bluuebunny/crossref_metadata_2025 huggingface dataset:
Association between fluid balance and mortality for heart failure and sepsis: a propensity score-matching analysis
Authors: Zhang Bufan , Guo Shaohua , Fu Zean , Wu Naishi , Liu Zhigang
Published: October 2022

Background

Fluid resuscitation is necessary to correct the sepsis-induced hypoperfusion, which is contradictory to the treatment of heart failure. This study explored the association between fluid balance (FB) of the first 24 h after ICU admission and mortality in critically ill patients with heart failure and sepsis.

Methods

Data were extracted from the Medical Information Mart for Intensive Care database. The locally weighted scatterplot smoothing (Lowess) method was used to demonstrate the relationship between FB and in-hospital mortality. Groups were divided into high FB (≥ 55.85 ml/kg) and low FB (< 55.85 ml/kg) according to the cut-off value of FB using Receiver operating characteristic analysis and Youden index method. The primary outcome was in-hospital mortality. Subgroup analyses, multivariable logistic regression analyses, and Kaplan-Meier curves were used to detect the association and survival difference between groups. Inverse probability treatment weighting (IPTW) and propensity score matching (PSM) were performed to minimize the bias of confounding factors and facilitate the comparability between groups.

Results

A total of 936 patients were included. The Lowess curve showed an approximate positive linear relationship for FB and in-hospital mortality. In the multivariable logistic regression adjusted model, high FB showed strong associations with in-hospital mortality (OR 2.53, 95% CI 1.60–3.99, p < 0.001) as compared to the low FB group. In IPTW and PSM models, high FB consistently showed higher in-hospital mortality (IPTW model: OR 1.94, 95% CI 1.52–2.49, p < 0.001; PSM model: OR 2.93, 95% CI 1.75–4.90, p < 0.001) and 30-day mortality (IPTW model: OR 1.65, 95% CI 1.29–2.10, p < 0.001; PSM model: OR 2.50, 95% CI 1.51–4.15, p < 0.001), compared with the low FB group.

Conclusion

For critically ill patients with heart failure and sepsis, high FB within the first 24 h after ICU admission could serve as an independent risk factor for in-hospital mortality and 30-day mortality. The avoidance of fluid overload exerts important effects on reducing mortality in such patients.
Medium-chain triglycerides may improve memory in non-demented older adults: a systematic review of randomized controlled trials
Authors: Giannos Panagiotis , Prokopidis Konstantinos , Lidoriki Irene , Triantafyllidis Konstantinos K. , Kechagias Konstantinos S. , Celoch Kamil , Candow Darren G. , Ostojic Sergej M. , Forbes Scott C.
Published: October 2022

Background

Ketosis has been exploited for its neuroprotective impact and treatment of neurological conditions via ketone production. Exogenous medium-chain triglyceride (MCT) supplementation may induce nutritional ketosis. The aim of this systematic review is to explore the effects of MCTs on memory function in older adults without cognitive impairment.

Methods

A systematic literature search of PubMed, Cochrane Library, Scopus, and Web of Science was employed from inception until April 2022 for randomized controlled trials (RCTs) in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines, investigating the impact of MCT oils on components of memory. Risk of bias (RoB2) tool was utilized for quality assessment.

Results

Six trials were included for qualitative synthesis, in which two studies examined the effect of MCTs through a ketogenic meal. MCT supplementation compared to controls was associated with improved indices of memory function in 4 out of 6 studies, particularly working memory. A meta-analysis was not employed due to the low number of studies, therefore, a true effect measure of MCT supplementation was not explored.

Conclusions

MCT supplementation may enhance working memory in non-demented older adults. These effects may be more prominent in individuals with lower baseline scores, from short and long-term supplementation. Further studies are warranted to confirm these findings in terms of optimal dose and MCTs composition, which may protect from memory decline during aging.
Association between oral intake magnesium and sarcopenia: a cross-sectional study
Authors: Yang Shih-Wei , Chen Yuan-Yuei , Chen Wei-Liang
Published: October 2022

Background

Sarcopenia is a common skeletal muscle disorder in the elderly population. The patients with sarcopenia increased the cost of care and the risk for hospitalization. Magnesium deficiency might increase reactive oxygen species and protein damage. The purpose of our study was to demonstrate the relation between oral intake magnesium and sarcopenia by European Working Group on Sarcopenia in Older People (EWGSOP) 2 definition.

Methods

Our study included 2532 participants with 1310 males and 1222 females. The multiple logistic regression model was designed to test the cross-sectional protective outcome of oral intake magnesium for sarcopenia.

Results

Oral intake magnesium had a protective outcome with sarcopenia (odd ratio (OR) = 0.997, 95% CI = 0.996, 0.998, P < 0.001). After fully adjusted, the significance persisted with OR = 0.998 (95% CI = 0.996, 0.999, P < 0.001).

Conclusion

Results of the present study showed the dose dependent relationship between oral intake magnesium and sarcopenia. Sufficient oral intake magnesium might prevent patient from sarcopenia.
Multiple cerebral infarctions due to calcified amorphous tumor growing rapidly from an antecedent infection and decreasing rapidly by detachment of fibrin and antithrombotic drugs: a case report
Authors: Kimura Motoya , Niwa Jun-Ichi , Ito Hideaki , Matsuyama Katsuhiko , Doyu Manabu
Published: October 2022

Background

Calcified amorphous tumor (CAT) of the heart is a rare non-neoplastic intracardiac mass, a calcium deposition surrounded by amorphous fibrous tissue, and possibly causes cerebral embolism. Even rarer is CAT associated with infection, and no CAT with antecedent infection has been reported to our knowledge. In addition, although some CAT in patients on hemodialysis has been reported to grow rapidly, no case has been reported on CAT that grew and diminished rapidly in a short period of time. Here, we report the case of an 82-year-old Japanese woman with normal renal function who developed multiple cerebral infarctions due to CAT that grew rapidly, associated with inflammation from an antecedent infection, and diminished rapidly by detachment of fibrin on the mass surface and antithrombotic drugs.

