bluuebunny/crossref_metadata_2025 huggingface dataset:
Potential therapeutic effects of milk-derived exosomes on intestinal diseases
Authors: Cui Zhifu , Amevor Felix Kwame , Zhao Xingtao , Mou Chunyan , Pang Jiaman , Peng Xie , Liu Anfang , Lan Xi , Liu Lingbin
Published: December 2023

Exosomes are extracellular vesicles with the diameter of 30 ~ 150 nm, and are widely involved in intercellular communication, disease diagnosis and drug delivery carriers for targeted disease therapy. Therapeutic application of exosomes as drug carriers is limited due to the lack of sources and methods for obtaining adequate exosomes. Milk contains abundant exosomes, several studies have shown that milk-derived exosomes play crucial roles in preventing and treating intestinal diseases. In this review, we summarized the biogenesis, secretion and structure, current novel methods used for the extraction and identification of exosomes, as well as discussed the role of milk-derived exosomes in treating intestinal diseases, such as inflammatory bowel disease, necrotizing enterocolitis, colorectal cancer, and intestinal ischemia and reperfusion injury by regulating intestinal immune homeostasis, restoring gut microbiota composition and improving intestinal structure and integrity, alleviating conditions such as oxidative stress, cell apoptosis and inflammation, and reducing mitochondrial reactive oxygen species (ROS) and lysosome accumulation in both humans and animals. In addition, we discussed future prospects for the standardization of milk exosome production platform to obtain higher concentration and purity, and complete exosomes derived from milk. Several in vivo clinical studies are needed to establish milk-derived exosomes as an effective and efficient drug delivery system, and promote its application in the treatment of various diseases in both humans and animals.
Highly hydrophilic and dispersed TiO2 nano-system with enhanced photocatalytic antibacterial activities and accelerated tissue regeneration under visible light
Authors: Lu Boyao , Zhang Jie , Zhu Guixin , Liu Tiqian , Chen Jinwei , Liang Xing
Published: December 2023

Titanium dioxide (TiO2)-based photodynamic antibacterial (PDA) agents present a novel approach for addressing drug-resistant bacterial infections and the associated tissue damage. However, the suboptimal dispersibility, negative charge, and weak photocatalytic activity under visible light of TiO2 hinder its practical applications. This study aimed to address these limitations by developing a highly hydrophilic and dispersed Zn-TiO2/reduced graphene oxide (rGO) (HTGZ) nano-system with exceptional visible light catalytic activity and tissue repair ability. HTGZ produced an antibacterial ratio over 98% within a short time, likely due to the enhanced production of reactive oxygen species under visible light. After being co-cultured for 4 days, L929 cells and BMSCs maintained over 90% activity, indicating that HTGZ had no significant cytotoxicity. Furthermore, the transcriptomic and metabolic analyses revealed that the antibacterial mechanism mainly came from the destruction of cell membranes and the disruption of various metabolic processes, such as purine metabolism and fatty acid biosynthesis. Critically, results of in vivo experiments had authenticated that HTGZ significantly promoted infected tissue regeneration by slaughtering bacteria and release Zn2+. After 14 days, the wound area was only one-third that of the control group. Overall, the enhanced antibacterial efficacy and wound-healing potential position HTGZ as a promising nano-antibacterial medication for the clinical treatment of infectious bacterial diseases.
A novel polymer enabled by polymerized small molecule strategy for tumor photothermal and photodynamic therapy
Authors: Xie Xin , Wang Ke , Zeng Jie , Xu Miao-Yan , Qu Xin-Hui , Xiang Zheng-Bin , Tou Fang-Fang , Huang Shaorong , Han Xiao-Jian
Published: December 2023

Photothermal therapy (PTT) and photodynamic therapy (PDT) are effective method for tumor treatment. However, the limited variety and quantity of photothermal agents (PTAs) and photosensitizer (PSs) are still major challenges. Moreover, the cell apoptosis mechanism induced by PDT and PTT is still elusive. A fused-ring small molecule acceptor–donor acceptor′ donor–acceptor (A-DA′D-A) type of Y5 (Scheme 1) has a narrow band-gap and strong light absorption. Herein, we used Y5 to polymerize with thiophene unit to obtain polymer PYT based on polymerized small molecule strategy, and PYT nanoparticles (PYT NPs) was prepared via one-step nanoprecipitation strategy with DSPE-PEG2000. PYT NPs had excellent biocompatibility, good photostability, high photothermal conversion efficiency (67%) and reactive oxygen species (ROS) production capacity under 808 nm laser irradiation (PYT NPs + NIR). In vitro and in vivo experiments revealed that PYT NPs + NIR had the ability to completely ablate tumor cells. It was demonstrated that cell apoptosis induced by PYT NPs + NIR was closely related to mitochondrial damage. This study provides valuable guidance for constructing high-performance organic PTAs and PSs for tumor treatment.
Health expenditure: how much is spent on health and care worker remuneration? An analysis of 33 low- and middle-income African countries
Authors: Toure Hapsatou , Aranguren Garcia Maria , Bustamante Izquierdo Juana Paola , Coulibaly Seydou , Nganda Benjamin , Zurn Pascal
Published: December 2023

Objectives

To assess the amount spent on health and care workforce (HCW) remuneration in the African countries, its importance as a proportion of country expenditure on health, and government involvement as a funding source.

