Dialysis parameters associated with SARS-CoV-2 infection and prognosis in end-stage kidney disease.

BACKGROUND: The Covid-19 pandemic has affected patients with end-stage kidney disease (ESKD). Whether dialysis parameters have a prognostic value in ESKD patients with Covid-19 remains unclear. MATERIALS AND METHODS: We retrospectively evaluated clinical characteristics, blood pressure (BP) and dialysis parameters in ESKD patients undergoing maintenance outpatient hemodialysis, with (Covid-ESKD) and without (No-Covid-ESKD) Covid-19, at four Brazilian hemodialysis facilities. The Covid-ESKD (n = 107; 54% females; 60.8 ± 17.7 years) and No-Covid-ESKD (n = 107; 62% females; 58.4 ± 14.6 years) groups were matched by calendar time. The average BP and dialysis parameters were calculated during the pre-infection, acute infection, and post-infection periods. The main outcomes were Covid-19 hospitalization and all-cause mortality. RESULTS: Covid-ESKD patients had greater intradialytic and postdialysis systolic BP and lower predialysis weight, postdialysis weight, ultrafiltration rate, and interdialytic weight gain during acute-illness compared to 1-week-before-illness, while these changes were not observed in No-Covid-ESKD patients. After 286 days of follow-up (range, 276-591), there were 18 Covid-19-related hospitalizations and 28 deaths among Covid-ESKD patients. Multivariable logistic regression analysis showed that increases in predialysis systolic BP from 1-week-before-illness to acute-illness (OR, 95%CI = 1.06, 1.02-1.10; p = .004) and Covid-19 vaccination (OR, 95%CI = 0.16, 0.04-0.69; p = .014) were associated with hospitalization in Covid-ESKD patients. Multivariable Cox-regression analysis showed that Covid-19-related hospitalization (HR, 95%CI = 5.17, 2.07-12.96; p < .001) and age (HR, 95%CI = 1.05, 1.01-1.08; p = .008) were independent predictors of all-cause mortality in Covid-ESKD patients. CONCLUSION: Acute Covid-19 illness is associated with variations in dialysis parameters of volume status in patients with ESKD. Furthermore, increases in predialysis BP during acute Covid-19 illness are associated with an adverse prognosis in Covid-ESKD patients.

Dialysis parameters were influenced by SARS-CoV-2 infection and may have prognostic value in patients with Covid-19.Increases in blood pressure during acute Covid-19 illness and the lack of vaccination for Covid-19 were predictors of hospitalization for Covid-19.Hospitalization for Covid-19 and age were independent risk factors for all-cause death.

Temporal trends in the contribution of modifiable cardiovascular risk factors to cardiovascular and all-cause mortality in patients undergoing myocardial perfusion imaging in a large city in Brazil.

BACKGROUND: Most cardiovascular (CV) events stem from modifiable risk factors, but it remains uncertain whether their impact on mortality has decreased in recent years as a result of treatment, particularly in low- and middle-income countries. We evaluated the temporal trends in the population attributable fraction (PAF) of modifiable risk factors to CV mortality in patients undergoing myocardial perfusion imaging (MPI) for suspected coronary artery disease in a large city in Brazil. METHODS: The cohort comprised 25,127 patients without established CV disease undergoing MPI in a referral center in Curitiba, Brazil, from 2010 to 2018. Baseline demographic, clinical and risk factors were prospectively collected. Modifiable risk factors encompassed hypertension, dyslipidemia, diabetes mellitus, sedentary lifestyle, obesity, and smoking. The primary outcome was CV death occurring up to 4 years of follow-up. The PAF of each risk factor was calculated for each triennium using multivariable Cox proportional regression models, adjusting for age, sex and family history of premature coronary disease. RESULTS: Over 9 years, there were 1438 deaths, 444 due to CV causes. In the first triennium, sedentary lifestyle exhibited the highest PAF (49%) for CV death, followed by hypertension (17%), diabetes mellitus (8%) and smoking habit (6%). The PAF for all risk factors combined remained relatively stable thorough the triennia (2010-2012: 57% vs 2013-2015: 64% vs 2016-2018: 47%, p = NS). CONCLUSION: In this large cohort of patients referred to MPI, the PAF of modifiable CV risk factors did not diminish in the last decade, with sedentary lifestyle having the largest contribution for CV mortality. CONDENSED ABSTRACT: This study examinated temporal trends in the impact of modifiable cardiovascular (CV) risk factors on CV and overall mortality in a cohort of 25,127 patients undergoing myocardial perfusion imaging from 2010 to 2018. Sedentary behavior consistently had the greatest impact on both CV and overall mortality, followed by hypertension and diabetes. Smoking had a lesser effect, while obesity showed no independent association with the outcomes. The contributions of these modifiable CV risk factors remained stable over the study period, suggesting that interventions promoting physical activity may be essential in mitigating the burden of CV disease.

