My Health Record (and E-scripts): essential new resource for physicians-a personal perspective.

From a personal perspective of an endocrinologist in private practice: Integration of the My Health Record into everyday clinical practice is time- and cost-saving, allows for more accurate record keeping and most importantly improves overall patient care. The main deficiency at present is incomplete uptake by medical specialists in private and public practice, as well as pathology and imaging service providers. We will all reap the benefits as these entities become engaged and contribute towards making this electronic medical record truly universal.

Design of the VIALE-M phase III trial of venetoclax and oral azacitidine maintenance therapy in acute myeloid leukemia.

Prevention of relapse is a major therapeutic challenge and an unmet need for patients with acute myeloid leukemia (AML). Venetoclax is a highly selective, potent, oral BCL-2 inhibitor that induces apoptosis in AML cells. When combined with azacitidine, it leads to prolonged overall survival and rapid, durable remissions in treatment-naive AML patients ineligible for intensive chemotherapy. VIALE-M is a randomized, double-blind, two-arm study to evaluate the safety and efficacy of venetoclax in combination with oral azacitidine (CC-486) as maintenance therapy in patients in complete remission with incomplete blood count recovery after intensive induction and consolidation therapies. The primary end point is relapse-free survival. Secondary outcomes include overall survival, minimal residual disease conversion and improvement in quality-of-life. Trial Registration Number: NCT04102020 (ClinicalTrials.gov).

A perceptual eyebox for near-eye displays.

In near-eye display systems that support three-dimensional (3D) augmented and virtual reality, a central factor in determining the user experience is the size of the eyebox. The eyebox refers to a volume where the eye receives an acceptable view of the image with respect to a set of criteria and thresholds. The size and location of this volume are primarily driven by optical architecture choices in which designers trade-off a number of constraints, such as field of view, image quality, and product design. It is thus important to clearly quantify how design decisions affect the properties of the eyebox. Recent work has started evaluating the eyebox in 3D based purely on optical criteria. However, such analyses do not incorporate perceptual criteria that determine visual quality, which are particularly important for binocular 3D systems. To address this limitation, we introduce the framework of a perceptual eyebox. The perceptual eyebox is the volume where the eye(s) must be located for the user to experience a visual percept falling within a perceptually-defined criterion. We combine optical and perceptual data to characterize an example perceptual eyebox for display visibility in augmented reality. The key contributions in this paper include: comparing the perceptual eyebox for monocular and binocular display designs, modeling the effects of user eye separation, and examining the effects of eye rotation on the eyebox volume.

The zone of comfort: Predicting visual discomfort with stereo displays.

Recent increased usage of stereo displays has been accompanied by public concern about potential adverse effects associated with prolonged viewing of stereo imagery. There are numerous potential sources of adverse effects, but we focused on how vergence-accommodation conflicts in stereo displays affect visual discomfort and fatigue. In one experiment, we examined the effect of viewing distance on discomfort and fatigue. We found that conflicts of a given dioptric value were slightly less comfortable at far than at near distance. In a second experiment, we examined the effect of the sign of the vergence-accommodation conflict on discomfort and fatigue. We found that negative conflicts (stereo content behind the screen) are less comfortable at far distances and that positive conflicts (content in front of screen) are less comfortable at near distances. In a third experiment, we measured phoria and the zone of clear single binocular vision, which are clinical measurements commonly associated with correcting refractive error. Those measurements predicted susceptibility to discomfort in the first two experiments. We discuss the relevance of these findings for a wide variety of situations including the viewing of mobile devices, desktop displays, television, and cinema.

Temporal presentation protocols in stereoscopic displays: Flicker visibility, perceived motion, and perceived depth.

Most stereoscopic displays rely on field-sequential presentation to present different images to the left and right eyes. With sequential presentation, images are delivered to each eye in alternation with dark intervals, and each eye receives its images in counter phase with the other eye. This type of presentation can exacerbate image artifacts including flicker, and the appearance of unsmooth motion. To address the flicker problem, some methods repeat images multiple times before updating to new ones. This greatly reduces flicker visibility, but makes motion appear less smooth. This paper describes an investigation of how different presentation methods affect the visibility of flicker, motion artifacts, and distortions in perceived depth. It begins with an examination of these methods in the spatio-temporal frequency domain. From this examination, it describes a series of predictions for how presentation rate, object speed, simultaneity of image delivery to the two eyes, and other properties ought to affect flicker, motion artifacts, and depth distortions, and reports a series of experiments that tested these predictions. The results confirmed essentially all of the predictions. The paper concludes with a summary and series of recommendations for the best approach to minimize these undesirable effects.

