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Abstract Objective: Statins have been shown to impact international normalized ratio (INR) when coadministered with warfarin. The aim of this study was to assess the effect of pitavastatin compared with rosuvastatin on steady-state pharmacodynamics (PD) of warfarin by measuring INR in healthy adult subjects. Methods: Subjects received oral doses of warfarin 5 mg once daily on days 1 through 3. The dose was titrated on days 4 through 9 to reach a steady-state INR of 1.5 to 2.2. Warfarin was continued on days 10 through 21 and pitavastatin 4 mg or rosuvastatin 40 mg was administered once daily on days 14 through 22. After a 14-day washout period, the process was repeated with the alternate statin. Study number: NK-104-4.03US. Results: For pitavastatin, mean INR changed from 1.73 ± 0.18 (n = 42) on day 14 before starting statin dosing, to 1.78 ± 0.29 (n = 42) on day 22 at treatment end; the difference in INR was not significant (p = 0.219). For rosuvastatin, mean INR increased significantly from 1.74 ± 0.20 (n = 43) at baseline to 1.90 ± 0.30 (n = 43) at treatment end (p < 0.001). Rosuvastatin caused a significantly greater increase in INR than pitavastatin (p < 0.001). Conclusion: Steady-state INR during warfarin treatment did not change significantly when pitavastatin 4 mg was added to the regimen, while a significant increase was observed when rosuvastatin 40 mg was added. The effect of rosuvastatin on INR was significantly larger than the effect of pitavastatin. This study is limited because it was done in healthy volunteers. Further studies in patient populations are needed to better understand the clinical significance of the results. [ABSTRACT FROM AUTHOR]

Individuals differ considerably in their vulnerability to task-induced stress, in part because of individual differences in cognitions of task demands. This study investigated the personality and cognitive factors that may control stress vulnerability, using a 'rapid information processing' task that was configured to overload attention. Stress response was assessed using the Dundee Stress State Questionnaire (Matthews, G. et al., 2002. Fundamental dimensions of subjective state in performance settings: task engagement, distress and worry. Emotion, 2, 315-340), as well as instruments assessing workload, appraisal and coping. Time pressure was manipulated as a between-subjects stress factor. Higher time pressure tended to elicit decreased effort and task engagement and avoidance coping. However, much of the variance in state response was attributable to individual differences in appraisal and coping. The personality trait of neuroticism related to some of these cognitive processes. Subjective state, appraisal and coping were also predictive of objective performance indices. Consistent with the transactional theory of stress, subjective states appear to correspond to configurations of cognitive processes that signal the participant's mode of adaptation to task demands. The findings underscore the importance of accommodating individual differences in selecting operators for handling overload, for designing interfaces and for training operators to manage overload successfully. [ABSTRACT FROM AUTHOR]

We present an unusual case of a medial meniscal tear in which a large fragment of meniscus was displaced posteriorly, outside the intercondylar notch, posterior to the posterior cruciate ligament (PCL). The appearance mimicked a second PCL posteriorly. The extensive longitudinal ("bucket-handle") tear was detached from the anterior horn of the meniscus but remained in continuity with the posterior tibial attachment. The fragment was prevented from displacement into the intercondylar notch by its large size, the ligament of Humphrey, and the anatomic location of the PCL. This case highlights the value of thin-section, high-resolution, cartilage-sensitive imaging, not only in defining the extent, location, and source of displaced meniscal fragments but also in demonstrating associated chondral injuries. [ABSTRACT FROM AUTHOR]

Study Design: A case report of traumatic atlanto-occipital dislocation complicated by the development of anterior and posterolateral pseudomeningoceles and the late development of syringohydromyelia is presented.Objective: To describe a unique post-traumatic and postsurgical course following atlanto-occipital dislocation.Summary Of Background Data: Syringomyelia is a significant potential long-term complication in patients recovering from traumatic atlanto-occipital dislocation. Cord enlargement and increased T2 signal can be a marker of abnormal cerebrospinal fluid flow dynamics. This "presyrinx state" can be seen before clinical evidence of neurologic compromise. Pseudomeningocele formation after atlanto-occipital dislocation is rare, with only 3 reported cases. To our knowledge, all reported cases describe retropharyngeal pseudomeningoceles, and posterolateral pseudomeningocele as seen in this case has not previously been described.Methods: A single case is reported with an emphasis on the imaging findings related to the patient's subsequent neurologic deterioration.Results: Following a pedestrian-motor vehicle collision, the patient received initial evaluation and treatment at a local foreign medical facility, where his cervical spine was cleared. Several days following stabilizing treatment and surgery, the patient was transferred to a foreign-based United States military medical facility and ultimately to our institution, where magnetic resonance imaging demonstrated occipitocervical dissociation. The patient was taken to the operating room for surgical stabilization. Four months after his index operation, the patient underwent halo removal. Follow-up magnetic resonance imaging revealed thickening of the cervical spinal cord in conjunction with diffuse high cord T2 signal and a small low cervical segment of syringomyelia. The patient was observed with follow-up magnetic resonance imaging obtained after 1 month. At this time, the low cervical syrinx had enlarged slightly, a small thoracic syrinx was observed, and cine imaging of cerebrospinal fluid flow demonstrated obstruction at the level of the foramen magnum. The patient was taken to the operating room fordecompression of the foramen magnum and posterior fossa and duraplasty. One month later, the patient's clinical condition began to deteriorate, and repeat imaging showed continued enlargement of the patient's syrinx and hydrocephalus. He was admitted for an urgent shunt procedure but unfortunately sustained cardiorespiratory arrest while on the ward awaiting surgery.Conclusions: Atlanto-occipital dislocation is rarely survivable, and delayed diagnosis can negatively affect long-term clinical outcome. This case illustrates how, despite early signs of improvement, post-traumatic syringomyelia may occur months or even years after spinal trauma and should always be considered in patients who experience late neurologic deterioration after atlanto-occipital dislocation. [ABSTRACT FROM AUTHOR]