SEDA 2024 update: enhancing the SEquence DAtaset builder for seamless integration into automated data analysis pipelines.

BACKGROUND: The initial version of SEDA assists life science researchers without programming skills with the preparation of DNA and protein sequence FASTA files for multiple bioinformatics applications. However, the initial version of SEDA lacks a command-line interface for more advanced users and does not allow the creation of automated analysis pipelines. RESULTS: The present paper discusses the updates of the new SEDA release, including the addition of a complete command-line interface, new functionalities like gene annotation, a framework for automated pipelines, and improved integration in Linux environments. CONCLUSION: SEDA is an open-source Java application and can be installed using the different distributions available ( https://www.sing-group.org/seda/download.html ) as well as through a Docker image ( https://hub.docker.com/r/pegi3s/seda ). It is released under a GPL-3.0 license, and its source code is publicly accessible on GitHub ( https://github.com/sing-group/seda ). The software version at the time of submission is archived at Zenodo (version v1.6.0, http://doi.org/10.5281/zenodo.10201605 ).

Antimalarial resistance risk in Mozambique detected by a novel quadruplex droplet digital PCR assay.

While the Plasmodium falciparum malaria parasite continues to cause severe disease globally, Mozambique is disproportionally represented in malaria case totals. Acquisition of copy number variations (CNVs) in the parasite genome contributes to antimalarial drug resistance through overexpression of drug targets. Of interest, piperaquine resistance is associated with plasmepsin 2 and 3 CNVs (pfpmp2 and pfpmp3, respectively), while CNVs in the multidrug efflux pump, multidrug resistance-1 (pfmdr1), increase resistance to amodiaquine and lumefantrine. These antimalarials are partner drugs in artemisinin combination therapies (ACTs) and therefore, CNV detection with accurate and efficient tools is necessary to track ACT resistance risk. Here, we evaluated ~300 clinically derived samples collected from three sites in Mozambique for resistance-associated CNVs. We developed a novel, medium-throughput, quadruplex droplet digital PCR (ddPCR) assay to simultaneously quantify the copy number of pfpmp3, pfpmp2, and pfmdr1 loci in these clinical samples. By using DNA from laboratory parasite lines, we show that this nanodroplet-based method is capable of detecting picogram levels of parasite DNA, which facilitates its application for low yield and human host-contaminated clinical surveillance samples. Following ddPCR and the application of quality control standards, we detected CNVs in 13 of 229 high-quality samples (prevalence of 5.7%). Overall, our study revealed a low number of resistance CNVs present in the parasite population across all three collection sites, including various combinations of pfmdr1, pfpmp2, and pfpmp3 CNVs. The potential for future ACT resistance across Mozambique emphasizes the need for continued molecular surveillance across the region.

Cost-effectiveness of semaglutide 2.4 mg in chronic weight management in Portugal.

