bluuebunny/crossref_metadata_2025_split huggingface dataset:
Kaposi's Sarcoma-Associated Herpesvirus Viral Interferon Regulatory Factor 4 (vIRF4) Perturbs the G
1
-S Cell Cycle Progression via Deregulation of the
cyclin D1
Gene
Authors: Lee Hye-Ra , Mitra Jaba , Lee Stacy , Gao Shou-Jiang , Oh Tae-Kwang , Kim Myung Hee , Ha Taekjip , Jung Jae U. 
Published: October 2015

ABSTRACT

Kaposi's sarcoma-associated herpesvirus (KSHV) infection modulates the host cell cycle to create an environment optimal for its viral-DNA replication during the lytic life cycle. We report here that KSHV vIRF4 targets the β-catenin/CBP cofactor and blocks its occupancy on the
cyclin D1
promoter, suppressing the G
1
-S cell cycle progression and enhancing KSHV replication. This shows that KSHV vIRF4 suppresses host G
1
-S transition, possibly providing an intracellular milieu favorable for its replication.
A Unique Multibasic Proteolytic Cleavage Site and Three Mutations in the HA2 Domain Confer High Virulence of H7N1 Avian Influenza Virus in Chickens
Authors: Abdelwhab El-Sayed M. , Veits Jutta , Tauscher Kerstin , Ziller Mario , Teifke Jens P. , Stech Jürgen , Mettenleiter Thomas C. 
Published: October 2015

ABSTRACT

In 1999, after circulation for a few months in poultry in Italy, low-pathogenic (LP) avian influenza (AI) H7N1 virus mutated into a highly pathogenic (HP) form by acquisition of a unique multibasic cleavage site (mCS), PEIPKGSRVRR*GLF (asterisk indicates the cleavage site), in the hemagglutinin (HA) and additional alterations with hitherto unknown biological function. To elucidate these virulence-determining alterations, recombinant H7N1 viruses carrying specific mutations in the HA of LPAI A/chicken/Italy/473/1999 virus (Lp) and HPAI A/chicken/Italy/445/1999 virus (Hp) were generated. Hp with a monobasic CS or carrying the HA of Lp induced only mild or no disease in chickens, thus resembling Lp. Conversely, Lp with the HA of Hp was as virulent and transmissible as Hp. While Lp with a multibasic cleavage site (Lp_CS445) was less virulent than Hp, full virulence was exhibited when HA2 was replaced by that of Hp. In HA2, three amino acid differences consistently detected between LP and HP H7N1 viruses were successively introduced into Lp_CS445. Q450L in the HA2 stem domain increased virulence and transmission but was detrimental to replication in cell culture, probably due to low-pH activation of HA. A436T and/or K536R restored viral replication
in vitro
and
in vivo
. Viruses possessing A436T and K536R were observed early in the HPAI outbreak but were later superseded by viruses carrying all three mutations. Together, besides the mCS, stepwise mutations in HA2 increased the fitness of the Italian H7N1 virus
in vivo
. The shift toward higher virulence in the field was most likely gradual with rapid optimization.

IMPORTANCE
In 1999, after 9 months of circulation of low-pathogenic (LP) avian influenza virus (AIV), a devastating highly pathogenic (HP) H7N1 AIV emerged in poultry, marking the largest epidemic of AIV reported in a Western country. The HPAIV possessed a unique multibasic cleavage site (mCS) complying with the minimum motif for HPAIV. The main finding in this report is the identification of three mutations in the HA2 domain that are required for replication and stability, as well as for virulence, transmission, and tropism of H7N1 in chickens. In addition to the mCS, Q450L was required for full virulence and transmissibility of the virus. Nonetheless, it was detrimental to virus replication and required A436T and/or K536R to restore replication, systemic spread, and stability. These results are important for better understanding of the evolution of highly pathogenic avian influenza viruses from low-pathogenic precursors.
Return to sport after open and microdiscectomy surgery versus conservative treatment for lumbar disc herniation: a systematic review with meta-analysis
Authors: Reiman Michael P , Sylvain Jonathan , Loudon Janice K , Goode Adam 
Published: October 2015