Question: Do individualised computer generated nutrition information and iterative feedback reduce dietary fat intake and increase fruit and vegetable intake? Design: Randomised controlled trial. Setting: The Netherlands. Participants: Participants were recruited through newspaper and radio advertisements. 762 participants completed the baseline questionnaire. Follow up was 85% (n=646, mean age 44 y, 82% women). Intervention: Participants were allocated to 1 of 3 groups, which differed by the type of nutrition information they received: a computer generated feedback letter individualised to the participant's dietary behaviour for fat, fruit, and vegetable intake and a second iterative feedback letter tailored to changes in dietary behaviour made after the first feedback letter (group 1, n=215); a computer generated feedback letter, which was the same as the one that group 1 participants received, without a second iterative feedback letter (group 2, n=211); and a general nutrition information letter that promoted a diet low in fat and high in fruits and vegetables (group 3, n=220). Main outcome measures: Self reported fat, fruit, and vegetable intake at 4 weeks after receiving the first nutrition information letter (first post-test) and 4 weeks after participants in group 1 received the interative feedback letter (final post-test). Main results: At the final post-test, mean fat points per day were higher in group 3 (27.5) than in both group 1 (25.6, p < 0.001) and group 2 (26.2, p=0.01), which showed that individualised computer generated feedback alone or combined with iterative feedback reduced fat intake more than a general nutrition information letter. There was no difference in fat points between groups 1 and 2. At the final post-test, mean number of servings of vegetables per day were higher in group 1 (1.20) than in group 3 (1.08, p=0.001), showing that individualised computer generated feedback plus iterative feedback increased vegetable intake more than a general nutrition information letter. There were no differences in vegetable intake between groups 1 and 2 or between groups 2 and 3. At the final post-test, mean number of servings of fruit per day were higher in group 1 (2.45) than in group 3 (2.02, p = 0.006), again showing the benefit of adding iterative feedback to individualised computer generated feedback. There were no differences in fruit intake between groups 1 and 2 or between groups 2 and 3. Conclusion: Computer generated individualised feedback plus iterative feedback had a greater effect on reducing fat and increasing fruit and vegetable intake than general nutrition information. [ABSTRACT FROM AUTHOR]

The etiology of interstitial cystitis/bladder pain syndrome (IC/BPS) is unknown but likely multifactorial. IC/BPS symptoms can be exacerbated by psychological stress, but underlying mechanisms remain to be defined. Transient receptor potential vanilloid 1 (TRPV1) channels, expressed on nerve fibers, have been implicated in bladder dysfunction and colonic hypersensitivity with stress in rodents. Histamine/H1R activation of TRPV1 + nerves increases bladder afferent fiber sensitivity to distension. TRPV1 channels are also expressed on mast cells, previously implicated in contributing to IC/BPS etiology and symptoms. We have examined the contribution of TRPV1 and mast cells to bladder dysfunction after repeated variate stress (RVS). RVS increased ( P ≤ 0.05) serum and fecal corticosterone expression and induced anxiety-like behavior in wild-type (WT) mice. Intravesical instillation of the selective TRPV1 antagonist capsazepine (CPZ) rescued RVS-induced bladder dysfunction in WT mice. Trpv1 knockout (KO) mice did not increase voiding frequency with RVS and did not exhibit increased serum corticosterone expression despite exhibiting anxiety-like behavior. Mast cell-deficient mice (B6.Cg- Kit w-sh ) failed to demonstrate RVS-induced increased voiding frequency or serum corticosterone expression, whereas control (no stress) mast cell-deficient mice had similar functional bladder capacity to WT mice. TRPV1 protein expression was significantly increased in the rostral lumbar (L1-L2) spinal cord and dorsal root ganglia (DRG) in WT mice exposed to RVS, but no changes were observed in lumbosacral (L6-S1) spinal segments or DRG. These studies demonstrated TRPV1 and mast cell involvement in RVS-induced increased voiding frequency and suggest that TRPV1 and mast cells may be useful targets to mitigate stress-induced urinary bladder dysfunction. NEW & NOTEWORTHY Using pharmacological tools and transgenic mice in a repeated variate stress (RVS) model in female mice, we demonstrate that transient receptor potential vanilloid 1 (TRPV1) and mast cells contribute to the increased voiding frequency observed following RVS. TRPV1 and mast cells should continue to be considered as targets to improve bladder function in stress-induced bladder dysfunction.

We report the first mass measurement of the proton-halo candidate ^{22}Al performed with the low energy beam ion trap facility's 9.4 T Penning trap mass spectrometer at facility for rare isotope beams. This measurement completes the mass information for the lightest remaining proton-dripline nucleus achievable with Penning traps. ^{22}Al has been the subject of recent interest regarding a possible halo structure from the observation of an exceptionally large isospin asymmetry [J. Lee et al., Large isospin asymmetry in Si22/O22 Mirror Gamow-Teller transitions reveals the halo structure of ^{22}Al, Phys. Rev. Lett. 125, 192503 (2020).PRLTAO0031-900710.1103/PhysRevLett.125.192503]. The measured mass excess value of ME=18 092.5(3)  keV, corresponding to an exceptionally small proton separation energy of S&#95;{p}=100.4(8)  keV, is compatible with the suggested halo structure. Our result agrees well with predictions from sd-shell USD Hamiltonians. While USD Hamiltonians predict deformation in the ^{22}Al ground state with minimal 1s&#95;{1/2} occupation in the proton shell, a particle-plus-rotor model in the continuum suggests that a proton halo could form at large quadrupole deformation. These results emphasize the need for a charge radius measurement to conclusively determine the halo nature.

Symptom exacerbation due to stress is prevalent in many disease states, including functional disorders of the urinary bladder (e.g., overactive bladder (OAB), interstitial cystitis/bladder pain syndrome (IC/BPS)); however, the mechanisms underlying the effects of stress on micturition reflex function are unclear. In this study we designed and evaluated a stress-induced symptom exacerbation (SISE) mouse model that demonstrates increased urinary frequency and somatic (pelvic and hindpaw) sensitivity. Cyclophosphamide (CYP) (35 mg/kg; i.p., every 48 hours for a total of 4 doses) or 7 days of repeated variate stress (RVS) did not alter urinary bladder function or somatic sensitivity; however, both CYP alone and RVS alone significantly (p ≤ 0.01) decreased weight gain and increased serum corticosterone. CYP treatment when combined with RVS for 7 days (CYP+RVS) significantly (p ≤ 0.01) increased serum corticosterone, urinary frequency and somatic sensitivity and decreased weight gain. CYP+RVS exposure in mice significantly (p ≤ 0.01) increased (2.6-fold) voiding frequency as we determined using conscious, open-outlet cystometry. CYP+RVS significantly (p ≤ 0.05) increased baseline, threshold, and peak micturition pressures. We also evaluated the expression of NGF, BDNF, CXC chemokines and IL-6 in urinary bladder in CYP alone, RVS alone and CYP+RVS mouse cohorts. Although all treatments or exposures increased urinary bladder NGF, BDNF, CXC and IL-6 content, CYP+RVS produced the largest increase in all inflammatory mediators examined. These results demonstrated that CYP alone or RVS alone creates a change in the inflammatory environment of the urinary bladder but does not result in a change in bladder function or somatic sensitivity until CYP is combined with RVS (CYP+RVS). The SISE model of CYP+RVS will be useful to develop testable hypotheses addressing underlying mechanisms where psychological stress exacerbates symptoms in functional bladder disorders leading to identification of targets and potential treatments., Competing Interests: Conflict of Interest The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