BACKGROUND: Obesity and overweight are a significant public health concern. Subcutaneous semaglutide 2.4 mg injection is a glucagon-like peptide-1 (GLP-1) analogue approved by the European Medicines Agency as an adjunct to a reduced calorie diet and increased physical activity (diet and exercise, D&E) for the treatment obesity and overweight in the presence of at least one weight related comorbidity. This study aimed to assess the cost-effectiveness of semaglutide 2.4 mg in combination with D&E compared to D&E alone for the Portuguese setting. METHODS: Analysis were conducted using the Core Obesity Model (COM) version 18, a Markov state transition cohort model, to predict the health outcomes and costs of weight related complications based on changes in surrogate endpoints. Efficacy and safety data were sourced from the STEP trials (Body Mass Index, systolic blood pressure and glycemic status) from a cohort of adults aged on average 48 years with obesity (BMI ≥ 30 kg/m2) and ≥ 1 obesity-related comorbidities, over a time horizon of 40 years. Costs were estimated from the perspective of the Portuguese National Health Service. Sensitivity analyses were conducted to test the robustness of results across a range of assumptions. RESULTS: On a patient level, Semaglutide 2.4 mg in addition to D&E compared to D&E alone, improved QALYs by 0.098 and yielded higher costs by 1,325 EUR over a 40-year time horizon, with an ICER of 13,459 EUR per QALY gained and 100% probability of cost-effectiveness at the given WTP. Semaglutide 2.4 mg remained cost-effective across all different scenarios and sensitivity analysis at a WTP of 20,000 EUR per QALY. Among the subpopulations examined, Semaglutide 2.4 mg yielded ICERs of 18,459 EUR for patients with BMI ≥ 30 kg/m2 and of 22,657 EUR for patients with BMI ≥ 35 kg/m2. CONCLUSIONS: Semaglutide 2.4 mg was cost-effective compared to D&E alone for patients with obesity (BMI ≥ 30 kg/m2) and weight related comorbidities in Portugal, over a 40-year time horizon.

Dual FGFR-targeting and pH-activatable ruthenium-peptide conjugates for targeted therapy of breast cancer.

Dysregulation of Fibroblast Growth Factor Receptors (FGFRs) signaling has been associated with breast cancer, yet employing FGFR-targeted delivery systems to improve the efficacy of cytotoxic agents is still sparsely exploited. Herein, we report four new bi-functional ruthenium-peptide conjugates (RuPCs) with FGFR-targeting and pH-dependent releasing abilities, envisioning the selective delivery of cytotoxic Ru complexes to FGFR(+)-breast cancer cells, and controlled activation at the acidic tumoral microenvironment. The antiproliferative potential of the RuPCs and free Ru complexes was evaluated in four breast cancer cell lines with different FGFR expression levels (SKBR-3, MDA-MB-134-VI, MCF-7, and MDA-MB-231) and in human dermal fibroblasts (HDF), at pH 6.8 and pH 7.4 aimed at mimicking the tumor microenvironment and normal tissues/bloodstream pHs, respectively. The RuPCs showed higher cytotoxicity in cells with higher level of FGFR expression at acidic pH. Additionally, RuPCs showed up to 6-fold higher activity in the FGFR(+) breast cancer lines compared to the normal cell line. The release profile of Ru complexes from RuPCs corroborates the antiproliferative effects observed. Remarkably, the cytotoxicity and releasing ability of RuPCs were shown to be strongly dependent on the conjugation of the peptide position in the Ru complex. Complementary molecular dynamic simulations and computational calculations were performed to help interpret these findings at the molecular level. In summary, we identified a lead bi-functional RuPC that holds strong potential as a FGFR-targeted chemotherapeutic agent.

Intraoperative Angle Measurement of Anatomical Structures: A Systematic Review.

Ensuring precise angle measurement during surgical correction of orientation-related deformities is crucial for optimal postoperative outcomes, yet there is a lack of an ideal commercial solution. Current measurement sensors and instrumentation have limitations that make their use context-specific, demanding a methodical evaluation of the field. A systematic review was carried out in March 2023. Studies reporting technologies and validation methods for intraoperative angular measurement of anatomical structures were analyzed. A total of 32 studies were included, 17 focused on image-based technologies (6 fluoroscopy, 4 camera-based tracking, and 7 CT-based), while 15 explored non-image-based technologies (6 manual instruments and 9 inertial sensor-based instruments). Image-based technologies offer better accuracy and 3D capabilities but pose challenges like additional equipment, increased radiation exposure, time, and cost. Non-image-based technologies are cost-effective but may be influenced by the surgeon's perception and require careful calibration. Nevertheless, the choice of the proper technology should take into consideration the influence of the expected error in the surgery, surgery type, and radiation dose limit. This comprehensive review serves as a valuable guide for surgeons seeking precise angle measurements intraoperatively. It not only explores the performance and application of existing technologies but also aids in the future development of innovative solutions.

Effects of Ivabradine on Myocardial Perfusion in Chronic Angina: A Prospective, Preliminary, Open-Label, Single-Arm Study.