Methods

Calculations are based on country-produced disaggregated health accounts data from 33 low- and middle-income African countries, disaggregated wherever possible by income and subregional economic group.

Results

Per capita expenditure HCW remuneration averaged US$ 38, or 29% of country health expenditure, mainly coming from domestic public sources (three-fifths). Comparable were the contributions from domestic private sources and external aid, measured at around one-fifth each—23% and 17%, respectively. Spending on HCW remuneration was uneven across the 33 countries, spanning from US$ 3 per capita in Burundi to US$ 295 in South Africa. West African countries, particularly members of the West African Economic and Monetary Union (WAEMU), were lower spenders than countries in the Southern African Development Community (SADC), both in terms of the share of country health expenditure and in terms of government efforts/participation. By income group, HCW remuneration accounted for a quarter of country health expenditure in low-income countries, compared to a third in middle-income countries. Furthermore, an average 55% of government health expenditure is spent on HCW remuneration, across all countries. It was not possible to assess the impact of fragile and vulnerable countries, nor could we draw statistics by type of health occupation.

Conclusions

The results clearly show that the remuneration of the health and care workforce is an important part of government health spending, with half (55%) of government health spending on average devoted to it. Comparing HCW expenditure components allows for identifying stable sources, volatile sources, and their effects on HCW investments over time. Such stocktaking is important, so that countries, WHO, and other relevant agencies can inform necessary policy changes.
Patient-derived scaffolds representing breast cancer microenvironments influence chemotherapy responses in adapted cancer cells consistent with clinical features
Authors: Leiva Maria Carmen , Gustafsson Anna , Garre Elena , Ståhlberg Anders , Kovács Anikó , Helou Khalil , Landberg Göran
Published: December 2023

Background

The tumor microenvironment clearly influences cancer progressing properties but less is known about how individual cancer microenvironments potentially moderate cancer treatment effects. By cultivating and treating cancer cell lines in patient-derived scaffolds (PDS), the impact of specific characteristics of individual cancer microenvironments can be incorporated in human-like growth modelling and cancer drug treatment testing.

Methods

PDSs from 78 biobanked primary breast cancer samples with known patient outcomes, were prepared and repopulated with donor breast cancer cell lines, followed by treatment with 5-fluorouracil or doxorubicin after cellular adaption to the various microenvironments. Cancer cell responses to the treatments were monitored by RNA-analyses, highlighting changes in gene sets representative for crucial tumor biological processes such as proliferation, cancer stem cell features, differentiation and epithelial-to-mesenchymal transition.

Results

The chemotherapy treatments induced distinct gene expression patterns in adapted cancer cells with clusters of similar treatment responses depending on the patient-derived cancer microenvironment used as growth substrate. The doxorubicin treatment displayed a favorable gene signature among surviving cancer cells with low proliferation (MKI67) and pluripotency features (NANOG, POU5F1), in comparison to 5-fluorouracil showing low proliferation but increased pluripotency. Specific gene changes monitored post-treatment were also significantly correlated with clinical data, including histological grade (NANOG), lymph node metastasis (SLUG) and disease-free patient survival (CD44).

Conclusions

This laboratory-based treatment study using patient-derived scaffolds repopulated with cancer cell lines, clearly illustrates that the human cancer microenvironment influences chemotherapy responses. The differences in treatment responses defined by scaffold-cultures have potential prognostic and treatment predictive values.
Defining a therapeutic range for adalimumab serum concentrations in the management of pediatric noninfectious uveitis, a step towards personalized treatment
Authors: Dehoorne Jo L. , Groth Helena , Carlé Emma , De Schrijver Ilse , Sys Celine , Delbeke Patricia , Kreps Elke O. , Renson Thomas , Bonroy Carolien
Published: December 2023

Background

Adalimumab is currently considered the most efficacious anti-TNFα agent for childhood noninfectious uveitis (NIU). The objective of this study was to define a therapeutic range for adalimumab trough levels in the treatment of childhood NIU.

Methods

A retrospective, observational, pilot study of 36 children with NIU aged < 18 years, treated with adalimumab. Serum adalimumab through levels and adalimumab anti-drug antibodies (ADA) were analysed at least 24 weeks after start adalimumab.

Results

Adalimumab trough levels were significantly higher in complete responders 11.8 μg/mL (range 6.9–33.0) compared to partial or non-responders 9,2 μg/mL (range 0–13.6) (p = 0,004). Receiver–operator characteristics analyses with an area under the curve of 0,749 (95% CI, 0,561–0,937) defined 9.6 µg/mL as the lower margin for the therapeutic range. This cut-off corresponds with a sensitivity of 88% and a specificity of 56% (positive predictive value, 85%; negative predictive value, 62.5%). A concentration effect curve defined 13 µg/mL as the upper margin. Approximately one-third (30.5%) of patients had an adalimumab trough concentration exceeding 13 µg/mL. Free ADA were observed in 2 patients (5.5%).

