Prolonged QRS duration on surface electrocardiogram is associated with left ventricular restrictive filling pattern.
Prolonged QRS duration is associated with decreased left ventricular (LV) systolic function. However, the relation between LV restrictive filling pattern (RFP) and QRS duration has not been investigated yet. The purpose of our study was to assess this relationship. We analyzed standard 12-lead surface electrocardiogram (ECG) of 155 consecutive patients. Mitral inflow and septal tissue velocities were obtained using the apical 4-chamber view with pulsed Doppler echocardiography. Patients were divided into 2 groups according to measured deceleration time (DT): restrictive (with DT ≤130 ms) or non-restrictive (with DT >130 ms). QRS duration was significantly longer in the restrictive group than in the non-restrictive group (0.101 vs. 0.090 s, p < 0.0001). QRS duration of >0.10 s was highly specific (82.6%), but modestly sensitive (64.7%), for the prediction of LV RFP. Multivariate analyses demonstrated that E/A ratio, peak E, peak A, septal e', and a' velocities were significantly associated with RFP. Prolonged QRS duration (>0.10 s) obtained from a standard resting 12-lead ECG is associated with LV RFP. However, the relationship of QRS duration with RFP was not independent of echocardiographic parameters.


CTRP3 attenuates diet-induced hepatic steatosis by regulating triglyceride metabolism.
CTRP3 is a secreted plasma protein of the C1q family that helps regulate hepatic gluconeogenesis and is downregulated in a diet-induced obese state. However, the role of CTRP3 in regulating lipid metabolism has not been established. Here, we used a transgenic mouse model to address the potential function of CTRP3 in ameliorating high-fat diet-induced metabolic stress. Both transgenic and wild-type mice fed a high-fat diet showed similar body weight gain, food intake, and energy expenditure. Despite similar adiposity to wild-type mice upon diet-induced obesity (DIO), CTRP3 transgenic mice were strikingly resistant to the development of hepatic steatosis, had reduced serum TNF-α levels, and demonstrated a modest improvement in systemic insulin sensitivity. Additionally, reduced hepatic triglyceride levels were due to decreased expression of enzymes (GPAT, AGPAT, and DGAT) involved in triglyceride synthesis. Importantly, short-term daily administration of recombinant CTRP3 to DIO mice for 5 days was sufficient to improve the fatty liver phenotype, evident as reduced hepatic triglyceride content and expression of triglyceride synthesis genes. Consistent with a direct effect on liver cells, recombinant CTRP3 treatment reduced fatty acid synthesis and neutral lipid accumulation in cultured rat H4IIE hepatocytes. Together, these results establish a novel role for CTRP3 hormone in regulating hepatic lipid metabolism and highlight its protective function and therapeutic potential in attenuating hepatic steatosis.


A model-based cost-effectiveness analysis of Patient Blood Management.
Patient blood management (PBM) is a multidisciplinary concept focused on the management of anaemia, minimisation of iatrogenic blood loss and rational use of allogeneic blood products. The aims of this study were: (i) to analyse post-operative outcome in patients with liberal vs restrictive exposure to allogeneic blood products and (ii) to evaluate the cost-effectiveness of PBM in patients undergoing surgery. A systematic literature review and meta-analysis were performed to compare post-operative complications in predominantly non-transfused patients (restrictive transfusion group) and patients who received one to three units of red blood cells (liberal transfusion group). Outcome measures included sepsis with/without pneumonia, acute renal failure, acute myocardial infarction and acute stroke. In a second step, a health economic model was developed to calculate cost-effectiveness of PBM (PBM-arm vs control-arm) for simulated cohorts of 10,000 cardiac and non-cardiac surgical patients based on the results of the meta-analysis and costs. Out of 478 search results, 22 studies were analysed in the meta-analysis. The pooled relative risk of any complication in the restrictive transfusion group was 0.43 for non-cardiac and 0.34 for cardiac surgical patients. In the simulation model, PBM was related to reduced complications (1,768 vs 1,245) and complication-related deaths (411 vs 304) compared to standard care. PBM-related costs of therapy exceeded costs of the control arm by € 150 per patient. However, total costs, including hospitalisation, were higher in the control-arm for both non-cardiac (€ 2,885.11) and cardiac surgery patients (€ 1,760.69). The incremental cost-effectiveness ratio including hospitalisation showed savings of € 30,458 (non-cardiac and cardiac surgery patients) for preventing one complication and € 128,023 (non-cardiac and cardiac surgery patients) for prevention of one complication-related death in the PBM-arm. Our results indicate that PBM may be associated with fewer adverse clinical outcomes compared to control management and may, thereby, be cost-effective.


Reducing inequalities in non-fatal accidents in England.
We investigated rates of non-fatal accidents recorded in the Health Survey for England. Between 1995/96 and 2001, rates fell in men although not in women. In contrast to other trends for health behaviours in the United Kingdom, for example smoking, there was no increased gap between male manual and non-manual groups.


Development and validation of a risk model for in-hospital worsening heart failure from the Acute Decompensated Heart Failure National Registry (ADHERE).
A subset of patients hospitalized with acute heart failure experiences in-hospital worsening heart failure, defined as persistent or worsening signs or symptoms requiring an escalation of therapy. We analyzed data from the Acute Decompensated Heart Failure National Registry (ADHERE) linked to Medicare claims to develop and validate a risk model for in-hospital worsening heart failure. Our definition of in-hospital worsening heart failure included events such as escalation of medical therapy (eg, inotropic medications) >12hours after admission. We considered candidate risk prediction variables routinely assessed at admission, including age, medical history, biomarkers, and renal function. We used logistic regression with robust standard errors to generate a risk model in a 66% random derivation sample; we validated the model in the remaining 34%. We evaluated the calibration and discrimination of the model in both samples. We evaluated 23,696 patients hospitalized with acute heart failure. Baseline characteristics were well matched in the derivation and validation samples, and the occurrence of in-hospital worsening heart failure was similar in both samples (15.4% and 15.6%, respectively). In the multivariable model, the strongest predictors of in-hospital worsening heart failure were increased troponin and creatinine. The model was well calibrated and had good discrimination in the derivation sample (c statistic, 0.74) and validation sample (c statistic, 0.72). The ADHERE worsening heart failure risk model is a clinical tool with good discrimination for use in patients hospitalized with acute heart failure to identify those at increased risk for in-hospital worsening heart failure. This tool may be useful to target treatment strategies for patients at high risk for in-hospital worsening heart failure.


Subcutaneous Adipose Tissue Metabolic Function and Insulin Sensitivity in People With Obesity.
We used stable isotope-labeled glucose and palmitate tracer infusions, a hyperinsulinemic-euglycemic clamp, positron emission tomography of muscles and adipose tissue after [18F]fluorodeoxyglucose and [15O]water injections, and subcutaneous adipose tissue (SAT) biopsy to test the hypotheses that 1) increased glucose uptake in SAT is responsible for high insulin-stimulated whole-body glucose uptake in people with obesity who are insulin sensitive and 2) putative SAT factors thought to cause insulin resistance are present in people with obesity who are insulin resistant but not in those who are insulin sensitive. We found that high insulin-stimulated whole-body glucose uptake in insulin-sensitive participants with obesity was not due to channeling of glucose into SAT but, rather, was due to high insulin-stimulated muscle glucose uptake. Furthermore, insulin-stimulated muscle glucose uptake was not different between insulin-sensitive obese and lean participants even though adipocytes were larger, SAT perfusion and oxygenation were lower, and markers of SAT inflammation, fatty acid appearance in plasma in relation to fat-free mass, and plasma fatty acid concentration were higher in the insulin-sensitive obese than in lean participants. In addition, we observed only marginal or no differences in adipocyte size, SAT perfusion and oxygenation, and markers of SAT inflammation between insulin-resistant and insulin-sensitive obese participants. Plasma fatty acid concentration was also not different between insulin-sensitive and insulin-resistant obese participants, even though SAT was resistant to the inhibitory effect of insulin on lipolysis in the insulin-resistant obese group. These data suggest that several putative SAT factors commonly implicated in causing insulin resistance are normal consequences of SAT expansion unrelated to insulin resistance.


A novel route for connexin 43 to inhibit cell proliferation: negative regulation of S-phase kinase-associated protein (Skp 2).
Accumulated evidence suggests that connexin43 (Cx43) serves as a tumor-suppressing gene. We have previously shownA. B. that Cx43 suppressed the G(1)-S phase cell cycle transition via increasing the level of p27 (Zhang, Y. W., et al., Oncogene, 20: 4138-4149, 2001). Here we report that Cx43 inhibited expression of Skp2, the human F-box protein that regulates p27 ubiquitination. This reduction was attributed to an increased degradation of Skp2. The Cx43 antisense oligonucleotide blocked this inhibitory effect of Cx43 on Skp2 expression and led to p27 down-regulation. In contrast, the antisense oligonucleotide of Skp2 induced a further increase in the level of p27. However, ectopic expression of Skp2 reversed the Cx43-induced Skp2 reduction, p27 accumulation, and cell proliferation inhibition. Cx43 increased p27 expression only in the SKP2 +/+ mouse embryo fibroblasts (MEFs), but not in the SKP2 -/- MEFs, indicating that Skp2 plays a critical role in the Cx43-induced p27 up-regulation. We also show that both Skp2 and p27 are required for Cx43 to inhibit cell proliferation, in that Cx43 hardly inhibited cell proliferation of the SKP2 -/- and p27 -/- MEFs, whereas it clearly did both in the SKP2 +/- and in the p27 +/- MEFs. Our findings suggest a new route for Cx43 to inhibit tumor growth by linking it with the key cell cycle regulators.


Semiquantitative analysis of telomerase activity in cervical cancer and precancerous lesions.
We investigated telomerase expression in cervical lesions and its diagnostic value for cervical cancer and the precancerous lesions. The subjects were 100 women who underwent cervical biopsy, comprising 16 normal cervix, 61 cervical intraepithelial neoplasia (CIN) and 23 invasive cervical cancer. Telomerase activity was detected by the telomerase repeat amplification protocol using a non-radioisotope system, and quantitated using a DNA image analyzing system. Telomerase was detected at 18.8% (3/16) in normal cervix, 32. 0% (8/25) in CIN I, 50.0% (3/6) in CIN II, 60.0% (18/30) in CIN III, and 91.3% (21/23) in invasive cervical cancer. Semiquantitation of telomerase activity was significantly higher in the subjects with invasive cancer than in those with CIN or a normal cervix (p<0.05). However, telomerase activity was not significantly different between the grades of CIN. Telomerase was detected in subjects with CIN, suggesting that telomerase expression is an early event in cervical carcinogenesis. Quantitation of telomerase activity may be helpful for the diagnosis of cervical cancer.


