Team Care for the Care Team: A Scoping Review of the Relational Dimensions of Collaboration in Healthcare Contexts.

Examining team care for the care team, this scoping literature review highlights the relational and compassionate dimensions of collaboration and teamwork that can alleviate healthcare worker suffering and promote well-being in challenging contexts of care. Its goal is to provide greater conceptual clarity about team care and examine the contextual dimensions regarding the needs and facilitators of team care. Analysis of the 48 retained texts identified three broad types of communicative practice that constitute team care: sharing; supporting; and leading with compassion. The environmental conditions facilitating team care included a caring team culture and specific and accessible organizational supports. These results are crystallized into a conceptual model of team care that situates team care within a system of team and organizational needs and anticipated outcomes. Gaps in the literature are noted and avenues for future research are suggested.

Regulation of extracellular progranulin in medial prefrontal cortex.

Progranulin is a secreted pro-protein that has anti-inflammatory and neurotrophic effects and is necessary for maintaining lysosomal function. Mutations in progranulin (GRN) are a major cause of frontotemporal dementia. Most pathogenic GRN mutations cause progranulin haploinsufficiency, so boosting progranulin levels is a promising therapeutic strategy. Progranulin is constitutively secreted, then taken up and trafficked to lysosomes. Before being taken up from the extracellular space, progranulin interacts with receptors that may mediate anti-inflammatory and growth factor-like effects. Modifying progranulin trafficking is a viable approach to boosting progranulin, but progranulin secretion and uptake by cells in the brain is poorly understood and may involve distinct mechanisms from other parts of the body. Understanding the cell types and processes that regulate extracellular progranulin in the brain could provide insight into progranulin's mechanism of action and inform design of progranulin-boosting therapies. To address this question we used microdialysis to measure progranulin in interstitial fluid (ISF) of mouse medial prefrontal cortex (mPFC). Grn+/- mice had approximately 50% lower ISF progranulin than wild-type mice, matching the reduction of progranulin in cortical tissue. Fluorescent in situ hybridization and immunofluorescence confirmed that microglia and neurons are the major progranulin-expressing cell types in the mPFC. Studies of conditional microglial (Mg-KO) and neuronal (N-KO) Grn knockout mice revealed that loss of progranulin from either cell type results in approximately 50% reduction in ISF progranulin. LPS injection (i.p.) produced an acute increase in ISF progranulin in mPFC. Depolarizing cells with KCl increased ISF progranulin, but this response was not altered in N-KO mice, indicating progranulin secretion by non-neuronal cells. Increasing neuronal activity with picrotoxin did not increase ISF progranulin. These data indicate that microglia and neurons are the source of most ISF progranulin in mPFC, with microglia likely secreting more progranulin per cell than neurons. The acute increase in ISF progranulin after LPS treatment is consistent with a role for extracellular progranulin in regulating inflammation, and may have been driven by microglia or peripheral immune cells. Finally, these data indicate that mPFC neurons engage in constitutive progranulin secretion that is not acutely changed by neuronal activity.

Non-Reproductive Sexual Behavior in Wild White-Thighed Colobus Monkeys (Colobus vellerosus).

Rare behaviors are often missing from published papers, hampering phylogenetic analyses. Here, we report, for the first time, masturbation and same-sex sexual behavior (SSB) in both male and female black-and-white colobus monkeys. We recorded these behaviors during 32 months of observation (1573 h of focal animal sampling) on Colobus vellerosus collected at the Boabeng-Fiema Monkey Sanctuary in Ghana. Males were observed masturbating and involved in SSB more than females. Subadult males were the age-sex class that engaged in both of these behaviors most often and a third of all SSB observed in young males occurred when they were forming an all-male band (AMB), which are temporally transient social groups in this species. Our data support that masturbation in males may be a sexual outlet for individuals that do not have a current sexual partner, while in females it may function in mate attraction by advertising receptivity. SSB may occur as an evolutionary byproduct but given the temporal clustering of observed events in males prior to AMB formation, our data best support the hypothesis that these behaviors facilitate male-male bonding (i.e., act as social glue). Within AMB's, males engage in coalitionary behavior to take over social groups containing females and strong bonds are important for success and later access to females, which could have selected for SSB in C. vellerosus.

Wild chimpanzees exhibit humanlike aging of glucocorticoid regulation.

Cortisol, a key product of the stress response, has critical influences on degenerative aging in humans. In turn, cortisol production is affected by senescence of the hypothalamic-pituitary-adrenal (HPA) axis, leading to progressive dysregulation and increased cortisol exposure. These processes have been studied extensively in industrialized settings, but few comparative data are available from humans and closely related species living in natural environments, where stressors are very different. Here, we examine age-related changes in urinary cortisol in a 20-y longitudinal study of wild chimpanzees (n = 59 adults) in the Kanyawara community of Kibale National Park, Uganda. We tested for three key features of HPA aging identified in many human studies: increased average levels, a blunted diurnal rhythm, and enhanced response to stressors. Using linear mixed models, we found that aging was associated with a blunting of the diurnal rhythm and a significant linear increase in cortisol, even after controlling for changes in dominance rank. These effects did not differ by sex. Aging did not increase sensitivity to energetic stress or social status. Female chimpanzees experienced their highest levels of cortisol during cycling (versus lactation), and this effect increased with age. Male chimpanzees experienced their highest levels when exposed to sexually attractive females, but this effect was diminished by age. Our results indicate that chimpanzees share some key features of HPA aging with humans. These findings suggest that impairments of HPA regulation are intrinsic to the aging process in hominids and are side effects neither of extended human life span nor of atypical environments.

