New specimens of middle Eocene omomyines (Primates, Omomyoidea) from the Uinta Basin of Utah and the Tornillo Basin of Texas, with clarification of the generic status of Ourayia, Mytonius, and Diablomomys.

In the middle Eocene, multiple lineages of North American omomyoids independently evolved body masses greater than 500 g. Most of these large-bodied omomyoids are known from small sample sizes, which has contributed to a lack of consensus regarding their alpha taxonomy. Here, we describe new Uintan omomyine specimens from the Uinta Basin of Utah and the Tornillo Basin of Texas. These new samples expand the hypodigms of Diablomomys dalquesti, Mytonius hopsoni, and Ourayia uintensis, and favor the recognition of new species of Mytonius and Ourayia based on specimens from the Tornillo Basin. These samples support the recognition of Diablomomys as a valid genus distinct from Omomys, Ourayia as a valid genus distinct from Macrotarsius, and Mytonius as a valid genus distinct from Ourayia. Although Diablomomys and Omomys co-occur in the late Uintan of the Tornillo Basin, Ourayia and Mytonius are time-successive taxa with a wide distribution across multiple Laramide basins. The data presented here reinforce the conclusion that the Uintan was a time period in which omomyines diversified to include a large number of taxa with body masses above Kay's threshold and frugivorous-folivorous diets. These data also provide evidence that North American primate faunas exhibited a shifting pattern of regional endemism during the middle Eocene. By the early Uintan, primate faunas from Southern California were already quite distinct from primate faunas of the central Rocky Mountains or Trans-Pecos Texas. By the late Uintan, primate faunas in all three regions demonstrated greater provincialism, with Trans-Pecos Texas and Southern California both exhibiting a large number of endemic primate taxa and sharing only a single primate genus (Macrotarsius) in common. This increase in primate endemism across the Uintan may be tied to changes in paleohabitats associated with the larger trend toward decreasing temperatures from the Early Eocene Climatic Optimum to the Eocene/Oligocene transition.

How do local authority plans to tackle obesity reflect systems thinking?

AIMS: A whole systems approach to tackling obesity has been recommended by Public Health England for several years. This qualitative study aimed to investigate whether systems thinking is reflected in local authority plans and strategies to tackle obesity, using the leverage points for intervention in a complex system, as a framework. METHOD: We sought to identify obesity strategies/plans for Southampton and 19 other local authority comparators (based on children's services and Office for National Statistics data). A healthy weight strategy was available for 10 local authorities and a qualitative document analysis was undertaken. The policy actions proposed in the plans were coded against the leverage points for intervention in a complex system and themes were developed to characterise interventions in each category. RESULTS: A majority of actions included in the plans were categorised as 'Numbers, Constants and Parameters' which reflect downstream measures. However, there were examples of actions that could act on higher leverage points. In addition, some local authority plans included interventions that could act on 10 of the 12 leverage points suggesting incorporation of systems thinking. CONCLUSIONS: Some local authority plans to tackle obesity do reflect systems thinking when viewed through the lens of the leverage points for intervention in a complex system. Interventions at higher leverage points should be prioritised by public health decision-makers, especially in a climate of competing agendas and limited resources.

Epicardial pacemaker implantation and outcome in eight pet ferrets (Mustela putorius furo).

