Association of dead space fraction to mortality in patients with COVID-19-related ARDS: A historical cohort observational study.

OBJECTIVE: To assess the correlation of dead space fraction (VD/VT) measured through time capnography, corrected minute volume (CMV) and ventilation ratio (VR) with clinical outcomes in COVID-19 patients requiring invasive mechanical ventilation. DESIGN: Observational study of a historical cohort. SETTING: University hospital in Medellin, Colombia. PARTICIPANTS: Patients aged 15 and above with a confirmed COVID-19 diagnosis admitted to the ICU and requiring mechanical ventilation. INTERVENTIONS: Measurement of VD/VT, CMV, and VR in COVID-19 patients. MAIN VARIABLES OF INTEREST: VD/VT, CMV, VR, demographic data, oxygenation indices and ventilatory parameters. RESULTS: During the study period, 1047 COVID-19 patients on mechanical ventilation were analyzed, of whom 446 (42%) died. Deceased patients exhibited a higher prevalence of advanced age and obesity, elevated Charlson index, higher APACHE II and SOFA scores, as well as an increase in VD/VT ratio (0.27 in survivors and 0.31 in deceased) and minute ventilation volume on the first day of mechanical ventilation. The multivariate analysis revealed independent associations to in-hospital mortality, higher VD/VT (HR 1.24; 95%CI 1.003-1.525; p = 0.046), age (HR 1.024; 95%CI 1.014-1.034; p < 0.001), and SOFA score at onset (HR: 1.036; 95%CI: 1.001-1.07; p = 0.017). CONCLUSIONS: VD/VT demonstrated an association with mortality in COVID-19 patients with ARDS on mechanical ventilation. These findings suggest that VD/VT measurement may serve as a severity marker for the disease.

Coronary Artery Embolism and Myocardial Infarction, case report.

Coronary embolism (CE) is a rare cause of non-atherosclerotic acute coronary syndrome (ACS). The clinical presentation is similar to ACS, and the diagnosis is supported by Shibata criteria. Atrial fibrillation is the main reported etiology in CE cases. Management includes percutaneous intervention with thromboaspiration and anticoagulation. The following case is a description of a patient with acute chest pain and recently diagnosed atrial fibrillation (AF) with a rapid ventricular response, is described. A thrombotic lesion in the distal right coronary artery (RCA) of embolic origin, was documented. Successful mechanical thromboaspiration was performed; intravascular ultrasound (IVUS) showed no thrombus, dissection, or atherosclerotic plaque. CE is an underdiagnosed cause of ACS; diagnosis relies on Shibata criteria, and patients experience worse outcomes in follow-up.

Stratification of Kidney Transplant Recipients Into Five Subgroups Based on Temporal Disease Trajectories.

Background: Kidney transplantation is the treatment of choice for patients with end-stage renal disease. Considerable clinical research has focused on improving graft survival and an increasing number of kidney recipients die with a functioning graft. There is a need to improve patient survival and to better understand the individualized risk of comorbidities and complications. Here, we developed a method to stratify recipients into similar subgroups based on previous comorbidities and subsequently identify complications and for a subpopulation, laboratory test values associated with survival. Methods: First, we identified significant disease patterns based on all hospital diagnoses from the Danish National Patient Registry for 5752 kidney transplant recipients from 1977 to 2018. Using hierarchical clustering, these longitudinal patterns of diseases segregate into 3 main clusters of glomerulonephritis, hypertension, and diabetes. As some recipients are diagnosed with diseases from >1 cluster, recipients are further stratified into 5 more fine-grained trajectory subgroups for which survival, stratified complication patterns as well as laboratory test values are analyzed. Results: The study replicated known associations indicating that diabetes and low levels of albumin are associated with worse survival when investigating all recipients. However, stratification of recipients by trajectory subgroup showed additional associations. For recipients with glomerulonephritis, higher levels of basophils are significantly associated with poor survival, and these patients are more often diagnosed with bacterial infections. Additional associations were also found. Conclusions: This study demonstrates that disease trajectories can confirm known comorbidities and furthermore stratify kidney transplant recipients into clinical subgroups in which we can characterize stratified risk factors. We hope to motivate future studies to stratify recipients into more fine-grained, homogenous subgroups to better discover associations relevant for the individual patient and thereby enable more personalized disease-management and improve long-term outcomes and survival.

