Identifying subtypes of heart failure from three electronic health record sources with machine learning: an external, prognostic, and genetic validation study.

BACKGROUND: Machine learning has been used to analyse heart failure subtypes, but not across large, distinct, population-based datasets, across the whole spectrum of causes and presentations, or with clinical and non-clinical validation by different machine learning methods. Using our published framework, we aimed to discover heart failure subtypes and validate them upon population representative data. METHODS: In this external, prognostic, and genetic validation study we analysed individuals aged 30 years or older with incident heart failure from two population-based databases in the UK (Clinical Practice Research Datalink [CPRD] and The Health Improvement Network [THIN]) from 1998 to 2018. Pre-heart failure and post-heart failure factors (n=645) included demographic information, history, examination, blood laboratory values, and medications. We identified subtypes using four unsupervised machine learning methods (K-means, hierarchical, K-Medoids, and mixture model clustering) with 87 of 645 factors in each dataset. We evaluated subtypes for (1) external validity (across datasets); (2) prognostic validity (predictive accuracy for 1-year mortality); and (3) genetic validity (UK Biobank), association with polygenic risk score (PRS) for heart failure-related traits (n=11), and single nucleotide polymorphisms (n=12). FINDINGS: We included 188 800, 124 262, and 9573 individuals with incident heart failure from CPRD, THIN, and UK Biobank, respectively, between Jan 1, 1998, and Jan 1, 2018. After identifying five clusters, we labelled heart failure subtypes as (1) early onset, (2) late onset, (3) atrial fibrillation related, (4) metabolic, and (5) cardiometabolic. In the external validity analysis, subtypes were similar across datasets (c-statistics: THIN model in CPRD ranged from 0·79 [subtype 3] to 0·94 [subtype 1], and CPRD model in THIN ranged from 0·79 [subtype 1] to 0·92 [subtypes 2 and 5]). In the prognostic validity analysis, 1-year all-cause mortality after heart failure diagnosis (subtype 1 0·20 [95% CI 0·14-0·25], subtype 2 0·46 [0·43-0·49], subtype 3 0·61 [0·57-0·64], subtype 4 0·11 [0·07-0·16], and subtype 5 0·37 [0·32-0·41]) differed across subtypes in CPRD and THIN data, as did risk of non-fatal cardiovascular diseases and all-cause hospitalisation. In the genetic validity analysis the atrial fibrillation-related subtype showed associations with the related PRS. Late onset and cardiometabolic subtypes were the most similar and strongly associated with PRS for hypertension, myocardial infarction, and obesity (p<0·0009). We developed a prototype app for routine clinical use, which could enable evaluation of effectiveness and cost-effectiveness. INTERPRETATION: Across four methods and three datasets, including genetic data, in the largest study of incident heart failure to date, we identified five machine learning-informed subtypes, which might inform aetiological research, clinical risk prediction, and the design of heart failure trials. FUNDING: European Union Innovative Medicines Initiative-2.

Upregulating sirtuin 6 ameliorates glycolysis, EMT and distant metastasis of pancreatic adenocarcinoma with krüppel-like factor 10 deficiency.

Krüppel-like factor 10 (KLF10) is a tumor suppressor in multiple cancers. In a murine model of spontaneous pancreatic adenocarcinoma (PDAC), additional KLF10 depletion accelerated distant metastasis. However, Klf10 knockout mice, which suffer from metabolic disorders, do not develop malignancy. The mechanisms of KLF10 in PDAC progression deserve further exploration. KLF10-depleted and KLF10-overexpressing PDAC cells were established to measure epithelial-mesenchymal transition (EMT), glycolysis, and migration ability. A murine model was established to evaluate the benefit of genetic or pharmacological manipulation in KLF10-depleted PDAC cells (PDACshKLF10). Correlations of KLF10 deficiency with rapid metastasis, elevated EMT, and glycolysis were demonstrated in resected PDAC tissues, in vitro assays, and murine models. We identified sirtuin 6 (SIRT6) as an essential mediator of KLF10 that modulates EMT and glucose homeostasis. Overexpressing SIRT6 reversed the migratory and glycolytic phenotypes of PDACshKLF10 cells. Linoleic acid, a polyunsaturated essential fatty acid, upregulated SIRT6 and prolonged the survival of mice injected with PDACshKLF10. Modulating HIF1α and NFκB revealed that EMT and glycolysis in PDAC cells were coordinately regulated upstream by KLF10/SIRT6 signaling. Our study demonstrated a novel KLF10/SIRT6 pathway that modulated EMT and glycolysis coordinately via NFκB and HIF1α. Activation of KLF10/SIRT6 signaling ameliorated the distant progression of PDAC.Clinical Trial Registration: ClinicalTrials.gov. identifier: NCT01666184.

