Partial splenectomy in sickle cell syndromes.
Partial splenectomy was carried out in four children with homozygous sickle cell disease and eight children with sickle cell beta thalassaemia. It was performed in order to preserve splenic contribution to the host defence against infections while suppressing hypersplenism or the risk of recurrence of acute splenic sequestration. Indications for this surgical operation were acute splenic sequestration (n = 1), hypersplenism (n = 5), and acute splenic sequestration and hypersplenism (n = 6). Surgery was uneventful in 11 patients. A significant reduction of blood requirements and a significant decrease of the number of hospitalisations/patient/year were observed after splenectomy. No recurrence of hypersplenism or acute splenic sequestration occurred and no severe infection was noticed during the follow up period after surgery (mean (SD) 4.2 (2.8) years; range 6 months-7 years). Mean haemoglobin concentration and leucocyte and platelet counts increased after surgery. The benefit of partial splenectomy compared with total splenectomy to treat acute splenic sequestration or hypersplenism in sickle cell disease is discussed.


Improving dideoxynucleotide-triphosphate utilisation by the hyper-thermophilic DNA polymerase from the archaeon Pyrococcus furiosus.
Polymerases from the Pol-I family which are able to efficiently use ddNTPs have demonstrated a much improved performance when used to sequence DNA. A number of mutations have been made to the gene coding for the Pol-II family DNA polymerase from the archaeon Pyrococcus furiosus with the aim of improving ddNTP utilisation. 'Rational' alterations to amino acids likely to be near the dNTP binding site (based on sequence homologies and structural information) did not yield the desired level of selectivity for ddNTPs. However, alteration at four positions (Q472, A486, L490 and Y497) gave rise to variants which incorporated ddNTPs better than the wild type, allowing sequencing reactions to be carried out at lowered ddNTP:dNTP ratios. Wild-type Pfu-Pol required a ddNTP:dNTP ratio of 30:1; values of 5:1 (Q472H), 1:3 (L490W), 1:5 (A486Y) and 5:1 (Y497A) were found with the four mutants; A486Y representing a 150-fold improvement over the wild type. A486, L490 and Y497 are on analpha-helix that lines the dNTP binding groove, but the side chains of the three amino acids point away from this groove; Q472 is in a loop that connects this alpha-helix to a second long helix. None of the four amino acids can contact the dNTP directly. Therefore, the increased selectivity for ddNTPs is likely to arise from two factors: (i) small overall changes in conformation that subtly alter the nucleotide triphosphate binding site such that ddNTPs become favoured; (ii) interference with a conformational change that may be critical both for the polymerisation step and discrimination between different nucleotide triphosphates.


Proinflammatory Cytokines and Oxidative Stress Decrease the Transport of Dopamine Precursor Tyrosine in Human Fibroblasts.
Proinflammatory cytokines and oxidative stress responses have been extensively implicated in the pathophysiology of neuropsychiatric disorders over the past 2 decades. Moreover, disturbed transport of the dopamine precursor (i.e., the amino acid tyrosine) has been demonstrated, in different studies, across fibroblast cell membranes obtained from neuropsychiatric patients. However, the role and influences of proinflammatory cytokines and oxidative stress, and the reasons for disturbed tyrosine transport in neuropsychiatric disorders, are still not evaluated. The present study aimed to assess the role of proinflammatory cytokines and oxidative stress, indicated in many neuropsychiatric disorders, in tyrosine transportation, by using human skin-derived fibroblasts. Fibroblasts obtained from a healthy control were used in this study. Fibroblasts were treated with proinflammatory cytokines (IL-1β, IFN-γ, IL-6, TNF-α), their combinations, and oxidative stress, optimized for concentrations and incubation time, to analyze the uptake of 14C-tyrosine compared to untreated controls. This study demonstrates that proinflammatory cytokines and oxidative stress decrease the transport of tyrosine (47% and 33%, respectively), which can alter dopamine synthesis. The functionality of the tyrosine transporter could be a new potential biomarker to target for discovering new drugs to counteract the effects of proinflammatory cytokines and oxidative stress in the pathophysiology of neuropsychiatric disorders.


GLISTR: glioma image segmentation and registration.
We present a generative approach for simultaneously registering a probabilistic atlas of a healthy population to brain magnetic resonance (MR) scans showing glioma and segmenting the scans into tumor as well as healthy tissue labels. The proposed method is based on the expectation maximization (EM) algorithm that incorporates a glioma growth model for atlas seeding, a process which modifies the original atlas into one with tumor and edema adapted to best match a given set of patient's images. The modified atlas is registered into the patient space and utilized for estimating the posterior probabilities of various tissue labels. EM iteratively refines the estimates of the posterior probabilities of tissue labels, the deformation field and the tumor growth model parameters. Hence, in addition to segmentation, the proposed method results in atlas registration and a low-dimensional description of the patient scans through estimation of tumor model parameters. We validate the method by automatically segmenting 10 MR scans and comparing the results to those produced by clinical experts and two state-of-the-art methods. The resulting segmentations of tumor and edema outperform the results of the reference methods, and achieve a similar accuracy from a second human rater. We additionally apply the method to 122 patients scans and report the estimated tumor model parameters and their relations with segmentation and registration results. Based on the results from this patient population, we construct a statistical atlas of the glioma by inverting the estimated deformation fields to warp the tumor segmentations of patients scans into a common space.


Pseudo-random single photon counting: a high-speed implementation.
Pseudo-random single photon counting (PRSPC) is a new time-resolved optical measurement method which combines the spread spectrum time-resolved method with single photon counting. A pseudo-random bit sequence is used to modulate a continuous wave laser diode, while single photon counting is used to build up the optical signal in response to the modulated excitation. Periodic cross-correlation is performed to obtain the temporal profile of the subject of interest. Compared with conventional time-correlated single photon counting (TCSPC), PRSPC enjoys many advantages such as low cost and high count rate without compromising the sensitivity and time-resolution. In this paper, we report a PRSPC system that can be used for high-speed acquisition of the temporal point spread function of diffuse photons. It can reach a photon count rate as high as 3 Mcps (counts per second). Phantom experiments have been conducted to demonstrate the system performance.


A clinically utilized intravenous continuous rate infusion of diltiazem does not significantly decrease systolic function in healthy dogs.
To determine if left ventricular systolic function on echocardiography, systemic blood pressure, and electrocardiography change with a clinically accepted intravenous (IV) diltiazem constant rate infusion (CRI) compared to a control. 10 healthy client-owned adult dogs. Prospective, masked, crossover study from May 27, 2021, to August 22, 2021. Dogs were randomized to receive diltiazem (loading dose of 240 μg/kg, IV followed by a CRI of 6 μg/kg/min for 300 minutes) or the same volume of 5% dextrose in water (D5W) administered IV followed by the opposite intervention after a 7-day washout. Blood pressure was monitored during each CRI, and echocardiographic and electrocardiographic studies were performed immediately before the CRI and during the last hour of the CRI. Postdiltiazem systolic time interval (STI) (median, 0.30; range, 0.16 to 0.34) was significantly lower than post-D5W STI (median, 0.32; range, 0.22 to 0.40; P = .046). All other echocardiographic parameters did not differ significantly between each of the groups after receiving diltiazem or D5W. Systemic blood pressure did not change significantly with either diltiazem (P = .450) or D5W (P = .940), and none of the dogs became hypotensive at any point in the study. Expectedly, negative dromotropy was observed with diltiazem. A significant decrease in left ventricular systolic function was not appreciated in healthy dogs receiving diltiazem at a clinically accepted intravenous infusion rate at this dosing regimen. Further studies are needed in dogs with cardiac disease.


Paradoxically decreased intracellular collagenase activity in macrophages from bronchoalveolar lavage fluid in current smokers and patients with obstructive ventilatory disorder.
The roles of matrix metalloproteinases (MMPs) in chronic obstructive pulmonary disease (COPD) have been studied. Macrophages are considered to release MMPs in the lung tissue. We measured intracellular collagenase activity in intact CD14(+)CD45++ cells from the bronchoalveolar lavage fluid (BALF) of patients with obstructive ventilatory impairment and other respiratory diseases. Collagenase activity in current smokers was significantly lower than those in non-smokers (3.25+/-0.54 versus 5.48+/-0.55; P=0.006), and also lower than those in ex-smokers (versus 6.54+/-1.54; P=0.019). We found a lower activity of collagenase in patients with FEV1/FVC below 70% than those with 70% or higher (2.68+/-0.59 versus 4.51+/-0.44; P=0.034). Mean value of FEV1/FVC in patients with collagenase activity of 4 or higher was significantly elevated as compared to those with the activity lower than 4 (83.3+/-3.3 versus 71.8+/-4.9; P=0.021). The discrepancy between increased release of MMPs by previous reports and decreased intracellular activity in our results, may be explained by the production of inactive form of MMPs is relatively increased in COPD. Our study may provide the future direction in investigating the mechanism of COPD. In clinics, this measurement in patients with smoking habits may be helpful to advise them to stop smoking, and to avoid progression to the irreversible obstructive disease.


The polyphenol resveratrol promotes skeletal growth in mice through a sirtuin 1-bone morphogenic protein 2 longevity axis.
The polyphenol resveratrol (RSV) exists in high quantities in certain foods (e.g. grapes and nuts). However, the capacity of RSV to confer physiological health benefits and a biological mechanism through which this might occur remains unclear. Aged, RSV-treated (300 mg·kg-1 ·day-1 ) and genetically modified [endothelial NOS (eNOS-/- )] female mice were assessed using histomorphometric and μCT analysis. Alongside in vivo analysis, molecular siRNA knockdown and pharmacological manipulation of eNOS, BMP2 and sirtuin 1 (SIRT1) and functional cellular assays in an osteoblast cell line panel, explored the mechanism through which RSV might impact overall bone volume. RSV promoted osteoblast activity and bone growth in vivo. RSV dose-dependently and simultaneously increased alkaline phosphatase (ALP) and eNOS levels. Similarly, NO-donor treatment increased ALP, runt homology transcription factor 2, BMP2 and stimulated bone formation, whilst eNOS-deficient mice displayed a bone loss phenotype. Moreover, RSV-induced increase in ALP and BMP2 expression was blocked in eNOS-/- osteoblasts and by BMP-inhibitor noggin. The longevity-linked SIRT1 enzyme was positively regulated by RSV and SIRT1 deletion reduced eNOS, BMP2 and ALP. Like eNOS deletion, loss of SIRT1 blocked RSV-induced osteoblast activity; however, SIRT1 levels remained unchanged in eNOS-/- mice, indicating RSV activation of SIRT1 stimulates BMP2 release via eNOS. This signalling axis is supported by decreased SIRT1, eNOS and BMP2 confirmed in old versus young bone. These findings suggest a new mechanism of action in bone remodelling and the ageing skeleton, where RSV positively impacts bone homeostasis via SIRT1 activation of BMP2.