Population-wide analysis of hospital laboratory tests to assess seasonal variation and temporal reference interval modification.

We identified mortality-, age-, and sex-associated differences in relation to reference intervals (RIs) for laboratory tests in population-wide data from nearly 2 million hospital patients in Denmark and comprising more than 300 million measurements. A low-parameter mathematical wave-based modification method was developed to adjust for dietary and environment influences during the year. The resulting mathematical fit allowed for improved association rates between re-classified abnormal laboratory tests, patient diagnoses, and mortality. The study highlights the need for seasonally modified RIs and presents an approach that has the potential to reduce over- and underdiagnosis, affecting both physician-patient interactions and electronic health record research as a whole.

Discovery of drug-omics associations in type 2 diabetes with generative deep-learning models.

The application of multiple omics technologies in biomedical cohorts has the potential to reveal patient-level disease characteristics and individualized response to treatment. However, the scale and heterogeneous nature of multi-modal data makes integration and inference a non-trivial task. We developed a deep-learning-based framework, multi-omics variational autoencoders (MOVE), to integrate such data and applied it to a cohort of 789 people with newly diagnosed type 2 diabetes with deep multi-omics phenotyping from the DIRECT consortium. Using in silico perturbations, we identified drug-omics associations across the multi-modal datasets for the 20 most prevalent drugs given to people with type 2 diabetes with substantially higher sensitivity than univariate statistical tests. From these, we among others, identified novel associations between metformin and the gut microbiota as well as opposite molecular responses for the two statins, simvastatin and atorvastatin. We used the associations to quantify drug-drug similarities, assess the degree of polypharmacy and conclude that drug effects are distributed across the multi-omics modalities.

Cerebrospinal fluid leak postnasopharyngeal swab for SARS-CoV-2 testing: A case report.

Background: Due to the SARS-CoV-2 virus pandemic and its rapid spread worldwide, an early and effective detection strategy was the nasopharyngeal reverse transcription polymerase swab tests, a procedure still performed today. A relatively safe procedure when done correctly, however, one of the rare complications reported in the literature includes a cerebrospinal fluid (CSF) leak. Case Description: A 69-year-old female patient presented to the emergency department with clear fluid rhinorrhea, clinically diagnosed with a CSF fistula after a SARS-CoV-2 nasopharyngeal swab. Resulting computed tomography and magnetic resonance images did not report any abnormalities; however, persistence of clear fluid rhinorrhea obligated pharmacological treatment without resolution, requiring insertion of a lumbar catheter to achieve clinical resolution. Conclusion: It is essential to train staff to correctly administer nasopharyngeal swabs and thus reduce the rate of complications, as well as early recognition of symptoms and signs of CSF fistula.

Integrate mechanistic evidence from new approach methodologies (NAMs) into a read-across assessment to characterise trends in shared mode of action.

Read-across approaches often remain inconclusive as they do not provide sufficient evidence on a common mode of action across the category members. This read-across case study on thirteen, structurally similar, branched aliphatic carboxylic acids investigates the concept of using human-based new approach methods, such as in vitro and in silico models, to demonstrate biological similarity. Five out of the thirteen analogues have preclinical in vivo studies. Three out of them induced lipid accumulation or hypertrophy in preclinical studies with repeated exposure, which leads to the read-across hypothesis that the analogues can potentially induce hepatic steatosis. To confirm the selection of analogues, the expression patterns of the induced differentially expressed genes (DEGs) were analysed in a human liver model. With increasing dose, the expression pattern within the tested analogues got more similar, which serves as a first indication of a common mode of action and suggests differences in the potency of the analogues. Hepatic steatosis is a well-known adverse outcome, for which over 55 adverse outcome pathways have been identified. The resulting adverse outcome pathway (AOP) network, comprised a total 43 MIEs/KEs and enabled the design of an in vitro testing battery. From the AOP network, ten MIEs, early and late KEs were tested to systematically investigate a common mode of action among the grouped compounds. The targeted testing of AOP specific MIE/KEs shows that biological activity in the category decreases with side chain length. A similar trend was evident in measuring liver alterations in zebra fish embryos. However, activation of single MIEs or early KEs at in vivo relevant doses did not necessarily progress to the late KE "lipid accumulation". KEs not related to the read-across hypothesis, testing for example general mitochondrial stress responses in liver cells, showed no trend or biological similarity. Testing scope is a key issue in the design of in vitro test batteries. The Dempster-Shafer decision theory predicted those analogues with in vivo reference data correctly using one human liver model or the CALUX reporter assays. The case study shows that the read-across hypothesis is the key element to designing the testing strategy. In the case of a good mechanistic understanding, an AOP facilitates the selection of reliable human in vitro models to demonstrate a common mode of action. Testing DEGs, MIEs and early KEs served to show biological similarity, whereas the late KEs become important for confirmation, as progression from MIEs to AO is not always guaranteed.

