Interactive effects between CDHR3 genotype and rhinovirus species for diagnosis and severity of respiratory tract infections in hospitalized children.

Rhinovirus (RV) is the leading pathogen causing childhood wheezing, with rhinovirus C (RV-C) species reported to cause asthma exacerbation. Allele A of single-nucleotide polymorphism (SNP) CDHR3_rs6967330 upregulates epithelial expression of RV-C receptors which results in more severe asthma exacerbations in children. Nevertheless, there are limited data on interactions between CDHR3 variants and their impact on severity of RV-related pediatric respiratory tract infections (RTIs). Medical records of RV-related RTIs in children aged below 18 years who were hospitalized in two public hospitals in 2015-2016 were independently reviewed by two paediatricians. Archived nasopharyngeal aspirates were retrieved for RV detection and sequencing as well as CDHR3 genotyping. HaploView v.5.0 and generalized multifactor dimensionality reduction (GMDR) analysis were employed for haplotypic assignment and gene-environment interaction analyses. Among 1019 studied cases, our results confirmed the relationship between RV-C species and more severe RTIs. Besides the top risk variant rs6967330-A, we identified rs140154310-T to be associated with RV-C susceptibility under the additive model [odds ratio (OR) 2.53, 95% CI 1.15-5.56; P = 0.021]. Rs140154310 was associated with wheezing illness (OR 2.38, 95% CI 1.12-5.04; P = 0.024), with such association being stronger in subjects who wheezed due to RV-C infections (OR 2.71, 95% CI 1.32-5.58; P = 0.007). Haplotype GAG constructed from rs4730125, rs6967330, and rs73195665 was associated with increased risk of RV-C infection (OR 1.71, 95% CI 1.11-2.65; P = 0.016) and oxygen supplementation (OR 1.93, 95% CI 1.13-3.30; P = 0.016). GMDR analyses revealed epistatic interaction between rs140154310 and rs6967330 of CDHR3 for RV-C infection (P = 0.001), RV-C-associated lower RTI (P = 0.004), and RV-C-associated wheeze (P = 0.007). There was synergistic gene-environmental interaction between rs3887998 and RV-C for more severe clinical outcomes (P < 0.001). To conclude, rs140154310-T is another risk variant for RV-C susceptibility and more severe RTIs. Synergistic epistatic interaction is found between CDHR3 SNPs and RV-C for RTI severity, which is likely mediated by susceptibility to RV-C. Haplotypic analysis and GMDR should be included in identifying prediction models of CDHR3 for childhood asthma and RTIs. IMPORTANCE This case-control study investigated the interaction between CDHR3 genotypes and rhinovirus (RV) species on disease severity in Hong Kong children hospitalized for respiratory tract infection (RTI). There were synergistic effects between RV-C and CDHR3 SNPs for RTI severity, which was mainly driven by RV-C. Specifically, rs6967330 and rs140154310 alone and their epistatic interaction were associated with RV-C-related and severe RTIs in our subjects. Therefore, genotyping of CDHR3 SNPs may help physicians formulate prediction models for severity of RV-associated RTIs.

Prevalence of metabolic syndrome in the United States National Health and Nutrition Examination Survey 2011-18.

PURPOSE: To estimate the prevalence of metabolic syndrome (MetS) in the US National Health and Nutrition Examination Survey (NHANES) 2011-18. METHODS: This study included 8183 eligible nonpregnant participants aged ≥20 years from the NHANES 2011-18. MetS was defined as the presence of at least three of the following components: central obesity, reduced high-density lipoprotein cholesterol, elevated triglycerides, elevated blood pressure, and elevated fasting blood glucose. The prevalence of MetS was estimated taking into account the complex sampling. The time trend was evaluated using logistic regression. RESULTS: The total prevalence of MetS increased from 37.6% [95% confidence interval (CI): 34.0%-41.4%] in 2011-12 to 41.8% (95% CI: 38.1%-45.7%) in 2017-18 (P for trend = .028). Among the MetS components, the prevalence of elevated glucose increased from 48.9% (95% CI: 45.7%-52.5%) in 2011-12 to 64.7% (95% CI: 61.4%-67.9%) in 2017-18 (P for trend <.001). The prevalence of MetS in participants with low educational attainment increased from 44.4% (95% CI: 38.8%-50.1%) in 2011-12 to 55.0% (95% CI: 50.8%-59.1%) in 2017-18 (P for trend = .01). CONCLUSION: The prevalence of MetS increased during 2011-18, notably in participants with low educational attainment. Lifestyle modification is needed to prevent MetS and the associated risks of diabetes and cardiovascular disease. Key messages What is already known on this topic: Prevalence of metabolic syndrome is an index of the cardiometabolic health of a population. What this study adds: The prevalence of metabolic syndrome in US adults increased during 2011-18, notably in participants with low educational attainment. How this study might affect research, practice, or policy: Lifestyle modification is needed to prevent metabolic syndrome and the associated risks of diabetes and cardiovascular disease.