INTRODUCTION/OBJECTIVES: Minimal information exists regarding epicardial pacemaker (EP) implantation in pet ferrets (Mustela putorius furo). The objectives were to describe the indications, surgical technique, and outcome of EP implantation in ferrets for the treatment of advanced atrioventricular block (AVB). ANIMALS, MATERIALS, AND METHODS: Eight client-owned ferrets presenting to five veterinary referral centers. Signalment, physical exam findings, diagnostic tests, anesthesia protocols, surgical implantation techniques, postoperative treatment plans, and EP interrogations were reviewed. Intra- and postoperative, minor and major, and EP-related complications were established. Descriptive statistics were performed to report complication rates. Survival analyses were performed. RESULTS: All ferrets had advanced AVB: 3/8 had high-grade second-degree and 5/8 had third-degree. The primary clinical signs were collapse and weakness. Seven EP were implanted via a transdiaphragmatic approach and one via a left intercostal thoracotomy. Intraoperative complications occurred in 2/8 ferrets, both major. One ferret with severe comorbidities died during general anesthesia. Postoperative pacemaker-related complications were minor: inappropriate sinus beat sensing in 2/8 and occasional muscle fasciculations in 1/8. Two ferrets were alive at the time of manuscript submission, at 10 and 21 months postoperatively. The overall median survival time was 24 months. CONCLUSIONS: Implantation of EP was performed successfully in most ferrets for treatment of advanced AVB and was well tolerated. Ferrets with advanced AVB may experience resolution of clinical signs associated with their cardiac disease following EP implantation. Additional studies are warranted to investigate the effects of epicardial pacing on survival times in this species.

Geometric morphometrics and anatomical network analyses reveal ecospace partitioning among geoemydid turtles from the Uinta Formation, Utah.

We present new fossil records of the geoemydid turtle Bridgeremys pusilla from the Uinta Formation of Utah. Turtles are abundant throughout the unit, and known taxa are similar to those from the older strata in the Upper Green River Basin in Wyoming from the Bridger and Washakie Formations. B. pusilla is known from Bridgerian deposits but was not previously known from after the Turtle Bluff Member of the Bridger Formation. The taxon was coveal with two species of the geoemydid Echmatemys (E. callopyge and E. wyomingensis), a common genus of extinct pond turtles known primarily from lacustrine and fluvial deposits in western North America, including the Uinta Basin. In addition to previously documented morphological differences, our geometric morphometric analyses revealed significant differences in epiplastral morphology between B. pusilla and the two coeval Echmatemys species. Bridgeremys pusilla shared several morphological characters with Testudinidae. However, our anatomical network analysis suggests that the carapace of B. pusilla distributed stress forces in a manner more similar to emydids (basal and derived) than to derived testudinoids (Testudinidae and Emydidae), including Echmatemys species. This finding changes our understanding of the ecology of the species and sheds light onto how geoemydid turtles of the Uinta Formation may have partitioned the available ecospace. These new Uintan records extend the geographic range of B. pusilla into the Uinta Basin and stratigraphically through the top of the Uinta Formation, extending the temporal range of the taxon by more than 4 million years through the Uintan North American Land Mammal Age to the base of the Duchesne River Formation.

Functional Adaptations in the Forelimb of the Snow Leopard (Panthera uncia).

The snow leopard (Panthera uncia) is anatomically and physiologically adapted for life in the rocky terrain of alpine zones in Central and South Asia. Panthera uncia is scansorial, and typically hunts solitarily by using overhead ambush of prey, rather than the typical stalking pattern of other large pantherines. In this study, we conducted dissections, detailed documentation, and illustrated the forelimb anatomy of two adult P. uncia specimens (1M/1F). Qualitative and quantitative data revealed an intriguing combination of functional adaptations illustrating a balance between the diverse demands of head-first descent, pouncing, climbing across rocky terrain, restraint of large prey, rapid pursuit, and navigating deep snow. In many forelimb proportions, P. uncia is intermediate between the cursorial Acinonyx jubatus (cheetah) and the scansorial forest dwelling Panthera onca (jaguar). Enlarged scapular and pectoral musculature provide stability to the shoulder girdle during grappling with large prey, as well as support during jumping and climbing. A small, unarticulated bony clavicle may provide greater stability to the forelimb, while still allowing flexibility. In the brachium and antebrachium of P. uncia, there is a functional compromise between the powerful grip needed for grasping large prey and the stability necessary for rapid pursuit of prey over uneven, rocky terrain. A unique bifurcation in the tendon of m. biceps brachii may provide additional functional stability at the radiohumeral joint. Intrinsic muscles of the palmar manus are broad and fleshy, acting as an enlarged surface area to evenly distribute body weight while walking on soft snow. However, muscles that act to provide fine manual manipulation are reduced, as in other large prey specialists. Overall, P. uncia displays morphological adaptive parallels with scansorial, large prey specializing pantherines, such as P. onca, while also showing adaptations for running.

