Outcomes on an inpatient oncology service after the introduction of hospitalist comanagement.

BACKGROUND: Smilow Cancer Hospital (SCH) introduced hospitalist comanagement to the inpatient oncology service to address long lengths of stay and oncologist burnout. OBJECTIVE: To determine the impact of hospitalists on inpatient quality outcomes and oncologist experience. INTERVENTIONS: Hospitalists were introduced to one of two inpatient oncology services at SCH. Patients were assigned to teams equally based on capacity. Outcomes on the oncologist-led, traditional service (TS) were compared with outcomes on the hospitalist service (HS) 6 months after program implementation. MAIN OUTCOMES AND MEASURES: Outcomes included patient volume, length of stay (LOS), early discharge, discharge time, and 30-day readmission rate. Mixed linear or Poisson models that accounted for multiple admissions during the study duration were used. Oncologist experience was measured by survey. RESULTS: During the study period, there were 713 discharges, 400 from the HS and 313 from the TS (p = .0003). There was no difference in demographics or severity of illness (SOI) between services. Following adjustment for age, sex, race/ethnicity, cancer type, and discharge disposition, the average LOS was 4.71 on the HS and 5.47 on the TS (p = .01). Adjusted early discharge rate was 6.22% on the HS and 2.06% on the TS (p = .01). Adjusted mean discharge time was 3:45 p.m. on HS and 4:16 p.m. on TS (p = .009). There was no difference in readmission rates. Oncologists reported less stress (p = .001) and a better ability to manage competing responsibilities (p < .0001) while working on the HS. CONCLUSIONS: Hospitalist comanagement significantly improved LOS, early discharge, time of discharge, and oncologist experience without an increase in 30-day readmissions.

Predictors of Family Dissatisfaction with Support During Neurocritical Care Shared Decision-Making.

BACKGROUND: There is a critical need to improve support for families making difficult shared decisions about patient care with clinicians in the neuroscience ICU (neuro-ICU). The aim of this study is to identify patient- and family-related factors associated with dissatisfaction with shared decision-making support among families of neuro-critically ill patients. METHODS: We conducted a retrospective observational cohort study using survey data that had been collected from a consecutive sample of family members of patients in the neuro-ICU (one family member per patient) at two US academic centers. Satisfaction with shared decision-making support on ICU discharge had been measured among family members using one specific Likert scale item on the Family Satisfaction in the ICU 24 survey, a validated survey instrument for families of patients in the ICU. We dichotomized top-box responses for this particular item as an outcome variable and identified available patient- and family-related covariates associated with dissatisfaction (i.e., less than complete satisfaction) via univariate and multivariate analyses. RESULTS: Among 355 surveys, 180 (49.5%) of the surveys indicated dissatisfaction with support during decision-making. In a multivariate model, no preexisting characteristics of families or patients ascertainable on ICU admission were predictive of dissatisfaction. However, among family factors determined during the ICU course, experiencing three or fewer formal family meetings (odds ratio 1.93 [confidence interval 1.13-3.31]; p = 0.01) was significantly predictive of dissatisfaction with decisional support in this cohort with an average patient length of stay of 8.6 days (SD 8.4). There was also a trend toward a family's decision to keep a patient as full code, without treatment limitations, being predictive of dissatisfaction (odds ratio 1.80 [confidence interval 0.93-3.51]; p = 0.08). CONCLUSIONS: Family dissatisfaction with neuro-ICU shared decision-making support is not necessarily predicted by any preexisting family or patient variables but appears to correlate with participating in fewer formal family meetings during ICU admission. Future studies to improve family satisfaction with neurocritical care decision-making support should have broad inclusion criteria for participants and should consider promoting frequency of family meetings as a core strategy.

Higher-risk myelodysplastic syndromes with del(5q): does the del(5q) matter?