Clinical Characteristics and Outcomes of Colorectal Cancer in the ColoCare Study: Differences by Age of Onset.

Early-onset colorectal cancer has been on the rise in Western populations. Here, we compare patient characteristics between those with early- (<50 years) vs. late-onset (≥50 years) disease in a large multinational cohort of colorectal cancer patients (n = 2193). We calculated descriptive statistics and assessed associations of clinicodemographic factors with age of onset using mutually-adjusted logistic regression models. Patients were on average 60 years old, with BMI of 29 kg/m2, 52% colon cancers, 21% early-onset, and presented with stage II or III (60%) disease. Early-onset patients presented with more advanced disease (stages III-IV: 63% vs. 51%, respectively), and received more neo and adjuvant treatment compared to late-onset patients, after controlling for stage (odds ratio (OR) (95% confidence interval (CI)) = 2.30 (1.82-3.83) and 2.00 (1.43-2.81), respectively). Early-onset rectal cancer patients across all stages more commonly received neoadjuvant treatment, even when not indicated as the standard of care, e.g., during stage I disease. The odds of early-onset disease were higher among never smokers and lower among overweight patients (1.55 (1.21-1.98) and 0.56 (0.41-0.76), respectively). Patients with early-onset colorectal cancer were more likely to be diagnosed with advanced stage disease, to have received systemic treatments regardless of stage at diagnosis, and were less likely to be ever smokers or overweight.

Diamagnetic group 6 tetrakis(di-tert-butylketimido)metal(IV) complexes.

The addition of 4 equiv of LiN=C-t-Bu(2) to CrCl(3), MoCl(5), and WCl(6) in diethyl ether produced the complexes M(N=C-t-Bu(2))(4) (M = Cr, Mo, W). Single-crystal X-ray diffraction studies revealed that the molecules have flattened tetrahedral geometries with virtual D(2d) symmetry in the solid state. (1)H and (13)C NMR spectra indicated that the complexes are diamagnetic, and a qualitative MO analysis showed that the orthogonal π-donor and -acceptor orbitals of the ketimide ligand cooperatively split the d(xy) and d(z2) orbitals sufficiently to allow spin pairing in the d(xy) orbital. A more sophisticated quantum-mechanical analysis of Cr(N=C-t-Bu(2))(4) using density functional/molecular mechanics methods confirmed the qualitative analysis by showing that the singlet state is 27 kcal/mol more stable than the triplet state.

Focus information is used to interpret binocular images.

Focus information-blur and accommodation-is highly correlated with depth in natural viewing. We examined the use of focus information in solving the binocular correspondence problem and in interpreting monocular occlusions. We presented transparent scenes consisting of two planes. Observers judged the slant of the farther plane, which was seen through the nearer plane. To do this, they had to solve the correspondence problem. In one condition, the two planes were presented with sharp rendering on one image plane, as is done in conventional stereo displays. In another condition, the planes were presented on two image planes at different focal distances, simulating focus information in natural viewing. Depth discrimination performance improved significantly when focus information was correct, which shows that the visual system utilizes the information contained in depth-of-field blur in solving binocular correspondence. In a second experiment, we presented images in which one eye could see texture behind an occluder that the other eye could not see. When the occluder's texture was sharp along with the occluded texture, binocular rivalry was prominent. When the occluded and occluding textures were presented with different blurs, rivalry was significantly reduced. This shows that blur aids the interpretation of scene layout near monocular occlusions.

Accommodation to multiple-focal-plane displays: Implications for improving stereoscopic displays and for accommodation control.