Improving pregnant women's diet and physical activity behaviours: the emergent role of health identity.

BACKGROUND: Women who gain too much weight in pregnancy are at increased risk of disease and of having children with increased risk. Interventions to improve health behaviours are usually designed for a general population of pregnant women, and trial outcomes show an average impact that does not represent the differences between individuals. To inform the development of future interventions, this study explored the factors that influenced women's diet and physical activity during pregnancy and aimed to identify the needs of these women with regards to lifestyle support. METHODS: Women who completed a trial of vitamin D supplementation and nurse support in pregnancy were invited to take part in an interview. Seventeen women were interviewed about their lifestyles during pregnancy, the support they had, and the support they wanted. Interview transcripts were coded thematically and analysed to understand the factors that influenced the diets and physical activity levels of these women and their engagement with resources that could provide support. RESULTS: Women identified barriers to eating well or being physically active, and pregnancy-specific issues like nausea and pain were common. Women's interest in maintaining a healthy lifestyle and their engagement with lifestyle support was related to the extent to which they self-identified as healthy people. Health-disengaged women were disinterested in talking about their lifestyles while health-focused women did not feel that they needed extra support. Women between these ends of the 'health identity' spectrum were interested in improving their health, and were able to identify barriers as well as sources of support. CONCLUSIONS: Lifestyle interventions in pregnancy should be adapted to meet the needs of individuals with different health identities, and encouraging a change in health identity may be one way of supporting sustained change in health behaviours.

Health service accreditation stimulating change in clinical care and human resource management processes: A study of 311 Australian hospitals.

OBJECTIVE: This study aimed to establish whether longitudinal participation in an accreditation program is translated into improvement in continuity of quality patient care and human resource management (HRM) processes outcomes. MATERIALS AND METHODS: This was a secondary data analysis of accreditation panel data from acute hospitals participating in the Australian Council on Healthcare Standards' Evaluation and Quality Improvement Program (EQuIP). EQuIP criteria data from 311 hospitals were collected by external surveyors across 2003-2006 (Time 1) and 2007-2010 (Time 2). Mandatory accreditation criteria ratings at Time 1 were used to determine hospital performance group membership (1 = below moderate, 2 = moderate, 3 = above moderate). Analysis was undertaken of ratings across continuity of quality patient care and HRM process criteria, at Time 1 and 2. RESULTS: Continuity of quality patient care and HRM processes improved across time in the three performance groups. Lower performing hospitals improved at a greater rate than moderate and higher performing hospitals. The groupings and performance order did not change over time. CONCLUSIONS: An accreditation program is an external driver that facilitates continual and systemic quality improvement changes to sub-systems with an organisation.

The experiences and support needs of people living at home with an enteral tube: a qualitative interview study.

BACKGROUND: The number of people with an enteral tube (ET) living at home is increasing globally and services to support them to manage this complex and life-changing intervention vary across regions. The present study aimed to gain an understanding of the experiences of people living at home with an ET and their carers, as well as to explore their views of supporting services and ET-related hospital admissions. METHODS: A qualitative inductive descriptive design was employed. Semi-structured, face-to-face interviews with a purposive sample of people with an ET living at home and carers were undertaken. Interviews were transcribed, initial codes were assigned for salient constructs, and these were then grouped and developed into themes and sub-themes. RESULTS: Nineteen people with ETs and 15 carers of people with ETs were interviewed. Five themes were generated: home better than hospital, feelings about the tube, living with the tube, help when you need it and cost for health service. Participants indicated the ET significantly influenced daily life. Participants described becoming used to coping with the ET at home over time and developing strategies to manage problems, avoid hospital admission and reduce resource waste. Variation in supporting services was described. CONCLUSIONS: People with ETs and their carers need considerable support from knowledgeable, responsive healthcare practitioners during the weeks following initial placement of the ET. Twenty-four hour services to support people with ETs should be designed in partnership with the aim of reducing burden, negative experience, waste and hospital admissions. National frameworks for home enteral nutrition could set the standard for support for people with ETs.

