Complete Influenza Vaccination Trends for Children Six to Twenty-Three Months.
Prevention of influenza among infants and young children is a public health priority because of their high risk for influenza-related complications. Depending on a child's age and previous influenza vaccination history, they are recommended to receive either 1 dose or 2 doses of influenza vaccine to be considered fully vaccinated against influenza for the season. We compared estimates of full (complete) influenza vaccination coverage of children 6 to 23 months across 10 consecutive influenza seasons (2002-2012), by race/ethnicity, age group, and by number of doses required to be fully vaccinated given child's vaccination history. National Immunization Survey data were used to estimate full influenza vaccination status among children 6 to 23 months on the basis of provider report. Estimates were computed by using Kaplan-Meier survival analysis methods. Full influenza vaccination coverage among children 6 to 23 months increased from 4.8% in the 2002-2003 influenza season to 44.7% in the 2011-2012 season. In all 10 influenza seasons studied, non-Hispanic black children and Hispanic children had lower full influenza vaccination coverage than non-Hispanic white children. For all 10 influenza seasons, full influenza vaccination coverage was higher among children requiring only 1 dose compared with those requiring 2 doses. Less than half of children 6 to 23 months in the United States, and an even a smaller percentage of Hispanic and non-Hispanic black children, are fully vaccinated against influenza. More implementation of evidence-based strategies that increase the percentage of children who are fully vaccinated is needed.


Thermo-optic coefficient measurement of liquids based on simultaneous temperature and refractive index sensing capability of a two-mode fiber interferometric probe.
A fiber-optic interferometric probe based on a two-mode fiber (TMF) is proposed and demonstrated for measuring the thermo-optic coefficients (TOCs) of liquid samples. The proposed probe can be simply fabricated by fusion-splicing a short piece of TMF to a lead single mode fiber (SMF) with small lateral offset, which makes interference between LP(01) and LP(02) modes. The sensing responses of the probe to temperature and surrounding refractive index (SRI) have been experimentally investigated to show the capability of simultaneous measurements; the phase change of the reflection spectrum was related to temperature variation and the intensity change was to SRI variation. The data analysis is made not only in the spectral domain but in the Fourier domain also to effectively quantify the measurements. The TOCs of several liquid samples including water, ethanol, and acetone have been obtained with the proposed method.


A polymorphism in the HLA-DPB1 gene is associated with susceptibility to multiple sclerosis.
We conducted an association study across the human leukocyte antigen (HLA) complex to identify loci associated with multiple sclerosis (MS). Comparing 1927 SNPs in 1618 MS cases and 3413 controls of European ancestry, we identified seven SNPs that were independently associated with MS conditional on the others (each P ≤ 4 x 10(-6)). All associations were significant in an independent replication cohort of 2212 cases and 2251 controls (P ≤ 0.001) and were highly significant in the combined dataset (P ≤ 6 x 10(-8)). The associated SNPs included proxies for HLA-DRB1*15:01 and HLA-DRB1*03:01, and SNPs in moderate linkage disequilibrium (LD) with HLA-A*02:01, HLA-DRB1*04:01 and HLA-DRB1*13:03. We also found a strong association with rs9277535 in the class II gene HLA-DPB1 (discovery set P = 9 x 10(-9), replication set P = 7 x 10(-4), combined P = 2 x 10(-10)). HLA-DPB1 is located centromeric of the more commonly typed class II genes HLA-DRB1, -DQA1 and -DQB1. It is separated from these genes by a recombination hotspot, and the association is not affected by conditioning on genotypes at DRB1, DQA1 and DQB1. Hence rs9277535 represents an independent MS-susceptibility locus of genome-wide significance. It is correlated with the HLA-DPB1*03:01 allele, which has been implicated previously in MS in smaller studies. Further genotyping in large datasets is required to confirm and resolve this association.


Drought Induced Changes in Growth, Osmolyte Accumulation and Antioxidant Metabolism of Three Maize Hybrids.
Consequences of drought stress in crop production systems are perhaps more deleterious than other abiotic stresses under changing climatic scenarios. Regulations of physio-biochemical responses of plants under drought stress can be used as markers for drought stress tolerance in selection and breeding. The present study was conducted to appraise the performance of three different maize hybrids (Dong Dan 80, Wan Dan 13, and Run Nong 35) under well-watered, low, moderate and SD conditions maintained at 100, 80, 60, and 40% of field capacity, respectively. Compared with well-watered conditions, drought stress caused oxidative stress by excessive production of reactive oxygen species (ROS) which led to reduced growth and yield formation in all maize hybrids; nevertheless, negative effects of drought stress were more prominent in Run Nong 35. Drought-induced osmolyte accumulation and strong enzymatic and non-enzymatic defense systems prevented the severe damage in Dong Dan 80. Overall performance of all maize hybrids under drought stress was recorded as: Dong Dan 80 > Wan Dan 13 > Run Nong 35 with 6.39, 7.35, and 16.55% yield reductions. Consequently, these biochemical traits and differential physiological responses might be helpful to develop drought tolerance genotypes that can withstand water-deficit conditions with minimum yield losses.


A randomized study to decrease the use of potentially inappropriate medications among community-dwelling older adults in a southeastern managed care organization.
Despite progress in describing the problem of potentially inappropriate medication (PIM) use, there have been few prospective studies demonstrating that interventions with specific medication criteria can make a difference in decreasing the use of problematic drugs in older adults. To design an intervention study to change physician behavior regarding PIM prescribing to older patients. A prospective randomized block design was used during an 18-month period from January 2001 to June 2002. The study population was primary care physicians (n = 355) in the Medicare + Choice product line of a southeastern managed care organization and their patients 65 years and older. There were 170 physicians in the treatment group and 185 in the control group. Physicians were assigned to the treatment or usual-care, groups using a randomization table, and each group included physicians who had and had not prescribed a PIM. Approximately 71% (84/118) of the physicians in the intervention group who prescribed a PIM completed and faxed back at least 1 potentially inappropriate medication form to the managed care organization. On 15.4% (260/1692) of the medication forms, physicians made some change regarding PIM use. Although many studies have addressed medication use among older adults, intervention studies aimed at influencing physician prescribing in this population are limited. This study describes a low-cost, replicable method to contact and educate physicians on drug therapy issues in older adults.


A second species of Etiennea (Coccidae: Coccoidea: Sternorrhyncha) from the New World.
The genus Etiennea Matile-Ferrero (Coccidae: Coccoidea) currently contains 19 species, all but one of them restricted to Africa, the exception being from Guyana. The present paper describes the adult female of a further species, Etiennea bursera sp. nov., from the New World (Mexico). The key in Hodgson (1991) is augmented to separate the new species from the others in the genus. The relationships of Etiennea to other coccid genera are briefly discussed.


Late glial swelling after acute cerebral hypoxia-ischemia in the neonatal rat: a combined magnetic resonance and histochemical study.
Secondary brain damage after transient cerebral hypoxia-ischemia (HI) is caused by a cascade of cellular events. In this study, complementary methods of magnetic resonance imaging and histochemistry were used to investigate the formation of cytotoxic and vasogenic edema during secondary brain damage induced by transient HI in 7-d-old rats. To elicit injury, 21 rats underwent right common carotid artery ligation followed by 1.5 h of 8% O2 exposure. Sequential apparent diffusion coefficient (ADC) and transversal relaxation time (T2) weighted magnetic resonance imaging were recorded for up to 3 d in 13 7-d-old rats. Eight animals were killed at various intervals between the end of HI and 21 h of recovery to perform histochemical assays using neuronal and astrocytic markers. Changes of the ADC revealed a biphasic function for the evolution of cytotoxic edema during the recovery period. At the end of HI, the ADC in the ipsilateral cortex was significantly decreased. Upon reoxygenation, it returned transiently to normal followed by a secondary, although less pronounced, decline after 8-48 h. After this, the ADC rose steadily. From 8 h of recovery, the proportion of vasogenic edema steadily increased as indicated by the T2 prolongation. At 21 h, the majority of glial cells showed immunoreactivity for glial fibrillary acidic protein and were of larger size, whereas the neurons were apoptotic. These results indicate that the delayed cerebral injury is accompanied by late glial swelling in conjunction with an enlarged interstitial space due to cell damage.


The role of initial and final states in molecular spectroscopies.
Interpreting experimental spectra of thin films of organic semiconductors is challenging, and understanding the relationship between experimental data obtained by different spectroscopic techniques requires a careful consideration of the initial and final states for each process. The discussion of spectroscopic data is frequently mired in confusion that originates in overlapping terminology with however distinct meaning in different spectroscopies. Here, we present a coherent framework that is capable of treating on equal footing most spectroscopies commonly used to investigate thin films of organic semiconductors. We develop a simple model for the expected energy level positions, as obtained by common spectroscopic techniques, and relate them to the energies of molecular states. Molecular charging energies in photoionization processes, as well as adsorption energies and the screening of molecular charges due to environmental polarization, are taken into account as the main causes for shifts of the measured spectroscopic features. We explain the relationship between these quantities, as well as with the transport gap, the optical gap and the exciton binding energy. Our considerations serve as a model for weakly interacting systems, e.g., various organic molecular crystals, where wave function hybridizations between adjacent molecules are negligible.


Supersolidity of undercoordinated and hydrating water.
Supersolidity of ice, which was proposed in 2013 and intensively verified since then [C. Q. Sun et al., Density, Elasticity, and Stability Anomalies of Water Molecules with Fewer than Four Neighbors, J. Phys. Chem. Lett., 2013, 4, 2565-2570; C. Q. Sun et al., Density and phonon-stiffness anomalies of water and ice in the full temperature range, J. Phys. Chem. Lett., 2013, 4, 3238-3244], refers to the water molecules being polarized by molecular undercoordination, which is associated with the skin of bulk ice, nanobubbles, and nanodroplets (often called confinement), or by the electrostatic field of ions in salt solutions [X. Zhang et al., Mediating relaxation and polarization of hydrogen-bonds in water by NaCl salting and heating, Phys. Chem. Chem. Phys., 2014, 16(45), 24666-24671; C. Q. Sun et al., (H, Li)Br and LiOH solvation bonding dynamics: molecular nonbond interactions and solute extraordinary capabilities, J. Phys. Chem. B, 2018, 122(3), 1228-1238]. From the perspective of hydrogen bond (O:H-O or HB with ":" representing the lone pairs on O2-) cooperative relaxation and polarization, this review features the recent progress and recommends future trends in understanding the bond-electron-phonon correlation in the supersolid phase. Supersolidity is characterized by a shorter and stiffer H-O bond, longer and softer O:H nonbond, deeper O 1s energy band, and longer photoelectron and phonon lifetimes. The supersolid phase is less dense, viscoelastic, and mechanically and thermally more stable. Furthermore, O:H-O bond cooperative relaxation offsets the boundaries of structural phases and increases the melting point while lowering the freezing temperature of ice, which is known as supercooling and superheating.