Complement Receptor 1 (CR1, CD35) Polymorphisms and Soluble CR1: A Proposed Anti-inflammatory Role to Quench the Fire of "Fogo Selvagem" Pemphigus Foliaceus.
Pemphigus foliaceus is an autoimmune disease that is sporadic around the world but endemic in Brazil, where it is known as fogo selvagem (FS). Characterized by autoantibodies against the desmosomal cadherin desmoglein 1, FS causes painful erosions, and crusts that may be widespread. The recognition of antigens, including exposed sugar moieties, activates the complement system. Complement receptor 1 (CR1, CD35), which is responsible for the Knops blood group on erythrocytes (York and McCoy antigens), is also expressed by antigen-presenting cells. This regulates the complement system by removing opsonized antigens, blocking the final steps of the complement cascade. Membrane-bound CR1 also fosters antigen presentation to B cells, whereas soluble CR1 has anti-inflammatory properties. CR1 gene polymorphisms have been associated with susceptibility to complex diseases. In order to investigate the association of CR1 polymorphisms with FS susceptibility, we developed a multiplex sequence-specific assay to haplotype eleven polymorphisms in up to 367 FS patients and 242 controls from an endemic area and 289 from a non-endemic area. We also measured soluble CR1 (sCR1) in the serum of 53 FS patients and 27 controls and mRNA levels in the peripheral blood mononuclear cells of 63 genotyped controls. The haplotypes CR1*3B2B (with the York antigen-encoded by p.1408Met) and CR1*3A2A (with p.1208Arg) were associated with protection against FS (OR = 0.57, P = 0.027, and OR = 0.46, P = 0.014, respectively). In contrast, the CR1*1 haplotype (with the McCoy antigen - encoded by p.1590Glu) was associated with FS susceptibility (OR = 4.97, P < 0.001). Heterozygote rs12034383*A/G individuals presented higher mRNA expression than homozygotes with the G allele (P = 0.04). The lowest sCR1 levels occurred in patients with active disease before treatment (P = 0.036). Patients in remission had higher levels of sCR1 than did healthy controls (P = 0.013). Among those under treatment, patients with localized lesions also presented higher sCR1 levels than those with generalized lesions (P = 0.0073). In conclusion, the Knops blood group seems to modulate susceptibility to the disease. Furthermore, corticosteroid treatment might increase sCR1 serum levels, and higher levels may play an anti-inflammatory role in patients with FS, limiting the distribution of lesions. Based on these results, we suggest CR1 as a potential new therapeutic target for the treatment of FS.


Ototoxicity caused by cisplatin is ameliorated by melatonin and other antioxidants.
The mechanism of the ototoxicity caused by cisplatin is based in the generation of reactive oxygen species, which interferes with the antioxidant protection of the organ of Corti. Conversely, the protection of the cochlea with antioxidants ameliorates the ototoxicity by cisplatin. The ototoxicity produced by cisplatin can be reversible or persistent, depending on the age of the patient, cumulative doses, number of chemotherapy cycles, history of noise exposure, and deteriorating renal function. We have obtained in rats an ototoxic chart utilizing cisplatin (10 mg/kg body weight injected intraperitoneally, once only). Together with this treatment, the animals were treated with melatonin in the drinking water (10 mg/L) or injected subcutaneously (250 microg), and with an antioxidant mixture, injected subcutaneously, composed of 0.25 mg alpha-tocopherol acid succinate, 3 mg ascorbic acid, 1 mg glutathione, and 60 mg N-acetylcysteine. The distortion product otoacoustic emissions were determined for a prolonged period of time for each animal. The ototoxicity produced by cisplatin was maximal from days 7 to 10 post-treatment, returning to normal values in a month. When melatonin and the antioxidant mixture were present, the recovery was between days 10 and 15 post-treatment, independent of the means of administration of the pineal product. We conclude that the ototoxicity caused by cisplatin is ameliorated by melatonin and other antioxidants.


Current state of transcatheter mitral valve repair with the MitraClip.
Many patients affected with mitral valve regurgitation suffer from multiple comorbidities. The MitraClip device provides a safe means of transcatheter valve repair in patients with suitable mitral valve anatomy who are at prohibitive risk for surgery. We describe our early procedural outcomes and present a summary of the current state of MitraClip technology in the United States. We performed a retrospective chart review of initial high-risk or inoperable patients who underwent MitraClip placement at our institution after completion of the EVEREST II study. We examined the primary outcome of 30-day mortality, and secondary outcomes included extent of reduction of mitral regurgitation (MR), New York Heart Association (NYHA) functional class improvement, length of stay, and major complications. A total of 115 high-risk patients (mean Society of Thoracic Surgeons predicted risk of mortality 9.4%±6.1%) underwent the MitraClip procedure at our institution between March 2009 and April 2014. Co-morbidities including coronary artery disease (67.8%), pulmonary disease (39.1%) and previous cardiac surgery (44.3%) were common. The device was placed successfully in all patients with a 30-day mortality of 2.6%. All patients demonstrated 3+ or 4+ MR on preoperative imaging, and 80.7% of patients had trace or 1+ MR at hospital discharge. NYHA class improved substantially, with 79% of patients exhibiting class III or IV symptoms pre-procedure and 81% reporting class I or II symptoms at one month follow-up. The MitraClip procedure provides a safe alternative to surgical or medical management for high-risk patients with MR and suitable valve anatomy. A comprehensive heart team approach is essential, with surgeons providing critical assessment of patient suitability for surgery versus percutaneous therapy as well as performance of the valve procedure.


O(2) modulates large-conductance Ca(2+)-dependent K(+) channels of rat chemoreceptor cells by a membrane-restricted and CO-sensitive mechanism.
Hypoxic inhibition of large-conductance Ca(2+)-dependent K(+) channels (maxiK) of rat carotid body type I cells is a well-established fact. However, the molecular mechanisms of such inhibition and the role of these channels in the process of hypoxic transduction remain unclear. We have examined the mechanisms of interaction of O(2) with maxiK channels exploring the effect of hypoxia on maxiK currents recorded with the whole-cell and the inside-out configuration of the patch-clamp technique. Hypoxia inhibits channel activity both in whole-cell and in excised membrane patches. This effect is strongly voltage- and Ca(2+)-dependent, being maximal at low [Ca(2+)] and low membrane potential. The analysis of single-channel kinetics reveals a gating scheme comprising three open and five closed states. Hypoxia inhibits channel activity increasing the time the channel spends in the longest closed states, an effect that could be explained by a decrease in the Ca(2+) sensitivity of those closed states. Reducing maxiK channels with dithiothreitol (DTT) increases channel open probability, whereas oxidizing the channels with 2,2'-dithiopyridine (DTDP) has the opposite effect. These results suggest that hypoxic inhibition is not related with a reduction of channel thiol groups. However, CO, a competitive inhibitor of O(2) binding to hemoproteins, fully reverts hypoxic inhibition, both at the whole-cell and the single-channel level. We conclude that O(2) interaction with maxiK channels does not require cytoplasmic mediators. Such interaction could be mediated by a membrane hemoprotein that, as an O(2) sensor, would modulate channel activity.


ATP hydrolysis on actin-related protein 2/3 complex causes debranching of dendritic actin arrays.
Extension of lamellipodia, an important dissipative process in cell motility, is driven by the turnover of a polarized dendritic array of actin filaments. Motility is driven by catalytic cycles of filament attachment to Wiskott-Aldrich syndrome protein (WASP)-activated actin-related protein (Arp)2/3 complex at the leading edge, branch formation, and detachment, allowing subsequent growth of branched filaments. The morphology, mechanical strength, and lifetime of the array are determined by the processes of filament branching, debranching, and treadmilling. All three processes are controlled by ATP hydrolysis. ATP hydrolysis on F-actin is known to be at the origin of treadmilling. Here, by using radiolabeled ATP covalently bound to Arp2/3, we show that ATP is hydrolyzed on Arp2, not on Arp3, after a delay following filament branching. Hydrolysis of ATP on Arp2 promotes debranching of filaments and acts as a clock that controls the stability of dendritic actin arrays in lamellipodia. Finally, we propose that hydrolysis of ATP on G-actin in the ternary G-actin-WASP-Arp2/3 complex on branch formation destabilizes the WASP-actin interface and energetically facilitates the detachment step in the branching reaction.


Serum osteocalcin in rheumatoid arthritis and other inflammatory arthritides: relation between inflammatory activity and the effect of glucocorticoids and remission inducing drugs.
Osteocalcin, a vitamin K dependent protein synthesised by osteoblasts, was measured in serum by radioimmunoassay in patients with rheumatoid arthritis (n = 36) and seronegative spondyloarthropathies (n = 23). The serum osteocalcin levels were decreased in both patient groups compared with the levels measured in age and sex matched healthy controls. We found no relation between serum osteocalcin and the disease duration or inflammatory activity of the patients who were without drug treatment at the first examination. After administration of glucocorticoids (20 mg prednisolone a day) circulating osteocalcin decreased significantly after one week of treatment. During gradual reduction of the steroid dosage osteocalcin returned to pretreatment values. Treatment with non-steroidal anti-inflammatory drugs (NSAIDs) did not influence circulating osteocalcin. During treatment with chloroquine or penicillamine serum osteocalcin increased significantly, concomitant with a reduction of the acute phase reactants. Controversy persists about the abnormality of bone turnover in rheumatic diseases, but our data suggest that the overall bone turnover is decreased in patients with rheumatoid arthritis and other inflammatory arthritides.


[Toll-like receptor 4: the potential therapeutic target for neuropathic pain].
Activation of microglia plays a vital role in the initiation and maintenance of specific neuropathic pain states. By activating microglia in central nervous system, Toll-like receptor 4 (TLR4) can promote the release of proinflammatory cytokines and neuroactive compounds, participate in the initiation and maintenance of neuropathic pain, and trigger the opiate side effects. Therefore, TLR4 may be a potential therapeutic target for neuropathic pain. Inhibition of TLR4 has shown some biological effects in neuropathic pain models and ibudilast (the TLR4 pathway-inhibiting agent) has been approved for for phase 2 clinical trials. This article briefly reviews the structure, function, and mechanism of TLR4 as well as the development of TLR4-targeted drugs.


