Effect of probiotics on depressive symptoms: A meta-analysis of human studies.
Accumulating data show that probiotics may be beneficial in reducing depressive symptoms. We conducted an updated meta-analysis and evaluated the effects of probiotics on depressive symptoms. A systematic search of six databases was performed, and the results were reported according to Preferred Reporting Items for Systematic Reviews and Meta-analyses, with the priori-defined protocol registered at PROSPERO (CRD42018107426). In total, 19 double-blind, randomized, placebo-controlled trials with a total of 1901 participants were included in the qualitative synthesis. Participants treated with probiotics showed significantly greater improvement in depressive symptoms than those receiving placebo. The clinical population was stratified by clinical diagnosis into those with major depressive disorder (MDD) and those with other clinical conditions. The beneficial effect of probiotics on depressive symptoms was significant in patients with MDD, but not in those with other clinical conditions and in the general population. In addition, multiple strains of probiotics were more effective in reducing depressive symptoms. In conclusion, altering the gut-brain axis with probiotics may be an approach to improve depression severity. It is essential to verify the efficacy of specific combinations or strains of probiotics for depressive symptoms by conducting studies with a larger sample size in the future.


Femoral morphology and femoropelvic musculoskeletal anatomy of humans and great apes: a comparative virtopsy study.
The proximal femoral morphology of fossil hominins is routinely interpreted in terms of muscular topography and associated locomotor modes. However, the detailed correspondence between hard and soft tissue structures in the proximal femoral region of extant great apes is relatively unknown, because dissection protocols typically do not comprise in-depth osteological descriptions. Here, we use computed tomography and virtopsy (virtual dissection) for non-invasive examination of the femoropelvic musculoskeletal anatomy in Pan troglodytes, P. paniscus, Gorilla gorilla, Pongo pygmaeus, and Homo sapiens. Specifically, we analyze the topographic relationship between muscle attachment sites and surface structures of the proximal femoral shaft such as the lateral spiral pilaster. Our results show that the origin of the vastus lateralis muscle is anterior to the insertion of gluteus maximus in all examined great ape specimens and humans. In gorillas and orangutans, the insertion of gluteus maximus is on the inferior (anterolateral) side of the lateral spiral pilaster. In chimpanzees, however, the maximus insertion is on its superior (posteromedial) side, similar to the situation in modern humans. These findings support the hypothesis that chimpanzees and humans exhibit a shared-derived musculoskeletal topography of the proximal femoral region, irrespective of their different locomotor modes, whereas gorillas and orangutans represent the primitive condition. Caution is thus warranted when inferring locomotor behavior from the surface topography of the proximal femur of fossil hominins, as the morphology of this region may contain a strong phyletic signal that tends to blur locomotor adaptation.


Influenza forecasting in human populations: a scoping review.
Forecasts of influenza activity in human populations could help guide key preparedness tasks. We conducted a scoping review to characterize these methodological approaches and identify research gaps. Adapting the PRISMA methodology for systematic reviews, we searched PubMed, CINAHL, Project Euclid, and Cochrane Database of Systematic Reviews for publications in English since January 1, 2000 using the terms "influenza AND (forecast* OR predict*)", excluding studies that did not validate forecasts against independent data or incorporate influenza-related surveillance data from the season or pandemic for which the forecasts were applied. We included 35 publications describing population-based (N = 27), medical facility-based (N = 4), and regional or global pandemic spread (N = 4) forecasts. They included areas of North America (N = 15), Europe (N = 14), and/or Asia-Pacific region (N = 4), or had global scope (N = 3). Forecasting models were statistical (N = 18) or epidemiological (N = 17). Five studies used data assimilation methods to update forecasts with new surveillance data. Models used virological (N = 14), syndromic (N = 13), meteorological (N = 6), internet search query (N = 4), and/or other surveillance data as inputs. Forecasting outcomes and validation metrics varied widely. Two studies compared distinct modeling approaches using common data, 2 assessed model calibration, and 1 systematically incorporated expert input. Of the 17 studies using epidemiological models, 8 included sensitivity analysis. This review suggests need for use of good practices in influenza forecasting (e.g., sensitivity analysis); direct comparisons of diverse approaches; assessment of model calibration; integration of subjective expert input; operational research in pilot, real-world applications; and improved mutual understanding among modelers and public health officials.


Variations of weight loss following gastric bypass and gastric band.
To compare and describe the weight loss outcomes from gastric bypass and gastric band so as to define the variation of excess weight loss (EWL) among individual patients, the time to onset of effect, and the durability of weight loss in severely obese adults. Gastric bypass and gastric band are the most common operations for obesity performed in the United States, but few reports have compared these 2 procedures. Patients (N = 1733, aged 18-65 years) met National Institutes of Health criteria for obesity surgery and underwent either gastric bypass or gastric band between March 1997 and November 2006. The selection of bypass versus band was based on patient/surgeon discussion. The evaluable sample consisted of 1518 patients. The percentage of EWL was assessed over 2 years. Successful weight loss was defined a priori as > or = 40% EWL in each of four 6-month postoperative measurement periods. The analyses included a mixed model and generalized estimating equation (GEE) model with repeated measures. Odds ratios and descriptive analyses were also provided. Gastric bypass was associated with less individual variation in weight loss than gastric band. Both procedures were associated with a significant EWL benefit (Treatment Group effect P < 0.0001), but they differed in terms of time to effect (Treatment Group x Period interaction effect P < 0.0001). The mean EWL for gastric bypass was greater at each measurement period (6, 12, 18, 24 months) compared with gastric band (P < 0.0001). Furthermore, at each of the postoperative measurement periods within each treatment group (bypass and band), the mean EWL was greater for those who had preoperative body mass index (BMI) < or = 50 kg/m2 than for those who had preoperative BMI > 50 kg/m2 (P < 0.0001). Gastric bypass was consistently associated with a greater likelihood of at least a 40% EWL in each of the 6-month postoperative measurement periods (GEE, P < 0.0001). The odds ratio estimates at months 6, 12, 18, and 24 were 18.2, 20.6, 15.5, and 9.1, respectively. Despite these clinically meaningful outcome differences, nearly all (> or = 93%) bypass and band patients who had > or = 40% EWL at 6, 12, or 18 months postoperatively maintained at least this level of success at 2 years. Gastric bypass produced more rapid, greater, and more consistent EWL across individuals over a 2-year postoperative period than gastric band.


Frontoparietal cortex controls spatial attention through modulation of anticipatory alpha rhythms.
A dorsal frontoparietal network, including regions in intraparietal sulcus (IPS) and frontal eye field (FEF), has been hypothesized to control the allocation of spatial attention to environmental stimuli. One putative mechanism of control is the desynchronization of electroencephalography (EEG) alpha rhythms (approximately 8-12 Hz) in visual cortex in anticipation of a visual target. We show that brief interference by repetitive transcranial magnetic stimulation (rTMS) with preparatory activity in right IPS or right FEF while subjects attend to a spatial location impairs identification of target visual stimuli approximately 2 s later. This behavioral effect is associated with the disruption of anticipatory (prestimulus) alpha desynchronization and its spatially selective topography in parieto-occipital cortex. Finally, the disruption of anticipatory alpha rhythms in occipital cortex after right IPS- or right FEF-rTMS correlates with deficits of visual identification. These results support the causal role of the dorsal frontoparietal network in the control of visuospatial attention, and suggest that this is partly exerted through the synchronization of occipital visual neurons.


Detection of katG Ser315Thr substitution in respiratory specimens from patients with isoniazid-resistant Mycobacterium tuberculosis using PCR-RFLP.
Mutations in the katG locus of catalase peroxidase in Mycobacterium tuberculosis (MTB) account for major isoniazid (INH) resistance. In the South China region, a collection of 906 respiratory specimens and 142 MTB isolates was used to evaluate the sensitivity and specificity of a PCR-RFLP method for the detection of INH resistance-associated mutations. Except for four catalase-negative MTB isolates, katG PCR for a 620-bp amplicon was successful for all purified MTB isolates. For respiratory specimens, diagnostic sensitivity and specificity of katG PCR was 85 and 100 %. Subsequent RFLP of the katG amplicons by MspI digestion identified that 51 % of INH-resistant MTB were associated with the Thr315 phenotype, and that codon 463 was a polymorphic site with no linkage to INH resistance. The Arg463 wild-type MTB isolates predominant in the Western world were replaced by isolates carrying Leu463 in the South China region. RFLP patterns of katG amplicons from respiratory specimens were identical to those of the corresponding MTB cultured colonies. This method has potential application for rapid diagnosis of INH resistance due to katG Ser315Thr mutation.


Adaptive Interventions and SMART Designs: Application to child behavior research in a community setting.
Heterogeneity between and within people necessitates the need for sequential personalized interventions to optimize individual outcomes. Personalized or adaptive interventions (AIs) are relevant for diseases and maladaptive behavioral trajectories when one intervention is not curative and success of a subsequent intervention may depend on individual characteristics or response. AIs may be applied to medical settings and to investigate best prevention, education, and community-based practices. AIs can begin with low-cost or low-burden interventions and followed with intensified or alternative interventions for those who need it most. AIs that guide practice over the course of a disease, program, or school year can be investigated through sequential multiple assignment randomized trials (SMARTs). To promote the use of SMARTs, we provide a hypothetical SMART in a Head Start program to address child behavior problems. We describe the advantages and limitations of SMARTs, particularly as they may be applied to the field of evaluation.


Multiple nuclear-replicating viruses require the stress-induced protein ZC3H11A for efficient growth.
The zinc finger CCCH-type containing 11A (ZC3H11A) gene encodes a well-conserved zinc finger protein that may function in mRNA export as it has been shown to associate with the transcription export (TREX) complex in proteomic screens. Here, we report that ZC3H11A is a stress-induced nuclear protein with RNA-binding capacity that localizes to nuclear splicing speckles. During an adenovirus infection, the ZC3H11A protein and splicing factor SRSF2 relocalize to nuclear regions where viral DNA replication and transcription take place. Knockout (KO) of ZC3H11A in HeLa cells demonstrated that several nuclear-replicating viruses are dependent on ZC3H11A for efficient growth (HIV, influenza virus, herpes simplex virus, and adenovirus), whereas cytoplasmic replicating viruses are not (vaccinia virus and Semliki Forest virus). High-throughput sequencing of ZC3H11A-cross-linked RNA showed that ZC3H11A binds to short purine-rich ribonucleotide stretches in cellular and adenoviral transcripts. We show that the RNA-binding property of ZC3H11A is crucial for its function and localization. In ZC3H11A KO cells, the adenovirus fiber mRNA accumulates in the cell nucleus. Our results suggest that ZC3H11A is important for maintaining nuclear export of mRNAs during stress and that several nuclear-replicating viruses take advantage of this mechanism to facilitate their replication.


