Postoperative radiotherapy omission in selected patients with early breast cancer following preoperative breast MRI (PROSPECT): primary results of a prospective two-arm study.

BACKGROUND: Adjuvant breast radiotherapy as a standard component of breast-conserving treatment for early cancer can overtreat many women. Breast MRI is the most sensitive modality to assess local tumour burden. The aim of this study was to determine whether a combination of MRI and pathology findings can identify women with truly localised breast cancer who can safely avoid radiotherapy. METHODS: PROSPECT is a prospective, multicentre, two-arm, non-randomised trial of radiotherapy omission in patients selected using preoperative MRI and postoperative tumour pathology. It is being conducted at four academic hospitals in Australia. Women aged 50 years or older with cT1N0 non-triple-negative breast cancer were eligible. Those with apparently unifocal cancer had breast-conserving surgery (BCS) and, if pT1N0 or N1mi, had radiotherapy omitted (group 1). Standard treatment including excision of MRI-detected additional cancers was offered to the others (group 2). All were recommended systemic therapy. The primary outcome was ipsilateral invasive recurrence rate (IIRR) at 5 years in group 1. Primary analysis occurred after the 100th group 1 patient reached 5 years follow-up. Quality-adjusted life-years (QALYs) and cost-effectiveness of the PROSPECT pathway were analysed. This study is registered with the Australian New Zealand Clinical Trials Registry (ACTRN12610000810011). FINDINGS: Between May 17, 2011, and May 6, 2019, 443 patients with breast cancer underwent MRI. Median age was 63·0 years. MRI detected 61 malignant occult lesions separate from the index cancer in 48 patients (11%). Of 201 group 1 patients who had BCS without radiotherapy, the IIRR at 5 years was 1·0% (upper 95% CI 5·4%). In group 1, one local recurrence occurred at 4·5 years and a second at 7·5 years. In group 2, nine patients had mastectomy (2% of total cohort), and the 5-year IIRR was 1·7% (upper 95% CI 6·1%). The only distant metastasis in the entire cohort was genetically distinct from the index cancer. The PROSPECT pathway increased QALYs by 0·019 (95% CI 0·008-0·029) and saved AU$1980 (95% CI 1396-2528) or £953 (672-1216) per patient. INTERPRETATION: PROSPECT suggests that women with unifocal breast cancer on MRI and favourable pathology can safely omit radiotherapy. FUNDING: Breast Cancer Trials, National Breast Cancer Foundation, Cancer Council Victoria, the Royal Melbourne Hospital Foundation, and the Breast Cancer Research Foundation.

Placentation defects are highly prevalent in embryonic lethal mouse mutants.

Large-scale phenotyping efforts have demonstrated that approximately 25-30% of mouse gene knockouts cause intrauterine lethality. Analysis of these mutants has largely focused on the embryo and not the placenta, despite the crucial role of this extraembryonic organ for developmental progression. Here we screened 103 embryonic lethal and sub-viable mouse knockout lines from the Deciphering the Mechanisms of Developmental Disorders program for placental phenotypes. We found that 68% of knockout lines that are lethal at or after mid-gestation exhibited placental dysmorphologies. Early lethality (embryonic days 9.5-14.5) is almost always associated with severe placental malformations. Placental defects correlate strongly with abnormal brain, heart and vascular development. Analysis of mutant trophoblast stem cells and conditional knockouts suggests that a considerable number of factors that cause embryonic lethality when ablated have primary gene function in trophoblast cells. Our data highlight the hugely under-appreciated importance of placental defects in contributing to abnormal embryo development and suggest key molecular nodes that govern placenta formation.

The landscape of current research on pediatric diffuse midline glioma: a quantitative analysis of shifts, leaders, and future avenues.