Minimal invasive surgical resection of myxomas: a three case series study / Resección quirúrgica mínimamente invasiva de mixomas: estudio de tres casos

Abstract Introduction and Objective Cardiac tumors are often unrecognized until autopsies are performed or diagnosed from routine studies based on unspecific symptoms. The most common type of tumor is the myxoma, although rare, upon diagnosis an urgent surgical resection is often required. Previously the ideal surgical approach was a standard median sternotomy, however recently newer surgical techniques have been employed with excellent results. We describe a recent surgical approach via the right lateral minithoracotomy as a minimally invasive intervention with three cases that evidence an appropriate and ideal surgical approach. Method and Patients We present three cases of minimally invasive myxoma resection via the right lateral minithoracotomy. Results and discussion In this three-case series study, no complications were reported peri-operatively nor at the 6 and 12-month follow-ups. In comparison with international literature, surgical approaches in Colombia are comparable with successful resection and little or no complications peri-operatively. Conclusions The right lateral minithoracotomy appears to be a safe approach in myxoma resection. We hope to enhance and promote the surgical community in Colombia to opt for alternative less invasive approaches in these type of cases, to ensure excellent results and promote further research as seen in other countries.

Resumen Introducción y Objetivo Los tumores cardíacos no suelen ser diagnosticados hasta la realización de autopsia o en otros casos como hallazgos incidentales. El tumor cardiaco más común es el mixoma, aunque es poco frecuente; en el momento del diagnóstico a menudo se requiere una resección quirúrgica urgente. Anteriormente el enfoque quirúrgico era una atriotomía abierta derecha; sin embargo, recientemente se han empleado técnicas quirúrgicas nuevas con excelentes resultados. Describimos una técnica quirúrgica reciente a través de la minitoracotomía lateral derecha como un método mínimamente invasivo con tres casos que evidencian un método quirúrgico apropiado e ideal. Métodos y pacientes: Se presentan tres casos de resección mínimamente invasiva de mixomas a través de una minitoracotomía lateral derecha. Resultados y discusión: Es estos tres casos no se reportaron complicaciones perioperatorias ni durante el seguimiento a los 6 y 12 meses. En comparación con otras series de casos en la literatura, el enfoque en Colombia ha sido comparable tanto en los resultados exitosos como con las técnicas quirúrgicas, sin complicaciones asociadas. Conclusiones La minitoracotomía lateral derecha puede ser considerada segura en resección de mixoma. Con este tipo de reportes se espera suscitar en la comunidad médica la elección de alternativas quirúrgicas mínimamente invasivas para garantizar excelentes resultados y promover la investigación, como se evidencia en el resto del mundo.

Optimizing drug selection from a prescription trajectory of one patient.

It is unknown how sequential drug patterns convey information on a patient's health status and treatment guidelines rarely account for this. Drug-agnostic longitudinal analyses of prescription trajectories in a population-wide setting are needed. In this cohort study, we used 24 years of data (1.1 billion prescriptions) from the Danish prescription registry to model the risk of sequentially redeeming a drug after another. Drug pairs were used to build multistep longitudinal prescription trajectories. These were subsequently used to stratify patients and calculate survival hazard ratios between the stratified groups. The similarity between prescription histories was used to determine individuals' best treatment option. Over the course of 122 million person-years of observation, we identified 9 million common prescription trajectories and demonstrated their predictive power using hypertension as a case. Among patients treated with agents acting on the renin-angiotensin system we identified four groups: patients prescribed angiotensin converting enzyme (ACE) inhibitor without change, angiotensin receptor blockers (ARBs) without change, ACE with posterior change to ARB, and ARB posteriorly changed to ACE. In an adjusted time-to-event analysis, individuals treated with ACE compared to those treated with ARB had lower survival probability (hazard ratio, 0.73 [95% CI, 0.64-0.82]; P < 1 × 10-16). Replication in UK Biobank data showed the same trends. Prescription trajectories can provide novel insights into how individuals' drug use change over time, identify suboptimal or futile prescriptions and suggest initial treatments different from first line therapies. Observations of this kind may also be important when updating treatment guidelines.