Conclusions

A therapeutic range of adalimumab trough levels of 9.6 to 13 µg/mL, which corresponds with an optimal clinical effect, was identified. Therapeutic drug monitoring may guide the optimisation of treatment efficacy in children with NIU in the treat-to-target era.
Lung infection or inflammation-a puzzling case of MDA-5 associated juvenile dermatomyositis
Authors: Vuppala Anusha , Sondhi Manush , Umer Sarwat
Published: December 2023

Background

Juvenile dermatomyositis (JDM) is an uncommon inflammatory myopathy predominantly affecting children under 18 years of age. Diagnosis relies on identifying specific clinical features, such as muscle weakness, skin rash, elevated muscle enzymes, and MRI and muscle biopsy findings. Autoantibodies associated with inflammatory myopathy offer valuable prognostic insights and can indicate the risk of internal organ involvement, though they are relatively rare in childhood myopathies. JDM can progress to interstitial lung disease (ILD) if associated with MDA5 antibodies, and immunosuppressive therapy constitutes the primary treatment approach.

Case presentation

We present a unique case of JDM complicated by disseminated histoplasmosis in a 12-year-old African American male cross-country runner with no prior medical history. He presented with unintentional weight loss and a rash on his hands, genitals, and fingertips, which persisted despite previous treatments. Diagnosis of JDM was confirmed through clinical and laboratory evaluations. Over time, the patient developed recurrent fevers, thrombocytopenia, and signs of ILD, leading to the identification of disseminated histoplasmosis as a complicating factor. Appropriate antifungal treatment resolved the infectious condition, while continued immunosuppression aided in managing JDM and ILD.

Conclusions

Juvenile dermatomyositis (JDM) remains a rare and intricate autoimmune disorder affecting young individuals. The presence of MDA5 antibodies in JDM patients can lead to severe complications like ILD, necessitating vigilant monitoring. Management includes immunosuppressive therapy, with glucocorticoids and mycophenolate mofetil proving effective, particularly in Clinically Amyopathic Dermatomyositis (CADM) cases. In cases of refractory disease, intravenous immunoglobulin (IVIG) plays a crucial role, offering a safe and beneficial adjunct to treatment. We emphasize the importance of recognizing atypical presentations of JDM, as it can lead to delays in diagnosis and treatment. Our case highlights the complexities of managing dual lung pathology, where a secondary infection exacerbated lung nodules and thrombocytopenia, while ILD was a consequence of atypical myopathy. Combining antifungal treatment with immunosuppression effectively managed both conditions and follow-up evaluations demonstrated improvement in ILD. Awareness of potential fungal infections in immunosuppressed JDM patients is crucial for successful treatment and patient outcomes.
Finite element mechanical analysis of ipsilateral approach and contralateral approach in unilateral bilateral endoscopic spine surgery
Authors: Li Wenzheng , Han Junjian , Xin Qingyun , Liu Qitao , Feng Chao , Liu Yichan , Zhang Dengjun
Published: December 2023

Background

Unilateral bilateral endoscopic spine surgery (UBE) is often performed to treat lumbar spinal stenosis and disc herniation. It has become a prominent method in endoscopic spine surgery because of its very low learning curve and broader operative field of vision. Currently, the ipsilateral approach and contralateral approach have been established for disc herniation in the foraminal area, intervertebral foramen region, or pedicle region. The contralateral method offers many benefits over the ipsilateral approach, including less bone labour during microsurgical decompression and the preservation of facet joints. However, because it uses the interlaminar window approach, it inevitably involves osteotomy of the patient’s superior and inferior articular processes, which may result in corresponding deterioration in the spine’s biomechanical stability and subsequent adjacent facet joint diseases caused by facet joint degeneration postoperatively.

Objective

As a result, the purpose of this work is to use a finite element model to evaluate how the ipsilateral approach and contralateral approach in unilateral bilateral endoscopic spine surgery affect spinal stability while treating identical intervertebral disc herniation.

Study design

In this study, a three-dimensional lumbar-sacral spine model was built and verified. Osteotomies were conducted for armpit-type lumbar disc herniation (LDH), periradicular-type LDH, and shoulder-type LDH. Postoperative lumbar spine models of the ipsilateral approach and contralateral approach in unilateral bilateral endoscopic spine surgery were developed. The von Mises stress on the endplate, shear force on the annulus fibrosus, pressure inside the intervertebral disc, and range of motion (ROM) of the L3 segment were all determined. The results of our well-validated model showed that osteotomy done in the ipsilateral approach deteriorated most biomechanical metrics.

Results

In the majority of loading conditions, the contralateral approach caused the intervertebral disc’s biomechanical properties to increase, and the ipsilateral approach caused the intervertebral disc’s biomechanical properties to increase sharply more than the contralateral approach.

Conclusion

The contralateral approach, which is now extensively employed in unilateral bilateral endoscopic spine surgery, may be regarded as an ideal surgical alternative for treating lumbar disc herniation without producing iatrogenic instability. This approach has a low facet joint reduction rate, minimum soft tissue injury, and precisely identifies the midline of the central spinal canal during the retraction of the thecal sac and nerve roots.
Multicentric Carpo-Tarsal Osteolysis Syndrome (MCTO) and “Function Profile”: a rehabilitative approach
Authors: Ronchetti Anna Bruna , Usai Marina , Savino Valentina , Scaglione Marco , Tacchino Chiara Maria , Bertamino Marta , Moretti Paolo , Di Rocco Maja
Published: December 2023

Background

Multicentric Carpo-Tarsal Osteolysis Syndrome (MCTO) is an autosomal dominant disease with increased bone reabsorption in the carpus and tarsus and the elbows, knees and spine. The disease is extremely heterogeneous and secondary and tertiary injuries vary widely and can lead to progressive disability and severe functional limitations. In addition to the available and upcoming drug therapies, physical medicine and rehabilitation are important treatment options. Currently, the indication and plan are overlooked, nonspecific and reported only for one patient.

