Clinical and Economic Impact of Hyperkalemia in Patients with Chronic Kidney Disease and Heart Failure.
Hyperkalemia (HK) is a concern for patients with chronic kidney disease (CKD) and heart failure (HF), and for those receiving treatments that inhibit the renin-angiotensin-aldosterone system (RAASi). An analysis of 1.7 million medical records of patients in the United States revealed that among individuals with more than 2 potassium values during 2007 to 2012, HK was detected in 34.6% of patients with CKD and 30.0% of patients with HF. To evaluate the association of HK and use of RAASi therapies at optimal and suboptimal doses in patients with CKD and/or HF with health care resource utilization and overall cost of care in a diverse cohort of commercially insured patients. This retrospective cohort study was conducted using medical and pharmacy claims from multiple regional health plans. Qualifying patients were ≥ 18 years old, continuously enrolled for 6 months before and throughout the study period (January 1, 2014, to December 31, 2015) and had an ICD-9-CM or ICD-10-CM diagnosis code of CKD and/or HF. Health care resource utilization, including hospital visits, length of stay, office visits, and associated medical and pharmacy costs, were assessed according to the 3 cohorts (CKD alone, HF alone, and concomitant CKD and HF). For the 3 cohorts, the results were also compared between patients with and without HK and between patients with and without RAASi use at optimal and suboptimal doses. Generalized linear models were used to further examine the predictors of medical and overall costs. In this study, 15,999 patients met inclusion criteria. Among patients using RAASi therapy, 26.8% received the optimal dose. Optimal dosing of RAASi was associated with decreased median outpatient office visits (8, 10, and 15, respectively, for patients with CKD, HF, and both CKD and HF) compared with suboptimal dosing of RAASi (12, 15, and 23, respectively). Similarly, optimal dosing of RAASi was associated with decreased overall median medical costs ($2,092, $4,144, and $7,762, respectively, for patients with CKD, HF, and both CKD and HF) compared with suboptimal dosing of RAASi ($3,121, $8,289, and $12,749, respectively). Patients with CKD, HF, or both CKD and HF, all in combination with HK, had higher overall costs, compared with those without HK. The results of this real-world analysis suggest that HK and suboptimal dosing of RAASI were associated with a median increase in outpatient office visits as well as increased overall medical costs among patients with CKD and/or HF. This evaluation of median costs suggests effective HK management may potentially reduce costs in patients with CKD and/or HF, including those currently receiving RAASi therapy. This study was conducted by Magellan Rx Management and funded by Relypsa. Brenner, Alvarez, and Oestreicher were employed by Relypsa during the development of this study and the writing of this manuscript. Polson, Lord, Kangethe, Speicher, and Farnum are employees of Magellan Rx Management, which received funding from Relypsa for conducting the retrospective study and writing the manuscript. Study concept and design were contributed by Lord, Polson, Brenner, Alvarez, and Oestreicher. Data collection and interpretation were performed by Polson and Kangethe, with assistance from Lord. The manuscript was written by Farnum, with assistance from Kangethe and Speicher and revised by all authors.


Mesenchymal stem cell therapy for nonmusculoskeletal diseases: emerging applications.
Mesenchymal stem cells are stem/progenitor cells originated from the mesoderm and can different into multiple cell types of the musculoskeletal system. The vast differentiation potential and the relative ease for culture expansion have established mesenchymal stem cells as the building blocks in cell therapy and tissue engineering applications for a variety of musculoskeletal diseases, including repair of fractures and bone defects, cartilage regeneration, treatment of osteonecrosis of the femoral head, and correction of genetic diseases such as osteogenesis imperfect. However, research in the past decade has revealed differentiation potentials of mesenchymal stem cells beyond lineages of the mesoderm, suggesting broader applications than originally perceived. In this article, we review the recent developments in mesenchymal stem cell research with respect to their emerging properties and applications in nonmusculoskeletal diseases.


Mitochondrial CR-1 variation in Sardinian hares and its relationships with other Old World hares (Genus Lepus).
Among the European fauna, the Sardinian hare (Lepus sp.) is peculiar in that it differs from all other hares inhabiting the continent. Here, we report on the variation of a 461 bp sequence of hypervariable domain 1 of the mitochondrial control region, examined in 42 hares collected throughout Sardinia and compared to the corresponding sequences of different Lepus taxa. Seventeen novel haplotypes were found in the Sardinian population, resulting in a haplotype diversity of 0.840 and a nucleotide diversity of 0.012. As a result of Bayesian and principal coordinates analyses, Sardinian hares were grouped with North African hares, constituting a monophyletic clade that diverges from all other Old World hares, including Cape hares from South Africa and East Asia. Hence, our data agree that populations inhabiting North Africa and Sardinia form a distinct taxon, which could possibly be included in the L. capensis superspecies. Moreover, two corresponding lineages can be found in Sardinia and Tunisia, providing evidence of a common origin of the two populations and thus supporting the hypothesis that North African hares were introduced into the island in historical times. Our data show that the two lineages differ in their geographic distribution throughout the island and that the wild Sardinian population also shows the signature of a postintroduction demographic expansion.


Gene selection for sample classifications in microarray experiments.
DNA microarray technology provides useful tools for profiling global gene expression patterns in different cell/tissue samples. One major challenge is the large number of genes relative to the number of samples. The use of all genes can suppress or reduce the performance of a classification rule due to the noise of nondiscriminatory genes. Selection of an optimal subset from the original gene set becomes an important prestep in sample classification. In this study, we propose a family-wise error (FWE) rate approach to selection of discriminatory genes for two-sample or multiple-sample classification. The FWE approach controls the probability of the number of one or more false positives at a prespecified level. A public colon cancer data set is used to evaluate the performance of the proposed approach for the two classification methods: k nearest neighbors (k-NN) and support vector machine (SVM). The selected gene sets from the proposed procedure appears to perform better than or comparable to several results reported in the literature using the univariate analysis without performing multivariate search. In addition, we apply the FWE approach to a toxicogenomic data set with nine treatments (a control and eight metals, As, Cd, Ni, Cr, Sb, Pb, Cu, and AsV) for a total of 55 samples for a multisample classification. Two gene sets are considered: the gene set omegaF formed by the ANOVA F-test, and a gene set omegaT formed by the union of one-versus-all t-tests. The predicted accuracies are evaluated using the internal and external crossvalidation. Using the SVM classification, the overall accuracies to predict 55 samples into one of the nine treatments are above 80% for internal crossvalidation. OmegaF has slightly higher accuracy rates than omegaT. The overall predicted accuracies are above 70% for the external crossvalidation; the two gene sets omegaT and omegaF performed equally well.


A Case of Shield Ulcer Due to Vernal Keratoconjunctivitis.
Corneal shield ulcer is an uncommon but serious complication of vernal keratoconjunctivitis (VKC) that can threaten visual acuity. We present a 12-year-old case with a corneal shield ulcer on the superior part of the cornea in the right eye. We learned from his history that he was treated with topical cyclosporine A (CsA) and corneal debridement was performed for the same complaints six months ago. His complaints recurred six months after ceasing topical CsA voluntarily. Topical anti-allergic and CsA treatments were commenced, we also performed corneal debridement. During his follow-ups, the corneal ulcer healed leaving a scar as opacity and neovascularization. This case highlights the role of the anti-inflammatory effect of CsA in preventing the recurrence of shield ulcers.


Genome sequence of Chrysodeixis chalcites nucleopolyhedrovirus, a baculovirus with two DNA photolyase genes.
The complete genome sequence of a single nucleocapsid nucleopolyhedrovirus recently isolated from Chrysodeixis chalcites (ChchNPV) was determined. The viral genome has a size of 149 622 bp and an overall G+C content of 39.1 mol%. The sequence contains 151 predicted open reading frames (ORFs) with a minimal size of 50 codons. The similarity of these ORFs with those of other completely sequenced baculoviruses was calculated using a newly developed database, named GECCO. Phylogenetic analysis of the whole genome confirmed the evolutionary relationship of ChchNPV with group II NPVs, as did the absence of the NPV group I-specific gp64 gene. It is the first group II NPV to encode proliferating cell nuclear antigen. Most noteworthy is the presence of two ORFs encoding a class II cyclobutane pyrimidine dimer DNA photolyase. These two ORFs share only 45 % amino acid identity and have different promoter motifs. Twenty-two additional unique baculovirus genes were identified, including a gene encoding a novel putative RING finger protein with a possible homologue in poxviruses.


Revolutionising food advertising monitoring: a machine learning-based method for automated classification of food videos.
Food advertising is an important determinant of unhealthy eating. However, analysing a large number of advertisements (ads) to distinguish between food and non-food content is a challenging task. This study aims to develop a machine learning-based method to automatically identify and classify food and non-food ad videos. Methodological study to develop an algorithm model that prioritises both accuracy and efficiency in monitoring and classifying advertising videos. From a collection of Brazilian television (TV) ads data, we created a database and split it into three sub-databases (i.e. training, validation and test) by extracting frames from ads. Subsequently, the training database was classified using the EfficientNet neural network. The best models and data-balancing strategies were investigated using the validation database. Finally, the test database was used to apply the best model and strategy, and results were verified with field experts. The study used 2124 recorded Brazilian TV programming hours from 2018 to 2020. It included 703 food ads and over 20 000 non-food ads, following the protocol developed by the INFORMAS network for monitoring food marketing on TV. The results showed that the EfficientNet neural network associated with the balanced batches strategy achieved an overall accuracy of 90·5 % on the test database, which represents a reduction of 99·9 % of the time spent on identifying and classifying ads. The method studied represents a promising approach for differentiating food and non-food-related video within monitoring food marketing, which has significant practical implications for researchers, public health policymakers, and regulatory bodies.


Single actuator alignment control for improved frequency stability of a cavity-based optical frequency reference.
We demonstrate a method of controlling the alignment of a laser beam to a Fabry-Perot resonator through synchronous detection of the misalignment arising from modulating the orientation of a single beam-steering mirror. The horizontal and vertical tilt of the mirror are modulated in quadrature to drive a circular motion of the beam orientation. A corresponding modulation of the intensity of the optical field circulating in the cavity is measured at either the reflected or transmitted port and demodulated synchronously to derive two error signals to indicate the vertical and horizontal misalignment. These signals are fed back to the beam-steering mirror to suppress fluctuations below 30 Hz. This method avoids the complexity of monitoring off-axis cavity modes and is particularly effective in the case where unwanted pointing fluctuations are introduced by one or two elements in the optical setup. We have applied the technique to two Fabry-Perot resonators in use as precision frequency references, delivering a result of 10 dB suppression of alignment fluctuations at 1 Hz and an improvement in frequency stability by up to a factor of 4.


