bluuebunny/crossref_metadata_2025 huggingface dataset:
Unmeasurable capillary C-reactive protein as one of the diagnostic clues of severe hematological pathologies in children in primary settings: Case series
Authors: Piteková Barbora , Zieg Jakub , Konopásek Patrik , Turecký Ladislav , Brenner Marcel , Gécz Jakub
Published: February 2024

Rationale:

The manuscript aimed to show that an unmeasurable capillary C-reactive protein (CRP) should be a red flag that can indicate a possible severe hematological pathology.

Patients concerns and diagnoses:

The authors present 3 case reports of children with fever examined at the pediatric emergency department. Fever is among the most frequently exhibited symptoms of acute pediatric infectious diseases. However, sometimes fever can be the manifestation of other serious noninfectious diseases. CRP is a marker widely used in clinical pediatric practice to help us evaluate inflammation and possible bacterial infection. All mentioned patients had unmeasurable CRP from capillary blood, even though venous CRP ranged from 14 to 21 mg/L. All of the patients were consequently diagnosed with severe hemato-oncological disease. Possible explanations are that a change in blood viscosity or an elevation of circulating immune complexes in the blood of patients with leukemia leads to malfunctioning immunoturbidimetry measurement.

Lesson:

Although these findings are very interesting and could lead to faster recognition of acute leukemia in pediatric clinical practice, further prospective study is needed for their confirmation.
The application of flipped classroom combined with team-based learning in the orthopedic clinical teaching
Authors: Shuai Liang , Huiwen Wu , Shihao Deng , Li Jun
Published: February 2024

Background:

Medical education has evolved rapidly, with the development of flipped classrooms and team-based learning based on lecture-based learning, but the novel model of combining flipped classrooms with team-based learning has been poorly investigated in orthopedic education.

Methods:

A femoral neck fracture teaching mode was chosen to 109 clinical internship students to explore the effectiveness of flipped classroom combined with team-based learning in internship education. They were enrolled and randomly divided into either the flipped classroom combined with team-based learning group (FTG, n = 55) or the traditional lecture-based classroom group (n = 54). All students completed the learning according to the course flow and took before-class and after-class tests. The questionnaires were used to compare students perceptions and satisfaction with the different teaching methods and were utilized to assess the strengths and weaknesses of the 2 groups.

Results:

The post-class test scores of both groups significantly improved compared to pre-class test scores. Regarding the post-class test scores, FTG’s was significantly higher than the traditional lecture-based classroom group’s, mainly in clinical areas such as imaging analysis, fracture classification, treatment options, and management of postoperative complications, but there was no significant difference in the mastery of basic theoretical knowledge. The students were more satisfied with the FTG and believed that it improved their various competencies, but with significantly more time spent.

Conclusion:

FTG is generally recognized as a promising option for training clinical interns and is worth spreading as it has outstanding merits in developing students clinical competence.
Spectacle-wearing compliance and its associated determinants among infants with bilateral corrective refractive errors: An observational study
Authors: Li Xiaoyan , Lin Xiaoshan , Tang Jinzhu , Hu Guifang
Published: February 2024

This study aimed to evaluate spectacle-wearing compliance and identify the determinants associated with it in infants with bilateral corrective refractive errors. Infants aged < 3 years with bilateral corrective refractive errors who were supplied with spectacles for > 1 month were enrolled at the pediatric comprehensive clinic of Zhongshan Ophthalmic Center. Spectacle-wearing compliance was evaluated by calculating the percentage of spectacle-wearing time in the awake time (STIT), and its potential determinants were identified based on interviews with the infants’ caregivers using univariate and multivariate logistic regression analysis. Pearson correlation analysis was performed to further determine the degree of correlation between spectacle-wearing compliance and weight of spectacles. A total of 366 infants (age: 20.85 ± 9.06 months, male: 54.92%) were included. The mean percentage of STIT was 64.00%±41.69%. The communication between caregivers of different infants regarding spectacle-wearing experience (P = .004, OR = 2.290, 95% confidence interval [CI] for OR = 1.301–4.029), perceptions of spectacle-wearing importance (P = .000, OR = 6.337, 95% CI for OR = 3.664–10.961), and weight of spectacles (P = .000, OR = 7.271, 95% CI for OR = 4.141–12.769) were significantly associated with spectacle-wearing compliance. Besides, spectacle-wearing compliance was positively correlated with the weight of spectacles (P < .01), exhibiting a decreasing trend with the weight of spectacles. Overall, spectacle-wearing compliance requires improvement. Moreover, efficient strategies aimed at improving spectacle-wearing compliance, such as enhancing communication between caregivers of different infants regarding spectacle-wearing experience, raising awareness about the importance of wearing spectacles, and reducing the weight of spectacles, are urgently needed.
The risk of common hypoglycemic and antihypertensive medications and COVID-19: A 2-sample Mendelian randomization study
Authors: Wang Ya , Li Kai , Zeng Jiaxing , Lu Shunyu , Deng Wangsheng
Published: February 2024

Background:

It has been reported that diabetes and hypertension increase the adverse outcomes of coronavirus disease 2019 (COVID-19). Aside from the inherent factors of diabetes and hypertension, it remains unclear whether antidiabetic or antihypertensive medications contribute to the increased adverse outcomes of COVID-19. The effect of commonly used antidiabetic and antihypertensive medications on COVID-19 outcomes has been inconsistently concluded in existing observational studies. Conducting a systematic study on the causal relationship between these medications and COVID-19 would be beneficial in guiding their use during the COVID-19 pandemic.