Methods

We describe a case series of MCTO patients diagnosed and followed by a centre to identify functional deficit as a potential clinical marker of disease progression for future etiological therapies. In addition, we define a symptomatic treatment approach and specific clinical management, including a patient-centred rehabilitation approach. Functional assessments are performed independently by a multidisciplinary group to establish the functional abilities of patients and the relationship between residual motor skills and their degree of autonomy and participation. We suggest a way to identify a rehabilitation plan based on a specific disease using the International Classification of Functioning, Disability and Health Children and Youth (ICF-CY).

Results

To define a reliable and reproducible “Function Profile”, through age and over time, we used to value the disease status according to the ICF-CY domains. It could be used to determine the complexity of the illness, its overall impact on the complexity of the person and the burden on the caregiver, and an eventual short- and long-term rehabilitation plan for MCTO and other ultra-rare diseases.

Conclusion

Based on the MCTO experience, we suggest a way to determine a rehabilitation plan based on a specific disease and patient needs, keeping in mind that often the final point is not recovering the full function but improving or maintaining the starting point. In all cases, each patient at the time of diagnosis requires a functional assessment that must be repeated over time to adjust the course of rehabilitation. The evaluations revealed the importance of early rehabilitation management in enhancing independence, participation and control of stress deconditioning, shrinking of muscle tendons and loss of movement to immobility.
Transcription factors in fibroblast plasticity and CAF heterogeneity
Authors: Melchionna Roberta , Trono Paola , Di Carlo Anna , Di Modugno Francesca , Nisticò Paola
Published: December 2023

In recent years, research focused on the multifaceted landscape and functions of cancer-associated fibroblasts (CAFs) aimed to reveal their heterogeneity and identify commonalities across diverse tumors for more effective therapeutic targeting of pro-tumoral stromal microenvironment. However, a unified functional categorization of CAF subsets remains elusive, posing challenges for the development of targeted CAF therapies in clinical settings.

The CAF phenotype arises from a complex interplay of signals within the tumor microenvironment, where transcription factors serve as central mediators of various cellular pathways. Recent advances in single-cell RNA sequencing technology have emphasized the role of transcription factors in the conversion of normal fibroblasts to distinct CAF subtypes across various cancer types.

This review provides a comprehensive overview of the specific roles of transcription factor networks in shaping CAF heterogeneity, plasticity, and functionality. Beginning with their influence on fibroblast homeostasis and reprogramming during wound healing and fibrosis, it delves into the emerging insights into transcription factor regulatory networks. Understanding these mechanisms not only enables a more precise characterization of CAF subsets but also sheds light on the early regulatory processes governing CAF heterogeneity and functionality. Ultimately, this knowledge may unveil novel therapeutic targets for cancer treatment, addressing the existing challenges of stromal-targeted therapies.
Update on the INTEnsive ambulance-delivered blood pressure Reduction in hyper-ACute stroke Trial (INTERACT4): progress and baseline features in 2053 participants
Authors: Chen Chen , Lin Yapeng , Liu Feifeng , Chen Xiaoying , Billot Laurent , Li Qiang , Guo Yiija , Liu Hueiming , Si Lei , Ouyang Menglu , Zhang Chunfang , Arima Hisatomi , Bath Philip M. , Ford Gary A. , Robinson Thompson , Sandset Else Charlotte , Saver Jeffrey L. , Sprigg Nikola , van der Worp H. Bart , Liu Gang , Song Lili , Yang Jie , Li Gang , Anderson Craig S. ,   for the INTERACT4 Investigators
Published: December 2023

Background and aims

Uncertainty persists over the effects of blood pressure (BP) lowering in acute stroke. The INTEnsive ambulance-delivered blood pressure Reduction in hyper-Acute stroke Trial (INTERACT4) aims to determine efficacy and safety of hyperacute intensive BP lowering in patients with suspected acute stroke. Given concerns over the safety of this treatment in the pre-hospital setting, particularly in relation to patients with intracerebral hemorrhage, we provide an update on progress of the study and profile of participants to date.

Methods

INTERACT4 is an ongoing multicentre, ambulance-delivered, randomized, open-label, blinded endpoint trial of pre-hospital BP lowering in patients with suspected acute stroke and elevated BP in China. Patients are randomized via a mobile phone digital system to intensive (target systolic BP [SBP] <140mmHg within 30 min) or guideline-recommended BP management. Primary outcome is an ordinal analysis of the full range of scores on the modified Rankin scale scores at 90 days.

Results

Between March 2020 and April 2023, 2053 patients (mean age 70 years, female 39%) were recruited with a mean BP 178/98 mmHg in whom 45% have a diagnosis of primary intracerebral hemorrhage upon arrival at hospital. At the time of presentation to hospital, the mean SBP was 160 and 170mmHg in the intensive and control groups (Δ10 mmHg), respectively. The independent data and safety monitoring board has not identified any safety concerns and recommended continuation of the trial. The sample size was reduced from 3116 to 2320 after meetings in August 2022 as the stroke mimic rate was persistently lower than initially estimated (6% vs 30%). The study is expected to be completed in late 2023 and the results announced in May 2024.