RNA sequence evolution with secondary structure constraints: comparison of substitution rate models using maximum-likelihood methods.
We test models for the evolution of helical regions of RNA sequences, where the base pairing constraint leads to correlated compensatory substitutions occurring on either side of the pair. These models are of three types: 6-state models include only the four Watson-Crick pairs plus GU and UG; 7-state models include a single mismatch state that combines all of the 10 possible mismatches; 16-state models treat all mismatch states separately. We analyzed a set of eubacterial ribosomal RNA sequences with a well-established phylogenetic tree structure. For each model, the maximum-likelihood values of the parameters were obtained. The models were compared using the Akaike information criterion, the likelihood-ratio test, and Cox's test. With a high significance level, models that permit a nonzero rate of double substitutions performed better than those that assume zero double substitution rate. Some models assume symmetry between GC and CG, between AU and UA, and between GU and UG. Models that relaxed this symmetry assumption performed slightly better, but the tests did not all agree on the significance level. The most general time-reversible model significantly outperformed any of the simplifications. We consider the relative merits of all these models for molecular phylogenetics.


Current state of care for the elderly in China in the context of an aging population.
The aim of the current study was to review the current state and characteristics of the elderly population in China in the context of aging, difficulties and challenges faced by older people, and efforts of the current Chinese Government in this area. The process of population aging in China began to accelerate in the late 1970s and has continued to increase at a rate of about 3.2% per year since then. This process took more than 45 years in developed countries, while it took only about 27 years in China, and aging may continue to increase for a long time. China is now moving toward a superannuated society due to declining fertility rates and increasing life expectancy. There is a great need for care due to the high disease burden among older people. However, more than 1 million "families have lost their only child", and this number is increasing annually by about 76,000; moreover, there are a large number of "deficient families [with an injured family member]" in China. These families face greater difficulties due to aging and need to rely on society for more support given the lack of care provided by their children or spouses. The current study has focused on improving the quality of life of older people, helping them achieve healthy aging, and to assist the country in further providing care for the elderly.


Financing national non-communicable disease responses.
Non-communicable diseases (NCDs) (also known as socially transmitted diseases) were conspicuously absent from the Millennium Development Goals and seemed to miss out on the 'golden years' of health funding despite causing more death and disability than any other disease group worldwide. The share of 'development assistance for health' dedicated to NCDs has remained at 1-2% of the total since 2000. This level of funding is insufficient to attain the nine targets in the World Health Organization (WHO) Global Action Plan on NCDs. In 2015 the Sustainable Development Goals - which include the target of reducing premature NCD mortality by a third - were endorsed by 193 countries. Whilst this commitment is welcome, the same text stresses the primacy of domestic financing, which is currently dominated by out-of-pocket payments in low- and middle-income countries (LMICs). This paper presents the findings of the WHO Global Coordination Mechanism on NCDs financing working group. The group was convened to explore NCD financing options with an emphasis on LMICs. The main sources of available finance include taxation, loans, engagement with the private sector, impact investment and innovative financing mechanisms. There is a role for development assistance to increase in the interim as raising additional revenue from these sources will take time. In the medium term it may be appropriate for international NCD funding to remain low where LMICs successfully assume financial responsibility for preventing and controlling NCDs. Countries will have to manage blends of innovative and traditional funding sources, whilst finding ways to boost tax revenue for NCDs.


Clinical Presentation, Long-Term Follow-Up, and Outcomes of 1001 Arrhythmogenic Right Ventricular Dysplasia/Cardiomyopathy Patients and Family Members.
Arrhythmogenic right ventricular dysplasia/cardiomyopathy (ARVD/C) is a progressive cardiomyopathy. We aimed to define long-term outcome in a transatlantic cohort of 1001 individuals. Clinical and genetic characteristics and follow-up data of ARVD/C index-patients (n=439, fulfilling of 2010 criteria in all) and family members (n=562) were assessed. Mutations were identified in 276 index-patients (63%). Index-patients presented predominantly with sustained ventricular arrhythmias (268; 61%). During a median follow-up of 7 years, 301 of the 416 index-patients presenting alive (72%) experienced sustained ventricular arrhythmias. Sudden cardiac death during follow-up occurred more frequently among index-patients without an implantable cardioverter-defibrillator (10/63, 16% versus 2/335, 0.6%). Overall, cardiac mortality and the need for cardiac transplantation were low (6% and 4%, respectively). Clinical characteristics and outcomes were similar in index-patients with and without mutations, as well as in those with familial and nonfamilial ARVD/C. ARVD/C was diagnosed in 207 family members (37%). Symptoms at first evaluation correlated with disease expression. Family members with mutations were more likely to meet Task Force Criteria for ARVD/C (40% versus 18%), experience sustained ventricular arrhythmias (11% versus 1%), and die from a cardiac cause (2% versus 0%) than family members without mutations. Long-term outcome was favorable in diagnosed and treated ARVD/C index-patients and family members. Outcome in index-patients was modulated by implantable cardioverter-defibrillator implantation, but not by mutation status and familial background of disease. One third of family members developed ARVD/C. Outcome in family members was determined by symptoms at first evaluation and mutations.


Mathematical analysis of the flow of hyaluronic acid around fascia during manual therapy motions.
More research is needed to understand the flow characteristics of hyaluronic acid (HA) during motions used in osteopathic manipulative treatment and other manual therapies. To apply a 3-dimensional mathematical model to explore the relationship between the 3 manual therapy motions (constant sliding, perpendicular vibration, and tangential oscillation) and the flow characteristics of HA below the fascial layer. The Squeeze Film Lubrication theory of fluid mechanics for flow between 2 plates was used, as well as the Navier-Stokes equations. The fluid pressure of HA increased substantially as fascia was deformed during manual therapies. There was a higher rate of pressure during tangential oscillation and perpendicular vibration than during constant sliding. This variation of pressure caused HA to flow near the edges of the fascial area under manipulation, and this flow resulted in greater lubrication. The pressure generated in the fluid between the muscle and the fascia during osteopathic manipulative treatment causes the fluid gap to increase. Consequently, the thickness between 2 fascial layers increases as well. Thus, the presence of a thicker fluid gap can improve the sliding system and permit the muscles to work more efficiently. The mathematical model employed by the authors suggests that inclusion of perpendicular vibration and tangential oscillation may increase the action of the treatment in the extracellular matrix, providing additional benefits in manual therapies that currently use only constant sliding motions.


Eye-movement-based assessment of visual function in patients with infantile nystagmus syndrome.
Infantile Nystagmus Syndrome (INS) is an ocular motor system dysfunction characterized by the rhythmic to-and-fro oscillations of the eyes. Traditionally, the assessment of INS visual function solely focused on null- or primary-position visual acuity. Our purpose is to use the past four decades of INS research to introduce a more complete assessment of visual function in patients with INS. All eye-movement data were obtained using high-speed digital video, infrared reflection, or scleral search coil systems. We have introduced four important aspects of a more complete INS visual function assessment: the eXpanded Nystagmus Acuity Function and visual acuity measurements in primary position; broadness of the eXpanded Nystagmus Acuity Function peak and high-acuity field; target acquisition time; and gaze-maintenance capability. Visual function in patients with INS is multifactorial and the simple assessment of primary position visual acuity is both inadequate and may not be the most important characteristic in overall visual function. A more complete visual function assessment should also include primary and lateral gaze eye-movement and visual acuity examinations, target acquisition time and gaze holding.


Signal transducer and activator of transcription 3 is a proviral host factor for hepatitis C virus.
Host factors play an important role in all facets of the hepatitis C virus (HCV) life cycle and one such host factor is signal transducer and activator of transcription 3 (STAT3). The HCV core protein has been shown to directly interact with and activate STAT3, while oxidative stress generated during HCV replication in a replicon-based model also induced STAT3 activation. However, despite these findings the precise role of STAT3 in the HCV life cycle remains unknown. We have established that STAT3 is actively phosphorylated in the presence of replicating HCV. Furthermore, expression of a constitutively active form of STAT3 leads to marked increases in HCV replication, whereas, conversely, chemical inhibition and small interfering RNA (siRNA) knockdown of STAT3 leads to significant decreases in HCV RNA levels. This strongly implicates STAT3 as a proviral host factor. As STAT3 is a transcription factor, up-regulation of a distinct set of STAT3-dependent genes may create an environment that is favorable for HCV replication. However, STAT3 has recently been demonstrated to positively regulate microtubule (MT) dynamics, by way of a direct sequestration of the MT depolymerizing protein Stathmin 1 (STMN1), and we provide evidence that STAT3 may exert its effect on the HCV life cycle by way of positive regulation of MT dynamics. We have demonstrated that STAT3 plays a role in the life cycle of HCV and have clarified the role of STAT3 as a proviral host factor.


Abnormal cervical cytology amongst women infected with human immunodeficiency virus in Limpopo province, South Africa.
Cervical cancer remains the major public problem worldwide and the most common gynaecological malignancy in the developing world, particularly in sub-Saharan Africa. To determine the prevalence of abnormal cervical cytology amongst women with and without human immunodeficiency virus (HIV) and examine the association between HIV and histological grading. The study was conducted in Limpopo province, which is the northernmost province of South Africa. The province has five district municipalities with one tertiary, five regional and thirty four district hospitals. We retrospectively reviewed cervical cancer cases in Limpopo province (LP) of South Africa, using data collected routinely by the National Health Laboratory Services (NHLS). The data on smears submitted for cytology between 2013 and 2015 were extracted from the Central Data Warehouse (CDW) database. A total of 84 466 women were screened for cervical cytology smears. Their mean age was 39.8 ± 13.6 years, with range from 15 to 113 years; 77.2% were in the age group 30 years and older and 19.6% had an abnormal cervical cytology result. Overall, 46.4% of the women screened for cervical cancer were HIV infected. A significantly higher proportion of HIV-positive women had abnormal cytology than HIV-negative women (31.8% vs. 9.2%). The prevalence of abnormal cytology amongst HIV-positive women is relatively high, and the risk appears to be significantly greater in all age groups. This finding highlights the need to ascertain HIV status of all women presenting with cervical cancer.


