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This article wonders how reconsidering conceptions of time in research with children could expand and complicate notions of childhoods. Drawing on Karen Barad’s (2016, 2018) writing on temporal entanglements alongside Katherine Stockton’s (2009) discussion of growing sideways, research is reviewed and data from a participatory study reexamined. These divergent notions of temporality blur boundaries between childhood and adulthood and privilege perspectives often marginalized. The conclusion discusses implications of temporal orientations when researching with children including conceptions of pandemic time.

State School Nurse Consultants provide leadership and technical assistance in many areas related to safety, education, and well-being of students. One area of assistance includes health surveillance and disease prevention. During the pandemic, summer of 2020, the legislative co-chairs of the New Jersey State School Nurses Association advocated for a State School Nurse Consultant position at the New Jersey Department of Education. The story of their relentless pursuit of legislation that would support this position is shared in this article archiving one of the most tumultuous times in recent school nursing history. Successful passage of a law to establish the position of a State School Nurse Consultant was only the initial step in a life-lesson about advocacy, patience, and collaboration. Learn about the roses and thorns of school nursing legislative advocacy and consider joining your affiliates’ legislative team!

BackgroundTelemedicine programs for the treatment of urinary tract infections (UTIs) offer an opportunity to reduce burdens on patients and providers. However, these programs are typically restricted to patients with uncomplicated UTIs. This real-world analysis evaluated treatment and resolution rates in a large-scale, national UTI telemedicine program inclusive of patients with uncomplicated and complicated UTIs.Methods and findingsWe conducted a retrospective analysis of data obtained from a commercially available telemedicine program for the treatment of UTIs among adult women in the US between 2017 and 2021 (n=51,474). The primary outcomes were the number of women who presented with symptoms of uncomplicated UTI, complicated UTI, and vaginal infection; prescription use and antibiotic type; symptom resolution within 7 days after appointment; and treatment failure or relapse. Most patients reported frequent urination (94.4%), urgency (94.5%), and dysuria (97.6%). Those with uncomplicated UTI symptoms represented the majority of patients (61.6%); however, a substantial number of patients (36.5%) also reported at least 1 symptom associated with a complicated UTI. One-fifth of patients (19.2%) reported at least 1 co-occurring symptom of vaginal infection or sexually transmitted infection. Across all treated patients, 94.0% received recommended antibiotics according to the clinical protocol. Of the treated patients who provided follow-up data (n=3,521), 89.7% reported 7-day symptom resolution. Symptom resolution rates were similar between patients with uncomplicated UTI symptoms (90.8%) and complicated UTI symptoms (87.9%), and symptom resolution among all treated patients (89.7%) was similar to reports for in-person standard of care.ConclusionsThese findings suggest that large-scale telemedicine programs for the treatment of UTIs can be effective in the treatment of complicated UTIs.

IntroductionPrograms aimed at modernizing thyroid care by pairing at-home sample collection methods with telehealth options may serve an important and emerging role in thyroid care. The primary objective of this analysis was to evaluate telehealth utilization, demographics, and clinical characteristics of a cohort of consumer initiated at-home lab thyroid test users who were also offered the option of follow-up telehealth consultations.MethodsThis was a retrospective analysis of real-world data from a de-identified consumer database of home-collected, mail-in Thyroid Tests utilized from March to May 2021 (n=8,152). The mean age was 38.6 (range 18-85) years and 86.6% of individuals identified as female.ResultsSeven percent of test takers fell into a thyroid dysfunction category (0.9% overthypothyroidism, 2.9% subclinical hypothyroidism, 0.1% overt-hypothyroidism, and 3.3% subclinical-hyperthyroidism). Twelve percent of the overall sample opted into a telehealth consultation, with 91.8% receiving a non-treatment telehealth consultation and 8.2% receiving a treatment telemedicine consultation. Sixteen percent of individuals with overt or subclinical thyroid dysfunction engaged in telehealth consultations. Of those opting into a treatment consultation, 59.3% reported a history of thyroid issues, 55.6% indicated wanting to discuss their current thyroid medication, and 48% received a prescription medication.DiscussionThe combination of at-home sample collection and telehealth is an innovative model for screening for thyroid disorders, monitoring thyroid function, and increasing access to care that can be implemented at a large scale and across a wide range of age groups.

