Comparing the efficacy of vaginal micronized progesterone gel and capsule for prevention of preterm birth in singleton pregnancies with short cervical length at midtrimester: an indirect comparison meta-analysis.
Objective: To evaluate the effectiveness of vaginal progesterone in preventing preterm birth in women with a singleton gestation and short cervical length and to determine which of the two formulations, micronized progesterone vaginal capsule versus vaginal gel containing micronized progesterone, is more effective for preventing preterm birth. Data sources: A systematic search was performed in the following databases: EMBASE, PubMed (MEDLINE), The Cochrane Library, and the Clinical Trials Registry (clinicaltrials.gov). Study eligibility criteria: Randomized controlled trials (RCTs), prospective and retrospective observational studies were included. We searched for progesterone administration to prevent preterm birth in asymptomatic women with a shortened cervix (<25 mm) measured by ultrasound in the second trimester of singleton pregnancy. Study appraisal and synthesis methods: Assessments of the risk of bias of RCTs were performed by applying the Cochrane Collaboration's Risk of Bias Tool; non-randomized control trials were evaluated with the Newcastle-Ottawa Scale (NOS). The primary outcome was preterm birth ≤33 weeks of gestation. Pooled relative risks (RR) and 95% CI's were calculated for dichotomous outcomes. Heterogeneity of treatment effect was assessed with the I2 statistic. We pooled results of the primary outcome for individual studies using a random-effect model. We then performed a network meta-analysis to pool indirect comparisons between the two formulations (gel vs capsule). This analysis was performed using the network meta-analysis package within the R environment. Results: Five studies met the inclusion criteria (4 RCTs, one cohort study) including 1,048 women. The meta-analysis demonstrated that vaginal micronized progesterone significantly reduces preterm birth risk, Risk Ratio = 0.63; 95% CI, 0.48-0.82; p = 0.0006; with no heterogeneity between the studies: I 2 = 0%. In the network meta-analysis, no significant difference was demonstrated (OR = 0.85; 95% CI, 0.43-1.69) between the effect of the two formulations of vaginal micronized progesterone (vaginal gel versus vaginal capsules) on the risk of PTB. Conclusion: Vaginal progesterone is associated with a decreased risk of premature birth in women with a shortened cervix in the second trimester of pregnancy. No differences were found between vaginal micronized progesterone in gel or capsule formulations. Systematic Review Registration: PROSPERO, identifier CRD42020165198.


Prevalence and predictors of polypharmacy among community-based individuals with traumatic spinal cord injury.
The objective of this study was to investigate the rate of polypharmacy and predictors in community-living people with traumatic spinal cord injury (TSCI). Cross-sectional study. Outpatient clinic of the rehabilitation hospital. Seventy-five patients with TSCI ≥ 12 months were included in this study. Demographic features were noted. American Spinal Injury Association Impairment Scale (AIS) was used to measure the neurological injury severity. Functional status was evaluated by Spinal Cord Independence Measure (SCIM) III. The Cumulative Illness Rating Scale (CIRS) was used to determine the comorbidities. Daily drug use ≥5 was considered to be polypharmacy. The mean age was 41.3 ± 16.1 years. The mean injury duration was 55.5 ± 51.6 months. Thirty-nine (52%) patients were married, while 36 (48%) lived alone. The mean body mass index (BMI) was 25.4 ± 5.1 kg/m². AIS upper and lower extremity motor scores were 45.5 ± 11.1 and 10.3 ± 15.8, respectively. The mean SCIM III score was 56.4 ± 18.8. The mean system involvement number measured by CIRS was 5.2 ± 1.7. Fifty-two (70%) patients were motor complete, while 23 (30%) were motor incomplete. Thirty-eight (50.7%) patients had falls, 28 (37.3%) had car accidents, 6 (8%) had violence, and 3 (4%) had sports-related accidents. The rate of falling history in the last 6 months was 16% (12 patients). Polypharmacy was found in 38 (50.7%) patients. The predictors of the polypharmacy, according to the Regression analysis, were complete injury (Exp (B) i.e. Odds ratio = 7.491), advancing age (Odds ratio = 1.061) and injury duration (Odds ratio = 1.020). In this study, more than half of the patients with chronic traumatic SCI had polypharmacy. The predictors of polypharmacy were completeness, advancing age, and longer injury duration.


Regulation of arsenate resistance in Desulfovibrio desulfuricans G20 by an arsRBCC operon and an arsC gene.
Desulfovibrio desulfuricans G20 grows and reduces 20 mM arsenate to arsenite in lactate-sulfate media. Sequence analysis and experimental data show that D. desulfuricans G20 has one copy of arsC and a complete arsRBCC operon in different locations within the genome. Two mutants of strain G20 with defects in arsenate resistance were generated by nitrosoguanidine mutagenesis. The arsRBCC operons were intact in both mutant strains, but each mutant had one point mutation in the single arsC gene. Mutants transformed with either the arsC1 gene or the arsRBCC operon displayed wild-type arsenate resistance, indicating that the two arsC genes were equivalently functional in the sulfate reducer. The arsC1 gene and arsRBCC operon were also cloned into Escherichia coli DH5alpha independently, with either DNA fragment conferring increased arsenate resistance. The recombinant arsRBCC operon allowed growth at up to 50 mM arsenate in LB broth. Quantitative PCR analysis of mRNA products showed that the single arsC1 was constitutively expressed, whereas the operon was under the control of the arsR repressor protein. We suggest a model for arsenate detoxification in which the product of the single arsC1 is first used to reduce arsenate. The arsenite formed is then available to induce the arsRBCC operon for more rapid arsenate detoxification.


Genetic diversity of native populations of Croton tetradenius Baill. using ISSR markers.
Brazil has about 300 Croton species in different types of vegetation. Croton tetradenius Baill., which is endemic to the Northeast region and predominant in the Caatinga vegetation, stands out among the several species of this genus. Considering the importance of knowing the genetic variability of a species, the objective of this study was to analyze the genetic diversity of the genotypes of natural populations of C. tetradenius in the State of Sergipe, using ISSR molecular markers. Forty individuals were sampled in four natural populations of the State of Sergipe, Brazil. Thirteen primers were used for DNA amplification using ISSR-PCR, totaling 77 amplified fragments, of which 94.8% were polymorphic. Results of the cluster analysis obtained by the Jaccard's similarity index, using the UPGMA method, resulted in the formation of six distinct clusters. Analysis of molecular variance (AMOVA), used to estimate the genetic variability among populations, revealed significant genetic variance (P < 0.01) between and within the studied populations, and most of the genetic diversity was found (87%) within populations. According to the Jaccard's similarity index, none of the studied plants was genetically identical. CTE210 and CTE305 presented high similarity index (0.76), while CTE105 presented low similarity index (<0.16) with all related individuals. ISSR markers were efficient and allowed the formation of a molecular profile, and had sufficient polymorphism to estimate the genetic variability between the accessions of the studied populations.


Modelling the spread of phocine distemper virus among harbour seals.
Data presented in earlier publications on the 1988 epizootic among seals in North West Europe show a pattern that is somewhat inconsistent with the predictions of the standard mathematical model of epidemics. We argue that for animals living in herds or colonies, such as seals, the mutual contact behaviour is such that models for the transmission of infectious diseases should be applied with special care for the distinction between numbers and densities. This is demonstrated by using a mechanistic description of the contacts among seals, which leads to a slightly different formulation of the model. Results of the analysis of this formulation are more in line with the data. The model introduced here can be applied to epidemics among all kinds of animals living in herds and in fact to any species with constant local density, independent of the total population size (i.e., occupying a variable area). Application of the traditional formulation, using different parameters for herds of different sizes, will give equally good results for non-lethal diseases. However, especially for diseases with a low R0 and high death rates, such as the phocine distemper virus (PDV) disease, the two model formulations give quite different results. Further analysis of the model is performed to determine the most important factors influencing such an epidemic. The survival of infected animals turns out to have a disproportionately great influence on the intensity of the epidemic. Therefore in the case of the PDV epizootic we conclude that marine pollution may not only have contributed to the high death rates, but, if so, it has intensified the epizootic as well.


Phage display selection can differentiate insecticidal activity of soybean cystatins.
Plant cysteine proteinase inhibitors (phytocystatins) have been implicated as defensive molecules against Coleopteran and Hemipteran insect pests. Two soybean cystatins, soyacystatin N (scN) and soyacystatin L (scL), have 70% sequence identity but scN is a much more potent inhibitor of papain, vicilin peptidohydrolase and insect gut proteinases. When these cystatins were displayed on phage particles, papain-binding affinity and CPI activity of scN were substantially greater than those of scL, in direct correlation with their relative CPI activity as soluble recombinant proteins. Furthermore, scN substantially delayed cowpea weevil (Callosobruchus maculatus (F.)) growth and development in insect feeding bioassays, whereas scL was essentially inactive as an insecticide. Papain biopanning selection of phage-displayed soyacystatins resulted in a 200-1000-fold greater enrichment for scN relative to scL. These results establish that binding affinity of cystatins can be used in phage display biopanning procedures to select variants with greater insecticidal activity, illustrating the potential of phage display and biopanning selection for directed molecular evolution of biological activity of these plant defensive proteins.


Features of potentially predictive biomarkers of chemotherapeutic efficacy in small cell lung cancer.
One-size-fits-all chemotherapy does not improve survival in patients with small cell lung cancer (SCLC). Excision repair cross-complementing group 1 (ERCC1), ribonucleotide reductase 1 (RRM1), thymidylate synthase (TS), and topoisomerase 2alpha (Topo2alpha) expression levels are predictive of chemotherapeutic efficacy in some malignancies. Our aim was to determine the expression levels of these proteins to assess their potential clinical utility in SCLC. We used an immunofluorescence-based automated quantitative technique to score RRM1, ERCC1, TS, and Topo2alpha levels in tumor specimens from 100 patients with SCLC and immunohistochemistry to semiquantitatively score levels of TS, 5-phosphoribosyl-glycinamide formyl-transferase, and folyl-polyglutamate synthase expression. Confocal microscopy was used for subcellular localization in SCLC cells. RRM1, ERCC1, and Topo2alpha staining was predominantly nuclear and TS mainly cytoplasmic. Using immunohistochemistry, we found that TS (antibody 106) and TS (antibody 4H4) scores were strongly correlated (r = 0.82, p < 0.0001). By automated quantitative technique, RRM1 and Topo2alpha levels were highly correlated (r = 0.56, p < 0.0001). ERCC1 and TS levels had a narrow and low range of expression. There was no correlation between any of these biomarkers and patients' age or sex. Considering this clinical evidence, expression levels of RRM1 and Topo2alpha may have utility for chemotherapy customization. Clinical validation of their predictive power is desirable in a prospective clinical trial.