Molecular mechanisms and targets of right ventricular fibrosis in pulmonary hypertension.

Right ventricular fibrosis is a stress response, predominantly mediated by cardiac fibroblasts. This cell population is sensitive to increased levels of pro-inflammatory cytokines, pro-fibrotic growth factors and mechanical stimulation. Activation of fibroblasts results in the induction of various molecular signaling pathways, most notably the mitogen-activated protein kinase cassettes, leading to increased synthesis and remodeling of the extracellular matrix. While fibrosis confers structural protection in response to damage induced by ischemia or (pressure and volume) overload, it simultaneously contributes to increased myocardial stiffness and right ventricular dysfunction. Here, we review state-of-the-art knowledge of the development of right ventricular fibrosis in response to pressure overload and provide an overview of all published preclinical and clinical studies in which right ventricular fibrosis was targeted to improve cardiac function.

Polarization-maintained propagation of a 2200 µm2 effective-area higher-order-mode in a bent optical fiber.

We report on the excitation and polarization preserved propagation of a very large effective-area (Aeff ∼ 2240 µm2) higher-order-mode in an optical fiber. A laser signal operating in the 1 µm wavelength region is transported in a Bessel-like LP0,4 mode over a 10 m long section of the polarization-maintaining higher-order-mode fiber. We observe that the light propagates through the fiber with >10 dB polarization-extinction-ratio as the fiber is coiled into circular loops of 40 cm diameter.

Correction to: The Sydney Heart Bank: improving translational research while eliminating or reducing the use of animal models of human heart disease.

In the original version of this article, the name of one of the authors is not correct. The correct name should be W. A. Linke, which is shown correctly in the authorgroup section above.

Trajectory of spirometric and exhaled nitric oxide measurements in Chinese schoolchildren with asthma.

BACKGROUND: Lung function growth occurs in most asthmatic children. A subgroup has subnormal lung function trajectory, but such data are limited in children. This prospective study characterized longitudinal changes of spirometric indices and fractional exhaled nitric oxide level (FeNO) among asthmatic children and identified their genetic and environmental determinants. METHODS: Chinese asthmatic children recruited from pediatric clinics underwent 5-year follow-up for pre-bronchodilator spirometric indices and FeNO. Fourteen asthma-associated single nucleotide polymorphisms (SNPs) were genotyped. Generalized estimating equation was used to analyze longitudinal changes of spirometric indices and FeNO. RESULTS: One hundred and ninety-three asthmatic children, aged 9.7 (1.9) years, had significant annual decline of 1.3% for forced vital capacity (FVC) and annual increase of 1.2% and 3.6% for FEV1 /FVC and FEF25-75 , respectively. Patients who received inhaled corticosteroid (ICS) had 2.4% lower baseline FEV1 /FVC but 0.81% higher annual increase in FEV1 . Body mass index (BMI) was associated inversely with FEV1 /FVC but positively with FEV1 % and FVC% changes. Asthma exacerbation was associated with lower FEV1 % and FVC% but not their longitudinal changes. When classified by FEV1 curve, one-quarter of patients had reduced lung function growth which was associated with female gender and lower spirometric and higher FeNO values at baseline. IL33_rs1342326 was associated with spirometric indices and FeNO, whereas GSDMB_rs2305480 was significantly associated with FEV1 /FVC change. CONCLUSION: Asthmatic children have annual decline in FVC and increase in FEV1 /FVC and FEF25-75 . Their lung function trajectory is influenced by gender, ICS treatment, BMI, and asthma exacerbations. IL33 and GSDMB may be candidate genes for their lung function growth.