Intracellular galectins control cellular responses commensurate with cell surface carbohydrate composition.
Galectins are β-galactoside-binding animal lectins primarily found in the cytosol, while their carbohydrate ligands are mainly distributed in the extracellular space. Cytosolic galectins are anticipated to accumulate on damaged endocytic vesicles through binding to glycans initially displayed on the cell surface and subsequently located in the lumen of the vesicles, and this can be followed by cellular responses. To facilitate elucidation of the mechanism underlying this process, we adopted a model system involving induction of endocytic vesicle damage with light that targets the endocytosed amphiphilic photosensitizer disulfonated aluminum phthalocyanine. We demonstrate that the levels of galectins around damaged endosomes are dependent on the composition of carbohydrates recognized by the proteins. By super resolution imaging, galectin-3 and galectin-8 aggregates were found to be distributed in distinct microcompartments. Importantly, galectin accumulation is significantly affected when cell surface glycans are altered. Furthermore, accumulated galectins can direct autophagy adaptor proteins toward damaged endocytic vesicles, which are also significantly affected following alteration of cell surface glycans. We conclude that cytosolic galectins control cellular responses reflect dynamic modifications of cell surface glycans.


Sleep and periodic limb movement in sleep in juvenile fibromyalgia.
Fibromyalgia has been recently recognized in children and adolescents as juvenile fibromyalgia (JF). In adult fibromyalgia, subjective complaints of nonrestorative sleep and fatigue are supported by altered polysomnographic findings including a primary sleep disorder known as periodic limb movements in sleep (PLMS) in some subjects. Although poor sleep is a diagnostic criterion for JF, few reports in the literature have evaluated specific sleep disturbances. Our objectives were to evaluate in a controlled study the polysomnographic findings of children and adolescents with JF for alterations in sleep architecture as well as possible PLMS not previously noted in this age group. Sixteen consecutive children and adolescents (15.0 +/- 2.6 years of age) diagnosed with JF underwent overnight polysomnography. Polysomnography was also performed on 14 controls (14.0 +/- 2.2 years of age) with no history of an underlying medical condition that could impact on sleep architecture. Respiratory variables, sleep stages, and limb movements were measured during sleep in all subjects. JF subjects differed significantly from controls in sleep architecture. JF subjects presented with prolonged sleep latency, shortened total sleep time, decreased sleep efficiency, and increased wakefulness during sleep. In addition, JF subjects exhibited excessive movement activity during sleep. Six of the JF subjects (38%) were noted to have an abnormally elevated PLMS index (>5/hour), indicating PLMS in these subjects. Our study demonstrated abnormalities in sleep architecture in children with JF. We also noted PLMS in a significant number of subjects. This has not been reported previously in children with this disorder. We recommend that children who are evaluated for JF undergo polysomnography including PLMS assessment. juvenile fibromyalgia; periodic limb movement in sleep; restless legs syndrome.


Bone marrow transplantation from genetically HLA-nonidentical donors in children with fatal inherited disorders excluding severe combined immunodeficiencies: use of two monoclonal antibodies to prevent graft rejection.
For children with life-threatening inborn errors of metabolism without a matched related bone marrow donor, transplantation from an HLA genetically nonidentical donor is the only therapeutic option. To reduce the high risk of graft rejection in this setting without increasing the conditioning regimen, a protocol based on the infusion of an antiadhesion antibody directed against the CD11a (leukocyte function-associated antigen 1 [LFA-1]) molecule was performed by the European Bone Marrow Transplantation-European Society for Immunodeficiency group with promising results. To optimize engraftment, and thereby survival, further, the additional blockade of a second important leukocyte adhesion and signalization pathway mediated by the CD2 and LFA-3 interaction was attempted in a multicenter protocol conducted by the European Bone Marrow Transplantation-European Society for Immunodeficiency group. Results of this study (ie, engraftment and survival) were compared with a historical control group that received the anti-LFA-1 antibody alone. Factors that may have affected engraftment and survival were also considered in this study. Forty-four children with inborn errors, including inherited immunodeficiencies (excluding severe combined immunodeficiencies), Chédiak-Higashi syndrome, familial hemophagocytic lymphohistiocytosis, and malignant osteopetrosis, received bone marrow from HLA-nonidentical related donors or from HLA-identical unrelated donors at 13 European centers between August 1990 and June 1993. Bone marrow was depleted of T cells by use of either erythrocyte (E) rosetting or monoclonal antibodies (MoAbs) to prevent graft-versus-host disease. The conditioning regimen consisted of busulfan and cyclophosphamide for all patients plus etoposide for patients with osteopetrosis, familial hemophagocytic lymphohistiocytosis, and Chédiak-Higashi syndrome. Infusions of MoAbs specific for the CD11a and the CD2 molecules were started 4 and 3 days, respectively, before and continued through the first 10 and 11 days, respectively, after bone marrow transplantation (a total of 14 injections). The overall sustained engraftment rate was 69.8%, with full chimerism in 80.6% of patients and no late graft rejection with the use of two MoAbs versus 65.7% and 58.1%, respectively, in the control group, in which only one MoAb was infused. The overall actuarial survival rate with a functional graft was 40.9%, with a mean follow-up of 39.3 months with two MoAbs versus 37.8% with one. The engraftment rate was significantly influenced by the T-cell depletion method, with better results for recipients of E rosette- depleted marrow (78.6% vs 20% for Campath 1-M plus complement-depleted marrows). Graft-versus-host disease and the kinetics of immune reconstitution were similar in both groups. The overall engraftment rate and overall survival rate with engraftment in patients treated with anti-LFA-1 and anti-CD2 were similar to those in patients treated with anti-LFA-1 antibody alone. However, although the number of patients is too small to draw definitive conclusions, results from the combined use of the two MoAbs indicates a trend toward better engraftment and survival after infusion of E rosette-depleted marrow. Further improvement in survival would demand additional strategies to hasten immunologic recovery.


New advances in DPYD genotype and risk of severe toxicity under capecitabine.
Deficiency in dihydropyrimidine dehydrogenase (DPD) enzyme is the main cause of severe and lethal fluoropyrimidine-related toxicity. Various approaches have been developed for DPD-deficiency screening, including DPYD genotyping and phenotyping. The goal of this prospective observational study was to perform exhaustive exome DPYD sequencing and to examine relationships between DPYD variants and toxicity in advanced breast cancer patients receiving capecitabine. Two-hundred forty-three patients were analysed (88.5% capecitabine monotherapy). Grade 3 and grade 4 capecitabine-related digestive and/or neurologic and/or hemato-toxicities were observed in 10.3% and 2.1% of patients, respectively. DPYD exome, along with flanking intronic regions 3'UTR and 5'UTR, were sequenced on MiSeq Illumina. DPD phenotype was assessed by pre-treatment plasma uracil (U) and dihydrouracil (UH2) measurement. Among the 48 SNPs identified, 19 were located in coding regions, including 3 novel variations, each observed in a single patient (among which, F100L and A26T, both pathogenic in silico). Combined analysis of deleterious variants *2A, I560S (*13) and D949V showed significant association with grade 3-4 toxicity (sensitivity 16.7%, positive predictive value (PPV) 71.4%, relative risk (RR) 6.7, p<0.001) but not with grade 4 toxicity. Considering additional deleterious coding variants D342G, S492L, R592W and F100L increased the sensitivity to 26.7% for grade 3-4 toxicity (PPV 72.7%, RR 7.6, p<0.001), and was significantly associated with grade 4 toxicity (sensitivity 60%, PPV 27.3%, RR 31.4, p = 0.001), suggesting the clinical relevance of extended targeted DPYD genotyping. As compared to extended genotype, combining genotyping (7 variants) and phenotyping (U>16 ng/ml) did not substantially increase the sensitivity, while impairing PPV and RR. Exploring an extended set of deleterious DPYD variants improves the performance of DPYD genotyping for predicting both grade 3-4 and grade 4 toxicities (digestive and/or neurologic and/or hematotoxicities) related to capecitabine, as compared to conventional genotyping restricted to consensual variants *2A, *13 and D949V.


Patterns and networks of language control in bilingual language production.
Many studies have examined the cognitive and neural mechanisms of bilingual language control, but few of them have captured the pattern information of brain activation. However, language control is a functional combination of both cognitive control and language production which demonstrates distinct patterns of neural representations under different language contexts. The first aim of the present study was to explore the brain activation patterns of language control using multivoxel pattern analysis (MVPA). During the experiment, Chinese-English bilinguals were instructed to name pictures in either Chinese or English according to a visually presented cue while being scanned with functional magnetic resonance imaging (fMRI). We found that patterns of neural activity in frontal brain regions including the left dorsolateral prefrontal cortex, left inferior frontal gyrus, left supplementary motor area, anterior cingulate cortex, bilateral precentral gyri, and the left cerebellum reliably discriminated between switch and non-switch conditions. We then modeled causal interactions between these regions by applying effective connectivity analyses based on an extended unified structure equation model (euSEM). The results showed that frontal and fronto-cerebellar connectivity were key components of the language control network. These findings further reveal the engagement of the cognitive control network in bilingual language production.