Psychological stress is associated with urinary bladder dysfunction (e.g., increased voiding frequency, urgency and pelvic pain); however, the mechanisms underlying the effects of stress on urinary bladder function are unknown. Transient receptor potential (TRP) channels (vanilloid family) may be potential targets for intervention due to their distribution in the LUT and role in pain. Here, we examine a model of repeated variate stress (RVS) of 2 week (wk) or 4 wk duration in female mice and its effects on bladder function, anxiety-like behavior, and TRPV transcript expression in urinary bladder and lumbosacral spinal cord and associated dorsal root ganglia (DRG). Using continuous infusion, open-outlet cystometry in conscious mice, RVS significantly (p ≤ 0.05) decreased infused volume and intermicturition interval. Bladder pressures (threshold, average, minimum, and maximum pressures) were unchanged with RVS. Quantitative PCR demonstrated significant (p ≤ 0.05) changes in TrpV1 and TrpV4 mRNA expression between control and RVS cohorts in the urothelium, lumbosacral spinal cord, and DRG. Future directions will examine the contribution of TRP channels on bladder function, somatic sensation and anxiety-like behavior following RVS., Competing Interests: Conflict of Interest The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

Background: High triglyceride levels are associated with increased cardiovascular risk, but whether reductions in these levels would lower the incidence of cardiovascular events is uncertain. Pemafibrate, a selective peroxisome proliferator-activated receptor α modulator, reduces triglyceride levels and improves other lipid levels., Methods: In a multinational, double-blind, randomized, controlled trial, we assigned patients with type 2 diabetes, mild-to-moderate hypertriglyceridemia (triglyceride level, 200 to 499 mg per deciliter), and high-density lipoprotein (HDL) cholesterol levels of 40 mg per deciliter or lower to receive pemafibrate (0.2-mg tablets twice daily) or matching placebo. Eligible patients were receiving guideline-directed lipid-lowering therapy or could not receive statin therapy without adverse effects and had low-density lipoprotein (LDL) cholesterol levels of 100 mg per deciliter or lower. The primary efficacy end point was a composite of nonfatal myocardial infarction, ischemic stroke, coronary revascularization, or death from cardiovascular causes., Results: Among 10,497 patients (66.9% with previous cardiovascular disease), the median baseline fasting triglyceride level was 271 mg per deciliter, HDL cholesterol level 33 mg per deciliter, and LDL cholesterol level 78 mg per deciliter. The median follow-up was 3.4 years. As compared with placebo, the effects of pemafibrate on lipid levels at 4 months were -26.2% for triglycerides, -25.8% for very-low-density lipoprotein (VLDL) cholesterol, -25.6% for remnant cholesterol (cholesterol transported in triglyceride-rich lipoproteins after lipolysis and lipoprotein remodeling), -27.6% for apolipoprotein C-III, and 4.8% for apolipoprotein B. A primary end-point event occurred in 572 patients in the pemafibrate group and in 560 of those in the placebo group (hazard ratio, 1.03; 95% confidence interval, 0.91 to 1.15), with no apparent effect modification in any prespecified subgroup. The overall incidence of serious adverse events did not differ significantly between the groups, but pemafibrate was associated with a higher incidence of adverse renal events and venous thromboembolism and a lower incidence of nonalcoholic fatty liver disease., Conclusions: Among patients with type 2 diabetes, mild-to-moderate hypertriglyceridemia, and low HDL and LDL cholesterol levels, the incidence of cardiovascular events was not lower among those who received pemafibrate than among those who received placebo, although pemafibrate lowered triglyceride, VLDL cholesterol, remnant cholesterol, and apolipoprotein C-III levels. (Funded by the Kowa Research Institute; PROMINENT ClinicalTrials.gov number, NCT03071692.)., (Copyright © 2022 Massachusetts Medical Society.)

Lamina propria interstitial cells that express the tyrosine kinase receptor, platelet-derived growth factor receptor alpha (PDGFRα) may play a role in urinary sensory signaling. Imatinib mesylate, also referred to as imatinib, is a tyrosine kinase inhibitor that can inhibit PDGFRα and has been widely used in urological research. We evaluated the functional effects of imatinib administration (via oral gavage or intravesical infusion) with two different experimental designs (prevention and treatment), in a cyclophosphamide (CYP)-induced cystitis (acute, intermediate, and chronic), male and female rodent model using conscious cystometry and somatic sensitivity testing. Imatinib significantly (0.0001 ≤ p ≤ 0.05) decreased voiding frequency and increased bladder capacity in acute CYP-induced cystitis, by the prevention (females) and treatment (females and males) designs. Imatinib was not effective in preventing or treating intermediate or chronic CYP-induced cystitis in either sex. Interestingly, in the prevention experiments, imatinib administration increased (0.0001 ≤ p ≤ 0.01) voiding frequency and decreased bladder capacity in control mice. However, in the treatment experiments, imatinib administration decreased (0.01 ≤ p ≤ 0.05) voiding frequency and increased bladder capacity in control mice. Bladder function improvements observed with imatinib treatment in acute CYP-induced cystitis mice remained and additionally improved with a second dose of imatinib 24 hours after CYP treatment. Imatinib administration did not affect pelvic somatic sensitivity in female mice with acute CYP-induced cystitis. Our studies suggest that (1) imatinib improves bladder function in mice with acute CYP-induced cystitis with a prevention and treatment design and (2) interstitial cells may be a useful target to improve bladder function in cystitis., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Perkins, Girard, Campbell and Vizzard.)

Imatinib mesylate is a tyrosine kinase inhibitor that inhibits platelet-derived growth factor receptor (PDGFR)-α, -β, stem cell factor receptor (c-KIT), and BCR-ABL. PDGFRα is expressed in a subset of interstitial cells in the lamina propria (LP) and detrusor muscle of the urinary bladder. PDGFRα + interstitial cells may contribute to bladder dysfunction conditions such as interstitial cystitis/bladder pain syndrome (IC/BPS) or overactive bladder (OAB). We have previously demonstrated that imatinib prevention via oral gavage or treatment via intravesical infusion improves urinary bladder function in mice with acute (4 hour, h) cyclophosphamide (CYP)-induced cystitis. Here, we investigate potential underlying mechanisms mediating the bladder functional improvement by imatinib using a prevention or treatment experimental design. Using qRT-PCR and ELISAs, we examined inflammatory mediators (NGF, VEGF, BDNF, CCL2, IL-6) previously shown to affect bladder function in CYP-induced cystitis. We also examined the distribution of phosphorylated (p) ERK and pAKT expression in the LP with immunohistochemistry. Imatinib prevention significantly (0.0001 ≤ p ≤ 0.05) reduced expression for all mediators examined except NGF, whereas imatinib treatment was without effect. Imatinib prevention and treatment significantly (0.0001 ≤ p ≤ 0.05) reduced pERK and pAKT expression in the upper LP (U. LP) and deeper LP (D. LP) in female mice with 4 h CYP-induced cystitis. Although we have previously demonstrated that imatinib prevention or treatment improves bladder function in mice with cystitis, the current studies suggest that reductions in inflammatory mediators contribute to prevention benefits of imatinib but not the treatment benefits of imatinib. Differential effects of imatinib prevention or treatment on inflammatory mediators may be influenced by the route and frequency of imatinib administration and may also suggest other mechanisms (e.g., changes in transepithelial resistance of the urothelium) through which imatinib may affect urinary bladder function following CYP-induced cystitis., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Perkins, Girard, Campbell, Hennig and Vizzard.)