Conclusions

INTERACT4 is on track to provide reliable evidence of the effectiveness of ambulance-delivered intensive BP lowering in patients with suspected acute stroke.

Trial registration

ClinicalTrials.gov NCT03790800; registered on 2 January 2019. Chinese Trial Registry ChCTR1900020534, registered on 7 January 2019.
Identification of isothiazolones analogues as potent bactericidal agents against antibiotic resistant CRE and MRSA strains
Authors: Jin Wenbin , Xu Chen , Dong Ning , Chen Kaichao , Zhang Die , Ning Jinhua , Li Yunbing , Zhang Guangfen , Ke Jin , Hou Anguo , Chen Linyun , Chen Sheng , Chan Kin-Fai
Published: December 2023

Carbapenem-resistant Enterobacterales (CRE) has emerged as a worldwide spread nosocomial superbug exhibiting antimicrobial resistance (AMR) to all current antibiotics, leaving limited options for treating its infection. To discovery novel antibiotics against CRE, we designed and synthesized a series of 14 isothiazol-3(2H)-one analogues subjected to antibacterial activity evaluation against Escherichia coli (E. coli) BL21 (NDM-1) and clinical strain E. coli HN88 for investigating their structure–activity relationships (SAR). The results suggested that 5-chloroisothiazolone core with an N-(4-chlorophenyl) substitution 5a was the most potent antibacterial activity against the E. coli BL21 (NDM-1) with MIC value of less than 0.032 μg/mL, which was at least 8000-fold higher than the positive control Meropenem (MRM). It also displayed 2048-fold potent than the positive control MRM against E. coli HN88. Additionally, SAR analysis supported the conclusion that compounds with a chloro-group substituted on the 5-position of the heterocyclic ring was much more potent than other positions. The board spectrum analysis suggested that compound 5a showed a promising antimicrobial activity on MRSA and CRE pathogens. Meanwhile, cytotoxicity study of compound 5a suggested that it had a therapeutic index value of 875, suggesting future therapeutic potential. In vivo efficacy study declared that compound 5a could also protect the BALB/c mice against American type culture collection (ATCC) 43,300. Further screening of our compounds against a collection of CRE strains isolated from patients indicated that compound 5 g displayed much stronger antibacterial activity compared with MRM. In conclusion, our studies indicated that isothiazolones analogues could be potent bactericidal agents against CRE and MRSA pathogens.
First report of cutaneous leishmaniasis caused by Leishmania donovani in Ethiopia
Authors: Amare Gashaw Azanaw , Mekonnen Gebeyaw Getnet , Kassa Mekibib , Addisu Ayenew , Kendie Desalegn Adane , Tegegne Banchamlak , Abera Adugna , Tadesse Dagimawie , Getahun Seid , Wondmagegn Yenesew Mihret , Merdekios Behailu , Asres Mezgebu Silamsaw , van Griensven Johan , Van der Auwera Gert , van Henten Saskia , Pareyn Myrthe
Published: December 2023

Background

Leishmaniasis is a common neglected tropical disease in Ethiopia. Visceral leishmaniasis (VL) caused by Leishmania donovani presents in the lowlands, while cutaneous leishmaniasis (CL) affects people living in the highlands. Although CL is described as being caused by Leishmania aethiopica, there is also evidence of L. tropica and L. major isolated from a patient, sand flies and potential reservoirs. Information on species causing CL in Ethiopia is patchy, and no nation-wide study has ever been done. Understanding which species are causing CL in Ethiopia can have important implications for patient management and disease prevention.

Methods

We analyzed stored routine samples and biobanked DNA isolates from previously conducted studies of CL patients from different centers in the north, center and south of Ethiopia. Species typing was performed using ITS-1 PCR with high-resolution melt (HRM) analysis, followed by HSP70 amplicon sequencing on a selection of the samples. Additionally, sociodemographic, clinical and laboratory data of patients were analyzed.

Results

Of the 226 CL samples collected, the Leishmania species could be determined for 105 (45.5%). Leishmania aethiopica was identified in 101 (96.2%) samples from across the country. In four samples originating from Amhara region, northwestern Ethiopia, L. donovani was identified by ITS-1 HRM PCR, of which two were confirmed with HSP70 sequences. While none of these four patients had symptoms of VL, two originated from known VL endemic areas.

Conclusions

The majority of CL was caused by L. aethiopica, but CL due to L. tropica and L. major cannot be ruled out. Our study is the first to our knowledge to demonstrate CL patients caused by L. donovani in Ethiopia. This should spark future research to investigate where, how and to which extent such transmission takes place, how it differs genetically from L. donovani causing VL and whether such patients can be diagnosed and treated successfully with the currently available tools and drugs.

Graphical Abstract
Deep learning predicts cervical lymph node metastasis in clinically node-negative papillary thyroid carcinoma
Authors: Zhou Li-Qiang , Zeng Shu-E. , Xu Jian-Wei , Lv Wen-Zhi , Mei Dong , Tu Jia-Jun , Jiang Fan , Cui Xin-Wu , Dietrich Christoph F.
Published: December 2023

Objectives

Precise determination of cervical lymph node metastasis (CLNM) involvement in patients with early-stage thyroid cancer is fairly significant for identifying appropriate cervical treatment options. However, it is almost impossible to directly judge lymph node metastasis based on the imaging information of early-stage thyroid cancer patients with clinically negative lymph nodes.

