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Objective To determine the long-term (12-year) effects of a conservative nurse-led intervention for postnatal urinary incontinence. Design Follow-up of a randomised controlled trial. Setting Community-based intervention in three centres (in the UK and New Zealand). Population A cohort of 747 women with urinary incontinence at 3 months after childbirth, of whom 471 (63%) were followed up after 12 years. Methods Women were randomly allocated to active conservative treatment after delivery (pelvic floor muscle training and bladder training), or to a control group receiving standard care. Main outcome measures Prevalence of urinary incontinence (primary outcome) and faecal incontinence, symptoms and signs of prolapse, and performance of pelvic floor muscle training at 12 years. Results The significant improvements relative to controls that had been found in urinary incontinence (60 versus 69%; risk difference, RD, −9.1%; 95% confidence interval, 95% CI, −17.3 to −1.0%) and faecal incontinence (4 versus 11%; RD −6.1%; 95% CI −10.8 to −1.6%) at 1 year did not persist for urinary incontinence (83 versus 80%; RD 2.1%; 95% CI −4.9 to 9.1%) or faecal incontinence (19 versus 15%; RD 4.3%; 95% CI −2.5 to 11.0%) at the 12-year follow up, irrespective of incontinence severity at trial entry. The prevalence of prolapse symptoms or objectively measured pelvic organ prolapse also did not differ between the groups. In the short term the intervention motivated more women to perform pelvic floor muscle training (83 versus 55%), but this fell in both groups by 12 years (52 versus 49%). Conclusions The moderate short-term benefits of a brief nurse-led conservative treatment for postnatal urinary incontinence did not persist. About four-fifths of women with urinary incontinence 3 months after childbirth still had this problem 12 years later. [ABSTRACT FROM AUTHOR]

The tension-free vaginal tape (TVT) was originally described using a cough test for tape adjustment. More recently, the usefulness of this technique has been questioned and the authors performed a case control series to address this issue. Patients after TVT performed with (n=52) or without cough test (n=54) were invited for review. Matching of the groups was undertaken for age, pre-existing urge incontinence, preoperative maximum flow rate (MFR) centile, concomitant anterior repair and length of follow up. There were no significant differences between groups for subjective cure, satisfaction, subjective symptoms of incontinence, frequency or nocturia. There were more symptoms of voiding dysfunction after cough test (p=0.019). Postoperative flowmetry did not differ significantly, but ultrasound data indicate that the cough test results in a tighter tape. In conclusion, avoiding the cough test seems to have no negative effect on patient satisfaction or subjective symptoms of stress incontinence in the short-term. [ABSTRACT FROM AUTHOR]

This pilot study tested the effectiveness of an intense, short-term upper-limb robotic therapy for improvement in motor outcomes among chronic stroke patients. We enrolled 30 subjects with upper-limb deficits due to stroke of at least 6 mo duration and with a Motor Power Assessment grade of 3 or less. Over 3 wk, 18 sessions of robot-assisted task-specific therapy were delivered with the use of a robotic exercise device that simulates a conventional therapy known as skateboard therapy. Primary outcome measures included reliable, validated impairment and disability measures of upper-limb motor function. Statistically significant improvements were observed for severely impaired participants when we compared baseline and posttreatment outcomes (p < 0.05). These results are important because they indicate that improvement is not limited to those with moderate impairments but is possible among severely impaired chronic stroke patients as well. Moderately and severely impaired patients in our study were able to tolerate a massed-practice therapy paradigm with intensive, frequent, and repetitive treatment. This information is useful in determining the optimal target population, intensity, and duration of robotic therapy and sample size for a planned larger trial. [ABSTRACT FROM AUTHOR]

A letter to the editor is presented in response to the article related to pelvic floor dysfunction in the previous issue is presented.

Diatoms in the Pseudo-nitzschia genus produce the neurotoxin domoic acid. Domoic acid bioaccumulates in shellfish, causing illness in humans and marine animals upon ingestion. In 2017, high domoic acid levels in shellfish meat closed shellfish harvest in Narragansett Bay, Rhode Island for the first and only time in history, although abundant Pseudo-nitzschia have been observed for over 60 years . To investigate whether an environmental factor altered endemic Pseudo-nitzschia physiology or new domoic acid-producing strain(s) were introduced to Narragansett Bay, we conducted weekly sampling from 2017 to 2019 and compared closure samples. Plankton-associated domoic acid was quantified by LC-MS/MS and Pseudo-nitzschia spp. were identified using a taxonomically improved high-throughput rDNA sequencing approach. Comparison with environmental data revealed a detailed understanding of domoic acid dynamics and seasonal multi-species assemblages. Plankton-associated domoic acid was low throughout 2017-2019, but recurred in fall and early summer maxima. Fall domoic acid maxima contained known toxic species as well as a novel Pseudo-nitzschia genotype. Summer domoic acid maxima included fewer species but also known toxin producers . Most 2017 closure samples contained the particularly concerning toxic species, P. australis , which also appeared infrequently during 2017-2019. Recurring Pseudo-nitzschia assemblages were driven by seasonal temperature changes, and plankton-associated domoic acid correlated with low dissolved inorganic nitrogen. Thus, the Narragansett Bay closures were likely caused by both resident assemblages that become toxic depending on nutrient status as well as the episodic introductions of toxic species from oceanographic and climatic shifts., Competing Interests: None declared., (© 2022 The Authors. Limnology and Oceanography published by Wiley Periodicals LLC on behalf of Association for the Sciences of Limnology and Oceanography.)