Expression of T cell receptor genes in an antigen-specific hybridoma and radiation-induced variants.
We have analyzed a series of mutants derived from a KLH-specific, I-E-restricted T hybridoma (FN1-18) which have lost antigen-reactivity while retaining both T cell receptor idiotypic determinants and the ability to respond to Con A. The variants have not gained any detectable alloreactivity, nor is there an obvious lesion in the mutants' beta chain DNA containing the utilized beta chain genes. This loss of antigen reactivity is due to a failure of stable production of the specific V beta-containing mRNA. Our results indicate that in FN1-18, the T cell receptor antigenic determinants are most likely carried by the alpha chain alone or by a complementation product of the V alpha FN1-18 with the V beta of BW5147. V beta FN1-18 represents a previously undescribed T cell receptor V region.


Opioid Crisis: No Easy Fix to Its Social and Economic Determinants.
The accepted wisdom about the US overdose crisis singles out prescribing as the causative vector. Although drug supply is a key factor, we posit that the crisis is fundamentally fueled by economic and social upheaval, its etiology closely linked to the role of opioids as a refuge from physical and psychological trauma, concentrated disadvantage, isolation, and hopelessness. Overreliance on opioid medications is emblematic of a health care system that incentivizes quick, simplistic answers to complex physical and mental health needs. In an analogous way, simplistic measures to cut access to opioids offer illusory solutions to this multidimensional societal challenge. We trace the crisis' trajectory through the intertwined use of opioid analgesics, heroin, and fentanyl analogs, and we urge engaging the structural determinants lens to address this formidable public health emergency. A broad focus on suffering should guide both patient- and community-level interventions.


Population genomics of secondary contact.
One common form of reticulate evolution arises as a consequence of secondary contact between previously allopatric populations. Using extensive coalescent simulations, we describe the conditions for, and extent of, the introgression of genetic material into the genome of a colonizing population from an endemic population. The simulated coalescent histories are sampled from models that describe the evolution of entire chromosomes, thereby allowing the expected length of introgressed haplotypes to be estimated. The results indicate that our ability to identify reticulate evolution from genetic data is highly variable and depends critically upon the duration of the period of allopatry, the timing of the secondary contact event, as well as the sizes of the populations at the time of contact. One particularly interesting result arises when secondary contact occurs close to the time of a severe founder event, in this case, genetic introgression can be substantially more difficult to detect. However, if secondary contact occurs after such a founding event, when the range of the colonizing population increases, introgression is more readily detectable across the genome. This result may have important implications for our ability to detect introgression between ancestrally bottlenecked modern human populations and archaic hominin species, such as Neanderthals.


Cellular expression of gut chitinase mRNA in the gastrointestinal tract of mice and chickens.
Recently, the second mammalian chitinase, designated acidic mammalian chitinase (AMCase), has been identified in human, mouse, and cow. In contrast to the earlier identified macrophage-derived chitinase (chitotriosidase), this chitinase is richly expressed in the gastrointestinal (GI) tract, suggesting its role in digestion of chitin-containing foods as well as defense against chitin-coated microorganisms and parasites. This in situ hybridization study first revealed cellular localization of the gut-type chitinase in the mouse and chicken. In adult mice, the parotid gland, von Ebner's gland, and gastric chief cells, all of which are exocrine cells of the serous type, expressed the gut chitinase mRNA. In the chicken, oxyntico-peptic cells in glandular stomach (proventriculus) and hepatocytes expressed the chitinase mRNA. Because cattle produce the gut chitinase (chitin-binding protein b04) only in the liver, the gut chitinases in mammals and birds have three major sources of production, i.e., the salivary gland, stomach, and liver. During ontogenetic development, the expression level in the parotid gland and stomach of mice increased to the adult level before weaning, whereas in the stomach of chickens intense signals were detectable in embryos from incubation day 7.


Thyroid Cancer Epidemiology in South Spain: a population-based time trend study.
Thyroid cancer (TC) is the most common malignant disease of the endocrine system. The aim of this study was to analyze incidence and mortality trends of TC (C73 according to ICD-O-3) in Granada (Southern Spain) during the period 1985-2013, by sex, age, and histological type. This is a population-based cross-sectional study. Incidence data were obtained from the population-based Cancer Registry of Granada. All newly diagnosed cases of thyroid cancer over the period 1985-2013 were included. Joinpoint regression analysis with age-standardized rates were used to estimate annual percentage change (APC), CI 95% and turning points in trends. Results are presented by sex, age group, and histological type. During the study period there were 1265 diagnosed cases of TC in Granada (72.6% in women). Incidence trends significantly increased in both men (APC: + 5.4%) and women (APC: + 4.7%). The most common histological types in both sexes were papillary (74.8%) and follicular (16.8%). The incidence has increased during the study period mainly due to papillary carcinoma, which has increased annually around 6% in both sexes. TC mortality trend during this period decreased in men (APC: -0.3%) and women (APC: -2.3%). Our data showed an increasing trend in incidence of thyroid cancer in Granada, especially in women between 55-64 years. Mortality showed a slight decrease trend during the study period in both sexes. Papillary carcinoma was the most common histological type, with an increase of the relative weight of papillary microcarcinomas. Our study is in accordance with the European and worldwide trends in thyroid cancer incidence and mortality and sex differences.


Stereotactic radiosurgery with and without checkpoint inhibition for patients with metastatic non-small cell lung cancer to the brain: a matched cohort study.
Immune checkpoint inhibitors (ICIs) improve survival in patients with advanced non-small cell lung cancer (NSCLC). Clinical trials examining the efficacy of ICIs in patients with NSCLC excluded patients with untreated brain metastases (BMs). As stereotactic radiosurgery (SRS) is commonly employed for NSCLC-BMs, the authors sought to define the safety and radiological and clinical outcomes for patients with NSCLC-BMs treated with concurrent ICI and SRS. A retrospective matched cohort study was performed on patients who had undergone SRS for one or more NSCLC-derived BMs. Two matched cohorts were identified: one that received ICI before or after SRS within a 3-month period (concurrent ICI) and one that did not (ICI naive). Locoregional tumor control, peritumoral edema, and central nervous system (CNS) adverse events were compared between the two cohorts. Seventeen patients (45 BMs) and 34 patients (92 BMs) composed the concurrent-ICI and ICI-naive cohorts, respectively. There was no statistically significant difference in overall survival (HR 0.99, 95% CI 0.39-2.52, p = 0.99) or CNS progression-free survival (HR 2.18, 95% CI 0.72-6.62, p = 0.11) between the two groups. Similarly, the 12-month local tumor control rate was 84.9% for tumors in the concurrent-ICI cohort versus 76.3% for tumors in the ICI-naive cohort (p = 0.94). Further analysis did reveal that patients receiving concurrent ICI had increased rates of CNS complete response for BMs treated with SRS (8/16 [50%] vs 5/32 [15.6%], p = 0.012) per the Response Assessment in Neuro-Oncology (RANO) criteria. There was also a shorter median time to BM regression in the concurrent-ICI cohort (2.5 vs 3.1 months, p < 0.0001). There was no increased rate of radiation necrosis or intratumoral hemorrhage in the patients receiving concurrent ICI (5.9% vs 2.9% in ICI-naive cohort, p = 0.99). There was no significant difference in the rate of peritumoral edema progression between the two groups (concurrent ICI: 11.1%, ICI naive: 21.7%, p = 0.162). The concurrent use of ICI and SRS to treat NSCLC-BM was well tolerated while providing more rapid BM regression. Concurrent ICI did not increase peritumoral edema or rates of radiation necrosis. Further studies are needed to evaluate whether combined ICI and SRS improves progression-free survival and overall survival for patients with metastatic NSCLC.


Parent perceptions of early prognostic encounters following children's severe traumatic brain injury: 'locked up in this cage of absolute horror'.
Little guidance exists for discussing prognosis in early acute care with parents following children's severe traumatic brain injury (TBI). Providers' beliefs about truth-telling can shape what is said, how it is said and how providers respond to parents. This study was part of a large qualitative study conducted in the US (42 parents/37 families) following children's moderate-to-severe TBI (2005-2007). Ethnography of speaking was used to analyse interviews describing early acute care following children's severe TBI (29 parents/25 families). Parents perceived that: (a) parents were disadvantaged by provider delivery; (b) negative outcome values dominated some provider's talk; (c) truth-telling involves providers acknowledging all possibilities; (d) framing the child's prognosis with negative medical certainty when there is some uncertainty could damage parent-provider relationships; (e) parents needed to remain optimistic; and (f) children's outcomes could differ from providers' early acute care prognostications. Parents blatantly and tacitly revealed their beliefs that providers play an important role in shaping parent reception of and synthesis of prognostic information, which constructs the family's ability to cope and participate in shared decision-making. Negative medical certainty created a fearful or threatening environment that kept parents from being fully informed.


Quality improvement in neurology: dementia management quality measures.
Professional and advocacy organizations have long urged that dementia should be recognized and properly diagnosed. With the passage of the National Alzheimer's Project Act in 2011, an Advisory Council for Alzheimer's Research, Care, and Services was convened to advise the Department of Health and Human Services. In May 2012, the Council produced the first National Plan to address Alzheimer's disease, and prominent in its recommendations is a call for quality measures suitable for evaluating and tracking dementia care in clinical settings. Although other efforts have been made to set dementia care quality standards, such as those pioneered by RAND in its series Assessing Care of Vulnerable Elders (ACOVE), practitioners, healthcare systems, and insurers have not widely embraced implementation. This executive summary (full manuscript available at www.neurology.org) reports on a new measurement set for dementia management developed by an interdisciplinary Dementia Measures Work Group (DWG) representing the major national organizations and advocacy organizations concerned with the care of individuals with dementia. The American Academy of Neurology (AAN), the American Geriatrics Society, the American Medical Directors Association, the American Psychiatric Association, and the American Medical Association-convened Physician Consortium for Performance Improvement led this effort. The ACOVE measures and the measurement set described here apply to individuals whose dementia has already been identified and properly diagnosed. Although similar in concept to ACOVE, the DWG measurement set differs in several important ways; it includes all stages of dementia in a single measure set, calls for the use of functional staging in planning care, prompts the use of validated instruments in patient and caregiver assessment and intervention, highlights the relevance of using palliative care concepts to guide care before the advanced stages of illness, and provides evidence-based support for its recommendations and guidance on the selection of instruments useful in tracking patient-centered outcomes. It also specifies annual reassessment and updating of interventions and care plans for dementia-related problems that affect families and other caregivers as well as individuals with dementia. Here, a brief synopsis of why major reforms in healthcare design and delivery are needed to achieve substantive improvements in the quality of care is first provided, and then the final measures approved for publication, dissemination, and implementation are listed.


