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Background: The dominant artery blood supply is a characteristic of hepatocellular carcinoma (HCC). However, it is not known whether the blood supply can predict the post-hepatectomy prognosis of patients with HCC. This retrospective study investigated the prognostic value of the portal venous and arterial blood supply estimated on triphasic liver CT (as a portal venous coefficient, PVC, and hepatic arterial coefficient, HAC, respectively) in patients with HCC following hepatectomy. Methods: HCC patients who were tested by triphasic liver CT 2 weeks before hepatectomy and received R0 hepatectomy at the Second Affiliated Hospital, Kunming Medical University between January 1, 2016 and December 31, 2020, were retrospectively screened. Their PVC and HAC, and other variables were analyzed for the prediction of overall survival (OS) and recurrence-free survival (RFS) using the least absolute shrinkage and selection operator and Cox proportional hazard regression models. Results: Four hundred and nineteen patients (53.2 ± 10.6 years of age and 370 men) were evaluated. A shorter OS was independently associated with higher blood albumin and total bilirubin grade [hazard ratio (HR) 2.020, 95% confidence interval (CI) 1.534-2.660], higher Barcelona Clinic Liver Cancer (BCLC) stage (HR 1.514, 95% CI 1.290-1.777), PVC ≤ 0.386 (HR 1.628, 95% CI 1.149-2.305), and HAC > 0.029 (HR 1.969, 95% CI 1.380-2.809). A shorter RFS was independently associated with male (HR 1.652, 95% CI 1.005-2.716), higher serum α-fetoprotein ≥ 400 ng/mL (HR 1.672, 95% CI 1.236-2.263), higher BCLC stage (HR 1.516, 95% CI 1.300-1.768), tumor PVC ≤ 0.386 (HR 1.641, 95% CI 1.198-2.249), and tumor HAC > 0.029 (HR 1.455, 95% CI 1.060-1.997). Conclusion: Tumor PVC or HAC before hepatectomy is valuable for independently predicting postoperative survival of HCC patients.
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Several X-linked genes escape from X chromosome inactivation (XCI), while differences in escape across cell types and tissues are still poorly characterized. Here, we developed scLinaX for directly quantifying relative gene expression from the inactivated X chromosome with droplet-based single-cell RNA sequencing (scRNA-seq) data. The scLinaX and differentially expressed gene analyses with large-scale blood scRNA-seq datasets consistently identified the stronger escape in lymphocytes than in myeloid cells. An extension of scLinaX to a 10x multiome dataset (scLinaX-multi) suggested a stronger escape in lymphocytes than in myeloid cells at the chromatin-accessibility level. The scLinaX analysis of human multiple-organ scRNA-seq datasets also identified the relatively strong degree of escape from XCI in lymphoid tissues and lymphocytes. Finally, effect size comparisons of genome-wide association studies between sexes suggested the underlying impact of escape on the genotype-phenotype association. Overall, scLinaX and the quantified escape catalog identified the heterogeneity of escape across cell types and tissues.
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Análise de Célula Única , Inativação do Cromossomo X , Inativação do Cromossomo X/genética , Humanos , Análise de Célula Única/métodos , Feminino , Linfócitos/metabolismo , Masculino , Estudo de Associação Genômica Ampla , Animais , Células Mieloides/metabolismo , Camundongos , Análise de Sequência de RNA/métodos , Especificidade de Órgãos , Genes Ligados ao Cromossomo X/genéticaRESUMO
OBJECTIVE: To comprehend the main characteristics and historical evolution of health financing transition in China. METHODS: Data were collected from various sources, including the Global Health Expenditure Database (GHED), China Health Statistics Yearbook, National Health Finance Annual Report, China ' s Total Health Expenditure Research Report, et al. Descriptive statistics and literature study was conducted. RESULTS: Since the beginning of the 21st century, most countries in the world had witnessed a transition of health financing, characterized by the expansion of health financing scale and the strengthening of public financing responsibility. Notably, China ' s health financing transition exhibited distinctive features. Firstly, there had been a more rapid expansion in health financing scale compared with global averages. Between 2000 and 2019, total health expenditure per capita experienced a remarkable increase of 816.6% at comparable prices, significantly surpassing average growth rates observed among other