Premise: Understanding evolutionary history and classifying discrete units of organisms remain overwhelming tasks, and lags in this workload concomitantly impede an accurate documentation of biodiversity and conservation management. Rapid advances and improved accessibility of sensitive high-throughput sequencing tools are fortunately quickening the resolution of morphological complexes and   thereby improving the estimation of species diversity. The recently described and critically endangered Banksia vincentia is morphologically similar to the hairpin banksia complex (B. spinulosa s.l.), a group of eastern Australian flowering shrubs whose continuum of morphological diversity has been responsible for taxonomic controversy and possibly questionable conservation initiatives., Methods: To assist conservation while testing the current taxonomy of this group, we used high-throughput sequencing to infer a population-scale evolutionary scenario for a sample set that is comprehensive in its representation of morphological diversity and a 2500-km distribution., Results: Banksia spinulosa s.l. represents two clades, each with an internal genetic structure shaped through historical separation by biogeographic barriers. This structure conflicts with the existing taxonomy for the group. Corroboration between phylogeny and population statistics aligns with the hypothesis that B. collina, B. neoanglica, and B. vincentia should not be classified as species., Conclusions: The pattern here supports how morphological diversity can be indicative of a locally expressed suite of traits rather than relationship. Oversplitting in the hairpin banksias is atypical since genomic analyses often reveal that species diversity is underestimated. However, we show that erring on overestimation can yield negative consequences, such as the disproportionate prioritization of a geographically anomalous population., (© 2022 State of New South Wales. American Journal of Botany published by Wiley Periodicals LLC on behalf of Botanical Society of America.)

Objectives: Autosomal dominant polycystic kidney disease (ADPKD) is the most common inherited kidney condition, accounting for 7%-10% of patients with kidney failure. Fundamental basic science and clinical research on ADPKD is underway worldwide but no one has yet considered which areas should be prioritised to maximise returns from limited future funding. The Polycystic Kidney Disease Charity began a priority setting partnership with the James Lind Alliance (JLA) in the UK in 2019-2020 to identify areas of uncertainty in the ADPKD care pathway and allow patients, carers and healthcare professionals to rank the 10 most important questions for research., Design: The scope covered ADPKD diagnosis and management, identifying new treatments to prevent/slow disease progression and practical, integrated patient support (https://pkdcharity.org.uk/research/for-researchers/adpkd-research-priorities). We used adapted JLA methodology. Initially, an independent information specialist collated uncertainties in ADPKD care from recent consensus conference proceedings and additional literature. These were refined into indicative questions with Steering Group oversight. Finally, the 10 most important questions were established via a survey and online consensus workshop., Setting: UK., Participants: 747 survey respondents (76% patients, 13% carers, 11% healthcare professionals); 23 workshop attendees., Results: 117 uncertainties in ADPKD care were identified and refined into 35 indicative questions. A shortlist of 17 questions was established through the survey. Workshop participants reached agreement on the top 10 ranking. The top three questions prioritised by patients, carers and healthcare professionals centred around slowing disease progression, identifying persons for early treatment and organising care to improve outcomes., Conclusions: Our shortlist reflects the varied physical, psychological and practical challenges of living with and treating ADPKD, and perceived gaps in knowledge that impair optimal care. We propose that future ADPKD research funding takes these priorities into account to focus on the most important areas and to maximise improvements in ADPKD outcomes., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2022. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

The expansions and contractions of a species' range in response to temporal changes in selective filters leave genetic signatures that can inform a more accurate reconstruction of their evolutionary history across the landscape. After a long period of continental decline, Australian rainforests settled into localized patterns of contraction or expansion during the climatic fluctuations of the Quaternary. The environmental impacts of recurring glacial and interglacial periods also intensified the arrival of new lineages from the Sunda shelf, and it can be expected that immigrant versus locally persistent taxa responded to environmental challenges in quantifiably different manner. To investigate how such differences impact on species' distribution, we contrast landscape genomic patterns and changes in habitat availability between a species with a long continental history on Doryphora sassafras and a Sunda-derived species (Toona ciliata), across a distributional overlap. Extensive landscape-level homogeneity across chloroplast and nuclear genomes for the Sunda-derived T. ciliata, characterize the genetic signature of a very recent invasion and a rapid southern "exploratory" expansion that had not been previously recorded in the Australian flora (i.e., of Gondwanan origin or Sahul-derived). In contrast, D. sassafras is consistent with other Sahul-derived species characterized by strong geographical divergence and regional differentiation. Interestingly, our findings suggest that admixture between genetically divergent populations during expansion events might be a contributing factor to the successful colonization of novel habitats. Overall, this study identifies some of the mechanisms regulating the rearrangements in species distributions and assemblage composition that follow major environmental shifts, and reminds us how a species' current range might not necessarily define species' habitat preference, with the consequence that estimates of past or future range might not always be reliable., (© 2022 The Authors. Evolution © 2022 The Society for the Study of Evolution.)

