Room-temperature macromolecular crystallography using a micro-patterned silicon chip with minimal background scattering.
Recent success at X-ray free-electron lasers has led to serial crystallography experiments staging a comeback at synchrotron sources as well. With crystal lifetimes typically in the millisecond range and the latest-generation detector technologies with high framing rates up to 1 kHz, fast sample exchange has become the bottleneck for such experiments. A micro-patterned chip has been developed from single-crystalline silicon, which acts as a sample holder for up to several thousand microcrystals at a very low background level. The crystals can be easily loaded onto the chip and excess mother liquor can be efficiently removed. Dehydration of the crystals is prevented by keeping them in a stream of humidified air during data collection. Further sealing of the sample holder, for example with Kapton, is not required. Room-temperature data collection from insulin crystals loaded onto the chip proves the applicability of the chip for macromolecular crystallography. Subsequent structure refinements reveal no radiation-damage-induced structural changes for insulin crystals up to a dose of 565.6 kGy, even though the total diffraction power of the crystals has on average decreased to 19.1% of its initial value for the same dose. A decay of the diffracting power by half is observed for a dose of D1/2 = 147.5 ± 19.1 kGy, which is about 1/300 of the dose before crystals show a similar decay at cryogenic temperatures.


Complication avoidance with pre-operative screening: insights from the Seattle spine team.
Complication rates for complex adult lumbar scoliosis surgery are unacceptably high. Standardized preoperative evaluation protocols have been shown to significantly reduce the likelihood of a spectrum of negative outcomes associated with complex adult lumbar scoliosis surgery. To increase patient safety and reduce complication risk, an entire medical and surgical team should work together to care for adult lumbar scoliosis patients. This article describes preoperative patient evaluation strategies with a particular focus on adult lumbar scoliosis surgery involving six or more levels of spinal fusion. Domains considered include recent preoperative evaluation literature, predictive risk modeling, the appropriate management of medical conditions, and the composition and activities of a multidisciplinary conference review team. An evidence-based comprehensive systematic preoperative surgical evaluation process is described.


Health-related quality of life, psychological distress, and adverse events in postmenopausal women with breast cancer who receive tamoxifen, exemestane, or anastrozole as adjuvant endocrine therapy: National Surgical Adjuvant Study of Breast Cancer 04 (N-SAS BC 04).
Health-related quality of life (HRQOL), symptoms of depression, and adverse events (AEs) were compared between Japanese postmenopausal patients with hormone-sensitive breast cancer (BC) who received adjuvant tamoxifen, exemestane, or anastrozole in an open-labeled, randomized, multicenter trial designated as the National Surgical Adjuvant Study of Breast Cancer (N-SAS BC) 04 substudy of the Tamoxifen Exemestane Adjuvant Multinational (TEAM) trial. During the first year of treatment, HRQOL and symptoms of depression were analyzed using the Functional Assessment of Cancer Therapy-Breast (FACT-B) and its Endocrine Symptom Subscale (ES), and the Center for Epidemiologic Studies Depression Scale (CES-D), respectively. In addition, predefined AEs were analyzed. A total of 166 eligible patients were randomly assigned to receive adjuvant tamoxifen, exemestane, or anastrozole. FACT-B scores increased after treatment began and remained significantly higher in the tamoxifen group than in the exemestane group or anastrozole group during the first year (P = 0.045). FACT-B scores were similar in the exemestane group and anastrozole group. ES scores and CES-D scores were similar in all treatment groups. Arthralgia and fatigue were less frequent, but vaginal discharge was more frequent in the tamoxifen group than in the exemestane group or anastrozole group. HRQOL was better in Japanese postmenopausal women treated with tamoxifen than those treated with exemestane or anastrozole. HRQOL and AEs were similar with exemestane and anastrozole. Given the results of the TEAM trial, upfront use of tamoxifen followed by an aromatase inhibitor (AI) may be an important option for adjuvant endocrine therapy in Japanese postmenopausal women.


Long Non-coding RNAs as Promising Therapeutic Approach in Ischemic Stroke: a Comprehensive Review.
In recent years, ischemic stroke (IS) has been one of the major causes of disability and mortality worldwide. The general mechanism of IS is based on reduced blood supply to neuronal tissue, resulting in neuronal cell damage by various pathological reactions. One of the main techniques for acute IS treatment entails advanced surgical approaches for restoration of cerebral blood supply but this is often associated with secondary brain injury, also known as ischemic reperfusion injury (I/R injury). Many researches have come to emphasize the significant role of long non-coding RNAs (lncRNAs) in IS, especially in I/R injury and their potential as therapeutic approaches. LncRNAs are non-protein transcripts that are able to regulate cellular processes and gene expression. Further, lncRNAs have been shown to be involved in neuronal signaling pathways. Several lncRNAs are recognized as key factors in the physiological and pathological processes of IS. In this review, we discuss the role of lncRNAs in neuronal injury mechanisms and their association with brain neuroprotection. Moreover, we identify the lncRNAs that show the greatest potential as novel therapeutic approaches in IS, which therefore merit further investigation in preclinical research. Graphical Abstract.


Phosphorus doping significantly enhanced the catalytic performance of cobalt-single-atom catalyst for peroxymonosulfate activation and contaminants degradation.
Increasing studies have been conducted to explore strategies for enhancing the catalytic performance of metal-doped C-N-based materials (e.g., cobalt (Co)-doped C3N5) via heteroatomic doping. However, such materials have been rarely doped by phosphorus (P) with the higher electronegativity and coordination capacity. In current study, a novel P and Co co-doped C3N5 (Co-xP-C3N5) was developed for peroxymonosulfate (PMS) activation and 2,4,4'-trichlorobiphenyl (PCB28) degradation. The PCB28 degradation rate increased by 8.16-19.16 times with Co-xP-C3N5 compared to conventional activators under similar reaction conditions (e.g., PMS concentration). The state-of-the-art techniques, including X-ray absorption spectroscopy and electron paramagnetic resonance etc., were applied to explore the mechanism of P doping for enhancing Co-xP-C3N5 activation. Results showed that P doping induced the formation of Co-P and Co-N-P species, which increased the contents of coordinated Co and improved Co-xP-C3N5 catalytic performance. The Co mainly coordinated with the first shell layer of Co1-N4, with successful P doping occurring in the second shell layer of Co1-N4. The P doping favored electron transfer from the C to N atom near Co sites and thus strengthened PMS activation owing to its higher electronegativity. These findings provide new strategy for enhancing the performance of single atom-based catalysts for oxidant activation and environmental remediation.


Refined Stratification Based on Baseline Concomitant Mutations and Longitudinal Circulating Tumor DNA Monitoring in Advanced EGFR-Mutant Lung Adenocarcinoma Under Gefitinib Treatment.
The optimal treatment for EGFR-mutant lung adenocarcinoma (LUAD) remains challenging because of intratumor heterogeneity. We aimed to explore a refined stratification model based on the integrated analysis of circulating tumor DNA (ctDNA) tracking. ctDNA was prospectively collected at baseline and at every 8 weeks in patients with advanced treatment-naive EGFR-mutant LUAD under gefitinib treatment enrolled in a phase 2 trial and analyzed using next-generation sequencing of a 168-gene panel. Three subgroups categorized by baseline comutations-EGFR-sensitizing mutations (59, 32.8%), EGFR-sensitizing mutations with tumor suppressor mutations (97, 53.9%), and EGFR-sensitizing mutations with other driver mutations (24, 13.3%)-exhibited distinct progression-free survival (13.2 [11.3-15.2] versus 9.3 [7.6-10.5] versus 4.0 [2.4-9.3] months) and overall survival (32.0 [29.2-41.5] versus 21.7 [19.3-27.0] versus 15.5 [10.5-33.7] months, respectively), providing evidence for initial stratification. A total of 63.7% of the patients achieved week 8 ctDNA clearance, with significant difference noted among the three subgroups (74.5% versus 64.0% versus 29.4%, respectively, p = 0.004, Fisher's exact test). Patients without week 8 ctDNA clearance had worse progression-free survival (clearance versus nonclearance 11.2 [9.9-13.2] versus 7.4 [5.6-9.6] months, p = 0.016, Cox regression], especially in the second subgroup [5.8 (5.6-11.5) months], suggesting the necessity of adaptive stratification during treatment. During follow-up, 56.0% and 20.8% of the patients eventually harbored p.T790M and non-p.T790M mutations, respectively, with a significant difference in non-p.T790M mutations among the three subgroups (7.5% versus 15.7% versus 80.0%, respectively, p < 0.001, Fisher's exact test), giving clues to postline treatment. The patients with baseline comutations and ctDNA nonclearance at first visit might require combined therapy because of the limited survival benefit of EGFR tyrosine kinase inhibitor monotherapy. We proposed a refined stratification mode for the whole-course management of EGFR-mutant LUAD.


Clinical spectrum, disease course and management outcome of post-fever retinitis cases: experience from a tertiary eye institute in central India.
To report a series of five cases with retinitis following episodes of febrile illness, its evaluation, management and outcome. Retrospective, consecutive case series of five patients presenting with acute retinitis, following a febrile illness. The retinal lesions had a sudden onset with rapid evolution, preceded by a febrile episode within one month of presentation, in all cases. Extensive serology and PCR testing were non-contributory toward identifying the etiology and guiding therapy. Systemic corticosteroid therapy was effective in hastening the resolution of lesions. Post-fever retinitis appears to be a distinct clinical form of acute hemorrhagic non-necrotizing retinitis without a uniformly identifiable cause, and some evidence pointing toward a para-infectious etiology secondary to flu-like illnesses. With an unusual morphological presentation and annual seasonal patterns in the endemic areas, it is important to differentiate this entity, from other forms of infectious retinitis, before initiating corticosteroid therapy.


(R)-alpha-methylhistamine augments neural, cholinergic bronchospasm in guinea pigs by histamine H1 receptor activation.
In the airways, activation of histamine H3-receptors with (R)-alpha-methylhistamine inhibits neurally induced cholinergic contractions in vitro and peptidergic responses in vivo. The role of histamine H3-receptors on the cholinergic bronchoconstriction induced by electrical stimulation of the dorsal medulla in guinea pigs was assessed in this study. There was no evidence for an H3-receptor mediated inhibition of cholinergic bronchospasm in vivo. However, there was potentiation of central cholinergic bronchoconstriction by (R)-alpha-methylhistamine or histamine by a mechanism involving H1-receptors. I.v. (R)-alpha-methylhistamine (0.3-3 mg/kg) or histamine (0.001-0.01 mg/kg) produced a transient bronchospasm and potentiated the bronchoconstriction due to medullary stimulation. These effects of (R)-alpha-methylhistamine and histamine were blocked by the histamine H1-antagonist, chlorpheniramine (30 micrograms/kg i.v.) but not by H2- or H3-receptor antagonists. (R)-alpha-Methyl-histamine did not potentiate the bronchoconstriction due to i.v. methacholine. Other bronchoconstrictor agents such as methacholine and serotonin did not potentiate the CNS-induced bronchospasm.


