Traumatic brain injury in the Netherlands, trends in emergency department visits, hospitalization and mortality between 1998 and 2012.
Traumatic brain injury (TBI) is a major cause of morbidity and mortality worldwide. The effects of epidemiological changes such as ageing of the population and increased traffic safety on the incidence of TBI are unknown. The objective of this study was to evaluate trends in TBI-related emergency department (ED) visits, hospitalization and mortality in the Netherlands between 1998 and 2012. This was a retrospective observational, longitudinal study. The main outcome measures were TBI-related ED visits, hospitalization and mortality. Between 1998 and 2012, there were 500 000 TBI-related ED visits in the Netherlands. In the same period, there were 222 000 TBI-related admissions and 17 000 TBI-related deaths. During this period, there was a 75% increase in ED visits for TBI and a 95% increase for TBI-related hospitalization; overall mortality because of TBI did not change significantly. Despite the overall increase in TBI-related ED visits, this increase was not evenly distributed among age groups or trauma mechanisms. In patients younger than 65 years, a declining trend in ED visits for TBI caused by road traffic accidents was observed. Among patients 65 years or older, ED visits for TBI caused by a fall increased markedly. TBI-related mortality shifted from mainly young (67%) and middle-aged individuals (<65 years) to mainly elderly (63%) individuals (≥65 years) between 1998 and 2012. The conclusions of this study did not change when adjusting for changes in age, sex and overall population growth. The incidence of TBI-related ED visits and hospitalization increased markedly between 1998 and 2012 in the Netherlands. TBI-related mortality occurred at an older age. These observations are probably the result of a change in aetiology of TBI, specifically a decrease in traffic accidents and an increase in falls in the ageing population. This hypothesis is supported by our data. However, ageing of the population is not the only cause of the changes observed; the observed changes remained significant when correcting for age and sex. The higher incidence of TBI with a relatively stable mortality rate highlights the importance of clinical decision rules to identify patients with a high risk of poor outcome after TBI.


Properties of elliptical-core two-mode fiber.
Polarization and modal birefringence of elliptical-core two-mode fibers are investigated. Wavelengths corresponding to zero group delay difference (GDD) between the two spatial modes and between the orthogonal polarizations are computed when the fiber parameters, i.e., the relative core/cladding index difference and the ratio of major over minor axis, are varied. Simple relationships between the zero GDD wavelengths and fiber parameters are obtained. With proper fiber design, zero GDD between the two spatial modes and the two orthogonal polarizations can be achieved at the same wavelength.


Dose-response characteristics of cholesterol-lowering drug therapies: implications for treatment.
To develop an optimal treatment strategy that reduces low-density lipoprotein (LDL) cholesterol levels and improves adherence to therapy by reviewing clinical trials that define the dose-response characteristics for 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors (statins), bile acid sequestrants, and niacin. Data were obtained from a MEDLINE search of the English-language literature published from 1975 through November 1995 and from an extensive bibliography review. Controlled, clinical trials were reviewed if they evaluated 1) the effectiveness and toxicity of one LDL cholesterol-lowering agent (statins, bile acid sequestrants, or niacin, at two or more doses) or 2) monotherapy with two LDL cholesterol-lowering agents at defined doses used alone and in combination. Studies that had fewer than 10 patients in a treatment group or that selected patients on the basis of previous response to therapy were not included. Trials were reviewed for overall methodology, inclusion and exclusion criteria, sources of bias, and outcomes. Dose-response relations for bile acid sequestrants and statins are nonlinear, and most of their LDL cholesterol-lowering effects can be obtained with lower doses. The few dose-response studies of niacin that have been done suggest that most of niacin's high-density lipoprotein cholesterol-increasing effect can also be achieved with relatively low doses, but higher doses are needed to substantially reduce LDL cholesterol levels. If bile acid sequestrants or niacin are added to statin therapy, the effect of combined therapy on LDL cholesterol levels is additive. The nonlinear dose-response relation of statins, bile acid sequestrants, and niacin and their additive LDL cholesterol-lowering effect when used together suggest a strategy for treating hypercholesterolemia that may optimize effectiveness while minimizing adverse effects and cost.


Alcoholic beverages and risk of renal cell cancer.
Using a mailed questionnaire, we investigated the risk of renal cell cancer in relation to different types of alcoholic beverages, and to total ethanol in a large population-based case-control study among Swedish adults, including 855 cases and 1204 controls. Compared to non-drinkers, a total ethanol intake of >620 g month(-1) was significantly related to a decreased risk of renal cell cancer (odds ratio (OR) 0.6, 95% confidence interval (CI) 0.4-0.9; P-value for trend=0.03). The risk decreased 30-40% with drinking more than two glasses per week of red wine (OR 0.6, 95% CI 0.4-0.9), white wine (OR 0.7, 95% CI 0.4-1.0), or strong beer (OR 0.6, 95% CI 0.4-1.0); there was a clear linear trend of decreasing risk with increasing consumption of these beverages (P-values for trends <0.05).


The use of procalcitonin in the diagnosis of bone and joint infection: a systemic review and meta-analysis.
Only a few studies have investigated the use of PCT in the diagnosis of bone and joint infection, and these studies have had relatively small sample sizes. We performed a systematic review and meta-analysis of the diagnostic performance of serum procalcitonin (PCT) in the identification of osteomyelitis and septic arthritis in patients who present with fever and orthopedic symptoms. EMBASE, MEDLINE, and Cochrane databases and the reference lists of relevant articles were searched, with no language restrictions, through February 2012. All original studies that reported the use of serum PCT alone or in comparison with other biomarkers for diagnosis of osteomyelitis and septic arthritis were included. Seven studies qualified for inclusion. These studies enrolled a total of 583 patients with suspected bone or joint infection, 131 of whom had confirmed osteomyelitis or septic arthritis. Analysis of the PCT data indicated a bivariate pooled sensitivity of 0.67 (95 % CI: 0.37-0.88), specificity of 0.90 (95 % CI: 0.78-0.96), a positive likelihood ratio (LR+) of 6.48 (95 % CI: 2.28-14.6), and a negative likelihood ratio (LR-) of 0.37 (95 % CI: 0.16-0.84). Use of a lower PCT cut-off value (0.2-0.3 ng/mL) improved the LR + to 6.66 and the LR- to 0.15. Analysis of the three studies that also measured serum C-reactive protein (CRP) indicated that CRP had an LR + of 1.39 (95 % CI: 1.17-1.65) and an LR- of 0.40 (95 % CI: 0.12-1.36). Our results indicate that PCT may be more suitable as an aid for rule-in diagnosis rather than for exclusion of septic arthritis or osteomyelitis and that use of a lower cut-off value for serum PCT may improve its diagnostic performance.


The lung environment controls alveolar macrophage metabolism and responsiveness in type 2 inflammation.
Fine control of macrophage activation is needed to prevent inflammatory disease, particularly at barrier sites such as the lungs. However, the dominant mechanisms that regulate the activation of pulmonary macrophages during inflammation are poorly understood. We found that alveolar macrophages (AlvMs) were much less able to respond to the canonical type 2 cytokine IL-4, which underpins allergic disease and parasitic worm infections, than macrophages from lung tissue or the peritoneal cavity. We found that the hyporesponsiveness of AlvMs to IL-4 depended upon the lung environment but was independent of the host microbiota or the lung extracellular matrix components surfactant protein D (SP-D) and mucin 5b (Muc5b). AlvMs showed severely dysregulated metabolism relative to that of cavity macrophages. After removal from the lungs, AlvMs regained responsiveness to IL-4 in a glycolysis-dependent manner. Thus, impaired glycolysis in the pulmonary niche regulates AlvM responsiveness during type 2 inflammation.


APCR, factor V gene known and novel SNPs and adverse pregnancy outcomes in an Irish cohort of pregnant women.
Activated Protein C Resistance (APCR), a poor anticoagulant response of APC in haemostasis, is the commonest heritable thrombophilia. Adverse outcomes during pregnancy have been linked to APCR. This study determined the frequency of APCR, factor V gene known and novel SNPs and adverse outcomes in a group of pregnant women. Blood samples collected from 907 pregnant women were tested using the Coatest Classic and Modified functional haematological tests to establish the frequency of APCR. PCR-Restriction Enzyme Analysis (PCR-REA), PCR-DNA probe hybridisation analysis and DNA sequencing were used for molecular screening of known mutations in the factor V gene in subjects determined to have APCR based on the Coatest Classic and/or Modified functional haematological tests. Glycosylase Mediated Polymorphism Detection (GMPD), a SNP screening technique and DNA sequencing, were used to identify SNPs in the factor V gene of 5 APCR subjects. Sixteen percent of the study group had an APCR phenotype. Factor V Leiden (FVL), FV Cambridge, and haplotype (H) R2 alleles were identified in this group. Thirty-three SNPs; 9 silent SNPs and 24 missense SNPs, of which 20 SNPs were novel, were identified in the 5 APCR subjects. Adverse pregnancy outcomes were found at a frequency of 35% in the group with APCR based on Classic Coatest test only and at 45% in the group with APCR based on the Modified Coatest test. Forty-eight percent of subjects with FVL had adverse outcomes while in the group of subjects with no FVL, adverse outcomes occurred at a frequency of 37%. Known mutations and novel SNPs in the factor V gene were identified in the study cohort determined to have APCR in pregnancy. Further studies are required to investigate the contribution of these novel SNPs to the APCR phenotype. Adverse outcomes including early pregnancy loss (EPL), preeclampsia (PET) and intrauterine growth restriction (IGUR) were not significantly more frequent in subjects with APCR compared to normal pregnant women however Pregnancy induced hypertension (PIH) was found to be associated with FVL in our study group.


Discovery and pharmacological characterization of AZD3229, a potent KIT/PDGFRα inhibitor for treatment of gastrointestinal stromal tumors.
Gastrointestinal stromal tumor (GIST) is the most common human sarcoma driven by mutations in KIT or platelet-derived growth factor α (PDGFRα). Although first-line treatment, imatinib, has revolutionized GIST treatment, drug resistance due to acquisition of secondary KIT/PDGFRα mutations develops in a majority of patients. Second- and third-line treatments, sunitinib and regorafenib, lack activity against a plethora of mutations in KIT/PDGFRα in GIST, with median time to disease progression of 4 to 6 months and inhibition of vascular endothelial growth factor receptor 2 (VEGFR2) causing high-grade hypertension. Patients with GIST have an unmet need for a well-tolerated drug that robustly inhibits a range of KIT/PDGFRα mutations. Here, we report the discovery and pharmacological characterization of AZD3229, a potent and selective small-molecule inhibitor of KIT and PDGFRα designed to inhibit a broad range of primary and imatinib-resistant secondary mutations seen in GIST. In engineered and GIST-derived cell lines, AZD3229 is 15 to 60 times more potent than imatinib in inhibiting KIT primary mutations and has low nanomolar activity against a wide spectrum of secondary mutations. AZD3229 causes durable inhibition of KIT signaling in patient-derived xenograft (PDX) models of GIST, leading to tumor regressions at doses that showed no changes in arterial blood pressure (BP) in rat telemetry studies. AZD3229 has a superior potency and selectivity profile to standard of care (SoC) agents-imatinib, sunitinib, and regorafenib, as well as investigational agents, avapritinib (BLU-285) and ripretinib (DCC-2618). AZD3229 has the potential to be a best-in-class inhibitor for clinically relevant KIT/PDGFRα mutations in GIST.