Introduction: Myelodysplastic Syndrome (MDS) represents a group of cancers characterized by abnormal blood cell formation and maturation, leading to various degrees of cytopenias and potential transformation to acute myeloid leukemia. Deletion of the long arm of chromosome 5 (del(5q)) is the most common clonal chromosomal anomaly in MDS, yet the population in this disease subtype is quite heterogeneous. This manuscript analyzes literature on high-risk MDS with del(5q) abnormalities.Areas covered: The paper will review outcomes with lenalidomide among high-risk MDS patients with del(5q). It will discuss the implications of harboring TP53 gene mutations, and share the data for allogeneic hematopoietic stem cell transplantations in this setting. Finally, the report evaluates the risk of disease progression in these patients.Expert commentary: Improved characterization of MDS has enhanced our understanding of patients with anomalies involving del(5q). Emerging literature is exploring combination therapy beyond lenalidomide, and next-generation sequencing may identify secondary mutations that could be an additional avenue for treatment.

Patterns of floral morphology in relation to climate and floral visitors.

BACKGROUND AND AIMS: The diversity of floral morphology among plant species has long captured the interest of biologists and led to the development of a number of explanatory theories. Floral morphology varies substantially within species, and the mechanisms maintaining this diversity are diverse. One possibility is that spatial variation in the pollinator fauna drives the evolution of spatially divergent floral ecotypes adapted to the local suite of pollinators. Another possibility is that geographic variation in the abiotic environment and local climatic conditions favours different floral morphologies in different regions. Although both possibilities have been shown to explain floral variation in some cases, they have rarely been competed against one another using data collected from large spatial scales. In this study, we assess floral variation in relation to climate and floral visitors in four oil-reward-specialized pollination interactions. METHODS: We used a combination of large-scale plant and pollinator samplings, morphological measures and climatic data. We analysed the data using spatial approaches, as well as traditional multivariate and structural equation modelling approaches. KEY RESULTS: Our results indicate that the four species have different levels of specialization, and that this can be explained by their climatic niche breadth. In addition, our results show that, at least for some species, floral morphology can be explained by the identity of floral visitors, with climate having only an indirect effect. CONCLUSIONS: Our results demonstrate that, even in very specialized interactions, both biotic and abiotic variables can explain a substantial amount of intraspecific variation in floral morphology.

Seronegative autoimmune autonomic ganglionopathy from dual immune checkpoint inhibition in a patient with metastatic melanoma.

BACKGROUND: Immune checkpoint inhibitors have improved clinical outcomes including survival in several malignancies but have also been associated with a range of immune-related adverse events (irAEs). Neurological irAEs are rare compared to the more typical skin, gastrointestinal, and endocrine toxicities, and are often underrecognized and challenging to diagnose. Here, we report a case of seronegative autoimmune autonomic ganglionopathy (AAG) induced by dual immune checkpoint inhibitor therapy (ICI) in a patient with metastatic melanoma. CASE PRESENTATION: A patient with metastatic melanoma was treated with ipilimumab and nivolumab. He developed a constellation of new symptoms including nausea, fatigue, and severe orthostatic hypotension refractory to fluid resuscitation. An infectious, cardiac, neurologic, and endocrine workup were unrevealing. Cardiovascular autonomic testing revealed poor sympathetic nervous system responses. He was diagnosed with seronegative AAG and significantly improved with immunomodulatory therapies including IVIG and steroids as well as varying doses of midodrine and fludrocortisone. He was able to restart nivolumab without recurrence of his symptoms. However, the AAG reoccurred when he was re-challenged with ipilimumab and nivolumab due to disease progression. While the AAG was manageable with steroids at that time, unfortunately his melanoma became resistant to ICI. CONCLUSIONS: Immune checkpoint inhibitors can have a wide range of unusual, rare irAEs, including neurotoxicity such as AAG. Clinicians should maintain suspicion for this toxicity so that treatment can be rapidly provided to avoid disability.

Primary Care Physician Involvement in Shared Decision Making for Critically Ill Patients and Family Satisfaction with Care.