CUDASW++2.0: enhanced Smith-Waterman protein database search on CUDA-enabled GPUs based on SIMT and virtualized SIMD abstractions.
Due to its high sensitivity, the Smith-Waterman algorithm is widely used for biological database searches. Unfortunately, the quadratic time complexity of this algorithm makes it highly time-consuming. The exponential growth of biological databases further deteriorates the situation. To accelerate this algorithm, many efforts have been made to develop techniques in high performance architectures, especially the recently emerging many-core architectures and their associated programming models. This paper describes the latest release of the CUDASW++ software, CUDASW++ 2.0, which makes new contributions to Smith-Waterman protein database searches using compute unified device architecture (CUDA). A parallel Smith-Waterman algorithm is proposed to further optimize the performance of CUDASW++ 1.0 based on the single instruction, multiple thread (SIMT) abstraction. For the first time, we have investigated a partitioned vectorized Smith-Waterman algorithm using CUDA based on the virtualized single instruction, multiple data (SIMD) abstraction. The optimized SIMT and the partitioned vectorized algorithms were benchmarked, and remarkably, have similar performance characteristics. CUDASW++ 2.0 achieves performance improvement over CUDASW++ 1.0 as much as 1.74 (1.72) times using the optimized SIMT algorithm and up to 1.77 (1.66) times using the partitioned vectorized algorithm, with a performance of up to 17 (30) billion cells update per second (GCUPS) on a single-GPU GeForce GTX 280 (dual-GPU GeForce GTX 295) graphics card. CUDASW++ 2.0 is publicly available open-source software, written in CUDA and C++ programming languages. It obtains significant performance improvement over CUDASW++ 1.0 using either the optimized SIMT algorithm or the partitioned vectorized algorithm for Smith-Waterman protein database searches by fully exploiting the compute capability of commonly used CUDA-enabled low-cost GPUs.


Flatulence and other discomforts associated with consumption of cowpea (Vigna unguiculata).
Abdominal discomfort after eating cowpeas is known to be a major constraint on their greater consumption. Problems associated with cowpea consumption were identified by questionnaire in 448 randomly selected families. Some (28%) of the respondents had never experienced flatulence. Those who did said it occurred when cowpeas were eaten at all (16.7%), as dinner (42%) or without other foods (15%). A subsample of 40 people who complained of serious abdominal discomfort were fed cowpeas cooked by eight different methods at three consecutive dinners for each method. The problems reported were indigestion, vomiting, diarrhoea, increased belching, bad breath, offensive stool, flatulence, constipation, mild abdominal discomfort and sleepiness. Many respondents complained of mild abdominal discomfort with undehulled cowpeas (72.5%) and dehulled cowpeas (42.5%) that had been cooked at atmospheric pressure. Only 12.5% of the respondents complained of discomfort with dehulled cowpeas cooked under extra pressure. Thus, dehulling resulted in substantial reduction in the frequency and incidence of reported discomforts but pressure cooking also had beneficial effects, probably because of the higher cooking temperature attained.


Antecedents and Outcomes of Abnormal Cranial Imaging in Moderately Preterm Infants.
To describe the frequency and findings of cranial imaging in moderately preterm infants (born at 290/7-336/7 weeks of gestation) across centers, and to examine the association between abnormal imaging and clinical characteristics. We used data from the Neonatal Research Network Moderately Preterm Registry, including the most severe early (≤28 days) and late (>28 days) cranial imaging. Stepwise logistic regression and CART analysis were performed after adjustment for gestational age, antenatal steroid use, and center. Among 7021 infants, 4184 (60%) underwent cranial imaging. These infants had lower gestational ages and birth weights and higher rates of small for gestational age, outborn birth, cesarean delivery, neonatal resuscitation, and treatment with surfactant, compared with those without imaging (P < .0001). Imaging abnormalities noted in 15% of the infants included any intracranial hemorrhage (13.2%), grades 3-4 intracranial hemorrhage (1.7%), cystic periventricular leukomalacia (2.6%), and ventriculomegaly (6.6%). Histologic chorioamnionitis (OR, 1.47; 95% CI, 1.19-1.83), gestational age (0.95; 95% CI, 0.94-0.97), antenatal steroids (OR, 0.55; 95% CI, 0.41-0.74), and cesarean delivery (OR, 0.66; 95% CI, 0.53-0.81) were associated with abnormal imaging. The center with the highest rate of cranial imaging, compared with the lowest, had a higher risk of abnormal imaging (OR, 2.08; 95% CI, 1.10-3.92). On the classification and regression-tree model, cesarean delivery, center, antenatal steroids, and chorioamnionitis, in that order, predicted abnormal imaging. Among the 60% of moderately preterm infants with cranial imaging, 15% had intracranial hemorrhage, cystic periventricular leukomalacia or late ventriculomegaly. Further correlation of imaging and long-term neurodevelopmental outcomes in moderately preterm infants is needed.


The classification and labeling of nonhomosexual gender dysphorias.
This report suggests systematic strategies for the descriptive classification of nonhomosexual gender identity disorders, based on clinical observations and research findings. The classification of biological males is considered first. A review of cross-gender taxonomies shows that previous observers have identified and labeled a homosexual type far more consistently than any other category of male gender dysphoric. It is suggested that the apparent difficulty in differentiating reliably among the nonhomosexual types results from the sharing of many overlapping characteristics by the various groups. This is supported by a review of informal, mostly clinical, observations and by the findings of three studies designed to test the hypothesis that the nonhomosexual gender dysphorias, together with transvestism, constitute a family of related disorders in men. It is concluded that the main varieties of nonhomosexual gender dysphoria are more similar to each other than any of them is to the homosexual type. Two recommendations, based on the foregoing review, are offered for the classification of male gender dysphorics in research studies. When the number of subjects is small, they may be classified simply as homosexual or nonhomosexual. When the number is larger, the nonhomosexual cases may be classified as heterosexual, bisexual, or analloerotic (unattracted to male or female partners, but not necessarily devoid of sexual drive or activities).


Curriculum strategies to improve baccalaureate nursing information technology outcomes.
Improving information technology (IT) outcomes is a top nursing education priority. Improving care access, quality, and cost effectiveness, IT skills are vital for professional development and advancement. Nursing programs have embraced distance learning and added informatics content, courses, and specific technologies; however, undergraduates' and educators' skills are still considered inadequate. Meanwhile, the Nursing Informatics specialty has moved beyond IT competency articulation and measurement. It is promoting information literacy to support evidence-based practice and the cultivation of clinical wisdom. The Technology Informatics Guiding Education Reform (TIGER) Initiative, a coalition aiming to advance IT outcomes in nursing education, has cited benchmarking and sharing best practices as key to achieving its goals. Thus, this article reports on the process, results, and implications of a project using curriculum strategies to enhance IT outcomes. A 3-year action plan directed faculty, student, and agency evaluation, curriculum mapping, model learning module, and documentation development.


Editing an α-globin enhancer in primary human hematopoietic stem cells as a treatment for β-thalassemia.
β-Thalassemia is one of the most common inherited anemias, with no effective cure for most patients. The pathophysiology reflects an imbalance between α- and β-globin chains with an excess of free α-globin chains causing ineffective erythropoiesis and hemolysis. When α-thalassemia is co-inherited with β-thalassemia, excess free α-globin chains are reduced significantly ameliorating the clinical severity. Here we demonstrate the use of CRISPR/Cas9 genome editing of primary human hematopoietic stem/progenitor (CD34+) cells to emulate a natural mutation, which deletes the MCS-R2 α-globin enhancer and causes α-thalassemia. When edited CD34+ cells are differentiated into erythroid cells, we observe the expected reduction in α-globin expression and a correction of the pathologic globin chain imbalance in cells from patients with β-thalassemia. Xenograft assays show that a proportion of the edited CD34+ cells are long-term repopulating hematopoietic stem cells, demonstrating the potential of this approach for translation into a therapy for β-thalassemia.β-thalassemia is characterised by the presence of an excess of α-globin chains, which contribute to erythrocyte pathology. Here the authors use CRISP/Cas9 to reduce α-globin expression in hematopoietic precursors, and show effectiveness in xenograft assays in mice.


Gel-free IEF in a membrane-sealed multicompartment cell for proteome prefractionation.
A minidevice for performing gel-free proteome prefractionation via conventional IEF in soluble carrier ampholyte buffers is reported here. It consists of a compact block of polyoxymethylene in which eight samples and two electrode chambers are machined. Each of the eight sample chambers can be filled with up to 120 microL of sample and has the following size: 7 mm width, 3 mm depth and 10 mm height. The anodic and cathodic compartments have the same width and height as the sample chambers, but with a depth of 6 mm, thus accepting up to 250 microL of electrodic solutions. Focusing is in general accomplished in 2 h with a voltage gradient of up to 1000 V (7 cm electrode distance). Easy fractionation and collection of the content of the eight chambers is achieved by simply pressing a rubber diaphragm against the edges of the thin walls separating each well, this automatically breaking liquid continuity. The performance of this device has been tested by subfractionating total cell lysates of a human cancer cell line (U2Os) and of Escherichia coli bacterial cells, and by analysing the content of each chamber by mono-dimensional SDS-PAGE and 2-D maps.


