Acarbose improved survival for Apc+/Min mice.
Acarbose blocks the digestion of complex carbohydrates, and the NIA Intervention Testing Program (ITP) found that it improved survival when fed to mice. Yet, we do not know if lifespan extension was caused by its effect on metabolism with regard to the soma or cancer suppression. Cancer caused death for ~80% of ITP mice. The ITP found rapamycin, an inhibitor to the pro-growth mTORC1 (mechanistic target of rapamycin complex 1) pathway, improved survival and it suppressed tumors in Apc+/Min mice providing a plausible rationale to ask if acarbose had a similar effect. Apc+/Min is a mouse model prone to intestinal polyposis and a mimic of familial adenomatous polyposis in people. Polyp-associated anemia contributed to their death. To address this knowledge gap, we fed two doses of acarbose to Apc+/Min mice. Acarbose improved median survival at both doses. A cross-sectional analysis was performed next. At both doses, ACA fed mice exhibited reduced intestinal crypt depth, weight loss despite increased food consumption and reduced postprandial blood glucose and plasma insulin, indicative of improved insulin sensitivity. Dose-independent and dose-dependent compensatory liver responses were observed for AMPK and mTORC1 activities, respectively. Only mice fed the high dose diet exhibited reductions in tumor number with higher hematocrits. Because low-dose acarbose improved lifespan but failed to reduced tumors, its effects seem to be independent of cancer. These data implicate the importance of improved carbohydrate metabolism on survival.


Novel Targeted Therapies for Metastatic Melanoma.
Oncogene-targeted therapy is a major component of precision oncology, and although patients with metastatic melanoma have experienced improved outcomes with this strategy, there are a number of potential therapeutic targets currently under study that may further increase the drug armamentarium for this patient population. In this review, we discuss the landscape of targeted therapies for patients with advanced melanoma, focusing on oncogene mutation-specific targets. In patients with typical BRAF V600-mutant melanoma, combination BRAF and MEK inhibition has surpassed outcomes compared with monotherapy with BRAF or MEK inhibition alone, and current strategies seek to address inevitable resistance mechanisms. For patients with NRAS-mutant melanoma, MEK inhibitor monotherapy and combined MEK and CDK4/6 inhibition are burgeoning strategies; for patients with KIT-mutant melanoma, tyrosine kinase inhibition is being leveraged, and for NF-1-mutant melanoma, mTOR and MEK inhibition is being actively evaluated. In patients with atypical, non-V600 BRAF-mutant melanoma, MEK inhibitor monotherapy is the potential novel targeted approach on the horizon. For advanced uveal melanoma, novel targets such as IMCgp100 and glembatumumab have shown activity in early studies. We review additional strategies that remain in the preclinical and early clinical pipeline, so there is much hope for the future of targeted agents for distinct molecular cohorts of patients with advanced melanoma.


Accuracy of an automated knowledge base for identifying drug adverse reactions.
Drug safety researchers seek to know the degree of certainty with which a particular drug is associated with an adverse drug reaction. There are different sources of information used in pharmacovigilance to identify, evaluate, and disseminate medical product safety evidence including spontaneous reports, published peer-reviewed literature, and product labels. Automated data processing and classification using these evidence sources can greatly reduce the manual curation currently required to develop reference sets of positive and negative controls (i.e. drugs that cause adverse drug events and those that do not) to be used in drug safety research. In this paper we explore a method for automatically aggregating disparate sources of information together into a single repository, developing a predictive model to classify drug-adverse event relationships, and applying those predictions to a real world problem of identifying negative controls for statistical method calibration. Our results showed high predictive accuracy for the models combining all available evidence, with an area under the receiver-operator curve of ⩾0.92 when tested on three manually generated lists of drugs and conditions that are known to either have or not have an association with an adverse drug event. Results from a pilot implementation of the method suggests that it is feasible to develop a scalable alternative to the time-and-resource-intensive, manual curation exercise previously applied to develop reference sets of positive and negative controls to be used in drug safety research.


Using Human Factors and Systems Engineering to Evaluate Readmission after Complex Surgery.
Our objective was to use a human factors and systems engineering approach to understand contributors to surgical readmissions from a patient and provider perspective. Previous studies on readmission have neglected the patient perspective. To address this gap and to better inform intervention design, we evaluated how transitions of care relate to and influence readmission from the patient and clinician perspective using the Systems Engineering Initiative for Patient Safety (SEIPS) model. Patients readmitted within 30 days of discharge after complex abdominal surgery were interviewed. A focus group of inpatient clinician providers was conducted. Questions were guided by the SEIPS framework and content was analyzed. Data were collected concurrently from the medical record for a mixed-methods approach. Readmission occurred a median of 8 days (range 1 to 25 days) after discharge. All patients had follow-up scheduled with their surgeon, but readmission occurred before this in 72% of patients. Primary readmission diagnoses included infection, gastrointestinal complications, and dehydration. Patients (n = 18) and clinician providers (n = 6) identified a number of factors during the transition of care that may have contributed to readmission, including poor patient and caregiver understanding; inadequate discharge preparation for home care; insufficient educational process and materials, negatively affected by electronic health record design; and inadequate care team communication. This is the first study to use a human factors and systems engineering approach to evaluate the impact of the quality of the transition of care and its influence on readmission from the patient and clinician perspective. Important targets for future interventions include enhancing the discharge process, improving education materials, and increasing care team coordination, with the overarching theme that improved patient and caregiver understanding and engagement are essential to decrease readmission and postdischarge health care use.


Five years of tree death in a Fagus-Magnolia forest, southeast Texas (USA).
Death of trees (>4.5 cm dbh) and saplings (1.4 m tall-4.5 cm dbh) was monitored over 5 years in a Southern Mixed Hardwood Forest to determine causes of death, death rates, and to assess the nature and direction of forest change. Most trees died standing (77%), presumably the result of pathogen attack or adverse physiological condition; knockdown by other trees (10%) and wind breakage (11%) were other common causes of death. Frequency of wind break and knockdown varied with size, but standing death did not. Most trees (64%) and some saplings (26%) died outright (complete death of the genetic individual); the others had sprouts or living residual parts. For some species, survival of residual parts was high, and so resprouting or persistence may be important in population recruitment. For others, low survival of residual parts means that sprouting does not effectively prolong the life of an individual. Most populations were stable or declining slightly. Shade-intolerant species showed higher death rates in small size classes than did the more tolerant species, so in the absence of disturbance one might expect some change in species composition toward the putative climax dominants.


@neurIST: infrastructure for advanced disease management through integration of heterogeneous data, computing, and complex processing services.
The increasing volume of data describing human disease processes and the growing complexity of understanding, managing, and sharing such data presents a huge challenge for clinicians and medical researchers. This paper presents the @neurIST system, which provides an infrastructure for biomedical research while aiding clinical care, by bringing together heterogeneous data and complex processing and computing services. Although @neurIST targets the investigation and treatment of cerebral aneurysms, the system's architecture is generic enough that it could be adapted to the treatment of other diseases. Innovations in @neurIST include confining the patient data pertaining to aneurysms inside a single environment that offers clinicians the tools to analyze and interpret patient data and make use of knowledge-based guidance in planning their treatment. Medical researchers gain access to a critical mass of aneurysm related data due to the system's ability to federate distributed information sources. A semantically mediated grid infrastructure ensures that both clinicians and researchers are able to seamlessly access and work on data that is distributed across multiple sites in a secure way in addition to providing computing resources on demand for performing computationally intensive simulations for treatment planning and research.


Evaluation of selected sidewalk pavement surfaces for vibration experienced by users of manual and powered wheelchairs.
Obstacles such as bumps, curb descents, and uneven driving surfaces cause vibrations that affect the wheelchair, and in turn, the wheelchair user. Chronic exposure can cause low-back pain, disk degeneration, and other harmful effects. Little research has been conducted to assess the vibrations experienced by wheelchair users. The purpose of this study was to conduct an evaluation of the vibration exposure during electric-powered wheelchair driving and mechanical energy requirements for manual wheelchair propulsion over selected sidewalk surfaces. The goal was to determine the criteria for a wheelchair-pedestrian access route that does not require excessive propulsive work or expose wheelchair users to potentially harmful vibrations. Ten unimpaired individuals participated in this study. Six sidewalk surfaces were tested. Measured variables included power of the acceleration per octave, mechanical work to propel over surfaces, peak acceleration, and frequency at which peak acceleration occurs. For both the manual and electric-powered wheelchair, at 1 m/s, significant differences were found in peak accelerations between the seat and footrest (P < 0.0001) and between the sidewalk surfaces (P = 0.004). The greatest risk for injury caused by shock and vibration exposure occurs at frequencies near the natural frequency of seated humans (4-15 Hz). The values for work required to propel over the surfaces tested were not statistically significantly different. Besides appearance and construction, the only distinguishing characteristic was surface roughness caused by the joints. When treating the poured concrete sidewalk as the standard, surfaces 2, 3, 5, and 6 compared most favorably in terms of vibration exposure, whereas surface 4 produced mixed results. Surfaces 2, 3, 5, and 6 yielded results that were similar to the poured concrete sidewalk and could be considered acceptable for wheelchair users. In conclusion, surfaces other than the traditional poured concrete can be used for pedestrian access routes without adding vibration exposure or reducing propulsion efficiency.


Spontaneous Coronary Artery Dissection in a Young Man.
Spontaneous coronary artery dissection (SCAD) is an idiosyncratic phenomenon by which a spontaneous separation of the intimal and medial layer in the coronary artery occurs with intramural hemorrhage in the absence of trauma. This intramural hematoma, in turn, leads to compression and occlusion of the arterial lumen. Unlike traumatic dissection of coronary arteries, more than half of SCAD heals spontaneously over time. SCAD is known to occur predominantly in women under the age of 50, particularly during pregnancy or peripartum period. Herein, we present a case of a 32-year-old man with an SCAD on the left anterior descending coronary artery. The discordance between clinical presentation and angiographic finding posed a unique challenge in therapeutic decision making. This case reminds clinicians that SCAD should be kept in mind as a differential diagnosis even for young men presenting with acute chest pain.