PURPOSE: An intensive care unit (ICU) patient's primary care physician (PCP) may be able to assist family with certain ICU shared medical decisions. We explored whether families of patients in nonopen ICUs who nevertheless report involvement of a patient's PCP in medical decision making are more satisfied with ICU shared decision making than families who do not. METHODS: Between March 2013 and December 2015, we administered the Family Satisfaction in the ICU 24 survey to family members of adult neuroscience ICU patients. We compared the mean score for the survey subsection regarding shared decision making (graded on a 100-point scale), as well as individual survey items, between those who reported the patient's PCP involvement in any medical decision making versus those who did not. RESULTS: Among 263 respondents, there was no difference in mean overall decision-making satisfaction scores for those who reported involvement (81.1; SD = 15.2) versus those who did not (80.1; SD = 12.8; P = .16). However, a higher proportion reporting involvement felt completely satisfied with their 1) inclusion in the ICU decision making process (75.9% vs 61.4%; P = .055), and 2) control over the care of the patient (73.6% vs 55.6%; P = .02), with no difference regarding consistency of clinical information provided by the medical team (64.8% vs 63.5%; P = 1.00). CONCLUSIONS: Families who report involvement of a patient's PCP in medical decision making for critically ill patients may be more satisfied than those who do not with regard to specific aspects of ICU decision making. Further research would help understand how best to engage PCPs in shared decisions.

Dedicated Afternoon Rounds for ICU Patients' Families and Family Satisfaction With Care.

OBJECTIVE: It was hypothesized that adding dedicated afternoon rounds for patients' families to supplement standard family support would improve overall family satisfaction with care in a neuroscience ICU. DESIGN: Pre- and postimplementation (pre-I and post-I) design. SETTING: Single academic neuroscience ICU. PATIENTS: Patients in the neuroscience ICU admitted for longer than 72 hours or made comfort measures only at any point during neuroscience ICU admission. INTERVENTION: The on-service attending intensivist and a neuroscience ICU nursing leader made bedside visits to families to address concerns during regularly scheduled, advertised times two afternoons each week. MEASUREMENTS AND MAIN RESULTS: One family member per patient during the pre-I and post-I periods was recruited to complete the Family Satisfaction in the ICU 24 instrument. Post-I respondents indicated whether they had participated in the afternoon rounds. For primary outcome, the mean pre-I and post-I composite Family Satisfaction in the ICU 24 scores (on a 100-point scale) were compared. A total of 146 pre-I (March 2013 to October 2014; capture rate, 51.6%) and 141 post-I surveys (October 2014 to December 2015; 47.2%) were collected. There was no difference in mean Family Satisfaction in the ICU 24 score between groups (pre-I, 89.2 ± 11.2; post-I, 87.4 ± 14.2; p = 0.6). In a secondary analysis, there was also no difference in mean Family Satisfaction in the ICU 24 score between the pre-I respondents and the 39.0% of post-I respondents who participated in family rounds. The mean Family Satisfaction in the ICU 24 score of the post-I respondents who reported no participation trended lower than the mean pre-I score, with fewer respondents in this group reporting complete satisfaction with emotional support (75% vs. 54%; p = 0.002), coordination of care (82% vs. 68%; p = 0.03), and frequency of communication by physicians (60% vs. 43%; p = 0.03). CONCLUSIONS: Dedicated afternoon rounds for families twice a week may not necessarily improve an ICU's overall family satisfaction. Increased dissatisfaction among families who do not or cannot participate is possible.

Effect of screw position on single cycle to failure in bending and torsion of a locking plate-rod construct in a synthetic feline femoral gap model.

OBJECTIVE: To evaluate the effect of screw position on strength and stiffness of a combination locking plate-rod construct in a synthetic feline femoral gap model. SAMPLE: 30 synthetic long-bone models derived from beechwood and balsa wood. PROCEDURES: 3 constructs (2 locking plate-rod constructs and 1 locking plate construct; 10 specimens/construct) were tested in a diaphyseal bridge plating configuration by use of 4-point bending and torsion. Variables included screw position (near the fracture gap and far from the fracture gap) and application of an intramedullary pin. Constructs were tested to failure in each loading mode to determine strength and stiffness. Failure was defined as plastic deformation of the plate or breakage of the bone model or plate. Strength, yield angle, and stiffness were compared by use of a Wilcoxon test. RESULTS: Placement of screws near the fracture gap did not increase bending or torsional stiffness in the locking plate-rod constructs, assuming the plate was placed on the tension side of the bone. Addition of an intramedullary pin resulted in a significant increase in bending strength of the construct. Screw positioning did not have a significant effect on any torsion variables. CONCLUSIONS AND CLINICAL RELEVANCE: Results of this study suggested that, in the investigated plate-rod construct, screw insertion adjacent to the fracture lacked mechanical advantages over screw insertion at the plate ends. For surgeons attempting to minimize soft tissue dissection, the decision to make additional incisions for screw placement should be considered with even more caution.

