Overgrowth and outcome after femoral shaft fracture in children younger than 2 years.
Twenty-one children younger than 2 years with a fractured femur were evaluated retrospectively to determine limb overgrowth, efficacy, and outcome after treatment with immediate spica casting. All children had spica casts placed without general anesthesia within 24 hours of admission. Followup averaged 51 months (range, 24-110 months). Average shortening in the spica cast at initial application was 0.5 cm (range, 0-1.8 cm). The average length of hospitalization was 2.2 days. Three patients went home the same day, and seven were discharged after a single overnight stay in the hospital. No patients underwent closed manipulation or a cast change for malalignment of the fracture. Child abuse was identified as the mechanism of injury in eight of 12 (67%) children younger than 1 year of age and in only one of nine (11%) children between 1 and 2 years of age. Leg lengths were determined by measurement with tape and graduated blocks. At followup, the average limb length inequality was 0 cm, with an average net growth of 0.5 cm (range, -0.5-1.8 cm). Only one child had a limb length inequality of more than 1 cm as measured with tape (20 months of age), and no child had a limb length inequality of more than 1 cm as measured with blocks. No child or parent reported any residual pain, limp, or limitation of activity. The results of this study suggest that overgrowth does occur in children younger than 2 years. Additionally, immediate spica casting with early discharge to home is associated with few complications, no functional limitations, and minimal limb length inequality.


How Would Low-Income Communities Prioritize Medicaid Spending?
Medicaid plays a critical role in low-income, minority, and medically underserved communities, particularly in states that have expanded Medicaid under the Affordable Care Act. Yet, the voices of underresourced communities are often unheard in decisions about how to allocate Medicaid's scarce resources, and traditional methods of public engagement are poorly suited to gathering such input. We argue that deliberative public engagement can be a useful tool for involving communities in setting Medicaid priorities. We engaged 209 residents of low-income, medically underserved Michigan communities in discussions about Medicaid spending priorities using an exercise in informed deliberation: CHAT (CHoosing All Together). Participants learned about Medicaid, deliberated in small groups, and set priorities both individually and collectively. Participants prioritized broad eligibility consistent with the ACA expansion, accepted some cost sharing, and prioritized spending in areas-including mental health-that are historically underfunded. Participants allocated less funding beyond benefit coverage, such as spending on healthy communities. Participants perceived the deliberative process as fair and informative, and they supported using it in the policy-making process. The choices of participants from low-income, medically underserved communities reflect a unique set of priorities and suggest that engaging low-income communities more deeply in Medicaid policy making might result in different prioritization decisions.


[Treatment of fungal keratitis by penetrating keratoplasty].
Fungal keratitis is basically treated by medications. Several cases of fungal keratitis were reported around the world to have been treated successfully by corneal graft--penetrating keratoplasty (PKP). Studies have shown that PKP is a useful treatment, preserves eye globe integrity, and rehabilitates vision in patients with advanced fungal keratitis. To study the use of penetrating keratoplasty for the treatment of severe fungal keratitis that could not be cured by antifungal medication. The authors conducted a retrospective analysis of all cases (five cases) of severe fungal keratitis treated and followed-up at the Department of Ophthalmology, Soroka University Medical Center during 2007 and 2008, in which therapeutic PKP was performed. There were one male and 4 females. The age range was between 27 and 78 years. The follow-up period ranged from 4 to 15 months. Corneal graft remained clear during follow-up in most patients. There was no recurrence of fungal infection and the visual acuity ranged from counting fingers (FC) from 50 cm to 6/36. Complications in some patients included graft rejection in one patient with re-graft which remained clear during follow-up period of 6 months, another patient had a minimal partial graft rejection and incipient cataract which didn't necessitate further intervention. PKP is an effective treatment for fungal keratitis that does not respond to antifungal medication. Early surgical intervention before deterioration is recommended.


Mutation in MRPS34 compromises protein synthesis and causes mitochondrial dysfunction.
The evolutionary divergence of mitochondrial ribosomes from their bacterial and cytoplasmic ancestors has resulted in reduced RNA content and the acquisition of mitochondria-specific proteins. The mitochondrial ribosomal protein of the small subunit 34 (MRPS34) is a mitochondria-specific ribosomal protein found only in chordates, whose function we investigated in mice carrying a homozygous mutation in the nuclear gene encoding this protein. The Mrps34 mutation causes a significant decrease of this protein, which we show is required for the stability of the 12S rRNA, the small ribosomal subunit and actively translating ribosomes. The synthesis of all 13 mitochondrially-encoded polypeptides is compromised in the mutant mice, resulting in reduced levels of mitochondrial proteins and complexes, which leads to decreased oxygen consumption and respiratory complex activity. The Mrps34 mutation causes tissue-specific molecular changes that result in heterogeneous pathology involving alterations in fractional shortening of the heart and pronounced liver dysfunction that is exacerbated with age. The defects in mitochondrial protein synthesis in the mutant mice are caused by destabilization of the small ribosomal subunit that affects the stability of the mitochondrial ribosome with age.


The indirect costs of back problems (dorsopathies) in Australians aged 45 to 64 years from 2015 to 2030: results from a microsimulation model, Health&WealthMOD2030.
This study projected the indirect costs of back problems through lost productive life years (PLYs) from the individual's perspective (lost disposable income), the governmental perspective (reduced taxation revenue, greater welfare spending), and the societal perspective (lost gross domestic product, GDP) from 2015 to 2030, using Health&WealthMOD2030-Australia's first microsimulation model on the long-term impacts of ill-health. Quantile regression analysis was used to examine differences in median weekly income, welfare payments, and taxes of people unable to work due to back problems with working full-time without back problems as comparator. National costs and lost GDP resulting from missing workers due to back problems were also projected. We projected that 90,000 people have lost PLYs due to back problems in 2015, increasing to 104,600 in 2030 (16.2% increase). People with lost PLYs due to back problems are projected to receive AU$340.91 less in total income and AU$339.77 more in welfare payments per week than full-time workers without back problems in 2030 and pay no income tax on average. National costs consisted of a loss of AU$2931 million in annual income in 2015, increasing to AU$4660 million in 2030 (60% increase). For government, extra annual welfare payments are projected to increase from AU$1462 million in 2015 to AU$1709 million in 2030 (16.9% increase), and lost annual taxation revenue to increase from AU$671 million in 2015 to $961 million in 2030 (43.2% increase). We projected losses in GDP of AU$10,543 million in 2015, increasing to AU$14,522 million in 2030 due to back problems.


Who is the Treatment-Seeking Young Adult with Severe Obesity: A Comprehensive Characterization with Emphasis on Mental Health.
To characterize treatment-seeking young adults (16-25 years) with severe obesity, particularly mental health problems. Cross-sectional study of 165 participants (132 women, 33 men) with BMI ≥35 kg/m2 or ≥30 kg/m2 with comorbidities, enrolling in a multidisciplinary obesity treatment program. Data collection at admission of present and life-time health issues including symptomatology of anxiety, depression (Hospital Anxiety and Depression Scale) and attention-deficit/hyperactivity disorder (Adult ADHD Self-Report scale); self-esteem (Rosenberg Self-Esteem Scale), suicide attempts, health-related quality of life (Short Form-36 Health Survey), psychosocial functioning related to obesity (Obesity-related Problems Scale), cardiorespiratory fitness (Astrand's bicycle ergometer test), somatic and psychiatric co-morbidities, cardiometabolic risk factors, and micronutritional status. We used multiple regression analysis to identify variables independently associated with present anxiety and depressive symptomatology. Mean body mass index was 39.2 kg/m2 (SD = 5.2). We found evidence of poor mental health, including present psychiatric diagnoses (29%), symptomatology of anxiety (47%), depression (27%) and attention-deficit/hyperactivity disorder (37%); low self-esteem (42%), attempted suicide (12%), and low quality of life (physical component score = 46, SD = 11.2; mental component score = 36, SD = 13.9, P<0.001 for difference). Variables independently associated with present anxiety symptomatology (R2 = 0.33, P<0.001) included low self-esteem (P<0.001) and pain (P = 0.003), whereas present depressive symptomatology (R2 = 0.38, P<0.001) was independently associated with low self-esteem (P<0.001), low cardiorespiratory fitness (P = 0.009) and obesity-related problems (P = 0.018). The prevalence of type 2 diabetes was 3%, and hypertension 2%. Insulin resistance was present in 82%, lipid abnormality in 62%, and poor cardiorespiratory fitness in 92%. Forty-eight percent had at least one micronutritional deficiency, vitamin D being the most common (35%). A wide range of health issues, including quite severe mental health problems, was prevalent in treatment-seeking young adults with severe obesity. These are likely to constitute a major treatment challenge, including options relating to bariatric surgery.


Alloreactive cytolytic T cell clones with dual recognition of HLA-B27 and HLA-DR2 antigens. Selective involvement of CD8 in their class I--directed cytotoxicity.
HLA-B27- responder cells were stimulated in vitro with HLA-B27.1+ lymphoblastoid cell lines, and alloreactive CTL clones were obtained by limiting dilution. Three of these clones specifically lysed B27.1+ targets. In addition, they also lysed homozygous DR2 targets with various degrees of efficiency, depending on the Dw specificity of the target cell. All three clones possessed a homogeneous CD3+,CD8+,CD4- phenotype and were also homogeneous upon subcloning. Cold-target inhibition analyses showed mutual inhibition of B27.1 target lysis by DR2 targets and vice versa. Lysis of B27.1 targets was selectively inhibited by anti-class I mAbs. In contrast, lysis of DR2 targets was inhibited only by anti-class II and anti-DR monomorphic antibodies, but not by anti-class I, anti-DQw1, or anti-DP antibodies. The results indicate that these clones display dual recognition for HLA-B27.1 and for HLA-DR2 and suggest that HLA-B27.1 may share at least one epitope that is closely related to some stimulatory Dw determinants present on the HLA-DR2 antigens. Lysis of both B27+ and DR+ targets was inhibited by an anti-CD3 mAb. In contrast, an anti-CD8 antibody selectively inhibited the B27- but not the DR2-directed killing by these clones. The data support a stabilizing role of CD8 through its binding to the same class I (but not class II) molecule on the target cell bound by the T cell antigen receptor.


