Machine learning with multimodal neuroimaging data to classify stages of Alzheimer's disease: a systematic review and meta-analysis.

In recent years, Alzheimer's disease (AD) has been a serious threat to human health. Researchers and clinicians alike encounter a significant obstacle when trying to accurately identify and classify AD stages. Several studies have shown that multimodal neuroimaging input can assist in providing valuable insights into the structural and functional changes in the brain related to AD. Machine learning (ML) algorithms can accurately categorize AD phases by identifying patterns and linkages in multimodal neuroimaging data using powerful computational methods. This study aims to assess the contribution of ML methods to the accurate classification of the stages of AD using multimodal neuroimaging data. A systematic search is carried out in IEEE Xplore, Science Direct/Elsevier, ACM DigitalLibrary, and PubMed databases with forward snowballing performed on Google Scholar. The quantitative analysis used 47 studies. The explainable analysis was performed on the classification algorithm and fusion methods used in the selected studies. The pooled sensitivity and specificity, including diagnostic efficiency, were evaluated by conducting a meta-analysis based on a bivariate model with the hierarchical summary receiver operating characteristics (ROC) curve of multimodal neuroimaging data and ML methods in the classification of AD stages. Wilcoxon signed-rank test is further used to statistically compare the accuracy scores of the existing models. With a 95% confidence interval of 78.87-87.71%, the combined sensitivity for separating participants with mild cognitive impairment (MCI) from healthy control (NC) participants was 83.77%; for separating participants with AD from NC, it was 94.60% (90.76%, 96.89%); for separating participants with progressive MCI (pMCI) from stable MCI (sMCI), it was 80.41% (74.73%, 85.06%). With a 95% confidence interval (78.87%, 87.71%), the Pooled sensitivity for distinguishing mild cognitive impairment (MCI) from healthy control (NC) participants was 83.77%, with a 95% confidence interval (90.76%, 96.89%), the Pooled sensitivity for distinguishing AD from NC was 94.60%, likewise (MCI) from healthy control (NC) participants was 83.77% progressive MCI (pMCI) from stable MCI (sMCI) was 80.41% (74.73%, 85.06%), and early MCI (EMCI) from NC was 86.63% (82.43%, 89.95%). Pooled specificity for differentiating MCI from NC was 79.16% (70.97%, 87.71%), AD from NC was 93.49% (91.60%, 94.90%), pMCI from sMCI was 81.44% (76.32%, 85.66%), and EMCI from NC was 85.68% (81.62%, 88.96%). The Wilcoxon signed rank test showed a low P-value across all the classification tasks. Multimodal neuroimaging data with ML is a promising future in classifying the stages of AD but more research is required to increase the validity of its application in clinical practice.

Intensive Longitudinal Methods Among Adults With Breast or Lung Cancer: Scoping Review.

BACKGROUND: Intensive longitudinal methods offer a powerful tool for capturing daily experiences of individuals. However, its feasibility, effectiveness, and optimal methodological approaches for studying or monitoring experiences of oncology patients remain uncertain. OBJECTIVE: This scoping review aims to describe to what extent intensive longitudinal methods with daily electronic assessments have been used among patients with breast or lung cancer and with which methodologies, associated outcomes, and influencing factors. METHODS: We searched the electronic databases (PubMed, Embase, and PsycINFO) up to January 2024 and included studies reporting on the use of these methods among adults with breast or lung cancer. Data were extracted on population characteristics, intensive monitoring methodologies used, study findings, and factors influencing the implementation of these methods in research and clinical practice. RESULTS: We identified 1311 articles and included 52 articles reporting on 41 studies. Study aims and intensive monitoring methodologies varied widely, but most studies focused on measuring physical and psychological symptom constructs, such as pain, anxiety, or depression. Compliance and attrition rates seemed acceptable for most studies, although complete methodological reporting was often lacking. Few studies specifically examined these methods among patients with advanced cancer. Factors influencing implementation were linked to both patient (eg, confidence with intensive monitoring system) and methodology (eg, option to use personal devices). CONCLUSIONS: Intensive longitudinal methods with daily electronic assessments hold promise to provide unique insights into the daily lives of patients with cancer. Intensive longitudinal methods may be feasible among people with breast or lung cancer. Our findings encourage further research to determine optimal conditions for intensive monitoring, specifically in more advanced disease stages.

A comprehensive study of colisepticaemia progression in layer chickens applying novel tools elucidates pathogenesis and transmission of Escherichia coli into eggs.