Polarization-maintaining, large-effective-area, higher-order-mode fiber.

Higher-order-mode (HOM) fibers guiding light in large-effective-area (Aeff) Bessel-like modes have recently generated great interest for high-power laser applications. A polarization-maintaining (PM) version of HOM fibers can afford the added possibility of coherent beam combination, improved material processing, and polarization multiplexing of high-power fiber lasers. We report a PM-HOM fiber for guiding Bessel-like modes with Aeff ranging from 1200-2800 µm2. The fiber modes exhibit a birefringence value that compares well with that of a conventional single-mode PM fiber (2×10-4), and exhibit a polarization extinction ratio ranging from 13-23 dB over meter-long fiber lengths, practical for amplifier systems. This fiber presents a unique platform for next-generation high-power fiber systems, as well as for the fundamental studies on deterministically polarized Bessel-like modes in fibers.

The Sydney Heart Bank: improving translational research while eliminating or reducing the use of animal models of human heart disease.

The Sydney Heart Bank (SHB) is one of the largest human heart tissue banks in existence. Its mission is to provide high-quality human heart tissue for research into the molecular basis of human heart failure by working collaboratively with experts in this field. We argue that, by comparing tissues from failing human hearts with age-matched non-failing healthy donor hearts, the results will be more relevant than research using animal models, particularly if their physiology is very different from humans. Tissue from heart surgery must generally be used soon after collection or it significantly deteriorates. Freezing is an option but it raises concerns that freezing causes substantial damage at the cellular and molecular level. The SHB contains failing samples from heart transplant patients and others who provided informed consent for the use of their tissue for research. All samples are cryopreserved in liquid nitrogen within 40 min of their removal from the patient, and in less than 5-10 min in the case of coronary arteries and left ventricle samples. To date, the SHB has collected tissue from about 450 failing hearts (>15,000 samples) from patients with a wide range of etiologies as well as increasing numbers of cardiomyectomy samples from patients with hypertrophic cardiomyopathy. The Bank also has hearts from over 120 healthy organ donors whose hearts, for a variety of reasons (mainly tissue-type incompatibility with waiting heart transplant recipients), could not be used for transplantation. Donor hearts were collected by the St Vincent's Hospital Heart and Lung transplantation team from local hospitals or within a 4-h jet flight from Sydney. They were flushed with chilled cardioplegic solution and transported to Sydney where they were quickly cryopreserved in small samples. Failing and/or donor samples have been used by more than 60 research teams around the world, and have resulted in more than 100 research papers. The tissues most commonly requested are from donor left ventricles, but right ventricles, atria, interventricular system, and coronary arteries vessels have also been reported. All tissues are stored for long-term use in liquid N or vapor (170-180 °C), and are shipped under nitrogen vapor to avoid degradation of sensitive molecules such as RNAs and giant proteins. We present evidence that the availability of these human heart samples has contributed to a reduction in the use of animal models of human heart failure.

[18F]tetrafluoroborate-PET/CT enables sensitive tumor and metastasis in vivo imaging in a sodium iodide symporter-expressing tumor model.

Cancer cell metastasis is responsible for most cancer deaths. Non-invasive in vivo cancer cell tracking in spontaneously metastasizing tumor models still poses a challenge requiring highest sensitivity and excellent contrast. The goal of this study was to evaluate if the recently introduced PET radiotracer [18F]tetrafluoroborate ([18F]BF4-) is useful for sensitive and specific metastasis detection in an orthotopic xenograft breast cancer model expressing the human sodium iodide symporter (NIS) as a reporter. In vivo imaging was complemented by ex vivo fluorescence microscopy and γ-counting of harvested tissues. Radionuclide imaging with [18F]BF4- (PET/CT) was compared to the conventional tracer [123I]iodide (sequential SPECT/CT). We found that [18F]BF4- was superior due to better pharmacokinetics, i.e. faster tumor uptake and faster and more complete clearance from circulation. [18F]BF4--PET was also highly specific as in all detected tissues cancer cell presence was confirmed microscopically. Undetected comparable tissues were similarly found to be free of metastasis. Metastasis detection by routine metabolic imaging with [18F]FDG-PET failed due to low standard uptake values and low contrast caused by adjacent metabolically active organs in this model. [18F]BF4--PET combined with NIS expressing disease models is particularly useful whenever preclinical in vivo cell tracking is of interest.