Osthole, a herbal compound, alleviates nucleus pulposus-evoked nociceptive responses through the suppression of overexpression of acid-sensing ion channel 3 (ASIC3) in rat dorsal root ganglion.
Osthole (Ost), a natural coumarin derivative, has been shown to inhibit many pro-inflammatory mediators and block voltage-gated Na+ channels. During inflammation, acidosis is an important pain inducer which activates nociceptors by gating depolarizing cationic channels, such as acid-sensing ion channel 3 (ASIC3). The aim of this study was to examine the effects of Ost on nucleus pulposus-evoked nociceptive responses and ASIC3 over-expression in the rat dorsal root ganglion, and to investigate the possible mechanism. Radicular pain was generated with application of nucleus pulposus (NP) to nerve root. Mechanical allodynia was evaluated using von Frey filaments with logarithmically incremental rigidity to calculate the 50% probability thresholds for mechanical paw withdrawal. ASIC3 protein expression in dorsal root ganglions (DRGs) was assessed with Western blot and immunohistochemistry. Membrane potential (MP) shift of DRG neurons induced by ASIC3-sensitive acid (pH6.5) was determined by DiBAC(4) (3) fluorescence intensity (F.I.). The NP-evoked mechanical hyperalgesia model showed allodynia for 3 weeks, and ASIC3 expression was up-regulated in DRG neurons, reaching peak on Day 7. Epidural administration of Ost induced a remarkable and prolonged antinociceptive effect, accompanied by an inhibition of over-expressed ASIC3 protein and of abnormal shift of MP. Amiloride (Ami), an antagonist of ASIC3, strengthened the antinociceptive effect of Ost. Up-regulation of ASIC3 expression may be associated with NP-evoked mechanical hyperalgesia. A single epidural injection of Ost decreased ASIC3 expression in DGR neurons and the pain in the NP-evoked mechanical hyperalgesia model. Osthole may be of great benefit for preventing chronic pain status often seen in lumbar disc herniation (LDH).


Clinicopathologic analysis of ampullary neoplasms in 450 patients: implications for surgical strategy and long-term prognosis.
Whether ampullary neoplasms are best surgically managed by pancreaticoduodenectomy versus local ampullectomy is controversial. We sought to examine the outcome of patients undergoing pancreaticoduodenectomy versus ampullectomy, as well as to identify factors predictive of lymph node metastasis in patients with ampullary neoplasms. Between 1970 and 2007, 450 patients who underwent surgical resection of ampullary adenoma or adenocarcinoma were identified from a prospective, single-institution database. Data on clinicopathologic factors, morbidity, mortality, and survival were analyzed. The initial surgical procedure was pancreaticoduodenectomy in 96.7% patients and ampullectomy in 3.3%. Final diagnosis was invasive adenocarcinoma (77.1%) or adenoma (22.9%). Median tumor size was similar for adenomas associated with an adenocarcinoma (2.5 cm) versus adenomas without invasive cancer (2.9 cm; P=0.71). Morbidity was comparable with pancreaticoduodenectomy (52.2%) versus ampullectomy (33.3%; P=0.15), as was 30-day mortality (pancreaticoduodenectomy, 2.1% versus ampullectomy, 0%; P=0.6). Metastatic disease to regional lymph nodes was present in 54.5% patients with adenocarcinoma. Factors associated with presence of lymph node metastasis included tumor size > or = 1 cm (OR 2.1), poor histologicgrade (OR 4.8), perineural invasion (OR 3.0), microscopic vessel invasion (OR 6.6), and depth of invasion > pT1 (OR 4.3; all P<0.05). Specifically, risk of lymph node metastasis increased with T stage (T1, 28.0%; T2, 50.9%; T3, 71.7%; T4, 77.3%; P<0.001). When surgery is indicated, radical resection is required for early invasive adenocarcinoma of the ampulla of Vater, as lymph node metastases are present in nearly 30% of patients with T1 disease. Pancreaticoduodenectomy should be the preferred approach for most ampullary neoplasms that require surgical resection.


Relationship between hepatic cytochrome P450 3A content and activity and the disposition of midazolam administered orally.
It was recently shown by others that the clearance of midazolam/kg body weight after iv administration correlates with hepatic cytochrome P450 (CYP or P450) 3A content in liver transplant patients. However, after po administration midazolam undergoes significant first-pass metabolism, with significant intestinal extraction. The relationship between hepatic CYP3A and midazolam disposition after po administration had not previously been investigated. The aim of this study was to compare intraindividually hepatic CYP3A content and activity with the in vivo pharmacokinetics of midazolam (7.5 mg) administered po. For 15 patients scheduled for partial liver resection, the AUC values for the observed time period (AUC0-5hr) and to infinity (AUCinf) and the clearance were determined. In a macroscopically normal area of resected liver tissue, the microsomal CYP3A4 content (nanomoles per nanomole of total P450) was measured by immunoblot analysis and parameters (apparent Vmax, apparent KM, and intrinsic clearance) for the microsomal alpha-hydroxylation of midazolam were determined. Clearance/kg in vivo correlated with the apparent Vmax (r2 = 0.45, p < 0.01) and the CYP3A4 content (r2 = 0.29, p < 0.05). We conclude that interindividual variability in the pharmacokinetics of po administered midazolam is in part determined by interindividual variability in the hepatic microsomal Vmax for the alpha-hydroxylation of midazolam. However, the relationship between the disposition of midazolam administered po and hepatic CYP3A content is weaker than that reported after iv administration, indicating the importance of the contribution of intestinal CYP3A to the in vivo disposition of midazolam administered po.


Use of a distraction plate for distal radial fractures with metaphyseal and diaphyseal comminution. Surgical technique.
Distal radial fractures with extensive comminution involving the metaphyseal-diaphyseal junction present a major treatment dilemma. Of particular difficulty are those fractures involving the articular surface. One approach is to apply a dorsal 3.5-mm plate extra-articularly from the radius to the third metacarpal, stabilizing the diaphysis and maintaining distraction across the radiocarpal joint. Twenty-two patients treated with a distraction plate for a comminuted distal radial fracture were included in the study. With use of three limited incisions, a 3.5-mm ASIF plate was applied in distraction dorsally from the radial diaphysis, bypassing the comminuted segment, to the long-finger metacarpal, where it was fixed distally. The articular surface was anatomically reduced and was secured with Kirschner wires or screws. Eleven of the twenty-two fractures were treated with bone-grafting. The plate was removed after fracture consolidation (at an average of 124 days), and wrist motion was initiated. All patients were followed prospectively with use of radiographs, physical examination, and DASH (Disabilities of the Arm, Shoulder and Hand) scores. All fractures united by an average of 110 days. Radiographs showed an average palmar tilt of 4.6 degrees and an average ulnar variance of neutral (0 degrees), whereas loss of radial length averaged 2 mm. Flexion and extension averaged 57 degrees and 65 degrees, respectively, and pronation and supination averaged 77 degrees and 76 degrees, respectively. The average DASH scores were 34 points at six months, 15 points at one year, and 11.5 points at the time of final follow-up (at an average of 24.8 months). According to the Gartland-Werley rating system, fourteen patients had an excellent result, six had a good result, and two had a fair result. Grip strength and the range of motion of the wrist at one year correlated inversely with the proximal extent of fracture comminution into the diaphysis. The duration of plate immobilization did not correlate with the range of motion of the wrist or with the DASH score at one year. The use of a distraction plate combined with reduction of the articular surface and bone-grafting when needed can be an effective technique for treatment of fractures of the distal end of the radius with extensive metaphyseal and diaphyseal comminution. A functional range of motion with minimal disability can be achieved despite a prolonged period of fixation with a distraction plate across the wrist joint.


Molecular epidemiology of infant botulism in California and elsewhere, 1976-2010.
Infant botulism (IB), first identified in California in 1976, results from Clostridium botulinum spores that germinate, multiply, and produce botulinum neurotoxin (BoNT) in the immature intestine. From 1976 to 2010 we created an archive of 1090 BoNT-producing isolates consisting of 1012 IB patient (10 outpatient, 985 hospitalized, 17 sudden death), 25 food, 18 dust/soils, and 35 other strains. The mouse neutralization assay determined isolate toxin type (56% BoNT/A, 32% BoNT/B). Amplified fragment-length polymorphism (AFLP) analysis of the isolates was combined with epidemiologic information. The AFLP dendrogram, the largest to date, contained 154 clades; 52% of isolates clustered in just 2 clades, 1 BoNT/A (n=418) and 1 BoNT/B (n=145). These clades constituted an endemic C. botulinum population that produced the entire clinical spectrum of IB. Isolates from the patient's home environment (dust/soil, honey) usually located to the same AFLP clade as the patient's isolate, thereby identifying the likely source of infective spores. C. botulinum A(B) strains were identified in California for the first time. Combining molecular methods and epidemiological data created an effective tool that yielded novel insights into the genetic diversity of C. botulinum and the clinical spectrum, occurrence, and distribution of IB in California.


Predictions of an inhomogeneous model: detection of local and extended spatial stimuli.
A two-dimensional spatially inhomogeneous model of the visual system is developed. It is based on the properties of cone spacing in the retina and on the hypothesis of uniform neural interactions (lateral inhibitions). Its quantitative predictions of the detection and discrimination (acuity) of various types of stimuli are studied. The model works well with local stimuli positioned at varied eccentricities as well as with extended stimuli (vertical cosine gratings windowed by two-dimensional windows), but a simple threshold detector was found to be insufficient to describe the increase of contrast sensitivity with the number of cycles of the cosine gratings at high frequencies. It is concluded that, even for one-dimensional stimuli, a two-dimensional approach is necessary and that other parameters such as imprecision of fixation, eye movements, and two-dimensional probability summation must be taken into account before resorting to more complex models.


Retiming of picosecond pulses by a cascaded second-order nonlinear process in quasi-phase-matched LiNbO3 waveguides.
A new technique for reducing timing jitter by using a cascaded second-order nonlinear process in quasi-phase-matched (QPM) LiNbO3 waveguides is proposed. It was found that the timing jitter of a signal at QPM wavelength is not transferred to the converted pulses during cascading in a 30-mm-long LiNbO3 QPM waveguide. Timing-jitter transfer characteristics in QPM LiNbO3 waveguides are evaluated by calculation of pulse evolution, and retiming of 1.5-ps pulses in 10- and 30-mm-long waveguides is demonstrated experimentally.