Maldevelopment of the cranio-facial-respiratory complex: A Darwinian perspective.
The mammalian Cranio-Facial-Respiratory Complex (CFRC) comprises several different biological tissues that collectively function under coordination from the central nervous and cardiorespiratory systems, primarily to breathe, eat and drink as well as integrating the sensory and motor systems for speech, communication and protective mechanisms. Anthropologists have long recognised that lifelong exposure to modern feeding regimens of readily available and highly processed foods, changes in breastfeeding and weaning, can impact expression of various phenotypic traits affecting the CFRC quite differently than does lifelong exposure to more traditional ancestral feeding regimens, typical of hunter-gather/foraging in non-Western-exposed cultures. The aim of this study is to highlight the role of the paediatric dentist in a multidisciplinary approach in which professionals working in and around the CFRC can actively prevent tooth decay and skeletal-dental malocclusion in the light of evolutionary oral medicine. As a result of changes in the environment, in the food quality, in eating and feeding practices starting from day one, two oral diseases of civilisation, tooth decay and skeletal-dental malocclusion, have both relatively recently reached worldwide epidemic proportions and afflict people of all ages. A multidisciplinary approach in which professionals working in and around the CFRC can actively promote prevention or reversal of dento-skeletal and myofunctional disorders, diagnose them when present and coordinate the appropriate therapy and life long maintenance programme.


fMRI protocol optimization for simultaneously studying small subcortical and cortical areas at 7 T.
Most fundamental cognitive processes rely on brain networks that include both cortical and subcortical structures. Studying such networks using functional magnetic resonance imaging (fMRI) requires a data acquisition protocol that provides blood-oxygenation-level dependent (BOLD) sensitivity across the entire brain. However, when using standard single echo, echo planar imaging protocols, researchers face a tradeoff between BOLD-sensitivity in cortex and in subcortical areas. Multi echo protocols avoid this tradeoff and can be used to optimize BOLD-sensitivity across the entire brain, at the cost of an increased repetition time. Here, we empirically compare the BOLD-sensitivity of a single echo protocol to a multi echo protocol. Both protocols were designed to meet the specific requirements for studying small, iron rich subcortical structures (including a relatively high spatial resolution and short echo times), while retaining coverage and BOLD-sensitivity in cortical areas. The results indicate that both sequences lead to similar BOLD-sensitivity across the brain at 7 T.


Cardiac mast cell-derived renin promotes local angiotensin formation, norepinephrine release, and arrhythmias in ischemia/reperfusion.
Having identified renin in cardiac mast cells, we assessed whether its release leads to cardiac dysfunction. In Langendorff-perfused guinea pig hearts, mast cell degranulation with compound 48/80 released Ang I-forming activity. This activity was blocked by the selective renin inhibitor BILA2157, indicating that renin was responsible for Ang I formation. Local generation of cardiac Ang II from mast cell-derived renin also elicited norepinephrine release from isolated sympathetic nerve terminals. This action was mediated by Ang II-type 1 (AT1) receptors. In 2 models of ischemia/reperfusion using Langendorff-perfused guinea pig and mouse hearts, a significant coronary spillover of renin and norepinephrine was observed. In both models, this was accompanied by ventricular fibrillation. Mast cell stabilization with cromolyn or lodoxamide markedly reduced active renin overflow and attenuated both norepinephrine release and arrhythmias. Similar cardioprotection was observed in guinea pig hearts treated with BILA2157 or the AT1 receptor antagonist EXP3174. Renin overflow and arrhythmias in ischemia/reperfusion were much less prominent in hearts of mast cell-deficient mice than in control hearts. Thus, mast cell-derived renin is pivotal for activating a cardiac renin-angiotensin system leading to excessive norepinephrine release in ischemia/reperfusion. Mast cell-derived renin may be a useful therapeutic target for hyperadrenergic dysfunctions, such as arrhythmias, sudden cardiac death, myocardial ischemia, and congestive heart failure.


n-Type silicon photoelectrochemistry in methanol: Design of a 10.1% efficient semiconductor/liquid junction solar cell.
n-Type Si electrodes in MeOH solvent with 0.2 M (1-hydroxyethyl)ferrocene, 0.5 mM (1-hydroxyethyl)ferricenium, and 1.0 M LiClO(4) exhibit air mass 2 conversion efficiencies of 10.1% for optical energy into electricity. We observe open-circuit voltages of 0.53 V and short-circuit quantum efficiencies for electron flow of nearly unity. The fill factor of the cell does not decline significantly with increases in light intensity, indicating substantial reduction in efficiency losses in MeOH solvent compared to previous nonaqueous n-Si systems. Matte etch texturing of the Si surface decreases surface reflectivity and increases photocurrent by 50% compared to shiny, polished Si samples. The high values of the open-circuit voltage observed are consistent with the presence of a thin oxide layer, as in a Schottky metal-insulator-semiconductor device, which yields decreased surface recombination and increased values of open-circuit voltage and short-circuit current. The n-Si system was shown to provide sustained photocurrent at air mass 2 levels (20 mA/cm(2)) for charge through the interface of >2,000 C/cm(2). The n-Si/MeOH system represents a liquid junction cell that has exceeded the 10% barrier for conversion of optical energy into electricity.


Suicide in psychiatric patients: case-control study in Singapore.
Persons with psychiatric illness, especially depression and schizophrenia, are at relatively high risk of suicide, but there are few studies that look at the Asian population. The aim of the present study was to identify the risk period and risk factors for suicide in psychiatric patients in Singapore. The nature of psychiatric care that was provided, both inpatient and outpatient, was also explored. This is a case-control study of 123 patients who committed suicide from 2003 to 2004. Controls were 123 surviving patients who were individually matched for age, gender, principal diagnosis and calendar time. The most common principal diagnoses among the suicide subjects were schizophrenia (46.3%) and depression (26.8%). Numerous factors were associated with significantly increased suicide risk. Stepwise conditional logistic regression showed that the following three independent factors best predicted suicide: history of attempted suicide using highly lethal means; coexisting significant physical illness; and delusions. Suicides occur mainly soon after discharge and after an outpatient consult. Subgroup analyses were done to distinguish between subjects who suicided early and late following discharge. Suicidal risk remains high in Singaporean psychiatric patients soon after discharge. They share some common risk factors for suicide identified in Western studies but the lower prevalence of substance abuse and comorbidity in Singaporean suicide subjects was one notable difference. The phenomena of suicides soon after discharge and outpatient review suggest the need for proper identification and more intensive follow up during this period.


Factors associated with caregiver burden for mothers of children undergoing Acute Lymphocytic Leukemia (ALL) treatment.
The present study examined the extent to which social support (SS) availability and satisfaction could predict the extent of caregiver burden (CB) among mothers of children with Acute Lymphocytic Leukemia (ALL). The study was a cross-sectional, descriptive-correlative study. It was conducted on a sample of 117 mothers whose children were undergoing treatment in a public hospital in Bam, Iran. The Norbeck Social Support Scale and the Caregiver Burden Scale were used to measuring study variables. The data were analyzed using Pearson's correlations, t-tests, ANOVAs, and linear regressions. Significant correlations were observed between CB and SS availability (r = -0.499, p < 0.001), SS satisfaction (r = -0.543, p < 0.001), the age of the child with cancer (r = -0.22, p = 0.01), and duration of treatment (r = 0.336, p < 0.001). Married mothers experienced less CB than those that were widowed or divorced. Within the regression equation, SS satisfaction, SS availability, marital status, and duration of treatment were the predictors of CB. Based on the results of the current study, mothers who have less SS, especially those who are single mothers, with younger children, and who have taken care of their child for an extended duration should be given special attention. Furthermore, it appears that there are distinct cultural variations amongst Iranian mothers which suggest that culture may impact upon SS availability. Results also suggest a need for interventions that enhance nurses' ability to provide support to caregivers and the broader family unit as a whole. Nurses in cancer care need to have psychological competencies to help family members of cancer patients especially mothers and more so those that are single mothers. As integral members of the patient care experience, nurses may be uniquely positioned to provide this needed psychosocial support.


Metachronous multiple primary malignant neoplasms of the stomach and the breast: report of two cases with review of literature.
Multiple primary malignant neoplasm is the occurrence of a second primary malignancy in the same patient within 6 months of the detection of first primary (synchronous), or 6 months or more after primary detection (metachronous). Multiple primary malignant neoplasms are not very frequently encountered in clinical practice. The relative risk for a second primary malignancy increases by 1.111-fold every month from the detection of the first primary malignancy in any individual. We present 2 patients treated for carcinoma of the breast who developed a metachronous primary malignancy in the stomach to highlight the rare occurrence of multiple primary malignant neoplasms. These tumors were histologically dissimilar, with distinct immunohistochemical parameters. The importance lies in carefully identifying the second primary malignancies, not dismissing them as metastases, and treating them accordingly.


Neural system identification model of human sound localization.
This paper examines the role of biological constraints in the human auditory localization process. A psychophysical and neural system modeling approach was undertaken in which performance comparisons between competing models and a human subject explore the relevant biologically plausible "realism constraints." The directional acoustical cues, upon which sound localization is based, were derived from the human subject's head-related transfer functions (HRTFs). Sound stimuli were generated by convolving bandpass noise with the HRTFs and were presented to both the subject and the model. The input stimuli to the model were processed using the Auditory Image Model of cochlear processing. The cochlear data were then analyzed by a time-delay neural network which integrated temporal and spectral information to determine the spatial location of the sound source. The combined cochlear model and neural network provided a system model of the sound localization process. Aspects of humanlike localization performance were qualitatively achieved for broadband and bandpass stimuli when the model architecture incorporated frequency division (i.e., the progressive integration of information across the different frequency channels) and was trained using variable bandwidth and center-frequency sounds. Results indicate that both issues are relevant to human sound localization performance.