BackgroundLumbar disc herniation has a prevalence of up to 58% in the athletic population. Lumbar discectomy is a common surgical procedure to alleviate pain and disability in athletes. We systematically reviewed the current clinical evidence regarding athlete return to sport (RTS) following lumbar discectomy compared to conservative treatment.MethodsA computer-assisted literature search of MEDLINE, CINAHL, Web of Science, PEDro, OVID and PubMed databases (from inception to August 2015) was utilised using keywords related to lumbar disc herniation and surgery. The design of this systematic review was developed using the guidelines of thePreferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA). Methodological quality of individual studies was assessed using the Downs and Black scale (0–16 points).ResultsThe search strategy revealed 14 articles. Downs and Black quality scores were generally low with no articles in this review earning a high-quality rating, only 5 articles earning a moderate quality rating and 9 of the 14 articles earning a low-quality rating. The pooled RTS for surgical intervention of all included studies was 81% (95% CI 76% to 86%) with significant heterogeneity (I2=63.4%, p<0.001) although pooled estimates report only 59% RTS at same level. Pooled analysis showed no difference in RTS rate between surgical (84% (95% CI 77% to 90%)) and conservative intervention (76% (95% CI 56% to 92%); p=0.33).ConclusionsStudies comparing surgical versus conservative treatment found no significant difference between groups regarding RTS. Not all athletes that RTS return at the level of participation they performed at prior to surgery. Owing to the heterogeneity and low methodological quality of included studies, rates of RTS cannot be accurately determined.
Prevalence of diabetes and impaired fasting glucose in Peru: report from PERUDIAB, a national urban population-based longitudinal study
Authors: Seclen Segundo N , Rosas Moises E , Arias Arturo J , Huayta Ernesto , Medina Cecilia A 
Published: October 2015

ObjectivesWe aimed to estimate the prevalences of diabetes and impaired fasting glucose (IFG) in a national sample in Peru and assess the relationships with selected sociodemographic variables.MethodsWe estimated prevalence in PERUDIAB study participants, a nationwide, stratified urban and suburban population selected by random cluster sampling. Between 2010 and 2012, questionnaires were completed and blood tests obtained from 1677 adults ≥25 years of age. Known diabetes was defined as participants having been told so by a doctor or nurse and/or receiving insulin or oral antidiabetic agents. Newly diagnosed diabetes was defined as fasting plasma glucose ≥126 mg/dL determined during the study and without a previous diabetes diagnosis. IFG was defined as fasting plasma glucose of 100–125 mg/dL.ResultsThe estimated national prevalence of diabetes was 7.0% (95% CI 5.3% to 8.7%) and it was 8.4% (95% CI 5.6% to 11.3%) in metropolitan Lima. No gender differences were detected. Known and newly diagnosed diabetes prevalences were estimated as 4.2% and 2.8%, respectively. A logistic regression response surface model showed a complex trend for an increased prevalence of diabetes in middle-aged individuals and in those with no formal education. Diabetes prevalence was higher in coastal (8.2%) than in highlands (4.5%; p=0.03), and jungle (3.5%; p<0.02) regions. The estimated national prevalence of IFG was 22.4%, higher in males than in females (28.3% vs 19.1%; p<0.001), and higher in coastal (26.4%) than in highlands (17.4%; p=0.03), but not jungle regions (14.9%; p=0.07).ConclusionsThis study confirms diabetes as an important public health problem, especially for middle-aged individuals and those with no formal education. 40% of the affected individuals were undiagnosed. The elevated prevalence of IFG shows that nearly a quarter of the adult population of Peru has an increased risk of diabetes.
Improving validated depression screen among adolescent population in primary care practice using electronic health records (EHR).
Authors: Sudhanthar Sathyanarayan , Thakur Kripa , Sigal Yakov , Turner Jane 
Published: October 2015

AbstractAdolescent depression, has been identified as one of the important risk factors for adolescent safety. The American Academy of Pediatrics (AAP) recommends screening the adolescent population for depression with a validated screening tool at least once a year. Given the time constraints in primary care, many physicians tend to rely more on clinical questioning to screen depression.This has the potential to miss many adolescents who may have mild to moderate depression which may prove detrimental to their emotional and physical health.Quality measures had consistently indicated that the validated adolescent depression screening rate in our two pediatric clinics was 10-15% in the past two years starting from 2012. There was a need to increase our screening rate for adolescent depression with a validated questionnaire. The stakeholders identified were physicians, nurses and the health information team (HIT).The Patient Health Questionnaire-2 (PHQ-2) is a standardized tool and serves as a good first step rapid screening of the population. A decision was made to implement the use of PHQ-2 to all the adolescents aged 11-21. A clinic flow protocol was developed. As the patient checks in, there will be a computer pop-up reminding nurses to administer the PHQ-2. The PHQ-2 self-scores in the Electronic Health Record (EHR) and if the score is three or more the nurses would automatically administer the PHQ-9 which is also embedded and self-scored in the EHR.After 12 months of implementing this project with four PDSA cycles, the adolescent depression-screening rate improved from 10-15% from the previous two years to 65% (six month period) and 82% at the end of the 12 month period. The rate of referral to mental health services had also increased in the same time period compared to the previous years. In conclusion, screening for adolescent depression with a brief validated tool in a busy primary care office is possible with the help of the EHR.
Immunohistochemical detection of cytoplasmic nucleophosmin in formalin-fixed paraffin-embedded marrow trephine biopsies in acute myeloid leukaemia
Authors: Lit Benny Man Wai , Kwong Yok Lam , Wong Kit Fai 
Published: October 2015