PURPOSE: Diffuse midline glioma (DMG) has seen a surge of research interest in recent years with the growth in knowledge of new avenues for potential treatments. However, no bibliometric review of the field has been conducted to visualize the current state of the field. Here, we use bibliometric mapping to visualize the knowledge structure, collaborations, and trends in the field. METHODS: A total of 1079 original and review articles from 1996 to 2023 on diffuse midline glioma were extracted from the Web of Science Core Collection on June 3, 2023. These files were analyzed with R and VOSviewer to construct bibliometric visualizations. RESULTS: Research interest in DMG has continued to grow, driven by publications of original research. Molecular characterization of DMG has been a key focus of recent literature, and terms relating to novel small molecules, mutations, immunotherapy, the blood-brain barrier, and liquid biopsy may be areas for future growth in the literature. Collaborating nations have generally been the North American and European nations, but other nations have begun to make their mark in the field. Leading and rising institutions and journals are described. CONCLUSION: Research in DMG may continue to focus on molecular characterization and new therapeutics based on this knowledge. Novel collaborations between rising nations and institutions in the field may aid in accelerating this research.

Cartilage-specific Sirt6 deficiency represses IGF-1 and enhances osteoarthritis severity in mice.

OBJECTIVES: Prior studies noted that chondrocyte SIRT6 activity is repressed in older chondrocytes rendering cells susceptible to catabolic signalling events implicated in osteoarthritis (OA). This study aimed to define the effect of Sirt6 deficiency on the development of post-traumatic and age-associated OA in mice. METHODS: Male cartilage-specific Sirt6-deficient mice and Sirt6 intact controls underwent destabilisation of the medial meniscus (DMM) or sham surgery at 16 weeks of age and OA severity was analysed at 6 and 10 weeks postsurgery. Age-associated OA was assessed in mice aged 12 and 18 months of age. OA severity was analysed by micro-CT, histomorphometry and scoring of articular cartilage structure, toluidine blue staining and osteophyte formation. SIRT6-regulated pathways were analysed in human chondrocytes by RNA-sequencing, qRT-PCR and immunoblotting. RESULTS: Sirt6-deficient mice displayed enhanced DMM-induced OA severity and accelerated age-associated OA when compared with controls, characterised by increased cartilage damage, osteophyte formation and subchondral bone sclerosis. In chondrocytes, RNA-sequencing revealed that SIRT6 depletion significantly repressed cartilage extracellular matrix (eg, COL2A1) and anabolic growth factor (eg, insulin-like growth factor-1 (IGF-1)) gene expression. Gain-of-function and loss-of-function studies in chondrocytes demonstrated that SIRT6 depletion attenuated, whereas adenoviral overexpression or MDL-800-induced SIRT6 activation promoted IGF-1 signalling by increasing Aktser473 phosphorylation. CONCLUSIONS: SIRT6 deficiency increases post-traumatic and age-associated OA severity in vivo. SIRT6 profoundly regulated the pro-anabolic and pro-survival IGF-1/Akt signalling pathway and suggests that preserving the SIRT6/IGF-1/Akt axis may be necessary to protect cartilage from injury-associated or age-associated OA. Targeted therapies aimed at increasing SIRT6 function could represent a novel strategy to slow or stop OA.

Age and oxidative stress regulate Nrf2 homeostasis in human articular chondrocytes.

OBJECTIVE: The purpose of this study was to investigate the effect of age and oxidative stress on regulation of nuclear factor erythroid-2-related factor 2 (Nrf2) in young, old, and osteoarthritic (OA) human articular chondrocytes. DESIGN: Levels of Nrf2 in primary human chondrocytes isolated from young, old, and OA donors were measured by immunoblotting, qPCR, and immunohistochemistry. Effects on levels of Nrf2, antioxidant proteins regulated by Nrf2, as well as p65, and the anabolic response to insulin-like growth factor-1 (IGF-1) were evaluated after induction of oxidative stress with menadione, Nrf2 knockdown with siRNA, and/or Nrf2 activation with RTA-408. RESULTS: Nrf2 protein levels were significantly lower in older adult chondrocytes (∼0.59 fold; p = 0.034) and OA chondrocytes (∼0.50 fold; p = 0.016) compared to younger cells. Menadione significantly increased Nrf2 protein levels in young chondrocytes by just under four-fold without changes in old chondrocytes. Nrf2 knockdown and activation differentially regulated levels of anti-oxidant proteins including sulfiredoxin and NAD(P)H quinone dehydrogenase 1. Nrf2 activation with RTA-408 also decreased basal p65 phosphorylation, increased aggrecan and type II collagen gene expression, and increased production of proteoglycans in OA chondrocytes treated with IGF-1. CONCLUSIONS: Targeted therapeutic strategies aimed at maintaining Nrf2 activity could be useful in maintaining chondrocyte homeostasis through maintenance of intracellular antioxidant function and redox balance.