Pathogenic biallelic variants in POL3RA have been associated with different disorders characterized by progressive neurological deterioration. These include the 4H leukodystrophy syndrome (hypomyelination, hypogonadotropic hypogonadism, and hypodontia) and adolescent-onset progressive spastic ataxia, as well as Wiedemann-Rautenstrauch syndrome (WRS), a recognizable neonatal progeroid syndrome. The phenotypic differences between these disorders are thought to occur mainly due to different functional effects of underlying POLR3A variants. Here we present the detailed clinical course of a 37-year-old woman in whom we identified a homozygous synonymous POLR3A variant c.3336G>A resulting in leaky splicing r.[3336ins192, =, 3243&#95;3336del94]. She presented at birth with intrauterine growth retardation, lipodystrophy, muscular hypotonia, and several WRS-like facial features, albeit without sparse hair and prominent scalp veins. She had no signs of developmental delay or intellectual disability. Over the years, above characteristic facial features, she showed severe postnatal growth retardation, global lipodystrophy, joint contractures, thoracic hypoplasia, scoliosis, anodontia, spastic quadriplegia, bilateral hearing loss, aphonia, hypogonadotropic hypogonadism, and cerebellar peduncles hyperintensities in brain imaging. These manifestations partially overlap the clinical features of the previously reported POLR3A-associated disorders, mostly mimicking the WRS. Thus, our study expands the POLR3A-mediated phenotypic spectrum and suggests existence of a phenotypic continuum underlying biallelic POLR3A variants., (© 2021 The Authors. American Journal of Medical Genetics Part A published by Wiley Periodicals LLC.)

Interstitial cystitis/bladder pain syndrome is a chronic inflammatory pelvic pain syndrome of unknown etiology characterized by a number of lower urinary tract symptoms, including increased urinary urgency and frequency, bladder discomfort, decreased bladder capacity, and pelvic pain. While its etiology remains unknown, a large body of evidence suggests a role for changes in neurotrophin signaling, particularly that of nerve growth factor (NGF) and brain-derived neurotrophic factor (BDNF). Here, we evaluated the effects of pharmacological inhibition of the NGF receptor TrkA, BDNF receptor TrkB, and pan-neurotrophin receptor p75 NTR on bladder function in acute (4-hour) and chronic (8-day) mouse models of cyclophosphamide (CYP)-induced cystitis. TrkA inhibition via ARRY-954 significantly increased intermicturition interval and bladder capacity in control and acute and chronic CYP-treatment conditions. TrkB inhibition via ANA-12 significantly increased intermicturition interval and bladder capacity in acute, but not chronic, CYP-treatment conditions. Interestingly, intermicturition interval and bladder capacity significantly increased following p75 NTR inhibition via LM11A-31 in the acute CYP-treatment condition, but decreased in the chronic condition, potentially due to compensatory changes in neurotrophin signaling or increased urothelial barrier dysfunction in the chronic condition. Our findings demonstrate that these receptors represent additional potent therapeutic targets in mice with cystitis and may be useful in the treatment of interstitial cystitis and other inflammatory disorders of the bladder., Competing Interests: Conflict of interest The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

Multiple sclerosis (MS), a chronic, often disabling, nervous system disease, affects over 2.3 million people worldwide. This research examined the lived experiences of 46 community-dwelling adults with MS. We conducted five focus groups that covered topics such as diagnosis, decision-making regarding MS treatment, learning about and paying for assistance, and unmet needs. Focus group transcripts were qualitatively analyzed to identify overarching themes. Participants described how MS affects both current and future physical and financial security, how they often feel unheard or misunderstood by loved ones and healthcare providers, and how MS support organizations provide a vital collaborative and compassionate environment. Our findings reflect the importance of MS support organizations, and the incorporation of social workers in MS care teams, as they can foster communication and empathy between parties, provide psycho- social treatment, and link patients to needed services.

Stress causes symptom exacerbation in functional disorders of the urinary bladder. However, the potential mediators and underlying mechanisms of stress effects on micturition reflex function are unknown. We have characterized PACAP (Adcyap1) and PAC1 receptor (Adcyap1r1) signaling in stress-induced urinary bladder dysfunction in mice. We determined PACAP and PAC1 transcripts and protein expressions in the urinary bladder and lumbosacral dorsal root ganglia (DRG) and spinal cord in repeated variate stress (RVS) or control mouse (handling only) groups. RVS in mice significantly (p ≤ 0.01) increased serum corticosterone and urinary bladder NGF content and decreased weight gain. PACAP and PAC1 mRNA and protein were differentially regulated in lower urinary tract tissues with changes observed in lumbosacral DRG and spinal cord but not in urinary bladder. RVS exposure in mice significantly (p ≤ 0.01) increased (2.5-fold) voiding frequency as determined using conscious cystometry. Intrabladder administration of the PAC1 receptor antagonist, PACAP(6-38) (300 nM), significantly (p ≤ 0.01) increased infused volume (1.5-2.7-fold) to elicit a micturition event and increased the intercontraction interval (i.e., decreased voiding frequency) in mice exposed to RVS and in control mice, but changes were smaller in magnitude in control mice. We also evaluated the effect of PAC1 blockade at the level of the urinary bladder on pelvic sensitivity in RVS or control mouse groups using von Frey filament testing. Intrabladder administration of PACAP(6-38) (300 nM) significantly (p ≤ 0.01) reduced pelvic sensitivity following RVS. PACAP/receptor signaling in the CNS and PNS contributes to increased voiding frequency and pelvic sensitivity following RVS and may represent a potential target for therapeutic intervention., (© 2020. Springer Science+Business Media, LLC, part of Springer Nature.)

Background: Coracoid impingement syndrome is an increasingly recognized etiology of anterior shoulder pain. Numerus studies have documented the coracohumeral distance (CHD) as a primary or secondary measurement in symptomatic individuals, but there lacks an evaluation of CHD in a large cohort of asymptomatic individuals. The purpose of this study was to quantify a normative distribution of the CHD in a large cohort of healthy, asymptomatic subjects with no history of impingement or shoulder instability., Methods: Incoming first-year students in the United States Military Academy were offered enrollment in this study as part of a prospective cohort to assess the normal anatomic relationships of the shoulder girdle. Magnetic resonance images were obtained, and a board-certified, fellowship-trained musculoskeletal radiologist performed measurements of the smallest distance from the coracoid to the humeral head on axial images., Results: Magnetic resonance images of 714 subjects were available for analysis, including 630 males and 84 females, with a total of 1120 individual shoulders with images of adequate quality. The mean CHD for all shoulders imaged was 13.7 mm. The mean CHD in male shoulders was 13.8 mm, and in female subjects the average was 12.4 mm., Conclusions: This study is the largest of its kind to evaluate the CHD in asymptomatic, healthy shoulders to date and demonstrates a mean CHD of 13.7 mm for all subjects. This information can help to standardize "normal" ranges and act as a comparison for future work, when taken in the context of age and imaging in neutral rotation., (Copyright © 2020 Journal of Shoulder and Elbow Surgery Board of Trustees. All rights reserved.)