Simplifying the lithium-marker technique used to assess the dietary intake of discretionary sodium in population studies.
1. Lithium has been used by Sanchez-Castillo et al. (Clin. Sci. 1987; 72, 81-6) for tracking sodium in order to monitor the domestic use of salt. The present study was designed to simplify the original protocol, which is too cumbersome for epidemiological studies. 2. A preliminary study conducted on nine volunteers showed that sharp modifications of lithium intake are detected within 24 h in urinary excretion. The average intake over a 5-day period could be predicted by the mean excretion of the last 3 days. Lithium recovery established from 1 baseline day and 3 plateau days was 95 +/- 6% (mean +/- SD), not significantly different from the recovery obtained by the integrated excretion curve over 12 days. 3. A simplified protocol was therefore developed, reducing to 4 the 12 days of urine collection originally required. 4. This simplified protocol was tested on five households (14 adults and five children). All domestic salt was substituted with lithium-tagged salt. Urine samples were collected on 1 baseline day and on 3 plateau days. The lithium/sodium ratio of all urine collections (both complete and incomplete) could be used to estimate the proportion of discretionary sodium. In our sample it was about 29% of total sodium intake. 5. The simplified protocol can thus be proposed for population studies.


Identification of divergent WH2 motifs by HMM-HMM alignments.
The actin cytoskeleton is a hallmark of eukaryotic cells. Its regulation as well as its interaction with other proteins is carefully orchestrated by actin interaction domains. One of the key players is the WH2 motif, which enables binding to actin monomers and filaments and is involved in the regulation of actin nucleation. Contrasting conserved domains, the identification of this motif in protein sequences is challenging, as it is short and poorly conserved. To identify divergent members, we combined Hidden-Markov-Model (HMM) to HMM alignments with orthology predictions. Thereby, we identified nearly 500 proteins containing so far not annotated WH2 motifs. This included shootin-1, an actin binding protein involved in neuron polarization. Among others, WH2 motifs of 'proximal to raf' (ptr)-orthologs, which are described in the literature, but not annotated in genome databases, were identified. In summary, we increased the number of WH2 motif containing proteins substantially. This identification of candidate regions for actin interaction could steer their experimental characterization. Furthermore, the approach outlined here can easily be adapted to the identification of divergent members of further domain families.


Dose to 'water-like' media or dose to tissue in MV photons radiotherapy treatment planning: still a matter of debate.
The difference between Monte Carlo Treatment Planning (MCTP) based on the assumption of 'water-like' tissues with densities obtained from CT procedures, or on tissue compositions derived from CT-determined densities, have been investigated. Stopping powers and electron fluences have been calculated for a range of media and body tissues for 6 MV photon beams, including changes in their physical data (density and stopping powers). These quantities have been used to determine absorbed doses using cavity theory. It is emphasized that tissue compositions given in ICRU or ICRP reports should not be given the standing of physical constants as they correspond to average values obtained for a limited number of human-body samples. It has been shown that mass stopping-power ratios to water are more dependent on patient-to-patient composition differences, and therefore on their mean excitation energies (I-values), than on mass density. Electron fluence in different media are also more dependent on media composition (and their I-values) than on density. However, as a consequence of the balance between fluence and stopping powers, doses calculated from their product are more constant than what the independent stopping powers and fluence variations suggest. Additionally, cancelations in dose ratios minimize the differences between the 'water-like' and 'tissue' approaches, yielding practically identical results except for bone, and to a lesser extent for adipose tissue. A priori, changing from one approach to another does not seem to be justified considering the large number of approximations and uncertainties involved throughout the treatment planning tissue segmentation and dose calculation procedures. The key issue continues to be the composition of tissues and their I-values, and as these cannot be obtained for individual patients, whatever approach is selected does not lead to significant differences from a water reference dose, the maximum of these being of the order of 5% for bone tissues. Considering, however, current developments in advanced dose calculation methods, planning in terms of dose-to-tissue should be the preferred choice, under the expectancy that progress in the field will gradually improve some of the crude approximations included in MCTP and numerical transport methods. The small differences obtained also show that a retrospective conversion from dose-to-tissue to dose-to-water, based on a widely used approach, would mostly increase the final uncertainty of the treatment planning process. It is demonstrated that, due to the difference between electron fluence distributions in water and in body tissues, the conversion requires an additional fluence correction that has so far been neglected. An improved expression for the conversion and data for the fluence correction factor are provided. These will be necessary even in a dose-to-tissue environment, for the normalization of the treatment plan to the reference dosimetry of the treatment unit, always calibrated in terms of absorbed dose to water.


The Role of Periodontitis and Periodontal Bacteria in the Onset and Progression of Alzheimer's Disease: A Systematic Review.
The evidence of a connection between the peripheral inflammatory processes and neurodegenerative diseases of the central nervous system is becoming more apparent. This review of the related literature highlights the most recent clinical, epidemiological, and in vitro studies trying to investigate possible connections between periodontal bacteria and the onset and progression of Alzheimer's disease. This review was conducted by searching databases such as PubMed and Scopus using keywords or combinations such as Alzheimer's Disease AND periodontal or dementia AND periodontitis OR periodontal. After eliminating overlaps and screening the articles not related to these issues, we identified 1088 records and proceeded to the selection of articles for an evaluation of the associative assumptions. The hypothesis suggested by the authors and confirmed by the literature is that the bacterial load and the inflammatory process linked to periodontal disease can intensify inflammation at the level of the central nervous system, favoring the occurrence of the disease. The analysis of the literature highlights how periodontal disease can directly contribute to the peripheral inflammatory environment by the introduction of periodontal or indirect pathogenic bacteria and proinflammatory cytokines locally produced at the periodontal level following bacterial colonization of periodontal defects.


A non-selective (amitriptyline), but not a selective (citalopram), serotonin reuptake inhibitor is effective in the prophylactic treatment of chronic tension-type headache.
Although the tricyclic antidepressant amitriptyline is extensively used in the prophylactic treatment of chronic tension-type headache, only few studies have investigated the efficacy of this treatment and the results are contradictory. In addition, the new selective serotonin reuptake inhibiting antidepressants, which are widely used in depression and of potential value in pain management, have never been investigated in a placebo controlled study of tension-type headache. The aim was to evaluate the efficacy of amitriptyline and of the selective serotonin reuptake inhibitor citalopram in chronic tension-type headache. Forty non-depressed patients with chronic tension type headache were included in a 32 week, double blind, placebo controlled, three-way crossover study. Thirty four patients completed the trial. Amitriptyline reduced area under the headache curve by 30% compared with placebo (P = 0.002), whereas citalopram had no significant effect (P = 0.68). Explanatory analyses showed that amitriptyline significantly reduced the duration of headache (P = 0.01), headache frequency (P = 0.01), and intake of analgesics (P = 0.02) but not headache intensity (P = 0.12). Although amitriptyline did not eliminate the headache, it provided a clinically important reduction of headache in the majority of otherwise treatment resistant patients. The differential effect of amitriptyline and citalopram indicates that mechanisms other than inhibition of serotonin reuptake are involved in the analgesic effect of the tricyclic antidepressants. Amitriptyline, but not citalopram, is valuable in the prophylactic treatment of chronic tension type headache.


Multiple P450s and Variation in Neuronal Genes Underpins the Response to the Insecticide Imidacloprid in a Population of Drosophila melanogaster.
Insecticide resistance is an economically important example of evolution in response to intense selection pressure. Here, the genetics of resistance to the neonicotinoid insecticide imidacloprid is explored using the Drosophila Genetic Reference Panel, a collection of inbred Drosophila melanogaster genotypes derived from a single population in North Carolina. Imidacloprid resistance varied substantially among genotypes, and more resistant genotypes tended to show increased capacity to metabolize and excrete imidacloprid. Variation in resistance level was then associated with genomic and transcriptomic variation, implicating several candidate genes involved in central nervous system function and the cytochrome P450s Cyp6g1 and Cyp6g2. CRISPR-Cas9 mediated removal of Cyp6g1 suggested that it contributed to imidacloprid resistance only in backgrounds where it was already highly expressed. Cyp6g2, previously implicated in juvenile hormone synthesis via expression in the ring gland, was shown to be expressed in metabolically relevant tissues of resistant genotypes. Cyp6g2 overexpression was shown to both metabolize imidacloprid and confer resistance. These data collectively suggest that imidacloprid resistance is influenced by a variety of previously known and unknown genetic factors.


NK cell activation in human hantavirus infection explained by virus-induced IL-15/IL15Rα expression.
Clinical infection with hantaviruses cause two severe acute diseases, hemorrhagic fever with renal syndrome (HFRS) and hantavirus pulmonary syndrome (HPS). These diseases are characterized by strong immune activation, increased vascular permeability, and up to 50% case-fatality rates. One prominent feature observed in clinical hantavirus infection is rapid expansion of natural killer (NK) cells in peripheral blood of affected individuals. We here describe an unusually high state of activation of such expanding NK cells in the acute phase of clinical Puumala hantavirus infection. Expanding NK cells expressed markedly increased levels of activating NK cell receptors and cytotoxic effector molecules. In search for possible mechanisms behind this NK cell activation, we observed virus-induced IL-15 and IL-15Rα on infected endothelial and epithelial cells. Hantavirus-infected cells were shown to strongly activate NK cells in a cell-cell contact-dependent way, and this response was blocked with anti-IL-15 antibodies. Surprisingly, the strength of the IL-15-dependent NK cell response was such that it led to killing of uninfected endothelial cells despite expression of normal levels of HLA class I. In contrast, hantavirus-infected cells were resistant to NK cell lysis, due to a combination of virus-induced increase in HLA class I expression levels and hantavirus-mediated inhibition of apoptosis induction. In summary, we here describe a possible mechanism explaining the massive NK cell activation and proliferation observed in HFRS patients caused by Puumala hantavirus infection. The results add further insights into mechanisms behind the immunopathogenesis of hantavirus infections in humans and identify new possible targets for intervention.