Colisepticaemia caused by avian pathogenic Escherichia coli (APEC) is a challenging disease due to its high economic importance in poultry, dubious pathogenesis and potential link with zoonosis and food safety. The existing in vitro studies can't define hallmark traits of APEC isolates, suggesting a paradigm shift towards host response to understand pathogenesis. This study investigated the comprehensive pathological and microbial progression of colisepticaemia, and transmission of E. coli into eggs using novel tools. In total 48 hens were allocated into three groups and were inoculated intratracheally with ilux2-E. coli PA14/17480/5-/ovary (bioluminescent strain), E. coli PA14/17480/5-/ovary or phosphate buffered saline. Infection with both strains led to typical clinical signs and lesions of colibacillosis as in field outbreaks. Based on lung histopathology, colisepticaemia progression was divided into four disease stages as: stage I (1-3 days post infection (dpi)), stage II (6 dpi), stage III (9 dpi) and stage IV (16 dpi) that were histologically characterized by predominance of heterophils, mixed cells, pyogranuloma, and convalescence, respectively. As disease progressed, bacterial colonization in host organs also decreased, revealed by the quantification of bacterial bioluminescence, bacteriology, and quantitative immunohistochemistry. Furthermore, immunofluorescence, immunohistochemistry, and bacteria re-isolation showed that E. coli colonized the reproductive tract of infected hens and reached to egg yolk and albumen. In conclusion, the study provides novel insights into the pathogenesis of colisepticemia by characterizing microbial and pathological changes at different disease stages, and of the bacteria transmission to table eggs, which have serious consequences on poultry health and food safety.

Nitroproteomics is instrumental for stratification and targeted treatments of astrocytoma patients: expert recommendations for advanced 3PM approach with improved individual outcomes.

Protein tyrosine nitration is a selectively and reversible important post-translational modification, which is closely related to oxidative stress. Astrocytoma is the most common neuroepithelial tumor with heterogeneity and complexity. In the past, the diagnosis of astrocytoma was based on the histological and clinical features, and the treatment methods were nothing more than surgery-assisted radiotherapy and chemotherapy. Obviously, traditional methods short falls an effective treatment for astrocytoma. In late 2021, the World Health Organization (WHO) adopted molecular biomarkers in the comprehensive diagnosis of astrocytoma, such as IDH-mutant and DNA methylation, which enabled the risk stratification, classification, and clinical prognosis prediction of astrocytoma to be more correct. Protein tyrosine nitration is closely related to the pathogenesis of astrocytoma. We hypothesize that nitroproteome is significantly different in astrocytoma relative to controls, which leads to establishment of nitroprotein biomarkers for patient stratification, diagnostics, and prediction of disease stages and severity grade, targeted prevention in secondary care, treatment algorithms tailored to individualized patient profile in the framework of predictive, preventive, and personalized medicine (PPPM; 3P medicine). Nitroproteomics based on gel electrophoresis and tandem mass spectrometry is an effective tool to identify the nitroproteins and effective biomarkers in human astrocytomas, clarifying the biological roles of oxidative/nitrative stress in the pathophysiology of astrocytomas, functional characteristics of nitroproteins in astrocytomas, nitration-mediated signal pathway network, and early diagnosis and treatment of astrocytomas. The results finds that these nitroproteins are enriched in mitotic cell components, which are related to transcription regulation, signal transduction, controlling subcellular organelle events, cell perception, maintaining cell homeostasis, and immune activity. Eleven statistically significant signal pathways are identified in astrocytoma, including remodeling of epithelial adherens junctions, germ cell-sertoli cell junction signaling, 14-3-3-mediated signaling, phagosome maturation, gap junction signaling, axonal guidance signaling, assembly of RNA polymerase III complex, and TREM1 signaling. Furthermore, protein tyrosine nitration is closely associated with the therapeutic effects of protein drugs, and molecular mechanism and drug targets of cancer. It provides valuable data for studying the protein nitration biomarkers, molecular mechanisms, and therapeutic targets of astrocytoma towards PPPM (3P medicine) practice. Supplementary Information: The online version contains supplementary material available at 10.1007/s13167-023-00348-y.

Factors Influencing the Total Functional Capacity Score as a Critical Endpoint in Huntington's Disease Research.

Background: The Total Functional Capacity (TFC) score is commonly used in Huntington's disease (HD) research. The classification separates each disease stage (1-5), e.g., as an inclusion criterion or endpoint in clinical trials accepted by the Food and Drug Administration (FDA). In addition to the quantification of age- and CAG-repeat-dependent effects as well as interacting effects of both on the TFC, we aimed to investigate factors influencing the TFC, such as neuropsychiatric, educational, and cognitive disease burden using data from the largest HD observational study to date. In addition, we analyzed data from pre-manifest stages to investigate the influence of the above-mentioned factors on the TFC in that stage. Methods: A moderated regression analysis was conducted to analyze the interaction effects of age and CAG-repeat length on the TFC in HD patients. A simple slope analysis was calculated to illustrate the effects. Depending on TFC results, motor-manifest patients were grouped into five stages. Data from pre-manifest participants were analyzed with regard to years to onset and CAP scores. Results: We identified N = 10,314 participants as manifest HD. A significant part of variance on the TFC was explained by age (R2 = 0.029, F (1;10,281) = 308.02, p < 0.001), CAG-repeat length (∆R2 = 0.132, ∆F (1;10,280) = 1611.22, p < 0.001), and their interaction (∆R2 = 0.049, ∆F (1;10,279) = 634.12, p < 0.001). The model explained altogether 20.9% of the TFC score's variance (F = 907.60, p < 0.001). Variance of psychiatric and cognitive symptoms significantly differed between stages. Exploratory analysis of median data in pre-manifest participants revealed the highest scores for neuropsychiatric changes between 5 to <20 years from the disease onset. Conclusions: TFC is mainly explained by the neurobiological factors, CAG-repeat length, and age, with subjects having more CAG-repeats showing a faster decline in function. Our study confirms TFC as a robust measure of progression in manifest HD.