LifeLab Southampton: a programme to engage adolescents with DOHaD concepts as a tool for increasing health literacy in teenagers -a pilot cluster-randomized control trial.

Adolescence is a critical time point in the lifecourse. LifeLab is an educational intervention engaging adolescents in understanding Developmental Origins of Health and Disease (DOHaD) concepts and the impact of the early life environment on future health, benefitting both their long-term health and that of the next generation. We aimed to assess whether engaging adolescents with DOHaD concepts improves scientific literacy and whether engagement alone improves health behaviours.Six schools were randomized, three to intervention and three to control. Outcome measures were changed in knowledge, and intended and actual behaviour in relation to diet and lifestyle. A total of 333 students completed baseline and follow-up questionnaires. At 12 months, intervention students showed greater understanding of DOHaD concepts. No sustained changes in behaviours were identified.Adolescents' engagement with DOHaD concepts can be improved and maintained over 12 months. Such engagement does not itself translate into behaviour change. The intervention has consequently been revised to include additional components beyond engagement alone.

Inter- and intra-rater reliability and agreement in determining subcutaneous tumour margins in dogs.

The objective of this prospective study was to evaluate agreement and reliability of calliper-based measurements of locally invasive subcutaneous malignant tumours in dogs. Four raters measured the longest diameter of 12 subcutaneous tumours (7 soft tissue sarcomas and 5 mast cell tumours) from 11 client-owned dogs during 3 randomized, blinded measurement trials, both pre- and post-sedation. Inter- and intra-rater reliability was evaluated using intra-class correlation coefficient (ICC) and agreement was evaluated using Bland-Altman plots. Inter- and intra-rater reliability was good (ICC range of 0.8694-0.89520) and excellent (ICC range of 0.9720-0.9966), respectively. For agreement calculations, an a priori clinically relevant limit of agreement of 10 mm was set. Inter- and intra-rater agreement was unacceptable with inter-rater limits of agreement ranging from 15.9 to 55.6 mm and intra-rater limit of agreement ranging from 11.9 to 28.1 mm. Review of the measurement trial photographs revealed that calliper orientation changes were frequent, occurring in 9/12 (75%) and 8/12 (67%) pre- and post-sedation cases. No significant correlation was found between inter-rater measurement standard deviations and calliper orientation changes or dog body condition score. These findings suggest veterinarians may have poor agreement in determining the gross edge of tumours, which is expected to introduce bias and inconsistency in tumour staging, assessing response to therapy, and surgical margin planning. Due to the potential consequences for veterinary cancer patients, future studies are needed to validate the present findings.

Characterizing Microscopical Invasion Patterns in Canine Mast Cell Tumours and Soft Tissue Sarcomas.

Stromal invasion is identified commonly in cutaneous malignancies; however, invasive patterns are defined inconsistently and their clinical relevance is uncertain. This study aimed to define objective, quantifiable histomorphological invasive patterns in low-grade canine mast cell tumours (MCTs) and grade I/II soft tissue sarcomas (STSs), and correlate invasive patterns with overall excisional status. Haematoxylin and eosin-stained glass slides prepared for routine histopathology of surgically-excised tumours from client-owned dogs were evaluated for invasion beyond their subgross edge, asymmetrical invasion, satellite lesions, lymphovascular invasion, perineurovascular growth, growth along fascial planes, intramuscular invasion and multicompartmental involvement. Digital histological tumour-free margins <1 mm in any direction were considered to represent an incomplete excision. Fifty-one dogs with 69 tumours (50 MCTs and 19 STSs) were included in the study. Invasion in both circumferential and deep directions was significantly greater in MCTs compared with STSs (exact 2-tailed P <0.0001 circumferential; P = 0.0095 deep). Within the MCT group, circumferential invasion was greater than deep invasion (P = 0.0076). Multivariate logistic regression analysis found two variables that were significantly associated with incomplete MCT excision: intraoperative grossly normal circumferential surgical margin size (odds ratio of 0.776, 95% confidence interval: 0.651-0.925) and asymmetry invasion index (odds ratio of 1.318, 95% confidence interval: 1.039-1.671). These data may help create evidence-based strategies for planning surgical resections of cutaneous malignancies. Presence of asymmetrical microscopical invasion might prompt pathologists to perform more comprehensive surgical margin evaluation.