Genomic analysis of a recombinant coxsackievirus A19 identified in Xinxiang, China, in 2019.
Coxsackievirus A19 (CV-A19) is an enterovirus belonging to the species Enterovirus C, and the prototype strain 8663 was isolated from a patient with Guillain-Barré syndrome in Japan. In this study, we determined the complete genome sequence of a CV-A19 isolate identified in a stool sample from a child with hand, foot, and mouth disease in Xinxiang, Henan, China, in 2019 and named it CV-A19 strain 2019103106/XX/CHN/2019 - 2019103106 for short. The genome of this virus consists of 7409 nucleotides, including a 6624-nucleotide open reading frame encoding a potential polyprotein precursor of 2207 amino acids. Compared with strain 8663, strain 2019103106 showed 85.1% nucleotide sequence identity in the complete genome and 85.6% identity in the VP1 coding region, reflecting their genetic divergence. Phylogenetic analysis of strain 2019103106 and other representative EV-C strains with sequences available in the GenBank database showed that CV-A19 strains could be grouped into two clusters based on the complete or 214-nucleotide partial VP1 coding regions, and 2019103106 belonged to cluster 1, with the closest relationship to CV-A19 strain SWG82 from Shandong, China. Phylogenetic trees based on the P2 and P3 coding regions highlighted the divergence between strains 2019103106 and 8663, implying that strain 2019103106 had undergone recombination. Further recombination analysis suggested that strains V18A-like CV-A1 and BBD26-like CV-A19 probably recombined to yield strain 2019103106. The present study points out the genetic diversity of CV-A19. It expands our understanding of the evolution of the CV-A19 genome, but more genome sequences of epidemic strains are needed to explain the phylogeny and evolutionary history of CV-A19 comprehensively.


New vs old: descriptors can affect patients' surgical preferences.
The objective of the study was to determine whether the designation of a procedure as newer leads more patients to choose that procedure over 1 that is designated as older. Women with stress incontinence read two 1-page descriptions of surgical procedures for treatment of stress incontinence and were asked to indicate which of the 2 surgical procedures they would choose whether they were going to choose surgical treatment. Randomly for half the participants, a rectus fascia sling was described as being a newer procedure and a mesh sling as an older procedure. For the other half of participants, a mesh sling was described as older and a fascia sling as newer. All participants were also asked whether, in general, they considered that newer surgical procedures were better than older surgical procedures and why. Forty-eight women of mean age 57 years (range, 33-82) were interviewed. Thirty-two patients (68%) chose the newer procedure, and 35 (74%) chose the fascia procedure, both percentages higher than would be expected by chance. When fascia was presented as being the newer procedure, it was chosen over the older mesh by 22 of 24 patients (92%), whereas when fascia was presented as being the older procedure, it was chosen over the newer mesh by a smaller margin. The great majority of patients (79%) stated that newer procedures are better in general. Our results suggest that the use of the words newer or older may overshadow other important information that physicians intend to convey during surgical counseling.


A novel malformation complex of bilateral and symmetric preaxial radial ray-thumb aplasia and lower limb defects with minimal facial dysmorphic features: a case report and literature review.
Radial hemimelia is a congenital abnormality characterised by the partial or complete absence of the radius. The longitudinal hemimelia indicates the absence of one or more bones along the preaxial (medial) or postaxial (lateral) side of the limb. Preaxial limb defects occurred more frequently with a combination of microtia, esophageal atresia, anorectal atresia, heart defects, unilateral kidney dysgenesis, and some axial skeletal defects. Postaxial acrofacial dysostoses are characterised by distinctive facies and postaxial limb deficiencies, involving the 5th finger, metacarpal/ulnar/fibular/and metatarsal. The patient, an 8-year-old-boy with minimal craniofacial dysmorphic features but with profound upper limb defects of bilateral and symmetrical absence of the radius and the thumbs respectively. In addition, there was a unilateral tibio-fibular hypoplasia (hemimelia) associated with hypoplasia of the terminal phalanges and malsegmentation of the upper thoracic vertebrae, causing effectively the development of thoracic kyphosis. In the typical form of the preaxial acrofacial dysostosis, there are aberrations in the development of the first and second branchial arches and limb buds. The craniofacial dysmorphic features are characteristic such as micrognathia, zygomatic hypoplasia, cleft palate, and preaxial limb defects. Nager and de Reynier in 1948, who used the term acrofacial dysostosis (AFD) to distinguish the condition from mandibulofacial dysostosis. Neither the facial features nor the limb defects in our present patient appear to be absolutely typical with the previously reported cases of AFD. Our patient expands the phenotype of syndromic preaxial limb malformation complex. He might represent a new syndromic entity of mild naso-maxillary malformation in connection with axial and extra-axial malformation complex.


Utility of Tc 99m HMPAO SPECT in the early diagnosis of Rasmussen's syndrome.
Neuroradiological examinations are important in the diagnosis of Rasmussen's syndrome (RS), but they frequently result normal in the early phase of the disease. We performed Tc 99m HMPAO SPECT (single photon emission computed tomography) on an 11-year, 5-month-old, right-handed girl, two months since the first seizure. SPECT showed a reduced uptake of HMPAO in the left temporal region despite normal results with magnetic resonance imaging (MRI). After six months, she developed epilepsia partialis continua, neurological signs appeared, and MRI showed cortical atrophy on the left side. SPECT seems to be a useful, inexpensive and diffuse technology able to give information in the early phases of RS useful in the prevention of serious consequences of the disease within a medical therapeutic program (ganciclovir or intravenous immunoglobulins).


Screening and characterization of a novel esterase from a metagenomic library.
Metagenomes from various environmental soils were screened using alpha-naphthyl acetate and Fast Blue RR for a novel ester-hydrolyzing enzyme on Escherichia coli. Stepwise fragmentations and subcloning of the initial insert DNA (30-40 kb) using restriction enzymes selected to exclude already known esterases with subsequent screenings resulted in a positive clone with a 2.5-kb DNA fragment. The cloned sequence included an open reading frame consisting of 1089 bp, designated as est25, encoding a protein of 363 amino acids with a molecular mass of about 38.3 kDa. Amino acid sequence analysis revealed only moderate identity (< or = 48%) to the known esterases/lipases in the databases containing the conserved sequence motifs of esterases/lipases, such as HGGG (residues 124-127), GxSxG (residues 199-203), and the putative catalytic triad composed of Ser201, Asp303, and His333. Est25 was functionally overexpressed in a soluble form in E. coli with optimal activity at pH 7.0 and 25 degrees C. The purified Est25 exhibited hydrolyzing activity toward p-nitrophenyl (NP)-fatty acyl esters with short-length acyl chains (< or = C6) with the highest activity toward p-NP-acetate (Km=1.0 mM and Vmax = 63.7 U/mg), but not with chain lengths > or = C8, demonstrating that Est25 is an esterase originated most likely from a mesophilic microorganism in soils. Est25 efficiently hydrolyzed (R,S)-ketoprofen ethyl ester with Km of 16.4 mM and Vmax of 59.1 U/mg with slight enantioselectivity toward (R)-ketoprofen ethyl ester. This study demonstrates that functional screening combined with the sequential uses of restriction enzymes to exclude already known enzymes is a useful approach for isolating novel enzymes from a metagenome.


A comprehensive genome variation map of melon identifies multiple domestication events and loci influencing agronomic traits.
Melon is an economically important fruit crop that has been cultivated for thousands of years; however, the genetic basis and history of its domestication still remain largely unknown. Here we report a comprehensive map of the genomic variation in melon derived from the resequencing of 1,175 accessions, which represent the global diversity of the species. Our results suggest that three independent domestication events occurred in melon, two in India and one in Africa. We detected two independent sets of domestication sweeps, resulting in diverse characteristics of the two subspecies melo and agrestis during melon breeding. Genome-wide association studies for 16 agronomic traits identified 208 loci significantly associated with fruit mass, quality and morphological characters. This study sheds light on the domestication history of melon and provides a valuable resource for genomics-assisted breeding of this important crop.


Implementing a depression screening algorithm in a memory clinic.
Improved and appropriate utilization of depression screening will increase the quality of life for those individuals with dementia who may have undetected or untreated depression. Depressive symptoms may be an early sign of dementia or occur at any stage. An algorithm was piloted in which initial cognitive screenings were administered prior to using either the Cornell Scale for Depression in Dementia (CSDD) screen or Geriatric Depression Scale Short Form (GDS-SF) screen. Findings included an increase in depression screening and an improvement of clinician knowledge of screening tools. This project enhanced knowledge among the clinicians, however, only one provider improved practices.


Difficulties maintaining prolonged fixation and attention-deficit/hyperactivity symptoms share genetic influences in childhood.
This study investigated the association between the ability to maintain prolonged (2-minute) fixation on a visual target and ADHD traits in a sample consisting of 120 monozygotic and 120 dizygotic twin pairs, aged 9 to 14 years. More intrusive saccades during the task was associated with higher level of parent-reported ADHD traits. Both intrusive saccades and ADHD symptoms had high heritability estimates, and there was a moderate genetic correlation between number of intrusive saccades and ADHD. This study suggests that inability to maintain ocular fixation for longer times is etiologically linked to ADHD traits in the general population.


Pancreatic arteriovenous malformation presenting as cysts: Doppler sonographic diagnosis.
A 50-year-old man presented with multiple lesions resembling cysts throughout the pancreas on gray-scale sonography. Pulsatile blood flow detected within the lesions on color Doppler sonography led to the diagnosis of pancreatic arteriovenous malformation (PAVM). Most previously reported PAVMs have been described as having a poorly defined, reticular, or mosaic-like hypoechoic appearance on gray-scale sonography; the cystic appearance of the PAVM seen in our case is unusual.