Therapeutic inertia in the management of hyperlipidaemia in type 2 diabetic patients: a cross-sectional study in the primary care setting.

OBJECTIVES: To study the prevalence of therapeutic inertia in lipid management among type 2 diabetic patients in the primary care setting and to explore associated factors. METHODS: This was a cross-sectional study involving type 2 diabetic patients with suboptimal lipid control followed up in all general out-patient clinics of Kowloon Central Cluster in Hong Kong from 1 October 2011 to 30 September 2013. Main outcome measures included prevalence of therapeutic inertia in low-density lipoprotein management among type 2 diabetic patients and its association with patient and physician characteristics. RESULTS: Based on an agreed standard, lipid control was suboptimal in 49.1% (n=9647) of type 2 diabetic patients who attended for a regular annual check-up (n=19 662). Among the sampled 369 type 2 diabetic patients with suboptimal lipid control, therapeutic inertia was found to be present in 244 cases, with a prevalence rate of 66.1%. When the attending doctors' profiles were compared, the mean duration of clinical practice was significantly longer in the therapeutic inertia group than the non-therapeutic inertia group. Doctors without prior training in family medicine were also found to have a higher rate of therapeutic inertia. Patients in the therapeutic inertia group had longer disease duration, a higher co-morbidity rate of cardiovascular disease, and a closer-to-normal low-density lipoprotein level. Logistic regression analysis revealed that lack of family medicine training among doctors was positively associated with the presence of therapeutic inertia whereas patient's low-density lipoprotein level was inversely associated. CONCLUSIONS: Therapeutic inertia was common in the lipid management of patients with type 2 diabetes in a primary care setting. Lack of family medicine training among doctors and patient's low-density lipoprotein level were associated with the presence of therapeutic inertia. Further study of the barriers and strategies to overcome therapeutic inertia is needed to improve patient outcome in this aspect of chronic disease management.

Pneumonectomy combined with SU5416 induces severe pulmonary hypertension in rats.

The SU5416 + hypoxia (SuHx) rat model is a commonly used model of severe pulmonary arterial hypertension. While it is known that exposure to hypoxia can be replaced by another type of hit (e.g., ovalbumin sensitization) it is unknown whether abnormal pulmonary blood flow (PBF), which has long been known to invoke pathological changes in the pulmonary vasculature, can replace the hypoxic exposure. Here we studied if a combination of SU5416 administration combined with pneumonectomy (PNx), to induce abnormal PBF in the contralateral lung, is sufficient to induce severe pulmonary arterial hypertension (PAH) in rats. Sprague Dawley rats were subjected to SuPNx protocol (SU5416 + combined with left pneumonectomy) or standard SuHx protocol, and comparisons between models were made at week 2 and 6 postinitiation. Both SuHx and SuPNx models displayed extensive obliterative vascular remodeling leading to an increased right ventricular systolic pressure at week 6 Similar inflammatory response in the lung vasculature of both models was observed alongside increased endothelial cell proliferation and apoptosis. This study describes the SuPNx model, which features severe PAH at 6 wk and could serve as an alternative to the SuHx model. Our study, together with previous studies on experimental models of pulmonary hypertension, shows that the typical histopathological findings of PAH, including obliterative lesions, inflammation, increased cell turnover, and ongoing apoptosis, represent a final common pathway of a disease that can evolve as a consequence of a variety of insults to the lung vasculature.

How to diagnose heart failure with preserved ejection fraction: the value of invasive stress testing.

Heart failure with preserved ejection fraction (HFpEF) is a growing healthcare burden worldwide and its prevalence is increasing. Diagnosing HFpEF is challenging and relies upon the presence of symptoms and/or signs of heart failure, preserved left ventricular systolic function, and evidence of diastolic dysfunction. Current diagnostic algorithms mainly rely on echocardiography (E/e') and biomarkers (NT-proBNP). However, only a minority of patients with HFpEF are identified, and especially HFpEF patients at an early stage of the disease are easily missed. We propose to incorporate invasive stress testing, by means of right heart catheterisation at rest and during exercise, and accurate assessment of right ventricular function, by means of cardiac magnetic resonance imaging. These additions to the current diagnostic work-up will improve diagnostic sensitivity and accurate staging of HFpEF patients.

