Patient Natural History Research Articles

Findings from the individualized management of a patient with Acyl-CoA Oxidase-1 (ACOX1) deficiency: A bedside-to-bench-to-bedside strategy

Acyl-CoA Oxidase-1 (ACOX1) deficiency (MIM 264470) is an autosomal recessive disease characterized by impairments in the desaturation of acyl-CoAs to 2-trans-enoyl-CoAs, which is the first step in the catalysis of the β-oxidative breakdown of very long chain fatty acids (VLCFA) occuring in peroxisomes. The deleterious accumulation of VLCFA in several organs, including the brain, is a key biochemical feature of this disease which has devastating neurological consequences. ACOX1 deficiency is ultra-rare; as such, few studies have been conducted to determine the leading causes of symptoms or uncover new therapeutics. When confronted with one such case, we decided to bring drug discovery tools to the patient's bedside in an attempt to identify a cure. A skin biopsy was performed on a young patient with ACOX1 deficiency, following which screening technologies and mass spectrometry analysis techniques were applied to design a cellular assay that enabled the direct measurement of the effect of small molecules on the patient's primary fibroblasts. This approach is particularly well adapted to inherited metabolic disorders such as ACOX1 deficiency. Through the evaluation of a proprietary library of repurposable drugs, we found that the anthelmintic drug niclosamide led to a significant reduction in VLCFA in vitro. This drug was subsequently administered to the patient for more than six years. This study outlines the screening and drug selection processes. Additionally, we present our comprehensive clinical and biochemical findings that aided in understanding the patient's natural history and analysis of the progression of the patient's symptoms throughout the treatment period. Although the patient's overall lifespan was extended compared to the average age at death in severe early onset cases of ACOX1 deficiency, we did not observe any definitive evidence of clinical or biochemical improvement during niclosamide treatment. Nonetheless, our study shows a good safety profile of long-term niclosamide administration in a child with a rare neurodegenerative disease, and illustrates the potential of individualized therapeutic strategies in the management of inherited metabolic disorders, which could benefit both patients and the broader scientific and medical communities.

Myocardial Infarction with Non-Obstructive Coronary Arteries: A Puzzle in Search of a Solution.

The term myocardial infarction with non-obstructive coronary arteries (MINOCA), defines a puzzling event occurring in the absence of obstructive coronary artery disease on coronary angiography and without an overt potential cause. However, a practical diagnostic work-up is often difficult, due to the heterogeneous etiologies and pathophysiology of MINOCA. This review aims to provide a comprehensive overview focusing on epidemiology, etiopathogenesis, diagnostic tools and therapeutic strategies for subjects with MINOCA, in order to provide a prompt and accurate diagnostic work-up and an adequate therapeutic approach in this subset population. This educational review was carried out by following the standard methods of the Cochrane Collaboration and the PRISMA statement. The terms "MINOCA" OR ("myocardial infarction" AND ("non-obstructive" OR "non-obstructive")) were searched in PubMed and Embase databases (in Title and/or Abstract) from 1st January 2003 until 31st May 2022. Etiologic findings, clinical presentation and the degree of hemodynamic impairment play a pivotal role in defining the patient's natural history and prognostic outcome, and may significantly impact on the decision-making strategies and therapeutic approaches. Despite further advances in diagnostic and therapeutic strategies, MINOCA remains a challenging conundrum in clinical practice. Clinicians should be aware of the different potential etiologies and pathogenic mechanisms of MINOCA, in order to carry out a comprehensive diagnostic work-up and implement a tailored therapeutic approach.

Cardiac herniation: A practical review in the emergency setting.

Albeit described since 1948, cardiac herniations still represent an under-recognized clinical entity in the general population, due to their difficult diagnostic detection and to a limited knowledge in clinical practice. This paper aims to provide an updated overview focusing on definition, clinical presentation and diagnostic work-up of cardiac herniations, as well as on further findings concerning prognoses and available therapeutic options. This narrative review was performed by following the standard methods of the Cochrane Collaboration and the PRISMA statement. A Pubmed search was conducted using the following keywords (in Title and/or Abstract): ("cardiac" OR "heart") AND ("herniation" OR "hernia"). All available high quality resources containing information on epidemiology, etiopathogenesis, clinical findings, diagnostic tools and therapeutic strategies, were included in our search. Causative agents, location and the degree of haemodynamic impairment were found to play a pivotal role in defining the patient's natural history and prognostic outcomes, and in detecting potential associated clinical conditions which may significantly impact on first line decision-making strategy. Cardiac herniations remain a rare and life-threatening pathological injury, whose knowledge is still very limited in clinical practice. Clinicians should be aware of such a clinical entity and of its wide spectrum of clinical manifestations, particularly in high-risk subsets of patients, in order to provide the most appropriate decision-making strategy and timely therapeutic approach.

Reconstructing the patient's natural history from electronic health records.