The effects of aging on hypoglossal motoneurons in rats.
Aging can result in a loss of neuronal cell bodies and a decrease in neuronal size in some regions of the brain and spinal cord. Motoneuron loss in the spinal cord is thought to contribute to the progressive decline in muscle mass and strength that occurs with age (sarcopenia). Swallowing disorders represent a large clinical problem in elderly persons; however, age-related alterations in cranial motoneurons that innervate muscles involved in swallowing have been understudied. We aimed to determine if age-related alterations occurred in the hypoglossal nucleus in the brainstem. If present, these changes might help explain alterations at the neuromuscular junction and changes in the contractile properties of tongue muscle that have been reported in older rats. We hypothesized that with increasing age there would be a loss of motoneurons and a reduction in neuronal size and the number of primary dendrites associated with each hypoglossal motoneuron. Neurons in the hypoglossal nucleus were visualized with the neuronal marker NeuN in young (9-10 months), middle-aged (24-25 months), and old (32-33 months) male F344/BN rats. Hypoglossal motoneurons were retrograde-labeled with injections of Cholera Toxin beta into the genioglossus muscle of the tongue and visualized using immunocytochemistry. Results indicated that the number of primary dendrites of hypoglossal motoneurons decreased significantly with age, while no age-associated changes were found in the number or size of hypoglossal motoneurons. Loss of primary dendrites could reduce the number of synaptic inputs and thereby impair function.


Feedback in clinical medical education.
In the setting of clinical medical education, feedback refers to information describing students' or house officers' performance in a given activity that is intended to guide their future performance in that same or in a related activity. It is a key step in the acquisition of clinical skills, yet feedback is often omitted or handled improperly in clinical training. This can result in important untoward consequences, some of which may extend beyond the training period. Once the nature of the feedback process is appreciated, however, especially the distinction between feedback and evaluation and the importance of focusing on the trainees' observable behaviors rather than on the trainees themselves, the educational benefit of feedback can be realized. This article presents guidelines for offering feedback that have been set forth in the literature of business administration, psychology, and education, adapted here for use by teachers and students of clinical medicine.


DNA polymerase beta is able to repair breaks in switch regions and plays an inhibitory role during immunoglobulin class switch recombination.
Immunoglobulin (Ig) class switch recombination (CSR) is initiated by activation-induced cytidine deaminase (AID), which converts cytosines to uracils in switch (S) regions. Subsequent excision of dU by uracil DNA glycosylase (UNG) of the base excision repair (BER) pathway is required to obtain double-strand break (DSB) intermediates for CSR. Since UNG normally initiates faithful repair, it is unclear how the AID-instigated S region lesions are converted into DSBs rather than correctly repaired by BER. Normally, DNA polymerase beta (Polbeta) would replace the dC deaminated by AID, leading to correct repair of the single-strand break, thereby preventing CSR. We address the question of whether Polbeta might be specifically down-regulated during CSR or inhibited from accessing the AID-instigated lesions, or whether the numerous AID-initiated S region lesions might simply overwhelm the BER capacity. We find that nuclear Polbeta levels are induced upon activation of splenic B cells to undergo CSR. When Polbeta(-/-) B cells are activated to switch in culture, they switch slightly better to IgG2a, IgG2b, and IgG3 and have more S region DSBs and mutations than wild-type controls. We conclude that Polbeta attempts to faithfully repair S region lesions but fails to repair them all.


Life history, aggregation and dormancy of the rubber plantation litter beetle, Luprops tristis, from the rubber plantations of moist south Western Ghats.
Life history, aggregation and dormancy of rubber plantation litter beetle Luprops tristis Fabricius, (Tenebrionidae: Coleoptera) is described from rubber plantation belts in the western slopes of Western Ghats from the south Indian state of Kerala. The life cycle lasted 12 months, including the 5 larval instars lasting 1 month, the 3 day pupal stage, and the adult stage that can last 11 months. The adult stage includes an inactive dormancy phase of 9 months in shelters and 1 month each of active pre-dormancy (feeding) and post-dormancy (feeding and reproduction) phases that occur in rubber plantation litter. Reproductive activities are confined to the post-dormancy phase. With the onset of summer rains, huge aggregations of adults invade residential buildings and enter into a state of dormancy for 9 months. Beetle aggregations were in the range of 0.5 million to 4.5 million individuals per residential building. Dormancy in L. tristis is best classified as oligopause, which is intermediate between quiescence and diapause. Adults and larvae feed preferentially on wilted rubber tree leaves. Age-specific variation in mortality during dormancy is distinct with higher survivability for adults that have a longer pre-dormancy period. Generations are non-overlapping.


The death valley of coal - Modelling COVID-19 recovery scenarios for steam coal markets.
This paper examines medium and long-term perspectives for global steam coal production and trade, considering the potential impacts of the COVID-19 pandemic and plausible recovery scenarios in its aftermath. We use an interdisciplinary approach to develop a range of stylized global coal demand scenarios until 2040 depicting the influence of the COVID-19 pandemic and resulting recovery stimuli. Additional insights are gained by adjusting trade restrictions of key countries within the coal sector model COALMOD-World to resemble plausible post-COVID-19 policy and market dynamics. Results indicate that the COVID-19 pandemic might cause an "L" or "\" shape instead of the hoped for "V" or "U" shaped recovery of the coal industry. Regional effects vary, as the Atlantic market dries out first, causing shifts in trade patterns in the Pacific market. Moreover, announced trade restrictions could change dramatically the composition of the international steam coal trade. However, even significantly reduced coal consumption levels in low-coal post-COVID-19 scenarios would still be too high to comply with the global climate targets. This emphasizes the importance of concentrated policy efforts in the pandemic aftermath to manage a coal decline consistent with global climate targets while bringing just transitions efforts substantially forward, in particular in vulnerable coal-dependent countries and regions.


Intrinsic apoptotic pathway activation increases response to anti-estrogens in luminal breast cancers.
Estrogen receptor-α positive (ERα+) breast cancer accounts for approximately 70-80% of the nearly 25,0000 new cases of breast cancer diagnosed in the US each year. Endocrine-targeted therapies (those that block ERα activity) serve as the first line of treatment in most cases. Despite the proven benefit of endocrine therapies, however, ERα+ breast tumors can develop resistance to endocrine therapy, causing disease progression or relapse, particularly in the metastatic setting. Anti-apoptotic Bcl-2 family proteins enhance breast tumor cell survival, often promoting resistance to targeted therapies, including endocrine therapies. Herein, we investigated whether blockade of anti-apoptotic Bcl-2 family proteins could sensitize luminal breast cancers to anti-estrogen treatment. We used long-term estrogen deprivation (LTED) of human ERα+ breast cancer cell lines, an established model of sustained treatment with and acquired resistance to aromatase inhibitors (AIs), in combination with Bcl-2/Bcl-xL inhibition (ABT-263), finding that ABT-263 induced only limited tumor cell killing in LTED-selected cells in culture and in vivo. Interestingly, expression and activity of the Bcl-2-related factor Mcl-1 was increased in LTED cells. Genetic Mcl-1 ablation induced apoptosis in LTED-selected cells, and potently increased their sensitivity to ABT-263. Increased expression and activity of Mcl-1 was similarly seen in clinical breast tumor specimens treated with AI + the selective estrogen receptor downregulator fulvestrant. Delivery of Mcl-1 siRNA loaded into polymeric nanoparticles (MCL1 si-NPs) decreased Mcl-1 expression in LTED-selected and fulvestrant-treated cells, increasing tumor cell death and blocking tumor cell growth. These findings suggest that Mcl-1 upregulation in response to anti-estrogen treatment enhances tumor cell survival, decreasing response to therapeutic treatments. Therefore, strategies blocking Mcl-1 expression or activity used in combination with endocrine therapies would enhance tumor cell death.


Determination of absolute configuration of chiral molecules using vibrational optical activity: a review.
Determination of the absolute handedness, known as absolute configuration (AC), of chiral molecules is an important step in any field related to chirality, especially in the pharmaceutical industry. Vibrational optical activity (VOA) has become a powerful tool for the determination of the AC of chiral molecules in the solution state after nearly forty years of evolution. VOA offers a novel alternative, or supplement, to X-ray crystallography, permitting AC determinations on neat liquid, oil, and solution samples without the need to grow single crystals of the pure chiral sample molecules as required for X-ray analysis. By comparing the sign and intensity of the measured VOA spectrum with the corresponding ab initio density functional theory (DFT) calculated VOA spectrum of a chosen configuration, one can unambiguously assign the AC of a chiral molecule. Comparing measured VOA spectra with calculated VOA spectra of all the conformers can also provide solution-state conformational populations. VOA consists of infrared vibrational circular dichroism (VCD) and vibrational Raman optical activity (ROA). Currently, VCD is used routinely by researchers in a variety of backgrounds, including molecular chirality, asymmetric synthesis, chiral catalysis, drug screening, pharmacology, and natural products. Although the application of ROA in AC determination lags behind that of VCD, with the recent implementation of ROA subroutines in commercial quantum chemistry software, ROA will in the future complement VCD for AC determination. In this review, the basic principles of the application of VCD to the determination of absolute configuration in chiral molecules are described. The steps required for VCD spectral measurement and calculation are outlined, followed by brief descriptions of recently published papers reporting the determination of AC in small organic, pharmaceutical, and natural product molecules.


Macroscopic nuclear spin diffusion constants of rotating polycrystalline solids from first-principles simulation.
A method for quantitatively calculating nuclear spin diffusion constants directly from crystal structures is introduced. This approach uses the first-principles low-order correlations in Liouville space (LCL) method to simulate spin diffusion in a box, starting from atomic geometry and including both magic-angle spinning (MAS) and powder averaging. The LCL simulations are fit to the 3D diffusion equation to extract quantitative nuclear spin diffusion constants. We demonstrate this method for the case of (1)H spin diffusion in ice and L-histidine, obtaining diffusion constants that are consistent with literature values for (1)H spin diffusion in polymers and that follow the expected trends with respect to magic-angle spinning rate and the density of nuclear spins. In addition, we show that this method can be used to model (13)C spin diffusion in diamond and therefore has the potential to provide insight into applications such as the transport of polarization in non-protonated systems.


Doctors' work: eulogy for my vocation.
I, like so many of those who filled the first ranks of family practice, often described my career choice as a calling, a vocation, something more than a meal ticket. It was a source not only of pride and conviction but also resentment and resistance to change. By mid career I was largely out of step with new movements in family medicine that veered from the generalist approach toward focused fellowships, added qualifications, and office practices that opted out of obstetrics and hospital work. As often happens, it was a patient of mine who brought the issue into focus and showed me the potential that lay in each encounter. We long for connection-doctor and patient alike-and for the skill and compassion to express it without judgment or self-denial. There is no higher calling.