Effects of Microbubble Size on Ultrasound-Induced Transdermal Delivery of High-Molecular-Weight Drugs.
The transdermal delivery of a wide range of high-molecular-weight drugs is limited by the stratum corneum layer of the epidermis representing a significant barrier to penetration across the skin. This study first determined the different effects of different-size ultrasound (US) contrast agents and microbubbles (MBs) for enhancing the transdermal delivery of high-molecular-weight drugs. The effects of US-mediated different-size (1.4, 2.1, and 3.5 μm) MBs (as a contrast agent) and ascorbyl tetraisopalmitate (VC-IP) on enhancing skin transdermal delivery were demonstrated both in vitro and in vivo. The results indicated that at a power density of 3 W/cm2 the penetration depth in group US combined with 3.5-μm MBs and penetrating VC-IP (U+3.5) was 34% and 14% higher than those in groups US combined with 1.4-μm MBs and penetrating VC-IP (U+1.4) and US combined with 2.1-μm MBs and penetrating VC-IP (U+2.1), respectively, for the agarose phantoms, while the corresponding increases for pigskin were 37% and 19%.In terms of the skin permeation of VC-IP, the VC-IP concentration in group U+3.5 was 23% and 10% higher in than those in groups U+1.4 and U+2.1, respectively. The whitening effect (luminosity index) of mice skin in group U+3.5 had increased (significantly) by 28% after 1 week, by 34% after 2 weeks, and tended to stabilize after 3 weeks (45%) in C57BL/6J mice over a 4-week experimental period. The results obtained in this study indicate that combining US with MBs of different sizes can produce different degrees of skin permeability so as to enhance the delivery of VC-IP to inhibit melanogenesis, without damaging the skin in mice.


Use of laser induced breakdown spectroscopy in the determination of gem provenance: beryls.
The provenance of gem stones has been of interest to geologists, gemologists, archeologists, and historians for centuries. Laser induced breakdown spectroscopy (LIBS) provides a minimally destructive tool for recording the rich chemical signatures of gem beryls (aquamarine, goshenite, heliodor, and morganite). Broadband LIBS spectra of 39 beryl (Be(3)Al(2)Si(6)O(18)) specimens from 11 pegmatite mines in New Hampshire, Connecticut, and Maine (USA) are used to assess the potential of using principal component analysis of LIBS spectra to determine specimen provenance. Using this technique, beryls from the three beryl-bearing zones in the Palermo #1 pegmatite (New Hampshire) can be recognized. However, the compositional variation within this single mine is comparable to that in beryls from all three states. Thus, a very large database with detailed location metadata will be required to routinely determine gem beryl provenance.


Genome Sequence of Kosakonia radicincitans Strain YD4, a Plant Growth-Promoting Rhizobacterium Isolated from Yerba Mate (Ilex paraguariensis St. Hill.).
Kosakonia radicincitans strain YD4 is a rhizospheric isolate from yerba mate (Ilex paraguariensis St. Hill.) with plant growth-promoting effects on this crop. Genes involved in different plant growth-promoting activities are present in this genome, suggesting its potential as a bioinoculant for yerba mate.


Evaluation of the effectiveness of anterior cruciate ligament injury prevention programme training components: a systematic review and meta-analysis.
Anterior cruciate ligament (ACL) injury prevention programmes have shown mixed results, which may be due to differing emphasis on training components. The purpose of this study was to (1) quantify the overall and relative duration of each training component encompassed within these programmes and (2) examine the effect of these durations on ACL injury rates. A systematic review was completed and meta-analyses performed on eligible studies to produce a pooled OR estimate of the effectiveness of these programmes. Meta-regression was used to detect any relationship that programme duration and the duration of individual training components had on ACL injury rates. 13 studies were included for review. Results of the meta-analyses revealed a significant reduction of injuries after preventative training programmes for all ACL injuries (pooled OR estimate of 0.612, 95% CI 0.44 to 0.85; p=0.004) and for non-contact ACL injuries (OR 0.351, 95% CI 0.23 to 0.54; p<0.001). Results of meta-regression analysis revealed that a greater duration of balance training was associated with a higher injury risk for ACL injury (p=0.04), while greater durations of static stretching was associated with a lower injury risk for non-contact ACL injuries (p=0.04). While ACL prevention programmes are successful in reducing the risk of ACL injury, the ideal combination and emphasis of training components within these programmes remains unclear. Evidence indicates that greater emphases on balance training and static stretching may be associated with an increase and decrease in injury risk, respectively.


A regulatory effect of IL-21 on T follicular helper-like cell and B cell in rheumatoid arthritis.
Interleukin (IL)-21 is a member of type I cytokine family. Recent studies indicate that IL-21 can promote T follicular helper (Tfh) cell differentiation and survival, a specialized T cell subset which provides help for B cell. It can also regulate the activation, proliferation and differentiation of human B cell and immunoglobulin (Ig) production as well as isotype switching of plasma cell. Rheumatoid arthritis (RA) is characterized by auto-antibodies overproduction such as rheumatoid factor (RF) and anti-cyclic citrullinated peptide (anti-CCP) antibody, suggesting a pivotal role of Tfh cell and B cell in the pathogenesis of RA. This study aimed to investigate whether IL-21 had a regulatory effect on Tfh cell and B cell in RA. Serum IL-21 concentrations were measured by ELISA. The correlations between serum IL-21 levels and clinical features of RA patients were analyzed by Spearman's rank test. The percentages of Tfh-like cells, IL-21 receptor (R) expression on Tfh-like cells and B cells in peripheral blood (PB) were analyzed by flow cytometry. Peripheral blood mononuclear cells (PBMC) were stimulated by rIL-21 (100 ng/ml) in the presence or absence of anti-CD40 and/or anti-IgM, and changes of IL-21R, activation-associated surface markers (CD25, CD69 and CD40), the proliferation, apoptosis and differentiation of B cells were analyzed by flow cytometry. Production of IgG and IgM in the culture supernatants was determined by ELISA. The results showed that the serum IL-21 levels in RA patients were significantly higher than that of healthy controls (HC). IL-21 concentrations were positively correlated with 28-joint count disease activity score (DAS28) and anti-CCP antibody in RA patients with high IL-21 levels. Furthermore, the frequencies of peripheral CXCR5+PD-1+CD4+ Tfh-like cells markedly increased in RA patients and the percentages of Tfh-like cells were positively correlated with DAS28 and anti-CCP antibody levels. Moreover, elevated IL-21 levels were also correlated with the frequencies of Tfh-like cells. IL-21R expression on both Tfh-like cells and B cells were significantly enhanced in RA patients. In cultures vitro, exogenous IL-21 upregulated IL-21R expression and activation-associated surface markers on B cells and promoted more B cell proliferation in RA than in HC. This IL-21-mediated effect could be reversed by IL-21R-specific neutralizing antibody. Importantly, IL-21 promoted more differentiation of B cell into plasmablast and higher levels of IgG and IgM production in RA than in HC. Increased serum IL-21 levels in RA patients correlate with DAS28, anti-CCP antibody and frequencies of Tfh-like cells. IL-21 supports B cell activation, proliferation and antibody secretion via IL-21R pathway. Thus, IL-21 may be involved in the pathogenesis of RA and antagonizing IL-21 could be a novel strategy for the therapy of RA.


COVID-19-associated coagulopathy and antithrombotic agents-lessons after 1 year.
COVID-19 is associated with a high incidence of thrombotic complications, which can be explained by the complex and unique interplay between coronaviruses and endothelial cells, the local and systemic inflammatory response, and the coagulation system. Empirically, an intensified dose of thrombosis prophylaxis is being used in patients admitted to hospital with COVID-19 and several guidelines on this topic have been published, although the insufficiency of high quality and direct evidence has led to weak recommendations. In this Viewpoint we summarise the pathophysiology of COVID-19 coagulopathy in the context of patients who are ambulant, admitted to hospital, and critically ill or non-critically ill, and those post-discharge from hospital. We also review data from randomised controlled trials in the past year of antithrombotic therapy in patients who are critically ill. These data provide the first high-quality evidence on optimal use of antithrombotic therapy in patients with COVID-19. Pharmacological thromboprophylaxis is not routinely recommended for patients who are ambulant and post-discharge. A first ever trial in non-critically ill patients who were admitted to hospital has shown that a therapeutic dose of low-molecular-weight heparin might improve clinical outcomes in this population. In critically ill patients, this same treatment does not improve outcomes and prophylactic dose anticoagulant thromboprophylaxis is recommended. In the upcoming months we expect numerous data from the ongoing antithrombotic COVID-19 studies to guide clinicians at different stages of the disease.


Comparative performance of multiplex salivary and commercially available serologic assays to detect SARS-CoV-2 IgG and neutralization titers.
Oral fluid (hereafter saliva) offers a non-invasive sampling method for the detection of SARS-CoV-2 antibodies. However, data comparing performance of salivary tests against commercially-available serologic and neutralizing antibody (nAb) assays are lacking. This study compared the performance of a multiplex salivary SARS-CoV-2 IgG assay targeting antibodies to nucleocapsid (N), receptor binding domain (RBD) and spike (S) antigens to three commercially-available SARS-CoV-2 serology enzyme immunoassays (EIAs) (Ortho Vitros, Euroimmun, and BioRad) and nAb. Paired saliva and plasma samples were collected from 101 eligible COVID-19 convalescent plasma (CCP) donors >14 days since PCR+ confirmed diagnosis. Concordance was evaluated using positive (PPA) and negative (NPA) percent agreement, overall percent agreement (PA), and Cohen kappa coefficient. The range between salivary and plasma EIAs for SARS-CoV-2-specific N was PPA: 54.4-92.1% and NPA: 69.2-91.7%, for RBD was PPA: 89.9-100% and NPA: 50.0-84.6%, and for S was PPA: 50.6-96.6% and NPA: 50.0-100%. Compared to a plasma nAb assay, the multiplex salivary assay PPA ranged from 62.3% (N) and 98.6% (RBD) and NPA ranged from 18.8% (RBD) to 96.9% (S). Combinations of N, RBD, and S and a summary algorithmic index of all three (N/RBD/S) in saliva produced ranges of PPA: 87.6-98.9% and NPA: 50-91.7% with the three EIAs and ranges of PPA: 88.4-98.6% and NPA: 21.9-34.4% with the nAb assay. A multiplex salivary SARS-CoV-2 IgG assay demonstrated comparable performance to three commercially-available plasma EIAs and a nAb assay, and may be a viable alternative to assist in screening CCP donors and monitoring population-based seroprevalence and vaccine antibody response.