Most stereoscopic displays present images at a single focal plane, resulting in "conflicts" between the stimuli to vergence and accommodation. Minimizing these conflicts is beneficial because they can cause distorted depth percepts, visual fatigue, and reduced stereoscopic performance. One proposed solution is to present a sum of images at multiple focal planes and to vary focal depth continuously by distributing image intensity across planes-a technique referred to as depth filtering. We evaluated this digital approximation to real-world variations in focal depth by measuring accommodation responses to depth-filtered stimuli at various simulated distances. Specifically, we determined the maximum image-plane separation that supported accurate and reliable accommodation. We used an analysis of retinal-image formation to predict when responses might be inaccurate. Accommodation to depth-filtered images was accurate and precise for image-plane separations up to ∼1 diopter, suggesting that depth filtering can be used to precisely match accommodation and vergence demands in a practical display. At larger plane separations, responses broke down in a manner consistent with our analysis. We develop this approach to consider how different spatial frequencies contribute to accommodation control. The results suggest that higher spatial frequencies contribute less to the accommodation response than has previously been thought.

Immunomodulatory Activity of a Colony-stimulating Factor-1 Receptor Inhibitor in Patients with Advanced Refractory Breast or Prostate Cancer: A Phase I Study.

PURPOSE: Tumor-associated macrophages correlate with increased invasiveness, growth, and immunosuppression. Activation of the colony-stimulating factor-1 receptor (CSF-1R) results in proliferation, differentiation, and migration of monocytes/macrophages. This phase I study evaluated the immunologic and clinical activity, and safety profile of CSF-1R inhibition with the mAb LY3022855. PATIENTS AND METHODS: Patients with advanced refractory metastatic breast cancer (MBC) or metastatic castration-resistant prostate cancer (mCRPC) were treated with LY3022855 intravenously in 6-week cycles in cohorts: (A) 1.25 mg/kg every 2 weeks (Q2W); (B) 1.0 mg/kg on weeks 1, 2, 4, and 5; (C) 100 mg once weekly; (D)100 mg Q2W. mCRPC patients were enrolled in cohorts A and B; patients with MBC were enrolled in all cohorts. Efficacy was assessed by RECIST and Prostate Cancer Clinical Trials Working Group 2 criteria. RESULTS: Thirty-four patients (22 MBC; 12 mCRPC) received ≥1 dose of LY3022855. At day 8, circulating CSF-1 levels increased and proinflammatory monocytes CD14DIMCD16BRIGHT decreased. Best RECIST response was stable disease in five patients with MBC (23%; duration, 82-302 days) and three patients with mCRPC (25%; duration, 50-124 days). Two patients with MBC (cohort A) had durable stable disease >9 months and a third patient with MBC had palpable reduction in a nontarget neck mass. Immune-related gene activation in tumor biopsies posttreatment was observed. Common any grade treatment-related adverse events were fatigue, decreased appetite, nausea, asymptomatic increased lipase, and creatine phosphokinase. CONCLUSIONS: LY3022855 was well tolerated and showed evidence of immune modulation. Clinically meaningful stable disease >9 months was observed in two patients with MBC.

High-speed switchable lens enables the development of a volumetric stereoscopic display.

Stereoscopic displays present different images to the two eyes and thereby create a compelling three-dimensional (3D) sensation. They are being developed for numerous applications including cinema, television, virtual prototyping, and medical imaging. However, stereoscopic displays cause perceptual distortions, performance decrements, and visual fatigue. These problems occur because some of the presented depth cues (i.e., perspective and binocular disparity) specify the intended 3D scene while focus cues (blur and accommodation) specify the fixed distance of the display itself. We have developed a stereoscopic display that circumvents these problems. It consists of a fast switchable lens synchronized to the display such that focus cues are nearly correct. The system has great potential for both basic vision research and display applications.

Relationship between GH-induced metabolic changes and changes in body composition: a dose and time course study in GH-deficient adults.