Changing patterns in mortality and disease outcomes for patients with systemic lupus erythematosus.
Survival of patients with systemic lupus erythematosus (SLE) has improved significantly, but new morbidities have emerged, leading to altered patterns of outcome in this disease. We examined changes in mortality and other outcomes over time in a large SLE cohort. A group of 1241 patients from the University of Toronto Lupus Clinic followed prospectively were divided into 4 entry cohorts - 1: 1970-1978, 2: 1979-1987, 3: 1988-1996, 4: 1997-2005. These cohorts were followed through four 9-year calendar periods defined over the same intervals. Both cohort and calendar effects were assessed for the following outcomes: mortality (standardized mortality ratio; SMR), disease activity over time (adjusted mean SLEDAI; AMS), cumulative damage (Systemic Lupus International Collaborating Clinics Damage Index; SDI), coronary artery disease (CAD), and osteonecrosis (ON). Cox regression models were used to further investigate mortality and the influence on it of the disease-related factors. Over the 36-year period of the study, 211 deaths occurred. The overall SMR in the first and last decades were 12.60 (95% CI: 9.13, 17.39) and 3.46 (95% CI: 2.71, 4.40) respectively. When SMR were stratified by the entry cohort and calendar period, there is evidence of a calendar-period effect but no cohort effect. The AMS decreased over the decades, while SDI, CAD, and ON increased. There were significant detrimental effects for male sex, CAD, AMS, SDI, and use of immunosuppressive drugs and significant protective effects for use of antimalarials and the effect of calendar period on mortality. Our study demonstrates improved survival in patients with SLE over a 36-year period. Disease-related variables included in the model are important factors for mortality in this SLE cohort, but could not completely explain the trend of improved survival over calendar period observed.


Sharing meals with institutionalized people with dementia: a natural experiment.
Nutritional deficiency can have dramatic effects on the physical and psychological status of older adults. Although food supplements can enhance nutritional status, several authors suggest that more ecological means could also have beneficial impacts. Therefore, a natural experiment was conducted to study the impact of changed mealtime experiences for people with Alzheimer-type dementia. Two special care units (in separate facilities) in France were included in this study: one implemented shared meal times between residents and caregivers and the other served as a comparison group. Weight was measured and staff observations were collected. Positive outcomes were observed for the experimental group. Implications for practice are discussed.


When classical music relaxes the brain: An experimental study using Ultrasound Brain Tissue Pulsatility Imaging.
Recent evidence suggests that biomechanical parameters of the brain, such as Brain Tissue Pulsatility (BTP), could be involved in emotional reactivity. However, no study has investigated the impact of an emotional task on BTP. We used the ultrasound method of Tissue Pulsatility Imaging (TPI) to assess changes in BTP to exciting and relaxing classical music, in a musical perception task, as a validated paradigm to assess emotional reactivity. 25 healthy volunteers were exposed via earphones to four 5-minute musical excerpts (two exciting and two relaxing musical excerpts) presented in a randomized order and intersected by 5 silence periods. Measures of BTP, Heart Rate (HR) and Skin Conductance (SC) were collected during the entire task. The BTP significantly decreased with relaxing music compared to silence, and especially with the excerpt 'Entrance of the Shades' by Minkus. The HR and SC, but not Heart Rate Variability, were also decreased with relaxing music. We found no significant effect of exciting music. We report, for the first time, that classical relaxing music decreases the amplitude of the brain pulsatile movements related to cerebral blood flow and mechanical properties of the brain parenchyma, which provides further evidence of the involvement of BTP in emotional reactivity. In addition, we validate the use of TPI as a non-invasive, portable and low cost tool for studies in psychophysiology, with the potential to be implemented as a biomarker in musicotherapy trials notably.


Adaptive correction method for an OCXO and investigation of analytical cumulative time error upper bound.
Traditional oscillators used in timing modules of CDMA and WiMAX base stations are large and expensive. Applying cheaper and smaller, albeit more inaccurate, oscillators in timing modules is an interesting research challenge. An adaptive control algorithm is presented to enhance the oscillators to meet the requirements of base stations during holdover mode. An oscillator frequency stability model is developed for the adaptive control algorithm. This model takes into account the control loop which creates the correction signal when the timing module is in locked mode. A recursive prediction error method is used to identify the system model parameters. Simulation results show that an oscillator enhanced by our adaptive control algorithm improves the oscillator performance significantly, compared with uncorrected oscillators. Our results also show the benefit of explicitly modeling the control loop. Finally, the cumulative time error upper bound of such enhanced oscillators is investigated analytically and comparison results between the analytical and simulated upper bound are provided. The results show that the analytical upper bound can serve as a practical guide for system designers.


Cysteine redox sensor in PKGIa enables oxidant-induced activation.
Changes in the concentration of oxidants in cells can regulate biochemical signaling mechanisms that control cell function. We have found that guanosine 3',5'-monophosphate (cGMP)-dependent protein kinase (PKG) functions directly as a redox sensor. The Ialpha isoform, PKGIalpha, formed an interprotein disulfide linking its two subunits in cells exposed to exogenous hydrogen peroxide. This oxidation directly activated the kinase in vitro, and in rat cells and tissues. The affinity of the kinase for substrates it phosphorylates was enhanced by disulfide formation. This oxidation-induced activation represents an alternate mechanism for regulation along with the classical activation involving nitric oxide and cGMP. This mechanism underlies cGMP-independent vasorelaxation in response to oxidants in the cardiovascular system and provides a molecular explantion for how hydrogen peroxide can operate as an endothelium-derived hyperpolarizing factor.


Photodynamic treatment of Chaoborus crystallinus larvae with chlorophyllin induces necrosis and apoptosis.
Chlorophyllin kills mosquito larvae (Culex, Aedes) in the aquatic habitat at low concentrations via photodynamic reactions under irradiation. The effects of chlorophyllin were investigated at the cellular level using the transparent larvae of Chaoborus crystallinus as a model system. Their transparency enabled in situ fluorescence investigation, showing that chlorophyllin accumulates in the intestine of the larvae. Uptake of chlorophyllin at room temperature took about 2 h. The fluorescence signal peaked after 5 h of incubation. Chlorophyllin accumulates up to about 15 ng per larvae. The intestine of treated larvae was dissected and stained with several dyes (acridine orange, Hoechst 33342 and propidium iodide). Apoptosis and necrosis increased with higher concentrations of chlorophyllin (to a smaller extent in dark controls) and were elevated in irradiated samples. Single cells from treated larvae were isolated and subjected to Annexin V flow cytometry. The fraction of apoptotic and necrotic cells increased significantly at a high chlorophyllin concentration (21.4 mg L(-1)) and under intensive irradiation. The activity of caspases-3, -8 and -9 as well as Bcl-2 and cytochrome c was investigated by means of western blot analysis. The data suggest a possible chlorophyllin concentration-dependent shift of the apoptotic pathway.


Genetic screening for synthetic lethal partners of polynucleotide kinase/phosphatase: potential for targeting SHP-1-depleted cancers.
A genetic screen using a library of 6,961 siRNAs led to the identification of SHP-1 (PTPN6), a tumor suppressor frequently mutated in malignant lymphomas, leukemias, and prostate cancer, as a potential synthetic lethal partner of the DNA repair protein polynucleotide kinase/phosphatase (PNKP). After confirming the partnership with SHP-1, we observed that codepletion of PNKP and SHP-1 induced apoptosis. A T-cell lymphoma cell line that is SHP-1 deficient (Karpas 299) was shown to be sensitive to a chemical inhibitor of PNKP, but resistance was restored by expression of wild-type SHP-1 in these cells. We determined that while SHP-1 depletion does not significantly impact DNA strand-break repair, it does amplify the level of reactive oxygen species (ROS) and elevate endogenous DNA damage. The ROS scavenger WR1065 afforded protection to SHP-1-depleted cells treated with the PNKP inhibitor. We propose that codisruption of SHP-1 and PNKP leads to an increase in DNA damage that escapes repair, resulting in the accumulation of cytotoxic double-strand breaks and induction of apoptosis. This supports an alternative paradigm for synthetic lethal partnerships that could be exploited therapeutically.


Negative emotions facilitate isometric force through activation of prefrontal cortex and periaqueductal gray.
Emotions are considered to modulate action readiness. Previous studies have demonstrated increased force production following exposure to emotionally arousing visual stimuli; however the neural mechanisms underlying how precise force output is controlled within varying emotional contexts remain poorly understood. To identify the neural correlates of emotion-modulated motor behaviour, twenty-two participants produced a submaximal isometric precision-grip contraction while viewing pleasant, unpleasant, neutral or blank images (without visual feedback of force output). Force magnitude was continuously recorded together with change in brain activity using functional magnetic resonance imaging. Viewing unpleasant images resulted in reduced force decay during force maintenance as compared with pleasant, neutral and blank images. Subjective valence and arousal ratings significantly predicted force production during maintenance. Neuroimaging revealed that negative valence and its interaction with force output correlated with increased activity in right inferior frontal gyrus (rIFG), while arousal was associated with amygdala and periaqueductal gray (PAG) activation. Force maintenance alone was correlated with cerebellar activity. These data demonstrate a valence-driven modulation of force output, mediated by a cortico-subcortical network involving rIFG and PAG. These findings are consistent with engagement of motor pathways associated with aversive motivation, eliciting defensive behaviour and action preparedness in response to negative emotional signals.


Differential requirement for CCR4 and CCR7 during the development of innate and adaptive αβT cells in the adult thymus.
αβT cell development depends upon serial migration of thymocyte precursors through cortical and medullary microenvironments, enabling specialized stromal cells to provide important signals at specific stages of their development. Although conventional αβT cells are subject to clonal deletion in the medulla, entry into the thymus medulla also fosters αβT cell differentiation. For example, during postnatal periods, the medulla is involved in the intrathymic generation of multiple αβT cell lineages, notably the induction of Foxp3(+) regulatory T cell development and the completion of invariant NKT cell development. Although migration of conventional αβT cells to the medulla is mediated by the chemokine receptor CCR7, how other T cell subsets gain access to medullary areas during their normal development is not clear. In this study, we show that combining a panel of thymocyte maturation markers with cell surface analysis of CCR7 and CCR4 identifies distinct stages in the development of multiple αβT cell lineages in the thymus. Although Aire regulates expression of the CCR4 ligands CCL17 and CCL22, we show that CCR4 is dispensable for thymocyte migration and development in the adult thymus, demonstrating defective T cell development in Aire(-/-) mice is not because of a loss of CCR4-mediated migration. Moreover, we reveal that CCR7 controls the development of invariant NKT cells by enabling their access to IL-15 trans-presentation in the thymic medulla and influences the balance of early and late intrathymic stages of Foxp3(+) regulatory T cell development. Collectively, our data identify novel roles for CCR7 during intrathymic T cell development, highlighting its importance in enabling multiple αβT cell lineages to access the thymic medulla.