Toxoplasma exports dense granule proteins beyond the vacuole to the host cell nucleus and rewires the host genome expression.
Toxoplasma gondii is the most widespread apicomplexan parasite and occupies a large spectrum of niches by infecting virtually any warm-blooded animals. As an obligate intracellular parasite, Toxoplasma has evolved a repertoire of strategies to fine-tune the cellular environment in an optimal way to promote growth and persistence in host tissues hence increasing the chance to be transmitted to new hosts. Short and long-term intracellular survival is associated with Toxoplasma ability to both evade the host deleterious immune defences and to stimulate a beneficial immune balance by governing host cell gene expression. It is only recently that parasite proteins responsible for driving these transcriptional changes have been identified. While proteins contained in the apical secretory Rhoptry organelle have already been identified as bona fide secreted effectors that divert host signalling pathways, recent findings revealed that dense granule proteins should be added to the growing list of effectors as they reach the host cell cytoplasm and nucleus and target various host cell pathways in the course of cell infection. Herein, we emphasize on a novel subfamily of dense granule residentproteins, exemplified with the GRA16 and GRA24 members we recently discovered as both are exported beyond the vacuole-containing parasites and reach the host cell nucleus to reshape the host genome expression.


[Resection of hepatic metastases of colo-rectal carcinoma. Indications and initial results].
We report our initial experience in the resection of metastases from colo-rectal cancer confined to the liver. Seventeen hepatic resections were performed in sixteen patients over a thirty-eight months period. Median age was 58 years (45-75). The extent of liver involvement was assessed by computerized tomographic portography and magnetic resonance. In fourteen cases there was a solitary lesion. Mean interval time between colo-rectal resection and hepatic resection was 18 months (0-69). Twelve major hepatic resections and five wedge resections were performed. There was not operative mortality. Seven patients received complementary chemotherapy. Mean follow-up was 14.8 months (2-34). One patient died from carcinoma of the lung, five patients (31.25%) are alive with recurrence of some sort (three recurrences being in the liver) and ten patients (62.5%) are free of disease. Indications for resection, methods used for identification of candidates, prognostic determinants and indications for complementary chemotherapy are discussed.


Early antiretroviral treatment reduces risk of bacille Calmette-Guérin immune reconstitution adenitis.
Two centres in Soweto and Cape Town, South Africa. To assess the effects of timing of initiation of antiretroviral treatment (ART) and other factors on the risk of bacille Calmette-Guérin (BCG) related regional adenitis due to immune reconstitution inflammatory syndrome (BCG-IRIS) in human immunodeficiency virus (HIV) infected infants. HIV-infected infants aged 6-12 weeks with CD4 count ≥25% enrolled in the Children with HIV Early Antiretroviral Therapy (CHER) Trial received early (before 12 weeks) or deferred (after immunological or clinical progression) ART; infants with CD4 count <25% all received early ART. All received BCG vaccination after birth. Reactogenicity to BCG was assessed prospectively during routine study follow-up. Of 369 infants, 32 (8.7%) developed BCG-IRIS within 6 months of starting ART, 28 (88%) within 2 months after ART initiation. Of the 32 cases, 30 (93.8%) had HIV-1 RNA > 750 000 copies/ml at initiation. Incidence of BCG-IRIS was 10.9 and 54.3 per 100 person-years (py) among infants with CD4 count ≥25% at enrolment receiving early (at median age 7.4 weeks) vs. deferred (23.2 weeks) ART, respectively (HR 0.24, 95%CI 0.11-0.53, P < 0.001). Infants with CD4 count <25% receiving early ART had intermediate incidence (41.7/100 py). Low CD4 counts and high HIV-1 RNA at initiation were the strongest independent risk factors for BCG-IRIS. Early ART initiation before immunological and/or clinical progression substantially reduces the risk of BCG-IRIS regional adenitis.


The impact of mental health nursing education on undergraduate nursing students' attitudes to consumer participation.
Consumer participation in all aspects of mental health service delivery, including the education of mental health professionals, is now a policy expectation in Australia. Whether education programs introducing nurses to mental health nursing lead to more favourable attitudes towards consumer participation is yet to be examined in pre-registration nursing programs in Australia. The current evaluation examined changes in scores for the Consumer Participation Survey for undergraduate nursing students (n = 68) in an Australian University. Data were analysed, using repeated measures t-test, to compare the pre- and post-test scores. There was a significant improvement in views on consumers participating as staff members. There were no statistically significant changes in attitudes towards consumer capacity and consumer involvement in care processes. Consumer participation in mental health care is now clearly articulated in Australian Government policy. For this to be successfully implemented a more comprehensive understanding of the ability of education to influence attitudes is required.


Multiple nutritional deficiencies in infants from a strict vegetarian community.
Severe nutritional deficiencies developed in four infants from a new vegan religious community. They had received breast milk until the age of 3 months; thereafter, breast milk was supplemented with or replaced by extremely low caloric-density preparations. All of the infants had profound protein-caloric malnutrition, severe rickets, osteoporosis, and vitamin B12 and other deficiencies. One infant died, while the three others had an uneventful recovery. After discharge of the infants from the hospital, the community responded well to a modification of the infants' diet, which did not violate their vegetarian philosophy. However, they refused to give their infants vitamin B12 on a regular basis.


Yield of brain 18F-FDG PET in evaluating patients with potentially operable non-small cell lung cancer.
The American College of Surgeons Oncology Group recently completed a trial evaluating the role of PET with 18F-FDG in patients with documented or suspected non-small cell lung cancer. Subjects underwent standard imaging to exclude metastatic disease before PET. Here, we report the yield of brain PET in evaluating, for potential intracranial metastases, patients who have undergone previous brain CT or MRI with negative findings. A total of 287 evaluable patients who had been registered from 22 institutions underwent whole-body 18F-FDG PET, including dedicated PET of the brain, after routine staging procedures had found no suggestion of metastatic disease. Patients were followed postoperatively for disease-free and overall survival, with a minimum follow-up of 6 mo. Patients with specific brain abnormalities identified by PET were further examined, and the findings were evaluated along with the results of CT and MRI, clinical management, and follow-up. In 4 patients, PET found focal 18F-FDG uptake in the brain suggestive of metastatic disease; however, metastatic disease was excluded clinically in all 4 by negative findings on further brain imaging. All 4 patients remained alive at follow-up (mean duration, 10.5 mo; range, 6-16 mo). In patients with suspected or proven non-small cell lung cancer considered resectable by standard imaging, including routine preoperative contrast-enhanced CT or MRI of the brain, PET of the brain provides no additional information regarding metastatic disease.


'It's because I like things… it's a status and he buys me airtime': exploring the role of transactional sex in young women's consumption patterns in rural South Africa (secondary findings from HPTN 068).
'Transactional sex', defined as a non-marital, non-commercial sexual relationship in which money or material goods are exchanged for sex, is associated with young women's increased vulnerability to HIV infection. Existing research illustrates that the motivations for transactional sex are complex. The fulfilment of psycho-social needs such as the need to belong to a peer group are important factors underlying young women's desires to obtain certain consumption items and thus engage in transactional sex. We use a mixed-methods approach to explore the relationship between transactional sex and consumption patterns among young women in rural Mpumalanga province, South Africa. In the secondary analysis of 693 sexually active young women, we use factor analysis to group the different consumption items and we use multivariable logistic regression to demonstrate the relationship between transactional sex and consumption patterns. The qualitative study uses five focus group discussions and 19 in-depth interviews to explore further young women's motivations for acquiring different consumption items. The quantitative results show that young women that engage in transactional sex have higher odds of consuming items for entertainment (e.g., movie tickets) than on practical items (e.g., food and groceries). The qualitative findings also revealed that young women's perceptions of items that were considered a 'need' were strongly influenced by peer pressure and a desire for improved status. Further, there was a perception that emerged from the qualitative data that relationships with sugar daddies offered a way to acquire consumer goods associated with a 'modern lifestyle', such as items for personal enhancement and entertainment. However, young women seem aware of the risks associated with such relationships. More importantly, they also develop relationship with partners of similar age, albeit with the continued expectation of material exchange, despite engaging in the relationship for love. This study shows that young women are willing to take certain risks in order to have a degree of financial independence. Interventions that provide alternative methods of attaining this independence, such as the provision of cash transfers may have potential in preventing them from engaging in transactional relationships. Further, the psycho-social reasons that drive young women's motivations for consumption items resulting in risky sexual behaviours need to be better understood.


Assessing Urban Wastewater System Upgrades Using Integrated Modeling, Life Cycle Analysis, and Shadow Pricing.
This study assesses the environmental impacts of four measures proposed for upgrading of the urban wastewater system of Eindhoven and the Dommel River in The Netherlands, against the base case, "do-nothing" option. The measures aim to reduce the overall environmental impact of the Eindhoven urban wastewater system (UWS) by targeting river dissolved oxygen depletion and ammonia peaks, reducing combined sewer overflows, and enhancing nutrient removal. The measures are evaluated using a life cycle analysis with the boundaries including the receiving river section by means of an integrated model of the UWS. An uncertainty analysis of the estimated impacts has been performed to support the outcomes. The study also uses the economic concept of shadow prices to assign relative weights of socio-economic importance to the estimated life cycle impacts. This novel integration of tools complements the assessments of this UWS with the inclusion of long-term global environmental impacts and the investigation of trade-offs between different environmental impacts through a single monetary unit. The results support the selection of deeper clarifiers as the most environmentally beneficial measure for upgrade.