Enteric nervous system: sensory transduction, neural circuits and gastrointestinal motility.
The gastrointestinal tract is the only internal organ to have evolved with its own independent nervous system, known as the enteric nervous system (ENS). This Review provides an update on advances that have been made in our understanding of how neurons within the ENS coordinate sensory and motor functions. Understanding this function is critical for determining how deficits in neurogenic motor patterns arise. Knowledge of how distension or chemical stimulation of the bowel evokes sensory responses in the ENS and central nervous system have progressed, including critical elements that underlie the mechanotransduction of distension-evoked colonic peristalsis. Contrary to original thought, evidence suggests that mucosal serotonin is not required for peristalsis or colonic migrating motor complexes, although it can modulate their characteristics. Chemosensory stimuli applied to the lumen can release substances from enteroendocrine cells, which could subsequently modulate ENS activity. Advances have been made in optogenetic technologies, such that specific neurochemical classes of enteric neurons can be stimulated. A major focus of this Review will be the latest advances in our understanding of how intrinsic sensory neurons in the ENS detect and respond to sensory stimuli and how these mechanisms differ from extrinsic sensory nerve endings in the gut that underlie the gut-brain axis.


Lumiflavin Enhances the Effects of Ionising Radiation on Ovarian Cancer Stem-Like Cells by Inhibiting Autophagy.
The development of Cancer Stem-like Cells (CSCs) is one of the main causes of ovarian cancer tolerance to radiotherapy. Autophagy is an adaptive process by which cells damage due to radiation. As a metabolite of riboflavin, lumiflavin can enhance the chemotherapeutic effects of cisplatin on ovarian cancer CSCs. This study aimed to investigate the synergistic effects of lumiflavin and ionising radiation on ovarian cancer CSCs and explore the association of this metabolite with autophagy. CSCs of human ovarian cancer cell lines HO8910 were treated with lumiflavin and rapamycin and then subjected to irradiation at a cumulative dose of 8 Gy. Cell proliferation ability, clonal formation ability, apoptosis rate, autophagy changes and autophagy-related protein changes were detected. Lumiflavin and ionising radiation synergistically reduced cell vitality and clone formation and increased the apoptosis of CSCs compared with irradiation alone. In addition, ionising radiation increased autophagy and the expression of associated proteins, whereas lumiflavin reduced those changes in autophagy progression. Moreover, rapamycin, an autophagy inhibitor, was observed to block the synergistic effects of lumiflavin and ionising radiation on CSC apoptosis. Lumiflavin can enhance the effects of ionising radiation on ovarian cancer CSCs. The mechanism by which these effects are exerted is related to blocking the autophagy pathway.


Light-up bioprobe with aggregation-induced emission characteristics for real-time apoptosis imaging in target cancer cells.
Specific bioprobes that are capable of real-time and targeted monitoring and imaging of cancer cell apoptosis are highly desirable for cancer diagnosis and the evaluation of cancer therapy efficacy. In this work, an asymmetric fluorescent light-up bioprobe with aggregation-induced emission (AIE) characteristics was designed and synthesized by the conjugation of two different hydrophilic peptides, caspase-specific Asp-Glu-Val-Asp (DEVD) and cyclic Arg-Gly-Asp (cRGD), onto a typical AIE luminogen of a tetraphenylsilole (TPS) unit. The asymmetric probe is almost non-emissive in aqueous solution and its fluorescence is significantly switched on in the presence of caspase-3. The fluorescence turn-on is due to the cleavage of the DEVD moiety by caspase-3, and the aggregation of released TPS-cRGD residues, which restricts the intramolecular rotations of TPS phenyl rings and populates the radiative decay channels. Application of the asymmetric light-up probe for real-time targeted imaging of cancer cell apoptosis is successfully demonstrated using integrin αvβ3 receptor overexpressing U87MG human glioblastoma cells as an example. The probe shows specific targeting capability to U87MG cancer cells by virtue of the efficient binding between cRGD and integrin αvβ3 receptors and is able to real-time monitor and image cancer cell apoptosis in a specific and sensitive manner.


Health Care Disparities Among U.S. Women of Reproductive Age by Level of Psychological Distress.
Background: Reproductive-age women have a high rate of contact with the health care system for reproductive health care. Yet, beyond pregnancy, little is known about psychological distress and unmet health care needs among these women. We examined reasons for delayed medical care and types of foregone care by level of psychological distress. Materials and Methods: We used a nationally representative sample of U.S. women aged 18-49, from the 2015-2016 National Health Interview Survey. Using the K6 screening tool for nonspecific psychological distress, we examined differences in reasons for delayed care and types of care foregone due to cost by level of psychological distress (none, moderate psychological distress [MPD], and severe psychological distress [SPD]). Results: Overall, 20% of U.S. women aged 18-49 had MPD (16%) or SPD (4%), equating to nearly 13 million women of reproductive age living with psychological distress. Women with SPD or MPD are more likely to have delayed and foregone care. Notably, women with SPD have higher odds of needing but not receiving mental health care (adjusted odds ratios [AOR] = 12.4, 95% confidence interval [CI] 8.4-18.4), specialist care (AOR = 3.6, 95% CI 2.6-5.1), and follow-up care (AOR = 3.5, 95% CI 2.4-5.1) due to cost than women with no psychological distress. Cost is the greatest barrier to timely medical care for women with MPD and SPD. Conclusions: Women of reproductive age with psychological distress face considerable structural and cost-related barriers to accessing health care, which may be exacerbated by their psychological state. Despite recent policy advances such as the Affordable Care Act, additional efforts by policymakers and providers are crucial to address the needs of this population.


The Needs, Use and Expectations of People Bereaved by Suicide Regarding Online Resources: An Online Survey.
Online resources constitute a new and effective way to obtain support or information during bereavement processes. However, little is known about the needs, use and expectations of people bereaved by suicide regarding online resources. The objective of our national cross-sectional online survey was to collect the use, needs and expectations of people bereaved by suicide regarding online resources. The data were collected from July to October 2021 through a 26-item online questionnaire hosted on the website LimeSurvey. A total of 401 respondents fully completed the questionnaire. Their mean age was 45.7. The majority of participants were women bereaved by the suicide of their child or partner. Half of the participants were bereaved for less than 3 years and benefited from counselling during their bereavement process. Three-quarters of the participants used the Internet for their bereavement process, mainly to obtain information on suicide bereavement and suicide prevention and to access testimonies of other people bereaved by suicide. Three-quarters of the participants found that available online resources for people bereaved by suicide are insufficient and expected a dedicated web platform to be developed. Finding information on suicide bereavement and on suicide prevention, discussing with a mental health professional and accessing testimonies of other people bereaved by suicide were expected by a majority of the participants regarding the future platform. Receiving counselling and being bereaved by the death of a child were the most important factors in explaining patterns of use and expectations regarding online resources. Our results offer precise insights into the needs, use and expectations of people bereaved by suicide regarding online resources. The development of web platforms offering access to reliable information on suicide bereavement and on suicide prevention to peers bereaved by suicide and help to seek counselling are urgently needed.


Determinants of participation in a fall assessment and prevention programme among elderly fallers in Hong Kong: prospective cohort study.
The study was undertaken to estimate the uptake rate of a fall prevention programme among older fallers and explore related factors. Fall injuries are a major cause nationally of the loss of independence in old age, but they are preventable. Acceptance of fall prevention programmes is therefore important to reduce the risk of falling. Patients aged ≥60 attending the Department of Accident & Emergency of a regional hospital in Hong Kong between 2006 and 2007 were recruited. The study included a baseline interview, focus group interview and a cross-sectional 1-year follow-up telephone survey to assess uptake and its related factors. A total 68% of 1194 older people attended the fall programme. Factors associated with programme participation included the perception of fall as being preventable [OR=3.47, 95% CI (1.59-7.56)] or recoverable [OR=1.73, 95% CI (1.06-2.82)], a safe outside environment; absence of chronic illness, and ability to walk without aids. Old-age people, those living in old-age homes and of lower education level were less likely to join the programme. Older people with the selected characteristics were less likely to attend the fall prevention programme, thus were less likely to benefit from them. Support from family/carers may be an important element in participation. In a nursing context, in primary care practice, all of these factors should be taken into account in any future development of a fall prevention programme in Hong Kong of this nature.


Randomized trial of steroid-free induction versus corticosteroid maintenance among orthotopic liver transplant recipients with hepatitis C virus: impact on hepatic fibrosis progression at one year.
Due to the known high recurrence rate of hepatitis C virus (HCV) among orthotopic liver transplant (OLT) recipients who receive tacrolimus+corticosteroid maintenance, use of steroid-free induction was considered. OLT recipients with HCV were randomized to receive tacrolimus+daclizumab (steroid-free) vs. tacrolimus+corticosteroids during 1999-2001 and then tacrolimus+mycophenolate mofetil (MMF)+daclizumab (steroid-free) vs. tacrolimus+MMF+corticosteroids during 2002-2005. Patients in the steroid-free arm of both periods received no steroids except for treating biopsy-proven rejection. Primary objective was to compare mean fibrosis stage at the 1-year protocol biopsy, between the steroid-free and corticosteroid arms, stratifying by period. No noticeable differences in mean fibrosis stage between the two treatment arms, either averaging across periods (P=0.99) or during either period (P>0.35) were found. Occurrence of acute rejection during the first year was the only factor associated with a significantly increased fibrosis stage at 1 year (P=0.0003); stage > or =2 was seen in 63% (17 of 27) vs. 19% (8 of 43) of those with vs. without rejection. In addition, MMF use was associated with significantly fewer patients experiencing acute rejection during the first 6 and 12 months posttransplant (P=0.006 and 0.046). Regarding steroid-related side effects, posttransplant diabetes mellitus occurred in 10% vs. 45%, and wound infection in 6% vs. 31% of steroid-free vs. corticosteroid patients (P=0.003 and 0.01). OLT recipients with HCV tolerated the steroid-free protocol with fewer side effects; however, its use had no apparent impact on hepatic fibrosis progression. Occurrence of acute rejection was strongly associated with increased hepatic fibrosis at 1 year, and MMF use appears to have significantly reduced the rejection rate.