High-resolution seismic constraints on flow dynamics in the oceanic asthenosphere.

Convective flow in the mantle and the motions of tectonic plates produce deformation of Earth's interior, and the rock fabric produced by this deformation can be discerned using the anisotropy of the seismic wave speed. This deformation is commonly inferred close to lithospheric boundaries beneath the ocean in the uppermost mantle, including near seafloor-spreading centres as new plates are formed via corner flow, and within a weak asthenosphere that lubricates large-scale plate-driven flow and accommodates smaller scale convection. Seismic models of oceanic upper mantle differ as to the relative importance of these deformation processes: seafloor spreading fabric is very strong just beneath the crust-mantle boundary (the Mohorovicic discontinuity, or Moho) at relatively local scales, but at the global and ocean-basin scales, oceanic lithosphere typically appears weakly anisotropic when compared to the asthenosphere. Here we use Rayleigh waves, recorded across an ocean-bottom seismograph array in the central Pacific Ocean (the NoMelt Experiment), to provide unique localized constraints on seismic anisotropy within the oceanic lithosphere-asthenosphere system in the middle of a plate. We find that azimuthal anisotropy is strongest within the high-seismic-velocity lid, with the fast direction coincident with seafloor spreading. A minimum in the magnitude of azimuthal anisotropy occurs within the middle of the seismic low-velocity zone, and then increases with depth below the weakest portion of the asthenosphere. At no depth does the fast direction correlate with the apparent plate motion. Our results suggest that the highest strain deformation in the shallow oceanic mantle occurs during corner flow at the ridge axis, and via pressure-driven or buoyancy-driven flow within the asthenosphere. Shear associated with motion of the plate over the underlying asthenosphere, if present, is weak compared to these other processes.

The gene regulatory basis of genetic compensation during neural crest induction.

The neural crest (NC) is a vertebrate-specific cell type that contributes to a wide range of different tissues across all three germ layers. The gene regulatory network (GRN) responsible for the formation of neural crest is conserved across vertebrates. Central to the induction of the NC GRN are AP-2 and SoxE transcription factors. NC induction robustness is ensured through the ability of some of these transcription factors to compensate loss of function of gene family members. However the gene regulatory events underlying compensation are poorly understood. We have used gene knockout and RNA sequencing strategies to dissect NC induction and compensation in zebrafish. We genetically ablate the NC using double mutants of tfap2a;tfap2c or remove specific subsets of the NC with sox10 and mitfa knockouts and characterise genome-wide gene expression levels across multiple time points. We find that compensation through a single wild-type allele of tfap2c is capable of maintaining early NC induction and differentiation in the absence of tfap2a function, but many target genes have abnormal expression levels and therefore show sensitivity to the reduced tfap2 dosage. This separation of morphological and molecular phenotypes identifies a core set of genes required for early NC development. We also identify the 15 somites stage as the peak of the molecular phenotype which strongly diminishes at 24 hpf even as the morphological phenotype becomes more apparent. Using gene knockouts, we associate previously uncharacterised genes with pigment cell development and establish a role for maternal Hippo signalling in melanocyte differentiation. This work extends and refines the NC GRN while also uncovering the transcriptional basis of genetic compensation via paralogues.

"Persistent Post-Operative Pain in Children - An Argument for a Transitional Pain Service in Pediatrics".

BACKGROUND: Persistent post-operative pain continues to occur in pediatric patients. Despite the growing amount of literature on causes, there is little discussion on treatment and prevention with a majority of studies focusing on specific surgeries. AIM: The aim of this retrospective chart study is to identify risk factors and clinical features of persistent post-operative pain after any surgery in a pediatric quaternary complex pain service, describe the pharmacologic and non-pharmacologic management in children, and explore options to improve outcomes, in particular, the introduction of a transitional pain service. METHODS: A retrospective chart review recorded demographics, gender, age, pain location and surgery type, treatment, and outcomes of 31 children identified through relevant registers over a 2-year period. RESULTS: A total of 31 children were positively identified as having persistent post-operative pain and were seen in the complex pain clinic. Consistent with the literature, most cases represented neuropathic pain and persistent post-operative pain was most commonly seen after orthopedic surgery. All but four children had resolution of their pain after implementing the pain management plan. Management was characterized by early intervention, emphasis on non-pharmacologic strategies, and conservative use of opioids. CONCLUSIONS: Identifying risk factors is useful, however putting strategies into place for prevention is necessary. Early intervention and the implementation of strategies before and immediately after are best provided by a transitional pain service.