The Use of Life-Sustaining Procedures in the Last Month of Life Is Associated With More Depressive Symptoms in Surviving Spouses.
Family caregivers of individuals with serious illness who undergo intensive life-sustaining medical procedures at the end of life may be at risk of negative consequences including depression. The objective of this study was to determine the association between patients' use of life-sustaining procedures at the end of life and depressive symptoms in their surviving spouses. We used data from the Health and Retirement Study, a longitudinal survey of U.S. residents, linked to Medicare claims data. We included married Medicare beneficiaries aged 65 years and older who died between 2000 and 2011 (n = 1258) and their surviving spouses. The use of life-sustaining procedures (i.e., intubation/mechanical ventilation, tracheostomy, gastrostomy tube insertion, enteral/parenteral nutrition, and cardiopulmonary resuscitation) in the last month of life was measured via claims data. Using propensity score matching, we compared change in depressive symptoms of surviving spouses. Eighteen percent of decedents underwent one or more life-sustaining procedures in the last month of life. Those whose spouses underwent life-sustaining procedures had a 0.32-point increase in depressive symptoms after death (scale range = 0-8) and a greater likelihood of clinically significant depression (odds ratio = 1.51) compared with a matched sample of spouses of those who did not have procedures (P < 0.05). Surviving spouses of those who undergo intensive life-sustaining procedures at the end of life experience a greater magnitude of increase in depressive symptoms than those whose spouses do not undergo such procedures. Further study of the circumstances and decision making surrounding these procedures is needed to understand their relationship with survivors' negative mental health consequences and how best to provide appropriate support.


Tuberculosis of spine: An experience of 30 cases over two years.
Tuberculosis of spine is still a very common condition in India. Here, the results of 30 cases of tuberculosis of spine treated in SSG Hospital, Vadodara, Gujarat, in the last two years, are reviewed. A total of 30 patients with tuberculosis of spine were treated in SSG Hospital in the last two years. They were classified into three groups, based on the GATA, GATA = Gulhane Askeri Tip Akademisi (Gulhane Military Medical Academy) classification for spinal tuberculosis, with few modifications. Their neurologic status was evaluated by the Frankel's grading. All the patients were started on four drug anti-tuberculosis medication given every alternate day as per the DOTS and RNTCP program of the Government of India for 6 months. Patients in group 1 were treated by bed rest, analgesics, and antituberculous drugs after confirmation of the diagnosis by CT-guided biopsy. Patients in group 2 were treated by surgical of USG-guided aspiration of abscesses followed by full course of antituberculous drugs. Twenty-one patients in group 3 underwent surgery. A single-stage anterior decompression and anterior fixation was done in all the cases. All the nine patients in group I and 2 responded well to medical management and were cured of the disease. Out of the 21 operated patients, 19 had significant improvement in neurological status and return to their normal activities. The first operated patient died. The neurological status of one patient did not improve till 1 month after surgery and was lost to follow-up. Thus, 100% of group 1 and 2 patients were cured of the disease and 90% of group 3 patients had good neurological recovery. If treated timely and adequately, the outcome for tuberculosis of spine is relatively good. Anterolateral approach to the spine with decompression and fixation gives good result with respect to neurological function.


Cultivating hepatocytes on printed arrays of HGF and BMP7 to characterize protective effects of these growth factors during in vitro alcohol injury.
The goal of the present study was to investigate hepato-protective effects of growth factor (GF) arrays during alcohol injury. Hepatocyte growth factor (HGF) and bone morphogenetic protein (BMP)7 were mixed with collagen (I) and robotically printed onto standard glass slides to create arrays of 500 microm diameter spots. Primary rat hepatocytes were seeded on top of the arrays forming clusters corresponding in size to the underlying protein spots. Cell arrays were then injured in culture by exposure to 100 mm ethanol for 48 h. Hepatocytes residing on GF spots were found to have less apoptosis then cells cultured on collagen-only spots. Least apoptosis (0.3% as estimated by TUNEL assay) was observed on HGF/BMP7/collagen spots whereas most apoptosis (17.3%) was seen on collagen-only arrays. Interestingly, the extent of alcohol-induced apoptosis in hepatocytes varied based on the concentration of printed GF. In addition to preventing apoptosis, printed GFs contributed to maintenance of epithelial phenotype during alcohol injury as evidenced by higher levels of E-cadherin expression in HGF-protected hepatocytes. Importantly, GF microarrays could be used to investigate heterotypic interactions in the context of liver injury. To highlight this, stellate cells - nonparenchymal liver cells involved in fibrosis - were added to hepatocytes residing on arrays of either HGF/collagen or collagen-only spots. Exposure of these cocultures to ethanol followed by RT-PCR analysis revealed that stellate cells residing alongside HGF-protected hepatocytes were significantly less activated (less fibrotic) compared to controls. Overall, our results demonstrate that GF microarray format can be used to screen anti-fibrotic and anti-apoptotic effects of growth factors as well as to investigate how signals delivered to a specific cell type modulate heterotypic cellular interactions.


A Review Study on Punica granatum L.
Punica granatum L (pomegranate) is a deciduous shrub, native to Iran. Nowadays, besides its use as a fruit, its medicinal properties have attracted the interest of researchers of many countries. Pomegranate fruit has medicinal properties such as anti-inflammatory and antibacterial activities. The pomegranate seed oil has inhibitory effect on skin and breast cancers. The pomegranate seed oil has phytoestrogenic compounds and the fruit is rich in phenolic compounds with strong antioxidant activity. Ellagic acid is one of the main components of pomegranate with phenolic structure and antioxidant activity. This review article presents the recently published findings on different aspects of this plant focusing on its medicinal properties.


Lung transplantation, ex-vivo reconditioning and regeneration: state of the art and perspectives.
Lung transplantation is the only therapeutic option for end-stage pulmonary failure. Nevertheless, the shortage of donor pool available for transplantation does not allow to satisfy the requests, thus the mortality on the waiting list remains high. One of the tools to overcome the donor pool shortage is the use of ex-vivo lung perfusion (EVLP) to preserve, evaluate and recondition selected lung grafts not otherwise suitable for transplantation. EVLP is nowadays a clinical reality and have several destinations of use. After a narrative review of the literature and looking at our experience we can assume that one of the chances to improve the outcome of lung transplantation and to overcome the donor pool shortage could be the tissue regeneration of the graft during EVLP and the immunomodulation of the recipient. Both these strategies are performed using mesenchymal stem cells (MSC). The results of the models of lung perfusion with MSC-based cell therapy open the way to a new innovative approach that further increases the potential for using of the lung perfusion platform.


Influence of self-efficacy on compliance to workplace exercise.
Continuous neck and shoulder pain is a common musculoskeletal complaint. Physical exercise can reduce pain symptoms, but compliance to exercise is a challenge. Exercise-specific self-efficacy has been found to be a predictor of participation in preplanned exercise. Little is known about the influence of exercise-specific self-efficacy on compliance to workplace physical exercise. To determine the influence of exercise-specific self-efficacy on compliance to specific strength exercises during working hours for laboratory technicians. We performed a cluster-randomized controlled trial, including laboratory technicians from two industrial production units in Copenhagen, Denmark. The participants were randomized to supervised specific strength exercises for the neck and shoulder muscles for 20 minutes three times a week (n = 282) or to a reference group (n = 255). The participants answered baseline and follow-up questions regarding self-efficacy and registered all exercises in a diary. Overall compliance to exercises was 45 %. Compliance in company A (private sector) differed significantly between the three self-efficacy groups after 20 weeks. The odds ratio of compliance was 2.37 for moderate versus low self-efficacy, and 2.93 for high versus low self-efficacy. No significant difference was found in company B (public sector) or in the intervention group as a whole. We did not find self-efficacy to be a general statistically significant predictor of compliance to exercises during 20 weeks, but found self-efficacy to be a predictor of compliance in a private sector setting. Workplace-specific differences might be present and should be taken into account.


Therapists' Experiences in Their Work With Sex Offenders and People With Pedophilia: A Literature Review.
This article presents a review of the literature that pertains to the experiences of therapists who work directly with child sex offenders and/or people with pedophilia. We draw together results from studies that attempted to identify how therapists experience such work and how they were personally impacted by it. Usually, such studies are embedded within one of the following theoretical frameworks: Secondary traumatic stress, compassion fatigue, vicarious traumatization and burnout. Most literature on the topic has therefore sought to determine to what extent and why, work-related stress responses may occur among these therapists. The aim of this paper is therefore to provide insight into this, arguably, important line of research, while evaluating the current knowledge as well as providing recommendations for future research efforts.


Experience-Dependent Accumulation of N6-Methyladenosine in the Prefrontal Cortex Is Associated with Memory Processes in Mice.
The RNA modification N(6)-methyladenosine (m(6)A) influences mRNA stability and cell-type-specific developmental programming, and is highly abundant in the adult brain. However, it has not been determined whether m(6)A is dynamically regulated by experience. Based on transcriptome-wide profiling of m(6)A, we report that the level of m(6)A increases in the medial prefrontal cortex (mPFC) of mice in response to behavioral experience. The modulation was enriched near the stop codon of mRNAs, including genes related to neuronal plasticity. In primary cortical neurons, in vitro, modulation of m(6)A by the RNA demethylase FTO influenced the degradation profiles of a subset of transcripts with modulated sites. In vivo, the expression of Fto and the m(6)A methyltransferase, Mettl3 correlated with the observed increase in m(6)A levels post-training. Furthermore, targeted knockdown of FTO in the mPFC led to enhanced consolidation of cued fear memory. Thus, together with its role in early development, the dynamic regulation of m(6)A in the adult brain serves as an important epitranscriptomic mechanism associated with behavioral adaptation. N(6)-methyladenosine (m(6)A) is the most prevalent internal modification on RNA, however, its cellular dynamics in vivo remains elusive. Here we provide the first demonstration of m(6)A upregulation in the mouse medial prefrontal cortex (mPFC) following behavioral training. Knocking down the m(6)A demethylase FTO in the mPFC, which increases total m(6)A level, results in enhanced consolidation of fear memory. Our findings suggest that m(6)A is regulated in an activity-dependent manner in the adult brain, and may function to fine-tune mRNA turnover during memory-related processes.