Routine assay for detection of IgG and IgM antiglobulins in seronegative and seropositive rheumatoid arthritis.
A convenient technique suitable for the routine estimation of IgM and IgG antiglobulins has been devised. The assay involves the binding of antiglobulins (rheumatoid factors) to rabbit immunoglobulin linked to the surface of plastic tubes; the amount of antiglobulin bound is then determined by adding radiolabelled antihuman IgG or IgM. Both antiglobulins were raised in virtually all seropositive rheumatoid arthritics, and 19 out of 22 seronegative patients had raised values for either IgM or IgG rheumatoid factors. The test should prove valuable in diagnosis and the results further emphasize autosensitization to IgG as a dominant immunological characteristic of different forms of rheumatoid arthritis.


Growth and evolution of a municipal pool safety and inspection program.
The city of Plano Health Department swimming pool safety and inspection program has been growing and evolving since 1992. Currently, five environmental health specialists inspect 370 permitted commercial swimming pools. The environmental health specialists, who are all well trained and are Certified Pool Operators by the National Swimming Pool Foundation, inspect each facility twice during the summer season. The department considers quality training for both inspectors and operators a priority. Violation rates have been variable across the program, but improved operator training is proving successful in many areas. The program also plays a role in swimming pool construction by providing plan review services and construction inspections. Increased involvement in construction and design has significantly reduced problems and improved compliance with new pools. This has resulted in a higher level of service and swimmer safety. Additionally, a net drop in chemistry violations has been shown over the last three years. The department is constantly evaluating safety in public and semi-public pools in Plano in an effort to provide a maximum level of swimmer safety.


The effect of plant inbreeding and stoichiometry on interactions with herbivores in nature: Echinacea angustifolia and its specialist aphid.
Fragmentation of once widespread communities may alter interspecific interactions by changing genetic composition of interacting populations as well as their abundances and spatial distributions. In a long-term study of a fragmented population of Echinacea angustifolia, a perennial plant native to the North American prairie, we investigated influences on its interaction with a specialist aphid and tending ants. We grew plant progeny of sib-matings (I), and of random pairings within (W) and between (B) seven remnants in a common field within 8 km of the source remnants. During the fifth growing season, we determined each plant's burden of aphids and ants, as well as its size and foliar elemental composition (C, N, P). We also assayed composition (C, N) of aphids and ants. Early in the season, progeny from genotypic classes B and I were twice as likely to harbor aphids, and in greater abundance, than genotypic class W; aphid loads were inversely related to foliar concentration of P and positively related to leaf N and plant size. At the end of the season, aphid loads were indistinguishable among genotypic classes. Ant abundance tracked aphid abundance throughout the season but showed no direct relationship with plant traits. Through its potential to alter the genotypic composition of remnant populations of Echinacea, fragmentation can increase Echinacea's susceptibility to herbivory by its specialist aphid and, in turn, perturb the abundance and distribution of aphids.


Health and risk behaviors in survivors of childhood acute myeloid leukemia: a report from the Children's Oncology Group.
Survivors of childhood acute myeloid leukemia (AML) face increased risks of chronic disease and secondary malignancies. Substance exposure may compound these risks. Participants were diagnosed with AML at <21 years of age and survived > or =5 years following diagnosis. All underwent chemotherapy alone or followed by autologous BMT (chemo +/- autoBMT) or underwent allogeneic BMT (alloBMT) if an HLA-matched related donor was available. Survivors completed a health questionnaire and a Youth Risk Behavior Survey (YRBS). Of eligible survivors, 117 were > or =18 years of age and completed a YRBS. Survivors were a mean age of 10 years at diagnosis and 24 years at interview. Of the substance exposures assessed by YRBS, tobacco, alcohol, and marijuana were most common. Twenty-two percent (22%) had smoked cigarettes in the last 30 days. One-quarter (25%) reported binge drinking in the last month. None of these exposures varied by treatment group. Less than 10% of survivors reported cocaine, heroin, or methamphetamine use. Men were more likely to report high substance exposure (P = 0.004). Sadness/suicidality score was associated with cancer-related anxiety (P = 0.006) and multiple health conditions (P = 0.006). This analysis reveals exposure to tobacco, alcohol, and marijuana in young adults with few differences based on treatment received. Survivors with cancer-related anxiety or multiple health conditions were more likely to report sadness/hopelessness.


The International Classification of Functioning, Disability and Health (ICF): a unifying model for the conceptual description of the rehabilitation strategy.
An important basis for the successful development of rehabilitation practice and research is a conceptually sound description of rehabilitation understood as a health strategy based on a universally accepted conceptual model and taxonomy of human functioning. With the approval of the International Classification of Functioning, Disability and Health (ICF) by the World Health Assembly in 2001 and the reference to the ICF in the World Health Assembly's resolution on "Disability, including prevention, management and rehabilitation" in 2005, we can now rely on a universally accepted conceptual model. It is thus time to initiate the process of evolving an ICF-based conceptual description that can serve as a basis for similar conceptual descriptions and according definitions of the professions applying the rehabilitation strategy and of distinct scientific fields of human functioning and rehabilitation research. In co-operation with the Physical and Rehabilitation Medicine (PRM) section of the European Union of Medical Specialists (UEMS) and its professional practice committee, we present a first tentative version of an ICF-based conceptual description in this paper. A brief definition describes rehabilitation as the health strategy applied by PRM and professionals in the health sector and across other sectors that aims to enable people with health conditions experiencing or likely to experience disability to achieve and maintain optimal functioning in interaction with the environment. Readers of the Journal of Rehabilitation Medicine are invited to contribute towards achieving an internationally accepted ICF-based conceptual description of rehabilitation by submitting commentaries to the Editor of this journal.


Multiple biomarkers for mortality prediction in peripheral arterial disease.
Few studies have assessed which biomarkers influence mortality risk among those with peripheral arterial disease (PAD). We analyzed data from 556 individuals identified to have PAD (i.e. ankle-brachial index ⩽ 0.9) with available measurements of C-reactive protein, the neutrophil-to-lymphocyte ratio (NLR), homocysteine, and the urinary albumin-to-creatinine ratio (UACR) in the 1999-2004 National Health and Nutrition Examination Survey. We investigated whether a combination of these biomarkers improved the prediction of all-cause and cardiovascular mortality beyond conventional risk factors. During follow-up (median, 8.1 years), 277 of 556 participants died; 63 deaths were attributed to cardiovascular disease. After adjusting for conventional risk factors, Cox proportional-hazards models showed the following to be most strongly associated with all-cause mortality (each is followed by the adjusted hazard ratio [HR] per 1 standard deviation increment in the log values): homocysteine (1.31), UACR (1.21), and NLR (1.20). UACR alone significantly predicted cardiovascular mortality (1.53). Persons in the highest quintile of multimarker scores derived from regression coefficients of significant biomarkers had elevated risks of all-cause mortality (adjusted HR, 2.45; 95% CI, 1.66-3.62; p for trend, <0.001) and cardiovascular mortality (adjusted HR, 2.20; 95% CI, 1.02-4.71; p for trend, 0.053) compared to those in the lowest two quintiles. The addition of continuous multimarker scores to conventional risk factors improved risk stratification of all-cause mortality (integrated discrimination improvement [IDI], 0.162; p<0.00001) and cardiovascular mortality (IDI, 0.058; p<0.00001). In conclusion, the addition of a continuous multimarker score to conventional risk factors improved mortality prediction among patients with PAD.


Identification of pheromone synergists for Rhynchophorus ferrugineus trapping systems from Phoenix canariensis palm volatiles.
Trapping systems for the red palm weevil, Rhynchophorus ferrugineus Olivier, rely on the use of natural plant odor sources to boost the attractiveness of the aggregation pheromone. The identification of the key odorants involved in attraction is essential in the development of a synthetic pheromone synergist to replace the nonstandardized use of plant material in traps. Canary Islands date palms (Phoenix canariensis) have become preferred hosts for R. ferrugineus in Europe; thus, the volatile profile of different P. canariensis plant materials, including healthy and infested tissues, is investigated in the present work by means of solid phase microextraction (SPME-GC-MS), aimed to identify pheromone synergists. The electroantennography (EAG) response of the compounds identified was recorded, as well as the preliminary field response of several EAG-active compounds. The so-called "palm esters" (ethyl acetate, ethyl propionate, ethyl butyrate, and propyl butyrate) elicit the strongest EAG responses but performed poorly in the field. Mixtures of esters and alcohols give evidence of better performance, but release rates need further optimization.


Trends in Incidence of Nicotine Use Disorder Among Adolescents in the Pediatric Hospital, 2012-2019.
To assess trends in the incidence of nicotine use disorder (NUD) and describe associated factors among adolescents in the pediatric emergency department (ED) and inpatient settings. We conducted a retrospective cohort study of all adolescents (11-18 years) with a hospital encounter (inpatient, observation, or ED) in the Pediatric Health Information System between January 1, 2012, and September 30, 2019. After excluding adolescents with a previous International Classification of Diseases, Ninth Revision, and International Classification of Diseases, Tenth Revision, NUD diagnosis in the past 2 years, adolescents with new NUD diagnosis (ie, NUD incidence) were identified. A multivariable generalized liner mixed model was used to assess adjusted NUD incidence and investigate the relationship of NUD with patient characteristics and any interactions between characteristics and time. Spearman's correlation coefficient was used to assess the correlation between NUD incidence and e-cigarette use reported among youth. Of 3 963 754 adolescents, 15 376 (0.4%) had a new diagnosis of NUD. Between 2012 and 2019, NUD incidence increased from 0.3% to 0.4% (P < .001). Findings from the time interaction effect analysis revealed increasing NUD incidence among certain subpopulations, including boys, those with a commercial or other insurance type, adolescents seen in the ED, those from the lowest and highest median household income quartile, and those in the South and West US Census regions. The correlation between NUD incidence and e-cigarette use among high school students was ρ = 0.884 (P = .006). The incidence of NUD among adolescents is increasing. Efforts to increase the screening and treatment of NUD among adolescents in the hospital, particularly among the at-risk populations identified, are needed.