Structural-vascular-functional correlation in type 2 non-proliferative macular telangiectasia.

PURPOSE: To correlate the structural-vascular-functional changes in type 2 non-proliferative macular telangiectasia (MacTel) using optical coherence tomography (OCT) angiography (OCTA). METHODS: In this retrospective study, OCTA and enface OCT image analysis of eyes with confirmed diagnosis of non-proliferative type 2 MacTel was performed. The 'MacTel area' was calculated by marking the outer boundary of an area affected by MacTel on superficial (SCP) and deep capillary plexus (DCP) on OCTA images and photoreceptor layer (PRL) on enface OCT scan. At every follow-up OCTA scan visit, best-corrected visual acuity, MacTel area and stage of disease was documented. Analyses between disease stage, MacTel area and logMAR visual acuity was carried out. RESULTS: In total, 38 single-visit OCTA scans of 22 patients were included. The mean age was 58.9 ± 10.98 years. An increase in disease severity stage correlated positively with MacTel area in SCP segmentations slab (r = 0.334; p = 0.04) and logMAR visual acuity (r = 0.338; p = 0.038). No correlation in the DCP area or PRL area (p > 0.05) was noted with disease stage. A statistically significant positive correlation was noted between the structural changes in PRL layer with vascular changes in SCP (p = 0.021) but not in DCP (p = 0.199). No correlation of visual acuity with changes in SCP, DCP or PRL was noted (p > 0.05). CONCLUSION: OCTA is a useful adjunct for determining disease severity in type 2 non-proliferative MacTel by assessing the structural-vascular changes. Further longitudinal studies need to be considered in future for understanding the pathomechanism of retinal damage in type 2 MacTel.

Disease Progression Stages and Burden in Patients with Duchenne Muscular Dystrophy Using Administrative Claims Supplemented by Electronic Medical Records.

INTRODUCTION: This study aims to identify stages of Duchenne muscular dystrophy (DMD) and assess the disease burden by progression stage using real-world administrative claims supplemented by relevant electronic medical record (EMR) data. METHODS: Claims and EMR data from the Decision Resources Group's Real World Data Repository (2011-2020) were used to identify patients with DMD by diagnosis code and to stratify them into four disease stages by diagnosis and procedure markers reflective of DMD progression. Clinical and medical history data from the Cooperative International Neuromuscular Research Group (CINRG) were used to validate the developed claims-based staging algorithm. The distribution and drivers by disease stage, as well as disease burden, were examined. RESULTS: A total of 938 (94%) of patients with DMD identified in claims/EMR data had sufficient information for stage classification. Patients were classified by stage based on patient characteristics and the presence or absence of progression markers such as genetic testing, wheelchair usage, scoliosis treatment, or ventilation assistance. Average ages at stages 1-4 are 7, 13, 18, and 23 years, respectively. Using natural history data, the claims-based staging algorithm was validated with high sensitivity and specificity rates. Both healthcare resource utilization and medical charges increased by stage. For example, the average annualized total charges were $17,688 (stage 1), $36,868 (stage 2), $72,801 (stage 3), and $167,285 (stage 4). CONCLUSIONS: Large-scale claims data supplemented by EMR data can be used to characterize DMD progression and evaluate disease burden which may inform the design of future real-world studies about DMD.

Empirical likelihood confidence interval for sensitivity to the early disease stage.

Disease status can naturally be classified into three or more ordinal stages rather than just being binary stages. Many works have been done for the estimation and inference procedure regarding three ordinal disease stages, which are non-disease, early disease, and full disease stages. The early disease stage can be very important for therapeutic intervention and prevention potentiality. As a diagnostic measure, sensitivity to the early disease stage is often used. In this article, we propose confidence intervals for the sensitivity to early disease stage based on given target specificity for non-disease stage and target sensitivity to full disease stage using both empirical likelihood (EL) and adjusted EL procedures. We compare the performance of the proposed EL confidence intervals with other procedures in our simulation study. The proposed procedures are further applied to Alzheimer's Disease Neuroimaging Initiative data set.