INTRODUCTION: Ivabradine reduces heart rate (HR), episodes of angina, and nitrate consumption, and increases exercise capacity in patients with chronic angina (CA). In this exploratory study, myocardial perfusion scintigraphy (MPS) was used to evaluate changes in the percentage of myocardial ischemia after ivabradine therapy in patients with CA. METHODS: This prospective, open-label, single-arm study included patients with CA receiving maximum tolerated doses of beta blockers, who had a resting HR ≥ 70 bpm and had experienced ischemia according to MPS during an exercise test at baseline. Participants received ivabradine 5 mg twice daily (titrated according to HR) concomitant with beta blockers. A second MPS was performed after 3 months, without interruption of treatment with beta blockers or ivabradine. The primary outcome was change in the percentage of myocardial ischemia from baseline to 3 months. Time to ischemia during the exercise test, the proportion of patients presenting angina during the exercise test, and health status, assessed using the seven-item Seattle Angina Questionnaire-7 (SAQ-7), were also evaluated. RESULTS: Twenty patients (3 females) with a mean (± standard deviation [SD]) age of 62.2 ± 6.5 years were included in the study, of whom 55% had diabetes, 70% had previous myocardial revascularization, and 45% had previous myocardial infarction. The percentage of patients with myocardial ischemia significantly decreased from baseline to 3 months after initiation of treatment with ivabradine (- 2.9%; 95% confidence interval [CI] - 0.3 to - 5.5; p = 0.031). Mean time to appearance of ischemia increased from 403 ± 176 s at baseline to 466 ± 136 s at 3 months after initiation of ivabradine (Δ62 s; 95% CI 18-106 s; p = 0.008), and the proportion of patients experiencing angina during the exercise test decreased from 40% at baseline to 5% also at 3 months (p = 0.016). Mean resting HR decreased from 76 ± 7 bpm at baseline to 55 ± 8 bpm at 3 months (p < 0.001). The mean SAQ-7 summary score improved from 69 ± 21 at baseline to 83 ± 12 at 3 months (p = 0.001). No serious adverse effects were reported. CONCLUSION: Ivabradine added to beta blockers was associated with a reduction in detectable myocardial ischemia by MPS in patients with CA. Infographic available for this article. TRIAL REGISTRATION: The trial has been retrospectively registered with the Brazilian Registry of Clinical Trials (REBEC) under the following number RBR-5fysqrh (date of registration: 30 November 2023).

Mitotic bookmarking by transcription factors: be aware of redundancy.

A recent report by Chervova, Molliex, et al. shows redundant functions for the transcription factors (TFs) ESRRB and NR5A2 as mitotic bookmarkers in mouse embryonic stem (ES) cells. These occupy some of their target sites in mitotic chromatin, ensuring their robust reactivation after cell division, including markers and regulators of pluripotency.

Effects of pasture management and supplementation on the productive performance of recently lambed ewes.

The hypothesis was tested that the performance of lactating ewes is affected by the supplementation level and pasture management. Two supplementation levels (0.5 and 1.0% of body weight, BW) and two pasture managements (mowed and non-mowed) were tested. Forty adult ewes (2 years old) with an average weight at lambing of 62.97 ± 7.0 kg (day 0) and an average the body condition score of 2.5 points (day 0) were evaluated. Verminosis was monitored with periodic deworming. The number of eggs per gram of feces (EPG) of ewes at lambing was used as a covariate for performance assessments. Ewes lost an average of 7.5 kg over the 90 days post-partum (12% BW). The weaning rate was 53%. The body condition of the ewes was influenced by the post-partum period. The ewes mobilized their body reserves in the first 30 days of lactation. Mowing management negatively affected the nutritive value of the forage. Supplementation with 0.5% BW was sufficient for nutritional management post-partum. Pasture management (mowed vs. not mowed) cannot prevent post-partum weight loss. Supplementation levels and pasture management altered the morphological and chemical components of the pasture.

Thoracic aortic aneurysms, a single center's 10-years experience and analysis of outcomes.