Machine learning for subtype definition and risk prediction in heart failure, acute coronary syndromes and atrial fibrillation: systematic review of validity and clinical utility.

BACKGROUND: Machine learning (ML) is increasingly used in research for subtype definition and risk prediction, particularly in cardiovascular diseases. No existing ML models are routinely used for cardiovascular disease management, and their phase of clinical utility is unknown, partly due to a lack of clear criteria. We evaluated ML for subtype definition and risk prediction in heart failure (HF), acute coronary syndromes (ACS) and atrial fibrillation (AF). METHODS: For ML studies of subtype definition and risk prediction, we conducted a systematic review in HF, ACS and AF, using PubMed, MEDLINE and Web of Science from January 2000 until December 2019. By adapting published criteria for diagnostic and prognostic studies, we developed a seven-domain, ML-specific checklist. RESULTS: Of 5918 studies identified, 97 were included. Across studies for subtype definition (n = 40) and risk prediction (n = 57), there was variation in data source, population size (median 606 and median 6769), clinical setting (outpatient, inpatient, different departments), number of covariates (median 19 and median 48) and ML methods. All studies were single disease, most were North American (n = 61/97) and only 14 studies combined definition and risk prediction. Subtype definition and risk prediction studies respectively had limitations in development (e.g. 15.0% and 78.9% of studies related to patient benefit; 15.0% and 15.8% had low patient selection bias), validation (12.5% and 5.3% externally validated) and impact (32.5% and 91.2% improved outcome prediction; no effectiveness or cost-effectiveness evaluations). CONCLUSIONS: Studies of ML in HF, ACS and AF are limited by number and type of included covariates, ML methods, population size, country, clinical setting and focus on single diseases, not overlap or multimorbidity. Clinical utility and implementation rely on improvements in development, validation and impact, facilitated by simple checklists. We provide clear steps prior to safe implementation of machine learning in clinical practice for cardiovascular diseases and other disease areas.

Excess deaths in people with cardiovascular diseases during the COVID-19 pandemic.

AIMS: Cardiovascular diseases (CVDs) increase mortality risk from coronavirus infection (COVID-19). There are also concerns that the pandemic has affected supply and demand of acute cardiovascular care. We estimated excess mortality in specific CVDs, both 'direct', through infection, and 'indirect', through changes in healthcare. METHODS AND RESULTS: We used (i) national mortality data for England and Wales to investigate trends in non-COVID-19 and CVD excess deaths; (ii) routine data from hospitals in England (n = 2), Italy (n = 1), and China (n = 5) to assess indirect pandemic effects on referral, diagnosis, and treatment services for CVD; and (iii) population-based electronic health records from 3 862 012 individuals in England to investigate pre- and post-COVID-19 mortality for people with incident and prevalent CVD. We incorporated pre-COVID-19 risk (by age, sex, and comorbidities), estimated population COVID-19 prevalence, and estimated relative risk (RR) of mortality in those with CVD and COVID-19 compared with CVD and non-infected (RR: 1.2, 1.5, 2.0, and 3.0).Mortality data suggest indirect effects on CVD will be delayed rather than contemporaneous (peak RR 1.14). CVD service activity decreased by 60-100% compared with pre-pandemic levels in eight hospitals across China, Italy, and England. In China, activity remained below pre-COVID-19 levels for 2-3 months even after easing lockdown and is still reduced in Italy and England. For total CVD (incident and prevalent), at 10% COVID-19 prevalence, we estimated direct impact of 31 205 and 62 410 excess deaths in England (RR 1.5 and 2.0, respectively), and indirect effect of 49 932 to 99 865 deaths. CONCLUSION: Supply and demand for CVD services have dramatically reduced across countries with potential for substantial, but avoidable, excess mortality during and after the pandemic.

Predictors of Intraspinal Pressure and Optimal Cord Perfusion Pressure After Traumatic Spinal Cord Injury.