Type II testicular germ cell tumors (TGCT) are the most frequently diagnosed solid malignancy in young men. Up to 15% of patients with metastatic non-seminomas show cisplatin resistance and a very poor survival rate due to lacking treatment options. Transcriptional cyclin-dependent kinases (CDK) have been shown to be effective targets in the treatment of different types of cancer. Here, we investigated the effects of the CDK inhibitors dinaciclib, flavopiridol, YKL-5-124, THZ1, NVP2, SY0351 and THZ531. An XTT viability assay revealed a strong cytotoxic impact of CDK7/12/13 inhibitor SY0351 and CDK9 inhibitor NVP2 on the TGCT wild-type cell lines (2102EP, NCCIT, TCam2) and the cisplatin-resistant cell lines (2102EP-R, NCCIT-R). The CDK7 inhibitor YKL-5-124 showed a strong impact on 2102EP, 2102EP-R, NCCIT and NCCIT-R cell lines, leaving the MPAF control cell line mostly unaffected. FACS-based analysis revealed mild effects on the cell cycle of 2102EP and TCam2 cells after SY0351, YKL-5-124 or NVP2 treatment. Molecular analysis showed a cell-line-specific response for SY0351 and NVP2 inhibition while YKL-5-124 induced similar molecular changes in 2102EP, TCam2 and MPAF cells. Thus, after TGCT subtype determination, CDK inhibitors might be a potential alternative for optimized and individualized therapy independent of chemotherapy sensitivity.

Objective: To determine the diagnostic performance of digital palpation of levator ani muscle (LAM) avulsion compared with translabial tomographic ultrasound imaging (TUI)., Methods: A cross-sectional study, incorporating 195 women involved in a longitudinal cohort study. Palpation for levator integrity was performed, followed by a four-dimensional translabial ultrasound. LAM avulsion defects were diagnosed in the presence of puborectalis muscle detachment from its insertion. Post-processing analysis of ultrasound volumes for LAM integrity on TUI was performed blinded against palpation findings. Agreement between methods was assessed using Cohen's κ., Results: In all, 388 paired assessments of LAM bilaterally, were available. Sixteen (8.2%) unilateral avulsion defects were detected on palpation. Sonographically, 31 (16%) were diagnosed with avulsions: 4.6% bilateral and 11.3% unilateral. An overall agreement of 91% was observed between digital palpation and TUI, yielding a Cohen's κ of 0.32 (95% confidence interval 0.15-0.48) demonstrating "fair agreement": and implying 25% sensitivity, 98% specificity, 63% positive predictive value, and 92% negative predictive value. Analysis of the first and last 20 palpations showed no change in performance during the 13-day study period., Conclusion: Assessment of LAM avulsion defects by digital palpation is feasible but may require substantial training. Confirmation by imaging is crucial, especially if the diagnosis of avulsion may influence clinical management., (© 2021 International Federation of Gynecology and Obstetrics.)