Low Grade Micropapillary Urothelial Carcinoma, Does It Exist? - Analysis of Management and Outcomes from the Surveillance, Epidemiology and End Results (SEER) Database.
To elucidate the oncologic behavior of Micropapillary Urothelial Bladder Carcinoma (MPBC), a rare aggressive variant histology. All MPBC patients in SEER 17 database were compared with those with traditional urothelial carcinoma (UC). Kaplan-Meier curves were used to determine OS and CSS. A Cox proportional hazards model (CPH) was constructed to test the effect of covariates on outcomes. From 2001-2008, 120 MPBC patients were identified, 0.1% of all bladder cancer. MPBC presented with more high grade (86.1% vs. 38.7%, p<0.0001) and more high stage disease (40.8% NMI vs. 90.4% NMI, p < 0.0001) than UC. Low grade (LG) NMI MPBC had worse OS and CSS compared to LG UC (p=0.0037, p<0.0001 respectively), and did no better than high grade (HG) NMI MPBC. No difference was detected between HG NMI MPBC and HG NMI UC pts. A CPH model controlling for stage, grade, treatment, age, race, and sex detected no significant survival difference in MPBC vs. UC (HR 1.04, p=0.7966). For NMI MPBC (n=49), only 4 patients underwent definitive therapy, of whom none died of disease. However, in those not receiving definitive therapy (n=45), 7 cancer specific deaths occurred (15.6%). Controlling for stage and grade, no survival difference could be detected between MPBC and UC. Low grade NMI MPBC behaved similarly to both high grade MPBC and high grade UC. We propose that all MPBC (regardless of grade) be managed as high grade disease, and that strong consideration for definitive therapy should be given in all cases.


Efficacy of continued alendronate for fractures in women with and without prevalent vertebral fracture: the FLEX trial.
In the Fracture Intervention Trial (FIT) Long Term Extension (FLEX) Trial, 10 years of alendronate (ALN) did not significantly reduce the risk of nonvertebral fractures (NVFs) compared with 5 years of ALN. Continuing ALN reduced the risk of clinical but not morphometric vertebral fractures regardless of baseline vertebral fracture status. In previous studies, ALN efficacy for NVF prevention in women without prevalent vertebral fracture was limited to those with femoral neck (FN) T-scores of -2.5 or less. To determine whether the effect of long-term ALN on fracture differs by vertebral fracture status and femoral neck (FN) T-score, we performed a post hoc analysis using FLEX data, a randomized, double-blind, placebo-controlled trial among 1099 postmenopausal women originally randomized to ALN in the FIT with mean ALN use of 5 years. In the FLEX Trial, women were randomized to placebo (40%) or ALN 5 mg/day (30%) or ALN 10 mg/day (30%) for an additional 5 years. Among women without vertebral fracture at FLEX baseline (n = 720), continuation of ALN reduced NVF in women with FLEX baseline FN T-scores of -2.5 or less [relative risk (RR) = 0.50, 95% confidence interval (CI) 0.26-0.96] but not with T-scores of greater than -2.5 and -2 or less (RR 0.79, 95% CI 0.37-1.66) or with T-scores of greater than -2 (RR 1.41, 95% CI 0.75-2.66; p for interaction = .019). Continuing ALN for 10 years instead of stopping after 5 years reduces NVF risk in women without prevalent vertebral fracture whose FN T-scores, achieved after 5 years of ALN, are -2.5 or less but does not reduce risk of NVF in women whose T-scores are greater than -2.


Cellular mechanism of endothelin-1 release by angiotensin and vasopressin.
Release of endothelin-1, a novel potent vasoconstrictor peptide originally isolated from endothelial cells, from cultured bovine endothelial cells has been shown to be stimulated by arginine vasopressin and angiotensin II. To elucidate the cellular mechanism by which endothelin-1 is released by these vasoconstrictors, we tested the effects of several compounds on the agonist-induced endothelin-1 release and studied the changes of cytosolic free Ca2+ concentrations and phosphoinositide breakdown by these agonists in cultured bovine endothelial cells. Protein kinase C inhibitors (H-7, staurosporine), an intracellular Ca2+ chelator, and an inhibitor of phospholipase C (neomycin), all abolished the agonist-induced endothelin-1 release, whereas the Ca2+ channel blocker nicardipine was ineffective. Although synthetic 1,2-diglyceride (diolein) dose dependently stimulated endothelin-1 release, downregulation of protein kinase C after pretreatment with phorbol ester resulted in decreased effects to increase endothelin-1 release by the agonists. Both arginine vasopressin and angiotensin II induced immediate and transient increases in intracellular Ca2+ levels of fura-2-loaded endothelial cells as well as formation of inositol trisphosphate; the agonist-induced intracellular Ca2+ increases were not affected either by nicardipine or by chelating extracellular Ca2+. The arginine vasopressin- and angiotensin II-induced intracellular Ca2+ increases, inositol trisphosphate formation, and endothelin-1 release were completely abolished by V1-receptor antagonist and saralasin, respectively. It is concluded that arginine vasopressin and angiotensin II stimulate the release of endothelin-1 by a common mechanism, involving receptor-mediated mobilization of intracellular Ca2+ and activation of protein kinase C in endothelial cells.


Focusing of radially and azimuthally polarized beams through a uniaxial crystal.
We calculated and measured the difference between focal positions of radially and azimuthally polarized beams after passing through a uniaxial crystal. Calculations were carried out on the basis of the ray optics and the vector diffraction theory. The results of the calculations were in good agreement with those of the experiment. In addition, we discussed the polarization selection in a hemispherical laser cavity that was used for the generation of a radially polarized beam by use of the birefringence of a c-cut Nd:YVO4 laser crystal [Opt. Lett. 31, 2151 (2006)]. The stability range of the laser cavity length for the generation of a radially polarized beam was also in good agreement with the differences mentioned above.


The current and future burden of cancer attributable to modifiable risk factors in Canada: Summary of results.
Nearly one in two Canadians are expected to be diagnosed with cancer in their lifetime. However, there are opportunities to reduce the impact of modifiable cancer risk factors through well-informed interventions and policies. Since no comprehensive Canadian estimates have been available previously, we estimated the proportion of cancer diagnosed in 2015 and the future burden in 2042 attributable to lifestyle and environmental factors, and infections. Population-based historical estimates of exposure prevalence and their associated risks for each exposure-cancer site pair were obtained to estimate population attributable risks, assuming the exposures were distributed independently and that the risk estimates were multiplicative. We estimated that between 33 and 37% (up to 70,000 cases) of incident cancer cases among adults aged 30 years and over in 2015 were attributable to preventable risk factors. Similar proportions of cancer cases in males (34%) and females (33%) were attributable to these risk factors. Tobacco smoking and a lack of physical activity were associated with the highest proportions of cancer cases. Cancers with the highest number of preventable cases were lung (20,100), colorectal (9800) and female breast (5300) cancer. If current trends in the prevalence of preventable risk factors continue into the future, we project that by 2042 approximately 102,000 incident cancer cases are expected to be attributable to these risk factors per year, which would account for roughly one-third of all incident cancers. Through various risk reduction interventions, policies and public health campaigns, an estimated 10,600 to 39,700 cancer cases per year could be prevented by 2042.


Monolithic self-Q-switched Cr,Nd:YAG laser.
We report the operation of a diode-pumped monolithic self-Q-switched Cr,Nd:YAG laser in which the codoped ions create saturable absorption for Nd(3+) laser emission at 1064 nm. With a 70-microm beam diameter in the gain medium, the Q-switched pulse has a duration of 3.5 ns and a peak power of 2 kW. The output is linearly polarized with an extinction ratio of 600:1. The pulse-to-pulse intensity fluctuation is less than the instrument resolution of 0.25%. A 5-mm-long KTP crystal butted against the monolithic cavity produces 2-ns-long pulses at 532nm with a peak power-conversion efficiency of 30%.


Besides adhesion: new perspectives of integrin functions in angiogenesis.
During angiogenic remodelling in embryo and adult life, endothelial cells lining blood vessel walls dynamically modify their integrin-mediated adhesive contacts with the surrounding extracellular matrix. However, besides regulating cell adhesion and migration, integrins dynamically participate in a network with soluble molecules and their receptors. Angiogenesis is characterized by opposing autocrine and paracrine loops of growth factors and semaphorins that regulate the activation of integrins on the endothelial surface through tyrosine kinase receptors (TKR) and the neuropilin/plexin system. Moreover, pro- and anti-angiogenic factors can directly bind integrins and regulate endothelial cell behaviour. This review summarizes the recent progress in understanding the reciprocal interactions between integrins, TKR, and semaphorin receptors.


Eating the right amount of fish: inverted U-shape association between fish consumption and cognitive performance and academic achievement in Dutch adolescents.
Fish consumption has shown its benefits for cognitive functioning in the elderly or children with disorders (e.g., autism, ADHD), but has rarely been investigated in relation to cognitive performance and school performance of healthy adolescents. We executed an observational study in 700 Dutch high school students aged 12-18 years. Fish consumption data, end term grades, scores on the Amsterdam Vocabulary Test, and scores on the Youth Self-Report were collected. Results revealed that 13.6% of the Dutch adolescents never ate fish, 6.4% met national guidelines, 16.9% reached half of the norm, and 63.1% did eat fish but too little to meet at least half of the norm. Analysis of variance, controlled for relevant covariates, showed significant differences between the four fish consumption groups in vocabulary (p=.05). A trend for significance was found for end term grades (p=.07). Contrast analyses demonstrated significant quadratic associations between fish consumption and vocabulary (p=.01) and end term grades (p=.01). Thus higher fish intake was associated with more advanced vocabulary and higher end term grades. However, eating more fish than the described norm seemed no longer beneficial.