Spike timing of distinct types of GABAergic interneuron during hippocampal gamma oscillations in vitro.
Gamma frequency (30-100 Hz) network oscillations occur in the intact hippocampus during awake, attentive behavior. Here, we explored the underlying cellular mechanisms in an in vitro model of persistent gamma-frequency oscillations, induced by bath application of 20 microm carbachol in submerged hippocampal slices at 30 +/- 1 degrees C. Current-source density analysis of the field oscillation revealed a prominent alternating sink-source pair in the perisomatic and apical dendritic regions of CA3. To elucidate the active events generating these extracellular dipoles, we examined the firing properties of distinct neuron types. Visually guided unit recordings were obtained from individual CA3 neurons followed by intracellular labeling for anatomical identification. Pyramidal cells fired at 2.82 +/- 0.7 Hz, close to the negative peak of the oscillation (0.03 +/- 0.65 msec), and often in conjunction with a negative spike-like component of the field potential. In contrast, all phase-coupled interneurons fired after this negative peak. Perisomatic inhibitory interneurons fired at high frequency (18.1 +/- 2.7 Hz), shortly after the negative peak (1.97 +/- 0.95 msec) and were strongly phase-coupled. Dendritic inhibitory interneurons fired at lower frequency (8.4 +/- 2.4 Hz) and with less fidelity and a longer delay after the negative peak (4.3 +/- 1.1 msec), whereas interneurons with cell body in the stratum radiatum often showed no phase relationship with the field oscillation. The phase and spike time data of individual neurons, together with the current-source density analysis, support a synaptic feedback model of gamma oscillations primarily involving pyramidal cells and inhibitory cells targeting their perisomatic region.


Brain activity during episodic retrieval of autobiographical and laboratory events: an fMRI study using a novel photo paradigm.
Functional neuroimaging studies of episodic memory retrieval generally measure brain activity while participants remember items encountered in the laboratory ("controlled laboratory condition") or events from their own life ("open autobiographical condition"). Differences in activation between these conditions may reflect differences in retrieval processes, memory remoteness, emotional content, retrieval success, self-referential processing, visual/spatial memory, and recollection. To clarify the nature of these differences, a functional MRI study was conducted using a novel "photo paradigm," which allows greater control over the autobiographical condition, including a measure of retrieval accuracy. Undergraduate students took photos in specified campus locations ("controlled autobiographical condition"), viewed in the laboratory similar photos taken by other participants (controlled laboratory condition), and were then scanned while recognizing the two kinds of photos. Both conditions activated a common episodic memory network that included medial temporal and prefrontal regions. Compared with the controlled laboratory condition, the controlled autobiographical condition elicited greater activity in regions associated with self-referential processing (medial prefrontal cortex), visual/spatial memory (visual and parahippocampal regions), and recollection (hippocampus). The photo paradigm provides a way of investigating the functional neuroanatomy of real-life episodic memory under rigorous experimental control.


Modeling household dynamics on Respiratory Syncytial Virus (RSV).
Respiratory Syncytial Virus (RSV) is the most common cause of respiratory tract infection in infants and children and shows increasing trend among elderly people worldwide. In many developing country settings, population and household structures have gone through some significant changes in the past decades, namely fewer births, more elderly population, and smaller household size but more RSV high-risk individuals. These dynamics have been captured in a mathematical model with RSV transmission dynamics to predict the disease burden on the detailed population for future targeted interventions. The population and disease dynamics model was constructed and tested against the hospitalization data for Acute Lower Respiratory Tract Infection due to RSV in rural Thai settings between 2005 and 2011. The proportion of extended families is predicted to increase by about 10% from 2005 to 2020, especially for those with elderly population, while the classic nuclear family type (with adults and children) will decline by about 10%. For RSV, infections from extended family type (approximately 60% of all household types) have majorly contributed to the force of infection (FOI). While the model predicted the increase of FOI from the extended family by 15% from 2005 to 2020, the FOI contributed by other household types would be either stable or decrease in the same time period. RSV incidence rate is predominantly high among babies (92.2%) and has been predicted to decrease slightly over time (from 940 to 864 cases per 100,000 population by 2020), while the incidence rates among children and elderly people may remain steadily low over the same period. However, the estimated incidence rates among elderly people were twice than those in children. The model predicts that approximately 60% of FOI for RSV will come from members of the extended family type. The incidence rate of RSV among children and elderly in extended families was about 20 times lower than that in infants and the trend is steady. Targeted intervention strategies, such as health education in some specific groups and targeted vaccination, may be considered, with the focus on extended family type. Target interventions on babies can lessen the transmission to children and elderly especially when transmission within households of extended family type is high.


Evaluation of a brief tailored motivational intervention to prevent early childhood caries.
This pragmatic randomized trial evaluated the effectiveness of a tailored educational intervention on oral health behaviors and new untreated carious lesions in low-income African-American children in Detroit, Michigan. Participating families were recruited in a longitudinal study of the determinants of dental caries in 1021 randomly selected children (0-5 years) and their caregivers. The families were examined at baseline in 2002-2004 (Wave I), 2004-2005 (Wave II) and 2007 (Wave III). Prior to Wave II, the families were randomized into two educational groups. An interviewer trained in applying motivational interviewing principles (MI) reviewed the dental examination findings with caregivers assigned to the intervention group (MI + DVD) and engaged the caregiver in a dialogue on the importance of and potential actions for improving the child's oral health. The interviewer and caregiver watched a special 15-minute DVD developed specifically for this project based on data collected at Wave I and focused on how the caregivers can 'keep their children free from tooth decay'. After the MI session, the caregivers developed their own preventive goals. Some families in this group chose not to develop goals and were offered the project-developed goals. The goals, if defined, were printed on glossy paper that included the child's photograph. Families in the second group (DVD-only) were met by an interviewer, shown the DVD, and provided with the project's recommended goals. Both groups of families received a copy of the DVD. Families in the MI + DVD group received booster calls within 6 months of the intervention. Both caregivers and the children were interviewed and examined after approximately 2 years (Wave III: 2007). After 6-month of follow-up, caregivers receiving MI + DVD were more likely to report checking the child for 'precavities' and making sure the child brushes at bedtime. Evaluation of the final outcomes approximately 2 years later found that caregivers receiving the MI + DVD were still more likely to report making sure the child brushed at bedtime, yet were no more likely to make sure the child brushed twice per day. Despite differences in one of the reported behaviors, children whose caregivers received the motivational intervention did not have fewer new untreated lesions at the final evaluation. This study found that a single motivational interviewing intervention may change some reported oral health behaviors, it failed to reduce the number of new untreated carious lesions.


Effect of preoperative chemotherapy on postoperative liver regeneration following hepatic resection as estimated by liver volume.
In order to analyze postoperative liver regeneration following hepatic resection after chemotherapy, we retrospectively investigated the differences in liver regeneration by comparing changes of residual liver volume in three groups: a living liver donor group and two groups of patients with colorectal liver metastases who did and did not undergo preoperative chemotherapy. This study included 32 patients who had at least segmental anatomical hepatic resection. Residual liver volume, early postoperative liver volume, and late postoperative liver volume were calculated to study the changes over time. From the histopathological analysis of chemotherapy-induced liver disorders, the effect on liver regeneration according to the histopathology of noncancerous liver tissue was also compared between the two colorectal cancer groups using Kleiner's score for steatohepatitis grading {Hepatology, 41(6):1313-1321, 2005} and sinusoidal obstruction syndrome (SOS) grading for sinusoidal obstructions {Ann Oncol, 15(3):460-466, 2004}. Assuming a preoperative liver volume of 100%, mean late postoperative liver volumes in the three groups (the living liver donor group and the colorectal cancer groups with or without chemotherapy) were 91.1%, 80.8%, and 81.3%, respectively, with about the same rate of liver regeneration among the three groups. Histopathological analysis revealed no correlation between either the Kleiner's scores or the SOS grading and liver regeneration. As estimated by liver volume, the level of liver regeneration was the same in normal livers, tumor-bearing livers, and post-chemotherapy tumor-bearing livers. Liver regeneration was not adversely affected by the extent to which steatosis or sinusoidal dilatation was induced in noncancerous tissue by chemotherapy in patients scheduled for surgery.


Studies in the mouse model identify strain variability as a major determinant of disease outcome in Leishmania infantum infection.
Visceral leishmaniasis is a severe and potentially fatal disease caused by protozoa of the genus Leishmania, transmitted by phlebotomine sandflies. In Europe and the Mediterranean region, L. infantum is the commonest agent of visceral leishmaniasis, causing a wide spectrum of clinical manifestations, including asymptomatic carriage, cutaneous lesions and severe visceral disease. Visceral leishmaniasis is more frequent in immunocompromised individuals and data obtained in experimental models of infection have highlighted the importance of the host immune response, namely the efficient activation of host's macrophages, in determining infection outcome. Conversely, few studies have addressed a possible contribution of parasite variability to this outcome. In this study, we compared three isolates of L. infantum regarding their capacity to grow in the organs of mice, the way they activate the host's macrophages and other components of the immune response and also their capacity to cope with host's antimicrobial mechanisms, namely reactive oxygen and nitrogen species. We found that the three parasite strains significantly differed regarding the degree to which they induced nitric oxide synthase (NOS2) and arginase expression in infected macrophages and the pattern of cytokine production they induced in the host, resulting in different degrees of inflammatory response in infected livers. Additionally, the three strains also significantly differed in their in vitro susceptibility to reactive oxygen and nitrogen species. This variability was reflected in the capacity of each strain to persist and proliferate in the organs of wild-type as well as NOS2- and phagocyte oxidase- deficient mice. The results obtained in this study show that parasite strain variability is an important determinant of disease outcome in L. infantum visceral leishmaniasis, with relevant implications for studies on host-pathogen interaction and also for leishmanicidal drug development.