The automatic extraction of a patient's natural history from Electronic Health Records (EHRs) is a critical step towards building intelligent systems that can reason about clinical variables and support decision making. Although EHRs contain a large amount of valuable information about the patient's medical care, this information can only be fully understood when analyzed in a temporal context. Any intelligent system should then be able to extract medical concepts, date expressions, temporal relations and the temporal ordering of medical events from the free texts of EHRs; yet, this task is hard to tackle, due to the domain specific nature of EHRs, writing quality and lack of structure of these texts, and more generally the presence of redundant information. In this paper, we introduce a new Natural Language Processing (NLP) framework, capable of extracting the aforementioned elements from EHRs written in Spanish using rule-based methods. We focus on building medical timelines, which include disease diagnosis and its progression over time. By using a large dataset of EHRs comprising information about patients suffering from lung cancer, we show that our framework has an adequate level of performance by correctly building the timeline for 843 patients from a pool of 989 patients, achieving a precision of 0.852.

Reconstructing the Patient's Natural History from Electronic Health Records

Reconstructing the Patient's Natural History from Electronic Health Records

Histology and Biaxial Mechanical Behavior of Abdominal Aortic Aneurysm Tissue Samples.

Abdominal aortic aneurysms (AAAs) represent permanent, localized dilations of the abdominal aorta that can be life-threatening if progressing to rupture. Evaluation of risk of rupture depends on understanding the mechanical behavior of patient AAA walls. In this project, a series of patient AAA wall tissue samples have been evaluated through a combined anamnestic, mechanical, and histopathologic approach. Mechanical properties of the samples have been characterized using a novel, strain-controlled, planar biaxial testing protocol emulating the in vivo deformation of the aorta. Histologically, the tissue ultrastructure was highly disrupted. All samples showed pronounced mechanical stiffening with stretch and were notably anisotropic, with greater stiffness in the circumferential than the axial direction. However, there were significant intrapatient variations in wall stiffness and stress. In biaxial tests in which the longitudinal stretch was held constant at 1.1 as the circumferential stretch was extended to 1.1, the maximum average circumferential stress was 330 ± 70 kPa, while the maximum average axial stress was 190 ± 30 kPa. A constitutive model considering the wall as anisotropic with two preferred directions fit the measured data well. No statistically significant differences in tissue mechanical properties were found based on patient gender, age, maximum bulge diameter, height, weight, body mass index, or smoking history. Although a larger patient cohort is merited to confirm these conclusions, the project provides new insight into the relationships between patient natural history, histopathology, and mechanical behavior that may be useful in the development of accurate methods for rupture risk evaluation.

Uncovering the natural history of cancer from post-mortem cross-sectional diameters of hepatic metastases

We develop a mathematical and statistical methodology for estimation of important unobservable characteristics of the individual natural history of cancer from a sample of cross-sectional diameters of liver metastases measured at autopsy. Estimation of the natural history of cancer is based on a previously proposed stochastic model of cancer progression tailored to this type of observations. The model accounts for primary tumour growth, shedding of metastases, their selection, latency and growth in a given secondary site. The model was applied to the aforementioned data on 428 liver metastases detected in one untreated small cell lung cancer patient. Identifiable model parameters were estimated by the method of maximum likelihood and through minimizing the [Formula: see text] distance between theoretical and empirical cumulative distribution functions. The model with optimal parameters provided an excellent fit to the data. Results of data analysis support, if only indirectly, the hypothesis of the existence of stem-like cancer cells in the case of small cell lung carcinoma and point to the possibility of suppression of metastatic growth by a large primary tumour. They also lead to determination of the lower and upper bounds for the age of cancer onset and expected duration of metastatic latency. Finally, model-based inference on the patient's natural history of cancer allowed us to conclude that resection of the primary tumour would most likely not have had a curative effect.

Insuficiencia cardiaca crónica

Chronic heart failure (CHF), congestive usually, is often the end stage of many heart diseases. Despite the undoubted progress in the treatment, CHF continues having high mortality rates and with frequent hospital admissions and re-admissions. Knowledge of patient's natural history is very important in order to address the disease and to prevent or delay the development of the syndrome in its fullest expression. The onset of CHF starts before symptoms, due to the presence of risk factors. The diagnosis is based on the symptoms and physical signs. Notwithstanding the measurement of plasma natriuretic peptide concentrations is the diagnostic key in patients with a suspected diagnosis of CHF, it is always necessary the echocardiography to identify structural or functional cardiac disorders.