Highly efficient CRISPR-Cas9-mediated editing identifies novel mechanosensitive microRNA-140 targets in primary human articular chondrocytes.
MicroRNA 140 (miR-140) is a chondrocyte-specific endogenous gene regulator implicated in osteoarthritis (OA). As mechanical injury is a primary aetiological factor in OA, we investigated miR-140-dependent mechanosensitive gene regulation using a novel CRISPR-Cas9 methodology in primary human chondrocytes. Primary (passage 1/2) human OA chondrocytes were isolated from arthroplasty samples (six donors) and transfected with ribonuclear protein complexes or plasmids using single guide RNAs (sgRNAs) targeting miR-140, in combination with Cas9 endonuclease. Combinations of sgRNAs and single/double transfections were tested. Gene editing was measured by T7 endonuclease 1 (T7E1) assay. miRNA levels were confirmed by qPCR in chondrocytes and in wild type murine femoral head cartilage after acute injury. Predicted close match off-targets were examined. Mechanosensitive miR-140 target validation was assessed in 42 injury-associated genes using TaqMan Microfluidic cards in targeted and donor-matched control chondrocytes. Identified targets were examined in RNAseq data from costal chondrocytes from miR-140-/- mice. High efficiency gene editing of miR-140 (90-98%) was obtained when two sgRNAs were combined with double RNP-mediated CRISPR-Cas9 transfection. miR-140 levels fell rapidly after femoral cartilage injury. Of the top eight miR-140 gene targets identified (P < 0.01), we validated three previously identified ones (septin 2, bone morphogenetic protein 2 and fibroblast growth factor 2). Novel targets included Agrin, a newly recognised pro-regenerative cartilage agent, and proteins associated with retinoic acid signalling and the primary cilium. We describe a highly efficient CRISPR-Cas9-mediated strategy for gene editing in primary human chondrocytes and identify several novel mechanosensitive miR-140 targets of disease relevance.


Optical filter requirements in an EML-based single-sideband PAM4 intensity-modulation and direct-detection transmission system.
The feasibility of a single sideband (SSB) PAM4 intensity-modulation and direct-detection (IM/DD) transmission based on a CMOS ADC and DAC is experimentally demonstrated in this work. To cost effectively build a >50 Gb/s system as well as to extend the transmission distance, a low cost EML and a passive optical filter are utilized to generate the SSB signal. However, the EML-induced chirp and dispersion-induced power fading limit the requirements of the SSB filter. To separate the effect of signal-signal beating interference, filters with different roll-off factors are employed to demonstrate the performance tolerance at different transmission distance. Moreover, a high resolution spectrum analysis is proposed to depict the system limitation. Experimental results show that a minimum roll-off factor of 7 dB/10GHz is required to achieve a 51.84Gb/s 40-km transmission with only linear feed-forward equalization.


Transformation of redox-sensitive to redox-stable iron-bound phosphorus in anoxic lake sediments under laboratory conditions.
Phosphorus (P) can be retained in mineral association with ferrous iron (Fe) as vivianite, Fe(II)3(PO4)2 ∙ 8 H2O, in lake sediments. The mineral is formed and remains stable under anoxic non-sulphidogenic conditions and, therefore, acts as a long-term P sink. In laboratory experiments under anoxic conditions, we investigated whether P adsorbed to amorphous Fe(III)-hydroxide functioned as a precursor phase of vivianite when added to different sediments as a treatment. The untreated sediments served as controls and were naturally Fe-rich (559 µmol/g DW) and Fe-poor (219 µmol/g DW), respectively. The solid P binding forms analysed by sequential extraction and X-ray diffraction were related to coinciding pore water analyses and the bacterial community compositions of the sediments by bacterial 16S rRNA gene amplicon sequencing. In the treatments, within a period of 40 d, 70 % of the redox-sensitive Fe(III)-P was transformed into redox-stable P, which contained vivianite. The mineral was supersaturated in the pore water, but the presence of Fe(III)-P functioning as a precursor was sufficient for measurable vivianite formation. The composition of the microbial community did not differ significantly (PERMANOVA, p = 0.09) between treatment and control of the naturally Fe-rich sediment. In the naturally Fe-poor sediment, the microbial community changed significantly (PERMANOVA, p = 0.001) in response to the addition of Fe(III)-P to the sediment. The freshly formed redox-stable P was not retransferred to a redox-sensitive compound by aeration for 24 h until 90 % O2 saturation was reached in the sediment slurry. We conclude that 1) Fe(III)-hydroxide bound P, resulting from oxic conditions at the sediment-water interface, is immobilised during anoxic conditions and stable even after re-oxygenation; 2) the process is feasible within the time scales of anoxic lake stratification periods; and 3) in relatively Fe-poor lakes, Fe dosing can provide excess Fe to form the precursor.


Experimental study of mouse cytomegalovirus infected mice.
In order to investigate the human cytomegalovirus (HCMV) infection, the mouse cytomegalovirus (MCMV) infected mice were experimentally studied. 6 to 8 week old female BALB/C mice with immunosuppression were selected to undergo the MCMV inoculations: intracranial inoculation and peritoneal inoculation. MCMV of the infected mice in various organs and tissues were detected by using beta-gal staining and in situ nucleic acid hybridization assay. The pathological changes were observed in HE staining paraffin-embedded sections. It was found that all the MCMV infected mice showed the retardation of growth and development, and feather looseness. Both intracranial inoculation of 10(4) PFU viruses or peritoneal inoculation of 10(6) PFU viruses resulted in the pathological changes, to some extent, of various organs and tissues in the mice. The pathological changes in liver were consistent with the amount of beta-gal staining positive cells, indicating the liver lesions were mainly caused by viral proliferation. It was also found that the viruses in the immunosuppressed mice subjected to intracranial inoculation could spread to whole body organs, while the viruses in the immunosuppressed mice subjected to intrapeitoneal inoculation couldn't spread to the brain, suggesting blood-brain barrier could prevent the virus from spreading to the brain.


Separation of bronchoalveolar cells from the guinea pig on continuous density gradients of Percoll: morphology and cytochemical properties of fractionated lung macrophages.
Cells recovered by lavage from lungs of normal guinea pigs were centrifuged on continuous density gradients of colloidal silica (Percoll). The gradient was divided into six fractions based on the banding pattern of cells. This pattern was highly reproducible from animal to animal. Cell types in the fractions were identified by morphological and cytochemical criteria and the volume of the cells was determined by measuring their diameter and tritiated water space. More than 70% of the cells put on the gradient were recovered in the six fractions and there was no selective loss of cell types. Macrophages comprised more than 95% of the cells in fractions 3, 4, and 5. These fractions were of intermediate density (1.037-1.078 gm/ml) and together contained more than 85% of the recovered macrophages. Fraction 6 (density 1.078-1.130 gm/ml) was enriched for lymphocytes and granulocytes. Macrophages in fraction 5 were smaller, had more densely staining cytoplasm, and exhibited more nonspecific cytoplasmic esterase activity than macrophages in other fractions (5 greater than 4 greater than 3 greater than 2). These results indicate that density-gradient centrifugation on Percoll is an efficient method for purifying guinea pig alveolar macrophages and demonstrate that macrophages that differ in bouyant density also differ in morphologic and cytochemical properties. In a companion paper we report that macrophages in fractions 3, 4, and 5 differ functionally as well [9].


[Micro RNA-155 expression in hemodialysis PBMC].
MicroRNAs (miR) are fragments of non-coding RNA acting at post-transcriptional level, which modulate gene expression, and play a key role in several pathophysiological pathways. The aim of this study is to analyze the expression of miR-155 in basal Peripheral Blood Mononuclear Cells (PBMC) of chronic hemodialysis (HD) patients, before and after standard 4 -hour sessions, and after PHA stimulation compared with PBMC from healthy subjects. miR-155 was isolated from chronic HD patients' PBMC and from PBMC derived from healthy subjects. Expression levels were quantified with Real-Time PCR; PCR reactions were performed using a specific thermocycler and cycle threshold levels were calculated using dedicated software. Blood samples were taken from HD patients after the long inter-dialytic interval. Data were expressed as MSE and statistical differences were calculated with t-test. Relative quantity (RQ) of pre-dialysis MiR-155 was 3.770.62 times higher than the control group (P=0,003). There was no significant difference before and after hemodialysis sessions. Pre-dialysis mir-155 RQ in PHA PBMC was 1.790.59 times higher than non stimulated PBMC (P=0.019). these preliminary data show a significant miR-155 up-regulation of HD PBMC when compared to PBMC from healthy individuals. An additional up-regulation was observed in HD PHA PBMC. Similar miR-155 expression was found in HD PBMC comparing pre and post-hemodialysis sessions.


[Effective factors in the outcome of head injury].
In this study, the data that could be obtained from our patient record system were investigated with respect to factors affecting the outcome in adult patients with head injury. The records of 356 adult head-injury patients (308 males, 48 females; mean age 43.1 +/- 18.6 years; range 17 to 87 years) hospitalized in Trakya University Hospital, Department of Neurosurgery and the Intensive Care Unit were examined. Results of the obtained data were analyzed statistically. Age (p = 0.012), use of airway tube (p < 0.001), Glasgow Coma Scale values determined at the injury site and in the Emergency Unit (p < 0.001), clustered systolic and diastolic tricuspid annulus values (p < 0.001), accompanying chest (p = 0.001) and abdominal (p = 0.041) injury, anisocoria (p = 0.001), pupillary light response (p < 0.001), intracranial radiologic findings such as subdural hematoma (p < 0.001), brain contusion (p = 0.006), traumatic subarachnoid hemorrhage (p < 0.001), traumatic intracranial hemorrhage (p = 0.005), and brain edema ( p < 0.001), performance of a surgical procedure (p < 0.001), and presence of nosocomial infection (p < 0.001) were demonstrated to cause significant differences in the outcome. CONCLUSION The main aim must be to reduce accidents in an effort to reduce the number of deaths due to head injuries; additionally, emergency and hospital care facilities should be developed with respect to head injury cases.


Implantation of bone mesenchymal stem cells overexpressing miRNA‑705 mitigated ischemic brain injury.
Ischemic brain damage remains the major cause of death and disability worldwide. Bone mesenchymal stem cell (BMSC) transplantation has been identified to serve important roles in cerebral infarction due to its multi‑directional differentiation and proliferative ability. However, the function of miR‑705 combined with BMSCs on ischemic brain injury remains to be fully elucidated. In the present study, an ischemic brain injury mouse model was constructed, and the mice were injected with BMSCs infected by lentiviral particles expressing miR‑705 (BMSCs‑Ad‑miR‑705) to explore the mechanism by which BMSCs‑Ad‑miR‑705 mitigates neurological deficits in ischemic brain damage. In the sham group, no significant neurological injury evaluated via neurological deficit scores was identified, the morphological structure of brain stained with HE was almost normal, and few apoptotic cells were detected by TUNEL assay. However, the PBS group exhibited significant brain damage (P<0.05). BMSCs‑Ad (BMSCs infected with control lentiviral particles) and BMSCs‑Ad‑miR‑705 markedly mitigated neurological injury, suppressed morphological damage and inhibited neuronal apoptosis, however promoted the mRNA levels of brain‑derived neurotrophic factor (BDNF) and vascular endothelial growth factor (VEGF) examined by reverse transcription‑quantitative polymerase chain reaction and western blotting. Notably, BMSCs‑Ad‑miR‑705 improved the outcome of BMSCs‑Ad transplantation. These data indicated that BMSCs‑Ad‑miR‑705 promoted the secretion of VEGF and BDNF, suppressed neuronal apoptosis, and stimulated neuronal regeneration, in turn mitigating the impairment of ischemic brain damage.