When Bothering is Part of Professional Practice: Interprofessional Collaboration and Institutional Influences in Primary Care.

In Western healthcare systems, increasing numbers of nurse practitioners are practicing in primary care organizations, and their integration onto interprofessional teams can be somewhat bumpy. In this article, we rely on the institutional theory of organizational communication to investigate the situated communication challenges faced by NPs as they integrate onto primary health care teams (RQ1), and how these local challenges manifested institutional features (RQ2). We analyze interview data from NPs, their physician partners, clinical nurses, and a network administrator for NPs at five family medicine clinics in Quebec, Canada. We found three main challenges to IP communication between NPs and physicians, namely a lack of time, the professional necessity of bothering, and talking to - and like - a doctor. We present the solutions that participants found to overcome or workaround these challenges. We also interpreted the institutional features that inflected - or "moored" - the situated communication practices and challenges reported by our participants to better understand how the local experience of IP communication is shaped by broader institutional forces.

Aggression, glucocorticoids, and the chronic costs of status competition for wild male chimpanzees.

Across vertebrates, high social status affords preferential access to resources, and is expected to correlate positively with health and longevity. Increasing evidence, however, suggests that although dominant females generally enjoy reduced exposure to physiological and psychosocial stressors, dominant males do not. Here we test the hypothesis that costly mating competition by high-ranking males results in chronic, potentially harmful elevations in glucocorticoid production. We examined urinary glucocorticoids (n = 8029 samples) in a 20-year longitudinal study of wild male chimpanzees (n = 20 adults) in the Kanyawara community of Kibale National Park, Uganda. We tested whether glucocorticoid production was associated with dominance rank in the long term, and with mating competition and dominance instability in the short term. Using mixed models, we found that both male aggression and glucocorticoid excretion increased when the dominance hierarchy was unstable, and when parous females were sexually available. Glucocorticoid excretion was positively associated with male rank in stable and unstable hierarchies, and in mating and non-mating contexts. Glucorticoids increased with both giving and receiving aggression, but giving aggression was the primary mechanism linking elevated glucocorticoids with high rank. Glucocorticoids also increased with age. Together these results show that investment in male-male competition increases cumulative exposure to glucocorticoids, suggesting a long-term tradeoff with health that may constrain the ability to maintain high status across the life course. Our data suggest that the relationship between social rank and glucocorticoid production often differs in males and females owing to sex differences in the operation of sexual selection.

Biallelic MADD variants cause a phenotypic spectrum ranging from developmental delay to a multisystem disorder.

In pleiotropic diseases, multiple organ systems are affected causing a variety of clinical manifestations. Here, we report a pleiotropic disorder with a unique constellation of neurological, endocrine, exocrine, and haematological findings that is caused by biallelic MADD variants. MADD, the mitogen-activated protein kinase (MAPK) activating death domain protein, regulates various cellular functions, such as vesicle trafficking, activity of the Rab3 and Rab27 small GTPases, tumour necrosis factor-α (TNF-α)-induced signalling and prevention of cell death. Through national collaboration and GeneMatcher, we collected 23 patients with 21 different pathogenic MADD variants identified by next-generation sequencing. We clinically evaluated the series of patients and categorized the phenotypes in two groups. Group 1 consists of 14 patients with severe developmental delay, endo- and exocrine dysfunction, impairment of the sensory and autonomic nervous system, and haematological anomalies. The clinical course during the first years of life can be potentially fatal. The nine patients in Group 2 have a predominant neurological phenotype comprising mild-to-severe developmental delay, hypotonia, speech impairment, and seizures. Analysis of mRNA revealed multiple aberrant MADD transcripts in two patient-derived fibroblast cell lines. Relative quantification of MADD mRNA and protein in fibroblasts of five affected individuals showed a drastic reduction or loss of MADD. We conducted functional tests to determine the impact of the variants on different pathways. Treatment of patient-derived fibroblasts with TNF-α resulted in reduced phosphorylation of the extracellular signal-regulated kinases 1 and 2, enhanced activation of the pro-apoptotic enzymes caspase-3 and -7 and increased apoptosis compared to control cells. We analysed internalization of epidermal growth factor in patient cells and identified a defect in endocytosis of epidermal growth factor. We conclude that MADD deficiency underlies multiple cellular defects that can be attributed to alterations of TNF-α-dependent signalling pathways and defects in vesicular trafficking. Our data highlight the multifaceted role of MADD as a signalling molecule in different organs and reveal its physiological role in regulating the function of the sensory and autonomic nervous system and endo- and exocrine glands.

Communication and Interprofessional Collaboration in Primary Care: From Ideal to Reality in Practice.