Changes in biochemical markers of bone turnover in women treated with raloxifene: influence of regression to the mean.
Measures with extreme magnitude are most likely to be the result of measurement variability. Repeated measurements genuinely lessen such variability, leading to a phenomenon known as regression to the mean (RTM), which may affect biochemical markers of bone turnover. We therefore studied four markers of bone turnover in the Multiple Outcomes of Raloxifene Evaluation (MORE) trial--serum procollagen type I C-propeptide (PICP), osteocalcin (OC), bone-specific alkaline phosphatase (BAP) and urinary type I collagen breakdown product (CTX)--among the 1704 women treated with raloxifene who had marker measurements and were at least 70% adherent, and among 915 control group patients. We examined the existence of RTM, and applied a method of adjustment for RTM of both baseline and follow-up results. We found that women who had the most extreme values tended to go in the opposite direction with the subsequent measurement, i.e., exhibited a pattern of RTM. For example, among women whose urinary CTX decreased at least 60% in the first 6 months, 61% had an increase in the next 6 months; and among those who had an increase in the first 6 months, 81% had a decrease in the next 6 months. We found a similar pattern for each of the four markers. When adjusting for RTM we obtained estimated true values of both baseline values and change in markers. These estimated true values were substantially different from the observed value when the latter was further from the mean. For example, for a 10% increase in urinary CTX in the first 6 months, after accounting for RTM we estimate that there was in fact a 3% decrease (80% confidence interval: -38% to 53%). We conclude that the few initial extreme marker responses observed in women treated with raloxifene represent RTM, and that one practical consequence is that patients with an increase in markers during the first 6 months should be continued on raloxifene therapy, because the values usually decrease later on.


Conservative surgical management of perforating Crohn's disease: side-to-side enteroenteric neoileocolic anastomosis: report of two cases.
Conservative surgical management of jejunoileal Crohn's disease is the first-choice treatment in plurioperated patients with high risk of small-bowel syndrome. Treatment is more controversial in patients with a limited disease and no previous surgery, especially in those with terminal ileitis. Even in those cases we advocate conservative surgical management because we have demonstrated regression of both symptoms and morphologic lesions. Contraindications to nonresectional surgery include the presence of abscesses and fistulas. Impending short-bowel syndrome represents a partial exception to this approach. In this article two cases of conservative surgery performed in plurioperated patients with perianastomotic perforating recurrent disease are presented. We have named this procedure "side-to-side enteroenteric neoileocolic anastomosis," which is a combination of small resections and conservative procedure. This operative strategy leads us to believe that nonresectional surgery could be selectively performed even in patients with perforating Crohn's disease.


Culture Conversion at 6 Months in Patients Receiving Delamanid-containing Regimens for the Treatment of Multidrug-resistant Tuberculosis.
Delamanid should be effective against highly resistant strains of Mycobacteriumtuberculosis, but uptake has been slow globally. In the endTB (expand new drug markets for TB) Observational Study, which enrolled a large, heterogeneous cohorts of patients receiving delamanid as part of a multidrug regimen, 80% of participants experienced sputum culture conversion within 6 months. Clinical Trials Registration. NCT02754765.


Comparing Rotary Bend Wire Fatigue Test Methods at Different Test Speeds.
Given its relatively simple setup and ability to produce results quickly, rotary bend fatigue testing is becoming commonplace in the medical device industry and is the subject of a new standard test method ASTM E2948-14. Although some research has been conducted to determine if results differ for different rotary bend fatigue test setups or test speeds, these parameters have not been extensively studied together. In this work, we investigate the effects of these two parameters on the fatigue life of three commonly used medical device alloys (ASTM F2063 nitinol, ASTM F138 stainless steel, and ASTM F1058 cobalt chromium). Results with three different rotary bend fatigue test setups revealed no difference in fatigue life among those setups. Increasing test speed, however, between 100 and 35,000 RPM led to an increased fatigue life for all three alloys studied (average number of cycles to fracture increased between 2.0 and 5.1 times between slowest and fastest test speed). Supplemental uniaxial tension tests of stainless steel wire at varying strain rates showed a strain rate dependence in the mechanical response which could in part explain the increased fatigue life at faster test speeds. How exactly strain rate dependence might affect the fatigue properties of different alloys at different alternating strain values requires further study. Given the difference in loading rates between benchtop fatigue tests and in vivo deformations, the potential for strain rate dependence should be considered when designing durability tests for medical devices and in extrapolating results of those tests to in vivo performance.


Multimorbidity as assessed by reporting of multiple causes of death: variations by period, sociodemographic characteristics and place of death among older decedents in England and Wales, 2001-2017.
Multimorbidity is common at older ages and is associated with disability, frailty and poor quality of life. Research using clinical databases and surveys has shown associations between multimorbidity and indicators of social disadvantage. Use of multiple coded death registration data has been proposed as an additional source which may also provide insights into quality of death certification. We investigate trends in reporting multiple causes of death during 2001-2017 among decedents aged 65 years and over included in a census-based sample of 1% of the England and Wales population (Office for National Statistics Longitudinal Study). Using Poisson regression analysis, we analyse variations in number of mentions of causes of death recorded by time period, place of death, age, sex and marital status at death and indicators of health status and individual and area socioeconomic disadvantage reported at the census prior to death. Number of mentions of causes recorded at death registration increased 2001-2017, increased with age, peaking among decedents aged 85-9 years, and was positively associated with indicators of prior disadvantage and poor health, although effects were small. Number of mentions was highest for hospital decedents and similar for those dying in care homes or their own homes. Socioeconomic disadvantage, prior poor health, dying in hospital and older age-although not extreme old age-are associated with dying with more recorded conditions. Results may reflect both differences in multimorbidity at death and variations in quality of medical certification of death. Quality of death certification for decedents in care homes needs further investigation.


Induction of cloacal and dermal skin glands of tiger salamander larvae, (Ambystoma tigrinum): effects of testosterone and prolactin.
Treatment of male and female tiger salamander larvae with testosterone (0.3 micrograms/g body weight/day) induced precocious formation of ventral cloacal glands and stimulated proliferation and differentiation of mucous and granular (serous) glands in the ventral dermis of the skin. Lower doses of testosterone produced no visible glandular effects but did cause hyperemia and edema in the cloacal region. Prolactin (0.5 micrograms/g body weight/day) enhanced the action of testosterone on the cloacal glands, increasing both the amount of gland induced and the degree of glandular secretion. There was no apparent effect of prolactin alone on cloacal glands or any effect of prolactin with or without testosterone on the dermal glands. The possible homology of the amphibian ventral cloacal gland to the mammalian prostate gland is discussed.


Life-Course Influence of Adolescent Behaviour Problems on Type 2 Diabetes in Midlife: Results from 1958 British Birth Cohort Study.
To assess whether there is a long-term relationship between childhood behaviour problems and type 2 diabetes in midlife. The study will also investigate whether any of such relationship is independent of other factors which may be associated with type 2 diabetes. Cohort study. A total of 9377 members of the 1958 British birth cohort participated in the biomedical survey at age 45 years. The cohort has been followed up at regular intervals in childhood (age 7, 11 and 16 years) and adulthood (23, 33, 42 and 45 years). Information regarding childhood behaviour collected during follow-ups at ages 7, 11 and 16 years. Type 2 diabetes assessed using HbA1c at age 45 years. Unadjusted estimates show that teachers reported adolescent behaviour problems at age of 16 are associated with increased risk of type 2 diabetes in midlife. After adjustment for potential confounders and mediators in childhood and adulthood, a relationship was observed between the severity of adolescent behaviour problems and type 2 diabetes risk in midlife (mild behaviour problems: OR 2.17, 95% CI 1.11-4.23; severe behaviour problems: OR 4.40, 95% CI 1.14-16.99). However, no such relationship was observed between behaviour problems at 7 and 11 years and type 2 diabetes in midlife. There is an association between adolescent behaviour problems and an increased risk of type 2 diabetes in midlife. Further molecular/genetic studies are required to understand the biological basis for this observed association.


Enhanced replication of porcine reproductive and respiratory syndrome (PRRS) virus in a homogeneous subpopulation of MA-104 cell line.
Two different cell populations, high- (MARC-145) and low-permissive cell clones (L-1) to porcine reproductive and respiratory syndrome (PRRS) virus, were derived from MA-104 cell line (parent cell: P) by cell cloning. Maximum virus yields in MARC-145, P, and L-1 cell clones were 10(8.5), 10(3.5), and 10(2.5) tissue culture infective dose 50 (TCID50)/0.1 ml, respectively. The MARC-145 cell clone supported replication of all 11 different porcine reproductive and respiratory syndrome virus isolates that were tested. These results indicated that the MARC-145 cells will be useful for PRRS virus replication.


What is the Role of Whole Blood Transfusions on Trauma Patients?
Whole blood use in trauma has historically been limited to military use, but in recent years, there has been increasing data for use in civilian trauma. Emerging clinical data demonstrate an associated survival benefit, while some authors have also identified decreased use of an overall number of blood products and decreased complications. Use of whole blood is gradually moving toward becoming the standard of care in the hemorrhaging trauma patient.


Examination stress, platelet peripheral benzodiazepine binding sites, and plasma hormone levels.
The maximal binding capacity (Bmax) and the equilibrium dissociation constant (KD) values for [3H]PK 11195 binding to peripheral benzodiazepine binding sites were measured in the platelets of subjects immediately after examination stress and 10 days later, as well as in unstressed controls. Increased (52%; p less than 0.05) Bmax, but unaltered KD, values were observed immediately after the stress as compared to the controls. Ten days after the stress, a slight decrease (15%) in the number of peripheral benzodiazepine binding sites was observed, but their values remained higher (29%) in comparison to unstressed controls. Levels of plasma stress hormones (cortisol, growth hormone, and prolactin) did not differ in the stressed subjects from those of the controls.


[Significance of genetic factors in the etiopathogenesis of allergic diseases].
It was established using the methods of genetic-mathematical analysis that the multifactorial model of heredity with uninterrupted distribution of liability is more adequate to the genetic system defining hereditary predisposition to allergoses.