Hyponatraemia as an adverse drug reaction of antipsychotic drugs: a case-control study in VigiBase.
Hyponatraemia due to antipsychotic use is a potentially serious problem; however, it is not known whether it is an adverse drug reaction (ADR) to antipsychotic use or is due to the underlying psychiatric disease. To estimate the strength of the association between antipsychotics and hyponatraemia or syndrome of inappropriate antidiuretic hormone secretion (SIADH), using information reported to the WHO Collaborating Centre for International Drug Monitoring, the Uppsala Monitoring Centre (UMC). The WHO global individual case safety report database system (VigiBase) maintained by the UMC. Case-control study, with cases being reports of hyponatraemia/SIADH, and controls being reports of other ADRs. Each case was sampled with ten controls sequencing in time from the date the corresponding case was entered into the database. The potential contribution of the chemical structures and receptor affinity (dopaminergic and/or serotonergic) of the antipsychotics was studied, as was the influence of concomitant use of other medications known to cause hyponatraemia. The strength of the association between antipsychotic use and hyponatraemia in comparison with other drugs was expressed as reporting odds ratio (ROR), a measure of disproportionality, with corresponding 95% CIs, adjusted for age, sex and concomitant medication associated with hyponatraemia. In addition, stratification by the presence or absence of concomitant medication was performed. Up to August 2008, 3 881 518 suspected ADRs were reported and filed in VigiBase, with 912 reports on hyponatraemia related to antipsychotics. The adjusted ROR for the association between antipsychotic use and hyponatraemia was 1.58 (95% CI 1.46, 1.70). The adjusted RORs did not vary for the different chemical structures or dopamine D(2) and serotonin 5-HT(2A) receptor affinity profiles. The ROR was 3.00 (95% CI 2.65, 3.39) for the association between hyponatraemia and antipsychotic use in the absence of concomitant medication associated with hyponatraemia, and 1.16 (95% CI 1.06, 1.28) in the presence of concomitant medication associated with hyponatraemia. Antipsychotic use may be associated with reporting of hyponatraemia. Moreover, the concomitant use of medication associated with hyponatraemia potentially leads to under-reporting of antipsychotic-associated hyponatraemia. We advise testing patients whose psychiatric and/or physical condition deteriorates while on antipsychotics for hyponatraemia.


A method to assess target gene involvement in angiogenesis in vitro and in vivo using lentiviral vectors expressing shRNA.
Current methods to study angiogenesis in cancer growth and development can be difficult and costly, requiring extensive use of in vivo methodologies. Here, we utilized an in vitro adipocyte derived stem cell and endothelial colony forming cell (ADSC/ECFC) co-culture system to investigate the effect of lentiviral-driven shRNA knockdown of target genes compared to a non-targeting shRNA control on cord formation using High Content Imaging. Cord formation was significantly reduced following knockdown of the VEGF receptor VEGFR2 in VEGF-driven cord formation and the FGF receptor FGFR1 in basic FGF (bFGF)-driven cord formation. In addition, cord formation was significantly reduced following knockdown of the transcription factor forkhead box protein O1 (FOXO1), a protein with known positive effects on angiogenesis and blood vessel stabilization in VEGF- and bFGF-driven cord formation. Lentiviral shRNA also demonstrated utility for stable knockdown of VEGFR2 and FOXO1 in ECFCs, allowing for interrogation of protein knockdown effects on in vivo neoangiogenesis in a Matrigel plug assay. In addition to interrogating the effect of gene knockdown in endothelial cells, we utilized lentiviral shRNA to knockdown specificity protein 1 (SP1), a transcription factor involved in the expression of VEGF, in U-87 MG tumor cells to demonstrate the ability to analyze angiogenesis in vitro in a tumor-driven transwell cord formation system and in tumor angiogenesis in vivo. A significant reduction in tumor-driven cord formation, VEGF secretion, and in vivo tumor angiogenesis was observed upon SP1 knockdown. Therefore, evaluation of target gene knockdown effects in the in vitro co-culture cord formation assay in the ADSC/ECFC co-culture, ECFCs alone, and in tumor cells translated directly to in vivo results, indicating the in vitro method as a robust, cost-effective and efficient in vitro surrogate assay to investigate target gene involvement in endothelial or tumor cell function in angiogenesis.


Strategic disinformation outperforms honesty in competition for social influence.
Competition for social influence is a major force shaping societies, from baboons guiding their troop in different directions, to politicians competing for voters, to influencers competing for attention on social media. Social influence is invariably a competitive exercise with multiple influencers competing for it. We study which strategy maximizes social influence under competition. Applying game theory to a scenario where two advisers compete for the attention of a client, we find that the rational solution for advisers is to communicate truthfully when favored by the client, but to lie when ignored. Across seven pre-registered studies, testing 802 participants, such a strategic adviser consistently outcompeted an honest adviser. Strategic dishonesty outperformed truth-telling in swaying individual voters, the majority vote in anonymously voting groups, and the consensus vote in communicating groups. Our findings help explain the success of political movements that thrive on disinformation, and vocal underdog politicians with no credible program.


Functionalized large pore mesoporous silica nanoparticles for gene delivery featuring controlled release and co-delivery.
Novel mesoporous silica nanoparticles (LPMSNs) functionalised with degradable poly(2-dimethylaminoethyl acrylate) (PDMAEA) have been developed (PDMAEA-LPMSNs) as nano-carriers for gene delivery. The unique design of PDMAEA-LPMSNs has endowed this system with multiple functions derived from both the organic and inorganic moieties. The cationic polymer unit binds to genetic molecules and undergoes a self-catalyzed hydrolysis in water to form a non-toxic anionic polymer poly(acrylic acid), allowing controlled release of siRNA in the cells. The nanopores of the LPMSNs provide a reservoir for storage and release of chloroquine to facilitate endosomal escape. The PDMAEA-LPMSN composites were characterized by elemental analysis (EA), X-ray photoelectron spectroscopy (XPS), solid-state 13C magic-angle spinning nuclear magnetic resonance (MAS-NMR), thermogravimetric analysis (TGA), and nitrogen sorption techniques. Their siRNA delivery performance was tested in a KHOS cell line, showing promising potential for co-delivery of genes and drugs.


Neuroimmune mechanisms in health and disease: 2. Disease.
In the second part of their article on the emerging field of neuroimmunology, the authors present an overview of the role of neuroimmune mechanisms in defence against infectious diseases and in immune disorders. During acute febrile illness, immune-derived cytokines initiate an acute phase response, which is characterized by fever, inactivity, fatigue, anorexia and catabolism. Profound neuroendocrine and metabolic changes take place: acute phase proteins are produced in the liver, bone marrow function and the metabolic activity of leukocytes are greatly increased, and specific immune reactivity is suppressed. Defects in regulatory processes, which are fundamental to immune disorders and inflammatory diseases, may lie in the immune system, the neuro endocrine system or both. Defects in the hypothalamus-pituitary-adrenal axis have been observed in autoimmune and rheumatic diseases, chronic inflammatory disease, chronic fatigue syndrome and fibromyalgia. Prolactin levels are often elevated in patients with systemic lupus erythematosus and other autoimmune diseases, whereas the bioactivity of prolactin is decreased in patients with rheumatoid arthritis. Levels of sex hormones and thyroid hormone are decreased during severe inflammatory disease. Defective neural regulation of inflammation likely plays a pathogenic role in allergy and asthma, in the symmetrical form of rheumatoid arthritis and in gastrointestinal inflammatory disease. A better understanding of neuroimmunoregulation holds the promise of new approaches to the treatment of immune and inflammatory diseases with the use of hormones, neurotransmitters, neuropeptides and drugs that modulate these newly recognized immune regulators.


SDHD Promoter Mutations Ablate GABP Transcription Factor Binding in Melanoma.
SDHD encodes subunit D of the succinate dehydrogenase complex, an integral membrane protein. Across cancer types, recurrent SDHD promoter mutations were reported to occur exclusively in melanomas, at a frequency of 4% to 5%. These mutations are predicted to disrupt consensus ETS transcription factor-binding sites and are correlated with both reduced SDHD gene expression and poor prognosis. However, the consequence of these mutations on SDHD expression in melanoma is still unclear. Here, we found that expression of SDHD in melanoma correlated with the expression of multiple ETS transcription factors, particularly in SDHD promoter wild-type samples. Consistent with the predicted loss of ETS transcription factor binding, we observed that recurrent hotspot mutations resulted in decreased luciferase activity in reporter assays. Furthermore, we demonstrated specific GABPA and GABPB1 binding to probes containing the wild-type promoter sequences, with binding disrupted by the SDHD hotspot promoter mutations in both quantitative mass spectrometry and band-shift experiments. Finally, using siRNA-mediated knockdown across multiple melanoma cell lines, we determined that loss of GABPA resulted in reduced SDHD expression at both RNA and protein levels. These data are consistent with a key role for GABPA/B1 as the critical ETS transcription factors deregulating SDHD expression in the context of highly recurrent promoter mutations in melanoma and warrant a detailed search for other recurrent promoter mutations that create or disrupt GABPA consensus sequences. Cancer Res; 77(7); 1649-61. ©2017 AACR.


ID Learning Unit-Diagnostics Update: Current Laboratory Methods for Rapid Pathogen Identification in Patients With Bloodstream Infections.
Diagnostic assays that rapidly identify bloodstream pathogens have the potential to improve patient outcomes and antibiotic stewardship efforts. Current tests are based on the detection of nucleic acids that are specific to a targeted pathogen or based on organism identification using mass spectrometry. Most rapid assays require a positive blood culture as their sample input and expedite pathogen identification by 24-72 hours. For those assays that also report detection of drug resistance markers, information on antimicrobial resistance is expedited by 48-96 hours. This learning unit reviews the basic principles of rapid microorganism identification assays for bloodstream infections with the aim of assisting clinicians in the interpretation and optimal utilization of test results.