The preproliferative stage in type 2 macular telangiectasia (MacTel type 2).

PURPOSE: To study clinical and imaging features of various stages of macular telangiectasia (MacTel type 2). METHODS: In this retrospective study, cases of MacTel type 2 with fluorescein angiography (FA), optical coherence tomography (OCT) and OCT-angiography (OCTA) imaging were included. Based on angiographic perifoveal fluorescence, two groups were formed: group 1: diffuse hyperfluoroscence and group 2: diffuse + focal hyperfluoroscence. Later, based on OCT features, group 2 was subdivided into group 2A: without SRNVM and group 2B: with SRNVM. Clinical, FA, OCT and OCTA features were analysed. Eyes showing conversion to the proliferative stage at final visit were noted. RESULTS: Ninety-four eyes of 48 patients were included. Group 1 (n = 28) showed diffuse perifoveal hyperfluoroscence, hyperreflective middle retinal layers, absent SRNVM (p = 0.006) on OCT and dilated perifoveal capillaries in deep capillary plexus (DCP) on OCTA. Group 2A (n = 40) showed diffuse + focal perifoveal hyperfluoroscence, hyperreflective middle retinal layers (p = 0.001), hyporeflective outer retina cavities (p = 0.021), absent SRNVM with dilated and bunching perifoveal capillaries (p = 0.004) in DCP. Group 2B (n = 26) showed late diffuse + focal perifoveal hyperfluoroscence, foveal contour irregularity (p = 0.002), retinal pigment clumps (p = 0.015) and SRNVM on OCT with bunching of capillaries in DCP and vessels in outer retina (p = 0.002). Five eyes showed conversion to group 2B at final visit. CONCLUSION: There exists a distinct disease stage called "preproliferative" MacTel type 2 showing clinical features of non-proliferative disease, diffuse + focal perifoveal hyperfluoroscence on FA, absent SRNVM on OCT and bunching perifoveal capillaries in DCP on OCTA. Its identification is important for suspecting proliferative disease, planning management and follow-up visit accordingly.

Functional relevance of macular telangiectasia (MacTel) area on multicolour imaging in type 2 MacTel.

PURPOSE: To analyse the correlation between area of macular telangiectasia (MacTel) involvement on multicolour (MC) imaging, disease stages and visual acuity in type 2 MacTel. METHODS: In this retrospective analysis of MC images, confirmed cases of type 2 MacTel were graded into different disease stages as per Gass and Blodi and Yannuzzi et al classification systems. The 'MacTel area' was calculated by marking the outer boundary of an area with abnormally increased reflectivity to confocal blue wavelength light. At every follow-up visit, best-corrected visual acuity, MacTel area and stage of disease on the MC image was documented. Analyses between disease stage, MacTel area and visual acuity was carried out. RESULTS: In total, 92 eyes of 49 patients were included in the study. The mean age was 59.6 ± 8.96 years. About 182 high-quality gradable MC images were available for analysis. There was a statistically significant difference in the visual acuity (p < 0.001) and area of involvement (p < 0.001) in the non-proliferative and proliferative type 2 MacTel groups. An increase in disease severity stage statistically correlated positively with Mactel area (r = 0.544; p < 0.001) and logMAR visual acuity (r = 0.329; p < 0.001). Over time, there was a significant increase in area of MacTel involvement (p = 0.012) with an associated decrease in the visual acuity (p = 0.023). CONCLUSION: The MacTel area measured on MC imaging showed a strong positive correlation with disease stage and a negative correlation with visual acuity. This could serve as a useful biomarker in clinical trials and understanding the natural history of the disease.

Recent advances in using diffusion tensor imaging to study white matter alterations in Parkinson's disease: A mini review.

Parkinson's disease (PD) is the second most common age-related neurodegenerative disease with cardinal motor symptoms. In addition to motor symptoms, PD is a heterogeneous disease accompanied by many non-motor symptoms that dominate the clinical manifestations in different stages or subtypes of PD, such as cognitive impairments. The heterogeneity of PD suggests widespread brain structural changes, and axonal involvement appears to be critical to the pathophysiology of PD. As α-synuclein pathology has been suggested to cause axonal changes followed by neuronal degeneration, diffusion tensor imaging (DTI) as an in vivo imaging technique emerges to characterize early detectable white matter changes due to PD. Here, we reviewed the past 5-year literature to show how DTI has helped identify axonal abnormalities at different PD stages or in different PD subtypes and atypical parkinsonism. We also showed the recent clinical utilities of DTI tractography in interventional treatments such as deep brain stimulation (DBS). Mounting evidence supported by multisite DTI data suggests that DTI along with the advanced analytic methods, can delineate dynamic pathophysiological processes from the early to late PD stages and differentiate distinct structural networks affected in PD and other parkinsonism syndromes. It indicates that DTI, along with recent advanced analytic methods, can assist future interventional studies in optimizing treatments for PD patients with different clinical conditions and risk profiles.