Prostate-specific antigen density predicts favorable pathology and biochemical recurrence in patients with intermediate-risk prostate cancer.
This study was designed to identify clinical predictors of favorable pathology and biochemical recurrence (BCR) in patients with intermediate-risk prostate cancer (IRPCa). Between 2006 and 2012, clinicopathological and oncological data from 203 consecutive men undergoing robot-assisted radical prostatectomy (RARP) for IRPCa were reviewed in a single-institutional retrospective study. Favorable pathology was defined as Gleason score ≤6 and organ-confined cancer as detected by surgical pathology. Logistic regression analysis was used to determine predictive variables of favorable pathology, and the Kaplan-Meier and multivariate Cox regression model were used to estimate BCR-free survival after RARP. Overall, 38 patients (18.7%) had favorable pathology after RARP. Lower quartile prostate-specific antigen density (PSAD) was associated with favorable pathology compared to the highest quartile PSAD after adjusting for preoperative PSA, clinical stage and biopsy Gleason score (odds ratio, 5.42; 95% confidence interval, 1.01-28.97; P = 0.048). During a median 37.8 (interquartile range, 24.6-60.2) months of follow-up, 66 patients experienced BCR. There were significant differences with regard to BCR free survival by PSAD quartiles (log rank, P = 0.003). Using a multivariable Cox proportion hazard model, PSAD was found to be an independent predictor of BCR in patients with IRPCa after RARP (hazard ratio, 4.641; 95% confidence interval, 1.109-19.417; P = 0.036). The incorporation of the PSAD into risk assessments might provide additional prognostic information and identify some patients in whom active surveillance would be appropriate in patients with IRPCa.


An analysis of alternatively spliced CD45 mRNA transcripts during T cell maturation in humans.
CD45 is a transmembrane protein tyrosine phosphatase found on nucleated hematopoietic cells. In humans, multiple protein isoforms of CD45 are produced by alternative mRNA splicing of exons 4, 5, and 6 coding for the extracellular portion. We measured all eight possible CD45 mRNA transcripts using RT-PCR in human thymocytes and T cell lines. We report that only six mRNA transcripts are present in T cells. The high mw CD45 mRNA transcripts containing exon 4 correlated with the stage of T cell maturation: abundant high mw transcripts (30.7% of all CD45 mRNA transcripts) were present in immature, CD3-4-8 triple-negative thymocytes which decreased (7.7%) in intermediate, CD4+8+ double-positive (DP) thymocytes and then increased (13.8% or 16.8%) in mature, CD4+8- or CD4-8+ single-positive thymocytes. In addition, there was a complex variation in the spliced mRNA transcripts coding for CD45R(O), CD45R(B), CD45R(BC), CD45R(AB), and CD45R(ABC) protein isoforms. High mw CD45 mRNA transcripts accumulated immediately prior to an important physiologic event such as thymocyte expansion. In addition, we identified linkage between RNA splicing of exons 5 and 6, and splicing of exon 5 only and exons 4, 5, and 6 in FACS-purified CD4+ and CD8+ thymocytes. These data support the developmental regulation of alternatively spliced CD45 mRNA transcripts and suggest that specific CD45 isoforms may play an important role at critical stages of T cell development.


Model evaluation of potential impacts of on-site wastewater systems on phosphorus in Turkey creek watershed.
Nutrient loading to surface water systems has traditionally been associated with agricultural sources. Sources such as on-site wastewater systems (OWS) may be of concern especially in rural, nonagricultural watersheds. The impact of various point and nonpoint sources including OWS in Turkey Creek Watershed was evaluated using the Watershed Analysis Risk Management Framework, which was calibrated using 10 yr of observed stream flow and total P concentrations. Doubling the population in the watershed or OWS septic tank effluent P concentration increased mean stream total P concentration by a factor of 1.05. Converting all the OWS to a conventional sewer system with a removal efficiency of 93% at the wastewater treatment plant increased the mean total P concentration at the watershed outlet by a factor of 1.26. Reducing the soil adsorption capacity by 50% increased the mean stream total P concentration by a factor of 3.2. Doubling the initial P concentration increased the mean stream total P concentration by a factor of 1.96. Stream flow and sediment transport also substantially affected stream P concentration. The results suggest that OWS contribution to stream P in this watershed is minimal compared with other factors within the simulated time frame of 10 yr.


Immunoblot analysis of human IgM, IgG and IgA responses to plasmid-encoded antigens of Yersinia enterocolitica serovar O3.
Human IgM, IgG and IgA responses after infection with Yersinia enterocolitica serovar O3 were studied by immunoblotting sera against whole-cell homogenates of a plasmid-containing strain of Y. enterocolitica O3 and a plasmid-free strain derived from it; each strain was grown in conditions expressive for the plasmid. The antibodies observed were directed against several plasmid-encoded polypeptides. The response against different bacterial components decreased uniformly with time and the persisting antibody production was directed against several epitopes. Strong reactions to the prominent plasmid-specified antigens of mol. wts (10(3] 26, 34, 45 and 52.5 were found more often with IgG-class antibodies than with IgM or IgA; the latter immunoglobulins recognised, respectively, antigens of mol. wt (10(3] 26 and 45 (IgM) and 26, 34 and 52.5 (IgA). Immunoblotting of sera from patients with yersinia-triggered reactive arthritis did not reveal any antigens that were involved additionally or specifically. However, IgA-mediated recognition of certain antigens of mol. wts (10(3] 26, 34 and 52.5 tended to persist longer in the arthritic patients.


Identification of new Guama and Group C serogroup bunyaviruses and an ungrouped virus from Southern Brazil.
From 1975 to 1978, 36 viruses were recovered from humans, bats, birds, sentinel mice and hamsters, and from mosquitoes collected in Coastal Brazil in the state of São Paulo. Identifications of 22 of these 36 viruses have been reported. Six of the remaining 14 isolates were shown to be Guama serogroup bunyaviruses. Two of these six were strains of a newly recognized virus for which the name Cananeia virus is proposed; another is a second newly recognized Guama serogroup virus for which the name Itimirim virus is proposed; a fourth is a strain of Bertioga virus and the other two are strains of Guaratuba virus. Before these studies Guaratuba virus was considered an ungrouped bunyavirus, but cross testing by complement-fixation demonstrated that this virus, and Mirim virus as well, should be considered members of the Guama serogroup. Another six viruses were shown to be strains of a single, newly recognized Group C bunyavirus for which the name Bruconha virus is proposed. Two strains of a single virus were shown by electron microscopy to belong to the family Bunyaviridae, but serologic relationships with other members of this family of viruses were not found; the name Enseada virus is proposed for this newly recognized agent.


Using a statistical natural language Parser augmented with the UMLS specialist lexicon to assign SNOMED CT codes to anatomic sites and pathologic diagnoses in full text pathology reports.
To address the problem of extracting structured information from pathology reports for research purposes in the STRIDE Clinical Data Warehouse, we adapted the ChartIndex Medical Language Processing system to automatically identify and map anatomic and diagnostic noun phrases found in full-text pathology reports to SNOMED CT concept descriptors. An evaluation of the system's performance showed a positive predictive value for anatomic concepts of 92.3% and positive predictive value for diagnostic concepts of 84.4%. The experiment also suggested strategies for improving ChartIndex's performance coding pathology reports.


Visualization of Peripheral Neuron Sensitization in a Surgical Mouse Model of Osteoarthritis by In Vivo Calcium Imaging.
To develop a method for analyzing sensory neuron responses to mechanical stimuli in vivo, and to evaluate whether these neuronal responses change after destabilization of the medial meniscus (DMM). DMM or sham surgery was performed in 10-week-old male C57BL/6 wild-type or Pirt-GCaMP3+/- mice. All experiments were performed 8 weeks after surgery. Knee and hind paw hyperalgesia were assessed in wild-type mice. The retrograde label DiI was injected into the ipsilateral knee to quantify the number of knee-innervating neurons in the L4 dorsal root ganglion (DRG) in wild-type mice. In vivo calcium imaging was performed on the ipsilateral L4 DRG of Pirt-GCaMP3+/- mice as mechanical stimuli (paw pinch, knee pinch, or knee twist) were applied to the ipsilateral hind limb. Eight weeks after surgery, mice subjected to DMM had more hyperalgesia in the knee and hind paw compared to mice subjected to sham surgery. Intraarticular injection of DiI labeled similar numbers of neurons in the L4 DRG of mice subjected to sham surgery and mice subjected to DMM. Increased numbers of sensory neurons responded to all 3 mechanical stimuli in mice subjected to DMM, as assessed by in vivo calcium imaging. The majority of responses in mice subjected to sham surgery and mice subjected to DMM were in small to medium-sized neurons, consistent with the size of nociceptors. The magnitude of responses was similar between mice subjected to sham surgery and mice subjected to DMM. Our findings indicate that increased numbers of small to medium-sized DRG neurons respond to mechanical stimuli 8 weeks after DMM surgery, suggesting that nociceptors have become sensitized by lowering the response threshold.


[Italian Registry Dialysis and Transplant 2011-2013].
The Italian Registry of Dialysis and Transplantation (RIDT) has recently resumed the collection of data of patients on RRT in Italy. Data were requested to Regional Registries for the years 2011-2013 and they contributed according to their possibilities. Eighteen Regions or autonomous Provinces provided data with various degrees of completeness and this made possible to bridge the gap between the current and the previous census (referring to 2010). Incidencedata were associated to a sample with a coverage of 77% of the national population (46/60 million inhabitants). Patients who started dialysis in these three years were, respectively, 168, 166 and 160 patients pmp. If we project this data to the national population is reasonable to think that 9500-10000 patients per year start the dialytic treatment. The prevalence of patients on dialysis in Italy range, in the 10 years of RIDT, between 750 and 825 patients pmp. Based on this we can reasonably estimate that in Italy there are 45-49000 dialysis patients. Incidence and prevalence vary widely in different regions. Mortalityon dialysis in Italy during the period 2011-2013 was on average 16.2 per 100 patient-years (95% CI: 16.1-16.7) with regional variation smaller than that observed in incidence and prevalence. In this paper, data analysis are presented in a direct and non comparative manner. However, it provides information on the status of the RRT in Italy and the temporal consistency of the data is a proof of their validity. Registry data were published in the official site of Italian Registry that can be reached through the website of SIN (www.sin-italy.org).