Disulfide-mediated stabilization of the IκB kinase binding domain of NF-κB essential modulator (NEMO).

Human NEMO (NF-κB essential modulator) is a 419 residue scaffolding protein that, together with catalytic subunits IKKα and IKKß, forms the IκB kinase (IKK) complex, a key regulator of NF-κB pathway signaling. NEMO is an elongated homodimer comprising mostly α-helix. It has been shown that a NEMO fragment spanning residues 44-111, which contains the IKKα/ß binding site, is structurally disordered in the absence of bound IKKß. Herein we show that enforcing dimerization of NEMO1-120 or NEMO44-111 constructs through introduction of one or two interchain disulfide bonds, through oxidation of the native Cys54 residue and/or at position 107 through a Leu107Cys mutation, induces a stable α-helical coiled-coil structure that is preorganized to bind IKKß with high affinity. Chemical and thermal denaturation studies showed that, in the context of a covalent dimer, the ordered structure was stabilized relative to the denatured state by up to 3 kcal/mol. A full-length NEMO-L107C protein formed covalent dimers upon treatment of mammalian cells with H2O2. Furthermore, NEMO-L107C bound endogenous IKKß in A293T cells, reconstituted TNF-induced NF-κB signaling in NEMO-deficient cells, and interacted with TRAF6. Our results indicate that the IKKß binding domain of NEMO possesses an ordered structure in the unbound state, provided that it is constrained within a dimer as is the case in the constitutively dimeric full-length NEMO protein. The stability of the NEMO coiled coil is maintained by strong interhelix interactions in the region centered on residue 54. The disulfide-linked constructs we describe herein may be useful for crystallization of NEMO's IKKß binding domain in the absence of bound IKKß, thereby facilitating the structural characterization of small-molecule inhibitors.

Mutation of nonessential cysteines shows that the NF-κB essential modulator forms a constitutive noncovalent dimer that binds IκB kinase-ß with high affinity.

NEMO (NF-κB essential modulator) associates with catalytic subunits IKKα and IKKß to form the IκB kinase (IKK) complex and is a key regulator of NF-κB pathway signaling. Biochemical and structural characterization of NEMO has been challenging, however, leading to conflicting data about basic biochemical properties such as the oligomeric state of active NEMO and its binding affinity for IKKß. We show that up to seven of NEMO's 11 cysteine residues can be mutated to generate recombinant full-length NEMO that is highly soluble and active. Using a fluorescence anisotropy binding assay, we show that full-length NEMO binds a 44-mer peptide encompassing residues 701-745 of IKKß with a K(D) of 2.2 ± 0.8 nM. The IKKß binding affinities of mutants with five and seven Cys-to-Ala substitutions are indistinguishable from that of wild-type NEMO. Moreover, when expressed in NEMO -/- fibroblasts, the five-Ala and seven-Ala NEMO mutants can interact with cellular IKKß and restore NF-κB signaling to provide protection against tumor necrosis factor α-induced cell death. Treatment of the NEMO-reconstituted cells with H2O2 led to the formation of covalent dimers for wild-type NEMO and the five-Ala mutant, but not for the seven-Ala mutant, confirming that Cys54 and/or Cys347 can mediate interchain disulfide bonding. However, the IKKß binding affinity of NEMO is unaffected by the presence or absence of interchain disulfide bonding at Cys54, which lies within the IKKß binding domain of NEMO, or at Cys347, indicating that NEMO exists as a noncovalent dimer independent of the redox state of its cysteines. This conclusion was corroborated by the observation that the secondary structure content of NEMO and its thermal stability were independent of the presence or absence of interchain disulfide bonds.

Development of a small D-enantiomeric Alzheimer's amyloid-ß binding peptide ligand for future in vivo imaging applications.