AimsNucleophosmin (NPM1) gene mutations resulting in cytoplasmic delocalisation of nucleophosmin (NPMc+) are the most common genetic abnormality in acute myeloid leukaemia (AML). In this study, we tested whether immunohistochemical (IHC) detection of cytoplasmic NPM1 (cNPM1) in formalin-fixed bone marrow trephine biopsies correlated withNPM1mutations and the prognostic impact ofNPM1and fms-related tyrosine kinase 3-internal tandem duplication (FLT3-ITD) gene mutations was also assessed.MethodsA total of 71 Chinese adult de novo AML cases were evaluated for cNPM1 by IHC where the bone marrow trephines were fixed in 10% buffered formalin and decalcified by 5% EDTA.NPM1andFLT3-ITD gene mutations were also investigated using PCR, fragment analysis and direct DNA sequencing.ResultsIHC analysis of cNPM1 had a very good sensitivity (86.7%) and excellent specificity (96.4%) forNPM1mutation. The positive predictive value was 86.7% and the negative predictive value was 96.4%.NPM1mutations andFLT3-ITD were closely associated (p=0.003). Patients with mutatedNPM1and withoutFLT3-ITD mutation have a longer overall survival (p=0.042) than patients with bothNPM1andFLT3-ITD mutations.ConclusionsOur results showed that IHC detection of cNPM1 in formalin-fixed trephine biopsies correlated well but not entirely withNPM1mutation. Furthermore,NPM1mutations were significantly more frequent inFLT3-ITD thanFLT3-wild-type cases.
Severe childhood obesity: an under-recognised and growing health problem
Authors: Bass Rosara , Eneli Ihuoma 
Published: October 2015

ABSTRACT
Childhood obesity is a serious and urgent public health problem. In the last 10 years, there has been a concerted effort in the USA and globally to develop and implement educational, medical and public health interventions designed to attenuate its growth. The success of these efforts was probably responsible for the plateau in the prevalence rate of childhood obesity noted in the last two years. While the attenuation of the overall prevalence of childhood obesity is promising, data from the same cohort reveal a concerning upward trend in the number of children with severe obesity. The consequences of severe childhood obesity can be devastating. When compared to their moderately obese peers, children with severe obesity are at greater risk for adult obesity, early atherosclerosis, hypertension, type 2 diabetes, metabolic syndrome, fatty liver disease and premature death. The determinants for severe obesity include the same lifestyle, environmental, familial and societal risk factors reported for overweight or obesity. While all these risk factors must be screened for, genetic influences are distinct considerations that may have greater bearing especially with early-onset obesity. Treatments for severe childhood obesity include lifestyle intervention, specialised low-calorie diets and bariatric surgery. Outcomes of these treatments vary, with bariatric surgery clearly the most successful of the three for both short-term and long-term weight loss. Severe obesity in children and adolescents remains a challenging health condition. The enormous medical, emotional and financial burden these children and their families endure signals an urgent need to further investigate and standardise treatment modalities and improve outcomes.
How men can help women in CS; winning 'computing's Nobel prize'
Authors: Barr Valerie , Stonebraker Michael 
Published: October 2015

The
Communications
Web site, http://cacm.acm.org, features more than a dozen bloggers in the BLOG@CACM community. In each issue of
Communications
, we'll publish selected posts or excerpts.