BackgroundWhether vaccination or natural infection provides greater benefit regarding the development of sustained immunity against SARS-CoV-2 remains unknown. Therefore, the aim of this study was to provide a direct comparison of IgG durability in vaccinated and unvaccinated adults.MethodsThis was a prospective, cross-sectional study of antibody durability in 1087 individuals with a median (IQR) age of 42 (35, 52) years who were unvaccinated and previously infected with SARS-CoV-2 (Arm 1, n=351) or vaccinated against the virus (Arm 2, n=737). Participants self-reported vaccination and infection history and provided self-collected serology samples using mailed collection kits.ResultsAnti-S1 IgG seroprevalence was 15.6% higher in vaccinated versus unvaccinated, previously-infected individuals across intervals ranging from 1 to 12 months and antibody survival was sustained near 100% through 12 months in the vaccinated group.ConclusionsThese findings suggest that vaccination as opposed to natural infection alone provides significant advantages in terms of sustained and effective immunity against prior variants of SARS-CoV-2. Future efforts to characterize SARS-CoV-2 immune responses should address hybrid immunity, booster status and formulation, and protection against (sub)variants of Omicron and future lineages, as well as weigh the potential impact of other immune system mechanisms.

Research suggests that the representation of violence against women in the media has resulted in an increased acceptance of attitudes favoring domestic violence. While prior work has investigated the relationship between violent media exposure and violent crime, there has been little effort to empirically examine the relationship between specific forms of violent media exposure and the perpetration of intimate partner violence. Using data collected from a sample of 148 inmates, the current study seeks to help fill these gaps in the literature by examining the relationship between exposure to various forms of pleasurable violent media and the perpetration of intimate partner violence (i.e., conviction and self-reported). At the bivariate level, results indicate a significant positive relationship between exposure to pleasurable television violence and self-reported intimate partner abuse. However, this relationship is reduced to insignificant levels in multivariable modeling. Endorsement of domestic violence beliefs and victimization experience were found to be the strongest predictors of intimate partner violence perpetration. Potential policy implications based on findings are discussed within.

Background: The chemokine, cytokine interleukin deficiency disorder defines the immune deficiency disease of fibromyalgia and a reduced ability to produce IL-6 and IL-8. Recent research has demonstrated improved outcomes in COVID-19 infections treated with IL-6 antagonists.9 These fibromyalgia cytokine deficient patients were screened for COVID-19 infections and associated morbidity and mortality rates. Methods: Two cohorts of FM/a test positive fibromyalgia patients were evaluated. Initially, 4,631 patients were screened to determine the occurrence of known COVID-19 infections. Subsequently, 2,195 FM/a test positive patients underwent COVID-19 antibody testing. Results: A total of 7,375 fibromyalgia patients were screened for the occurrence of COVID-19 infections. Of these, 4,631 individuals responded to an email-based inquiry to determine the occurrence of documented COVID-19 infections. Only 10 reported having symptoms consistent with and were diagnosed with COVID-19 by a healthcare professional, making for an incidence of .22%. Another 2,195 fibromyalgia patients completed health questionnaires and COVID-19 antibody testing and 82 had evidence of COVID-19 antibodies with 42 exhibiting symptoms and confirmed diagnoses. Of the remaining, 23 were asymptomatic. There were no deaths and only 1 hospitalization in this group. Conclusion: Individuals with FM/a test positive fibromyalgia have a reduced ability to produce IL-6 and IL-8 which play significant roles in the cytokine storm complications associated with COVID-19 infections. When screened for evidence of past COVID-19 infections, these patients experienced an extremely low incidence of COVID-19 infections based upon antibody testing, there were no mortalities and the level of morbidity was significantly below what has been reported in general populations.

Some adipocytes are produced from bone marrow hematopoietic stem cells. In vitro studies previously indicated that these bone marrow-derived adipocytes (BMDAs) were generated from adipose tissue macrophage (ATM) that lose their hematopoietic markers and acquire mesenchymal markers prior to terminal adipogenic differentiation. Here we interrogated whether this hematopoietic-to-mesenchymal transition drives BMDA production In vitro. We generated transgenic mice in which the lysozyme gene promoter (LysM) indelibly labeled ATM with green fluorescent protein (GFP). We discovered that adipose stroma contained a population of LysM-positive myeloid cells that simultaneously expressed hematopoietic/myeloid markers (CD45 and CD11b), and mesenchymal markers (CD29, PDGFRa and Sca-1) typically found on conventional adipocyte progenitors. These cells were capable of adipogenic differentiation In vitro and In vitro, while other stromal populations deficient in PDGFRa and Sca-1 were non-adipogenic. BMDAs and conventional adipocytes expressed common fat cell markers but exhibited little or no expression of hematopoietic and mesenchymal progenitor cell markers. The data indicate that BMDAs are produced from ATM simultaneously expressing hematopoietic and mesenchymal markers rather than via a stepwise hematopoietic-to-mesenchymal transition. Because BMDA production is stimulated by high fat feeding, their production from hematopoietic progenitors may maintain adipocyte production when conventional adipocyte precursors are diminished.