Determinants of prescription drug use by adolescents with intellectual disabilities in Taiwan.
Direct family caregivers of population-based adolescents with intellectual disabilities in Taiwan were surveyed regarding their perceptions of the use of prescribed medication and its relationship with health-related behaviors, medical care and preventive health utilization of people with intellectual disabilities. Cross-sectional data on 1419 adolescents 12-17 years of age was collected from the 2007 National Survey on Healthy Behaviors and Preventive Health Utilizations of People with Intellectual Disabilities in Taiwan. Multiple logistic regression models were used to examine risk profiles in relation to the use of prescribed medication and other relevant variables: participant characteristics, health-related behaviors, medical care and preventive health utilization. The results indicate that 47.1% of subjects were accompanied by other impairments, the morbidity prevalence was 16.5% and 23.8% of subjects were reported to have used prescribed medication regularly in the past 6 months. The main reasons for medication use were epilepsy (36.9%), psychiatric problems (24.2%) and gastrointestinal problems (6.3%). A large majority of caregivers reported that the subject's health status was excellent (15.4%), good (38%) or fair (38%), and only 6.5% were reported to be in bad health. Finally, data were analyzed using a logistic regression model to identify possible reasons for drug use. The following factors correlate with the regular use of prescribed medication by adolescents with intellectual disabilities: Down syndrome, possession of a Major Illness Card, a history of smoking, an additional impairment, reported health status, outpatient care and acceptance of other specific medical examinations. Our principal conclusion was that these data indicate a need for more education on a variety of issues, including predisposition, healthy behavior, medical care and preventive health utilization issues as they relate to prescribed medication use, and assessment of the long-term effects of drug use on people with intellectual disabilities.


Netrin 1 mediates spinal cord oligodendrocyte precursor dispersal.
In spinal cord, oligodendrocyte precursors that give rise to myelin-forming cells originate in a restricted domain of the ventral ventricular zone. During development, these cells migrate widely throughout the spinal cord. Netrin 1 is expressed at the ventral ventricular zone during oligodendrocyte precursors emigration, and, in vitro, netrin 1 acts as chemorepellent and antagonizes platelet-derived growth factor (PDGF) chemoattraction. Oligodendrocyte precursors express the netrin receptors DCC and UNC5 and function-blocking anti-DCC antibody inhibits chemorepulsion of ventral spinal cord explants and netrin-secreting cells. In spinal cord slice preparations, addition of function-blocking anti-DCC antibody or netrin 1 dramatically inhibits oligodendrocyte precursor migration from the ventral ventricular zone. These data indicate the initial dispersal of oligodendrocyte precursors from their localized origin is guided by a chemorepellent response to netrin 1.


Horizontal cells expressing melanopsin x are novel photoreceptors in the avian inner retina.
In the vertebrate retina, three types of photoreceptors-visual photoreceptor cones and rods and the intrinsically photosensitive retinal ganglion cells (ipRGCs)-converged through evolution to detect light and regulate image- and nonimage-forming activities such as photic entrainment of circadian rhythms, pupillary light reflexes, etc. ipRGCs express the nonvisual photopigment melanopsin (OPN4), encoded by two genes: the Xenopus (Opn4x) and mammalian (Opn4m) orthologs. In the chicken retina, both OPN4 proteins are found in ipRGCs, and Opn4x is also present in retinal horizontal cells (HCs), which connect with visual photoreceptors. Here we investigate the intrinsic photosensitivity and functioning of HCs from primary cultures of embryonic retinas at day 15 by using calcium fluorescent fluo4 imaging, pharmacological inhibitory treatments, and Opn4x knockdown. Results show that HCs are avian photoreceptors with a retinal-based OPN4X photopigment conferring intrinsic photosensitivity. Light responses in HCs appear to be driven through an ancient type of phototransduction cascade similar to that in rhabdomeric photoreceptors involving a G-protein q, the activation of phospholipase C, calcium mobilization, and the release of the inhibitory neurotransmitter GABA. Based on their intrinsic photosensitivity, HCs may have a key dual function in the retina of vertebrates, potentially regulating nonvisual tasks together with their sister cells, ipRGCs, and with visual photoreceptors, modulating lateral interactions and retinal processing.


ERS International Congress 2020 Virtual: highlights from the Allied Respiratory Professionals Assembly.
This article provides an overview of outstanding sessions that were (co)organised by the Allied Respiratory Professionals Assembly during the European Respiratory Society International Congress 2020, which this year assumed a virtual format. The content of the sessions was mainly targeted at allied respiratory professionals, including respiratory function technologists and scientists, physiotherapists, and nurses. Short take-home messages related to spirometry and exercise testing are provided, highlighting the importance of quality control. The need for quality improvement in sleep interventions is underlined as it may enhance patient outcomes and the working capacity of healthcare services. The promising role of digital health in chronic disease management is discussed, with emphasis on the value of end-user participation in the development of these technologies. Evidence on the effectiveness of airway clearance techniques in chronic respiratory conditions is provided along with the rationale for its use and challenges to be addressed in future research. The importance of assessing, preventing and reversing frailty in respiratory patients is discussed, with a clear focus on exercise-based interventions. Research on the impact of disease-specific fear and anxiety on patient outcomes draws attention to the need for early assessment and intervention. Finally, advances in nursing care related to treatment adherence, self-management and patients' perspectives in asthma and chronic obstructive pulmonary disease are provided, highlighting the need for patient engagement and shared decision making. This highlights article provides readers with valuable insight into the latest scientific data and emerging areas affecting clinical practice of allied respiratory professionals.


Towards the planning and design of disturbance patterns across scales to counter biological invasions.
The way in which disturbances from human land use are patterned in space across scales can have important consequences for efforts to govern human/environment with regard to, but not only, invasive spread-dispersal processes. In this context, we explore the potential of disturbance patterns along a continuum of scales as proxies for identifying the geographical regions prone to spread of invasive plant species. To this end, we build on a previous framework of cross-scale disturbance patterns, exercising the approach for the Apulia region (South Italy). We first review procedures and results introducing disturbance maps and sliding windows to measure composition (amount) and configuration (contagion) of disturbance patterns both for real and simulated landscapes from random, multifractal and hierarchical neutral models. We introduce cross-scale disturbance profiles obtained by clustering locations from real and simulated landscapes, which are used as foils for comparison to the real landscapes on the same pattern transition space. Critical percolation thresholds derived from landscape observations and theoretical works are discussed in order to identify critical scale domains. With reference to the actual land use and invasive alien flora correlates of disturbance patterns, a cross-scale "invasibility" map of the Apulia region is derived, which shows sub-regions and scale domains with different potentials for the invasive spread of undesirable species. We discuss the potential effect of contagious and non-contagious disturbances like climate change and why multifractal-like disturbance patterns might be more desirable than others to counter biological invasions in a multi-scale and multi-level context of adaptive planning, design and management of disturbance.


Biliary 1-hydroxypyrene as a biomarker of exposure to polycyclic aromatic hydrocarbons in fish.
The aim of this study was the assessment of the Svitava and Svratka rivers contamination by polycyclic aromatic hydrocarbons (PAH) using 1-hydroxypyrene (1-OHP) concentrations in fish bile as a biomarker. Levels of 1-OHP were determined by reverse phase HPLC with fluorescence detection. For valid assessment of bile accumulation levels, the 1-OHP concentration was normalized to the biliary protein content. The content of 1-OHP was correlated with the PAH content of river bottom sediments. The highest level of 1-OHP in fish bile (136.1 ng.mg-1 protein) was found at the locality Rajhradice, which is situated downstream of Brno. Also the greatest level of sum of PAHs was found at this locality (17.1 microg.g-1 dry mass). Significant positive correlation (p< or =0.05) between the level of 1-OHP and sum of PAHs in sediment was found only in case of sediments collected in the same month as fish samples (in June). Our results document that 1-OHP in fish bile is a suitable biochemical marker for the assessment of aquatic ecosystem contamination by PAHs.


Predicting protein lysine phosphoglycerylation sites by hybridizing many sequence based features.
Post-translational modification (PTM) is essential for many biological processes. Covalent and generally enzymatic modification of proteins can impact the activity of proteins. Modified proteins would have more complex structures and functions. Knowing whether a specific residue is modified or not is significant to unravel the function and structure of this protein. As experimental approaches to discover protein PTM sites are always costly and time consuming, computational prediction methods are desirable alternative methods. Lysine phosphoglycerylation is a type of newly discovered PTM that is related to glycolytic process and glucose metabolism. Since the lysine phosphoglycerylation process requires no catalytic enzyme, its site selectivity mechanism is still not fully understood. In this study, we designed a novel computational method, namely PhoglyPred, to identify lysine phosphoglycerylation sites. By utilizing several different protein sequence descriptors, PhoglyPred achieved an overall accuracy of 90.3% in a Jackknife test, which is better than other state-of-the-art predictors. By analyzing the importance of different features using the F-score, we found several important sequence features, which may benefit future studies in understanding the site selectivity mechanism of lysine phosphoglycerylation.


Applying gene silencing technology to contraception.
Population control of feral animals is often difficult, as it can be dangerous for the animals, labour intensive and expensive. Therefore, a useful tool for control of animal populations would be a non-surgical method to induce sterility. Our laboratories utilize methods aimed at targeting brain cells in vivo with vehicles that deliver a payload of either inhibitory RNAs or genes intended to correct cellular dysfunction. A useful framework for design of a new approach will be the combination of these methods with the intended goal to produce a technique that can be used to non-invasively sterilize cats and dogs. For this approach to succeed, it has to meet several conditions: the target gene must be essential for fertility; the method must include a mechanism to effectively and specifically silence the gene of interest; the method of delivering the silencing agent must be minimally invasive, and finally, the silencing effect must be sustained for the lifespan of the target species, so that expansion of the population can be effectively prevented. In this article, we discuss our work to develop gene silencing technology to induce sterility; we will use examples of our previous studies demonstrating that this approach is viable. These studies include (i) the use of viral vectors able to disrupt reproductive cyclicity when delivered to the regions of the brain involved in the control of reproduction and (ii) experiments with viral vectors that are able to ameliorate neuronal disease when delivered systemically using a novel approach of gene therapy.


