bluuebunny/crossref_metadata_2025 huggingface dataset:
Efficacy and safety of mirogabalin for chemotherapy-induced peripheral neuropathy: a prospective single-arm trial (MiroCIP study)
Authors: Misawa Sonoko , Denda Tadamichi , Kodama Sho , Suzuki Takuji , Naito Yoichi , Kogawa Takahiro , Takada Mamoru , Suichi Tomoki , Shiosakai Kazuhito , Kuwabara Satoshi ,   on behalf of the MiroCIP study group, Saito Go , Hino Aoi , Imanishi Shunsuke , Ureshino Norio , Satomi Daisuke , Tanabe Yuko , Hanaoka Yutaka , Miyamoto Atsushi , Suzuki Takeshi , Naganuma Atsushi , Yanagita Yasuhiro , Sekine Katsutoshi , Kusano Fumihiko , Nakamura Masato , Imazeki Hiroshi
Published: November 2023

Background

Chemotherapy-induced peripheral neuropathy (CIPN) is a painful, dose-limiting adverse effect of commonly used chemotherapeutic agents. The purpose of this exploratory study was to evaluate the efficacy and safety of mirogabalin in patients with moderate to severe CIPN during chemotherapy and the effects of 12 weeks’ intervention on chemotherapy completion and CIPN severity.

Methods

Patients experiencing moderate to severe CIPN while undergoing oxaliplatin- or taxane-containing chemotherapy for colorectal, gastric, non-small-cell lung, or breast cancer received mirogabalin at between 5 and 15 mg twice daily. The primary endpoint was change in numeric rating scale (NRS) score for pain from baseline to week 12. Secondary endpoints included NRS scores for tingling and sleep, completion of chemotherapy, severity of CIPN, and quality of life (QOL) scores. The safety endpoint was incidence of adverse events.

Results

Of 58 patients who consented to participation, 52 were eligible and constituted the full analysis set and safety analysis set. From baseline to week 12 (last observation carried forward [LOCF]), NRS score decreased by 30.9%: mean change (95% confidence interval [CI]), − 1.7 (− 2.4 to − 1.0) (p < 0.001). Patients with baseline NRS of ≥ 6 experienced a 44.0% reduction in score from baseline to week 12 (LOCF): mean change (95% CI), − 3.3 (− 5.0 to − 1.5) (p = 0.002). Chemotherapy was discontinued in 18 (34.6%) patients; CIPN led to discontinuation in only 2 (3.8%). There was no notable worsening of CIPN severity in terms of Common Terminology Criteria for Adverse Events grade or Modified Total Neuropathy Score-reduced, although use of pain medications during chemotherapy might cause worsening of CIPN due to underestimation of subjective symptoms. QOL score based on the EuroQol five-dimensional descriptive system did not worsen during the 12 weeks. Thirty-one percent of patients experienced adverse drug reactions, and the most common event was somnolence (13.5%). Serious adverse events and death occurred in 3 patients and 1 patient, respectively; however, they were unrelated to mirogabalin treatment.

Conclusions

Intervention with mirogabalin during chemotherapy may be effective and safe for cancer patients with moderate to severe CIPN. It can contribute to completion of chemotherapy without worsening of CIPN.

Trial registration

Japan Registry of Clinical Trials (jRCTs031210101, registered 20/5/2021).
The effect of China’s many-child policy on the number of births and the prevalence of serious teratogenic and disabling defects in Hunan Province
Authors: Xie Donghua , Wei Jianhui , Wang Aihua , Xiong Lili , Zou Kehan , Xie Zhiqun , Fang Junqun
Published: November 2023

Background

To research the effect of China’s many-child policy on the number of births and the prevalence of serious teratogenic and disabling defects (STDDs) in Hunan province.

Methods

We performed an observational study based on the Birth Defect (BD) Surveillance System of Hunan Province and chose STDD case cards. From 2012–2022, we defined the following 4 periods: the one-child policy (OCP) (2012.01–2013.12), partial two-child policy (PTCP) (2014.1–2015.12), universal two-child policy (UTCP) (2016.1–2020.12), and the early stage of the three-child policy (ETCP) (2021.1–2022.12). Crude odds ratios (ORs) and 95% confidence intervals (CIs) were calculated to examine the association of policy changes with STDDs. Crame′rʹs V was calculated to estimate the effect sizes. Joinpoint regression analysis and annual percent change (APC) were used for each segment of the trend.

Results

A total of 1,652,079 births were included in this analysis. Joinpoint regression analysis showed that the number of perinatal births increased from 2012 to 2017, with APC = 9.52 (95% CI: 7.2 to 11.8), and decreased from 2017 to 2022, with an APC = -10.04 (95% CI: -11.9 to -8.1). The number of mothers over 30 years old gradually increased, from 25.54% during the OCP period to 54.05% during the ETCP period (Ptrend < 0.001).

With policy changes, the total prevalence of STDDs increased from 28.10 per 10,000 births during the period of OCP into 46.77 per 10,000 births during the ETCP period by 66.44%. The live birth prevalence of STDDs increased only during the ETCP period (PTCP: OR = 1.27, 95% CI: 0.99–1.24, p = 0.057, UTCP: OR = 1.22, 95% CI: 0.99–1.52, p = 0.067, ETCP: OR = 1.75, 95% CI: 1.37–2.24, p < 0.001). Over the past ten years, there was a decrease in the gestational age at diagnosis (*F = 772.520, p < 0.001), from 24.49 ± 5.65 weeks in 2012 to 20.77 ± 5.17 weeks in 2022. From 2012 to 2022, the percentage of deaths within 7 days decreased with APC = -18.85 (95% CI: -26.4— -10.5, P > 0.05).