Case presentation

The patient developed fever after dental treatment and found musical hallucination on the left ear worsened in degree and frequency. In a nearby clinic, she was treated with antibiotics, and her body temperature turned to normal in approximately 1 month. She presented to our hospital for workup on the worsened musical hallucination. Magnetic resonance imaging (MRI) showed multiple cerebral infarctions, and transthoracic echocardiography (TTE) revealed an immobile hyperechoic mass with an acoustic shadow arising from a posterior cusp of the mitral valve. CAT was suspected and treated with apixaban and aspirin. Follow-up MRI and TTE showed newly developed multiple cerebral infarctions and rapidly diminished CAT. Cardiac surgery was performed to resect the CAT. The pathological findings showed calcifications surrounded by amorphous fibrous tissue including fibrin, indicating CAT. The patient’s symptoms improved and no cerebral infarctions recurred in 4 months follow-up.

Conclusion

Inflammation from an antecedent infection can cause CAT to grow rapidly. Fibrous tissue including fibrin may attach to the surface of CAT, resulting in multiple cerebral infarctions. Fibrous tissue may detach and disappear by antithrombotic drugs, leading to a rapid diminishment of CAT in size.
Identification of a novel pathogenic TBCK variant in a Chinese patient with infantile hypotonia with psychomotor retardation and characteristic facies type 3 (IHPRF3): a case report
Authors: Tan Hao-Yi , Wang Bin , Song Yuan-Zong
Published: October 2022

Background

Infantile hypotonia with psychomotor retardation and characteristic facies type 3(IHPRF3) (OMIM #616,900) is an autosomal recessive disorder caused by biallelic pathogenic variants of the TBCK gene, and to date, this disease was reported rather limitedly in number and all described cases were Caucasians.

Case presentation

This paper reported the clinical and genetic features of a Chinese patient with IHPRF3. The patient was a 15-month-old male with global developmental delay, profound hypotonia, and typical facial dysmorphic features including mildly coarse facial appearance, hypertelorism, tented upper lip, exaggerated Cupid’s bow, macroglossia and arched eyebrows. Magnetic Resonance Imaging (MRI) analysis of the brain revealed slightly widened bilateral ventricles and subarachnoid space. On genetic analysis, the patient was homozygous for a novel TBCK variant c.247C > T(p.Arg83Ter). The parents were both carriers without any positive symptoms or signs. With an extremely low frequency (0.0000082) in Exome Aggregation Consortium, the variant has not been reported in any other databases or official literatures, and was diagnosed to be pathogenic according to the American College of Medical Genetics and Genomics(ACMG) standards and guidelines. Neurorehabilitation training did not work well and the long-term prognosis remained to be observed.

Conclusions

This study reported the clinical and molecular features of the first non-Caucasian patient with IHPRF3 arising from a novel homozygous TBCK mutation, which provided a novel molecular marker for the definite diagnosis of IHPRF3 patients and for its genetic counseling and prenatal diagnosis in the affected families.
Prevalence of prediabetes and diabetes vary by ethnicity among U.S. Asian adults at healthy weight, overweight, and obesity ranges: an electronic health record study
Authors: Vicks William S. , Lo Joan C. , Guo Lynn , Rana Jamal S. , Zhang Sherry , Ramalingam Nirmala D. , Gordon Nancy P.
Published: October 2022

Background

Asian adults develop Type 2 diabetes at a lower body mass index (BMI) compared to other racial/ethnic groups. We examined the variation in prevalence of prediabetes and diabetes among Asian ethnic groups within weight strata by comparing middle-aged Chinese, Filipino, South Asian, and White adults receiving care in the same integrated healthcare delivery system.

Methods

Our retrospective cross-sectional U.S. study examined data from 283,110 (non-Hispanic) White, 33,263 Chinese, 38,766 Filipino, and 17,959 South Asian adults aged 45–64 years who were members of a Northern California health plan in 2016 and had measured height and weight. Prediabetes and diabetes were classified based on laboratory data, clinical diagnoses, or diabetes pharmacotherapy. Age-standardized prevalence of prediabetes and diabetes were compared by race/ethnicity within healthy weight, overweight, and obesity categories, using standard BMI thresholds for White adults (18.5 to < 25, 25 to < 30, ≥ 30 kg/m2) and lower BMI thresholds for Asian adults (18.5 to < 23, 23 to < 27.5, ≥ 27.5 kg/m2). Prevalence ratios (PRs) were used to compare the prevalence of diabetes and prediabetes for Asian groups to White adults in each weight category, adjusted for age and BMI.

Results

Across all weight categories, diabetes prevalence was higher for Asian than White adults, and among Asian groups it was highest for Filipino and South Asian adults. Compared to White, PRs for South Asian men/women at healthy BMI were 1.8/2.8 for prediabetes and 5.9/8.0 for diabetes, respectively. The PRs for Filipino men/women at healthy BMI were 1.8/2.6 for prediabetes and 5.0/7.5 for diabetes, respectively. For Chinese men/women at healthy BMI, the PRs for prediabetes (2.1/2.9) were similar to Filipino and South Asian, but the PRs for diabetes were lower (2.1/3.4).

