The Pacific Lamprey Entosphenus tridentatus, an anadromous fish native to the northern Pacific Ocean and bordering freshwater habitats, has recently experienced steep declines in abundance and range ...contractions along the West Coast of North America. During the early 1990s, Native American tribes recognized the declining numbers of lamprey and championed their importance. In 2012, 26 entities signed a conservation agreement to coordinate and implement restoration and research for Pacific Lamprey. Regional plans have identified numerous threats, monitoring needs, and strategies to conserve and restore Pacific Lamprey during their freshwater life stages. Prime among these are needs to improve lamprey passage, restore freshwater habitats, educate stakeholders, and implement lamprey‐specific research and management protocols. Key unknowns include range‐wide trends in status, population dynamics, population delineation, limiting factors, and marine influences. We synthesize these key unknowns, with a focus on the freshwater life stages of lamprey in the Columbia River basin.
Individuals with Angelman syndrome (AS) suffer sleep disturbances that severely impair quality of life. Whether these disturbances arise from sleep or circadian clock dysfunction is currently ...unknown. Here, we explored the mechanistic basis for these sleep disorders in a mouse model of Angelman syndrome (Ube3a(m-/p+) mice). Genetic deletion of the maternal Ube3a allele practically eliminates UBE3A protein from the brain of Ube3a(m-/p+) mice, because the paternal allele is epigenetically silenced in most neurons. However, we found that UBE3A protein was present in many neurons of the suprachiasmatic nucleus--the site of the mammalian circadian clock--indicating that Ube3a can be expressed from both parental alleles in this brain region in adult mice. We found that while Ube3a(m-/p+) mice maintained relatively normal circadian rhythms of behavior and light-resetting, these mice exhibited consolidated locomotor activity and skipped the timed rest period (siesta) present in wild-type (Ube3a(m+/p+)) mice. Electroencephalographic analysis revealed that alterations in sleep regulation were responsible for these overt changes in activity. Specifically, Ube3a(m-/p+) mice have a markedly reduced capacity to accumulate sleep pressure, both during their active period and in response to forced sleep deprivation. Thus, our data indicate that the siesta is governed by sleep pressure, and that Ube3a is an important regulator of sleep homeostasis. These preclinical findings suggest that therapeutic interventions that target mechanisms of sleep homeostasis may improve sleep quality in individuals with AS.
Angelman syndrome (AS) is a severe neurodevelopmental disorder caused by loss of expression of the maternal copy of the UBE3A gene. Individuals with AS have severe sleep dysfunction that affects their cognition and presents challenges to their caregivers. Unfortunately, current treatment strategies have limited efficacy due to a poor understanding of the mechanisms underlying sleep disruptions in AS. Here we demonstrate that abnormal sleep patterns arise from a deficit in accumulation of sleep drive, uncovering the Ube3a gene as a novel genetic regulator of sleep homeostasis. Our findings encourage a re-evaluation of current treatment strategies for sleep dysfunction in AS, and suggest that interventions that promote increased sleep drive may alleviate sleep disturbances in individuals with AS.
Veno-venous extracorporeal membrane oxygenation is increasingly used for severe but potentially reversible acute respiratory failure in adults; however, there are limited data regarding long-term ...morbidity. At our institution, most patients requiring veno-venous extracorporeal membrane oxygenation have been followed up by a single physician. Our primary aim was to describe the serial long-term morbidity for respiratory, musculoskeletal and psychological functioning.
A retrospective audit of inpatient and outpatient medical records was conducted. A total of 125 patients treated with veno-venous extracorporeal membrane oxygenation for primary respiratory failure were included. The patients were young (mean (standard deviation) age 43.7 (4.1) years), obese (mean (standard deviation) body mass index 30.8 (10.4) kg/m2), and mostly were male (59%). Most patients (60%) had no comorbidities.
The survival rate to discharge was 70%, with body mass index and the number of comorbidities being independent predictors of survival on multiple logistic regression analysis. Over half (57%) of the Australian survivors had regular outpatient follow-up. They had a median of three reviews (range 1-9) over a median of 11.8 months (range 1.5-79) months. Breathlessness and weakness resolved in most within six months, with lung function abnormalities taking longer to resolve. Over half (60%) returned to employment within six months of discharge. Over a quarter (29%) displayed symptoms of anxiety, depression or post-traumatic stress disorder.
•Alginates with high M content foul (bind to) hydrophobic membranes at low and neutral pH.•M has been shown by quantum chemical calculations to be to be uniquely amphiphilic.•A hydrophobic patch on M ...allows alginate polymers containing M to bind to a hydrophobic surface.•The mechanism of alginate binding to a hydrophobic membrane (polypropylene) has been demonstrated by MD simulations.•The hydrophobic patch of M is essential for the functioning of the enzyme mannuronan C-5 epimerase AlgE4.