Sleep-wake disturbances 3 years after traumatic brain injury.
6 months after traumatic brain injury (TBI), almost three out of four patients suffer from sleep-wake disturbances (SWD) such as post-traumatic hypersomnia (increased sleep need of ≥2 h compared with before injury), excessive daytime sleepiness (EDS), fatigue and insomnia. The long-term course of post-traumatic SWD, however, is unknown. To assess the prevalence and characteristics of post-traumatic SWD 3 years after trauma. Prospective longitudinal clinical study in 51 consecutive TBI patients (43 males, eight females, mean age 40±16 years). EDS (as assessed by the Epworth sleepiness scale), fatigue (fatigue severity scale), post-traumatic hypersomnia (sleep length per 24 h), insomnia, depression and anxiety. Post-traumatic SWD were found in 34 patients (67%): post-traumatic hypersomnia in 14 (27%), EDS in six (12%), fatigue in 18 patients (35%) and insomnia in five patients (10%). SWD were not associated with severity or localisation of, or time interval since, TBI. Insomnia was linked to depressive symptoms. This prospective study shows that 3 years after TBI, two out of three patients suffer from residual SWD, particularly fatigue and post-traumatic hypersomnia. In 45% of TBI patients, SWD appear directly related to the trauma itself.


Effectiveness of Foot Orthoses Versus Corticosteroid Injection for Plantar Heel Pain: The SOOTHE Randomized Clinical Trial.
Plantar heel pain is a common foot complaint that causes significant disability and poorer health-related quality of life. Foot orthoses and corticosteroid injection are effective treatments for plantar heel pain; however, it is unclear whether one is more effective than the other. The aim of this trial was to compare the effectiveness of foot orthoses and corticosteroid injection for plantar heel pain. In this parallel-group, assessor-blinded, randomized clinical trial, participants received prefabricated, arch-contouring foot orthoses or a single ultrasound-guided corticosteroid injection. The primary outcome measure was the foot pain subscale of the Foot Health Status Questionnaire at 4 and 12 weeks. One hundred three participants aged 21 to 72 years (63 female) with plantar heel pain were recruited from the community and received an intervention. For the primary outcome of foot pain, corticosteroid injection was more effective at week 4 (adjusted mean difference, 8.2 points; 95% confidence interval: 0.6, 15.8 points). However, foot orthoses were more effective at week 12 (adjusted mean difference, 8.5 points; 95% confidence interval: 0.2, 16.8 points). Although these findings were statistically significant, the differences between the interventions did not meet the previously calculated minimal important difference value of 12.5 points. Corticosteroid injection is more effective than foot orthoses at week 4, but this effect does not last; and appropriately contoured foot orthoses are more effective than corticosteroid injection at week 12. However, patients may not notice a clinically worthwhile difference between the interventions. Therapy, level 1b. J Orthop Sports Phys Ther 2019;49(7):491-500. Epub 26 May 2019. doi:10.2519/jospt.2019.8807.


Risk factors for cervical intraepithelial neoplasm in Alaska Native women: a pilot study.
Although rates for invasive cervical cancer have declined over the past twenty years among Alaska Native women, they continue to show high rates of pre-invasive cervical lesions (cervical intraepithelial neoplasia, or CIN). We investigated risk factors for CIN II/III among Alaska Native women in a pilot case-control study. Cases (n = 26) included women with biopsy-proven CIN II/III, while controls (n = 52) had normal cervical epithelium. The strongest risks associated with CIN II/III were HPV infection of any type (Crude Odds Ratio [OR] 8.4, 95% Confidence Interval [CI]: 2.9-29.4), HPV 16 infection (OR 40.8, 95% CI: 9.4-176.4), and a family history of cervical dysplasia (OR 3.9, 95% CI: 1.3-11.3). We also found that use of depot-medroxy progesterone acetate was associated with CIN (OR 3.0, 95% CI: 1.1-8.5). A larger investigation would be necessary to allow adequate evaluation of these, and other, risk factors for CIN among Alaska Native women.


Drawing-Based Procedural Modeling of Chinese Architectures.
This paper presents a novel modeling framework to build 3D models of Chinese architectures from elevation drawing. Our algorithm integrates the capability of automatic drawing recognition with powerful procedural modeling to extract production rules from elevation drawing. First, different from the previous symbol-based floor plan recognition, based on the novel concept of repetitive pattern trees, small horizontal repetitive regions of the elevation drawing are clustered in a bottom-up manner to form architectural components with maximum repetition, which collectively serve as building blocks for 3D model generation. Second, to discover the global architectural structure and its components' interdependencies, the components are structured into a shape tree in a top-down subdivision manner and recognized hierarchically at each level of the shape tree based on Markov Random Fields (MRFs). Third, shape grammar rules can be derived to construct 3D semantic model and its possible variations with the help of a 3D component repository. The salient contribution lies in the novel integration of procedural modeling with elevation drawing, with a unique application to Chinese architectures.


Stereotactic body radiation therapy for prostate cancer: systematic review and meta-analysis of prospective trials.
Background: Despite the increasing worldwide utilization of stereotactic body radiation therapy (SBRT) for prostate cancer, there are no known summative data regarding its safety and efficacy. To address this knowledge gap, we conducted a PRISMA-guided systematic review and meta-analysis of prospective prostate SBRT trials. Results: Fourteen trials with a total of 2,038 patients were included. Median follow-up was 37 months (range 6-55 months). Most patients had cT1-T2a, Gleason ≤7 disease with median pre-treatment PSAs of 5-10; 1,042 (51%) were low-risk, 744 (37%) were intermediate-risk, 158 (8%) were high-risk, and the remainder were unreported. Doses ranged from 33.5-50.0 Gy, most typically in 5 fractions, with nearly all studies delivering nondaily fractionation with some type of daily image guidance. Outcomes were converted into counts at the end of one year. The pooled rate of FFBF was 98% [95% confidence interval, 97-98%]. The pooled rate of late grade ≥3 gastrointestinal and genitourinary toxicities were 1% [0-5%] and 2% [1-3%], respectively. Methods: PubMed and Google Scholar were queried for prospective studies evaluating survival and/or toxicity outcomes in SBRT (≤5 fractions) for localized prostate cancer. Pooled rates of freedom from biochemical failure (FFBF) and late grades ≥3 gastrointestinal (GI) and genitourinary (GU) toxicities were assessed. Meta-analysis of proportions was logit transformed and pooled using generalized linear mixed models (both fixed and random effects) and subsequently back transformed to standard proportions. Conclusions: Despite the lack of long-term follow-up and heterogeneity of the available evidence, prostate SBRT affords appropriate biochemical control with few high-grade toxicities. These data have implications for ongoing worldwide utilization of prostate SBRT as well as ongoing prospective investigations.


Adaptive, convergent origins of the pygmy phenotype in African rainforest hunter-gatherers.
The evolutionary history of the human pygmy phenotype (small body size), a characteristic of African and Southeast Asian rainforest hunter-gatherers, is largely unknown. Here we use a genome-wide admixture mapping analysis to identify 16 genomic regions that are significantly associated with the pygmy phenotype in the Batwa, a rainforest hunter-gatherer population from Uganda (east central Africa). The identified genomic regions have multiple attributes that provide supporting evidence of genuine association with the pygmy phenotype, including enrichments for SNPs previously associated with stature variation in Europeans and for genes with growth hormone receptor and regulation functions. To test adaptive evolutionary hypotheses, we computed the haplotype-based integrated haplotype score (iHS) statistic and the level of population differentiation (FST) between the Batwa and their agricultural neighbors, the Bakiga, for each genomic SNP. Both |iHS| and FST values were significantly higher for SNPs within the Batwa pygmy phenotype-associated regions than the remainder of the genome, a signature of polygenic adaptation. In contrast, when we expanded our analysis to include Baka rainforest hunter-gatherers from Cameroon and Gabon (west central Africa) and Nzebi and Nzime neighboring agriculturalists, we did not observe elevated |iHS| or FST values in these genomic regions. Together, these results suggest adaptive and at least partially convergent origins of the pygmy phenotype even within Africa, supporting the hypothesis that small body size confers a selective advantage for tropical rainforest hunter-gatherers but raising questions about the antiquity of this behavior.


The global epidemic of HIV infection among men who have sex with men.
In the last few years, there have been reports of new, newly identified and resurging epidemics of HIV infection among men who have sex with men (MSM). This article reviews and summarizes the global epidemic of HIV infection among MSM. In the Western world, the increase in notifications of new HIV infections among MSM is continuing. Steep increases in reports of new HIV diagnoses among MSM were also seen in the developed economies of East Asia. In the developing world, epidemiologic studies have now established the presence of MSM populations in Africa, China and Russia and a high HIV prevalence among them. High and increasing HIV prevalence was also reported from South and Southeast Asia, and Latin America and the Caribbean. HIV continues to spread among MSM on a global level. Current prevention efforts have been unable to contain or reduce HIV transmission in this population. Additional behavioral and biomedical interventions are urgently needed.


Binding of Ku protein to DNA. Measurement of affinity for ends and demonstration of binding to nicks.
Ku, also known as nuclear Factor IV, is an abundant nuclear DNA-binding protein which requires free DNA ends for the initial interaction with double-stranded DNA (dsDNA) and can bind at multiple sites along dsDNA in an energy-independent manner. Its function in vivo is unknown, but it has been implicated in both DNA replication and repair and in transcriptional control. We have used an electrophoretic mobility shift assay to further define the DNA binding properties of the Ku protein. Titration of Ku to a fixed amount of any of several target linear dsDNA fragments produced ladders of shifted bands proportional to the length of DNA, confirming the multiple binding activity of Ku and demonstrating its sequence-independent nature. Using a short DNA fragment with one Ku binding site, the binding constant of Ku for dsDNA ends was calculated to be 2.4 x 10(9) M-1. Competitive inhibition experiments confirmed the requirement of a free DNA end for binding by Ku and demonstrated that Ku binds isolated nicks in dsDNA. Nick binding was also observed directly using radiolabeled singly nicked circular DNA. The relative affinities of Ku for specific nick sites and free DNA ends were approximately equal, and nick binding was sequence-independent. Finally, in a study of a possible role for Ku in protecting or repairing damaged DNA, Ku was shown to inhibit the ability of T4 DNA ligase to circularize linear dsDNA molecules, demonstrating that some Ku molecules remain at the DNA terminus rather than translocate. A similar inhibition was not observed at nicks. These experiments document a new DNA binding specificity for Ku and further suggest that the high affinity end and nick binding activity is biologically relevant to its functions in vivo.