countries worldwide (102.1%). Secondly, greater efforts had been made to strengthen the responsibilities of public financing. From 2000 to 2019, there was a substantial decrease of 30.6 percentage points in the proportion of out-of-pocket health expenditure as a share of total health expenditure. This decline was significantly larger than the average reduction observed among other countries worldwide (5.6 percentage points). Thirdly, there had been a significant shift in government health expenditure allocation patterns, with an increased emphasis on "demand-side subsidies" surpassing "supply-side subsidies". Within the realm of "supply-side subsidies", funding directed towards hospitals had notably increased and surpassed that allocated to primary healthcare institutions and public health institutions. Based on these distinctive characteristics, this paper expanded China ' s health financing transition into three dimensions: Scale dimension, structure dimension and flow dimension. Using a comprehensive analytical framework, the history of China ' s health financing transition was roughly divided into four stages: The planned economy stage, the economic transition stage, the post-SARS stage and the new health system reform stage. The main features and evolutionary logic associated with each stage were analyzed. CONCLUSION: Above all, the health financing system should be enhanced in terms of vertical "embeddedness" and horizontal "complementarity". Moreover, the significance of health financing transition in preserving hidden value and mitigating public risk should be emphasized, and there is a need for an improved two-way trade-off mechanism that balances value and risk. Additionally, the ethical principles associated with health financing transition should be considered comprehensively, while optimizing budget decision-making within the government ' s actual governance model. Lastly, it is crucial to recognize the overall and profound impact of modern medicine development and explore long-term strategies and pathways for health financing transition in China.
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Gastos em Saúde , Financiamento da Assistência à Saúde , China , Gastos em Saúde/tendências , Humanos , Financiamento Governamental/tendênciasRESUMO
In this study, we explored the changes in plant community diversity and their relationship with soil factors under shrub encroachment pressure by selecting four marsh areas in Sanjiang Plain with different degrees of shrub cover (a, 0≤a≤100%), including marsh with no shrub encroachment (a=0), light shrub encroachment (0
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Biodiversidade
, Solo
, Áreas Alagadas
, China
, Solo/química
, Dinâmica Populacional
, Poaceae/crescimento & desenvolvimento
, Plantas/classificação
, Desenvolvimento Vegetal
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OBJECTIVE: The purpose of this study was to determine the technical feasibility and safety of middle meningeal arterial (MMA) embolization combined with drilling drainage in the treatment of acute epidural hematoma (AEDH) by comparing it with traditional craniotomy in the treatment. METHODS: One hundred seventeen patients with AEDH treated for MMA embolization combined with drilling and drainage or craniotomy hematoma removal from January 2017 to September 2020 were retrospectively analyzed and divided into a craniotomy group (n=85) and a minimally invasive group (n=32). Hematoma removal was performed in the craniotomy group, and MMA embolization combined with drilling and drainage was performed in the minimally invasive group. The general clinical data, imaging data, surgery, and follow-up of the 2 groups were compared and analyzed. RESULTS: Compared with the craniotomy group, the residual hematoma volume in the minimally invasive group was higher than in the craniotomy group. The average postoperative drainage duration in the minimally invasive group was longer than in the craniotomy group. Compared with the craniotomy group, the minimally invasive group was associated with shorter operative time, less intraoperative bleeding, and lower rates of postoperative rebleeding. In addition, the incidence of postoperative complications and length of hospitalization in the minimally invasive group were significantly shortened. CONCLUSION: Middle meningeal arterial embolization combined with drilling and drainage in the treatment of AEDH caused by MMA active bleeding is safe, effective, and more minimally invasive, and can be promoted and applied.