BACKGROUND/OBJECTIVES: We recently developed techniques to monitor intraspinal pressure (ISP) and spinal cord perfusion pressure (SCPP) from the injury site to compute the optimum SCPP (SCPPopt) in patients with acute traumatic spinal cord injury (TSCI). We hypothesized that ISP and SCPPopt can be predicted using clinical factors instead of ISP monitoring. METHODS: Sixty-four TSCI patients, grades A-C (American spinal injuries association Impairment Scale, AIS), were analyzed. For 24 h after surgery, we monitored ISP and SCPP and computed SCPPopt (SCPP that optimizes pressure reactivity). We studied how well 28 factors correlate with mean ISP or SCPPopt including 7 patient-related, 3 injury-related, 6 management-related, and 12 preoperative MRI-related factors. RESULTS: All patients underwent surgery to restore normal spinal alignment within 72 h of injury. Fifty-one percentage had U-shaped sPRx versus SCPP curves, thus allowing SCPPopt to be computed. Thirteen percentage, all AIS grade A or B, had no U-shaped sPRx versus SCPP curves. Thirty-six percentage (22/64) had U-shaped sPRx versus SCPP curves, but the SCPP did not reach the minimum of the curve, and thus, an exact SCPPopt could not be calculated. In total 5/28 factors were associated with lower ISP: older age, excess alcohol consumption, nonconus medullaris injury, expansion duroplasty, and less intraoperative bleeding. In a multivariate logistic regression model, these 5 factors predicted ISP as normal or high with 73% accuracy. Only 2/28 factors correlated with lower SCPPopt: higher mean ISP and conus medullaris injury. In an ordinal multivariate logistic regression model, these 2 factors predicted SCPPopt as low, medium-low, medium-high, or high with only 42% accuracy. No MRI factors correlated with ISP or SCPPopt. CONCLUSIONS: Elevated ISP can be predicted by clinical factors. Modifiable factors that may lower ISP are: reducing surgical bleeding and performing expansion duroplasty. No factors accurately predict SCPPopt; thus, invasive monitoring remains the only way to estimate SCPPopt.

Visibility Graph Analysis of Intraspinal Pressure Signal Predicts Functional Outcome in Spinal Cord Injured Patients.

To guide management of patients with acute spinal cord injuries, we developed intraspinal pressure monitoring from the injury site. Here, we examine the complex fluctuations in the intraspinal pressure signal using network theory. We analyzed 7097 h of intraspinal pressure data from 58 patients with severe cord injuries. Intraspinal pressure signals were split into hourly windows. Each window was mapped into a visibility graph as follows. Vertical bars were drawn at 0.1 Hz representing signal amplitudes. Each bar produced a node, thus totalling 360 nodes per graph. Two nodes were linked with an edge if the straight line through the nodes did not intersect a bar. We computed several topological metrics for each graph including diameter, modularity, eccentricity, and small-worldness. Patients were followed up for 20 months on average. Our data show that the topological structure of intraspinal pressure visibility graphs is highly sensitive to pathological events at the injury site, including cord compression (high intraspinal pressure), ischemia (low spinal cord perfusion pressure), and deranged autoregulation (high spinal pressure reactivity index). These pathological changes correlate with long graph diameter, high modularity, high eccentricity and reduced small-worldness. In a multivariate logistic regression model, age, neurological status on admission, and average node eccentricity were independent predictors of neurological improvement. We conclude that analysis of intraspinal pressure fluctuations after spinal cord injury as graphs, rather than as time series, captures clinically important information. Our novel technique may be applied to other signals recorded from injured central nervous system (CNS); for example, intracranial pressure, tissue metabolite, and oxygen levels.

Twenty-seven year surveillance of blood transfusion recipients infected with HIV-1 in Hebei Province, China.

We conducted an investigation of blood management in which blood transfusion recipients underwent molecular biological analysis, to trace the possible source of HIV infection. Epidemiological investigation was carried out among HIV-infected individuals. Blood transfusion recipients infected with HIV were tracked for the date of transfusion, reason for transfusion, hospital where transfusion was received, source of blood, components of transfusion, number of transfusions, and transfusion volume. A total of 285 blood transfusion recipients infected with HIV-1 were detected in Hebei over the study period, with 42.81% (122/285) detected through clinical diagnostic testing. These cases showed a concentrated distribution in southern Hebei, with local outbreak characteristics. A census of the population in Shahe County, which had a high concentration of cases, revealed that recipients of blood transfusions had an HIV infection rate of 15.54% (92/592). Post-transfusion infection frequently occurred among blood transfusion recipients at township medical institutions, with a peak in 1995. Owing to late detection of HIV infection among blood transfusion recipients, the rates of spousal transmission and mother-to-child transmission reached 20.87% and 28.05%, respectively. Around 1995, community medical institutions did not screen for HIV antibodies among paid blood donors, which was an important cause of the outbreak of HIV-1 infection among blood transfusion recipients. Our findings indicate that cases of blood transfusion-related infection decreased rapidly with gradual improvement in the HIV screening system for blood donors that began in 1995, particularly after full implementation of HIV nucleic acid testing of volunteer blood donors was begun in 2015.

