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Background: Given the increasing prevalence of the physician burnout, this study provides new insights into the antecedents driving burnout and turnover intent. By introducing the concept of physician fortitude, we develop a valid and statistically-reliable measure that increases our understanding of these issues., Methods: A two-sample design was employed. Using a sample of 909 physicians, Advanced Practice Providers (APPs) and healthcare leaders, exploratory factor analysis was employed to create a 12-item fortitude scale. In the second study, using a sample of 212 of practicing physicians, APPs and healthcare leaders, bivariate and tetrachoric correlations, and ordinary least square regression modeling were able to establish reliability and validity., Results: The fortitude scale shows sufficient reliability. Moreover, we found significant support for convergent and criterion-related validity. Fortitude was significantly related to all three subdimensions of burnout, including emotional exhaustion (r = -.62, p < .01), depersonalization (r = -.70, p < .01) and personal accomplishment (r = .65, p < .01), and turnover intent (r = -.55, p < .01). Moreover, the fortitude measure explained more variance in all three subdimensions of burnout and turnover intent compared to common measures, including grit, hardiness, mental toughness and resilience (p < .01)., Conclusions: Results from this study empirically demonstrate that fortitude is significantly related to burnout, and turnover intent. This new fortitude measure adds a new perspective to assist in the development of more effective interventions. Opportunities for future research are discussed., (© 2024. The Author(s).)

Tight relationships exist in the local Universe between the central stellar properties of galaxies and the mass of their supermassive black hole (SMBH) 1-3 . These suggest that galaxies and black holes co-evolve, with the main regulation mechanism being energetic feedback from accretion onto the black hole during its quasar phase 4-6 . A crucial question is how the relationship between black holes and galaxies evolves with time; a key epoch to examine this relationship is at the peaks of star formation and black hole growth 8-12 billion years ago (redshifts 1-3) 7 . Here we report a dynamical measurement of the mass of the black hole in a luminous quasar at a redshift of 2, with a look back in time of 11 billion years, by spatially resolving the broad-line region (BLR). We detect a 40-μas (0.31-pc) spatial offset between the red and blue photocentres of the Hα line that traces the velocity gradient of a rotating BLR. The flux and differential phase spectra are well reproduced by a thick, moderately inclined disk of gas clouds within the sphere of influence of a central black hole with a mass of 3.2 × 10 8  solar masses. Molecular gas data reveal a dynamical mass for the host galaxy of 6 × 10 11  solar masses, which indicates an undermassive black hole accreting at a super-Eddington rate. This suggests a host galaxy that grew faster than the SMBH, indicating a delay between galaxy and black hole formation for some systems., (© 2024. The Author(s).)

Upregulation of the proto-oncogene T-cell leukemia/lymphoma 1A (TCL1A) is causally implicated in various B-cell and T-cell malignancies. High-level TCL1A correlates with aggressive disease features and inferior clinical outcomes. However, the molecular and cell biological consequences of, particularly nuclear, TCL1A are not fully elucidated. We observed here in mouse models of subcellular site-specific TCL1A-induced lymphomagenesis that TCL1A exerts a strong transforming impact via nuclear topography. In proteomic screens of TCL1A-bound molecules in chronic lymphocytic leukemia (CLL) cells and B-cell lymphoma lines, we identified regulators of cell cycle and DNA repair pathways as novel TCL1A interactors, particularly enriched under induced DNA damage and mitosis. By functional mapping and in silico modeling, we specifically identified the mitotic checkpoint protein, cell division cycle 20 (CDC20), as a direct TCL1A interactor. According to the regulatory impact of TCL1A on the activity of the CDC20-containing mitotic checkpoint and anaphase-promoting complexes during mitotic progression, TCL1A overexpression accelerated cell cycle transition in B-cell lymphoma lines, impaired apoptotic damage responses in association with pronounced chromosome missegregation, and caused cellular aneuploidy in Eμ-TCL1A mice. Among hematopoietic cancers, CDC20 levels seem particularly low in CLL. CDC20 expression negatively correlated with TCL1A and lower expression marked more aggressive and genomically instable disease and cellular phenotypes. Knockdown of Cdc20 in TCL1A-initiated murine CLL promoted aneuploidy and leukemic acceleration. Taken together, we discovered a novel cell cycle-associated effect of TCL1A abrogating controlled cell cycle transition. This adds to our concept of oncogenic TCL1A by targeting genome stability. Overall, we propose that TCL1A acts as a pleiotropic adapter molecule with a synergistic net effect of multiple hijacked pathways., (© 2023 by The American Society of Hematology.)

During its orbit around the four million solar mass black hole Sagittarius A* the star S2 experiences significant changes in gravitational potential. We use this change of potential to test one part of the Einstein equivalence principle: the local position invariance (LPI). We study the dependency of different atomic transitions on the gravitational potential to give an upper limit on violations of the LPI. This is done by separately measuring the redshift from hydrogen and helium absorption lines in the stellar spectrum during its closest approach to the black hole. For this measurement we use radial velocity data from 2015 to 2018 and combine it with the gravitational potential at the position of S2, which is calculated from the precisely known orbit of S2 around the black hole. This results in a limit on a violation of the LPI of |β&#95;{He}-β&#95;{H}|=(2.4±5.1)×10^{-2}. The variation in potential that we probe with this measurement is six magnitudes larger than possible for measurements on Earth, and a factor of 10 larger than in experiments using white dwarfs. We are therefore testing the LPI in a regime where it has not been tested before.