Methods:

We employed the 2-sample Mendelian randomization approach to assess the causal relationship between 5 commonly used antidiabetic medications (SGLT-2 inhibitors, Sulfonylureas, Insulin analogues, Thiazolidinediones, GLP-1 analogues) and 3 commonly used antihypertensive medications (calcium channel blockers [CCB], ACE inhibitors, β-receptor blockers [BB]), and COVID-19 susceptibility, hospitalization, and severe outcomes. The genetic variations in the drug targets of the 5 antidiabetic medications and 3 antihypertensive medications were utilized as instrumental variables. European population-specific genome-wide association analysis (GWAS) data on COVID-19 from the Host Genetics Initiative meta-analyses were obtained, including COVID-19 susceptibility (n = 2597,856), COVID-19 hospitalization (n = 2095,324), and COVID-19 severity (n = 1086,211). The random-effects inverse variance-weighted estimation method was employed as the primary assessment technique, with various sensitivity analyses conducted to evaluate heterogeneity and pleiotropy.

Results:

There were no potential associations between the genetic variations in the drug targets of the 5 commonly used antidiabetic medications (SGLT-2 inhibitors, Sulfonylureas, Insulin analogues, Thiazolidinediones, GLP-1 analogues) and the 3 commonly used antihypertensive medications (CCBs, ACE inhibitors, BBs) with COVID-19 susceptibility, hospitalization, and severity (allP > .016).

Conclusion:

The findings from this comprehensive Mendelian randomization analysis suggest that there may be no causal relationship between the 5 commonly used antidiabetic medications (SGLT-2 inhibitors, Sulfonylureas, Insulin analogues, Thiazolidinediones, GLP-1 analogues) and the 3 commonly used antihypertensive medications (CCBs, ACE inhibitors, BBs) with COVID-19 susceptibility, hospitalization, and severity.
Identification of an 8 HPV-related RNA signature as a novel prognostic biomarker for squamous cell carcinoma of the head and neck
Authors: Mei Zhang , Zhengdong Luo , Shupeng Liu , Xin Zhang , Lei Wang , Wang Chuanxin
Published: February 2024

Squamous cell carcinoma of the head and neck (SCCHN) is a commonly detected cancer worldwide. Human papillomavirus (HPV) is emerging as an important risk factor affecting SCCHN prognosis. Therefore, identification of HPV status is essential for effective therapies in SCCHN. The aim of this study was to investigate the prognostic value of HPV-associated RNA biomarkers for SCCHN. The clinical data, survival data, and RNA-seq data of SCCHN were downloaded from The Cancer Genome Atlas database. Before the differential expression analysis, the heterogeneity between the 2 groups (HPV+ vs HPV−) of samples was analyzed using principal component analysis. The differentially expressed genes (DEGs) between HPV+ and HPV− SCCHN samples were analyzed using the R edgeR package. The Gene Ontology functional annotations, including biological process, molecular function and cellular component (CC), and Kyoto Encyclopedia of Genes And Genomes pathways enriched by the DEGs were analyzed using DAVID. The obtained matrix was analyzed by weighed gene coexpression network analysis. A total of 350 significant DEGs were identified through differential analysis, and these DEGs were significantly enriched in functions associated with keratinization, and the pathway of neuroactive ligand-receptor interaction. Moreover, 72 hub genes were identified through weighed gene coexpression network analysis. After the hub genes and DEGs were combined, we obtained 422 union genes, including 65 survival-associated genes. After regression analysis, a HPV-related prognostic model was established, which consisted of 8 genes, including Clorf105, CGA, CHRNA2, CRIP3, CTAG2, ENPP6, NEFH, and RNF212. The obtained regression model could be expressed by an equation as follows: risk score = 0.065 × Clorf105 + 0.012 × CGA + 0.01 × CHRNA2 + 0.047 × CRIP3 + 0.043 × CTAG2–0.034 × ENPP6 − 0.003 × NEFH − 0.068 × RNF212. CGA interacted with 3 drugs, and CHRNA2 interacted with 11 drugs. We have identified an 8 HPV-RNA signature associated with the prognosis of SCCHN patients. Such prognostic model might serve as possible candidate biomarker and therapeutic target for SCCHN.
Diagnostic value of angiography-derived index of microcirculatory resistance (AMR) for coronary microcirculatory dysfunction (CMD) and its prognostic significance in patients with chronic coronary syndromes in the smoking population
Authors: Qiu Zhongjue , Wang Yong , Liu Yang , Zhou Zhou , Wang Zhen
Published: February 2024