Stereotactic laser anterior corpus callosotomy for Lennox-Gastaut syndrome.

OBJECTIVE: Corpus callosotomy is an effective palliative treatment for drug-resistant Lennox-Gastaut syndrome (LGS). Laser interstitial thermal therapy has been increasingly used in the treatment of epilepsy. Here, we assess the safety and effectiveness of minimally invasive stereotactic laser anterior corpus callosotomy (SLACC) for drop attacks in LGS. METHODS: We reviewed sequential cases of patients with medically intractable LGS who underwent SLACC using a two-cannula technique between November 2014 and July 2019. Pre- and postoperative magnetic resonance imaging was used to measure the anteroposterior length of callosal ablation (contrast-enhancing lesion) and estimated disconnection (gap in tract projections on diffusion tensor imaging). Patients were followed longitudinally to assess clinical outcomes. RESULTS: Ten patients were included in this study. The median age was 33 (range = 11-52) years, median duration of epilepsy was 26 (range = 10-49) years, and median duration of postoperative follow-up was 19 (range = 6-40) months. In the anteroposterior direction, 53 ± 7% (mean ± SD) of the corpus callosum was ablated and 62 ± 19% of the corpus callosum was estimated to be disconnected. Six (60%) of 10 patients achieved >80% seizure reduction, two (20%) of whom became seizure-free. Eight (80%) patients had >80% reduction in drop attacks, five (50%) of whom became free of drop attacks. Three patients subsequently underwent laser posterior callosotomy with further improvement in drop attacks and/or overall seizure frequency. One patient had an asymptomatic intracerebral hemorrhage along the cannula tract. One patient developed significant aggression after becoming seizure-free. SIGNIFICANCE: Seizure outcomes following SLACC were comparable to previously reported outcomes of open callosotomy, with reasonable safety profile. SLACC appears to be an effective alternative to open anterior corpus callosotomy with minimal postoperative discomfort and a short recovery period.

Loss of the chromatin modifier Kdm2aa causes BrafV600E-independent spontaneous melanoma in zebrafish.

KDM2A is a histone demethylase associated with transcriptional silencing, however very little is known about its in vivo role in development and disease. Here we demonstrate that loss of the orthologue kdm2aa in zebrafish causes widespread transcriptional disruption and leads to spontaneous melanomas at a high frequency. Fish homozygous for two independent premature stop codon alleles show reduced growth and survival, a strong male sex bias, and homozygous females exhibit a progressive oogenesis defect. kdm2aa mutant fish also develop melanomas from early adulthood onwards which are independent from mutations in braf and other common oncogenes and tumour suppressors as revealed by deep whole exome sequencing. In addition to effects on translation and DNA replication gene expression, high-replicate RNA-seq in morphologically normal individuals demonstrates a stable regulatory response of epigenetic modifiers and the specific de-repression of a group of zinc finger genes residing in constitutive heterochromatin. Together our data reveal a complex role for Kdm2aa in regulating normal mRNA levels and carcinogenesis. These findings establish kdm2aa mutants as the first single gene knockout model of melanoma biology.

Stereotactic laser interstitial thermal therapy for epilepsy associated with solitary and multiple cerebral cavernous malformations.