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Craniotomia , Drenagem , Embolização Terapêutica , Hematoma Epidural Craniano , Artérias Meníngeas , Humanos , Embolização Terapêutica/métodos , Feminino , Hematoma Epidural Craniano/cirurgia , Hematoma Epidural Craniano/terapia , Masculino , Craniotomia/métodos , Estudos Retrospectivos , Pessoa de Meia-Idade , Artérias Meníngeas/cirurgia , Drenagem/métodos , Adulto , Resultado do Tratamento , Idoso , Complicações Pós-Operatórias , Procedimentos Cirúrgicos Minimamente Invasivos/métodos , Estudos de Viabilidade , Duração da Cirurgia , Terapia CombinadaRESUMO
Identifying the causal variants and mechanisms that drive complex traits and diseases remains a core problem in human genetics. The majority of these variants have individually weak effects and lie in non-coding gene-regulatory elements where we lack a complete understanding of how single nucleotide alterations modulate transcriptional processes to affect human phenotypes. To address this, we measured the activity of 221,412 trait-associated variants that had been statistically fine-mapped using a Massively Parallel Reporter Assay (MPRA) in 5 diverse cell-types. We show that MPRA is able to discriminate between likely causal variants and controls, identifying 12,025 regulatory variants with high precision. Although the effects of these variants largely agree with orthogonal measures of function, only 69% can plausibly be explained by the disruption of a known transcription factor (TF) binding motif. We dissect the mechanisms of 136 variants using saturation mutagenesis and assign impacted TFs for 91% of variants without a clear canonical mechanism. Finally, we provide evidence that epistasis is prevalent for variants in close proximity and identify multiple functional variants on the same haplotype at a small, but important, subset of trait-associated loci. Overall, our study provides a systematic functional characterization of likely causal common variants underlying complex and molecular human traits, enabling new insights into the regulatory grammar underlying disease risk.
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This study was performed to investigate the frequency of angiogenic T cells (CD4+ Tang cells) among CD4+ T cells in patients with hepatitis B-induced liver cirrhosis (HBV-LC) and to evaluate the predictive role of these cells in the clinical outcome. In total, 185 patients with HBV-LC were recruited to measure the frequency of CD4+ Tang cells and chemokine levels using flow cytometry. RESULTS: There was 11.4% of death after 3-momth follow-up. The AUC for the ability of the frequency of CD4+ Tang cell to predict death was 0.724 (higher than those for the MELD score, FIB-4 score, and Child-Pugh classification). Cox regression analysis revealed an association between the frequency of CD4+ Tang cells and a 3-month survival chance. CONCLUSIONS: The lower frequency of CD4+ T ang cells was correlated with the severity of HBV-LC and may serve as a prognostic predictor.
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Linfócitos T CD4-Positivos , Cirrose Hepática , Humanos , Masculino , Feminino , Cirrose Hepática/virologia , Prognóstico , Pessoa de Meia-Idade , Linfócitos T CD4-Positivos/imunologia , Adulto , Hepatite B/complicações , Citometria de Fluxo , Quimiocinas/sangue , Hepatite B Crônica/complicações , IdosoRESUMO
BACKGROUND: Previous research has indicated that the rupture of intracranial aneurysm (IA) is a significant contributor to mortality from stroke. The objective of this present study was to examine the infiltration patterns in ruptured intracranial aneurysm (RIA), with the aim of generating insights that could inform the development of effective immunotherapeutic approaches. METHODS: To achieve this, we obtained Gene Expression Omnibus datasets pertaining to ruptured aneurysms, encompassing a total of 19 unruptured intracranial aneurysms (UIA) and 27 RIA. Subsequently, we conducted differential gene analysis and immune cell analysis specifically for the RIA. RESULTS: According to the conducted studies, the analysis has identified 10 hub genes within key modules. Through the utilization of Kyoto Encyclopedia of Genes and Genomes pathway and gene ontology terms analyses, it has been established that genes exhibiting differential expression are associated with immune cell infiltration in the aneurysm wall. Furthermore, the implementation of the CIBERSORT algorithm has revealed that there are 22 distinct immune cells between RIA and tissues of UIA. IA samples contained a higher proportion of macrophages M1, mast cells resting, and CD4 naive T cells, while macrophages M0 and neutrophils were relatively lower in RIA compared with those in UIA. CONCLUSION: The current study initially identified highly conservative hub genes and immune cell infiltration patterns in IA. Data presented in the current study improved understanding of immune genes that drive IA which can be exploited in development of effective immunotherapies.