Genetic Dissection of Morphometric Traits Reveals That Phytochrome B Affects Nucleus Size and Heterochromatin Organization in Arabidopsis thaliana.
Microscopically visible chromatin is partitioned into two major components in Arabidopsis thaliana nuclei. On one hand, chromocenters are conspicuous foci of highly condensed "heterochromatic" domains that contain mostly repeated sequences. On the other hand, less condensed and gene-rich "euchromatin" emanates from these chromocenters. This differentiation, together with the dynamic nature of chromatin compaction in response to developmental and environmental stimuli, makes Arabidopsis a powerful system for studying chromatin organization and dynamics. Heterochromatin dynamics can be monitored by measuring the Heterochromatin Index, i.e., the proportion of nuclei displaying well-defined chromocenters, or the DNA fraction of chromocenters (relative heterochromatin fraction). Both measures are composite traits, thus their values represent the sum of effects of various underlying morphometric properties. We exploited genetic variation between natural occurring accessions to determine the genetic basis of individual nucleus and chromocenter morphometric parameters (area, perimeter, density, roundness, and heterogeneity) that together determine chromatin compaction. Our novel reductionist genetic approach revealed quantitative trait loci (QTL) for all measured traits. Genomic colocalization among QTL was limited, which suggests a complex genetic regulation of chromatin compaction. Yet genomic intervals of QTL for nucleus size (area and perimeter) both overlap with a known QTL for heterochromatin compaction that is explained by natural polymorphism in the red/far-red light and temperature receptor Phytochrome B. Mutant analyses and genetic complementation assays show that Phytochrome B is a negative regulator of nucleus size, revealing that perception of climatic conditions by a Phytochrome-mediated hub is a major determinant for coordinating nucleus size and heterochromatin compaction.


ACOG Clinical Updates Summary: Incidental Radiologic Findings: Primary and Preventive Care Review.
Over the past several decades, the use of cross-sectional imaging has steadily increased largely because of increasing refinements in imaging technology. The progressive improvement in both spatial and temporal resolution of imaging modalities over the years has enabled radiologists to diagnose and characterize disorders with increasing accuracy. However, improved resolution has led to the increased detection of imaging findings that may or may not be clinically relevant. Such incidental findings or "incidentalomas" may be difficult to differentiate from clinically relevant lesions. Radiologists may provide disparate recommendations regarding incidental or indeterminate findings when interpreting results of gynecologic and obstetric imaging examinations in routine clinical practice. Vague recommendations pose challenges for referring clinicians who are unable to determine the clinical relevance of such lesions. Therefore, a general awareness of incidental lesions for any given abdominal or thoracic organ is important for obstetrician-gynecologists involved in the management of patients who require imaging studies. The aim of this monograph is to aid obstetrician-gynecologists in the detection, characterization, and management of incidentally detected lesions that may be encountered on routine women's imaging examinations.


Hydration of calcium oxide surface predicted by reactive force field molecular dynamics.
In this work, we present the parametrization of Ca-O/H interactions within the reactive force field ReaxFF, and its application to study the hydration of calcium oxide surface. The force field has been fitted using density functional theory calculations on gas phase calcium-water clusters, calcium oxide bulk and surface properties, calcium hydroxide, bcc and fcc Ca, and proton transfer reactions in the presence of calcium. Then, the reactive force field has been used to study the hydration of the calcium oxide {001} surface with different water contents. Calcium oxide is used as a catalyzer in many applications such as CO(2) sequestration and biodiesel production, and the degree of surface hydroxylation is a key factor in its catalytic performance. The results show that the water dissociates very fast on CaO {001} bare surfaces without any defect or vacancy. The surface structure is maintained up to a certain amount of water, after which the surface undergoes a structural rearrangement, becoming a disordered calcium hydroxyl layer. This transformation is the most probable reason for the CaO catalytic activity decrease.


Improving safety of the continual reassessment method via a modified allocation rule.
This article proposes a novel criterion for the allocation of patients in phase I dose-escalation clinical trials, aiming to find the maximum tolerated dose (MTD). Conventionally, using a model-based approach, the next patient is allocated to the dose with the toxicity estimate closest (in terms of the absolute or squared distance) to the maximum acceptable toxicity. This approach, however, ignores the uncertainty in point estimates and ethical concerns of assigning a lot of patients to overly toxic doses. In fact, balancing the trade-off between how accurately the MTD can be estimated and how many patients would experience adverse events is one of the primary challenges in phase I studies. Motivated by recent discussions in the theory of estimation in restricted parameter spaces, we propose a criterion that allows to balance these explicitly. The criterion requires a specification of one additional parameter only that has a simple and intuitive interpretation. We incorporate the proposed criterion into the one-parameter Bayesian continual reassessment method and show, using simulations, that it can result in similar accuracy on average as the original design, but with fewer toxic responses on average. A comparison with other model-based dose-escalation designs, such as escalation with overdose control and its modifications, demonstrates that the proposed design can result in either the same mean accuracy as alternatives but fewer toxic responses or in a higher mean accuracy but the same number of toxic responses. Therefore, the proposed design can provide a better trade-off between the accuracy and the number of patients experiencing adverse events, making the design a more ethical alternative over some of the existing methods for phase I trials.


Depression from the perspective of modern and Persian medicine.
Depression is one of the five most-common diseases globally, and is expected to be the second leading cause of disability by 2020 and its economic and social burden is a major problem worldwide. The aim of this research was to elucidate the causes and symptoms of depression according to Persian Medicine (PM) and classic medicine. In this study, works that were investigated were the Canon of Medicine, Al-Hawi Fi Teb, Kamel Al-Sina'a, Zakhireh Kharazmshahi and Exir A'azam. Classic medicine sources investigated were Kaplan and Sadock's Synopsis of Psychiatry and related articles in the Web of Science, Medline, Scopus, SID and Magiran. Research was done from January through April 2017, using keywords. To explain the biologic causes, various factors including humoral dystemperaments, cold and hot dystemperaments of chief organs especially heart and brain and some qualitative and quantitative changes in medical spirit should be considered. According to manuscripts some mental-emotional events in life can cause these changes. They independently may cause depression. Semiologically some symptoms and signs happen consequently to in the above-mentioned causes which are in common with depression signs and symptoms including grief, crying, low libido, weight loss, appetite and sleep disorders, exhaustion, slow cognitive processing, indecisiveness and willingness to die. The major biological causes of depression is a group of dystemperamental syndromes (hot, cold, dry, and wet) on different bodily structures (humors, organs, and spirits). So preventive and therapeutic strategies for depression couldn't be the same for all patients and the treatment should be designed according to the exact diagnosis.


Assessment of the anthelmintic activity of medicinal plant extracts and purified condensed tannins against free-living and parasitic stages of Oesophagostomum dentatum.
Plant-derived condensed tannins (CT) show promise as a complementary option to treat gastrointestinal helminth infections, thus reducing reliance on synthetic anthelmintic drugs. Most studies on the anthelmintic effects of CT have been conducted on parasites of ruminant livestock. Oesophagostomum dentatum is an economically important parasite of pigs, as well as serving as a useful laboratory model of helminth parasites due to the ability to culture it in vitro for long periods through several life-cycle stages. Here, we investigated the anthelmintic effects of CT on multiple life cycle stages of O. dentatum. Extracts and purified fractions were prepared from five plants containing CT and analysed by HPLC-MS. Anthelmintic activity was assessed at five different stages of the O. dentatum life cycle; the development of eggs to infective third-stage larvae (L3), the parasitic L3 stage, the moult from L3 to fourth-stage larvae (L4), the L4 stage and the adult stage. Free-living larvae of O. dentatum were highly susceptible to all five plant extracts. In contrast, only two of the five extracts had activity against L3, as evidenced by migration inhibition assays, whilst three of the five extracts inhibited the moulting of L3 to L4. All five extracts reduced the motility of L4, and the motility of adult worms exposed to a CT-rich extract derived from hazelnut skins was strongly inhibited, with electron microscopy demonstrating direct damage to the worm cuticle and hypodermis. Purified CT fractions retained anthelmintic activity, and depletion of CT from extracts by pre-incubation in polyvinylpolypyrrolidone removed anthelmintic effects, strongly suggesting CT as the active molecules. These results suggest that CT may have promise as an alternative parasite control option for O. dentatum in pigs, particularly against adult stages. Moreover, our results demonstrate a varied susceptibility of different life-cycle stages of the same parasite to CT, which may offer an insight into the anthelmintic mechanisms of these commonly found plant compounds.


Cost-Effectiveness Analysis to Inform Randomized Controlled Trial Design in Chronic Pain Research: Methods for Guiding Decisions on the Addition of a Run-In Period.
Run-In (RI) periods can be used to improve the validity of randomized controlled trials (RCTs), but their utility in Chronic Pain (CP) RCTs is debated. Cost-effectiveness analysis (CEA) methods are commonly used in evaluating the results of RCTs, but they are seldom used for designing RCTs. We present a step-by-step overview to objectively design RCTs via CEA methods and specifically determine the cost effectiveness of a RI period in a CP RCT. We applied the CEA methodology to data obtained from several noninvasive brain stimulation CP RCTs, specifically focusing on (1) defining the CEA research question, (2) identifying RCT phases and cost ingredients, (3) discounting, (4) modeling the stochastic nature of the RCT, and (5) performing sensitivity analyses. We assessed the average cost-effectiveness ratios and incremental cost effectiveness ratios of varied RCT designs and the impact on cost-effectiveness by the inclusion of a RI period vs. No-Run-In (NRI) period. We demonstrated the potential impact of varying the number of institutions, number of patients that could be accommodated per institution, cost and effectiveness discounts, RCT component costs, and patient adherence characteristics on varied RI and NRI RCT designs. In the specific CP RCT designs that we analyzed, we demonstrated that lower patient adherence, lower baseline assessment costs, and higher treatment costs all necessitated the inclusion of an RI period to be cost-effective compared to NRI RCT designs. Clinical trialists can optimize CP RCT study designs and make informed decisions regarding RI period inclusion/exclusion via CEA methods.