OBJECTIVE: The authors sought to perform a preliminary assessment of the safety and effectiveness of stereotactic laser interstitial thermal therapy (LITT) for patients with cerebral cavernous malformation (CCM)-related epilepsy. METHODS: The authors retrospectively analyzed 6 patients with CCM-related epilepsy who underwent LITT. Pre-, intra-, and postoperative brain MRI studies were used to characterize preoperative CCM volume, ablation volume, and postablation hemosiderin volume. Clinical outcomes were assessed postoperatively during clinic follow-up visits or phone interviews. RESULTS: LITT was performed in 7 CCMs in 6 patients. Two patients had familial CCM disease with multifocal lesions. Four treated CCMs were extratemporal, and 3 were in or near the visual pathways. The median follow-up was 25 (range 12-39) months. Five of 6 (83%) patients achieved seizure freedom (Engel I classification), of whom 4 (67%) were Engel IA and 1 was Engel IC after a single seizure on postoperative day 4. The remaining patient had rare seizures (Engel II). One patient had a nondisabling visual field deficit. There were no hemorrhagic complications. All patients were discharged within 24 hours postablation. MRI 3-11 months after ablation demonstrated expected focal necrosis and trace hemosiderin-related T2 hypointensity measuring 9%-44% (median 24%) of the original lesion volume, with significant (p = 0.04) volume reduction. CONCLUSIONS: LITT is a minimally invasive option for treating CCM-related epilepsy with seizure outcomes comparable to those achieved with open lesionectomy. The precision of LITT allows for the obliteration of eloquent, deep, small, and multifocal lesions with low complication rates, minimal postoperative discomfort, and short hospital stays. In this study the feasibility and benefits of this method were demonstrated in 2 patients with multifocal lesions.

Airway Morphological Changes in Pierre Robin Sequence: A Retrospective Study.

OBJECTIVE: To investigate airway morphology changes in patients with Pierre Robin sequence (PRS) pre-/post-mandibular distraction osteogenesis (MDO) and to compare morphologic changes to age-matched controls. DESIGN: Retrospective case-control study. SETTING: Urban, academic, tertiary medical center. PATIENTS, PARTICIPANTS: Fifteen patients with PRS after MDO to relieve upper airway obstruction (UAO) (2008-2018); age-matched controls for post-MDO patients. INTERVENTIONS: Mandibular distraction osteogenesis, curvilinear internal mandibular distractors. MAIN OUTCOME MEASURES: (1) Physiologic improvement after MDO (apnea-hypopnea index; minimum oxygen saturation); (2) airway size (volume, surface area, length, mean/minimum cross-sectional area), shape (lateral:anterior-posterior ratio, cross-sectional area ratios, uniformity, sphericity), and changes with MDO; and (3) post-MDO airway size, shape versus age-matched controls. RESULTS: Airway size increased after MDO (volume, P = .01; surface area, P = .02; length, P = .01), as did cross-sectional area (mean, P = .02; minimum, P = .02; minimum retropalatal, P = .05, mid-retroglossal, P = .02). Post-MDO PRS airways were larger than controls (volume, P < .01; surface area, P < .01; length, P < .01, cross-sectional area, P = .03). Airway shape remained nonuniform and flat post-MDO; control airways were round. Two syndromic patients required repeat MDO and had subphysiologic post-MDO airway cross-sectional area. Post-MDO PRS patients with supraphysiologic cross-sectional area along the entire airway had no UAO recurrence. CONCLUSIONS: In this small, heterogenous patient sample, MDO increases airway size, may preferentially affect the retropalatal airway, and often results in supraphysiologic airway dimensions. These retropalatal changes may be important in relieving severe UAO in patients with PRS. Generalizability of our results is limited by small cohort size and patient heterogeneity.

Effect of a load distribution system on mobility and performance during simulated and field hiking while under load.

This study was conducted to test a modular scalable vest-load distribution system (MSV-LDS) against the plate carrier system (PC) currently used by the United States Marine Corps. Ten Marines engaged in 1.6 km load carriage trials in seven experimental conditions in a laboratory study. Kinematic, kinetic, and spatiotemporal gait parameters, muscle activity (electromyography), heart rate, caloric expenditure, shooting reaction times, and subjective responses were recorded. There was lower mean trapezius recruitment for the PC compared with the MSV-LDS for all conditions, and muscle activity was similar to baseline for the MSV-LDS. Twenty-seven Marines carrying the highest load were evaluated in the field, which measured an increase in energy expenditure with MSV-LDS; however, back discomfort was reduced. The field evaluation showed significantly reduced estimated ground reaction force on flat-ground segments with the MSV-LDS, and the data suggest both systems were comparable with respect to mobility and energy cost. Practitioner summary: This study found that a novel load distribution system appears to redistribute load for improved comfort as well as reduce estimated ground reaction force when engaged in hiking activities. Further, hiking with a load distribution system enables more neutral walking posture. Implications of load differences in loads carried are examined. Abbreviations: AGRF: anterior-posterior ground reaction forces; CAREN: Computer Assisted Rehabilitation Environment; GRF: ground reaction forces; HR: heart rate; ML-GRF: mediolateral ground reaction forces; MOLLE: Modular Lightweight Load-carrying Equipment; MSV-LDS: modular scalable vest-load distribution system; NHRC: Naval Health Research Center; PC: plate carrier; PPE: personal protective equipment; RPE: rating of perceived exertion; SAPI: small arms protective insert; sEMG: surface electromyography; USMC: United States Marine Corps; VGRF: Ground reaction forces in the vertical.