Cement-augmented pedicle screw for thoracolumbar degenerative diseases with osteoporosis: a systematic review and meta-analysis.
Cement-augmentation pedicle screws have been widely used in spinal internal fixation surgery combined with osteoporosis in recent years, which can significantly improve the fixation strength, but compared with conventional methods, whether it has more advantages is still inconclusive of evidencebased medicine. To systematically evaluate the efficacy and safety of cement-augmented pedicle screw in the treatment of thoracolumbar degenerative diseases with osteoporosis. We searched PubMed, Embase, and Cochrane Library for studies published from the establishment of the database up until June 2023. We included studies that concerning the cement-augmented pedicle screw and the traditional pedicle screw placement for thoracolumbar degenerative diseases with osteoporosis. We excluded repeated publication, researches without full text, incomplete information or inability to conduct data extraction and animal experiments, case report, reviews and systematic reviews. STATA 15.1 software was used to analyze the data. A total of 12 studies were included in this meta-analysis. The sample size of patients were totally 881, of which, 492 patients in cement-augmented screw group and 389 patients in conventional screw group. Meta-analysis results showed that Japanese Orthopaedic Association (JOA) score (WMD = 1.69, 95% CI 1.15 to 2.22), intervertebral space height (WMD = 1.66, 95% CI 1.03 to 2.29) and post-operation fusion rate (OR = 2.80, 95% CI 1.49 to 5.25) were higher in the cement-augmented screw group than those in the conventional screw group. Operation time was longer in the cement-augmented screw group than that in the conventional screw group (WMD = 15.47, 95% CI 1.25 to 29.70). Screw loosening rate was lower in the cement-augmented screw group than those in the conventional screw group (OR = 0.13, 95% CI 0.07 to 0.22). However, hospitalization time, intraoperative blood loss and Visual analog scale (VAS) score were not significantly different between the two groups (P > 0.05). Compared with conventional pedicle screw placement, cement-augmented pedicle screw is more effective in the treatment of osteoporotic thoracolumbar degenerative disease by improving fusion rate and interbody height, reducing the incidence of screw loosening, and elevating long-term efficacy.


Gender Disparities in Academic Productivity and Promotion Among Endocrine Surgery Faculty.
Academic rank and metrics such as total publications (pubs) and H-index are indicators to measure academic achievement. This study aims to determine whether there are gender differences in academic productivity or faculty appointments among endocrine surgeons in the United States. A database was generated from the American Association of Endocrine Surgeons (AAES) website. Community or academic practice was designated by institution affiliation and faculty appointment. Academic metrics, including pubs, H-index, and weighted-RCR (relative citation ratio), were obtained from public databases. A total of 258 AAES members were affiliated with an academic institution. The majority were men (58%). Overall, men in endocrine surgery had higher academic metrics: pubs (56.0 [26-134], 23.0 [11-56], P < 0.0001), H-index (19.0 [11-35], 9.0 [5-21], P < 0.0001), weighted-RCR (63.5 [22-193], 24.1 [8-74], P < 0.005) and rank (associate professor or professor, P < 0.0001). Subgroup analysis accounting for time in practice found no difference in total publications, weighted RCR, or faculty appointments between genders in practice for 0-5 y. However, among surgeons in practice for 6-10 y, men had higher academic metrics (pubs: 31.0 [16-79], 18.5 [9-33]; RCR: 46.0 [14-102], 13.3 [9-34]) and faculty appointments (all P < 0.05). There are gender disparities in academic productivity and faculty appointment among US endocrine surgeons. While junior faculty show no gender differences in most indicators of academic productivity or rank, men with 6-10 y in practice have higher average academic metrics and rank. Whether the absence of gender disparities among junior faculty is a sustainable reflection of recent efforts to encourage equal mentorship and professional opportunities or whether disparities will manifest as faculty progress remains to be determined.


Influence of a distraction task on the involuntary reflex contraction of the pelvic floor muscles following cough.
To explore the involvement of a distraction task in involuntary reflex pelvic floor muscle contraction following cough. Informed consent was obtained from 33 healthy volunteers. Involuntary contraction of the external anal sphincter (EAS) was induced by means of coughing. Cough efforts were elicited by electronic order. The electromyographic (EMG) activity of the EAS was recorded during involuntary contraction elicited by coughing. The trials were carried out twice: combined (or not) with a mental distraction task; the paced auditory serial additional test (PASAT). Reaction time (RT) defined as latency between the stimulus and maximum EAS EMG activity (RT1), latency between the stimulus and external intercostal (EIC) muscle EMG activity (RT2), latency between EIC EMG activity and EAS EMG activity (RT3), duration of the contraction, and the area under the EAS EMG activity curve (perineal contraction) were measured. The distraction task altered anticipation of the PFM contraction: RT3 was -80.00 ms (IQR -107; -56) without the PASAT versus -56.67 ms (IQR: -94; -2) with the distraction task (ratio 0.71, P = 0.0045, Wilcoxon test). RT2 was altered during the distraction task: 583.33 ms (IQR: 344-775) without PASAT versus 652.71 ms (503-790) during PASAT (ratio 1.12, P = 0.031, Wilcoxon test). Finally, when the two conditions (respectively with and without the mental distraction task) were compared, there was a significant difference between the area under the EAS EMG activity curve (0.0115 mv sec vs. 0.0103 mv sec, ratio 0.90, P = 0.023). The mental distraction task altered involuntary reflex contraction of the pelvic floor muscles. Neurourol. Urodynam. 36:160-165, 2017. © 2015 Wiley Periodicals, Inc.


Effects of ultrafine and fine particulate and gaseous air pollution on cardiac autonomic control in subjects with coronary artery disease: the ULTRA study.
Previous studies have shown an association between elevated concentrations of particulate air pollution and cardiovascular morbidity and mortality. Therefore, the association between daily variation of ultrafine and fine particulate air pollution and cardiac autonomic control measured as heart rate variability (HRV) was studied in a large multicenter study in Amsterdam, the Netherlands, Erfurt, Germany, and Helsinki, Finland. Elderly subjects (n=37 in Amsterdam, n=47 in both Erfurt and Helsinki) with stable coronary artery disease were followed for 6 months with biweekly clinical visits. During the visits, ambulatory electrocardiogram was recorded during a standardized protocol including a 5-min period of paced breathing. Time and frequency domain analyses of HRV were performed. A statistical model was built for each center separately. The mean 24-h particle number concentration (NC) (1,000/cm(3)) of ultrafine particles (diameter 0.01-0.1 microm) was 17.3 in Amsterdam, 21.1 in Erfurt, and 17.0 in Helsinki. The corresponding values for PM2.5 were 20.0, 23.1, and 12.7 microg/m(3). During paced breathing, ultrafine particles, NO(2), and CO were at lags of 0-2 days consistently and significantly associated with decreased low-to-high frequency ratio (LF/HF), a measure of sympathovagal balance. In a pooled analysis across the centers, LF/HF decreased by 13.5% (95% confidence interval: -20.1%, -7.0%) for each 10,000/cm(3) increase in the NC of ultrafine particles (2-day lag). PM2.5 was associated with reduced HF and increased LF/HF in Helsinki, whereas the opposite was true in Erfurt, and in Amsterdam, there were no clear associations between PM2.5 and HRV. The results suggest that the cardiovascular effects of ambient ultrafine and PM2.5 can differ from each other and that their effect may be modified by the characteristics of the exposed subjects and the sources of PM2.5.


Mixed genotypes of Orientia tsutsugamushi in conserved genes and a single immune-dominant tsa56 genotype discovered from a patient with scrub typhus in Hainan Island, China: a case report.
Orientia tsutsugamushi (O. tsutsugamushi), an obligate intracellular bacterium, is transmitted to humans through infected larval trombiculid mite bites, causing scrub typhus. Mixed genotypes of O. tsutsugamushi in canonical conserved genes were reported in 8-25% of blood samples from patients. Yet, there are few clinical descriptions of these mixed O. tsutsugamushi-infected patients. We report a patient with scrub typhus complicated with pulmonary involvement and hepatic dysfunction, who carried mixed genotypes of the conserved genes but had a single immune-dominant 56-kDa type-specific antigen (tsa56) genotype. The patient was successfully recovered by doxycycline treatment. In this reported case, both patient's eschar and blood samples have repeatedly shown the same results, i.e., no variants were discovered in tsa56 gene that bears multiple hypervariable regions. Whereas the selected highly conserved genes were identified with up to 32 variants in a 2700 base-pair concatenated sequence. The prevalence, disease severity and mechanism of these single-tsa56-genotype mixed infections remain to be investigated on a large scale with more cases.


Radiation therapy: neoadjuvant, adjuvant, or not at all.
Clinical trial data show that radiation enhances local tumor control of extremity sarcomas with acceptable morbidity when sophisticated radiation techniques are combined with limb-sparing resections performed by oncologic surgeons with sarcoma expertise. Similar controlled data is not available for retroperitoneal sarcomas but some studies suggest a benefit for radiotherapy. Radiation can be delivered by external beam or brachytherapy; it can be given pre-operatively, post-operatively, or intra-operatively. Indications for and advances in radiation therapy are discussed in this article.


Practical use of Direct Oral Anti Coagulants (DOACs) in the older persons with atrial fibrillation.
Direct Oral Anticoagulants (DOACs) consistently demonstrated a greater net clinical benefit compared to Vitamin K Antagonists (VKAs) also in persons aged 75 years and over, who account for the largest proportion of AF patients; however, major uncertainties in DOACs prescription have to do with this age group. In this review, persistent uncertainties and implications of frailty and geriatric syndromes on DOACs prescription, and practical use of DOACs in real-world older persons, and will be discussed.


Germinated barley foodstuff exhibits different adsorption properties for hydrophilic versus hydrophobic bile acids.
Germinated barley foodstuff (GBF), a type of dietary fiber, exhibits therapeutic effects in ulcerative colitis (UC) patients. However, the precise mechanisms responsible for these effects are still under investigation. On the other hand, it has been suggested that bile salts in the gut lumen play an important role in the integrity of the intestinal mucosa. The aim of the present study was to investigate the ability of GBF to adsorb bile salts in vitro. The binding capacities of GBF, enzymatically digested GBF (GBF-fiber), and alpha-cellulose for unconjugated and conjugated bile salts were measured using Langmuir's method. The morphology of these fibers was observed by light and fluorescence microscopy. GBF adsorbed bile salts very strongly, especially hydrophobic bile salts. Even after enzymatic digestion, the GBF fiber still exhibited strong binding capacity, whereas alpha-cellulose exhibited very low binding capacity. Microscopically, GBF consists mainly of aleurone, a lattice-like cell wall with cytoplasm enclosed. After enzymatic digestion, the cytoplasm was also digested. GBF possesses a great capacity to adsorb bile salts. This may be part of the mechanism for the therapeutic effects of GBF in UC patients.


What is new in epithelioid hemangioendothelioma of the liver?
An unusual hepatic vascular neoplasm has been delineated in recent years. It has characteristic morphologic features consisting of multiple nodules with relatively acellular centers which may be focally calcified. More peripherally there is a cellular zone containing elongated or plump tumor cells embedded in a fibromyxoid stroma. At the outer edge of the nodules, and particularly in vessels, the tumor cells may assume an epithelioid appearance. The tumor cells exhibit focally positive staining for Factor VIII related antigen and Weibel Palade bodies may be seen on electron microscopy. The tumor is malignant, but may have an indolent course over many years. It may be associated with hepatic cirrhosis and pulmonary osteoarthropathy. Other organs, particularly the lung and soft tissues are frequently involved.


