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The objective was to evaluate total and incident mesh exposure rates at least 2 years after minimally invasive total hysterectomy and sacrocolpopexy. Secondary aims were to evaluate surgical success and late adverse events.This extension study included women previously enrolled in the multicenter randomized trial of permanent vs delayed-absorbable suture with lightweight mesh forstage II uterovaginal prolapse. Owing to COVID-19, women were given the option of an in-person (questionnaires and examination) or telephone visit (questionnaires only). The primary outcome was total and incident suture or mesh exposure, or symptoms suggestive of mesh exposure in women without an examination. Secondary outcomes were surgical success, which was defined as no subjective bulge, no prolapse beyond the hymen, and no pelvic organ prolapse retreatment, and adverse events.A total of 182 out of 200 previously randomized participants were eligible for inclusion, of whom 106 (58%) women (78 in-person and 28 via questionnaire only) agreed to the extension study. At a mean of 3.9 years post-surgery, the rate of mesh or suture exposure was 7.7% (14 out of 182) of whom only 2 were incident cases reported after 1-year follow-up. None reported vaginal bleeding or discharge, dyspareunia, or penile dyspareunia. Surgical success was 93 out of 106 (87.7%): 13 out of 94 (13.8%) failed by bulge symptoms, 2 out of 78 (2.6%) by prolapse beyond the hymen, 1 out of 85 (1.2%) by retreatment with pessary, and 0 by retreatment with surgery. There were no serious adverse events.The rate of incident mesh exposure between 1 and 3.9 years post-surgery was low, success rates remained high, and there were no delayed serious adverse events.

Renal innate immune cell accumulation and inflammation are associated with hypertension. Time restricted feeding (TRF) has been reported to decrease inflammation and blood pressure. Whether TRF can decrease blood pressure by decreasing renal innate immune cells in hypertension is unknown.We determined whether TRF can decrease blood pressure in two separate mouse models of hypertension, N(G)-nitro-L-arginine methyl ester hydrochloride-induced hypertension (LHTN) and salt-sensitive hypertension (SSHTN). Once hypertension was established after 2 days, TRF (12-h food/12-h no food) for 4 weeks significantly decreased systolic blood pressure in both LHTN and SSHTN mice despite no differences in the amount of food eaten or body weight between groups. Activated macrophages and dendritic cells in the kidneys of both LHTN and SSHTN mice were decreased significantly in mice that underwent TRF. This was associated with an improvement in kidney function (decreased serum creatinine, decreased fractional excretion of sodium, and increased creatinine clearance) which achieved significance in LHTN mice and trended towards improvement in SSHTN mice.Our findings demonstrate that TRF can significantly decrease renal innate immune cells and blood pressure in two mouse models of hypertension.

This study aimed to determine if children playing field hockey small-sided games (SSG) have different levels of physiological, performance and perceptual responses, compared to traditional hockey. Fifteen school hockey players (10–12 y) played eight matches over four months. Traditional games (n = 4) were played on a full-sized pitch with 11 players per team, and SSG were played as two-separate games (n = 8), with 7 players per team on a half-field pitch. Heart rate, movement data and match involvement were collected during the game. Participants were asked their session rating of perceived exertion (sRPE) and completed an enjoyment questionnaire. There were more possessions per player in the SSG format compared to traditional (53.9 ± 2.5 vs. 36.8 ± 6.5, [ d = 3.83]). Number of shots on goal, total goals, penalty corners and circle penetrations were increased in SSG compared to traditional games ( d = 1.11–1.83). Mean and maximum heart rate, sRPE, enjoyment, total distance run, meters per minute, distance run at low velocity and high velocity were similar for both formats, with no significant difference between them. SSG increased match involvements, allowing more participation than the traditional format, without compromising the physiological (e.g. heart rate), performance (e.g. total distance) and perceptual (e.g. sRPE) workload.

Objective To compare mesh and permanent suture exposure rates in the first year after minimally invasive total hysterectomy and sacrocolpopexy with a light-weight polypropylene mesh using permanent or delayed absorbable sutures. Methods Across five centers in the United States, women were randomized to permanent or delayed absorbable suture for vaginal attachment of a Y-mesh during hysterectomy and sacrocolpopexy for stage II prolapse and worse. The primary outcome was mesh or permanent suture exposure in the first year after surgery. The secondary outcome was to compare a composite measure for success defined as leading edge of prolapse not beyond the hymen and apex not descended more than one third vaginal length, and no subjective bulge and no prolapse retreatment. Patients completed a pelvic examination including the pelvic organ prolapse quantification system and questionnaires at baseline, 6 weeks and 1 year postsurgery. A sample size of 80 per group was planned to compare the rate of mesh or permanent suture exposure in the permanent compared with delayed absorbable groups. Results From April 2015 to May 2019, 204 patients (n=102 permanent; n=102 delayed absorbable) were randomized. One hundred ninety-eight women had follow-up data, with 182 (93%) completing 1-year follow-up: 95 of 99 (96%) permanent, 87 of 101 (86%) delayed absorbable. The total rate of mesh or permanent suture exposure was 12 of 198 (6.1%): 5.1% for permanent compared with 7.0% for delayed absorbable (risk ratio 0.73, 95% CI 0.24-2.22). The majority (9/12) were asymptomatic. Composite success was 93% for permanent compared with 95% for delayed absorbable suture, P=.43). Six (3.0%) women had a serious adverse event. Conclusion Suture type used for vaginal graft attachment did not influence mesh or permanent suture exposure rates. Funding source Boston Scientific Corporation. Clinical trial registration ClinicalTrials.gov, NCT02277925.