To improve patient-centered care, many health care systems are mandating interprofessional collaboration (IPC). However, in many primary care contexts, IPC is still nascent and fraught with tension. Communication is thought to be a key determinant of IPC, but few studies empirically examine IP communication practices. Therefore, we report here on the qualitative portion of a mixed methods pilot study investigating observed IPC and communication in primary care clinics in Quebec, Canada. Studying actual communication practices to understand collaborative activities, we seek to investigate how the ideals of patient centeredness and clinical democracy put forward in the IP literature stack up against actual IPC practice in primary care. Qualitative data was gathered by shadowing health professionals in two primary care clinics, and analyzed through thematic coding. A typology of observed IP practices was created and compared to the continuum of interprofessional collaborative practice. Further analysis focused on how participants made sense of their collaboration, especially why, how and with whom they collaborated. Findings were grouped into three categories of communicative actions: coordinating sequential efforts; assisting others' sensemaking; and working to understand together. Implications for practice and future research are discussed.

Clinical spectrum of individuals with pathogenic NF1 missense variants affecting p.Met1149, p.Arg1276, and p.Lys1423: genotype-phenotype study in neurofibromatosis type 1.

We report 281 individuals carrying a pathogenic recurrent NF1 missense variant at p.Met1149, p.Arg1276, or p.Lys1423, representing three nontruncating NF1 hotspots in the University of Alabama at Birmingham (UAB) cohort, together identified in 1.8% of unrelated NF1 individuals. About 25% (95% confidence interval: 20.5-31.2%) of individuals heterozygous for a pathogenic NF1 p.Met1149, p.Arg1276, or p.Lys1423 missense variant had a Noonan-like phenotype, which is significantly more compared with the "classic" NF1-affected cohorts (all p < .0001). Furthermore, p.Arg1276 and p.Lys1423 pathogenic missense variants were associated with a high prevalence of cardiovascular abnormalities, including pulmonic stenosis (all p < .0001), while p.Arg1276 variants had a high prevalence of symptomatic spinal neurofibromas (p < .0001) compared with "classic" NF1-affected cohorts. However, p.Met1149-positive individuals had a mild phenotype, characterized mainly by pigmentary manifestations without externally visible plexiform neurofibromas, symptomatic spinal neurofibromas or symptomatic optic pathway gliomas. As up to 0.4% of unrelated individuals in the UAB cohort carries a p.Met1149 missense variant, this finding will contribute to more accurate stratification of a significant number of NF1 individuals. Although clinically relevant genotype-phenotype correlations are rare in NF1, each affecting only a small percentage of individuals, together they impact counseling and management of a significant number of the NF1 population.

Human-like adrenal development in wild chimpanzees: A longitudinal study of urinary dehydroepiandrosterone-sulfate and cortisol.

The development of the adrenal cortex varies considerably across primates, being most conspicuous in humans, where a functional zona reticularis-the site of dehydroepiandrosterone-sulfate (DHEA/S) production-does not develop until middle childhood (5-8 years). Prior reports suggest that a human-like adrenarche, associated with a sharp prepubertal increase in DHEA/S, may only occur in the genus Pan. However, the timing and variability in adrenarche in chimpanzees remain poorly described, owing to the lack of longitudinal data, or data from wild populations. Here, we use urine samples from East African chimpanzees (Pan troglodytes schweinfurthii) collected over 20 years at Kanyawara in Kibale National Park, Uganda, to trace the developmental trajectories of DHEAS (n = 1,385 samples, 53 individuals) and cortisol (n = 12,726 samples, 68 individuals). We used generalized additive models (GAM) to investigate the relationship between age, sex, and hormone levels. Adrenarche began earlier in chimpanzees (~2-3 years) compared with what has been reported in humans (6-8 years) and, unlike humans, male and female chimpanzees did not differ significantly in the timing of adrenarche nor in DHEAS concentrations overall. Similar to what has been reported in humans, cortisol production decreased through early life, reaching a nadir around puberty (8-11 years), and a sex difference emerged with males exhibiting higher urinary cortisol levels compared with females by early adulthood (15-16 years). Our study establishes that wild chimpanzees exhibit a human-like pattern of cortisol production during development and corroborates prior reports from captive chimpanzees of a human-like adrenarche, accompanied by significant developmental increases in DHEAS. While the role of these developmental hormone shifts are as yet unclear, they have been implicated in stages of rapid behavioral development once thought unique to humans, especially in regard to explaining the divergence of female and male social behavior before pubertal increases in gonadal hormones.

Cell-Specific Deletion of PGC-1α from Medium Spiny Neurons Causes Transcriptional Alterations and Age-Related Motor Impairment.