Co-assembly of curcumin and a cystine bridged peptide to construct tumor-responsive nano-micelles for efficient chemotherapy.
The effective uptake and release of hydrophobic antitumor drugs in cancer cells is a practical challenge for tumor chemotherapy. Many methods were developed to conquer it through modifying drug molecules with hydrophilic groups, or fabricating nanodrugs based on hydrophilic materials. In recent years, peptides have attracted significant interest as part of a promising platform for fabricating nanodrugs due to their low cytotoxicity, favorable variability and self-assembly property. In this study, a cystine bridged peptide (CBP) was designed to co-assemble with a hydrophobic antitumor drug curcumin (CCM), to form a tumor-responsive nanodrug. The hydrophilicity of the peptide promotes the water-dispersity of nanodrugs, and the disulfide bond in cystine, which is cleavable by glutathione (GSH), was involved considering the overexpressed GSH in tumor microenvironments. In vitro and in vivo tests on cervical cancer cells revealed that the obtained nanodrug can rapidly dissociate at tumor sites and inhibit the tumor growth with limited side effects on healthy tissues.


Pituitary homeobox 1 (Ptx1) is differentially expressed during pituitary development.
Pituitary homeobox 1 (Ptx1) is a homeodomain-containing transcription factor acting on transcription of all pituitary hormone genes. Its expression is first detected in the stomodeal ectoderm and is maintained in all derivatives of this structure, including Rathke's pouch. We now show that Ptx1 is expressed in all pituitary cells but that it is differentially expressed in different lineages at both the messenger RNA and protein levels. On day 12.5 of mouse embryonic development, cells expressing the highest levels of Ptx1 are restricted to the forming pars tuberalis, also called the rostral tip, a region where the first alpha-glycoprotein subunit-expressing cells appear. Coimmunolocalization studies reveal that alpha-glycoprotein subunit-positive cells express the highest levels of Ptx1 throughout development and in the adult gland. The quantitative differences in Ptx1 expression in pituitary cell lineages may relate to a role in cell proliferation, lineage commitment, and/or the control of organ development.


Comparison of two educational methods (family-centered and patient-centered) on hemodialysis: Related complications.
Hypotension and muscular cramp are the common complications of hemodialysis. Effective control of hemodialysis complications increases the survival time and the quality of life of patients on hemodialysis. Considering that failure to follow a therapeutic plan is one of the most prevalent causes of hemodialysis complications, the present research was conducted to study the effect of two educational methods (family-centered and patient-centered) on some complications that occur during hemodialysis. This clinical trial was performed from June to November 2012 in the hemodialysis ward of Imam Khomeini Hospital and Tehran Amir Aalam Hospital. Research samples included 60 patients in the age range of 18-65 years who were randomly included in patient-centered education (30 people in even days) and family-centered education (30 people in odd days). Blood pressure and muscle cramp were checked using researcher-made checklist in three stages (before and at the second and fourth week after intervention). Hypotension (before the start of dialysis, at the first, second, and third hour, and at the end hours) and muscle cramp (in the middle of hemodialysis and the end half an hour) were also checked. Data were analyzed using SPSS software, version 16, with Chi-square test, Fisher test, and independent t-test. Before intervention, the two groups did not show significant difference in terms of hypotension [with P = 0.91 and variations mean of 1.60 (1.30)] and muscle cramp [with P = 0.50 and variations mean of 1.06 (1.01)]. In the second and fourth week after intervention, there was significant difference between the two groups in terms of hypotension [with P = 0.016 and variations mean of 0.70 (0.70) and P = 0.02 and variations mean of 0.86 (0.62)] and muscle cramp [with P = 0.01 and variations mean of 0.46 (0.86) and P = 0.02 and variations mean of 1 (1.05)]. Considering that the study results showed that family-centered education was more effective on reduction of hemodialysis complications than patient-centered education, it is recommended that educational interventions relating to therapeutic program should be done in patients under hemodialysis, with participation of families.


Species identification of coagulase-negative staphylococci from urinary tract isolates.
A new scheme for identification of coagulase-negative staphylococci was applied to 138 consecutive urinary isolates of coagulase-negative staphylococci. The most common species were Staphylococcus epidermidis (53%), S. hominis (12%), and S. haemolyticus (10%). S. saprophyticus comprised only 5%. The disk method for antibiotic susceptibility for all species grouped together disclosed resistance most commonly to penicillin (35%), tetracycline (33%), methicillin (27%), and sulfonamide (24%). This pattern was also seen specifically with S. epidermidis. Further studies are needed to determine the incidence of species-specific antibiotic resistance and species-specific infection by site. This may be of particular interest in those patients with nosocomial infections due to coagulase-negative staphylococci.


Determination of competitive isotherms of enantiomers by a hybrid inverse method using overloaded band profiles and the periodic state of the simulated moving-bed process.
A procedure for determination of adsorption isotherms in simulated moving-bed (SMB) chromatography is presented. The parameters of a prescribed adsorption isotherm model and rate constants are derived using a hybrid inverse method, which incorporates overloaded band profiles of the racemic mixture and breakthrough data from a single frontal experiment. The latter are included to reduce the uncertainty on the estimated saturation capacity, due to the dilution of the chromatograms with respect to the injected concentrations. The adsorption isotherm model is coupled with an axially dispersed flow model with finite mass-transfer rate to describe the experimental band profiles. The numerical constants of the isotherm model are tuned so that the calculated and measured band profiles match as much as possible. The accuracy of the isotherm model is then checked against the cyclic steady state (CSS) of the target SMB process, which is readily and cheaply obtained experimentally on a single-column set-up. This experiment is as expensive and time consuming as just a few breakthrough experiments. If necessary, the isotherm parameters are adjusted by applying the inverse method to the experimental CSS concentration profile. The method is successfully applied to determine the adsorption isotherms of Trögers base enantiomers on Chiralpak AD/methanol system. The results indicate that the proposed inverse method offers a reliable and quick approach to determine the competitive adsorption isotherms for a specific SMB separation.


Comparison of BTA stat and NMP22 tests in the detection of bladder cancer.
This study aimed to compare the BTA (bladder tumour antigen) stat and urinary nuclear matrix protein (NMP22) tests in the detection of bladder cancer. The office-based qualitative BTA stat and the laboratory-based quantitative NMP22 tests were studied in the same urine samples obtained from 49 patients with a high suspicion of bladder cancer and 20 healthy subjects. A tumour was identified in 36 patients after the cystoscopy. BTA stat demonstrated a sensitivity of 89%, which was superior to the sensitivity of 66.6% with the NMP22 test in detecting the bladder cancer (p < 0.02). The sensitivities for grade I tumours with BTA stat and NMP22 were 55.5% and 33.3%, respectively. The sensitivity of BTA stat was 100% for tumour categories except for the pTa and grade I tumours. No positive result was observed with both tests among the healthy subjects. The specificities for BTA stat and NMP22 were 78.7% and 69.6%, respectively. The BTA stat test was significantly more sensitive than the NMP22 test in the detection of bladder cancer. Although the sensitivity of BTA stat was not sufficient to replace cystoscopy, its ease and low cost may play a role in reducing the number of control cystoscopies, especially in patients with low risk of progression.


Cloning and expression of the pepD gene of Escherichia coli.
Peptidase D of Escherichia coli, cleaving the unusual dipeptide carnosine, was found to be encoded by the ColE1 hybrid plasmid pLC44-11. From this plasmid the pepD gene was subcloned into small vectors. As shown by successive reduction of the flanking sequences of genomic DNA, the order of genes in the region at 6 min of the E. coli K12 map is phoE, pepD, in the clockwise orientation. Insertional inactivation of the pepD gene and expression of recombinant plasmids in maxicells allowed the identification of the pepD product as a 52 kDa protein. Comparison with the 100 kDa protein molecular mass determined by gel filtration suggests that active peptidase D is probably a dimer.


Randomized controlled trial protocol to investigate the antiplatelet therapy effect on extracellular vesicles (AFFECT EV) in acute myocardial infarction.
Activated platelets contribute to thrombosis and inflammation by the release of extracellular vesicles (EVs) exposing P-selectin, phosphatidylserine (PS) and fibrinogen. P2Y12 receptor antagonists are routinely administered to inhibit platelet activation in patients after acute myocardial infarction (AMI), being a combined antithrombotic and anti-inflammatory therapy. The more potent P2Y12 antagonist ticagrelor improves cardiovascular outcome in patients after AMI compared to the less potent clopidogrel, suggesting that greater inhibition of platelet aggregation is associated with better prognosis. The effect of ticagrelor and clopidogrel on the release of EVs from platelets and other P2Y12-exposing cells is unknown. This study compares the effects of ticagrelor and clopidogrel on (1) the concentrations of EVs from activated platelets (primary end point), (2) the concentrations of EVs exposing fibrinogen, exposing PS, from leukocytes and from endothelial cells (secondary end points) and (3) the procoagulant activity of plasma EVs (tertiary end points) in 60 consecutive AMI patients. After the percutaneous coronary intervention, patients will be randomized to antiplatelet therapy with ticagrelor (study group) or clopidogrel (control group). Blood will be collected from patients at randomization, 48 hours after randomization and 6 months following the index hospitalization. In addition, 30 age- and gender-matched healthy volunteers will be enrolled in the study to investigate the physiological concentrations and procoagulant activity of EVs using recently standardized protocols and EV-dedicated flow cytometry. Concentrations of EVs will be determined by flow cytometry. Procoagulant activity of EVs will be determined by fibrin generation test. The compliance and response to antiplatelet therapy will be assessed by impedance aggregometry. We expect that plasma from patients treated with ticagrelor (1) contains lower concentrations of EVs from activated platelets, exposing fibrinogen, exposing PS, from leukocytes and from endothelial cells and (2) has lower procoagulant activity, when compared to patients treated with clopidogrel. Antiplatelet therapy effect on EVs may identify a new mechanism of action of ticagrelor, as well as create a basis for future studies to investigate whether lower EV concentrations are associated with improved clinical outcomes in patients treated with P2Y12 antagonists.


