Molecular and physiologic changes in the SpaceX Inspiration4 civilian crew.

Human spaceflight has historically been managed by government agencies, such as the NASA Twins Study1, but new commercial spaceflight opportunities have opened spaceflight to a broader population. In 2021, the SpaceX Inspiration4 mission launched the first-ever all civilian crew to low Earth orbit, which included the youngest American astronaut (age 29), novel in-flight experimental technologies (handheld ultrasound imaging, smartwatch wearables, and immune profiling), ocular alignment measurements, and new protocols for in-depth, multi-omic molecular and cellular profiling. Here we report the primary findings from the 3-day spaceflight mission, which induced a broad range of physiological and stress responses, neurovestibular changes indexed by ocular misalignment, and altered neurocognitive functioning, some of which match long-term spaceflight2, but almost all of which did not differ from baseline (pre-flight) after return to Earth. Overall, these preliminary civilian spaceflight data suggest that short-duration missions do not pose a significant health risk, and moreover present a rich opportunity to measure the earliest phases of adaptation to spaceflight in the human body at anatomical, cellular, physiologic, and cognitive levels. Finally, these methods and results lay the foundation for an open, rapidly expanding biomedical database for astronauts3, which can inform countermeasure development for both private and government-sponsored space missions.

Anti-Tubercular-Therapy-Induced Severe Thrombocytopenia Presenting as a Vocal Cord Bleed With Massive Hemoptysis Causing Mortality: A Catastrophic Combination.

Severe thrombocytopenia induced by anti-tubercular therapy (ATT) is a rare but potentially life-threatening complication. Severe thrombocytopenia is a known adverse effect of ATT, but its association with fatal hemoptysis is rare. Hematemesis and hemoptysis are two serious symptoms that indicate bleeding from the upper gastrointestinal and the lower respiratory tract, respectively. We report a rare case of a 65-year-old man, a diagnosed case of tuberculosis on ATT, who presented with massive hemoptysis. On navigating the bleed, the source was found to be a vocal cord bleed, which further led to massive clot formation in the left bronchus, leading to the collapse of the subsequent lung, leading to mortality. This case emphasizes the importance of recognizing ATT as a potential cause of bleeding and considering causes of massive hematemesis that are not gastrointestinal. It also highlights the need for a thorough evaluation of the airway in such patients.

Motility and swimming: universal description and generic trajectories.

Autonomous locomotion is a ubiquitous phenomenon in biology and in physics of active systems at microscopic scale. This includes prokaryotic, eukaryotic cells (crawling and swimming) and artificial swimmers. An outstanding feature is the ability of these entities to follow complex trajectories, ranging from straight, curved (circular, helical...), to random-like ones. The non-straight nature of these trajectories is often explained as a consequence of the asymmetry of the particle or the medium in which it moves, or due to the presence of bounding walls, etc... Here, we show that for a particle driven by a concentration field of an active species, straight, circular and helical trajectories emerge naturally in the absence of asymmetry of the particle or that of suspending medium. Our proof is based on general considerations, without referring to an explicit form of a model. We show that these three trajectories correspond to self-congruent solutions. Self-congruency means that the states of the system at different moments of time can be made identical by an appropriate combination of rotation and translation of the coordinate space. We show that these solutions are exhibited by spherically symmetric particles as a result of a series of pitchfork bifurcations, leading to spontaneous symmetry breaking in the concentration field driving the particle motility. Self-congruent dynamics in one and two dimensions are analyzed as well. Finally, we present a simple explicit nonlinear exactly solvable model of fully isotropic phoretic particle that shows the transitions from a non-motile state to straight motion to circular motion to helical motion as a series of spontaneous symmetry-breaking bifurcations. Whether a system exhibits or not a given trajectory only depends on the numerical values of parameters entering the model, while asymmetry of swimmer shape, or anisotropy of the suspending medium, or influence of bounding walls are not necessary.

Unveiling the Prevalence and Factors of Workplace Bullying in Primary Healthcare Settings: A Cross-Sectional Study in Jeddah City, Saudi Arabia.