Fluorescein Leakage and Optical Coherence Tomography Features of Choroidal Neovascularization Secondary to Pathologic Myopia.
We compare the fluorescein angiography (FA) patterns with morphologic alterations detectable on spectral-domain OCT (SD-OCT) in myopic choroidal neovascularization (mCNV) and evaluate whether they influence the effects of intravitreal ranibizumab (IVRI) in an as-needed (PRN) regimen. The 49 patients enrolled in this prospective case series underwent a complete ophthalmologic examination, including best-corrected visual acuity (BCVA), FA, and SD-OCT assessment. The main outcome measure was correlation between FA patterns and SD-OCT features. Secondary outcomes were changes in BCVA and central macular thickness (CMT), and characterization of subretinal hyperreflective exudation (SHE). Three main patterns were identified on the FA: no (5%), minimal (35%), and profuse (59%) leakage CNV. Comparison between minimal versus profuse leakage CNV subtypes revealed no difference regarding baseline and final BCVA, CNV area, choroidal thickness, final CMT, and proportion of intraretinal cysts, subretinal fluid, and external limiting membrane (ELM) interruption; however, the minimal leakage CNV subgroup revealed a lower percentage of SHE (P = 0.0039), required fewer IVRI (P = 0.003), and showed a baseline smaller CMT (P = 0.004). Patients presenting with SHE showed a similar baseline BCVA to those without exudation, but displayed greater final BCVA improvement. CMT was greater at the baseline and the reduction also was more marked. CNV area achieved a significant reduction only in eyes with SHE. ELM interruption was present in all cases compared to 86.3% of eyes without SHE. Lastly, the eyes with SHE required more injections (P = 0.04). Different patterns of mCNV may be identified in FA and they correlate with specific SD-OCT alterations. Moreover, the type of FA leakage may assist in identifying more active mCNV.


Synthesis and antiviral evaluation of cyclic and acyclic 2-methyl-3-hydroxy-4-pyridinone nucleoside derivatives.
A series of cyclic and acyclic nucleoside analogues derived from 3-hydroxy-4-pyridinone were synthesized using the Vorbrüggen reaction. Iron chelation studies, and antiviral evaluation against a broad panel of viruses, were performed. The pK(a) value of ligand 25 and the stability constant of the corresponding iron(III) complex were compared to those of deferiprone. The pFe(3+) values were found to be similar. Some compounds showed moderate activity against both wild-type HSV-1 and HSV-2, as well as against a thymidine kinase deficient strain of HSV-1. These results suggest a novel mode of action for this group of nucleoside analogues.


Can lemon juice be an alternative to potassium citrate in the treatment of urinary calcium stones in patients with hypocitraturia? A prospective randomized study.
To investigate that lemon juice could be an alternative to potassium citrate in the treatment of urinary calcium stones in patients with hypocitraturia, 30 patients with hypocitraturic urinary calcium stones were enrolled into study. The patients were divided into three groups equally. Exactly 60 mEq/day fresh lemon juice ( approximately 85 cc/day) and potassium citrate (60 mEq/day) were given to the patients of first and second group, respectively. Dietary recommendations were made for the third group. Blood and 24-h urine tests were performed before treatment and repeated 3 months later. The differences between demographic datas of groups were not significant. There was no significant difference between values of blood tests performed before and after treatment in all groups. Statistically significant differences were found between pre- and post-treatment urine values in each group. Although there was no significant difference between pre-treatment citrate levels of the groups. A significant difference was found between post-treatment citrate levels of the groups. There was 2.5-, 3.5- and 0.8-fold increase in urinary citrate level of lemon juice, potassium citrate and dietary recommendation groups, respectively. Urinary calcium level was decreased only in lemon juice and potassium citrate groups after treatment. While there was no significant difference between pre- and post-treatment urinary oxalate levels in all groups, a significant decrease in urinary uric acid levels was determined in all groups. We suggest that lemon juice can be an alternative in the treatment of urinary calcium stones in patients with hypocitraturia. Additionally, dietary recommendations can increase effectiveness of the treatment.


Sinus Surgery Is Associated with a Decrease in Aspirin-Induced Reaction Severity in Patients with Aspirin Exacerbated Respiratory Disease.
Nasal polyps influence the burden of aspirin-exacerbated respiratory disease (AERD) by contributing to eicosanoid production. AERD is diagnosed through graded aspirin challenges. It is not known how sinus surgery affects aspirin challenge outcomes. To investigate the effects of endoscopic sinus surgery (ESS) on aspirin-induced reaction severity and on the levels of eicosanoids associated with these reactions. Twenty-eight patients with AERD were challenged with aspirin before and 3 to 4 weeks after ESS. Respiratory parameters and plasma and urine levels of eicosanoids were compared before and after challenges. Before ESS, AERD diagnosis was confirmed in all study patients by aspirin challenges that resulted in hypersensitivity reactions. After ESS, reactions to aspirin were less severe in all patients and 12 of 28 patients (43%, P < .001) had no detectable reaction. A lack of clinical reaction to aspirin was associated with lower peripheral blood eosinophilia (0.1 K/μL [interquartile range (IQR) 0.1-0.3] vs 0.4 K/μL [IQR 0.2-0.8]; P = .006), lower urinary leukotriene E4 levels after aspirin challenge (98 pg/mg creatinine [IQR 61-239] vs 459 pg/mg creatinine [IQR 141-1344]; P = .02), and lower plasma prostaglandin D2 to prostaglandin E2 ratio (0 [±0] vs 0.43 [±0.2]; P = .03), compared with those who reacted. Sinus surgery results in decreased aspirin sensitivity and a decrease in several plasma and urine eicosanoid levels in patients with AERD. Diagnostic aspirin challenges should be offered to patients with suspected AERD before ESS to increase diagnostic accuracy. Patients with established AERD could undergo aspirin desensitizations after ESS as the severity of their aspirin-induced hypersensitivity reactions lessens.


Mathematical models of tumour and normal tissue response.
The historical application of mathematics in the natural sciences and in radiotherapy is compared. The various forms of mathematical models and their limitations are discussed. The Linear Quadratic (LQ) model can be modified to include (i) radiobiological parameter changes that occur during fractionated radiotherapy, (ii) situations such as focal forms of radiotherapy, (iii) normal tissue responses, and (iv) to allow for the process of optimization. The inclusion of a variable cell loss factor in the LQ model repopulation term produces a more flexible clonogenic doubling time, which can simulate the phenomenon of 'accelerated repopulation'. Differential calculus can be applied to the LQ model after elimination of the fraction number integers. The optimum dose per fraction (maximum cell kill relative to a given normal tissue fractionation sensitivity) is then estimated from the clonogen doubling times and the radiosensitivity parameters (or alpha/beta ratios). Economic treatment optimization is described. Tumour volume studies during or following teletherapy are used to optimize brachytherapy. The radiation responses of both individual tumours and tumour populations (by random sampling 'Monte-Carlo' techniques from statistical ranges of radiobiological and physical parameters) can be estimated. Computerized preclinical trials can be used to guide choice of dose fractionation scheduling in clinical trials. The potential impact of gene and other biological therapies on the results of radical radiotherapy are testable. New and experimentally testable hypotheses are generated from limited clinical data by exploratory modelling exercises.


Coevolution of sender and receiver: effect on local mate preferecnce in cricket frogs.
Mate recognition in frogs requires congruence of call characters, such as dominant frequency, and properties ofthe auditory system, such as frequency sensitivity of inner ear organs. Two neighboring populations of cricket frogs (Acri crepitans) exhibit statistically significant differences in the dominant frequency of the advertisement call and the frequency to which the basilar papilla of the inner ear is most sensitive. Call frequency and frequency sensitivity are matched within but differ between populations. These characters usually are negatively correlated with body size, and thus their congruence and coevolution often is explained by pleiotropic effects of size. However, within this species call frequency and frequency sensitivity ofthe basilar papilla evolved independent of body size, yielding local mate preferences that could contribute to genetic differentiation among neighboring populations.


Track: A randomized controlled trial of a digital health obesity treatment intervention for medically vulnerable primary care patients.
Obesity continues to disproportionately affect medically vulnerable populations. Digital health interventions may be effective for delivering obesity treatment in low-resource primary care settings. Track is a 12-month randomized controlled trial of a digital health weight loss intervention in a community health center system. Participants are 351 obese men and women aged 21 to 65years with an obesity-related comorbidity. Track participants are randomized to usual primary care or to a 12-month intervention consisting of algorithm-generated tailored behavior change goals, self-monitoring via mobile technologies, daily self-weighing using a network-connected scale, skills training materials, 18 counseling phone calls with a Track coach, and primary care provider counseling. Participants are followed over 12months, with study visits at baseline, 6, and 12months. Anthropometric data, blood pressure, fasting lipids, glucose and HbA1C and self-administered surveys are collected. Follow-up data will be collected from the medical record at 24months. Participants are 68% female and on average 50.7years old with a mean BMI of 35.9kg/m(2). Participants are mainly black (54%) or white (33%); 12.5% are Hispanic. Participants are mostly employed and low-income. Over 20% of the sample has hypertension, diabetes and hyperlipidemia. Almost 27% of participants currently smoke and almost 20% score above the clinical threshold for depression. Track utilizes an innovative, digital health approach to reduce obesity and chronic disease risk among medically vulnerable adults in the primary care setting. Baseline characteristics reflect a socioeconomically disadvantaged, high-risk patient population in need of evidence-based obesity treatment.


Complexity of human T-cell antigen receptor beta-chain constant- and variable-region genes.
Immune systems of vertebrates function via two types of effector cells, B and T cells, which are capable of antigen-specific recognition. The immunoglobulins, which serve as antigen receptors on B cells, have been well characterized with respect to gene structure, unlike the T-cell receptors. Recently, cDNA clones thought to correspond to the beta-chain locus of the human and mouse T-cell receptor have been described. The presumptive beta-chain clones detect gene rearrangement specifically in T-cell DNA and show homology with immunoglobulin light chains. The similarity of the T-cell beta-chain gene system to the immunoglobulin genes has been further demonstrated by the recent observation of variable- and constant-region gene segments as well as joining segments and putative diversity segments. We report here the characterization of cDNA and genomic clones encoding human T-cell receptor beta-chain genes. There are two constant-region genes (C beta 1 and C beta 2), each capable of rearrangement and expression as RNA. The gene arrangement, analogous to that of mouse beta-chain genes, shows strong evolutionary conservation of the dual C beta gene system in these two species.