INTRODUCTION: Thoracic aortic aneurysms (TAAs) are an increasingly prevalent pathology with significant associated morbidity and mortality. Thoracic endovascular aortic repair (TEVAR) is the primary line of treatment. The purpose of this study was to analyse a single center's experience in the treatment of TAAs and identify possible risk factors for worse outcomes. METHODS: A retrospective review of our institutional database was done to identify all patients treated for TAAs in a 10-year period, from 1 January 2012 to 31 December 2022. Data were extracted from patients' medical records. Primary outcome was all-cause mortality and secondary outcomes were procedure related morbidity (vascular access complications, medullary ischaemia, stroke, endoleaks, migration, aneurysm sac enlargement >5 mm) and need for reintervention at 1-, 6- and 12-month follow-up. A descriptive and inferential analysis of the data was performed. Statistical analyses were conducted using the IBM Statistical Package for Social Sciences (SPSS) software. RESULTS: We identified 34 patients treated for TAAs in this period. Mean age was 68 years [47-87] and 79.4% of patients were male. Mean aneurysm diameter was 63 mm [35-100], 55.9% fusiform and 44.1% saccular. The majority (91.2%) were located at the descending thoracic aorta and 3 (8.8%) of them extended to the aortic arch. The most common aetiology was degenerative in 22 patients (64.7%), followed by aortic dissection in 8 patients (23.5%). Elective surgery was performed in 19 (61.3%) patients and 12 (38.7%) had urgent repair. TEVAR was the treatment of choice in 24 (77.4%) patients, and the remaining 7 (22.6%) were treated with hybrid surgery. Mean length of hospital stay was 10 days [2-80] (6 days for elective repair versus 16 days for urgent repair, p = .016). Follow-up period ranged from 1 month to 10 years. At 1 year follow-up, all-cause mortality was 15%, morbidity was 30% (with 6 (22%) patients having a type Ia endoleak) and need for reintervention was 22%. Aneurysm diameter was a significant risk factor for procedure related morbidity (median diameter of 73.5 mm versus 56.0 mm in patients with no morbidity; p = .027). The presence of type Ia endoleak was significantly associated with higher reintervention rates (p = .001), but not with higher mortality rates (p = .515). Age, female sex, aetiology and urgent repair weren't associated with any significant differences in the outcomes. CONCLUSIONS: TEVAR proved to be effective in the treatment of TAAs, with good outcomes at short and mid-term follow-up. TAAs should be diagnosed earlier and be promptly treated when meeting criteria to prevent worse outcomes.

Three-dimensional printed exoskeletons and orthoses for the upper limb-A systematic review.

This systematic review aims to assess and summarize the current landscape in exoskeletons and orthotic solutions developed for upper limb medical assistance, which are partly or fully produced using 3-dimensional printing technologies and contain at least the elbow or the shoulder joints. The initial search was conducted on Web of Science, PubMed, and IEEEXplore, resulting in 92 papers, which were reduced to 72 after removal of duplicates. From the application of the inclusion and exclusion criteria and selection questionnaire, 33 papers were included in the review, being divided according to the analyzed joints. The analysis of the selected papers allowed for the identification of different solutions that vary in terms of their target application, actuation type, 3-dimensional printing techniques, and material selection, among others. The results show that there has been far more research on the elbow joint than on the shoulder joint, which can be explained by the relative complexity of the latter. Moreover, the findings of this study also indicate that there is still a gap between the research conducted on these devices and their practical use in real-world conditions. Based on current trends, it is anticipated that the future of 3-dimensional printed exoskeletons will revolve around the use of flexible and high-performance materials, coupled with actuated devices. These advances have the potential to replace the conventional fabrication methods of exoskeletons with technologies based on additive manufacturing.

Medullary Compression by a Cervical Osteochondroma in a Patient with Multiple Hereditary Exostoses: A Case Report.

CASE: A 19-year-old man with Multiple Hereditary Exostoses presented with cervical pain without neurological symptoms and/or signs. Magnetic resonance revealed a large C2 osteochondroma, occupying a part of the medullary canal. He was submitted to an en bloc resection with hemilaminectomy without fusion. At the 1-year follow-up, he presented resolution of pain and no neurological symptoms or signs, without cervical instability or radiological signs of disease recurrence. CONCLUSION: Cervical osteochondroma is usually asymptomatic. Neurological compression and differentiation to chondrosarcoma are the main concerns. Surgical excision allows the local cure of the disease and is usually performed without fusion.