Hierarchical Bayesian measurement models for continuous reproduction of visual features from working memory.
The article presents Bayesian hierarchical modeling frameworks for two measurement models for visual working memory. The models can be applied to the distributions of responses on a circular feature dimension, as obtained with the continuous reproduction (a.k.a. delayed estimation) task. The first measurement model is a mixture model that describes the response distributions as a mixture of one (Zhang & Luck, 2008) or several (Bays, Catalao, & Husain, 2009) von-Mises distribution(s) and a uniform distribution. The second model is a novel, interference-based measurement model. We present parameter recovery simulations for both models, demonstrating that the hierarchical framework enables precise parameter estimates when a small number of trials are compensated by a large number of subjects. Simulations with the mixture model show that the Bayesian hierarchical framework minimizes the previously observed estimation bias for memory precision in conditions of low performance. Unbiased and reasonably precise parameter estimates can also be obtained from the interference measurement model, though some parameters of this model demand a relatively large amount of data for precise measurement. Both models are applied to two experimental data sets. Experiment 1 measures the effect of memory set size on the model parameters. Experiment 2 provides evidence for the assumption in the interference model that the target feature tends to be confused with features of those nontargets that are close to the target on the dimension used as retrieval cue.


Effects of pay for performance on the quality of primary care in England.
A pay-for-performance scheme based on meeting targets for the quality of clinical care was introduced to family practice in England in 2004. We conducted an interrupted time-series analysis of the quality of care in 42 representative family practices, with data collected at two time points before implementation of the scheme (1998 and 2003) and at two time points after implementation (2005 and 2007). At each time point, data on the care of patients with asthma, diabetes, or coronary heart disease were extracted from medical records; data on patients' perceptions of access to care, continuity of care, and interpersonal aspects of care were collected from questionnaires. The analysis included aspects of care that were and those that were not associated with incentives. Between 2003 and 2005, the rate of improvement in the quality of care increased for asthma and diabetes (P<0.001) but not for heart disease. By 2007, the rate of improvement had slowed for all three conditions (P<0.001), and the quality of those aspects of care that were not associated with an incentive had declined for patients with asthma or heart disease. As compared with the period before the pay-for-performance scheme was introduced, the improvement rate after 2005 was unchanged for asthma or diabetes and was reduced for heart disease (P=0.02). No significant changes were seen in patients' reports on access to care or on interpersonal aspects of care. The level of the continuity of care, which had been constant, showed a reduction immediately after the introduction of the pay-for-performance scheme (P<0.001) and then continued at that reduced level. Against a background of increases in the quality of care before the pay-for-performance scheme was introduced, the scheme accelerated improvements in quality for two of three chronic conditions in the short term. However, once targets were reached, the improvement in the quality of care for patients with these conditions slowed, and the quality of care declined for two conditions that had not been linked to incentives. Continuity of care was reduced after the introduction of the scheme.


Effect of phytoncide from trees on human natural killer cell function.
We previously reported that the forest environment enhanced human natural killer (NK) cell activity, the number of NK cells, and intracellular anti-cancer proteins in lymphocytes, and that the increased NK activity lasted for more than 7 days after trips to forests both in male and female subjects. To explore the factors in the forest environment that activated human NK cells, in the present study we investigate the effect of essential oils from trees on human immune function in twelve healthy male subjects, age 37-60 years, who stayed at an urban hotel for 3 nights from 7.00 p.m. to 8.00 a.m. Aromatic volatile substances (phytoncides) were produced by vaporizing Chamaecyparis obtusa (hinoki cypress) stem oil with a humidifier in the hotel room during the night stay. Blood samples were taken on the last day and urine samples were analysed every day during the stay. NK activity, the percentages of NK and T cells, and granulysin, perforin, granzyme A/B-expressing lymphocytes in blood, and the concentrations of adrenaline and noradrenaline in urine were measured. Similar control measurements were made before the stay on a normal working day. The concentrations of phytoncides in the hotel room air were measured. Phytoncide exposure significantly increased NK activity and the percentages of NK, perforin, granulysin, and granzyme A/B-expressing cells, and significantly decreased the percentage of T cells, and the concentrations of adrenaline and noradrenaline in urine. Phytoncides, such as alpha-pinene and beta-pinene, were detected in the hotel room air. These findings indicate that phytoncide exposure and decreased stress hormone levels may partially contribute to increased NK activity.


A tell-tail sign of chromatin: histone mutations drive pediatric glioblastoma.
Recent genomic analyses of pediatric glioblastoma, a poorly understood tumor with dismal outcome, have identified mutations in histone H3 variants that affect critical amino acids in the tail. The findings extend discoveries of chromatin regulator inactivation and gain-of-function mutations by documenting alteration of a modifiable histone residue in human cancer.


PBPK modelling of inter-individual variability in the pharmacokinetics of environmental chemicals.
Generic PBPK models, applicable to a large number of substances, coupled to parameter databases and QSAR modules, are now available for predictive modelling of inter-individual variability in the absorption, distribution, metabolism and excretion of environmental chemicals. When needed, Markov chain Monte Carlo methods and multilevel population models can be jointly used for a Bayesian calibration of a PBPK model, to improve our understanding of the determinants of population heterogeneity and differential susceptibility. This article reviews those developments and illustrates them with recent applications to environmentally relevant questions.


Single subject and group whole-brain fMRI mapping of male genital sensation at 7 Tesla.
Processing of genital sensations in the central nervous system of humans is still poorly understood. Current knowledge is mainly based on neuroimaging studies using electroencephalography (EEG), magneto-encephalography (MEG), and 1.5- or 3- Tesla (T) functional magnetic resonance imaging (fMRI), all of which suffer from limited spatial resolution and sensitivity, thereby relying on group analyses to reveal significant data. Here, we studied the impact of passive, yet non-arousing, tactile stimulation of the penile shaft using ultra-high field 7T fMRI. With this approach, penile stimulation evoked significant activations in distinct areas of the primary and secondary somatosensory cortices (S1 & S2), premotor cortex, insula, midcingulate gyrus, prefrontal cortex, thalamus and cerebellum, both at single subject and group level. Passive tactile stimulation of the feet, studied for control, also evoked significant activation in S1, S2, insula, thalamus and cerebellum, but predominantly, yet not exclusively, in areas that could be segregated from those associated with penile stimulation. Evaluation of the whole-brain activation patterns and connectivity analyses indicate that genital sensations following passive stimulation are, unlike those following feet stimulation, processed in both sensorimotor and affective regions.


Interfacial water facilitates energy transfer by inducing extended vibrations in membrane lipids.
We report the complete assignment of the vibrational spectrum of dipalmitoylphosphatidylcholine (DPPC), which belongs to the most ubiquitous membrane phospholipid family, phosphatidylcholine. We find that water hydrating the lipid headgroups enables efficient energy transfer across membrane leaflets on sub-picosecond time scales. The emergence of spatially extended vibrational modes upon hydration, underlies this phenomenon. Our findings illustrate the importance of collective molecular behavior of biomembranes and reveal that hydrated lipid membranes can act as efficient media for the transfer of vibrational energy.


Long-term results of Perioperative High Dose Rate Brachytherapy (PHDRB) and external beam radiation in adult patients with soft tissue sarcomas of the extremities and the superficial trunk: Final results of a prospective controlled study.
To analyze toxicity, patterns of failure, and survival in 106 adult patients with soft tissue sarcomas of the extremity and the superficial trunk treated in a prospective controlled trial of combined Perioperative High Dose Rate Brachytherapy (PHDRB) and external beam radiotherapy (EBRT). Patients were treated with surgical resection and 16 Gy or 24 Gy of PHDRB for negative or close/positive margins, respectively. EBRT (45 Gy) was added postoperatively. Adjuvant chemotherapy was given to selected patients with high-grade tumors. The median follow-up was 7.1 years (range, 0.6-16.0). Grade ≥3 adverse events were observed in 22 patients (20.8%), and grade ≥4 events in 14 patients (13.2%). No grade 5 events were noted. Multivariate analysis (p = 0.003) found that Grade ≥3 toxic events increased with increasing implant volume (TV100). Local control, locoregional control, and distant control rates at 5 and 10 years were 89% and 87%, 82% and 80% and 75% and 69%, respectively. Multivariate analysis (p = 0.024) found that positive margins correlated with decreased local control. Disease-free survival and overall survival rates at 5 and 10 years were 64% and 59% and 73% and 62%, respectively. In multivariate analysis, disease-free survival rates decreased with increasing tumor size (p = 0.0001) and inadequate margins (p = 0.024), and overall survival decreased with increasing tumor size (p = 0.001) and male gender (p = 0.039). The combination of conservative surgery, high-dose PHDRB, and EBRT produces adequate function and local control in the majority of patients with soft tissue sarcomas of the extremities and the superficial trunk, including a substantial percentage of cases with positive margins. Patients with larger tumors are at a higher risk of complications, treatment failure, and cancer-related death and require an individualized treatment approach.


Changing over-the-counter ephedrine and pseudoephedrine products to prescription only: impacts on methamphetamine clandestine laboratory seizures.
Clandestine laboratory operators commonly extract ephedrine and pseudoephedrine-precursor chemicals used to synthesize methamphetamine-from over-the-counter cold/allergy/sinus products. To prevent this activity, two states, Oregon in 07/2006 and Mississippi in 07/2010, implemented regulations classifying ephedrine and pseudoephedrine as Schedule III substances, making products containing them available by prescription only. Using simple pre-regulation versus post-regulation comparisons, reports claim that the regulations have substantially reduced clandestine laboratory seizures (an indicator of laboratory prevalence) in both states, motivating efforts to implement similar regulation nationally. This study uses ARIMA-intervention time-series analysis to more rigorously evaluate the regulations' impacts on laboratory seizures. Monthly counts of methamphetamine clandestine laboratory seizures were extracted from the Clandestine Laboratory Seizure System (2000-early 2011) for Oregon, Mississippi and selected nearby states (for quasi-control). Seizures in Oregon and nearby western states largely bottomed out months before Oregon's regulation, and changed little thereafter. No significant impact for Oregon's regulation was found. Mississippi and nearby states generally had elevated seizures before Mississippi's regulation. Mississippi experienced a regulation-associated drop of 28.9 seizures (50.2%) in the series level (p<0.01), while nearby states exhibited no comparable decline. Oregon's regulation encountered a floor effect, making any sizable impact infeasible. Mississippi, however, realized a substantial impact, suggesting that laboratories, if sufficiently extant, can be meaningfully impacted by prescription precursor regulation. It follows that national prescription precursor regulation would have little impact in western states with low indicated laboratory prevalence, but may be of significant use in regions facing higher indicated prevalence.