Novel insights into muscarinic acetylcholine receptor function using gene targeting technology.
Muscarinic acetylcholine receptors (mAChRs) modulate the activity of an extraordinarily large number of physiological functions. Individual members of the mAChR family (M(1)-M(5)) are expressed in a complex, overlapping fashion in most tissues and cell types. However, the identification of the precise physiological roles of individual mAChR subtypes remains a challenging task because, with the exception of a few snake toxins, mAChR ligands that can activate or inhibit specific mAChR subtypes with a high degree of selectivity are not yet available. Knowledge of the specific roles of mAChR subtypes is of considerable interest for the development of novel, clinically useful mAChR ligands. In this article, recent studies of mutant mouse strains developed, using gene targeting techniques, to be deficient in one of the three G(q)-coupled mAChR subtypes (M(1), M(3) and M(5)) are discussed. These investigations have led to many important new insights into the physiological roles of these receptor subtypes.


Effect of environmental conditions on aggregation and fibril formation of barstar.
The dependence on environmental conditions of the assembly of barstar into amyloid fibrils was investigated starting from the nonnative, partially folded state at low pH (A-state). The kinetics of this process was monitored by CD spectroscopy and static and dynamic light scattering. The morphology of the fibrils was visualized by electron microscopy, while the existence of the typical cross-beta structure substantiated by solution X-ray scattering. At room temperature, barstar in the A-state is unable to form amyloid fibrils, instead amorphous aggregation is observed at high ionic strength. Further destabilization of the structure is required to transform the polypeptide chain into an ensemble of conformations capable of forming amyloid fibrils. At moderate ionic strength (75 mM NaCl), the onset and the rate of fibril formation can be sensitively tuned by increasing the temperature. Two types of fibrils can be detected differing in their morphology, length distribution and characteristic far UV CD spectrum. The formation of the different types depends on the particular environmental conditions. The sequence of conversion: A-state-->fibril type I-->fibril type II appears to be irreversible. The transition into fibrils is most effective when the protein chain fulfills particular requirements concerning secondary structure, structural flexibility and tendency to cluster.


Electrically Driven Hot-Carrier Generation and Above-Threshold Light Emission in Plasmonic Tunnel Junctions.
Above-threshold light emission from plasmonic tunnel junctions, when emitted photons have energies significantly higher than the energy scale of incident electrons, has attracted much recent interest in nano-optics, while the underlying physics remains elusive. We examine above-threshold light emission in electromigrated tunnel junctions. Our measurements over a large ensemble of devices demonstrate a giant (∼104) material-dependent photon yield (emitted photons per incident electrons). This dramatic effect cannot be explained only by the radiative field enhancement due to localized plasmons in the tunneling gap. Emission is well described by a Boltzmann spectrum with an effective temperature exceeding 2000 K, coupled to a plasmon-modified photonic density of states. The effective temperature is approximately linear in the applied bias, consistent with a suggested theoretical model describing hot-carrier dynamics driven by nonradiative decay of electrically excited localized plasmons. Electrically generated hot carriers and nontraditional light emission could open avenues for active photochemistry, optoelectronics, and quantum optics.


Mutations at the distal and proximal sites of cytochrome P-450d changed regio-specificity of acetanilide hydroxylations.
Regio-specificities of acetanilide hydroxylations were studied for 11 distal, 9 proximal and 3 aromatic mutants of cytochrome P-450d. Ratios of turnover numbers among these products were remarkably changed depending on the mutants. For example, the ratio of turnover number, para:ortho:meta = 7:0.1:0.3 for the wild type changed to 11:4:3 for a distal mutant, Thr322Ala, or to 13:13:1 for a proximal mutant, Arg455Gly. It was suggested that regio-specificities of microsomal P-450 enzymes are controlled cooperatively by the whole structure of the protein molecules which influences the tertiary structure of the distal environment.


Surgical management of left main coronary artery aneurysm.
To date only 7 patients with left main coronary artery aneurysm associated with atherosclerosis have undergone surgical treatment. This report reviews a case of atherosclerotic aneurysm of the left main coronary artery with concurrent stenotic coronary artery disease that was successfully treated by direct approach to the left main coronary artery aneurysm and establishment of coronary artery bypass grafts.


Relationship between rate and extent of catechin absorption and plasma antioxidant status.
Flavonoids are described to exert a large array of biological activities, which are mostly ascribed to their radical-scavenging, metal chelating and enzyme modulation ability. Most of these evidences have been obtained by in vitro studies on individual compounds and at doses largely exceeding those dietary. Little is known about a possible relationship between rate and extent of the absorption and modifications of plasma antioxidants. To elucidate this aspect, human volunteers were supplemented with single doses of green tea catechins in free (Greenselect) or phospholipid complex form (Greenselect Phytosome) equivalent to 400 mg epigallocatechingallate (EGCg). EGCg was chosen as biomarker for green tea catechin absorption, and its time course plasma concentration was correlated to the subsequent percent variations of plasma ascorbate, total glutathione, alpha-tocopherol, beta-carotene and Total Radical Antioxidant Parameter (TRAP). Green tea catechins were absorbed more extensively when administered as phospholipid complex rather than as free catechins. Single dose intake of both forms of catechins produced a transient decrease (10-20%) of plasma ascorbate and total glutathione and an increase of plasma TRAP (16-19%). These variations were consistent with the plasmatic levels of EGCg, ascorbate and total glutathione.


Potentiation by propranolol of stress-induced changes in passive avoidance and open-field emergence tests in mice.
Noradrenergic and serotonergic systems are known to be stimulated during various forms of stress. The present study examined the effect of the beta-adrenergic serotonin1A receptor blocker propranolol on the ability of stress to elicit behavioral inhibition in mice. Mice were given the drug before immobilization or tube-restraint stress, and then were tested for either passive avoidance performance or time to emerge into an open field. Propranolol markedly potentiated stress-induced increases in latency in both of these tests, suggesting that it exacerbated reactions to stress. These results agree with previous data indicating that under certain conditions, propranolol can potentiate the effects of stress in rodents. The results support the hypothesis that the response of the noradrenergic and/or serotonergic systems to stress may have anxiolytic or antistress effects.


Cellular mechanisms by which tumor necrosis factor-alpha produces disruption of the blood-brain barrier.
The first goal of the present study was to determine the effect of tumor necrosis factor-alpha (TNF-alpha) on the permeability of the blood-brain barrier in vivo. The second goal of this study was to investigate cellular pathways responsible for changes in permeability of the blood-brain barrier in response to TNF-alpha. We examined the pial microcirculation in rats using intravital fluorescence microscopy. Permeability of the blood-brain barrier was quantitated by calculating the clearance of fluorescent-labeled dextran (mol. wt=10,000; FITC-dextran-10K) during superfusion with vehicle, tumor necrosis factor (TNF-alpha; 10 ng/ml), TNF-alpha in the presence of an inhibitor of soluble guanylate cyclase (ODQ; 1.0 microM), and TNF-alpha in the presence of an inhibitor of protein tyrosine kinase (genistein; 10 microM). During superfusion with vehicle, clearance of FITC-dextran-10K from pial vessels remained relatively constant during the experimental period. In contrast, superfusion with TNF-alpha markedly increased clearance of FITC-dextran-10K from the cerebral microcirculation. Topical application of ODQ and genistein, significantly inhibited increases in permeability of the blood-brain barrier to FITC-dextran-10K during application of TNF-alpha. Thus, TNF-alpha increases the permeability of the blood-brain barrier to a moderately sized molecule via a mechanism which appears to involve activation of soluble guanylate cyclase and protein tyrosine kinase. In light of evidence suggesting that TNF-alpha production is increased during cerebrovascular trauma, we suggest that the findings of this study may contribute to our understanding of the pathogenesis of disruption of the blood-brain barrier during brain trauma and inflammation.


Novel therapeutic strategy for uterine endometrial cancers.
In general, tumors induce angiogenic factors specific to them, which leads to angiogenesis with tumor progression. However, angiogenesis in uterine endometrial cancers is complicated because the hormone dependency in their growth also modifies the angiogenic potential. Therefore, angiogenic potential in uterine endometrial cancers must be thoroughly analyzed. The upstream of the vascular endothelial growth factor (VEGF) gene conserves estrogen-responsive elements. Progesterone primed with estrogen induces thymidine phosphorylase (TP) in the uterine endometrium. Sex steroid-dependent VEGF and TP are highly expressed in early-stage and well-differentiated uterine endometrial cancers, and basic fibroblast growth factor (bFGF) is highly expressed in advanced and poorly differentiated uterine endometrial cancers. A transcriptional factor for angiogenesis, E26 transformation specific (ETS-1), is linked to VEGF in well-differentiated uterine endometrial cancers, and to bFGF in poorly differentiated uterine endometrial cancers. Therefore, even if dedifferentiation and angiogenic switching occur due to tumor progression and long-term hormone therapy, the inhibition of ETS-1, along with inhibition of the main angiogenic factors, may be an effective strategy to suppress uterine endometrial cancers as a novel antiangiogenic therapy.


Use of bisphosphonates in metastatic breast cancer: single institution review at the Dr. H. Bliss Murphy Cancer Centre.
Bone metastases occur in 65-75% of patients with metastatic breast cancer. These patients are at risk of developing skeletal-related events (SREs). SREs are defined as any pathological fracture, spinal cord compression, hypercalcemia, and surgery or radiation required for treatment of bone metastases. Bisphosphonates are used to prevent the development of SREs. The purpose of this study is to review the incidence of SREs in metastatic breast cancer patients with bony disease in Newfoundland and Labrador and to determine if there is an association between SREs and the type of bisphosphonate therapy given. This retrospective chart review includes all metastatic breast cancer patients with bony disease treated at the Dr. H. Bliss Murphy Cancer Centre from 2008 to 2010. Patient demographics, treatment received, and treatment changes were collected. Patients at the Centre received bisphosphonate, pamidronate or zolendronic acid to prevent SREs. The prescribing pattern of bisphosphonates was collected. The occurrences of SREs were then compared to the type of treatment received. Sixty-five patients with breast cancer and bony metastasis were identified using the provincial tumor registry, three patients were excluded from the review as their charts could not be located. Following the initial diagnosis of bone metastasis, 8 patients (12.7%) were started on zolendronic acid, 50 patients (80.6%) were started on pamidronate, and 4 (6.4%) received no treatment. Six patients (75%) on zolendronic acid experienced one SRE; however, none experienced multiple SREs. Thirty-one patients (62%) on pamidronate experienced one SRE, and ten (20%) had multiple SREs. Of the 31 patients on pamidronate with an SRE, 4 (12.9%) were switched to zolendronic acid. Three of the four (75%) had multiple SREs despite treatment changes. Of the six patients on zolendronic acid with SREs, none were switched to pamidronate. Our results show that the majority of patients with breast cancer, who develop bony metastases in Newfoundland and Labrador, are initially treated with the bisphosphonate, pamidronate. Over 60% of these patients experienced at least one SRE, and 20% had more than two SREs. A small proportion of the patients were initially started on zolendronic acid, and this group had better outcomes with fewer SREs and none had more than two SREs. It appears that zolendronic acid is superior to pamidronate in preventing SREs; however, zolendronic acid is being used primarily as second-line in Newfoundland and Labrador.