H2O2 oxidation of cysteine residues in c-Jun N-terminal kinase 2 (JNK2) contributes to redox regulation in human articular chondrocytes.

Reactive oxygen species (ROS), in particular H2O2, regulate intracellular signaling through reversible oxidation of reactive protein thiols present in a number of kinases and phosphatases. H2O2 has been shown to regulate mitogen-activated protein kinase (MAPK) signaling depending on the cellular context. We report here that in human articular chondrocytes, the MAPK family member c-Jun N-terminal kinase 2 (JNK2) is activated by fibronectin fragments and low physiological levels of H2O2 and inhibited by oxidation due to elevated levels of H2O2 The kinase activity of affinity-purified, phosphorylated JNK2 from cultured chondrocytes was reversibly inhibited by 5-20 µm H2O2 Using dimedone-based chemical probes that react specifically with sulfenylated cysteines (RSOH), we identified Cys-222 in JNK2, a residue not conserved in JNK1 or JNK3, as a redox-reactive site. MS analysis of human recombinant JNK2 also detected further oxidation at Cys-222 and other cysteines to sulfinic (RSO2H) or sulfonic (RSO3H) acid. H2O2 treatment of JNK2 resulted in detectable levels of peptides containing intramolecular disulfides between Cys-222 and either Cys-213 or Cys-177, without evidence of dimer formation. Substitution of Cys-222 to alanine rendered JNK2 insensitive to H2O2 inhibition, unlike C177A and C213A variants. Two other JNK2 variants, C116A and C163A, were also resistant to oxidative inhibition. Cumulatively, these findings indicate differential regulation of JNK2 signaling dependent on H2O2 levels and point to key cysteine residues regulating JNK2 activity. As levels of intracellular H2O2 rise, a switch occurs from activation to inhibition of JNK2 activity, linking JNK2 regulation to the redox status of the cell.

Relationship of Estimated GFR and Albuminuria to Concurrent Laboratory Abnormalities: An Individual Participant Data Meta-analysis in a Global Consortium.

RATIONALE & OBJECTIVE: Chronic kidney disease (CKD) is complicated by abnormalities that reflect disruption in filtration, tubular, and endocrine functions of the kidney. Our aim was to explore the relationship of specific laboratory result abnormalities and hypertension with the estimated glomerular filtration rate (eGFR) and albuminuria CKD staging framework. STUDY DESIGN: Cross-sectional individual participant-level analyses in a global consortium. SETTING & STUDY POPULATIONS: 17 CKD and 38 general population and high-risk cohorts. SELECTION CRITERIA FOR STUDIES: Cohorts in the CKD Prognosis Consortium with data for eGFR and albuminuria, as well as a measurement of hemoglobin, bicarbonate, phosphorus, parathyroid hormone, potassium, or calcium, or hypertension. DATA EXTRACTION: Data were obtained and analyzed between July 2015 and January 2018. ANALYTICAL APPROACH: We modeled the association of eGFR and albuminuria with hemoglobin, bicarbonate, phosphorus, parathyroid hormone, potassium, and calcium values using linear regression and with hypertension and categorical definitions of each abnormality using logistic regression. Results were pooled using random-effects meta-analyses. RESULTS: The CKD cohorts (n=254,666 participants) were 27% women and 10% black, with a mean age of 69 (SD, 12) years. The general population/high-risk cohorts (n=1,758,334) were 50% women and 2% black, with a mean age of 50 (16) years. There was a strong graded association between lower eGFR and all laboratory result abnormalities (ORs ranging from 3.27 [95% CI, 2.68-3.97] to 8.91 [95% CI, 7.22-10.99] comparing eGFRs of 15 to 29 with eGFRs of 45 to 59mL/min/1.73m2), whereas albuminuria had equivocal or weak associations with abnormalities (ORs ranging from 0.77 [95% CI, 0.60-0.99] to 1.92 [95% CI, 1.65-2.24] comparing urinary albumin-creatinine ratio > 300 vs < 30mg/g). LIMITATIONS: Variations in study era, health care delivery system, typical diet, and laboratory assays. CONCLUSIONS: Lower eGFR was strongly associated with higher odds of multiple laboratory result abnormalities. Knowledge of risk associations might help guide management in the heterogeneous group of patients with CKD.