Characterization of serum biomarkers and antibody responses against Prevotella spp. in preclinical and new-onset phase of rheumatic diseases.

Introduction: The characterization of the influence of the microbiota on the development and drug responses during rheumatic diseases has intensified in recent years. The role of specific bacteria during disease development has become a central research question. Notably, several lines of evidence point to distinct microbes, e.g., Prevotella copri (P. copri) being targeted by antibodies in clinical phases of rheumatic diseases. Methods: In the present study, we compiled a broad collection of human serum samples from individuals at risk of developing RA, chronic RA patients as well as patients with new-onset of rheumatic diseases. We evaluated the presence of inflammatory biomarkers in our serum collection as well as serum antibody responses against novel, genetically distinct isolates of P. copri and several oral pathobionts. Results: Our analysis revealed the presence of increased levels of inflammatory markers already in pre-clinical and new onset rheumatoid arthritis. However, antibody reactivity against the microbes did not differ between patient groups. Yet, we observed high variability between the different P. copri strains. We found total serum IgG levels to slightly correlate with IgG antibody responses against P. copri, but no relation between the latter and presence or prevalence of P. copri in the intestine. Discussion: In conclusion, our work underlined the importance of strain-level characterization and its consideration during further investigations of host-microbiota interactions and the development of microbiome-based therapeutic approaches for treating rheumatic diseases.

Factores predictores de recurrencia del cáncer de endometrio / Predictors of the endometrium cancer recurrence

Resumen OBJETIVO: Determinar qué factores favorecen la predicción de recurrencia de cáncer de endometrio en diferentes estadios de la enfermedad. MATERIALES Y MÉTODOS: Estudio retrospectivo efectuado en un grupo de pacientes con cáncer de endometrio atendidas entre el 2017 y 2020 en el Hospital Juan Ramón Jiménez de Huelva, España. Variables de análisis: edad, grado de diferenciación tumoral, invasión miometrial, estadio posquirúrgico e infiltración al espacio linfovascular, en todas las pacientes con recidiva. El análisis estadístico se procesó en el programa SPSS v23. Habiéndose realizado un análisis de Kolmogorov- Smirnov y tras haber obtenido un resultado no normal, se utilizó la prueba de χ2 para los datos categóricos paramétricos, e independientemente se aplicó la prueba U de Mann Whitney para los datos no paramétricos. Los valores de p < 0.01 se consideraron estadísticamente significativos. RESULTADOS: Se reunieron 9 pacientes con recidiva tumoral y seguimiento de 5 años luego del diagnóstico primario. Conforme al análisis estadístico no se encontró una relación de dependencia entre las variables recidiva e invasión miometrial (χ2 = 4.780; p = 0.092), recidiva y grado tumoral (χ2 = 7.765; p = 0.051) y recidiva y el estadio posquirúrgico (χ2 = 10.200, p = 0.070). Por el contrario, se observó relación de dependencia entre las variables afectación ganglionar e infiltración al espacio linfovascular positiva (χ2 = 9.954, Cc = 0.235, p < 0.01). En todas las pacientes se evaluó la infiltración al espacio linfovascular. Ésta fue negativa en 141 casos y 4 de estos casos tuvieron recurrencia de la enfermedad. 5 de 9 pacientes con recurrencia de la enfermedad tenían infiltración al espacio linfovascular positiva. CONCLUSIONES: Lo aquí encontrado muestra que más de la mitad de las pacientes con recurrencia de la enfermedad tuvieron infiltración al espacio linfovascular. Cuando ésta fue negativa hubo una reducción del riesgo de 2.8% de padecer una recurrencia.

Abstract OBJECTIVE: To determine which factors favor the prediction of endometrial cancer recurrence at different stages of the disease. MATERIALS AND METHODS: Retrospective study performed in a group of patients with endometrial cancer attended between 2017 and 2020 at the Juan Ramón Jiménez Hospital in Huelva, Spain. Analysis variables: age, degree of tumor differentiation, myometrial invasion, post-surgical stage and infiltration to the lymphovascular space, in all patients with recurrence. The statistical analysis was processed in SPSS v23. Having performed a Kolmogorov-Smirnov analysis and having obtained a non-normal result, a 2 test was used for parametric categorical data, and independently the Mann Whitney U test was used for non-parametric data. Values of p < 0.01 were considered statistically significant. RESULTS: Nine patients with tumor recurrence and 5-year follow-up after primary diagnosis were collected. According to the statistical analysis, no dependency relationship was found between the variables recurrence and myometrial invasion (χ2 = 4.780; p = 0.092), recurrence and tumor grade (χ2 = 7.765; p = 0.051) and recurrence and post-surgical stage (χ2 = 10.200, p = 0.070). In contrast, a dependency relationship was observed between the variables nodal involvement and positive lymphovascular space infiltration (χ2 = 9.954, Cc = 0.235, p < 0.01). The existence of infiltration of the lymphovascular space was evaluated in all patients. This was negative in 141 cases and 4 of these cases had disease recurrence. 5 of 9 patients with disease recurrence had positive lymphovascular space infiltration. CONCLUSIONS: The findings here show that more than half of the patients with disease recurrence have infiltration to the lymphovascular space and, in addition, if the infiltration to the lymphovascular space is negative, there is a 2.8% reduced risk of recurrence.