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Aneurisma Roto , Aneurisma Intracraniano , Humanos , Aneurisma Intracraniano/genética , Aneurisma Roto/genética , Aneurisma Roto/metabolismoRESUMO
BACKGROUND: In the wake of China's relaxed zero-COVID policy, there was a surge in coronavirus disease 2019 (COVID-19) infections. This study aimed to examine the infection status and health service utilization among Beijing residents during a widespread outbreak, and to explore the factors that affected utilization of health services due to COVID-19. METHODS: A cross-sectional survey was conducted among Beijing residents from 13 January to 13 February 2023, collecting information on socio-demographic characteristics, health behaviours, COVID-19 infection status, utilization of health services and depressive symptoms. Multivariate Tobit regression was used for data analysis. RESULTS: Among the 53 924 participants, 14.7% were older than 60 years, 63.7% were female and 84.8% were married. In total, 44 992 of the 53 924 individuals surveyed (83.4%) contracted COVID-19 during 2020-2023, and 25.2% (13 587) sought corresponding health services. The majority of individuals (85.6%) chose in-person healthcare, while 14.4% chose internet-based healthcare. Among those who chose in-person healthcare, 58.6% preferred primary healthcare institutions and 41.5% were very satisfied with the treatment. Factors affecting health service utilization include being female (ß = -0.15, P < 0.001), older than 60 years (ß = 0.23, P < 0.01), non-healthcare workers (ß = -0.60, P < 0.001), rich self-rated income level (ß = 0.59, P < 0.001), having underlying disease (ß = 0.51, P < 0.001), living alone (ß = -0.19, P < 0.05), depressive symptoms (ß = 0.06, P < 0.001) and healthy lifestyle habits, as well as longer infection duration, higher infection numbers and severe symptoms. CONCLUSION: As COVID-19 is becoming more frequent and less severe, providing safe and accessible healthcare remains critical. Vulnerable groups such as the elderly and those with underlying conditions need reliable health service. Prioritizing primary healthcare resources and online medical services have played a vital role in enhancing resource utilization efficiency.
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COVID-19 , Idoso , Humanos , Feminino , Masculino , Estudos Transversais , Pequim/epidemiologia , Aceitação pelo Paciente de Cuidados de Saúde , Instalações de SaúdeRESUMO
It is unclear whether Gross Domestic Product (GDP) and greenness have additional modifying effects on the association between air pollution and respiratory system disease. Utilizing a time-stratified case-crossover design with a distributed lag linear model, we analyzed the association between six pollutants (PM2.5, PM10, NO2, SO2, O3, and CO) and 555,498 respiratory hospital admissions in Beijing from 1st January 2016 to 31st December 2019. We employed conditional logistic regression, adjusting for meteorological conditions, holidays and influenza, to calculate percent change of hospitalization risk. Subsequently, we performed subgroup analysis to investigate potential effect modifications using a two-sample z test. Every 10 µg/m3 increase in PM2.5, PM10, NO2, SO2, and O3 led to increases of 0.26% (95%CI: 0.17%, 0.35%), 0.15% (95%CI: 0.09%, 0.22%), 0.61% (95%CI: 0.44%, 0.77%), 1.72% (95%CI: 1.24%, 2.21%), and 0.32% (95%CI: 0.20%, 0.43%) in admissions, respectively. Also, a 1 mg/m3 increase in CO levels resulted in a 2.50% (95%CI: 1.96%, 3.04%) rise in admissions. The links with NO2 (p < 0.001), SO2 (p < 0.001), O3 (during the warm season, p < 0.001), and CO (p < 0.001) were significantly weaker among patients residing in areas with higher levels of greenness. No significant modifying role of GDP was observed. Greenness can help mitigate the effects of air pollutants, while the role of GDP needs further investigation.
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CdZnTe (CZT) is a new type of compound semiconductor that has emerged in recent years. Compared to other semiconductor materials, it possesses an ideal bandgap, high density, and high electron mobility, rendering it an excellent room-temperature composite semiconductor material for X-ray and γ-ray detectors. Due to the exceptional performance of CZT material, detectors manufactured using it exhibit high energy resolution, spatial resolution, and detection efficiency. They also have the advantage of operating at room temperature. CZT array detectors, furthermore, demonstrate outstanding spatial detection and three-dimensional imaging capabilities. Researchers worldwide have conducted extensive studies on this subject. This paper, building upon this foundation, provides a comprehensive analysis of CZT crystals and CZT array detectors and summarizes existing research to offer valuable insights for envisioning new detector methodologies.