Clinical inquiries. Does anticoagulation prevent thrombosis for persons with fractures distal to the hip?
Low-molecular-weight heparin (LMWH) prophylaxis significantly reduces the total incidence of deep venous thrombosis (DVT) for patients with lower-limb fractures managed with surgical fixation and cast immobilization (strength of recommendation [SOR]: A, based on multiple randomized controlled studies [RCTs]). Evidence is insufficient to show whether LMWH specifically reduces the risk of clinically significant DVTs, and recommendations on its use are conflicting (SOR: C, based on expert opinion). Evidence is insufficient to recommend for or against warfarin prophylaxis for DVT in fractures distal to the hip (SOR: C, based on expert opinion).


Preoperative Bariatric Surgery Predictors of Type 2 Diabetes Remission.
Obesity represents a significant proportion of the global public health burden, with the World Health Organization (WHO) estimating more than 600 million people are affected worldwide. Unfortunately, the epidemic of obesity is linked to the increased prevalence of associated metabolic diseases such as type 2 diabetes mellitus (T2DM). Bariatric surgery as an intervention has been shown to provide sustainable weight loss, and also leads to superior short- and long-term metabolic benefits including T2DM remission. Despite this added advantage conferred by bariatric surgery, emerging evidence has shown that not all patients with T2DM achieve remission postoperatively. As such, to improve patient selection and optimize preoperative counselling, research has focused on the preoperative predictors of T2DM remission following bariatric surgery. Herein, we provide a critical review of the current literature addressing preoperative predictors of T2DM remission and highlight the current gaps in the literature. The review comprised a multistage advanced electronic search of the Ovid/Medline, Embase, and Cochrane online libraries to identify available studies published over the last decade.


The relative importance of premortem acidosis and postmortem interval for human brain gene expression studies: selective mRNA vulnerability and comparison with their encoded proteins.
To help account for the variable quality and quantity of RNA in human brain, we have studied the effect of premortem (agonal state) and postmortem factors on the detection of poly(A)+mRNA and eight mRNAs. For comparison, the influence of the same factors upon gene products encoded by the mRNAs was studied immunocytochemically or by receptor autoradiography. Brain pH declined with increasing age at death and was related to agonal state severity, but was independent of postmortem interval and the histological presence of hypoxic changes. By linear regression, pH was significantly associated with the abundance of several of the RNAs, but not with poly(A)+mRNA, immunoreactivities, or binding site densities. Postmortem interval had a limited influence upon mRNA and protein products. Freezer storage time showed no effect. Parallel rat brain studies showed no relationship between postmortem interval (0-48 h) and amounts of total RNA, poly(A)+RNA, or two individual mRNAs; however, RNA content was reduced by 40% at 96 h after death. pH is superior to clinical assessments of agonal state or mode of death in predicting mRNA preservation. It provides a simple means to improve human brain gene expression studies. pH is stable after death and during freezer storage and can be measured either in cerebrospinal fluid or in homogenised tissue.


Monitoring of muscle motor evoked potentials during cerebral aneurysm surgery: intraoperative changes and postoperative outcome.
The authors in this study evaluated muscle motor evoked potentials (MMEPs) elicited by transcranial electrical stimulation (TES) and direct cortical stimulation as a means of monitoring during cerebral aneurysm surgery. The analysis focused on the value and frequencies of any intraoperative changes and their correlation to the postoperative motor status. One hundred nineteen patients undergoing surgery for 148 cerebral aneurysms were included in the study. Muscle motor evoked potentials were elicited by a train of five constant-current anodal stimuli with an individual pulse duration of 0.5 msec and a stimulation rate of 2 Hz. Stimulation intensity was up to 240 mA for TES and up to 33 mA for direct cortical stimulation. The MMEPs were continuously recorded from the abductor pollicis brevis and tibialis anterior muscles bilaterally and from the biceps brachii and extensor digitorum communis muscles contralateral to the surgical side. The motor status was evaluated immediately after surgery and 7 days later. In 97% of the patients MMEPs were recordable for continuous neurophysiological monitoring of the vascular territory of interest throughout the surgery. In 14 patients significant intraoperative MMEP changes occurred, resulting in a transient motor deficit in one patient and a permanent motor deficit in six. The permanent loss of MMEPs in three patients was followed by a permanent severe motor deficit in one patient and severe clinical deterioration in the other two. Data in this study demonstrated that MMEPs are a useful means of intraoperative neurophysiological monitoring of motor pathway integrity and predicting postoperative motor status. The intraoperative loss of MMEPs reliably predicts both severe and permanent postoperative motor deficits.


Trends in alcohol and tobacco use among Brazilian students: 1989 to 2010.
OBJECTIVE To analyze temporal trends of the prevalence of alcohol and tobacco use among Brazilian students.METHODS We analyzed data published between 1989 and 2010 from five epidemiological surveys on students from the 6th to the 12th grade of public schools from the ten largest state capitals of Brazil. The total sample consisted of 104,104 students and data were collected in classrooms. The same collection tool - a World Health Organization self-reporting questionnaire - and sampling and weighting procedures were used in the five surveys. The Chi-square test for trend was used to compare the prevalence from different years.RESULTS The prevalence of alcohol and tobacco use varied among the years and cities studied. Alcohol consumption decreased in the 10 state capitals (p < 0.001) throughout 21 years. Tobacco use also decreased significantly in eight cities (p < 0.001). The highest prevalence of alcohol use was found in the Southeast region in 1993 (72.8%, in Belo Horizonte) and the lowest one in Belem (30.6%) in 2010. The highest past-year prevalence of tobacco use was found in the South region in 1997 (28.0%, in Curitiba) and the lowest one in the Southeast in 2010 (7.8%, in Sao Paulo).CONCLUSIONS The decreasing trend in the prevalence of tobacco and alcohol use among students detected all over the Country can be related to the successful and comprehensive Brazilian antitobacco and antialcohol policies. Despite these results, the past-year prevalence of alcohol consumption in the past year remained high in all Brazilian regions.


Real-time monitoring β-lactam/β-lactamase inhibitor (BL/BLI) mixture towards the bacteria porin pathway at single molecule level.
Multidrug-resistant bacteria are a great concern and a problem that must be addressed. Extended-spectrum β-lactamases are a common defence mechanism of bacteria to make β-lactam (BL) antibiotics ineffective. β-Lactamase inhibitors (BLIs) are consequently designed and are often clinically prescribed with a BL antibiotic to hinder degradation. Current studies focusing on how BL antibiotics or BLIs interact solely with the bacterial outer membrane nanopores (porins) on reaching the periplasmic side using a nanopore-based sensing technique. In electrochemical studies, the bias voltage allows real-time monitoring of BL antibiotics, BLIs and their mixture through the porin pathway at the single-molecule level. Here we consider the most abundant membrane protein from Escherichia coli (i.e. OmpF), purify and reconstitute the membrane protein in an artificial lipid bilayer and then study its ex vivo electrochemical behaviour. We show the piperacillin/tazobactam mixture interacts with OmpF, whereas the substrate interacts under the maximum bandwidth. The power spectrum analysis of the ionic current trace demonstrates the ampicillin/sulbactram mixture requires more energy than ampicillin alone to pass through the porin pathway. Our results demonstrate that clinically relevant combinations (e.g. piperacillin/tazobactam and ampicillin/sulbactam) interact more strongly with OmpF than either the BL antibiotic or the BLI alone. We suggest a quick and relatively cheap screening method to test the ability of BL antibiotics/BLIs to cross the bacterial cellular membrane.


Management of Postoperative Pain: A Clinical Practice Guideline From the American Pain Society, the American Society of Regional Anesthesia and Pain Medicine, and the American Society of Anesthesiologists' Committee on Regional Anesthesia, Executive Committee, and Administrative Council.
Most patients who undergo surgical procedures experience acute postoperative pain, but evidence suggests that less than half report adequate postoperative pain relief. Many preoperative, intraoperative, and postoperative interventions and management strategies are available for reducing and managing postoperative pain. The American Pain Society, with input from the American Society of Anesthesiologists, commissioned an interdisciplinary expert panel to develop a clinical practice guideline to promote evidence-based, effective, and safer postoperative pain management in children and adults. The guideline was subsequently approved by the American Society for Regional Anesthesia. As part of the guideline development process, a systematic review was commissioned on various aspects related to various interventions and management strategies for postoperative pain. After a review of the evidence, the expert panel formulated recommendations that addressed various aspects of postoperative pain management, including preoperative education, perioperative pain management planning, use of different pharmacological and nonpharmacological modalities, organizational policies, and transition to outpatient care. The recommendations are based on the underlying premise that optimal management begins in the preoperative period with an assessment of the patient and development of a plan of care tailored to the individual and the surgical procedure involved. The panel found that evidence supports the use of multimodal regimens in many situations, although the exact components of effective multimodal care will vary depending on the patient, setting, and surgical procedure. Although these guidelines are based on a systematic review of the evidence on management of postoperative pain, the panel identified numerous research gaps. Of 32 recommendations, 4 were assessed as being supported by high-quality evidence, and 11 (in the areas of patient education and perioperative planning, patient assessment, organizational structures and policies, and transitioning to outpatient care) were made on the basis of low-quality evidence. This guideline, on the basis of a systematic review of the evidence on postoperative pain management, provides recommendations developed by a multidisciplinary expert panel. Safe and effective postoperative pain management should be on the basis of a plan of care tailored to the individual and the surgical procedure involved, and multimodal regimens are recommended in many situations.


Crusting of stored dairy slurry to abate ammonia emissions: pilot-scale studies.
Storage of cattle slurry is a significant source of ammonia (NH3) emissions. Emissions can be reduced by covering slurry stores, but this can incur significant costs, as well as practical and technical difficulties. In this pilot-scale study, slurry was stored in small tanks (500 L) and the effectiveness of natural crust development for reducing NH3 emissions was assessed in a series of experiments. Also, factors important in crust development were investigated. Measurements were made of crust thickness and specially adapted tank lids were used to measure NH3 emissions. Slurry dry matter (DM) content was the most important factor influencing crust formation, with no crust formation on slurries with a DM content of <1%. Generally, crusts began to form within the first 10 to 20 d of storage, at which time NH3 emission rates would decrease. The formation of a natural crust reduced NH3 emissions by approximately 50%. The type of bedding used in the free stall barn did not influence crust formation, nor did ambient temperature or air-flow rate across the slurry surface. There was a large difference in crust formation between slurries from cattle fed a corn (Zea mays L.) silage-based diet and those fed a grass silage-based diet, although dietary differences were confounded with bedding differences. The inclusion of a corn starch and glucose additive promoted crust formation and reduced NH3 emission. The maintenance of a manageable crust on cattle slurry stores is recommended as a cost-effective means of abating NH3 emissions from this phase of slurry management.