Burst abdomen and incisional hernia: a prospective study of 1129 major laparotomies.
Burst abdomen and incisional herniation are continuing problems for the general surgeon. A prospective study was carried out to define the extent of the problem. Over five years from 1975 to 1980 a total of 1129 major laparotomy wounds in adults were assessed at regular intervals for 12 months after operation. There were 19 burst abdomens (1.7%) and 84 incisional hernias (7.4%). The introduction of the mass-closure technique reduced the incidence of burst abdomen from over 3% in 1975 to 0.95% in 1979. It did not, however, improve the rate for incisional hernias, which was 7.6% in 1979. Many factors are associated with incisional herniation: old age, male sex, obesity, bowel surgery, type of suture, chest infection, abdominal distension, and, most important, wound infection. More work is needed to find the ideal method of wound closure, and efforts should be made to eliminate wound infection.


Efficacy of ciprofloxacin and clarithromycin in acute bacterial exacerbations of complicated chronic bronchitis: interim analysis. Bronchitis Study Group.
In a multicenter, community-based study involving more than 300 primary care physicians in the United States, the efficacy and safety of ciprofloxacin and clarithromycin were compared in the treatment of patients with complicated or severe acute bacterial exacerbations of chronic bronchitis (i.e., those who had failed previous antibiotic treatment within the prior 2 to 4 weeks; those with susceptibility data suggestive of a resistant pathogen; those having three or more acute exacerbations of chronic bronchitis [AECB] within the past year; and those having three or more comorbid conditions). Patients were randomized to either ciprofloxacin (CIP) 750 mg BID or clarithromycin (CLR) 500 mg BID, both administered for 10 days; all patients were treated on an outpatient basis. Clinical response at the end of therapy was the primary efficacy variable. An interim analysis was performed on the results from 743 patients (369 CIP, 374 CLR) with clinical and bacteriologic evidence of a bronchopulmonary infection who had completed an ongoing study as of the end of May 1997. Three hundred nine pathogens were isolated before therapy, including Haemophilus spp (75 isolates), Moraxella catarrhalis (67 isolates), Staphylococcus aureus (55 isolates), and Streptococcus pneumoniae (23 isolates). Seven hundred eighteen patients (97%) were included in the efficacy-valid population. Clinical success at the end of therapy was observed in 90% (272 of 302) and 88% (274 of 313) of efficacy-valid patients treated with CIP and CLR, respectively (95% confidence interval [CI] = -2.4 to 7.6). Corresponding rates for the intent-to-treat population were also 90% (283 of 314) and 88% (281 of 321), respectively (95% CI = -2.3 to 7.5). The bacteriologic response for efficacy-valid patients at the end of therapy was 98% (119 of 122) for CIP-treated and 93% (103 of 111) for CLR-treated patients (95% CI = -0.8 to 10.2). The eradication rates for the three most commonly isolated gram-negative pathogens were 100% for CIP-treated and 95% for CLR-treated patients and 96% each for the two most commonly isolated gram-positive organisms. Superinfections due to respiratory tract pathogens were more common in the CLR group (10 organisms) than in the CIP group (4 organisms). Seventy-four (20%) CIP-treated and 62 (17%) CLR-treated patients reported 118 and 103 respective study-emergent adverse events. Headache, abdominal pain, diarrhea, nausea, and vomiting in CIP-treated patients and diarrhea, nausea, vomiting, and taste perversion in CLR-treated patients were the most commonly reported adverse events. Treatment of patients with complicated or severe AECB with CIP 750 mg BID was associated with rates of clinical success and bacteriologic eradication similar to those with CLR.


Wavefront control by stacked metal-dielectric hole array with variable hole shapes.
A stacked metal-dielectric hole array (SHA) containing rectangular holes whose shape gradually varies in-plane is proposed as a means of achieving wavefront control. The dependence of the transmitted phase on the frequency can be tuned by the hole shape, in particular the length of the sides that are normal to the incident polarization. The combination of periodic holes along the polarization direction and the gradual change in hole shape normal to the polarization direction produce an inclined wavefront for 1-dimensional beam steering. An in-plane phase difference of 0.6π using an SHA with a thickness of one-sixth of the wavelength has been experimentally demonstrated.


Acoustic assessment of fracture healing. Capabilities and limitations of "a lost art".
The ability of bone to conduct sound was applied clinically over 50 years ago to identify the presence of fresh fractures, although the technique has become a relatively "a lost art" as more sophisticated X-ray and other imaging techniques have been developed. The objective of this report is to challenge clinical orthopaedic surgeons unfamiliar with the technique to explore this simple beside method in the clinical management of fractures. A portable computer-based vibrational analysis device was employed and experiments conducted to objectively evaluate the capabilities of auscultatory percussion techniques. Auscultatory percussion can, with certain limitations, detect the presence of fractures, assess qualitatively the progress of healing, detect delayed or nonunions, and indicate when sufficiently firm continuity has occurred to permit early mobilization or loadbearing. Vibrational assessment is, however, subject to systematic and random errors, and thus cannot always discriminate between the stages of healing in a fractured bone; in addition, various artifacts can lead to significant uncertainty in the diagnosis. Nevertheless, auscultatory percussion is a useful tool in clinical fracture management, and particularly where roentgenographic facilities are inadequate or not available. Computerized vibrational analysis can be used in place of classical percussion/stethoscope methods by those with poor tonal capabilities,or when more objective record keeping is desired.


Placental polyp: a rare cause of iron deficiency anemia.
Placental polyps are defined as pedunculated or polypoid fragments of placenta or ovular membranes retained for an indefinite period of time into the uterus after abortion or child birth. An important cause of retention is placental accretism, an abnormal adherence of the placenta into the uterine wall. Chronic cases are rarely reported in the literature. In these cases, the placental retention in the immediate postpartum is not followed by heavy bleeding what makes the diagnosis challenging. We report a rare case of iron-deficiency anemia in a multiparous 29-year-old female patient two years after the last delivery. She sought medical care with clinical symptoms of anemia and recent menses alterations. There was no history of abortion. On gynecological examination, there was a twofold enlarged uterus, and the pelvic ultrasound revealed an image compatible with an endometrial polyp. She underwent open hysterectomy because of uncontrollable bleeding followed by hypotension after curettage. The histolopathologic examination revealed a partially hyalinized and necrotic placental polyp.


Spotlight on unmet needs in stroke prevention: The PIONEER AF-PCI, NAVIGATE ESUS and GALILEO trials.
Atrial fibrillation (AF) is a major healthcare concern, being associated with an estimated five-fold risk of ischaemic stroke. In patients with AF, anticoagulants reduce stroke risk to a greater extent than acetylsalicylic acid (ASA) or dual antiplatelet therapy (DAPT) with ASA plus clopidogrel. Non-vitamin K antagonist oral anticoagulants (NOACs) are now a widely-accepted therapeutic option for stroke prevention in non-valvular AF (NVAF). There are particular patient types with NVAF for whom treatment challenges remain, owing to sparse clinical data, their high-risk nature or a need to harmonise anticoagulant and antiplatelet regimens if co-administered. This article focuses on three randomised controlled trials (RCTs) that are investigating the utility of rivaroxaban, a direct, oral, factor Xa inhibitor, in additional areas of stroke prevention where data for anticoagulants are lacking: oPen-label, randomized, controlled, multicentre study explorIng twO treatmeNt stratEgiEs of Rivaroxaban and a dose-adjusted oral vitamin K antagonist treatment (PIONEER AF-PCI); New Approach riVaroxoban Inhibition of factor Xa in a Global trial vs Aspirin to prevenT Embolism in Embolic Stroke of Undetermined Source (NAVIGATE ESUS); and Global study comparing a rivAroxaban-based antithrombotic strategy to an antipLatelet-based strategy after transcatheter aortIc vaLve rEplacement to Optimize clinical outcomes (GALILEO). Data from these studies present collaborative efforts to build upon existing registrational Phase III data for rivaroxaban, driving the need for effective and safe treatment of a wider range of patients for stroke prevention.


Hypothalamic opiatergic tone during pregnancy, parturition and lactation in the rat.
The concentrations of beta-endorphin have been shown to change in the rat brain during pregnancy and lactation. This study has been performed in order to analyze whether also brain opioid receptors might undergo significant modifications during these two physiological situations. The maximal binding capacity (Bmax) and the constant of affinity (Ka) of the mu-subpopulation of opioid receptors have been evaluated in the hypothalami of female rats at different stages of pregnancy (7, 15 and 22 days), on the day of parturition (12-18 h after delivery) and 6-8 days postpartum (both in lactating and in nonlactating animals). Female rats killed on the day of estrus served as controls. The receptor binding assay has been performed utilizing [3H]-dihydromorphine [( 3H]-DHM) as the ligand for the mu-opioid receptors. Hypothalamic concentrations of beta-endorphin as well as serum levels of luteinizing hormone (LH), follicle-stimulating hormone (FSH) and prolactin have also been evaluated by radioimmunoassay. The results showed that the concentration of hypothalamic mu-opioid receptors increased during pregnancy, being significantly higher than in the controls at days 15 and 22 of gestation. After delivery, the concentration of these receptors returned towards control values, regardless on whether the animals were lactating or not. The Ka values of [3H]-DHM for the mu-receptors did not change significantly in the different groups of experimental animals. Hypothalamic beta-endorphin content showed a modest though not significant increase at the end of gestation (day 22) and returned to control values 12-18 h after delivery.(ABSTRACT TRUNCATED AT 250 WORDS)


Morphological and functional damage of the retina caused by intravitreous indocyanine green in rat eyes.
This study was designed to investigate the influence of intravitreal indocyanine green (ICG) on retinal morphology and function. Brown Norway rats eyes ( n=24) were vitrectomized by the injection of 0.05 ml of 100% SF(6) gas. Two weeks later, ICG solution was injected into the vitreous cavity of vitrectomized eyes at a dose of 25 mg/ml, 2.5 mg/ml, 0.25 mg/ml or 0.025 mg/ml (0.05 ml/eye). Retinal toxicity was histologically assessed by light microscopy on day 10. The retinal function was also evaluated by electroretinography (ERG) in the low-dose groups (0.25 mg/ml and 0.025 mg/ml) after 10 days and again after 2 months,. Sham-operated eyes (SF(6) injected followed by 0.05 ml of BSS plus, n=6) were used as controls. In the high-dose group (25 mg/ml ICG), the retinal structure was severely deformed and the retinal pigment epithelium partly disappeared. In eyes with 2.5 mg/ml ICG, the retinal structure was also affected but less strongly so than with 25 mg/ml. No apparent pathologic change was observed in the low-dose groups (0.25 mg/ml or 0.025 mg/ml) by light microscopy. In contrast, 10 days later the amplitude of dark-adapted a- and b-waves of ERGs in the eyes of low-dose group rats were found to have decreased. In addition the light-adapted b-waves did not change significantly. These changes remained for 2 months. Even at a low dose (0.025 mg/ml), intravitreous ICG induced functional damage of the retina without any apparent morphological damage. This information should be taken into account when clinically administering ICG into the vitreous cavity.