Morphological variation, phylogenetic relationships, and geographic distribution of the Baenidae (Testudines), based on new specimens from the Uinta Formation (Uinta Basin), Utah (USA).

We described newly discovered baenid specimens from the Uintan North American Land Mammal Age (NALMA), in the Uinta Formation, Uinta Basin, Utah. These specimens include a partial skull and several previously undescribed postcranial elements of Baena arenosa, and numerous well-preserved shells of B. arenosa and Chisternon undatum. Baenids from the Uintan NALMA (46.5-40 Ma) are critical in that they provide valuable insight into the morphology and evolution of the diverse and speciose baenid family near the end of its extensive radiation, just prior to the disappearance of this clade from the fossil record. These Uintan specimens greatly increase the known variation in these late-surviving taxa and indicate that several characters thought to define these species should be reassessed. The partial cranium of B. arenosa, including portions of the basicranium, neurocranium, face, and lower jaw, was recently recovered from Uinta B sediments. While its morphology is consistent with known specimens of B. arenosa, we observed several distinct differences: a crescent-shaped condylus occipitalis that is concave dorsally, tuberculum basioccipitale that flare out laterally, and a distinct frontal-nasal suture. The current sample of plastral and carapacial morphology considerably expands the documented variation in the hypodigms of B. arenosa and C. undatum. Novel shell characters observed include sigmoidal extragular-humeral sulci, and small, subtriangular gular scutes. Subadult specimens reveal ontogenetic processes in both taxa, and demonstrate that diagnostic morphological differences between them were present from an early developmental age.

Cross-sectional observational survey of serum biochemistry values in a population of 69 adult female alpacas (Vicugna pacos) in South Australia.

Blood samples were collected from 69 'healthy' female alpacas aged ≥12 months from 11 properties in South Australia. The 10-90 percentile ranges of the 16/19 analytes measured in this sample population were within the published ranges of four healthy alpaca populations from other geographic locations. Marginal exceptions were glutamate dehydrogenase and bicarbonate. Potassium was notably elevated, probably because of haemolysis of some samples. The sample size was insufficient to provide the appropriate statistical power to define diagnostic references ranges according to international standards. The health status of the sample population of alpacas was presumptive based on a physical examination.

Of mice and men: novel insights regarding constitutive and recruitable brown adipocytes.

Recently, there has been great attention given to the possibility of combating obesity by targeting brown fat activity or increasing differentiation of brown adipocytes in white fat depots through a process termed 'browning'. Sympathetic innervation of brown and white adipose tissues provides adrenergic input that drives thermogenesis and regulates fatty acid metabolism, as well as stimulating adipogenesis of recruitable brown adipocyte tissue (rBAT, also known as beige or brite) in white fat. Other factors acting in an endocrine or autocrine/paracrine manner in adipose tissue may also stimulate browning. There have been significant recent advances in understanding the mechanisms of increasing adipose tissue energy expenditure, as well as how brown adipocytes appear in white fat depots, including via de novo adipogenesis from tissue precursor cells. In this article, we integrate this new knowledge with a historical perspective on the discovery of 'browning'. We also provide an overview of constitutive BAT vs rBAT in mouse and human.

Geochronological and taxonomic revisions of the middle Eocene Whistler Squat Quarry (Devil's Graveyard Formation, Texas) and implications for the early Uintan in Trans-Pecos Texas.