Conclusion

Many-child policies were associated with a moderate increase in fertility especially for women in urban areas and older women. However, they have lost the ability to control birth since 2017. The total prevalence of STDDs increased over the entire period, but the live birth prevalence increased only during the ETCP period. The gestational age at diagnosis decreased and the percentage of deaths within 7 days decreased.
Long-term respiratory consequences of COVID-19 related pneumonia: a cohort study
Authors: Eizaguirre Saioa , Sabater Gladis , Belda Sònia , Calderón Juan Carlos , Pineda Victor , Comas-Cufí Marc , Bonnin Marc , Orriols Ramon
Published: November 2023

Background

Our aims were to describe respiratory sequelae up to 12 months after discharge in COVID-19 patients with severe pneumonia requiring non-invasive respiratory support therapies.

Methods

This study was undertaken at University Hospital Doctor Josep Trueta (Girona, Spain) between March 2020 and June 2020. Three months after discharge, we evaluated their dyspnoea and performed Saint George’s respiratory questionnaire, pulmonary function tests, blood test, 6-min walking test, and a high-resolution CT (HRCT). At the six and 12-month follow-up, we repeated all tests except for pulmonary function, 6-min walking test, and HRCT, which were performed only if abnormal findings had been previously detected.

Results

Out of the 94 patients recruited, 73% were male, the median age was 62.9 years old, and most were non-smokers (58%). When comparing data three and 12 months after discharge, the percentage of patients presenting dyspnoea ≥ 2 decreased (19% vs 7%), the quality-of-life total score improved (22.8% vs 18.9%; p = 0.019), there were less abnormal results in the pulmonary function tests (47% vs 23%), the 6-min walking test distance was enhanced (368.3 m vs 390.7 m, p = 0.020), ground glass opacities findings waned (51.6% vs 11.5%), and traction bronchiectasis increased (5.6% vs 15.9%). Only age showed significant differences between patients with and without pulmonary fibrotic-like changes.

Conclusion

Most patients improved their clinical condition, pulmonary function, exercise capacity and quality of life one year after discharge. Nonetheless, pulmonary fibrotic-like changes were observed during the follow-ups.
Effects of two novel denture cleansers on multispecies microbial biofilms, stain removal and the denture surface: an in vitro study
Authors: Kaypetch Rattiporn , Rudrakanjana Pachara , Tua-ngam Peerapong , Tosrisawatkasem Orada , Thairat Sarut , Tonput Pairin , Tantivitayakul Pornpen
Published: November 2023

Background

The continuously increasing demand for removable denture appliances and the importance of adequate denture cleaning have led to the development of various denture cleansing products. The aim of this study was to evaluate the efficacy of two novel denture cleansing agents (GE and TM) and three commonly available cleansers (0.5% sodium hypochlorite; NaClO, 0.12% chlorhexidine gluconate; CHX, and Polident®; POL) on multispecies microbial biofilm formation, stain removal and physical properties of dentures.

Methods

The antimicrobial activities of denture cleansing agents were determined against major oral opportunistic pathogens including Streptococcus mutans, Staphylococcus aureus, Escherichia coli and Candida albicans, using time-kill assays. Multispecies microbial biofilms grown on acrylic resins for 72 h were generated to determine the antibiofilm effects of cleansing agents by confocal laser scanning microscopy (CLSM). Evaluations of the tea and coffee stain removal properties and the alterations in the physical properties of dentures were also performed. The toxicity of cleanser residues released from denture acrylics to fibroblast cells was investigated using MTT assay.

Results

All denture cleansing agents tested could effectively kill oral bacteria and Candida albicans. Furthermore, after immersion for more than 3 h, the cleansers Polident®, GE and TM could efficiently penetrate and inhibit multispecies denture biofilms with effects similar to 10 min of immersion in 0.5% NaClO. However, immersion in 0.12% CHX for 20 min showed less antibiofilm activity. The NaClO solution had the highest efficacy for removing stains from the artificial teeth. Conversely, the CHX solution enhanced tea and coffee staining, and the teeth immersed in this solution showed clinically unacceptable colour changes (ΔE > 5.5). However, the colour differences of teeth stained and immersed in POL, GE and TM cleansers were in the clinically acceptable range. There was no significant difference among the POL, GE and TM cleansers in terms of stain removal efficacy. The cleansers GE and TM did not alter the surface roughness and colour of the materials, moreover the residues of both cleansers did not exhibit cytotoxicity.

Conclusion

Two novel denture cleansing agents containing natural products, GE and TM exhibited effective antimicrobial activity, antibiofilm and stain removal capabilities without toxicity or disturbance of the physical properties of acrylics.
Impact of COVID-19 on selected essential public health services – lessons learned from a retrospective record review in the Free State, South Africa
Authors: Heunis Christo , Chikobvu Perpetual , Muteba Michel , Kigozi-Male Gladys , Engelbrecht Michelle , Mushori Providence
Published: November 2023

Background

In an attempt to discern lessons to improve future pandemic responses, this study measured the effects of the COVID-19 pandemic on essential public health services (EPHSs) related to primary health care (PHC) and outpatient department (OPD) utilisation, antiretroviral treatment (ART) commencement, drug-susceptible tuberculosis (DS-TB) confirmation and treatment commencement, and Bacillus Calmette-Guérin (BCG) coverage, in the Free State province of South Africa during January 2019 to March 2021.