Government policy interventions to reduce human antimicrobial use: protocol for a systematic review and meta-analysis.
Antimicrobial resistance (AMR) is a recognized threat to global public health. Increasing AMR and a dry pipeline of novel antimicrobial drugs have put AMR in the international spotlight. One strategy to combat AMR is to reduce antimicrobial drug consumption. Governments around the world have been experimenting with different policy interventions, such as regulating where antimicrobials can be sold, restricting the use of last-resort antimicrobials, funding AMR stewardship programs, and launching public awareness campaigns. To inform future action, governments should have access to synthesized data on the effectiveness of large-scale AMR interventions. This planned systematic review will (1) identify and describe previously evaluated government policy interventions to reduce human antimicrobial use and (2) estimate the effectiveness of these different strategies. An electronic search strategy has been developed in consultation with two research librarians. Seven databases (MEDLINE, CINAHL, EMBASE, CENTRAL, PAIS Index, Web of Science, and PubMed excluding MEDLINE) will be searched, and additional studies will be identified using several gray literature search strategies. To be included, a study must (1) clearly describe the government policy and (2) use a rigorous design to quantitatively measure the impact of the policy on human antibiotic use. The intervention of interest is any policy intervention enacted by a government or government agency in any country to change human antimicrobial use. Two independent reviewers will screen for eligibility using criteria defined a priori. Data will be extracted with Covidence software using a customized extraction form. If sufficient data exists, a meta-analysis by intervention type will be conducted as part of the effectiveness review. However, if there are too few studies or if the interventions are too heterogeneous, data will be tabulated and a narrative synthesis strategy will be used. This evidence synthesis is intended for use by policymakers, public health practitioners, and researchers to inform future government policies aiming to address antimicrobial resistance. This review will also identify gaps in the evidence about the effectiveness of different policy interventions to inform future research priorities. PROSPERO CRD42017067514 .


An electron transfer driven magnetic switch: ferromagnetic exchange and spin delocalization in iron verdazyl complexes.
The verdazyl 'pincer' ligand, 1-isopropyl-3,5-dipyridyl-6-oxoverdazyl (dipyvd), coordinates iron to form a series of pseudooctahedral coordination compounds [Fe(dipyvd)2]n+ (n = 0-3). In the case where n = 2, the molecular geometry and physical and spectral properties are consistent with a low spin (S = 0) iron(ii) ion coordinated by two ferromagnetically coupled radical ligands. Upon one electron reduction, the room temperature effective magnetic moment of the complex jumps from μeff = 2.64 to μeff = 5.86 as a result of spin crossover of the iron atom combined with very strong ferromagnetic coupling of the remaining ligand centered unpaired electron with the metal center. The sign of the exchange is opposite to that observed in other high spin iron/radical ligand systems and appears to be a result of delocalization of the ligand unpaired electron across the whole molecule. The large change in magnetic properties, combined with a delocalized electronic structure and accessible redox potentials, suggests the utility of this and related systems in the development of novel molecular spintronic devices.


The multilayered interlaced network (MIN) in the sporoplasm of the microsporidium Anncaliia algerae is derived from Golgi.
This study provides evidence for the Golgi-like activity of the multilayered interlaced network (MIN) and new ultrastructural observations of the MIN in the sporoplasm of Anncaliia algerae, a microsporidium that infects both insects and humans. The MIN is attached to the end of the polar tubule upon extrusion from the germinating spore. It surrounds the sporoplasm, immediately below its plasma membrane, and most likely maintains the integrity of the sporoplasm, as it is pulled through the everting polar tube. Furthermore, the MIN appears to deposit its dense contents on the surface of the sporoplasm within minutes of spore discharge thickening the plasma membrane. This thickening is characteristic of the developmental stages of the genus Anncaliia. The current study utilizes transmission electron microscopy (TEM), enzyme histochemistry, and high voltage TEM (HVEM) with 3D tomographic reconstruction to both visualize the structure of the MIN and demonstrate that the MIN is a Golgi-related structure. The presence of developmentally regulated Golgi in the Microsporidia has been previously documented. The current study extends our understanding of the microsporidial Golgi and is consistent with the MIN being involved in the extracellular secretion in Anncaliia algerae. This report further illustrates the unique morphology of the MIN as illustrated by HVEM using 3D tomography.


Molecular mechanisms underlying the activation of mammalian primordial follicles.
In humans and other mammalian species, the pool of resting primordial follicles serves as the source of developing follicles and fertilizable ova for the entire length of female reproductive life. One question that has intrigued biologists is: what are the mechanisms controlling the activation of dormant primordial follicles. Studies from previous decades have laid a solid, but yet incomplete, foundation. In recent years, molecular mechanisms underlying follicular activation have become more evident, mainly through the use of genetically modified mouse models. As hypothesized in the 1990s, the pool of primordial follicles is now known to be maintained in a dormant state by various forms of inhibitory machinery, which are provided by several inhibitory signals and molecules. Several recently reported mutant mouse models have shown that a synergistic and coordinated suppression of follicular activation provided by multiple inhibitory molecules is necessary to preserve the dormant follicular pool. Loss of function of any of the inhibitory molecules for follicular activation, including PTEN (phosphatase and tensin homolog deleted on chromosome 10), Foxo3a, p27, and Foxl2, leads to premature and irreversible activation of the primordial follicle pool. Such global activation of the primordial follicle pool leads to the exhaustion of the resting follicle reserve, resulting in premature ovarian failure in mice. In this review, we summarize both historical and recent results on mammalian primordial follicular activation and focus on the up-to-date knowledge of molecular networks controlling this important physiological event. We believe that information obtained from mutant mouse models may also reflect the molecular machinery responsible for follicular activation in humans. These advances may provide a better understanding of human ovarian physiology and pathophysiology for future clinical applications.


Possible Airborne Person-to-Person Transmission of Mycobacterium bovis - Nebraska 2014-2015.
Mycobacterium bovis, one of several mycobacteria of the M. tuberculosis complex, is a global zoonotic pathogen that primarily infects cattle. Humans become infected by consuming unpasteurized dairy products from infected cows; possible person-to-person airborne transmission has also been reported. In April 2014, a man in Nebraska who was born in Mexico was determined to have extensive pulmonary tuberculosis (TB) caused by M. bovis after experiencing approximately 3 months of cough and fever. Four months later, a U.S.-born Hispanic girl from a nearby town who had been ill for 4-5 months was also determined to have pulmonary TB caused by M. bovis. The only social connection between the two patients was attendance at the same church, and no common dietary exposure was identified. Both patients had pulmonary cavities on radiography and acid-fast bacilli (AFB) on sputum-smear microscopy, indicators of being contagious. Whole-genome sequencing results of the isolates were nearly indistinguishable. Initial examination of 181 contacts determined that 39 (22%) had latent infection: 10 (42%) of 24 who had close exposure to either patient, 28 (28%) of 100 who were exposed to one or both patients in church, and one (2%) of 57 exposed to the second patient at a school. Latent infection was diagnosed in six contacts on follow-up examination, 2 months after an initial negative test result, for an overall latent infection rate of 25%. No infected contacts recalled consuming unpasteurized dairy products, and none had active TB disease at the initial or secondary examination. Persons who have M. bovis TB should be asked about consumption of unpasteurized dairy products, and contact investigations should follow the same guidance as for M. tuberculosis TB.


Differences in quality of life in home-dwelling persons and nursing home residents with dementia - a cross-sectional study.
Dementia often eventually leads to dependency on others and finally to residential care. However, in Norway about half of the dementia population lives at home, due to individual and political wishes. There is scarce and inconclusive knowledge of how living in a nursing home differs from living at home for persons with dementia (PWDs) with regard to their quality of life (QoL). The first aim of the study was therefore to compare QoL, cognitive and physical functions, social contacts, sleep patterns, physical activity levels, exposure to light, and medication of PWDs in nursing homes and home-dwelling PWDs, and whether living in nursing homes was associated with a lower QoL than living at home for PWDs. A second aim was to examine if possible differences between residencies in QoL were consistent over time. The cross-sectional study was based on baseline data from two RCT studies of PWDs. A total of 15 nursing homes with adapted units for PWDs and 23 adapted day care centres for home-dwelling PWDs recruited 78 and 115 participants respectively. Trained nurses scored sociodemographic data, level of dementia (on the Clinical Dementia Rating scale), amount of medication, and QoL (QUALID). Sleep patterns, physical activity levels, and light exposure were measured by actigraphy. A multiple regression analysis was used to test the association between residency and QoL. The association between residency and change in QoL over time was investigated by linear regression analysis of a subsample with follow-up data. Home-dwelling PWDs showed significantly higher QoL than PWDs in nursing homes. This difference was maintained even after stratifying on the severity of dementia. Home-dwelling PWDs with moderate dementia showed significantly less use of walking aids, more social contact, higher levels of activity and exposure to daylight, and less use of psychotropic medications. The regression model explained 28 % of the variance in QoL in persons with moderate dementia. However, only residency contributed significantly in the model. Residency also significantly predicted negative change over time in QoL. The study indicated that living at home as long as possible is not only desirable for economic or health political reasons but also is associated with higher QoL for persons with moderate dementia. More studies are needed to investigate how QoL could be increased for PWDs in nursing homes.


Evaluation by angiography of the lateral dominance of the drainage of the dural venous sinuses.
Venous drainage dominance of the dural venous sinuses may be defined as the drainage only or mainly into one of the transverse sinuses, as shown by bilateral carotid angiography. The aim of this study was to evaluate the venous drainage dominance in bilateral carotid angiograms of 189 cases retrospectively. Among these cases 41.3% showed drainage mainly to the right side, 37.6% showed equal drainage to each side, 18.5% showed drainage mainly to the left side, 2.1% showed drainage only to the right side and 0.53% showed drainage only to the left side. Cerebral venous drainage dominance is of great importance and should be considered before operations on patients for radical neck dissection, removal of tumors in the neck that invade the internal jugular vein or tumors of the glomus jugulare which may require ligation of the internal jugular vein.