Cross-talk between guanidinoacetate neurotoxicity, memory and possible neuroprotective role of creatine.
Guanidinoacetate Methyltransferase deficiency is an inborn error of metabolism that results in decreased creatine and increased guanidinoacetate (GAA) levels. Patients present neurological symptoms whose mechanisms are unclear. We investigated the effects of an intrastriatal administration of 10 μM of GAA (0.02 nmol/striatum) on energy metabolism, redox state, inflammation, glutamate homeostasis, and activities/immunocontents of acetylcholinesterase and Na+,K+-ATPase, as well as on memory acquisition. The neuroprotective role of creatine was also investigated. Male Wistar rats were pretreated with creatine (50 mg/kg) or saline for 7 days underwenting stereotactic surgery. Forty-eight hours after surgery, the animals (then sixty-days-old) were divided into groups: Control, GAA, GAA + Creatine, and Creatine. Experiments were performed 30 min after intrastriatal infusion. GAA decreased SDH, complexes II and IV activities, and ATP levels, but had no effect on mitochondrial mass/membrane potential. Creatine totally prevented SDH and complex II, and partially prevented COX and ATP alterations. GAA increased dichlorofluorescein levels and decreased superoxide dismutase and catalase activities. Creatine only prevented catalase and dichlorofluorescein alterations. GAA increased cytokines, nitrites levels and acetylcholinesterase activity, but not its immunocontent. Creatine prevented such effects, except nitrite levels. GAA decreased glutamate uptake, but had no effect on the immunocontent of its transporters. GAA decreased Na+,K+-ATPase activity and increased the immunocontent of its α3 subunit. The performance on the novel object recognition task was also impaired. Creatine partially prevented the changes in glutamate uptake and Na+,K+-ATPase activity, and completely prevented the memory impairment. This study helps to elucidate the protective effects of creatine against the damage caused by GAA.


Seeded Bayesian Networks: constructing genetic networks from microarray data.
DNA microarrays and other genomics-inspired technologies provide large datasets that often include hidden patterns of correlation between genes reflecting the complex processes that underlie cellular metabolism and physiology. The challenge in analyzing large-scale expression data has been to extract biologically meaningful inferences regarding these processes - often represented as networks - in an environment where the datasets are often imperfect and biological noise can obscure the actual signal. Although many techniques have been developed in an attempt to address these issues, to date their ability to extract meaningful and predictive network relationships has been limited. Here we describe a method that draws on prior information about gene-gene interactions to infer biologically relevant pathways from microarray data. Our approach consists of using preliminary networks derived from the literature and/or protein-protein interaction data as seeds for a Bayesian network analysis of microarray results. Through a bootstrap analysis of gene expression data derived from a number of leukemia studies, we demonstrate that seeded Bayesian Networks have the ability to identify high-confidence gene-gene interactions which can then be validated by comparison to other sources of pathway data. The use of network seeds greatly improves the ability of Bayesian Network analysis to learn gene interaction networks from gene expression data. We demonstrate that the use of seeds derived from the biomedical literature or high-throughput protein-protein interaction data, or the combination, provides improvement over a standard Bayesian Network analysis, allowing networks involving dynamic processes to be deduced from the static snapshots of biological systems that represent the most common source of microarray data. Software implementing these methods has been included in the widely used TM4 microarray analysis package.


Co-production of biohydrogen and biomethane from food waste and paper waste via recirculated two-phase anaerobic digestion process: Bioenergy yields and metabolic distribution.
To achieve the co-production of H2 and CH4, co-digestion of food waste (FW) and paper waste (PW) was performed on the recirculated two-phase anaerobic digestion (R-TPAD). The PW content in the feedstock increased from 0% to 20%, 40% and 50% (in total solids) with FW as the rest. The results showed that bioH2 and bioCH4 were simultaneously and stably produced in the long-term operation. With the increasing PW content, the removal efficiency of volatile solids decreased slightly from 84.9% to 78.4%; the bioH2 yields increased from 50 to 79 NL-H2/kg-VSfed while the bioCH4 yields decreased from 426 to 329 NL-CH4/kg-VSfed. With the fixed amount of FW, adding PW could significantly increase the total bioenergy yields. The relative abundance showed that the key H2-producing bacteria, Caproiciproducens and Thermoanaerobacterium, increased after PW addition. The microbial distribution suggests that the H2-producers were recirculated to the first stage after proliferating in the second stage.


Update to CDC's U.S. Medical Eligibility Criteria for Contraceptive Use, 2016: Revised Recommendations for the Use of Hormonal Contraception Among Women at High Risk for HIV Infection.
CDC's U.S. Medical Eligibility Criteria for Contraceptive Use (U.S. MEC) (first published in 2010 and updated in 2016) provides evidence-based guidance for the safe use of contraceptive methods among U.S. women with certain characteristics or medical conditions (1), and is adapted from global guidance from the World Health Organization (WHO) and kept up to date based on continual review of published literature (2).* CDC recently evaluated the evidence and the updated WHO guidance on the risk for human immunodeficiency virus (HIV) acquisition among women using hormonal contraception.† After careful review, CDC adopted the updated WHO guidance for inclusion in the U.S. MEC guidance; this guidance states that the advantages of progestin-only injectable contraceptive use (including depot medroxyprogesterone acetate [DMPA]) by women at high risk for HIV infection outweigh the theoretical or proven risks (U.S. MEC category 2). The guidance also includes an accompanying updated clarification, which states that "there continues to be evidence of a possible increased risk of acquiring HIV among progestin-only injectable users. Uncertainty exists about whether this is due to methodological issues with the evidence or a real biological effect. In many settings, unintended pregnancies and/or pregnancy-related morbidity and mortality are common, and progestin-only injectables are among the few types of methods widely available. Women should not be denied the use of progestin-only injectables because of concerns about the possible increased risk. Women considering progestin-only injectables should be advised about these concerns, about the uncertainty over whether there is a causal relationship, and about how to minimize their risk of acquiring HIV." Recommendations for other hormonal contraceptive methods (including combined hormonal methods, implants, and progestin-only pills) remain the same; there is no restriction for their use among women at high risk for HIV infection (U.S. MEC category 1).


[Familial Mediterranean fever].
Familial Mediterranean Fever is a genetically determined disease occurring predominantly in Arabs, Armenians, Jews and very rarely in Turks. It is characterized by moderately elevated body temperature and by abdominal, pulmonary or arthritic complaints. These symptoms are recurrent appearing at short intervals and persisting for not more than two days. Renal amyloidosis may be a complication. Thus, treatment should be continued for life. The pathomechanism of the disease is not clear. Colchicine has been shown to give good symptomatic relief. Surprisingly, the prolonged use of this mitotic poison is virtually devoid of untoward side effects, even in pregnancy and childhood.


ENPP2 Methylation in Health and Cancer.
Autotaxin (ATX) encoded by Ectonucleotide Pyrophosphatase/Phosphodiesterase 2 (ENPP2) is a key enzyme in Lysophosphatidic Acid (LPA) synthesis implicated in cancer. Although its aberrant expression has been reported, ENPP2 methylation profiles in health and malignancy are not described. We examined in silico the methylation of ENPP2 analyzing publicly available methylome datasets, to identify Differentially Methylated CpGs (DMCs) which were then correlated with expression at gene and isoform levels. Significance indication was set to be FDR corrected p-value < 0.05. Healthy tissues presented methylation in all gene body CGs and lower levels in Promoter Associated (PA) regions, whereas in the majority of the tumors examined (HCC, melanoma, CRC, LC and PC) the methylation pattern was reversed. DMCs identified in the promoter were located in sites recognized by multiple transcription factors, suggesting involvement in gene expression. Alterations in methylation were correlated to an aggressive phenotype in cancer cell lines. In prostate and lung adenocarcinomas, increased methylation of PA CGs was correlated to decreased ENPP2 mRNA expression and to poor prognosis parameters. Collectively, our results corroborate that methylation is an active level of ATX expression regulation in cancer. Our study provides an extended description of the methylation status of ENPP2 in health and cancer and points out specific DMCs of value as prognostic biomarkers.


Mean platelet volume levels predict pulmonary artery hypertension in patients with atrial septal defect.
Some reports have shown increased platelet aggregation and activation in patients with pulmonary artery hypertension (PAH). Mean platelet volume (MPV) is a simple and easy method of assessing platelet function. We aimed to investigate the mean platelet volume levels in patients with atrial septal defect (ASD) and the association between MPV levels and pulmonary artery hypertension. One hundred and forty consecutive patients (42 males and mean age 35 +/- 9 y) and forty healthy controls (15 males and mean age 35 +/- 4 y) were enrolled in the study between December 2008 and February 2011. The ASD group demonstrated a significantly higher right ventricular size and pulmonary artery pressure than the control group (42 +/- 4 mm vs. 36 +/- 3 mm and 43 +/- 12 mmHg vs. 32 +/- 11 mmHg; P < 0.001 and P < 0.001, respectively). MPV levels were higher in the ASD group than the control group (9.3 +/- 1.2 fl vs. 8.6 +/- 0.8 fl, P < 0.001). There was a significant, positive correlation between MPV and systolic pulmonary artery pressure (PAP) (r = 0.542 and P < 0.001) in the ASD group. MPV was also significantly correlated with right ventricular size but not ASD diameter in the ASD group (r = 0.441, P < 0.001 and r = 0.126, P = 0.268, respectively). In receiver operating characteristics curve analysis, the cut-off value of MPV levels was > 8.7 fl and had 82% sensitivity and 63% specificity in predicting pulmonary artery hypertension. In the present study, we found that MPV levels, an indicator of platelet activation, were significantly higher in patients with ASD and correlated with systolic pulmonary artery pressure and right ventricular diameter.


Sesamin mitigates inflammation and oxidative stress in endothelial cells exposed to oxidized low-density lipoprotein.
Sesamin, a lignan from sesame oil, has been shown to have antihypertensive and antioxidative properties. This study examined the effects of sesamin on oxidized low-density lipoprotein (oxLDL)-induced endothelial dysfunction. Oxidative stress was determined by measuring the generation of intracellular reactive oxygen species (ROS) and by measuring the expression levels of superoxide dismutase (SOD) and endothelial nitric oxide synthase (eNOS). To assess the pro-inflammatory effects of oxLDL, ELISA was used to detect IL-8 expression, endothelin-1 (ET-1) secretion, and nuclear factor-kappaB (NF-kappaB) activation. The expression of adhesion molecules (ICAM-1, VCAM-1, and E-selectin) was examined by flow cytometry. In addition, several apoptotic signaling pathways were also investigated. The data showed that sesamin significantly ameliorated oxLDL-induced ROS generation and SOD-1 inactivation. Sesamin also attenuated the oxLDL-induced activation of NF-kappaB, suggesting that the inhibitory effects of sesamin on IL-8 and ET-1 release, adhesion molecule expression, and the adherence of THP-1 cells were at least partially through the blockade of NF-kappaB activation. Furthermore, sesamin attenuated oxLDL-induced apoptotic features, such as intracellular calcium accumulation and the subsequent collapse of mitochondrial membrane potential, release of cytochrome c, and activation of caspase-3. Results from this study may provide insight into possible molecular mechanisms underlying sesamin's beneficial effects against oxLDL-mediated vascular endothelial dysfunction.