The Whistler Squat Quarry (TMM 41372) of the lower Devil's Graveyard Formation in Trans-Pecos Texas is a middle Eocene fossil locality attributed to Uintan biochronological zone Ui1b. Specimens from the Whistler Squat Quarry were collected immediately above a volcanic tuff with prior K/Ar ages ranging from ∼47-50 Ma and below a tuff previously dated to ∼44 Ma. New 40Ar/39Ar analyses of both of the original tuff samples provide statistically indistinguishable ages of 44.88±0.04 Ma for the lower tuff and 45.04±0.10 Ma for the upper tuff. These dates are compatible with magnetically reversed sediments at the site attributable to C20r (43.505-45.942 Ma) and a stratigraphic position above a basalt dated to 46.80 Ma. Our reanalysis of mammalian specimens from the Whistler Squat Quarry and a stratigraphically equivalent locality significantly revises their faunal lists, confirms the early Uintan designation for the sites, and highlights several biogeographic and biochronological differences when compared to stratotypes in the Bridger and Uinta Formations. Previous suggestions of regional endemism in the early Uintan are supported by the recognition of six endemic taxa (26% of mammalian taxa) from the Whistler Squat Quarry alone, including three new taxa. The revised faunal list for the Whistler Squat Quarry also extends the biostratigraphic ranges of nine non-endemic mammalian taxa to Ui1b.

Health service accreditation reinforces a mindset of high-performance human resource management: lessons from an Australian study.

OBJECTIVE: To investigate whether an accreditation program facilitates healthcare organizations (HCOs) to evolve and maintain high-performance human resource management (HRM) systems. DESIGN: Cross-sectional multimethod study. SETTING AND PARTICIPANTS: Healthcare organizations participating in the Australian Council on Healthcare Standards Evaluation and Quality Improvement Program (EQuIP 4) between 2007 and 2011. MAIN OUTCOME MEASURES: Ratings across the EQuIP 4 HRM criteria, a clinical performance measure, surveyor reports (HRM information) and interview data (opinions and experiences regarding HRM and accreditation). RESULTS: Healthcare organizations identified as high performing on accreditation HRM criteria seek excellence primarily because of internal motivations linked to best practice. Participation in an accreditation program is a secondary and less significant influence. Notwithstanding, the accreditation program provides the HCO opportunity for internal and external review and assessment of their performance; the accreditation activities are reflective learning and feedback events. CONCLUSIONS: This study reveals that HCOs that pursue highly performing HRM systems use participation in an accreditation program as an opportunity. Their organizational mindset is to use the program as a tool by which to reflect and obtain feedback on their performance so to maintain or improve their management of staff and delivery of care.

Exome sequencing identifies mutations in KIF14 as a novel cause of an autosomal recessive lethal fetal ciliopathy phenotype.

Gene discovery using massively parallel sequencing has focused on phenotypes diagnosed postnatally such as well-characterized syndromes or intellectual disability, but is rarely reported for fetal disorders. We used family-based whole-exome sequencing in order to identify causal variants for a recurrent pattern of an undescribed lethal fetal congenital anomaly syndrome. The clinical signs included intrauterine growth restriction (IUGR), severe microcephaly, renal cystic dysplasia/agenesis and complex brain and genitourinary malformations. The phenotype was compatible with a ciliopathy, but not diagnostic of any known condition. We hypothesized biallelic disruption of a gene leading to a defect related to the primary cilium. We identified novel autosomal recessive truncating mutations in KIF14 that segregated with the phenotype. Mice with autosomal recessive mutations in the same gene have recently been shown to have a strikingly similar phenotype. Genotype-phenotype correlations indicate that the function of KIF14 in cell division and cytokinesis can be linked to a role in primary cilia, supported by previous cellular and model organism studies of proteins that interact with KIF14. We describe the first human phenotype, a novel lethal ciliary disorder, associated with biallelic inactivating mutations in KIF14. KIF14 may also be considered a candidate gene for allelic viable ciliary and/or microcephaly phenotypes.

Unusually high levels of n-6 polyunsaturated fatty acids in whale sharks and reef manta rays.