Introduction Bullying in workplaces can lead to serious and deleterious effects on both the health and well-being of individuals. In a healthcare environment, bullying can lead to life-threatening adverse outcomes for patients and healthcare workers. The aim of this study was to evaluate the prevalence and factors of bullying among primary healthcare workers in Jeddah, Saudi Arabia. Methods This cross-sectional study targeted physicians and nurses in Jeddah healthcare centers and used a Negative Acts Questionnaire-Revised (NAQ-R) to evaluate participants' exposure to bullying. The chi-square test was used to examine the relationship between the outcome and other variables. Results The majority of participants (59.8%) had more than 10 years of experience and were nurses (56.6%). The majority of participants (69.4%) scored below 33 on the NAQ-R scale, while 19.9% scored between 33 and 45, and 10.7% scored over 45. Most perpetrators were references/patients (22.4%), supervisors (19.2%), department managers, or general managers (19.2%). Of all participants, 28.8% had experienced workplace bullying (WPB), and 31.7% witnessed it over the past five years. Being subjected to WPB (P < 0.001), being bullied by a manager (P < 0.001), and experiencing and witnessing WPB over the past five years (P < 0.001) correlated with higher NAQ-R scores. Years of experience were significantly associated with NAQ-R scores (P = 0.016). Conclusions This study indicates bullying among a third of healthcare workers, mainly perpetrated by patients and managers. Years of experience and manager offenses, experiencing and witnessing WPB were associated with higher bullying rates. Therefore, there is an urgent need for antibullying policies, awareness campaigns, education programs, effective communication, conflict resolution, leadership training, and transparent culture to address this problem.

Urinary Bladder Carcinoma in Females: A Clinico-Pathological Assessment.

BACKGROUND: Urinary bladder cancer is an uncommon cancer in females. Despite not being an infrequent encounter, female bladder cancer remains a poorly defined entity. There is a paucity of literature regarding bladder cancer in females, especially in North India. OBJECTIVE: This study aims to evaluate the clinico-pathological profile of bladder cancer in female patients managed at a single centre in north India. MATERIALS AND METHODS: This retrospective observational study was carried out in a tertiary care centre in North India. Medical records and a database of female patients with bladder cancer treated between January 2012 and January 2021 were retrieved. Data regarding age, duration of disease, associated comorbidity, histopathological variants, and outcomes were studied. RESULTS: Out of 56 female patients with bladder masses, 55 had transitional cell carcinoma (TCC), while one had pheochromocytoma. Painless hematuria (80.3%) was the commonest presentation. At the time of presentation, 5 patients (9.1%) had muscle-invasive bladder cancer (T2-T4), while 50 patients had non-muscle-invasive disease, out of which 31 (56.4%) patients had high-grade and 19 (34.5%) patients had low-grade papillary carcinoma. Twenty-three patients (41.8%) had a history of exposure to domestic chulha (open wood-burning cooking stove), and 11 patients (20%) were smokers; six patients (10.9%) were exposed to both risk factors. CONCLUSIONS: Female bladder cancer was most prevalent in the sixth decade of life, with the majority of patients having a high-grade but non-muscle-invasive disease. Of all the risk factors, chulha exposure was the main risk factor in the aetiology of female bladder cancer.

Exogenous Cushing Syndrome and Hip Fracture Due to Over-the-Counter Supplement (Artri King).

The most common cause of Cushing syndrome (CS) is exposure to exogenous glucocorticoids. There is an increasing incidence of adulterated over-the-counter (OTC) supplements containing steroids. We present a case of Artri King (AK)-induced CS in a 40-year-old woman who presented with an intertrochanteric fracture of her right femur. Laboratory testing revealed suppressed cortisol and adrenocorticotropic hormone, which was consistent with suppression of the hypothalamic-pituitary-adrenal (HPA) axis. Following the cessation of the AK supplement, the patient's HPA axis recovered, and the clinical manifestations of CS improved. This case emphasizes the need for better regulation of OTC supplements and the need for cautious use.