Gemcitabine-Vitamin E Prodrug-Loaded Micelles for Pancreatic Cancer Therapy.

Pancreatic cancer (PC) is an aggressive cancer subtype presenting unmet clinical challenges. Conventional chemotherapy, which includes antimetabolite gemcitabine (GEM), is seriously undermined by a short half-life, its lack of targeting ability, and systemic toxicity. GEM incorporation in self-assembled nanosystems is still underexplored due to GEM's hydrophilicity which hinders efficient encapsulation. We hypothesized that vitamin E succinate-GEM prodrug (VES-GEM conjugate) combines hydrophobicity and multifunctionalities that can facilitate the development of Pluronic® F68 and Pluronic® F127 micelle-based nanocarriers, improving the therapeutic potential of GEM. Pluronic® F68/VES-GEM and Pluronic® F127/VES-GEM micelles covering a wide range of molar ratios were prepared by solvent evaporation applying different purification methods, and characterized regarding size, charge, polydispersity index, morphology, and encapsulation. Moreover, the effect of sonication and ultrasonication and the influence of a co-surfactant were explored together with drug release, stability, blood compatibility, efficacy against tumour cells, and cell uptake. The VES-GEM conjugate-loaded micelles showed acceptable size and high encapsulation efficiency (>95%) following an excipient reduction rationale. Pluronic® F127/VES-GEM micelles evidenced a superior VES-GEM release profile (cumulative release > 50%, pH = 7.4), stability, cell growth inhibition (<50% cell viability for 100 µM VES-GEM), blood compatibility, and extensive cell internalization, and therefore represent a promising approach to leveraging the efficacy and safety of GEM for PC-targeted therapies.

Multifaceted Strategy Based on Automated Text Messaging After a Recent Heart Failure Admission: The MESSAGE-HF Randomized Clinical Trial.

Importance: Readmissions after an index heart failure (HF) hospitalization are a major contemporary health care problem. Objective: To evaluate the feasibility and efficacy of an intensive telemonitoring strategy in the vulnerable period after an HF hospitalization. Design, Setting, and Participants: This randomized clinical trial was conducted in 30 HF clinics in Brazil. Patients with left ventricular ejection fraction less than 40% and access to mobile phones were enrolled up to 30 days after an HF admission. Data were collected from July 2019 to July 2022. Intervention: Participants were randomly assigned to a telemonitoring strategy or standard care. The telemonitoring group received 4 daily short message service text messages to optimize self-care, active engagement, and early intervention. Red flags based on feedback messages triggered automatic diuretic adjustment and/or a telephone call from the health care team. Main Outcomes and Measures: The primary end point was change in N-terminal pro-brain natriuretic peptide (NT-proBNP) from baseline to 180 days. A hierarchical win-ratio analysis incorporating blindly adjudicated clinical events (cardiovascular deaths and HF hospitalization) and variation in NT-proBNP was also performed. Results: Of 699 included patients, 460 (65.8%) were male, and the mean (SD) age was 61.2 (14.5) years. A total of 352 patients were randomly assigned to the telemonitoring strategy and 347 to standard care. Satisfaction with the telemonitoring strategy was excellent (net promoting score at 180 days, 78.5). HF self-care increased significantly in the telemonitoring group compared with the standard care group (score difference at 30 days, -2.21; 95% CI, -3.67 to -0.74; P = .001; score difference at 180 days, -2.08; 95% CI, -3.59 to -0.57; P = .004). Variation of NT-proBNP was similar in the telemonitoring group compared with the standard care group (telemonitoring: baseline, 2593 pg/mL; 95% CI, 2314-2923; 180 days, 1313 pg/mL; 95% CI, 1117-1543; standard care: baseline, 2396 pg/mL; 95% CI, 2122-2721; 180 days, 1319 pg/mL; 95% CI, 1114-1564; ratio of change, 0.92; 95% CI, 0.77-1.11; P = .39). Hierarchical analysis of the composite outcome demonstrated a similar number of wins in both groups (telemonitoring, 49 883 of 122 144 comparisons [40.8%]; standard care, 48 034 of 122 144 comparisons [39.3%]; win ratio, 1.04; 95% CI, 0.86-1.26). Conclusions and Relevance: An intensive telemonitoring strategy applied in the vulnerable period after an HF admission was feasible, well-accepted, and increased scores of HF self-care but did not translate to reductions in NT-proBNP levels nor improvement in a composite hierarchical clinical outcome. Trial Registration: ClinicalTrials.gov Identifier: NCT04062461.