Objective The purpose of this study was to determine whether suppression of ovarian function (gonadotropin-releasing hormone agonist [GnRHAG ]) for 24 weeks in premenopausal women approaching menopause causes changes in body composition and a decline in free-living physical activity energy expenditure (PAEE) and whether endurance exercise training attenuates the changes. Methods Premenopausal women who were approaching menopause (mean [SD]: age 46 [3] years, BMI 26.3 [4.8] kg/m2 ) were randomized to 24 weeks of GnRHAG (n = 14), GnRHAG + Exercise (n = 11), or placebo (n = 9). Endurance exercise was performed 4 days per week with the goal of expending 200 to 300 kcal per session. Primary outcome measurements included body composition by dual-energy x-ray absorptiometry, total daily energy expenditure (TDEE), and PAEE by doubly labeled water, and resting energy expenditure (REE) by indirect calorimetry. Results Changes in TDEE, PAEE, REE, or body composition were not different between groups. However, within the GnRHAG group, fat mass increased (mean [SE]: total 1.7 [0.4] kg, trunk 0.9 [0.2] kg, leg 0.6 [0.2] kg) and fat-free leg mass decreased (mean [SE]: -0.4 [0.2] kg) significantly. Conclusions In premenopausal women approaching menopause, ovarian hormone suppression resulted in increased adiposity without alterations in TDEE, PAEE, or REE.

Significance Recently, histone deacetylase 11 (HDAC11) was shown to function as an enzyme that removes lipids such as myristoyl groups from lysines in proteins, yet only one substrate of HDAC11 has been reported. Here, we define gravin-α/A kinase–anchoring protein 12 as a second HDAC11 substrate. By demyristoylating gravin-α in adipocytes, HDAC11 prevents β-adrenergic receptors (β-ARs), which are G protein–coupled receptors (GPCRs), from translocating to membrane microdomains that are required for downstream protective signaling by protein kinase A (PKA). These findings demonstrate a role for reversible lysine myristoylation in the control of GPCR signaling and lay the foundation for developing therapeutics for obesity based on enhancing β-AR signaling in adipose tissue by manipulating the HDAC11:gravin-α axis.

SUMOylation, the covalent conjugation of small ubiquitin-like modifier (SUMO) proteins to protein substrates, has been reported to suppress type I interferon (IFN1) responses. TAK-981, a selective small molecule inhibitor of SUMOylation, pharmacologically reactivates IFN1 signaling and immune responses against cancers. In vivo treatment of wild type mice with TAK-981 upregulated IFN1 gene expression in blood cells and splenocytes. Ex vivo treatment of mouse and human dendritic cells promoted their IFN1-dependent activation, and vaccination studies in mice demonstrated stimulation of antigen cross-presentation and T cell priming in vivo. TAK-981 also directly stimulated T cell activation, driving enhanced T cell sensitivity and response to antigen ex vivo. Consistent with these observations, TAK-981 inhibited growth of syngeneic A20 and MC38 tumors in mice, dependent upon IFN1 signaling and CD8(+) T cells, and associated with increased intratumoral T and NK cell number and activation. Combination of TAK-981 with anti-PD1 or anti-CTLA4 antibodies improved the survival of mice bearing syngeneic CT26 and MC38 tumors. In conclusion, TAK-981 is a first in class SUMOylation inhibitor that promotes anti-tumor immune responses by activation of IFN1 signaling. TAK-981 is currently being studied in phase I clinical trials (NCT03648372, NCT04074330, NCT04776018 and NCT04381650) for the treatment of patients with solid tumors and lymphomas.

An SLC30A9-associated cerebro-renal syndrome was first reported in consanguineous Bedouin kindred by Perez et al. in 2017. While the function of the gene has not yet been fully elucidated, it may be implicated in Wnt signaling, nuclear regulation, as well as cell and mitochondrial zinc regulation. In this research report, we present a female proband with two distinct, inherited autosomal recessive loss-of-function SLC30A9 variants from unrelated parents. To our knowledge, this is the first reported case of a possible SLC30A9-associated cerebro-renal syndrome in a non-consanguineous family. Furthermore, a limited statistical analysis was conducted to identify possible allele frequency differences between populations. Our findings provide further support for an SLC30A9-associated cerebro-renal syndrome and may help further clarify the gene’s function.

Every year, 2 million women reach menopause in the United States, and they may spend 40% or more of their life in a postmenopausal state. In the years immediately preceding menopause—known as the menopause transition (or perimenopause)—changes in hormones and body composition increase a woman’s overall cardiometabolic risk. In this narrative review, we summarize the changes in weight, body composition, and body fat distribution, as well as the changes in energy intake, energy expenditure, and other cardiometabolic risk factors (lipid profile, glucose metabolism, sleep health, and vascular function), that occur during the menopause transition. We also discuss the benefits of lifestyle interventions in women in the earlier stages of menopause before these detrimental changes occur. Finally, we discuss how to include perimenopausal women in research studies so that women across the life-span are adequately represented.