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Follow us on Twitter at http://twitter.com/blogCACM
http://cacm.acm.org/blogs/blog-cacm
Valerie Barr suggests how men can better promote women in computing, while Michael Stonebraker shares how it feels to receive the top honor in the computer science field.
Analysis of mTOR Gene Aberrations in Melanoma Patients and Evaluation of Their Sensitivity to PI3K–AKT–mTOR Pathway Inhibitors
Authors: Kong Yan , Si Lu , Li Yiqian , Wu Xiaowen , Xu Xiaowei , Dai Jie , Tang Huan , Ma Meng , Chi Zhihong , Sheng Xinan , Cui Chuanliang , Guo Jun 
Published: October 2015

Abstract
Purpose: mTOR is a validated target in cancer. It remains to be determined whether melanoma patients bearing mTOR mutation could be selected for treatment with PI3K–AKT–mTOR pathway inhibitors.
Experimental Design: A total of 412 melanoma samples were included. Gene aberrations in all exons of mTOR were detected by Sanger sequencing and confirmed by using Agilent's SureSelect Target Enrichment System. HEK293T cells stably expressing mTOR mutants were constructed by using transcription activator-like effector nucleases technique. Function of mTOR mutants and in vitro sensitivity of gain-of-function mTOR mutations to PI3K–AKT–mTOR pathway inhibitors were analyzed.
Results: The overall incidence of somatic nonsynonymous mutations of mTOR was 10.4% (43/412). mTOR nonsynonymous mutations were relatively more frequent in acral (11.0%) and mucosal (14.3%) melanomas than in chronic sun-induced damage (CSD; 6.7%) and non-CSD (3.4%) melanomas. Of the 43 cases with mTOR mutations, 41 different mutations were detected, affecting 25 different exons. The median survival time for melanoma patients with mTOR nonsynonymous mutation was significantly shorter than that for patients without mTOR nonsynonymous mutation (P = 0.028). Transient expression of mTOR mutants in HEK293T cells strongly activated the mTOR–p70S6K pathway. In HEK293T cells with stable expression of H1968Y or P2213S mTOR mutants, LY294002 and AZD5363 showed higher potency than temsirolimus or BYL719 in inhibiting the PI3K–AKT–mTOR pathway and cell proliferation.
Conclusions: mTOR nonsynonymous mutations are frequent in melanoma patients. mTOR nonsynonymous mutation may predict a worse prognosis of melanoma. Clinical trials with PI3K–AKT–mTOR pathway inhibitors may be beneficial for melanoma patients with specific mTOR mutations. Clin Cancer Res; 22(4); 1018–27. ©2015 AACR.
A Phase I First-in-Human Study of Nesvacumab (REGN910), a Fully Human Anti–Angiopoietin-2 (Ang2) Monoclonal Antibody, in Patients with Advanced Solid Tumors
Authors: Papadopoulos Kyriakos P. , Kelley Robin Kate , Tolcher Anthony W. , Razak Albiruni R. Abdul , Van Loon Katherine , Patnaik Amita , Bedard Philippe L. , Alfaro Ariceli A. , Beeram Muralidhar , Adriaens Lieve , Brownstein Carrie M. , Lowy Israel , Kostic Ana , Trail Pamela A. , Gao Bo , DiCioccio A. Thomas , Siu Lillian L. 
Published: October 2015

Abstract
Purpose: Nesvacumab (REGN910) is a fully human immunoglobulin G1 (IgG1) monoclonal antibody that specifically binds and inactivates the Tie2 receptor ligand Ang2 with high affinity, but shows no binding to Ang1. The main objectives of this trial were to determine the safety, tolerability, dose-limiting toxicities (DLT), and recommended phase II dose (RP2D) of nesvacumab.
Experimental Design: Nesvacumab was administered intravenously every two weeks with dose escalations from 1 to 20 mg/kg in patients with advanced solid tumors.
Results: A total of 47 patients were treated with nesvacumab. No patients in the dose escalation phase experienced DLTs, therefore a maximum tolerated dose (MTD) was not reached. The most common nesvacumab-related adverse events were fatigue (23.4%), peripheral edema (21.3%), decreased appetite, and diarrhea (each 10.6%; all grade ≤ 2). Nesvacumab was characterized by linear kinetics and had a terminal half-life of 6.35 to 9.66 days in a dose-independent manner. Best response by RECIST 1.1 in 43 evaluable patients included 1 partial response (adrenocortical carcinoma) of 24 weeks duration. Two patients with hepatocellular carcinoma had stable disease (SD) &gt; 16 weeks, with tumor regression and &gt;50% decrease in α-fetoprotein. Analyses of putative angiogenesis biomarkers in serum and tumor biopsies were uninformative for treatment duration.
Conclusions: Nesvacumab safety profile was acceptable at all dose levels tested. Preliminary antitumor activity was observed in patients with treatment-refractory advanced solid tumors. On the basis of cumulative safety, antitumor activity, pharmacokinetic and pharmacodynamic data, the 20 mg/kg dose was determined to be the RP2D. Clin Cancer Res; 22(6); 1348–55. ©2015 AACR.
Micheli Anterior Cruciate Ligament Reconstruction in Skeletally Immature Youths
Authors: Willimon S. Clifton , Jones Christopher R. , Herzog Mackenzie M. , May Keith H. , Leake Melissa J. , Busch Michael T. 
Published: October 2015