Multiple lines of evidence indicate that a reduction in the expression and function of the transcriptional coactivator peroxisome proliferator-activated receptor gamma coactivator-1α (PGC-1α) is associated with neurodegeneration in diseases such as Huntington's disease (HD). Polymorphisms in the PGC-1α gene modify HD progression and PGC-1α expression is reduced in striatal medium spiny neurons (MSNs) of HD patients and mouse models. However, neither the MSN-specific function of PGC-1α nor the contribution of PGC-1α deficiency to motor dysfunction is known. We identified novel, PGC-1α-dependent transcripts involved in RNA processing, signal transduction, and neuronal morphology and confirmed reductions in these transcripts in male and female mice lacking PGC-1α specifically in MSNs, indicating a cell-autonomous effect in this population. MSN-specific PGC-1α deletion caused reductions in previously identified neuronal and metabolic PGC-1α-dependent genes without causing striatal vacuolizations. Interestingly, these mice exhibited a hypoactivity with age, similar to several HD animal models. However, these newly identified PGC-1α-dependent genes were upregulated with disease severity and age in knock-in HD mouse models independent of changes in PGC-1α transcript, contrary to what would be predicted from a loss-of-function etiological mechanism. These data indicate that PGC-1α is necessary for MSN transcriptional homeostasis and function with age and that, whereas PGC-1α loss in MSNs does not replicate an HD-like phenocopy, its downstream genes are altered in a repeat-length and age-dependent fashion. Understanding the additive effects of PGC-1α gene functional variation and mutant huntingtin on transcription in this cell type may provide insight into the selective vulnerability of MSNs in HD.SIGNIFICANCE STATEMENT Reductions in peroxisome proliferator-activated receptor gamma coactivator-1α (PGC-1α)-mediated transcription have been implicated in the pathogenesis of Huntington's disease (HD). We show that, although PGC-1α-dependent transcription is necessary to maintain medium spiny neuron (MSN) function with age, its loss is insufficient to cause striatal atrophy in mice. We also highlight a set of genes that can serve as proxies for PGC-1α functional activity in the striatum for target engagement studies. Furthermore, we demonstrate that PGC-1α-dependent genes are upregulated in a dose- and age-dependent fashion in HD mouse models, contrary to what would be predicted from a loss-of-function etiological mechanism. However, given this role for PGC-1α in MSN transcriptional homeostasis, it is important to consider how genetic variation in PGC-1α could contribute to mutant-huntingtin-induced cell death and disease progression.

Recurrent De Novo and Biallelic Variation of ATAD3A, Encoding a Mitochondrial Membrane Protein, Results in Distinct Neurological Syndromes.

ATPase family AAA-domain containing protein 3A (ATAD3A) is a nuclear-encoded mitochondrial membrane protein implicated in mitochondrial dynamics, nucleoid organization, protein translation, cell growth, and cholesterol metabolism. We identified a recurrent de novo ATAD3A c.1582C>T (p.Arg528Trp) variant by whole-exome sequencing (WES) in five unrelated individuals with a core phenotype of global developmental delay, hypotonia, optic atrophy, axonal neuropathy, and hypertrophic cardiomyopathy. We also describe two families with biallelic variants in ATAD3A, including a homozygous variant in two siblings, and biallelic ATAD3A deletions mediated by nonallelic homologous recombination (NAHR) between ATAD3A and gene family members ATAD3B and ATAD3C. Tissue-specific overexpression of borR534W, the Drosophila mutation homologous to the human c.1582C>T (p.Arg528Trp) variant, resulted in a dramatic decrease in mitochondrial content, aberrant mitochondrial morphology, and increased autophagy. Homozygous null bor larvae showed a significant decrease of mitochondria, while overexpression of borWT resulted in larger, elongated mitochondria. Finally, fibroblasts of an affected individual exhibited increased mitophagy. We conclude that the p.Arg528Trp variant functions through a dominant-negative mechanism that results in small mitochondria that trigger mitophagy, resulting in a reduction in mitochondrial content. ATAD3A variation represents an additional link between mitochondrial dynamics and recognizable neurological syndromes, as seen with MFN2, OPA1, DNM1L, and STAT2 mutations.

Prognostic significance of baseline metabolic tumor volume in relapsed and refractory Hodgkin lymphoma.

Identification of prognostic factors for patients with relapsed/refractory Hodgkin lymphoma (HL) is essential for optimizing therapy with risk-adapted approaches. In our phase 2 study of positron emission tomography (PET)-adapted salvage therapy with brentuximab vedotin (BV) and augmented ifosfamide, carboplatin, and etoposide (augICE), we assessed clinical factors, quantitative PET assessments, and cytokine and chemokine values. Transplant-eligible patients with relapsed/refractory HL received 2 (cohort 1) or 3 (cohort 2) cycles of weekly BV; PET-negative patients (Deauville score ≤2) proceeded to autologous stem cell transplantation (ASCT) whereas PET-positive patients received augICE before ASCT. Serum cytokine and chemokine levels were measured at baseline and after BV. Metabolic tumor volume (MTV) and total lesion glycolysis were measured at baseline, after BV, and after augICE. Sixty-five patients enrolled (45, cohort 1; 20, cohort 2); 49 (75%) achieved complete response and 64 proceeded to ASCT. Three-year overall survival and event-free survival (EFS) were 95% and 82%, respectively. Factors predictive for EFS by multivariable analysis were baseline MTV (bMTV) (P < .001) and refractory disease (P = .003). Low bMTV (<109.5 cm3) and relapsed disease identified a favorable group (3-year EFS, 100%). For patients who received a transplant, bMTV and pre-ASCT PET were independently prognostic; 3-year EFS for pre-ASCT PET-positive patients with low bMTV was 86%. In this phase 2 study of PET-adapted therapy with BV and augICE for relapsed/refractory HL, bMTV and refractory disease were independent prognostic factors for EFS. Furthermore, bMTV improved the predictive power of pre-ASCT PET. Future studies should optimize efficacy and tolerability of salvage therapy by stratifying patients according to risk factors such as bMTV.