Methods

A pre-post study design comparing EPHS performance between 2019 and 2020/21 was employed. Routinely collected data were analysed. An interrupted time series analysis was used to measure changes in service use and outcomes from January 2019 to March 2021. Median changes were compared using Wilcoxon rank-sum tests. A 5% statistical significance level was considered.

Results

Over the study period, the median values for the annual number of PHC visits was 1.80, 55.30% for non-referred OPD visits, 69.40% for ART commencement, 95.10% and 18.70% for DS-TB confirmation and treatment commencement respectively, and 93.70% for BCG coverage. While BCG coverage increased by 5.85% (p = 0.010), significant declines were observed in PHC utilisation (10.53%; p = 0.001), non-referred OPD visits (12.05%; p < 0.001), and ART commencement (9.53%; p = 0.017) rates. Given the importance of PHC in addressing a new pandemic, along with the existing HIV and TB epidemics – as well as the entire quadruple burden of disease – in South Africa, the finding that the PHC utilisation rate statistically significantly decreased in the Free State post-COVID-19 commencement is particularly concerning.

Conclusions

The lessons learned from this retrospective review attest to a measure of resilience in EPHS delivery in the Free State in as far as a significant hike in BCG vaccination over the study period, 2019–2020/21 was observed. As evidenced by a decline in PHC service utilisation and the decreased numbers of new patients commencing ART, we also learned that EPHS delivery in the province was fragile.
Training and competence perception differences in otolaryngology and head and neck surgery training program – an anonymous electronic national survey
Authors: Hirshoren Nir , Zemer Tali Landau , Shauly-Aharonov Michal , Weinberger Jeffrey M. , Eliashar Ron
Published: November 2023

Background

Otorhinolaryngology / Head and Neck Surgery consists of different sub-specialties, each comprising unique characteristics and challenges. Herein, we investigate the use of a uniform national electronic questionnaire for curriculum planning. Main outcome measures: (1) Analyze the residents’ perception of the different sub-specialties training programs and their competence capabilities. (2) Identify sub-specialties requiring attention. (3) Investigate the characteristics associated with competence perception.

Methods

This is a national cross sectional study. An anonymous electronic questionnaire was emailed to all registered Otorhinolaryngology / Head and Neck Surgery residents.

Results

63.5% registered residents responded to the questionnaire. Two sub-specialties, Rhinology and Laryngology, are located in the extremities of the residents’ perceptions of competence and training (p < 0.0001), despite similar complexity perception (means 6.10 and 6.01, respectively). Rhinology is perceived as the most well-trained sub-specialty, both surgically and clinically (means 7.08 and 7.66, respectively), whereas Laryngology is bottom scaled (means 5.16 and 6.14, respectively). The same is true for perceived competence, surgical and clinical, in Rhinology (means 6.80 and 8.02, respectively) compared to Laryngology (means 5.04 and 6.75, respectively). Significant positive correlations were found between training, competence perception and workload (“golden training triangle”).

Conclusions

Each ORL-HNS sub-specialty comprises different characteristics and a different learning curve, necessitating a tailored training program. Recognizing its sub-specialties distinctive features may assist in establishment of better-adapted learning curves in residency programs. Herein, we examine the use of anonymous electronic national survey. Laryngology, bottom ranked, is a prototype of a relatively new surgical discipline. Rhinology, ranked top by the residents, is an exemplar of a sub-specialty with an optimal ‘educational environment’. Moreover, we have established golden training triangle, implicating, highlights the essential role of institutional and senior staff for proper residency teaching. We demonstrate and advocate the benefit of using an anonymous electronic questionnaire.
Is a bio-psychosocial approach model possible at the first level of health services in the Democratic Republic of Congo? An organizational analysis of six health centers in South Kivu
Authors: Molima Christian Eboma Ndjangulu , Karemere Hermès , Makali Samuel , Bisimwa Ghislain , Macq Jean
Published: November 2023

Background

The health system, in the Democratic Republic of Congo, is expected to move towards a more people-centered form of healthcare provision by implementing a biopsychosocial (BPS) approach. It’s then important to examine how change is possible in providing healthcare at the first line of care. This study aims to analyze the organizational capacity of health centers to implement a BPS approach in the first line of care.

Methods

A mixed descriptive and analytical study was conducted from November 2017 to February 2018. Six health centers from four Health Zones (South Kivu, Democratic Republic of Congo) were selected for this study. An organizational analysis of six health centers based on 15 organizational capacities using the Context and Capabilities for Integrating Care (CCIC) as a theoretical framework was conducted. Data were collected through observation, document review, and individual interviews with key stakeholders. The annual utilization rate of curative services was analyzed using trends for the six health centers. The organizational analysis presented three categories (Basic Structures, People and values, and Key Processes).