To compare the safety and effectiveness of dermal bovine transvaginal graft, Xenform, to native tissue in the surgical treatment of anterior and/or apical pelvic organ prolapse. This study was designed in conjunction with Food and Drug Administration requirements.This was a prospective, non-randomized, parallel cohort, multi-center trial. The primary objective was to demonstrate noninferiority between transvaginal graft and native tissue repair at 36 months compared to baseline. Treatment success was based on a composite of objective and subjective measures. The co-primary outcome was the rate of serious device- or procedure-related adverse events. A total of 228 patients at 25 sites were included in the study arm and 485 patients underwent native tissue repair. Propensity score stratification was applied to achieve balance between treatment groups. Study outcomes were compared in per protocol and intent-to-treat analysis.The primary outcome, treatment success at 36 months, was 83.6% (191/228) for transvaginal graft and 80.5% (390/485) native tissue repair (0.2%, 90% confidence interval [-5.6% to 5.9%]), demonstrating noninferiority at a preset margin of -12%. The overall rate of severe adverse events was 5.3% (12/228) in transvaginal graft vs 2.7% (13/485) in native tissue repair groups. The study group demonstrated noninferiority in serious adverse events at the preset margin of 11.6% (2.0%, 90% confidence interval [-0.8% to 4.7%]). There were no reports of graft erosion, and graft exposure rates were low (0.9% [2/228]).Transvaginal repair of anterior and/or apical prolapse with a biological graft is noninferior to traditional native tissue repair in effectiveness and safety at 36 months.

Hypertension is associated with inflammation and decreased kidney function. Studies of cardiovascular function have observed that time-restricted feeding (TRF), a form of intermittent fasting, is associated with decreased blood pressure, decreased inflammation, and improved kidney function. We hypothesized that implementation of a time-restricted feeding protocol in hypertensive mice would decrease systolic blood pressure and increase kidney function. C57BL6/J mice were randomly assigned to either an L-arginine methyl ester hydrochloride (LNAME)-induced hypertension (LHTN) model, where they received LNAME in their drinking water, or a salt-sensitive hypertension (SSHTN) model, where they received a 4% high salt diet following LNAME priming and a washout period. Two days following introduction of LNAME or the high salt diet, mice were either provided food ad libitum or placed on a 12-hour TRF protocol, where they were only allowed to eat from 8PM to 8AM. Hypertensive mice receiving TRF treatment displayed a significantly decreased systolic blood pressure (SBP) after 4 weeks when compared to the control hypertensive groups (LHTN SBP: 164±1 vs. 149±2 mmHg, p

Developmental methylmercury (MeHg) exposure selectively targets the cerebral and cerebellar cortices, as seen by disruption of cytoarchitecture and glutamatergic (GLUergic) neuron hypoplasia. To begin to understand the mechanisms of this loss of GLUergic neurons, we aimed to develop a model of developmental MeHg neurotoxicity in human-induced pluripotent stem cells differentiating into cortical GLUergic neurons. Three dosing paradigms at 0.1 μM and 1.0 μM MeHg, which span different stages of neurodevelopment and reflect toxicologically relevant accumulation levels seen in human studies and mammalian models, were established. With these exposure paradigms, no changes were seen in commonly studied endpoints of MeHg toxicity, including viability, proliferation, and glutathione levels. However, MeHg exposure induced changes in mitochondrial respiration and glycolysis and in markers of neuronal differentiation. Our novel data suggests that GLUergic neuron hypoplasia seen with MeHg toxicity may be due to the partial inhibition of neuronal differentiation, given the increased expression of the early dorsal forebrain marker FOXG1 and corresponding decrease in expression on neuronal markers MAP2 and DCX and the deep layer cortical neuronal marker TBR1. Future studies should examine the persistent and latent functional effects of this MeHg-induced disruption of neuronal differentiation as well as transcriptomic and metabolomic alterations that may mediate MeHg toxicity.