This study aims to analyze the prognostic significance of angiographic microvascular resistance (AMR) derived from functional coronary angiography in diagnosing coronary microvascular dysfunction (CMD) among patients with chronic coronary syndrome (CCS), particularly focusing on the prognostic significance of CMD in smokers. Additionally, this study assesses the prognostic significance of the diagnostic accuracy of the AMR index for CMD in CCS patients within the smoking population. Seventy-five CCS patients were studied for IMR measurement between June 2018 and December 2020, classified into CMD and non-CMD groups. Pearson correlation analyzed AMR and IMR relationship, while ROC curves determined AMR’s predictive value for CMD with optimal cutoff value. An additional 223 CCS patients were included for AMR measurements. The study’s primary endpoint was MACE occurrence, followed up through telephone calls. COX one-way analysis and Kaplan–Meier analysis evaluated the association between AMR and MACE risk. In the study, 52% of patients were diagnosed with CMD, and the AUC under the AMR curve for predicted IMR ≥ 25 was 0.90 (95% CI: 0.79–0.95). The CMD group had a higher proportion of female patients, smokers, and those with hypertension and diabetes mellitus compared to the non-CMD group (all P < .05). The CMD group exhibited higher AMR values than the non-CMD group (3.20 ± 0.5 vs 1.95 ± 0.45, P < .01), with a significant correlation between AMR and IMR (R
2 = 0.81, P < .001). The ROC curve illustrated AMR’s effectiveness in diagnosing CMD in CCS patients, using IMR as the gold standard, with the optimal cutoff value of AMR = 2.6mmHgs/cm (sensitivity: 90.5%, specificity: 81.5%). Patients with AMR ≥ 2.6mmHgs/cm had a higher risk of MACE events (HR = 6.00; 95% CI: 1.59–22.67). AMR in patients with CCS was significantly correlated with IMR and demonstrated good diagnostic accuracy. AMR ≥ 2.6 mm Hg*s/cm was associated with an increased risk of MACE occurrence and served as a valuable prognostic factor. In patients with CCS, AMR has a high diagnostic performance, In patients with CCS who smoke, impaired coronary microvascular function as assessed by AMR is significant and is an independent predictor of MACE.
Comparison of 3 diagnostic methods for pulmonary tuberculosis in suspected patients with negative sputum smear or no sputum
Authors: Cheng Xiaopeng , Chen Lerong , Wan Wenli , Peng Jianping , Wu Liangliang , Xin Jing , Cai Jianying
Published: February 2024

Study design:

To explore the diagnostic value of 3 methods for sputum smear-negative and non-sputum patients with suspected pulmonary tuberculosis (TB).

Methods:

This prospective study enrolled sputum smear-negative and non-sputum patients with suspected TB admitted to Jiangxi Chest Hospital between January 2020 and December 2022. The 3 methods were bronchoalveolar lavage fluid (BALF)-acid-fast bacillus (AFB) smear, GeneXpert MTB/RIF, and gene chip for Mycobacterium strain identification. The diagnostic performance of the 3 tests was evaluated with BALF Mycobacterium culture + BALF-AFB smear + GeneXpert MTB/RIF + Gene chip as the gold standard.

Results:

A total of 456 samples were collected from 114 patients with suspected TB. Twenty-four patients were diagnosed with TB. The combination of GeneXpert MTB/RIF and gene chip for Mycobacterium strain identification yielded the highest area under the receiver operating characteristics curve (AUC) of 0.953 and had sensitivity of 90.57%, specificity of 100%, positive predictive value (PPV) of 100%, negative predictive value (NPV) of 92.42%, accuracy of 95.61%. GeneXpert MTB/RIF achieved AUC of 0.906, sensitivity of 81.13%, specificity of 100%, PPV of 100%, NPV of 85.92%, accuracy of 91.23%. BALF-AFB smear had AUC of 0.519, sensitivity of 3.77%, specificity of 100%, PPV of 100%, NPV of 54.46%, and accuracy of 55.26%. The combination of GeneXpert MTB/RIF and gene chip for Mycobacterium strain identification yielded the highest κ of 0.911, while BALF-AFB smear had the lowest κ value of 0.040.

Conclusion:

For TB in sputum smear-negative and non-sputum patients using BALF Mycobacterium culture + BALF-AFB smear + GeneXpert MTB/RIF + Gene chip as the gold standard, BALF-AFB smear showed low diagnostic performance, while, though GeneXpert MTB/RIF and gene chip had good diagnostic performance, combining GeneXpert MTB/RIF and gene chip improved the diagnostic value to a great extent.
Investigation of the relationship between the changes in vaginal microecological enzymes and human papillomavirus (HPV) infection
Authors: Li Jiawei , Jiang Li , Wang Chunhua , Meng Jin , Wang Huifang , Jin Haihong
Published: February 2024

This study aims to investigate the relationship between the human papillomavirus (HPV) infection and the altered vaginal microecological environment of patients. Initially, HPV genotyping and microecological detection were performed in 1281 subjects in the Department of Obstetrics and Gynecology of The First Hospital of Qinhuangdao (Qinhuangdao, China). The relationship between the enzymes of vaginal microecology, that is, proline aminopeptidase and acetylglucosaminidase, and vaginal inflammatory diseases, as well as the prognosis of HPV infection, was analyzed. The experimental findings indicated a close relationship between the expression of positive prolyl aminopeptidase and trichomonas vaginitis, as well as bacterial vaginitis. In addition, the expression of acetylglucosaminidase is closely associated with trichomonas vaginitis and vulvovaginal candidiasis. Furthermore, the observations indicated that positive prolyl aminopeptidase and acetylglucosaminidase could increase the risk of various subtypes of HPV infection in patients. The receiver operating characteristic curve analysis presented that the expression of prolyl aminopeptidase and acetylglucosaminidase could offer exceptional diagnostic efficacy, indicating their association with persistent HPV infection. In summary, our results highlighted that the expression of positive prolyl aminopeptidase and acetylglucosaminidase in the vaginal microecology could be substantially correlated to the occurrence and the development of vaginal inflammatory diseases, as well as the outcome and the risk of persistent HPV infection.
Implications of climatic change on sickle cell anemia: A review
Authors: Obeagu Emmanuel Ifeanyi , Obeagu Getrude Uzoma
Published: February 2024