Evaluation of the effectiveness of topical repellent distributed by village health volunteer networks against Plasmodium spp. infection in Myanmar: A stepped-wedge cluster randomised trial.
The World Health Organization has yet to endorse deployment of topical repellents for malaria prevention as part of public health campaigns. We aimed to quantify the effectiveness of repellent distributed by the village health volunteer (VHV) network in the Greater Mekong Subregion (GMS) in reducing malaria in order to advance regional malaria elimination. Between April 2015 and June 2016, a 15-month stepped-wedge cluster randomised trial was conducted in 116 villages in Myanmar (stepped monthly in blocks) to test the effectiveness of 12% N,N-diethylbenzamide w/w cream distributed by VHVs, on Plasmodium spp. infection. The median age of participants was 18 years, approximately half were female, and the majority were either village residents (46%) or forest dwellers (40%). No adverse events were reported during the study. Generalised linear mixed modelling estimated the effect of repellent on infection detected by rapid diagnostic test (RDT) (primary outcome) and polymerase chain reaction (PCR) (secondary outcome). Overall Plasmodium infection detected by RDT was low (0.16%; 50/32,194), but infection detected by PCR was higher (3%; 419/13,157). There was no significant protection against RDT-detectable infection (adjusted odds ratio [AOR] = 0.25, 95% CI 0.004-15.2, p = 0.512). In Plasmodium-species-specific analyses, repellent protected against PCR-detectable P. falciparum (adjusted relative risk ratio [ARRR] = 0.67, 95% CI 0.47-0.95, p = 0.026), but not P. vivax infection (ARRR = 1.41, 95% CI 0.80-2.47, p = 0.233). Repellent effects were similar when delayed effects were modelled, across risk groups, and regardless of village-level and temporal heterogeneity in malaria prevalence. The incremental cost-effectiveness ratio was US$256 per PCR-detectable infection averted. Study limitations were a lower than expected Plasmodium spp. infection rate and potential geographic dilution of the intervention. In this study, we observed apparent protection against new infections associated with the large-scale distribution of repellent by VHVs. Incorporation of repellent into national strategies, particularly in areas where bed nets are less effective, may contribute to the interruption of malaria transmission. Further studies are warranted across different transmission settings and populations, from the GMS and beyond, to inform WHO public health policy on the deployment of topical repellents for malaria prevention. Australian and New Zealand Clinical Trials Registry (ACTRN12616001434482).


Reactive oxygen species are involved in smoking-induced dysfunction of nitric oxide biosynthesis and upregulation of endothelial nitric oxide synthase: an in vitro demonstration in human coronary artery endothelial cells.
Our group has previously shown that human umbilical vein endothelial cells exposed to smokers' serum decreased nitric oxide (NO) production and endothelial nitric oxide synthase (eNOS) activity in the presence of increased eNOS expression. In the present study, we examined whether these observations extended to human coronary artery endothelial cells (HCAECs). In addition, the role of reactive oxygen species in the observed alterations was examined. HCAECs were incubated with serum from 10 nonsmokers and 15 smokers for 12 hours with or without the addition of either polyethylene glycol-superoxide dismutase (PEG-SOD, 300 U/mL), PEG-SOD+PEG-catalase (1000 U/mL), chelerythrine (3 micromol/L), or tetrahydrobiopterin (20 micromol/L). At the end of incubation, NO, eNOS protein, and eNOS activity were measured from the same culture. HCAECs incubated with smokers' serum alone showed significantly lower NO production (P<0.05) and eNOS activity (P<0.005) but higher eNOS expression (P<0.005) compared with nonsmokers. In smokers, addition of PEG-SOD, PEG-SOD+PEG-catalase, or tetrahydrobiopterin significantly (P<0.05) improved NO levels and eNOS activity. Interestingly, in the same smokers, a significant decrease in eNOS expression was only seen with the addition of PEG-SOD+PEG-catalase (P<0.05) and treatment with PEG-SOD alone insignificantly increased eNOS expression. The present study indicates that in vitro, HCAECs show similar changes in NO biosynthesis as human umbilical vein endothelial cells when exposed to smokers' serum and also confirms that oxidative stress plays a central role in smoking-mediated dysfunction of NO biosynthesis in endothelial cells. Furthermore, these data support other studies suggesting a role for hydrogen peroxide in the upregulation of eNOS.


Test site predicts HIV care linkage and antiretroviral therapy initiation: a prospective 3.5 year cohort study of HIV-positive testers in northern Tanzania.
Linkage to HIV care is crucial to the success of antiretroviral therapy (ART) programs worldwide, loss to follow up at all stages of the care continuum is frequent, and long-term prospective studies of care linkage are currently lacking. Consecutive clients who tested HIV-positive were enrolled from four HIV testing centers (1 health facility and 3 community-based centers) in the Kilimanjaro region of Tanzania as part of the larger Coping with HIV/AIDS in Tanzania (CHAT) prospective observational study. Biannual interviews were conducted over 3.5 years, assessing care linkage, retention, and mental health. Bivariable and multivariate logistic regression analyses were conducted to determine associations with early death (prior to the second follow up interview) and delayed (>6 months post-test) or failed care linkage. A total of 263 participants were enrolled between November, 2008 and August, 2009 and 240 participants not already linked to care were retained in the final dataset. By 6 months after enrollment, 169 (70.4 %) of 240 participants had presented to an HIV care and treatment facility; 41 (17.1 %) delayed more than 6 months, 15 (6.3 %) died, and 15 (6.3 %) were lost to follow up. Twenty-six patients died before their second follow up visit and were analyzed in the early death group (10.8 %). Just 15 (9.6 %) of those linked to care had started ART within 6 months, but 123 (89.1 %) of patients documented to be ART eligible by local guidelines had started ART by the end of 3.5 years. On multivariate analysis, male gender (OR 1.72; 95 % CI 1.08, 2.75), testing due to illness (OR 1.63; 95 % CI 1.01, 2.63), and higher mean depression scale scores (4 % increased risk per increase in depression score; 95 % CI 1 %, 8 %) were associated with early death. Testing at a community versus a hospital-based site (OR 2.89; 95 % CI 1.79, 4.66) was strongly associated with delaying or never entering care. Nearly 30 % of the cohort did not have timely care linkage, ART initiation was frequently delayed, and testing at a hospital outpatient department versus community-based testing centers was strongly associated with successful care linkage.


High-resolution synchrotron imaging shows that root hairs influence rhizosphere soil structure formation.
In this paper, we provide direct evidence of the importance of root hairs on pore structure development at the root-soil interface during the early stage of crop establishment. This was achieved by use of high-resolution (c. 5 μm) synchrotron radiation computed tomography (SRCT) to visualise both the structure of root hairs and the soil pore structure in plant-soil microcosms. Two contrasting genotypes of barley (Hordeum vulgare), with and without root hairs, were grown for 8 d in microcosms packed with sandy loam soil at 1.2 g cm-3 dry bulk density. Root hairs were visualised within air-filled pore spaces, but not in the fine-textured soil regions. We found that the genotype with root hairs significantly altered the porosity and connectivity of the detectable pore space (> 5 μm) in the rhizosphere, as compared with the no-hair mutants. Both genotypes showed decreasing pore space between 0.8 and 0.1 mm from the root surface. Interestingly the root-hair-bearing genotype had a significantly greater soil pore volume-fraction at the root-soil interface. Effects of pore structure on diffusion and permeability were estimated to be functionally insignificant under saturated conditions when simulated using image-based modelling.


Classification of suicide attempters in schizophrenia using sociocultural and clinical features: A machine learning approach.
Suicide is a major concern for those afflicted by schizophrenia. Identifying patients at the highest risk for future suicide attempts remains a complex problem for psychiatric interventions. Machine learning models allow for the integration of many risk factors in order to build an algorithm that predicts which patients are likely to attempt suicide. Currently it is unclear how to integrate previously identified risk factors into a clinically relevant predictive tool to estimate the probability of a patient with schizophrenia for attempting suicide. We conducted a cross-sectional assessment on a sample of 345 participants diagnosed with schizophrenia spectrum disorders. Suicide attempters and non-attempters were clearly identified using the Columbia Suicide Severity Rating Scale (C-SSRS) and the Beck Suicide Ideation Scale (BSS). We developed four classification algorithms using a regularized regression, random forest, elastic net and support vector machine models with sociocultural and clinical variables as features to train the models. All classification models performed similarly in identifying suicide attempters and non-attempters. Our regularized logistic regression model demonstrated an accuracy of 67% and an area under the curve (AUC) of 0.71, while the random forest model demonstrated 66% accuracy and an AUC of 0.67. Support vector classifier (SVC) model demonstrated an accuracy of 67% and an AUC of 0.70, and the elastic net model demonstrated and accuracy of 65% and an AUC of 0.71. Machine learning algorithms offer a relatively successful method for incorporating many clinical features to predict individuals at risk for future suicide attempts. Increased performance of these models using clinically relevant variables offers the potential to facilitate early treatment and intervention to prevent future suicide attempts.


Rhizobacteria modify plant-aphid interactions: a case of induced systemic susceptibility.
Beneficial microbes, such as plant growth-promoting rhizobacteria and mycorrhizal fungi, may have a plant-mediated effect on insects aboveground. The plant growth-promoting rhizobacterium Pseudomonas fluorescens can induce systemic resistance in Arabidopsis thaliana against several microbial pathogens and chewing insects. However, the plant-mediated effect of these beneficial microbes on phloem-feeding insects is not well understood. Using Arabidopsis as a model, we here report that P. fluorescens has a positive effect on the performance (weight gain and intrinsic rate of increase) of the generalist aphid Myzus persicae, while no effect was recorded on the crucifer specialist aphid Brevicoryne brassicae. Additionally, transcriptional analyses of selected marker genes revealed that in the plant-microbe interaction with M. persicae, rhizobacteria (i) prime the plant for enhanced expression of LOX2, a gene involved in the jasmonic acid (JA)-regulated defence pathway, and (ii) suppress the expression of ABA1, a gene involved in the abscisic acid (ABA) signalling pathway, at several time points. In contrast, almost no effect of the plant-microbe interaction with B. brassicae was found at the transcriptional level. This study presents the first data on rhizobacteria-induced systemic susceptibility to an herbivorous insect, supporting the pattern proposed for other belowground beneficial microbes and aboveground phloem feeders. Moreover, we provide further evidence that at the transcript level, soil-borne microbes modify plant-aphid interactions.