Laboratory test of Single Landmark registration method for ultrasound-based navigation in laparoscopy using an open-source platform.
Test the feasibility of the novel Single Landmark image-to-patient registration method for use in the operating room for future clinical trials. The algorithm is implemented in the open-source platform CustusX, a computer-aided intervention research platform dedicated to intraoperative navigation and ultrasound, with an interface for laparoscopic ultrasound probes. The Single Landmark method is compared to fiducial landmark on an IOUSFAN (Kyoto Kagaku Co., Ltd., Japan) soft tissue abdominal phantom and T2 magnetic resonance scans of it. The experiments show that the accuracy of the Single Landmark registration is good close to the registered point, increasing with the distance from this point (12.4 mm error at 60 mm away from the registered point). In this point, the registration accuracy is mainly dominated by the accuracy of the user when clicking on the ultrasound image. In the presented set-up, the time required to perform the Single Landmark registration is 40% less than for the FLRM. The Single Landmark registration is suitable for being integrated in a laparoscopic workflow. The statistical analysis shows robustness against translational displacements of the patient and improvements in terms of time. The proposed method allows the clinician to accurately register lesions intraoperatively by clicking on these in the ultrasound image provided by the ultrasound transducer. The Single Landmark registration method can be further combined with other more accurate registration approaches improving the registration at relevant points defined by the clinicians.


Expertise in law, medicine, and health care.
As the practice of science-based medical evidence has challenged the medical profession to consider the scientific bases for its methods and procedures, on a seemingly parallel path, the United States Supreme Court's 1993 decision in Daubert v. Merrell Dow Pharmaceuticals has challenged the legal system to consider the science underlying claims of medical expertise. This article examines how the legal system has responded to that challenge and why the response has been more limited than many had expected; the implications of the legal system's approach to scrutiny of claims of medical expertise for the practice of science-based medical evidence; and, the central elements of any meaningful change in legal assessments of expertise in medicine and health care.


Verbal learning strategy following mild traumatic brain injury.
That learning and memory deficits persist many years following mild traumatic brain injury (mTBI) is controversial due to inconsistent objective evidence supporting subjective complaints. Our prior work demonstrated significant reductions in performance on the initial trial of a verbal learning task and overall slower rate of learning in well-motivated mTBI participants relative to demographically matched controls. In our previous work, we speculated that differences in strategy use could explain the differences in rate of learning. The current study serves to test this hypothesis by examining strategy use on the California Verbal Learning Test-Second Edition. Our present findings support the primary hypothesis that mTBI participants under-utilize semantic clustering strategies during list-learning relative to control participants. Despite achieving comparable total learning scores, we posit that the persisting learning and memory difficulties reported by some mTBI patients may be related to reduced usage of efficient internally driven strategies that facilitate learning. Given that strategy training has demonstrated improvements in learning and memory in educational and occupational settings, we offer that these findings have translational value in offering an additional approach in remediation of learning and memory complaints reported by some following mTBI.


Antimicrobial food packaging based on sustainable Bio-based materials for reducing foodborne Pathogens: A review.
Improvements in the effectiveness of packaging materials can help to prevent foodborne pathogens and reduce environmental waste. Traditionally, food is packaged in plastic that is rarely recyclable, negatively impacting the environment. Biodegradable packaging materials play an important role in maintaining the health of ecosystems. However, there are limitations in the utilization of bio-based materials, including poor barrier and mechanical properties which frequently cause a shorter shelf life compared to conventional food packaging materials. The incorporation of different nanomaterial in bio-based polymers such as (Chitosan, potato starch, carboxymethyl cellulose (CMC), corn starch and Arabic gum) can improve the various properties packaging materials by enhancing the antimicrobial activity, therefore preventing foodborne pathogens, correspondingly bringing notable enhancement in the bio-based materials properties as food packaging materials. This review deliberates the potential of using bionanocomposite films to solve the issues of both environmental waste and to reduce the spoilage of food products.


Hand-held dynamometry in patients with haematological malignancies: measurement error in the clinical assessment of knee extension strength.
Hand-held dynamometry is a portable and inexpensive method to quantify muscle strength. To determine if muscle strength has changed, an examiner must know what part of the difference between a patient's pre-treatment and post-treatment measurements is attributable to real change, and what part is due to measurement error. This study aimed to determine the relative and absolute reliability of intra and inter-observer strength measurements with a hand-held dynamometer (HHD). Two observers performed maximum voluntary peak torque measurements (MVPT) for isometric knee extension in 24 patients with haematological malignancies. For each patient, the measurements were carried out on the same day. The main outcome measures were the intraclass correlation coefficient (ICC +/- 95%CI), the standard error of measurement (SEM), the smallest detectable difference (SDD), the relative values as % of the grand mean of the SEM and SDD, and the limits of agreement for the intra- and inter-observer '3 repetition average' and the 'highest value of 3 MVPT' knee extension strength measures. The intra-observer ICCs were 0.94 for the average of 3 MVPT (95%CI: 0.86-0.97) and 0.86 for the highest value of 3 MVPT (95%CI: 0.71-0.94). The ICCs for the inter-observer measurements were 0.89 for the average of 3 MVPT (95%CI: 0.75-0.95) and 0.77 for the highest value of 3 MVPT (95%CI: 0.54-0.90). The SEMs for the intra-observer measurements were 6.22 Nm (3.98% of the grand mean (GM) and 9.83 Nm (5.88% of GM). For the inter-observer measurements, the SEMs were 9.65 Nm (6.65% of GM) and 11.41 Nm (6.73% of GM). The SDDs for the generated parameters varied from 17.23 Nm (11.04% of GM) to 27.26 Nm (17.09% of GM) for intra-observer measurements, and 26.76 Nm (16.77% of GM) to 31.62 Nm (18.66% of GM) for inter-observer measurements, with similar results for the limits of agreement. The results indicate that there is acceptable relative reliability for evaluating knee strength with a HHD, while the measurement error observed was modest. The HHD may be useful in detecting changes in knee extension strength at the individual patient level.


Expression of extracellular calcium-sensing receptor in human osteoblastic MG-63 cell line.
We have previously shown the expression of the extracellular calcium (Ca2+o)-sensing receptor (CaR) in osteoblast-like cell lines, and others have documented its expression in sections of murine, bovine, and rat bone. The existence of the CaR in osteoblasts remains controversial, however, since some studies have failed to document its expression in the same osteoblast-like cell lines. The goals of the present study were twofold. 1) We sought to determine whether the CaR is expressed in the human osteoblast-like cell line, MG-63, which has recently been reported by others not to express this receptor. 2) We investigated whether the CaR, if present in MG-63 cells, is functionally active, since most previous studies have not proven the role of the CaR in mediating known actions of Ca2+o on osteoblast-like cells. We used immunocytochemistry and Western blotting with the specific, affinity-purified anti-CaR antiserum 4637 as well as Northern blot analysis and RT-PCR using a riboprobe and PCR primers specific for the human CaR, respectively, to show readily detectable CaR protein and mRNA expression in MG-63 cells. Finally, we employed the patch-clamp technique to show that an elevation in Ca2+o as well as the specific, allosteric CaR activator NPS R-467 (0.5 microM), but not its less active stereoisomer NPS S-467 (0.5 microM), activate an outward K+ channel in MG-63 cells, strongly suggesting that the CaR in MG-63 cells is not only expressed but is functionally active.


A visual guide to expected blood levels of long-acting injectable risperidone in clinical practice.
Risperidone is the only second-generation (atypical) antipsychotic medication available in a long-acting injectable formulation. The mechanism of drug delivery and the pharmacokinetics of this medication are distinctively different from the first-generation injectable depot medications. Antipsychotic blood levels have been reported in carefully managed single-dose and multiple-dose studies of long-acting risperidone. However, there have been no studies of blood levels produced by the variability in doses and schedules that may occur in clinical practice. Mathematical modeling allows for estimation of blood levels in a variety of clinical scenarios that have yet to be studied empirically. This paper presents mathematically modeled representations of antipsychotic blood levels in clinical situations with long-acting risperidone, with the goal of helping professionals, patients, and family members make informed decisions regarding treatment. A model of single-dose pharmacokinetics was derived from a published, empirical single-dose study. The model was used to prepare graphs of expected multiple-dose schedules consistent with clinical situations, using empirically validated assumptions. The model was validated by comparison of the results of multiple-dose modeling with published empirical multi-dose data. Graphs of expected blood levels in several clinical situations are presented. Future empirical studies are required to fully validate these results. Mathematical models of antipsychotic blood levels in various common situations allow a better appreciation of the novel pharmacokinetics of long-acting injectable risperidone, which may lead to more informed decision-making.


Differential effects of low and high-dose estradiol on airway reactivity in ovariectomized rats.
The aim of this animal study was to test the hypothesis that low and high doses of 17beta-estradiol (E2) may differentially influence airway responsiveness. Ovariectomized female rats received either placebo or E2 (10 or 100 microg/kg per day) for 21 days. The concentration of inhaled acetylcholine (ACh) required to double pulmonary resistance (EC200 RL) was calculated as the in vivo index of airway responsiveness. Ex vivo airway responsiveness was evaluated by the cumulative concentration-response curve (CCRC) of isolated tracheal segments. Rats treated with low-dose E2 were less responsive to ACh than rats given either placebo or high-dose E2 (P=0.003). Ex vivo, low-dose E2 treatment decreased (P=0.01) and high-dose E2 increased the potency of ACh (P<0.001) compared to placebo. E2 treatment did not alter smooth muscle cross-sectional area or epithelium thickness. Accumulation of liquid within the tracheal mucosa was moderately enhanced by high-dose E2 treatment compared with animals given either placebo or low-dose E2 (P=0.03). We conclude that E2 treatment has differential, dose-dependent effects on airway responsiveness to acetylcholine.