Seroprevalence of Antibodies to SARS-CoV-2 in 10 Sites in the United States, March 23-May 12, 2020.
Reported cases of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection likely underestimate the prevalence of infection in affected communities. Large-scale seroprevalence studies provide better estimates of the proportion of the population previously infected. To estimate prevalence of SARS-CoV-2 antibodies in convenience samples from several geographic sites in the US. This cross-sectional study performed serologic testing on a convenience sample of residual sera obtained from persons of all ages. The serum was collected from March 23 through May 12, 2020, for routine clinical testing by 2 commercial laboratory companies. Sites of collection were San Francisco Bay area, California; Connecticut; south Florida; Louisiana; Minneapolis-St Paul-St Cloud metro area, Minnesota; Missouri; New York City metro area, New York; Philadelphia metro area, Pennsylvania; Utah; and western Washington State. Infection with SARS-CoV-2. The presence of antibodies to SARS-CoV-2 spike protein was estimated using an enzyme-linked immunosorbent assay, and estimates were standardized to the site populations by age and sex. Estimates were adjusted for test performance characteristics (96.0% sensitivity and 99.3% specificity). The number of infections in each site was estimated by extrapolating seroprevalence to site populations; estimated infections were compared with the number of reported coronavirus disease 2019 (COVID-19) cases as of last specimen collection date. Serum samples were tested from 16 025 persons, 8853 (55.2%) of whom were women; 1205 (7.5%) were 18 years or younger and 5845 (36.2%) were 65 years or older. Most specimens from each site had no evidence of antibodies to SARS-CoV-2. Adjusted estimates of the proportion of persons seroreactive to the SARS-CoV-2 spike protein antibodies ranged from 1.0% in the San Francisco Bay area (collected April 23-27) to 6.9% of persons in New York City (collected March 23-April 1). The estimated number of infections ranged from 6 to 24 times the number of reported cases; for 7 sites (Connecticut, Florida, Louisiana, Missouri, New York City metro area, Utah, and western Washington State), an estimated greater than 10 times more SARS-CoV-2 infections occurred than the number of reported cases. During March to early May 2020, most persons in 10 diverse geographic sites in the US had not been infected with SARS-CoV-2 virus. The estimated number of infections, however, was much greater than the number of reported cases in all sites. The findings may reflect the number of persons who had mild or no illness or who did not seek medical care or undergo testing but who still may have contributed to ongoing virus transmission in the population.


Effect of travel distance on household demand for typhoid vaccines: implications for planning.
Typhoid fever causes millions of illnesses and hundreds of thousands of deaths yearly. Vaccinations would mitigate this problem, but the users would probably have to pay some or most of the cost. Several willingness-to-pay studies have assessed the effect of price on private demand to provide a basis for financial planning of campaigns, but the effect of travel distance, which is a potentially important determinant of demand, has not been studied. This paper thus has two objectives: (i) conduct a willingness-to-pay survey to assess the effects of distance, price and other variables on the private demand for typhoid vaccinations in a rural township of China where a campaign is under consideration; and (ii) embed the demand function in a mathematical model to address three planning questions; should each village have its own clinic, would one clinic be best or should the number of clinics be something in-between? Private vaccine demand was found to depend on and be inelastic with respect to both price and travel distance. A 1-km increase in distance caused the number of vaccinations demanded to decrease the same as a $0.5 increase in price. Thus, the marginal rate of substitution was $0.5 per km. A single clinic would be best for the township only if diseconomies of scale in supplying vaccinations exceeded the marginal rate of substitution. Otherwise, multiple clinics close to users would be optimal. Thus, deciding the number, location and capacities of clinics for vaccination planning is as important as deciding what price(s) to charge.


Genetic variants in the vitamin d receptor are associated with advanced prostate cancer at diagnosis: findings from the prostate testing for cancer and treatment study and a systematic review.
Low levels of plasma vitamin D have been implicated as a possible risk factor for both prostate cancer incidence and advanced disease, and recent phase II trials suggest that vitamin D supplementation might delay progression of prostate cancer. Common polymorphisms in the vitamin D receptor (VDR) are associated with VDR activity and are therefore potentially useful proxies for assessing whether vitamin D is causally related to advanced prostate cancer. We genotyped five well-known VDR polymorphisms in 1,604 men with prostate cancer from the Prostate Testing for Cancer and Treatment study. Our aim was to examine the association between VDR polymorphisms and cancer stage (localized versus advanced) as well as cancer grade (Gleason score <7 versus >or=7). Moreover, we also carried out a systematic review and meta-analysis of 13 similar studies. As a result of our meta-analysis, we revealed three polymorphisms, BsmI, ApaI, and TaqI, associated with high Gleason score with an overall summary odds ratios (95% confidence intervals) of 1.12 (1.00-1.25; bb versus BB + Bb), 1.25 (1.02-1.53; aa versus AA + Aa), and 0.82 (0.69-0.98; Tt + tt versus TT), respectively. The haplotype analysis revealed that the BsmI (B)-ApaI (A)-TaqI (t) participants compared with BsmI (b)-ApaI (a)-TaqI (T) individuals were less likely to have high Gleason scores (odds ratio, 0.84; 95% confidence interval, 0.71-1.00; P(unadjusted) = 0.050; P(adjusted) = 0.014). Our finding provides some support for the hypothesis that low levels of vitamin D may increase the risk of prostate cancer progression.


Tumor-selective drug activation: a GDEPT approach utilizing cytochrome P450 1A1 and AQ4N.
Drug metabolizing transgene products, which activate bioreductive cytotoxins, can be used to target treatment-resistant hypoxic tumors. The prodrug AQ4N is bioreduced in hypoxic cells by cytochrome P450s (CYPs) to the cytotoxin AQ4. Previously we have shown that intra-tumoral injection of CYP3A4 and CYP2B6 transgenes with AQ4N and radiation inhibits tumor growth. Here we examine the ability of other CYPs, in particular CYP1A1, to metabolize AQ4N, and to enhance radiosensitization. Metabolism of AQ4N was assessed using microsomes prepared from baculovirus-infected cells transfected with various CYP isoforms. AQ4N metabolism was most efficient with CYP1A1 (66.7 nmol/min/pmol) and 2B6 (34.4 nmol/min/pmol). Transient transfection of human CYP1A1+/-CYP reductase (CYPRED) was investigated in hypoxic RIF-1 mouse cells in vitro using the alkaline comet assay. There was a significant increase in DNA damage following transient transfection of CYP1A1 compared to non-transfected cells; inclusion of CYPRED provided no additional effect. In vivo, a single intra-tumoral injection of a CYP1A1 construct in combination with AQ4N (100 mg/kg i.p.) and 20 Gy X-rays caused a 16-day delay in tumor regrowth compared to tumors receiving AQ4N plus radiation and empty vector (P=0.0344). The results show the efficacy of a CYP1A1-mediated GDEPT strategy for bioreduction of AQ4N.


Informing trait-based ecology by assessing remotely sensed functional diversity across a broad tropical temperature gradient.
Spatially continuous data on functional diversity will improve our ability to predict global change impacts on ecosystem properties. We applied methods that combine imaging spectroscopy and foliar traits to estimate remotely sensed functional diversity in tropical forests across an Amazon-to-Andes elevation gradient (215 to 3537 m). We evaluated the scale dependency of community assembly processes and examined whether tropical forest productivity could be predicted by remotely sensed functional diversity. Functional richness of the community decreased with increasing elevation. Scale-dependent signals of trait convergence, consistent with environmental filtering, play an important role in explaining the range of trait variation within each site and along elevation. Single- and multitrait remotely sensed measures of functional diversity were important predictors of variation in rates of net and gross primary productivity. Our findings highlight the potential of remotely sensed functional diversity to inform trait-based ecology and trait diversity-ecosystem function linkages in hyperdiverse tropical forests.


A model to predict survival following liver retransplantation.
In the current era of critical-organ shortage, one of the most controversial questions facing transplantation teams is whether hepatic retransplantation, which has historically been associated with increased resource utilization and diminished survival, should be offered to a patient whose first allograft is failing. Retransplantation effectively denies access to orthotopic liver transplantation (OLT) to another candidate and further depletes an already-limited organ supply. The study group was comprised of 1,356 adults undergoing hepatic retransplantation in the United States between 1990 and 1996 as reported to the United Network for Organ Sharing (UNOS). We analyzed numerous donor and recipient variables and created Cox proportional-hazards models on 900 randomly chosen patients, validating the results on the remaining cohort. Five variables consistently provided significant predictive power and made up the final model: age, bilirubin, creatinine, UNOS status, and cause of graft failure. Although both hepatitis C seropositivity and donor age were significant by univariate and multivariate analyses, neither contributed independently to the estimation of prognosis when added to the final model. The final model was highly predictive of survival (whole model chi2 = 139.63). The risk scores for individual patients were calculated, and patients were assigned into low-, medium-, and high-risk groups (P <.00001). The low degree of uncertainty in the probability estimates as reflected by confidence intervals, even in our high-risk patients, underscores the applicability of our model as an adjunct to clinical judgment. We have developed and validated a model that uses five readily accessible "bedside" variables to accurately predict survival in patients undergoing liver retransplantation.


Imbalance between pSmad3 and Notch induces CDK inhibitors in old muscle stem cells.
Adult skeletal muscle robustly regenerates throughout an organism's life, but as the muscle ages, its ability to repair diminishes and eventually fails. Previous work suggests that the regenerative potential of muscle stem cells (satellite cells) is not triggered in the old muscle because of a decline in Notch activation, and that it can be rejuvenated by forced local activation of Notch. Here we report that, in addition to the loss of Notch activation, old muscle produces excessive transforming growth factor (TGF)-beta (but not myostatin), which induces unusually high levels of TGF-beta pSmad3 in resident satellite cells and interferes with their regenerative capacity. Importantly, endogenous Notch and pSmad3 antagonize each other in the control of satellite-cell proliferation, such that activation of Notch blocks the TGF-beta-dependent upregulation of the cyclin-dependent kinase (CDK) inhibitors p15, p16, p21 and p27, whereas inhibition of Notch induces them. Furthermore, in muscle stem cells, Notch activity determines the binding of pSmad3 to the promoters of these negative regulators of cell-cycle progression. Attenuation of TGF-beta/pSmad3 in old, injured muscle restores regeneration to satellite cells in vivo. Thus a balance between endogenous pSmad3 and active Notch controls the regenerative competence of muscle stem cells, and deregulation of this balance in the old muscle microniche interferes with regeneration.


Teicoplanin levels in bone and joint infections: are standard doses subtherapeutic?
Previously published data suggest that a trough serum teicoplanin level of > or = 20 mg/l is predictive of improved outcomes in serious staphylococcal infection. We investigated how dose regimen and patient characteristics impact on trough teicoplanin levels in patients with musculoskeletal infection, in order to help standardise teicoplanin use. We prospectively collected data for 141 clinically stable adults with bone and joint infection treated as outpatients with teicoplanin. Patients with end stage renal failure were excluded. The most frequently used teicoplanin dose regimens were 400 mg or 600 mg i.v. once daily. Trough levels were available for 78% of episodes, of which 51% were > or = 20 mg/l. Unsurprisingly, a level of > or = 20 mg/l occurred more often with a dose of 600 mg than with lower doses (p=0.005). There was no significant relationship between teicoplanin level and age, body weight or creatinine clearance, but male gender was associated with lower trough levels than female gender (p=0.03). These data suggest that teicoplanin levels of > or = 20 mg/l for bone and joint infection in stable adult patients are best achieved with a daily dose of at least 600 mg.