Sickle cell anemia (SCA) is a hereditary blood disorder characterized by abnormal hemoglobin, causing red blood cells to assume a sickle shape, leading to various complications. Climate change has emerged as a significant global challenge, influencing environmental conditions worldwide. This paper explores the implications of climatic variations on the prevalence, management, and outcomes of SCA. Climate change affects weather patterns, leading to altered temperatures, increased frequency of extreme weather events, and variations in humidity levels. These changes can have a profound impact on individuals living with SCA. High temperatures exacerbate the symptoms of SCA, potentially triggering painful vaso-occlusive crises due to dehydration and increased blood viscosity. Conversely, cold temperatures may induce vaso-occlusion by causing blood vessels to constrict. Changes in rainfall patterns might also affect water accessibility, which is crucial for maintaining adequate hydration, particularly in regions prone to droughts. The management of SCA is multifaceted, involving regular medical care, hydration, and avoiding triggers that could precipitate a crisis. Adverse weather events and natural disasters can disrupt healthcare infrastructure and access to essential medications and resources for SCA patients, especially in vulnerable communities. To mitigate the implications of climatic change on SCA, interdisciplinary strategies are essential. These strategies may include enhancing healthcare systems’ resilience to climate-related disruptions, implementing adaptive measures to address changing environmental conditions, and promoting public awareness and education on managing SCA amidst climate variability. In conclusion, climatic variations pose significant challenges for individuals with SCA, affecting the prevalence, management, and outcomes of the disease.
Splenic marginal zone lymphoma with monoclonal IgG: A case report
Authors: Zhang Xupai , Ren Shihui , Zhang Nan , Wang Xiao , Qiu Lin , Sun Haoping , Yi Hai , Fan Fangyi
Published: February 2024

Rationale:

Splenic marginal zone lymphoma (SMZL), an indolent small B-cell lymphoma, is uncommon, and part of the patients exist plasmocytic differentiation and secrete monoclonal paraproteins including IgM predominantly. SMZL with monoclonal IgG is rarer.

Patient concerns:

We report a case of SMZL (49-year-old, male) with monoclonal IgG, MYD88L265P mutation and hepatitis B virus infection.

Diagnoses:

The patient was presented to our hospital with aggravating complaints of dizziness, fatigue, postprandial abdominal distension, and night sweats. The diagnosis was confirmed by clinical manifestations, immunophenotype, bone marrow pathology.

Interventions:

The patient received rituximab-based chemotherapy and sequential ibrutinib in combination with entecavir.

Outcomes:

After 1 year of follow-up, his blood routine examination had returned to normal with normal level of albumin and significantly lower globulin than before, and the spleen was of normal size.

Lessons:

We conclude that rituximab-based chemotherapy is the main treatment option for the patients with SMZL, and Bruton’s tyrosine kinase inhibitor has also shown beneficial efficacy.
Pulmonary Physician Consultancy in Emergency Services in Turkiye (PuPCEST) – a cross-sectional multicenter study
Authors: Erçen Diken Özlem , Kaya Şerife , Bektaş Aksoy Hayriye , Ekici Aydanur , Çapraz Aylin , Tabaru Ali , Şengören Dikiş Özlem , Arpağ Hüseyin , Yildiz Hanifi , Kiliç Talat , Özdemir Tarkan , Gülhan Pinar Yildiz , Arslan Sulhattin , Ogan Nalan , Doğan Canan , Tutar Ümit , Başlilar Şeyma , Esendağli Dorina , Kirkil Gamze , Doğan Ömer Tamer , Toru Erbay Ümran , Ayvaci Aysun , Tosun Mustafa , Uğur Chousein Efsun Gonca , Niksarlioğlu Elif Yelda , Olcay Sabri Serhan , Özkisa Tuncer , Hocanli İclal , Karadağ Mehmet , Özçelik Neslihan , Oktay Nuray , Şentürk Elvan , Arslan Sertaç , Pekcan Özyurt Sibel , Cerit Ahu , Nennicioğlu Yasemin , Atilla Nurhan , Üney İbrahim Halil , Elverişli Mehmet Fatih , Berk Serdar , Baha Ayşe , Erik Nur , Ölmez Hasan , Kaçmaz Berat , Erzurumluoğlu Hüseyin , Demirdöğen Çetinoğlu Ezgi , Özlü Tevfik
Published: February 2024

Pulmonology is one of the branches that frequently receive consultation requests from the emergency department. Pulmonology consultation (PC) is requested from almost all clinical branches due to the diagnosis and treatment of any respiratory condition, preoperative evaluation, or postoperative pulmonary problems. The aim of our study was to describe the profile of the pulmonology consultations received from emergency departments in Turkiye. A total of 32 centers from Turkiye (the PuPCEST Study Group) were included to the study. The demographic, clinical, laboratory and radiological data of the consulted cases were examined. The final result of the consultation and the justification of the consultation by the consulting pulmonologist were recorded. We identified 1712 patients, 64% of which applied to the emergency department by themselves and 41.4% were women. Eighty-five percent of the patients had a previously diagnosed disease. Dyspnea was the reason for consultation in 34.7% of the cases. The leading radiological finding was consolidation (13%). Exacerbation of preexisting lung disease was present in 39% of patients. The most commonly established diagnoses by pulmonologists were chronic obstructive pulmonary disease (19%) and pneumonia (12%). While 35% of the patients were discharged, 35% were interned into the chest diseases ward. The majority of patients were hospitalized and treated conservatively. It may be suggested that most of the applications would be evaluated in the pulmonology outpatient clinic which may result in a decrease in emergency department visits/consultations. Thus, improvements in the reorganization of the pulmonology outpatient clinics and follow-up visits may positively contribute emergency admission rates.
HER2-positive is an independent indicator for predicting pathological complete response to neoadjuvant therapy and Ki67-changed after neoadjuvant chemotherapy predicts favorable prognosis in Chinese women with locally advanced breast cancer
Authors: Fang Yutong , Zhang Qunchen , Wu Yuan , Wu Jundong
Published: February 2024