Conclusion

Chinese, Filipino, and South Asian adults have higher prevalence of prediabetes and diabetes than White adults in all weight categories, despite using lower BMI thresholds for weight classification in Asian groups. Within Asian ethnic groups, Filipino and South Asian adults had considerably higher diabetes prevalence than Chinese adults. Our data emphasize the disproportionate metabolic risk among middle-aged Asian adults and underscore the need for diabetes screening among high-risk Asian groups at healthy BMI levels.
Size selection and placement of pedicle screws using robot-assisted versus fluoroscopy-guided techniques for thoracolumbar fractures: possible implications for the screw loosening rate
Authors: Du Sheng-yang , Dai Jun , Zhou Zhen-tao , Shan Bing-chen , Jiang Feng-xian , Yang Jing-yan , Cao Lei , Zhou Xiao-zhong
Published: October 2022

Background

There has been increased development of robotic technologies for the accuracy of percutaneous pedicle screw placement. However, it remains unclear whether the robot really optimize the selection of screw sizes and enhance screw stability. The purpose of this study is to compare the sizes (diameter and length), placement accuracy and the loosening rate of pedicle screws using robotic-assisted versus conventional fluoroscopy approaches for thoracolumbar fractures.

Methods

A retrospective cohort study was conducted to evaluate 70 consecutive patients [34 cases of robot-assisted percutaneous pedicle screw fixation (RAF) and 36 of conventional fluoroscopy-guided percutaneous pedicle screw fixation (FGF)]. Demographics, clinical characteristics, and radiological features were recorded. Pedicle screw length, diameter, and pedicle screw placement accuracy were assessed. The patients’ sagittal kyphosis Cobb angles (KCA), anterior vertebral height ratios (VHA), and screw loosening rate were evaluated by radiographic data 1 year after surgery.

Results

There was no significant difference in the mean computed tomography (CT) Hounsfield unit (HU) values, operation duration, or length of hospital stay between the groups. Compared with the FGF group, the RAF group had a lower fluoroscopy frequency [14 (12–18) vs. 21 (16–25), P < 0.001] and a higher “grade A + B” pedicle screw placement rate (96.5% vs. 89.4%, P < 0.05). The mean screw diameter was 6.04 ± 0.55 mm in the RAF group and 5.78 ± 0.50 mm in the FGF group (P < 0.001). The mean screw length was 50.45 ± 4.37 mm in the RAF group and 48.63 ± 3.86 mm in the FGF group (P < 0.001). The correction loss of the KCA and VHR of the RAF group was less than that of the FGT group at the 1-year follow-up [(3.8 ± 1.8° vs. 4.9 ± 4.2°) and (5.5 ± 4.9% vs. 6.4 ± 5.7%)], and screw loosening occurred in 2 out of 34 patients (5.9%) in the RAF group, and 6 out of 36 patients (16.7%) in the FGF group, but there were no significant differences (P > 0.05).

Conclusion

Compared with the fluoroscopy-guided technique, robotic-assisted spine surgery decreased radiation exposure and optimizes screw trajectories and dimensions intraoperatively. Although not statistically significant, the loosening rate of the RAF group was lower that of than the FGT group.
Stories of paediatric palliative care: a qualitative study exploring health care professionals’ understanding of the concept
Authors: Riiser Kirsti , Holmen Heidi , Winger Anette , Steindal Simen A. , Castor Charlotte , Kvarme Lisbeth Gravdal , Lee Anja , Lorentsen Vibeke Bruun , Misvaer Nina , Früh Elena Albertini
Published: October 2022

Background

By sharing patient stories, health care professionals (HCPs) may communicate their attitudes, values and beliefs about caring and treatment. Previous qualitative research has shown that HCPs usually associate paediatric palliative care (PPC) with death or dying and that they find the concept challenging to understand and difficult to implement. Attending to HCPs’ stories may provide a richer account of their understanding of PPC. Thus, the aim of this study was to explore PPC stories narrated by HCPs to gain increased insight into their understanding of what PPC entails.

Methods

This qualitative study collected data from four focus group interviews with 21 HCPs from different units in two Norwegian hospitals. Stories told by the HCPs to illustrate their comprehension of PPC were analysed following thematic analysis procedures.

Results

Four themes were identified illustrating what PPC meant to the participants: creating spaces for normality, providing tailored support for the family, careful preparations for saying goodbye and experiencing dilemmas and distress. The stories centred on family care, particularly relating to dramatic or affective situations when the death of a child was imminent.

Conclusion

The stories reflect how the HCPs view PPC as a specific field of health care that requires particular professional sensitivity, including good communication, collaboration and planning. Thus, the HCPs in this study demonstrated knowledge about the core qualities needed to succeed in PPC. However, similar to previous research, the stories illustrate that how HCPs speak about PPC is strongly associated with end-of-life care, and by that the HCPs do not capture the breadth of the PPC concept. The findings highlight the importance of increasing knowledge about the meaning and content of PPC among HCPs in order to maintain quality of life for all children with life-limiting or life-threatening conditions throughout their illness trajectory.
A novel signature model based on mitochondrial-related genes for predicting survival of colon adenocarcinoma
Authors: Gao Hongli , Xing Fei
Published: October 2022

Background

Colon cancer is the foremost reason of cancer-related mortality worldwide. Colon adenocarcinoma constitutes 90% of colon cancer, and most patients with colon adenocarcinoma (COAD) are identified until advanced stage. With the emergence of an increasing number of novel pathogenic mechanisms and treatments, the role of mitochondria in the development of cancer, has been studied and reported with increasing frequency.