Result

This research describes three components in the organization of health services on a biopsychosocial model (Basic Structures, People and values, and Key processes). The current functioning of health centers in South Kivu shows strengths in the Basic Structures component. The health centers have physical characteristics and resources (financial, human) capable of operating health services. Weaknesses were noted in organizational governance through sharing of patient experience, valuing patient needs in Organizational/Network Culture, and Focus on Patient Centeredness & Engagement as well as partnering with other patient care channels.

Conclusion

This study highlighted the predisposition of health centers to implement a BPS approach to their organizational capacities. The study highlights how national policies could regulate the organization of health services on the front line by relying more on the culture of teamwork in the care structures and focusing on the needs of the patients. Paying particular attention to the values of the agents and specific key processes could enable the implementation of the BPS approach at the health center level.
Relapse of acute myeloid leukemia after allogeneic stem cell transplantation: immune escape mechanisms and current implications for therapy
Authors: Sauerer Tatjana , Velázquez Giuliano Filippini , Schmid Christoph
Published: November 2023

Acute myeloid leukemia (AML) is a heterogeneous disease characterized by the expansion of immature myeloid cells in the bone marrow (BM) and peripheral blood (PB) resulting in failure of normal hematopoiesis and life-threating cytopenia. Allogeneic hematopoietic stem cell transplantation (allo-HCT) is an established therapy with curative potential. Nevertheless, post-transplant relapse is common and associated with poor prognosis, representing the major cause of death after allo-HCT. The occurrence of relapse after initially successful allo-HCT indicates that the donor immune system is first able to control the leukemia, which at a later stage develops evasion strategies to escape from immune surveillance. In this review we first provide a comprehensive overview of current knowledge regarding immune escape in AML after allo-HCT, including dysregulated HLA, alterations in immune checkpoints and changes leading to an immunosuppressive tumor microenvironment. In the second part, we draw the line from bench to bedside and elucidate to what extend immune escape mechanisms of relapsed AML are yet exploited in treatment strategies. Finally, we give an outlook how new emerging technologies could help to improve the therapy for these patients, and elucidate potential new treatment options.
Missense variants in CYP4B1 associated with increased risk of lung cancer among Chinese Han population
Authors: Yang Yongqin , Yuan Shan , Yan Shouchun , Dong Kuaini , Yang Yonghui
Published: November 2023

Introduction

Understanding the etiology and risk factors of lung cancer (LC) is the key to developing scientific and effective prevention and control strategies for LC. CYP4B1 genetic polymorphism has been reported to be associated with susceptibility to various diseases. We aimed to explore the association between CYP4B1 genetic variants and LC susceptibility.

Methods

One thousand three hundred thirty-nine participants were recruited to perform an association analysis through SNPStats online software. Statistical analysis of this study was mainly completed by SPSS 22.0 software. False-positive report probability analysis (FPRP) to detect whether the positive findings were noteworthy. Finally, the interaction of SNP-SNP in LC risk was evaluated by multi-factor dimensionality reduction.

Results

We found evidence that missense variants in CYP4B1 (rs2297810, rs4646491, and rs2297809) are associated with LC susceptibility. In particular, genotype GA of CYP4B1-rs2297810 was significantly associated with an increased risk of LC in both overall and stratified analyses (genotype GA: OR (95% CI) = 1.35 (1.08-1.69), p = 0.010). CYP4B1-rs4646491 (overdominant: OR (95% CI) = 1.30 (1.04-1.62), p = 0.023) and CYP4B1-rs2297809 (genotype CT: OR (95% CI) = 1.26 (1.01-1.59), p = 0.046) are also associated with an increased risk of LC. FPRP analysis showed that all positive results in this study are noteworthy findings

Conclusion

Three missense variants in CYP4B1 (rs2297810, rs4646491, and rs2297809) are associated with increasing risk of LC.
Inhibition of UTX/KDM6A improves recovery of spinal cord injury by attenuating BSCB permeability and macrophage infiltration through the MLCK/p-MLC pathway
Authors: Xie Yong , Luo Zixiang , Peng Wei , Liu Yudong , Yuan Feifei , Xu Jiaqi , Sun Yi , Lu Hongbin , Wu Tianding , Jiang Liyuan , Hu Jianzhong
Published: November 2023

Spinal cord injury (SCI) can prompt an immediate disruption to the blood–spinal cord barrier (BSCB). Restoring the integrity of this barrier is vital for the recovery of neurological function post-SCI. The UTX protein, a histone demethylase, has been shown in previous research to promote vascular regeneration and neurological recovery in mice with SCI. However, it is unclear whether UTX knockout could facilitate the recovery of the BSCB by reducing its permeability. In this study, we systematically studied BSCB disruption and permeability at different time points after SCI and found that conditional UTX deletion in endothelial cells (ECs) can reduce BSCB permeability, decrease inflammatory cell infiltration and ROS production, and improve neurological function recovery after SCI. Subsequently, we used RNA sequencing and ChIP-qPCR to confirm that conditional UTX knockout in ECs can down-regulate expression of myosin light chain kinase (MLCK), which specifically mediates myosin light chain (MLC) phosphorylation and is involved in actin contraction, cell retraction, and tight junctions (TJs) protein integrity. Moreover, we found that MLCK overexpression can increase the ratio of p-MLC/MLC, further break TJs, and exacerbate BSCB deterioration. Overall, our findings indicate that UTX knockout could inhibit the MLCK/p-MLC pathway, resulting in decreased BSCB permeability, and ultimately promoting neurological recovery in mice. These results suggest that UTX is a promising new target for treating SCI.