Aortic diameter as a function of age, gender, and body surface area.
An aortic aneurysm is defined as a 50% or greater increase in diameter compared with normal levels or the level of the left renal vein. However, normal diameters for many aortic segments are not known, and the aortic segment at the left renal vein may be enlarged. The purpose of this study was to determine normal diameters of the thoracic and abdominal aortas in relationship to age, gender, and body size. Aortic diameters (ADs) were determined at four anatomic levels: thoracic aorta, abdominal aorta at the celiac axis, renal arteries, and midway between the renal arteries and the bifurcation. ADs were determined with the use of a video analyzer and an electronic caliper. Computed tomographic scans (n = 389) obtained for nonvascular diagnoses were analyzed according to gender, age, height, weight, and body surface area (BSA). At all levels and in each decade the AD is significantly greater in men than in women (p < 0.0001). BSA is a better predictor of size than height or weight. AD increased with age at all levels, and there was a positive correlation between the AD and BSA and gender. Expected ADs for each aortic segment may be calculated according to regression equations. Age-, gender-, and BSA-matched patients with abdominal aortic aneurysms revealed significant enlargements in all proximal aortic segments. AD at a given level is a function of gender, age, and BSA. When these variables are known, it is possible to calculate an expected AD. The AD is greater at all levels in patients with abdominal aortic aneurysms and in men compared with women.


Real-time EEG feedback during simultaneous EEG-fMRI identifies the cortical signature of motor imagery.
Motor imagery (MI) combined with real-time electroencephalogram (EEG) feedback is a popular approach for steering brain-computer interfaces (BCI). MI BCI has been considered promising as add-on therapy to support motor recovery after stroke. Yet whether EEG neurofeedback indeed targets specific sensorimotor activation patterns cannot be unambiguously inferred from EEG alone. We combined MI EEG neurofeedback with concurrent and continuous functional magnetic resonance imaging (fMRI) to characterize the relationship between MI EEG neurofeedback and activation in cortical sensorimotor areas. EEG signals were corrected online from interfering MRI gradient and ballistocardiogram artifacts, enabling the delivery of real-time EEG feedback. Significantly enhanced task-specific brain activity during feedback compared to no feedback blocks was present in EEG and fMRI. Moreover, the contralateral MI related decrease in EEG sensorimotor rhythm amplitude correlated inversely with fMRI activation in the contralateral sensorimotor areas, whereas a lateralized fMRI pattern did not necessarily go along with a lateralized EEG pattern. Together, the findings indicate a complex relationship between MI EEG signals and sensorimotor cortical activity, whereby both are similarly modulated by EEG neurofeedback. This finding supports the potential of MI EEG neurofeedback for motor rehabilitation and helps to better understand individual differences in MI BCI performance.


Using integrative therapies to treat women with chronic pelvic pain.
Chronic pelvic pain is a common gynecologic complaint, affecting about 5% of American women. The differential diagnosis is broad, including many medical diseases, surgical indications, musculoskeletal problems, and somatic dysfunctions. Women are more affected than men by pelvic pain because their bodies are subject to more changes. These changes include a cyclic hormonal milieu, major alterations in biomechanics during pregnancy, psychosocial stress, and other modifications during and after childrearing, and more adjustments during menopause. Both medical and surgical approaches to management exist, but integrative modes of therapy address the body-mind-spirit continuum. Osteopathic manipulative treatment is a valuable option for many affected women from childbirth to menopause.


Generation of Trypanosoma cruzi-specific CD8+ T-cell immunity is unaffected by the absence of type I interferon signaling.
Trypanosoma cruzi is a protozoan parasite that causes human Chagas' disease, a leading source of congestive heart failure in Central and South America. CD8+ T cells are critical for control of T. cruzi infection, and CD8+ T cells recognizing the immunodominant trans-sialidase gene-encoded peptide TSKB20 (ANYKFTLV) account for approximately 30% of the total CD8+ T-cell population at the peak of infection in C57BL/6 mice. Type I interferons (IFN-I) are pleiotropic cytokines that play a critical role in both innate and adaptive immunity against a variety of infections, but their induction and their role in infection are dictated by the infectious agent. Because type I IFNs and IFN-responsive genes are evident early after T. cruzi infection of host cells, we examined the influence of IFN-I on the development of CD8+ T-cell responses during this infection. Mice lacking the receptor for IFN-I (IFNARKO) and their wild-type counterparts both developed chronic infections and generated similar frequencies of immunodominant TSKB20- and subdominant TSKB18-specific CD8+ T cells following T. cruzi infection. In contrast, peak TSKB20-specific CD8+ T-cell responses generated during infection with vaccinia virus engineered to express TSKB20 were approximately 2.5-fold lower in IFNARKO mice than B6 mice, although after viral clearance, the frequencies of TSKB20-specific CD8+ T cells stabilized at similar levels. Together, these data suggest that IFN-I induction and biology are dependent upon the microbial context and emphasize the need to investigate various infection models for a full understanding of CD8+ T-cell development.


Reimbursement for acute care nurse practitioner services.
Until the passage of the Balanced Budget Act of 1997, acute care nurse practitioners could not be directly reimbursed for inpatient services provided to Medicare patients. With the enactment of this legislation, acute care nurse practitioners may now be directly compensated for care provided. The historical and contextual issues that surround reimbursement for nursing and advanced practice nursing services are reviewed to serve as a foundation for understanding the current Medicare reimbursement regulations. The implications of the Balanced Budget Act of 1997 for acute care nurse practitioners and their professional colleagues are critically examined. The language of the Balanced Budget Act of 1997 and the subsequent rules and regulations issued by the Health Care Financing Administration are reviewed with specific focus on implications for acute care nurse practitioners. The opportunities for reimbursement for services provided by acute care nurse practitioners are more extensive than ever before. Acute care nurse practitioners and their physician colleagues will be wise to become fully conversant with the changes in Medicare reimbursement regulations.


Antiplasmodial quinones from Pentas longiflora and Pentas lanceolata.
The dichloromethane/methanol (1:1) extracts of the roots of Pentas longiflora and Pentas lanceolata showed low micromolar (IC(50) = 0.9-3 µg/mL) IN VITRO antiplasmodial activity against chloroquine-resistant (W2) and chloroquine-sensitive (D6) strains of PLASMODIUM FALCIPARUM. Chromatographic separation of the extract of PENTAS LONGIFLORA led to the isolation of the pyranonaphthoquinones pentalongin (1) and psychorubrin (2) with IC(50) values below 1 µg/mL and the naphthalene derivative mollugin (3), which showed marginal activity. Similar treatment of Pentas lanceolata led to the isolation of eight anthraquinones ( 4-11, IC(50) = 5-31 µg/mL) of which one is new (5,6-dihydroxydamnacanthol, 11), while three--nordamnacanthal (7), lucidin-ω-methyl ether (9), and damnacanthol (10)--are reported here for the first time from the genus Pentas. The compounds were identified by NMR and mass spectroscopic techniques.


Microwave frequency modulation in continuous-wave far-infrared ESR utilizing a quasi-optical reflection bridge.
We report the development of the frequency-modulation (FM) method for measuring electron spin resonance (ESR) absorption in the 210- to 420GHz frequency range. We demonstrate that using a high-frequency ESR spectrometer without resonating microwave components enables us to overcome technical difficulties associated with the FM method due to nonlinear microwave-elements, without sacrificing spectrometer performance. FM was achieved by modulating the reference oscillator of a 13GHz Phase-Locked Dielectric Resonator Oscillator, and amplifying and frequency-multiplying the resulting millimeter-wave radiation up to 210, 315 and 420GHz. ESR spectra were obtained in reflection mode by a lock-in detection at the fundamental modulation frequency, and also at the second and third harmonic. Sensitivity of the setup was verified by conduction electron spin resonance measurement in KC60.


Hirschsprung's disease in the UK and Ireland: incidence and anomalies.
To describe clinical characteristics and preoperative management of a national cohort of infants with Hirschsprung's disease (HD). Population-based cohort study of all live-born infants with HD born in the UK and Ireland from October 2010 to September 2012. All 28 paediatric surgical centres in the UK and Ireland. 305 infants presenting before 6 months of age with histologically proven HD. Incidence, clinical characteristics including gestational age, birth weight, gender, associated anomalies; age and clinical features at presentation; and use of rectal washouts or stoma. The incidence of HD in the UK and Ireland was 1.8 per 10 000 live births (95% CI 1.5 to 1.9). Male to female ratio was 3.3:1. An associated anomaly was identified in 23% (69), with 15% (47) having a recognisable syndrome. The proportion of infants who presented and were diagnosed in the neonatal period was 91.5% (279) and 83.9% (256), respectively. 23.9% (73) and 44.2% (135) passed meconium within 24 and 48 hours of birth. 81% (246) first presented to a hospital without tertiary paediatric surgical services, necessitating interhospital transfer. Initial colonic decompression was by rectal washouts in 86.2% (263) and by defunctioning stoma in 12.8% (39). Subsequently, 27.4% (72) of infants failed management with rectal washouts and required a delayed stoma, resulting in 36.4% (111) of infants having a stoma. In this population-based cohort, presentation outside the neonatal period was rare. Nearly half of the infants with HD passed meconium within 48 hours of birth and over one third were managed with a stoma.


Traditional and Complementary Medicine Use Among Indigenous Cancer Patients in Australia, Canada, New Zealand, and the United States: A Systematic Review.
Cancer 'patients' are increasingly using traditional indigenous and complementary medicines (T&CM) alongside conventional medical treatments to both cure and cope with their cancer diagnoses. To date T&CM use among Indigenous cancer patients from Australia, Canada, New Zealand, and the United States has not been systematically reviewed. We systematically searched bibliographic databases to identify original research published between January 2000 and October 2017 regarding T&CM use by Indigenous cancer patients in Australia, Canada, New Zealand, and the United States. Data from records meeting eligibility criteria were extracted and appraised for quality by 2 independent reviewers. Twenty-one journal articles from 18 studies across all 4 countries met our inclusion criteria. T&CM use ranged from 19% to 57.7% (differing across countries). T&CM was mostly used concurrently with conventional cancer treatments to meet their spiritual, emotional, social, and cultural needs; however, bush, traditional, and herbal medicines were used in a minority of cases as an alternative. Our findings highlight the importance of T&CM use to Indigenous cancer patients across these 4 countries; we identified multiple perceived spiritual, emotional and cultural benefits to its use. The patient's perception of their health professional's attitudes toward T&CM in some cases hindered or encouraged the patient's disclosure. Additional research is required to further explore the use and disclosure of T&CM among Indigenous cancer patients to help inform and ensure effective, safe, coordinated care for Indigenous cancer patients that relies on shared open decision making and communication across patients, communities, and providers.