Childhood conditions, pathways to entertainment work and current practices of female entertainment workers in Cambodia: Baseline findings from the Mobile Link trial.
Entertainment venues have been identified as an important location for HIV prevention due to the increasing number of young female entertainment and sex workers at these venues. The purpose of this study is to increase understanding of the childhood conditions, pathways to entertainment work and current practices of female entertainment workers (FEWs) in Cambodia. Data used for this study were collected in April 2018 as part of the baseline survey of the Mobile Link, a randomized controlled trial to improve sexual and reproductive health of FEWs in Cambodia. We used a stratified random sampling method to recruit 600 FEWs for face-to-face interviews using a structured questionnaire. Descriptive analyses were performed. Most participants came from childhood homes without electricity (82.0%) or running water (87.0%). Most women moved to the city in the last ten years (80.5%) for economic reasons (43.7%). About a third worked in the garment industry prior to the entertainment industry (36.7%). Participation in transactional sex in the past three months was reported by 36.0%. Women reported low condom use practices with non-paying partners (23.4% used a condom at last sex), excessive and forced alcohol use at work (33.1% reported being forced to drink alcohol at work more than once a month), low modern contraception use (31.4% was using modern contraception), and experiences of gender-based violence (23.3% reported verbal threats, physical abuse or forced sex in the past six months). This information will help to support the development of future individual and structural level interventions for the safety and support of FEWs. In addition, these results may contribute to an evidence base that can inform policy level changes intended to support the realization of full human rights for entertainment works in Cambodia including the rights to health, safety and respectful employment.


Complications in MS patients after CCSVI procedures abroad (Calgary, AB).
The "chronic cerebrospinal venous insufficiency" or "CCSVI" hypothesis, namely that multiple sclerosis (MS) is caused by abnormalities in the azygous and internal jugular veins with subsequent alterations in venous hemodynamics in the central nervous system, has been a dominant topic in MS care in Canada over the past year. Although there is no methodologically rigorous evidence to support this hypothesis presently, a considerable number of MS patients have undergone endovascular CCSVI procedures. Such procedures include angioplasty or stent placement in jugular and azygous veins. The safety and efficacy of these procedures is unknown, but not without risk. Chart and patient review of five patients with confirmed MS followed in Calgary were undertaken after patients came to medical attention by referral or admission secondary to complications believed to be associated with CCSVI procedures. Complications upon investigation and review included internal jugular vein stent thrombosis, cerebral sinovenous thrombosis, stent migration, cranial nerve injury and injury associated with venous catheterization. As the debate about CCSVI and its relationship to MS continues, the complications and risks associated with venous stenting and angioplasty in jugular and azygous veins are becoming clearer. As increasing numbers of MS patients are seeking such procedures, these five cases represent the beginning of a wave of complications for which standardized care guidelines do not exist. Our experience and that of our colleagues will be used to develop guidelines and strategies to monitor and manage these patients as their numbers increase.


Role of Sirtuin-1 in Neonatal Hypoxic-Ischemic Encephalopathy and Its Underlying Mechanism.
BACKGROUND Neonatal hypoxic-ischemic encephalopathy (HIE) is a dreaded disease and one of the leading causes of severe neurological dysfunction in neonates. The present study explored the functions of Sirtuin-1 (SIRT1) in neonatal HIE. MATERIAL AND METHODS A HIE neonatal rat model was generated to determine SIRT1 levels in brain tissues. Cell apoptosis and cell viability were analyzed by flow cytometry and MTT assay. qRT-PCR and Western blot analysis were used to assess gene mRNA and protein levels. Subsequently, the effect of SIRT1 on HIE was investigated in vitro by constructing an oxygen-glucose deprivation (OGD) cell model. RESULTS The effective construction of the HIE rat model was confirmed by the enhanced brain cell apoptosis and the increased expression of HIE-related molecular markers, including S100 calcium-binding protein B (S100B) and neuron-specific enolase (NSE). SIRT1 expression was downregulated in HIE rat brain tissues. These findings indicated that SIRT1 was downregulated in neuronal cells subjected to OGD. In addition, enhanced cell viability and reduced cell apoptosis were observed, suggesting that SIRT1 overexpression relieved OGD-induced neuronal cell injury. Transfection with SIRT1-siRNA further increased OGD-induced neuronal cell injury, evidenced by decreased cell viability and enhanced cell apoptosis. Finally, SIRT1 overexpression significantly downregulated p-p65 protein expression. CONCLUSIONS Our findings revealed that SIRT1 may be a novel and promising therapy target for HIE treatment.


Preoperative cerebral aneurysm assessment by three-dimensional magnetic resonance angiography: feasibility of surgery without conventional catheter angiography.
In this study, we aimed to assess whether surgery could be performed in patients with cerebral aneurysms by using three-dimensional (3-D) magnetic resonance (MR) angiography alone, without conventional catheter angiography. A total of 108 patients who had undergone MR angiography and aneurysm surgery between January 1998 and January 2004 were enrolled in this study. The study subjects included 49 patients without subarachnoid hemorrhage (SAH) and 59 patients with SAH. In our preliminary study, 13 patients without SAH were diagnosed using 3-D MR angiography compared with catheter angiography and 3-D computed tomographic angiography before surgery. The 3-D MR angiography demonstrated all 18 unruptured aneurysms that were detected by catheter angiography. Thirty-six patients without SAH and 59 patients with SAH were examined using 3-D MR angiography. In 33 patients (91.6%) without SAH and 56 patients (94.9%) with SAH, we were able to reach a diagnosis on the basis of 3-D MR angiography alone. A majority of aneurysms were regular-sized and located in the anterior part of the circle of Willis. A total of 89 patients (93.7%) who underwent surgery with the aid of 3-D MR angiography alone were treated successfully and had no complications related to the lack of information that might have been gathered by catheter angiography. The 3-D MR angiography provided the authors with the aneurysm locations as well as with surgically important information regarding the configuration of the aneurysmal sac and neck and its relationship with the surrounding vessels. In the remaining 6 patients, 3-D MR angiography was followed by catheter angiography to acquire additional diagnostic confirmation. The results of this study support the notion that 3-D MR angiography can replace conventional catheter angiography for preoperative assessment in the majority of regular-sized anterior circulation aneurysms.


Human multidrug resistance associated protein 4 confers resistance to camptothecins.
The multidrug resistance associated protein (MRP) 4 is a member of the adenosine triphosphate (ATP)-binding cassette transporter family. Camptothecins (CPTs) have shown substantial anticancer activity against a broad spectrum of tumors by inhibiting DNA topoisomerase I, but tumor resistance is one of the major reasons for therapeutic failure. P-glycoprotein, breast cancer resistance protein, MRP1, and MRP2 have been implicated in resistance to various CPTs including CPT-11 (irinotecan), SN-38 (the active metabolite of CPT-11), and topotecan. In this study, we explored the resistance profiles and intracellular accumulation of a panel of CPTs including CPT, CPT-11, SN-38, rubitecan, and 10-hydroxy-CPT (10-OH-CPT) in HepG2 cells with stably overexpressed human MRP4. Other anticancer agents such as paclitaxel, cyclophosphamide, and carboplatin were also included. HepG2 cells were transfected with an empty vehicle plasmid (V/HepG2) or human MRP4 (MRP4/HepG2). The resistance profiles of test drugs in exponentially growing V/HepG2 and MRP4/HepG2 cells were examined using the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazonium bromide (MTT) assay with 4 or 48 h exposure time of the test drug in the absence or presence of various MRP4 inhibitors. The accumulation of CPT-11, SN-38, and paclitaxel by V/HepG2 and MRP4/HepG2 cells was determined by validated high-performance liquid chromatography methods. Based on the resistance folds from the MTT assay with 48 h exposure time of the test drug, MRP4 conferred resistance to CPTs tested in the order 10-OH-CPT (14.21) > SN-38 carboxylate (9.70) > rubitecan (9.06) > SN-38 lactone (8.91) > CPT lactone (7.33) > CPT-11 lactone (5.64) > CPT carboxylate (4.30) > CPT-11 carboxylate (2.68). Overall, overexpression of MRP4 increased the IC50 values 1.78- to 14.21-fold for various CPTs in lactone or carboxylate form. The resistance of MRP4 to various CPTs tested was significantly reversed in the presence of dl-buthionine-(S,R)-sulfoximine (BSO, a gamma-glutamylcysteine synthetase inhibitor), MK571, celecoxib, or diclofenac (all MRP4 inhibitors). In addition, the accumulation of CPT-11 and SN-38 over 120 min in MRP4/HepG2 cells was significantly reduced compared to V/HepG2 cells, whereas the addition of celecoxib, MK571, or BSO significantly increased their accumulation in MRP4/HepG2 cells. There was no significant difference in the intracellular accumulation of paclitaxel in V/HepG2 and MRP4/HepG2 cells, indicating that P-glycoprotein was not involved in the observed resistance to CPTs in this study. MRP4 also conferred resistance to cyclophosphamide and this was partially reversed by BSO. However, MRP4 did not increase resistance to paclitaxel, carboplatin, etoposide (VP-16), 5-fluorouracil, and cyclosporine. Human MRP4 rendered significant resistance to cyclophosphamide, CPT, CPT-11, SN-38, rubitecan, and 10-OH-CPT. CPT-11 and SN-38 are substrates for MRP4. Further studies are needed to explore the role of MRP4 in resistance, toxicity, and pharmacokinetics of CPTs and cyclophosphamide.


Alternative life histories in Xiphophorus multilineatus: evidence for different ages at sexual maturity and growth responses in the wild.
In order to examine potential trade-offs in alternative life histories of the high-backed pygmy swordtail Xiphophorus multilineatus, otoliths were used from wild-caught males to determine if sneaker males had the advantage of maturing earlier in natural environments. The sneakers matured significantly earlier than courters, but there was no difference among the three courter variants. In addition, analyses suggested that the effect of the pituitary locus on size at sexual maturity and growth rates was a consequence of age at sexual maturity. Finally, one of the courter variants had a significantly different relationship between age and size at sexual maturity than the other variants, suggesting that in this variant, age at sexual maturity may be more closely related to size and therefore may be less plastic in its growth responses.