The addition of nonnative species and loss of native species has modified the composition of communities globally. Although changes in β-diversity have been well documented, there is a need for studies incorporating multiple time periods, more than one dimension of biodiversity, and inclusion of nestedness and turnover components to understand the underlying mechanisms structuring community composition and assembly. Here, we examined temporal changes in functional dissimilarity of fish communities of the Laurentian Great Lakes and compared these changes to those of taxonomic dissimilarity by decade from 1870 to 2010. Jaccard-derived functional dissimilarity index was used to quantify changes in functional β-diversity within communities, between all possible pairs of communities, and using a multiple-site index among all communities. β-diversity was partitioned into components of nestedness and turnover, and changes were examined over time. Similar to patterns in taxonomic dissimilarity, each community functionally differentiated from the historical community of 1870, with Lake Superior changing the most (~24%) and Lake Ontario the least (~14%). Although communities have become taxonomically homogenized, functional β-diversity among all communities has increased over time, indicating functional differentiation. This is likely due to functional similarity between the communities being historically high (i.e., ~88% similar in 1870). The higher taxonomic relative to functional turnover indicates that the species being replaced between communities are functionally redundant, which could occur given the harsh environmental conditions of the region and/or as a result of the recent glacial history of the region. High functional nestedness across communities reflects dispersal limitations, with smaller communities being functional subsets of large communities closer to source populations. The functional differentiation observed is likely due to nonnative species with functional traits unique to the region establishing or the loss of functionally redundant native species; however, it is important to note that patterns of homogenization were periodically observed through time. Our study demonstrates the possible factors regulating diversity in the Laurentian Great Lakes fish communities, that patterns of taxonomic and functional β-diversity are dynamic over time and vary in the magnitude and direction of change, and that taxonomic diversity should not be used to predict changes in functional diversity., (© 2020 by the Ecological Society of America.)

Fluorescent light energy (FLE) has been used to treat various injured tissues in a non-pharmacological and non-thermal fashion. It was applied to stimulate cell proliferation, accelerate healing in chronic and acute wounds, and reduce pain and inflammation. FLE has been shown to reduce pro-inflammatory cytokines while promoting an environment conducive to healing. A possible mechanism of action of FLE is linked to regulation of mitochondrial homeostasis. This work aims to investigate the effect of FLE on mitochondrial homeostasis in an in vitro model of inflammation. Confocal microscopy and gene expression profiling were performed on cultures of inflamed human dermal fibroblasts treated with either direct light from a multi-LED lamp, or FLE from either an amorphous gel or sheet hydrogel matrix. Assessment using confocal microscopy revealed mitochondrial fragmentation in inflamed cells, likely due to exposure to inflammatory cytokines, however, mitochondrial networks were restored to normal 24-h after treatment with FLE. Moreover, gene expression analysis found that treatment with FLE resulted in upregulation of uncoupling protein 1 ( UCP1 ) and carnitine palmitoyltransferase 1B ( CPT1B ) genes, which encode proteins favoring mitochondrial ATP production through oxidative phosphorylation and lipid β-oxidation, respectively. These observations demonstrate a beneficial effect of FLE on mitochondrial homeostasis in inflamed cells.

Transient receptor potential vanilloid family member 4 (TRPV4) transcript and protein expression increased in the urinary bladder and lumbosacral dorsal root ganglia of transgenic mice with chronic urothelial overexpression of nerve growth factor (NGF-OE). We evaluated the functional role of TRPV4 in bladder function with open-outlet cystometry, void spot assays, and natural voiding (Urovoid) assays with the TRPV4 antagonist HC-067047 (1 μM) or vehicle in NGF-OE and littermate wild-type (WT) mice. Blockade of TRPV4 at the level of the urinary bladder significantly ( P ≤ 0.01) increased the intercontraction interval (2.2-fold) and void volume (2.6-fold) and decreased nonvoiding contractions (3.0-fold) in NGF-OE mice, with lesser effects (1.3-fold increase in the intercontraction interval and 1.3-fold increase in the void volume) in WT mice. Similar effects of TRPV4 blockade on bladder function in NGF-OE mice were demonstrated with natural voiding assays. Intravesical administration of HC-067047 (1 µM) significantly ( P ≤ 0.01) reduced pelvic sensitivity in NGF-OE mice but was without effect in littermate WT mice. Blockade of urinary bladder TRPV4 or intravesical infusion of brefeldin A significantly ( P ≤ 0.01) reduced (2-fold) luminal ATP release from the urinary bladder in NGF-OE and littermate WT mice. The results of the present study suggest that TRPV4 contributes to luminal ATP release from the urinary bladder and increased voiding frequency and pelvic sensitivity in NGF-OE mice.

Participation refers to a state of health in which a person is able to fully engage in roles and life situations. Adults living with and beyond cancer often report persistent participation restrictions that affect their productivity and quality of life. The American Occupational Therapy Foundation convened a group of scientists from seven different disciplines in a Planning Grant Collective (PGC) to stimulate research to identify scalable ways to preserve and optimize participation among cancer survivors. Participants identified challenges, prioritized solutions, and generated novel research questions that move beyond symptom and impairment mitigation as outcomes to identify interventions that improve participation in roles and life situations. This article summarizes the PGC discussion and recommendations regarding three challenges: (a) the dynamic and multi-faceted nature of participation, (b) a need to integrate the concept of participation within the culture of oncology, and (c) identification of priority areas in which new lines of research regarding participation would be most impactful.

Background: The rotator cuff muscles are critical secondary stabilizers in the shoulder. Increased glenoid retroversion and rotator cuff strength have been associated with the risk of posterior shoulder instability; however, the effect of increased glenoid retroversion on rotator cuff strength remains unclear., Purpose/hypothesis: The purpose was to examine the association between glenoid version and rotator cuff strength in the shoulder in a young and healthy population with no history of shoulder instability. The hypothesis was that increased glenoid retroversion would be associated with increases in rotator cuff muscle strength., Study Design: Cross-sectional study; Level of evidence, 3., Methods: A prospective cohort study was conducted over a 4-year period within a high-risk population to identify the risk factors for shoulder instability. Analyzed participants included 574 freshmen entering a United States service academy. Baseline data collected upon entry into the study included magnetic resonance imaging measurements of glenoid version. Rotator cuff strength was also assessed at baseline using a handheld dynamometer. Internal and external rotation strength were assessed with the glenohumeral joint positioned in neutral and in 45° of abduction. The current study represents an analysis of the baseline data from this cohort., Results: The mean age, height, and weight of participants was 18.77 ± 0.97 years, 176.81 ± 8.48 cm, and 73.80 ± 12.45 kg, respectively. The mean glenoid version at baseline was 7.79°± 4.85° of retroversion. Univariate linear regression analyses demonstrated that increased glenoid retroversion was associated with increased internal and external rotation strength of the rotator cuff in neutral and 45° of abduction ( P < .001). Similar results were observed in multivariable models controlling for important confounding variables., Conclusion: The results of this study demonstrate that as glenoid retroversion increases, internal and external rotation strength of the rotator cuff also increase in a young and healthy athletic population. These compensatory changes may contribute to increased glenohumeral dynamic stability in the presence of worse static stability with increasing retroversion.