Differences in gut microbiota structure in patients with stages 4-5 chronic kidney disease.

The gut microbiota can affect human metabolism, immunity, and other biologic pathways through the complex gut-kidney axis (GKA), and in turn participate in the occurrence and development of kidney disease. In this study, 39 patients with stage 4-5 chronic kidney disease (CKD) and 40 healthy individuals were recruited and 16S rDNA sequencing was performed to analyze the V3-V4 conserved regions of their microbiota. A total of 795 operational taxonomic units (OTUs) shared between groups or specific to each group were obtained, among which 255 OTUs with significant differences between the two groups were identified (P<0.05). Adonis differential analysis showed that the diversity of gut microbiota was highly correlated with CKD stages 4-5. Additionally, 61 genera with differences in the two groups were identified (P<0.05) and 111 species with significant differences in the phyla, classes, orders, families, and genera between the two groups were identified (P<0.05). The differential bacterial genera with the greatest contribution were, in descending order: c_Bacteroidia, o_Bacteroidales, p_Bacteroidetes, c_Clostridia, o_Clostridiales, etc. Those with the greatest contribution in stages 4-5 CKD were, in descending order: p_Proteobacteria, f_Enterobacteriaceae, o_Enterobacteriales, c_Gammaproteobacteria, c_Bacilli, etc. The results suggest that the diversity of the microbiota may affect the occurrence, development, and outcome of the terminal stages of CKD.

Challenges, facilitators and barriers to screening study participants in early disease stages-experience from the MACUSTAR study.

BACKGROUND: Recruiting asymptomatic participants with early disease stages into studies is challenging and only little is known about facilitators and barriers to screening and recruitment of study participants. Thus we assessed factors associated with screening rates in the MACUSTAR study, a multi-centre, low-interventional cohort study of early stages of age-related macular degeneration (AMD). METHODS: Screening rates per clinical site and per week were compiled and applicable recruitment factors were assigned to respective time periods. A generalized linear mixed-effects model including the most relevant recruitment factors identified via in-depth interviews with study personnel was fitted to the screening data. Only participants with intermediate AMD were considered. RESULTS: A total of 766 individual screenings within 87 weeks were available for analysis. The mean screening rate was 0.6 ± 0.9 screenings per week among all sites. The participation at investigator teleconferences (relative risk increase 1.466, 95% CI [1.018-2.112]), public holidays (relative risk decrease 0.466, 95% CI [0.367-0.591]) and reaching 80% of the site's recruitment target (relative risk decrease 0.699, 95% CI [0.367-0.591]) were associated with the number of screenings at an individual site level. CONCLUSIONS: Careful planning of screening activities is necessary when recruiting early disease stages in multi-centre observational or low-interventional studies. Conducting teleconferences with local investigators can increase screening rates. When planning recruitment, seasonal and saturation effects at clinical site level need to be taken into account. TRIAL REGISTRATION: ClinicalTrials.gov NCT03349801 . Registered on 22 November 2017.

Magnesium levels in children with chronic kidney disease stages 1-3 / Niveles de magnesio en niños con enfermedad renal crónica estadios 1-3

ABSTRACT Objective: The objective of this study was to assess serum and urinary magnesium levels in children who have chronic kidney disease stages 1-3. Methods: Eighty-seven patients who were followed at pediatric nephrology department for chronic kidney disease were included in the study. Age, gender, magnesium, dietary magnesium, and creatinine levels, and fractionated magnesium excretion for all cases were recorded. Patients with chronic kidney disease and control groups were compared in terms of these data. Results: Thirty-nine cases with chronic kidney disease were stage 1, 26 were stage 2, and 22 were stage 3. Average age was 9.9 ± 2.8 years in the control group and 10.2 ± 2.6 years in the chronic kidney disease group. The serum magnesium levels were significantly higher in the stage 3 group than in the control group (P<0.001). Also, in stage 3, fractionated magnesium excretion levels were higher compared to the control group (P<0.001). Conclusion: In chronic kidney disease with advancing renal failure, hypermagnesemia is frequently seen. Serum magnesium levels should be measured periodically in all the children with chronic kidney disease stage 3 to investigate magnesium abnormalities and assess clinical results.