Antibacterial activities of essential oils from Iranian medicinal plants on extended-spectrum β-lactamase-producing Escherichia coli.
The extended-spectrum beta-lactamase (ESBL) -producing Escherichia coli strains can lead to various infections particularly urinary tract infections. The main objective of this investigation was to evaluate the antibacterial activities of essential oils (EOs) from different Iranian medicinal plants against TEM gene positive ESBL-producing E. coli strains isolated from urine samples of patients with urinary tract infections. EOs were extracted using hydrodistillation method. E. coli strains were isolated by different specific Medias. ESBL-producing E. coli strains were isolated from urine samples of patients with urinary tract infections in Shiraz hospital, Iran. Then, ESBL- producing strains were identified using double disk synergy test, phenotypic disc confirmatory test and polymerase chain reaction (PCR) for TEM gene detection. The antibacterial activity of the EOs from different plants (Achillea wilhelmsii C. Koch, Echinophora platyloba DC., Lallemantia royleana, Nepeta persica Boiss., Pulicaria vulgaris Gaertn., Salvia nemorosa, and Satureja intermedia C.A.Mey) and antibiotics against ESBL-producing strains was studied using the microdilution method for the evaluation of the minimum inhibitory concentration (MIC). The 103 out of 295 E. coli strains with 97 (90.65%) TEM gene distributions were identified as ESBL-producing strains. All of the EOs derived from different plants displayed high inhibitory effects against ESBL-producing E. coli strains. The results of our investigations may propose a good treatment option against resistant infectious bacteria.


Establishing value through pharmacoeconomics: the emerging third objective in clinical trials.
Establishing the value of a new medicine by applying the tools and methods of pharmacoeconomics has become an important third objective in many clinical trials. The pharmacoeconomic investigator conducting research in clinical trials must understand and conform to the rules and procedures governing the clinical trial process. This article addresses some of the vital yet often overlooked details associated with conducting pharmacoeconomic research in clinical trials. The protocol, the informed consent form, the data collection instruments, the study initiation, and the final study report are all discussed. Additionally, limitations of the study results are reviewed.


Glucocorticoid receptor gene expression in adipose tissue and associated metabolic risk in black and white South African women.
Black women have lower visceral adipose tissue (VAT) but are less insulin sensitive than white women; the mechanisms responsible are unknown. The study aimed to test the hypothesis that variation in subcutaneous adipose tissue (SAT) sensitivity to glucocorticoids might underlie these differences. Body fatness (dual energy X-ray absorptiometry) and distribution (computerized tomography), insulin sensitivity (SI, intravenous and oral glucose tolerance tests), and expression of 11β-hydroxysteroid dehydrogenase-1 (11HSD1), hexose-6-phosphate dehydrogenase and glucocorticoid receptor-α (GRα), as well as genes involved in adipogenesis and inflammation were measured in abdominal deep SAT, superficial SAT and gluteal SAT (GLUT) depots of 56 normal-weight or obese black and white premenopausal South African (SA) women. We used a combination of univariate and multivariate statistics to evaluate ethnic-specific patterns in adipose gene expression and related body composition and insulin sensitivity measures. Although 11HSD1 activity and mRNA did not differ by ethnicity, GRα mRNA levels were significantly lower in SAT of black compared with white women, particularly in the GLUT depot (0.52±0.21 vs 0.91±0.26 AU, respectively, P<0.01). In black women, lower SAT GRα mRNA levels were associated with increased inflammatory gene transcript levels and abdominal SAT area, and reduced adipogenic gene transcript levels, VAT/SAT ratio and SI. Abdominal SAT 11HSD1 activity associated with increased VAT area and decreased SI in white, but not in black women. In black SA women, downregulation of GRα mRNA levels with obesity and reduced insulin sensitivity, possibly via increased SAT inflammation, is associated with reduced VAT accumulation.


Effectiveness of Interventions for Reducing Sedentary Behaviour in Older Adults Living in Long-Term Care Facilities: A Protocol for a Systematic Review.
Background. Sedentary behaviour (SB) is an important risk factor for several health-related outcomes. The prevalence of SB is alarmingly high in older adults, who spend on average 9.4 h being sedentary each day, making them the most sedentary of all age groups. Objectives. The primary objective of this review is to assess the impact of interventions aimed at reducing SB in older adults (aged 60 years and older) living in long-term care facilities (LTCFs). The research question for this systematic review is as follows: in older people living in LTCFs, do interventions aimed at reducing SB, compared to usual care, result in a decrease in SB daily time or a reduction in the length of prolonged and uninterrupted sitting bouts? Data sources. Only peer-reviewed articles will be included in this systematic review, articles will be identified using the PICO method in seven different databases. Participants and interventions. Any primary intervention study (including randomized controlled trials, non-randomized controlled trials, and cohort studies) with the aim to reduce SB daily time or shorten the length of prolonged and uninterrupted sitting bouts in older adults living in LTCFs will be included. After searching databases, abstracts of the studies will be screened, and, after retrieving full text articles, data extraction will be conducted by two independent reviewers. Study appraisal and synthesis methods. The review will adhere to PRISMA reporting guidelines. Risk of bias (RoB) will be assessed using ROBINS-I or the RoB 2.0 tool and will be discussed with a third reviewer. The data will be grouped according to study design, with separate analysis for randomised and non-randomised designs. Results. The primary outcomes will be SB or time spent sedentary, assessed before and after the intervention. For the outcomes with the same measurement units, the pooled mean differences will be calculated. Standardised mean differences will be calculated for the outcomes with different measurement units. The data not suitable in numbers will be synthesised narratively. The strength of evidence of the outcomes will be assessed using GRADE assessment. If the data are suitable for quantitative analysis, we plan to use the Revman software to conduct a meta-analysis. Conclusions and implications of key findings. This protocol can serve as a valuable resource for other researchers interested in conducting similar systematic reviews or meta-analyses in the field of SB and older adult health.


Lengthy one-dimensional magnetite (Fe3O4) sub-microfibers with excellent electrochemical performance.
One dimensional Fe3O4 sub-microfibers with an average diameter of about 920nm and length of about 25μm were prepared by hydrothermal synthesis in the presence of sodium citrate (Na3cit). The physicochemical properties were characterized by X-ray powder diffraction (XRD), Fourier transform infrared spectroscopy (FTIR), transmission electron microscopy (TEM), and scanning electron microscopy (SEM). It was found that Fe3O4 crystal nuclei were generated from different Fe2+-citrate complexes under hydrothermal conditions and Na3cit as a capping agent promoted the formation of Fe3O4 microfibers. The Fe3O4 nanocrystals grew along the (110) axis on the exposed (111) facet, and then further formed microfibers via an oriented attachment mechanism during the collisions. Polyvinylpyrrolidine (PVP) was more conducive to microfibers growth in comparison to polyethyleneglycol 4000 (PEG-4000), cetyltrimethylammonium bromide (CTAB) and sodium dodecyl sulfate (SDS). The electrochemical measurements show that the Fe3O4 sub-microfibers had a specific capacitance of 117.6Fg-1 with good cycling performance.


Examination of posttraumatic stress disorder symptom networks using clinician-rated and patient-rated data.
Network theory, which conceptualizes psychiatric disorders as networks of interacting symptoms, may provide a useful framework for understanding psychopathology. However, questions have arisen regarding the stability and generalizability of network analytic methods, with some researchers arguing that symptom networks have limited replicability. The aim of this study was to evaluate assessment modality as one possible source of instability in the estimation of posttraumatic stress disorder (PTSD) symptom networks. We estimated two cross-sectional DSM-5 PTSD symptom networks in 378 U.S. veterans: one using data from a clinician-rated assessment instrument (Clinician-Administered PTSD Scale for DSM-5; CAPS-5) and one using data from a self-rated questionnaire (the PTSD Checklist for DSM-5; PCL-5). We calculated centrality indices, conducted community structure analyses, and compared the strength and structure of the networks. The CAPS-5 and PCL-5 symptom networks were highly similar, challenging the notion that network methods produce unreliable results due to estimations consisting primarily of measurement error. Furthermore, each network contained distinct symptom communities that only partially overlapped with the DSM-5 PTSD symptom clusters. These findings may provide guidance for future revisions of the DSM, suggest hypotheses about how PTSD symptoms interact, and inform recent debate about replicability of psychopathology symptom networks. (PsycINFO Database Record


Enhanced herbicide metabolism induced by 2,4-D in herbicide susceptible Lolium rigidum provides protection against diclofop-methyl.
The auxinic herbicide 2,4-D amine is known, in vitro, as a cytochrome P450 inducer. The current study uses 2,4-D pre-treatment, at the whole plant level, to study mechanism(s) of non-target site based herbicide resistance to the ACCase-inhibiting herbicide diclofop-methyl in Lolium rigidum. The 2,4-D pre-treatment caused up to 10-fold shift in LD50 and GR50 in dose-response to subsequently applied diclofop-methyl in a herbicide susceptible L. rigidum population. Foliar uptake and translocation of (14) C-diclofop-methyl did not differ in 2,4-D pre-treated versus untreated plants. HPLC analysis revealed that de-esterification of diclofop-methyl to toxic diclofop acid was similar, but further metabolism of diclofop acid to non-toxic metabolites was significantly (1.8-fold) faster in 2,4-D pre-treated than untreated plants. HPLC profile of major polar metabolites was similar when L. rigidum and diclofop-methyl tolerant wheat were compared, but wheat metabolised diclofop acid three-fold faster than L. rigidum. In addition, 2,4-D pre-treatment also induced cross-protection against the ALS-inhibiting herbicide chlorsulfuron, and the known P450 inhibitor malathion can reverse this effect. Protection against diclofop-methyl provided by 2,4-D pre-treatment in susceptible L. rigidum is associated with higher rates of herbicide metabolism, mirroring that identified in field-evolved, non-target site-based diclofop-methyl resistant populations. 2,4-D may induce higher level expression of herbicide-metabolising genes hence providing protection, and therefore, this 2,4-D induction system can be used, in combination with other genomic approaches, to assist isolating cytochrome P450 and other genes that are involved in herbicide metabolism and endow herbicide resistance in L. rigidum.


Utilization and determinants of in-hospital cardiac catheterization in patients with acute coronary syndrome from the Middle East.
We assessed the use and determinants of cardiac catheterization during index admissions, among patients with acute coronary syndrome (ACS) in the Middle East. Data were analyzed from 8150 consecutive ACS patients enrolled prospectively. The overall rate of cardiac catheterization was 20%. Major predictors of cardiac catheterization were university hospitals, hospitals with catheterization facilities, physician type, and Gulf citizenship. High-risk patients were catheterized less compared to low-risk patients; odds ratio (OR) 0.44, 95% confidence interval (CI): 0.33-0.60, P < .001 and OR 0.68, 95% CI: 0.48-0.98, P = .037 for patients with non-ST-elevation ACS and ST-elevation myocardial infarction, respectively. The use of cardiac catheterization in patients with ACS from Middle East is low. It is related more to hospital characteristics than to baseline risks. There is a need to explore ways to increase overall rate of in-hospital cardiac catheterization in the region and direct it to patients who would benefit most.