Cost Effectiveness of Stapled Haemorrhoidopexy and Traditional Excisional Surgery for the Treatment of Haemorrhoidal Disease.
Our objective was to compare the cost effectiveness of stapled haemorrhoidopexy (SH) and traditional haemorrhoidectomy (TH) in the treatment of grade II-IV haemorrhoidal disease from the perspective of the UK national health service. An economic evaluation was conducted alongside an open, two-arm, parallel-group, pragmatic, multicentre, randomised controlled trial conducted in several hospitals in the UK. Patients were randomised into either SH or TH surgery between January 2011 and August 2014 and were followed up for 24 months. Intervention and subsequent resource use data were collected using case review forms and questionnaires. Benefits were collected using the EQ-5D-3L (EuroQoL-five dimensions-three levels) instrument. The primary economic outcome was incremental cost measured in pounds (£), year 2016 values, relative to the incremental benefit, which was estimated using quality-adjusted life-years (QALYs). Cost and benefits accrued in the second year were discounted at 3.5%. The base-case analysis was based on imputed data. Uncertainty was explored using univariate sensitivity analyses. Participants (n = 777) were randomised to SH (n = 389) or TH (n = 388). The mean cost of SH was £337 (95% confidence interval [CI] 251-423) higher than that of TH and the mean QALYs were -0.070 (95% CI -0.127 to -0.011) lower than for TH. The base-case cost-utility analysis indicated that SH has zero probability of being cost effective at both the £20,000 and the £30,000 threshold. Results from the sensitivity analyses were similar to those from the base-case analysis. The evidence suggests that, on average, the total mean costs over the 24-month follow-up period were significantly higher for the SH arm than for the TH arm. The QALYs were also, on average, significantly lower for the SH arm. These results were supported by the sensitivity analyses. Therefore, in terms of cost effectiveness, TH is a superior surgical treatment for the management of grade II-IV haemorrhoids when compared with SH.


Gaussian process functional regression modeling for batch data.
A Gaussian process functional regression model is proposed for the analysis of batch data. Covariance structure and mean structure are considered simultaneously, with the covariance structure modeled by a Gaussian process regression model and the mean structure modeled by a functional regression model. The model allows the inclusion of covariates in both the covariance structure and the mean structure. It models the nonlinear relationship between a functional output variable and a set of functional and nonfunctional covariates. Several applications and simulation studies are reported and show that the method provides very good results for curve fitting and prediction.


Gastric function and histology in chronic renal failure.
Gastric function and histology were investigated in 24 patients with untreated chronic renal failure. At endoscopy nine patients had oesophagitis, 12 patients were considered to have gastritis, and the duodenum appeared inflamed in 20 patients. Endoscopic biopsies were taken at standard sites in the stomach and duodenum; gastritis was found in all patients, and 17 patients had duodenitis. Stimulated acid secretion was impaired in seven out of 20 patients and acid hypersecretion was found in a further two patients. Pepsin output correlated well with acid output in these patients. Fasting serum gastrin levels were elevated in 12 of the 19 patients tested. Patients with atrophic gastritis had low acid outputs and hypergastrinaemia, and when extensive gastritis was present, the patients tended to have more severe renal failure and hyposecretion of acid. Three patients were studied again after regular haemodialysis or renal transplantation and were found to show marked endoscopic and histological improvement.


Longitudinal evidence on punctal plug use in an elderly population.
The purpose of this study was to determine whether changes in Medicare reimbursement for punctal plug insertion were associated with a decrease in the incidence of insertion and dry eye diagnosis. Incident cases of dry eye syndrome (DES) diagnoses and punctal plug insertions among Medicare beneficiaries were identified from Medicare 5% Part B from 1994 to 2008, using a 3-year look-back. Dry eye syndrome diagnoses and punctal plug insertion codes were ascertained from the international classification of diseases and current procedural terminology codes. Medicare payment data were obtained from the Centers for Medicare and Medicaid Services from 1994 to 2008 for punctal plug insertion. Rates were calculated for both the incidence of DES and the use of punctal plugs. From 2001 to 2008, inflation-adjusted Medicare reimbursement for punctal plug insertion decreased 55.1%, whereas the Medicare population-adjusted incidence of dry eye diagnosis increased 23.3%. Nine percent of individuals diagnosed with DES between 1991 and 2008 underwent punctal plug placement with a mean of 2.0 plugs placed per patient. Total punctal plug placement increased 322.2% between 1994 and 2003, and then reached a plateau. First-time punctal plug insertion rates within 365 days of DES diagnosis increased 111.8% from 1994 to 2002, and then declined 47.0% from 2002 to 2008. Although the frequency of DES diagnosis in the Medicare population has increased over time, first-time punctal plug insertion rates, especially within the first year following DES diagnosis, have declined coincidently with the increasing presence of a medical alternative and declining Medicare payment. Choice of therapies may have cost and care implications.


Calcium and Magnesium Use for Oxaliplatin-Induced Neuropathy: A Case Study to Assess How Quickly Evidence Translates Into Practice.
Substantial research efforts have focused on methods of treating and preventing oxaliplatin-associated neuropathy, the dose-limiting toxicity associated with this drug. Administration of intravenous calcium and magnesium (CaMg) before and after oxaliplatin has been the most studied approach to preventing oxaliplatin-induced neuropathy. Although early reports demonstrated potential benefit, subsequent larger trials failed to confirm the efficacy of CaMg in preventing this adverse effect. This article explores how accumulating evidence for and against the use of CaMg for preventing oxaliplatin-induced neuropathy has impacted clinical practice.


FACT complex is required for DNA demethylation at heterochromatin during reproduction in Arabidopsis.
The DEMETER (DME) DNA glycosylase catalyzes genome-wide DNA demethylation and is required for endosperm genomic imprinting and embryo viability. Targets of DME-mediated DNA demethylation reside in small, euchromatic, AT-rich transposons and at the boundaries of large transposons, but how DME interacts with these diverse chromatin states is unknown. The STRUCTURE SPECIFIC RECOGNITION PROTEIN 1 (SSRP1) subunit of the chromatin remodeler FACT (facilitates chromatin transactions), was previously shown to be involved in the DME-dependent regulation of genomic imprinting in Arabidopsis endosperm. Therefore, to investigate the interaction between DME and chromatin, we focused on the activity of the two FACT subunits, SSRP1 and SUPPRESSOR of TY16 (SPT16), during reproduction in Arabidopsis We found that FACT colocalizes with nuclear DME in vivo, and that DME has two classes of target sites, the first being euchromatic and accessible to DME, but the second, representing over half of DME targets, requiring the action of FACT for DME-mediated DNA demethylation genome-wide. Our results show that the FACT-dependent DME targets are GC-rich heterochromatin domains with high nucleosome occupancy enriched with H3K9me2 and H3K27me1. Further, we demonstrate that heterochromatin-associated linker histone H1 specifically mediates the requirement for FACT at a subset of DME-target loci. Overall, our results demonstrate that FACT is required for DME targeting by facilitating its access to heterochromatin.


A systematic review of health economic evaluations of proton beam therapy for adult cancer: Appraising methodology and quality.
With high treatment costs and limited capacity, decisions on which adult patients to treat with proton beam therapy (PBT) must be based on the relative value compared to the current standard of care. Cost-utility analyses (CUAs) are the gold-standard method for doing this. We aimed to appraise the methodology and quality of CUAs in this area. We performed a systematic review of the literature to identify CUA studies of PBT in adult disease using MEDLINE, EMBASE, EconLIT, NHS Economic Evaluation Database (NHS EED), Web of Science, and the Tufts Medical Center Cost-Effectiveness Analysis Registry from 1st January 2010 up to 6th June 2018. General characteristics, information relating to modelling approaches, and methodological quality were extracted and synthesized narratively. Seven PBT CUA studies in adult disease were identified. Without randomised controlled trials to inform the comparative effectiveness of PBT, studies used either results from one-armed studies, or dose-response models derived from radiobiological and epidemiological studies of PBT. Costing methods varied widely. The assessment of model quality highlighted a lack of transparency in the identification of model parameters, and absence of external validation of model outcomes. Furthermore, appropriate assessment of uncertainty was often deficient. In order to foster credibility, future CUA studies must be more systematic in their approach to evidence synthesis and expansive in their consideration of uncertainties in light of the lack of clinical evidence.


Bis(hy-droxy-ammonium) hexa-chlorido-platinate(IV)-18-crown-6 (1/2).
In the title complex, (NH3OH)2[PtCl6]·2C12H24O6, the Pt(IV) atom is coordinated by six chloride anions in a slightly distorted octa-hedral geometry. The Pt-Cl bond lengths are comparable to those reported for other hexa-chlorido-platinate(IV) species. The hy-droxy-ammonium groups act as linkers between the [PtCl6](2-) anion and the crown ether mol-ecules. The anion is linked to two hy-droxy-ammonium cations via O-H⋯Cl hydrogen bonds and each hy-droxy-ammonium moiety is linked to a crown ether mol-ecule by hydrogen bonds between ammonium H atoms and 18-crown-6 O atoms. The crown ether mol-ecules have the classic crown shape in which all O atoms are located in the inner part of the crown ether ring and all -CH2- groups are turned to the outside.


Tunable frequency combs based on dual microring resonators.
In order to achieve efficient parametric frequency comb generation in microresonators, external control of coupling between the cavity and the bus waveguide is necessary. However, for passive monolithically integrated structures, the coupling gap is fixed and cannot be externally controlled, making tuning the coupling inherently challenging. We design a dual-cavity coupled microresonator structure in which tuning one ring resonance frequency induces a change in the overall cavity coupling condition. We demonstrate wide extinction tunability with high efficiency by engineering the ring coupling conditions. Additionally, we note a distinct dispersion tunability resulting from coupling two cavities of slightly different path lengths, and present a new method of modal dispersion engineering. Our fabricated devices consist of two coupled high quality factor silicon nitride microresonators, where the extinction ratio of the resonances can be controlled using integrated microheaters. Using this extinction tunability, we optimize comb generation efficiency as well as provide tunability for avoiding higher-order mode-crossings, known for degrading comb generation. The device is able to provide a 110-fold improvement in the comb generation efficiency. Finally, we demonstrate open eye diagrams using low-noise phase-locked comb lines as a wavelength-division multiplexing channel.