Impaired Vitamin D Signaling in T Cells From a Family With Hereditary Vitamin D Resistant Rickets.

The active form of vitamin D, 1,25-dihydroxyvitamin D3 (1,25(OH)2D3), mediates its immunomodulatory effects by binding to the vitamin D receptor (VDR). Here, we describe a new point mutation in the DNA-binding domain of the VDR and its consequences for 1,25(OH)2D3 signaling in T cells from heterozygous and homozygous carriers of the mutation. The mutation did not affect the overall structure or the ability of the VDR to bind 1,25(OH)2D3 and the retinoid X receptor. However, the subcellular localization of the VDR was strongly affected and the transcriptional activity was abolished by the mutation. In heterozygous carriers of the mutation, 1,25(OH)2D3-induced gene regulation was reduced by ~ 50% indicating that the expression level of wild-type VDR determines 1,25(OH)2D3 responsiveness in T cells. We show that vitamin D-mediated suppression of vitamin A-induced gene regulation depends on an intact ability of the VDR to bind DNA. Furthermore, we demonstrate that vitamin A inhibits 1,25(OH)2D3-induced translocation of the VDR to the nucleus and 1,25(OH)2D3-induced up-regulation of CYP24A1. Taken together, this study unravels novel aspects of vitamin D signaling and function of the VDR in human T cells.

Disease trajectory browser for exploring temporal, population-wide disease progression patterns in 7.2 million Danish patients.

We present the Danish Disease Trajectory Browser (DTB), a tool for exploring almost 25 years of data from the Danish National Patient Register. In the dataset comprising 7.2 million patients and 122 million admissions, users can identify diagnosis pairs with statistically significant directionality and combine them to linear disease trajectories. Users can search for one or more disease codes (ICD-10 classification) and explore disease progression patterns via an array of functionalities. For example, a set of linear trajectories can be merged into a disease trajectory network displaying the entire multimorbidity spectrum of a disease in a single connected graph. Using data from the Danish Register for Causes of Death mortality is also included. The tool is disease-agnostic across both rare and common diseases and is showcased by exploring multimorbidity in Down syndrome (ICD-10 code Q90) and hypertension (ICD-10 code I10). Finally, we show how search results can be customized and exported from the browser in a format of choice (i.e. JSON, PNG, JPEG and CSV).

Immunoglobulin G4-related gastric pseudotumor - An impostor: Case report.

INTRODUCTION: Gastric pseudotumors are rare entities whose clinical presentation resembles typical gastric neoplasias, often making them unrecognized unless other causes are considered. PRESENTATION OF CASE: We present a case report of a patient that debuts with dysphagia, with an abdominal computed axial tomography (CAT) scan revealing a mass at the gastro-esophageal junction suggestive of malignant origin, with studies revealing it to be Immunoglobulin G4-related (IgG4). DISCUSSION: The diagnosis and identification of IgG4-related gastric pseudotumors is very complicated, often and most commonly an incidental diagnosis upon histologic analysis, as is the situation in this case. CONCLUSION: Understanding its clinical course and early diagnosis can reduce unwarranted surgical intervention in some patients with IgG4-related disease.

Emergency esophagojejunostomy in type IV hiatal hernia: A case report.

Reconstruction of the digestive tract is a surgical challenge; we propose a novel and successful alternative using a large vascularized pedicled jejunum anastomosed to the cervical esophagus in an emergency situation. A 65-year-old female patient in follow-up due to a gigantic type IV paraesophageal hernia, whom underwent surgical hernial defect correction, had friable gastric tissue and esophageal lesions that forced an urgent esophagojejunostomy. Immediate post-operative recovery had no incidents and during the outpatient follow-up no complications were reported. This case report represents a paradigm change in the impossibility of raising the vascularized pedicled jejunum to the neck in an emergency situation.