Methods

We systematically analyzed the effect of mitochondria-related genes in COAD utilizing RNA sequencing dataset from The Cancer Genome Atlas database and 1613 mitochondrial function-related genes from MitoMiner database. Our approach consisted of differentially expressed gene, gene set enrichment analysis, gene ontology terminology, Kyoto Encyclopedia of Genes and Genomes, independent prognostic analysis, univariate and multivariate analysis, Kaplan–Meier survival analysis, immune microenvironment correlation analysis, and Cox regression analysis.

Results

Consequently, 8 genes were identified to construct 8 mitochondrial-related gene model by applying Cox regression analysis, CDC25C, KCNJ11, NOL3, P4HA1, QSOX2, Trap1, DNAJC28, and ATCAY. Meanwhile, we assessed the connection between this model and clinical parameters or immune microenvironment. Risk score was an independent predictor for COAD patients’ survival with an AUC of 0.687, 0.752 and 0.762 at 1-, 3- and 5-year in nomogram, respectively. The group with the highest risk score had the lowest survival rate and the worst clinical stages. Additionally, its predictive capacity was validated in GSE39582 cohort.

Conclusion

In summary, we established a prognostic pattern of mitochondrial-related genes, which can predict overall survival in COAD, which may enable a more optimized approach for the clinical treatment and scientific study of COAD. This gene signature model has the potential to improve prognosis and treatment for COAD patients in the future, and to be widely implemented in clinical settings. The utilization of this mitochondrial-related gene signature model may be benefit in the treatments and medical decision-making of COAD.
Dynamic prediction of life-threatening events for patients in intensive care unit
Authors: Hu Jiang , Kang Xiao-hui , Xu Fang-fang , Huang Ke-zhi , Du Bin , Weng Li
Published: October 2022

Background

Early prediction of patients’ deterioration is helpful in early intervention for patients at greater risk of deterioration in Intensive Care Unit (ICU). This study aims to apply machine learning approaches to heterogeneous clinical data for predicting life-threatening events of patients in ICU.

Methods

We collected clinical data from a total of 3151 patients admitted to the Medical Intensive Care Unit of Peking Union Medical College Hospital in China from January 1st, 2014, to October 1st, 2019. After excluding the patients who were under 18 years old or stayed less than 24 h at the ICU, a total of 2170 patients were enrolled in this study. Multiple machine learning approaches were utilized to predict life-threatening events (i.e., death) in seven 24-h windows (day 1 to day 7) and their performance was compared.

Results

Light Gradient Boosting Machine showed the best performance. We found that life-threatening events during the short-term windows can be better predicted than those in the medium-term windows. For example, death in 24 h can be predicted with an Area Under Curve of 0.905. Features like infusion pump related fluid input were highly related to life-threatening events. Furthermore, the prediction power of static features such as age and cardio-pulmonary function increased with the extended prediction window.

Conclusion

This study demonstrates that the integration of machine learning approaches and large-scale high-quality clinical data in ICU could accurately predict life-threatening events for ICU patients for early intervention.
Identification of DNA methylation-regulated differentially expressed genes in RA by integrated analysis of DNA methylation and RNA-Seq data
Authors: Zhang Runrun , Chang Cen , Jin Yehua , Xu LingXia , Jiang Ping , Wei Kai , Xu Linshuai , Guo Shicheng , Sun Songtao , He Dongyi
Published: October 2022

Objective

To identify novel DNA methylation-regulated differentially expressed genes (MeDEGs) in RA by integrated analysis of DNA methylation and RNA-Seq data.

Methods

The transcription and DNA methylation profiles of 9 RA and 15 OA synovial tissue were generated by RNA-Seq and Illumina 850K DNA methylation BeadChip. Gene set enrichment analysis (GSEA) and Weighted gene co-expression network analysis (WGCNA) were used to analyze methylation-regulated expressed genes by R software. The differentially expressed genes (DEGs), differentially methylated probes (DMPs), differentially methylated genes (DMGs) were analyzed by DESeq and ChAMP R package. The functional correlation of MeDEGs was analyzed by Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG). The protein–protein interaction (PPI) network of MeDEGs was constructed by STRING and Reactome FI Cytoscape Plugin. Correlation analysis between methylation level and mRNA expression was conducted with R software.

Results

A total of 17,736 genes, 25,578 methylated genes and 755,852 methylation probes were detected. A total of 16,421 methylation-regulated expressed genes were obtained. The GSEA showed that these genes are associated with activation of immune response, adaptive immune response, Inflammatory response in C5 (ontology gene sets). For KEGG analysis, these genes are associated with rheumatoid arthritis, NF-kappa B signaling pathway, T cell receptor signaling pathway. The WGCNA showed that the turquoise module exhibited the strongest correlation with RA (R = 0.78, P = 1.27 × 10− 05), 660 genes were screened in the turquoise module. A total of 707 MeDEGs were obtained. GO analysis showed that MeDEGs were enriched in signal transduction, cell adhesion for BP, enriched in plasma membrane, integral component of membrane for CC, and enriched in identical protein binding, calcium ion binding for MF. The KEGG pathway analysis showed that the MeDEGs were enriched in calcium signaling pathway, T cell receptor signaling pathway, NF-kappa B signaling pathway, Rheumatoid arthritis. The PPI network containing 706 nodes and 882 edges, and the enrichment p value < 1.0 × 10− 16. With Cytoscape, based on the range of more than 10 genes, a total of 8 modules were screened out. Spearman correlation analysis showed RGS1(cg10718027), RGS1(cg02586212), RGS1(cg10861751) were significantly correlated with RA.