Feasibility of 2 × 24-h dietary recalls combined with a food-recording booklet, using EPIC-Soft, among schoolchildren.
The aim of this study was to evaluate the feasibility of the suggested trans-European methodology for undertaking representative dietary surveys among schoolchildren: 2 × 24-h dietary recalls (24-HDRs) combined with a food-recording booklet, using EPIC-Soft (the software developed to conduct 24-HDRs in the European Prospective Investigation into Cancer and Nutrition (EPIC) Study) pc-program. A total of 75 children aged 7-8 years and 70 children aged 12-13 years old were recruited through the Civil Registration System in Denmark, and 57 children aged 7-8 years and 47 children aged 12-13 years were recruited through schools in Spain. Each child with one parent completed two face-to-face 24-HDRs, combined with optional use of a food-recording booklet (FRB) to be filled in by the child, a parent or other proxy persons for preparing the recalls. Feasibility was evaluated by questionnaires completed by parents, children and interviewers, and by selected data from the 24-HDRs. The face-to-face interviews with the child and a parent together are confirmed as feasible. The children participated actively in the interviews, the oldest children being most active. The children, parents and interviewers agreed that children needed help from the parents, and that parents were of help to the child. In both countries, other proxy persons, such as teachers or the school cafeteria staff, were involved before the interview, and the majority of the parents and children reported that the FRB had been a help for the child during the interview. Further results point at specific needed improvements of the tools. The evaluated method is shown feasible in two culturally diverse European populations. However, the feasibility study also points to specific improvements of tools and data collection protocol that are strongly recommended before implementation of the method in each country of a pan-European dietary survey.


Progenitor cells are mobilized by acute psychological stress but not beta-adrenergic receptor agonist infusion.
Stimuli that activate the sympathetic nervous system, such as acute psychological stress, rapidly invoke a robust mobilization of lymphocytes into the circulation. Experimental animal studies suggest that bone marrow-derived progenitor cells (PCs) also mobilize in response to sympathetic stimulation. Here we tested the effects of acute psychological stress and brief pharmacological β-adrenergic (βAR) stimulation on peripheral PC numbers in humans. In two studies, we investigated PC mobilization in response to an acute speech task (n=26) and βAR-agonist (isoproterenol) infusion (n=20). A subset of 8 participants also underwent the infusion protocol with concomitant administration of the βAR-antagonist propranolol. Flow cytometry was used to enumerate lymphocyte subsets, total progenitor cells, total haematopoietic stem cells (HSC), early HSC (multi-lineage potential), late HSC (lineage committed), and endothelial PCs (EPCs). Both psychological stress and βAR-agonist infusion caused the expected mobilization of total monocytes and lymphocytes and CD8(+) T lymphocytes. Psychological stress also induced a modest, but significant, increase in total PCs, HSCs, and EPC numbers in peripheral blood. However, infusion of a βAR-agonist did not result in a significant change in circulating PCs. PCs are rapidly mobilized by psychological stress via mechanisms independent of βAR-stimulation, although the findings do not exclude βAR-stimulation as a possible cofactor. Considering the clinical and physiological relevance, further research into the mechanisms involved in stress-induced PC mobilization seems warranted.


Changes in network centrality of psychopathology symptoms between the COVID-19 outbreak and after peak.
The current study investigated the mechanism and changes in psychopathology symptoms throughout the COVID-19 outbreak and after peak. Two studies were conducted separately in China during outbreak and the after peak stages, with 2540 participants were recruited from February 6 to 16, 2020, and 2543 participants were recruited from April 25 to May 5, 2020. The network models were created to explore the relationship between psychopathology symptoms both within and across anxiety and depression, with anxiety measured by the Generalized Anxiety Disorder-7 and depression measured by the Patient Health Questionnaire-9. Symptom network analysis was conducted to evaluate network and bridge centrality, and the network properties were compared between the outbreak and after peak. Noticeably, psychomotor symptoms such as impaired motor skills, restlessness, and inability to relax exhibited high centrality during the outbreak, which still relatively high but showed substantial remission during after peak stage (in terms of strength, betweenness, or bridge centrality). Meanwhile, symptoms of irritability (strength, betweenness, or bridge centrality) and loss of energy (bridge centrality) played an important role in the network after the peak of the pandemic. This study provides novel insights into the changes in central features during the different COVID-19 stages and highlights motor-related symptoms as bridge symptoms, which could activate the connection between anxiety and depression. The results revealed that restrictions on movement were associated with worsen in psychomotor symptoms, indicating that future psychological interventions should target motor-related symptoms as priority.


Regulation of the human topoisomerase IIalpha gene promoter in confluence-arrested cells.
Expression of DNA topoisomerase IIalpha mRNA and protein reflects the proliferative state of mammalian cell lines and tissues with high levels in actively cycling cells but marked down-regulation during serum deprivation or cell density-induced growth arrest. Using stably integrated gene fusions comprising the human topoisomerase IIalpha promoter with a growth hormone reporter gene, we have localized elements required for the differential activity of the topoisomerase IIalpha promoter in proliferating and confluence-arrested cells. Deletion analysis localized the region of the promoter that responded to changes in the cellular growth state to between -101 and -144 base pairs. Mutation analysis identified an inverted CCAAT box (ICB) located at -108 to -104 as necessary for promoter down-regulation in confluence-arrested cells, while several other potential cis-acting elements, including four additional ICBs, were shown not to be required. The critical ICB was recognized in vitro by the CCAAT box binding factor, NF-Y, with levels of binding activity higher in extracts from proliferating cells than from confluence-arrested cells. We conclude that the differential regulation of topoisomerase IIalpha gene expression in cycling and confluence-arrested cells is mediated, at least in part, through proliferation-specific binding of factors to an ICB element in the gene promoter.


A randomized comparison of every-2-week darbepoetin alfa and weekly epoetin alfa for the treatment of chemotherapy-induced anemia in patients with breast, lung, or gynecologic cancer.
An important clinical question is the relative efficacy of the most common dosages of darbepoetin alfa (Aranesp; Amgen Inc.; Thousand Oaks, CA) 200 microg every 2 weeks (Q2W) and epoetin alfa (Procrit; Ortho Biotech Products, LP; Raritan, NJ) 40,000 U weekly (QW) for the treatment of chemotherapy-induced anemia. We designed three concurrent randomized, open-label, multicenter, identical trials (with the exception of tumor type criteria of breast, gynecologic, or lung cancer) of darbepoetin alfa and epoetin alfa in patients with chemotherapy-induced anemia to validate the Patient Satisfaction Questionnaire for Anemia (PSQ-An) treatment tool and to compare the efficacies and safety profiles of these two agents. In each trial, patients were randomized 1:1 to receive either darbepoetin alfa at a dose of 200 microg Q2W or epoetin alfa at a dose of 40,000 U QW for up to 16 weeks. The PSQ-An was assessed for validity, feasibility, and reliability. Secondary clinical endpoints were analyzed using the primary analysis set. Both individual trial analyses and a protocol-specified combined analysis of data from all three trials were conducted. Overall, 312 patients (157 darbepoetin alfa; 155 epoetin alfa) were randomized and received study drug. Baseline characteristics were similar in both treatment groups in each trial and overall. The PSQ-An was valid, feasible, and reliable. In general, no difference between treatment groups was observed for hemoglobin- and transfusion-based endpoints in each individual trial or in the combined analysis. From exploratory analyses, achievement and maintenance of a hemoglobin target range (11-13 g/dl) were similar in both groups. No differences in safety were observed. With the PSQ-An, formal comparisons of the impact of anemia therapies on patients and caregivers can be made in future prospective studies. Further, darbepoetin alfa (200 microg Q2W) and epoetin alfa (40,000 U QW) appear to achieve comparable clinical and hematologic outcomes.


IFCC Working Group Recommendations for Assessing Commutability Part 3: Using the Calibration Effectiveness of a Reference Material.
A process is described to assess the commutability of a reference material (RM) intended for use as a calibrator based on its ability to fulfill its intended use in a calibration traceability scheme to produce equivalent clinical sample (CS) results among different measurement procedures (MPs) for the same measurand. Three sources of systematic error are elucidated in the context of creating the calibration model for translating MP signals to measurand amounts: calibration fit, calibrator level trueness, and commutability. An example set of 40 CS results from 7 MPs is used to illustrate estimation of bias and variability for each MP. The candidate RM is then used to recalibrate each MP, and its effectiveness in reducing the systematic error among the MPs within an acceptable level of equivalence based on medical requirements confirms its commutability for those MPs. The RM is declared noncommutable for MPs for which, after recalibration, the CS results do not agree with those from other MPs. When a lack of agreement is found, other potential causes, including lack of calibration fit, should be investigated before concluding the RM is noncommutable. The RM is considered fit for purpose for those MPs where commutability is demonstrated.


Eosinophils and neutrophils in biopsies from the middle ear of atopic children with otitis media with effusion.
The majority of patients with otitis media with effusion (OME) and atopy have been shown to have elevated levels of eosinophil cationic protein (ECP) in their middle ear fluid. The mechanism underlying these elevated levels of ECP is not clear. The purpose of this study was to investigate the feasibility of a quantitative determination of eosinophils and neutrophils in the middle ear lining by specific immunocytochemical markers, in order to study the extent of the involvement of these cells in patients with OME. Bilateral middle ear biopsies from five children with persistent OME and atopy confirmed by in vitro testing were evaluated for the presence of eosinophils and neutrophils with monoclonal antibodies against specific granule proteins. Five subjects who had no signs of effusion or infection but were undergoing routine tympanoplasty for dry perforations served as controls. The biopsies were embedded in a plastic resin to improve the structural preservation of the target cells and to increase the resolution in the light microscope. Dual markers were used to determine which marker was better for eosinophils and neutrophils, respectively. The following markers were used: eosinophil cationic protein (EG2), and eosinophil peroxidase (EPO) for eosinophils and myeloperoxidase (MPO) and human neutrophil lipocalin (HNL) for neutrophils. Antibodies against EPO gave a more localized and intense staining than antibodies against EG2. Antibodies against HNL appear more specific to neutrophils than antibodies against MPO that also recognize monocytes. The number of cells was determined both in the tissue and in the mucus covering the epithelium. Eosinophils and neutrophils were present in the subepithelial connective tissue and in the mucus blanket in the middle ear of patients with OME in significantly higher number than in the control group. In general, there were more inflammatory cells in the mucus than in the tissue itself, but the number of inflammatory cells in the mucus showed a significant positive correlation with the number of inflammatory cells in the tissue. There was a significant positive correlation between the number of neutrophils and the number of eosinophils in the tissue as well as in the mucus, irrespective of which marker was used. The results of this study show the feasibility of using specific antibodies to identify eosinophils and neutrophils in the middle ear. The initial data suggest that atopic children with OME have higher numbers of such cells as compared to non-OME controls.