PGP9.5 methylation in diffuse-type gastric cancer.
Diffuse-type gastric cancer (DGC) is the most deadly form of gastric cancer and is frequently accompanied by peritoneal dissemination and metastasis. The specific molecular events involved in DGC pathogenesis remain elusive. Accumulating evidence of epigenetic inactivation in tumor suppressor genes led us to conduct a comprehensive screen to identify novel methylated genes in human cancers using pharmacologic unmasking and subsequent microarray analysis. We compared differential RNA expression profiles of DGC and intestinal-type gastric cancer (IGC) cell lines treated with 5-aza-2'-deoxycytidine using microarrays containing 22,284 genes. We identified 16 methylated genes, including many novel genes, in DGC cell lines and studied PGP9.5 with particular interest. In primary gastric cancers, PGP9.5 was found to be more frequently methylated in DGCs (78%) than in IGCs (36%; DGC versus IGC, P < 0.05). Furthermore, real-time methylation-specific PCR analysis of PGP9.5 showed relatively higher methylation levels in DGC than in IGC. Our data thus implicate a molecular event common in the DGC phenotype compared with IGC.


Three weeks of creatine monohydrate supplementation affects dihydrotestosterone to testosterone ratio in college-aged rugby players.
This study investigated resting concentrations of selected androgens after 3 weeks of creatine supplementation in male rugby players. It was hypothesized that the ratio of dihydrotestosterone (DHT, a biologically more active androgen) to testosterone (T) would change with creatine supplementation. Double-blind placebo-controlled crossover study with a 6-week washout period. Rugby Institute in South Africa. College-aged rugby players (n = 20) volunteered for the study, which took place during the competitive season. Subjects loaded with creatine (25 g/day creatine with 25 g/day glucose) or placebo (50 g/day glucose) for 7 days followed by 14 days of maintenance (5 g/day creatine with 25 g/day glucose or 30 g/day glucose placebo). Serum T and DHT were measured and ratio calculated at baseline and after 7 days and 21 days of creatine supplementation (or placebo). Body composition measurements were taken at each time point. After 7 days of creatine loading, or a further 14 days of creatine maintenance dose, serum T levels did not change. However, levels of DHT increased by 56% after 7 days of creatine loading and remained 40% above baseline after 14 days maintenance (P < 0.001). The ratio of DHT:T also increased by 36% after 7 days creatine supplementation and remained elevated by 22% after the maintenance dose (P < 0.01). Creatine supplementation may, in part, act through an increased rate of conversion of T to DHT. Further investigation is warranted as a result of the high frequency of individuals using creatine supplementation and the long-term safety of alterations in circulating androgen composition. STATEMENT OF CLINICAL RELEVANCE: Although creatine is a widely used ergogenic aid, the mechanisms of action are incompletely understood, particularly in relation to dihydrotestosterone, and therefore the long-term clinical safety cannot be guaranteed.


The effect of a residential care pharmacist on medication administration practices in aged care: A controlled trial.
With the ageing of the population also comes increasing comorbidities and the use of multiple medications and administration methods, along with greater susceptibility to adverse drug reactions. Dosage form modification to facilitate drug administration in older adults can be potentially problematic as altering the original licensed formulation can affect medication safety and efficacy. The reporting of adverse drug reactions and medication incidents is a key strategy in avoiding preventable adverse drug events for aged care residents. This study evaluated the effect of an on-site clinical pharmacist on reducing inappropriate dosage form modification and staff time spent on medication administration, and optimizing the documentation of drug allergies, adverse drug reactions and medication incidents. A pilot-controlled trial was performed in a purposive sample of two residential aged care homes. Both homes belonged to the same organization; the study site had 104 beds and the control site had 100 beds. All permanent residents were eligible for inclusion in the study if written consent was provided. A residential care pharmacist position was implemented at the study site for six months, with a focus on performing medication reviews and quality improvement activities. Observational audits of medication rounds were performed, and documentation relating to allergies, adverse drug reactions, and medication incidents was obtained from both sites before and after the pharmacist trial period. At the study site, there was a significant reduction over the trial in the proportion of inappropriate dosage form modification (from 24% to 0% of all dosage form modifications; P < 0.01). Mean time spent on medication rounds per resident reduced from 4.8 minutes per resident (SD 1.1) to 3.2 minutes per resident (SD 1.7) per round (P < 0.05). The incidence of previous allergy and adverse drug reaction documentation significantly improved from 77% of residents pre-study to 100% of residents post-study (P < 0.01). Mean monthly medication incident reports significantly improved from 13.3 (SD 7.4) pre-study to 25.7 (SD 10.8) post-study (P < 0.05). There was no change in these outcomes at the control site. Including a pharmacist in a residential aged care home can improve medication administration practices by reducing inappropriate dosage form modification and staff time spent on medication administration rounds, and increasing the documentation of resident allergies, adverse drug reactions and medication incidents. These findings warrant further exploration in a large randomized controlled trial.


Toward the diffraction limit with transmissive x-ray lenses in astronomy.
We develop an analytical approach to refractive, blazed diffractive, and achromatic x-ray lenses of scalable dimensions for energies from 1 to 20 keV. Based on the parabolic wave equation, their wideband imaging properties are compared and optimized for a given spectral range. Low-Z lens materials for massive cores and rugged alternatives, such as polycarbonate or Si for flat Fresnel components, are investigated with respect to their suitability for diffraction-limited high-energy astronomy. Properly designed "hybrid" combinations can serve as an approach to x-ray telescopes with an enhanced efficiency throughout the whole considered band, nearly regardless of their inherent absorption.


Evaluation of tumor-specific promoter activities in melanoma.
Gene therapy is a novel therapy for melanoma. To date, however, there is still no powerful tumor specific promoter (TSP) to restrict the transgene expression in melanoma cells. In order to define a useful TSP for targeting in the context of melanoma gene therapy, four promoters, the cyclooxygenase-2 (Cox-2), alpha-chemokine SDF-1 receptor (CXCR4), epithelial glycoprotein 2 (EGP-2), and survivin, were tested in both established melanoma cell lines and primary melanoma cells. We employed recombinant adenoviral vectors (reAds) each with a candidate TSP (the Cox-2, CXCR4, EGP-2, or survivin), a reporter luciferase gene, and a poly-A signal, all of which were inserted into the E1-deleted region. A reAdGL3Bcytomegalovirus (CMV), containing the CMV promoter and luciferase gene, was used as a positive control to normalize the luciferase activity. Luciferase activity was measured in multiple tumor cell lines and two primary melanoma cell cultures after infection with reAds. Human epithelial melanocytes, HEM, were used as normal control. In contrast to three other promoters, the survivin promoter exhibited the highest activities within both melanoma cell lines and primary melanoma cells, but not in HEMs. Additionally, the survivin promoter exhibited very low activities in major mouse organs including the liver, in vivo. EGP-2 is not active in melanoma; messenger RNA expressions were correlated to promoter activities both in melanoma cell lines and primary cell cultures. Thus, these data suggest that the survivin promoter achieved a 'tumor-on/liver-off' profile, and thus represents a potentially useful tumor-specific promoter with applications for transcriptional targeting of Ad vector-based cancer gene therapy or oncolysis to melanoma.


Novel One Lung Ventilation Strategy (OLV) for a Patient with Complete Unilateral Endobronchial Obstruction Causing Hypoxic Respiratory Failure.
BACKGROUND Mechanical ventilation strategies for one lung ventilation (OLV) differ from conventional modalities in that it can adapt to greater degrees of ventilation/perfusion (V/Q) mismatch. We present a case of cancer causing complete unilateral endobronchial obstruction with refractory hypoxia that improved with OLV strategy. CASE REPORT Our patient was an elderly male, admitted to our intensive care unit (ICU) on mechanical ventilation with worsening hypoxic respiratory failure secondary to lung mass and post-obstructive atelectasis. The patient developed refractory hypoxia on high conventional ventilator settings. Chest x-ray (CXR) showed opacification on left lung with ipsilateral mediastinal shift. Bronchoscopy revealed complete obstruction of the left main stem bronchus by a fungating mass. OLV strategy was then implemented. The patient had improved hypoxia despite unchanged CXR. CONCLUSIONS We propose that ventilating a patient with a complete unilateral endobronchial obstruction is physiologically similar to ventilating a patient with OLV. In such cases, OLV strategies may improve refractory hypoxia by minimizing V/Q mismatch and should be considered.


Upper airway response in workers exposed to fuel oil ash: nasal lavage analysis.
Among other constituents, fuel oil ash contains vanadium pentoxide, a known respiratory irritant. Exposure to ambient vanadium pentoxide dust has been shown to produce irritation of the eyes, nose, and throat. The usefulness of nasal lavage in detecting an inflammatory response to exposure to fuel oil ash among 37 boilermakers and utility workers was investigated. A baseline lavage was performed on the morning of the first day back to work after an average of 114 days away from work (range 36 hours to 1737 days). A lavage was performed after exposure on the morning three days after the baseline lavage. Exposure to respirable particulate matter of diameter < or = 10 microns (PM10) and respirable vanadium dust were estimated with daily work diaries and a personal sampling device for respirable particulates. These estimates were made for each subject on each workday during the three days between lavages. For each subject, the adjusted change in polymorphonuclear cells was calculated by dividing the change in polymorphonuclear cell counts by the average of the counts before and after exposure. The association between the adjusted polymorphonuclear cell counts and exposure was assessed with multiple linear regression, adjusted for age and current smoking. Personal sampling (one to 10 hour time weighted average) showed a range of PM10 concentrations of 50 to 4510 micrograms/m3, and respirable vanadium dust concentration of 0.10 to 139 micrograms/m3. In smokers the adjusted polymorphonuclear cell count was not significantly different from zero (-0.1%, P > 0.5), but in nonsmokers it was significantly greater than zero (+50%, P < 0.05). In both non-smokers and smokers, there was considerable variability in adjusted polymorphonuclear cell counts and a dose-response relation between these adjusted cell counts and either PM10 or respirable vanadium dust exposure could not be found. A significant increase in polymorphonuclear cells in non-smokers but not smokers was found. This suggests that in non-smokers, exposure to fuel oil ash is associated with upper airway inflammation manifested as increased polymorphonuclear cell counts. The lack of an increase in polymorphonuclear cells in smokers may reflect either a diminished inflammatory response or may indicate that smoking masks the effect of exposure to fuel oil ash.