Graphical Abstract
Clinical value of Cyclin D1 and P21 in the differential diagnosis of papillary thyroid carcinoma
Authors: Wang Chen-chen , Lu Dan-dan , Shen Ming-hong , Chen Ru-lei , Zhang Zhi-hong , Lv Jing-huan
Published: November 2023

Background

With the continuous discovery of new borderline thyroid lesions and benign and malignant “gray areas”, coupled with the limitations of traditional immune indicators, the differential diagnosis of papillary thyroid carcinoma (PTC) has become more difficult. Cyclin D1 and P21 are cell cycle regulators involved in the occurrence and metastasis of multiple tumors, including PTC, but their specific functions are unclear.

Methods

In our study, immunohistochemical staining was used to explore the expression of Cyclin D1 and P21 in PTC, paracancerous tissue, follicular adenoma (FA) and papillary thyroid hyperplasia. In addition, their relationship with the clinicopathological features of PTC and their differential diagnostic value in distinguishing between intralymph node PTC metastases and intralymph node ectopic thyroid tissue were studied.

Results

Among 200 primary PTC lesions, Cyclin D1 and P21 were found to be expressed in 186 (93.00%) and 177 (88.50%), respectively, and their expression levels were significantly higher in PTC tissue than in adjacent tissue, FA tissue and papillary thyroid hyperplasia tissue (P < 0.05). The expression levels of Cyclin D1 and P21 were positively correlated with tumor size and lymph node metastasis (P < 0.05) but not with sex, age, number of tumor lesions, histological subtype, chronic lymphocytic thyroiditis or TNM stage (P < 0.05). The expression levels of Cyclin D1 and P21 were significantly correlated (P < 0.05). The positivity rates of Cyclin D1 and P21 in intralymph node PTC metastases were 97.96% (48/49) and 89.80% (44/49), respectively, which were significantly higher than those in intralymph node ectopic thyroid tissue (P < 0.05). The sensitivity (Se) and negative predictive value (NPV) of Cyclin D1 and P21 detection alone or in combination were higher than those of the combined detection of the classical antibody markers CK19, HBME-1 and Galectin-3. Besides, the Se, Sp, PPV and NPV of Cyclin D1 and P21 in differentiating intralymph node PTC metastases and intralymph node ectopic thyroid tissue were higher.

Conclusions

The results of our study show that Cyclin D1 and P21 are highly sensitive and specific markers for the diagnosis of PTC that are superior to traditional classical antibodies. And, these two markers are of great value in the differential diagnosis of intralymph node PTC metastases and intralymph node ectopic thyroid tissue.
Pathologist-trained machine learning classifiers developed to quantitate celiac disease features differentiate endoscopic biopsies according to modified marsh score and dietary intervention response
Authors: Gruver Aaron M. , Lu Haiyan , Zhao Xiaoxian , Fulford Angie D. , Soper Michael D. , Ballard Darryl , Hanson Jeffrey C. , Schade Andrew E. , Hsi Eric D. , Gottlieb Klaus , Credille Kelly M.
Published: November 2023

Background

Histologic evaluation of the mucosal changes associated with celiac disease is important for establishing an accurate diagnosis and monitoring the impact of investigational therapies. While the Marsh-Oberhuber classification has been used to categorize the histologic findings into discrete stages (i.e., Type 0-3c), significant variability has been documented between observers using this ordinal scoring system. Therefore, we evaluated whether pathologist-trained machine learning classifiers can be developed to objectively quantitate the pathological changes of villus blunting, intraepithelial lymphocytosis, and crypt hyperplasia in small intestine endoscopic biopsies.

Methods

A convolutional neural network (CNN) was trained and combined with a secondary algorithm to quantitate intraepithelial lymphocytes (IEL) with 5 classes on CD3 immunohistochemistry whole slide images (WSI) and used to correlate feature outputs with ground truth modified Marsh scores in a total of 116 small intestine biopsies.

Results

Across all samples, median %CD3 counts (positive cells/enterocytes) from villous epithelium (VE) increased with higher Marsh scores (Type 0%CD3 VE = 13.4; Type 1–3%CD3 VE = 41.9, p < 0.0001). Indicators of villus blunting and crypt hyperplasia were also observed (Type 0–2 villous epithelium/lamina propria area ratio = 0.81; Type 3a-3c villous epithelium/lamina propria area ratio = 0.29, p < 0.0001), and Type 0–1 crypt/villous epithelial area ratio = 0.59; Type 2–3 crypt/villous epithelial area ratio = 1.64, p < 0.0001). Using these individual features, a combined feature machine learning score (MLS) was created to evaluate a set of 28 matched pre- and post-intervention biopsies captured before and after dietary gluten restriction. The disposition of the continuous MLS paired biopsy result aligned with the Marsh score in 96.4% (27/28) of the cohort.