Mechanisms for carbon uptake in the small-bodied Halophila johnsonii and large-bodied Thalassia testudinum were compared using photosynthesis measurements (oxygen flux) with, and without, the extracellular carbonic anhydrase inhibitor acetazolamide (AZ) and TRIS buffer. Our results indicated T. testudinum and H. johnsonii both utilize external membrane-bound carbonic anhydrase to facilitate dehydration of HCO3− into CO2(aq). T. testudinum also utilizes an active proton (H+) pump to create localized H+ gradients within the boundary layer and it derives a larger portion of photosynthetic carbon from bicarbonate than H. johnsonii. Stable carbon isotope composition (δ13C) of T. testudinum and H. johnsonii leaves under high and reduced irradiance were also compared to evaluate photosynthetic carbon use. Isotope ratios of H. johnsonii were significantly more negative than T. testudinum at a high-light field site (−10.44 ± 0.26‰ vs −9.25 ± 0.25‰). In contrast, there was no significant difference in isotope ratios between species for plants maintained in a greenhouse under reduced photosynthetically active radiation. This suggests photosynthesis of T. testudinum is more carbon limited or more reliant on bicarbonate for photosynthesis than H. johnsonii under high-light conditions. Although photosynthesis of both species is expected to increase in response to greater CO2(aq) availability, ocean acidification and its CO2(aq) enrichment of seawater may have greater benefits for H. johnsonii compared to T. testudinum, whose photosynthesis relies more heavily on HCO3− use.

Glycans attached to immunoglobulin G (IgG) directly affect this antibody effector functions and regulate inflammation at several levels. The composition of IgG glycome changes significantly with age. In women, the most notable change coincides with the perimenopausal period. Aiming to investigate the effect of estrogen on IgG glycosylation, we analysed IgG and total serum glycomes in 36 healthy premenopausal women enrolled in a randomized controlled trial of the gonadotropin-releasing hormone analogue (GnRHAG) leuprolide acetate to lower gonadal steroids to postmenopausal levels and then randomized to transdermal placebo or estradiol (E2) patch. The suppression of gonadal hormones induced significant changes in the IgG glycome, while E2 supplementation was sufficient to prevent changes. The observed glycan changes suggest that depletion of E2 primarily affects B cell glycosylation, while liver glycosylation stays mostly unchanged. To determine whether previously identified IgG GWAS hits RUNX1, RUNX3, SPINK4, and ELL2 are involved in downstream signaling mechanisms, linking E2 with IgG glycosylation, we used the FreeStyle 293-F transient system expressing IgG antibodies with stably integrated CRISPR/dCas9 expression cassettes for gene up- and downregulation. RUNX3 and SPINK4 upregulation using dCas9-VPR resulted in a decreased IgG galactosylation and, in the case of RUNX3, a concomitant increase in IgG agalactosylation.

Regional adipose tissue distribution differs between men and women. Differences in the accumulation of adipose tissue as well as the regulation of secretion of a number of products from adipose tissue are under the control of sex steroids, which act through a wide variety of mechanisms, both direct and indirect, to tailor metabolism to the unique needs of each sex. A fuller understanding of sex-based differences in adipose tissue function may help with tailored strategies for disease prevention and treatment and provide insights into fundamental differences in the processes that regulate nutrient homeostasis and body weight.

Reducing estrogen in women results in decreases in energy expenditure, but the mechanism(s) remain largely unknown. We postulate that the loss of estrogens in women is associated with increased accumulation of bone marrow (BM)-derived adipocytes in white adipose tissue, decreased activity of brown adipose tissue, and reduced levels of physical activity. Regular exercise may counteract the effects of estrogen deficiency.

PURPOSE: To determine the effects of 5 months of ovarian hormone suppression in pre-menopausal women on objectively measured physical activity (PA). METHODS: Participants (age = 35±8 yr; body mass index = 27±6 kg·m(−2)) received monthly intramuscular injections of gonadotropin releasing hormone agonist therapy (GnRH(AG)) which suppresses pituitary gonadotropins and results in suppression of ovarian sex hormones. Women were randomized to receive concurrent transdermal E(2) (GnRH(AG)+E(2); n=30) or placebo (GnRH(AG)+PL, n=31). PA was assessed for 1 week before and during each month of the 5-month intervention using a hip-worn accelerometer (Actical, Mini Mitter Co., Inc., Bend, OR). Estimates of time spent in sedentary, light, and moderate-to-vigorous physical activity (MVPA) were derived using a previously published equation. Subsets of participants in each group were also randomized to a supervised progressive resistance exercise training program. RESULTS: Total MVPA tended towards being higher (p=0.08) in the GnRH(AG)+E(2) group at month 4. There were no significant effects of intervention or time in sedentary or light PA. In the subset of women who did not participate in structured exercise training for which Actical data were obtained (N=16 in each group), total MVPA was higher at month 4 (p=0.01). CONCLUSION: Physical activity levels appear to be maintained at a higher level in women undergoing pharmacological suppression of ovarian function with E(2) add back when compared with women treated with placebo. These data provide proof of concept data that E(2) contributes to the regulation of PA in humans. However, given the exploratory nature of this study, future confirmatory investigations will be necessary.