Emergency medicine considerations in atrial fibrillation.
Atrial fibrillation (AF) is an abnormal heart rhythm which may lead to stroke, heart failure, and death. Emergency physicians play a role in diagnosing AF, managing symptoms, and lessening complications from this dysrhythmia. This review evaluates recent literature and addresses ED considerations in the management of AF. Emergency physicians should first assess patient clinical stability and evaluate and treat reversible causes. Immediate cardioversion is indicated in the hemodynamically unstable patient. The American Heart Association/American College of Cardiology, the European Society of Cardiology, and the Canadian Cardiovascular Society provide recommendations for management of AF. If hemodynamically stable, rate or rhythm control are options for management of AF. Physicians may opt for rate control with medications, with beta blockers and calcium channel blockers the predominant medications utilized in the ED. Patients with intact left ventricular function should be rate controlled to <110 beats per minute. Rhythm control is an option for patients who possess longer life expectancy and those with AF onset <48 h before presentation, anticoagulated for 3-4 weeks, or with transesophageal echocardiography demonstrating no intracardiac thrombus. Direct oral anticoagulants are a safe and reliable option for anticoagulation. Clinical judgment regarding disposition is recommended, but literature supports discharging stable patients who do not have certain comorbidities. Proper diagnosis and treatment of AF is essential to reduce complications. Treatment and overall management of AF include rate or rhythm control, cardioversion, anticoagulation, and admission versus discharge. This review discusses ED considerations regarding AF management.


Integration of a Notch-dependent mesenchymal gene program and Bmp2-driven cell invasiveness regulates murine cardiac valve formation.
Cardiac valve formation is crucial for embryonic and adult heart function. Valve malformations constitute the most common congenital cardiac defect, but little is known about the molecular mechanisms regulating valve formation and homeostasis. Here, we show that endocardial Notch1 and myocardial Bmp2 signal integration establish a valve-forming field between 2 chamber developmental domains. Patterning occurs through the activation of endocardial epithelial-to-mesenchymal transition (EMT) exclusively in prospective valve territories. Mice with constitutive endocardial Notch1 activity ectopically express Hey1 and Heyl. They also display an activated mesenchymal gene program in ventricles and a partial (noninvasive) EMT in vitro that becomes invasive upon BMP2 treatment. Snail1, TGF-β2, or Notch1 inhibition reduces BMP2-induced ventricular transformation and invasion, whereas BMP2 treatment inhibits endothelial Gsk3β, stabilizing Snail1 and promoting invasiveness. Integration of Notch and Bmp2 signals is consistent with Notch1 signaling being attenuated after myocardial Bmp2 deletion. Notch1 activation in myocardium extends Hey1 expression to nonchamber myocardium, represses Bmp2, and impairs EMT. In contrast, Notch deletion abrogates endocardial Hey gene transcription and extends Bmp2 expression to the ventricular endocardium. This embryonic Notch1-Bmp2-Snail1 relationship may be relevant in adult valve disease, in which decreased NOTCH signaling causes valve mesenchyme cell formation, fibrosis, and calcification.


Data for sale: trust, confidence and sharing health data with commercial companies.
Powered by 'big health data' and enormous gains in computing power, artificial intelligence and related technologies are already changing the healthcare landscape. Harnessing the potential of these technologies will necessitate partnerships between health institutions and commercial companies, particularly as it relates to sharing health data. The need for commercial companies to be trustworthy users of data has been argued to be critical to the success of this endeavour. I argue that this approach is mistaken. Our interactions with commercial companies need not, and should not, be based on trust. Rather, they should be based on confidence. I begin by elucidating the differences between trust, reliability, and confidence, and argue that trust is not the appropriate attitude to adopt when it comes to sharing data with commercial companies. I argue that what we really should want is confidence in a system of data sharing. I then provide an outline of what a confidence-worthy system of data sharing with commercial companies might look like, and conclude with some remarks about the role of trust within this system.


Approaches to protect and maintain health care services in armed conflict - meeting SDGs 3 and 16.
The escalation of conflict in the Middle East coincides with an emerging trend of attacks on healthcare. Protection of health personnel, health services and humanitarian workers is no longer respected. This compromises the achievement of the United Nations Sustainable Development Goals 3 - towards health for all, and 16 - towards justice and peace. The Centre for Global Health at the University of Oslo, the Peace Research Institute Oslo and the Norwegian Red Cross co-organised a meeting exploring how conflict impacts health systems and potential solutions to protect and maintain health care services.


Diffusion tensor imaging of neuropsychiatric symptoms in mild cognitive impairment and Alzheimer's dementia.
Neuropsychiatric symptoms (NPS) occur frequently in mild cognitive impairment (MCI) and Alzheimer's dementia (AD). The authors examined the relationship between NPS and white-matter integrity in these conditions. Twenty-two individuals with MCI and 23 with mild AD underwent clinical assessments including the Neuropsychiatric Inventory Questionnaire and 3.0-tesla magnetic resonance scans. Fractional anisotropy (FA) was measured in the following manually-drawn regions of interest (ROI): fornix, cingulum bundle, splenium, and cerebral peduncles (control region). The probability of having NPS by tertile of ROI FA was assessed by logistic regression. Because associations were similar within MCI and AD groups, the two groups were combined. Compared with those in the highest tertile, participants within the lowest anterior cingulum (AC) FA tertile were more likely to exhibit irritability, agitation, dysphoria, apathy, and nighttime behavioral disturbances. After adjusting for Mini-Mental State Exam status, participants in the lowest versus highest tertile of AC FA were more likely to report irritability. Using DTI, low AC FA was associated with increased odds of irritability in mild AD and MCI participants. Further imaging studies are necessary to elucidate the role of the AC in the pathophysiology of neuropsychiatric symptoms in AD and MCI.


The Effect of Latent Binary Variables on the Uncertainty of the Prediction of a Dichotomous Outcome Using Logistic Regression Based Propensity Score Matching.
Logistic regression based propensity score matching is a widely used method in case-control studies to select the individuals of the control group. This method creates a suitable control group if all factors affecting the output variable are known. However, if relevant latent variables exist as well, which are not taken into account during the calculations, the quality of the control group is uncertain. In this paper, we present a statistics-based research in which we try to determine the relationship between the accuracy of the logistic regression model and the uncertainty of the dependent variable of the control group defined by propensity score matching. Our analyses show that there is a linear correlation between the fit of the logistic regression model and the uncertainty of the output variable. In certain cases, a latent binary explanatory variable can result in a relative error of up to 70% in the prediction of the outcome variable. The observed phenomenon calls the attention of analysts to an important point, which must be taken into account when deducting conclusions.


Coherent combining of pulsed fiber amplifiers in the nonlinear chirp regime with intra-pulse phase control.
Two high pulse contrast (> 95 dB) polarization maintaining all-fiber amplifier chains were coherently combined to generate 0.42 mJ, 1 ns 25 kHz pulses with 79% efficiency despite 38 radians of intra-pulse phase distortion. A recursive intra-pulse phase compensation method was utilized to correct for the large nonlinear chirp providing a path for improved coherent waveform control of nanosecond pulse trains.


Parental perceptions of weight terminology that providers use with youth.
Little research has been performed to examine patient perceptions of weight-related language, especially related to childhood obesity. In this study we assessed parental perceptions of weight-based terminology used by health care providers to describe a child's excess weight and assessed perceived connotations associated with these terms including stigma, blame, and motivation to reduce weight. A national sample of American parents with children aged 2 to 18 years (N = 445) completed an online survey to assess their perceptions of 10 common terms to describe excess body weight in youth (including "extremely obese," "high BMI," "weight problem," "unhealthy weight," "weight," "heavy," "obese," "overweight," "chubby," and "fat"). Parents were asked to use a 5-point rating scale to indicate how much they perceived each term to be desirable, stigmatizing, blaming, or motivating to lose weight. Regression models revealed that the terms "weight" and "unhealthy weight" were rated as most desirable, and "unhealthy weight" and "weight problem" were rated as the most motivating to lose weight. The terms "fat," "obese," and "extremely obese" were rated as the most undesirable, stigmatizing, blaming, and least motivating. Parents' ratings were consistent across sociodemographic variables, body weight, and child's body weight. The results of this study have important implications for the improvement of health care for youth with obesity; it may be advantageous for health care providers to use or avoid using specific weight-based language during discussions about body weight with families. Pediatricians play a key role in obesity prevention and treatment, but their efforts may be undermined by stigmatizing or offensive language that can hinder important discussions about children's health.


Identification of Bartonella rochalimae in Guinea Pigs (Cavia porcellus) and Fleas Collected from Rural Peruvian Households.
In the present study, we tested 391 fleas collected from guinea pigs (Cavia porcellus) (241 Pulex species, 110 Ctenocephalides felis, and 40 Tiamastus cavicola) and 194 fleas collected from human bedding and clothing (142 Pulex species, 43 C. felis, five T. cavicola, and four Ctenocephalides canis) for the presence of Bartonella DNA. We also tested 83 blood spots collected on Flinders Technology Associates (FTA) cards from guinea pigs inhabiting 338 Peruvian households. Bartonella DNA was detected in 81 (20.7%) of 391 guinea pig fleas, in five (2.6%) of 194 human fleas, and in 16 (19.3%) of 83 guinea pig blood spots. Among identified Bartonella species, B. rochalimae was the most prevalent in fleas (89.5%) and the only species found in the blood spots from guinea pigs. Other Bartonella species detected in fleas included B. henselae (3.5%), B. clarridgeiae (2.3%), and an undescribed Bartonella species (4.7%). Our results demonstrated a high prevalence of zoonotic B. rochalimae in households in rural areas where the research was conducted and suggested a potential role of guinea pigs as a reservoir of this bacterium.


Neural ECM in regeneration and rehabilitation.
Neural extracellular matrix (ECM) is different from the normal ECM in other organs in that it has low fibrous protein content and high carbohydrate content. One of the key carbohydrate components in the brain ECM is chondroitin sulfate proteoglycans (CSPGs). Over the last two decades, the view of CSPGs has changed drastically, from the initial regeneration inhibitor to plasticity regulators present in the perineuronal nets to the most recent view that certain CSPG isoforms may even be growth promoters. In this chapter, we aim to address a few current progresses of CSPGs in regulating plasticity and rehabilitation in various pathological conditions in the central nervous system.