Conclusions

Machine learning classifiers can be developed to objectively quantify histologic features and capture additional data not achievable with manual scoring. Such approaches should be further investigated to improve biopsy evaluation, especially for clinical trials.
A comparative study on point cloud down-sampling strategies for deep learning-based crop organ segmentation
Authors: Li Dawei , Wei Yongchang , Zhu Rongsheng
Published: November 2023

The 3D crop data obtained during cultivation is of great significance to screening excellent varieties in modern breeding and improvement on crop yield. With the rapid development of deep learning, researchers have been making innovations in aspects of both data preparation and deep network design for segmenting plant organs from 3D data. Training of the deep learning network requires the input point cloud to have a fixed scale, which means all point clouds in the batch should have similar scale and contain the same number of points. A good down-sampling strategy can reduce the impact of noise and meanwhile preserve the most important 3D spatial structures. As far as we know, this work is the first comprehensive study of the relationship between multiple down-sampling strategies and the performances of popular networks for plant point clouds. Five down-sampling strategies (including FPS, RS, UVS, VFPS, and 3DEPS) are cross evaluated on five different segmentation networks (including PointNet +  + , DGCNN, PlantNet, ASIS, and PSegNet). The overall experimental results show that currently there is no strict golden rule on fixing down-sampling strategy for a specific mainstream crop deep learning network, and the optimal down-sampling strategy may vary on different networks. However, some general experience for choosing an appropriate sampling method for a specific network can still be summarized from the qualitative and quantitative experiments. First, 3DEPS and UVS are easy to generate better results on semantic segmentation networks. Second, the voxel-based down-sampling strategies may be more suitable for complex dual-function networks. Third, at 4096-point resolution, 3DEPS usually has only a small margin compared with the best down-sampling strategy at most cases, which means 3DEPS may be the most stable strategy across all compared. This study not only helps to further improve the accuracy of point cloud deep learning networks for crop organ segmentation, but also gives clue to the alignment of down-sampling strategies and a specific network.
The use of post-cycle therapy is associated with reduced withdrawal symptoms from anabolic-androgenic steroid use: a survey of 470 men
Authors: Grant Bonnie , Kean Joseph , Vali Naim , Campbell John , Maden Lorraine , Bijral Prun , Dhillo Waljit S. , McVeigh James , Quinton Richard , Jayasena Channa N.
Published: November 2023

Background

Anabolic–androgenic steroids (AAS) mimic the effects of testosterone and may include testosterone itself; they are used for body enhancement within the general population. AAS use has been linked with increased mortality, cardiovascular disease, mental health disorders, and infertility. AAS-induced hypogonadism can persist for an uncertain time period despite cessation, during which men may report physical and neuropsychiatric symptoms. In an attempt to mitigate these symptoms and expedite testicular recovery, many men self-administer post-cycle-therapy (PCT), typically involving human chorionic gonadotrophin (hCG) and selective oestrogen receptor modulators (SERMs), which are known to potently stimulate testicular function. However, this practice has no objective evidence of effectiveness to lessen the severity or duration of hypogonadal symptoms.

Methods

An anonymous survey of four-hundred-and-seventy men using AAS explored the symptoms they experienced when ceasing AAS use; the effect of PCT on relieving their symptoms, and their perceived role for health service support.

Results

The majority of respondents were white, aged 18–30 years old, and working in skilled manual work. 51.7% (n = 243) reported no issues with AAS use, but 35.3% reported increased aggression. 65.1% (n = 306) of respondents had attempted AAS cessation and 95.1% of these experienced at least one symptom upon AAS cessation. Low mood, tiredness and reduced libido were reported in 72.9%, 58.5% and 57.0% of men stopping AAS use, respectively, with only 4.9% reporting no symptoms. PCT had been used by 56.5% of respondents with AAS cessation and mitigated cravings to restart AAS use, withdrawal symptoms and suicidal thoughts by 60%, 60% and 50%, respectively. The effect of stopping AAS on body composition and recovery of testosterone or fertility was a concern in 60.5% and 52.4%, respectively. Most respondents felt PCT should be prescribed under medical supervision in the community.

Conclusions

Our survey suggests that the majority of men stopping AAS use are using some form of PCT. Some self-reported symptoms of AAS-induced hypogonadism such as cravings to restart AAS use reduce by 60% and suicidal thoughts reduce by 50%. These individuals are concerned about the negative effect of AAS use and cessation. This study provides crucial information for planning future research to evaluate the effects of PCT on symptoms when men stop AAS use.
Use of focal radiotherapy boost for prostate cancer: radiation oncologists’ perspectives and perceived barriers to implementation
Authors: Zhong Allison Y. , Lui Asona J. , Katz Matthew S. , Berlin Alejandro , Kamran Sophia C. , Kishan Amar U. , Murthy Vedang , Nagar Himanshu , Seible Daniel , Stish Bradley J. , Tree Alison C. , Seibert Tyler M.
Published: November 2023

Background

In a recent phase III randomized control trial, delivering a focal radiotherapy (RT) boost to tumors visible on MRI was shown to improve disease-free survival and regional/distant metastasis-free survival for patients with prostate cancer—without increasing toxicity. The aim of this study was to assess how widely this technique is being applied in current practice, as well as physicians’ perceived barriers toward its implementation.

Methods

We invited radiation oncologists to complete an online questionnaire assessing their use of intraprostatic focal boost in December 2022 and February 2023. To include perspectives from a broad range of practice settings, the invitation was distributed to radiation oncologists worldwide via email list, group text platform, and social media.