Deficiency in mevalonate kinase (MVK) causes systemic inflammation. However, the molecular mechanisms linking the mevalonate pathway to inflammation remain obscure. Geranylgeranyl pyrophosphate, a non-sterol intermediate of the mevalonate pathway, is the substrate for protein geranylgeranylation, a protein post-translational modification that is catalyzed by protein geranylgeranyl transferase I (GGTase I). Pyrin is an innate immune sensor that forms an active inflammasome in response to bacterial toxins. Mutations in MEFV (encoding human PYRIN) result in autoinflammatory familial Mediterranean fever syndrome. We found that protein geranylgeranylation enabled Toll-like receptor (TLR)-induced activation of phosphatidylinositol-3-OH kinase (PI(3)K) by promoting the interaction between the small GTPase Kras and the PI(3)K catalytic subunit p110δ. Macrophages that were deficient in GGTase I or p110δ exhibited constitutive release of interleukin 1β that was dependent on MEFV but independent of the NLRP3, AIM2 and NLRC4 inflammasomes. In the absence of protein geranylgeranylation, compromised PI(3)K activity allows an unchecked TLR-induced inflammatory responses and constitutive activation of the Pyrin inflammasome.

Individuals seeking academic employment opportunities often do so by exploring hiring announcements that are advertised online through Academy of Criminal Justice Sciences, American Society of Criminology, and The Chronicle of Higher Education. Because limited educational resources and budget constraints can impact hiring decisions that are made at institutions of higher learning over time, it is important for candidates to consider exactly what employers are looking for in prospective professionals and to see how they measure up to the demands brought on by academic job searches. Using quantitative content analyses of recent job postings on popular academic job search websites, this study explores recent trends in the hiring of criminology and criminal justice professionals, paying particular attention to exactly which positions are being sought after by colleges and universities and how the presence of online technology has changed hiring trends within our field.

Adipose tissue is a highly dynamic organ that undergoes continuous cell turnover. A pool of adipocyte progenitor cells (APCs) located within the stromal-vascular fraction of adipose tissue is the source of de novo adipogenesis in adults. We now appreciate that APCs arise from multiple lineages, varying both between and within adipose tissue depots. Importantly, APC lineage appears to be a key factor in determining adipocyte phenotype and the overall metabolic characteristics of a given fat depot. Importantly, each fat depot acts as an endocrine organ playing a role in maintaining overall physiological homeostasis.

White adipocytes in adults are typically derived from tissue resident mesenchymal progenitors. The recent identification of de novo production of adipocytes from bone marrow progenitor-derived cells in mice challenges this paradigm and indicates an alternative lineage specification that adipocytes exist. We hypothesized that alternative lineage specification of white adipocytes is also present in human adipose tissue. Bone marrow from transgenic mice in which luciferase expression is governed by the adipocyte-restricted adiponectin gene promoter was adoptively transferred to wild-type recipient mice. Light emission was quantitated in recipients by in vivo imaging and direct enzyme assay. Adipocytes were also obtained from human recipients of hematopoietic stem cell transplantation. DNA was isolated, and microsatellite polymorphisms were exploited to quantify donor/recipient chimerism. Luciferase emission was detected from major fat depots of transplanted mice. No light emission was observed from intestines, liver, or lungs. Up to 35% of adipocytes in humans were generated from donor marrow cells in the absence of cell fusion. Nontransplanted mice and stromal-vascular fraction samples were used as negative and positive controls for the mouse and human experiments, respectively. This study provides evidence for a nontissue resident origin of an adipocyte subpopulation in both mice and humans.—Gavin, K. M., Gutman, J. A., Kohrt, W. M., Wei, Q., Shea, K. L., Miller, H. L., Sullivan, T. M., Erickson, P. F., Helm, K. M., Acosta, A. S., Childs, C. R., Musselwhite, E., Varella-Garcia, M., Kelly, K., Majka, S. M., Klemm, D. J. De novo generation of adipocytes from circulating progenitor cells in mouse and human adipose tissue.