On the nature of growth and new growth based on experiments designed to reveal a structure and function for laboratory space. Part II. An approach to the structure of space through quantum field theory with examples of possible biological relevance.
A previous paper in this series described experiments and observations which could have been produced by properties derived from the quality of laboratory space. In particular, action at a distance was of commonplace occurrence. It was argued that support for this idea was forthcoming from two recent developments in physics, that of non-linear thermodynamics and that of quantum mechanics followed by quantum electrodynamics. The first permitted the concept of a formative or structuring role for energy permeating matter the second the concept of a structure and function for space. One of these functions was to provide for the creation of subatomic particles and thus of matter. This creativity is achieved from an origin in a non-observable world where the equations have no terms for distance or time. The demonstration of the insignificance of distance in the experiments reported using both crystal and biological growth was used to infer that events in this growth process were similarly preceeded by events in the non-observable world. The implications of such an origin for growth and new growth are discussed.


Illness perceptions among cardiac patients: relation to depressive symptomatology and sex.
This study examined cardiovascular disease (CVD) illness perceptions and how they relate to depressive symptomatology among women and men. Acute coronary syndrome (ACS) patients at two hospitals were approached, and 661 consented to participate (504 men, 157 women; 75% response rate). Participants completed a survey including the Hospital Anxiety and Depression Scale (HADS) and Illness Perception Questionnaire (IPQ). Women perceived a significantly more chronic course (P<.001) and more cyclical episodes (P<.05) than men did, while men perceived greater personal control (P<.001) and treatability (P<.05) than women did. Participants perceived diet, heredity, and stress as the greatest CVD causes. For women (F=5.49, P<.001), greater depressive symptomatology was significantly related to younger age (P<.05), lower activity status (P<.001), and perceiving a chronic time course (P<.01). For men (F=7.68, P<.001), greater depressive symptomatology was significantly related to being non-white (P<.05), lower activity status (P<.001), less exercise behavior (P=.01), and three illness perceptions, namely, perceiving a chronic course (P<.05), greater consequences (P<.001), and lower treatability (P<.05). Women, compared with men, are more likely to attribute CVD to causes beyond their control and to perceive CVD as a chronic, untreatable condition. Illness perceptions were related to depressive symptomatology, which suggests that interventions to reframe these perceptions may be warranted to improve emotional health in the context of CVD.


Physiological and anti-oxidative response of biologically and chemically synthesized iron oxide: Zea mays a case study.
The synthesis methodology, particle size and shape, dose optimization, and toxicity studies of nano-fertilizers are vital prior to their field application. This study investigates the comparative response of chemically synthesized and biologically synthesized iron oxide nanorods (NRs) using moringa olefera along with bulk FeCl3 on summer maize (Zea mays). It is found that FeCl3 salt and chemically synthesized iron oxides NRs caused growth retardation and impaired plant physiological and anti-oxidative activities at a concentration higher than 25 mg/L due to toxicity by over accumulation. While iron released form biologically synthesized NRs have shown significantly positive results even at 50 mg/L due to their low toxicity, an improved leaf area (13%), number of leaves per plant (26%), total chlorophyll content (80%) and nitrate content (6%) with biologically synthesized NRs are obtained. Moreover, the plant anti-oxidative activity also increased on treatment with biologically synthesized NRs because of their ability to form a complex with metal ions. These findings suggest that biologically synthesized iron oxides NRs are an efficient iron source and can last for a long time. Thus, proving that nanofertilizer are required to have specific surface chemistry to release the nutrient in an appropriate concentration for better plant growth.


Factors impacting functional health and resource utilization following abdominal aortic aneurysm repair by open and endovascular techniques.
We assessed the impact on patient outcomes of comorbidities and type of aneurysm repair, open vs. endovascular aortic repair (EVAR). Functional health status was measured prospectively using the Short Form 36 (SF-36) Health Survey. Length of stay (LOS) and need for postdischarge resources (nursing and rehabilitation) were compared between groups. We reviewed the records of 218 patients (126 open, 92 EVAR) who underwent intervention between 1998 and 2003. The SF-36 was completed preoperatively and at intervals ranging from 2 weeks to 1 year after intervention. To identify factors impacting outcome, univariate and multivariate analyses were performed. Overall mortality was 1.9%: 3.2% for open repair and 0% for EVAR (p = 0.13). Physical and mental health were higher during the 3 months following EVAR compared with open repair: physical function (PF) (65.2 +/- 4.1 vs. 54.0 +/- 4.1), vitality (VT) (55.5 +/- 2.5 vs. 44.9 +/- 3.4), and emotional role (ER) (74.9 +/- 5.0 vs. 51.4 +/- 6.7) (analysis of variance p < 0.05). Women following EVAR had decreased physical summary scores (PSS) (34.8 +/- 2.5 vs. 40.4 +/- 1.1, p < 0.05) compared with men postprocedure despite no difference preoperatively. Congestive heart failure (CHF) was an independent factor that negatively impacted PF, body pain (BP), and PSS. EVAR was associated with improved VT and ER. Differences among open repair and EVAR diminished over time. LOS (in days) was greater for open vs. EVAR (9.2 +/- 0.78 vs. 2.0 +/- 0.17) and in women following both open (11.8 +/- 1.5 vs. 8.0 +/- 0.9) and EVAR (3.2 +/- 0.9 vs. 1.8 +/- 0.1) procedures (p < 0.05). Factors that adversely affected LOS were open repair, age, renal insufficiency, pulmonary disease, CHF, and female gender. Following EVAR, patients were less likely to require home care or transfer to a rehabilitation facility than after open repair (14.1 vs. 36.0%, p < 0.05). Women were significantly more likely to require postdischarge care after open repair (48.7 vs. 30.1%) and EVAR (41.7 vs. 10.0%) (p < 0.05). Logistic regression identified female gender, open repair, advanced age, and pulmonary disease as independent predictors of need for postdischarge care. Those patients undergoing abdominal aortic aneurysm (AAA) repair by open technique (compared to EVAR) had significantly impaired functional health with regard to PF, VT, and ER in the first 3 months after surgery. CHF and hypertension also significantly impaired individual functional health scores. Of significance was that female gender was associated with increased LOS and increased utilization of postdischarge nursing and rehabilitation resources following both open and endovascular surgery for AAA.


Irradiation of pre-packaged sliced cooked meat products with low and normal sodium content.
Irradiation experiments were carried out with pre-packaged sliced cooked meat products with different initial counts of Enterobacteriaceae and mesophilic aerobic bacteria. In low-sodium meat products Enterobacteriaceae could effectively be inactivated in refrigerated or frozen products by irradiation with a dose of 1 or 2 kGy respectively, provided the number of these bacteria was below 10(3) to 10(4) per g. The low-sodium meat products involved endured above treatment without being seriously affected as to sensory qualities. Shelf-life of salted cooked meat products could be prolonged by irradiating the frozen product. Irradiation with a dose of 2 kGy enabled uncooled storage of the product for a restricted period (5-7 days). Best results were obtained for meat products with a salt content in the brine phase of greater than 4.0% (w/w) and having a good hygienic quality, i.e. an initial bacterial count below 10(4)/g. Packaging in a gas atmosphere (CO2) slightly enhanced protection as compared to vacuum packaging. Off-flavours as a result of irradiation of salted cooked meat products varied from slight to strong and depended on the type of product.


Spike synchronization of chaotic oscillators as a phase transition.
We study how a locally coupled array of spiking chaotic systems synchronizes to an external driving in a short time. Synchronization means spike separation at adjacent sites much shorter than the average inter-spike interval; a local lack of synchronization is called a defect. The system displays sudden spontaneous defect disappearance at a critical coupling strength suggesting an existence of a phase transition. Below critical coupling, the system reaches order at a definite amplitude of an external input; this order persists for a fixed time slot. Thus, the array behaves as an excitable-like system, even though the single element lacks such a property.


A rare case of carbimazole-induced hepatitis in a patient with Graves' disease.
Although carbimazole-induced hepatitis is rare, clinicians should be aware of this potential complication and offer alternative treatment early.


Preoperative cardiac function parameters as valuable predictors for nurses to recognise delirium after cardiac surgery: A prospective cohort study.
Delirium is a common postoperative complication after cardiac surgery. The relationship between delirium and cardiac function has not been fully elucidated. The aim of this study was to identify the association between preoperative cardiac function and delirium among patients after cardiac surgery. We prospectively recruited 635 cardiac surgery patients with a planned cardiac intensive care unit admission. Postoperative delirium was diagnosed using the confusion assessment method for the intensive care unit. Preoperative cardiac function was assessed using N-terminal prohormone of brain natriuretic peptide (NT-proBNP), New York Heart Association functional classification and left ventricular ejection fraction. Delirium developed in 73 patients (11.5%) during intensive care unit stay. NT-proBNP level (odds ratio (OR) 1.24, 95% confidence interval (CI) 1.01-1.52) and New York Heart Association functional classification (OR 2.34, 95% CI 1.27-4.31) were both independently associated with the occurrence of delirium after adjusting for various confounders. The OR of delirium increased with increasing NT-proBNP levels after the turning point of 7.8 (log-transformed pg/ml). The adjusted regression coefficients were 1.19 (95% CI 0.95-1.49, P=0.134) for NT-proBNP less than 7.8 (log-transformed pg/ml) and 2.78 (95% CI 1.09-7.12, P=0.033) for NT-proBNP greater than 7.8 (log-transformed pg/ml). No association was found between left ventricular ejection fraction and postoperative delirium. Preoperative cardiac function parameters including NT-proBNP and New York Heart Association functional classification can predict the incidence of delirium following cardiac surgery. We suggest incorporating an early determination of preoperative cardiac function as a readily available risk assessment for delirium prior to cardiac surgery.