RESUMEN Objetivo: El objetivo de este estudio fue evaluar los niveles de magnesio sérico y urinario en niños con enfermedad renal crónica en estadios 1-3. Material y métodos: Se incluyeron en el estudio 87 pacientes que tuvieron seguimiento en el servicio de nefrología pediátrica por enfermedad renal crónica. Se registraron los siguientes datos: edad, sexo, niveles de magnesio, ingesta de alimentos con magnesio, y creatinina, así como también la excreción fraccionada de magnesio para todos estos casos. Sobre la base de dichos datos, se compararon los pacientes con enfermedad renal crónica y los grupos de control. Resultados: De los 87 casos de enfermedad renal crónica, 39 se hallaban en estadio 1; 26, en estadio 2, y 22, en estadio 3. La edad promedio fue de 9,9 ± 2,8 años en el grupo control y de 10,2 ± 2,6 años en el grupo de enfermedad renal crónica. Los niveles de magnesio en suero fueron significativamente más altos en el grupo del estadio 3 que en el grupo control (p <0,001). Además, en el estadio 3, los niveles de excreción fraccionada de magnesio fueron más altos en comparación con el grupo control (p <0,001). Conclusión: En la enfermedad renal crónica con insuficiencia renal avanzada, se observa con frecuencia una hipermagnesemia. Los niveles séricos de magnesio deben medirse periódicamente en todos los niños con enfermedad renal crónica en estadio 3 para investigar las anomalías del magnesio y evaluar los resultados clínicos.

Current treatment options for hepatocellular carcinoma.

Hepatocellular carcinoma remains a serious global disease. Its incidence is increasing. Standard procedures have been developed for each stage. The complexity of this disease shows that the selection of patients in stage 0/A for different types of surgical treatment is very complicated. Treatment methods of stage B, especially locoregional treatment represented by TACE (transarterial chemoembolization or radioembolization of TARE), radiofrequency ablation and others, move freely to lower and higher stages as adjunctive therapy. Lenvatinib can replace TACE with equal efficacy in cases where locoregional treatment cannot be used. Until 2016, the only systemic treatment option for stage C was sorafenib. Lenvatinib became a second-line drug to show non-inferiority to sorafenib in OS. Retrospective analyzes revealed that patients who responded to the treatment with lenvatinib or sorafenib had a median survival of over 22 months. Sequential treatment with sorafenib and regorafenib in the RESOURCE study with a median survival of more than 24 months was similar. Ramucirumab was effective only in patients with high AFP levels. The study demonstrated the importance of selecting patients according to prognostic factors (extrahepatic spread and vascular invasion). Second-line cabozantinib has shown the same benefit as regorafenib. In the second line, immunotherapy represented by anti PD-1 antibodies nivolumab and pembrolizumab was used. Sequential administration after sorafenib prolonged the median overall survival of about 22 months. We currently have sorafenib and lenvatinib in the first line, regorafenib, cabozantinib, ramucirumab (AFP 400 μg/L), pembrolizumab and nivolumab in the second line. The possibilities of monotherapy have been exhausted. The discovery of a synergistic effect of angiogenesis inhibitors, which convert a cold tumor into a hot one and facilitate the efficacy of anti-PD-1 / anti-PDL-1 antibodies, has led to a highly effective combination therapy. In study IMbrave150, the combination of atezolizumab and bevacizumab was successfully used compared to sorafenib in the first-line treatment. Additional studies are currently underway using other tyrosin kinase inhibitors - regorafenib, lenvatinib and cabozantinib - in combination with nivolumab, ipilimumab and pembrolizumab. This development of treatment at all stages evoked with renewed urgency the need to find a suitable way to search for the early stages of HCC and to create a more effective system for selecting patients for the most appropriate treatment.

Prognostic imaging biomarkers for diabetic kidney disease (iBEAt): study protocol.

BACKGROUND: Diabetic kidney disease (DKD) remains one of the leading causes of premature death in diabetes. DKD is classified on albuminuria and reduced kidney function (estimated glomerular filtration rate (eGFR)) but these have modest value for predicting future renal status. There is an unmet need for biomarkers that can be used in clinical settings which also improve prediction of renal decline on top of routinely available data, particularly in the early stages. The iBEAt study of the BEAt-DKD project aims to determine whether renal imaging biomarkers (magnetic resonance imaging (MRI) and ultrasound (US)) provide insight into the pathogenesis and heterogeneity of DKD (primary aim) and whether they have potential as prognostic biomarkers in DKD (secondary aim). METHODS: iBEAt is a prospective multi-centre observational cohort study recruiting 500 patients with type 2 diabetes (T2D) and eGFR ≥30 ml/min/1.73m2. At baseline, blood and urine will be collected, clinical examinations will be performed, and medical history will be obtained. These assessments will be repeated annually for 3 years. At baseline each participant will also undergo quantitative renal MRI and US with central processing of MRI images. Biological samples will be stored in a central laboratory for biomarker and validation studies, and data in a central data depository. Data analysis will explore the potential associations between imaging biomarkers and renal function, and whether the imaging biomarkers improve the prediction of DKD progression. Ancillary substudies will: (1) validate imaging biomarkers against renal histopathology; (2) validate MRI based renal blood flow measurements against H2O15 positron-emission tomography (PET); (3) validate methods for (semi-)automated processing of renal MRI; (4) examine longitudinal changes in imaging biomarkers; (5) examine whether glycocalyx and microvascular measures are associated with imaging biomarkers and eGFR decline; (6) explore whether the findings in T2D can be extrapolated to type 1 diabetes. DISCUSSION: iBEAt is the largest DKD imaging study to date and will provide valuable insights into the progression and heterogeneity of DKD. The results may contribute to a more personalised approach to DKD management in patients with T2D. TRIAL REGISTRATION: Clinicaltrials.gov ( NCT03716401 ).