Non-linear Dynamical Analysis of Intraspinal Pressure Signal Predicts Outcome After Spinal Cord Injury.

The injured spinal cord is a complex system influenced by many local and systemic factors that interact over many timescales. To help guide clinical management, we developed a technique that monitors intraspinal pressure from the injury site in patients with acute, severe traumatic spinal cord injuries. Here, we hypothesize that spinal cord injury alters the complex dynamics of the intraspinal pressure signal quantified by computing hourly the detrended fluctuation exponent alpha, multiscale entropy, and maximal Lyapunov exponent lambda. 49 patients with severe traumatic spinal cord injuries were monitored within 72 h of injury for 5 days on average to produce 5,941 h of intraspinal pressure data. We computed the spinal cord perfusion pressure as mean arterial pressure minus intraspinal pressure and the vascular pressure reactivity index as the running correlation coefficient between intraspinal pressure and arterial blood pressure. Mean patient follow-up was 17 months. We show that alpha values are greater than 0.5, which indicates that the intraspinal pressure signal is fractal. As alpha increases, intraspinal pressure decreases and spinal cord perfusion pressure increases with negative correlation between the vascular pressure reactivity index vs. alpha. Thus, secondary insults to the injured cord disrupt intraspinal pressure fractality. Our analysis shows that high intraspinal pressure, low spinal cord perfusion pressure, and impaired pressure reactivity strongly correlate with reduced multi-scale entropy, supporting the notion that secondary insults to the injured cord cause de-complexification of the intraspinal pressure signal, which may render the cord less adaptable to external changes. Healthy physiological systems are characterized by edge of chaos dynamics. We found negative correlations between the percentage of hours with edge of chaos dynamics (-0.01 ≤ lambda ≤ 0.01) vs. high intraspinal pressure and vs. low spinal cord perfusion pressure; these findings suggest that secondary insults render the intraspinal pressure more regular or chaotic. In a multivariate logistic regression model, better neurological status on admission, higher intraspinal pressure multi-scale entropy and more frequent edge of chaos intraspinal pressure dynamics predict long-term functional improvement. We conclude that spinal cord injury is associated with marked changes in non-linear intraspinal pressure metrics that carry prognostic information.

Baseline Investigation of HIV-1 Primary Drug Resistance Among Newly Diagnosed Treatment-Naïve HIV-1 Individuals in Hebei, China.

Human immunodeficiency virus (HIV) primary drug resistance (PDR) has influenced the long-term therapeutic effects of antiretroviral drugs. However, for the overall PDR prevalence in China, no report was found in published articles. In our study, an extensive cross-sectional investigation based on all newly diagnosed treatment-naive HIV-infected individuals was conducted. The overall prevalence of HIV-1 PDR among newly diagnosed treatment-naive HIV-1 individuals was 8.3% (60/720), obviously beyond the warning line (5.0%) set by WHO. The prevalence of PDR to PIs, nucleoside reverse transcriptase inhibitors, and non-nucleoside reverse transcriptase inhibitors was 4.9% (35/720), 0.4% (3/720), and 2.5% (18/720), respectively. Moreover, the occurrence of HIV-1 PDR strains was random among different prefectures. HIV-1 PDR strains were extensively circulating among the sexual contact population inside and outside the Hebei province, especially between neighboring provinces and Hebei. Hebei province has become the moderate level PDR epidemic area. Enhanced surveillance for PDR is necessary among treatment-naïve individuals in Hebei, and we must take effective measures to cut off the spread of HIV PDR strains.

Regional Transmission Pattern of HIV-1 Non-CRF01_AE Strains Circulating in Hebei Province, China.