La reconstrucción del tracto digestivo es un reto quirúrgico. Proponemos una alternativa novedosa y exitosa utilizando un gran yeyuno pediculado vascularizado anastomosado al esófago cervical en situación de emergencia. Una paciente de 65 años en seguimiento por una hernia paraesofágica tipo IV requirió corrección quirúrgica del defecto herniario; tenía tejido gástrico friable y lesiones esofágicas que forzaron una esofagoyeyunostomía urgente. La recuperación posoperatoria inmediata no tuvo incidentes y el seguimiento ambulatorio no mostró complicaciones. Este reporte de caso rompe el paradigma de la imposibilidad de ascender el yeyuno pediculado vascularizado al cuello en una situación de emergencia.

Left diaphragmatic hernia following thoracoabdominal aortic repair: A case report.

INTRODUCTION: Diaphragmatic hernias are somewhat rare complications of thoracoabdominal interventions. Given their late clinical manifestations and misdiagnosis, their incidence is unknown. These hernias have a high mortality risk when an emergency intervention is warranted due to complications from visceral strangulation. CASE PRESENTATION: We present the case of a 67-year-old male with prior history of thoracoabdominal aortic repair, who reconsults due to upper gastrointestinal bleeding. Upon arrival, imaging shows a left diaphragmatic herniation with migration of the stomach, omentum and spleen to the thoracic cavity. Through laparoscopic approach, a left diaphragmatic hernial defect is identified with protrusion of half the stomach, omentum and the posterior aspect of the spleen with a sub capsular tear. Additionally, a severe adhesion syndrome on the chest wall and diaphragm were also evident, with entrapment of the inferior lobe of the left lung. The contents were successfully reduced, however pulmonary decortication and extensive adhesiolysis through thoracoscopy was required for complete extraction, enabling a primary repair without tension. CONCLUSIONS: We present an infrequent pathology without an established incidence, which has relevant clinical and surgical implications at any level of care, in this case requiring interdisciplinary management. The suspicion of diaphragmatic hernia in a patient with past medical history of thoracoabdominal aortic repair with non-specific gastrointestinal symptoms is essential. We emphasize the importance of clinical suspicion of this complication once the surgical precedent has been identified.

Age-stratified longitudinal study of Alzheimer's and vascular dementia patients.

INTRODUCTION: Similar symptoms, comorbidities and suboptimal diagnostic tests make the distinction between different types of dementia difficult, although this is essential for improved work-up and treatment optimization. METHODS: We calculated temporal disease trajectories of earlier multi-morbidities in Alzheimer's disease (AD) dementia and vascular dementia (VaD) patients using the Danish National Patient Registry covering all hospital encounters in Denmark (1994 to 2016). Subsequently, we reduced the comorbidity space dimensionality using a non-linear technique, uniform manifold approximation and projection. RESULTS: We found 49,112 and 24,101 patients that were diagnosed with AD or VaD, respectively. Temporal disease trajectories showed very similar disease patterns before the dementia diagnosis. Stratifying patients by age and reducing the comorbidity space to two dimensions, showed better discrimination between AD and VaD patients in early-onset dementia. DISCUSSION: Similar age-associated comorbidities, the phenomenon of mixed dementia, and misdiagnosis create great challenges in discriminating between classical subtypes of dementia.

Effect of the addition of cactus (O. ficus-indica) to the lactating sows' diet on piglet development at lactation and post-weaning.

OBJECTIVE: The aim was to evaluate the effect of cactus (Opuntia ficus-indica) to the lactating sows' diet on piglet development at lactation and post-weaning. MATERIALS AND METHODS: Twenty-four litters of hybrids sows were evaluated in this study. The sows were divided into two groups: Control (CG), sows fed conventionally and experimental (EG), sows fed with commercial fed plus cactus. Post-weaning, the piglets of both groups were monitored up to the 20 kg liveweight (LW). It was evaluated, lactation (in sows): feed intake (FI), milk production (MP), and quality (MQ) and LW of the piglet. Post-weaning (in piglets): FI, LW, and length of intestinal villi (LIV) at 0, 24 h, and 42 days post-weaning. RESULTS: FI sow-1 was higher in EG (p < 0.05). MP, MQ, and LW piglet-1 at weaning were equal (p > 0.05). FI piglet-1 in the sixth and eighth week of age was higher in EG (p < 0.05); at the end of weaning phase, EG presented higher LW (p < 0.05): 8.4% more. LIV of the jejunum were higher (p < 0.05) in EG at 48 h (28.8%) and 42 days post-weaning (29.9%). At day 0, post-weaning LIV of the descending portion was higher (p < 0.05) in CG (1,571.0 µm) versus EG (1,058.0 µm). At day 42, post-weaning LIV of the transverse portion was higher (p < 0.05) in EG: 23.7% higher. CONCLUSION: Cactus intake in lactating sows does not affect the piglet development. However, post-weaning piglets present higher LIV in jejunum and transverse portion, aspect that improves LW.