Longitudinal access and exposure to green-blue spaces and individual-level mental health and well-being: protocol for a longitudinal, population-wide record-linked natural experiment.
Studies suggest that access and exposure to green-blue spaces (GBS) have beneficial impacts on mental health. However, the evidence base is limited with respect to longitudinal studies. The main aim of this longitudinal, population-wide, record-linked natural experiment, is to model the daily lived experience by linking GBS accessibility indices, residential GBS exposure and health data; to enable quantification of the impact of GBS on well-being and common mental health disorders, for a national population. This research will estimate the impact of neighbourhood GBS access, GBS exposure and visits to GBS on the risk of common mental health conditions and the opportunity for promoting subjective well-being (SWB); both key priorities for public health. We will use a Geographic Information System (GIS) to create quarterly household GBS accessibility indices and GBS exposure using digital map and satellite data for 1.4 million homes in Wales, UK (2008-2018). We will link the GBS accessibility indices and GBS exposures to individual-level mental health outcomes for 1.7 million people with general practitioner (GP) data and data from the National Survey for Wales (n=~12 000) on well-being in the Secure Anonymised Information Linkage (SAIL) Databank. We will examine if these associations are modified by multiple sociophysical variables, migration and socioeconomic disadvantage. Subgroup analyses will examine associations by different types of GBS. This longitudinal study will be augmented by cross-sectional research using survey data on self-reported visits to GBS and SWB. All data will be anonymised and linked within the privacy protecting SAIL Databank. We will be using anonymised data and therefore we are exempt from National Research Ethics Committee (NREC). An Information Governance Review Panel (IGRP) application (Project ID: 0562) to link these data has been approved.The research programme will be undertaken in close collaboration with public/patient involvement groups. A multistrategy programme of dissemination is planned with the academic community, policy-makers, practitioners and the public.


Differences in spiking patterns among cortical neurons.
Spike sequences recorded from four cortical areas of an awake behaving monkey were examined to explore characteristics that vary among neurons. We found that a measure of the local variation of interspike intervals, L(V), is nearly the same for every spike sequence for any given neuron, while it varies significantly among neurons. The distributions of L(V) values for neuron ensembles in three of the four areas were found to be distinctly bimodal. Two groups of neurons classified according to the spiking irregularity exhibit different responses to the same stimulus. This suggests that neurons in each area can be classified into different groups possessing unique spiking statistics and corresponding functional properties.


The genetic architecture of behavioral traits in a spider.
The existence of consistent individual differences in behavior has been shown in a number of species, and several studies have found observable sex differences in these behaviors, yet their evolutionary implications remain unclear. Understanding the evolutionary dynamics of behavioral traits requires knowledge of their genetic architectures and whether this architecture differs between the sexes. We conducted a quantitative genetic study in a sexually size-dimorphic spider, Larinioides sclopetarius, which exhibits sex differences in adult lifestyles. We observed pedigreed spiders for aggression, activity, exploration, and boldness and used animal models to disentangle genetic and environmental influences on these behaviors. We detected trends toward (i) higher additive genetic variances in aggression, activity, and exploration in males than females, and (ii) difference in variances due to common environment/maternal effects, permanent environment and residual variance in aggression and activity with the first two variances being higher in males for both behaviors. We found no sex differences in the amount of genetic and environmental variance in boldness. The mean heritability estimates of aggression, activity, exploration, and boldness range from 0.039 to 0.222 with no sizeable differences between females and males. We note that the credible intervals of the estimates are large, implying a high degree of uncertainty, which disallow a robust conclusion of sex differences in the quantitative genetic estimates. However, the observed estimates suggest that sex differences in the quantitative genetic architecture of the behaviors cannot be ruled out. Notably, the present study suggests that genetic underpinnings of behaviors may differ between sexes and it thus underscores the importance of taking sex differences into account in quantitative genetic studies.


Alcohol intake and death from cancer in a prospective Chinese elderly cohort study in Hong Kong.
In observational studies of Western populations, moderate alcohol use is usually associated with lower cancer mortality rates. However, moderate alcohol use (regular drinking of moderate amounts) is socially patterned. Evidence from other contexts can clarify such observations. We examined the association of moderate alcohol use with death from cancer in older Chinese adults from a developed non-Western setting, where occasional alcohol drinking (less than once per week of small amounts) is typical. Multivariable Cox regression analysis was used to assess the adjusted associations of alcohol use with death from cancer using a population-based prospective cohort of 66 820 Chinese aged ≥ 65 years enrolled from July 1998 to December 2001 at all the 18 Elderly Health Centres of the Hong Kong Government Department of Health, and followed till 30 May 2012. After follow-up for about 10.5 years, 6335 cancer deaths were identified. Most current alcohol users were social drinkers (<1/week). Moderate drinkers had a similar risk of death from non-oesophageal cancer as never drinkers, but a higher risk of oesophageal cancer, adjusted for age, sex, socioeconomic position, lifestyle and health status. Social drinking (<1/week) was associated with a lower risk of death from non-oesophageal cancer, but not from oesophageal cancer. In a non-Western setting, no association of moderate alcohol use with death from cancer was found. Occasional social drinking (<1/week) was associated with a lower risk of cancer, suggesting that moderate alcohol use is not protective, but in any setting the attributes of being a typical drinker may be.


Evaluation of pain on use of electrosurgery and diode lasers in the management of gingival hyperpigmentation: A comparative study.
Gingival depigmentation is a periodontal plastic surgical procedure whereby the gingival hyperpigmentation is removed by various techniques such as electrosurgery, cryosurgery, abrasion with diamond bur and lasers. The aim of this study was to determine the pain levels during the gingival depigmentation procedure using electrosurgery and lasers. Twenty patients, both male and female, between the ages of 20 and 40 years were randomly allocated into two groups of 10 patients each: Those undergoing depigmentation with electrosurgery (Group I) and those by diode lasers (Group II). Patients of both groups were asked to define the level of pain and discomfort by using the Visual Analog Scale (VAS) intraoperatively, 24 h post-operatively and 1 week post-operatively. Both the groups showed a decrease in the pain levels, which was statistically highly significant 1 week post-operatively when compared 24 h post-operatively. There was a statistically highly significant difference in the pain levels between the electrosurgery and the lasers groups after 24 h (P < 0.001), with the lasers group demonstrating lesser pain and discomfort. Although there was no significant difference between the two groups intraoperatively and 1 week post-operatively on comparison, lesser mean scores were observed for the lasers group. The growing concern for esthetic requires the removal of hyperpigmentated gingival areas to create a confident and pleasant smile, which could be easily attained by using either electrosurgery or lasers. This study concluded that lasers produce lesser pain and discomfort compared with electrosurgery during gingival depigmentation.


Tropomodulin 1 expression driven by NF-κB enhances breast cancer growth.
Triple-negative breast cancers (TNBC), which include the basal-like and claudin-low disease subtypes, are aggressive malignancies for which effective therapeutic targets are lacking. NF-κB activation has an established role in breast malignancy, and it is higher in TNBC than other breast cancer subtypes. On this basis, we hypothesized that proteins derived from NF-κB target genes might be molecular targets for TNBC therapy. In this study, we conducted a microarray-based screen for novel NF-κB-inducible proteins as candidate therapeutic targets, identifying tropomodulin 1 (TMOD1) as a lead candidate. TMOD1 expression was regulated directly by NF-κB and was significantly higher in TNBC than other breast cancer subtypes. TMOD1 elevation is associated with enhanced tumor growth in a mouse tumor xenograft model and in a 3D type I collagen culture. TMOD1-dependent tumor growth was correlated with MMP13 induction, which was mediated by TMOD1-dependent accumulation of β-catenin. Overall, our study highlighted a novel TMOD1-mediated link between NF-κB activation and MMP13 induction, which accounts in part for the NF-κB-dependent malignant phenotype of TNBC.


Protective effects of various ratios of DHA/EPA supplementation on high-fat diet-induced liver damage in mice.
A sedentary lifestyle and poor diet are risk factors for the progression of non-alcoholic fatty liver disease. However, the pathogenesis of hepatic lipid accumulation is not completely understood. Therefore, the present study explored the effects of dietary supplementation of various ratios of docosahexaenoic acid (DHA) and eicosapentaenoic acid (EPA) on a high-fat diet-induced lipid metabolism disorder and the concurrent liver damage. Using high-fat diet-fed C57BL/6 J mice as the animal model, diets of various ratios of DHA/EPA (2:1, 1:1, and 1:2) with an n-6/n-3 ratio of 4:1 were prepared using fish and algae oils enriched in DHA and/or EPA and sunflower seed oils to a small extent instead of the high-fat diet. Significantly decreased hepatic lipid deposition, body weight, serum lipid profile, inflammatory reactions, lipid peroxidation, and expression of adipogenesis-related proteins and inflammatory factors were observed for mice that were on a diet supplemented with DHA/EPA compared to those in the high-fat control group. The DHA/EPA 1:2 group showed lower serum triglycerides (TG), total cholesterol (TC), and low-density lipoprotein-cholesterol levels, lower SREBP-1C, FAS, and ACC-1 relative mRNA expression, and higher Fra1 mRNA expression, with higher relative mRNA expression of enzymes such as AMPK, PPARα, and HSL observed in the DHA/EPA 1:1 group. Lower liver TC and TG levels and higher superoxide dismutase levels were found in the DHA/EPA 2:1 group. Nonetheless, no other notable effects were observed on the biomarkers mentioned above in the groups treated with DHA/EPA compared with the DHA group. The results showed that supplementation with a lower DHA/EPA ratio seems to be more effective at alleviating high-fat diet-induced liver damage in mice, and a DHA/EPA ratio of 1:2 mitigated inflammatory risk factors. These effects of n-3 polyunsaturated fatty acids (PUFA) on lipid metabolism may be linked to the upregulation of Fra1 and attenuated activity of c-Jun and c-Fos, thus ultimately reducing the severity of the lipid metabolism disorder and liver damage to some extent.