Methods

Preoperative US images (BMUS and CDFI) of 1031 clinically node negative PTC patients definitively diagnosed on pathology from two independent hospitals were divided into training set, validation set, internal test set, and external test set. An ensemble deep learning model based on ResNet-50 was built integrating clinical variables, BMUS, and CDFI images using a bagging classifier to predict metastasis of CLN. The final ensemble model performance was compared with expert interpretation.

Results

The ensemble deep convolutional neural network (DCNN) achieved high performance in predicting CLNM in the test sets examined, with area under the curve values of 0.86 (95% CI 0.78–0.94) for the internal test set and 0.77 (95% CI 0.68–0.87) for the external test set. Compared to all radiologists averaged, the ensemble DCNN model also exhibited improved performance in making predictions. For the external validation set, accuracy was 0.72 versus 0.59 (p = 0.074), sensitivity was 0.75 versus 0.58 (p = 0.039), and specificity was 0.69 versus 0.60 (p = 0.078).

Conclusions

Deep learning can non-invasive predict CLNM for clinically node-negative PTC using conventional US imaging of thyroid cancer nodules and clinical variables in a multi-institutional dataset with superior accuracy, sensitivity, and specificity comparable to experts.

Critical relevance statement

Deep learning efficiently predicts CLNM for clinically node-negative PTC based on US images and clinical variables in an advantageous manner.

Key points

• A deep learning-based ensemble algorithm for predicting CLNM in PTC was developed.

• Ultrasound AI analysis combined with clinical data has advantages in predicting CLNM.

• Compared to all experts averaged, the DCNN model achieved higher test performance.

Graphical Abstract
Predicting tumor deposits in rectal cancer: a combined deep learning model using T2-MR imaging and clinical features
Authors: Jin Yumei , Yin Hongkun , Zhang Huiling , Wang Yewu , Liu Shengmei , Yang Ling , Song Bin
Published: December 2023

Background

Tumor deposits (TDs) are associated with poor prognosis in rectal cancer (RC). This study aims to develop and validate a deep learning (DL) model incorporating T2-MR image and clinical factors for the preoperative prediction of TDs in RC patients.

Methods and methods

A total of 327 RC patients with pathologically confirmed TDs status from January 2016 to December 2019 were retrospectively recruited, and the T2-MR images and clinical variables were collected. Patients were randomly split into a development dataset (n = 246) and an independent testing dataset (n = 81). A single-channel DL model, a multi-channel DL model, a hybrid DL model, and a clinical model were constructed. The performance of these predictive models was assessed by using receiver operating characteristics (ROC) analysis and decision curve analysis (DCA).

Results

The areas under the curves (AUCs) of the clinical, single-DL, multi-DL, and hybrid-DL models were 0.734 (95% CI, 0.674–0.788), 0.710 (95% CI, 0.649–0.766), 0.767 (95% CI, 0.710–0.819), and 0.857 (95% CI, 0.807–0.898) in the development dataset. The AUC of the hybrid-DL model was significantly higher than the single-DL and multi-DL models (both p < 0.001) in the development dataset, and the single-DL model (p = 0.028) in the testing dataset. Decision curve analysis demonstrated the hybrid-DL model had higher net benefit than other models across the majority range of threshold probabilities.

Conclusions

The proposed hybrid-DL model achieved good predictive efficacy and could be used to predict tumor deposits in rectal cancer.

Critical relevance statement

The proposed hybrid-DL model achieved good predictive efficacy and could be used to predict tumor deposits in rectal cancer.

Key points

• Preoperative non-invasive identification of TDs is of great clinical significance.

• The combined hybrid-DL model achieved good predictive efficacy and could be used to predict tumor deposits in rectal cancer.

• A preoperative nomogram provides gastroenterologist with an accurate and effective tool.

Graphical Abstract
Mesenchymal stem cells and dental implant osseointegration during aging: from mechanisms to therapy
Authors: Ma Yang , Wang Siyuan , Wang Hui , Chen Xiaoyu , Shuai Yi , Wang Huiming , Mao Yingjie , He Fuming
Published: December 2023

Dental implants are widely used to replace missing teeth, providing patients with unparalleled levels of effectiveness, convenience, and affordability. The biological basis for the clinical success of dental implants is osseointegration. Bone aging is a high-risk factor for the reduced osseointegration and survival rates of dental implants. In aged individuals, mesenchymal stem cells (MSCs) in the bone marrow show imbalanced differentiation with a reduction in osteogenesis and an increase in adipogenesis. This leads to impaired osseointegration and implant failure. This review focuses on the molecular mechanisms underlying the dysfunctional differentiation of aged MSCs, which primarily include autophagy, transcription factors, extracellular vesicle secretion, signaling pathways, epigenetic modifications, microRNAs, and oxidative stress. Furthermore, this review addresses the pathological changes in MSCs that affect osseointegration and discusses potential therapeutic interventions to enhance osseointegration by manipulating the mechanisms underlying MSC aging.
Targeting ST8SIA6-AS1 counteracts KRASG12C inhibitor resistance through abolishing the reciprocal activation of PLK1/c-Myc signaling
Authors: Wang Yafang , Yao Mingyue , Li Cheng , Yang Kexin , Qin Xiaolong , Xu Lansong , Shi Shangxuan , Yu Chengcheng , Meng Xiangjun , Xie Chengying
Published: December 2023

Background

KRASG12Cinhibitors (KRASG12Ci) AMG510 and MRTX849 have shown promising efficacy in clinical trials and been approved for the treatment of KRASG12C-mutant cancers. However, the emergence of therapy-related drug resistance limits their long-term potential. This study aimed to identify the critical mediators and develop overcoming strategies.