Risk of hemorrhage from de novo cerebral aneurysms.
A small percentage of patients will develop a completely new or de novo aneurysm after discovery of an initial aneurysm. The natural history of these lesions is unknown. The authors undertook this statistical evaluation a large cohort of patients with both ruptured and unruptured de novo aneurysms with the aim of analyzing risk factors for rupture and estimating a risk of subarachnoid hemorrhage (SAH). A review of a prospectively maintained database of all aneurysm patients treated by the vascular neurosurgery service of Goodman Campbell Brain and Spine from 1976-2010 was performed. Of the 4718 patients, 611 (13%) had long-term follow-up imaging. The authors identified 27 patients (4.4%) with a total of 32 unruptured de novo aneurysms from routine surveillance imaging. They identified another 10 patients who presented with a new SAH from a de novo aneurysm after treatment of their original aneurysm. The total study group was thus 37 patients with a total of 42 de novo aneurysms. The authors then compared the 27 patients with incidentally discovered aneurysms with the 10 patients with SAH. A statistical analysis was performed, comparing the 2 groups with respect to patient and aneurysm characteristics and risk factors. Thirty-seven patients were identified as having true de novo aneurysms. This group had a female predominance and a high percentage of smokers. These 37 patients had a total of 42 de novo aneurysms. Ten of these 42 aneurysms hemorrhaged. De novo aneurysms in both the SAH and non-SAH group were anatomically small (< 10 mm). The estimated risk of hemorrhage over 5 years was 14.5%, higher than the expected SAH risk of small, unruptured aneurysms reported in the ISUIA (International Study of Unruptured Intracranial Aneurysms) trial. There was no statistically significant correlation between hemorrhage and any of the following risk factors: hypertension, diabetes, tobacco and alcohol use, polycystic kidney disease, or previous SAH. There was a statistically significant between-groups difference with respect to patient age, with the mean patient age being significantly older in the SAH aneurysm group than in the non-SAH group (p = 0.047). This is likely reflective of longer follow-up and discovery time, as the mean length of time between initial treatment and discovery of the de novo aneurysm was longer in the SAH group (p = 0.011). While rare, de novo aneurysms may have a risk for SAH that is comparatively higher than the risk associated with similarly sized, small, initially discovered unruptured saccular aneurysms. The authors therefore recommend long-term follow-up for all patients with aneurysms, and they consider a more aggressive treatment strategy for de novo aneurysms than for incidentally discovered initial aneurysms.


Glucagon: role in the hyperglycemia of diabetes mellitus.
Glucagon suppression by somatostatin reduces or abolishes hyperglycemia in dogs made insulin-deficient by somatostatin, alloxan, or total pancreatectomy. This suggests that the development of severe diabetic hyperglycemia requires the presence of glucagon, whether secreted by pancreatic or newly identified gastrointestinal A cells, as well as a lack of insulin. Glucagon suppression could improve therapeutic glucoregulation in diabetes.


Etirinotecan pegol: development of a novel conjugated topoisomerase I inhibitor.
Irinotecan is a very active chemotherapeutic agent used for the treatment of several malignancies, including colorectal cancer, gastroesophageal tumors, lung cancer, breast cancer, ovarian cancer, and primary brain tumors. Irinotecan exerts its antineoplastic effects through its active metabolite 7-ethyl-10-hydroxycamptothecin. This metabolite is also responsible for the classic side effects associated with irinotecan that include diarrhea and neutropenia. A pegylated form of this agent, etirinotecan pegol, is undergoing clinical development with the main goal of increasing its therapeutic efficacy and its safety. This agent decreases the maximal exposure to 7-ethyl-10-hydroxycamptothecin while providing continuous exposure to the treated tumor. The half-life of etirinotecan pegol is 50 days and it has been studied in different schedules: weekly, every other week, and once every 3 weeks. The maximum tolerated dose of etirinotecan pegol was found to be 145 mg/m(2). There have already been two phase II clinical trials published showing the efficacy of this novel agent in the treatment of metastatic ovarian and breast cancer. The side effect profile was acceptable for most patients, with a number of patients experiencing diarrhea and even neutropenia.


High-resolution genome-wide scan of genes, gene-networks and cellular systems impacting the yeast ionome.
To balance the demand for uptake of essential elements with their potential toxicity living cells have complex regulatory mechanisms. Here, we describe a genome-wide screen to identify genes that impact the elemental composition ('ionome') of yeast Saccharomyces cerevisiae. Using inductively coupled plasma - mass spectrometry (ICP-MS) we quantify Ca, Cd, Co, Cu, Fe, K, Mg, Mn, Mo, Na, Ni, P, S and Zn in 11890 mutant strains, including 4940 haploid and 1127 diploid deletion strains, and 5798 over expression strains. We identified 1065 strains with an altered ionome, including 584 haploid and 35 diploid deletion strains, and 446 over expression strains. Disruption of protein metabolism or trafficking has the highest likelihood of causing large ionomic changes, with gene dosage also being important. Gene over expression produced more extreme ionomic changes, but over expression and loss of function phenotypes are generally not related. Ionomic clustering revealed the existence of only a small number of possible ionomic profiles suggesting fitness tradeoffs that constrain the ionome. Clustering also identified important roles for the mitochondria, vacuole and ESCRT pathway in regulation of the ionome. Network analysis identified hub genes such as PMR1 in Mn homeostasis, novel members of ionomic networks such as SMF3 in vacuolar retrieval of Mn, and cross-talk between the mitochondria and the vacuole. All yeast ionomic data can be searched and downloaded at http://www.ionomicshub.org. Here, we demonstrate the power of high-throughput ICP-MS analysis to functionally dissect the ionome on a genome-wide scale. The information this reveals has the potential to benefit both human health and agriculture.


Alpha-amylase inhibitory activity and phytochemical study of Zhumeria majdae Rech. f. and Wendelbo.
Zhumeria majdae (Lamiaceae) is an endemic species growing in the South parts of Iran especially Hormozgan province. The plant is so-called Mohrekhosh locally and widely used for medicinal purposes including stomachache and dysmenorrhea. In order to separation and identification of the main flavonoid glycosides of the plant (aerial parts including leaves, stems, flowers, and fruits were used) and evaluation of its alpha-amylase inhibitory (AAI) activity, methanolic extract was prepared and fractionated to botanolic portion. Isolation of the main compounds of the butanol extract of the plant have been performed using different column chromatography methods such as high-performance liquid chromatography (C18 column) and Sephadex LH-20 as well. The isolated compounds were identified by Hydrogen-1 nuclear magnetic resonance and Carbon-13 nuclear magnetic resonance spectra and comparison with those reported in previous literature. Moreover, inhibitory activity of the butanolic extract of the plant against alpha-amylase enzyme was examined in different concentrations (15-30 mg/mL), where acarbose used as a positive control. Three flavonoid glycosides: Linarin (1), hispidulin-7-O-(4-O-acetyl-rutinoside) (2), hispidulin-7-O-rutinoside (3) were successfully identified in the extract. The activity of alpha amylase enzyme was dose-dependently suppressed by the butanol extract. The extract exhibited the highest inhibition at 30 mg/mL toward enzyme (77.9 ± 2.1%), while acarbose inhibited the enzyme at 20 mg/mL by 73.9 ± 1.9%. The inhibitory concentrations of 50% for the extract and acarbose were calculated at 24.5 ± 2.1 and 6.6 ± 3.1 mg/mL, respectively. Z. majdae contains glycosylated flavones and could be a good candidate for anti-diabetic evaluations in animal and clinical trials due to possessing AAI activity.


Tunable range enhancement of Brillouin-erbium fiber laser utilizing Brillouin pump pre-amplification technique.
We demonstrate an enhanced multiwavelength L-band Brillouin-erbium fiber laser (BEFL), in which the Brillouin pump is pre-amplified before entering the single-mode fiber. The Brillouin pump pre-amplification provided by the Erbium-doped fiber has created higher intensity of Brillouin Stokes line generated in the single-mode fiber that leads to the homogenous gain saturation. Thus the built-up of self-lasing cavity modes is suppressed in a wider wavelength range. In contrary to the conventional linear-cavity BEFL, the number of output channels is enhanced within the same tuning range.


Results from Mozambique's 2014 Report Card on Physical Activity for Children and Youth.
This paper describes the procedures and development of the first Mozambican Report Card on Physical Activity in Children and Adolescents. Comprehensive searches for data related to indicators of physical activity (PA) were completed by a committee of physical activity and sports specialists. Grades were assigned to each indicator consistent with the process and methodology outlined by the Active Healthy Kids Canada Report Card model. Seven indicators of PA were graded. The following grades were assigned: Overall Physical Activity Levels, B; Organized Sport Participation, F; Active Play, C; Active Transportation, B; Schools, C; Community and the Built Environment, F; and Government, C. Sedentary Behaviors and Family and Peers were not graded due to the lack of available information. PA behaviors of children and young people of Mozambique are positively influenced by the rural environment and are largely related to subsistence activities and outdoor play, and absence of motorized transport. In turn, urban areas are declining in active habits and opportunities due largely to rapid urbanization and lack of planning that favors active transport and play.


A spontaneous mutation affects programmed cell death during development of the rat eye.
We have discovered a spontaneous mutation in the Sprague-Dawley rat with a novel eye phenotype that we have named Nuc1. The Nuc1 mutation behaves as a single semi-dominant locus with an intermediate phenotype in the heterozygotes. Heterozygotes exhibit nuclear cataracts. Homozygous Nuc1 rats are fully viable and have microphthalmia, retinal abnormalities and disruption of lens structure shortly before birth. The homozygous mutant shows no obvious pathology outside of the eye, indicating that the mutation is highly eye specific in its effects. An unusual feature of the mutation is that it prevents the normal programmed loss of nuclei from lens fiber cells, but does not affect the loss of other organelles. TUNEL, light, and electron microscopic studies show normal intact nuclei in lens fibers, in contrast to many other models with degenerate nuclei and unlike normal lenses where no such nuclei remain. The beaded filament protein, filensin, is down-regulated in fibers of Nuc1, while heat shock cognate 70 is up-regulated. Homozygous retinas are thicker than normal, and TUNEL labeling indicates roughly half the number of apoptotic cells compared to a wild-type retina. The transient layer of Chievitz persists in adult Nuc1 retina, indicative of delayed development. Hence, Nuc1 is a novel mutation that could be an eye-specific regulator of apoptosis.