Malignant abdominal paraganglioma presenting as a giant intra-peritoneal mass

INTRODUCTIONParaganglioma is a malignant tumor that arises from the extra adrenal paraganglionic cells of the sympathetic or parasympathetic systems. Herein, we present a case of abdominal mass of unknown histology that underwent a very difficult surgical mass resection. Its final histologic diagnosis was non-functional paraganglioma that was presented as a huge intra-peritoneal mass. PRESENTATION OF CASEThe patient was a 55-year-old Iranian lady who referred to our center with a giant abdominal mass. Fine needle aspiration (FNA) biopsy showed undifferentiated carcinoma. After laparotomy for mass resection pathology evaluation revealed; malignant paraganglioma, non-metastatic type. Further post-operative patients evaluations showed that the tumor was sporadic in nature and the subsequent patient's natural history was uneventful. DISCUSSIONPathologic evaluations have key roles in the exact diagnosis of abdominal masses with unidentified sources. For the paragangliomas, all of them should be regarded malignant until proved otherwise. However, combined use of biochemical markers, immunohistochemical techniques (IHC), and genetic analysis have key roles in the diagnosis and treatment of paragangliomas. Additionally, surgical removal is the proved curative way of paraganglioma treatment. CONCLUSIONAsymptomatic intra-peritoneal paraganglioma is very rare, especially its malignant variety. This case emphasizes that full pathologic investigation would reveal the exact nature of idiopathic abdominal masses, especially in the state of absence of typical clinical and para-clinical symptoms.

Cost-Effectiveness Analysis of the Early Conversion of Tacrolimus to Mammalian Target of Rapamycin Inhibitors in Patients with Renal Transplantation

Background Renal replacement therapies which consist of renal transplantation and dialysis are the only treatment options for patients with terminal renal failure. These therapies have changed the outcome from being fatal to being a chronic disease. Kidney transplantation involves the use of immunosuppressive agents to prevent rejection. Currently, several immunosuppressive agents have shown efficacy, safety, and different costs. Objective The aim was to evaluate the cost-effectiveness of early conversion from tacrolimus to mammalian target of rapamycin inhibitors sirolimus or everolimus versus continuous treatment with tacrolimus among renal transplantat patients in Colombia. Methods We performed systematic literature review to extract data for clinical effectiveness and safety of tacrolimus replacement schemes for immunosuppressive therapy in renal transplantation in adults. A Markov model in TreeAge was developed, simulating the patient's natural history with renal transplantation. The perspective of the Colombian Health System was used, including only direct costs. The cost-effectiveness ratio and incremental cost-effectiveness ratio were estimated. Deterministic and probabilistic sensitivity analyses were performed. A 5% discount rate was applied in costs and health results. Results Results for the replacement of tacrolimus to sirolimus are provided. The cost per year of additional life gained for sirolimus was Col$2,441,171.43; the cost for avoided loss was Col$4,014,152.84. The acceptability curve shows that a strategy with sirolimus is the most cost-effective one. Conclusions This study suggested that the sirolimus strategy is cost-effective in Colombia for patients with renal transplantation using as threshold less than three times the gross domestic product (GDP) per capita of Colombia per life of years gained.

Hyperactive behaviour in the mouse model of mucopolysaccharidosis IIIB in the open field and home cage environments

Mucopolysaccharidosis IIIB (MPS IIIB) is a lysosomal storage disorder characterized by severe behavioural disturbances and progressive loss of cognitive and motor function. There is no effective treatment, but behavioural testing is a valuable tool to assess neurodegeneration and the effect of novel therapies in mouse models of disease. Several groups have evaluated behaviour in this model, but the data are inconsistent, often conflicting with patient natural history. We hypothesize that this discrepancy could be due to differences in open field habituation and home cage behaviour. Eight-month-old wild-type and MPS IIIB mice were tested in a 1-h open field test, performed 1.5 h after lights on, and a 24-h home cage behaviour test performed after 24 h of acclimatization. In the 1-h test, MPS IIIB mice were hyperactive, with increased rapid exploratory behaviour and reduced immobility time. No differences in anxiety were seen. Over the course of the test, differences became more pronounced with maximal effects at 1 h. The 24-hour home cage test was less reliable. There was evidence of increased hyperactivity in MPS IIIB mice, however, immobility was also increased, suggesting a level of inconsistency in this test. Performance of open field analysis within 1-2 h after lights on is probably critical to achieving maximal success as MPS IIIB mice have a peak in activity around this time. The open field test effectively identifies hyperactive behaviour in MPS IIIB mice and is a significant tool for evaluating effects of therapy on neurodegeneration.

Can we eliminate placebo in ALS clinical trials?

BACKGROUND: Previous studies concluded that the decline in strength in patients with amyotrophic lateral sclerosis (ALS) is a linear function. If so, a patient's natural history might serve as the control, instead of placebo, in a clinical trial.METHODS: A placebo‐controlled ALS clinical trial included a natural history phase, followed by a 6‐month treatment phase. Each patient's forced vital capacity (FVC) score and maximal voluntary isometric contraction (MVIC) raw scores were measured monthly, standardized, and averaged into megascores. For 138 patients, the arm, leg, FVC, arm+leg combination, and arm+leg+FVC combination megascore slopes during the natural history phase and during the placebo phase were compared.RESULTS: The mean slope of megascores during the natural history phase and the mean slope during the placebo phase were not different for the arm, leg, and arm+leg megascores, but were different for the FVC and arm+leg+FVC combination megascores.CONCLUSIONS: Natural history controls may be useful in ALS exploratory trials that use arm megascore slope as the primary outcome measure. However, there are distinct limitations to the use of natural history controls, so that Phase 3 ALS clinical trials require placebo controls.