Pulmonary deposition of nebulised pentamidine isethionate: effect of nebuliser type, dose, and volume of fill.
An estimate of the absolute pulmonary deposition of nebulised pentamidine isethionate was obtained in nine patients with AIDS. Two nebuliser systems were compared, System 22 Mizer (Medic-Aid) and Respirgard II (Marquest), with 50 and 150 mg doses of pentamidine in a 3 ml solution driven by an air flow of 6 l/min with the patient in the sitting position. The 50 mg pentamidine dose was repeated with a 6 ml fill with both devices. The nebuliser cloud was labelled with technetium-99m human serum albumin (Ventocol) and lung deposition was measured with a gamma camera. Of the two nebulisers studied, System 22 Mizer delivered more drug to the lungs as a whole and to each individual lung region, including the peripheral and upper zones. For the 50 mg dose the mean (SEM) total pulmonary deposition with the 3 and the 6 ml fill respectively was 2.63 (0.34) and 3.71 (0.41) mg for the System 22 Mizer and 1.37 (0.26) and 1.45 (0.18) mg for the Respirgard II. For the 150 mg dose the System 22 Mizer delivered 7.16 (1.02) mg and the Respirgard II 4.34 (0.57) mg. Increasing the volume of fill from 3 to 6 ml increased pulmonary deposition with System 22 Mizer, and this was related to an increase in nebuliser output. Neither pulmonary deposition nor nebuliser output was increased by using a 6 ml solution in the Respirgard II. Increasing the volume of fill prolonged the time required for nebulisation with both nebulisers. The System 22 Mizer produced more nonpulmonary (gastric and oropharyngeal) deposition of drug, more frequent local adverse effects (cough, burning in the throat, and a metallic taste), and small reductions in lung function, particularly with the 150 mg pentamidine dose. Thus nebuliser type, volume of fill, and nebuliser dose affect the pulmonary deposition of pentamidine. A 300 mg dose of pentamidine via a Respirgard II is generally recommended as providing effective prophylaxis; our results suggest that similar pulmonary deposition can be produced with System 22 Mizer and 150 mg pentamidine. A clinical trial would be needed to show whether this regimen provides similar prophylactic benefit.


Refocusing Nursing's Lens on Followership.
The nursing profession has long acknowledged the importance of leadership and like many other professions has been criticized as "leader-centric." The role of leadership is to influence followers towards a common goal. Leaders, therefore, must have a clear understanding of followership, including the factors that promote followers' effectiveness and engagement. They must be able to identify following and non-following behaviours, and they must practice leadership styles that support effective followership. Although nurse authors in the 1980s and early 1990s advocated for the inclusion of followership in nursing education and practice, the role has received little attention. Currently, it is not included in standards and guidelines, and there are few nursing research studies on this topic. Our understanding of leadership is incomplete without also understanding followership; without the following role, there is no leadership role. The purpose of this article is to focus the lens on followership, clarify what it is, outline the different styles, explain the importance of the role to nursing and offer recommendations that guide its integration into the nursing profession.


Trends in annual incidence of methicillin-resistant Staphylococcus aureus (MRSA) infection in HIV-infected and HIV-uninfected patients.
We describe trends in incidence rates of methicillin-resistant Staphylococcus aureus (MRSA) in HIV-infected and HIV-uninfected patients enrolled in a large northern California Health Plan, and the ratio of MRSA to methicillin-susceptible S. aureus (MSSA) case counts. Between 1995 and 2010, 1549 MRSA infections were diagnosed in 14060 HIV-infected patients (11·0%) compared to 89546 MRSA infections in 6597396 HIV-uninfected patients (1·4%) (P = 0·00). A steady rise in MRSA infection rates began in 1995 in HIV-uninfected patients, peaking at 396·5 infections/100000 person-years in 2007. A more rapid rise in MRSA infection rates occurred in the HIV-infected group after 2000, peaking at 3592·8 infections/100000 in 2005. A declining trend in MRSA rates may have begun in 2008-2009. Comparing the ratio of MRSA to MSSA case counts, we observed that HIV-infected patients shouldered a greater burden of MRSA infection during most years of study follow-up compared to HIV-uninfected patients.


Text-based discovery in biomedicine: the architecture of the DAD-system.
Current scientific research takes place in highly specialized contexts with poor communication between disciplines as a likely consequence. Knowledge from one discipline may be useful for the other without researchers knowing it. As scientific publications are a condensation of this knowledge, literature-based discovery tools may help the individual scientist to explore new useful domains. We report on the development of the DAD-system, a concept-based Natural Language Processing system for PubMed citations that provides the biomedical researcher such a tool. We describe the general architecture and illustrate its operation by a simulation of a well-known text-based discovery: The favorable effects of fish oil on patients suffering from Raynaud's disease [1].


Effect of heat treatment on nutritional quality of germinated legume seeds.
The effect of heat treatment of germinated soybean, lupin, and black bean on chemical composition and protein utilization in rats was evaluated. Heat treatment caused complete inactivation of trypsin inhibitors whereas it did not affect phytic acid levels. Proximate components, minerals, and amino acids did not change, but low molecular weight sugars were affected by heat treatment differently for each germinated legume. The sugar digestibility ratio (total digestible sugars/total nondigestible sugars) in germinated black beans doubled after heat treatment. True protein digestibility (TD) increased with heat treatment only in germinated soybean. Net protein utilization was markedly improved (20%) with heat treatment in germinated soybean and lupin. Utilizable protein of heat-treated germinated legumes was 289, 236, and 132 g/kg of legume dry weight for soybean, lupin, and black bean, respectively. Supplementation with methionine did not alter TD but improved all other indices of protein utilization in the germinated legumes, particularly in black bean. All three germinated legumes become equivalent in protein quality when heating and supplementation with methionine are combined with germination. The use of germinated heat-treated soybean, lupin, and black bean on their own and/or as food ingredients is nutritionally advantageous due to the low content of nondigestible oligosaccharides and the high protein utilization.


Nanostructural evolution of one-dimensional BaTiO₃ structures by hydrothermal conversion of vertically aligned TiO₂ nanotubes.
The use of TiO2 nanotube (NT) arrays as templates for hydrothermal conversion of one-dimensional barium titanate (BaTiO3) structures is considered a promising synthesis approach, even though the formation mechanisms are not yet fully understood. Herein we report a nanostructural study by means of XRD and (HR)TEM of high aspect ratio TiO2-NTs hydrothermally converted into BaTiO3. The nanostructure shows two different and well-defined regions: at the top the conversion involves complete dissolution of NTs and subsequent precipitation of BaTiO3 crystals by homogeneous nucleation, followed by the growth of dendritic structures by aggregation and oriented attachment mechanisms. Instead, at the bottom, the low liquid/solid ratio, due to the limited amount of Ba solution that infiltrates the NTs, leads to the rapid crystallization of such a solution into BaTiO3, thus allowing the NTs to act as a template for the formation of highly oriented one-dimensional nanostructures. The in-depth analysis of the structural transformations that take place during the formation of the rod-like arrays of BaTiO3 could help elucidate the conversion mechanism, thus paving the way for the optimization of the synthesis process in view of new applications in energy harvesting devices, where easy and low temperature processing, controlled composition, morphology and functional properties are required.


Histone Variant H2A.Z.2 Mediates Proliferation and Drug Sensitivity of Malignant Melanoma.
Histone variants are emerging as key regulatory molecules in cancer. We report a unique role for the H2A.Z isoform H2A.Z.2 as a driver of malignant melanoma. H2A.Z.2 is highly expressed in metastatic melanoma, correlates with decreased patient survival, and is required for cellular proliferation. Our integrated genomic analyses reveal that H2A.Z.2 controls the transcriptional output of E2F target genes in melanoma cells. These genes are highly expressed and display a distinct signature of H2A.Z occupancy. We identify BRD2 as an H2A.Z-interacting protein, levels of which are also elevated in melanoma. We further demonstrate that H2A.Z.2-regulated genes are bound by BRD2 and E2F1 in an H2A.Z.2-dependent manner. Importantly, H2A.Z.2 deficiency sensitizes melanoma cells to chemotherapy and targeted therapies. Collectively, our findings implicate H2A.Z.2 as a mediator of cell proliferation and drug sensitivity in malignant melanoma, holding translational potential for novel therapeutic strategies.


Current concentrations, temporal trends and determinants of persistent organic pollutants in breast milk of New Zealand women.
Breast milk samples of 39 first time mothers aged 20-30 were collected in 2007-2010 from rural and urban areas of New Zealand, following the fourth World Health Organization coordinated survey protocol. Samples were individually analysed for persistent organic pollutants (POPs) including dioxins and furans (PCDD/Fs), polychlorinated biphenyls (PCBs), organochlorine pesticides (OCPs) and polybrominated diphenyl ethers (PBDEs). The lipid adjusted concentrations of PCDD/Fs (mean toxic equivalent (TEQ): 3.54 pg/g) and PCBs (mean TEQ 1.29 pg/g) were low in comparison to those reported for other countries, and concentrations of dieldrin (10 ng/g) and p,p'-DDE (379 ng/g) and PBDEs were in the mid-range. Breast milk concentrations of PCDD/F-TEQ, PCB-TEQ, dieldrin and p,p'-DDE were significantly higher in rural compared to urban areas (+23%, 33%, 59%, and 44% respectively), while concentrations of several PBDEs and lindane were higher in urban areas. Concentrations of PCDD/Fs, PCBs and OCPs, but not PBDEs, increased with age, and higher body mass index was associated with lower concentrations of PCBs. Despite New Zealand's low body burdens of many chlorinated POPs in comparison to other countries, breast milk concentrations continued to decrease over time, with a decrease by half over the last 10 years for PCDD/F-TEQ (-40%), PCB-TEQ (-54%) and OCPs -34 to -90%), indicating that regulatory measures continue to have beneficial effects. Continued monitoring is needed particularly for the brominated POPs for which little New Zealand specific data is available.