Conclusions

RGS1 can be used as novel methylated biomarkers for RA.
Simplified regimen of combined low-dose rituximab for autoimmune encephalitis with neuronal surface antibodies
Authors: Du Ying , Zhao Chao , Liu Juntong , Li Chuan , Yan Qi , Li Lin , Hao Yunfeng , Yao Dan , Si Huaxing , Zhao Yingjun , Zhang Wei
Published: October 2022

Background

Autoimmune encephalitis (AE) with neuronal surface antibodies (NSAbs) presents pathogenesis mediated by B cell-secreting antibodies. Rituximab is a second-line choice for the treatment for AE with NSAbs, which can cause B cell depletion via targeting CD20. However, the optimal protocol and dosage of rituximab combined with first-line therapy for NSAbs-associated AE remains unclear so far. In this study, we explored the efficacy and safety of low-dose rituximab combined with first-line treatment for NSAbs-associated AE.

Methods

Fifty-nine AE patients with NSAbs were enrolled, and retrospectively divided into common first-line therapy (41 patients) and combined low-dose rituximab (100 mg induction weekly with 3 circles, followed by 100 mg reinfusion every 6 months) with first-line therapy (18 patients). Outcome measures included changes in the Clinical Assessment Scale for Autoimmune Encephalitis (CASE) score (primary endpoint), changes in the modified Rankin Scale (mRS), the Mini-mental State Examination (MMSE), the patient and caregiver Neuropsychiatric Inventory (NPI) score at each visit (baseline, discharge, 6 months, 12 months and last follow-up) between two groups (secondary endpoint), as well as oral prednisone dosage, relapse and adverse effects during follow-up.

Results

Compared with traditional first-line therapy group, for primary outcome, CASE scores at last follow-up were significantly improved in combined rituximab group, as well as markedly improving changes of CASE scores between baseline and each visit. While changes of mRS, MMSE and NPI scores, as secondary endpoint, were all markedly accelerating improvement between baseline and each visit, as well as both oral prednisone dosage and relapse were also greatly reduced during follow-up. Meanwhile, longitudinal analysis in combination of rituximab cohort also revealed persistently marked amelioration in a series of scales from baseline even more than 1 year. Moreover, analysis in rituximab subgroup showed no difference in any clinical outcomes between combination with single first-line and with repeated first-line treatment (≥ 2 times), while compared to delayed combination with rituximab (> 3 months), early initiation of combination (≤ 3 months) might achieve better improvements in CASE and MMSE assessment even 1 year later. No rituximab-correlated serious adverse events have been reported in our patients.

Conclusions

Our simplified regimen of combined low-dose rituximab firstly showed significantly accelerating short-term recovery and long-term improvement for AE with NSAbs, in parallel with markedly reduced prednisone dosage and clinical relapses. Moreover, opportunity of protocol showed earlier initiation (≤ 3 months) with better long-term improvement.
Comparing biological effectiveness guided plan optimization strategies for cranial proton therapy: potential and challenges
Authors: Hahn Christian , Heuchel Lena , Ödén Jakob , Traneus Erik , Wulff Jörg , Plaude Sandija , Timmermann Beate , Bäumer Christian , Lühr Armin
Published: October 2022

Background

To introduce and compare multiple biological effectiveness guided (BG) proton plan optimization strategies minimizing variable relative biological effectiveness (RBE) induced dose burden in organs at risk (OAR) while maintaining plan quality with a constant RBE.

Methods

Dose-optimized (DOSEopt) proton pencil beam scanning reference treatment plans were generated for ten cranial patients with prescription doses ≥ 54 Gy(RBE) and ≥ 1 OAR close to the clinical target volume (CTV). For each patient, four additional BG plans were created. BG objectives minimized either proton track-ends, dose-averaged linear energy transfer (LETd), energy depositions from high-LET protons or variable RBE-weighted dose (DRBE) in adjacent serially structured OARs. Plan quality (RBE = 1.1) was assessed by CTV dose coverage and robustness (2 mm setup, 3.5% density), dose homogeneity and conformity in the planning target volumes and adherence to OAR tolerance doses. LETd, DRBE (Wedenberg model, α/βCTV = 10 Gy, α/βOAR = 2 Gy) and resulting normal tissue complication probabilities (NTCPs) for blindness and brainstem necrosis were derived. Differences between DOSEopt and BG optimized plans were assessed and statistically tested (Wilcoxon signed rank, α = 0.05).

Results

All plans were clinically acceptable. DOSEopt and BG optimized plans were comparable in target volume coverage, homogeneity and conformity. For recalculated DRBE in all patients, all BG plans significantly reduced near-maximum DRBE to critical OARs with differences up to 8.2 Gy(RBE) (p < 0.05). Direct DRBE optimization primarily reduced absorbed dose in OARs (average ΔDmean = 2.0 Gy; average ΔLETd,mean = 0.1 keV/µm), while the other strategies reduced LETd (average ΔDmean < 0.3 Gy; average ΔLETd,mean = 0.5 keV/µm). LET-optimizing strategies were more robust against range and setup uncertaintes for high-dose CTVs than DRBE optimization. All BG strategies reduced NTCP for brainstem necrosis and blindness on average by 47% with average and maximum reductions of 5.4 and 18.4 percentage points, respectively.