Great cervical vein invasion of thyroid carcinoma.
Intraluminal tumor thrombus in great cervical veins as a result of thyroid carcinoma is extremely rare. Three patients (2 Hürthle cell, 1 papillary carcinoma) were surgically treated for thyroid carcinoma associated with tumor thrombus in the great cervical veins. Tumor thrombus in the internal jugular vein due to extension of thyroid carcinoma was found in these 3 patients. Segmental resection of the internal jugular vein was performed in all cases and a tumor thrombectomy from subclavian vein was accomplished in 1 patient. Histological examination verified intraluminal tumor thrombus resulting from invasion of thyroid carcinoma in all patients. The postoperative follow-up period ranged from 1 to 2 years. Of 2 patients undergoing completion thyroidectomy, 1 died of distant metastasis, the other underwent reoperation for local recurrence. The patient who had a definitive primary surgical procedure is free of recurrence. Appropriate initial surgical procedure in rare cases of thyroid carcinoma associated with intraluminal tumor thrombus in great cervical veins seems to improve the clinical outcome of the disease.


Evaluation of Enamel Roughness in Vitro After Orthodontic Bracket Debonding Using Different Methods of Residual Adhesive Removal.
The aim of the present study was to compare different techniques for resin remnant removal (RRR) after orthodontic bracket debonding and to evaluate alterations on the dental enamel caused by these methods. The null hypothesis tested was that there is no difference between RRR techniques in relationship the changes caused on the dental enamel. A total of 75 bovine mandibular permanent incisors were used in the study. Brackets were bonded and debonded in each tooth in two experimental regions. Five RRR techniques were used in the experimental groups (n=15): Group 1-diamond bur (6-bladed), Group 2-diamond bur (12-bladed), Group 3-diamond bur (30-bladed), Group 4-aluminum oxide sandblasting (AOS), and Group 5-Er:YAG laser. Enamel surface was evaluated using profilometry, and surface roughness analysis was performed at three time intervals: before bracket bonding, after RRR techniques, and after final polishing. Qualitative analyses of the enamel surfaces were performed using scanning electron microscopy. Multiblade burs showed the best results, and the 30-bladed bur created a less irregular enamel surface. AOS caused greater enamel wear, and Er:YAG laser caused more surface irregularity. The null hypothesis was rejected. The multiblade burs were the least harmful than the other techniques. Enamel surface roughness after using the 30-blade bur was similar to the original enamel. These results indicate that the type of bur tested (30-bladed) can be indicated to remove resin remnants after bracket debonding.


Hormonal correlates of paternal responsiveness in new and expectant fathers.
Little is known about the physiological and behavioral changes that expectant fathers undergo prior to the birth of their babies. We measured hormone concentrations and responses to infant stimuli in expectant and new fathers living with their partners to determine whether men can experience changes that parallel the dramatic shifts seen in pregnant women. We obtained two blood samples from couples at one of four times before or after the birth of their babies. After the first sample, the couples were exposed to auditory, visual, and olfactory cues from newborn infants (test of situational reactivity). Men and women had similar stage-specific differences in hormone levels, including higher concentrations of prolactin and cortisol in the period just before the births and lower postnatal concentrations of sex steroids (testosterone or estradiol). Men with more pregnancy (couvade) symptoms and men who were most affected by the infant reactivity test had higher prolactin levels and greater post-test reduction in testosterone. Hormone concentrations were correlated between partners. This pattern of hormonal change in men and other paternal mammals, and its absence in nonpaternal species, suggests that hormones may play a role in priming males to provide care for young.


Pattern of domestic violence from 2011 to 2015 in Beira, Mozambique.
Violence against women represents a violation of a fundamental human right and is a significant cause of death and disability worldwide. In developing countries, this issue is particularly dramatic and in sub-Saharan Africa were reached 65% of women reporting domestic violence. In this study, we assessed the burden and pattern of domestic violence registered at Beira Central Hospital, Mozambique from 2011 to 2015. We performed a descriptive analysis of data collected at the CHB Legal Medicine Service. In five years, are recorded a total amount of 1,491 admissions for domestic violence of which 1307 were females. About 80% of all female cases are represented by the 11-40 age range and, in almost 90% the aggressor was the current or past partner. More than 75% were cases of repeated violence and in more than 60% there were minors attending the phenomenon. It is crucial to act immediately and with a multi-disciplinary approach in order to fight domestic violence, especially against women due to its dramatic consequences as isolation, inability to work, loss of wages, lack of participation in regular activities and limited ability to care for themselves and their children.


Shepherding in a Self-gravitating Disk of Trans-Neptunian Objects.
A relatively massive and moderately eccentric disk of trans-Neptunian objects (TNOs) can effectively counteract apse precession induced by the outer planets, and in the process shepherd highly eccentric members of its population into nearly stationary configurations that are antialigned with the disk itself. We were sufficiently intrigued by this remarkable feature to embark on an extensive exploration of the full spatial dynamics sustained by the combined action of giant planets and a massive trans-Neptunian debris disk. In the process, we identified ranges of disk mass, eccentricity, and precession rate that allow apse-clustered populations that faithfully reproduce key orbital properties of the much-discussed TNO population. The shepherding disk hypothesis is, to be sure, complementary to any potential ninth member of the solar system pantheon, and could obviate the need for it altogether. We discuss its essential ingredients in the context of solar system formation and evolution, and argue for their naturalness in view of the growing body of observational and theoretical knowledge about self-gravitating disks around massive bodies, extra-solar debris disks included.


Development and Evaluation of a Protease Inhibitor Antiretroviral Drug-Loaded Carbon Nanotube Delivery System for Enhanced Efficacy in HIV Treatment.
The primary objective of this study was to enhance the effectiveness of the protease inhibitor antiretroviral drug by designing a novel delivery system using carboxylated multiwalled carbon nanotubes (COOH-MWCNTs). To achieve this, Fosamprenavir calcium (FPV), a prodrug of amprenavir known for inhibiting the proteolytic cleavage of immature virions, was selected as the protease inhibitor antiretroviral drug, and loaded onto COOH-MWCNTs using a direct loading method. The structural specificity of the drug-loaded MWCNTs, the percent entrapment efficiency, and in vitro drug release were rigorously evaluated for the developed formulation, referred to as FPV-MWCNT. Fourier transform infrared (FTIR) spectroscopy, Field emission scanning electron microscopy (FE-SEM), Raman spectroscopy, and atomic force microscopy (AFM) techniques were employed to confirm the structural integrity and specificity of the FPV-MWCNT formulation. The results demonstrated a remarkable entrapment efficiency of 79.57±0.4%, indicating the successful loading of FPV onto COOH-MWCNTs. FE-SEM and AFM analyses further confirmed the well-dispersed and elongated structure of the FPV-MWCNT formulation, without any signs of fracture, ensuring the stability and integrity of the drug delivery system. Moreover, particle size analysis revealed an average size of 290.1 nm, firmly establishing the nanoscale range of the formulation, with a zeta potential of 0.230 mV, signifying the system's colloidal stability. In vitro drug release studies conducted in methanolic phosphate buffer saline (PBS) at pH 7.4 and methanolic acetate buffer at pH 5 demonstrated sustained drug release from the FPV-MWCNT formulation. Over a period of 96 h, the formulation exhibited a cumulative drug release of 91.43±2.3%, showcasing the controlled and sustained release profile. Furthermore, hemolysis studies indicated a notable reduction in the toxicity of both FPV and MWCNT upon conjugation, although the percent hemolysis increased with higher concentrations, suggesting the need for careful consideration of dosage levels. In conclusion, the findings from this study underscore the potential of the FPV-MWCNT formulation as an effective and promising drug-conjugated system for delivering antiretroviral drugs. The successful encapsulation, sustained drug release, and reduced toxicity make FPV-MWCNT a compelling candidate for enhancing the therapeutic efficacy of protease inhibitor antiretroviral drugs in the treatment of HIV. The developed delivery system holds great promise for future advancements in HIV treatment and paves the way for further research and development in the field of drug delivery utilizing carbon nanotube-based systems.


Evaluation of confirmatory data following the Article 12 MRL review for flonicamid.
The applicant ISK Biosciences Europe N.V, submitted a request to the competent national authority in Finland to evaluate the confirmatory data that were identified for flonicamid in the framework of the maximum residue level (MRL) review under Article 12 of Regulation (EC) No 396/2005 as not available. In order to address the data gaps, the applicant provided method validation data for hops, residue trials on cherries, plums, tomatoes and melons and referred to results from trials in cucumbers and storage stability and hydrolysis studies which have been assessed in previous EFSA outputs. The provided information was considered sufficient to address the confirmatory data gaps for hops, cherries, plums, tomatoes and aubergines, courgettes and cucurbits with inedible peel. EFSA updated the most recent consumer risk assessment for flonicamid and concluded that for the crops under assessment, the long-term and short-term dietary intake is unlikely to present a risk to consumer health.


Nuclear magnetic resonance imaging (MRI).
This article discusses the basic concepts of Magnetic Resonance Imaging (MRI) with the intention to introduce the subject to uninitiated. The MRI technique is a powerful noninvasive probe of the body's internal anatomy. In MRI, the images are produced not by X-rays, but through the use of non-ionizing radiowaves that stimulate transitions between spin states of nuclei in a magnetic field when passed through the body. The time required for the nucleus to return to equilibrium gives information about the environment of that nucleus. In this way tissue abnormalities can be determined in vivo. This article covers the basis of MRI phenomena, the concept of magnetic moment of the sample, NMR exalation and emission and the equipment necessary to observe these NMR properties. The primary agents used to increase tissue contrast in MRI are also mentioned. Finally the importance and prospects of this technique in Pakistan have been discussed.