Not all prostate cancer is the same - patient perceptions: an Asia-Pacific region study.

OBJECTIVE: To explore the perceptions of patients living with different stages of prostate cancer across the Asia-Pacific (APAC) region, as while extensive quantitative research has been undertaken into outcomes of treatments for prostate cancer, little in the way of qualitative research has been performed looking at subjective perceptions of patients in regard to their perceived deficits in the treatment of this condition and such research is particularly lacking in reference to the APAC region. PATIENTS AND METHODS: Initial 45-min qualitative research interrogatory interviews were conducted with 12 patients from Australia, China and Japan to identify themes that were significant to patients in the management of prostate cancer. Thereafter, 150 patients with different stages of prostate cancer underwent 30-min online (Australia) or computer-assisted/personal interviews categorised on the five key themes identified, in order to more fully clarify the nature of patient perceptions of how their prostate cancer had been treated and the issues they felt could be more fully addressed in order to improve the management of this condition. RESULTS: Interviews indicated common challenges and unmet needs among patients, including: (i) patients' feelings and emotional state change during their disease journey, (ii) patients lack of knowledge about prostate cancer and disease progression prior to diagnosis, (iii) patients felt shared decision-making was uncommon, (iv) patients have misperceptions about surgery, and (v) patients have unmet needs for greater information and support to manage their condition. CONCLUSIONS: These patient perceptions of unmet needs in prostate cancer management stand in contrast to patient awareness of other common diseases such as heart failure and diabetes. Such unmet needs vary across disease stages and between different nationalities. Patients with prostate cancer in the APAC region appear to have gaps in knowledge about their disease and wish for greater information, support and public awareness about prostate cancer.

Hematological changes of endogenic intoxication, non-specific reactivity and inflammation activity indices in hiv-infected patients.

OBJECTIVE: The aim: To establish changes in hematological parameters of endogenous intoxication, nonspecific reactivity, activity of inflammation in HIV-infected persons, to improve verification of the clinical stage of the disease. PATIENTS AND METHODS: Materials and methods: Anamnestic, clinical, laboratory data. The statistical processing was performed in the Microsoft Office Excel 2010 and IBM SPSS Statistic 23 computer software, variational statistics processing (Student's t-criteria). RESULTS: Results: 51 HIV-infected were examined (main group) and 44 clinically anamnestic healthy blood donors (comparison group). The study included 46 patients (5 were withdrawn due to failure to meet criteria - severe septic condition). All patients were divided into three groups: A1 - all patients, 46 persons, men 76.0%, women - 24.0%; A2 - 11 people with I-III stages of HIV infection, men 72,7%, women - 27,3%; A3 - 35 HIV infected with stage IV disease, men 76.0%, women - 24.0%. All patients had an increase in intoxication indices and sex-dependent changes. Nonspecific reactivity indices in group A1 were above the norm, independent of gender except the index of neutrophils and lymphocyte (NLR). Below the norm is the immunoreactivity index (IR), the lymphocyte-monocyte ratio index (LMR), the lymphocyte index (Ilymph), the index of allergization (IA). Indices of nonspecific reactivity of A2 patients exceeded the norm and were independent of sex, with the exception of IR, Ilymph, IA, which were reduced. Non-specific reactivity indices are increased in HIV-infected group A3. Below the norm were IR, LMR, Ilymph, IA. Analyzing the activity indexes of inflammation, it became clear that the Krebs index (KI) was increased in all groups of patients; lymphocyte-granulocyte index (ILG) in groups A1 and A3 is less than normal, unlike patients in group A2, where it remained within the normal range. The leukocyte ratio and erythrocyte sedimentation rate (ILESR) in A1 and A3 have increased rates, unlike in A2, where the index is smaller. CONCLUSION: Conclusions: Men are predominantly HIV positive. The systemic immune response is more pronounced in women. There is a progressive impairment of immunological reactivity, indicating an immunodeficiency of the cell type with a decrease in nonspecific anti-infective protection. Patients with stage IV of HIV infection have moderate and severe inflammatory reactions, impaired reactivity, and are more pronounced in women.