Alzheimer's disease (AD) is a devastating disease affecting predominantly the aging population. One of the characteristic pathological hallmarks of AD are neuritic plaques, consisting of amyloid-ß peptide (Aß). While there has been some advancement in diagnostic classification of AD patients according to their clinical severity, no fully reliable method for pre-symptomatic diagnosis of AD is available. To enable such early diagnosis, which will allow the initiation of treatments early in the disease progress, neuroimaging tools are under development, making use of Aß-binding ligands that can visualize amyloid plaques in the living brain. Here we investigate the properties of a newly designed series of D-enantiomeric peptides which are derivatives of ACI-80, formerly called D1, which was developed to specifically bind aggregated Aß1-42. We describe ACI-80 derivatives with increased stability and Aß binding properties, which were characterized using surface plasmon resonance and enzyme-linked immunosorbent assays. The specific interactions of the lead compounds with amyloid plaques were validated by ex vivo immunochemistry in transgenic mouse models of AD. The novel compounds showed increased binding affinity and are promising candidates for further development into in vivo imaging compounds.

Fluorine-18 labeling of three novel D-peptides by conjugation with N-succinimidyl-4-[18F]fluorobenzoate and preliminary examination by postmortem whole-hemisphere human brain autoradiography.

INTRODUCTION: ß-Amyloid (Aß) plaques and neurofibrillary tangles are the main characteristics of Alzheimer's disease (AD). Positron emission tomography (PET), a high-resolution, sensitive, and noninvasive imaging technique, has been widely utilized in visualizing the localization of plaques and tangles and thereby distinguishing between AD and healthy controls. A small 12-mer D-enantiomeric peptide (amino acid sequence=QSHYRHISPAQV), denoted as D1, has high binding affinity to Aß in vitro in the sub-micromolar range, and consequently, its radiolabeled analogues have a potential as radioligands for visualizing amyloid plaques in vivo by PET. AIM: The aims of the present work were to develop three different potent D1 derivative peptides labeled with fluorine-18 and to examine them in the AD and control postmortem human brain by autoradiography (ARG). METHODS: Three different D1 derivative peptides were radiolabeled with fluorine-18 ([(18)F]ACI-87, [(18)F]ACI-88, [(18)F]ACI-89) using the prosthetic group N-succinimidyl-4-[(18)F]fluorobenzoate ([(18)F]SFB) and purified by high performance liquid chromatography (HPLC). Preliminary ARG measurements were performed in AD and control brains. RESULTS: The three fluorine-18-labeled d-peptides were obtained in a total synthesis time of 140 min with radiochemical purity higher than 98%. The specific radioactivities of the three different D1 derivative peptides were between 9 and 113 GBq/µmol. ARG demonstrated a higher radioligand uptake in the cortical gray matter and the hippocampus in the AD brain as compared to age-matched control brain. CONCLUSIONS: Fluorine-18 labeling of the three novel D1 derivative peptides using [(18)F]SFB was successfully accomplished. Higher contrast between AD and control brain slices demonstrates their potential applicability for further use in vivo by PET.

Distribution and binding of 18F-labeled and 125I-labeled analogues of ACI-80, a prospective molecular imaging biomarker of disease: a whole hemisphere post mortem autoradiography study in human brains obtained from Alzheimer's disease patients.

One of the major pathological landmarks of Alzheimer's disease and other neurodegenerative diseases is the presence of amyloid deposits in the brain. The early non-invasive visualization of amyloid is a major objective of recent diagnostic neuroimaging approaches, including positron emission tomography (PET), with an eye on follow-up of disease progression and/or therapy efficacy. The development of molecular imaging biomarkers with binding affinity to amyloid in the brain is therefore in the forefront of imaging biomarker and radiochemistry research. Recently, a dodecamer peptide (amino acid sequence=QSHYRHISPAQV; denominated D1 or ACI-80) was identified as a prospective ligand candidate, binding with high ex vivo affinity to L-Aß-amyloid (K(d): 0.4 µM). In order to assess the ligand's capacity to visualize amyloid in Alzheimer's disease (AD), two (125)I labeled and three (18)F labeled analogues of the peptide were synthesized and tested in post mortem human autoradiography experiments using whole hemisphere brain slices obtained from deceased AD patients and age matched control subjects. The (18)F-labeled radioligands showed more promising visualization capacity of amyloid that the (125)I-labeled radioligands. In the case of each (18)F radioligands the grey matter uptake in the AD brains was significantly higher than that in control brains. Furthermore, the grey matter: white matter uptake ratio was over ~2, the difference being significant for each (18)F-radioligands. The regional distribution of the uptake of the various radioligands systematically shows a congruent pattern between the high uptake regions and spots in the autoradiographic images and the disease specific signals obtained in adjacent or identical brain slices labeled with histological, immunohistochemical or autoradiographic stains for amyloid deposits or activated astrocytes. The present data, using post mortem human brain autoradiography in whole hemisphere human brains obtained from deceased AD patients and age matched control subjects, support the visualization capacity of the radiolabeled ACI-80 analogues of amyloid deposits in the human brain. Further studies are warranted to explore the usefulness of the (18)F-labeled analogues as in vivo molecular imaging biomarkers in diagnostic PET studies.