Elucidation of the intrinsic optical properties of hydrogen-bonded and protonated flavin chromophores by photodissociation action spectroscopy.
A model system of the flavin chromophore was synthesized and investigated for its intrinsic optical properties by gas phase action spectroscopy using an ion storage ring. An ammonium group was anchored to this flavin chromophore to allow its transfer to the gas phase by electrospray ionization and for studying the influence of hydrogen bonding and a nearby positive charge. According to calculations one of the hydrogen atoms of the ammonium group favorably forms an intramolecular ionic hydrogen bond to one of the oxygen atoms of the flavin chromophore, and this interaction was found to cause a blueshift of the S0 → S1 transition and a redshift of the S0 → S2 transition. For comparison, the S0 → S1 transition shows little solvent dependence (only in regard to the degree of fine structure). In addition, the influence of protonation of the flavin chromophore was elucidated by experimental and theoretical studies of a simple flavin system. While the position of the S0 → S1 absorption was at identical positions in the gas phase for the intramolecularly hydrogen-bonded and protonated flavin systems, the S0 → S2 absorption was further redshifted for the protonated species. This redshift resulting from protonation was also observed in solution.


Adaptive functioning and depressive symptoms in school-aged children.
This paper is a report of a secondary data analysis to the hypothesis that a child's resourcefulness moderates the relationships between the primary female caregiver's variables (depressive symptoms and learned resourcefulness) and the child's outcomes (depressive symptoms and adaptive functioning). School-aged children between 10 and 12 years of age are at an important stage of development characterized by dramatic biological and psychosocial challenges. Maladaptive functioning and depressive symptoms increase markedly in this stage. To prevent long-term effects of depressive symptoms and impaired adaptive functioning, identifying moderators of the relationship between stress and these mental health indicators is critical. A secondary analysis was conducted in 2004 using the data obtained in 2000 from a community-based sample of 122 school students aged 10-12 years and their primary female caregivers in four suburban public schools in Northeastern Ohio. Instruments included the Self-Control Schedule, Beck Depression Inventory, the Children's version of the Self-Control Schedule, the Children's Community Living Skills Scale, and the Children's Depression Inventory. Children's resourcefulness significantly moderated the relationship between their female caregiver's depressive symptoms and their own adaptive functioning (P<0.01). Children's resourcefulness had a statistically significant impact on depressive symptoms and adaptive functioning (P<0.001). The key to reducing depressive symptoms and enhancing adaptive functioning among middle school children is to build their resourcefulness skills, especially in children whose female caregivers are depressed. This is an important role for school nurses.


The sensitivity of different environments to radioactive contamination.
This paper describes modelling calculations carried out to determine the sensitivity of various rural and semi-natural environments to radionuclide contamination by (137)Cs, (90)Sr, and (131)I released during a major nuclear accident. Depositions of 1000 Bq/m(3) were assumed for each radionuclide. Four broad types of environments were considered: agricultural, forest or tundra, freshwater aquatic, and coastal marine. A number of different models were applied to each environment. The annual dose to a human population receiving most or all of its food and drinking water from a given environment was taken as a broad measure of sensitivity. The results demonstrated that environmental sensitivity was highly radionuclide specific, with (137)Cs generally giving the highest doses during the first year, especially for adults, in terrestrial and freshwater pathways. However, in coastal marine environments, (131)I and (239)Pu were more significant. Sensitivity was time dependent with doses for the first year dominating those for the 2nd and 10th years after deposition. In agricultural environments the ingestion dose from (137)Cs was higher for adults than other age groups, whereas for (90)Sr and (131)I, the ingestion dose was highest for infants. The dependence of sensitivity on social and economic factors such as individual living habits, food consumption preferences, and agricultural practices is discussed.


Depression in Alzheimer's disease: the effect of serotonin receptor gene variation.
This study investigated possible associations between selected polymorphisms in the serotonin receptor genes, 5-HT2A and 5-HT2C, with the presence of co-morbid depressive illness at baseline in a community based cohort of 158 patients with late onset patients with Alzheimer's disease (AD). An association was found between the presence of major depressive illness at baseline and both the 5-HT2A and 5-HT2C polymorphisms. Specifically, homozygous carriers of the 5-HT2A C102 allele were five times more likely to have major depressive illness than heterozygotes. In addition, homozygous or hemizygous carriers of the 5-HT2C Ser allele were 12 times more likely to have major depressive illness than homozygous or hemizygous carriers of the 5-HT2C Cys allele.


Phenotype Similarity Regression for Identifying the Genetic Determinants of Rare Diseases.
Rare genetic disorders, which can now be studied systematically with affordable genome sequencing, are often caused by high-penetrance rare variants. Such disorders are often heterogeneous and characterized by abnormalities spanning multiple organ systems ascertained with variable clinical precision. Existing methods for identifying genes with variants responsible for rare diseases summarize phenotypes with unstructured binary or quantitative variables. The Human Phenotype Ontology (HPO) allows composite phenotypes to be represented systematically but association methods accounting for the ontological relationship between HPO terms do not exist. We present a Bayesian method to model the association between an HPO-coded patient phenotype and genotype. Our method estimates the probability of an association together with an HPO-coded phenotype characteristic of the disease. We thus formalize a clinical approach to phenotyping that is lacking in standard regression techniques for rare disease research. We demonstrate the power of our method by uncovering a number of true associations in a large collection of genome-sequenced and HPO-coded cases with rare diseases.


Problem-based self-care groups versus cognitive behavioural therapy for persons on sick leave due to common mental disorders: a randomised controlled study.
To evaluate the interventional capacity of problem based method groups (PBM) regarding mental health and work ability compared to cognitive behavioural therapy (CBT) for persons on sick leave due to common mental disorders. In a randomised controlled design the experimental group received PBM and the control group received CBT. Outcomes were measured by the Hospital Anxiety and Depression Scale (HADS), the Stress and Crisis Inventory 93 (SCI-93) and the Dialogue about Working Ability instrument (DOA). Twenty-two participants in the PBM group and 28 in the CBT group completed intervention. Both groups showed significant lower scores on the two HADS subscales. Regarding stress the PBM group showed significant decrease in one (out of three) subscales of SCI-93. The CBT group showed significant decrease on all subscales of SCI-93. Regarding work ability the PBM group showed significant higher scores on one of five subscales of DOA. The CBT group showed significant higher scores on four of five subscales of DOA. Between groups there were significant differences to the favour of CBT on one of two subscales of HADS, all three subscales of SCI-93 and on two of the five subscales of DOA. PBM seem to be able to reduce anxiety- and depression symptoms. CBT showed to be superior to PBM in reducing symptoms in all aspects of mental health, except for anxiety, in which they seem equally effective. Regarding work ability CBT showed to be superior, with significant effect on more aspects compared to PBM.


Development of a lab-on-a-chip method for rapid assay of Xylella fastidiosa subsp. pauca strain CoDiRO.
Xylella fastidiosa subsp. pauca strain CoDiRO, a pathogen responsible for Olive Quick Decline Syndrome (OQDS), is strongly threatening the agricultural-based economy of South Italy and making its typical landscape collapse. The bacteria can also infect more than other twenty woody or shrub species and quarantine programs are carried out in Italy. Since symptoms of OQDS like leaf scorching and wilting of canopy may appear several months after infection and some hosts are asymptomatic, a tool for the rapid and early screening of plants is desirable, in order to plan a sudden control strategy and apply programs for pest management. X. fastidiosa detection is usually performed by ELISA and PCR methods. In this work, the two standard methods are compared with an innovative on-chip detection strategy for X. fastidiosa assay from leaves samples, based on an electrochemical transduction method. The realized lab-on-chip includes also a microfluidic module and its performances are competitive with conventional diagnostic methods in terms of reliability, but with further advantages of portability, low-costs and ease of use. Thus, the proposed technology has the potential to provide a useful assay method for large-scale monitoring programs.


A large-scale RNA interference screen identifies genes that regulate autophagy at different stages.
Dysregulated autophagy is central to the pathogenesis and therapeutic development of cancer. However, how autophagy is regulated in cancer is not well understood and genes that modulate cancer autophagy are not fully defined. To gain more insights into autophagy regulation in cancer, we performed a large-scale RNA interference screen in K562 human chronic myeloid leukemia cells using monodansylcadaverine staining, an autophagy-detecting approach equivalent to immunoblotting of the autophagy marker LC3B or fluorescence microscopy of GFP-LC3B. By coupling monodansylcadaverine staining with fluorescence-activated cell sorting, we successfully isolated autophagic K562 cells where we identified 336 short hairpin RNAs. After candidate validation using Cyto-ID fluorescence spectrophotometry, LC3B immunoblotting, and quantitative RT-PCR, 82 genes were identified as autophagy-regulating genes. 20 genes have been reported previously and the remaining 62 candidates are novel autophagy mediators. Bioinformatic analyses revealed that most candidate genes were involved in molecular pathways regulating autophagy, rather than directly participating in the autophagy process. Further autophagy flux assays revealed that 57 autophagy-regulating genes suppressed autophagy initiation, whereas 21 candidates promoted autophagy maturation. Our RNA interference screen identifies identified genes that regulate autophagy at different stages, which helps decode autophagy regulation in cancer and offers novel avenues to develop autophagy-related therapies for cancer.


Examination of the follicular lymphoma international prognostic index (FLIPI) in the National LymphoCare study (NLCS): a prospective US patient cohort treated predominantly in community practices.
Because follicular lymphoma (FL) patients have heterogeneous outcomes, the FL international prognostic index (FLIPI) was developed to risk-stratify patients and to predict survival. However, limited data exist regarding the role of FLIPI in the era of routine first-line rituximab (R) and R-chemotherapy regimens and in the setting of community oncology practices. We evaluated the outcome data from the National LymphoCare Study (NLCS), a prospective, observational cohort study, which collects data on patients with FL in the United States (US) community practices. Among 1068 male and 1124 female patients with FLIPI data, most were treated in US community practices (79%); 35% were FLIPI good risk, 30% intermediate risk, and 35% poor risk. FLIPI risk groups were significant predictors of overall survival (OS) and progression-free survival (PFS) for patients who undergo watchful waiting (WW), and those who receive non-R-containing regimens, R-alone, and R-chemotherapy combinations. In the setting of contemporary practice with routine R use, stratifying patients into good, intermediate, and poor FLIPI risk groups predicts distinct outcomes in terms of OS and PFS. FLIPI remains an important prognostic index in the R era and should be used in clinical practices to support discussions about prognosis.