Methods

By using RNA sequencing, RT-qPCR and immunoblotting, we identified and validated the upregulation of c-Myc activity and the amplification of the long noncoding RNA ST8SIA6-AS1 in KRASG12Ci-resistant cells. The regulatory axis ST8SIA6-AS1/Polo-like kinase 1 (PLK1)/c-Myc was investigated by bioinformatics, RNA fluorescence in situ hybridization, RNA immunoprecipitation, RNA pull-down and chromatin immunoprecipitation. Gain/loss-of-function assays, cell viability assay, xenograft models, and IHC staining were conducted to evaluate the anti-cancer effects of co-inhibition of ST8SIA6-AS1/PLK1 pathway and KRAS both in vitro and in vivo.

Results

KRASG12Ci sustainably decreased c-Myc levels in responsive cell lines but not in cell lines with intrinsic or acquired resistance to KRASG12Ci. PLK1 activation contributed to this ERK-independent c-Myc stability, which in turn directly induced PLK1 transcription, forming a positive feedback loop and conferring resistance to KRASG12Ci. ST8SIA6-AS1 was found significantly upregulated in resistant cells and facilitated the proliferation of KRASG12C-mutant cancers. ST8SIA6-AS1 bound to Aurora kinase A (Aurora A)/PLK1 and promoted Aurora A-mediated PLK1 phosphorylation. Concurrent targeting of KRAS and ST8SIA6-AS1/PLK1 signaling suppressed both ERK-dependent and -independent c-Myc expression, synergistically led to cell death and tumor regression and overcame KRASG12Ci resistance.

Conclusions

Our study deciphers that the axis of ST8SIA6-AS1/PLK1/c-Myc confers both intrinsic and acquired resistance to KRASG12Ci and represents a promising therapeutic target for combination strategies with KRASG12Ci in the treatment of KRASG12C-mutant cancers.
Discharge mode conversion of bending flexible electrodes
Authors: Zhou Desheng , Li Jiayin , Tang Xin , Kim Minkwan
Published: December 2023

Printed flexible electrodes have attracted widespread attention due to the low-cost process, large-area printing and resource saving. The performances of a flexible electrode in different applications is studied by researchers. In this paper, the characteristics of a flexible electrode with different bending angles are experimentally studied. Electrical, optical and productions characteristics are illustrated to demonstrate the performance of dielectric barrier discharge with a flexible electrode. Furthermore, the electrical fields are studied to explain the transfer of discharge mode and the corresponding discharge products.
The Grey Matter of the Cerebral Convolutions
Authors: Galway
Published: December 2023

The microscopy of the grey matter of the cerebral hemispheres is a subject which has occupied in recent years the attention of numerous observers; but the accounts of different writers are sadly conflicting, and the layers which they describe are so variously and even arbitrarily enumerated, that it is difficult to compare their descriptions in detail.
The Origin and Distribution of Microzymes (Bacteria) in Water, and the Circumstances which determine their Existence in the Tissues and Liquids of the Living Body
Authors: Burdon-Sanderson John
Published: December 2023

In my previous report on the intimate pathology of contagion, microzymes were defined as living particles which in their earliest state are spheroids, and do not exceed of an inch in diameter, but subsequently elongate into rods. As regards the conditions of their development, their existence was said to be associated with the commencement of putrefactive decomposition of nitrogenous compounds. The question of their origin and destiny was left unanswered. It was left undecided whether on the one hand “they constitute a race of more or less similar individuals, each of which springs from and reproduces its like,” or, on the other, are “germs in which a specific form is wrapped up,” capable of developing to the higher organisms from which they spring.
Note on Immersion Object-Glasses for the Microscope
Authors: Pigott Royston
Published: December 2023

It is a curious fact that, though several writers in this country and America have taken up the question of immersion objectives, very different opinions have been expressed as to the causes of the advantages obtained. One writer boldly asserts that the aperture of an immersion lens can never exceed 80°. The following experiment points to a very different conclusion.
The Luminous Organs and Light of the PennatulÆ
Authors: Panceri
Published: December 2023

The memoir presented to the Academy under the title indicated above commences by the enumeration of the authors who have witnessed the phosphorescence of the zoophites in question. Although omitting the observers who limit themselves to stating the fact that light is emitted by the Pennatulidæ, I ought specially to mention Spallanzani, Blainville, Delle Chiaje, and Forbes, as having already described the luminous waves which are seen traversing these little polypes when they have been recently touched. ‘Hitherto neither methodical experiments have been made towards determining the conditions of this phenomenon, nor special researches to discover whether these animals really possess true luminous organs. Formerly it was generally believed that the mucus which clothed the exterior of the had the power of giving light in such a way that the finger which touched and pressed these little polypes became covered itself with luminous matter.
On the Differences Between the Nominal and Solar Focal Length of English Object-Glasses
Authors: Pigott Royston
Published: December 2023