Swedish guidelines for the treatment of pain in tonsil surgery in pediatric patients up to 18 years.
Surgery of the tonsils often causes severe pain lasting for many days as been shown by data from the National Tonsil Surgery Register in Sweden. Tonsillotomy is associated with fewer readmissions due to bleeding, number of days requiring analgesics and health care contacts due to pain compared to tonsillectomy. The register data demonstrate the necessity of better-evidenced based pain treatment guidelines for tonsil-surgery. To develop evidenced based pain treatment guidelines for tonsil-surgery in Sweden. The evidence based guidelines were designed by an updated literature review and from the clinical expertise in the pediatric pain field, which thereafter were reviewed by ENT-doctors and anesthetists from each ENT-clinic in Sweden. A multimodal pain treatment approach is advocated, including premedication and administration during anesthesia, with paracetamol (acetaminophen), clonidine and betamethasone. If not given as a premedication the combination can be administered intravenously in the initial phase of anesthesia. At the end of surgery, if no bleeding problems, cox-inhibitors can be given. After discharge from hospital, the recommendations for pain relief are paracetamol combined with cox-inhibitors (ibuprofen, diclofenac) and if needed oral clonidine in favor of opioids. When pain intensity decreases, discontinue the analgesic treatment in the following order: opioid, clonidine, paracetamol and at last ibuprofen. The need for analgesic treatment after tonsillectomy is usually 5-8 days, after tonsillotomy only 3-5 days. Parents are recommended to contact the hospital if the child has difficulties in drinking or eating adequately and/or suffers from pain despite taking the recommended medication regularly. Swedish guidelines for tonsil-surgery provide practical evidence-based pain treatment recommendations.


Evaluation of impact of statin use on development of CPK elevation during daptomycin therapy.
Because both daptomycin and statins may increase creatine phosphokinase (CPK) levels, the manufacturer of daptomycin suggests considering holding statins during daptomycin therapy. Published evidence suggests potential detrimental effects of withdrawing statin therapy. The objectives of this study were to determine the impact of concurrent statin therapy on peak CPK values, incidence of CPK elevation in patients receiving daptomycin therapy, and clinical factors associated with increased risk of developing CPK elevation. This was a single-center, retrospective cohort study of patients ≥18 years of age who received daptomycin for ≥72 hours and had ≥1 follow-up CPK during a 5-year period. A Kaplan-Meier curve was used to evaluate time to CPK elevation. Cox regression analyses were used to compare the risk of developing elevated CPK between 3 study groups: those receiving daptomycin alone, daptomycin with concurrent statin therapy, and statin therapy held while on daptomycin. 498 patients were included in the study-384 received daptomycin alone, 63 received daptomycin concurrent with statin, and 51 with statin held during daptomycin therapy. Cumulative incidence of CPK elevation was 5.1% and 12% at 7 and 14 days. Those on daptomycin and statin concurrent therapy demonstrated an approximately 2-fold risk of CPK elevation compared with those having their statin therapy held, but the overall group effect was not statistically significant (P = .17). Our findings suggest that holding statin during daptomycin therapy may not be necessary, but may indicate need for increased frequency of CPK monitoring when these medications are used concurrently.


Tmem88a mediates GATA-dependent specification of cardiomyocyte progenitors by restricting WNT signaling.
Biphasic control of WNT signaling is essential during cardiogenesis, but how the pathway switches from promoting cardiac mesoderm to restricting cardiomyocyte progenitor fate is unknown. We identified genes expressed in lateral mesoderm that are dysregulated in zebrafish when both gata5 and gata6 are depleted, causing a block to cardiomyocyte specification. This screen identified tmem88a, which is expressed in the early cardiac progenitor field and was previously implicated in WNT modulation by overexpression studies. Depletion of tmem88a results in a profound cardiomyopathy, secondary to impaired cardiomyocyte specification. In tmem88a morphants, activation of the WNT pathway exacerbates the cardiomyocyte deficiency, whereas WNT inhibition rescues progenitor cells and cardiogenesis. We conclude that specification of cardiac fate downstream of gata5/6 involves activation of the tmem88a gene to constrain WNT signaling and expand the number of cardiac progenitors. Tmem88a is a novel component of the regulatory mechanism controlling the second phase of biphasic WNT activity essential for embryonic cardiogenesis.


The curvelet transform for image denoising.
We describe approximate digital implementations of two new mathematical transforms, namely, the ridgelet transform and the curvelet transform. Our implementations offer exact reconstruction, stability against perturbations, ease of implementation, and low computational complexity. A central tool is Fourier-domain computation of an approximate digital Radon transform. We introduce a very simple interpolation in the Fourier space which takes Cartesian samples and yields samples on a rectopolar grid, which is a pseudo-polar sampling set based on a concentric squares geometry. Despite the crudeness of our interpolation, the visual performance is surprisingly good. Our ridgelet transform applies to the Radon transform a special overcomplete wavelet pyramid whose wavelets have compact support in the frequency domain. Our curvelet transform uses our ridgelet transform as a component step, and implements curvelet subbands using a filter bank of a; trous wavelet filters. Our philosophy throughout is that transforms should be overcomplete, rather than critically sampled. We apply these digital transforms to the denoising of some standard images embedded in white noise. In the tests reported here, simple thresholding of the curvelet coefficients is very competitive with "state of the art" techniques based on wavelets, including thresholding of decimated or undecimated wavelet transforms and also including tree-based Bayesian posterior mean methods. Moreover, the curvelet reconstructions exhibit higher perceptual quality than wavelet-based reconstructions, offering visually sharper images and, in particular, higher quality recovery of edges and of faint linear and curvilinear features. Existing theory for curvelet and ridgelet transforms suggests that these new approaches can outperform wavelet methods in certain image reconstruction problems. The empirical results reported here are in encouraging agreement.


Failure to up-regulate VEGF165b in maternal plasma is a first trimester predictive marker for pre-eclampsia.
Pre-eclampsia is a pregnancy-related condition characterized by hypertension, proteinuria and endothelial dysfunction. VEGF(165)b, formed by alternative splicing of VEGF (vascular endothelial growth factor) pre-mRNA, inhibits VEGF(165)-mediated vasodilation and angiogenesis, but has not been quantified in pregnancy. ELISAs were used to measure means+/-S.E.M. plasma VEGF(165)b, sEng (soluble endoglin) and sFlt-1 (soluble fms-like tyrosine kinase-1). At 12 weeks of gestation, the plasma VEGF(165)b concentration was significantly up-regulated in plasma from women who maintained normal blood pressure throughout their pregnancy (normotensive group, 4.90+/-1.6 ng/ml; P<0.01, as determined using a Mann-Whitney U test) compared with non-pregnant women (0.40+/-0.22 ng/ml). In contrast, in patients who later developed pre-eclampsia, VEGF(165)b levels were lower than in the normotensive group (0.467+/-0.209 ng/ml), but were no greater than non-pregnant women. At term, plasma VEGF(165)b concentrations were greater than normal in both pre-eclamptic (3.75+/-2.24 ng/ml) and normotensive (10.58 ng/ml+/-3.74 ng/ml; P>0.1 compared with pre-eclampsia) pregnancies. Patients with a lower than median plasma VEGF(165)b at 12 weeks had elevated sFlt-1 and sEng pre-delivery. Concentrations of sFlt-1 (1.20+/-0.07 and 1.27+/-0.18 ng/ml) and sEng (4.4+/-0.18 and 4.1+/-0.5 ng/ml) were similar at 12 weeks of gestation in the normotensive and pre-eclamptic groups respectively. Plasma VEGF(165)b levels were elevated in pregnancy, but this increase is delayed in women that subsequently develop pre-eclampsia. In conclusion, low VEGF(165)b may therefore be a clinically useful first trimester plasma marker for increased risk of pre-eclampsia.


Distribution and Antibiotic Resistance Profiles of Salmonella enterica in Rural Areas of North Carolina After Hurricane Florence in 2018.
In this study, water samples were analyzed from a rural area of North Carolina after Hurricane Florence in 2018 and the distribution of the ttrC virulence gene of Salmonella enterica were investigated. We also examined the distribution of culturable S. enterica and determined their antibiotic resistance profiles. Antibiotic resistance genes (ARGs) in the classes of aminoglycoside, beta-lactam, and macrolide-lincosamide-streptogramin B (MLSB) were targeted in this study. The ttrC gene was detected in 23 out of 25 locations. There was a wider and higher range of the ttrC gene in flooded water versus unflooded water samples (0-2.12 × 105 copies/L vs. 0-4.86 × 104 copies/L). Culturable S. enterica was isolated from 10 of 25 sampling locations, which was less prevalent than the distribution of the ttrC gene. The antibiotic resistance profiles were not distinct among the S. enterica isolates. The aminoglycoside resistance gene aac(6')-Iy had the highest relative abundance (around 0.05 copies/16S rRNA gene copy in all isolates) among all ARGs. These findings suggested that the 2018 flooding event led to higher copy numbers of the ttrC genes of S. enterica in some flooded water bodies compared to those in unflooded water bodies. The high ARG level and similar ARG profiles were observed in all S. enterica isolates from both flooded and unflooded samples, suggesting that the antibiotic resistance was prevalent in S. enterica within this region, regardless of flooding.


Accuracy of Thresholds Based on Cadence and Lifestyle Counts per Minute to Detect Outdoor Walking in Older Adults With Mobility Limitations.
To determine the optimal threshold, based on cadence and lifestyle counts per minute, to detect outdoor walking in mobility-limited older adults. Older adults (N = 25, median age: 77.0 years, interquartile range: 10.5) wore activity monitors during 80 outdoor walks. Walking bouts were identified manually (reference standard) and compared with identification using cadence thresholds (≥30, ≥35, ≥40, ≥45, and ≥50 steps/min) and >760 counts per minute using low frequency extension analysis. Median walking bout duration was 10.5 min (interquartile range 4.8) and median outdoor walking speed was 0.70 m/s (interquartile range 0.20). Cadence thresholds of ≥30, ≥35, and ≥40 steps/min demonstrated high sensitivity (1.0, 95% confidence intervals [0.95, 1.0]) to detect walking bouts; estimates for specificity and positive predictive value were highest for ≥40 steps/min. A cadence threshold of ≥40 steps/min is recommended for detecting sustained outdoor walking in this population.


Bothrops Jararaca Snake Venom Modulates Key Cancer-Related Proteins in Breast Tumor Cell Lines.
Cancer is characterized by the development of abnormal cells that divide in an uncontrolled way and may spread into other tissues where they may infiltrate and destroy normal body tissue. Several previous reports have described biochemical anti-tumorigenic properties of crude snake venom or its components, including their capability of inhibiting cell proliferation and promoting cell death. However, to the best of our knowledge, there is no work describing cancer cell proteomic changes following treatment with snake venoms. In this work we describe the quantitative changes in proteomics of MCF7 and MDA-MB-231 breast tumor cell lines following treatment with Bothrops jararaca snake venom, as well as the functional implications of the proteomic changes. Cell lines were treated with sub-toxic doses at either 0.63 μg/mL (low) or 2.5 μg/mL (high) of B. jararaca venom for 24 h, conditions that cause no cell death per se. Proteomics analysis was conducted on a nano-scale liquid chromatography coupled on-line with mass spectrometry (nLC-MS/MS). More than 1000 proteins were identified and evaluated from each cell line treated with either the low or high dose of the snake venom. Protein profiling upon venom treatment showed differential expression of several proteins related to cancer cell metabolism, immune response, and inflammation. Among the identified proteins we highlight histone H3, SNX3, HEL-S-156an, MTCH2, RPS, MCC2, IGF2BP1, and GSTM3. These data suggest that sub-toxic doses of B. jararaca venom have potential to modulate cancer-development related protein targets in cancer cells. This work illustrates a novel biochemical strategy to identify therapeutic targets against cancer cell growth and survival.