Feasibility of Performing Supine Percutaneous Nephrolithotomy for Solitary Renal Pelvic Stones (1.5-3 cm) Under Spinal Anaesthesia: A Single-Centre Study.

Introduction Percutaneous nephrolithotomy (PCNL) procedure has evolved over the years and one such evolution has been the introduction of supine PCNL by Valdivia in 1987. This approach offers the added advantage of safe access in patients with compromised cardiovascular and pulmonary function. General anesthesia is the preferred anesthetic technique for PCNL. However, in the last decade, there has been an increase in the usage of regional anesthesia for this procedure. We share our experience of supine PCNL for solitary renal pelvic stones under regional anesthesia. Aim and objective To assess the feasibility, safety, and efficacy of supine PCNL for solitary renal pelvic stones sized 1.5 to 3 cm under spinal anesthesia. Material and methods This was a retrospective record review of 35 patients (21 male) who underwent supine PCNL under regional anesthesia between January 2022 till December 2022 at our institute. All patients had a solitary renal pelvic calculus sized 1.5-3 cm. Intraoperative and postoperative data were analyzed. Results The mean age of patients was 38.5 ± 15 years. The postoperative pain visual analog scale (VAS) score was <5 in 31 (89%) and >5 in 4 (11%) patients. The mean hospital stay was 3.33 ± 0.88 days. Mean fall in hemoglobin level was 0.49 ± 0.43 mg/dL. Postoperatively, mild hematuria occurred in three patients (8.5%) and fever occurred in two (5.7%) patients. There was no injury to adjacent organs in this series. Blood transfusion was required only in one patient. Complete stone clearance was achieved in all patients. Conclusion In experienced hands, supine PCNL under regional anesthesia is a feasible, safe, and effective approach with minimal morbidity.

The role of p53 and ki67 in predicting clinical outcome in breast cancer patients.

Background: ">ki67 may be used as a proliferative index in addition to estrogen receptor (ER), progesterone receptor (PR), and human epidermal growth factor receptor 2 (HER2) negative status. p53 gene expression is a well-known biomarker in breast cancer and its role in predicting clinical outcome remains unclear. The current study aimed to determine the relationship between p53 gene mutation and ki67 expression, their clinical characteristics, and overall survival (OS), and to differentiate the significance of p53 and ki67 as the prognostic value in breast cancer patients. Methods: ">In this study, 135 patients were enrolled in the study from December 2015 to May 2017. Medical records for all patients were reviewed prospectively. The inclusion criteria included age more than 18 years with histologically proven breast cancer and willingness to be enrolled in p53 genetic study. Exclusion criteria included dual malignancy, male breast cancer, with a loss to follow-up during the study. Results: ">The mean survival of patients with ki67 ≤20 index was 42.7 months (95% confidence interval [CI] 38.7-46.7) and 129 months (95% CI 101.3-157.2) in patients with ki67 >20. The mean OS was 145 months (95% CI 105.6-185.5) in the p53 wild-type group and 106 months (95% CI 78.0-133.0) in the p53 mutated group, as illustrated. Conclusion: ">Our results indicated that p53 mutational status and high ki67 might have an essential impact on overall survival, with p53 mutated patients having a poorer outcome than p53 wild type patients.

Rare Intramuscular Myxoma Involving the Pterygoid and Masseteric Muscles: A Case Report.

Myxomas, characterized by abundant mucoid stroma and spindle cells, represent a subset of benign soft tissue tumors. Intramuscular myxomas in the maxillofacial region are rare, posing diagnostic challenges. We present the case of a 58-year-old male who reported limited jaw movement. Physical examination revealed asymmetry, restricted mouth opening, and left lateral jaw movement. Imaging confirmed a well-defined myxomatous mass. Core needle biopsy confirmed an intramuscular myxoma involving the pterygoid and masseteric muscles. A multidisciplinary team opted for surveillance due to its benign nature. Follow-up at six months showed stable findings, supporting the decision for non-surgical management. This case highlights the diagnostic and management challenges of rare intramuscular myxomas in the maxillofacial region. A comprehensive diagnostic work-up, including clinical, radiological, and histopathological data, is crucial. Non-surgical management, guided by a benign nature, underscores the importance of judicious and multidisciplinary approaches. Regular follow-up contributes to understanding the natural history of intramuscular myxomas, emphasizing the need for vigilant monitoring in soft tissue tumor management.