Total gastrectomy in systemic scleroderma when anti-reflux surgery is not viable: A case report.

INTRODUCTION: Systemic scleroderma is an autoimmune disease that can affect the respiratory system and the gastrointestinal tract. When diffuse lung disease and pulmonary hypertension develop, a lung transplant is usually considered as treatment. This option, however, is not feasible in the presence of concomitant gastroesophageal reflux disease. In this case, medical therapy is initially warranted. If this fails, surgical approach may be considered in order for the patient to be a lung transplant candidate. CASE PRESENTATION: A 56-year-old female, with previous history of intestinal pneumonitis, mild pulmonary hypertension and gastroesophageal reflux secondary to systemic scleroderma, is considered for lung transplant. Initially, due to persistent gastroesophageal reflux, a transplant was not a viable. This was corrected with an open gastrectomy with roux-en-Y anastomosis. Follow-up one week later revealed normal anatomy, adequate esophageal-jejunal anastomosis, and adequate contrast medium transit via esophagogram. Additionally, there was no evidence of contrast medium reflux indicating a resolved gastroesophageal reflux disease. This led to the patient becoming a candidate for lung transplant. DISCUSSION: We suggest an open gastrectomy with roux-en-Y anastomosis as an alternative to the Nissen fundoplication for patients with connective tissue disease that develop terminal pulmonary consequences and require a lung transplant.

A Comparative Assessment Study of Known Small-Molecule Keap1-Nrf2 Protein-Protein Interaction Inhibitors: Chemical Synthesis, Binding Properties, and Cellular Activity.

Inhibiting the protein-protein interaction (PPI) between the transcription factor Nrf2 and its repressor protein Keap1 has emerged as a promising strategy to target oxidative stress in diseases, including central nervous system (CNS) disorders. Numerous non-covalent small-molecule Keap1-Nrf2 PPI inhibitors have been reported to date, but many feature suboptimal physicochemical properties for permeating the blood-brain barrier, while others contain problematic structural moieties. Here, we present the first side-by-side assessment of all reported Keap1-Nrf2 PPI inhibitor classes using fluorescence polarization, thermal shift assay, and surface plasmon resonance-and further evaluate the compounds in an NQO1 induction cell assay and in counter tests for nonspecific activities. Surprisingly, half of the compounds were inactive or deviated substantially from reported activities, while we confirm the cross-assay activities for others. Through this study, we have identified the most promising Keap1-Nrf2 inhibitors that can serve as pharmacological probes or starting points for developing CNS-active Keap1 inhibitors.

sAOP: linking chemical stressors to adverse outcomes pathway networks.

MOTIVATION: Adverse outcome pathway (AOP) is a toxicological concept proposed to provide a mechanistic representation of biological perturbation over different layers of biological organization. Although AOPs are by definition chemical-agnostic, many chemical stressors can putatively interfere with one or several AOPs and such information would be relevant for regulatory decision-making. RESULTS: With the recent development of AOPs networks aiming to facilitate the identification of interactions among AOPs, we developed a stressor-AOP network (sAOP). Using the 'cytotoxitiy burst' (CTB) approach, we mapped bioactive compounds from the ToxCast data to a list of AOPs reported in AOP-Wiki database. With this analysis, a variety of relevant connections between chemicals and AOP components can be identified suggesting multiple effects not observed in the simplified 'one-biological perturbation to one-adverse outcome' model. The results may assist in the prioritization of chemicals to assess risk-based evaluations in the context of human health. AVAILABILITY AND IMPLEMENTATION: sAOP is available at http://saop.cpr.ku.dk. SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics online.