ADPKD is the most common genetic disease of the kidney leading to end-stage renal disease necessitating renal replacement therapy at any time between the 1 st and 8 th decades of life due to widely variable rates of disease progression. This presents significant patient anxiety and a significant prognostic and therapeutic challenge. Tolvaptan is the only approved drug licensed to slow ADPKD progression by reducing renal cystic expansion but side-effects can limit its efficacy. To address the need to identify new biomarkers to monitor progression of ADPKD and to evaluate the therapeutic effects of Tolvaptan, proteomic analysis was conducted on defined (40-100nm) urinary exosomes isolated from ADPKD patients phenotyped and clinically monitored over a 10-year period. Comparative Gene Ontology analysis of Tandem Mass Tag labelled mass spectrometry-derived protein profiles from urinary exosomes from ADPKD patients with rapid (>10ml/min/5 years decline in estimated glomerular filtration rate) versus slow progression showed distinctive patterns of pathway up-regulation. Clear discrimination between rapid and slowly-progressive profiles were seen in all stages functional decline in ADPKD patients whether with mild (>70ml/min), moderate (50-69ml/min) or severe (<49ml/min) disease at onset. Discriminatory pathways and proteins included Notch-, integrin- and growth factor-signalling; microtubular kinase, vesicular proteins and epidermal growth factor substrates. Confocal microscopy of fluorescently-labelled normal versus ADPKD epithelial cell-derived exosomes in vitro also identified ADPKD-dependent abnormalities in intracellular vesicular trafficking and implicated changes in ADPKD-dependent exosome secretion and target cell uptake as factors underlying urinary exosome excretion biomarker properties. Comparative proteomic analysis of urinary exosomal proteins in individual patients before and after treatment with Tolvaptan for 4 years also identified distinct patterns of pathway modification dependent on the degree of effectiveness of the therapeutic response. Up-regulation of Wnt-pathway and vesicular proteins were characteristic of urinary exosomes from ADPKD patients with good responses to Tolvaptan while upregulation of angiogenesis pathways and additional molecular forms of vasopressin receptor AVPR2 were characteristic in urinary exosomes of ADPKD patients with poor responses. Taken together, these studies conclude that proteomic profiling of urinary exosome biomarkers provides a specific, sensitive and practical non-invasive method to identify and monitor the rate of disease progression and the effects of Tolvaptan therapy in individual ADPKD patients. This provides a means to identify those patients most likely to benefit maximally from therapy and to progress towards a personalization of ADPKD prognosis and management., Competing Interests: The authors declare no competing interests., (© 2021 The Authors. Published by Elsevier B.V.)

The effectiveness and predictability of 2 different oral appliance (OA) designs to reduce the respiratory event index (REI) in moderate and severe obstructive sleep apnea (OSA) patients requires elucidation. The primary aim of the trial was to determine if 2 widely used midline-traction and bilateral-thrust OA designs differ in effectiveness to reduce the REI within a single test population categorized by OSA severity. Moderate and severe adult OSA patients, who were previously prescribed continuous positive airway pressure therapy (CPAP) but were dissatisfied with it ( n = 56), were studied by home-polygraphy in a randomized crossover trial using either midline-traction with restricted mouth opening (MR) or bilateral thrust with opening permitted (BP) design OAs. OAs were used nightly for 4 wk (T2) followed by a 1-wk washout period, then 4 wk (T4) using the alternate OA. REI and oxygen saturation (SaO 2 ) were primary outcomes, while predictability and efficacy comparison of the 2 OAs were secondary outcomes. Thirty-six participants had used MR and BP OAs during both 4-wk study legs. Twenty (55.6%) MR OA-using participants, 25 (69.4%) BP OA-using participants, and 16 (44.4%) participants using both OAs had significant REI reductions. Overall baseline (T0) median REI (interquartile range) of 33.7 (20.7-54.9) was reduced to 18.0 (8.5-19.4) at T2 and to 12.5 (8.2-15.9) at T4 ( P < 0.001). Comparison of the 2 sequence groups' (MR-BP and BP-MR) REI showed the median differences between T0 and T2 and T4 were highly significant ( P < 0.001). Regression analysis predicted about half of all users will have REIs between 8 and 16 after 2 mo. Baseline overjet measures >2.9 mm predicted greater OA advancement at T4. Mean and minimum SaO 2 did not change significantly from T0 to T2 or T4. MR and BP OA designs similarly attenuated REI in moderate and severe OSA individuals who completed the 8-wk study protocol with greater REI reduction in those with severe OSA (ClinicalTrials.gov NCT03219034).

Retinoic acid (RA) activates RA receptors (RAR), resulting in RA response element (RARE)-dependent gene expression in renal collecting duct (CD). Emerging evidence supports a protective role for this activity in acute kidney injury (AKI) and chronic kidney disease (CKD). Herein, we examined this activity in RARE-LacZ transgenic mice and by RARE-Luciferase reporter assays in CD cells, and investigated how this activity responds to neurotransmitters and mediators of kidney injury. In RARE-LacZ mice, Adriamycin-induced heavy albuminuria was associated with reduced RA/RAR activity in CD cells. In cultured CD cells, RA/RAR activity was repressed by acetylcholine, albumin, aldosterone, angiotensin II, high glucose, cisplatin and lipopolysaccharide, but was induced by aristolochic acid I, calcitonin gene-related peptide, endothelin-1, gentamicin, norepinephrine and vasopressin. Compared with age-matched normal human CD cells, CD-derived renal cystic epithelial cells from patients with autosomal recessive polycystic kidney disease (ARPKD) had significantly lower RA/RAR activity. Synthetic RAR agonist RA-568 was more potent than RA in rescuing RA/RAR activity repressed by albumin, high glucose, angiotensin II, aldosterone, cisplatin and lipopolysaccharide. Hence, RA/RAR  in CD cells is a convergence point of regulation by neurotransmitters and mediators of kidney injury, and may be a novel therapeutic target.