Fatty acid (FA) signature analysis has been increasingly used to assess dietary preferences and trophodynamics in marine animals. We investigated FA signatures of connective tissue of the whale shark Rhincodon typus and muscle tissue of the reef manta ray Manta alfredi. We found high levels of n-6 polyunsaturated fatty acids (PUFA), dominated by arachidonic acid (20:4n-6; 12-17 % of total FA), and comparatively lower levels of the essential n-3 PUFA-eicosapentaenoic acid (20:5n-3; ~1 %) and docosahexaenoic acid (22:6n-3; 3-10 %). Whale sharks and reef manta rays are regularly observed feeding on surface aggregations of coastal crustacean zooplankton during the day, which generally have FA profiles dominated by n-3 PUFA. The high levels of n-6 PUFA in both giant elasmobranchs raise new questions about the origin of their main food source.

Evaluating the impact of pre-transplant desensitization utilizing a plasmapheresis and low-dose intravenous immunoglobulin protocol on BK viremia in renal transplant recipients.

BACKGROUND: A correlation exists between polyomavirus BK (BKV) viremia in renal transplant recipients (RTR) and the degree of immunosuppression. However, the impact of pre-transplant desensitization on the incidence of BKV viremia is unknown. METHODS: This retrospective study evaluated living-donor RTR between January 2004 and December 2008 receiving routine BKV viral load monitoring. Patients were divided into those who underwent pre-transplant desensitization (n = 20) and those who did not (n = 71). The primary endpoint was the incidence of BKV viremia at 1 year post transplant. RESULTS: All demographic data were similar, except for more female patients (65% vs. 36.6%; P = 0.0392) in the desensitized group. More desensitized patients had a previous transplant (75% vs. 12.7%; P < 0.0001) and were more likely to be induced with basiliximab (75% vs. 35.2%; P = 0.0021). Following transplantation, antibody-mediated rejection (AMR) rates were highest in the desensitized group (55% vs. 1.4%; P < 0.0001). The incidence of BKV viremia at 1 year post transplant was significantly higher in desensitized patients (45% vs. 19.7%; P = 0.0385). Desensitization was also associated with a higher prevalence of BKV viremia at any time post transplant (50% vs. 22.5%; P = 0.0245), polyomavirus-associated nephropathy (20% vs. 2.8%; P = 0.0198) and BKV-related allograft loss (10% vs. 0%; P = 0.0464). Also of note, in a subgroup analysis of only our desensitized patients, it did not appear that development of AMR significantly impacted the incidence of BKV viremia in these individuals. CONCLUSIONS: This analysis reveals that pre-transplant desensitization significantly increases the risk for BKV viremia and nephropathy.

Transcriptional intermediary factor 1γ binds to the anaphase-promoting complex/cyclosome and promotes mitosis.

The anaphase-promoting complex/cyclosome (APC/C) is an ubiquitin ligase that functions during mitosis. Here we identify the transcriptional regulator, transcriptional intermediary factor 1γ, TIF1γ, as an APC/C-interacting protein that regulates APC/C function. TIF1γ is not a substrate for APC/C-dependent ubiquitylation but instead, associates specifically with the APC/C holoenzyme and Cdc20 to affect APC/C activity and progression through mitosis. RNA interference studies indicate that TIF1γ knockdown results in a specific reduction in APC/C ubiquitin ligase activity, the stabilization of APC/C substrates, and an increase in the time taken for cells to progress through mitosis from nuclear envelope breakdown to anaphase. TIF1γ knockdown cells are also characterized by the inappropriate presence of cyclin A at metaphase, and an increase in the number of cells that fail to undergo metaphase-to-anaphase transition. Expression of a small interfering RNA-resistant TIF1γ species relieves the mitotic phenotype imposed by TIF1γ knockdown and allows for mitotic progression. Binding studies indicate that TIF1γ is also a component of the APC/C-mitotic checkpoint complex (MCC), but is not required for MCC dissociation from the APC/C once the spindle assembly checkpoint (SAC) is satisfied. TIF1γ inactivation also results in chromosome misalignment at metaphase and SAC activation; inactivation of the SAC relieves the mitotic block imposed by TIF1γ knockdown. Together these data define novel functions for TIF1γ during mitosis and suggest that a reduction in APC/C ubiquitin ligase activity promotes SAC activation.