Impact of estrogenic compounds on DNA integrity in human spermatozoa: evidence for cross-linking and redox cycling activities.
A great deal of circumstantial evidence has linked DNA damage in human spermatozoa with adverse reproductive outcomes including reduced fertility and high rates of miscarriage. Although oxidative stress is thought to make a significant contribution to DNA damage in the male germ line, the factors responsible for creating this stress have not been elucidated. One group of compounds that are thought to be active in this context are the estrogens, either generated as a result of the endogenous metabolism of androgens within the male reproductive tract or gaining access to the latter as a consequence of environmental exposure. In this study, a wide variety of estrogenic compounds were assessed for their direct effects on human spermatozoa in vitro. DNA integrity was assessed using the Comet and TUNEL assays, lesion frequencies were quantified by QPCR using targets within the mitochondrial and nuclear (beta-globin) genomes, DNA adducts were characterized by mass spectrometry and redox activity was monitored using dihydroethidium (DHE) as the probe. Of the estrogenic and estrogen analogue compounds evaluated, catechol estrogens, quercetin, diethylstilbestrol and pyrocatechol stimulated intense redox activity while genistein was only active at the highest doses tested. Other estrogens and estrogen analogues, such as 17beta-estradiol, nonylphenol, bisphenol A and 2,3-dihydroxynaphthalene were inactive. Estrogen-induced redox activity was associated with a dramatic loss of motility and, in the case of 2-hydroxyestradiol, the induction of significant DNA fragmentation. Mass spectrometry also indicated that catechol estrogens were capable of forming dimers that can cross-link the densely packed DNA strands in sperm chromatin, impairing nuclear decondensation. These results highlight the potential importance of estrogenic compounds in creating oxidative stress and DNA damage in the male germ line and suggest that further exploration of these compounds in the aetiology of male infertility is warranted.


Cannabinoids for symptom management in children with cancer: A systematic review and meta-analysis.
Despite the widespread use of medical cannabis, little is known regarding the safety, efficacy, and dosing of cannabis products in children with cancer. The objective of this study was to systematically appraise the existing published literature for the use of cannabis products in children with cancer. This systematic review, registered with the International Prospective Register of Systematic Reviews (CRD42020187433), searched four databases: MEDLINE, Embase, PsycINFO, and the Cochrane Library. Abstracts and full texts were screened in duplicate. Data on types of cannabis products, doses, formulations, frequencies, routes of administration, indications, and clinical and demographic details as well as reported efficacy outcomes were extracted. Data on cannabinoid-related adverse events were also summarized. Out of 34,611 identified citations, 19 unique studies with a total of 1927 participants with cancer were included: eight retrospective chart reviews, seven randomized controlled trials, two open-label studies, and two case reports. The included studies reported the use of various cannabis products for the management of symptoms. Cannabinoids were commonly used for the management of chemotherapy-induced nausea and vomiting (11 of 19 [58%]). In controlled studies, somnolence, dizziness, dry mouth, and withdrawal due to adverse events were more commonly associated with the use of cannabinoids. Across all included studies, no serious cannabis-related adverse events were reported. Although there is evidence to support the use of cannabis for symptom management, in children with cancer, there is a lack of rigorous evidence to inform the dosing, safety, and efficacy of cannabinoids. Because of the increasing interest in using cannabis, there is an urgent need for more research on medical cannabis in children with cancer.


Random dominance and childhood migraine: a new marker? A controlled study of laterality in children with migraine.
We assessed various aspects of laterality by direct observation in children with migraine and peer controls, with special reference to the frequency of random dominance. This frequency varied with the test battery used, being lower on the Edinburgh and Oldfield inventories which measure hand-use preference, and higher on the Handedness index and Spontaneous gestural index, which explore "genetic laterality". Random dominance would seem to be a new marker of migraine in childhood, for use alongside the hyperreactivity marker found in a previous study.


Prevalence of Osteoporosis in Women in Buenos Aires Based on Bone Mineral Density at the Lumbar Spine and Femur.
The aim of the study was to report values for osteoporosis (OP) prevalence in Buenos Aires. Bone mineral density (BMD) at different skeletal sites was measured from November 2012 to July 2014. Participants were recruited through a newspaper advertisement inviting women at least 50 yr of age to receive free BMD measurement. After signing an informed consent form, 5448 women living in Buenos Aires and surrounding districts were studied. Lumbar spine (L1-L4), femur neck, and total hip BMDs were measured (Lunar Prodigy, software version 12.3 GE, Madison, WI, USA). OP was defined as a T-score ≤-2.5 at the lumbar spine or the femoral neck. Results showed that 1021 out of 5448 studied subjects (18.7%) had OP at the lumbar spine or the femoral neck. Comparison of age of the population sample with reference data for the general population showed a moderate (+0.6%) increase in prevalence. Prevalence of OP was low, up to the age of 70 yr when based on femoral neck BMD only. Conversely, the prevalence of OP at the lumbar spine, which was reportedly high in women up to the age of 70 yr, tended to level off over that age. The results of the total femur only added a slight (+0.7%) nonsignificant increase to the OP prevalence. A total 346,500 out of 1,853,000 women aged 50+ yr in Buenos Aires had OP at the lumbar spine or femoral neck, whereas only 163,500 had OP at the upper femur, reducing the number by 53%. The present study assessed OP prevalence in the most densely populated urban area in Argentina. The results are similar to those reported for Caucasian populations in the United States and Canada. As measurement of only the BMD of femoral neck overlooks the diagnosis in half of the women, future studies should include measurement of the lumbar spine in combination with the femoral neck for a more accurate estimation of OP prevalence.


Outcomes of successful vs. failed contemporary chronic total occlusion percutaneous coronary intervention.
There are limited contemporary data on the impact of success vs. failure on the outcomes of chronic total occlusion (CTO) percutaneous coronary intervention (PCI). We conducted a systematic review and a meta-analysis of contemporary studies that compared the outcomes in patients who underwent successful vs. failed contemporary (2010 onwards) CTO PCI. We performed a sensitivity analysis limited to studies that started enrollment after the publication of the hybrid algorithm in 2012. We included five studies with a total of 6,084 patients (successful CTO PCI n = 4,861, failed CTO PCI n = 1,223). During a median follow-up time of 12 months (range 6-60 months), successful CTO PCI was associated with a lower risk of major adverse cardiovascular events [OR: 0.61, 95% CI (0.41, 0.92), p = 0.02, I2 = 63%] and all-cause death [OR: 0.57, 95% CI (0.33, 0.99), p = 0.05, I2 = 60%]. Both groups had similar risk of myocardial infarction (MI) [OR 0.69, 95% CI (0.43, 1.10), p = 0.38, I2 = 80%], target vessel revascularization (TVR) [OR: 0.56, 95% CI (0.25, 1.27), p = 0.17, I2 = 80%], and stroke [OR: 0.52, 95% CI (0.14, 1.91), p = 0.33, I2 = 0%]. In contemporary practice, successful CTO PCI was associated with a lower incidence of MACE driven by lower all-cause mortality compared with failed CTO PCI at a median follow-up of 1 year.


Liver-directed surgery of neuroendocrine metastases: What is the optimal strategy?
Neuroendocrine tumors (NETs) frequently metastasize to the liver. Operative debulking offers symptomatic relief and improved survival; however, the frequent presence of multifocal, bilobar disease and high recurrence rates introduces doubt regarding their optimal management. Parenchyma-sparing debulking (PSD) procedures (ablation, enucleation, wedge resections) may offer similar survival improvements as resection while minimizing morbidity and preserving functional liver tissue. Clinicopathologic variables from 228 patients with small bowel or pancreatic NETs managed operatively at one institution were collected. Liver-directed surgery was carried out when substantial debulking was deemed feasible. Survival was assessed by use of the Kaplan-Meier method. A total of 108 patients with pancreatic NET or small bowel NET underwent liver-directed surgery with primarily PSD procedures. Nearly two-thirds of patients achieved 70% cytoreduction and 84% had concurrent resection of their primary. The median number of lesions treated was 6 (range, 1-36). There were no 30-day operative mortalities. The 30-day major complication rate was 13.0%. Patients who achieved 70% cytoreduction enjoyed improved progression free (median 3.2 years) and overall survival (median not reached). PSD procedures are safe and can achieve significant cytoreduction, which is associated with improved survival. Lowering the debulking target threshold to 70% may benefit NET patients by increasing eligibility for cytoreduction.


ATP13A2 deficiency induces a decrease in cathepsin D activity, fingerprint-like inclusion body formation, and selective degeneration of dopaminergic neurons.
Kufor-Rakeb syndrome (KRS) was originally described as an autosomal recessive form of early-onset parkinsonism with pyramidal degeneration and dementia. ATP13A2 was identified as the causative gene in KRS. ATP13A2 encodes the ATP13A2 protein, which is a lysosomal type5 P-type ATPase, and ATP13A2 mutations are linked to autosomal recessive familial parkinsonism. Here, we report that normal ATP13A2 localizes in the lysosome, whereas disease-associated variants remain in the endoplasmic reticulum. Cathepsin D activity was decreased in ATP13A2-knockdown cells that displayed lysosome-like bodies characterized by fingerprint-like structures. Furthermore, an atp13a2 mutation in medaka fish resulted in dopaminergic neuronal death, decreased cathepsin D activity, and fingerprint-like structures in the brain. Based on these results, lysosome abnormality is very likely to be the primary cause of KRS/PARK9.


Spin generation via bulk spin current in three-dimensional topological insulators.
To date, spin generation in three-dimensional topological insulators is primarily modelled as a single-surface phenomenon, attributed to the momentum-spin locking on each individual surface. In this article, we propose a mechanism of spin generation where the role of the insulating yet topologically non-trivial bulk becomes explicit: an external electric field creates a transverse pure spin current through the bulk of a three-dimensional topological insulator, which transports spins between the top and bottom surfaces. Under sufficiently high surface disorder, the spin relaxation time can be extended via the Dyakonov-Perel mechanism. Consequently, both the spin generation efficiency and surface conductivity are largely enhanced. Numerical simulation confirms that this spin generation mechanism originates from the unique topological connection of the top and bottom surfaces and is absent in other two-dimensional systems such as graphene, even though they possess a similar Dirac cone-type dispersion.