Cardiac disease detection from ECG signal using discrete wavelet transform with machine learning method.

OBJECTIVES: Cardiac disease is the leading cause of death worldwide. If a proper diagnosis is made early, cardiovascular problems can be prevented. The ECG test is a diagnostic method used on the screen for heart disease. Based on a combination of multi-field extraction and nonlinear analysis of ECG data, this paper presents a framework for automated detection of heart disease. The main aim of this study is to develop a model for future diagnosis of cardiac vascular disease using ECG analysis and symptom-based detection. METHODS: Discrete wavelet transform and Nonlinear Vector Decomposed Neural Network methods are used to predict Cardiac disease. Here is the discrete wavelet transform used for preprocessing to remove unwanted noise or artifacts. The neural network was fed with thirteen clinical features as input which was then trained using a non-linear vector decomposition of the presence or absence of heart disease. RESULTS: The modules were implemented, trained, and tested using UCI and Physio net data repositories. The sensitivity, specificity and accuracy of this research work are 92.0%, 89.33% and 90.67% CONCLUSIONS: The proposed approach can discover complex non-linear correlations between dependent and independent variables without requiring traditional statistical training. The suggested approach improves ECG classification accuracy, allowing for more accurate cardiac disease diagnosis. The accuracy of ECG categorization in identifying cardiac illness is far greater than these other approaches.

Fibrotic activity quantified in serum by measurements of type III collagen pro-peptides can be used for prognosis across different solid tumor types.

Due to activation of fibroblast into cancer-associated fibroblasts, there is often an increased deposition of extracellular matrix and fibrillar collagens, e.g. type III collagen, in the tumor microenvironment (TME) that leads to tumor fibrosis (desmoplasia). Tumor fibrosis is closely associated with treatment response and poor prognosis for patients with solid tumors. To assure that the best possible treatment option is provided for patients, there is medical need for identifying patients with high (or low) fibrotic activity in the TME. Measuring unique collagen fragments such as the pro-peptides released into the bloodstream during fibrillar collagen deposition in the TME can provide a non-invasive measure of the fibrotic activity. Based on data from 8 previously published cohorts, this review provides insight into the prognostic value of quantifying tumor fibrosis by measuring the pro-peptide of type III collagen in serum of a total of 1692 patients with different solid tumor types and discusses the importance of tumor fibrosis for understanding prognosis and for potentially guiding future drug development efforts that aim at overcoming the poor outcome associated with a fibrotic TME.

Cellular Fitness Phenotypes of Cancer Target Genes from Oncobiology to Cancer Therapeutics.

To define the growing significance of cellular targets and/or effectors of cancer drugs, we examined the fitness dependency of cellular targets and effectors of cancer drug targets across human cancer cells from 19 cancer types. We observed that the deletion of 35 out of 47 cellular effectors and/or targets of oncology drugs did not result in the expected loss of cell fitness in appropriate cancer types for which drugs targeting or utilizing these molecules for their actions were approved. Additionally, our analysis recognized 43 cellular molecules as fitness genes in several cancer types in which these drugs were not approved, and thus, providing clues for repurposing certain approved oncology drugs in such cancer types. For example, we found a widespread upregulation and fitness dependency of several components of the mevalonate and purine biosynthesis pathways (currently targeted by bisphosphonates, statins, and pemetrexed in certain cancers) and an association between the overexpression of these molecules and reduction in the overall survival duration of patients with breast and other hard-to-treat cancers, for which such drugs are not approved. In brief, the present analysis raised cautions about off-target and undesirable effects of certain oncology drugs in a subset of cancers where the intended cellular effectors of drug might not be good fitness genes and that this study offers a potential rationale for repurposing certain approved oncology drugs for targeted therapeutics in additional cancer types.