Ostensibly hydrophilic alginates are known to foul hydrophobic membranes, under various conditions. Here, controlled experiments have been conducted at high and low pH on the fouling of a polypropylene membrane by alginate and the results suggest that the observed fouling is due to an intrinsic property of the alginate. Thus quantum chemical calculations on the M and G monomers of alginate reveal that M adopts an equilibrium geometry that is hydrophilic on one face and hydrophobic on the other, i.e. is potentially amphiphilic. Molecular dynamics simulations on short alginate chains of different sequences interacting with a modelled polypropylene surface, show that this characteristic is carried over to the polymer and results in hydrophobic patches along the chain that facilitate attractive interactions with the polypropylene surface. This concept is buttressed by an analysis of the binding characteristics of a previously reported X-ray structure of the mannuronan C-5 epimerase AlgE4 enzyme.
Background
Conflicting data exist on predictors of nodal metastases and their impact on survival in patients with pancreatic neuroendocrine tumors (PNETs). We aim to identify factors associated with ...lymph node involvement and evaluate the effect of nodal metastases on survival.
Methods
All patients undergoing surgery for PNETs in the Surveillance, Epidemiology, and End Results (SEER) tumor registry from 1988 to 2010 were included. Predictors of lymph node involvement and disease-specific survival (DSS) were evaluated using logistic regression and Cox regression, respectively.
Results
Patients (1,915) underwent surgery for a PNET (62 % nonfunctional). Nodal positivity was associated with increasing tumor size (
p
< 0.001) and grade (
p
< 0.001). Unadjusted DSS at 5 years was 81 % for N0, 74 % for Nx, and 69 % for N1, respectively, (
p
< 0.001). After adjustment for tumor size and grade, DSS was significantly decreased in N1 patients (HR 1.57; 95 % CI 1.23–1.95). For patients who had at least one node examined and had low-grade PNETs <1 cm, no nodal metastases were found.
Conclusions
High tumor grade and increasing size predict nodal metastases in patients with PNETs. N1 status is independently associated with decreased DSS. Low-grade tumors <1 cm may be observed or enucleated.
Objectives
Primary objectives: to determine whether local anaesthetic transperineal prostate (LATP) biopsy improves the detection of clinically significant prostate cancer (csPCa), defined as ...International Society of Urological Pathology (ISUP) Grade Group ≥2 disease (i.e., any Gleason pattern 4 disease), compared to transrectal ultrasound‐guided (TRUS) prostate biopsy, in biopsy‐naïve men undergoing biopsy based on suspicion of csPCa. Secondary objectives: to compare (i) infection rates, (ii) health‐related quality of life, (iii) patient‐reported procedure tolerability, (iv) patient‐reported biopsy‐related complications (including bleeding, bruising, pain, loss of erectile function), (v) number of subsequent prostate biopsy procedures required, (vi) cost‐effectiveness, (vii) other histological parameters, and (viii) burden and rate of detection of clinically insignificant PCa (ISUP Grade Group 1 disease) in men undergoing these two types of prostate biopsy.
Patients and Methods
The TRANSLATE trial is a UK‐wide, multicentre, randomised clinical trial that meets the criteria for level‐one evidence in diagnostic test evaluation. TRANSLATE is investigating whether LATP biopsy leads to a higher rate of detection of csPCa compared to TRUS prostate biopsy. Both biopsies are being performed with an average of 12 systematic cores in six sectors (depending on prostate size), plus three to five target cores per multiparametric/bi‐parametric magnetic resonance imaging lesion. LATP biopsy is performed using an ultrasound probe‐mounted needle‐guidance device (either the ‘Precision‐Point’ or BK UA1232 system). TRUS biopsy is performed according to each hospital's standard practice. The study is 90% powered to detect a 10% difference (LATP biopsy hypothesised at 55% detection rate for csPCa vs 45% for TRUS biopsy). A total of 1042 biopsy‐naïve men referred with suspected PCa need to be recruited.
Conclusions
This trial will provide robust prospective data to determine the diagnostic ability of LATP biopsy vs TRUS biopsy in the primary diagnostic setting.