Intermittent Running and Cognitive Performance after Ketone Ester Ingestion.
Ingestion of exogenous ketones alters the metabolic response to exercise and may improve exercise performance, but it has not been explored in variable-intensity team sport activity, or for effects on cognitive function. On two occasions in a double-blind, randomized crossover design, 11 male team sport athletes performed the Loughborough Intermittent Shuttle Test (part A, 5 × 15-min intermittent running; part B, shuttle run to exhaustion), with a cognitive test battery before and after. A 6.4% carbohydrate-electrolyte solution was consumed before and during exercise either alone (PLA) or with 750 mg·kg of a ketone ester (KE) supplement. Heart rate, RPE, and 15-m sprint times were recorded throughout, and serial venous blood samples were assayed for plasma glucose, lactate, and β-hydroxybutyrate. KE resulted in plasma β-hydroxybutyrate concentrations of ~1.5 to 2.6 mM during exercise (P < 0.001). Plasma glucose and lactate concentrations were lower during KE compared with PLA (moderate-to-large effect sizes). Heart rate, RPE, and 15-m sprint times did not differ between trials. Run time to exhaustion was not different (P = 0.126, d = 0.45) between PLA (mean = 268 s, 95% confidence interval [CI] = 199-336 s) and KE (mean = 229 s, 95% CI = 178-280 s). Incorrect responses in a multitasking test increased from pre- to postexercise in PLA (mean = 1.8, 95% CI = -0.6 to 4.1) but not in KE (mean = 0.0, 95% CI = -1.8 to 1.8) (P = 0.017, d = 0.70). Compared with carbohydrate alone, coingestion of a KE by team sport athletes attenuated the rise in plasma lactate concentrations but did not improve shuttle run time to exhaustion or 15-m sprint times during intermittent running. An attenuation of the decline in executive function after exhausting exercise suggests a cognitive benefit after KE ingestion.


Removal of instrumentation for postoperative spine infection: systematic review.
Currently, no consensus exists as to whether patients who develop infection of the surgical site after undergoing instrumented fusion should have their implants removed at the time of wound debridement. Instrumentation removal may eliminate a potential infection nidus, but removal may also destabilize the patient's spine. The authors sought to summarize the existing evidence by systematically reviewing published studies that compare outcomes between patients undergoing wound washout and instrumentation removal with outcomes of patients undergoing wound washout alone. The primary objectives were to determine 1) whether instrumentation removal from an infected wound facilitates infection clearance and lowers morbidity, and 2) whether the chronicity of the underlying infection affects the decision to remove instrumentation. PRISMA guidelines were used to review the PubMed/MEDLINE, Embase, Cochrane Library, Scopus, Web of Science, and ClinicalTrials.gov databases to identify studies that compared patients with implants removed and patients with implants retained. Outcomes of interest included mortality, rate of repeat wound washout, and loss of correction. Fifteen articles were included. Of 878 patients examined in these studies, 292 (33%) had instrumentation removed. Patient populations were highly heterogeneous, and outcome data were limited. Available data suggested that rates of reoperation, pseudarthrosis, and death were higher in patients who underwent instrumentation removal at the time of initial washout. Three studies recommended that instrumentation be uniformly removed at the time of wound washout. Five studies favored retaining the original instrumentation. Six studies favored retention in early infections but removal in late infections. The data on this topic remain heterogeneous and low in quality. Retention may be preferred in the setting of early infection, when the risk of underlying spine instability is still high and the risk of mature biofilm formation on the implants is low. However, late infections likely favor instrumentation removal. Higher-quality evidence from large, multicenter, prospective studies is needed to reach generalizable conclusions capable of guiding clinical practice.


Sampled-Data State Feedback Stabilization of Boolean Control Networks.
In this letter, we investigate the sampled-data state feedback control (SDSFC) problem of Boolean control networks (BCNs). Some necessary and sufficient conditions are obtained for the global stabilization of BCNs by SDSFC. Different from conventional state feedback controls, new phenomena observed the study of SDSFC. Based on the controllability matrix, we derive some necessary and sufficient conditions under which the trajectories of BCNs can be stabilized to a fixed point by piecewise constant control (PCC). It is proved that the global stabilization of BCNs under SDSFC is equivalent to that by PCC. Moreover, algorithms are given to construct the sampled-data state feedback controllers. Numerical examples are given to illustrate the efficiency of the obtained results.


Helical carbon tubes derived from epitaxial Cu-MOF coating on textile for enhanced supercapacitor performance.
The design and development of the supercapacitors containing metal oxides and carbon materials is very important for energy-storage devices in laboratory and industry. In this study, we report a helical carbon tube material derived from epitaxial Cu-MOF coating on textile by calcination treatment. The electrochemical performance obtained from the cyclic voltammetry (CV), galvanostatic charge/discharge (GCD) and cyclic stability measurements indicates that such a hybrid carbon material with a unique structure has a very high areal capacitance of 1812 mF cm-2 at a current density of 1 mA cm-2, and the material also has a good recyclability of 90% after 2000 cycles. This study combines the advantages of MOF- and cotton textile-derived carbon materials, and this study can serve as a guidance to improve the capacitance performance of supercapacitors.


Interleukin-6 regulation of transforming growth factor (TGF)-beta receptor compartmentalization and turnover enhances TGF-beta1 signaling.
Transforming growth factor (TGF)-beta1 is a key cytokine involved in the pathogenesis of fibrosis in many organs, whereas interleukin (IL)-6 plays an important role in the regulation of inflammation. Recent reports demonstrate interaction between the two cytokines in disease states. We have assessed the effect of IL-6 on TGF-beta1 signaling and defined the mechanism by which this occurred. Stimulation of Smad-responsive promoter (SBE)4-Lux activity by TGF-beta1 was significantly greater in the presence of IL-6 than that induced by TGF-beta1 alone. Augmented TGF-beta1 signaling following the addition of IL-6 appeared to be mediated through binding to the cognate IL-6 receptor, the presence of which was confirmed by fluorescence-activated cell sorting and Stat-specific signaling. TGF-beta1 receptors internalize by both caveolin-1 (Cav-1) lipid raft and early endosome antigen 1 (EEA-1) non-lipid raft pathways, with non-lipid raft-associated internalization increasing TGF-beta1 signaling. Affinity labeling of TGF-beta1 receptors demonstrated that IL-6 stimulation resulted in increased partitioning of TGF-beta receptors to the non-lipid raft fraction. There was no change in expression of Cav-1; however, following IL-6 stimulation, co-immunoprecipitation demonstrated decreased association of IL-6 receptor with Cav-1. Increased TGF-beta1-dependent Smad signaling by IL-6 was significantly attenuated by inhibition of clathrin-mediated endocytosis and augmented by depletion of membrane cholesterol. These results indicate that IL-6 increased trafficking of TGF-beta1 receptors to non-lipid raft-associated pools results in augmented TGF-beta1 Smad signaling.


3D analysis of the proximal interphalangeal joint kinematics during flexion.
Dynamic joint motion recording combined with CT-based 3D bone and joint surface data is accepted as a helpful and precise tool to analyse joint. The purpose of this study is to demonstrate the feasibility of these techniques for quantitative motion analysis of the interphalangeal joint in 3D. High resolution motion data was combined with an accurate 3D model of a cadaveric index finger. Three light-emitting diodes (LEDs) were used to record dynamic data, and a CT scan of the finger was done for 3D joint surface geometry. The data allowed performing quantitative evaluations such as finite helical axis (FHA) analysis, coordinate system optimization, and measurement of the joint distances in 3D. The FHA varies by 4.9 ± 1.7° on average. On average, the rotation in adduction/abduction and internal/external rotation were 0.3 ± 0.91° and 0.1 ± 0.97°, respectively. During flexion, a translational motion between 0.06 mm and 0.73 mm was observed. The proposed technique and methods appear to be feasible for the accurate assessment and evaluation of the PIP joint motion in 3D. The presented method may help to gain additional insights for the design of prosthetic implants, rehabilitation, and new orthotic devices.


Association of dietary soy genistein intake with lung function and asthma control: a post-hoc analysis of patients enrolled in a prospective multicentre clinical trial.
Broad dietary patterns have been linked to asthma but the relative contribution of specific nutrients is unclear. Soy genistein has important anti-inflammatory and other biological effects that might be beneficial in asthma. A positive association was previously reported between soy genistein intake and lung function but not with asthma exacerbations. To conduct a post-hoc analysis of patients with inadequately controlled asthma enrolled in a prospective multicentre clinical trial to replicate this association. A total of 300 study participants were included in the analysis. Dietary soy genistein intake was measured using the Block Soy Foods Screener. The level of soy genistein intake (little or no intake, moderate intake, or high intake) was compared with baseline lung function (pre-bronchodilator forced expiratory volume in 1 second (FEV(1))) and asthma control (proportion of participants with an episode of poor asthma control (EPAC) and annualised rates of EPACs over a 6-month follow-up period. Participants with little or no genistein intake had a lower baseline FEV(1) than those with a moderate or high intake (2.26 L vs. 2.53 L and 2.47 L, respectively; p=0.01). EPACs were more common among those with no genistein intake than in those with a moderate or high intake (54% vs. 35% vs. 40%, respectively; p<0.001). These findings remained significant after adjustment for patient demographics and body mass index. In patients with asthma, consumption of a diet with moderate to high amounts of soy genistein is associated with better lung function and better asthma control.


Inflammation-induced intussusceptive angiogenesis in murine colitis.
Intussusceptive angiogenesis is a morphogenetic process that forms new blood vessels by the division of a single blood vessel into two lumens. Here, we show that this process of intraluminal division participates in the inflammation-induced neovascularization associated with chemically induced murine colitis. In studies of both acute (4-7 days) and chronic (28-31 days) colitis, intravital microscopy of intravascular tracers demonstrated a twofold reduction in blood flow velocity. In the acute colitis model, the decreased velocity was associated with marked dilatation of the mucosal plexus. In contrast, chronic inflammation was associated with normal caliber vessels and duplication (and triplication) of the quasi-polygonal mucosal plexus. Scanning electron microscopy (SEM) of intravascular corrosion casts suggested that pillar formation and septation, previously linked to the morphogenetic process of intussusceptive angiogenesis, were present within days of the onset of inflammation. Four weeks after the onset of inflammation, SEM of vascular corrosion casts demonstrated replication of the mucosal plexus without significant evidence of sprouting angiogenesis. These data suggest that mucosal capillaries have comparable aggregate cross-sectional area in acute and chronic colitis; however, there is a significant increase in functional capillary density in chronic colitis. We conclude that intussusceptive angiogenesis is a fundamental mechanism of microvascular adaptation to prolonged inflammation.