Higher serum PD-L1 level predicts increased overall survival with lapatinib versus trastuzumab in the CCTG MA.31 phase 3 trial.

BACKGROUND: The purpose of this retrospective biomarker study of the Canadian Cancer Trials Group (CCTG) MA.31 randomized phase 3 trial (lapatinib vs trastuzumab) of HER2-positive metastatic breast cancer (MBC) was to evaluate the prognostic and predictive biomarker utility of pretreatment serum programmed death ligand 1 (PD-L1) levels. METHODS: CCTG MA.31 accrued 652 HER2-positive patients; 387 had serum available (185 in the trastuzumab arm and 202 in the lapatinib arm). The Ella immunoassay platform (ProteinSimple, San Jose, California) was used to quantitate serum PD-L1 levels. Stepwise forward Cox multivariable analyses were performed for progression-free survival and overall survival (OS). RESULTS: In the whole trial population, continuous pretreatment serum PD-L1 levels were not associated with OS. However, within the trastuzumab arm, a higher continuous pretreatment serum PD-L1 level was significant for shorter OS (hazard ratio [HR], 3.85; P = .04), but within the lapatinib arm, pretreatment serum PD-L1 was not associated with OS (P = .37). In the whole trial, in a multivariable analysis for OS, serum PD-L1 (median cut point) remained a significant independent covariate (HR, 2.38; P = .001). There was a significant interaction between treatment arm and continuous serum PD-L1 (bootstrap method; P = .0025): at or above 214.2 pg/mL (the 89th percentile), serum PD-L1 was associated with significantly shorter OS with trastuzumab treatment versus lapatinib treatment. CONCLUSIONS: In the CCTG MA.31 trial, serum PD-L1 was a significant predictive factor: a higher pretreatment serum PD-L1 level was associated with shorter OS with trastuzumab treatment but with longer OS with lapatinib treatment. Immune evasion may decrease the effectiveness of trastuzumab therapy. Further evaluation of elevated serum PD-L1 in advanced breast cancer is warranted to identify patients with HER2-positive MBC who may benefit from novel immune-targeted therapies in addition to trastuzumab.

The Impact of Impulsivity and Emotional Dysregulation on Comorbid Bipolar Disorder and Borderline Personality Disorder.

The symptomatic overlap between borderline personality disorder (BPD) and bipolar disorder (BD) is a topic of scientific and academic debates. Emotional dysregulation and impulsivity are common features of both disorders. Several studies have shown that both BPD and BD lie on a spectrum; others have suggested that they are separate entities that coexist.  BPD is characterized by impulsive and dangerous behaviors such as driving recklessly, inappropriate sexual behavior, eating disorders, and substance abuse. BD, during a manic episode, is known for their impulsive and risk-taking behavior like hypersexuality, excessive spending, and substance abuse.  The current literature review aims to provide an overview of the impact of impulsivity and emotional dysregulation on comorbid bipolar disorder and borderline personality disorder. Our study results showed that patients with comorbid BPD and BD struggle with impulsive actions and have difficulty controlling their emotions. They are also highly susceptible to anxiety disorders like obsessive-compulsive disorder (OCD), post-traumatic stress disorder (PTSD), and somatoform disorders. Patients with comorbid BPD and BD struggle with severe psychosocial morbidity and an increased risk of suicide. In patients with only one disease, misdiagnosis is a common phenomenon due to the overlapping symptoms of BPD and BD.

Does Catheter Ablation Lower the Long-Term Risk of Stroke and Mortality in Patients with Atrial Fibrillation? A Concise Review of the Current State of Knowledge.