MRI features of gastrocnemius musculotendinopathy in herding dogs.

Pelvic limb lameness that was localized clinically to the lateral gastrocnemius head was observed in dogs without history of trauma. The aim of this retrospective study was to describe magnetic resonance imaging (MRI) findings of this condition. Nine dogs were identified, eight Border Collies and one Australian Shepherd. They all had chronic pelvic limb lameness; no signs of joint effusion or instability were present. In MR images there was high signal intensity in the lateral head of the gastrocnemius muscle around the sesamoid bone in T2-weighted, T2*-weighted, and STIR images and an iso- to mildly hyperintense signal in T1-weighted images with marked contrast enhancement. The abnormal signal intensity most likely represents a myotendinous strain. The breed affiliation to Border Collies is striking, and a relation to biomechanical forces or motion pattern may be possible. Except for the dog with the most extensive lesion all dogs had an excellent outcome.

An Ultrasound Assisted Anchoring Technique (BoneWelding Technology) for Fixation of Implants to Bone - A Histological Pilot Study in Sheep.

The BoneWelding((R)) Technology offers new opportunities to anchor implants within bone. The technology melted the surface of biodegradable polymer pins by means of ultrasound energy to mould material into the structures of the predrilled bone. Temperature changes were measured at the sites of implantation in an in vitro experiment. In the in vivo part of the study two types of implants were implanted in the limb of sheep to investigate the biocompatibility of the method. One implant type was made of PL-DL-lactide (PLA), the second one was a titanium core partially covered with PLA. Healing period was 2 and 6 months, with 3 sheep per group. Bone samples were evaluated radiologically, histologically and histomorphometrically for bone remodeling and inflammatory reactions. Results demonstrated mild and short temperature increase during insertion. New bone formed at the implant without evidence of inflammatory reaction. The amount of adjacent bone was increased compared to normal cancellous bone. It was concluded that the BoneWelding((R)) Technology proved to be a biocompatible technology to anchor biodegradable as well as titanium-PLA implants in bone.

Enhancing the mechanical integrity of the implant-bone interface with BoneWelding technology: determination of quasi-static interfacial strength and fatigue resistance.

The BoneWelding technology is an innovative bonding method, which offers new alternatives in the treatment of fractures and other degenerative disorders of the musculoskeletal system. The BoneWelding process employs ultrasonic energy to liquefy a polymeric interface between orthopaedic implants and the host bone. Polymer penetrates the pores of the surrounding bone and, following a rapid solidification, forms a strong and uniform bond between implant and bone. Biomechanical testing was performed to determine the quasi-static push-out strength and fatigue performance of 3.5-mm-diameter polymeric dowels bonded to a bone surrogate material (Sawbones solid and cellular polyurethane foam) using the BoneWelding process. Fatigue tests were conducted over 100,000 cycles of 20-100 N loading. Mechanical test results were compared with those obtained with a comparably-sized, commercial metallic fracture fixation screw. Tests in surrogate bone material of varying density demonstrated significantly superior mechanical performance of the bonded dowels in comparison to conventional bone screws (p < 0.01), with holding strengths approaching 700 N. Even in extremely porous host material, the performance of the bonded dowels was equivalent to that of the bone screws. For both cellular and solid bone analog materials, failure always occurred within the bone analog material surrounding and distant to the implant; the infiltrated interface was stronger than the surrounding bone analog material. No significant decrease in interfacial strength was observed following conditioning in a physiological saline solution for a period of 1 month prior to testing. Ultrasonically inserted implants migrated, on average, less than 20 microm over, and interfacial stiffness remained constant the full duration of fatigue testing. With further refinement, the BoneWelding technology may offer a quicker, simpler, and more effective method for achieving strong fixation and primary stability for fracture fixation or other orthopaedic and dental implant applications.