Niche partitioning can lead to differences in the range dynamics of plant species through its impacts on habitat availability, dispersal, or selection for traits that affect colonization and persistence. We investigated whether niche partitioning into upland and riparian habitats differentiates the range dynamics of two closely related and sympatric eastern Australian trees: the mountain water gum (Tristaniopsis collina) and the water gum (T. laurina). Using genomic data from SNP genotyping of 480 samples, we assessed the impact of biogeographic barriers and tested for signals of range expansion. Circuit theory was used to model isolation-by-resistance across three palaeo-environment scenarios: the Last Glacial Maximum, the Holocene Climate Optimum and present-day (1950-2014). Both trees showed similar genetic structure across historically dry barriers, despite evidence of significant environmental niche differentiation and different post-glacial habitat shifts. Tristaniopsis collina exhibits the signature of serial founder effects consistent with recent or rapid range expansion, whilst T. laurina has genetic patterns consistent with long-term persistence in geographically isolated populations despite occupying a broader bioclimatic niche. We found the minor influence of isolation-by-resistance on both species, though other unknown factors appear to shape genetic variation. We postulate that specialized recruitment traits (adapted to flood-disturbance regimes) rather than habitat availability limited post-glacial range expansion in T. laurina. Our findings indicate that niche breadth does not always facilitate range expansion through colonization and migration across barriers, though it can promote long-term persistence in situ.

Background: Levator ani muscle (LAM) and anal sphincter injuries are common after vaginal birth and are associated with pelvic organ prolapse and anal incontinence., Aims: Our objective was to investigate long-term association between delivery mode, LAM avulsion and obstetric anal sphincter injuries (OASIS) in women at least 20 years after their first birth., Methods: All women recruited at 'index birth' of the Dunedin (New Zealand) arm of ProLong (PROlapse and incontinence LONG-term research) Study, were invited to have translabial and transperineal ultrasound assessment of LAM and anal sphincters. Post-processing analysis of imaging data was performed blinded against delivery data. Statistical analysis was performed using the χ 2 test and results are expressed as odds ratios (OR)., Results: Of the initial 1250 participants, 196 women returned for examination. Mean age was 50.8 years with a mean body mass index of 27.6 and median parity was three. They were seen on average 23 years after their first delivery. Four data sets were unavailable and one declined ultrasound assessment, leaving 191 for analysis. LAM avulsion was diagnosed in 29 (15.2%), and 24 women (12.6%) had significant anal sphincter defect. LAM avulsion was associated with forceps delivery (OR 2.45, 95% CI 1.04-5.80, P = 0.041). Forceps conveyed a greater risk of OASIS (21%) compared to a spontaneous vaginal delivery (11%) but did not reach statistical significance., Conclusions: Forceps delivery is associated with long-term injurious effect on pelvic floor structures. Discussions of the long-term negative impact of pelvic floor structures and their functions are necessary to achieve an informed consent toward an operative vaginal delivery., (© 2019 The Royal Australian and New Zealand College of Obstetricians and Gynaecologists.)

Background: Measures of long-term success of total hip arthroplasty (THA) over the past 50 years have focused primarily on implant survival, with less evidence on long-term functional outcomes., Questions/purposes: We aimed to study 20-to-40-year functional outcomes after primary THA. We investigated the extent to which (1) functional outcomes after THA are maintained long term; (2) patient characteristics such as age, hip disease diagnosis, and comorbidities affect recovery of function and survivorship after THA; and (3) patients' overall function after THA is affected by the need for revision, the aging process, and associated comorbidities., Methods: We retrospectively reviewed outcomes of the senior author's patients between 1968 and 1993. Of 1207 patients, we identified 167 patients (99 female, 68 male; 276 primary THAs) who were at least 65 years old at follow-up and had at least 20 years of follow-up. Mean age at surgery was 55 years; mean follow-up time was 27 years. Bilateral THAs were performed in 109 patients (65%), and revisions in 81 patients (48.5%). Clinical outcomes including pain level, walking ability, range of motion, and overall function were determined by the Hospital for Special Surgery (HSS) hip scoring system. Contralateral and revision surgery, as well as patient age, sex, and body mass index, were included as covariates. To account for unequally spaced follow-up time points and competing causes of functional decline (e.g., age, contralateral hip disease, and need for revision THA), a latent class mixed model approach was used to identify unobserved classes of patients who had similar outcomes. Linear, quadratic, and piecewise-polynomial growth models were considered for class identification. The best fitting model was determined based on Bayesian information criterion., Results: A four-class model of this patient population was identified: (1) the Elderly Class, who had a mean age of 62 years at the time of primary THA; (2) the Bilateral Class, who underwent simultaneous or staged bilateral THA; (3) the Revision Class, who required at least one revision; and (4) the Youngest Class, who had a mean age of 49 years. After an initial period of improvement in all groups, the functional trajectory diverged according to classifications. Age was the strongest determinant of long-term outcome, with HSS hip scores in the Elderly Class declining after about 20 years. The Youngest Class maintained good-to-excellent hip function for over 30 years. Revision THA and contralateral THA accounted for a temporary decline in function, after which overall good function was regained for the long term., Conclusions: All classes in the study population enjoyed good-to-excellent outcomes after THA for about 20 years. Thereafter, functional decline was attributed more to aging than to the need for revision. One or more revision THA did not negatively influence long-term clinical outcomes, suggesting that, even for younger patients, symptoms, rather than the avoidance of possible revision, should be the primary determining factor when indicating THA., Competing Interests: Conflict of InterestPhilip D. Wilson, Jr., MD, Leslee Wong, BA, Yuo-Yu Lee, PhD, and Stephen Lyman, PhD, declare that they have no conflicts of interest. Charles N. Cornell, MD, reports receiving personal fees as a consultant from Exactech, outside the submitted work. Dr. Cornell recused himself from oversight of the peer review of this article.