Novel Tumor Organoid-Based Mouse Model to Study Image Guided Radiation Therapy of Rectal Cancer After Noninvasive and Precise Endoscopic Implantation.

PURPOSE: Preoperative (neoadjuvant) radiation therapy (RT) is an essential part of multimodal rectal cancer therapy. Recently, total neoadjuvant therapy (TNT), which combines simultaneous radiochemotherapy with additional courses of chemotherapy, has emerged as an effective approach. TNT achieves a pathologic complete remission in approximately 30% of resected patients, opening avenues for treatment strategies that avoid radical organ resection. Furthermore, recent studies have demonstrated that anti-programmed cell death protein 1 immunotherapy can induce clinical complete responses in patients with specific genetic alterations. There is significant potential to enhance outcomes through intensifying, personalizing, and de-escalating treatment approaches. However, the heterogeneous response rates to RT or TNT and strategies to sensitize patients without specific genetic changes to immunotherapy remain poorly understood. METHODS AND MATERIALS: We developed a novel orthotopic mouse model of rectal cancer based on precisely defined endoscopic injections of tumor organoids that reflect tumor heterogeneity. Subsequently, we employed endoscopic- and computed tomography-guided RT and validated rectal tumor growth and response rates to therapy using small-animal magnetic resonance imaging and endoscopic follow-up. RESULTS: Rectal tumor formation was successfully induced in all mice after 2 organoid injections. Clinically relevant RT regimens with 5 × 5 Gy significantly delayed clinical signs of tumor progression and significantly improved survival. Consistent with human disease, rectal tumor progression correlated with the development of liver and lung metastases. Notably, long-term survivors after RT showed no evidence of tumor recurrence, as demonstrated by in vivo radiologic tumor staging and histopathologic examination. CONCLUSIONS: Our novel mouse model combines orthotopic tumor growth via noninvasive and precise rectal organoid injection and small-animal RT. This model holds significant promise for investigating the effect of tumor cell-intrinsic aspects, genetic alterations of the host, and exogenous factors (eg, nutrition or microbiota) on RT outcomes. Furthermore, it allows for the exploration of combination therapies involving chemotherapy, immunotherapy, or novel targeted therapies.

Multifaceted strategy based on automated text messaging after a recent heart failure admission: the MESSAGE-HF Randomized Clinical Trial

IMPORTANCE: Readmissions after an index heart failure (HF) hospitalization are a major contemporary health care problem. OBJECTIVE: To evaluate the feasibility and efficacy of an intensive telemonitoring strategy in the vulnerable period after an HF hospitalization. DESIGN, SETTING, AND PARTICIPANTS: This randomized clinical trial was conducted in 30 HF clinics in Brazil. Patients with left ventricular ejection fraction less than 40% and access to mobile phones were enrolled up to 30 days after an HF admission. Data were collected from July 2019 to July 2022. INTERVENTION: Participants were randomly assigned to a telemonitoring strategy or standard care. The telemonitoring group received 4 daily short message service text messages to optimize self-care, active engagement, and early intervention. Red flags based on feedback messages triggered automatic diuretic adjustment and/or a telephone call from the health care team. MAIN OUTCOMES AND MEASURES: The primary end point was change in N-terminal pro-brain natriuretic peptide (NT-proBNP) from baseline to 180 days. A hierarchical win-ratio analysis incorporating blindly adjudicated clinical events (cardiovascular deaths and HF hospitalization) and variation in NT-proBNP was also performed. RESULTS: Of 699 included patients, 460 (65.8%) were male, and the mean (SD) age was 61.2 (14.5) years. A total of 352 patients were randomly assigned to the telemonitoring strategy and 347 to standard care. Satisfaction with the telemonitoring strategy was excellent (net promoting score at 180 days, 78.5). HF self-care increased significantly in the telemonitoring group compared with the standard care group (score difference at 30 days, -2.21; 95% CI, -3.67 to -0.74; P = .001; score difference at 180 days, -2.08; 95% CI, -3.59 to -0.57; P = .004). Variation of NT-proBNP was similar in the telemonitoring group compared with the standard care group (telemonitoring: baseline, 2593 pg/mL; 95% CI, 2314-2923; 180 days, 1313 pg/mL; 95% CI, 1117-1543; standard care: baseline, 2396 pg/mL; 95% CI, 2122-2721; 180 days, 1319 pg/mL; 95% CI, 1114-1564; ratio of change, 0.92; 95% CI, 0.77-1.11; P = .39). Hierarchical analysis of the composite outcome demonstrated a similar number of wins in both groups (telemonitoring, 49 883 of 122 144 comparisons [40.8%]; standard care, 48 034 of 122 144 comparisons [39.3%]; win ratio, 1.04; 95% CI, 0.86-1.26). CONCLUSIONS and relevance: An intensive telemonitoring strategy applied in the vulnerable period after an HF admission was feasible, well-accepted, and increased scores of HF self-care but did not translate to reductions in NT-proBNP levels nor improvement in a composite hierarchical clinical outcome.