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The depletion of disruptive variation caused by purifying natural selection (constraint) has been widely used to investigate protein-coding genes underlying human disorders1-4, but attempts to assess constraint for non-protein-coding regions have proved more difficult. Here we aggregate, process and release a dataset of 76,156 human genomes from the Genome Aggregation Database (gnomAD)-the largest public open-access human genome allele frequency reference dataset-and use it to build a genomic constraint map for the whole genome (genomic non-coding constraint of haploinsufficient variation (Gnocchi)). We present a refined mutational model that incorporates local sequence context and regional genomic features to detect depletions of variation. As expected, the average constraint for protein-coding sequences is stronger than that for non-coding regions. Within the non-coding genome, constrained regions are enriched for known regulatory elements and variants that are implicated in complex human diseases and traits, facilitating the triangulation of biological annotation, disease association and natural selection to non-coding DNA analysis. More constrained regulatory elements tend to regulate more constrained protein-coding genes, which in turn suggests that non-coding constraint can aid the identification of constrained genes that are as yet unrecognized by current gene constraint metrics. We demonstrate that this genome-wide constraint map improves the identification and interpretation of functional human genetic variation.
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Genoma Humano , Genômica , Modelos Genéticos , Mutação , Humanos , Acesso à Informação , Bases de Dados Genéticas , Conjuntos de Dados como Assunto , Frequência do Gene , Genoma Humano/genética , Mutação/genética , Seleção GenéticaRESUMO
The harmonic mode-locking (HML) "invisible" pulsation (IP) is reported, here, in a bidirectional passively mode-locked fiber laser (BPMLFL). With the help of dispersive Fourier transform (DFT) technology, it is found that due to the alike nonlinear effects experienced by two pulse trains in HML, their evolution is consistent during the IP. Further, as the increase of pump power, period-doubling bifurcations (PDBs) can be observed based on the IP phenomenon in the HML regime, the PDB path experienced by the HML from steady to chaotic is statistically obtained. Finally, the IP and PDB in the bidirectional laser are reproduced and studied through numerical simulations. The effect of IP on the coherence of solitons is further analyzed. We believe our research results will provide new insights into the study of soliton dynamics in fiber lasers.
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RATIONALE: Brain arteriovenous malformations (BAVMs) are a relatively rare but very dangerous developmental abnormality of the blood vessels. Intracranial hemorrhage is the most common clinical manifestation of BAVMs, and has a high rate of rebleeding, disability, and mortality, which has a serious impact on patients' quality of life and working ability. Endovascular intervention was a new technique that emerged in recent years. Anhydrous ethanol embolization has been used with satisfactory results in the treatment of peripheral arteriovenous malformations, but there is a lack of practice in the treatment of BAVMs. We tried to treat BAVMs by embolizing malformed vessels with anhydrous alcohol in order to provide a safe and effective treatment for more patients with BAVMs. PATIENT CONCERNS: The patient was admitted to our hospital in the emergency department with "sudden onset of headache for more than 4 hours." At the time of admission, the patient was clearly conscious, not mentally alert, spoke fluently, and had a normal level of orientations. The direct and indirect responses to light were blunted. The patient's muscle strength, muscle tone, and sensation of the extremities were normal. National Institute of Health stroke scale score was 1. Head computed tomography at the onset suggested a right occipital hemorrhage and hematoma formation. DIAGNOSES: Brain arteriovenous malformations (BAVMs) were suspected based on preoperative imaging findings. INTERVENTIONS: After obtaining the consent of the patient and their family members, we performed whole brain angiography to determine the location of the lesion, and then, with the help of high-pressure cooker technology, targeted embolization of interventional BAVM was performed. The high-pressure cooker technology was achieved through spring coils, and the embolic material was anhydrous ethanol. OUTCOMES: The surgery was successful, and the patient recovered well without recurrence. LESSON: The successful performance of this surgery illustrates the feasibility of anhydrous ethanol-targeted ablation for BAVMs.