Toxicological Investigation of Soils with the Solid-phase Flash Assay: Comparison with Other Ecotoxicological Tests.
A new direct-contact toxicity test, the solid-phase flash assay, which utilises photobacteria in direct contact with soil particles during the exposure, was evaluated on four soil samples. Samples HTNT1 and HTNT2 originated from former military sites in Germany, and were highly contaminated with nitroaromatics (approximately 20g/kg), lead and polycyclic aromatic hydrocarbons. Samples LMKW1 and LMKW2, from bioremediation stacks in Germany, were mainly contaminated with mineral oils. The solid-phase flash assay was applied to soil-water slurries, and the results were compared with the toxicity data for soil-water extracts obtained by using various conventional ecotoxicological tests, in which photobacteria, crustaceans, protozoa and algae were used as test organisms. The LMKW1 and LMKW2 samples were not toxic (EC20 > 12.5%) according to all the tests applied, except for the Photobacterium phosphoreum conventional luminescence-inhibition test for LMKW1 (15-minute EC20 = 5.4%(. The HTNT1 and HTNT2 samples were toxic according to all the tests applied, with the majority of EC20 values being lower than 1%. The solid-phase flash assay (1 minute of extraction and 30 seconds of exposure time) gave comparable results to the conventional tests. Therefore, this flash assay could be applied as a fast screening test in parallel with conventional toxicity tests that use soil 24-hour extracts. The flash assay results will be ready by the start of the conventional assays, and could serve as range-finders for these slower and more expensive tests.


Pharmacology of Thiopurine Therapy in Inflammatory Bowel Disease and Complete Blood Cell Count Outcomes: A 5-Year Database Study.
Thiopurines are the prerequisite for immunomodulation in inflammatory bowel disease (IBD) therapy. When administered in high (oncological) dose, thiopurine metabolites act as purine antagonists, causing DNA-strand breakage and myelotoxicity. In lower IBD dosages, the mode of action is primarily restricted to anti-inflammatory effects. Then, myelosuppression and hepatotoxicity are the most common adverse events of thiopurines. The aim of this study was to assess the effect of thiopurine metabolites on hematologic and hepatic parameters and to determine which patient characteristics are related to generation of thiopurine metabolites. The authors scrutinized the therapeutic drug monitoring database of the VU University medical center and subsequently merged this database with the Clinical Laboratory database of our hospital covering the same time period (2010-2015). The authors included 940 laboratory findings of 424 unique patients in this study. Concentrations of 6-thioguanine nucleotides (6-TGN) correlated negatively with red blood cell count, white blood cell count, and neutrophil count in both azathioprine (AZA) and mercaptopurine users. There was a positive correlation with mean corpuscular volume. In patients using 6-thioguanine, 6-TGN concentrations correlated positively with white blood cell count. Furthermore, there was an inverse correlation between patient's age and 6-TGN concentrations in patients using AZA or 6-thioguanine, and we observed an inverse correlation between body mass index and 6-TGN concentrations in patients using AZA or mercaptopurine. No relations were observed with liver test abnormalities. Thiopurine derivative therapy influenced bone marrow production and the size of red blood cells. Age and body mass index were important pharmacokinetic factors in the generation of 6-TGN.


Associations between respiratory symptoms, bronchial response to methacholine, and atopy in two age groups of schoolchildren.
Data on respiratory symptoms were obtained on 2503 schoolchildren aged 7 and 11 in Southampton by means of a self administered parental questionnaire. Children were classified into seven symptom groups from which 330 were tested for bronchial responsiveness to less than or equal to 6.4 mumol methacholine and skin tested for the presence of atopy. The symptoms of wheeze, cough, and shortness of breath were all significantly associated both with each other and bronchial responsiveness to methacholine but only wheeze was associated with atopy. The association of wheeze with both bronchial responsiveness to methacholine and atopy remained highly significant when controlling for the symptoms of cough and shortness of breath. Neither cough nor shortness of breath, however, were significantly related to bronchial responsiveness to methacholine when controlling for the symptom of wheeze. This study therefore calls into question the epidemiological relevance of these two symptoms as diagnostic features of asthma, particularly in the absence of wheeze, although they may be useful indicators of morbidity. Wheeze was not related to bronchial responsiveness to methacholine in the absence of atopy or to atopy in the absence of bronchial responsiveness to methacholine but was strongly related to the combination of the two phenomena. The presence of these three characteristics could therefore indicate a discrete disease entity. The decrease in the prevalence of cough between 7 and 11 years appeared to be mirrored by a similar decrease in the prevalence of wheeze when the symptom was not associated with the combination of bronchial responsiveness to methacholine and atopy. On the basis of these findings and those of others we suggest that the latter group may represent children with a separate disease entity(ies) or with residual symptoms secondary to acute viral or other infections of the lower respiratory tract.


A radioimmunoassay using a monoclonal antibody to monitor the course of epithelial ovarian cancer.
The murine monoclonal antibody OC 125 reacts with an antigen (CA 125) common to most nonmucinous epithelial ovarian carcinomas. An assay has been developed to detect CA 125 in serum. By this assay, only 1 per cent of 888 apparently healthy persons and 6 per cent of 143 patients with nonmalignant disease had serum CA 125 levels above 35 U per milliliter. In contrast, 83 of 101 patients (82 per cent) with surgically demonstrated ovarian carcinoma had elevated levels of antigen. In 38 patients with epithelial ovarian carcinoma monitored on 2 to 18 occasions during 2 to 60 months, antigen levels ranged from less than 1 to more than 8000 U per milliliter. Rising or falling levels of CA 125 correlated with progression or regression of disease in 42 of 45 instances (93 per cent). Determination of CA 125 levels may aid in monitoring the response to treatment in patients with epithelial ovarian cancer.


[Acoustic thermometry of the patient brain with traumatic brain injury].
Non-invasive deep brain acoustic thermometry is carried out for two patients at Burdenko Neurosurgery Institute. This method is based on the measurements of the own thermal acoustic radiation of the investigated object. These two patients have got the brain injury. Some of their skull bones are absent. Infrared thermometry was also used to measure the surface temperature of the forehead skin. On the basis of the experimental data the temperatures deep within the brain were reconstructed. The values for the two patients are equal to 37.3 0.7 and 37.0 0.3 degrees C.


Prognostic value of MET copy number gain in non-small-cell lung cancer: an updated meta-analysis.
The alterations of MET have been detected in non-small-cell lung cancer (NSCLC). However, the prognostic impact of MET gene copy number gain (CNG) has not been consistent among studies. We performed this meta-analysis to evaluate the prognostic value of high MET CNG in patients with NSCLC. A systematic computerized search of the electronic databases including PubMed, EMBASE, Google scholar, and Cochrane Library (up to November 2017) was carried out. From twenty-one studies, 7,647 patients were included in the pooled analysis of hazard ratios (HRs) with 95% confidence intervals (CIs) for disease-free survival or overall survival. Compared with patients with NSCLC showing low MET CNG, those with tumors harboring high MET CNG showed significantly worse survival (HR = 1.45, 95% CI: 1.16-1.80, p = 0.001). Subgroup analyses showed that high MET CNG significantly correlated with a poor prognosis especially in patients with adenocarcinoma (HR = 1.41, 95% CI: 1.11-1.79, p = 0.005) and Asian populations (HR = 1.58, 95% CI: 1.32-1.88, p < 0.00001). In conclusion, this meta-analysis indicates that high MET CNG is an adverse prognostic factor in patients with NSCLC. Subgroup analyses suggest that high MET CNG is associated with a worse prognosis, especially in patients with adenocarcinoma and Asian populations. However, large prospective studies using standardized methods based on the homogeneous populations are warranted to validate the prognostic value of MET amplification in patients with NSCLC.


Alopecia Areata-Quality of Life Index Questionnaire (Reliability and Validity of the Persian Version) in Comparison to Dermatology Life Quality Index.
Alopecia areata (AA) is an autoimmune disease with an incidence of 2% globally and plays a key role in the quality of life (QOL) of patients with AA. It has been recently shown that there are no sufficient disease-specific questionnaires to assess the QOL in patients with AA. This study tried to evaluate the validity and reliability of the Persian version of AA-Quality of Life Index (AA-QLI) and compare it with the Dermatology Life Quality Index (DLQI) questionnaire. During 1 year, 100 individuals were enrolled in this study and asked to complete the DLQI questionnaire and AA-QLI questionnaire. First of all, we enrolled 25 individuals for evaluating the validity of the Persian version of the questionnaire, and after achieving the proper validity, 75 additional patients were enrolled in this project. The results showed that the test had an appropriate validity (P < 0.001, R = 0.76), reliability (P < 0.001 , internal stability R = 0.89), and (α = 0.91). In this study, we observed that the scores of both questionnaires are quite close. In this regard, in both questionnaires, females had higher scores in comparison to males (P = 0.03), and also both of them correlated with age, age of onset of disease, and skin involvement percentage. The Persian version of the AA-QLI questionnaire is valid and reliable. The QOL of AA patients needs to be considered more seriously. Psychological evaluation of patients is one of the important suggestions in this study.


Keratinocyte migration in the developing eyelid requires LIMK2.
In vitro studies have identified LIMK2 as a key downstream effector of Rho GTPase-induced changes in cytoskeletal organization. LIMK2 is phosphorylated and activated by Rho associated coiled-coil kinases (ROCKs) in response to a variety of growth factors. The biochemical targets of LIMK2 belong to a family of actin binding proteins that are potent modulators of actin assembly and disassembly. Although numerous studies have suggested that LIMK2 regulates cell morphology and motility, evidence supportive of these functions in vivo has remained elusive. In this study, a knockout mouse was created that abolished LIMK2 biochemical activity resulting in a profound inhibition of epithelial sheet migration during eyelid development. In the absence of LIMK2, nascent eyelid keratinocytes differentiate and acquire a pre-migratory phenotype but the leading cells fail to nucleate filamentous actin and remain immobile causing an eyes open at birth (EOB) phenotype. The failed nucleation of actin was associated with significant reductions in phosphorylated cofilin, a major LIMK2 biochemical substrate and potent modulator of actin dynamics. These results demonstrate that LIMK2 activity is required for keratinocyte migration in the developing eyelid.