The adaptive optics system for the second-generation VLT-interferometer (VLTI) instrument GRAVITY consists of a novel cryogenic near-infrared wavefront sensor to be installed at each of the four unit telescopes of the Very Large Telescope (VLT). Feeding the GRAVITY wavefront sensor with light in the 1.4 to 2.4 micrometer band, while suppressing laser light originating from the GRAVITY metrology system, custom-built optical components are required. In this paper, we present the development of a quantitative near-infrared point diffraction interferometric characterization technique, which allows measuring the transmitted wavefront error of the silicon entrance windows of the wavefront sensor cryostat. The technique can be readily applied to quantitative phase measurements in the near-infrared regime. Moreover, by employing a slightly off-axis optical setup, the proposed method can optimize the required spatial resolution and enable real time measurement capabilities. The feasibility of the proposed setup is demonstrated, followed by theoretical analysis and experimental results. Our experimental results show that the phase error repeatability in the nanometer regime can be achieved.

Objective: This study compared the durability of glycemic control of twice-daily insulin lispro mix 75/25 (LM75/25: 75% insulin lispro protamine suspension/25% lispro) and once-daily insulin glargine, added to oral antihyperglycemic drugs in type 2 diabetes patients., Research Design and Methods: During the initiation phase, patients were randomized to LM75/25 or glargine. After 6 months, patients with A1C ≤ 7.0% advanced to the maintenance phase for ≤ 24 months. The primary objective was the between-group comparison of duration of maintaining the A1C goal., Results: Of 900 patients receiving LM75/25 and 918 patients receiving glargine who completed initiation, 473 and 419, respectively, had A1C ≤ 7.0% and continued into maintenance. Baseline characteristics except age were similar in this group. Median time of maintaining the A1C goal was 16.8 months for LM75/25 (95% CI 14.0-19.7) and 14.4 months for glargine (95% CI 13.4-16.8; P = 0.040). A1C goal was maintained in 202 LM75/25-treated patients (43%) and in 147 glargine-treated patients (35%; P = 0.006). No differences were observed in overall, nocturnal, or severe hypoglycemia. LM75/25 patients had higher total daily insulin dose (0.45 ± 0.21 vs. 0.37 ± 0.21 units/kg/day) and more weight gain (5.4 ± 5.8 vs. 3.7 ± 5.6 kg) from baseline. Patients taking LM75/25 and glargine with lower baseline A1C levels were more likely to maintain the A1C goal (P = 0.043 and P < 0.001, respectively)., Conclusions: A modestly longer durability of glycemic control was achieved with LM75/25 compared with glargine. Patients with lower baseline A1C levels were more likely to maintain the goal, supporting the concept of earlier insulin initiation.

We present a novel approach for deconvolution of 3D image stacks of cortical tissue taken by mosaic/optical-sectioning technology, using a transmitted light brightfield microscope. Mosaic/optical-sectioning offers the possibility of imaging large volumes (e.g. from cortical sections) on a millimetre scale at sub-micrometre resolution. However, a blurred contribution from out-of-focus light results in an image quality that usually prohibits 3D quantitative analysis. Such quantitative analysis is only possible after deblurring by deconvolution. The resulting image quality is strongly dependent on how accurate the point spread function used for deconvolution resembles the properties of the imaging system. Since direct measurement of the true point spread function is laborious and modelled point spread functions usually deviate from measured ones, we present a method of optimizing the microscope until it meets almost ideal imaging conditions. These conditions are validated by measuring the aberration function of the microscope and tissue using a Shack-Hartmann sensor. The analysis shows that cortical tissue from rat brains embedded in Mowiol and imaged by an oil-immersion objective can be regarded as having a homogeneous index of refraction. In addition, the amount of spherical aberration that is caused by the optics or the specimen is relatively low. Consequently the image formation is simplified to refraction between the embedding and immersion medium and to 3D diffraction at the finite entrance pupil of the objective. The resulting model point spread function is applied to the image stacks by linear or iterative deconvolution algorithms. For the presented dataset of large 3D images the linear approach proves to be superior. The linear deconvolution yields a significant improvement in signal-to-noise ratio and resolution. This novel approach allows a quantitative analysis of the cortical image stacks such as the reconstruction of biocytin-stained neuronal dendrites and axons.