Conclusions

All BG strategies reduced variable RBE-induced NTCPs to OARs. Reducing LETd in high-dose voxels may be favourable due to its adherence to current dose reporting and maintenance of clinical plan quality and the availability of reported LETd and dose levels from clinical toxicity reports after cranial proton therapy. These optimization strategies beyond dose may be a first step towards safely translating variable RBE optimization in the clinics.
Dissecting super-enhancer driven transcriptional dependencies reveals novel therapeutic strategies and targets for group 3 subtype medulloblastoma
Authors: Li Meng , Han Yujie , Wang Chaochen , Kang Wenfeng , Jiang Wenyan , Zhang Lei , Tang Yujie
Published: October 2022

Background

Medulloblastoma is the most common malignant pediatric brain tumor and group 3 subtype medulloblastoma (G3-MB) exhibits the worst prognosis. Super enhancers (SEs) are large clusters of enhancers that play important roles in cancer through transcriptional control of cell identity genes, oncogenes and tumor-dependent genes. Dissecting SE-driven transcriptional dependencies of cancer leads to identification of novel oncogenic mechanisms, therapeutic strategies and targets.

Methods

Integrative SE analyses of primary tissues and patient-derived tumor cell lines of G3-MB were performed to extract the conserved SE-associated gene signatures and their oncogenic potentials were evaluated by gene expression, tumor-dependency and patient prognosis analyses. SE-associated subtype-specific upregulated tumor-dependent genes, which were revealed as members of SE-driven core transcriptional regulatory network of G3-MB, were then subjected to functional validation and mechanistic investigation. SE-associated therapeutic potential was further explored by genetic or pharmaceutical targeting of SE complex components or SE-associated subtype-specific upregulated tumor-dependent genes individually or in combination, and the underlying therapeutic mechanisms were also examined.

Results

The identified conserved SE-associated transcripts of G3-MB tissues and cell lines were enriched of subtype-specifically upregulated tumor-dependent genes and MB patients harboring enrichment of those transcripts exhibited worse prognosis. Fourteen such conserved SE-associated G3-MB-specific upregulated tumor-dependent genes were identified to be members of SE-driven core transcriptional regulatory network of G3-MB, including three well-recognized TFs (MYC, OTX2 and CRX) and eleven newly identified downstream effector genes (ARL4D, AUTS2, BMF, IGF2BP3, KIF21B, KLHL29, LRP8, MARS1, PSMB5, SDK2 and SSBP3). An OTX2-SE-ARL4D regulatory axis was further revealed to represent a subtype-specific tumor dependency and therapeutic target of G3-MB via contributing to maintaining cell cycle progression and inhibiting neural differentiation of tumor cells. Moreover, BET inhibition with CDK7 inhibition or proteasome inhibition, two combinatory strategies of targeting SE complex components (BRD4, CDK7) or SE-associated effector gene (PSMB5), were shown to exhibit synergistic therapeutic effects against G3-MB via stronger suppression of SE-associated transcription or higher induction of ER stress, respectively.

Conclusions

Our study verifies the oncogenic role and therapeutic potential of SE-driven transcriptional dependencies of G3-MB, resulting in better understanding of its tumor biology and identification of novel SE-associated therapeutic strategies and targets.
Patient-specific modeling of stroma-mediated chemoresistance of pancreatic cancer using a three-dimensional organoid-fibroblast co-culture system
Authors: Schuth Sebastian , Le Blanc Solange , Krieger Teresa G. , Jabs Julia , Schenk Miriam , Giese Nathalia A. , Büchler Markus W. , Eils Roland , Conrad Christian , Strobel Oliver
Published: October 2022

Background

Cancer-associated fibroblasts (CAFs) are considered to play a fundamental role in pancreatic ductal adenocarcinoma (PDAC) progression and chemoresistance. Patient-derived organoids have demonstrated great potential as tumor avatars for drug response prediction in PDAC, yet they disregard the influence of stromal components on chemosensitivity.

Methods

We established direct three-dimensional (3D) co-cultures of primary PDAC organoids and patient-matched CAFs to investigate the effect of the fibroblastic compartment on sensitivity to gemcitabine, 5-fluorouracil and paclitaxel treatments using an image-based drug assay. Single-cell RNA sequencing was performed for three organoid/CAF pairs in mono- and co-culture to uncover transcriptional changes induced by tumor-stroma interaction.

Results

Upon co-culture with CAFs, we observed increased proliferation and reduced chemotherapy-induced cell death of PDAC organoids. Single-cell RNA sequencing data evidenced induction of a pro-inflammatory phenotype in CAFs in co-cultures. Organoids showed increased expression of genes associated with epithelial-to-mesenchymal transition (EMT) in co-cultures and several potential receptor-ligand interactions related to EMT were identified, supporting a key role of CAF-driven induction of EMT in PDAC chemoresistance.