More than half of adults with epilepsy undergoing resective epilepsy surgery achieve long-term seizure freedom and might consider withdrawing antiseizure medications. We aimed to identify predictors ...of seizure recurrence after starting postoperative antiseizure medication withdrawal and develop and validate predictive models. We performed an international multicentre observational cohort study in nine tertiary epilepsy referral centres. We included 850 adults who started antiseizure medication withdrawal following resective epilepsy surgery and were free of seizures other than focal non-motor aware seizures before starting antiseizure medication withdrawal. We developed a model predicting recurrent seizures, other than focal non-motor aware seizures, using Cox proportional hazards regression in a derivation cohort (n = 231). Independent predictors of seizure recurrence, other than focal non-motor aware seizures, following the start of antiseizure medication withdrawal were focal non-motor aware seizures after surgery and before withdrawal adjusted hazard ratio (aHR) 5.5, 95% confidence interval (CI) 2.7-11.1, history of focal to bilateral tonic-clonic seizures before surgery (aHR 1.6, 95% CI 0.9-2.8), time from surgery to the start of antiseizure medication withdrawal (aHR 0.9, 95% CI 0.8-0.9) and number of antiseizure medications at time of surgery (aHR 1.2, 95% CI 0.9-1.6). Model discrimination showed a concordance statistic of 0.67 (95% CI 0.63-0.71) in the external validation cohorts (n = 500). A secondary model predicting recurrence of any seizures (including focal non-motor aware seizures) was developed and validated in a subgroup that did not have focal non-motor aware seizures before withdrawal (n = 639), showing a concordance statistic of 0.68 (95% CI 0.64-0.72). Calibration plots indicated high agreement of predicted and observed outcomes for both models. We show that simple algorithms, available as graphical nomograms and online tools (predictepilepsy.github.io), can provide probabilities of seizure outcomes after starting postoperative antiseizure medication withdrawal. These multicentre-validated models may assist clinicians when discussing antiseizure medication withdrawal after surgery with their patients.
Due to the extensive host range of influenza A viruses, it is difficult to determine the best diagnostic algorithm to efficiently screen samples from a variety of host species for influenza A ...viruses. While there are some influenza diagnostic algorithms that are specific to host species, to our knowledge, no single algorithm exists for the characterization of influenza A viruses across multiple host species. In this paper, we propose an algorithm that can serve as a guide for screening human, animal, and environmental samples for influenza A viruses of high human and animal health importance.
Objective: PTSD in female veterans and service members (SMs) is understudied, and new, effective treatments for PTSD are needed. Reconsolidation of Traumatic Memories (RTM) is a brief, manualized ...treatment for PTSD previously piloted in RCTs of male veterans and SMs. Here we examine RTM's effect on military women with PTSD. Method: We report a waitlist RCT using 30 military-connected females with DSM-IV-TR PTSD diagnoses, including current-month nightmares or flashbacks. Trauma types include military sexual trauma, other sexual traumas, combat, and other trauma types. Participants were randomized to treatment or waitlist. Of those enrolled, 97% completed treatment. Independent psychometricians, blinded to treatment condition, evaluated participants at intake, postwait, and two weeks post. The clinician took follow-up measures at six months and one year. The primary measure was the PTSD Symptom Scale-Interview (PSS-I). The secondary measure was the PTSD Checklist. Participants received up to three 120-min sessions of RTM. Results: RTM eliminated intrusive symptoms and significantly decreased symptom scale ratings in 90% (n = 27) of participants, versus 0% of controls (p < .001). Two-week treatment group PSS-I scores dropped 33.9 points versus 3.9 points for postwait controls (g = 3.7; 95% CI 2.5, 4.8; p < .001). Treatment results were stable to 1 year. Conclusions: RTM effectively treated PTSD, independent of trauma source in female SMs and veterans effectively replicating previous results in male populations. Further research is recommended.
Clinical Impact Statement
This study presents the Reconsolidation of Traumatic Memories Protocol for posttraumatic stress disorder (PTSD) and tests its effectiveness for female veterans and active duty service members. The treatment is brief, and nontraumatizing, and its high rates of PTSD remission are maintained for at least one year. The PTSD-diagnosed participants included many with military sexual traumas. The results for all participants were comparable to male veterans and service members in two other trials.
Notochord-derived Sonic Hedgehog (Shh) is essential for dorsoventral patterning of the overlying neural tube. Increasing concentration and duration of Shh signal induces progenitors to acquire ...progressively more ventral fates. We show that Notch signalling augments the response of neuroepithelial cells to Shh, leading to the induction of higher expression levels of the Shh target gene Ptch1 and subsequently induction of more ventral cell fates. Furthermore, we demonstrate that activated Notch1 leads to pronounced accumulation of Smoothened (Smo) within primary cilia and elevated levels of full-length Gli3. Finally, we show that Notch activity promotes longer primary cilia both in vitro and in vivo. Strikingly, these Notch-regulated effects are Shh independent. These data identify Notch signalling as a novel modulator of Shh signalling that acts mechanistically via regulation of ciliary localisation of key components of its transduction machinery.
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