Barriers to regeneration in the mammalian central nervous system (CNS) include the presence of inhibitory factors like myelin-associated glycoprotein (MAG) that block re-growth of injured axons. Inhibition by MAG antagonizes the induction of integrin-based substrate adhesions in axonal growth cones by brain-derived neurotrophic factor (BDNF). Here, using a novel approach to overcome inhibitory actions of MAG by activating integrins, we provide cellular and molecular evidence that integrin activity modulates the actions of chemotropic cues on substrate adhesions and supports axon regeneration in vertebrates. Potentiating integrin activity in cultured spinal neurons blocked negative integrin remodeling and inhibition of axon outgrowth induced by MAG, but also restored BDNF-dependent integrin clustering and stimulated outgrowth. In a zebrafish complete spinal cord transection model, combined integrin activation and BDNF treatment synergistically triggered functional regeneration of long projection axons that lack regenerative capacity from the hindbrain. The combined treatment also promoted functional repair even in the presence of exogenous mammalian inhibitory factors, including MAG, which alone impaired recovery of swimming movements. Thus, integrin activation state plays complementary roles in modulating the output activity of opposing cues on integrin-based adhesions and supports functional nerve regenerationin vivo. Our findings reveal effective reversal of downstream actions of inhibitory cues, thereby overcoming a major barrier to regeneration in the mammalian CNS, while simultaneously supporting neurotrophin-stimulated outgrowth. Discovery of therapeutic strategies targeting integrin activation state therefore holds promise for promoting axon regeneration after traumatic injury, which is a critical step in restoring connectivity and functional recovery.

SummaryFollowing injury, the mammalian spinal cord forms a glial scar and fails to regenerate. In contrast, spinal cord tissue of vertebrate fish regenerates and restores function. Cord transection in zebrafish (Danio rerio) initially causes paralysis and neural cell death, with subsequent ependymal glial proliferation, extension of bipolar glia across the lesion, and neurogenesis. Axons extending from spared and nascent neurons along trans-lesional glial bridges restore functional connectivity. Here we report that glucocorticoids directly target the regeneration supporting changes in ependymal glia to inhibit neural repair. This effect is independent of hematogenic immune cells or microglia. Furthermore, glucocorticoid receptor signaling in ependymal glia is inversely regulated in rat models of spinal cord injury compared to zebrafish. The blockade of neural regeneration by glucocorticoids via a direct effect on ependymal glia has important clinical implications concerning the putative therapeutic benefit of corticosteroids in early management of spinal cord injury.

We compared changes in academic achievement across 3 years between children in elementary schools receiving the Academic Achievement and Physical Activity Across the Curriculum intervention (A+PAAC), in which classroom teachers were trained to deliver academic lessons using moderate-to-vigorous physical activity (MVPA) compared to a non-intervention control. Elementary schools in eastern Kansas (n=17) were cluster randomized to A+PAAC (N=9, target ≥ 100 min/wk.) or control (N=8). Academic achievement (math, reading, spelling) was assessed using the Wechsler Individual Achievement Test-Third Edition (WIAT-III) in a sample of children (A+PAAC = 316, Control = 268) in grades 2 and 3 at baseline (Fall 2011) and repeated each spring across 3 years. On average 55 min/wk. of A+PACC lessons were delivered each week across the intervention. Baseline WIAT-III scores (math, reading, spelling) were significantly higher in students in A+PAAC compared with control schools and improved in both groups across 3 years. However, linear mixed modeling, accounting for baseline between group differences in WIAT-III scores, ethnicity, family income, and cardiovascular fitness, found no significant impact of A+PAAC on any of the academic achievement outcomes as determined by non-significant group by time interactions. A+PAAC neither diminished or improved academic achievement across 3-years in elementary school children compared with controls. Our target of 100 min./wk. of active lessons was not achieved; however, students attending A+PAAC schools received an additional 55 min./wk. of MVPA which may be associated with both physical and mental health benefits, without a reduction in time devoted to academic instruction.

Glioblastoma multiforme (GBM) is the most common primary brain tumor, with a median survival of only 15 months. A subpopulation of cells, the brain tumor stem cells (BTSCs), may be responsible for the malignancy of this disease. Xenografts have proven to be a robust model of human BTSCs, but the effects of long-term passaging have yet to be determined. Here we present a study detailing changes in BTSC multipotency, invasive migration, and proliferation after serial passaging of human GBM xenografts. Immunocytochemistry and tumorsphere formation assays demonstrated the presence of BTSCs in both early generation (EG-BTSCs; less than 15 passages) and late generation (LG-BTSCs; more than 24 passages) xenografts. The EG-BTSCs upregulated expression of lineage markers for neurons and oligodendrocytes upon differentiation, indicating multipotency. In contrast, the LG-BTSCs were restricted to an astrocytic differentiation. Quantitative migration and proliferation assays showed that EG-BTSCs are more migratory and proliferative than LG-BTSCs. However, both populations respond similarly to the chemokine SDF-1 by increasing invasive migration. These differences between the EG- and LG-BTSCs were correlated with a significant decrease in nanog expression as determined by qRT-PCR. Mice implanted intracranially with EG-BTSCs showed shorter survival when compared to LG-BTSCs. Moreover, differentiation prior to implantation of EG-BTSCs, but not LG-BTSCs, led to increased survival. Thus, nanog may identify multipotent BTSCs. Furthermore, limited passaging of xenografts preserves these multipotent BTSCs, which may be an essential underlying feature of GBM lethality.