Coral Reef Aorta: Literature Review and Analysis of the Published Cases in the Last 20 Years.

BACKGROUND: Coral reef aorta (CRA) is defined by the presence of heavily calcified exophytic plaques that protrude into the aortic lumen. However, the exact causes and development of this condition are still not fully understood. When the aortic branches are affected, it can result in various symptoms. Despite ongoing research, there is currently no established consensus on the best treatment for CRA. This review aims to examine the latest findings regarding the clinical presentation and approach to treating patients with CRA. METHODS: We conducted a systematic electronic search of the literature using the PubMed and Embase databases. Throughout the search, we adhered to the guidelines outlined in the PRISMA framework. From the identified publications, we extracted information pertaining to patients' characteristics, symptoms, and types of treatment from a total of 124 cases reported over the past 20 years. The primary focus of our analysis was to assess the improvement of signs and symptoms, as well as to evaluate any postoperative complications. To achieve this, we performed both descriptive and inferential analyses on the collected data. Additionally, we conducted subgroup analyses based on treatment types and symptoms observed at presentation, presenting the findings in the form of odds ratios (ORs). RESULTS: After removing duplicate articles, we carefully screened the titles of 67 retrieved articles and excluded those that did not align with the purpose of our study. Subsequently, we thoroughly analyzed the remaining 41 articles along with their references, ultimately including 29 studies that were deemed most relevant for our systematic review. We examined a total of 124 cases of patients diagnosed with CRA, comprising 77 (62.1%) females and 48 (38.7%) males, with a mean age of 59 years (range: 37-84). The predominant signs and symptoms observed were intermittent claudication, reported in 57 (46.0%) patients, followed by refractory hypertension in 45 (36.3%) patients, intestinal angina in 28 (22.6%) patients, and renal insufficiency in 15 (12.1%) patients. Among the treated patients, 110 (88.7%) underwent open surgery repair (OSR), 11 (8.9%) received endovascular treatment, and 3 (2.4%) underwent laparoscopy. Postoperatively, a significant number of patients experienced substantial relief or complete resolution of their symptoms, as well as improved control of hypertension and renal function. In the group of patients treated with OSR, the inhospital stay mortality rate was 10.9%, the morbidity rate was 28.2%, and the reintervention rate was 15.5%. The high mortality rate during hospital stays in this group may be associated with such invasive procedures performed on patients who have substantial cardiovascular burden and multiple comorbidities. Conversely, no postoperative complications were reported in the group of patients treated with endovascular procedures or laparoscopic surgery. CONCLUSIONS: While coral reef aorta (CRA) is considered a rare condition, it is crucial for the medical community to remain vigilant about its diagnosis, particularly in patients presenting with symptoms such as intermittent claudication, refractory hypertension, renal impairment, or intestinal angina. Based on the findings of this review, both OSR and endovascular treatment have shown promise as viable therapeutic options. Although endovascular therapies may not always be feasible or may have reduced durability in these calcified bulky lesions, they should be considered in patients with multiple comorbidities, due to the high postoperative mortality rates associated with more invasive approaches. Additionally, these endoluminal procedures have demonstrated good patency rates during the 18-month follow-up period. It is essential to emphasize that the treatment strategy should be determined on a case-by-case basis, involving a multidisciplinary team to tailor it to the specific needs of each individual patient.