Regional variation in the treatment and prevention of peritoneal dialysis-related infections in the Peritoneal Dialysis Outcomes and Practice Patterns Study.

BACKGROUND: Peritoneal dialysis (PD)-related infections lead to significant morbidity. The International Society for Peritoneal Dialysis (ISPD) guidelines for the prevention and treatment of PD-related infections are based on variable evidence. We describe practice patterns across facilities participating in the Peritoneal Dialysis Outcomes and Practice Patterns Study (PDOPPS). METHODS: PDOPPS, a prospective cohort study, enrolled nationally representative samples of PD patients in Australia/New Zealand (ANZ), Canada, Thailand, Japan, the UK and the USA. Data on PD-related infection prevention and treatment practices across facilities were obtained from a survey of medical directors'. RESULTS: A total of 170 centers, caring for >11 000 patients, were included. The proportion of facilities reporting antibiotic administration at the time of PD catheter insertion was lowest in the USA (63%) and highest in Canada and the UK (100%). Exit-site antimicrobial prophylaxis was variably used across countries, with Japan (4%) and Thailand (28%) having the lowest proportions. Exit-site mupirocin was the predominant exit-site prophylactic strategy in ANZ (56%), Canada (50%) and the UK (47%), while exit-site aminoglycosides were more common in the USA (72%). Empiric Gram-positive peritonitis treatment with vancomycin was most common in the UK (88%) and USA (83%) compared with 10-45% elsewhere. Empiric Gram-negative peritonitis treatment with aminoglycoside therapy was highest in ANZ (72%) and the UK (77%) compared with 10-45% elsewhere. CONCLUSIONS: Variation in PD-related infection prevention and treatment strategies exist across countries with limited uptake of ISPD guideline recommendations. Further work will aim to understand the impact these differences have on the wide variation in infection risk between facilities and other clinically relevant PD outcomes.

The zebrafish reference genome sequence and its relationship to the human genome.

Zebrafish have become a popular organism for the study of vertebrate gene function. The virtually transparent embryos of this species, and the ability to accelerate genetic studies by gene knockdown or overexpression, have led to the widespread use of zebrafish in the detailed investigation of vertebrate gene function and increasingly, the study of human genetic disease. However, for effective modelling of human genetic disease it is important to understand the extent to which zebrafish genes and gene structures are related to orthologous human genes. To examine this, we generated a high-quality sequence assembly of the zebrafish genome, made up of an overlapping set of completely sequenced large-insert clones that were ordered and oriented using a high-resolution high-density meiotic map. Detailed automatic and manual annotation provides evidence of more than 26,000 protein-coding genes, the largest gene set of any vertebrate so far sequenced. Comparison to the human reference genome shows that approximately 70% of human genes have at least one obvious zebrafish orthologue. In addition, the high quality of this genome assembly provides a clearer understanding of key genomic features such as a unique repeat content, a scarcity of pseudogenes, an enrichment of zebrafish-specific genes on chromosome 4 and chromosomal regions that influence sex determination.

Effects of Performance-Based Training on Gait and Balance in Individuals With Incomplete Spinal Cord Injury.