Systems biology in alternatives: the importance of human-based studies.
The aim of research in the FRAME Alternatives Laboratory at the University of Nottingham Medical School is summarised, i.e. to use human cell culture-based projects and in vivo studies in human volunteers as alternatives to the use of rodent models in the study of human disease. This is especially important when the available animal models do not adequately represent the pathophysiological situation in humans. The approach is exemplified by summaries of studies on the effects of starvation on skeletal muscle in human volunteers, and on lipid metabolism in obese female volunteers.


Derivation and characterization of hematopoietic cells from human embryonic stem cells.
In vitro, the aggregation of pluripotent human embryonic stem cells (hESC) into cell clusters termed embryoid bodies (EB) allows for the spontaneous differentiation of hESC into progeny representing endoderm, mesoderm, and ectoderm lineages. During human EB (hEB) differentiation, stochastic emergence of hematopoietic cells can be enhanced by a combination of hematopoietic cytokines and the ventral mesoderm inducer bone morphogenetic protein (BMP)-4. Dependent on the presence of hematopoietic cytokines and BMP-4, vascular endothelial growth factor (VEGF-A165) selectively promotes erythropoietic development toward the primitive lineage. The effects of VEGF-A165 can be augmented by erythropoietin (EPO). Hematopoietic cells are derived from a rare subpopulation of hemogenic precursors during hEB development. These hemogenic precursors lack CD45, but express PECAM-1, Flk-1, and VE-cadherin (hereinafter CD45(neg)PFV) and are solely responsible for hematopoietic cell fate. Human ESC-derived hematopoietic cells have similar colony and cellular morphologies to those derived from committed adult hematopoietic tissues, and also show repopulating capacity in immune deficient mice after intrabone marrow transplantation. In this chapter, we describe methods that have been successfully applied in our laboratory, including (1) generation of hematopoietic cells by EB formation; (2) augmentation of hematopoiesis by use of hematopoietic cytokines and BMP-4; (3) promotion of erythropoietic development by addition of VEGF-A165 and EPO; (4) isolation of CD45(neg)PFV hemogenic precursors and generation of hematopoietic cells from these precursors; and (5) characterization of hESC-derived hematopoietic cells in vitro and in vivo.


Influence of smoking on the prognostic value of cardiovascular computed tomography coronary angiography.
Computed tomography coronary angiography (CTA) is an important non-invasive imaging modality increasingly used for the diagnosis and prognosis of coronary artery disease (CAD). The purpose of the current study was to determine the influence of smoking status on the prognostic value of CTA in patients with suspected or known CAD. In 1207 patients (57% male, age 57 ± 12 years) referred for CTA, the presence of significant CAD (≥ 50% stenosis) was determined. During follow-up (FU) the following events were recorded: all cause mortality, and non-fatal infarction. The prognostic value of CTA in smokers and non-smokers was compared using an interaction term in the Cox proportional hazard regression analysis. Significant CAD was observed in 327 patients (27%), and 273 patients (23%) were smokers. During a median FU time of 2.2 years, an event occurred in 50 patients. After correction for baseline characteristics including smoking in a multivariate model, significant CAD remained an independent predictor of events. Furthermore, a significant interaction (P < 0.05) was observed between significant CAD and smoking. The annualized event rate in smokers with significant CAD was 8.78% compared with 0.99% in smokers without significant CAD (P < 0.001). In non-smokers with significant CAD the annualized event rate was 2.07% compared with 1.01% in non-smokers without significant CAD (P= 0.058). The prognostic value of CTA was significantly influenced by smoking status. The event rates in patients with significant CAD were approximately four-fold higher in smokers compared with non-smokers. These findings suggest that smoking cessation needs to be aggressively pursued, especially in smokers with significant CAD.


Transabdominal uterine artery Doppler between 11 and 14 weeks of gestation for the prediction of outcome in high-risk pregnancies.
To assess the value of early transabdominal uterine artery Doppler ultrasound for the prediction of gestational outcomes in pregnancies at high risk for preeclampsia. This was an observational study. Doppler ultrasound of the uterine arteries at 11-14 weeks of gestation was performed in 76 women at high risk for preeclampsia. Abnormal uterine Doppler was defined by the presence of bilateral notching or by a mean resistance index (RI) >0.80. Adverse outcomes evaluated were preeclampsia, fetal growth restriction, placental abruption, intrauterine death, and complications requiring delivery before 34 weeks of gestation. Among 76 women, 30 (39%) had abnormal uterine Doppler and 46 (61%) had normal Doppler waveform configuration and RI. Abnormal uterine flow was related to a significantly higher incidence of preeclampsia (17% vs. 0%; p = 0.0041), fetal growth restriction (27% vs. 0%; p = 0.0002), intrauterine death (13% vs. 0%; p = 0.0109), and iatrogenic preterm delivery (20% vs. 2%; p = 0.0086). When the Doppler was normal, the negative predictive value for complications requiring delivery before 34 weeks was 98%. Normal impedance to flow in uterine arteries between 11 and 14 weeks of gestation is strongly related to a normal pregnancy outcome in women at high risk for preeclampsia.


In vitro biliary clearance of angiotensin II receptor blockers and 3-hydroxy-3-methylglutaryl-coenzyme A reductase inhibitors in sandwich-cultured rat hepatocytes: comparison with in vivo biliary clearance.
Previous reports have indicated that in vitro biliary clearance (Cl(biliary)) determined in sandwich-cultured hepatocytes correlates well with in vivo Cl(biliary) for limited sets of compounds. This study was designed to estimate the in vitro Cl(biliary) in sandwich-cultured rat hepatocytes (SCRHs) of angiotensin II receptor blockers and HMG-CoA reductase inhibitors that undergo limited metabolism, to compare the estimated Cl(biliary) values with published in vivo Cl(biliary) data in rats, and to characterize the mechanism(s) of basolateral uptake and canalicular excretion of these drugs in rats. The average biliary excretion index (BEI) and in vitro Cl(biliary) values of olmesartan, valsartan, pravastatin, rosuvastatin, and pitavastatin were 15, 19, 43, 45, and 20%, respectively, and 1.7, 3.2, 4.4, 46.1, and 34.6 ml/min/kg, respectively. Cl(biliary) predicted from SCRHs, accounting for plasma unbound fraction, correlated with reported in vivo Cl(biliary) for these drugs. The rank order of Cl(biliary) values predicted from SCRHs was consistent with in vivo Cl(biliary) values. Bromosulfophthalein inhibited the uptake of all drugs. BEI and Cl(biliary) values of olmesartan, valsartan, pravastatin, and rosuvastatin, known multidrug resistance-associated protein (Mrp) 2 substrates, were reduced in SCRHs from Mrp2-deficient (TR(-)) compared with wild-type (WT) rats. Although Mrp2 plays a minor role in pitavastatin biliary excretion, pitavastatin BEI and Cl(biliary) were reduced in TR(-) compared with WT SCRHs; Bcrp expression in SCRHs from TR(-) rats was decreased. In conclusion, in vitro Cl(biliary) determined in SCRHs can be used to estimate and compare in vivo Cl(biliary) of compounds in rats and to characterize transport proteins responsible for their hepatic uptake and excretion.


A randomized non-pharmacological intervention study for prevention of ischaemic heart disease: baseline results Inter99.
Various strategies have been used to induce lifestyle changes to reduce ischaemic heart disease (IHD) with various successes. The aim of Inter99 is to assess the effect on IHD incidence of individually tailored non-pharmacological intervention on lifestyle using a newly developed computer-based health educational tool. The article describes the study and baseline results. From a population of 61,301 individuals two random samples (high intensity intervention group (A), n = 11,708; low intensity intervention group (B), n = 1308) are screened to assess their absolute risk of IHD. Those at high risk receive individual lifestyle counselling. Individuals in group A are furthermore offered lifestyle counselling in groups on smoking cessation or physical activity/diet over a 6-month period. Individuals in group B are referred to their GP. High-risk persons are re-counselled after 1 and 3 years and the whole group is re-invited after 5 years. The remaining 48,285 (group C) are followed by questionnaire. The total population is followed through central registers. Intermediate end-points are changes in lifestyle, cholesterol, blood pressure and body mass index. Final end-point is reduction in incidence of IHD. The randomization leads to comparable groups. Participation rate was 52.5%. A total of 60% fulfilled the predetermined criteria for being at high risk for developing IHD. After an individual lifestyle counselling 41% accepted group-based counselling. This large randomized population based trial discloses a noticeable need for and acceptance of lifestyle intervention in the general population.


N2O5 reactive uptake kinetics and chlorine activation on authentic biomass-burning aerosol.
We examined the reactive uptake of dinitrogen pentoxide (N2O5) to authentic biomass-burning aerosol (BBA) using a small chamber reservoir in combination with an entrained aerosol flow tube. BBA was generated from four different fuel types and the reactivity of N2O5 was probed from 30 to 70% relative humidity (RH). The N2O5 reactive uptake coefficient, γ(N2O5), depended upon RH, fuel type, and to a lesser degree on aerosol chloride mass fractions. The γ(N2O5) ranged from 2.0 (±0.4) ×10-3 on black needlerush derived BBA at 30% RH to 6.0 (±0.6) ×10-3 on wiregrass derived BBA at 65% RH. Major N2O5 reaction products were observed including gaseous ClNO2 and HNO3 and particulate nitrate, and used to create a reactive nitrogen budget. Black needlerush BBA had the most particulate chloride, and the only measured ClNO2 yield > 1%. The ClNO2 yield on black needlerush decayed from an initial value of ∼100% to ∼30% over the course of the burn experiment, suggesting a depletion of BBA chloride over time. Black needlerush was also the only fuel for which the reactive nitrogen budget indicated other N-containing products were generated. Generally, the results suggest limited chloride availability for heterogeneous reaction for BBA in the RH range probed here, including BBA with chloride mass fractions on the higher end of previously reported values (∼17-34%). Though less than fresh sea spray aerosol, ∼50%. We use these measured quantities to discuss the implications for nocturnal aerosol nitrate formation, the chemical fate of N2O5(g), and the availability of particulate chloride for activation in biomass burning plumes.