Wheelchair Shuttle Test for Assessing Aerobic Fitness in Youth With Spina Bifida: Validity and Reliability.
Testing aerobic fitness in youth is important because of expected relationships with health. The purpose of the study was to estimate the validity and reliability of the Shuttle Ride Test in youth who have spina bifida and use a wheelchair for mobility and sport. Ths study is a validity and reliability study. The Shuttle Ride Test, Graded Wheelchair Propulsion Test, and skill-related fitness tests were administered to 33 participants for the validity study (age = 14.5 ± 3.1 y) and to 28 participants for the reliability study (age = 14.7 ± 3.3 y). No significant differences were found between the Graded Wheelchair Propulsion Test and the Shuttle Ride Test for most cardiorespiratory responses. Correlations between the Graded Wheelchair Propulsion Test and the Shuttle Ride Test were moderate to high (r = .55-.97). The variance in peak oxygen uptake (VO2peak) could be predicted for 77% of the participants by height, number of shuttles completed, and weight, with large prediction intervals. High correlations were found between number of shuttles completed and skill-related fitness tests (CI = .73 to -.92). Intraclass correlation coefficients were high (.77-.98), with a smallest detectable change of 1.5 for number of shuttles completed and with coefficients of variation of 6.2% and 6.4% for absolute VO2peak and relative VO2peak, respectively. When measuring VO2peak directly by using a mobile gas analysis system, the Shuttle Ride Test is highly valid for testing VO2peak in youth who have spina bifida and use a wheelchair for mobility and sport. The outcome measure of number of shuttles represents aerobic fitness and is also highly correlated with both anaerobic performance and agility. It is not possible to predict VO2peak accurately by using the number of shuttles completed. Moreover, the Shuttle Ride Test is highly reliable in youth with spina bifida, with a good smallest detectable change for the number of shuttles completed.


Modeling the Seasonal Cycle of Iron and Carbon Fluxes in the Amundsen Sea Polynya, Antarctica.
The Amundsen Sea Polynya (ASP) is distinguished by having the highest net primary production per unit area in the coastal Antarctic. Recent studies have related this high productivity to the presence of fast-melting ice shelves, but the mechanisms involved are not well understood. In this study we describe the first numerical model of the ASP to represent explicitly the ocean-ice interactions, nitrogen and iron cycles, and the coastal circulation at high resolution. The study focuses on the seasonal cycle of iron and carbon, and the results are broadly consistent with field observations collected during the summer of 2010-2011. The simulated biogeochemical cycle is strongly controlled by light availability(dictated by sea ice, phytoplankton self-shading, and variable sunlight). The micronutrient iron exhibits strong seasonality, where scavenging by biogenic particles and remineralization play large compensating roles. Lateral fluxes of iron are also important to the iron budget, and our results confirm the key role played by inputs of dissolved iron from the buoyancy-driven circulation of melting ice shelf cavities (the "meltwater pump"). The model suggests that westward flowing coastal circulation plays two important roles: it provides additional iron to the ASP and it collects particulate organic matter generated by the bloom and transports it to the west of the ASP. As a result, maps of vertical particulate organic matter fluxes show highest fluxes in shelf regions located west of the productive central ASP. Overall, these model results improve our mechanistic understanding of the ASP bloom, while suggesting testable hypotheses for future field efforts.


A randomized double-blind crossover comparison of continuous and intermittent subcutaneous administration of opioid for cancer pain.
ABSTRACT Although the preferred route of opioid administration is oral, patients with cancer often require an alternative route. Options include continuous subcutaneous infusion (CSCI) or regularly scheduled intermittent subcutaneous injections (ISCI). CSCI maintains steady drug levels, theoretically avoiding the "bolus effect" of nausea and sedation immediately post-dose, and breakthrough pain prior to the next dose. However, portable infusion pumps can be costly to use. The Edmonton Injector is an inexpensive portable device for ISCI. CSCI and ISCI have not been directly compared. The objective of this trial was to compare CSCI and ISCI of opioid for treatment of cancer pain. Patients were recruited from two tertiary palliative care units. Eligibility criteria included stable cancer pain requiring opioid therapy, need for parenteral route, and normal cognition. Patients were randomly assigned to receive opioid by CSCI by portable pump or ISCI by Edmonton Injector for 48 hours, followed by crossover to the alternative modality for 48 hours. During each phase, placebo was administered by the alternative modality. The study was closed after 12 patients were entered, due to slow accrual. Eleven patients completed the study. There were no differences between CSCI and ISCI in mean visual analogue score (VAS) for pain, nausea or drowsiness; categorical rating score of pain; number of breakthrough opioid doses per day; global rating of treatment effectiveness; or adverse effects. In all cases, patients and investigators expressed no preference for one modality over another. Further research is required to confirm that opioid administration by CSCI and ISCI provide similar analgesic and adverse effects.


COVID-19 Infection and Its Influence in Otorhinolaryngology-Head and Neck Surgery.
Introduction The novel coronavirus disease 2019 pandemic has rapidly spread worldwide, challenging healthcare resources and communities to an unprecedent degree. Simultaneously, the amount of clinical and scientific information released has overwhelmed journal platforms. Objectives This review aims to summarize the available diagnostic tools and current guidelines to safely assist patients while limiting the exposure of otolaryngologists during this pandemic. Data Synthesis Key articles were retrieved from the following databases: PubMed, Lancet, Springer Nature, BioMed Central, JAMA network and MEDLINE, as well as updated documents from the Spanish Ministry of Health, World Health Organization, Centers for Disease Control and Prevention, Spanish Association of Surgeons, ENT-UK, American College of Surgeons, and American Academy of Otolaryngology-Head and Neck Surgery. The terms used for the search were: COVID-19 , Test COVID , Surgery in COVID , 2019-nCoV , ' coronavirus' , and SARS-CoV-2 . A total of 10,245 papers were retrieved. The inclusion criteria for the review included: COVID-19 testing ( n = 531), society guidelines for otolaryngology-head and neck surgery patient care in the outpatient clinic ( n = 10) and surgical ( n = 18) settings. Studies not related to COVID-19 diagnosis were excluded. Conclusion Healthcare institutions around the world are outlining their own protocols regarding laboratory testing and personnel protective equipment usage based upon medical societies recommendations during the COVID-19 pandemic. We have summarized the available laboratory tests and their respective sensitivity and specificity. Moreover, clinical guidelines from different societies were reviewed and summarized to facilitate guidance for otolaryngologists in the operating room and in the clinical settings.


First successful stabilization of consolidated amorphous calcium phosphate (ACP) by cold sintering: toward highly-resorbable reactive bioceramics.
In the field of bone regeneration, some clinical conditions require highly-resorbable, reactive bone substitutes to rapidly initiate tissue neo-formation. In this view, Amorphous Calcium Phosphates (ACP) appear as well suited bioceramics taking into account their high metastability. However, the metastability also leads to difficulties of sintering without transformation into crystalline compounds. In this work, various calcium phosphate samples (co)doped with carbonate (CO32-) and magnesium ions were synthesized by the double decomposition method in alkaline media using ammonium and potassium hydroxide solutions. The obtained amorphous powders possess an exceptionally-high carbonate content up to 18.3 wt%. Spark Plasma Sintering (SPS) at very low temperature (150 °C) was then utilized to consolidate initial powders with the view to preserve their amorphous character. The influence of the introduction of different apatite growth inhibitors such as carbonate (CO32-) and magnesium ions was studied. XRD and FTIR analyses revealed that sintered ceramics generally consisted in highly carbonated low-crystallinity apatites, which are expected to have higher solubility than conventional apatite-based systems. However, most interestingly, modulation of the doping conditions allowed us to retain, for the first time, the amorphous character of ACP powders after SPS. Such consolidated ACP compounds may now be considered as a new family of bioceramics with high metastability allowing the fast release of bioactive ions upon resorption.


Pentose Phosphate Shunt Modulates Reactive Oxygen Species and Nitric Oxide Production Controlling Trypanosoma cruzi in Macrophages.
Metabolism provides substrates for reactive oxygen species (ROS) and nitric oxide (NO) generation, which are a part of the macrophage (Mφ) anti-microbial response. Mφs infected with Trypanosoma cruzi (Tc) produce insufficient levels of oxidative species and lower levels of glycolysis compared to classical Mφs. How Mφs fail to elicit a potent ROS/NO response during infection and its link to glycolysis is unknown. Herein, we evaluated for ROS, NO, and cytokine production in the presence of metabolic modulators of glycolysis and the Krebs cycle. Metabolic status was analyzed by Seahorse Flux Analyzer and mass spectrometry and validated by RNAi. Tc infection of RAW264.7 or bone marrow-derived Mφs elicited a substantial increase in peroxisome proliferator-activated receptor (PPAR)-α expression and pro-inflammatory cytokine release, and moderate levels of ROS/NO by 18 h. Interferon (IFN)-γ addition enhanced the Tc-induced ROS/NO release and shut down mitochondrial respiration to the levels noted in classical Mφs. Inhibition of PPAR-α attenuated the ROS/NO response and was insufficient for complete metabolic shift. Deprivation of glucose and inhibition of pyruvate transport showed that Krebs cycle and glycolysis support ROS/NO generation in Tc + IFN-γ stimulated Mφs. Metabolic profiling and RNAi studies showed that glycolysis-pentose phosphate pathway (PPP) at 6-phosphogluconate dehydrogenase was essential for ROS/NO response and control of parasite replication in Mφ. We conclude that IFN-γ, but not inhibition of PPAR-α, supports metabolic upregulation of glycolytic-PPP for eliciting potent ROS/NO response in Tc-infected Mφs. Chemical analogs enhancing the glucose-PPP will be beneficial in controlling Tc replication and dissemination by Mφs.


Evaluation of performance of Streamlined Liner of the Pharynx Airway™, Laryngeal Mask Airway-ProSeal and endotracheal tube in prone position: A prospective, randomised study.
Airway used in prone position should be efficacious and safe. The Streamlined Liner of the Pharynx Airway (SLIPA™) and Laryngeal Mask Airway-ProSeal (PLMA) provide better airway seal and protection against aspiration. We planned to evaluate the performance of SLIPA™, PLMA and endotracheal tube (ETT) in prone position. 114 adult patients undergoing elective surgery in prone position under general anaesthesia were randomised into Group-T (ETT), Group-S (SLIPA™) and Group-P (PLMA). Airways were inserted in supine position and patients turned prone subsequently. Airway characteristics, ventilatory parameters and complications were noted. One-way analysis of variance, Mann-Whitney U-test and Chi-square or Fisher's exact test were used. Tidal volumes, peak airway pressure and compliance were comparable at all times. Leak pressure was significantly higher (P < 0.001) in Group-T (mean leak pressure = 40 cmH2O) when compared to Group-S and Group-P at all the times of recording, and there was no significant difference between Group-S and Group-P. The number of patients requiring airway/neck manipulation in prone position was significantly higher (P < 0.001) in Group-S (19 [55.9%]) when the three groups were compared (none in Group-T) and in comparison with Group-P (5 [14.7%], P < 0.001). On airway removal, the incidence of complications and airway reaction was significantly higher in Group-T. Group-S had a significantly higher incidence of dysphagia at 2 h postoperatively. ETT was most efficacious. SLIPA™ and PLMA were efficacious, safe and less stimulating to the airway during removal. More patients required SLIPA™ airway/neck manipulation.