Goldilocks and the Raster Grid: Selecting Scale when Evaluating Conservation Programs.
Access to high quality spatial data raises fundamental questions about how to select the appropriate scale and unit of analysis. Studies that evaluate the impact of conservation programs have used multiple scales and areal units: from 5x5 km grids; to 30m pixels; to irregular units based on land uses or political boundaries. These choices affect the estimate of program impact. The bias associated with scale and unit selection is a part of a well-known dilemma called the modifiable areal unit problem (MAUP). We introduce this dilemma to the literature on impact evaluation and then explore the tradeoffs made when choosing different areal units. To illustrate the consequences of the MAUP, we begin by examining the effect of scale selection when evaluating a protected area in Mexico using real data. We then develop a Monte Carlo experiment that simulates a conservation intervention. We find that estimates of treatment effects and variable coefficients are only accurate under restrictive circumstances. Under more realistic conditions, we find biased estimates associated with scale choices that are both too large or too small relative to the data generating process or decision unit. In our context, the MAUP may reflect an errors in variables problem, where imprecise measures of the independent variables will bias the coefficient estimates toward zero. This problem may be pronounced at small scales of analysis. Aggregation may reduce this bias for continuous variables, but aggregation exacerbates bias when using a discrete measure of treatment. While we do not find a solution to these issues, even though treatment effects are generally underestimated. We conclude with suggestions on how researchers might navigate their choice of scale and aerial unit when evaluating conservation policies.


Abuse in the caregiving relationship between older people with memory disorders and family caregivers: A systematic review.
To synthesize what is known about elder abuse and relationship factors associated with abuse between caregivers and older people with memory disorders at home. Concerns about abuse in the caring relationship between older people with memory disorders and family caregivers have increased. Abuse is associated with negative outcomes on older people's health, quality of life, and zest for life. Abuse in the caring relationship manifests in financial exploitation, neglect, mistreatment, and physical issues. Systematic review. Databases including Scopus, PubMed/Medline, SveMed+ , Cinalh, SonINDEX, and ProQuest were searched using keywords about abuse in the caring relationship between older people with memory disorders and family caregivers at home. Articles published between 2005-2019 were retrieved and underwent data analysis and knowledge synthesis. The review was presented under the categories of the dyadic approach of elder abuse in connection with the role of caregiver (risk) and care recipient (vulnerability) by Fulmer et al. (2005). The search process led to 12 quantitative studies, including an intervention, a prospective, nine surveys, and a cross-sectional structural interview. Findings were synthesized and presented under 'personal', 'physical and psychological', and 'social' domains indicating the bilateral roles of caregiver and care recipient leading to abuse. This review depicted factors influencing abuse in the caring relationship between older people with memory disorders and their family caregivers at home. They included family caregivers' psychological issues, knowledge of memory disorders and modifications, previous caring relationship, social support, number of care recipients, and care recipients' functional level. This review identifies what influences elder abuse by family caregivers using the dyadic approach and explains how abuse can be prevented through suggested strategies. The review findings are relevant to multidisciplinary healthcare providers and can guide the provision of support, screening and assessment, educational programs, and legislative initiatives.


High prevalence of cardiovascular risk factors among policemen in Puducherry, South India.
Diabetes mellitus and hypertension (HT) are common diseases in adulthood, pre-disposing to many cardiovascular complications, posing a major public health challenge. Few studies have reported increased prevalence of cardiovascular disease risk factors and type 2 diabetes in policemen. Hence, this study aims to assess the prevalence of cardiovascular risk factors such as diabetes, HT, smoking, alcohol intake, and obesity among policemen. A cross-sectional study was carried out in 2008-2009 among 256 policemen in Puducherry, South India. Policemen were selected by simple random sampling. Socio-demographic details and some of the risk factors such as alcohol intake and smoking history were obtained using a pre-tested, structured questionnaire. Presence of stress was measured using the professional life stress score questionnaire. Blood pressure, waist circumference, and hip circumference were measured by standard methods. Fasting blood sugar was estimated using a glucometer. Serum cholesterol was also measured. Lipid profile was measured for a randomly chosen subgroup of 50 participants. Mean age of study participants was 40.9 years (SD ± 10.9). Out of the study subjects, 23% (n = 60) were known diabetic and 16.8% (n = 43) were known hypertensive. Prevalence of diabetes among study participants was 33.6% (CI: 27.8%-39.6%). Prevalence of HT among study participants was 30.5% (CI: 24.9%-36.5%). Seventy percent (n = 178) had at least moderate range of stress in their life related to their profession and 4% (n = 11) had stress as a "problem" in their life. Burden of cardiovascular risk factors such as diabetes and HT was high among police personnel of Puducherry.


Evaluation of dentolabial parameters as part of a comprehensive esthetic analysis.
Analysis of the facial features and lip movements in relation to teeth, achieved by evaluating the facial, dentolabial, and phonetic parameters, should be the first step in prosthetic rehabilitation. This article focuses on dentolabial analysis, presenting a systematic approach to evaluating the relationship between the teeth and the lips and lower third of the face. The parameters evaluated include tooth exposure, incisal edge position, smile width, labial corridor, interincisal line vs. midline, and occlusal plane vs commissural line. Here two parameters of dentolabial analysis are explored in depth: incisal edge position (with regard to both incisal curve and incisal profile) and orientation of the incisal plane, which is a portion of the occlusal plane. Methods for identifying both parameters are outlined, and their role in the achieving successful esthetic results in prosthetic treatment is discussed.


Emphysema Quantification Using Ultralow-Dose CT With Iterative Reconstruction and Filtered Back Projection.
The purpose of this study was to evaluate agreement between standard-dose CT (SDCT) and ultralow-dose CT (ULDCT) findings with respect to emphysema quantification. ULDCT images were reconstructed with and without iterative reconstruction (IR). Adaptive iterative dose reduction with 3D processing was used for IR. Fifty patients who underwent SDCT and ULDCT were included. The tube current for SDCT was 250 mA, and that for ULDCT was 10 mA. SDCT, ULDCT without IR, and ULDCT with IR were used for emphysema quantification. The low-attenuation volume percentage (LAV%) in the lungs at four thresholds (-970, -950, -930, and -910 HU), mean lung attenuation, and total lung volume were computed. Concordance correlation coefficients (CCC) were used to assess the agreement of emphysema quantification between SDCT and ULDCT. The LAV% CCC values were 0.310-0.789 between SDCT and ULDCT without IR and 0.934-0.966 between SDCT and ULDCT with IR. The agreement of LAV% improved when IR was used for ULDCT. The mean lung attenuation CCC value between SDCT and ULDCT without IR was substantial (0.957), whereas that between SDCT and ULDCT with IR was poor (0.890). The total lung volume CCC values were substantial (0.982 with IR, 0.983 without IR). ULDCT with and without IR can substitute for SDCT in emphysema quantification.


Effects of visual attentional load on low-level auditory scene analysis.
The sharing of processing resources between the senses was investigated by examining the effects of visual task load on auditory event-related brain potentials (ERPs). In Experiment 1, participants completed both a zero-back and a one-back visual task while a tone pattern or a harmonic series was presented. N1 and P2 waves were modulated by visual task difficulty, but neither mismatch negativity (MMN) elicited by deviant stimuli from the tone pattern nor object-related negativity (ORN) elicited by mistuning from the harmonic series was affected. In Experiment 2, participants responded to identity (what) or location (where) in vision, while ignoring sounds alternating in either pitch (what) or location (where). Auditory ERP modulations were consistent with task difficulty, rather than with task specificity. In Experiment 3, we investigated auditory ERP generation under conditions of no visual task. The results are discussed with respect to a distinction between process-general (N1 and P2) and process-specific (MMN and ORN) auditory ERPs.


Pirh2, a ubiquitin E3 ligase, inhibits p73 transcriptional activity by promoting its ubiquitination.
p73, a homolog of the tumor suppressor p53, transactivates many p53 target genes, leading to apoptosis or cell-cycle arrest. p73 has recently been reported to play an important role in tumor suppression in a mouse model. Here, we show that Pirh2 physically interacted with p73 and downregulated p73 function through its E3 ligase activity. Pirh2 promoted p73 ubiquitination in vivo and in vitro. Intriguingly, Pirh2 primarily used K63-linked chains to ubiquitinate p73 in vitro, but in vivo, Pirh2 utilized K11-, K29-, K48-, and K63-linked chains to promote p73 ubiquitination. Depletion of Pirh2 by siRNA significantly reduced the ubiquitination of p73 in p53 null cells. Ectopic expression of Pirh2 repressed p73-dependent transcriptional activity, but the levels of p73 were not decreased. We consistently showed that ablation of endogenous Pirh2 restored p73-mediated transactivational activity. We found that Pirh2 repressed p73 transcriptional activity by directly inhibiting the p73 transcript, and p73 repression by Pirh2 was required for p73-dependent transcriptional activity and G(1) arrest but not for apoptosis. This study provides evidence that the ubiquitination of p73 mediated by Pirh2 represents an important pathway for controlling the suppressive function of p73. Furthermore, the data suggest a link between the transcriptional activity of p73 and its ubiquitination.


An aquaporin 4 antisense oligonucleotide loaded, brain targeted nanoparticulate system design.
Aquaporins (AQPs), members of the water-channel protein family, are highly expressed in brain tissue especially in astrocytic end-feet. They are important players for water hemostasis during development of cytotoxic as well as vasogenic edema. Increased expression of AQPs is important in pathophysiology of neurological diseases such as neuroinflammation and ischemia. Unfortunately, there are a few pharmacological inhibitors of AQP4 with several side effects limiting their translation as a drug for use in clinical conditions. Another therapeutic approach is using antisense oligonucleotides (ASOs) to block AQP4 activity. These are short, synthetic, modified nucleic acids that bind RNA to modulate its function. However, they cannot pass the blood brain barrier (BBB). To overcome this obstacle we designed a nanoparticulate system made up of chitosan nanoparticles surface modified with PEG and conjugated with monoclonal anti transferrin receptor-1 antibody via streptavidin-biotin binding. The nanocarrier system could be targeted to the transferrin receptor-1 at the brain endothelial capillaries through monoclonal antibodies. It is hypothesized that the nanoparticles could pass the BBB via receptor mediated transcytosis and reach brain parenchyma. Particle size, zeta potential, loading capacity and release profiles of nanoparticles were investigated. It was observed that all types of chitosau (CS) nanoparticles had positive zeta potential values and nanoparticle particle size distribution varied between 100 and 800 nm. The association efficiency of ASOs into the nanoparticles was between 80-97% and the release profiles of the nanoparticles exhibited an initial burst effect followed by a controlled release. The results showed that the designed chitosan based nanocarriers could be a promising carrier system to transport nucleic acid based drugs to brain parenchyma.