Comparative demography of commercially important parrotfish species from Micronesia.
Fishery-independent sampling was used to determine growth patterns, life span, mortality rates and timing of maturation and sex change in 12 common parrotfishes (Labridae: tribe Scarinae) from five genera (Calotomus, Cetoscarus, Chlorurus, Hipposcarus and Scarus) in Micronesia. Interspecific variation in life-history traits was explored using multivariate analysis. All species displayed strong sex-specific patterns of length-at-age among which males reached larger asymptotic lengths. There was a high level of correlation among life-history traits across species. Relationships between length-based and age-based variables were weakest, with a tenuous link between maximum body size and life span. Cluster analysis based on similarities among life-history traits demonstrated that species were significantly grouped at two major levels. The first grouping was driven by length-based variables (lengths at maturity and sex change and maximum length) and separated the small- and large-bodied species. Within these, species were grouped by age-based variables (age at maturity, mortality and life span). Groupings based on demographic and life-history features were independent of phylogenetic relationships at the given taxonomic level. The results reiterate that body size is an important characteristic differentiating species, but interspecific variation in age-based traits complicates its use as a life-history proxy. Detailed life-history metrics should facilitate future quantitative assessments of vulnerability to overexploitation in multispecies fisheries.


Lactose Intolerance in Adults: Biological Mechanism and Dietary Management.
Lactose intolerance related to primary or secondary lactase deficiency is characterized by abdominal pain and distension, borborygmi, flatus, and diarrhea induced by lactose in dairy products. The biological mechanism and lactose malabsorption is established and several investigations are available, including genetic, endoscopic and physiological tests. Lactose intolerance depends not only on the expression of lactase but also on the dose of lactose, intestinal flora, gastrointestinal motility, small intestinal bacterial overgrowth and sensitivity of the gastrointestinal tract to the generation of gas and other fermentation products of lactose digestion. Treatment of lactose intolerance can include lactose-reduced diet and enzyme replacement. This is effective if symptoms are only related to dairy products; however, lactose intolerance can be part of a wider intolerance to variably absorbed, fermentable oligo-, di-, monosaccharides and polyols (FODMAPs). This is present in at least half of patients with irritable bowel syndrome (IBS) and this group requires not only restriction of lactose intake but also a low FODMAP diet to improve gastrointestinal complaints. The long-term effects of a dairy-free, low FODMAPs diet on nutritional health and the fecal microbiome are not well defined. This review summarizes recent advances in our understanding of the genetic basis, biological mechanism, diagnosis and dietary management of lactose intolerance.


Determination of amitriptyline and its major basic metabolites in human urine by high-performance liquid chromatography.
A high-performance liquid chromatographic method for the routine, simultaneous determination of amitriptyline and its basic metabolites in human urine has been developed. 10-Hydroxylated metabolites are analyzed as their 10,11-dehydro analogs, and primary and secondary amines as their N-trifluoroacetyl derivatives. The use of gradient elution enables amitryptyline, nortriptyline trifluoroacetate, desmethylnortriptyline trifluoroacetate, and the corresponding 10, 11-dehydro analogs to be separated from both each other and from the internal standard used. In this way all six compounds may be conveniently measured in a single chromatogram, with good sensitivity and accuracy. Following administration of a single oral dose (25 mg) of amitriptyline hydrochloride to two human subjects, no unchanged drug was found in any of the urine samples analyzed up to 72 hr after dosing, and only small amounts of nortriptyline and desmethylnortriptyline were observed. 10-hydroxynortriptyline was the major biotransformation product (about 40% of the dose) in urine, with 10-hydroxyamitriptyline and 10-hydroxydesmethylnortriptyline present as minor metabolites. During 72 hr after administration, approximately 60% of the dose was recovered as these five metabolites.


Time trends in biological fertility in Western Europe.
We investigated trends in biological fertility in a comprehensive analysis of 5 major European data sets with data on time to pregnancy (TTP) and proportion of contraceptive failures. In particular, we distinguished a period effect from a birth cohort effect (lifelong tendency) in both sexes. Attempts at conception not resulting in birth were excluded. We analyzed data on pregnancies occurring in 9,247 couples between 1953 and 1993 and performed sensitivity analyses to check the robustness of findings. Separate analyses of each time effect showed an increasing fertility trend. Mutually adjusted analyses demonstrated that this rise was visible as a male cohort effect for both TTP and contraceptive failure. On the other hand, the female birth cohort effect showed a slight fall in the first half of the study period for both TTP and contraceptive failure. As a period effect, fertility remained generally stable, the slight trends in TTP and contraceptive failure being in opposite directions, likely indicating an artifact. The rising trend accords with most previous evidence. The increasing trend in male fertility does not contradict the previously reported semen quality deterioration, the effects of which are calculated to be small. The declining female fertility accords with a falling dizygotic twinning rate during the same period.


Endometriosis and angiogenesis.
Endometriosis is a common gynecological condition, responsible for significant morbidity and social-economic impact. Although the condition has been recognized for many years, the underlying pathophysiology is poorly understood. In turn, this results in inadequate treatment and high recurrence rates. Various theories try to explain the presence of endometrial tissue outside the uterine cavity. However, none of them can explain all disease locations and appearances, and it is unclear how these fragments establish into endometriotic lesions. New vessel formation has long been recognized as a feature of endometriosis, often clearly visible at laparoscopy. Recent work has focused on identifying the role of vascularization in the pathogenesis of endometriosis, by allowing lesions to establish and grow. In this review the authors outline the basic mechanisms of angiogenesis and vasculogenesis in the human eutopic endometrium, and consider how this data can be applied to endometriotic implants. Furthermore, the authors discuss molecular mechanisms of angiogenesis and vasculogenesis, and how this may be used to therapeutic advantage in the treatment of endometriosis.


Nanophase-separated polymer films as high-performance antireflection coatings
Optical surfaces coated with a thin layer to improve light transmission are ubiquitous in everyday optical applications as well as in industrial and scientific instruments. Discovered first in 1817 by Fraunhofer, the coating of lenses became standard practice in the 1930s. In spite of intensive research, broad-band antireflection coatings are still limited by the lack of materials with low refractive indices. A method based on the phase separation of a macromolecular liquid to generate nanoporous polymer films is demonstrated that creates surfaces with high optical transmission.


Evaluation of data transformations and validation of a model for the effect of temperature on bacterial growth.
The temperature of chilled foods is an important variable for controlling microbial growth in a production and distribution chain. Therefore, it is essential to model growth as a function of temperature in order to predict the number of organisms as a function of temperature and time. This article deals with the correct variance-stabilizing transformation of the growth parameters A (asymptotic level), mu (specific growth rate), and lambda (lag time). This is of importance for the regression analysis of the data. A previously gathered data set and model for the effect of temperature on the growth of Lactobacillus plantarum (M. H. Zwietering, J. T. de Koos, B. E. Hasenack, J. C. de Wit, and K. van 't Riet, Appl. Environ. Microbiol. 57:1094-1101, 1991) is extended with new data. With the total data set (original and new data), a variance-stabilizing transformation is selected in order to determine which transformation should precede fitting. No transformation for the asymptote data, a square root for the growth rate, and a logarithmic transformation for the lag time were found to be appropriate. After these transformations, no significant correlation was found between the variance and the magnitude of the variable. Model corrections were made and model parameters were estimated by using the original data. With the new data, the models were validated by comparing the lack of fit of the models with the measurement error, using an F test. The predictions of the models for mu and lambda were adequate. The model for A showed a systematic deviation, and therefore a new model for A is proposed.


Multiparametric magnetic resonance imaging in prostate cancer: present and future.
The purpose of this article is to review the current status of advanced MRI techniques based on anatomic, metabolic and physiologic properties of prostate cancer with a focus on their impact in managing prostate cancer patients. Prostate cancer can be identified based on reduced T2 signal intensity on MRI, increased choline and decreased citrate and polyamines on magnetic resonance spectroscopic imaging (MRSI), decreased diffusivity on diffusion tensor imaging (DTI), and increased uptake on dynamic contrast enhanced (DCE) imaging. All can be obtained within a 60-min 3T magnetic resonance exam. Each complementary method has inherent advantages and disadvantages: T2 MRI has high sensitivity but poor specificity; magnetic resonance spectroscopic imaging has high specificity but poor sensitivity; diffusion tensor imaging has high spatial resolution, is the fastest, but sensitivity/specificity needs to be established; dynamic contrast enhanced imaging has high spatial resolution, but requires a gadolinium based contrast agent injection, and sensitivity/specificity needs to be established. The best characterization of prostate cancer in individual patients will most likely result from a multiparametric (MRI/MRSI/DTI/DCE) exam using 3T magnetic resonance scanners but questions remain as to how to analyze and display this large amount of imaging data, and how to optimally combine the data for the most accurate assessment of prostate cancer. Histological correlations or clinical outcomes are required to determine sensitivity/specificity for each method and optimal combinations of these approaches.


Construction and validation of tissue microarrays of ductal carcinoma in situ and terminal duct lobular units associated with invasive breast carcinoma.
Construction of tissue microarrays (TMAs) to efficiently characterize large sets of noninvasive epithelial lesions in the breast by immunohistochemistry is an appealing investigative approach, but presents technical challenges. We report methodologic studies performed to optimize methods for building TMAs from noninvasive breast tissues collected in a large case-control study of breast cancer. Using a manual arraying technique with 2.0-mm diameter needles, we constructed TMAs from specimens obtained from 32 women with breast cancer containing the following targets: (1) 28 terminal duct lobular units (TDLUs); (2) 28 ductal carcinomas in situ, and (3) 23 invasive carcinomas. Using careful target selection, we achieved representation of approximately 80% of noninvasive targets with sustained preservation through section 30 of the TMAs. Immunohistochemical staining of TDLU targets demonstrated positive staining for estrogen receptor (ER) in 30.8% of tubules and for progesterone receptor (PR) in 50.0%. To establish an efficient method to evaluate staining results in TDLUs, we created a categorical scoring system to approximate the percentage of tubules containing positive stained cells (<10%, 10% to 50%, >or=50%), and compared the results with those obtained by tubule counting. Comparison between the two methods demonstrated exact agreement for 70.8% of ER and 79.2% of PR stains without two-category discrepancies. ER/PR expression levels in multiple (up to 4) noninvasive targets of the same tissue type (TDLU or DCIS) from a single block showed good correlation. These data suggest that it is feasible to produce TMAs of noninvasive breast structures, albeit with careful selection of targets, and that immunostains of such cores may permit efficient immunohistochemical characterization of peritumoral tissues. Additional exploration of this approach is needed.