Nicotinamide Phosphoribosyltransferase in Smooth Muscle Cells Maintains Genome Integrity, Resists Aortic Medial Degeneration, and Is Suppressed in Human Thoracic Aortic Aneurysm Disease.

RATIONALE: The thoracic aortic wall can degenerate over time with catastrophic consequences. Vascular smooth muscle cells (SMCs) can resist and repair artery damage, but their capacities decline with age and stress. Recently, cellular production of nicotinamide adenine dinucleotide (NAD+) via nicotinamide phosphoribosyltransferase (Nampt) has emerged as a mediator of cell vitality. However, a role for Nampt in aortic SMCs in vivo is unknown. OBJECTIVES: To determine whether a Nampt-NAD+ control system exists within the aortic media and is required for aortic health. METHODS AND RESULTS: Ascending aortas from patients with dilated aortopathy were immunostained for NAMPT, revealing an inverse relationship between SMC NAMPT content and aortic diameter. To determine whether a Nampt-NAD+ control system in SMCs impacts aortic integrity, mice with Nampt-deficient SMCs were generated. SMC-Nampt knockout mice were viable but with mildly dilated aortas that had a 43% reduction in NAD+ in the media. Infusion of angiotensin II led to aortic medial hemorrhage and dissection. SMCs were not apoptotic but displayed senescence associated-ß-galactosidase activity and upregulated p16, indicating premature senescence. Furthermore, there was evidence for oxidized DNA lesions, double-strand DNA strand breaks, and pronounced susceptibility to single-strand breakage. This was linked to suppressed poly(ADP-ribose) polymerase-1 activity and was reversible on resupplying NAD+ with nicotinamide riboside. Remarkably, we discovered unrepaired DNA strand breaks in SMCs within the human ascending aorta, which were specifically enriched in SMCs with low NAMPT. NAMPT promoter analysis revealed CpG hypermethylation within the dilated human thoracic aorta and in SMCs cultured from these tissues, which inversely correlated with NAMPT expression. CONCLUSIONS: The aortic media depends on an intrinsic NAD+ fueling system to protect against DNA damage and premature SMC senescence, with relevance to human thoracic aortopathy.

GRIN2B encephalopathy: novel findings on phenotype, variant clustering, functional consequences and treatment aspects.

BACKGROUND: We aimed for a comprehensive delineation of genetic, functional and phenotypic aspects of GRIN2B encephalopathy and explored potential prospects of personalised medicine. METHODS: Data of 48 individuals with de novo GRIN2B variants were collected from several diagnostic and research cohorts, as well as from 43 patients from the literature. Functional consequences and response to memantine treatment were investigated in vitro and eventually translated into patient care. RESULTS: Overall, de novo variants in 86 patients were classified as pathogenic/likely pathogenic. Patients presented with neurodevelopmental disorders and a spectrum of hypotonia, movement disorder, cortical visual impairment, cerebral volume loss and epilepsy. Six patients presented with a consistent malformation of cortical development (MCD) intermediate between tubulinopathies and polymicrogyria. Missense variants cluster in transmembrane segments and ligand-binding sites. Functional consequences of variants were diverse, revealing various potential gain-of-function and loss-of-function mechanisms and a retained sensitivity to the use-dependent blocker memantine. However, an objectifiable beneficial treatment response in the respective patients still remains to be demonstrated. CONCLUSIONS: In addition to previously known features of intellectual disability, epilepsy and autism, we found evidence that GRIN2B encephalopathy is also frequently associated with movement disorder, cortical visual impairment and MCD revealing novel phenotypic consequences of channelopathies.

Whole body perfusion strategy for aortic arch repair under moderate hypothermia.

INTRODUCTION: Aortic arch reconstruction under moderate hypothermia is commonly performed with antegrade cerebral perfusion (ACP) for brain protection; however, hypothermia alone is often solely relied upon for visceral and lower body protection. We investigated whether the addition of simultaneous lower body perfusion to ACP (whole body perfusion - WBP) may ameliorate the metabolic derangements of moderate hypothermic circulatory arrest (MHCA). METHODS: Between 2008 and 2014, 106 consecutive patients underwent elective or emergent aortic arch surgery with MHCA, with either ACP only (44 patients, 66±12 years, 30% female) or WBP (62 patients, 61±15 years, 31% female). Primary outcomes included 30-day/in-hospital mortality, intensive care unit (ICU) and hospital lengths of stay (LOS) and specific parameters of metabolic recovery. RESULTS: There were no significant differences between the groups in 30-day/in-hospital mortality (ACP: 3 (6.8%), WBP: 2 (3.2%); p=0.65), stroke (ACP: 1 (2.3%), WBP: 1 (1.6%); p=1.0) or renal failure (ACP: 2 (4.5%), WBP: 1 (1.5%); p=0.57). In the WBP group, we identified a significant reduction in lactate level at ICU admission (ACP 5.5 vs. WBP 3.5 mmol/L; p=0.002), time to lactate normalization (p=0.014) and median ICU length-of-stay (ACP 3 vs. WBP 1 days; p=0.049). There was no difference in post-operative creatinine (ACP: 104, WBP: 107 µmol/L; p=0.66). After multivariable regression adjustment, perfusion strategy no longer remained an independent predictor of ICU discharge time (p=0.09), however, cardiopulmonary bypass time (p=0.02), age (p=0.012) and emergent surgery (p=0.02) were. CONCLUSIONS: A WBP strategy during aortic arch reconstruction with MHCA may be associated with more rapid normalization of metabolic parameters and reduced ICU length of stay compared to using ACP alone. Further evaluation with a randomized trial is warranted.