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Embolização Terapêutica , Malformações Arteriovenosas Intracranianas , Humanos , Qualidade de Vida , Malformações Arteriovenosas Intracranianas/diagnóstico por imagem , Malformações Arteriovenosas Intracranianas/terapia , Encéfalo , Resultado do Tratamento , Embolização Terapêutica/métodos , Angiografia Cerebral , Etanol , Estudos RetrospectivosRESUMO
Statistical fine-mapping prioritizes putative causal variants from a large number of candidate variants, and is widely used in expression quantitative loci (eQTLs) studies. In eQTL fine-mapping, the existence of causal variants for gene expression is not guaranteed, since the genetic heritability of gene expression explained by nearby (cis-) variants is limited. Here we introduce a refined fine-mapping algorithm, named Knockoff-Finemap combination (KFc). KFc estimates the probability that the causal variant(s) exist in the cis-window of a gene through construction of knockoff genotypes (i.e. a set of synthetic genotypes that resembles the original genotypes), and uses it to adjust the posterior inclusion probabilities (PIPs). Utilizing simulated gene expression data, we show that KFc results in calibrated PIP distribution with improved precision. When applied to gene expression data of 465 genotyped samples from the Japan COVID-19 Task Force (JCTF), KFc resulted in significant enrichment of a functional score as well as reporter assay hits in the top PIP bins. When combined with functional priors derived from an external fine-mapping study (GTEx), KFc resulted in a significantly higher proportion of hematopoietic trait putative causal variants in the top PIP bins. Our work presents improvements in the precision of a major fine-mapping algorithm.
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Pressure-induced phases of ZnO have attracted considerable attention owing to their excellent electronic and optical properties. This study provides a vital insight into the electronic structure, optical characteristics, and structural properties of the AsTi (Bi) phase of ZnO under high pressure via the DFT-based first-principles approach. The phase transformation from BN(Bk) to the Bi phase of ZnO is estimated at 16.1 GPa using local density approximation, whereas the properties are explored precisely by the hybrid functional B3LYP. The electronic structure exploration confirms that the Bi phase is an insulator with a wider direct bandgap, which expands by increasing pressure. The dielectric function evidenced that the Bi phase behaves as a dielectric in the visible region and a metallic material at 18 eV. Optical features such as the refractive index and loss function revealed the transparent nature of the Bi phase in the UV range. Moreover, the considered Bi phase is found to possess a high absorption coefficient in the ultraviolet region. This research provides strong theoretical support for the development of Bi-phase ZnO-based optoelectronic and photovoltaic devices.
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Aims The aim of this study was to investigate the anti-tumor efficacy of brucine on intrahepatic cholangiocarcinoma (ICC). Methods ICC QBC939 cells were treated with brucine, cell viability, cell cycle and apoptosis were analyzed using CCK-8 and flow cytometry. The expression of COX-2 and apoptosis related proteins Casp3, Bax and Bcl-2 were detected by Western blot analysis. QBC939 cells were subcutaneously transplanted into nude mice and the mice were injected with brucine intraperitoneally. The expression of Ki67, COX-2 and apoptosis related proteins were detected by immunohistochemical staining and Western blot analysis. Results Brucine significantly inhibited the proliferation and cell cycle progression while promoted the apoptosis of QBC939 cells. The expression of the apoptotic proteins Casp3 and Bax was upregulated, while the expression of Bcl-2 and COX-2 was downregulated in QBC939 cells with brucine treatment. Moreover, the overexpression of COX-2 could antagonize the effects of brucine on QBC939 cells. In vivo, brucine inhibited subcutaneous tumor formation in nude mice, and the expression of Ki67, COX-2 and Bcl-2 decreased while the expression of Casp3 and Bax increased in tumor tissues from nude mice with brucine treatment. Conclusions Brucine can significantly inhibit the progression of cholangiocarcinoma in vitro and in vivo, and the mechanism may be related to the inhibition of COX-2 expression.
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Atopic dermatitis (AD) is a skin disease that is heterogeneous both in terms of clinical manifestations and molecular profiles. It is increasingly recognized that AD is a systemic rather than a local disease and should be assessed in the context of whole-body pathophysiology. Here we show, via integrated RNA-sequencing of skin tissue and peripheral blood mononuclear cell (PBMC) samples along with clinical data from 115 AD patients and 14 matched healthy controls, that specific clinical presentations associate with matching differential molecular signatures. We establish a regression model based on transcriptome modules identified in weighted gene co-expression network analysis to extract molecular features associated with detailed clinical phenotypes of AD. The two main, qualitatively differential skin manifestations of AD, erythema and papulation are distinguished by differential immunological signatures. We further apply the regression model to a longitudinal dataset of 30 AD patients for personalized monitoring, highlighting patient heterogeneity in disease trajectories. The longitudinal features of blood tests and PBMC transcriptome modules identify three patient clusters which are aligned with clinical severity and reflect treatment history. Our approach thus serves as a framework for effective clinical investigation to gain a holistic view on the pathophysiology of complex human diseases.