Malaria parasites form filamentous cell-to-cell connections during reproduction in the mosquito midgut.
Physical contact is important for the interaction between animal cells, but it can represent a major challenge for protists like malaria parasites. Recently, novel filamentous cell-cell contacts have been identified in different types of eukaryotic cells and termed nanotubes due to their morphological appearance. Nanotubes represent small dynamic membranous extensions that consist of F-actin and are considered an ancient feature evolved by eukaryotic cells to establish contact for communication. We here describe similar tubular structures in the malaria pathogen Plasmodium falciparum, which emerge from the surfaces of the forming gametes upon gametocyte activation in the mosquito midgut. The filaments can exhibit a length of > 100 μm and contain the F-actin isoform actin 2. They actively form within a few minutes after gametocyte activation and persist until the zygote transforms into the ookinete. The filaments originate from the parasite plasma membrane, are close ended and express adhesion proteins on their surfaces that are typically found in gametes, like Pfs230, Pfs48/45 or Pfs25, but not the zygote surface protein Pfs28. We show that these tubular structures represent long-distance cell-to-cell connections between sexual stage parasites and demonstrate that they meet the characteristics of nanotubes. We propose that malaria parasites utilize these adhesive "nanotubes" in order to facilitate intercellular contact between gametes during reproduction in the mosquito midgut.


Cognitive and social activities and long-term dementia risk: the prospective UK Million Women Study.
Although dementia is associated with non-participation in cognitive and social activities, this association might merely reflect the consequences of dementia, rather than any direct effect of non-participation on the subsequent incidence of dementia. Because of the slowness with which dementia can develop, unbiased assessment of any such direct effects must relate non-participation in such activities to dementia detection rates many years later. Prospective studies with long-term follow-up can help achieve this by analysing separately the first and second decade of follow-up. We report such analyses of a large, 20-year study. The UK Million Women Study is a population-based prospective study of 1·3 million women invited for National Health Service (NHS) breast cancer screening in median year 1998 (IQR 1997-1999). In median year 2001 (IQR 2001-2003), women were asked about participation in adult education, groups for art, craft, or music, and voluntary work, and in median year 2006 (IQR 2006-2006), they were asked about reading. All participants were followed up through electronic linkage to NHS records of hospital admission with mention of dementia, the first mention of which was the main outcome. Comparing non-participation with participation in a particular activity, we used Cox regression to assess fully adjusted dementia risk ratios (RRs) during 0-4, 5-9, and 10 or more years, after information on that activity was obtained. In 2001, 851 307 women with a mean age of 60 years (SD 5) provided information on participation in adult education, groups for art, craft, or music, and voluntary work. After 10 years, only 9591 (1%) had been lost to follow-up and 789 339 (93%) remained alive with no recorded dementia. Follow-up was for a mean of 16 years (SD 3), during which 31 187 (4%) had at least one hospital admission with mention of dementia, including 25 636 (3%) with a hospital admission with dementia mentioned for the first time 10 years or more after follow-up began. Non-participation in cognitive or social activities was associated with higher relative risks of dementia detection only during the first decade after participation was recorded. During the second decade, there was little association. This was true for non-participation in adult education (RR 1·04, 99% CI 0·98-1·09), in groups for art, craft, or music (RR 1·04, 0·99-1·09), in voluntary work (RR 0·96, 0·92-1·00), or in any of these three (RR 0·99, 0·95-1·03). In 2006, 655 118 women provided information on reading. For non-reading versus any reading, there were similar associations with dementia, again with strong attenuation over time since reading was recorded, but longer follow-up is needed to assess this reliably. Life has to be lived forwards, but can be understood only backwards. Long before dementia is diagnosed, there is a progressive reduction in various mental and physical activities, but this is chiefly because its gradual onset causes inactivity and not because inactivity causes dementia. UK Medical Research Council, Cancer Research UK.


Brain damage from perinatal asphyxia: correlation of MR findings with gestational age.
MR scans of 25 patients who suffered asphyxia at known gestational ages were reviewed retrospectively. The gestational ages of the patients at the time of asphyxia ranged from 24 to 46 weeks. The MR pattern of brain damage in patients with prolonged partial asphyxia was seen to evolve in a predictable manner corresponding to the known maturation of the brain and its vascular supply. Patients at 24- and 26-weeks gestational age had irregularly enlarged ventricular trigones with minimal periventricular gliosis. Patients at 28-34 weeks had variably dilated ventricles with periventricular gliosis. The 36-week neonate had mild cortical and subcortical atrophy and gliosis superimposed on deep white matter and periventricular gliosis. Term neonates had significant cortical and subcortical gliosis and atrophy in the parasagittal watershed areas. Postterm neonates (44-46 weeks) showed cortical and subcortical watershed gliosis and atrophy with sparing of the immediate periventricular region. Two children suffered cardiocirculatory arrest; their scans revealed a different pattern of brain damage, demonstrating primarily brainstem, thalamic, and basal ganglia involvement. MR appears to be a powerful tool in the assessment of brain damage resulting from perinatal asphyxia that gives important clues to the time and nature of the asphyxia.


Therapeutic approaches to the regulation of metabolism of high-density lipoprotein. Novel HDL-directed pharmacological intervention and exercise.
High-density lipoprotein (HDL) and low-density lipoprotein (LDL) particles transport cholesterol in plasma and play an important role in cellular cholesterol homeostasis, which influences cell function. The risk of coronary artery disease (CAD) associated with high levels of LDL-cholesterol (LDL-C) can be reduced by treatment with statins, which reduce LDL-C levels by inhibiting cellular cholesterol synthesis. However, patients who are treated with high doses of statins, especially secondary CAD prevention, regardless of their resulting LDL-C levels, are still at high risk of CAD. Therefore, there has been growing interest in HDL-directed therapies. Inhibitors of cholesteryl ester transfer protein (CETP) substantially increase HDL-C levels (by 31-138%). However, it is still unclear whether or not CETP inhibitors can reduce the risk of CAD associated with low HDL-C levels, while reconstituted HDL or apolipoprotein A-I mimetic peptides increase the functionality of HDL. Low levels of HDL-C are often complicated with metabolic disorders, including hypertriglyceridemia, metabolic syndrome, and type 2 diabetes mellitus, and lifestyle changes are effective for correcting these conditions. Physical activity and exercise training increase HDL-C levels, especially HDL2-C levels, by multiple mechanisms. Therefore, although using HDL-directed therapies that increase HDL-C levels and/or improve the function of HDL is a reasonable approach for reducing the residual risk of CAD as a complement to LDL-C-lowering therapy, lifestyle modifications including exercise to improve metabolic disorders should be considered as the first option.


High dose escalation of intracoronary adenosine in the assessment of fractional flow reserve: A retrospective cohort study.
Maximal hyperaemia for fractional flow reserve (FFR) may not be achieved with the current recommended doses of intracoronary adenosine. Higher doses (up to 720 μg) have been reported to optimize hyperaemic stimuli in small dose-response studies. Real-world data from a large cohort of patients is needed to evaluate FFR results and the safety of high-dose escalation. This is a retrospective study aimed to evaluate the safety and frequency of FFR ≤0.8 after high-dose escalation of intracoronary adenosine. Data were extracted from the medical databases of two university hospitals. Increasing doses (100, 200, 400, 600, and 800 μg) of adenosine were administered as intracoronary boluses until FFR ≤0.8 was achieved or heart block developed. The percentage of FFR ≤0.8 after higher-dose escalation was compared with those at conventional doses, and the predictors for FFR ≤0.8 after higher doses were analysed. In the 1163 vessels of 878 patients, 402 vessels (34.6%) achieved FFR ≤0.8 at conventional doses and 623 vessels (53.6%) received high-dose escalation. An additional 84 vessels (13.5%) achieved FFR ≤0.8 after high-dose escalation. No major complications developed during high-dose escalation. Borderline FFR (0.81-0.85) at the conventional dose, stenosis >60%, and triple-vessel disease increased the likelihood of FFR ≤0.8 after high-dose escalation, but chronic kidney disease decreased it. For vessels of borderline FFR at conventional doses, 46% achieved FFR ≤0.8 after high-dose escalation. In conclusion, High-dose escalation of intracoronary adenosine increases the frequency of FFR ≤0.8 without major complications. It could be especially feasible for borderline FFR values near the 0.8 diagnostic threshold.


Two resource distribution strategies for dynamic mitigation of influenza pandemics.
As recently pointed out by the Institute of Medicine, the existing pandemic containment and mitigation models lack the dynamic decision support capabilities. We present two simulation-based optimization models for developing dynamic predictive resource distribution strategies for cross-regional pandemic outbreaks. In both models, the underlying simulation mimics the disease and population dynamics of the affected regions. The quantity-based optimization model generates a progressive allocation of limited quantities of mitigation resources, including vaccines, antiviral, administration capacities, and social distancing enforcement resources. The budget-based optimization model strives instead allocating a total resource budget. Both models seek to minimize the impact of ongoing outbreaks and the expected impact of potential outbreaks. The models incorporate measures of morbidity, mortality, and social distancing, translated into the societal and economic costs of lost productivity and medical expenses. The models were calibrated using historic pandemic data and implemented on a sample outbreak in Florida, with over four million inhabitants. The quantity-based model was found to be inferior to the budget-based model, which was advantageous in its ability to balance the varying relative cost and effectiveness of individual resources. The models are intended to assist public health policy makers in developing effective distribution policies for mitigation of influenza pandemics.