Background: Determining the amount of glenoid bone loss in patients after anterior glenohumeral instability events is critical to guiding appropriate treatment. One of the challenges in treating the shoulder instability of young athletes is the absence of clear data showing the effect of each event., Purpose: To prospectively determine the amount of bone loss associated with a single instability event in the setting of first-time and recurrent instability., Study Design: Cohort study; Level of evidence, 2., Methods: The authors conducted a prospective cohort study of 714 athletes surveilled for 4 years. Baseline assessment included a subjective history of shoulder instability. Bilateral noncontrast shoulder magnetic resonance imaging (MRI) was obtained for all participants with and without a history of previous shoulder instability. The cohort was prospectively followed during the study period, and those who sustained an anterior glenohumeral instability event were identified. Postinjury MRI with contrast was obtained and compared with the screening MRI. Glenoid width was measured for each patient's pre- and postinjury MRI. The projected total glenoid bone loss was calculated and compared for patients with a history of shoulder instability., Results: Of the 714 athletes (1428 shoulders) who were prospectively followed during the 4-year period, 22 athletes (23 shoulders) sustained a first-time anterior instability event (5 dislocations, 18 subluxations), and 6 athletes (6 shoulders) with a history of instability sustained a recurrent anterior instability event (1 dislocation, 5 subluxations). On average, there was statistically significant glenoid bone loss (1.84 ± 1.47 mm) after a single instability event ( P < .001), equivalent to 6.8% (95% CI, 4.46%-9.04%; range, 0.71%-17.6%) of the glenoid width. After a first-time instability event, 12 shoulders (52%) demonstrated glenoid bone loss ≥5% and 4 shoulders, ≥13.5%; no shoulders had ≥20% glenoid bone loss. Preexisting glenoid bone loss among patients with a history of instability was 10.2% (95% CI, 1.96%-18.35%; range, 0.6%-21.0%). This bone loss increased to 22.8% (95% CI, 20.53%-25.15%; range, 21.2%-26.0%) after additional instability ( P = .0117). All 6 shoulders with recurrent instability had ≥20% glenoid bone loss., Conclusion: Glenoid bone loss of 6.8% was observed after a first-time anterior instability event. In the setting of recurrent instability, the total calculated glenoid bone loss was 22.8%, with a high prevalence of bony Bankart lesions (5 of 6). The findings of this study support early stabilization of young active patients after a first-time anterior glenohumeral instability event.

The hard (ixodid) ticks Amblyomma americanum and Amblyomma maculatum are found throughout the southeastern United States. To study the effects of water inundation, which is an increasingly common phenomenon in many coastal areas, unfed adult A. americanum and A. maculatum ticks were tested for survival by submergence in three water conditions: freshwater, brackish water, and saltwater. The results demonstrated a significant difference in survival between the two species in all three water conditions, with A. maculatum ticks surviving a shorter time underwater than A. americanum ticks. There is also a significant difference in A. americanum survival among the different water conditions, with the highest mortality in saltwater and the lowest in freshwater. Amblyomma americanum ticks survived the longest in freshwater (70 d), followed by brackish water (64 d), and the shortest survival was in saltwater (46 d), while the longest any A. maculatum tick survived was 24 d in freshwater. These findings demonstrate that any short-term flooding events, e.g., less than a week, would not likely eliminate these species of ticks in the flooded area., (Copyright © 2018 Elsevier GmbH. All rights reserved.)

Juvenile segmental progeroid syndromes are rare, heterogeneous disorders characterized by signs of premature aging affecting more than one tissue or organ starting in childhood. Hutchinson-Gilford progeria syndrome (HGPS), caused by a recurrent de novo synonymous LMNA mutation resulting in aberrant splicing and generation of a mutant product called progerin, is a prototypical example of such disorders. Here, we performed a joint collaborative study using massively parallel sequencing and targeted Sanger sequencing, aimed at delineating the underlying genetic cause of 14 previously undiagnosed, clinically heterogeneous, non-LMNA-associated juvenile progeroid patients. The molecular diagnosis was achieved in 11 of 14 cases (~ 79%). Furthermore, we firmly establish biallelic mutations in POLR3A as the genetic cause of a recognizable, neonatal, Wiedemann-Rautenstrauch-like progeroid syndrome. Thus, we suggest that POLR3A mutations are causal for a portion of under-diagnosed early-onset segmental progeroid syndromes. We additionally expand the clinical spectrum associated with PYCR1 mutations by showing that they can somewhat resemble HGPS in the first year of life. Moreover, our results lead to clinical reclassification in one single case. Our data emphasize the complex genetic and clinical heterogeneity underlying progeroid disorders.

BackgroundHutchinson-Gilford progeria syndrome (HGPS) is an ultra-rare, fatal, segmental premature aging syndrome caused by the aberrant lamin A protein, progerin. The protein farnesyltransferase inhibitor, lonafarnib, ameliorates some aspects of cardiovascular and bone disease.MethodsWe performed a prospective longitudinal survey of plasma proteins in 24 children with HGPS (an estimated 10% of the world's population at the time) at baseline and on lonafarnib therapy, compared with age- and gender-matched controls using a multi-analyte, microsphere-based immunofluorescent assay.ResultsThe mean levels for 23/66 (34.8%) proteins were significantly lower and 7/66 (10.6%) were significantly higher in HGPS samples compared with those in controls (P≤0.05). Six proteins whose concentrations were initially lower normalized with lonafarnib therapy: interleukins 1α, 7, and 13, beta-2 microglobulin, C-reactive protein, and myoglobin. Alpha-2 macroglobulin, a protease inhibitor associated with stroke, was elevated at baseline and subsequently normalized with lonafarnib therapy.ConclusionThis is the first study to employ a multi-analyte array platform in HGPS. Novel potential biomarkers identified in this study should be further validated by correlations with clinical disease status, especially proteins associated with cardiovascular disease and those that normalized with lonafarnib therapy.