Rat brain angiotensin II receptors: effects of intracerebroventricular angiotensin II infusion.
Angiotensin II (Ang II) was infused into a lateral cerebral ventricle of male Sprague-Dawley rats and its effects on blood pressure, water balance and specific [125I]Ang II binding to brain and adrenal tissues were studied. The infusion was maintained at a rate of 500 ng/microliter/h for 6 days using subcutaneously implanted osmotic minipumps. A control group was infused intracerebroventricularly (i.c.v.) with 0.9% saline at a rate of 1 microliter/h for 6 days. Angiotensin II treated rats showed a four-fold increase in water intake and urine volume and a moderate increase in blood pressure; these effects were not observed in rats given saline i.c.v. There was no significant difference in [125I]Ang II binding site density or binding affinity in either the hypothalamus-thalamus-septum-midbrain (HTSM) or the brainstem between Ang II-treated and saline-treated groups. In addition, [125I]Ang II binding sites in the adrenals were also unaffected by i.c.v. infusion of Ang II. The results suggest that brain Ang II receptors are unresponsive to increased Ang II levels in cerebrospinal fluid.


IL-6 levels, nutritional status, and mortality in prevalent hemodialysis patients.
The influence of serum IL-6 levels on nutritional status in chronic hemodialysis (HD) patients remains to be elucidated. The present report describes a prospective longitudinal study of IL-6 levels and nutritional parameters to determine whether high IL-6 levels are independently associated with nutritional status over time in a cohort of prevalent hemodialysis patients. 85 clinically stable hemodialysis patients (37.6% women), with a mean age of 66.5 ± 10.6 years, were studied after exclusion of patients with BMI < 20 kg/m(2) and/or serum albumin <35 g/L. IL-6, dietary energy and protein intake, and biochemical markers of nutrition and body composition (anthropometry and bioimpedance analysis) were measured at baseline and at 6, 12, 18, and 24 months following enrollment. Observation of this cohort was continued over 2 additional years. IL-6 levels increased with time in both unadjusted (linear estimate: 2.57 ± 0.44 pg/ml per 2 yrs; P = 0.001) and adjusted models (linear estimate: 2.35 ± 0.57 pg/ml per 2 yrs; P = 0.049). Significant reductions of daily energy intake, laboratory markers (albumin, transferrin, cholesterol, creatinine), and body composition (fat mass) with higher IL-6 levels were observed over the duration of the longitudinal observation period. However, none of the studied parameters were associated with changes in IL-6 levels over time (IL-6-by-time interactions were NS). Furthermore, cumulative incidences of survival were correlated with the baseline serum IL-6 levels (P = 0.004 by log-rank test). Finally, for each pg/ml increase in IL-6 level, the hazard ratio for death from all causes was 1.06 (95% CI 1.01 to 1.10) after adjustment for demographic and clinical parameters. Our results suggest that higher serum IL-6 levels are associated with all-cause mortality without additional changes in clinical and laboratory markers of nutritional status in clinically stable HD patients.


Relationships between physical performance and knee and hip osteoarthritis: findings from the European Project on Osteoarthritis (EPOSA).
poor physical performance (PP) is known to be associated with disability, lower quality of life and higher mortality rates. Knee and hip osteoarthritis (OA) might be expected to contribute to poor PP, through joint pain and restricted range of movement. Both clinical and self-reported OA are often used for large-scale community and epidemiological studies. to examine the relationships between hip and knee OA and PP in a large data set comprising cohorts from six European countries. a total of 2,942 men and women aged 65-85 years from the Germany, Italy, Netherlands, Spain, Sweden and the UK were recruited. Assessment included an interview and clinical assessment for OA. PP was determined from walking speed, chair rises and balance (range 0-12); low PP was defined as a score of ≤9. the mean (SD) age was 74.2 (5.1) years. Rates of self-reported OA were much higher than clinical OA. Advanced age, female gender, lower educational attainment, abstinence from alcohol and higher body mass index were independently associated with low PP. Clinical knee OA, hip OA or both were associated with a higher risk of low PP; OR (95% CI) 2.93 (2.36, 3.64), 3.79 (2.49, 5.76) and 7.22 (3.63, 14.38), respectively, with relationships robust to adjustment for the confounders above as well as pain. lower limb OA at the hip and knee is associated with low PP, and for clinical diagnosis relationships are robust to adjustment for pain. Those at highest risk have clinical OA at both sites.


Dynamic modeling and analysis of the rotor-stator coupling system of a coaxial contra-rotating gearbox.
In this paper, a main gearbox using an encased differential gear train to achieve coaxial contra-rotating is considered, and a dynamic modeling method of the rotor-stator coupling system of the gearbox based on box model updating is introduced. The transverse torsional dynamic model of the gear transmission subsystem is established based on the lumped parameter method. The finite element model of the box is updated according to the modal test data, and the reduced dynamic parameters of the box are obtained. According to the displacement coordination condition, the dynamic model of the rotor-stator system of the gearbox is established. The vibration response of the transmission components with or without the coupling box is calculated by numerical integration, and the response of the box caused by the dynamic support reaction force is analyzed by the finite element method. The results show that the vibration peak and fluctuation range of the transmission parts with coupling box are smaller than those without coupling box. The box response at the support of the input bevel gear pair is large, while that at the support of the output shaft is small.


Flares in patients with systemic lupus erythematosus are associated with daily psychological stress.
The aetiology of systemic lupus erythematosus (SLE) remains unclear. Clinical observations and a small number of studies performed so far suggest an association between psychological stress and self-reported symptoms of SLE patients. This longitudinal study was designed to investigate whether daily psychological stress is associated with flares in SLE patients, measured by clinical and laboratory parameters. Female SLE patients (n = 41) were followed over a period of six months. Daily stress was monitored by a hand-held PC diary programmed with 44 items based on standardized measures and clinical experience. Once every four weeks patients visited the outpatient clinic for medical evaluation. Disease activity was evaluated using the European Consensus Lupus Activity Measurement (ECLAM), laboratory parameters, and intake of steroids. Classification and regression tree (CART) patient-wise analyses revealed that SLE patients with vs. without flares using complement and ECLAM as activity measures show greater negative self-ratings in mood, and social duties (p < 0.01). In addition, mixed model analysis of variance showed that daily hassles with social relationships were significantly associated with flares in SLE measured by an increase in steroid medication >5mg/d (p < 0.01). These results suggest that psychological stress is associated with flares in SLE. Particularly daily stress with social relationships and social duties may be factors to be related to the course of disease activity in SLE.


A Review of Player Monitoring Approaches in Basketball: Current Trends and Future Directions.
Fox, JL, Scanlan, AT, and Stanton, R. A review of player monitoring approaches in basketball: current trends and future directions. J Strength Cond Res 31(7): 2021-2029, 2017-Effective monitoring of players in team sports such as basketball requires an understanding of the external demands and internal responses, as they relate to training phases and competition. Monitoring of external demands and internal responses allows coaching staff to determine the dose-response associated with the imposed training load (TL), and subsequently, if players are adequately prepared for competition. This review discusses measures reported in the literature for monitoring the external demands and internal responses of basketball players during training and competition. The external demands of training and competition were primarily monitored using time-motion analysis, with limited use of microtechnology being reported. Internal responses during training were typically measured using hematological markers, heart rate, various TL models, and perceptual responses such as rating of perceived exertion (RPE). Heart rate was the most commonly reported indicator of internal responses during competition with limited reporting of hematological markers or RPE. These findings show a large discrepancy between the reporting of external and internal measures and training and competition demands. Microsensors, however, may be a practical and convenient method of player monitoring in basketball to overcome the limitations associated with current approaches while allowing for external demands and internal responses to be recorded simultaneously. The triaxial accelerometers of microsensors seem well suited for basketball and warrant validation to definitively determine their place in the monitoring of basketball players. Coaching staff should make use of this technology by tracking individual player responses across the annual plan and using real-time monitoring to minimize factors such as fatigue and injury risk.


Introduction and spread of variegated squirrel bornavirus 1 (VSBV-1) between exotic squirrels and spill-over infections to humans in Germany.
The variegated squirrel bornavirus 1 (VSBV-1) is a recently discovered emerging viral pathogen which causes severe and eventually fatal encephalitis in humans after contact to exotic squirrels in private holdings and zoological gardens. Understanding the VSBV-1 epidemiology is crucial to develop, implement, and maintain surveillance strategies for the detection and control of animal and human infections. Based on a newly detected human encephalitis case in a zoological garden, epidemiological squirrel trade investigations and molecular phylogeny analyses of VSBV-1 with temporal and spatial resolution were conducted. Phylogenetic analyses indicated a recent emergence of VSBV-1 in European squirrel holdings and several animal-animal and animal-human spill-over infections. Virus phylogeny linked to squirrel trade analysis showed the introduction of a common ancestor of the known current VSBV-1 isolates into captive exotic squirrels in Germany, most likely by Prevost's squirrels (Callosciurus prevostii). The links of the animal trade between private breeders and zoos, the likely introduction pathway of VSBV-1 into Germany, and the role of a primary animal distributor were elucidated. In addition, a seroprevalence study was performed among zoo animal caretakers from VSBV-1 affected zoos. No seropositive healthy zoo animal caretakers were found, underlining a probable high-case fatality rate of human VSBV-1 infections. This study illustrates the network and health consequences of uncontrolled wild pet trading as well as the benefits of molecular epidemiology for elucidation and future prevention of infection chains by zoonotic viruses. To respond to emerging zoonotic diseases rapidly, improved regulation and control strategies are urgently needed.


Safety and Efficacy Considerations of Gabapentin as Adjunctive Therapy to Opioids in the Perioperative Setting for Older Adults.
While opioids have historically been the initial choice of analgesic for both acute and chronic pain, legislative and deprescribing trends as a result of the opioid epidemic have demonstrated an increase in the use of adjunctive therapies. These adjunctive agents are being utilized with increased frequency, especially in older adult patients, as a mechanism to mitigate any likelihood of dependency and in an effort to provide multimodal pain management. As this patient population can be more challenging because of comorbidities, the presence of polypharmacy, pharmacokinetic, and pharmacodynamic changes, it is important to evaluate the risk of any relevant adverse effects for opioids and adjuncts that can lead to higher risk of opioid toxicities. Gabapentin is one of the most commonly added adjunctive medications; however, its safety and efficacy in conjunction with opioids has not been exclusively considered in older adult patients in the perioperative setting. This report will summarize available evidence for gabapentin as an adjunctive therapy to opioids in older adult patients undergoing surgery.