Why the Tsirelson Bound? Bub's Question and Fuchs' Desideratum.
To answer Wheeler's question "Why the quantum?" via quantum information theory according to Bub, one must explain both why the world is quantum rather than classical and why the world is quantum rather than superquantum, i.e., "Why the Tsirelson bound?" We show that the quantum correlations and quantum states corresponding to the Bell basis states, which uniquely produce the Tsirelson bound for the Clauser-Horne-Shimony-Holt (CHSH) quantity, can be derived from conservation per no preferred reference frame (NPRF). A reference frame in this context is defined by a measurement configuration, just as with the light postulate of special relativity. We therefore argue that the Tsirelson bound is ultimately based on NPRF just as the postulates of special relativity. This constraint-based/principle answer to Bub's question addresses Fuchs' desideratum that we "take the structure of quantum theory and change it from this very overt mathematical speak ... into something like [special relativity]." Thus, the answer to Bub's question per Fuchs' desideratum is, "the Tsirelson bound obtains due to conservation per NPRF".


Manual therapy and exercise for neck pain: A systematic review.
Manual therapy is often used with exercise to treat neck pain. This cervical overview group systematic review update assesses if manual therapy, including manipulation or mobilisation, combined with exercise improves pain, function/disability, quality of life, global perceived effect, and patient satisfaction for adults with neck pain with or without cervicogenic headache or radiculopathy. Computerized searches were performed to July 2009. Two or more authors independently selected studies, abstracted data, and assessed methodological quality. Pooled relative risk (pRR) and standardized mean differences (pSMD) were calculated. Of 17 randomized controlled trials included, 29% had a low risk of bias. Low quality evidence suggests clinically important long-term improvements in pain (pSMD-0.87(95% CI:-1.69,-0.06)), function/disability, and global perceived effect when manual therapy and exercise are compared to no treatment. High quality evidence suggests greater short-term pain relief [pSMD-0.50(95% CI:-0.76,-0.24)] than exercise alone, but no long-term differences across multiple outcomes for (sub)acute/chronic neck pain with or without cervicogenic headache. Moderate quality evidence supports this treatment combination for pain reduction and improved quality of life over manual therapy alone for chronic neck pain; and suggests greater short-term pain reduction when compared to traditional care for acute whiplash. Evidence regarding radiculopathy was sparse. Specific research recommendations are made.


The current role of transcranial surgery in the management of pituitary adenomas.
The aim of this study was to determine the factors influencing the use of a transcranial (TC) approach in pituitary adenomas and suggest a decision-making tree for the surgical strategy. The data for 23 (4.6%) patients who underwent TC surgery from amongst 494 pituitary adenomas were retrospectively analyzed. Eight factors on magnetic resonance imaging (MRI) that could predict a difficult transsphenoidal (TS) surgery were noted. Adverse findings at TS surgery leading to a 2nd stage TC surgery were documented. Eighteen of the 23 cases were giant adenomas. Thirteen patients underwent TC surgery alone or as an initial approach when combined with TS while 10 underwent 2nd stage TC surgery following a TS approach. Most cases in the first group had 3 or more radiological factors in combination with a small sella. The 2nd group had higher sellar tumor volumes and fewer unfavourable radiological factors that led to the initial use of the TS approach. A hard, fibrous consistency or a significant residue obscured from the surgeon's view, and difficulty in hemostasis were additional factors prompting the use of a TC approach. Tumor excision ≥90% could be achieved in 13 cases (56.5%). Post-operative RT was administered in 12 patients. There were 2 deaths (8.7%) and the major morbidity rate was 43 %. Despite advances in endoscopic surgery the TC approach may be required in 5% of cases. A study of the preoperative MRI for factors that predict difficulty with the TS approach might encourage the surgeon to consider a TC surgery either as an initial approach or combined with a TS surgery.


Longitudinal investigation of the age-related bacterial diversity in the feces of commercial pigs.
The importance of bacteria in the gastrointestinal tracts of animals is widely acknowledged as important. However, very little is known about composition and distribution of the microbial population in lower intestinal tracts of animals. Because most bacterial species in pig intestines have not been cultured, it has been difficult to analyze bacterial diversity by conventional culture methods. Even with the development of culture independent 16S rRNA gene sequencing, the previous methods were slow and labor intensive. Therefore, high throughput pyrosequencing of 16S rDNA libraries was used in this study in order to explore the bacterial diversity of the pig feces. In our two trials, fecal samples from individual pigs were collected five times at 3-week intervals, and the 16S rRNA genes in the community DNAs from fecal samples were sequenced and analyzed. This longitudinal study design identified that microbial populations in the feces of the each pig continued to change as pigs aged. The variations of bacterial diversity of the animals were affected by less abundant bacterial components of the feces. These results help us to understand the age-related bacterial diversity in the commercial pig feces.


Association between serotonin 5-HT-2C receptor gene (HTR2C) polymorphisms and obesity- and mental health-related phenotypes in a large population-based cohort.
Studies have shown that common single-nucleotide polymorphisms (SNPs) in the serotonin 5-HT-2C receptor (HTR2C) are associated with antipsychotic agent-induced weight gain and the development of behavioural and psychological symptoms. We aimed to analyse whether variation in the HTR2C is associated with obesity- and mental health-related phenotypes in a large population-based cohort. Six tagSNPs, which capture all common genetic variation in the HTR2C gene, were genotyped in 4978 men and women from the European Prospective Investigation into Cancer (EPIC)-Norfolk study, an ongoing prospective population-based cohort study in the United Kingdom. To confirm borderline significant associations, the -759C/T SNP (rs3813929) was genotyped in the remaining 16 003 individuals from the EPIC-Norfolk study. We assessed social and psychological circumstances using the Health and Life Experiences Questionnaire. Genmod models were used to test associations between the SNPs and the outcomes. Logistic regression was performed to test for association of SNPs with obesity- and mental health- related phenotypes. Of the six HTR2C SNPs, only the T allele of the -759C/T SNP showed borderline significant associations with higher body mass index (BMI) (0.23 kg m(-2); (95% confidence interval (CI): 0.01-0.44); P=0.051) and increased risk of lifetime major depressive disorder (MDD) (Odds ratio (OR): 1.13 (95% CI: 1.01-1.22), P=0.02). The associations between the -759C/T and BMI and lifetime MDD were independent. As associations only achieved borderline significance, we aimed to validate our findings on the -759C/T SNP in the full EPIC-Norfolk cohort (n=20 981). Although the association with BMI remained borderline significant (beta=0.20 kg m(-2); 95% CI: 0.04-0.44, P=0.09), that with lifetime MDD (OR: 1.01; 95% CI: 0.94-1.09, P=0.73) was not replicated. Our findings suggest that common HTR2C gene variants are unlikely to have a major role in obesity- and mental health-related traits in the general population.


Deprescribing antihypertensive treatment in nursing home patients and the effect on blood pressure.
It is debatable whether treating multimorbid nursing home patients with antihypertensive drugs produces beneficial effects. Most cardiovascular guidelines promote treatment; few have advice on how to deprescribe when treatment may no longer be necessary. We investigated the effect of medication review on antihypertensive drug use and the association between cognition, blood pressure, and prescribing. From August 2014 to December 2015, 765 patients from 72 units (clusters) in 32 Norwegian nursing homes were included in a 4-month, multicentre, cluster-randomized, controlled trial, with 9-month follow-up. Patients ≥ 65 years old with antihypertensive treatment (n = 295, 39%) were randomized to systematic medication review where the physician received support from peers (collegial mentoring) or were given care as usual (control condition). Outcome measures were the number of antihypertensive drugs, systolic blood pressure, and pulse. We used hospitalizations and deaths as criteria to assess harm. At baseline, each patient used 9.2 ± 3.5 regular drugs, and 1.6 ± 0.7 antihypertensives. Mean blood pressure was 128/71 mmHg and 9% had a systolic pressure ≥ 160 mmHg. Between baseline and month four, antihypertensives were deprescribed to a significantly higher extent in the intervention group (n = 43, 32%) compared to control (n = 11, 10%); Incidence Rate Ratio = 0.8, 95% CI = 0.7-0.9. In the intervention group, there was an immediate increase in systolic blood pressure when antihypertensives were reduced, from baseline 128 ± 19.5 mmHg to 143 ± 25.5 mmHg at month four. However, at month nine, the blood pressure had reverted to baseline values (mean 134 mmHg). Deprescription did not affect pulse and systolic pressure. The number of hospitalizations was higher in control patients at month four (P = 0.031) and nine (P = 0.041). A systematic medication review supported by collegial mentoring significantly decreased the use of antihypertensive drugs in nursing home patients without an effect on the systolic blood pressure over time.


The cytoskeletal regulatory scaffold protein GIT2 modulates mesenchymal stem cell differentiation and osteoblastogenesis.
G protein-coupled receptor kinase interacting protein 2 (GIT2) is a signaling scaffold protein involved in the regulation of cytoskeletal structure, membrane trafficking, and G protein-coupled receptor internalization. Since dynamic cytoskeletal reorganization plays key roles both in osteoblast differentiation and in the maintenance of osteoclast polarity during bone resorption, we hypothesized that skeletal physiology would be altered in GIT2(-/-) mice. We found that adult GIT2(-/-) mice have decreased bone mineral density and bone volume in both the trabecular and cortical compartments. This osteopenia was associated with decreased numbers of mature osteoblasts, diminished osteoblastic activity, and increased marrow adiposity, suggesting a defect in osteoblast maturation. In vitro, mesenchymal stem cells derived from GIT2(-/-) mice exhibited impaired differentiation into osteoblasts and increased adipocyte differentiation, consistent with a role for GIT2 in mesenchymal stem cell fate determination. Despite elevated osteoclast inducing cytokines and osteoclast numbers, GIT2(-/-) mice also exhibit impaired bone resorption, consistent with a further role for GIT2 in regulating osteoclast function. Collectively, these findings underscore the importance of the cytoskeleton in both osteoblast and osteoclast function and demonstrate that GIT2 plays essential roles in skeletal metabolism, affecting both bone formation and bone resorption in vivo.