HIV-1 genetic diversity has recently been more and more complicated in Hebei province. To know about the transmission pattern of HIV-1 in Hebei, the phylogenetic analysis of non-CRF01_AE strains was performed using the maximum-likelihood (ML) method. Four clusters and two clusters were observed in the CRF07_BC and subtype B ML tree, respectively. Of these clusters, men who have sex with men (MSM) sequences were the most frequent, and no pure heterosexual cluster was found in this study. Our findings highlighted the close transmission relationship between the main HIV-1 non-CRF01_AE strains and the sexual exposure especially among MSM between neighboring provinces, such as Beijing and Liaoning, and Hebei. This provides new evidence that the main strains of HIV-1 were introduced into Hebei through sexual exposure especially among MSM from neighboring provinces, suggesting that it is urgent for us to take measures together with neighboring provinces to cut off HIV-1 dissemination chain through MSM.

Continuous Monitoring and Visualization of Optimum Spinal Cord Perfusion Pressure in Patients with Acute Cord Injury.

The optimum spinal cord perfusion pressure (SCPP) after traumatic spinal cord injury (TSCI) is unknown. Here, we describe techniques to compute and display the optimum SCPP in real time. We recruited adults within 72 h of severe TSCI (American Spinal Injuries Association [ASIA] grades A-C). A pressure probe and a microdialysis catheter were placed on the injured cord. SCPP was computed as mean arterial pressure (MAP) minus intraspinal pressure (ISP), spinal pressure reactivity index (sPRx) as the running ISP/MAP correlation coefficient, and continuous optimum SCPP (cSCPPopt) as the SCPP that minimizes sPRx in a moving 4-h window. In 45 patients, we monitored ISP and blood pressure. In 14 patients, we also monitored injury site metabolism. cSCPPopt could be computed 45% of the time. Mean cSCPPopt varied by up to 60 mm Hg between patients. Each patient's cSCPPopt varied with time (standard deviation 10-20 mm Hg). Color-coded maps showing the sPRx/SCPP curve evolution enhanced visualization of cSCPPopt. Periods when SCPP ≈ cSCPPopt were associated with low injury site glucose, high pyruvate, and high lactate. Mean SCPP deviation from cSCPPopt correlated with worse neurological outcome at 9-12 months: ASIA grade improved in 30% of patients with <5 mm Hg deviation, 10% of patients with 5-15 mm Hg deviation, and no one with >15 mm Hg deviation. We conclude that real-time computation and visualization of cSCPPopt after TSCI are feasible. cSCPPopt appears to enhance glucose utilization at the injury site and varies widely between and within patients. Our data suggest that targeting cSCPPopt after TSCI might improve neurological outcome.

HIV-1 molecular epidemiology among newly diagnosed HIV-1 individuals in Hebei, a low HIV prevalence province in China.

New human immunodeficiency virus type 1 (HIV-1) diagnoses are increasing rapidly in Hebei. The aim of this study presents the most extensive HIV-1 molecular epidemiology investigation in Hebei province in China thus far. We have carried out the most extensive systematic cross-sectional study based on newly diagnosed HIV-1 positive individuals in 2013, and characterized the molecular epidemiology of HIV-1 based on full length gag-partial pol gene sequences in the whole of Hebei. Nine HIV-1 genotypes based on full length gag-partial pol gene sequence were identified among 610 newly diagnosed naïve individuals. The four main genotypes were circulating recombinant form (CRF)01_AE (53.4%), CRF07_BC (23.4%), subtype B (15.9%), and unique recombinant forms URFs (4.9%). Within 1 year, three new genotypes (subtype A1, CRF55_01B, CRF65_cpx), unknown before in Hebei, were first found among men who have sex with men (MSM). All nine genotypes were identified in the sexually contracted HIV-1 population. Among 30 URFs, six recombinant patterns were revealed, including CRF01_AE/BC (40.0%), CRF01_AE/B (23.3%), B/C (16.7%), CRF01_AE/C (13.3%), CRF01_AE/B/A2 (3.3%) and CRF01_AE/BC/A2 (3.3%), plus two potential CRFs. This study elucidated the complicated characteristics of HIV-1 molecular epidemiology in a low HIV-1 prevalence northern province of China and revealed the high level of HIV-1 genetic diversity. All nine HIV-1 genotypes circulating in Hebei have spread out of their initial risk groups into the general population through sexual contact, especially through MSM. This highlights the urgency of HIV prevention and control in China.