OBJECTIVE: Although growth hormone (GH)-induced changes in fat and protein metabolism are likely to underlie changes in body composition, the relationship has not been clearly defined. The aim was to study the effects of dose and time course on substrate metabolism and relate to body compositional changes during GH treatment. DESIGN: In an open randomised-controlled study, 16 GH-deficient adults were randomised to treatment with GH 3 microg/kg/d (low dose, n=6) or 6 microg/kg/d (higher dose, n=10) for 12 weeks. Changes in whole body protein metabolism, estimated using the leucine turnover technique, and resting energy expenditure (REE) were assessed after short-term GH (two weeks) and longer-term GH (12 weeks). Changes in lean body mass (LBM) and fat mass (FM) over 12 weeks were assessed by DXA. RESULTS: The maximal changes in leucine oxidation (Lox) (-3.9+/-1.1 versus +0.8+/-1.8 micromol/min, p=0.03) and REE (+132+/-36 versus -28+/-41 kcal/d, p=0.01) were significantly greater in the higher, than the low dose group. FM fell (-1.4+/-0.4 kg, p=0.005) and LBM increased (+2.2+/-0.7 kg, p=0.01) significantly in the higher dose group only. The acute reduction in Lox at two weeks in the higher dose group was no longer significant after 12 weeks. The change in Lox after two (r=-0.53, p=0.035), but not 12, weeks was significantly correlated with the change in LBM. CONCLUSIONS: GH-induced changes in protein metabolism were influenced by the dose and duration of GH treatment. Suppression of protein oxidation occurred soon after initiation of GH in the higher dose group and predicted a later gain in LBM. Early assessment of whole body protein metabolism may allow prediction of the anabolic potential of GH.

Synthesis of zinc hydrazonide complexes.

The zinc hydrazonide complexes [ClZn(CH(2)C(Me)=NNMe(2))(py)](2), [ClZn(CH(2)C(t-Bu)=NNMe(2))](2), [Zn(CH(2)C(Me)=NNMe(2))(2)](2), Zn(CH(2)C(i-Pr)=NNMe(2))(2), and Zn(CH(2)C(t-Bu)=NNMe(2))(2) were synthesized by salt metathesis reactions, and the coordination polymer [EtZn(CH(2)C(Me)=NNMe(2))](n) was obtained from the reaction between excess ZnEt(2) and [Zn(CH(2)C(Me)=NNMe(2))(2)](2). Single crystal X-ray crystallography studies revealed that the hydrazonide ligands were bound to zinc as chelating alkyl ligands. The ligand precursor [Li(CH(2)C(i-Pr)=NNMe(2))(THF)](n) was also structurally characterized. In the anion of [Li(CH(2)C(i-Pr)=NNMe(2))(THF)](n), the hydrazonide ligand in [EtZn(CH(2)C(Me)=NNMe(2))](n), and the bridging hydrazonide ligands in [Zn(CH(2)C(Me)=NNMe(2))(2)](2) and [ClZn(CH(2)C(Me)=NNMe(2))(py)](2), there is evidence for three-center charge delocalization. In solution, the dimer [Zn(CH(2)C(Me)=NNMe(2))(2)](2) is in equilibrium with the monomer Zn(CH(2)C(Me)=NNMe(2))(2). The thermodynamic parameters DeltaH degrees = 55.8(2.9) kJ/mol, DeltaS degrees = 144(2) J/mol K, and DeltaG degrees (298K) = 13(2) kJ/mol for the equilibrium were obtained from a variable temperature (1)H NMR study.

Vergence-accommodation conflicts hinder visual performance and cause visual fatigue.

Three-dimensional (3D) displays have become important for many applications including vision research, operation of remote devices, medical imaging, surgical training, scientific visualization, virtual prototyping, and more. In many of these applications, it is important for the graphic image to create a faithful impression of the 3D structure of the portrayed object or scene. Unfortunately, 3D displays often yield distortions in perceived 3D structure compared with the percepts of the real scenes the displays depict. A likely cause of such distortions is the fact that computer displays present images on one surface. Thus, focus cues-accommodation and blur in the retinal image-specify the depth of the display rather than the depths in the depicted scene. Additionally, the uncoupling of vergence and accommodation required by 3D displays frequently reduces one's ability to fuse the binocular stimulus and causes discomfort and fatigue for the viewer. We have developed a novel 3D display that presents focus cues that are correct or nearly correct for the depicted scene. We used this display to evaluate the influence of focus cues on perceptual distortions, fusion failures, and fatigue. We show that when focus cues are correct or nearly correct, (1) the time required to identify a stereoscopic stimulus is reduced, (2) stereoacuity in a time-limited task is increased, (3) distortions in perceived depth are reduced, and (4) viewer fatigue and discomfort are reduced. We discuss the implications of this work for vision research and the design and use of displays.