Bile acid imbalance causes progressive familial intrahepatic cholestasis type 2 (PFIC2) or type 3 (PFIC3), severe liver diseases associated with genetic defects in the biliary bile acid transporter bile salt export pump (BSEP; ABCB11) or phosphatidylcholine transporter multidrug resistance protein 3 (MDR3; ABCB4), respectively. Mdr2 -/- mice (a PFIC3 model) develop progressive cholangitis, ductular proliferation, periportal fibrosis, and hepatocellular carcinoma (HCC) because the nonmicelle-bound bile acids in the bile of these mice are toxic. We asked whether the highly hydrophilic bile acids generated by Bsep -/- mice could protect Mdr2 -/- mice from progressive liver damage. We generated double-KO (DKO: Bsep -/- and Mdr2 -/- ) mice. Their bile acid composition resembles that of Bsep -/- mice, with increased hydrophilic muricholic acids, tetrahydroxylated bile acids (THBAs), and reduced hydrophobic cholic acid. These mice lack the liver pathology of their Mdr2 -/- littermates. The livers of DKO mice have gene expression profiles very similar to Bsep -/- mice, with 4,410 of 6,134 gene expression changes associated with the Mdr2 -/- mutation being suppressed. Feeding with THBAs partially alleviates liver damage in the Mdr2 -/- mice. Hydrophilic changes to biliary bile acid composition, including introduction of THBA, can prevent the progressive liver pathology associated with the Mdr2 -/- (PFIC3) mutation., (Copyright © 2019 Wang et al.)

Objectives: This study aimed to ascertain the association between levator avulsion and pelvic organ prolapse (POP)., Methods: This was a cross-sectional study involving 195 women enrolled in a longitudinal cohort study and seen 20 years after an index birth. All had a standardized patient-administered questionnaire, the International Continence Society Pelvic Organ Prolapse Quantification assessment and 4D translabial ultrasound. Main outcome measures were objective POP clinically and on translabial ultrasound. Postimaging assessment of levator integrity and sonographically determined pelvic organ descent was done blinded against other data., Results: Of 195 women who were seen a mean of 23 (range, 19.4-46.2) years after their first birth, one declined ultrasound assessment and was excluded, leaving 194. Mean age was 50.2 (range 36.9-66.5) years with a mean body mass index (BMI) of 27.6 (range, 18.3-54.3) kg/m 2 . Median parity was 3 (range 1-14). Ninety-one percent (n = 176) had delivered vaginally. Eighteen percent (n = 34) were symptomatic of prolapse. Clinically, 36% (n = 69) had significant POP. Levator avulsion was diagnosed in 16% (n = 31). Mean levator avulsion defect score was 2.2 (range, 0-12). On univariate analysis, levator avulsion and levator avulsion defect score were associated with clinically and sonographically significant POP, that is, odds ratio 2.6 (1.2-5.7), P = .01; and odds ratio 3.3 (1.4-7.7); P = .003, respectively; Ba (P < .001); bladder (P < .001); uterine (P < .001) and rectal ampulla (P = .009) descent, but not POP symptoms, C, and Bp. Multivariate analysis controlling for potential confounders confirmed our findings., Conclusions: Levator avulsion is associated with female pelvic organ prolapse, especially of the anterior and central compartments. This association may become stronger with aging., (© 2018 by the American Institute of Ultrasound in Medicine.)