Suppressing sex hormones in women for 1 wk reduces resting energy expenditure (REE). The effects of more chronic suppression on REE and other components of total energy expenditure (TEE), and whether the reduction in REE is specifically due to loss of estradiol (E2), are not known. We compared the effects of 5 mo of sex hormone suppression (gonadotropin releasing hormone agonist therapy, GnRHAG) with placebo (PL) or E2 add-back therapy on REE and the components of TEE. Premenopausal women received GnRHAG (leuprolide acetate 3.75 mg/mo) and were randomized to receive transdermal therapy that was either E2 (0.075 mg/d; n = 24; means ± SD, aged = 37 ± 8 yr, BMI = 27.3 ± 6.2 kg/m2) or placebo ( n = 21; aged = 34 ± 9 yr, BMI = 26.8 ± 6.2 kg/m2). REE was measured by using a metabolic cart, and TEE, sleep EE (SEE), exercise EE (ExEE, 2 × 30 min bench stepping), non-Ex EE (NExEE), and the thermic effect of feeding (TEF) were measured by using whole room indirect calorimetry. REE decreased in GnRHAG+PL [mean (95% CI), −54 (−98, −15) kcal/d], but not GnRHAG+E2 [+6 (−33, +45) kcal/d] (difference in between-group changes, P < 0.05). TEE decreased in GnRHAG+PL [−128 (−214, −41) kcal/d] and GnRHAG+E2 [−96 (−159, −32) kcal/d], with no significant difference in between-group changes ( P = 0.55). SEE decreased similarly in both GnRHAG+PL [−0.07 (−0.12, −0.03) kcal/min] and GnRHAG+E2 [−0.07 (−0.12, −0.02) kcal/min]. ExEE decreased in GnRHAG+PL [−0.46 (−0.79, −0.13) kcal/min], but not GnRHAG+E2 [−0.30 (−0.65, +0.06) kcal/min]. There were no changes in TEF or NExEE in either group. In summary, chronic pharmacologic suppression of sex hormones reduced REE and this was prevented by E2 therapy.

This supplement has been sponsored by Bayer HealthCare. Please see acknowledgements for full disclaimer. Prescribing Information can be found in the appendices. L.GB.COM.05.2015.11280. Date of preparation: June 2015 This paper provides expert recommendations on administration of aflibercept in wet age-related macular degeneration (AMD) after Year 1 (Y1), based on a roundtable discussion held in London, UK in November 2014. The goals of treatment after Y1 are to maintain visual and anatomical gains whilst minimising treatment burden and using resources effectively. The treatment decision should be made at the seventh injection visit (assuming the label has been followed) in Y1, and three approaches are proposed: (a) eyes with active disease on imaging/examination but with stable visual acuity (VA) at the end of Y1 should continue with fixed 8-weekly dosing; (b) eyes with inactive disease on imaging/examination and stable VA should be managed using a ‘treat and extend' (T&E) regimen. T&E involves treating and then extending the interval until the next treatment, by 2-week intervals, to a maximum of 12 weeks, provided the disease remains inactive. If there is new evidence of disease activity, treatment is administered and the interval to the next treatment shortened; and (c) if there has been no disease activity for ≥3 consecutive visits, a trial of monitoring without treatment may be appropriate, initiated at the end of Y1 or at any time during Y2. Where possible, VA testing, OCT imaging and injection should be performed at the same visit. The second eye should be monitored to detect fellow eye involvement. In bilateral disease, the re-treatment interval should be driven by the better-seeing eye or, if the VA is similar, the eye with the more active disease.

To evaluate patient visual acuity outcomes and blindness rates attributable to wet AMD with a potential 5-year follow-up from intravitreal ranibizumab treatment (IVTR) in south-east Scotland. Data was analysed from 104 eyes of 96 patients who initiated treatment prior to September 2008. The main outcome measures were LogMAR visual acuity, number of clinic visits and the number of injections. Annual blind registration data in south-east Scotland were analysed using blind certifications recorded by the Royal National Institute of Blind People. Patients had a mean clinical follow-up of 4 years and 1 month and a mean loss of 5.5 letters over the study period. Of the treated eyes 9.6% gained ≥15 letters whilst 24.0% lost ≥15 letters during this period. An average of 9.56 injections were administered per patient. The age-sex standardised incidence of legal blindness attributable to wet AMD in south-east Scotland peaked at 9.1 cases per 100 000 of the population in 2006 in either eye. Following the introduction of IVTR there were annual decreases in the incidence of blindness attributable to AMD falling to a trough of 4.8 cases per 100 000 of the population in 2011. This study demonstrates that the majority of patients in a south-east Scotland maintain their vision following IVTR in wet AMD in the real-world setting. Our study also suggests that the introduction of IVTR has had population wide benefits in reducing the blindness attributable to wet AMD in the south-east Scotland population.