Cognitive consequences of regression of cerebral small vessel disease.
Recent studies have shown that neuroimaging markers of cerebral small vessel disease can also regress over time. We investigated the cognitive consequences of regression of small vessel disease markers. Two hundred and seventy-six participants of the RUNDMC study underwent neuroimaging and cognitive assessments at three time-points over 8.7 years. We semi-automatically assessed white matter hyperintensities volumes and manually rated lacunes and microbleeds. We analysed differences in cognitive decline and accompanying brain atrophy between participants with regression, progression and stable small vessel disease by analysis of variance. Fifty-six participants (20.3%) showed regression of small vessel disease markers: 31 (11.2%) white matter hyperintensities regression, 10 (3.6%) vanishing lacunes and 27 (9.8%) vanishing microbleeds. Participants with regression showed a decline in overall cognition, memory, psychomotor speed and executive function similar to stable small vessel disease. Participants with small vessel disease progression showed more cognitive decline compared with stable small vessel disease (p < 0.001 for cognitive index and memory; p < 0.01 for executive function), although significance disappeared after adjusting for age and sex. Loss of total brain, gray matter and white matter volume did not differ between participants with small vessel disease regression and stable small vessel disease, while participants with small vessel disease progression showed more volume loss of total brain and gray matter compared to those with stable small vessel disease (p < 0.05), although significance disappeared after adjustments. Regression of small vessel disease markers was associated with similar cognitive decline compared to stable small vessel disease and did not accompany brain atrophy, suggesting that small vessel disease regression follows a relatively benign clinical course. Future studies are required to validate these findings and to assess the role of vascular risk factor control on small vessel disease regression and possible recovery of clinical symptoms. Our findings of comparable cognitive decline between participants with regression and stable small vessel disease might suggest that small vessel disease regression has a relative benign cognitive outcome.


Nonspecific effects of oral vaccination with live-attenuated Salmonella Typhi strain Ty21a.
Epidemiological and immunological evidence suggests that some vaccines can reduce all-cause mortality through nonspecific changes made to innate immune cells. Here, we present the first data to describe the nonspecific immunological impact of oral vaccination with live-attenuated Salmonella Typhi strain Ty21a. We vaccinated healthy adults with Ty21a and assessed aspects of innate and adaptive immunity over the course of 6 months. Changes to monocyte phenotype/function were observed for at least 3 months. Changes to innate and adaptive immune cell cytokine production in response to stimulation with vaccine and unrelated nonvaccine antigens were observed over the 6-month study period. The changes that we have observed could influence susceptibility to infection through altered immune responses mounted to subsequently encountered pathogens. These changes could influence all-cause mortality.


How people know their risk preference.
People differ in their willingness to take risks. Recent work found that revealed preference tasks (e.g., laboratory lotteries)-a dominant class of measures-are outperformed by survey-based stated preferences, which are more stable and predict real-world risk taking across different domains. How can stated preferences, often criticised as inconsequential "cheap talk," be more valid and predictive than controlled, incentivized lotteries? In our multimethod study, over 3,000 respondents from population samples answered a single widely used and predictive risk-preference question. Respondents then explained the reasoning behind their answer. They tended to recount diagnostic behaviours and experiences, focusing on voluntary, consequential acts and experiences from which they seemed to infer their risk preference. We found that third-party readers of respondents' brief memories and explanations reached similar inferences about respondents' preferences, indicating the intersubjective validity of this information. Our results help unpack the self perception behind stated risk preferences that permits people to draw upon their own understanding of what constitutes diagnostic behaviours and experiences, as revealed in high-stakes situations in the real world.


T(11;18)(q21;q21)-positive gastrointestinal MALT lymphomas are heterogeneous with respect to the V(H) gene mutation status.
To investigate how t(11;18)(q21;q21)-positive gastrointestinal MALT lymphomas relate to other marginal zone lymphomas with respect to the somatic mutation pattern of the V(H) genes and the expression of the marker CD27. The V(H) gene of 7 t(11;18)(q21;q21)-positive gastrointestinal MALT lymphomas was amplified by PCR using family specific V(H) primers and a consensus J(H) primer. PCR products were sequenced and mutation analysis of the CDR and the FR regions was performed. All cases were immunostained for CD27. One case showed unmutated V(H) genes while the others showed mutated V(H) genes with mutation frequencies ranging from 1.3 to 14.7% and with evidence of antigen selection in 2 cases. These data suggest that the translocation t(11;18)(q21;q21) can target either B-cells at different stages of differentiation or naive B-cells that retain the capacity to differentiate upon antigen stimulation. All cases but one displayed weak to strong CD27 expression which did not correlate with the V(H) gene mutation status. t(11;18)(q21;q21)-positive gastrointestinal MALT lymphomas are heterogeneous with respect to the V(H) mutation status and CD27 is not a marker of somatically mutated B-cells.


Financial access to health care in Karuzi, Burundi: a household-survey based performance evaluation.
In 2003, Médecins Sans Frontières, the provincial government, and the provincial health authority began a community project to guarantee financial access to primary health care in Karuzi province, Burundi. The project used a community-based assessment to provide exemption cards for indigent households and a reduced flat fee for consultations for all other households. An evaluation was carried out in 2005 to assess the impact of this project. Primary data collection was through a cross-sectional household survey of the catchment areas of 10 public health centres. A questionnaire was used to determine the accuracy of the community-identification method, households' access to health care, and costs of care. Household socioeconomic status was determined by reported expenditures and access to land. Financial access to care at the nearest health centre was ensured for 70% of the population. Of the remaining 30%, half experienced financial barriers to access and the other half chose alternative sites of care. The community-based assessment increased the number of people of the population who qualified for fee exemptions to 8.6% but many people who met the indigent criteria did not receive a card. Eighty-eight percent of the population lived under the poverty threshold. Referring to the last sickness episode, 87% of households reported having no money available and 25% risked further impoverishment because of healthcare costs even with the financial support system in place. The flat fee policy was found to reduce cost barriers for some households but, given the generalized poverty in the area, the fee still posed a significant financial burden. This report showed the limits of a programme of fee exemption for indigent households and a flat fee for others in a context of widespread poverty.


BRCA1/2 testing in hereditary breast and ovarian cancer families II: impact on relationships.
Members of hereditary breast and ovarian cancer (HBOC) families often express concern during genetic counseling about the impact of BRCA1/2 testing on close relatives. Yet whether there are likely to be adverse effects of either the decision to undergo genetic testing or the results of testing on family relationships is unknown. One purpose of this study was to assess the impact on close family relationships. Within a randomized trial of breast cancer genetic counseling methods, members of 13 HBOC families were offered BRCA1/2 testing for a known family mutation. The Family Relationship Index (FRI) of the Family Environment Scale (FES) was used to measure perceived family cohesion, conflict, and expressiveness at baseline and again 6-9 months following the receipt of test results, or at the equivalent time for those who declined testing. Participants (n = 212) completed baseline and follow-up questionnaires. Comparisons were made between testers and non-testers as well as between those who tested positive and negative for the family mutation. One hundred eighty-one participants elected to undergo genetic testing (85%) and 47 (26%) were identified to have a mutation. After adjusting for baseline family relationship scores, counseling intervention, gender and marital status, non-testers reported a greater increase in expressiveness (P = 0.006) and cohesion (P = 0.04) than testers. Individuals who tested positive reported a decrease in expressiveness (P = 0.07), although as a trend. Regardless of test decision or test result, those who were randomized to a client-centered counseling intervention reported a decrease in conflict (P = 0.006). Overall, study results suggest that undergoing genetic testing and learning ones BRCA1/2 status may affect family relationships. Those individuals who declined testing reported feeling closer to family members and more encouraged to express emotions to other family members demonstrating potential benefit from the offer of testing. Since those who tested positive reported feeling less encouraged to express their emotions within the family, we recommend helping clients to identify others with whom they feel comfortable sharing their thoughts and feelings about their positive gene status and increased cancer risk.


A comparison of five stroke scales with measures of disability, handicap, and quality of life.
Recently much debate has arisen on the appropriateness of assessing stroke outcomes with stroke impairment scales. Our purpose was to study the relationship between long-term impairments and functional outcomes in terms of disability, handicap, and quality of life. We studied 87 patients who had a stroke 6 months earlier. Impairments were scored on five stroke scales: the Orgogozo Scale, the National Institutes of Health scale, the Canadian Neurological Scale, the Mathew scale, and the Scandinavian Stroke Scale. Disability was assessed with the Barthel Index, handicap with the Rankin scale, and quality of life with the Sickness Impact Profile. The linear relationship between stroke scales and functional scales was assessed with correlation coefficients. We used regression analyses to explain functional health. The stroke scales were highly related to one another (range, r = -.85 to .92). The correlation between stroke scales and functional scales was < .70 and decreased from Barthel (mean r2 = 47.5%) to Rankin (mean r2 = 36.5%) to Sickness Impact Profile (mean r2 = 33%). Stroke scales were rather poorly correlated with patients' psychosocial conditions (mean r2 = 11.5%). Functional health status was mainly related to leg power and orientation. The standardized stroke scale weights of the explanatory items were lower than their standardized regression weights. Stroke scales only partly explain functional health. The impact of impairments on functional outcomes seems to be underestimated by the stroke scale weights. The correlation patterns give empirical support to the hierarchical structure of the International Classification of Impairments, Disabilities and Handicaps.


Are antipsychotic prescribing patterns different in older and younger adults?: a survey of 1357 psychiatric inpatients in Toronto.
To compare antipsychotic prescribing patterns in younger (aged 59 years or younger) and older (aged 60 years or older) patients with psychotic or mood disorders. Pharmacy records of all patients discharged from the Centre for Addiction and Mental Health over a 21-month period were reviewed. A total of 1357 patients who were prescribed an antipsychotic at the time of their discharge were included in the analysis (956 with a primary psychotic disorder and 401 with a primary mood disorder). World Health Organization-defined daily doses were used as the standardized dosing unit. Both in patients with a primary psychotic disorder and in patients with a primary mood disorder, the prescribing patterns were similar in older and younger patients, with no statistical difference in the proportions receiving first-generation antipsychotics, second-generation antipsychotics (SGAs), multiple antipsychotics, or long-acting (depot) antipsychotics. Overall, the mean daily antipsychotic doses were lower only in the older group of patients with a primary mood disorder. However, the mean dose of SGAs was about 30% lower in older patients in both diagnostic groups. Regardless of age, patients with a mood disorder were prescribed lower doses of antipsychotics than those with a psychotic disorder. Our data suggest that older patients are prescribed lower antipsychotic dosages primarily when using SGAs. This finding emphasizes the need for dose-finding studies assessing both the efficacy and the safety of antipsychotics in older patients with a psychotic or mood disorder.