Results

263 radiation oncologist participants responded. The highest-represented countries were the United States (42%), Mexico (13%), and the United Kingdom (8%). The majority of participants worked at an academic medical center (52%) and considered their practice to be at least partially genitourinary (GU)-subspecialized (74%). Overall, 43% of participants reported routinely using intraprostatic focal boost. Complete GU-subspecialists were more likely to implement focal boost, with 61% reporting routine use. In both high-income and low-to-middle-income countries, less than half of participants routinely use focal boost. The most cited barriers were concerns about registration accuracy between MRI and CT (37%), concerns about risk of additional toxicity (35%), and challenges to accessing high-quality MRI (29%).

Conclusions

Two years following publication of a randomized trial of patient benefit without increased toxicity, almost half of the radiation oncologists surveyed are now routinely offering focal RT boost. Further adoption of this technique might be aided by increased access to high-quality MRI, better registration algorithms of MRI to CT simulation images, physician education on benefit-to-harm ratio, and training on contouring prostate lesions on MRI.
Mitral valve replacement using a collar-reinforced mitral prosthesis for severe mitral annular calcification, which secures implantation in both the supra-annular and intra-atrial positions: a case report
Authors: Morishita Atsushi , Tomioka Hideyuki , Katahira Seiichiro , Hoshino Takeshi , Hanzawa Kazuhiko
Published: November 2023

Background

Appropriate management of mitral annular calcification associated with mitral valve surgery must be determined on a case-by-case basis. However, an established procedure remains uncertain.

Case presentation

This report describes a surgical case of severe mitral and aortic valve stenosis associated with severe mitral annular calcification in a 71-year-old woman who underwent mitral valve replacement with a collar-reinforced mitral prosthesis. The patient underwent surgical repair after the treatment for heart failure. As the present patient was deemed to be at high risk for conventional mitral valve replacement, we applied a composite prosthetic valve that was enlarged circumferentially on the ventricular side of the prosthesis with a bovine pericardial patch. First, the solid calcium bar was left untouched and only the friable calcified mass that was easily scattered was removed. Subsequently, the prosthesis was secured by two mattress sutures placed in the intra-atrial position at the region of the extended calcified myocardium. Additionally, ten mattress sutures were placed in the supra-annular position at the other regions capable of passing stitches from the ventricular side to the atrial side. Finally, a 1.5 cm wide trimmed bovine pericardial collar was sutured circumferentially from the annulus to the atrial wall using running 4–0 polypropylene for reinforcement. Although temporary hemodialysis was performed for acute renal failure, the patient remained asymptomatic.

Conclusions

The present case suggests that mitral valve replacement using a collar-reinforced mitral prosthesis may be an effective technique for severe mitral annular calcification. To avoid catastrophic complications associated with treatment for severely calcified annulus, it is crucial to make a prudent preoperative decision regarding the surgical strategy under circumstances where conventional mitral valve replacement is impossible.
Effects of COVID-19 infection in patients with autoimmune pulmonary alveolar proteinosis: a single-center study
Authors: Duan Chuanxin , Zhou Wangji , Zhang Miaoyan , Cheng Chongsheng , Xu Wenshuai , Dai Jinrong , Meng Shuzhen , Chen Keqi , Zhao Yang , Liu Song , Wang Shao-Ting , Yang Yanli , Xu Kai-Feng , Tian Xinlun
Published: November 2023

Background

Autoimmune pulmonary alveolar proteinosis (aPAP) is a rare interstitial lung disease. COVID-19 is associated with worse prognosis in previous lung diseases patients. But the prognosis of aPAP patients after infection with COVID-19 is unclear. In December 2022, China experienced a large-scale outbreak of Omicron variant of the SARS-CoV-2. In this study, we aim to explore the clinical outcomes of aPAP patients infected with COVID-19.

Results

A total of 39 aPAP patients were included in this study. 30.77% patients had a decrease in oxygen saturation after COVID-19 infection. We compared the two groups of patients with or without decreased oxygen saturation after COVID-19 infection and found that patients who had previous oxygen therapy (decreased oxygen saturation vs. non decreased oxygen saturation: 6/12 vs. 4/27, P = 0.043), with lower baseline arterial oxygen partial pressure (74.50 ± 13.61 mmHg vs. 86.49 ± 11.92 mmHg, P = 0.009), lower baseline DLCO/VA% [77.0 (74.3, 93.6) % vs. 89.5 (78.2, 97.4) %, P = 0.036], shorter baseline 6MWD [464 (406, 538) m vs. 532 (470, 575) m, P = 0.028], higher disease severity score (P = 0.017), were more likely to have decreased oxygen saturation after COVID-19 infection.

Conclusion

aPAP patients with poor baseline respiration have a higher probability of hypoxia after COVID-19 infection, but fatal events were rare.
Mitochondrial dysfunction in Parkinson’s disease – a key disease hallmark with therapeutic potential
Authors: Henrich Martin T. , Oertel Wolfgang H. , Surmeier D. James , Geibl Fanni F.
Published: November 2023