Some bona fide adult adipocytes arise de novo from a bone marrow-derived myeloid lineage. These studies further demonstrate that adipose tissue stroma contains a resident population of myeloid cells capable of adipocyte and multilineage mesenchymal differentiation. These resident myeloid cells lack hematopoietic markers and express mesenchymal and progenitor cell markers. Because bone marrow mesenchymal progenitor cells have not been shown to enter the circulation, we hypothesized that myeloid cells acquire mesenchymal differentiation capacity in adipose tissue. We fabricated a 3-dimensional fibrin matrix culture system to define the adipose differentiation potential of adipose tissue-resident myeloid subpopulations, including macrophages, granulocytes and dendritic cells. Our data show that multilineage mesenchymal potential was limited to adipose tissue macrophages, characterized by the acquisition of adipocyte, osteoblast, chondrocyte and skeletal muscle myocyte phenotypes. Fibrin hydrogel matrices stimulated macrophage loss of hematopoietic cell lineage determinants and the expression of mesenchymal and progenitor cell markers, including integrin β1. Ablation of integrin β1 in macrophages inhibited adipocyte specification. Therefore, some bona fide adipocytes are specifically derived from adipose tissue-resident macrophages via an integrin β1-dependent hematopoietic-to-mesenchymal transition, whereby they become capable of multipotent mesenchymal differentiation. The requirement for integrin β1 highlights this molecule as a potential target for controlling the production of marrow-derived adipocytes and their contribution to adipose tissue development and function.

E1 enzymes activate ubiquitin or ubiquitin-like proteins (Ubl) via an adenylate intermediate and initiate the enzymatic cascade of Ubl conjugation to target proteins or lipids. Ubiquitin-fold modifier 1 (Ufm1) is activated by the E1 enzyme Uba5, and this pathway is proposed to play an important role in the endoplasmic reticulum (ER) stress response. However, the mechanisms of Ufm1 activation by Uba5 and subsequent transfer to the conjugating enzyme (E2), Ufc1, have not been studied in detail. In this work, we found that Uba5 activated Ufm1 via a two-step mechanism and formed a binary covalent complex of Uba5∼Ufm1 thioester. This feature contrasts with the three-step mechanism and ternary complex formation in ubiquitin-activating enzyme Uba1. Uba5 displayed random ordered binding with Ufm1 and ATP, and its ATP-pyrophosphate (PPi) exchange activity was inhibited by both AMP and PPi. Ufm1 activation and Uba5∼Ufm1 thioester formation were stimulated in the presence of Ufc1. Furthermore, binding of ATP to Uba5∼Ufm1 thioester was required for efficient transfer of Ufm1 from Uba5 to Ufc1 via transthiolation. Consistent with the two-step activation mechanism, the mechanism-based pan-E1 inhibitor, adenosine 5'-sulfamate (ADS), reacted with the Uba5∼Ufm1 thioester and formed a covalent, tight-binding Ufm1-ADS adduct in the active site of Uba5, which prevented further substrate binding or catalysis. ADS was also shown to inhibit the Uba5 conjugation pathway in the HCT116 cells through formation of the Ufm1-ADS adduct. This suggests that further development of more selective Uba5 inhibitors could be useful in interrogating the roles of the Uba5 pathway in cells.

Plants of the threatened seagrass, Halophila johnsonii Eiseman, from a riverine and marine population were exposed to a series of salinity treatments within mesocosms. Survival and maximum photochemical efficiencies of PSII (Fv/Fm) were measured in response to varied frequency, duration, and amplitude of hyposalinity exposures. Both populations exhibited high survival after two cycles of short, pulsed hyposalinity treatments (100% and 89%, respectively). However, two cycles of long pulses of low salinity resulted in 100% mortality for marine H. johnsonii and >50% mortality for riverine plants. After two cycles of gradual salinity reduction to a salinity of 5, survival for marine and riverine plants was also low (22% and 33%, respectively). Fv/Fm values of riverine H. johnsonii were relatively high (0.65-0.70) after a single short pulse or gradual reduction to salinity of 10. Fv/Fm values of marine plants were lower in these two treatments and exhibited greater declines following a single, long pulse to a salinity of 10 or after a single gradual reduction to a salinity of 5. Fv/Fm values showed riverine plants were also more resistant to repeated pulses of moderate low salinity than marine plants. Our results indicate wide tolerances of H. johnsonii to short pulses of hyposalinity, but suggest that repeated or prolonged hyposalinity stress at near-tolerance salinity levels can have additive effects on photosynthetic health and survival. Differences in resilience of marine and riverine H. johnsonii populations are consistent with previous suggestions that estuarine ecophenes are more tolerant to hyposalinity than marine populations.

It is well established that neuroinflammation is associated with the progression of many neurodegenerative diseases, including Parkinson's disease (PD). Activated microglia and elevated levels of pro-inflammatory cytokines such as interleukin-1β (IL-1β) have been found in the brain and cerebrospinal fluid of PD patients, suggesting that IL-1β may be involved in the pathogenesis of this disease. This study aimed to knock down the expression of the interleukin-1 type 1 receptor (IL-1R1) to evaluate any potential therapeutic effect of limiting the action of IL-1β in the substantia nigra following a unilateral intrastriatal 6-hydroxydopamine (6-OHDA) lesion in rats. Adult Sprague-Dawley rats received intranigral injections of shRNA specific for IL-1R1, followed 2 weeks later by intrastriatal 6-OHDA. Injection of IL-1R1 shRNA did not prevent 6-OHDA-induced loss of motor function or loss of nigral dopamine neurons. IL-1R1 expression was increased in the midbrain following 6-OHDA injection; this effect was attenuated in 6-OHDA-treated animals that had received IL-1R1 shRNA. These data suggest that while IL-1R1 was increased in 6-OHDA-treated animals and reduced following shRNA injection, the neurodegeneration induced by 6-OHDA was not mediated through IL-1R1.