Patterns of care among patients receiving sequential targeted therapies for advanced renal cell carcinoma: A retrospective chart review in the USA.
To assess real-world treatment patterns of targeted therapies after failure of first-line tyrosine kinase inhibitors in patients with advanced renal cell carcinoma. A large, retrospective review of medical charts of patients with advanced renal cell carcinoma in the USA was carried out. Descriptive statistics were used to summarize physicians' and patients' characteristics, treatment sequences, and reasons for treatment choices. P-values were calculated using χ2 -tests for categorical variables and Wilcoxon rank-sum tests for continuous variables. A descriptive comparison was carried out between current results and those of a previous treatment pattern study conducted in 2012 to identify changes in treatment patterns over time. Sunitinib and everolimus remained the most commonly-used first and second targeted therapies, respectively. Among patients who continued to a third targeted therapy, everolimus and axitinib were the most commonly-used treatments after second targeted therapy with a tyrosine kinase inhibitor and a mammalian target of rapamycin inhibitor, respectively. The use of pazopanib as first targeted therapy, and of axitinib and sorafenib as second targeted therapies, increased over time. Efficacy, treatment guidelines and a different mechanism of action were the main reasons given by physicians for choosing among second targeted therapies after failure of a first tyrosine kinase inhibitor. The results of the present study document patterns of care during a period of rapid and ongoing therapeutic advancement in advanced renal cell carcinoma. Sequencing of therapies warrants ongoing analysis in light of new agents entering the advanced renal cell carcinoma treatment landscape.


IoT-Based Applications in Healthcare Devices.
The last decade has witnessed extensive research in the field of healthcare services and their technological upgradation. To be more specific, the Internet of Things (IoT) has shown potential application in connecting various medical devices, sensors, and healthcare professionals to provide quality medical services in a remote location. This has improved patient safety, reduced healthcare costs, enhanced the accessibility of healthcare services, and increased operational efficiency in the healthcare industry. The current study gives an up-to-date summary of the potential healthcare applications of IoT- (HIoT-) based technologies. Herein, the advancement of the application of the HIoT has been reported from the perspective of enabling technologies, healthcare services, and applications in solving various healthcare issues. Moreover, potential challenges and issues in the HIoT system are also discussed. In sum, the current study provides a comprehensive source of information regarding the different fields of application of HIoT intending to help future researchers, who have the interest to work and make advancements in the field to gain insight into the topic.


Nitrate-Rich Beetroot Juice Reduces Blood Pressure in Tanzanian Adults with Elevated Blood Pressure: A Double-Blind Randomized Controlled Feasibility Trial.
In Sub-Saharan Africa, current strategies are struggling to control the burgeoning hypertension epidemic. Dietary interventions such as inorganic nitrate or folic acid supplementation could represent promising strategies for reducing blood pressure (BP) in this setting. This feasibility study explores the effects of dietary inorganic nitrate supplementation, alone or in combination with folic acid, on BP in Tanzanian adults with elevated BP in Tanzania. A placebo-controlled, double-blind, randomized controlled feasibility trial was conducted. Forty-seven middle-aged and older participants (age: 50-70 y, BMI: 26.3-29.1 kg/m2) were randomly assigned to 3 conditions for a period of 60 d: 1) high-nitrate beetroot juice (∼400 mg nitrate) and folic acid (∼5 mg folic acid) (N + F), 2) high-nitrate beetroot juice and placebo (N + P), or 3) nitrate-depleted beetroot juice and placebo (P + P). Clinic and 24-h ambulatory BP and measurements of compliance in plasma (nitrate and folate concentrations) and saliva (nitrate and nitrite) were obtained at baseline, 30 d, and 60 d. Baseline resting systolic and diastolic BP (mean ± SD) was 151.0 ± 19.4 mm Hg and 91.8 ± 11.7 mm Hg, respectively. Compliance to the interventions was high (>90%) in all groups which was confirmed by the significant increase in nitrate and folic acid concentrations in plasma and saliva samples in the treatment arms. After 60 d, 24-h systolic BP dropped by -10.8 ± 9.8 mm Hg (P < 0.001), -6.1 ± 13.2 mm Hg (P = 0.03), and -0.3 ± 9.7 mm Hg (P = 0.83) in the N + P, N + F, and P + P groups, respectively. There was a significant decrease in 24-h diastolic BP in the N + P group (-5.4 ± 5.0 mm Hg, P = 0.004), whereas changes were not significant in the N + F (-1.8 ± 8.1 mm Hg, P = 0.32) and P + P (1.6 ± 8.3 mm Hg, P = 0.43) groups. Dietary inorganic nitrate represents a potential nutritional strategy to lessen the hypertension epidemic in Sub-Saharan Africa. These findings support the rationale for future long-term investigations exploring the efficacy of dietary nitrate for lowering BP and attenuating cardiovascular disease risk in this setting.This trial was registered at isrctn.com as ISRCTN67978523.


Inoculum effect with cefazolin among clinical isolates of methicillin-susceptible Staphylococcus aureus: frequency and possible cause of cefazolin treatment failure.
Methicillin (meticillin)-susceptible Staphylococcus aureus (MSSA) strains producing large amounts of type A beta-lactamase (Bla) have been associated with cefazolin failures, but the frequency and impact of these strains have not been well studied. Here we examined 98 MSSA clinical isolates and found that 26% produced type A Bla, 15% type B, 46% type C, and none type D and that 13% lacked blaZ. The cefazolin MIC(90) was 2 microg/ml for a standard inoculum and 32 microg/ml for a high inoculum, with 19% of isolates displaying a pronounced inoculum effect (MICs of >or=16 microg/ml with 10(7) CFU/ml) (9 type A and 10 type C Bla producers). At the high inoculum, type A producers displayed higher cefazolin MICs than type B or C producers, while type B and C producers displayed higher cefamandole MICs. Among isolates from hemodialysis patients with MSSA bacteremia, three from the six patients who experienced cefazolin failure showed a cefazolin inoculum effect, while none from the six patients successfully treated with cefazolin showed an inoculum effect, suggesting an association between these strains and cefazolin failure (P = 0.09 by Fisher's exact test). In summary, 19% of MSSA clinical isolates showed a pronounced inoculum effect with cefazolin, a phenomenon that could explain the cases of cefazolin failure previously reported for hemodialysis patients with MSSA bacteremia. These results suggest that for serious MSSA infections, the presence of a significant inoculum effect with cefazolin could be associated with clinical failure in patients treated with this cephalosporin, particularly when it is used at low doses.


Randomized controlled trial of gabapentin as an adjunct to perioperative analgesia in total hip arthroplasty patients.
Gabapentin was investigated as a single-dose adjunct to morphine for postoperative pain management. The primary objective was to determine if gabapentin given preoperatively and for two days postoperatively as part of multimodal analgesia would decrease postoperative morphine consumption in patients undergoing primary total hip arthroplasty (THA). The study group included 102 patients aged 19-90 years who were undergoing primary THA in a single joint with no contraindications to the study medications, no chronic pain syndrome, and no chronic opioid use. Intervention group patients (n = 48) received gabapentin 600 mg po preoperatively and 200 mg postoperatively on the day of surgery. They were continued on gabapentin at 200 mg three times daily for two days. Control group patients (n = 54) received placebo in a similar fashion. Preoperatively, all patients were given 30 mg of ketorolac intravenously and acetaminophen 1000 mg po. Postoperatively, they received intravenous patient-controlled analgesia with morphine, along with ketorolac 15 mg iv and acetaminophen 1000 mg po every six hours. The primary outcome was mean (SD) postoperative morphine consumption at 72 hr which was 55.8 (39.2) mg in the gabapentin groups vs 60.7 (37.2) mg for the control group (mean difference, -4.91 mg, 95% confidence intervals [CI]: -21.2 to 11.35; P = 0.550). There were no significant differences between the groups regarding secondary outcomes: pain scores, side effects, range of motion. Patient satisfaction on day 3 was more favourable in the placebo group. Length of hospitalization was marginally shorter in the placebo group. This trial indicated that gabapentin treatment had no clinically important reduction in postoperative morphine consumption at 72 hr in patients undergoing THA. Multimodal analgesia may account for the similar primary and secondary outcomes found in the groups. This trial was registered at ClinicalTrials.gov, number: NCT01307202.


Anemia and dementia among the elderly: the São Paulo Ageing & Health Study.
Anemia and dementia are common diseases among the elderly, but conflicting data are available regarding an association between these two conditions. We analyzed data from the São Paulo Ageing & Health Study to address the relationship between anemia and dementia. This cross-sectional observational study included participants aged 65 years and older from a deprived area of the borough of Butantan, São Paulo, Brazil. Data about demographics, education, income, and cognitive and daily life function were collected, as well as blood samples. Anemia and dementia were defined according to WHO and DSM-IV criteria, respectively. Of the 2267 subjects meeting the inclusion criteria, 2072 agreed to participate in the study; of whom 1948 had a valid total blood count and were included in the analysis. Anemia was diagnosed in 203 (10.2%) participants and dementia in 99 (5.1%). The frequency of anemia was higher in patients with dementia according to univariate analysis (odds ratio (OR) = 2.00, 95% confidence interval (CI) = 1.17-3.41, p = 0.01), but this association was not present after adjusting for age (OR = 1.33, 95% CI = 0.76-2.33, p = 0.32). Further multivariate adjustment did not change the results. Although anemia and dementia are frequent disorders in older people, we found their relationship to be mediated exclusively by aging in this low-income population from São Paulo.


Role of the Microenvironment in Liver Metastasis: From Pre- to Prometastatic Niches.
Liver metastases remain a major barrier to successful management of malignant disease, particularly for cancers of the gastrointestinal tract but also for other malignancies, such as breast carcinoma and melanoma. The ability of metastatic cells to survive and proliferate in the liver is determined by the outcome of complex, reciprocal interactions between tumor cells and different local resident subpopulations, including the sinusoidal endothelium, stellate, Kupffer, and inflammatory cells that are mediated through cell-cell and cell-extracellular matrix adhesion and the release of soluble factors. Cross-communication between different hepatic resident cells in response to local tissue damage and inflammation and the recruitment of bone marrow cells further enhance this intercellular communication network. Both resident and recruited cells can play opposing roles in the progression of metastasis, and the balance of these divergent effects determines whether the tumor cells will die, proliferate, and colonize the new site or enter a state of dormancy. Moreover, this delicate balance can be tilted in favor of metastasis, if factors produced by the primary tumor precondition the microenvironment to form niches of activated resident cells that promote tumor expansion. This review aims to summarize current knowledge on these diverse interactions and the impact they can have on the clinical management of hepatic metastases. Clin Cancer Res; 22(24); 5971-82. ©2016 AACR.