The growing body of evidence suggests that breast cancer (BC) who achieve pathological complete response (pCR) after neoadjuvant chemotherapy (NAC) may experience a more favorable prognosis. The objective of this study is to investigate the correlation between clinicopathologic parameters of locally advanced breast cancer (LABC) patients and the outcomes of NAC, with the aim of identifying predictive indicators for pCR. Additionally, we seek to examine the conversion of IHC markers in pCR patients following NAC and its impact on the prognosis of BC patients. We conducted a study involving 126 patients with LABC. Clinicopathological parameters associated with pCR were subjected to univariate and multivariate analysis. Kaplan–Meier (KM) curves and the log-rank test were used to compare the statistical difference in prognosis in different groups of patients. Additionally, we used difference and consistency tests to examine the conversion of immunohistochemistry (IHC) markers following NAC. The status of estrogen receptor (ER), progesterone receptor (PR), human epidermal growth factor receptor 2 (HER2) and molecular subtypes of BC were associated with pCR in the univariate analysis (all P < .05), which may be potential markers to predict pCR. HER2 was identified as an independent factor for predicting pCR in the multivariate analysis. The pCR rate of HER2-positive patients who received NAC combined targeted therapy was higher than that of patients who only received NAC (P = .003). The disease-free survival (DFS) rate of TNBC patients who achieved pCR was significantly higher than that of non-pCR TNBC patients (P = .026). The IHC marker conversion after NAC mainly existed in PR (P = .041). Ki67 expression decreased in the luminal B subtype and increased in the HER2 enriched subtype after NAC (all P < .001). Patients with Ki67 expression change after NAC had longer overall survival (OS) and DFS than unchanged patients (all P < .05). HER2-positive is an independent indicator for predicting pCR, and HE2-positive patients who received NAC combined targeted therapy were favorable to achieving pCR. IHC markers of BC patients exhibit varying degrees of alterations after NAC, and changes in Ki67 expression after NAC could serve as a marker to predict a better prognosis.
Macrocytic anemias
Authors: Koury Mark J. , Hausrath Daniel J.
Published: February 2024

Purpose of review

Over the last century, the diseases associated with macrocytic anemia have been changing with more patients currently having hematological diseases including malignancies and myelodysplastic syndrome. The intracellular mechanisms underlying the development of anemia with macrocytosis can help in understanding normal erythropoiesis. Adaptations to these diseases involving erythroid progenitor and precursor cells lead to production of fewer but larger red blood cells, and understanding these mechanisms can provide information for possible treatments.

Recent findings

Both inherited and acquired bone marrow diseases involving primarily impaired or delayed erythroid cell division or secondary adaptions to basic erythroid cellular deficits that results in prolonged cell division frequently present with macrocytic anemia.

Summary of findings

In marrow failure diseases, large accumulations of iron and heme in early stages of erythroid differentiation make cells in those stages especially susceptible to death, but the erythroid cells that can survive the early stages of terminal differentiation yield fewer but larger erythrocytes that are recognized clinically as macrocytic anemia. Other disorders that limit deoxynucleosides required for DNA synthesis affect a broader range of erythropoietic cells, but they also lead to macrocytic anemia. The source of macrocytosis in other diseases remains uncertain.
Postoperative Complications and Mobilization Following Major Abdominal Surgery With Versus Without Fitness Tracker-based Feedback (EXPELLIARMUS)
Authors:   CHIR-Net SIGMA Study Group, Mihaljevic Andre L.
Published: February 2024

Objective:

To determine whether daily postoperative step goals and feedback through a fitness tracker (FT) reduce the rate of postoperative complications after surgery.

Background:

Early and enhanced postoperative mobilization has been advocated to reduce postoperative complications, but it is unknown whether FT alone can reduce morbidity.

Methods:

EXPELLIARMUS was performed at 11 University Hospitals across Germany by the student-led clinical trial network SIGMA. Patients undergoing major abdominal surgery were enrolled, equipped with an FT, and randomly assigned to the experimental (visible screen) or control intervention (blackened screen). The experimental group received daily step goals and feedback through the FT. The primary end point was postoperative morbidity within 30 days using the Comprehensive Complication Index (CCI). All trial visits were performed by medical students in the hospital with the opportunity to consult a surgeon-facilitator who also obtained informed consent. After discharge, medical students performed the 30-day postoperative visit through telephone and electronic questionnaires.