Our English opticians have been somewhat hardly accused of pretending, for trade purposes, that the focal length of their object-glasses is misrepresented, and that they are really of a much deeper character than the name they bear.
Microcythœmia; a Morbid Condition of the Blood hitherto undescribed1
Authors: Vanlair  , Masius
Published: December 2023

In this memoir the authors designate by the name of “microcythémie” a disease of which they believe the principal character to consist in a special alteration of the blood morphologically expressed by the presence of an enormous number of red corpuscles different from the ordinary red corpuscles. To these they assign the name “microcytes,” from their small size, and the name microcythœmia is formed on the model of leucocythœmia. The observation of one case furnished the authors with the chief groundwork of their paper, and we shall follow them in prefixing a short relation of it to our summary of the memoir.
Study on the clinical effect of percutaneous transforaminal endoscopic discectomy combined with annulus fibrosus repair in the treatment of single-segment lumbar disc herniation in young and middle-aged patients
Authors: Zhao Ya-fei , Tian Bin-wu , Ma Qiu-shuang , Zhang Meng
Published: December 2023

Objective: To explore the clinical effect of percutaneous transforaminal endoscopic discectomy (PTED) combined with annulus fibrosus repair in the treatment of single-segment lumber disc herniation (LDH) in young and middle-aged patients.

Methods: Ninty-six patients with single-segment LDH admitted to Baoding First Central Hospital from March 2021 to November 2022 were selected in the retrospective study. The patients were divided into endoscopic group and combined group according to different surgical methods. The surgical conditions, VAS score and ODI score the two groups of patients were compared, as well as the postoperative review results.

Results: There were 50 patients in the endoscopic group the average operation time was 43.68 ± 10.77 minutes, the average intraoperative blood loss was 35.38 ± 10.02 ml, there were seven cases of surgical segment recurrence and 10 cases of postoperative intervertebral instability at the surgical segment. There were 46 patients in the combined group, the average operation time was 52.26 ± 8.39 minutes, the average intraoperative blood loss was 39.23 ± 9.02ml, there was one case of surgical segment recurrence and two cases of surgical segment intervertebral instability. The operation time (t=-4.328, P<0.01), postoperative recurrence cases (χ2=4.386, P<0.05) and intervertebral instability cases (χ2=5.366, P<0.05) of the two groups of patients). The difference was statistically significant. There was no significant difference in intraoperative blood loss between the two groups (t=-1.965, P>0.05). For six months after surgery, the differences in VAS and ODI scores between the two groups were statistically significant. In addition, there were statistically significant differences in the VAS scores and ODI scores of the two groups of patients at each time point after surgery compared with those before surgery (P<0.05).

Conclusion: The clinical efficacy of PTED combined with annulus fibrosus repair showed better clinical efficacy than PTED alone, and it can reduce the occurrence of surgical segment recurrence and intervertebral instability, suggesting that PTED combined with annulus fibrosus repair may be worthy of promotion in clinical practice.

doi: https://doi.org/10.12669/pjms.40.3.3419

How to cite this: Zhao Y, Tian B, Ma Q, Zhang M. Study on the clinical effect of percutaneous transforaminal endoscopic discectomy combined with annulus fibrosus repair in the treatment of single-segment lumbar disc herniation in young and middle-aged patients. Pak J Med Sci. 2024;40(3):---------. doi: https://doi.org/10.12669/pjms.40.3.3419

This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.
The clinical value of serum-related indexes in differentiating simple premature thelarche from idiopathic central precocious puberty
Authors: Cui Hai-jing , Liu Peng , Liu Xin-guang , Du Wen-zhong , Wang Xia
Published: December 2023

Objective: To explore the changes of serum-related indexes at different time points, so as to identify the critical time of converting from simple premature thelarche (PT) to idiopathic central precocious puberty (ICPP).

Methods: This is a retrospective study. The subjects of the study were 50 girls with PT who were admitted to the Children’s Hospital of Hebei Province from January 2019 to September 2020. The enrolled 50 children were divided into the conversion group(n=12) and the non-conversion group(n=38) according to whether PT was converted into ICPP during follow-up. Furthermore, the levels of serum-related indexes and uterine and ovarian volumes were compared after the diagnosis of PT.

Results: The IGF-1 and IGFBP-3 levels of children in the conversion group began to change significantly from six months after the diagnosis, with statistically significant differences when compared with the levels of children at the initial diagnosis, three months and those of the non-conversion group at the same time points (p<0.05). The levels of vitamin-D, DHEA and leptin began to change significantly at nine months after the diagnosis (p<0.05). Besides, uterine and ovarian volumes in the conversion group began to increase significantly six months after the diagnosis, with statistically significant differences when compared with those in the non-conversion group (p<0.05).

Conclusion: Findings in our study suggest that regular monitoring of vitamin-D, IGF-1, IGFBP-3, DHEA and leptin levels, and uterine and ovarian volumes can predict the conversion from PT to ICPP at an early stage.

doi: https://doi.org/10.12669/pjms.40.3.7447

How to cite this: Cui H, Liu P, Liu X, Du W, Wang X. The clinical value of serum-related indexes in differentiating simple premature thelarche from idiopathic central precocious puberty. Pak J Med Sci. 2024;40(3):---------. doi: https://doi.org/10.12669/pjms.40.3.7447

This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.