valuable submaximal cardiorespiratory index; however, its characteristics in endurance athletes remain unknown. In this study, we a) investigated OUES between different time intervals, b) assessed their prediction power for VO2peak, and c) derived new prediction equations for OUES tailored for well-trained individuals.

Materials and Methods: A total of 77 male (age = 21.4 ± 4.8 yrs; BMI = 22.1 ± 1.6 kg·m−2; peak oxygen uptake = 4.40 ± 0.64 L·min−1) and 63 female individuals (age = 23.4 ± 4.3 yrs; BMI = 23.1 ± 1.6 kg·m−2; peak oxygen uptake = 3.21 ± 0.48 L·min−1) underwent the cycling cardiopulmonary exercise test. OUES was measured at 75%, 90%, and 100% of exercise duration. Prediction power and new models were derived with the multiple linear regression method.

Results: In male subjects, OUES [mL·min−1/L·min−1] from 75% = 4.53 ± 0.90, from 90% = 4.52 ± 0.91, and from 100% = 4.41 ± 0.87. In female subjects, OUES [mL·min−1/L·min−1] from 75% = 3.50 ± 0.65, from 90% = 3.49 ± 0.62, and from 100% = 3.41 ± 0.58. OUES did not differ between time intervals in male (p = 0.65) and female individuals (p = 0.69). OUES strongly predicts peak VO2 independently from the measuring interval (β = 0.71–0.80; R2 = 0.50–0.63). The prediction model designed for elite athletes was OUES [mL·min−1/L·min−1] = −1.54 + 2.99; BSA [m2]—0.0014; (age [in years]; sex [1 = male, 2 = female]) (R2 = 0.36).

Conclusion: OUES enables an accurate prediction of peak cardiorespiratory fitness in elite endurance athletes. OUES is a feasible alternative to maximal exercise testing. A new prediction equation should be used for highly trained individuals. Physicians should understand OUES physiology to properly assess the cardiorespiratory response to exercise in athletic cohorts.
Fuling production areas in China: climate and distribution changes (A.D. 618–2100)
Authors: Jiang Yunlu , Ren Aoyu , Sun Xue , Yang Bin , Peng Huasheng , Huang Luqi
Published: January 2024

Through a meticulous analysis of ancient Chinese literature, this study comprehensively documents the geographical distribution of Fuling, a traditional Chinese medicinal material, during the Tang, Song, Ming, and Qing dynasties spanning from the seventh to the twentieth century in China. Based on the contemporary distribution information of Fuling, we utilized the maximum entropy (MaxEnt) model to simulate the suitable distribution areas of Fuling under both present-day conditions and in the future (2081~2100). The findings reveal that climate change has influenced the distribution of Fuling production areas. The shifts in Fuling’s origin during different periods in ancient and modern times align with climate fluctuations and concurrent societal development. During the Tang and Song dynasties, Fuling primarily originated in northern China. However, it migrated southward during the Little Ice Age (LIA) and has recently shown a slight northward shift, in line with the climate fluctuations of the LIA and contemporary global warming trends. This study offers a comprehensive analysis of the changes in the distribution and production areas of Fuling over a 1500-year period, encompassing ancient, modern, and future periods. The results provide critical insights for adjusting Fuling cultivation areas in response to climate change and for further exploration of the mechanisms through which climate impacts the growth of Fuling.
Trauma and psychosocial adversity in youth with autism spectrum disorder and intellectual disability
Authors: Palmer Sarah J. , Dvir Yael
Published: January 2024

Traumatic experiences contribute significantly to behavioral and mood dysregulation syndromes presenting for treatment to behavioral health settings. Individuals with Autism Spectrum Disorder (ASD), Intellectual Disability (ID) and developmental delay experience traumatic events more frequently than their typically developing peers. However, measures used to identify trauma related disorders and treatment thereof are based on typically developing individuals. Regardless of the baseline characteristics of individuals who experience trauma, trauma exposure is the result of multiple interdependent environmental, social, and familial characteristics. We used the “ecological systems analysis approach” to structure our review of the impact of trauma on those with ASD and ID. In addition, the COVID-19 pandemic which exposed the global population to a collective trauma, has also catalyzed investigations into the challenges faced by members of society most dependent on social services. Children with ASD and ID were among those vulnerable individuals, and the COVID-19 pandemic has allowed researchers to better understand the impact of a collective trauma on those individuals. It is imperative that we understand current research and recommendations for identifying and treating trauma-related disorders in individuals with developmental disorders to best inform clinical practice and directions for future research in this area.