Results:

A total of 347 patients were enrolled. Baseline characteristics were comparable between the 2 groups. The mean age of patients was 58 years, and 71% underwent surgery for malignant disease, with the most frequent indications being pancreatic, colorectal, and hepatobiliary malignancies. Roughly one-third of patients underwent laparoscopic surgery. No imputation for the primary end point was necessary as data completeness was 100%. There was no significant difference in the CCI between the 2 groups in the intention-to-treat analysis (mean±SD CCI experimental group: 23±24 vs. control: 22±22; 95% CI: −6.1, 3.7; P=0.628). All secondary outcomes, including quality of recovery, 6-minute walking test, length of hospital stay, and step count until postoperative day 7 were comparable between the 2 groups.

Conclusions:

Daily step goals combined with FT-based feedback had no effect on postoperative morbidity. The EXPELLIARMUS shows that medical students can successfully conduct randomized controlled trials in surgery.
Evidence based noninvasive presurgical evaluation for patients with drug resistant epilepsies
Authors: Trinka Eugen , Koepp Matthias , Kalss Gudrun , Kobulashvili Teia
Published: February 2024

Purpose of review

To review the current practices and evidence for the diagnostic accuracy and the benefits of presurgical evaluation.

Recent findings

Preoperative evaluation of patients with drug-resistant focal epilepsies and subsequent epilepsy surgery leads to a significant proportion of seizure-free patients. Even those who are not completely seizure free postoperatively often experience improved quality of life with better social integration. Systematic reviews and meta-analysis on the diagnostic accuracy are available for Video-electroencephalographic (EEG) monitoring, magnetic resonance imaging (MRI), electric and magnetic source imaging, and functional MRI for lateralization of language and memory. There are currently no evidence-based international guidelines for presurgical evaluation and epilepsy surgery.

Presurgical evaluation is a complex multidisciplinary and multiprofessional clinical pathway. We rely on limited consensus-based recommendations regarding the required staffing or methodological expertise in epilepsy centers.
Structure and ligand binding in the putative anti-microbial peptide transporter protein, YejA
Authors: Ackroyd Bryony K. , Dodson Eleanor J. , Mehboob Javeria , Dowle Adam A. , Thomas Gavin H. , Wilkinson Anthony J.
Published: February 2024

YejABEF is an ATP-binding cassette transporter that is implicated in the sensitivity of Escherichia coli to anti-microbial peptides, the best-characterized example being microcin C, a peptide-nucleotide antibiotic that targets aspartyl-tRNA synthetase. Here the structure of the extracellular solute binding protein, YejA, has been determined, revealing an oligopeptide-binding protein fold enclosing a ligand-binding pocket larger than those of other peptide-binding proteins of known structure. Prominent electron density in this cavity defines an undecapeptide sequence LGEPRYAFNFN, an observation that is confirmed by mass spectrometry. In the structure, the peptide interactions with the protein are mediated by main chain hydrogen bonds with the exception of Arg5 whose guanidinium side chain makes a set of defining polar interactions with four YejA residues. More detailed characterization of purified recombinant YejA, by a combination of ESI and MALDI-mass spectrometry as well as thermal shift assays, reveals a set of YejA complexes containing overlapping peptides 10–19 residues in length. All contain the sequence LGEPRYAFN. Curiously, these peptides correspond to residues 8–26 of the mature YejA protein, which belong to a unique N-terminal extension that distinguishes YejA from other cluster C oligopeptide binding proteins of known structure. This 35-residue extension is well-ordered and packs across the surface of the protein. The undecapeptide ligand occupies only a fraction of the enclosed pocket volume suggesting the possibility that much larger peptides or peptide conjugates could be accommodated, though thermal shift assays of YejA binding to antimicrobial peptides and peptides unrelated to LGEPRYAFNFN have not provided evidence of binding. While the physiological significance of this ‘auto-binding’ is not clear, the experimental data suggest that it is not an artefact of the crystallization process and that it may have a function in the sensing of periplasmic or membrane stress.
Annotation and assessment of functional variants in regulatory regions using epigenomic data in farm animals
Authors: Ma Ruixian , Kuang Renzhuo , Zhang Jingcheng , Sun Jiahao , Xu Yueyuan , Zhou Xinbo , Han Zheyu , Hu Mingyang , Wang Daoyuan , Fu Yuhua , Zhang Yong , Li Xinyun , Zhu Mengjin , Zhao Shuhong , Xiang Tao , Shi Mengwei , Zhao Yunxia
Published: February 2024

Background

Understanding the functional impact of genetic variants is essential for advancing animal genomics and improving livestock breeding. Variants that disrupt transcription factor (TF) motifs provide a means to assess functional potential, but the lack of TF ChIP-seq data for farm animals presents a challenge.

Results

To address this, we curated nearly 900 epigenomic datasets from 10 farm animal species and annotated eight regulatory regions to assess how variants affect TF motifs. Over 127 million candidate functional variants were classified into five functional confidence categories across the species. Variants with high confidence were enriched in eQTLs and trait-associated SNPs, showing greater potential to affect gene expression and phenotypes. Incorporating these functional variants into genomic prediction models improved the accuracy of Estimated Breeding Values (EBVs). Active variants also revealed trait-related tissues, and single-cell RNA sequencing (scRNA-seq) identified the cell types most associated with production traits. To facilitate research, we developed the Integrated Functional Mutation (IFmut) platform, enabling users to explore variant functions easily. Our study provides a flexible platform and resource for studying genomic variation in farm animals, setting a new standard for research and breeding strategies.