Background: The management of anterior cruciate ligament (ACL) tears in the skeletally immature patient remains controversial. Outcomes on a physeal-sparing technique using the iliotibial band for combined intra-articular and extra-articular ACL reconstruction, called the Micheli technique, have been described and reported by the original authors. Purpose: To evaluate the clinical outcomes of a physeal-sparing technique using the iliotibial band for combined intra-articular and extra-articular ACL reconstruction. Study Design: Case series; Level of evidence, 4. Methods: Between 2005 and 2011, all patients who underwent Micheli ACL reconstruction performed by a single surgeon were identified. A minimum of 3 years’ growth remaining was a prerequisite for Micheli reconstruction. Patients were excluded if postoperative follow-up was less than 1 year. Patients were evaluated for functional outcomes, satisfaction, graft survival, radiographic and clinical evidence of growth disturbance, and the need for additional procedures. Results: Twenty-one patients (22 knees) met the inclusion criteria for this study. The mean age at the time of surgery was 11.8 years (range, 9.9-14.0 years). All patients were male. There were 4 concomitant meniscal repairs and 5 partial meniscectomies performed. All patients (100%) completed follow-up at a mean duration of 3.0 years (range, 1.0-6.9 years). Overall, 6 knees (27%) underwent reoperation. Of these, 3 knees (14%) underwent revision ACL surgery: 2 revision reconstructions at 2.8 and 4.0 years postoperatively and 1 graft shrinkage at 4.7 months postoperatively. Three knees (14%) underwent subsequent meniscal procedures, including 2 partial meniscectomies and 1 meniscal repair. Of the 19 knees that did not require revision ACL surgery, the median patient satisfaction score was 10 (range, 9-10). The mean Pediatric International Knee Documentation Committee score was 96.5 ± 2.9, and the mean Lysholm score was 95.0 ± 6.1. The median preinjury Tegner activity level was 8 (range, 6-10), and the median postoperative Tegner activity level was 8 (range, 6-10). Of the 19 knees that did not require revision ACL surgery, all had a normal Lachman test result, with a firm endpoint and normal pivot shift. At follow-up, 53% of knees had closed physes. There were no angular deformities or limb-length discrepancies. Conclusion: At a mean 3-year follow-up, the study findings confirmed excellent functional outcomes, a low ACL revision rate, and no growth disturbances. Patients returned to their preoperative activity level after reconstruction. This procedure offers a safe and effective ACL reconstruction option in children with several years of growth remaining.
Physical function and body composition in kidney transplant recipients over time with physiotherapy intervention
Authors: Huang Katherin Shilin , Cheah Sophia Chen Hui , Yi-Shern Kee Terence , Ng Cindy Li Whye 
Published: October 2015

Introduction: The long-term usage of immunosuppressants post-kidney transplantation often results in adverse effects such as weight gain, osteoporosis and an increased risk of cardiovascular diseases. Physical activity has been shown to have a protective effect against these adverse effects. This paper aims to investigate the changes over time in physical function and body composition in kidney transplant recipients with a home exercise regimen prescribed by a physiotherapist. Methods: Forty-two kidney transplant recipients aged 45 ± 12 years were recruited before transplant and reviewed at fixed time points after transplant. Body composition, hand grip strength and functional exercise capacity were measured at every session. A home exercise regimen was prescribed and modified when appropriate. Results: There was an observed trend towards an improvement in functional exercise capacity in terms of six-minute walk distance. There was no change in body weight, fat mass and skeletal muscle mass. Conclusion: There may be a need to provide supervised exercise training programmes for kidney transplant recipients in bringing about positive changes in body composition as well as ensure compliance to exercise training after transplant. Further research is needed for more conclusive results.