Factors predicting ablation site recurrence following percutaneous microwave ablation of colorectal hepatic metastases.
Microwave ablation (MWA) is a recognised treatment option for liver metastases. The size of the tumour is a well-established factor that influences the success of MWA. However, the effect of "heat sink" on the success of MWA for hepatic metastases is unclear. The aim of this study was to determine whether heat sink effect is a factor that contributes to ablation site recurrence (ASR). A prospectively maintained database of patients who underwent percutaneous MWA for treatment of colorectal liver metastases was analysed. Imaging and demographic characteristics were compared between metastases that recurred following ablation and those that did not. Proximity to a large hepatic vein was defined as <10 mm. 126 ablations in 87 patients met the inclusion criteria and were studied over a median follow-up period of 28 (12-75) months. ASR was detected in 43 ablations (34%) and was associated with clinical risk score (CRS) ≥2 (OR 2.2 95% CI 1.3-3.3, p = 0.029), metastasis size (OR 0.953 95% CI (0.929-0.978), p < 0.001) and proximity to a large hepatic vein (OR 7.5 95%CI 2.4-22.8, p < 0.001). Proximity to a large hepatic vein was not associated with reduced overall survival (OS) but was associated with liver-specific recurrence (HR 4.7 95%CI 1.7-12.5, p = 0.004). In addition to tumour size proximity to large hepatic venous structures is an independent predictor of ASR and liver-specific recurrence following MWA. However, this was not associated with overall survival.


Promoting cancer screening. A randomized, controlled trial of three interventions.
To determine effective methods of promoting routine cancer screening, we randomly assigned 62 internal medicine residents to receive cancer screening reminders (computer-generated lists of overdue tests at patients' visits), audit with feedback (monthly seminars about screening, with feedback about their performance rates), or no intervention (controls). Half of the residents in each group also were randomized to receive patient education (patients received literature and notices of overdue tests). We reviewed a sample of each physician's medical records to assess performance of seven tests during 9-month periods before and after initiating the interventions. Cancer screening reminders increased performance of six of seven tests; audit with feedback, four of seven tests; and patient education, one of two targeted breast cancer screening tests. The results indicate that the cancer screening reminders strategy was the most effective in promoting the performance of routine cancer screening tests.


Myt1l safeguards neuronal identity by actively repressing many non-neuronal fates.
Normal differentiation and induced reprogramming require the activation of target cell programs and silencing of donor cell programs. In reprogramming, the same factors are often used to reprogram many different donor cell types. As most developmental repressors, such as RE1-silencing transcription factor (REST) and Groucho (also known as TLE), are considered lineage-specific repressors, it remains unclear how identical combinations of transcription factors can silence so many different donor programs. Distinct lineage repressors would have to be induced in different donor cell types. Here, by studying the reprogramming of mouse fibroblasts to neurons, we found that the pan neuron-specific transcription factor Myt1-like (Myt1l) exerts its pro-neuronal function by direct repression of many different somatic lineage programs except the neuronal program. The repressive function of Myt1l is mediated via recruitment of a complex containing Sin3b by binding to a previously uncharacterized N-terminal domain. In agreement with its repressive function, the genomic binding sites of Myt1l are similar in neurons and fibroblasts and are preferentially in an open chromatin configuration. The Notch signalling pathway is repressed by Myt1l through silencing of several members, including Hes1. Acute knockdown of Myt1l in the developing mouse brain mimicked a Notch gain-of-function phenotype, suggesting that Myt1l allows newborn neurons to escape Notch activation during normal development. Depletion of Myt1l in primary postmitotic neurons de-repressed non-neuronal programs and impaired neuronal gene expression and function, indicating that many somatic lineage programs are actively and persistently repressed by Myt1l to maintain neuronal identity. It is now tempting to speculate that similar 'many-but-one' lineage repressors exist for other cell fates; such repressors, in combination with lineage-specific activators, would be prime candidates for use in reprogramming additional cell types.


ALG-2/AGO-Dependent mir-35 Family Regulates DNA Damage-Induced Apoptosis Through MPK-1/ERK MAPK Signaling Downstream of the Core Apoptotic Machinery in Caenorhabditis elegans.
MicroRNAs (miRNAs) associate with argonaute (AGO) proteins to post-transcriptionally modulate the expression of genes involved in various cellular processes. Herein, we show that loss of the Caenorhabditis elegans AGO gene alg-2 results in rapid and significantly increased germ cell apoptosis in response to DNA damage inflicted by ionizing radiation (IR). We demonstrate that the abnormal apoptosis phenotype in alg-2 mutant animals can be explained by reduced expression of mir-35 miRNA family members. We show that the increased apoptosis levels in IR-treated alg-2 or mir-35 family mutants depend on a transient hyperactivation of the C. elegans ERK1/2 MAPK ortholog MPK-1 in dying germ cells. Unexpectedly, MPK-1 phosphorylation occurs downstream of caspase activation and depends at least in part on a functional cell corpse-engulfment machinery. Therefore, we propose a refined mechanism, in which an initial proapoptotic stimulus by the core apoptotic machinery initiates the engulfment process, which in turn activates MAPK signaling to facilitate the demise of genomically compromised germ cells.


Improved clinical investigation and evaluation of high-risk medical devices: the rationale and objectives of CORE-MD (Coordinating Research and Evidence for Medical Devices).
In the European Union (EU) the delivery of health services is a national responsibility but there are concerted actions between member states to protect public health. Approval of pharmaceutical products is the responsibility of the European Medicines Agency, whereas authorizing the placing on the market of medical devices is decentralized to independent 'conformity assessment' organizations called notified bodies. The first legal basis for an EU system of evaluating medical devices and approving their market access was the medical device directives, from the 1990s. Uncertainties about clinical evidence requirements, among other reasons, led to the EU Medical Device Regulation (2017/745) that has applied since May 2021. It provides general principles for clinical investigations but few methodological details-which challenges responsible authorities to set appropriate balances between regulation and innovation, pre- and post-market studies, and clinical trials and real-world evidence. Scientific experts should advise on methods and standards for assessing and approving new high-risk devices, and safety, efficacy, and transparency of evidence should be paramount. The European Commission recently awarded a Horizon 2020 grant to a consortium led by the European Society of Cardiology and the European Federation of National Associations of Orthopaedics and Traumatology, that will review methodologies of clinical investigations, advise on study designs, and develop recommendations for aggregating clinical data from registries and other real-world sources. The CORE-MD project (Coordinating Research and Evidence for Medical Devices) will run until March 2024; here we describe how it may contribute to the development of regulatory science in Europe.


MRI Predictors of Recurrence and Outcome after Acute Transverse Myelitis of Unidentified Etiology.
The early prediction of recurrence after an initial event of transverse myelitis helps to guide preventive treatment and optimize outcomes. Our aim was to identify MR imaging findings predictive of relapse and poor outcome in patients with acute transverse myelitis of unidentified etiology. Spinal MRIs of 77 patients (mean age, 36.3 ± 20 years) diagnosed with acute transverse myelitis were evaluated retrospectively. Only the patients for whom an underlying cause of myelitis could not be identified within 3 months of symptom onset were included. Initial spinal MR images of patients were examined in terms of lesion extent, location and distribution, brain stem extension, cord expansion, T1 signal, contrast enhancement, and the presence of bright spotty lesions and the owl's eyes sign. The relapse rates and Kurtzke Expanded Disability Status Scale scores at least 1 year (range, 1-14 years) after a myelitis attack were also recorded. Associations of MR imaging findings with clinical variables were studied with univariate associations and binary log-linear regression. Differences were considered significant for P values < .05. Twenty-seven patients (35.1%) eventually developed recurrent disease. Binary logistic regression revealed 3 main significant predictors of recurrence: cord expansion (OR, 5.30; 95% CI, 1.33-21.11), contrast enhancement (OR, 5.05; 95% CI, 1.25-20.34), and bright spotty lesions (OR, 3.63; 95% CI, 1.06-12.43). None of the imaging variables showed significant correlation with the disability scores. Cord expansion, contrast enhancement, and the presence of bright spotty lesions could be used as early MR imaging predictors of relapse in patients with acute transverse myelitis of unidentified etiology. Collaborative studies with a larger number of patients are required to validate these findings.


Working Memory Network Changes in ALS: An fMRI Study.
We used amyotrophic lateral sclerosis (ALS) as a model of prefrontal dysfunction in order to re-assess the potential neuronal substrates of two sub processes of working memory, namely information storage and filtering. To date it is unclear which exact neuronal networks sustain these two processes and the prefrontal cortex was suggested to play a crucial role both for filtering out of irrelevant information and for the storage of relevant information in memory. Other research has attributed information storage to more posterior brain regions, including the parietal cortex and stressed the role of subcortical areas in information filtering. We studied 14 patients suffering from ALS and the same number of healthy controls in an fMRI-task that allowed calculating separate storage and filtering scores. A brain volume analysis confirmed prefrontal atrophy in the patient group. Regarding their performance in the working memory task, we observed a trend toward slightly impaired storage capabilities whereas filtering appeared completely intact. Despite the rather subtle behavioral deficits we observed marked changes in neuronal activity associated with ALS: Compared to healthy controls patients showed significantly reduced hemodynamic responses in the left occipital cortex and right prefrontal cortex in the storage contrast. The filter contrast on the other hand revealed a relative hyperactivation in the superior frontal gyrus of the ALS patients. This hyperactivation might reflect a possible compensational mechanism for the prefrontal degeneration found in ALS. The reduced hemodynamic responses in the storage contrast might reflect a disruption of prefrontal top-down control of posterior brain regions, a process which was especially relevant in the most difficult high load memory task. Taken together, the present study demonstrates marked neurophysiological changes in ALS patients compared to healthy controls during the filtering and storage of information in spite of largely intact behavior. With respect to the neuronal substrates of the two working memory processes under investigation here, the results suggest that it is rather the degree to which top-down control is required for task completion that determines prefrontal cortex involvement than the specific nature of the process, i.e., storage vs. filtering.