Conclusion

The results indicated that evaluating functional potential by annotating and categorizing variants that interfere with transcription factor motifs can help elucidate changes in gene expression and phenotype. By focusing on high-confidence variants enriched in eQTL and trait-associated SNPs, it improves the accuracy of genomic predictions in research and breeding strategies.
A systems-based approach to uterine fibroids identifies differential splicing associated with abnormal uterine bleeding
Authors: Wang CY , Philpott M , O’Brien DP , Ndungu A , Malzahn J , Maritati M , Mehta N , Gamble V , Martinez-Burgo B , Bonham S , Fischer R , Garbutt K , Becker CM , Manek S , Harris AL , Sacher F , Obendorf M , Schmidt N , Mueller J , Zollner T , Zondervan KT , Kessler BM , Oppermann U , Cribbs AP
Published: February 2024

Uterine fibroids (UFs), benign tumours prevalent in up to 80% of women of reproductive age, are associated with significant morbidity, including abnormal uterine bleeding, pain and infertility. Despite identification of key genomic alterations in MED12 and HMGA2, the pathogenic mechanisms underlying UFs and heavy menstrual bleeding (HMB) remain poorly understood. To correlate systematically genetic, transcriptional and proteomic phenotypes, our study involved an integrative analysis of fibroid, myometrium and endometrium tissues from 137 patients, utilising genome-wide SNP arrays, targeted sequencing, RNA sequencing and proteomics. Our findings reveal 39.7% of UFs possess MED12 mutations, alongside novel variants in genes such as COL4A5 and COL4A6. Multi-omics factor analysis of integrated protein and mRNA highlighted differential regulation related to extracellular matrix remodelling, proteolysis and homeostasis in fibroid versus myometrium tissues, and distinct gene sets associated with RNA splicing in the endometrium of patients with HMB, particularly in MED12-mutated fibroids. Our study proposes a model, which is supported byin vivoevidence, where altered signalling of MED12-mutated fibroids influences RNA transcript isoform expression in endometrium, potentially leading to abnormal uterine bleeding. This integrative approach unravels complex molecular pathways in UF pathogenesis and HMB, offering novel insights for targeted therapeutic development.
TumFlow: An AI Model for Predicting New Anticancer Molecules
Authors: Rigoni Davide , Yaddehige Sachithra , Bianchi Nicoletta , Sperduti Alessandro , Moro Stefano , Taccioli Cristian
Published: February 2024

Motivation

Melanoma is a severe form of skin cancer increasing globally with about 324.000 cases in 2020, making it the fifth most common cancer in the United States. Conventional drug discovery methods face limitations due to the inherently time consuming and costly. However, the emergence of artificial intelligence (AI) has opened up new possibilities. AI models can effectively simulate and evaluate the properties of a vast number of potential drug candidates, substantially reducing the time and resources required by traditional drug discovery processes. In this context, the development of AI normalizing flow models, employing machine learning techniques to create new molecular structures, holds great promise for accelerating the discovery of effective anticancer therapies.

Results

This manuscript introduces a novel AI model, namedTumFlow, aimed at generating new molecular entities with potential therapeutic value in cancer treatment. It has been trained on the comprehensive NCI-60 dataset, encompassing thousands of molecules tested across 60 tumour cell lines, with a specific emphasis on the melanoma SK-MEL-28 cell line. The model successfully generated new molecules with predicted improved efficacy in inhibiting tumour growth while being synthetically feasible. This represents a significant advancement over conventional generative models, which often produce molecules that are challenging or impossible to synthesize. Furthermore,TumFlowhas also been utilized to optimize molecules known for their efficacy in clinical melanoma treatments. This led to the creation of novel molecules with a predicted enhanced likelihood of effectiveness against melanoma, currently undocumented on PubChem.

Availability and Implementation

https://github.com/drigoni/TumFlow.

Supplementary information

Uploaded.
Roles of progranulin and FRamides in neural versus non-neural tissues on dietary restriction-related longevity and proteostasis inC. elegans
Authors: Mir Dilawar Ahmad , Cox Matthew , Horrocks Jordan , Ma Zhengxin , Rogers Aric
Published: February 2024

Dietary restriction (DR) mitigates loss of proteostasis associated with aging that underlies neurodegenerative conditions including Alzheimer’s disease and related dementias. Previously, we observed increased translational efficiency of certain FMRFamide-like neuropeptide (flp) genes and the neuroprotective growth factor progranulin geneprgn-1under dietary restriction inC. elegans. Here, we tested the effects offlp-5,flp-14,flp-15andpgrn-1on lifespan and proteostasis under both standard and dietary restriction conditions. We also tested and distinguished function based on their expression in either neuronal or non-neuronal tissue. Lowering the expression ofpgrn-1andflpgenes selectively in neural tissue showed no difference in survival under normal feeding conditions nor under DR in two out of three experiments performed. Reduced expression offlp-14in non-neuronal tissue showed decreased lifespan that was not specific to DR. With respect to proteostasis, a genetic model of DR from mutation of theeat-2gene that showed increased thermotolerance compared to fully fed wild type animals demonstrated no change in thermotolerance in response to knockdown ofpgrn-1orflpgenes. Finally, we tested effects on motility in a neural-specific model of proteotoxicity and found that neuronal knockdown ofpgrn-1andflpgenes improved motility in early life regardless of diet. However, knocking these genes down in non-neuronal tissue had variable results. RNAi targetingflp-14increased motility by day seven of adulthood regardless of diet. Interestingly, non-neuronal RNAi ofpgrn-1decreased motility under standard feeding conditions while DR increased motility for this gene knockdown by day seven (early mid-life). Results show thatpgrn-1,flp-5,flp-14, andflp-15do not have major roles in diet-related changes in longevity or whole-body proteostasis. However, reduced expression of these genes in neurons increases motility early in life in a neural-specific model of proteotoxicity, whereas knockdown of non-neuronal expression mostly increases motility in mid-life under the same conditions.
Characterizing the pharmacological interaction of the antimalarial combination artefenomel-piperaquine in healthy volunteers with induced blood stagePlasmodium falciparum
Authors: Abd-Rahman Azrin N. , Kaschek Daniel , Kümmel Anne , Webster Rebecca , Potter Adam J. , Odedra Anand , Woolley Stephen D , Llewellyn Stacey , Webb Lachlan , Marquart Louise , Chalon Stephan , El Gaaloul Myriam , McCarthy James S. , Möhrle Jörg J. , Barber Bridget E.
Published: February 2024