Durable survival after chemotherapy in a HIV patient with Burkitt's lymphoma presenting with massive upper gastrointestinal bleeding.

Massive upper gastrointestinal bleeding is an uncommon presentation of Burkitt's lymphoma in a patient with HIV/AIDS, and is seldom reported in the literature. A 39-year-old man who has sex with men presented with abdominal pain and massive haematemesis and a rapid drop in haemoglobin level to 4.8 g/dL. Upper gastrointestinal endoscopy showed a large blood clot in the stomach, and an emergency laparotomy was performed because of unstable haemodynamics. This showed active bleeding from multiple tumours in the fundus and body of the stomach. The patient underwent gastrectomy and gastric biopsy confirmed Burkitt's lymphoma. Further tests showed lymphoma involvement in bone marrow and central nervous system. The patient tested positive for HIV, and had a CD4 count of 212 cells/mm(3) and viral load of 18,000 copies/mL at diagnosis. He was commenced on a chemotherapy regimen of CODOX-M/IVAC, and highly active antiretroviral therapy consisting of indinavir, stavudine and lamivudine. The major side effect was peripheral neuropathy. Infective complications during chemotherapy were controlled by broad-spectrum antibiotics and anti-fungal agents. Complete remission of the lymphoma was achieved after the chemotherapy and remission was maintained for more than 14 years.

Novel genes and variants associated with IgA nephropathy by co-segregating with the disease phenotypes in 10 IgAN families.

BACKGROUND: Previously, a large proportion of the genetic components predisposing individuals to IgA nephropathy (IgAN) have been unidentified. Familial IgAN is enriched with genetic variations predisposing individuals to the disease. Whole exome sequencing is an effective way to explore disease-causing genes and gene variants. METHODS: We performed exome sequencing on the probands from each of ten IgAN families, and on one of the unaffected member from 7 of the families. Sanger sequencing, bioinformatics and co-segregation analysis were performed for all available family members to detect deleterious genetic variation. The relatedness of the families was tested by haplotype analyses. RESULTS: Six deleterious variants in 4 genes were observed to be associated with IgA nephropathy by co-segregating with the disease phenotypes in study families. MYCT1 p.Asp22Glufs*34 was associated with IgAN by co-segregating with its phenotypes in families 2, 7, and 9; DEFA4 p.Ala8Pro, p.Ala8Val, c.172+1G>T co-segregated in families 1, 2, and 3; ZNF543 p.Pro226Ala co-segregated in families 3, 5, and 6 and CARD8 p.Val98Lysfs*26 co-segregated in families 7 and 8. Among these genes, MYCT1, CARD8 and ZNF543 are novel. Our haplotype analyses showed that families in which the same variation(s) were co-segregating with IgAN were unrelated, except for DEFA4. Of the families carrying DEFA4, families 2 and 3 were possibly related, but not family 1, indicating that common genes/variations in these families were not due to the same founder. Interfamilial sharing of different co-segregating genes was also observed, demonstrating the polygenic nature of this disease. CONCLUSIONS: We discovered 6 deleterious variants in 4 genes associated with familial IgAN. These genes are good candidate genes that appear to be causally related to IgAN and warrant further study.

Drug-drug interactions in patients treated for cancer: a prospective study on clinical interventions.