Consequences of Incorrect Focus Cues in Stereo Displays.

Conventional stereo displays produce images in which focus cues - blur and accommodation - are inconsistent with the simulated depth. We have developed new display techniques that allow the presentation of nearly correct focus. Using these techniques, we find that stereo vision is faster and more accurate when focus cues are mostly consistent with simulated depth; furthermore, viewers experience less fatigue when focus cues are correct or nearly correct.

Evaluation of the effect of the EGFR antibody-drug conjugate ABT-414 on QT interval prolongation in patients with advanced solid tumors likely to over-express EGFR.

PURPOSE: ABT-414 is an antibody-drug conjugate (ADC) being developed for the treatment of tumors harboring amplification of the epidermal growth factor receptor (EGFR). This study evaluated the potential of ABT-414 to prolong the QT interval as part of the initial phase 1 study (NCT01741727). METHODS: Data from patients who received ABT-414 monotherapy at a dose of 1-4 mg/kg once every 3 weeks or 1 or 1.5 mg/kg weekly for 2 out of every 3 weeks (alternate schedule) by intravenous infusion were included in the analysis of triplicate 12-lead ECGs obtained before dosing and through 168 h after dosing. Data from time-matched pharmacokinetic samples and QT interval assessments were evaluated using linear mixed-effects modeling to determine the effects of ABT-414, total ABT-806, and cysteine-maleimidocaproyl monomethyl auristatin F (Cys-mcMMAF) on the QT interval corrected using Fridericia's formula (QTcF). RESULTS: Fifty-one patients were included in the analyses. ABT-414 had no clinically meaningful effect on QTcF. Using pooled data from doses ≥2 mg/kg, the estimated mean ∆QTcF reached a maximum of 4.30 ms after dosing, with a one-sided 95% upper confidence bound of 8.32 ms. The exposure-response analysis showed no statistically significant relationship between ΔQTcF and the concentration of any analyte (P > 0.05). No patient had a QTcF value >480 ms or a ∆QTcF value >30 ms. CONCLUSIONS: ABT-414 had no clinically meaningful effect on the QTcF interval at doses being evaluated for treatment of patients with solid tumors.

3D Displays.

Creating realistic three-dimensional (3D) experiences has been a very active area of research and development, and this article describes progress and what remains to be solved. A very active area of technical development has been to build displays that create the correct relationship between viewing parameters and triangulation depth cues: stereo, motion, and focus. Several disciplines are involved in the design, construction, evaluation, and use of 3D displays, but an understanding of human vision is crucial to this enterprise because in the end, the goal is to provide the desired perceptual experience for the viewer. In this article, we review research and development concerning displays that create 3D experiences. And we highlight areas in which further research and development is needed.

Temporal HbA1c patterns amongst patients with type 2 diabetes referred for specialist care: Data from the S4S-DINGO-Diabetes Informatics Group.

AIMS: To evaluate the achievement of HbA1c targets in patients with type 2 diabetes mellitus in specialist practice. METHODS: This audit was undertaken by members of the S4S Diabetes Informatics Group (DINGO), a consortium of Australian endocrinologists in private practice who contribute de-identified data from their electronic medical record, Audit 4 (Software 4 Specialists, S4S, Australia & New Zealand) for audit purposes. Data from patients with type 2 diabetes was extracted. Inclusion criteria were: initial age<70years, baseline HbA1c>7% (53mmol/mol), with at least another HbA1c recorded in the next 2years, and a minimum of 2years follow-up. Data was analysed using a linear mixed effects model. RESULTS: Of the 4796 patients in the dataset with type 2 diabetes mellitus, 1379 patients fulfilled inclusion criteria. The median age at initial consultation was 57 (49-64)years. The median baseline HbA1c was 8.7 (7.8-9.8)% (72mmol/mol). There was a 1.0% reduction in HbA1c to 7.7 (7.1-8.6)% (61mmol/mol) (p<0.0001) in the first 3-6months following referral, after which there were no further changes. The initial reduction was maintained with minimal loss of control at 4years. By 3-6months, 24% of patients achieved the target HbA1c. CONCLUSIONS: Referral of patients with type 2 diabetes to an endocrinologist reduces HbA1c, and the effect is sustained over the medium term; however only a minority of patients reach targets.