The influence of male takeovers on female dispersal in Colobus vellerosus.

Male takeovers affect male tenure, female mate choice and ultimately, individual reproductive success in group-living primates. In social systems with female philopatry and high male reproductive skew, male takeovers largely determine female mate choice, whereas in species with female dispersal, females have the option of deserting a new male. We focused on a species with facultative female dispersal to investigate which factors promote female desertion of males after takeover, using 15 cases (12 for which we have complete data on the takeover process and the female dispersal outcome). These cases took place in nine groups of Colobus vellerosus between 2001 and 2013 at the Boabeng-Fiema Monkey Sanctuary, Ghana. Quick takeovers were usually achieved by single adult males and were never followed by female dispersal. Slow takeovers involved several males, and these takeovers were regularly accompanied by female emigration. Infant attacks and infanticide by males occurred during both kinds of takeovers, but females with dependent offspring never dispersed, regardless of whether their infant was attacked or killed by the new male(s). Subadult females, who were not constrained by the presence of infants, dispersed more often after slow takeovers than after quick takeovers. Whether female dispersal post-takeover is an expression of female mate choice, or occurs to avoid the social upheaval surrounding slow takeovers, remains to be investigated. Am. J. Primatol. 79:e22436, 2017. © 2015 Wiley Periodicals, Inc.

Comparison of isoflurane and sevoflurane in cardiac surgery: a randomized non-inferiority comparative effectiveness trial.

PURPOSE: Volatile anesthetics possess cardioprotective properties, but it is unknown if the cardioprotective effects extend equally to all members of the class. Although sevoflurane is a relatively newer anesthetic than isoflurane, its introduction into practice was not preceded by a head-to-head comparison with isoflurane in a trial focusing on clinically important outcomes. Our objective was to determine whether sevoflurane was non-inferior to isoflurane on a clinically important primary outcome in a heterogeneous group of adults undergoing cardiac surgery. METHODS: This was a pragmatic randomized non-inferiority comparative effectiveness clinical trial in 464 adults having coronary artery bypass graft and/or single valve surgery during November 2011 to March 2014. The intervention was maintenance of anesthesia with sevoflurane (n = 231) or isoflurane (n = 233) administered at a dose of 0.5-2.0 MAC throughout the entire operation. All caregivers were blinded except for the anesthesiologist and perfusionist. The primary outcome was a composite of intensive care unit (ICU) length of stay ≥ 48 hr and all-cause 30-day mortality. We hypothesized that sevoflurane would be non-inferior to isoflurane (non-inferiority margin < 10% based on an expected event rate of 25%). Secondary outcomes included prolonged ICU stay, 30- and 365-day all-cause mortality, inotrope or vasopressor usage, new-onset hemodialysis or atrial fibrillation, stroke, and readmission to the ICU. RESULTS: No losses to follow-up occurred. The primary outcome occurred in 25% of sevoflurane patients and 30% of isoflurane patients (absolute difference, -5.4%; one-sided 95% confidence interval, 1.4), thus non-inferiority was declared. Sevoflurane was not superior to isoflurane for the primary outcome (P = 0.21) or for any secondary outcomes. CONCLUSION: Sevoflurane is non-inferior to isoflurane on a composite outcome of prolonged ICU stay and all-cause 30-day mortality. Sevoflurane is not superior to isoflurane on any other of the clinically important outcomes. This trial was registered at clinicaltrials.gov; NCT01477151.