Guanidinoacetic Acid Regulates Myogenic Differentiation and Muscle Growth Through miR-133a-3p and miR-1a-3p Co-mediated Akt/mTOR/S6K Signaling Pathway.
Guanidinoacetic acid (GAA), an amino acid derivative that is endogenous to animal tissues including muscle and nerve, has been reported to enhance muscular performance. MicroRNA (miRNA) is a post-transcriptional regulator that plays a key role in nutrient-mediated myogenesis. However, the effects of GAA on myogenic differentiation and skeletal muscle growth, and the potential regulatory mechanisms of miRNA in these processes have not been elucidated. In this study, we investigated the effects of GAA on proliferation, differentiation, and growth in C2C12 cells and mice. The results showed that GAA markedly inhibited the proliferation of myoblasts, along with the down-regulation of cyclin D1 (CCND1) and cyclin dependent kinase 4 (CDK4) mRNA expression, and the upregulation of cyclin dependent kinase inhibitor 1A (P21) mRNA expression. We also demonstrated that GAA treatment stimulated myogenic differentiation 1 (MyoD) and myogenin (MyoG) mRNA expression, resulting in an increase in the myotube fusion rate. Meanwhile, GAA supplementation promoted myotube growth through increase in total myosin heavy chain (MyHC) protein level, myotubes thickness and gastrocnemius muscle cross-sectional area. Furthermore, small RNA sequencing revealed that a total of eight miRNAs, including miR-133a-3p and miR-1a-3p cluster, showed differential expression after GAA supplementation. To further study the function of miR-133a-3p and miR-1a-3p in GAA-induced skeletal muscle growth, we transfected miR-133a-3p and miR-1a-3p mimics into myotube, which also induced muscle growth. Through bioinformatics and a dual-luciferase reporter system, the target genes of miR-133a-3p and miR-1a-3p were determined. These two miRNAs were shown to modulate the Akt/mTOR/S6K signaling pathway by restraining target gene expression. Taken together, these findings suggest that GAA supplementation can promote myoblast differentiation and skeletal muscle growth through miR-133a-3p- and miR-1a-3p-induced activation of the AKT/mTOR/S6K signaling pathway.


How much of the placebo 'effect' is really statistical regression?
Statistical regression to the mean predicts that patients selected for abnormalcy will, on the average, tend to improve. We argue that most improvements attributed to the placebo effect are actually instances of statistical regression. First, whereas older clinical trials susceptible to regression resulted in a marked improvement in placebo-treated patients, in a modern series of clinical trials whose design tended to protect against regression, we found no significant improvement (median change 0.3 per cent, p greater than 0.05) in placebo-treated patients. Secondly, regression can yield sizeable improvements, even among biochemical tests. Among a series of 15 biochemical tests, theoretical estimates of the improvement due to regression by selection of patients as high abnormals (i.e. 3 standard deviations above the mean) ranged from 2.5 per cent for serum sodium to 26 per cent for serum lactate dehydrogenase (median 10 per cent); empirical estimates ranged from 3.8 per cent for serum chloride to 37.3 per cent for serum phosphorus (median 9.5 per cent). Thus, we urge caution in interpreting patient improvements as causal effects of our actions and should avoid the conceit of assuming that our personal presence has strong healing powers.


Mapping, monitoring, and surveillance of neglected tropical diseases: towards a policy framework.
As national programmes respond to the new opportunities presented for scaling up preventive chemotherapy programmes for the coadministration of drugs to target lymphatic filariasis, onchocerciasis, schistosomiasis, soil-transmitted helminthiasis, and trachoma, possible synergies between existing disease-specific policies and protocols need to be examined. In this report we compare present policies for mapping, monitoring, and surveillance for these diseases, drawing attention to both the challenges and opportunities for integration. Although full integration of all elements of mapping, monitoring, and surveillance strategies might not be feasible for the diseases targeted through the preventive chemotherapy approach, there are opportunities for integration, and we present examples of integrated strategies. Finally, if advantage is to be taken of scaled up interventions to address neglected tropical diseases, efforts to develop rapid, inexpensive, and easy-to-use methods, whether disease-specific or integrated, should be increased. We present a framework for development of an integrated monitoring and evaluation system that combines both integrated and disease-specific strategies.


Development of a recombinant antigen for antibody-based diagnosis of Mycoplasma bovis infection in cattle.
Mycoplasma bovis induces various clinical manifestations in cattle, such as mastitis, arthritis, and pneumonia. We have evaluated the immunoreactivity of three variable surface proteins (Vsps) of M. bovis, namely VspA, VspB, and VspC, with sera collected from herds with mycoplasmosis or from cattle experimentally infected with M. bovis. Western blot analysis revealed that the Vsps are the predominant antigens recognized by the host humoral response during M. bovis infection. The immunoreactivity of VspA, VspB, and VspC with host antibodies was independent of the clinical manifestations, the geographical origin of the M. bovis isolates, the mode of infection, and the animal's history. Moreover, the results showed that Vsp-specific host antibodies can be detected about 10 days after experimental infection and for up to several months. The full-length or truncated versions of the VspA product were overexpressed in Escherichia coli as fusion proteins (FP-VspA). Recombinant products showed strong immunoreactivity with the Vsp-specific monoclonal antibodies 1A1 and 1E5, with the corresponding epitopes localized at the VspA N-terminal and C-terminal ends, respectively. Anti-M. bovis sera of cattle naturally or experimentally infected also strongly recognized the full-length FP-VspA. The seroreactivity of sera collected from cattle between 6 and 10 days after experimental infection was weaker with truncated versions of VspA lacking the 1E5 epitope than with the full-length VspA or the truncated versions lacking the 1A1 epitope. Overall, the results indicate that the Vsps, despite their inter- and intraclonal variability, may be applied as target antigens in serodiagnostic assays for epidemiological studies.


Group- plus home-based Tai Chi program improves functional health among patients with coronary heart disease: a randomized controlled trial.
Tai Chi is a promising exercise option in cardiac rehabilitation to manage coronary heart disease (CHD). Increasing attention was paid on home-based cardiac rehabilitation to improve participation rate, but no study has yet emphasized the effect of home-based Tai Chi. A single-blinded randomized controlled trial is used to examine the effects of a group- plus home-based Tai Chi program on functional health. Ninety-eight community-dwelling patients with CHD were randomly assigned to the Tai Chi and control groups. Participants in the Tai Chi group attended 6-week group- plus 6-week home-based Tai Chi program. Outcome measures included physical functions, cardiovascular risk factors, and exercise self-efficacy. Data were collected at baseline, 6-week, 12-week, and 24-week. Intervention effects were analysed using the generalized estimating equation model. Compared with changes in the control group, the intervention group achieved significant improvements in aerobic endurance, lower-body strength, agility and dynamic balance, diastolic blood pressure, and exercise self-efficacy over the 24-week study period (all Ps < 0.05). Intervention adherence was high (79.6% of participants attending >75% of all Tai Chi sessions). This Tai Chi program significantly improved the functional health of patients with CHD, indicating that Tai Chi could be taught in group sessions and then continued independently as a home exercise routine for health promotion.


Transfer of momentum from different arm segments to a light movable target during a straight punch thrown by expert boxers.
The aim of this study was to determine the relationship between the reductions in momentum of punching arm segments and the impulse of the impact force when boxers throw a punch at a movable target with a mass almost equal to that of the human head. Nine male expert collegiate boxers threw a rear-hand straight punch at the target with their full effort. The reductions in momentum of the upper arm, forearm and fist plus glove of the punching arm during impact and the impulse were determined using a motion capture system and an accelerometer attached to the target. The reduction in momentum of the punching arm explained approximately 95% of the impulse: 40%, 35% and 20% for the upper arm, forearm and fist plus glove, respectively. The Pearson correlation coefficient between the peak and impulse of the impact force was 0.902. These results suggest that for boxers increasing the momentum of the punching arm rather than that of the other body segments immediately before the impact is effective at increasing the impulse of the punch into the face of an opponent.


The effect of rosuvastatin on incident pneumonia: results from the JUPITER trial.
Evidence from observational studies have raised the possibility that statin treatment reduces the incidence of certain bacterial infections, particularly pneumonia. We analyzed data from a randomized controlled trial of rosuvastatin to examine this hypothesis. We analyzed data from the randomized, double-blind, placebo-controlled JUPITER trial (Justification for the Use of Statins in Prevention: an Intervention Trial Evaluating Rosuvastatin). In this trial, 17,802 healthy participants (men 50 years and older and women 60 and older) with a low-density lipoprotein (LDL) cholesterol level below 130 mg/dL (3.4 mmol/L) and a high-sensitivity C-reactive protein level of 2.0 mg/L or greater were randomly assigned to receive either rosuvastatin or placebo. We evaluated the incidence of pneumonia on an intention-to-treat basis by reviewing reports of adverse events from the study investigators, who were unaware of the treatment assignments. Among 17,802 trial participants followed for a median of 1.9 years, incident pneumonia was reported as an adverse event in 214 participants in the rosuvastatin group and 257 in the placebo group (hazard ratio [HR] 0.83, 95% confidence interval [CI] 0.69-1.00). In analyses restricted to events occurring before a cardiovascular event, pneumonia occurred in 203 participants given rosuvastatin and 250 given placebo (HR 0.81, 95% CI 0.67-0.97). Inclusion of recurrent pneumonia events did not modify this effect (HR 0.81, 95% CI 0.67-0.98), nor did adjustment for age, sex, smoking, metabolic syndrome, lipid levels and C-reactive protein level. Data from this randomized controlled trial support the hypothesis that statin treatment may modestly reduce the incidence of pneumonia. (ClinicalTrials.gov trial register no. NCT0023968.).


Replication concerns in sports and exercise science: a narrative review of selected methodological issues in the field.
Known methodological issues such as publication bias, questionable research practices and studies with underpowered designs are known to decrease the replicability of study findings. The presence of such issues has been widely established across different research fields, especially in psychology. Their presence raised the first concerns that the replicability of study findings could be low and led researchers to conduct large replication projects. These replication projects revealed that a significant portion of original study findings could not be replicated, giving rise to the conceptualization of the replication crisis. Although previous research in the field of sports and exercise science has identified the first warning signs, such as an overwhelming proportion of significant findings, small sample sizes and lack of data availability, their possible consequences for the replicability of our field have been overlooked. We discuss the consequences of the above issues on the replicability of our field and offer potential solutions to improve replicability.