Predicting which nonnative species become invasive is critical for their successful management, and Charles Darwin provided predictions based on species' relatedness. However, Darwin provided two opposing predictions about the relatedness of introduced nonnatives to indigenous species. First, environmental fit is the dominant factor determining invader success; thus, we should expect that invasive species are closely related to local native residents. Alternatively, if competition is important, we should expect successful invaders are distantly related to the native residents. These opposing expectations are referred to as Darwin's naturalization conundrum. The results of studies that examine nonnative species relatedness to natives are largely inconsistent. This inconsistency arises from the fact that studies occur at different spatial and temporal scales, and at different stages of invasion, and so implicitly examine different mechanisms. Further, while species have evolved ecological differences, the mode and tempo of evolution can affect species' differences, complicating the predictions from simple hypotheses. We outline unanswered questions and provide guidelines for collecting the data required to test competing hypotheses.

Importance: Hutchinson-Gilford progeria syndrome (HGPS) is an extremely rare fatal premature aging disease. There is no approved treatment., Objective: To evaluate the association of monotherapy using the protein farnesyltransferase inhibitor lonafarnib with mortality rate in children with HGPS., Design, Setting, and Participants: Cohort study comparing contemporaneous (birth date ≥1991) untreated patients with HGPS matched with treated patients by age, sex, and continent of residency using conditional Cox proportional hazards regression. Treatment cohorts included patients from 2 single-group, single-site clinical trials (ProLon1 [n = 27; completed] and ProLon2 [n = 36; ongoing]). Untreated patients originated from a separate natural history study (n = 103). The cutoff date for patient follow-up was January 1, 2018., Exposure: Treated patients received oral lonafarnib (150 mg/m2) twice daily. Untreated patients received no clinical trial medications., Main Outcomes and Measures: The primary outcome was mortality. The primary analysis compared treated patients from the first lonafarnib trial with matched untreated patients. A secondary analysis compared the combined cohorts from both lonafarnib trials with matched untreated patients., Results: Among untreated and treated patients (n = 258) from 6 continents, 123 (47.7%) were female; 141 (54.7%) had a known genotype, of which 125 (88.7%) were classic (c.1824C>T in LMNA). When identified (n = 73), the primary cause of death was heart failure (79.4%). The median treatment duration was 2.2 years. Median age at start of follow-up was 8.4 (interquartile range [IQR], 4.8-9.5) years in the first trial cohort and 6.5 (IQR, 3.7-9.0) years in the combined cohort. There was 1 death (3.7%) among 27 patients in the first trial group and there were 9 deaths (33.3%) among 27 patients in the matched untreated group. Treatment was associated with a lower mortality rate (hazard ratio, 0.12; 95% CI, 0.01-0.93; P = .04). In the combined cohort, there were 4 deaths (6.3%) among 63 patients in the treated group and 17 deaths (27.0%) among 63 patients in the matched untreated group (hazard ratio, 0.23; 95% CI, 0.06-0.90; P = .04)., Conclusions and Relevance: Among patients with HGPS, lonafarnib monotherapy, compared with no treatment, was associated with a lower mortality rate after 2.2 years of follow-up. Study interpretation is limited by its observational design.

Background: People living with HIV-1 infection are at greater risk for cardiovascular disease than seronegative adults. Treatment of dyslipidaemia with statins has been challenging in people with HIV because of an increased potential for drug interactions due to competing cytochrome P450 metabolism between statins and commonly used antiretroviral agents. Neither pitavastatin nor pravastatin depend on cytochrome P450 for primary metabolism. We aimed to assess the safety and efficacy of pitavastatin versus pravastatin in adults with HIV and dyslipidaemia., Methods: In the INTREPID (HIV-infected patieNts and TREatment with PItavastatin vs pravastatin for Dyslipidemia) randomised, double-blind, active-controlled, phase 4 trial (INTREPID, we recruited adults aged 18-70 years with controlled HIV (with CD4 counts >200 cells per μL and HIV-1 RNA <200 copies per mL) on antiretroviral therapy for at least 6 months and dyslipidaemia (LDL cholesterol 3·4-5·7 mmol/L and triglycerides ≤4·5 mmol/L) from 45 sites in the USA and Puerto Rico. Patients being treated with darunavir, or who had homozygous familial hypercholesterolaemia or any condition causing secondary dyslipidaemia, or a history of statin intolerance, diabetes, or coronary artery disease were not eligible. We randomly assigned patients (1:1) to pitavastatin 4 mg or pravastatin 40 mg with matching placebos once daily orally for 12 weeks, followed by a 40 week safety extension. Randomisation was stratified by viral hepatitis B or C coinfection and computer-generated. Investigators, patients, study staff, and those assessing outcomes were masked to treatment group. The primary endpoint was percentage change in fasting serum LDL cholesterol from baseline to week 12 and the primary efficacy analysis was done in the modified intention-to-treat population. The safety analysis included all patients who took at least one dose of study medication. This study is registered with ClinicalTrials.gov, number NCT01301066., Findings: Between Feb 23, 2011, and March 29, 2013, we randomly assigned 252 patients to the pitavastatin (n=126) or pravastatin group (n=126). LDL cholesterol reduction was 31·1% with pitavastatin and 20·9% with pravastatin (least squares mean difference -9·8%, 95% CI -13·8 to -5·9; p<0·0001) at 12 weeks. At week 52, four patients (3%) in the pitavastatin group and six (5%) in the pravastatin group had virological failure, with no significant difference between treatments. Both treatments had neutral effects on glucose metabolism parameters. 85 patients treated with pitavastatin (68%) and 88 patients treated with pravastatin (70%) reported treatment-emergent adverse events, and these caused study discontinuation in six patients (5%) versus five patients (4%). No serious adverse event occurred in more than one participant and none were treatment-related according to investigator assessment. The most common treatment-emergent adverse events were diarrhoea in the pitavastatin group (n=12, 10%) and upper respiratory tract infection in the pravastatin group (n=14, 11%). 11 treatment-emergent serious adverse events were noted in seven patients (6%) in the pitavastatin group (atrial septal defect, chronic obstructive pulmonary disease, chest pain, diverticulitis, enterovesical fistula, gastroenteritis, viral gastroenteritis, herpes dermatitis, multiple fractures, respiratory failure, and transient ischaemic attack) and four events in three patients (2%) in the pravastatin group (cerebrovascular accident, arteriosclerosis coronary artery, myocardial infraction, and muscle haemorrhage). In the pravastatin treatment group, one additional patient discontinued due to an adverse event (prostate cancer that was diagnosed during the screening period, 42 days before first dose of study treatment, and therefore was not a treatment-emergent adverse event)., Interpretation: The INTREPID results support guideline recommendations for pitavastatin as a preferred drug in the treatment of dyslipidaemia in people with HIV., Funding: Kowa Pharmaceuticals America and Eli Lilly and Company., (Copyright © 2017 Elsevier Ltd. All rights reserved.)