HIV-1 drug-resistant mutations and related risk factors among HIV-1-positive individuals experiencing treatment failure in Hebei Province, China.

BACKGROUND: To understand HIV-1 drug resistance in 11 prefectures of Hebei Province, China, we implemented a cross-sectional HIV-1 molecular epidemiological survey. METHODS: Blood samples were collected from 122 newly diagnosed drug-naïve HIV-1-positive individuals and 229 antiretroviral therapy (ART)-failure individuals from 11 prefectures in Hebei Province, China. Patient demographic data were obtained via face-to-face interviews using a standardized questionnaire when blood samples were collected. Genotyping of HIV-1 drug resistance (DR) was implemented using an in-house assay. RESULTS: In this study, the overall prevalence of HIV-1 DR was 35.5%. The prevalence of HIV-1 DR in participants experiencing treatment failure and ART-naïve participants was 51.9 and 5.9%, respectively. Mutations in protease inhibitors, nucleoside reverse transcriptase inhibitors (NRTIs), and non-NRTI (NNRTIs), as well as dual and multiple mutations were extensively seen in participants experiencing treatment failure. The proportions of NNRTI mutations (χ2 = 9.689, p = 0.002) and dual mutations in NRTIs and NNRTIs (χ2 = 39.958, p < 0.001) in participants experiencing treatment failure were significantly higher than those in ART-naïve participants. The distributions of M184V/I and M41L mutations differed significantly among three main HIV-1 genotypes identified. Viral load, symptoms in the past 3 months, CD4 counts, transmission route, and the duration of ART were found to be associated with HIV-1 DR. CONCLUSIONS: Our results suggest that new prevention and control strategies should be formulated according to the epidemic characteristics of HIV-1-resistant strains in Hebei Province, where antiretroviral drugs are widely used.

Krüpple-like factor 10 regulates radio-sensitivity of pancreatic cancer via UV radiation resistance-associated gene.

BACKGROUND AND PURPOSE: Krüpple-like factor 10 (Klf10), an early response gene of TGFß, was reported to be a prognostic biomarker for pancreatic cancer survival. The role of Klf10 in predicting tumor response to cancer treatment is unknown. MATERIALS AND METHODS: Genetically manipulated MiaPaCa and Panc-1 cells were established to evaluate clonogenic survival, autophagy, apoptosis and DNA repair after radiation. The interaction between Klf10 and UV radiation resistance-associated gene (UVRAG) was demonstrated by ChiP-PCR and luciferase reporter assay. Orthotopic murine tumor model and clinical specimens were used to evaluate radio-sensitivity of pancreatic cancer. RESULTS: We found Klf10 silencing correlates with enhanced pancreatic cancer clonogenic survival and murine tumor growth after radiation. UVRAG was an essential down-stream mediator transcriptionally suppressed by Klf10. Silencing UVRAG mRNA in Klf10 depleted Panc-1 cells reversed the radio-resistant phenotypes including decreased apoptosis and enhanced DNA repair as well as autophagy. Metformin, an anti-diabetic agent, was found to increase Klf10 and suppress UVRAG expression to improve radiation cytotoxicity in pancreatic cancer. The predictive value of Klf10 in radiation response and the inverse correlation with UVRAG were confirmed in cohorts of pancreatic cancer patients. CONCLUSIONS: Klf10 is a potential biomarker in predicting and sensitizing radiation effect in pancreatic cancer.

Surveillance of Transmitted Drug Resistance in HIV-1-Infected Youths Aged 16 to 25 Years, a Decade After Scale-up of Antiretroviral Therapy in Hebei, China.

Sexual exposure has been the predominant route of HIV-1 spread in Hebei Province, China. However, little information is available on HIV-1-transmitted drug resistance (TDR) among HIV-1-infected youths aged 16 to 25 years who are infected with HIV-1 and sexually active. In this study, the overall prevalence of TDR was 6.6% (10/152), a moderate level (5.0%-15.0%) according to World Health Organization Threshold Survey guidelines. However, the prevalence of TDR to protease inhibitors and nonnucleoside reverse transcriptase inhibitors was 4.6% (7/152) and 2.0% (3/152), respectively, which correspond to a low level (<5.0%). All TDR mutations (M46L/I, Y181C, K101E, and G190E) were found only in youths infected with HIV-1 through sexual activity. The prevalence of TDR among heterosexuals (10.0%, 3/30) was higher than that among men who have sex with men (5.8%, 7/120). TDR mutations resided in CRF01_AE (M46I/L and G190E) and subtype B (Y181C and K101E). Our findings will provide useful information on which drug regimens to use in treating the newly infected people with HIV-1.