Introduction and Hypothesis: Levator ani muscle (LAM) and anal sphincter tears are common after vaginal birth and are associated with female pelvic organ prolapse and anal incontinence. The impact of subsequent births on LAM and external anal sphincter (EAS) integrity is less well defined. The objective of this study was to determine the prevalence of LAM and EAS trauma in primiparous (VP1) and multiparous (VP2+) women who had delivered vaginally to assess if there were differences between the two groups. The null hypothesis was: there is no significant difference in the prevalence of LAM and EAS trauma between the two groups., Methods: This was a cross-sectional study involving 195 women, participants of the Dunedin arm of the ProLong study (PROlapse and incontinence LONG-term research study) seen 20 years after their index birth. Assessment included a standardized questionnaire, ICS POP-Q and 4D translabial ultrasound. Post-imaging analysis of LAM and EAS integrity was undertaken blinded against other data. Statistical analysis was performed using Fisher's exact test and results were expressed as odds ratios (OR)., Results: LAM avulsion and EAS defects were diagnosed in 31 (16%) and 24 (12.4%) women respectively. No significant difference in the prevalence of levator avulsion and EAS defects between primiparous (VP1) and multiparous (VP2+) women who had delivered vaginally (OR 1.9, 95% CI 0.72-5.01, p = 0.26) and (OR 1.2, 95% CI 0.4-3.8, p = 0.76) respectively., Conclusions: Most LAM avulsions and EAS defects seem to be caused by the first vaginal birth. Subsequent vaginal deliveries after the first were unlikely to cause further LAM trauma.

Background: Prehistoric human activities have contributed to the dispersal of many culturally important plants. The study of these traditional interactions can alter the way we perceive the natural distribution and dynamics of species and communities. Comprehensive research on native crops combining evolutionary and anthropological data is revealing how ancient human populations influenced their distribution. Although traditional diets also included a suite of non-cultivated plants that in some cases necessitated the development of culturally important technical advances such as the treatment of toxic seed, empirical evidence for their deliberate dispersal by prehistoric peoples remains limited. Here we integrate historic and biocultural research involving Aboriginal people, with chloroplast and nuclear genomic data to demonstrate Aboriginal-mediated dispersal of a non-cultivated rainforest tree., Results: We assembled new anthropological evidence of use and deliberate dispersal of Castanospermum australe (Fabaceae), a non-cultivated culturally important riparian tree that produces toxic but highly nutritious water-dispersed seed. We validated cultural evidence of recent human-mediated dispersal by revealing genomic homogeneity across extensively dissected habitat, multiple catchments and uneven topography in the southern range of this species. We excluded the potential contribution of other dispersal mechanisms based on the absence of suitable vectors and current distributional patterns at higher elevations and away from water courses, and by analyzing a comparative sample from northern Australia., Conclusions: Innovative studies integrating evolutionary and anthropological data will continue to reveal the unexpected impact that prehistoric people have had on current vegetation patterns. A better understanding of how traditional practices shaped species' distribution and assembly will directly inform cultural heritage management strategies, challenge "natural" species distribution assumptions, and provide innovative baseline data for pro-active biodiversity management.

Biomarkers, the measurable indicators of biological conditions, are fast becoming a popular approach in providing information to track disease processes that could lead to novel therapeutic interventions for chronic conditions. Inherited, chronic kidney disease affects millions of people worldwide and although pharmacological treatments exist for some conditions, there are still patients whose only option is kidney dialysis and kidney transplantation. In the past 10 years, certain chronic kidney diseases have been reclassified as ciliopathies. Cilia in the kidney are antenna-like, sensory organelles that are required for signal transduction. One of the signalling pathways that requires the primary cilium in the kidney is Wnt signalling and it has three components such as canonical Wnt, non-canonical Wnt/planar cell olarity (PCP) and non-canonical Wnt/Ca 2+ signalling. Identification of the novel role of ATM INteractor (ATMIN) as an effector molecule in the non-canonical Wnt/PCP pathway has intrigued us to investigate its potential role in chronic kidney disease. ATMIN could thus be an important biomarker in disease prognosis and treatment that might lighten the burden of chronic kidney disease and also affect on its progression., (© 2016 The Author(s); published by Portland Press Limited on behalf of the Biochemical Society.)

Purpose of Review: There is increasing awareness of the importance of intrapartum events for future pelvic floor morbidity in women. In this review, we summarize recent evidence and potential consequences for clinical practice., Recent Findings: Both epidemiological evidence and data from perinatal imaging studies have greatly improved our understanding of the link between childbirth and later morbidity. The main consequences of traumatic childbirth are pelvic organ prolapse (POP) and anal incontinence. In both instances the primary etiological pathways have been identified: levator trauma in the case of POP and anal sphincter tears in the case of anal incontinence. As most such trauma is occult, imaging is required for diagnosis., Summary: Childbirth-related major maternal trauma is much more common than generally assumed, and it is the primary etiological factor in POP and anal incontinence. Both sphincter and levator trauma can now be identified on imaging. This is crucial not only for clinical care and audit, but also for research. Postnatally diagnosed trauma can serve as intermediate outcome measure in intervention trials, opening up multiple opportunities for clinical research aimed at primary and secondary prevention.