RéSUMé: OBJECTIF: Les agents anesthésiques volatils possèdent des propriétés cardioprotectrices, mais nous ne savons pas si ces effets cardioprotecteurs sont équivalents pour tous les agents de cette classe. Bien que le sévoflurane soit un anesthésique plus récent que l'isoflurane, son introduction dans notre pratique n'a pas été précédée par une comparaison directe à l'isoflurane dans une étude s'intéressant à d'importants critères d'évaluation cliniques. Notre objectif était de déterminer si le sévoflurane était non inférieur à l'isoflurane en relation à un critère d'évaluation principal important d'un point de vue clinique dans un groupe hétérogène d'adultes subissant une chirurgie cardiaque. MéTHODE: Nous avons réalisé une étude clinique randomisée et pragmatique d'efficacité comparative et de non-infériorité auprès de 464 adultes subissant des pontages coronariens et/ou une chirurgie valvulaire unique entre novembre 2011 et mars 2014. L'intervention consistait en le maintien de l'anesthésie à l'aide de sévoflurane (n = 231) ou d'isoflurane (n = 233) administré à une dose de 0,5-2,0 MAC tout au long de l'opération. Aucun intervenant ne connaissait l'agent utilisé, à l'exception de l'anesthésiologiste et du perfusionniste. Le critère d'évaluation principal était une composée de la durée de séjour à l'unité de soins intensifs (USI) ≥ 48 h et de la mortalité, toutes causes confondues, à 30 jours. Nous avons émis l'hypothèse que le sévoflurane ne serait pas inférieur à l'isoflurane (marge de non-infériorité < 10 % sur la base d'un taux de complications attendu de 25 %). Les critères d'évaluation secondaires comprenaient un séjour prolongé à l'USI, la mortalité toutes causes confondues à 30 et à 365 jours, l'utilisation d'inotropes ou de vasopresseurs, une hémodialyse ou une fibrillation auriculaire nouvelles, un accident vasculaire cérébral et une réadmission à l'USI. RéSULTATS: Nous n'avons perdu aucun patient au suivi. Le critère d'évaluation principal est survenu chez 25 % des patients ayant reçu du sévoflurane et 30 % des patients ayant reçu de l'isoflurane (différence absolue, −5,4 %; intervalle de confiance unilatéral 95 %, 1,4): la non-infériorité a donc été déclarée. Le sévoflurane n'était pas supérieur à l'isoflurane en ce qui touchait au critère d'évaluation principal (P = 0,21) ou aux critères d'évaluation secondaires. CONCLUSION: Le sévoflurane n'est pas inférieur à l'isoflurane selon un critère d'évaluation composé d'une durée de séjour prolongée à l'USI et de la mortalité toutes causes confondues à 30 jours. Le sévoflurane n'est pas supérieur à l'isoflurane en ce qui touche à n'importe quel autre critère clinique important. Cette étude a été enregistrée au ClinicalTrials.gov, numéro NCT01477151.

Higher-risk mitral valve operations after previous sternotomy: endoscopic, minimally invasive approach improves patient outcomes.

BACKGROUND: Reoperative mitral valve (MV) surgery is associated with significant morbidity and mortality; however, endoscopic minimally invasive surgical techniques may preserve the surgical benefits of conventional mitral operations while potentially reducing perioperative risk and length of stay (LOS) in hospital. METHODS: We compared the outcomes of consecutive patients who underwent reoperative MV surgery between 2000 and 2014 using a minimally invasive endoscopic approach (MINI) with those of patients who underwent a conventional sternotomy (STERN). The primary outcome was in-hospital/30-day mortality. Secondary outcomes included blood product transfusion, LOS in hospital and in the intensive care unit (ICU), and postoperative complications. RESULTS: We included 132 patients in our study: 40 (mean age 68 ± 14 yr, 70% men) underwent MINI and 92 (62 ± 13 yr, 40% men) underwent STERN. The MINI group had significantly more comorbidities than the STERN group. While there were no significant differences in complications, all point estimates suggested lower mortality and morbidity in the MINI than the STERN group (in-hospital/ 30-day mortality 5% v. 11%, p = 0.35; composite any of 10 complications 28% v. 41%, p = 0.13). Individual complication rates were similar between the MINI and STERN groups, except for intra-aortic balloon pump requirement (IABP; 0% v. 12%, p = 0.034). MINI significantly reduced the need for any blood transfusion (68% v. 84%, p = 0.036) or packed red blood cells (63% v. 79%, p = 0.042), fresh frozen plasma (35% v. 59%, p = 0.012) and platelets (20% v. 40%, p = 0.024). It also significantly reduced median hospital LOS (8 v. 12 d, p = 0.014). An exploratory propensity score analysis similarly demonstrated a significantly reduced need for IABP (p < 0.001) and a shorter mean LOS in the ICU (p = 0.046) and in hospital (p = 0.047) in the MINI group. CONCLUSION: A MINI approach for reoperative MV surgery reduces blood product utilization and hospital LOS. Possible clinically relevant differences in perioperative complications require assessment in randomized clinical trials.