Mitochondrial dysfunction is strongly implicated in the etiology of idiopathic and genetic Parkinson’s disease (PD). However, strategies aimed at ameliorating mitochondrial dysfunction, including antioxidants, antidiabetic drugs, and iron chelators, have failed in disease-modification clinical trials. In this review, we summarize the cellular determinants of mitochondrial dysfunction, including impairment of electron transport chain complex 1, increased oxidative stress, disturbed mitochondrial quality control mechanisms, and cellular bioenergetic deficiency. In addition, we outline mitochondrial pathways to neurodegeneration in the current context of PD pathogenesis, and review past and current treatment strategies in an attempt to better understand why translational efforts thus far have been unsuccessful.
Anti-tumor activity of all-trans retinoic acid in gastric-cancer: gene-networks and molecular mechanisms
Authors: Guarrera Luca , Kurosaki Mami , Garattini Silvio-Ken , Gianni’ Maurizio , Fasola Gianpiero , Rossit Luca , Prisciandaro Michele , Di Bartolomeo Maria , Bolis Marco , Rizzo Paola , Nastasi Claudia , Foglia Marika , Zanetti Adriana , Paroni Gabriela , Terao Mineko , Garattini Enrico
Published: November 2023

Background

Gastric-cancer is a heterogeneous type of neoplastic disease and it lacks appropriate therapeutic options. There is an urgent need for the development of innovative pharmacological strategies, particularly in consideration of the potential stratified/personalized treatment of this tumor. All-Trans Retinoic-acid (ATRA) is one of the active metabolites of vitamin-A. This natural compound is the first example of clinically approved cyto-differentiating agent, being used in the treatment of acute promyelocytic leukemia. ATRA may have significant therapeutic potential also in the context of solid tumors, including gastric-cancer. The present study provides pre-clinical evidence supporting the use of ATRA in the treatment of gastric-cancer using high-throughput approaches.

Methods

We evaluated the anti-proliferative action of ATRA in 27 gastric-cancer cell-lines and tissue-slice cultures from 13 gastric-cancer patients. We performed RNA-sequencing studies in 13 cell-lines exposed to ATRA. We used these and the gastric-cancer RNA-sequencing data of the TCGA/CCLE datasets to conduct multiple computational analyses.

Results

Profiling of our large panel of gastric-cancer cell-lines for their quantitative response to the anti-proliferative effects of ATRA indicate that approximately half of the cell-lines are characterized by sensitivity to the retinoid. The constitutive transcriptomic profiles of these cell-lines permitted the construction of a model consisting of 42 genes, whose expression correlates with ATRA-sensitivity.  The model predicts that 45% of the TCGA gastric-cancers are sensitive to ATRA. RNA-sequencing studies performed in retinoid-treated gastric-cancer cell-lines provide insights into the gene-networks underlying ATRA anti-tumor activity. In addition, our data demonstrate that ATRA exerts significant immune-modulatory effects, which seem to be largely controlled by IRF1 up-regulation. Finally, we provide evidence of a feed-back loop between IRF1 and DHRS3, another gene which is up-regulated by ATRA.

Conclusions

ATRA is endowed with significant therapeutic potential in the stratified/personalized treatment gastric-cancer. Our data represent the fundaments for the design of clinical trials focusing on the use of ATRA in the personalized treatment of this heterogeneous tumor. Our gene-expression model will permit the development of a predictive tool for the selection of ATRA-sensitive gastric-cancer patients. The immune-regulatory responses activated by ATRA suggest that the retinoid and immune-checkpoint inhibitors constitute rational combinations for the management of gastric-cancer.
A classification of the plantar intrinsic foot muscles based on the physiological cross‐sectional area and muscle fiber length in healthy young adult males
Authors: Kusagawa Yuki , Kurihara Toshiyuki , Maeo Sumiaki , Sugiyama Takashi , Kanehisa Hiroaki , Isaka Tadao
Published: November 2023

Background

Plantar intrinsic foot muscles (PIFMs) are composed of 10 muscles and play an essential role in achieving functional diversity in the foot. Previous studies have identified that the morphological profiles of PIFMs vary between individuals. The morphological profiles of a muscle theoretically reflect its output potentials: the physiological cross‐sectional area (PCSA) of a muscle is proportional to its maximum force generation, and the muscle fiber length (FL) is its shortening velocity. This implies that the PCSA and FL may be useful variables for characterizing the functional diversity of the individual PIFM. The purpose of this study was to examine how individual PIFMs can be classified based on their PCSA and FL.

Methods

In 26 healthy young adult males, the muscle volume and muscle length of seven PIFMs (abductor hallucis, ABDH; abductor digiti minimi, ABDM; adductor hallucis oblique head, ADDH‐OH; ADDH transverse head, ADDH‐TH; flexor digitorum brevis, FDB; flexor hallucis brevis, FHB; quadratus plantae, QP) were measured using magnetic resonance imaging. The PCSA and FL of each of the seven PIFMs were then estimated by combining the data measured from the participants and those of muscle architectural parameters documented from cadavers in previous studies. A total of 182 data samples (26 participants × 7 muscles) were classified into clusters using k‐means cluster analysis. The optimal number of clusters was evaluated using the elbow method.

Results

The data samples of PIFMs were assigned to four clusters with different morphological profiles: ADDH‐OH and FHB, characterised by large PCSA and short FL (high force generation and slow shortening velocity potentials); ABDM and FDB, moderate PCSA and moderate FL (moderate force generation and moderate shortening velocity potentials); QP, moderate PCSA and long FL (moderate force generation and rapid shortening velocity potentials); ADDH‐TH, small PCSA and moderate FL (low force generation and moderate shortening velocity potentials). ABDH components were assigned equivalently to the first and second clusters.

Conclusions

The approach adopted in this study may provide a novel perspective for interpreting the PIFMs' function based on their maximal force generation and shortening velocity potentials.