Metabolic profile of injured human spinal cord determined using surface microdialysis.

The management of patients having traumatic spinal cord injury would benefit from understanding and monitoring of spinal cord metabolic states. We hypothesized that the metabolism of the injured spinal cord could be visualized using Kohonen self-organizing maps. Sixteen patients with acute, severe spinal cord injuries were studied. Starting within 72 h of the injury, and for up to a week, we monitored the injury site hourly for tissue glucose, lactate, pyruvate, glutamate, and glycerol using microdialysis as well as intraspinal pressure and spinal cord perfusion pressure. A Kohonen map, which is an unsupervised, self-organizing topology-preserving neural network, was used to analyze 3366 h of monitoring data. We first visualized the different spinal cord metabolic states. Our data show that the injured cord assumes one or more of four metabolic states. On the basis of their metabolite profiles, we termed these states near-normal, ischemic, hypermetabolic, and distal. We then visualized how patients' intraspinal pressure and spinal cord perfusion pressure affect spinal cord metabolism. This revealed that for more than 60% of the time, spinal cord metabolism is patient-specific; periods of high intraspinal pressure or low perfusion pressure are not associated with specific spinal cord metabolic patterns. Finally, we determined relationships between spinal cord metabolism and neurological status. Patients with complete deficits have shorter periods of near-normal spinal cord metabolic states (7 ± 4% vs. 58 ± 12%, p < 0.01, mean ± standard error) and more variable injury site metabolic responses (metabolism spread in 70 ± 11 vs. 40 ± 6 hexagons, p < 0.05), compared with patients who have incomplete neurological deficits. We conclude that Kohonen maps allow us to visualize the metabolic responses of the injured spinal cord and may thus aid us in treating patients with acute spinal cord injuries.

Bone marrow derived macrophages fuse with intestine stromal cells and contribute to chronic fibrosis after radiation.

BACKGROUND AND PURPOSE: Bone marrow-derived cells (BMDC) have been demonstrated to play a critical role in intestine regeneration. However, organ fibrosis was one of the major side effects of bone marrow (BM) transplantation. It warrants further investigation on the mechanisms of BM cell therapy in radiation induced intestine damage. MATERIALS AND METHODS: We established three murine models to evaluate BMDC within intestines after radiation, including cre-loxP system of transgenic mice. In vitro co-culture between murine BM with human intestine stromal cells was also performed to measure the level of fusion and fibrosis after treatment with anti-fibrotic agents or after macrophage depletion. RESULTS: Despite complete recovery of epithelial mucosa from radiation damage, we found persistent proliferation and repopulation of BMDC within the lamina propria. Fusion between BM derived monocytic and intestine stromal cells correlated with the level of fibrosis and proliferation index. Depleting macrophages genetically using CD11b-DTR mouse model or pharmacologically using clodronate liposome reduced the level of cell fusion and intestine fibrosis. CONCLUSIONS: Fibrotic cues from intestine enhance fusion between BM-derived monocytes/macrophages with intestine stromal cells. The fusion hybrids promote cell cycle re-entry, proliferation and reinforce fibrosis signal. Depleting macrophages interferes with cell fusion and ameliorates radiation-induced intestine fibrosis.

Recombinant Patterns of Nine Novel HIV-1 Recombinant Strains Identified in Hebei Province, China.

We found cluster 1 and cluster 2 that were identified as two potential circulating recombinant forms (CRFs) by analyzing the recombinant breakpoints and phylogenetic tree. Three sequences composed of CRF01_AE, subtype C, and potential subtype B (N/A) in cluster 1 had nearly identical recombinant breakpoints, and four sequences composed of CRF01_AE and subtype B in cluster 2 possessed identical breakpoints. Demographic characteristics indicated that there were no epidemiological linkages among three subjects in cluster 1 and four subjects in cluster 2, respectively. Likewise, two unique recombinant forms (URFs) were found in this study: one URF was composed of subtype C and subtype B, and subtype B was inserted into a backbone of subtype C; another URF was composed of subtype C, subtype B, CRF01_AE, and subtype A2. It was inferred that the potential novel CRFs and URFs have spread into general populations, suggesting that the series research of novel recombinant strains will be a priority for our researches in the future.