Darwin's naturalization conundrum describes the paradigm that community assembly is regulated by two opposing processes, environmental filtering and competitive interactions, which predict both similarity and distinctiveness of species to be important for establishment. Our goal is to use long-term, large-scale, and high-resolution temporal data to examine diversity patterns over time and assess whether environmental filtering or competition plays a larger role in regulating community assembly processes. We evaluated Darwin's naturalization conundrum and how functional diversity has changed in the Laurentian Great Lakes fish community from 1870 to 2010, which has experienced frequent introductions of non-native species and extirpations of native species. We analyzed how functional diversity has changed over time by decade from 1870 to 2010 at three spatial scales (regional, lake, and habitat) to account for potential noninteractions between species at the regional and lake level. We also determined which process, environmental filtering or competitive interactions, is more important in regulating community assembly and maintenance by comparing observed patterns to what we would expect in the absence of an ecological mechanism. With the exception of one community, all analyses show that functional diversity and species richness has increased over time and that environmental filtering regulates community assembly at the regional level. When examining functional diversity at the lake and habitat level, the regulating processes become more context dependent. This study is the first to examine diversity patterns and Darwin's conundrum by integrating long-term, large-scale, and high-resolution temporal data at multiple spatial scales. Our results confirm that Darwin's conundrum is highly context dependent.

Background: Hutchinson-Gilford progeria syndrome (HGPS) is a fatal sporadic autosomal dominant premature ageing disease caused by single base mutations that optimise a cryptic splice site within exon 11 of the LMNA gene. The resultant disease-causing protein, progerin, acts as a dominant negative. Disease severity relies partly on progerin levels., Methods and Results: We report a novel form of somatic mosaicism, where a child possessed two cell populations with different HGPS disease-producing mutations of the same nucleotide-one producing severe HGPS and one mild HGPS. The proband possessed an intermediate phenotype. The mosaicism was initially discovered when Sanger sequencing showed a c.1968+2T>A mutation in blood DNA and a c.1968+2T>C in DNA from cultured fibroblasts. Deep sequencing of DNA from the proband's blood revealed 4.7% c.1968+2T>C mutation, and 41.3% c.1968+2T>A mutation., Conclusions: We hypothesise that the germline mutation was c.1968+2T>A, but a rescue event occurred during early development, where the somatic mutation from A to C at 1968+2 provided a selective advantage. This type of mosaicism where a partial phenotypic rescue event results from a second but milder disease-causing mutation in the same nucleotide has not been previously characterised for any disease., (Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://www.bmj.com/company/products-services/rights-and-licensing/.)

The Microsporidia are a major group of intracellular fungi and important parasites of animals including insects, fish, and immunocompromised humans. Microsporidian genomes have undergone extreme reductive evolution but there are major differences in genome size and structure within the group: some are prokaryote-like in size and organisation (<3 Mb of gene-dense sequence) while others have more typically eukaryotic genome architectures. To gain fine-scale, population-level insight into the evolutionary dynamics of these tiny eukaryotic genomes, we performed the broadest microsporidian population genomic study to date, sequencing geographically isolated strains of Spraguea, a marine microsporidian infecting goosefish worldwide. Our analysis revealed that population structure across the Atlantic Ocean is associated with a conserved difference in ploidy, with American and Canadian isolates sharing an ancestral whole genome duplication that was followed by widespread pseudogenisation and sorting-out of paralogue pairs. While past analyses have suggested de novo gene formation of microsporidian-specific genes, we found evidence for the origin of new genes from noncoding sequence since the divergence of these populations. Some of these genes experience selective constraint, suggesting the evolution of new functions and local host adaptation. Combining our data with published microsporidian genomes, we show that nucleotide composition across the phylum is shaped by a mutational bias favoring A and T nucleotides, which is opposed by an evolutionary force favoring an increase in genomic GC content. This study reveals ongoing dramatic reorganization of genome structure and the evolution of new gene functions in modern microsporidians despite extensive genomic streamlining in their common ancestor., (© The Author 2016. Published by Oxford University Press on behalf of the Society for Molecular Biology and Evolution.)

Meniscal injuries are an extremely common cause of knee pain. Meniscal repairs performed with concomitant anterior cruciate ligament reconstruction appear to heal at a higher rate than meniscal repairs performed in isolation. This may be due in part to the release of marrow elements into the knee and the time of meniscal repair. In cases of isolated meniscal repair, some orthopedic surgeons use microfracture to release marrow elements into the joint as an adjunct to enhance meniscal healing. This study evaluated rates of meniscal tear healing with or without the performance of microfracture in a goat (Capra hircus) model. Forty castrated young adult male goats underwent either a horizontal or a longitudinal 1.0-cm meniscal tear with or without microfracture. All procedures were performed open, in a bloodless field. Meniscal tears were created in the peripheral half of the body of the medial meniscus. The goats were euthanized at 6 months, and meniscal tears were analyzed and classified as complete healing, partial healing, or no healing by direct visualization. A probe was used as an aid to evaluate and classify the meniscal tears. Twenty (87%) of 23 goat meniscal tears showed at least partial healing when performed with concomitant microfracture. Only 5 (29%) of 17 menisci showed any healing in goats that did not receive microfracture. This difference in healing rates was statistically significant (P<.001). Fifteen (65%) meniscal tears accomplished with microfracture were completely healed, whereas only 2 (12%) menisci showed complete healing without microfracture (P<.001). The results of this study suggest that the release of bone marrow elements into the knee by microfracture improves meniscal healing rates., (Copyright 2016, SLACK Incorporated.)

How honest or reliable signaling can evolve and be maintained has been a major question in evolutionary biology. The question is especially puzzling for a particular class of signals used in aggressive interactions: threat signals. Here, we report a study on song sparrows (Melospiza melodia) in which we assayed males with playbacks on their territories to quantify their aggressiveness (flights and close proximity) and aggressive signaling levels (rates of soft song, a close-range signal reliably predicting attack) and asked whether these traits affect individuals' survival on territory. We found that the effect of aggressive signaling via soft song interacted with aggressive behaviors such that there was a negative correlational selection: among males with low aggression, those males that signaled at higher levels (over-signalers) had higher survival whereas among males with high aggression those that signaled at low levels (under-signalers) survived longer. In other words, males that deviate from reliable signaling have a survival advantage. These results, along with previous research that suggested most of the deviation from reliable signaling in this system is in the form of under-signaling (high-aggression males signaling at low levels) pose a puzzle for future research on how this reliable signaling system is maintained., (© 2015 The Author(s). Evolution © 2015 The Society for the Study of Evolution.)

The diagnosis of congenital and acquired bleeding disorders in infants requires an understanding of developmental haemostasis and the effect on laboratory testing. A systematic approach to bleeding in neonates will aid clinicians in the diagnosis and treatment, which may be caused by a wide variety of diseases. The clinical setting will help to direct the diagnostic pathway. This review will focus on the presentation and diagnosis of congenital and acquired bleeding disorders, including platelet disorders. Current research in this field is ongoing, including investigation into neonatal platelets and their different functionalities, platelet transfusion thresholds and how changes in coagulation factors may be linked to other homeostatic mechanisms., (Copyright © 2015 Elsevier Ireland Ltd. All rights reserved.)