Transversus abdominis plane (TAP) blocks-a review.
Effective post-operative pain management can positively influence patient outcome. Multimodal analgesic regimes are often limited by side-effects. Epidural analgesia may be resource-consuming, restrict mobility and have negative cardiovascular and gastrointestinal consequences. Consequently, there is a need for regional anaesthetic techniques to minimise opioid use, and provide alternatives to epidurals, especially within the context of minimally invasive abdominal surgery and enhanced recovery programmes. This review aims to evaluate the evidence base underlying Transversus abdominis plane (TAP) blockade. A literature search was performed using the PubMed database (http://www.ncbi.nlm.nih.gov/pubmed/) using the parameters 'transversus abdominis plane' and 'TAP'. The references within were then searched for applicable studies. Case reports and correspondence were excluded. Thirteen studies assessed technique and mechanisms of action. Fourteen clinical studies involved a total of 1250 patients. Seven studies (6 Randomised Controlled Trials, RCTs) demonstrated reductions in post-operative morphine requirements (33.3%-73.1%). Five RCTs demonstrated concomitant improvements in pain scores. Five RCTs demonstrated reduced opioid side effects. The one study assessing functional outcome (a Prospective Controlled Trial, PCT) demonstrated earlier return of gastrointestinal function and hospital discharge. The limited evidence to date suggests that TAP blockade is an effective adjunct to multimodal post-operative analgesia following a range of abdominal surgical procedures. Whether TAP blocks are a viable alternative to epidural analgesia remains to be determined. However, it is likely that as this technique grows in popularity its role, particularly that in enhanced recovery programmes, will be better delineated and refined.


Inherent charge-shifting polyelectrolyte multilayer blends: a facile route for tunable protein release from surfaces.
Recent research has highlighted degradable multilayer films that enable the programmed release of different therapeutics. Multilayers constructed by the layer-by-layer (LbL) deposition that can undergo disassembly have been demonstrated to be of considerable interest, particularly for biomedical surface coatings due to their versatility and mild aqueous processing conditions, enabling the inclusion of biologic drugs with high activity. In this study, we examine the controlled release of a protein using a different mechanism for film disassembly, the gradual dissociation of film interactions under release conditions. Poly(β-amino ester)s and poly(L-lysine) (PLL) were used as the positively charged multilayer components coassembled with a model negatively charged antigen protein, ovalbumin (Ova). The release of the protein from these multilayer films is dominated by the slow shift in the charge of components under physiological pH conditions rather than by hydrolytic degradative release. The time scale of release can be varied over almost 2 orders of magnitude by varying the ratio of the two polyamines in the deposition solution. The highly versatile and tunable properties of these films form a basis for designing controlled and sequential delivery of drug coatings using a variety of polyions.


Objective physical and mental markers of self-reported fatigue in women undergoing (neo)adjuvant chemotherapy for early-stage breast cancer.
Objective, treatment-independent markers of cancer-related fatigue are needed to advance clinical trials. In the current study, the authors evaluated physical, neurocognitive, and serologic markers for correlation with self-reported fatigue before and after (neo)adjuvant chemotherapy for patients with early-stage breast cancer. Women with AJCC TNM Stage I-III breast cancer consented to assessment before and after the completion of 4 cycles of dose-dense doxorubicin and cyclophosphamide. Assessment included self-reported fatigue (using the Brief Fatigue Inventory), depression (using the Center for Epidemiologic Studies-Depression Scale [CES-D]), Pittsburgh Sleep Quality Index, and 28 objective measures (grip strength in dominant and nondominant hands, 6-minute walk, daily total energy expenditure, 14 neurocognitive tests, and 10 serologic markers). Generalized linear regression models of fatigue were constructed (1 model per marker), and adjusted for depression, timing before/after chemotherapy, menopausal status, obesity, and educational level. P values were adjusted to control the False Discovery Rate. Of 28 subjects, 3 withdrew without completing baseline assessments. Prechemotherapy and postchemotherapy data were available for the evaluation of physical measures (25 subjects aged 50.6 ± 9.5 years), neurocognitive tests (22 subjects), and serologic markers (10 subjects). On covariate-adjusted analysis, interleukin (IL)-12 was found to be associated with fatigue at both assessments (P<.01). Serum eotaxin (P < .01), IL-1RA (P < .01), monocyte chemoattractant protein 1 (MCP-1) (P<.01), and performance on 2 neurocognitive (Trail Making) tests (P<.01 and P = .02, respectively) were found to be inversely associated with fatigue before chemotherapy but not afterward, whereas daily energy expenditure, serum MCP-1, and serum macrophage inflammatory protein 1a (MIP-1a) were found to be associated with fatigue after receipt of chemotherapy but not before (P<.01 for each). The association between energy expenditure and fatigue was detectable only if an actively athletic subject with outlier values of energy expenditure was excluded. Serum IL-12 merits confirmatory testing as an objective, treatment-independent measure of fatigue in patients with early-stage breast cancer. Cancer 2017;123:1810-1816. © 2017 The Authors. Cancer published by Wiley Periodicals, Inc. on behalf of American Cancer Society. This is an open access article under the terms of the Creative Commons Attribution-NonCommercial-NoDerivs License, which permits use and distribution in any medium, provided the original work is properly cited, the use is non-commercial and no modifications or adaptations are made.


Cancer incidence in Thailand, 1988-1991.
Results from three cancer registries (Chiang Mai, Khon Kaen, and Songkhla) in different regions of Thailand and from a cancer survey in the population of Bangkok during the years 1988-1991 are presented, together with an estimate of the incidence of cancer for the country as a whole. Overall, liver cancer is the most frequent malignancy, but there are large regional differences in incidence and in histological type, with very high rates of cholangiocarcinoma in the northeast (associated with endemic opisthorchiasis) but a more even distribution of hepatocellular carcinoma. Lung cancer is second in frequency, with the highest rates in northern Thailand, where the incidence in women (Age Standardized Rate, 37.4 per 100,000) is among the highest in the world. A link with tobacco smoking is suggested by similarly raised rates, especially in women, for cancers of the larynx and pancreas. Cervical cancer is the most common malignancy in women, with relatively little regional variation in risk, while the incidence of breast cancer is low. Other cancer sites showing moderately increased rates include the lip and oral cavity, particularly in females from the north and northeast, where the chewing of betel nut remains common among older generations, nasopharyngeal cancer, carcinoma of the esophagus in the southern region, and penile cancer, especially in the north and northeast. Previous studies which have investigated the etiological factors underlying these patterns are reviewed, and the implications for future research and for national cancer control policies are discussed.


Adolescent angst: enrollment on clinical trials.
Survival among adolescents and young adults (AYAs) ages 15 to 39 with cancer has not improved to the same extent as that of pediatric and older adult cancer patients, which is thought to relate, in part, to the lower participation of AYAs in clinical trials. Because significant efforts have been made to improve clinical trial enrollment for AYAs, we (1) present contemporary clinical trial enrollment rates by cancer type, sociodemographic characteristics, and treatment setting and (2) discuss provider-, patient-, and system-level barriers to clinical trial participation. Contemporary studies examining clinical trial enrollment among AYAs have continued to find low overall participation relative to pediatric populations, with most studies observing no significant improvements in enrollment over time. In addition to age and cancer type, enrollment varies by treatment setting, health insurance, and race/ethnicity. Access to available clinical trials may be increased by appropriate referral of AYAs to pediatric and adult specialty cancer centers with studies relevant to the AYA population because most AYAs are treated in the community setting. Even with similar access to trials, however, AYAs may be less likely to participate, and therefore, future efforts should focus on better understanding and addressing barriers to enrollment as well as improving education and outreach regarding clinical trials.


Vegetation Changes Attributable to Refugees in Africa Coincide with Agricultural Deforestation.
The recent adoption of the Global Compact on Refugees formally recognizes not only the importance of supporting the nearly 26 million people who have sought asylum from conflict and persecution but also of easing the pressures on receiving areas and host countries. However, few countries may enforce the Compact out of concern over the economic or environmental repercussions of hosting refugees. We examine whether narratives of refugee-driven landscape change are empirically generalizable to continental Africa, which fosters 34% of all refugees. Estimates of the causal effects of the number of refugees-located in 493 camps distributed across 49 African countries-on vegetation from 2000 to 2016 are provided. Using a quasi-experimental design, we find refugees bear a small increase in vegetation condition while contributing to increased deforestation. Such a combination is mainly explained not by land clearance and massive biomass extraction but by agricultural expansion in refugee-hosting areas. A one percent increase in the number of refugees amplifies the transition from dominant forested areas to cropland by 1.4 percentage points. These findings suggest that changes in vegetation condition may ensue with the elevation of population-based constraints on food security.


Thermodynamic analysis of ligand-induced changes in protein thermal unfolding applied to high-throughput determination of ligand affinities with extrinsic fluorescent dyes.
The quantification of protein-ligand interactions is essential for systems biology, drug discovery, and bioengineering. Ligand-induced changes in protein thermal stability provide a general, quantifiable signature of binding and may be monitored with dyes such as Sypro Orange (SO), which increase their fluorescence emission intensities upon interaction with the unfolded protein. This method is an experimentally straightforward, economical, and high-throughput approach for observing thermal melts using commonly available real-time polymerase chain reaction instrumentation. However, quantitative analysis requires careful consideration of the dye-mediated reporting mechanism and the underlying thermodynamic model. We determine affinity constants by analysis of ligand-mediated shifts in melting-temperature midpoint values. Ligand affinity is determined in a ligand titration series from shifts in free energies of stability at a common reference temperature. Thermodynamic parameters are obtained by fitting the inverse first derivative of the experimental signal reporting on thermal denaturation with equations that incorporate linear or nonlinear baseline models. We apply these methods to fit protein melts monitored with SO that exhibit prominent nonlinear post-transition baselines. SO can perturb the equilibria on which it is reporting. We analyze cases in which the ligand binds to both the native and denatured state or to the native state only and cases in which protein:ligand stoichiometry needs to treated explicitly.