OBJECTIVE: To determine changes in balance and gait following a task-specific, performance-based training protocol for overground locomotor training (OLT) in individuals with motor-incomplete spinal cord injury (iSCI). DESIGN: Convenience sample, prepilot and postpilot study. SETTING: Human performance research laboratory. PARTICIPANTS: Adults (N=15; 12 men and 3 women; mean age [y] ± SD, 41.5±16.9), American Spinal Injury Association Impairment Scale C or D, >6 months post-spinal cord injury. INTERVENTIONS: Two 90-minute OLT sessions per week over 12 to 15 weeks. OLT sessions were built on 3 principles of motor learning: practice variability, task specificity, and progressive overload (movement complexity, resistance, velocity, volume). Training used only voluntary movements without body-weight support, robotics, electrical stimulation, or bracing. Subjects used ambulatory assistive devices as necessary. MAIN OUTCOME MEASURES: Berg Balance Scale (BBS), Spinal Cord Injury Functional Ambulation Inventory (SCI-FAI) gait parameters, spatiotemporal measures of gait (step length, step width, percent stance, stance:swing ratio) from 7 participants who walked across a pressure-sensitive walkway. RESULTS: Fourteen participants completed the OLT protocol and 1 participant completed 15 sessions due to scheduled surgery. The BBS scores showed a mean improvement of 4.53±4.09 (P<.001). SCI-FAI scores showed a mean increase of 2.47±3.44 (P=.01). Spatiotemporal measures of gait showed no significant changes. CONCLUSION: This pilot demonstrated improvements in balance and selected gait characteristics using a task-specific, performance-based OLT for chronic iSCI.

Efficacy and acceptability of treatment to eradicate nasal Staphylococcus aureus carriage among haemodialysis patients.

AIM: For patients requiring haemodialysis, the risk of Staphylococcus aureus disease is higher in those colonized and persists while the person requires haemodialysis, necessitating frequent decolonization. However, the duration of successful decolonization is not known. This study aimed to determine the duration of efficacy of decolonization in intermittent and persistent S. aureus carriers requiring haemodialysis using two decolonization strategies. METHODS: We screened 100 outpatients requiring haemodialysis for S. aureus carriage and then decolonized 14 intermittent carriers and 18 persistent carriers. Participants were invited to undertake two decolonization attempts, using systemic or topical antibiotics 12 weeks apart. Nasal swabs were taken weekly to determine the duration of successful decolonization. RESULTS: Decolonization was successful in 24/32 (75%) participants and the median duration of decolonization was 35 days (95% confidence interval (CI) 11-59). The median duration of S. aureus decolonization was significantly shorter for persistent carriers (19 days, 95% CI 13-25 days) in comparison with intermittent carriers (70 days, 95% CI 61-79 days; P < 0.01). 28/52 (54%) post-decolonization surveys indicated that they would use the treatment again, 14/52 (27%) surveys indicated that they would not use the treatment again, and 10/52 (19%) were undecided. 16/53 (30%) decolonization attempts resulted in an adverse drug reaction. CONCLUSION: Staphylococcus aureus decolonization using topical or systemic treatments was successful for many haemodialysis patients, and provided a month free of S. aureus colonization. Although decolonization treatment provided a shorter duration of success for persistent carriers in comparison with intermittent carriers, persistent carriers are likely to gain the most from effective decolonization strategies.

Predicting outcomes within an innovative post-acute rehabilitation model for older adults.

BACKGROUND: Understanding the provision of health services to community-dwelling older adults is of great importance due to regulatory changes within post-acute care. The aim of this study was to illustrate pathways by which older adults, within an innovative post-acute care delivery model, move to either independence or re-admission back into higher levels of care to maximize the value of rehabilitation delivery. METHODS: Clinical data specific to an episode of care (n = 30,001) provided to Medicare beneficiaries treated via a rehabilitation house-calls model of care in their homes and senior living communites were separated into training and test sets. Classification trees were fit on the training set's administrative and clinical variables. Descriptive statistics were calculated for the overall sample, patient characteristics, clinical characteristics, and clinical outcomes. RESULTS: Subjects were 83.3 years on average, 69.4% were female, and 62.2% were seen in their own homes while 37.8% were in senior living. The key variables predictive of progressing to independence were total number of visits, the presence of the Patient Specific Functional Scale (PSFS), PSFS score at discharge and change in PSFS. Prediction accuracy of the classification tree on the test set was 82.4%. CONCLUSIONS: Older adults progress to a higher degree of independence, instead of higher levels of care, via several distinct pathways within a rehabilitation house-calls model of care. A mix of service utilization and outcome variables are key predictors of each pathway and may be used to maximize the value of service delivery. Further examination of the predictors of outcome using administrative datasets drawn from different sub-sets of older adults across the post-acute care continuum is warranted.