Background

The combination antimalarial artefenomel-piperaquine failed to achieve target efficacy in a phase 2b study in Africa and Vietnam. We retrospectively evaluated whether characterizing the pharmacological interaction of this antimalarial combination in a volunteer infection study (VIS) would have enabled prediction of the phase 2b study results.

Methods

Twenty-four healthy adults enrolled over three consecutive cohorts were inoculated withPlasmodium falciparum-infected erythrocytes on day 0. Participants were randomized within each cohort to one of 7 dose combination groups and administered a single oral dose of artefenomel-piperaquine on day 8. Participants received definitive antimalarial treatment with artemether-lumefantrine upon parasite regrowth or on day 42±2. The General Pharmacodynamic Interaction (GPDI) model implemented in the Bliss Independence additivity criterion was developed to characterize the pharmacological interaction between artefenomel and piperaquine. Simulations based on the model were performed to predict the outcomes of the phase 2b combination study.

Results

For a dose of 800 mg artefenomel administered with 640 mg, 960 mg, or 1440 mg piperaquine, the simulated adequate parasitological response at day 28 (APR28), incorporating actual patient pharmacokinetic (PK) data from the phase 2b trial, was 69.4%, 63.9%, and 74.8%, respectively. These results closely matched the observed APR28in the phase 2b trial of 67.0%, 65.5%, and 75.4% respectively.

Conclusions

These results indicate that VIS offer an efficient means for informing antimalarial combination trials conducted in the field, potentially expediting clinical development.

Trial registration

This study was registered onClinicalTrials.govon 31 May 2018 with registration numberNCT03542149.
AlphaCRV: A Pipeline for Identifying Accurate Binder Topologies in Mass-Modeling with AlphaFold
Authors: Guzmán-Vega Francisco J. , Arold Stefan T.
Published: February 2024

The speed and accuracy of deep learning-based structure prediction algorithms makes it now possible to perform in silico “pull-downs” to identify protein-protein interactions at a proteome-wide scale. However, existing scoring algorithms struggle to accurately identify correct interactions at such a large scale, resulting in an excessive number of false positives. Here, we introduce AlphaCRV, a Python package that helps identify correct interactors in a one-against-many AlphaFold screen by clustering, ranking, and visualizing conserved binding topologies, based on protein sequence and fold.
Does amplitude compression help or hinder attentional neural speech tracking?
Authors: Orf Martin , Hannemann Ronny , Obleser Jonas
Published: February 2024

Amplitude compression is an indispensable feature of contemporary audio production and especially relevant in modern hearing aids. The cortical fate of amplitude-compressed speech signals is not well-studied, however, and may yield undesired side effects: We hypothesize that compressing the amplitude envelope of continuous speech reduces neural tracking. Yet, leveraging such a ‘compression side effect’ on unwanted, distracting sounds could potentially support attentive listening if effectively reducing their neural tracking. In this study, we examined 24 young normal-hearing (NH) individuals, 19 older hearing-impaired (HI) individuals, and 12 older normal-hearing individuals. Participants were instructed to focus on one of two competing talkers while ignoring the other. Envelope compression (1:8 ratio, loudness-matched) was applied to one or both streams containing short speech repeats. Electroencephalography (EEG) allowed us to quantify the cortical response function and degree of speech tracking. With compression applied to the attended target stream, HI participants showed reduced behavioural accuracy, and compressed speech yielded generally lowered metrics of neural tracking. Importantly, we found that compressing the ignored stream resulted in a stronger neural representation of the uncompressed target speech. Our results imply that intelligent compression algorithms, with variable compression ratios applied to separated sources, could help individuals with hearing loss suppress distraction in complex multi-talker environments.

Significant statement

Amplitude compression, integral in contemporary audio production and hearing aids, poses an underexplored cortical challenge. Compressing the amplitude envelope of continuous speech is hypothesized to diminish neural tracking. Yet, capitalizing on this ’compression side effect’ for distracting sounds might enhance attentive listening. Studying normal-hearing (NH), older hearing-impaired (HI), and older normal hearing individuals in dual-talker scenarios, we applied envelope compression to speech streams. Both NH and HI participants showed diminished neural tracking with compression on the speech streams. Despite weaker tracking of a compressed distractor, HI individuals exhibited stronger neural representation of the concurrent target. This suggests that adaptive compression algorithms, employing variable ratios for distinct sources, could aid individuals with hearing loss in suppressing distractions in complex multi-talker environments.