Manganese-induced parkinsonism in methcathinone abusers: bio-markers of exposure and follow-up.
Methcathinone abuse is a new cause of manganism. The psychostimulant is prepared from pseudoephedrine using potassium permanganate as an oxidant. We describe the clinical, biological, neuroimaging characteristics and follow-up results in a large Estonian cohort of intravenous methcathinone users. During 2006-2012 we studied 38 methcathinone abusers with a mean age of 33 years. Subjects were rated by the Unified Parkinson's Disease Rating Scale (UPDRS), Hoehn and Yahr (HY), and Schwab and England (SE) rating scales. Twenty-four cases were reassessed 9-70 (20 ± 15) months after the initial evaluation. Manganese (Mn) in plasma and hair was analysed by inductively coupled plasma-atom emission spectrometry. Magnetic resonance imaging (MRI) was performed in 11, and single-photon emission computed tomography (SPECT) with iodobenzamide (IBZM) in eight subjects. The average total UPDRS score was 43 ± 21. The most severely affected domains in UPDRS Part III were speech and postural stability, the least affected domain was resting tremor. At follow-up there was worsening of HY and SE rating scales. Subjects had a higher mean level of Mn in hair (2.9 ± 3.8 ppm) than controls (0.82 ± 1.02 ppm), P = 0.02. Plasma Mn concentrations were higher (11.5 ± 6.2 ppb) in active than in former users (5.6 ± 1.8 ppb), P = 0.006. Active methcathinone users had increased MRI T1-signal intensity in the globus pallidus, substantia nigra and periaquaductal gray matter. IBZM-SPECT showed normal symmetric tracer uptake in striatum. Methcathinone abusers develop a distinctive hypokinetic syndrome. Though the biomarkers of Mn exposure are characteristic only of recent abuse, the syndrome is not reversible.


Communication: A reduced scaling J-engine based reformulation of SOS-MP2 using graphics processing units.
We present a low-prefactor, cubically scaling scaled-opposite-spin second-order Møller-Plesset perturbation theory (SOS-MP2) method which is highly suitable for massively parallel architectures like graphics processing units (GPU). The scaling is reduced from O(N⁵) to O(N³) by a reformulation of the MP2-expression in the atomic orbital basis via Laplace transformation and the resolution-of-the-identity (RI) approximation of the integrals in combination with efficient sparse algebra for the 3-center integral transformation. In contrast to previous works that employ GPUs for post Hartree-Fock calculations, we do not simply employ GPU-based linear algebra libraries to accelerate the conventional algorithm. Instead, our reformulation allows to replace the rate-determining contraction step with a modified J-engine algorithm, that has been proven to be highly efficient on GPUs. Thus, our SOS-MP2 scheme enables us to treat large molecular systems in an accurate and efficient manner on a single GPU-server.


Management of intraneural fibro-lipoma of the median nerve and the role of Pressure-Specified Sensory Device (PSSD) for the patient's motor and sensorial evaluations.
The intraneural fibro-lipoma is a benign, uncommon tumor which is characterised with infiltration of the epineurium and perineurium by fibrofatty tissue. The preoperative diagnosis is difficult. However, the Pressure-Specified Sensory Device (PSSD) may support identifying the earliest stages of intraneural fibro-lipoma when traditional electrodiagnostic testing will not be able to detect a change in peripheral nerve function. Five patients (3 male, 2 female, age 23-53; mean 41 years) with intraneural fibro-lipoma were operated on. Grip strength, pinch strength and sensorial functions were assessed in all patients before surgery and at the end of the follow-up period by PSSD. The patients were followed-up for 7 to 24 months (mean; 12 month). All patient's condition improved dramatically following the operation and all patients had total relief of pain and paresthesia. The decompression of intraneural fibro-lipoma of the nerve with limited excision and epineurotomy without sacrificing the main nerve and its branches is the ideal surgical procedure. We recommend the use of PSSD in the investigation of patients with peripheral nerve compression, and chronic unusual volar forearm and wrist swelling. PSSD is an important tool for pre-operative evaluation and diagnosis of intraneural fibro-lipoma.


Physiological basis of interactive responses to temperature and salinity in coastal marine invertebrate: Implications for responses to warming.
Developing physiological mechanistic models to predict species' responses to climate-driven environmental variables remains a key endeavor in ecology. Such approaches are challenging, because they require linking physiological processes with fitness and contraction or expansion in species' distributions. We explore those links for coastal marine species, occurring in regions of freshwater influence (ROFIs) and exposed to changes in temperature and salinity. First, we evaluated the effect of temperature on hemolymph osmolality and on the expression of genes relevant for osmoregulation in larvae of the shore crab Carcinus maenas. We then discuss and develop a hypothetical model linking osmoregulation, fitness, and species expansion/contraction toward or away from ROFIs. In C. maenas, high temperature led to a threefold increase in the capacity to osmoregulate in the first and last larval stages (i.e., those more likely to experience low salinities). This result matched the known pattern of survival for larval stages where the negative effect of low salinity on survival is mitigated at high temperatures (abbreviated as TMLS). Because gene expression levels did not change at low salinity nor at high temperatures, we hypothesize that the increase in osmoregulatory capacity (OC) at high temperature should involve post-translational processes. Further analysis of data suggested that TMLS occurs in C. maenas larvae due to the combination of increased osmoregulation (a physiological mechanism) and a reduced developmental period (a phenological mechanisms) when exposed to high temperatures. Based on information from the literature, we propose a model for C. maenas and other coastal species showing the contribution of osmoregulation and phenological mechanisms toward changes in range distribution under coastal warming. In species where the OC increases with temperature (e.g., C. maenas larvae), osmoregulation should contribute toward expansion if temperature increases; by contrast in those species where osmoregulation is weaker at high temperature, the contribution should be toward range contraction.


Comparison between computed tomography multislice and high-field magnetic resonance in the diagnostic evaluation of patients with renal masses.
Renal masses are a common finding in diagnostic imaging; these lesions usually are solid or cystic, benign or malignant, and the correct diagnosis may be difficult. The aim of our study was the comparison of multi-slice computed tomography (MSCT) and high-field magnetic resonance (MR) in the diagnostic evaluation of renal masses. We studied 29 patients, 16 men and 13 women aged 8-85 years (mean 61±17 years) with histo-cytological diagnosis of renal masses (n=31), of which the majority (74%; n=23) was represented by malignant lesions [renal cell carcinoma (Ca) =16, chromophobe renal cell Ca =2, squamous cell Ca =1, urothelial Ca =2, lymphoma =1, Wilms tumor =1]; the remaining 8 masses (26%) were benign (pyelonephritis =2, simple cyst =1, hematic cyst =1, lipoma =1 and oncocytoma =3). All patients underwent MSCT and MR (3.0 Tesla) before and after contrast injection; the images were evaluated in double-blind by two expert radiologists. The results of the images were then compared with the histo-cytological data to calculate the values of diagnostic accuracy for both methods in the identification and characterization of renal masses. The benign or malignant nature of the lesions was established according to the regularity of the margins, presence or absence of significant contrast enhancement, infiltration of perirenal fat and vascular invasion. The concordance of the results of the two imaging techniques was then calculated using the coefficient Kappa Cohen. For both identification and characterization of renal masses, MSCT and MR showed comparable values of diagnostic accuracy with a significant concordance (k=1); in particular, the diagnostic accuracy of MSCT/MR was 100%/100% for lesion identification, 90%/90% for lesion characterization in terms of benign or malignant nature, 97%/97% for the evaluation of lesion edges, 90%/90% for the assessment of lesion contrast enhancement, 93%/93% for the evaluation of peri-renal fat infiltration and 96%/96% for the evaluation of vascular infiltration. Only in three cases of oncocytoma the two imaging methods were both inaccurate for diagnosis of benignity classifying the lesions as probably malignant on the basis of the absence of central scar and of dynamic contrast enhancement pattern. The results of our study show comparable diagnostic accuracy of computed tomography (CT) and MR for the identification and characterization of expansive renal lesions. High-field MR is, therefore, a valid alternative to MSCT in the evaluation of renal masses avoiding exposure to ionizing radiation.


Are religiousness and death attitudes associated with the wish to die in older people?
A wish to die is common in older persons and is associated with increased mortality. Several risk factors have been identified, but the association between religiousness and a wish to die in older adults has been underexplored, and the association between death attitudes and the presence of a wish to die has not been investigated yet. The aim of this study is to explore the relationship between religiousness and death attitudes on the one hand and wish to die on the other hand, adjusting for clinical factors such as the presence of depression or somatic disorder. The sample comprised 113 older inpatients (from a psychiatric and somatic ward) with a mean age of 74 years. Psychiatric diagnoses were assessed by the Structured Clinical Interview for DSM-IV Disorders, and logistic regression analyses estimated the unique contribution of religiousness and death attitudes to the wish to die, controlling for socio-demographic variables, depressive disorder, and somatic symptoms. Both religiousness and death attitudes were associated with a wish to die in univariate models. Adding these variables in a multivariate logistic hierarchical model, death attitudes remained significant predictors but religiousness did not; 55% of the pseudovariance of the wish to die was explained by these variables, with an effective size of 0.89. Major depressive episode, somatic symptoms, Fear of Death, and Escape Acceptance were the most important predictors of the wish to die. This study suggests that how older adults perceive death partly determines whether they have a wish to die. There may be a clinical, patient-oriented benefit in discussing with older patients about how they perceive death, as this can play a role in the early detection (and prevention) of death or suicide ideation and associated behaviors in older adults.


Sarcocystis in mice inoculated with toxoplasma-like oocysts from cat feces.
Sarcocysts morphologically similar to Sarcocystis muris were observed in mice after inoculation with Toxoplasma-like oocysts found in feces of a stray cat. Cats that were fed mice infected with the oocysts shed similar oocysts in their feces. Sarcocysts were found histologically in about 50 percent of mice inoculated with 40,000 or more oocysts and examined 42 days or longer after exposure. Most inoculated mice developed low Toxoplasma dye-test antibody titers 3 to 4 weeks after exposure, but Toxoplasma antibody was usually not detectable in infected cats.


A Scientific Foundation of Simulation Games for the Analysis and Design of Complex Systems.
Background. The use of simulation games for complex systems analysis and design has been acknowledged about 50 years ago. However, articles do not combine all salient factors for successful simulation games, and often stem from a clear view of one particular field of science only. With combining multiple disciplines, connect analysis and design as well as research and practice, we provide deep insights in design and use of simulation games. Aim. This article analyzes the design and evaluation process of a variety of game-based projects and activities, using existing scientific concepts and approaches, in order to establish games as a valid research tool. Our focus lies on the approach towards the use of games as design instrument; using them as an intervention in a larger, complex context, in order to design this context. With our contribution, we aim at providing insights and recommendations on the design and use of games as valid research tools, the limitations of this use, possible pitfalls, but also best practices. Method. We carried out a literature review of related work to identify the most important scientific concepts related to our approach of game design. Further use of combined quantitative and qualitative case study analyses highlights the design process and results of our own game studies. Results. The analyses yielded a consolidated conceptualization of simulation games as research instruments in complex systems analysis and design. The results also include methods for the evaluation of simulation games, additional evaluation methods, and limitations to use simulation games as research instruments. Conclusions. We propose guidelines for using simulation games as research instruments that may be of value to practitioners and scientists alike. Recommendation. We recommend practitioners and scientists to apply the guidelines presented here in their efforts to analyze and design complex systems.