Synthesis and Structural Characterization of Tantalum(IV) Amido Compounds.

Tantalum(IV) amido complexes have been synthesized from Ta(V) precursors. Ta(N(SiMe(3))(2))(2)Cl(3) reacts with Na/Hg to give Ta(N(SiMe(3))(2))(2)Cl(2), and Ta(NEt(2))(2)Cl(3) reacts with LiNPh(2) and Na/Hg to yield Ta(NPh(2))(2)(NEt(2))(2). Ta(N(SiMe(3))(2))(2)Ph(2) is prepared by reacting Ta(N(SiMe(3))(2))(2)Cl(2) with LiPh. Attempts to prepare other organometallic derivatives failed to yield clean products. X-ray crystallographic studies show that Ta(N(SiMe(3))(2))(2)Cl(2), Ta(N(SiMe(3))(2))(2)Ph(2), and Ta(NPh(2))(2)(NEt(2))(2) have distorted tetrahedral geometries.

Synthesis of Indium Amide Compounds.

Indium trichloride reacts with 3 equiv of lithium amide in diethyl ether to give In(NRR')(3) (R = Ph or t-Bu, R' = SiMe(3); R = t-Bu, R' = SiHMe(2)) and with 3 or 4 equiv of LiNMe(SiMe(3)) to yield Li[In{NMe(SiMe(3))}(4)]. The chloride also reacts with LiNPh(2) in THF to give the salt Li[In(NPh(2))(3)Cl] and with LiNRR' in pyridine to yield the neutral adduct In(NRR')(3)(py) (R = R' = Ph; R = Me, R' = SiMe(3)). The volatile liquids In[N(t-Bu)(SiHMe(2))](3) and In[NMe(SiMe(3))](3)(py) react with p-Me(2)Npy to form the solid compounds In[N(t-Bu)(SiHMe(2))](3)(p-Me(2)Npy) and In[NMe(SiMe(3))](3)(p-Me(2)Npy), respectively. X-ray crystallographic studies show that In(NPh(2))(3)(py), In[N(t-Bu)(SiHMe(2))](3)(p-Me(2)Npy), and the ether adduct of In[NPh(SiMe(3))](3) contain nearly planar In(amide)(3) fragments. Crystallographic studies also show that the anion in the salt [Li(THF)(4)][In(NPh(2))(3)Cl] is nearly tetrahedral and in [Li(p-Me(2)Npy)][In{NMe(SiMe(3))}(4)] the tetrahedral-like anion is bound to the Li cation via two amide nitrogens. The Li in the latter structure is also bonded to p-Me(2)Npy, resulting in a planar three-coordinate geometry for Li. Crystal data are the following. C(31)H(52)N(3)OSi(3)In at -50 degrees C: P2(1)/n (monoclinic), a = 11.003(2) Å, b = 18.678(3) Å, c = 17.618(3) Å, beta = 95.42(1) degrees, and Z = 4. C(41)H(35)N(4)In.C(7)H(8) at -50 degrees C: P&onemacr; (triclinic), a = 10.112(2) Å, b = 12.786(3) Å, c = 15.870(5) Å, alpha = 87.42(2) degrees, beta = 74.95(2) degrees, gamma = 78.15(2) degrees, and Z = 2. C(25)H(58)N(5)Si(3)In at -50 degrees C: P2(1)/c (monoclinic), a = 9.797(3) Å, b = 18.203(6) Å, c = 19.592(5) Å, beta = 100.27(2) degrees, and Z = 4. C(52)H(62)ClInLiN(3)O(4) at 23 degrees C: P2(1)/n (monoclinic), a = 16.076(2) Å, b = 17.185(2) Å, c = 18.447(3) Å, beta = 97.41(1) degrees, and Z = 4. C(23)H(58)InLiN(6)Si(4) at 23 degrees C: P&onemacr; (triclinic), a = 15.792(3) Å, b = 16.345(3) Å, c = 16.678(3) Å, alpha = 62.69(1) degrees, beta = 81.00(1) degrees, gamma = 86.94(1) degrees, and Z = 4.