Conclusions

Our results demonstrate the potential of personalized PDAC co-cultures models not only for drug response profiling but also for unraveling the molecular mechanisms involved in the chemoresistance-supporting role of the tumor stroma.
Analgesic efficacy of local versus proximal nerve blocks after hallux valgus surgery: a systematic review
Authors: Ravanbod Hamid Reza
Published: October 2022

Background

Hallux valgus (HV) surgery is an orthopaedic procedure that commonly causes mild to moderate postoperative pain. Effective management of this pain has become an important element of modern hallux valgus surgical treatment. A local anaesthetic (LA) with an antinociceptive effect can control this pain. However, relatively few papers have evaluated this strategy in depth. The objective of the current systematic review was to address this demand by comparing the efficacy of proximal and local blocks in controlling postoperative pain following hallux valgus surgery.

Main text

Ovid‐MEDLINE, Cochrane Central, PubMed, Web of Science (WOS), Scopus, and Embase were searched from their inceptions through December 29, 2021. Observational and clinical trial publications in peer‐reviewed English‐language journals with a sample size of at least 20 were included. The trials involved adults over 18 who could describe their discomfort and had a bunionectomy. The included studies were evaluated using the Cochrane risk of bias 2 method. Descriptive analysis synthesised the results.

Among the 439 articles identified, five studies compromising 459 participants were included. Ankle blocks were superior to control in two studies (P = 0.001, P < 0.001) and superior to local blocks in one study (P < 0.001). Additionally, one study showed that popliteal and ankle blocks administered with lidocaine or levobupivacaine were equivalent (P = 0.123 and P = 0.055, respectively). However, one of these five included studies indicated that ankle blocks were not effective (P = 0.123) in reducing postoperative pain.

Conclusions

The key findings presented herein suggest that regional blocks effectively reduce postoperative pain and that an ankle block has more supportive evidence for its effectiveness. However, an adequate assessment of the effectiveness of various administrative routes was challenging due to the lack of reliable evidence. This needs to be addressed in future studies.

Trial registration

PROSPERO registration: CRD42022307974.
Hao-Fountain syndrome and genital disorders: report of a new possible association
Authors: Zampieri Nicola , Pulvirenti Rebecca , Pedrazzoli Eleonora , Camoglio Francesco Saverio
Published: October 2022

Background

Hao-Fountain syndrome is a neurodevelopmental disorder characterized by global developmental delay, variably impaired intellectual development with significant speech delay and, in some males patients, it has been reported an association with hypogonadism. At present less than 50 cases are reported in literature.

Case presentation

We report a case of this rare syndrome in a young female with isolated tubal torsion; our patients had different hospitalizations without treatment but during the last episode we decide to perform an abdominal surgical explortion. This is the first case in Literature with a new USP7 mutation.

Conclusions

This case opens new perspective in this rare syndrome and a review approach to isolated tubal torsion. These symptoms should be always well checked.
Personalized Disease Prevention (PDP): study protocol for a cluster-randomized clinical trial
Authors: Taksler Glen B. , Le Phuc , Hu Bo , Alberts Jay , Flynn Allen J. , Rothberg Michael B.
Published: October 2022

Background

The US Preventive Services Task Force recommends 25 primary preventive services for middle-aged adults, but it can be difficult to do them all.

Methods

The Personalized Disease Prevention (PDP) cluster-randomized clinical trial will evaluate whether patients and their providers benefit from an evidence-based decision tool to prioritize preventive services based on their potential to improve quality-adjusted life expectancy. The decision tool will be individualized for patient risk factors and available in the electronic health record. This Phase III trial seeks to enroll 60 primary care providers (clusters) and 600 patients aged 40–75 years. Half of providers will be assigned to an intervention to utilize the decision tool with approximately 10 patients each, and half will be assigned to usual care. Mixed-methods follow-up will include collection of preventive care utilization from electronic health records, patient and physician surveys, and qualitative interviews. We hypothesize that quality-adjusted life expectancy will increase by more in patients who receive the intervention, as compared with controls.

Discussion

PDP will test a novel, holistic approach to help patients and providers prioritize the delivery of preventive services, based on patient risk factors in the electronic health record.

Trial registration

ClinicalTrials.gov NCT05463887. Registered on July 19, 2022.
Xanthohumol microbiome and signature in adults with Crohn’s disease (the XMaS trial): a protocol for a phase II triple-masked, placebo-controlled clinical trial
Authors: Langley Blake O. , Ryan Jennifer Joan , Phipps John , Buttolph Lita , Bray Brenna , Aslan Joseph E. , Metz Thomas O. , Stevens Jan F. , Bradley Ryan
Published: October 2022

Background

Xanthohumol (XN), a bioactive flavonoid from Humulus lupulus with anti-inflammatory properties, has potential benefits for patients with Crohn’s disease (CD), a type of inflammatory bowel disease. We recently completed and published results of a placebo-controlled phase I clinical trial demonstrating the safety and tolerability of 24 mg XN daily for 8 weeks. The present study aims to evaluate the safety and tolerability of the same dose of XN adults with clinically active CD in a placebo-controlled phase II clinical trial. Additional aims will assess the impact of XN on inflammatory biomarkers, platelet function, CD clinical activity, and stool microbial composition. The metabolism of XN will also be evaluated. This article provides a model protocol for consideration in investigations of XN or other natural products in disease states.

Methods

A triple-masked, randomized, placebo-controlled trial will be conducted in adults with clinically active CD. Participants (n ≤ 32) will be randomized to either 24 mg encapsulated XN per day or placebo and followed for 8 weeks. Throughout the trial, participants will be queried for adverse events. Biomarkers of clinical safety, blood and stool markers of inflammation, platelet function, Crohn’s Disease Activity Index score, stool microbial composition, and XN metabolite profiles in blood, urine, and stool will be assessed every 2 weeks.