Growth/differentiation factor (GDF)5 and glial cell line-derived neurotrophic factor (GDNF) are neurotrophic factors that promote the survival of midbrain dopaminergic neurons in vitro and in vivo. Both factors have potent neurotrophic and neuroprotective effects in rat models of Parkinson's disease (PD) and represent promising new therapies for PD. The aim of this study was to investigate the expression of GDF5, GDNF and their receptors in the nigrostriatal dopaminergic system in rat models of PD. It found that endogenous GDF5, GDNF and their receptors are differentially expressed in two 6-hydroxydopamine lesion models of PD. In both striatal and medial forebrain bundle (MFB) lesion models, striatal levels of GDF5 mRNA increased at 10 days post-lesion, while GDNF mRNA levels in the nigrostriatal system decreased after 10 and 28 days. Midbrain mRNA levels for both GDF5 receptors transiently increased after striatal lesion, whereas those of two GDNF receptors decreased at later time-points in both models. Despite the fact that exogenous GDF5 and GDNF have comparable effects on dopaminergic neurons in vitro and in vivo, their endogenous responses to neurotoxic injury are different. This highlights the importance of studying neurotrophic factor expression at distinct disease stages and in various animal models of PD.

The ubiquitin-proteasome system (UPS) comprises a network of enzymes that is responsible for maintaining cellular protein homeostasis. The therapeutic potential of this pathway has been validated by the clinical successes of a number of UPS modulators, including proteasome inhibitors and immunomodulatory imide drugs (IMiDs). Here we identified TAK-243 (formerly known as MLN7243) as a potent, mechanism-based small-molecule inhibitor of the ubiquitin activating enzyme (UAE), the primary mammalian E1 enzyme that regulates the ubiquitin conjugation cascade. TAK-243 treatment caused depletion of cellular ubiquitin conjugates, resulting in disruption of signaling events, induction of proteotoxic stress, and impairment of cell cycle progression and DNA damage repair pathways. TAK-243 treatment caused death of cancer cells and, in primary human xenograft studies, demonstrated antitumor activity at tolerated doses. Due to its specificity and potency, TAK-243 allows for interrogation of ubiquitin biology and for assessment of UAE inhibition as a new approach for cancer treatment.

The buccinator flap is currently one of the best techniques for the reconstruction of defects in the oral cavity and other sites. Reconstruction of the palate is a major challenge because of the functional consequences of the excision of lesions in this area. The main goal is to maintain separation between the mouth and the nose. We have done a cross-sectional retrospective descriptive study of a series of cases reconstruction of palatal defects with buccinator flap at the University Hospital Miguel Servet in Zaragoza during a six-year period and compared our results, morbidity, and mortality with those of published series. The main complication was partial loss of the flap. We have analysed the reasons for this and report the steps needed to avoid it.

Hysterectomy, with or without oophorectomy, is associated with increased cardiovascular disease (CVD) risk due, in part, to an adverse CVD risk factor profile. Large artery stiffening, a biomarker of vascular aging, increases the risk for CVD. We determined whether hysterectomy with or without bilateral oophorectomy (BLO) is associated with arterial stiffening in healthy postmenopausal women.We conducted a cross-sectional study including estrogen-deficient postmenopausal women who had a hysterectomy with ovarian preservation (n = 24; mean ± SE age, 59 ± 1 y) or with BLO (n = 21; 58 ± 2 y) and had no hysterectomy/no BLO (n = 58; 58 ± 1 y). Arterial stiffness (arterial compliance and β stiffness index) was measured by ultrasonography of the carotid artery.Carotid artery compliance was lower in women with hysterectomy alone and in women with hysterectomy with BLO compared with women with no hysterectomy (0.66 ± 0.03 and 0.71 ± 0.06 vs 0.89 ± 0.03 mm/mm Hg × 10, respectively, both P0.05). There were no differences in traditional CVD risk factors (ie, adiposity, blood pressure and fasted lipids and lipoproteins, glucose, and insulin) between the groups. After adjustment for age, menopause duration, previous menopausal hormone therapy duration, parity, waist-to-hip ratio, systolic blood pressure, and sex hormone-binding globulin, hysterectomy status remained a significant predictor of arterial compliance.These results indicate that hysterectomy status (with or without BLO) is associated with greater arterial stiffening in estrogen-deficient postmenopausal women. The greater arterial stiffening with hysterectomy was not related to an adverse CVD risk profile. Large artery stiffening may be an important mechanism by which hysterectomy increases the risk of CVD in postmenopausal women.