Introduction: Polycystic kidney disease (PKD) is a common genetic disease in which renal enlargement and loss of function is caused by progressive expansion of tubular cysts. To reverse the detrimental effects of PKD gene mutation(s) and to slow cystic expansion, new drug therapies are required., Areas Covered: The underlying cell biology leading to identification of molecular targets for PKD is reviewed. Specific focus is on studies published at the early pre-clinical level. These include genetic and epigenetic modulators, and drugs to slow cystic expansion and disease progression. Discussion of specific drugs and clinical trials is not within the scope of this article. Literature research methods included EndNote and PubMed online searches using keyword combinations: polycystic kidneys disease, pre-clinical, molecular targets, signal transduction, genetic modulators, epigenetic, therapeutic, receptors, kinases. Where possible, the most recent citations concerning a given target are referenced., Expert Opinion: It is suggested that the most promising targets for future therapeutic development are those that target upstream signaling events at cell membranes, such as the vasopressin-2 receptor (AVPR2), EGFR/ErbB2, and the β-1-integrin receptor, as well as the intracellular integrator kinase, c-Src.

Aims: A bipolar multi-electrode 7 Fr-compatible balloon-catheter radiofrequency (RF) renal denervation system (Vessix™ Renal Denervation System; Boston Scientific, Marlborough, MA, USA) was evaluated for safety in domestic swine., Methods and Results: Renal arteries of 27 swine received overlapping treatments proximally/single treatments distally to mimic balloon overlap clinically. Each histopathology cohort (30, 90, 180 days) had four RF-treated and three sham-treated (no RF energy delivered) animals, with the response of artery/surrounding nerves to bilateral treatment examined (42 arteries). Scanning electron microscopy of the renal artery flow surface for endothelialisation was performed in six additional pigs (three at each of 30 and 90 days: 12 arteries) following unilateral whole artery treatment with proximal overlap: RF one side, sham the other side. Power was ~1 watt, treatment duration 30 seconds, target temperature 68°C. Renal histology and assessment for off-target injury was performed in all 27 swine. Renal artery thermal injury was transmural and segmental involving <10% to >90% of the circumference (typically 30-60%) with segmental neointimal hyperplasia exceeding shams but haemodynamically trivial (maximum stenosis 17.7%). Healing of necrotic arterial media was by replacement fibrosis. Overlying nerves also became fibrotic. Endothelialisation was focally incomplete at 30 days but confluent at 90 days. No off-target injury occurred outside the renal arteries., Conclusions: Safety was demonstrated.

Because RNA lacks strong intrinsic fluorescence, it has proven challenging to track RNA molecules in real time. To address this problem and to allow the purification of fluorescently tagged RNA complexes, we have selected a high affinity RNA aptamer called RNA Mango. This aptamer binds a series of thiazole orange (fluorophore) derivatives with nanomolar affinity, while increasing fluorophore fluorescence by up to 1,100-fold. Visualization of RNA Mango by single-molecule fluorescence microscopy, together with injection and imaging of RNA Mango/fluorophore complex in C. elegans gonads demonstrates the potential for live-cell RNA imaging with this system. By inserting RNA Mango into a stem loop of the bacterial 6S RNA and biotinylating the fluorophore, we demonstrate that the aptamer can be used to simultaneously fluorescently label and purify biologically important RNAs. The high affinity and fluorescent properties of RNA Mango are therefore expected to simplify the study of RNA complexes.

Background: The management of brain metastases in patients with germ cell tumors remains controversial. The authors assessed the outcome in this patient group after the introduction of GAMEC chemotherapy (14-day cisplatin, high-dose methotrexate, etoposide, and actinomycin-D with filgrastim support) and cessation of the routine use of cranial irradiation., Methods: Data were recorded prospectively from 39 patients with germ cell tumors and concurrent brain metastases who received treatment before and after the advent of GAMEC after they relapsed on conventional cisplatin-based chemotherapy. Neurosurgery was offered to selected patients. Radiotherapy generally was used only as a salvage therapy after chemotherapy failure. The primary outcome measure was overall survival and was depicted using a Kaplan-Meier plot., Results: The 3-year overall survival rates were 38% for the whole cohort, 69% for those who presented with brain metastases at diagnosis (group 1), and 21% and 0% for those who developed metastases after initial chemotherapy (group 2) and while receiving chemotherapy (group 3), respectively. For the whole cohort, the median overall survival was 10.6 months (range, 5.5 months to not evaluable); and, for groups 1, 2, and 3 individually, the overall survival was not yet reached (range, from 7.4 months to not evaluable), 6.2 months (range, 2.1-15.3 months), and 2.7 months (range, from 0.6 months to not evaluable), respectively. The 3-year survival rate for those who received GAMEC chemotherapy was 56% compared with 27% for those who received chemotherapy pre-GAMEC., Conclusions: The prognosis for patients with germ cell tumors and brain metastases seems less bleak than previously thought. It is possible to achieve long-term survival with chemotherapy alone., (© 2014 American Cancer Society.)