BACKGROUND: Drug-drug interactions (DDIs) are of major concern in oncology, since cancer patients typically take many concomitant medications. Retrospective studies have been conducted to determine the prevalence of DDIs. However, prospective studies on DDIs needing interventions in cancer patients have not yet been carried out. Therefore, a prospective study was designed to identify DDIs leading to interventions among ambulatory cancer patients receiving anticancer treatment. PATIENTS AND METHODS: Patients starting with a new treatment regimen with i.v. or oral anticancer medication were asked to participate. The patients' medication was checked for DDIs by using drug interaction software. An expert team of clinical pharmacologists evaluated the relevance of these identified DDIs. If a DDI was qualified as potentially clinically relevant, an intervention was proposed to the treating (hemato)oncologist. Several variables were studied as determinants for performing an intervention. Descriptive statistics and uni- and multivariate logistic regression analyses were carried out. RESULTS: In this study, 302 patients were included. A total of 603 DDIs were identified by the drug interaction software and judged by the expert team. Of all 603 DDIs, 120 DDIs were considered potentially clinically relevant. These 120 DDIs, present in a total of 81 patients, resulted in a clinical intervention already executed by the (hemato)oncologist in 39 patients (13%), while an additional intervention was proposed by a clinical pharmacologist in 42 patients (14%). The number of comorbidities and the number of 'over-the-counter' drugs were identified as determinants. CONCLUSIONS: Clinical interventions on DDIs are frequently required among patients starting with anticancer therapy. Structured screening for these potentially clinically relevant DDIs, by (hemato)oncologists in close collaborations with clinical pharmacologists, should take place before the start and during anticancer treatment. CLINICAL TRIALS NUMBER: This study was registered at the Dutch Trial Registry under number NTR3760.

Minimal effects on ex vivo coagulation during mild therapeutic hypothermia in post cardiac arrest patients.

OBJECTIVES: Mild therapeutic hypothermia (MTH) is being used to improve neurological outcome and survival in patients successfully resuscitated after cardiac arrest. The impact on coagulation may be difficult to assess since most coagulation parameters are measured at 37°C and not at actual body core temperature. Therefore we investigated the effects of MTH both at body core (target) temperature of 32°C and at 37°C. METHODS: Patients admitted at the ICU after cardiac arrest treated with MTH. Baseline blood samples, measured at 37°C were taken directly at arrival. The second and third samples were drawn within 1h and 24h after reaching target temperature and were measured at 32°C and 37°C. A final sample was drawn when the patient returned to normotemperature (measured at 37°C). Clotting time (CT) and maximum clotting formation (MCF) were measured with thromboelastometry. RESULTS: Upon reaching target temperature (32°C) Extem and Intem CT were increased compared to baseline with 57s (49-75) to 65s (59-72) and 165s (144-183) to 193s (167-212) respectively (median with IQR; P<0.05), with a further significant increase after 24h of hypothermia with 68s (57-80) and 221s (196-266). Samples analyzed at 32°C showed a significant longer CT of 12s in Extem and 33s in Intem compared to 37°C. MCF was not affected by MTH or adjustment of temperature. CONCLUSION: The mild effect of MTH on coagulation parameters remains unidentified when measured at 37°C. Although measurements at 32°C differ from those at 37°C, this does not appear to be of clinical relevance as all values were still within the reference range.

The effect of audible alarms on anaesthesiologists' response times to adverse events in a simulated anaesthesia environment: a randomised trial.

Alarms are ubiquitous in anaesthetic practice, but their net effect on anaesthesiologists' performance and patient safety is debated. In this study, 27 anaesthesiologists performed two simulation sessions in random order; one session was programmed to include an alarm condition, with a standard, frequent, clearly audible alarm sound. During these sessions, adverse events were simulated and anaesthesiologists' response times to these events were recorded. Perceived workload was assessed with the NASA Task Load Index. Response times to adverse events and perceived workload were similar in both groups. Pooled response times to atrial fibrillation and desaturation were fast, with a median (range [IQR]) of 8 (4-14 [1-41]) s and 9 (6-16 [1-44]) s, respectively. Pooled response times to an ST segment elevation on the ECG and an obstructed intravenous line were significantly slower, with median (IQR[range]) times of 34 (21-76[4-300]) s and 227 (95-399 [2-600]) s, respectively (p < 0.001). This study shows that in a simulated anaesthesia environment, response times to adverse events are similar in the absence or presence of an audible alarm, and that response times to various critical events differ.

Seven-core erbium-doped double-clad fiber amplifier pumped simultaneously by side-coupled multimode fiber.

We demonstrate a seven-core erbium-doped fiber amplifier in which all the cores were pumped simultaneously by a side-coupled tapered multimode fiber. The amplifier has multicore (MC) MC inputs and MC outputs, which can be readily spliced to MC transmission fiber for amplifying space division multiplexed signals. Gain over 25 dB was obtained in each of the cores over a 40-nm bandwidth covering the C-band.