Natural history of Krabbe disease - a nationwide study in Germany using clinical and MRI data.
Krabbe disease or globoid cell leukodystrophy is a severe neurodegenerative disorder caused by a defect in the GALC gene leading to a deficiency of the enzyme ß-galactocerebrosidase. The aim of this work was to describe the natural disease course covering the whole spectrum of the disease. Natural history data were collected with a standardized questionnaire, supplemented by medical record data. We defined different forms of the disease according to Abdelhalim et al. (2014). Developmental and disease trajectories were described based on the acquisition and loss of milestones as well as the time of first clearly identifiable symptoms and needs such as spasticity, seizures and tube feeding. MRI was assessed using the scoring system by Loes et al. (1999) and in addition a pattern recognition approach, based on Abdelhalim et al. (2014). Thirty-eight patients were identified, from 27 of these patients 40 MRIs were available; 30 (79%) had an infantile onset, showing first symptoms in their first year of life, almost all (27 out of 30) starting in the first six months. A later onset after the first year of life was observed in 8 patients (21%, range 18 months to 60 years). Irritability, abnormalities in movement pattern as well as general developmental regression were the first symptoms in the infantile group; disease course was severe with rapid progression, e.g. loss of visual fixation, need for tube feeding and then an early death. Gait disorders were the first symptoms in all patients of the later onset groups; progression was variable. The different forms of the disease were characterized by different MRI patterns (infantile: diffuse white matter involvement and cerebellar structures specifically affected, later onset: parieto-occipital white matter and splenium affected, adult: motor tracts specifically affected). This is the first description of the natural history of Krabbe disease in a larger European cohort using developmental, clinical and MRI data. We would like to highlight the very different clinical and MRI characteristics of the later onset forms. These data are important for counselling affected patients and families and may serve as a basis for future treatment trials.


A higher non-severe hypoglycaemia rate is associated with an increased risk of subsequent severe hypoglycaemia and major adverse cardiovascular events in individuals with type 2 diabetes in the LEADER study.
Hypoglycaemia is a common side effect of insulin and some other antihyperglycaemic agents used to treat diabetes. Severe hypoglycaemia has been associated with adverse cardiovascular events in trials of intensive glycaemic control in type 2 diabetes. The relationship between non-severe hypoglycaemic episodes (NSHEs) and severe hypoglycaemia in type 2 diabetes has been documented. However, an association between more frequent NSHEs and cardiovascular events has not been verified. This post hoc analysis of the LEADER (Liraglutide Effect and Action in Diabetes: Evaluation of Cardiovascular Outcome Results) trial aimed to confirm whether there is an association between NSHEs and severe hypoglycaemic episodes in individuals with type 2 diabetes. In addition, the possible association between NSHEs and major adverse cardiac events (MACE), cardiovascular death and all-cause mortality was investigated. LEADER was a double-blind, multicentre, placebo-controlled trial that found that liraglutide significantly reduced the risk of MACE compared with the placebo. In this post hoc analysis, we explored, in all LEADER participants, whether the annual rate of NSHEs (defined as self-measured plasma glucose <3.1 mmol/l [56 mg/dl]) was associated with time to first severe hypoglycaemic episode (defined as an episode requiring the assistance of another person), time to first MACE, time to cardiovascular death and time to all-cause mortality. Participants with <2 NSHEs per year were used as reference for HR estimates. Cox regression with a time-varying covariate was used. We demonstrate that there is an association between NSHEs (2-11 NSHEs per year and ≥12 NSHEs per year) and severe hypoglycaemic episodes (unadjusted HRs 1.98 [95% CI 1.43, 2.75] and 5.01 [95% CI 2.84, 8.84], respectively), which was consistent when baseline characteristics were accounted for. Additionally, while no association was found between participants with 2-11 NSHEs per year and adverse cardiovascular outcomes, higher rates of NSHEs (≥12 episodes per year) were associated with higher risk of MACE (HR 1.50 [95% CI 1.01, 2.23]), cardiovascular death (HR 2.08 [95% CI 1.17, 3.70]) and overall death (HR 1.80 [95% CI 1.11, 2.92]). The analysis of data from the LEADER trial demonstrated that higher rates of NSHEs were associated with both a higher risk of severe hypoglycaemia and adverse cardiovascular outcomes in individuals with type 2 diabetes. Therefore, irrespective of the cause of this association, it is important that individuals with high rates of hypoglycaemia are identified so that the potentially increased risk of cardiovascular events can be managed and steps can be taken to reduce NSHEs. ClinicalTrials.gov (NCT01179048).


Topo-optical reactions and polarization optical analysis of human lymphocytes.
The latent birefringence of lymphocyte membranes of various species may readily be studied and analysed by various topo-optical reactions. The membranes of glutaraldehyde-fixed and PBS-washed lymphocytes show continuous birefringence with thiazine- and quinoline dyes. According to polarization optical analysis thiazine dye-stained cells are radially positive, whereas quinoline dye-stained cells are radially negative spherites, i.e. thiazine dye molecules are in a perpendicular, quinoline dye molecules in a parallel orientation relative to the membrane surface. These findings suggest that in lymphocyte membranes glycoproteins are primarily responsible for the topo-optical reactions. The actual conformational state of the glycoprotein components is a decisive factor not only in dye binding but also in the orientation of dye molecules. Heparin treatment directs attention to an important interaction between heparin and membrane glycoproteins. With the aid of the critical electrolyte concentration (CEC) technique we were able to demonstrate an ultrastructural differences between human erythrocyte and human lymphocyte membranes. After this procedure the birefringence of erythrocyte membranes was lost, whereas that of lymphocyte membranes did not change. There were no differences between the topo-optical reactions of T and B lymphocytes.


Dynamics, structure and performance of shoot populations of the rhizomatous herb Solidago canadensis L. in abandoned pastures.
Two shoot populations of the rhizomatous, patchforming herb Solidago canadensis were studied throughout a developmental cycle in two abandoned pasture sites in southern Ontario. The shoot cohorts that emerged in spring dominated the two populations; subsequent recruitment was very low. Shoot mortality was highest in June and was concentrated in the smallest size classes. Both populations showed a pronounced bimodal size structure for most of the growth cycle. Relative growth rate of shoots declined as the growing season progressed and tended to be lowest in the smallest size classes. Inflorescence production depended on shoot size. The calculated relationship between log mean weight and log density of shoots was not constant during the growth cycle and the calculated maximum biomass values do not transgress the 'ultimate' thinning line suggested from previously published data.


Protocol for the development of a core outcome set for autologous fat grafting to the breast.
One in eight women will develop breast cancer in their lifetime. Reconstruction is routinely offered to patients and can be autologous and/or implant based. One area of growing interest in autologous fat grafting (AFG). Our group recently published a systematic review and meta-analysis of this topic which showed 51 different outcomes were being utilized in the published literature, with substantial heterogeneity in their definitions. A Delphi consensus exercise amongst key stakeholders will be conducted using the long list of 51 outcomes generated through our previous work. We will first group these according to the six domains previously identified; oncological, clinical, aesthetic and functional, patient-reported, process and radiological. Through sequential rounds of voting, the long list of outcomes will be narrowed down using predefined rules of agreement. No patients will be involved in this study and ethical approval is not required. The research will be published in a peer-reviewed journal. It will also be presented at national and international conferences in the fields of plastic, reconstructive and aesthetic surgery as well as breast surgery and at more general surgical and methodological conferences. It will be disseminated electronically and in print. Brief reports of the review findings will be disseminated directly to the appropriate audiences of surgeons and societies through email and other modes of communication.


Marijuana use and physical dating violence among adolescents and emerging adults: A systematic review and meta-analysis.
As restrictions on marijuana are loosened, there is concern of a coming increase in marijuana use among adolescents and emerging adults, which could be coupled with commensurate increases in behavioral problems associated with use, such as physical dating violence (PDV). To summarize what is known about the association between marijuana use and PDV victimization and perpetration among 11-21year olds, we conducted a systematic review and meta-analysis of the relevant literature published between 2003 and 2015. Candidate articles were identified with a systematic search, and we used inclusion and exclusion criteria to review titles, abstracts, and the full text of studies for consideration. There were 13 articles examining marijuana in association with PDV; five addressed victimization and 11 addressed perpetration. Findings suggest that marijuana use is associated with a 54% increase in the odds PDV victimization, and a 45% increase in the odds of perpetration. Findings suggest that dating violence is a correlate of marijuana use, and that association is strongest among adolescents (vs. emerging adults) and girls (vs. boys). Therefore, it should be routinely included as a core data item in marijuana surveillance systems, so as to allow for behavioral monitoring.


Enhancing NLO performance by utilizing tyrian purple dye as donor moiety in organic DSSCs with end capped acceptors: A theoretical study.
A series of new organic dyes (T1-T6) with nonfullerene acceptors have been theoretically designed around the chemical structure of tyrian purple (T) natural dye. For their ground state energy parameters, all the molecular geometries of those dyes were optimized by density functional theory (DFT) at its Becke, 3-parameter, Lee-Yang-Parr (B3LYP) level of theory with 6-31G+(d,p) basis sets. When benchmarking against several long range and range separated levels of theory, the Coulomb attenuated B3LYP (CAM-B3LYP) produced most accurate absorption maxima (λmax) value to that of T so it was further employed for further Time dependent DFT (TD-DFT) calculations. Frontier molecular orbitals (FMOs) with natural bond orbital (NBO) studies were used to study their intra molecular charge transfer (ICT). All of the dyes had their energy gaps (Eg) values between their FMOs to range around 0.96-3.39 eV, whereas the starting reference dye had an Eg of 1.30 eV. Their ionization potential (IP) values were ranged to be 3.07-7.25 eV which indicated their nature to loss electrons. The λ max in chloroform was marginally red-shifted with a value 600-625 from T (580 nm). The dye T6 showed its highest linear polarizability (<α>), and first and second order hyperpolarizabilities (β and γ). The synthetic experts can find the present research to design finest NLO materials for current and future uses.


[Cowden's syndrome].
Multiple hamartoma and neoplasia syndrome, or Cowden's disease, is a genodermatosis inherited as an autosomal dominant trait with variable expressivity. We describe a woman with classic mucocutaneous features of the syndrome: facial papules, acral keratoses, oral mucosal papillomatosis, oral polyps and scrotal tongue. As a child she had strabismus. Her family history is positive for the disease, and a sister died of malignant melanoma. The check-up revealed chronic lymphocytic thyroiditis. A checklist for use in screening patients with Cowden's disease is proposed.