CONTEXTE: Les réopérations de la valve mitrale (VM) sont associées à une morbidité et à une mortalité importantes. Cependant, il semblerait que les techniques chirurgicales endoscopiques à effraction minimale préservent les avantages des opérations traditionnelles de la VM tout en réduisant potentiellement les risques périopératoires et la durée d'hospitalisation. MÉTHODES: Nous avons comparé les résultats de patients consécutifs ayant subi une réopération de la VM entre 2000 et 2014 selon une approche endoscopique à effraction minimale (groupe MINI) à ceux de patients ayant subi une sternotomie classique (groupe STERN). Le résultat primaire à l'étude était la mortalité intrahospitalière ou dans les 30 premiers jours, et les résultats secondaires, la transfusion de produits sanguins, la durée du séjour à l'hôpital et à l'unité des soins intensifs (USI), ainsi que les complications postopératoires. RÉSULTATS: Nous avons retenu 132 patients : 40 (âge moyen de 68 ± 14 ans, 70 % d'hommes) dans le groupe MINI et 92 (âge moyen de 62 ± 13 ans, 40 % d'hommes) dans le groupe STERN. Les patients du groupe MINI présentaient un nombre significativement plus élevé de comorbidités que ceux du groupe STERN. Aucune différence significative n'a été observée quant aux complications, mais toutes les estimations ponctuelles pointaient vers une mortalité et une morbidité moindres dans le groupe MINI (mortalité intrahospitalière ou dans les 30 premiers jours : 5 % c. 11 %, p = 0,35; morbidité combinée à la présence d'au moins une complication parmi 10 possibles : 28 % c. 41 %, p = 0,13). Les taux de complications individuels étaient semblables chez les patients des 2 groupes, sauf pour l'exigence de ballon de contrepulsion intra-aortique (BCIA; 0 % c. 12 %, p = 0,034). L'approche MINI a réduit significativement le taux de transfusion de sang (68 % c. 84 %, p = 0,036) ou de concentrés de globules rouges (63 % c. 79 %, p = 0,042), de plasma frais congelé (35 % c. 59 %, p = 0,012) et de plaquettes (20 % c. 40 %, p = 0,024), en plus de diminuer significativement la durée médiane d'hospitalisation (8 jours c. 12 jours, p = 0,014). En outre, une analyse exploratoire du score de propension a révélé une réduction significative du BCIA (p < 0,001) ainsi qu'une durée moyenne de séjour à l'USI (p = 0,046) et à l'hôpital (p = 0,047) plus courte dans le groupe MINI. CONCLUSION: Le recours à l'approche endoscopique à effraction minimale pour les réopérations de la VM diminuerait le recours aux produits sanguins et la durée d'hospitalisation. En ce qui a trait aux complications périopératoires, il faudra procéder à des essais cliniques aléatoires pour évaluer les différences possiblement pertinentes sur le plan clinique.

PET-adapted sequential salvage therapy with brentuximab vedotin followed by augmented ifosamide, carboplatin, and etoposide for patients with relapsed and refractory Hodgkin's lymphoma: a non-randomised, open-label, single-centre, phase 2 study.

BACKGROUND: Pre-transplantation (18)F-fluorodeoxyglucose (FDG) PET-negativity is one of the strongest predictors of outcome after high-dose therapy and autologous stem-cell transplant (HDT/ASCT) for patients with relapsed or refractory Hodgkin's lymphoma. In this study, we assessed the feasibility and activity of PET-adapted salvage therapy with brentuximab vedotin, followed by augmented ifosfamide, carboplatin, and etoposide (ICE). METHODS: In this non-randomised, open-label, single-centre, phase 2 trial, we enrolled patients with relapsed or refractory Hodgkin's lymphoma who had failed one previous doxorubicin-containing chemotherapy regimen. All patients received weekly infusions of 1·2 mg/kg brentuximab vedotin on days 1, 8, and 15 for two 28 day cycles. After completion of brentuximab vedotin treatment, patients received a PET scan. Patients who achieved PET-negative status (a Deauville score of 1 or 2) proceeded directly to HDT/ASCT; those with persistent abnormalities on PET received two cycles of augmented ICE (augICE; two doses of ifosfamide 5000 mg/m(2) in combination with mesna 5000 mg/m(2) continuous infusion over 24 h, days 1 and 2; one dose of carboplatin AUC 5, day 3; three doses of etoposide 200 mg/m(2) every 12 h, day 1) before consideration for HDT/ASCT. Only patients with persistent abnormalities on PET after brentuximab vedotin received augICE; however, all patients in the intention-to-treat population were assessed for the primary outcome, which was the proportion of patients who were PET-negative after brentuximab vedotin alone or brentuximab vedotin followed by augICE. This study is registered with ClinicalTrials.gov, number NCT01508312, and is no longer accruing patients. FINDINGS: Between Jan 5, 2012, and Oct 4, 2013, we enrolled 46 patients. One patient was deemed ineligible, and not evaluable, before treatment initiation owing to having nodular, lymphocyte-predominant Hodgkin's lymphoma and thus 45 patients received treatment. After brentuximab vedotin, 12 patients (27%, 95% CI 13-40) were PET-negative and proceeded to HDT/ASCT. 33 (73%, 95% CI 60-86) patients were PET-positive after brentuximab vedotin; one PET-positive patient withdrew consent, therefore 32 PET-positive patients received augICE, 22 (69%, 95% CI 53-85) of whom were PET-negative. Overall, 34 patients (76%, 95% CI 62-89) achieved PET-negativity. All 44 patients who completed treatment as per protocol proceeded to receive HDT/ASCT. Brentuximab vedotin was well tolerated and associated with few grade 3-4 adverse events including hyperglycaemia (two [4%] patients, grade 3), nausea (one [2%], grade 3), hypoglycaemia (one [2%], grade 3 and one [2%], grade 4), and hypocalcaemia (one [2%], grade 3 and one [2%], grade 4). INTERPRETATION: PET-adapted sequential salvage therapy with brentuximab vedotin followed by augICE resulted in a high proportion of patients with relapsed or refractory Hodgkin's lymphoma achieving PET-negativity, and therefore could optimise the chance of cure after HDT/ASCT. FUNDING: Seattle Genetics.