Context-dependent anticodon recognition by class I lysyl-tRNA synthetases.
Lysyl-tRNA synthesis is catalyzed by two unrelated families of aminoacyl-tRNA synthetases. In most bacteria and all eukarya, the known lysyl-tRNA synthetases (LysRSs) are subclass IIb-type aminoacyl-tRNA synthetases, whereas many archaea and a scattering of bacteria contain an unrelated class I-type LysRS. Examination of the recognition of partially modified tRNA(Lys) anticodon variants by a bacterial (from Borrelia burgdorferi) and an archaeal (from Methanococcus maripaludis) class I lysyl-tRNA synthetase revealed differences in the pattern of anticodon recognition between the two enzymes. U35 and U36 were both important for recognition by the B. burgdorferi enzyme, whereas only U36 played a role in recognition by M. maripaludis LysRS. Examination of the phylogenetic distribution of class I LysRSs suggested a correlation between recognition of U35 and U36 and the presence of asparaginyl-tRNA synthetase (AsnRS), which also recognizes U35 and U36 in the anticodon of tRNA(Asn). However, the class II LysRS of Helicobacter pylori, an organism that lacks AsnRS, also recognizes both U35 and U36, indicating that the presence of AsnRS has solely influenced the phylogenetic distribution of class I LysRSs. These data suggest that competition between unrelated aminoacyl-tRNA synthetases for overlapping anticodon sequences is a determinant of the phylogenetic distribution of extant synthetase families. Such patterns of competition also provide a basis for the two separate horizontal gene transfer events hypothesized in the evolution of the class I lysyl-tRNA synthetases.


Viscosupplementation for knee osteoarthritis: systematic review and meta-analysis.
To evaluate the effectiveness and safety of viscosupplementation for pain and function in patients with knee osteoarthritis. Systematic review and meta-analysis of randomised trials. Searches were conducted of Medline, Embase, and the Cochrane Central Register of Controlled Trials (CENTRAL) databases from inception to 11 September 2021. Unpublished trials were identified from the grey literature and trial registries. Randomised trials comparing viscosupplementation with placebo or no intervention for knee osteoarthritis treatment. The prespecified primary outcome was pain intensity. Secondary outcomes were function and serious adverse events. Pain and function were analysed as standardised mean differences (SMDs). The prespecified minimal clinically important between group difference was -0.37 SMD. Serious adverse events were analysed as relative risks. Two reviewers independently extracted relevant data and assessed the risk of bias of trials using the Cochrane risk of bias tool. The predefined main analysis was based only on large, placebo controlled trials with ≥100 participants per group. Summary results were obtained through a random effects meta-analysis model. Cumulative meta-analysis and trial sequential analysis under a random effects model were also performed. 169 trials provided data on 21 163 randomised participants. Evidence of small study effects and publication biases was observed for pain and function (Egger's tests with P<0.001 and asymmetric funnel plots). Twenty four large, placebo controlled trials (8997 randomised participants) included in the main analysis of pain indicated that viscosupplementation was associated with a small reduction in pain intensity compared with placebo (SMD -0.08, 95% confidence interval -0.15 to -0.02), with the lower bound of the 95% confidence interval excluding the minimal clinically important between group difference. This effect corresponds to a difference in pain scores of -2.0 mm (95% confidence interval -3.8 to -0.5 mm) on a 100 mm visual analogue scale. Trial sequential analysis for pain indicated that since 2009 there has been conclusive evidence of clinical equivalence between viscosupplementation and placebo. Similar conclusions were obtained for function. Based on 15 large, placebo controlled trials on 6462 randomised participants, viscosupplementation was associated with a statistically significant higher risk of serious adverse events than placebo (relative risk 1.49, 95% confidence interval 1.12 to 1.98). Strong conclusive evidence indicates that viscosupplementation leads to a small reduction in knee osteoarthritis pain compared with placebo, but the difference is less than the minimal clinically important between group difference. Strong conclusive evidence indicates that viscosupplementation is also associated with an increased risk of serious adverse events compared with placebo. The findings do not support broad use of viscosupplementation for the treatment of knee osteoarthritis. PROSPERO CRD42021236894.


Genotoxic effects of environmental estrogen-like compounds in CHO-K1 cells.
Some environmental estrogen-like compounds, such as bisphenol A (BPA), 4-nonylphenol (NP), 4-octylphenol (OP), propyl p-hydroxybenzoate (P-PHBA), and butyl p-hydroxybenzoate (B-PHBA), synthetic estrogen, diethylstilbestrol (DES), and natural estrogen, 17beta-estradiol (E2), were studied for their genotoxicity in CHO-K1 cells using sister-chromatid exchange (SCE), chromosome aberration (CA), and DNA strand break (comet) assays. Six of the chemicals, excluding E2, caused DNA migration in the comet assay and induced SCEs at one or more of the highest doses. Among the chemicals, OP produced an especially high incidence of SCEs. Structural CA was induced by five of the chemicals, excluding OP and NP, and BPA, E2, and DES also induced aneuploid cells. E2 and DES particularly increased the rate of polyploidy at high doses. The incidence of colchicine-mitosis-like (c-mitotic) figures suggesting spindle disrupting effects was also detected with five of the chemicals, excluding OP and NP, and six of the chemicals, excluding E2, caused endoreduplication (ERD), a form of nuclear polyploidization induced by block of cell cycle at G2 phase, at one or more high doses. Our present results suggest that OP and NP cause repairable DNA damage, including SCEs, and do not result in CA, while the damage caused by DES, BPA, P-PHBA, and B-PHBA results in the induction of CAs together with SCEs probably because of imperfect repair. We are unable to explain the observation that the DNA damage caused by E2 resulted in CA induction but not DNA migration or SCE induction, except for speculating that the DNA damage is different from that caused by DES and the estrogen-like chemicals. Our findings also suggest that E2, DES and BPA have aneuploidogenic properties, and that the former two of chemicals also are polyploidy-inducing agents.


Adaptive top-down suppression of hippocampal activity and the purging of intrusive memories from consciousness.
When reminded of unwanted memories, people often attempt to suppress these experiences from awareness. Prior work indicates that control processes mediated by the dorsolateral prefrontal cortex (DLPFC) modulate hippocampal activity during such retrieval suppression. It remains unknown whether this modulation plays a role in purging an intrusive memory from consciousness. Here, we combined fMRI and effective connectivity analyses with phenomenological reports to scrutinize a role for adaptive top-down suppression of hippocampal retrieval processes in terminating mnemonic awareness of intrusive memories. Participants either suppressed or recalled memories of pictures depicting faces or places. After each trial, they reported their success at regulating awareness of the memory. DLPFC activation was greatest when unwanted memories intruded into consciousness and needed to be purged, and this increased engagement predicted superior control of intrusive memories over time. However, hippocampal activity was decreased during the suppression of place memories only. Importantly, the inhibitory influence of the DLPFC on the hippocampus was linked to the ensuing reduction in intrusions of the suppressed memories. Individuals who exhibited negative top-down coupling during early suppression attempts experienced fewer involuntary memory intrusions later on. Over repeated suppressions, the DLPFC-hippocampus connectivity grew less negative with the degree that they no longer had to purge unwanted memories from awareness. These findings support a role of DLPFC in countermanding the unfolding recollection of an unwanted memory via the suppression of hippocampal processing, a mechanism that may contribute to adaptation in the aftermath of traumatic experiences.


Inverted duplication deletion of 8P: characterization by standard cytogenetic and SNP array analyses.
Inverted 8p duplication deletions are recurrent chromosomal rearrangements that most often arise through non-allelic homologous recombination (NAHR) during maternal meiosis between segmental duplications made up of the olfactory receptor (OR) gene clusters. The presence of a paracentric inversion polymorphism in 8p23.1, found in approximately 26% of European population, may trigger meiotic misalignment and NAHR between the OR gene repeats. We report clinical, cytogenetic, and molecular findings in a 4 year 8 month-old female with concomitant inverted duplication and terminal deletion of chromosome 8p. The girl, the first child of unrelated parents, was born at term, by normal delivery, after an uneventful pregnancy. Clinical examination revealed dysmorphic features, pectus excavatum, hypertonia, severe developmental delay. Brain ultrasound and MRI showed agenesis of the corpus callosum without other abnormalities. Conventional cytogenetic analysis identified additional material on chromosome 8 at band p21. SNP array analysis further characterized the abnormality as a duplication of about 31.3 Mb, from 8p23.1 to 8p11.1, and additionally revealed a terminal deletion of about 6.8 Mb, from 8p23.3 to 8p23.1. Genomic microarray also identified a region of disomy between deletion and duplication. Chromosome analysis of both parents revealed normal results. Based on clinical examination, conventional cytogenetics and SNP array, we established the diagnosis of inverted duplication deletion of 8p. SNP array analysis precisely defined the breakpoints of rearrangement and, by identifying a region of disomy between the duplication and deletion, indicated that NAHR between segmental duplications was the most likely mechanism for this type of abnormality.


The role of estrogen, immune function and aging in heart transplant outcomes.
Aging and loss of estrogen suppress immune function, potentially improving survival after orthotopic heart transplant (OHT). The effect of female aging on OHT outcomes is unknown. Between 1995 and 2015, 41,299 adult OHT recipients (24.3% women) were studied using a retrospective multi-institutional cohort. Patients were stratified by age and gender into premenopausal (18-39 years), perimenopausal (40-49 years), and postmenopausal (≥50 years) groups. Kaplan-Meier survival analyses and risk-adjusted models examined gender differences across groups at one, five, and ten years. Kaplan-Meier survival was equivalent for postmenopausal women and men, and lower for premenopausal women than men at all time points (p ≤ 0.05). Postmenopausal women had higher risk-adjusted five-year survival than premenopausal women (AOR 1.61, 95% CI 1.15-2.25, p = 0.006). Premenopausal women have lower unadjusted survival than men after OHT. Post-menopausal women have significantly better five-year survival than pre-menopausal women. Menopause may contribute to improved survival after OHT.