Calf blood pressure: clinical implications and correlations with arm blood pressure in infants and young children.
Indirect measurement of lower extremity blood pressure is often used in the clinical setting, although normative data after the newborn period are not readily available. Indirect blood pressure (BP) measurement was obtained in the right arms and right calves of 148 healthy infants and young children 2 weeks to 3 years of age. All measurements were made using an oscillometric device. The infants and children are quiet or asleep and in the supine position. A BP cuff of proper size was chosen. Three measurements were made in both extremities; the average of the second and third measurements was used for all analyses. Age correlated better with calf systolic blood pressure (SBPc) than with arm SBP (SBPa) (r = .52 vs .17). Calf diastolic blood pressure (DBPc) and calf mean blood pressure (MBPc) correlated moderately poorly with age (r = .37 and .39, respectively). There was no order effect. SBPc correlated best with height (r = .53), then age (r = .52), and, finally, weight (r = .51). The correlation between BPc and BPa was moderately low. The correlation of SBPc with SBPa was r = .46; that of DBPc with DBPa was r = .37; and that of MBPc with MBPa was r = .41. From birth to 6 months, SBPc was slightly lower than SBPa (1 to 3 mm Hg). SBPc increased linearly relative to SBPa and began to exceed SBPa at 6 months of age. The pattern of DBP and MBP was similar. Wide variability of blood pressure parameters was noted between the infants and children at all ages. Reference data are presented for BPc and the difference between BPc and BPa in healthy infants and children from 2 weeks to 3 years of age. BPc is not equivalent to BPa and should not be arbitrarily substituted. Because of the wide variability among healthy infants and children, SBPc measurements should be interpreted with caution when evaluating for coarctation of the aorta.


Update on Colon Ischemia: Recent Insights and Advances.
Colon ischemia (CI) is the most common manifestation of ischemic injury to the gastrointestinal (GI) tract. This usually self-limited disease is being diagnosed more frequently, and the list of known causes is increasing. Local hypoperfusion and reperfusion injury are both thought to contribute to the disease process, which manifests with a wide spectrum of injury including reversible colopathy (subepithelial hemorrhage and edema), transient colitis, chronic colitis, stricture, gangrene, and fulminant universal colitis. The distribution is usually segmental with left-sided disease (e.g., inferior mesenteric artery distribution) being more frequently observed than right-sided involvement (e.g., superior mesenteric artery distribution). Any portion of the colon can be affected, but the anatomic distribution of CI recently has been shown to be associated with outcome. Patients with isolated-right colon ischemia (IRCI) have a different presentation and worse outcomes than other distributions of disease. Although somewhat variable depending on disease location, CI presents with cramping abdominal pains over the segment of colon involved followed by a short course of bloody diarrhea. Diagnosis is usually made clinically and is supported with serologic, radiologic, and colonoscopic findings. Colonoscopy is the most accurate diagnostic study. Most patients respond to conservative supportive therapy although some with more severe disease require antimicrobials and/or surgical intervention.


Quantitative EEG analysis of executive dysfunction in Parkinson disease.
Quantitative EEG evaluation in Parkinson disease (PD) reveals diffuse slowing. This is the first quantitative EEG evaluation of the differences between PD with and without executive dysfunction (ExD). The subjects were 32 PD patients without remarkable dementia. The lack of ischemic lesions was confirmed by magnetic resonance imaging. ExD was defined as <70 points on the age-controlled standardized score of the Behavioral Assessment of the Dysexecutive Syndrome. Absolute power was measured for four frequency bands from delta to beta. Electrodes were placed at frontal pole, frontal, central, parietal, occipital, and temporal locations. Spectral ratio was calculated as the sum of power values for alpha and beta waves divided by the sum of values for the slow waves. In multiple logistic regression analysis of each electrode location, the dependent variable was ExD or not, and the independent variables were spectral ratio, age, and Unified Parkinson Disease Rating Scale. The only significant predictor of ExD was spectral ratio at the frontal pole (P = 0.031) and frontal (P = 0.048) locations. PD with ExD exhibited an increase in slow wave activity and a decrease in alpha and fast wave activities in these locations. These findings indicated that the ExD in PD was caused by frontal dysfunction.


Expanding the Spectrum of Chronic Immune Sensory Polyradiculopathy: CISP-Plus.
Sensory loss with normal nerve conduction studies (NCS) from focal sensory root inflammatory demyelination is characteristic of chronic immune sensory polyradiculopathy (CISP). However, nonpure cases involving motor and distal sensory nerves exist (CISP-plus). We hypothesize that CISP-plus and CISP are fundamentally part of the same syndrome through comparison of clinical, neurophysiologic, and pathologic features. CISP-plus (primary dorsal root with lesser motor and sensory nerve involvement) and CISP cases were retrospectively analyzed (1986-2019). We identified 44 CISP-plus and 28 CISP cases (n = 72) with 86% (38/44) of patients with CISP-plus and 79% (22/28) of patients with CISP experiencing imbalance. On examination, large fiber sensory loss was present in 98% (43/44) of patients with CISP-plus and 96% (27/28) of patients with CISP. Gait ataxia was evident in 93% (41/44) of patients with CISP-plus and 79% (22/28) of patients with CISP. Mild distal weakness was common in CISP-plus (75%, 33/44). NCS showed mild abnormalities in all patients with CISP-plus and were normal (by definition) in all patients with CISP. Elevated CSF protein, slowing of somatosensory evoked potentials, and MRI root enhancement occurred in most CISP-plus and CISP cases. Eleven CISP-plus nerve biopsies showed loss of large myelinated fibers and onion-bulb formations, most prominent in rootlet biopsies. Immunotherapy resulted in marked improvement of gait ataxia in 84% (27/32) of patients with CISP-plus and 93% (13/14) of patients with CISP with return to normal neurologic examination in half (25/46). The recognition of CISP-plus expands the spectrum of CIDP by combining CISP-plus (predominant sensory polyradiculopathy with mild motor and sensory nerve involvement) with pure CISP (focal sensory polyradiculopathy) together as proximal sensory CIDP.


Properties and use of genetically encoded FRET sensors for cytosolic and organellar Ca2+ measurements.
In the last 15 years, there has been an explosion in the development of genetically encoded biosensors that report enzyme activity, chemical transformation, or concentration of ions and molecules in living cells. Currently, there are well over 120 biosensors of different cellular targets. As a general design principle, these sensors convert a molecular event, such as the binding of a molecule to a sensing domain or a signal-induced change in protein conformation, into a change in the sensor's fluorescence properties. In contrast to small-molecule sensors, genetically encoded sensors are generated when sensor-encoding nucleic acid sequences, which have been introduced by transgenic technologies, are translated in cells, tissues, or organisms. One of the best developed classes of biosensors is the genetically encoded Ca(2+) indicators (GECIs). Here, we briefly summarize the properties of ratiometric GECIs and describe how they are used to quantify Ca(2+) in specific cellular locations, such as the cytosol, nucleus, endoplasmic reticulum, and mitochondria.


Improved GPCR ligands from nanobody tethering.
Antibodies conjugated to bioactive compounds allow targeted delivery of therapeutics to cell types of choice based on that antibody's specificity. Here we develop a new type of conjugate that consists of a nanobody and a peptidic ligand for a G protein-coupled receptor (GPCR), fused via their C-termini. We address activation of parathyroid hormone receptor-1 (PTHR1) and improve the signaling activity and specificity of otherwise poorly active N-terminal peptide fragments of PTH by conjugating them to nanobodies (VHHs) that recognize PTHR1. These C-to-C conjugates show biological activity superior to that of the parent fragment peptide in vitro. In an exploratory experiment in mice, a VHH-PTH peptide conjugate showed biological activity, whereas the corresponding free peptide did not. The lead conjugate also possesses selectivity for PTHR1 superior to that of PTH(1-34). This design approach, dubbed "conjugation of ligands and antibodies for membrane proteins" (CLAMP), can yield ligands with high potency and specificity.


Spatial structure, cooperation and competition in biofilms.
Bacteria often live within matrix-embedded communities, termed biofilms, which are now understood to be a major mode of microbial life. The study of biofilms has revealed their vast complexity both in terms of resident species composition and phenotypic diversity. Despite this complexity, theoretical and experimental work in the past decade has identified common principles for understanding microbial biofilms. In this Review, we discuss how the spatial arrangement of genotypes within a community influences the cooperative and competitive cell-cell interactions that define biofilm form and function. Furthermore, we argue that a perspective rooted in ecology and evolution is fundamental to progress in microbiology.


Frame-based stereotactic implantation of cystoventricular shunts for treating acquired intracerebral cysts.
The treatment of symptomatic, progressive or recurrent acquired intracerebral cysts is challenging, especially when they are localized in eloquent structures. In addition to resection, endoscopic fenestration, or stereotactic puncture, the implantation of a cystoventricular shunt by stereotactic guidance (SCVS) has been reported as a minimally invasive procedure; however, only scarce data are available regarding its feasibility and efficacy. Here, the authors evaluated the feasibility and efficacy of frame-based SCVS in patients with acquired intracranial cysts. In this single-center retrospective analysis, the authors included all patients with acquired intracerebral cysts treated by SCVS following a standardized prospective protocol between 2012 and 2020. They analyzed clinical symptoms, complications, and radiological outcome with regard to cyst volume reduction by 3D volumetry. Thirty-four patients (17 females and 17 males; median age 44 years, range 5-77 years) were identified. The median initial cyst volume was 11.5 cm3 (range 1.6-71.6 cm3), and the mean follow-up was 20 months (range 1-82 months). At the last follow-up, 27 of 34 patients (79%) showed a cyst volume reduction of more than 50%. Initial symptoms improved or resolved in 74% (n = 25) and remained stable in 24% (n = 8). No permanent clinical deterioration after treatment was observed. The total complication rate was 5.9%, comprising transient neurological deterioration (n = 1) and ventriculitis (n = 1). There were no deaths. The overall recurrence rate was 11.8%. In this study, SCVS proved to be a safe, minimally invasive, and effective treatment with reliable long-term volume reduction, resulting in clinical improvement and a minor complication rate.