Discussion

We describe the protocol for a phase II clinical trial that evaluates the safety and tolerability of XN in adults with active CD, as well as evaluate metabolism and mechanisms that are relevant to CD and other diseases with underlying inflammation and/or gut permeability. The effects of XN on inflammatory biomarkers, platelet function, the microbiota, and multi-omics biomarkers measured in this phase II trial of adults with CD will be compared to the effects of XN in healthy adults in our previous phase I trial. The results of the study will advance the evidence guiding the use of XN in patients with CD.

Trial registration

ClinialTrials.gov NCT04590508. Registered on October 19, 2020
High-dose Intensity-modulated proton therapy versus Standard-dose Intensity-modulated RadIation therapy for esophageal squamous cell carcinoma (HI-SIRI): study protocol for a randomized controlled clinical trial
Authors: Lertbutsayanukul Chawalit , Kitpanit Sarin , Kannarunimit Danita , Chakkabat Chakkapong , Oonsiri Sornjarod , Thephamongkhol Kullathorn , Puataweepong Putipun , Katanyoo Kanyarat , Sukhaboon Jirasak , Tovanabut Chokaew , Chongsathientham Sirikanya , Treeratsapanich Pornravee , Soonthornrak Jirarat , Prayongrat Anussara
Published: October 2022

Background

Chemoradiotherapy is the standard of care for esophageal cancer as a neoadjuvant treatment before surgery, or as a definitive treatment for unresectable disease. Intensity-modulated radiotherapy (IMRT) has been considered the standard radiation technique. However, patients suffer from treatment-related toxicities, and most die from disease progression or recurrence. With emerging technological advancement, proton therapy has theoretical advantages over IMRT because it offers apparent dosimetric benefits to allow dose escalation to the target while better sparing surrounding tissues such as the lungs, heart, liver, and spinal cord. The purpose of this study protocol is to investigate the survival benefit of proton therapy using modern intensity-modulated proton therapy (IMPT) compared to standard IMRT for esophageal cancer.

Methods

This is a two-arm open phase II/III multi-institution randomized controlled trial. Eligible patients will have histologically confirmed squamous cell carcinoma of the thoracic esophagus with no evidence of tracheoesophageal/esophagobronchial fistula or distant metastasis. After stratification according to resectability status (resectable vs. borderline resectable/unresectable), a total of 232 patients will be randomized to receive IMPT or IMRT using a 1:1 allocation ratio. In resectable cases, surgical resection following concurrent chemoradiation will be attempted for the patients who are medically fit at the time of surgery. In those with initially borderline resectable/unresectable disease, definitive concurrent chemoradiation will be performed. The phase II study will assess safety (toxicity and postoperative complications) and feasibility (recruitment rate and chemoradiation dose modification) in 40 patients into each arm. The study will then continue into phase III, further recruit 76 patients into each arm, and compare progression-free survival between IMPT vs IMRT groups. The secondary endpoints will be overall survival, local and distant control, toxicities, health-related quality of life, and cost-utility. This protocol describes a detailed radiotherapy and chemotherapy.

Discussion

This randomized clinical trial will demonstrate the clinical benefit of IMPT in esophageal cancer treatment in terms of survival and toxicity outcomes which will further establish high-level evidence for radiation modality in squamous cell carcinoma of the thoracic esophagus.

Trial registration

TCTR20200310006. Registered 10 March 2020.
Use of a real-time risk-prediction model to identify pediatric patients at risk for thromboembolic events: study protocol for the Children’s Likelihood Of Thrombosis (CLOT) trial
Authors: Walker Shannon C. , French Benjamin , Moore Ryan , Domenico Henry J. , Wanderer Jonathan P. , Balla Sreenivasa , Creech C. Buddy , Byrne Daniel W. , Wheeler Allison P.
Published: October 2022

Background

Pediatric patients have increasing rates of hospital-associated venous thromboembolism (HA-VTE), and while several risk-prediction models have been developed, few are designed to assess all general pediatric patients, and none has been shown to improve patient outcomes when implemented in routine clinical care.

Methods

The Children’s Likelihood Of Thrombosis (CLOT) trial is an ongoing pragmatic randomized trial being conducted starting November 2, 2020, in the inpatient units at Monroe Carell Jr. Children’s Hospital at Vanderbilt in Nashville, TN, USA. All admitted patients who are 21 years of age and younger are automatically enrolled in the trial and randomly assigned to receive either the current standard-of-care anticoagulation practice or the study intervention. Patients randomized to the intervention arm are assigned an HA-VTE risk probability that is calculated from a validated VTE risk-prediction model; the model is updated daily with the most recent clinical information. Patients in the intervention arm with elevated risk (predicted probability of HA-VTE ≥ 0.025) have an additional review of their clinical course by a team of dedicated hematologists, who make recommendations including pharmacologic prophylaxis with anticoagulation, if appropriate. The anticipated enrollment is approximately 15,000 patients. The primary outcome is the occurrence of HA-VTE. Secondary outcomes include initiation of anticoagulation, reasons for not initiating anticoagulation among patients for whom it was recommended, and adverse bleeding events. Subgroup analyses will be conducted among patients with elevated HA-VTE risk.

Discussion

This ongoing pragmatic randomized trial will provide a prospective assessment of a pediatric risk-prediction tool used to identify hospitalized patients at elevated risk of developing HA-VTE. 

Trial registration

ClinicalTrials.gov NCT04574895. Registered on September 28, 2020. Date of first patient enrollment: November 2, 2020.