Atrial fibrillation (AF) is the most common cardiac arrhythmia worldwide and carries a significant risk of morbidity and mortality. Multiple trials have highlighted the benefit of catheter ablation over medical therapy in restoring sinus rhythm and improving quality of life. Whether it reduces long-term risk of stroke and mortality is still unclear. We performed a literature search using the PubMed database to review the current state of knowledge regarding the long-term outcomes of stroke and mortality in ablated patients compared to patients who receive medical therapy. Our review mainly consisted of recent randomized controlled trials and large observational studies.  Results from large observational studies show that catheter ablation significantly reduces the risk of stroke in high-risk patients and mortality compared to medical therapy. However, randomized controlled trials have only demonstrated a mortality benefit in patients with comorbid systolic heart failure. In patients with paroxysmal AF, ablation therapy significantly limits the progression to persistent AF and has a higher efficacy in restoring sinus rhythm. Maintenance of sinus rhythm is the most important factor associated with lower long term risk of stroke and mortality. Large randomized controlled trials similar to the Catheter Ablation Versus Anti-arrhythmic Drug Therapy for Atrial Fibrillation (CABANA) trial are still needed to clarify whether catheter ablation is superior over medical therapy in improving the long-term outcomes of stroke and mortality.

Catheter Ablation vs. Medical Treatment in Patients With Atrial Fibrillation.

Atrial fibrillation has become the most commonly seen cardiac arrhythmia in clinical practice affecting almost 5.6 million Americans with that number expected to rise in the near future. The current literature review is aimed to assess the efficacy of catheter ablation in the treatment of patients with atrial fibrillation when compared to standard medical therapy. A PubMed search for studies of "Atrial Fibrillation" found 83,251 articles. Following the application of inclusion/exclusion criteria, we identified 44 articles of relevance that compared catheter ablation and medical therapy in the treatment of atrial fibrillation. These 44 articles included 20 Observational studies, eight randomized clinical trials, three clinical trials, five cohort studies, and eight review articles. Our review determined that catheter ablation was associated with a much lower rate of reoccurrence of atrial fibrillation when compared to medical therapy, as well as decreased cardiovascular outpatient visits and thromboembolic complications. The effect of quality on life when compared to medical treatment, however, was found to be inconclusive.

Dosimetric impact of variable bladder filling on IMRT planning for locally advanced carcinoma cervix.

BACKGROUND: To evaluate the dosimetric impact of variable bladder filling on target and organ at risk (OARs) in cervical cancer patients undergoing chemoradiation. Forty consecutive patients with cervical cancer underwent radiotherapy planning as per the departmental protocol. All patients were asked to empty their bowel and bladder before simulation and catheterization was done. Normal saline was instilled into the bladder through Foleys till the patient had a maximal urge to urinate. Pelvic cast fabrication and CT simulation was done. Then, 30%, 50%, and 100% of the instilled saline was removed and rescans taken. Planning was done on full bladder (X) and the same plan applied to the contours with bladder volumes 0.7X (PLAN70), 0.5X (PLAN50), and empty (PLAN0). A dose of 50 Gy/25# was prescribed to the PTV and plans evaluated. Intensity-modulated radiotherapy plans with full bladder were implemented for each patient. Shifts in the center of mass (COM) of the cervix/uterus with variable bladder filling identified were noted. Statistical analysis was performed using SPSS software. A p value < 0.05 was considered significant. RESULTS: Bladder volume in 70%, 50%, and empty bladder planning was 78.34% (388.35 + 117.44 ml), 64.44% (320.60 + 106.20 ml), and 13.63% (62.60 + 23.12 ml), respectively. The mean dose received by 95% PTV was 49.76 Gy + 1.30 Gy. Though the difference in target coverage was significant between PLAN100 and other plans, the mean difference was minimal. A decrease in bladder filling resulted in an increase in OAR dose. Variation in the increase in dose to OARs was not significant if bladder filling was > 78.34% and > 64.44% of a full bladder with respect to the bowel and rectal/bladder doses, respectively. Inconsistent bladder filling led to a maximal shift in COM (uterus/cervix) in the Y- and Z-axis. CONCLUSION: Bladder filling variations have an impact on cervico-uterine motion/shape, thereby impacting the dose to the target and OARs. It is recommended to have a threshold bladder volume of at least 70-75% of optimally filled bladder during daily treatment. TRIAL REGISTRATION: Institutional review board (IRB) registered by Drug Controller General (India) with registration number ECR/10/Ins/DC/2013. Trial Registration number - RGCIRC/IRB/44/2016, registered and approved on the 14th of May 2016.