Multiple sclerosis (MS) is the most common chronic inflammatory, demyelinating disease of the CNS and results in neurological disability. Existing immunomodulatory and immunosuppressive approaches lower the number of relapses but do not cure or reverse existing deficits nor improve long-term disability in MS patients.Monogenic antibodies were described as treatment options for MS, however the immunogenicity of mouse antibodies hampered the efficacy of potential therapeutics in humans. Availability of improved antibody production technologies resulted in a paradigm shift in MS treatment strategies. In this review, an overview of immunotherapies for MS that use conventional monoclonal antibodies reactive to immune system and their properties and mechanisms of action will be discussed, including recent advances in MS therapeutics and highlight natural autoantibodies (NAbs) that directly target CNS cells.Recent challenges for MS therapy are the identification of relevant molecular and cellular targets, time frame of treatment, and antibody toxicity profiles to identify safe treatment options for MS patients. The application of monoclonal antibody therapies with better biological efficacy associated with minimum side effects possesses huge clinical potential. Advances in monoclonal antibody technologies that directly target cells of nervous system may promote the CNS regeneration field from bench to bedside.

The action of many extracellular guidance cues on axon pathfinding requires Ca2+influx at the growth cone (Hong et al., 2000; Nishiyama et al., 2003; Henley and Poo, 2004), but how activation of guidance cue receptors leads to opening of plasmalemmal ion channels remains largely unknown. Analogous to the chemotaxis of amoeboid cells (Parent et al., 1998; Servant et al., 2000), we found that a gradient of chemoattractant triggered rapid asymmetric PI(3,4,5)P3accumulation at the growth cone's leading edge, as detected by the translocation of a GFP-tagged binding domain of Akt inXenopus laevisspinal neurons. Growth cone chemoattraction required PI(3,4,5)P3production and Akt activation, and genetic perturbation of polarized Akt activity disrupted axon pathfindingin vitroandin vivo. Furthermore, patch-clamp recording from growth cones revealed that exogenous PI(3,4,5)P3rapidly activated TRP (transient receptor potential) channels, and asymmetrically applied PI(3,4,5)P3was sufficient to induce chemoattractive growth cone turning in a manner that required downstream Ca2+signaling. Thus, asymmetric PI(3,4,5)P3elevation and Akt activation are early events in growth cone chemotaxis that link receptor activation to TRP channel opening and Ca2+signaling. Altogether, our findings reveal that PI(3,4,5)P3elevation polarizes to the growth cone's leading edge and can serve as an early regulator during chemotactic guidance.

Graded distributions of extracellular cues guide developing axons toward their targets. A network of second messengers - Ca(2+) and cyclic nucleotides - shapes cue-derived information into either attractive or repulsive signals that steer growth cones bidirectionally. Emerging evidence suggests that such guidance signals create a localized imbalance between exocytosis and endocytosis, which in turn redirects membrane, adhesion and cytoskeletal components asymmetrically across the growth cone to bias the direction of axon extension. These recent advances allow us to propose a unifying model of how the growth cone translates shallow gradients of environmental information into polarized activity of the steering machinery for axon guidance.

Foraging behaviour and habitat selection occur as hierarchical processes. Understanding the factors that govern foraging and habitat selection thus requires investigation of those processes over the scales at which they occur. We investigated patterns of habitat use by African elephants (Loxodonta africana) in relation to vegetation greenness to investigate the scale at which that landscape attribute was most closely related to distribution of elephant locations. We analysed Global Positioning System radio-collar locations for 15 individuals, using the Normalized Difference Vegetation Index as a representation of vegetation greenness in a Geographic Information Systems framework. We compared the importance of vegetation greenness at three spatial scales: the total home range, the seasonal home range and the 16-day home range. During the wet season, seasonal home ranges for both sexes were associated with intermediate greenness within the total home range; there was no evidence of selection based on greenness at finer scales. During the dry season, the strongest associations were within the 16-day home range: individual locations for males tended to be in areas of intermediate greenness, and those for females were in areas of intermediate and high greenness. Our findings suggest that the role of vegetation greenness varies with the scale of analysis, likely reflecting the hierarchical processes involved in habitat selection by elephants.