We built and characterized an optical system that emulates the optical characteristics of an 8m-class telescope like the Very Large Telescope. The system contains rotating glass phase-screens to generate realistic atmosphere-like optical turbulence, as needed for testing multiconjugate adaptive optics systems. In this paper we present an investigation of the statistical properties of two phase-screens etched on glass-plate surfaces, obtained from Silios Technologies. Those etched screens are highly transmissive (above 85%) from 0.45 to 2.5 microm. From direct imaging, their Fried parameter r0 values (0.43+/-0.04 microm and 0.81+/-0.03 microm, respectively, at 0.633 microm) agree with the expectation to within 10%. This is also confirmed by a comparison of measured and expected Zernike coefficient variances. Overall, we find that those screens are quite reproducible, allowing sub-millimetre r0 values, which were difficult to achieve in the past. We conclude that the telescope emulator and phase-screens form a powerful atmospheric turbulence generator allowing systematic testing of different kinds of AO instrumentation.

We test the statistical properties of static, atmospherelike wave fronts in glass that allow repeatable testing of astronomical adaptive optics instrumentation. The technology is mask-structured ion exchange (MSI) in glass and has significant advantages over other transmissive technologies. The screens are easy to clean, are insensitive to ambient temperature changes, and have high optical-to-near-infrared transmission. However, the effective coherence length (r0) on each of the fabricated screens is systematically too large or, equivalently, the fabricated aberrations are too weak. Despite this strong caveat, the screens appear to be quite useful: Long-exposure point-spread functions have realistic shapes, and power spectrum indices closely match those of the computer-generated wave fronts. Most significant, stacking screens with similar r0 values reduced r0 by the amount predicted by turbulence theory. The refractivity of MSI screens remains unmeasured. Finally, we present our design of an optical system that emulates the key characteristics of the Very Large Telescope, made to contain glass phase screens and to mimic an array of stars for multiconjugate adaptive optics system testing.

Background: Based on its success as a transplant immunosuppressor, there is intense interest in using rapamycin in the treatment of progressive glomerulopathies involving native kidneys. However, we call attention to the potential toxicity associated with the use of rapamycin in this setting., Methods: We conducted a study to examine the efficacy and safety of rapamycin in patients with progressive chronic renal failure. Eleven patients with either focal segmental glomerulosclerosis, immunoglobulin A nephropathy, membranous nephropathy or membrano-proliferative glomerulonephritis and progressive renal failure (defined as an increase in >25% of baseline serum creatinine over the last year or loss of glomerular filtration rate > or =5 ml/min/year as determined by the Cockcroft-Gault formula), proteinuria > or =1.0 g/24 h and with a creatinine clearance of > or 20 ml/min/1.73 m(2) were entered into a 12 month study. Patients were treated with rapamycin, starting at 5 mg/day, orally, aiming for target blood levels of 7-10 ng/dl. All patients were on treatment with an angiotensin-converting enzyme inhibitor and/or an angiotensin receptor blocker, aiming to control blood pressure < or =145/90 mmHg., Results: Six patients developed acute renal failure, defined as an increase in serum creatinine > or =0.5 mg/dl (baseline: 3.2+/-0.9 mg/dl; peak: 5.6+/-1.6 mg/dl; P<0.01, paired t-test). In four patients, discontinuation of the drug resulted in improvement of renal function close to baseline levels. One patient required haemodialysis and had no subsequent recovery of renal function. In another patient, renal function recovered after discontinuation of the drug and then rapamycin was resumed at a lower dose when creatinine returned to baseline. This resulted in a second acute increase in serum creatinine that failed to return to baseline when the medication was discontinued. Four other patients had the following adverse events: skin rash, severe hypertriglyceridaemia, diarrhoea and hyperkalaemia. In none of the subjects were rapamycin levels >15 ng/dl., Conclusions: Rapamycin can cause nephrotoxicity in some patients with chronic glomerulopathies. Whether the toxicity is solely related to rapamycin, due to the combination of proteinuria and rapamycin, or other unknown factor use is presently undetermined.

The yeast Snf3 protein has been described to function as a sensor for low concentrations of extracellular glucose. We have found that Snf3 is able to transduce a signal in the complete absence of extracellular glucose. High basal activity of the HXT7 promoter during growth on ethanol required Snf3 as well as other components of the signalling pathway activated by Snf3. Moreover, the C-terminal domain of Snf3 was sufficient to complement the role of Snf3 in this regulation. As the C-terminal tail of Snf3 interacted with other components at the plasma membrane independent of the carbon source, our data suggest that Snf3 is involved in signalling complexes which can be activated by other signals than extracellular glucose.

The electronics, computing hardware, and computing used to provide real-time modal control for a laser guide-star adaptive optics system are presented. This approach offers advantages in the control of unobserved modes, the elimination of unwanted modes (e.g., tip and tilt), and automatic handling of the case of low-resolution lens arrays. In our two-step modal implementation, the input vector of gradients is first decomposed into a Zernike polynomial mode by a least-squares estimate. The number of modes is assumed to be less than or equal to the number of actuators. The mode coefficients are then available for collection and analysis or for the application of modal weights. Thus the modal weights may be changed quickly without recalculating the full matrix. The control-loop integrators are at this point in the algorithm. To calculate the deformable-mirror drive signals, the mode coefficients are converted to the zonal signals by a matrix multiply. When the number of gradients measured is less than the number of actuators, the integration in the control loop will be done on the lower-resolution grid to avoid growth of unobserved modes. These low-resolution data will then be effectively interpolated to yield the deformable-mirror drive signals.