Efficacy and Safety of Direct Factor Xa Inhibitors Versus Warfarin in Prevention of Primary and Secondary Ischemic Strokes in Non-Valvular Atrial Fibrillation: A Literature Review.

Ischemic stroke remains a major cause of mortality and morbidity in patients with atrial fibrillation. The use of appropriate anticoagulants reduces the risk of ischemic stroke in these patients. The current literature review is aimed to analyze the follow-up efficacy and safety of direct factor Xa inhibitors versus warfarin in the prevention of primary and secondary ischemic stroke, risk of major and minor bleedings, and food and drug interaction in patients with atrial fibrillation (AF). We selected PubMed as our database and we found 83,611 articles using the regular keyword 'atrial fibrillation'. We found 2,224 articles using the regular keywords 'direct factor Xa inhibitors' and 'atrial fibrillation'. Finally, we obtained 326 studies using MeSH keywords: atrial fibrillation, direct factor Xa inhibitors, and warfarin. Ultimately, 46 articles were selected after applying the inclusion/exclusion criteria. All studies were randomized controlled trials (RCT) or clinical trials. Analysis of all studies showed that direct factor Xa inhibitors are superior to warfarin in the prevention of ischemic stroke in patients with non-valvular AF, with a lower rate of major and minor bleeding events and lower foods and drug interaction. Unlike warfarin, direct factor Xa inhibitors do not need frequent blood monitoring and dose adjustment. We found that warfarin and other vitamin K inhibitors may promote the calcification of heart valves and coronary arteries. There is some evidence that direct factor Xa inhibitors may slightly reverse these calcifications in coronary arteries and heart valves.

Collagen fragments quantified in serum as measures of desmoplasia associate with survival outcome in patients with advanced pancreatic cancer.

Pancreatic ductal adenocarcinoma (PDAC) patients have poor prognosis and poor response to treatment. This is largely due to PDAC being associated with a dense and active stroma and tumor fibrosis (desmoplasia). Desmoplasia is characterized by excessive degradation and formation of the extracellular matrix (ECM) generating collagen fragments that are released into circulation. We evaluated the association of specific collagen fragments measured in pre-treatment serum with outcome in patients with PDAC. Matrix metalloprotease (MMP)-degraded type I collagen (C1M), type III collagen (C3M), type IV collagen (C4M) and a pro-peptide of type III collagen (PRO-C3) were measured by ELISA in pre-treatment serum from a randomized phase 3 clinical trial of patients with stage III/IV PDAC treated with 5-fluorouracil based therapy (n = 176). The collagen fragments were evaluated for their correlation (r, Spearman) with serum CA19-9 and for their association with overall survival (OS) based on Cox-regression analyses. In this phase 3 PDAC trial, pre-treatment serum collagen fragment levels were above the reference range for 67%-98% of patients, with median values in PDAC approximately two-fold higher than reference levels. Collagen fragment levels did not correlate with CA19-9 (r = 0.049-0.141, p = ns). On a continuous basis, higher levels of all collagen fragments were associated with significantly shorter OS. When evaluating degradation (C3M) and formation (PRO-C3) of type III collagen further, higher PRO-C3 was associated with poor OS (>25th percentile cut-point, HR = 2.01, 95%CI = 1.33-3.05) and higher C3M/PRO-C3 ratio was associated with improved OS (>25th percentile cut-point, HR = 0.53, 95%CI = 0.34-0.80). When adjusting for CA19-9 and clinical covariates, PRO-C3 remained significant (HR = 1.65, 95%CI = 1.09-2.48). In conclusion, collagen remodeling quantified in pre-treatment serum as a surrogate measure of desmoplasia was significantly associated with OS in a phase 3 clinical PDAC trial, supporting the link between desmoplasia, tumorigenesis, and response to treatment. If validated, these biomarkers may have prognostic and/or predictive potential in future PDAC trials.