Referral patterns and genetic testing outcomes in a contemporary hereditary renal cancer clinic.

OBJECTIVES: Multidisciplinary hereditary tumor clinics are a collaborative format to identify and treat patients with genetic cancer predispositions. The hereditary renal cancer clinic at Indiana University is comprised of a urologic oncologist, medical oncologist, clinical geneticist, and genetic counselor. The clinic holds regular tumor board meetings, where patient histories, pedigrees, imaging, pathology, and management plans are collectively reviewed and discussed. Here we report the contemporary experience for our hereditary renal cancer clinic, with description and analysis of referral patterns, patient profiles, and genetic testing outcomes. MATERIALS AND METHODS: A retrospective review of an IRB-approved, prospectively maintained database of patients seen in the hereditary renal cancer clinic was performed. Patient characteristics, genetic testing results, and disease characteristics were reported and analyzed. RESULTS: A total of 142 patients seen in clinics from January 2018 to June 2023 were included. Patient's median age was between 40 and 49 years old, and 88.7% were Caucasian. The most common reasons for referral were early-onset renal tumors (40%), known hereditary renal cancer syndrome (29%), and hereditary renal cancer syndrome screening (13%). Of those with a tissue diagnosis of renal cell carcinoma, 46.2% were clear cell subtype. The presence of nonrenal syndromic features concerning for hereditary renal tumor syndrome was predictive of pathogenic mutation identification (OR 13.45, P < 0.0001). Patient race and presence of multifocal tumors were not predictive of pathogenic mutation identification. When restricting analysis to patients with an established renal malignancy, high-grade tumor histology was predictive of a pathogenic mutation (OR 8.17, P = 0.012), though higher pathologic stage and nonclear cell histology were not. Referral for early-onset renal tumor (age < 45 years) predicted lower likelihood of pathogenic mutations (OR 0.10, P = 0.0002). FH gene mutations were the most commonly identified pathogenic mutations. Genetic testing of family members (cascade testing) was recommended to 9 patients seen in clinic; a pathogenic mutation was subsequently identified in all but one of these families. CONCLUSIONS: These findings are useful for referring physicians and patients in determining patient referral to hereditary cancer clinics, and for counseling patients undergoing genetic testing. Data from non-Caucasian patients and evolving implications of variants of unclear significance (VUS) may represent future research directions for hereditary renal cancer clinics.

[Influence of extreme weather conditions on the deployment volume of emergency medical services]. / Einfluss von Wetterextrema auf Einsatzzahlen im Notarztdienst.

BACKGROUND: Due to global warming a worldwide increase in the frequency and intensity of heat waves have been forecast. In the context of the overall increasing number of emergency service calls, weather-induced effects on the number of calls are highly relevant. We evaluated the influence of extreme temperatures on emergency medical services. MATERIALS AND METHODS: The study was conducted in Bochum, Germany. The authors examined the data from 16,767 emergency calls. In addition, the daily updated temperature data were collected for each emergency doctor call. Data were collected from 01 January 2014 until 31 December 2015. The primary question was the influence of extremes of the perceived temperature (PT; on the day of the call and the three previous days) on the diagnosis group of cardiovascular diseases. A secondary question was the influence of extremes of the temperature parameters (air temperature, PT, physiological equivalent temperature [PET]) on the day of call and the three previous days. RESULTS: A total of 16,767 calls were assessed. The threshold values (upper and lower 5%) were -8.7 and 32.5 °C for PT and -0.7 and 26.7 °C for air temperature. Examination of the PT indicated a significantly increased rate of calls for cold spells on the day of the call (RR = 1.14; p = 0.033) as well as a lag effect of 3 days (RR = 1.1; p = 0.049). CONCLUSION: The present study shows that during cold spells there is an increased rate of calls for cardiovascular diseases. This effect is not only observable on the extreme day itself but also 3 days later.

Atrophy of optic nerve detected by transorbital sonography in patients with demyelinating diseases of the central nervous system.

BACKGROUND AND PURPOSE: Transorbital sonography (TOS) has emerged as promising imaging method for the diagnosis and follow-up of acute optic neuritis (ON). Available studies report an increase in the optic nerve diameter (OND) and the optic nerve sheath diameter (ONSD) in the case of a first episode of ON in the affected eye compared to either the contralateral unaffected eye or controls. However, the utility of TOS in the case of recurrent episodes of ON has never been assessed. METHODS: In our prospective cohort study, the diagnostic utility of TOS in patients with demyelinating diseases of the central nervous system was assessed, and the association between TOS, optical coherence tomography (OCT) and visual evoked potentials was examined further. RESULTS: Seventy-eight patients with a history of demyelinating disorders of the central nervous system (mean age 38.2 ± 14.2 years; 24% with acute ON) were included. No differences in the OND (3.2 ± 0.5 mm vs. 3.2 ± 0.4 mm) and ONSD (5.1 ± 0.8 mm vs. 5.1 ± 0.7 mm) measurements were found between patients with and without acute ON. Papillary swelling was more frequent in patients with acute ON (14.2% vs. 1.5%, P = 0.002). Patients with a history of previous ON were found to have lower OND (P < 0.001) and ONSD (P = 0.007) compared to patients without a history of previous ON. TOS measurements were inversely associated with disease duration and positively correlated with OCT findings. No association with visual evoked potential measurements was found. CONCLUSION: No evidence was found for TOS-sensitive differences in the OND and ONSD of patients with demyelinating diseases, according to the presence of acute ON. The association between TOS and OCT measurements deserves further investigation.

[Acute on chronic renal failure in a 62-year-old man with ANCA-associated vasculitis]. / Neue Nierenfunktionsverschlechterung bei einem 62-jährigen Patienten mit ANCA-assoziierter Vaskulitis.

We describe a patient with ANCA (antineutrophil cytoplasmic antibodies) associated vasculitis and acute-on-chronic renal failure. He had initially presented with severe pulmonary hemorrhage and anuric renal failure and improved rapidly with immunosuppressive therapy. Repeat renal biopsy revealed candida interstitial nephritis. Candida was also detected in bronchoalveolar lavage. Kidney function improved with long-term antifungal therapy. This report adds induction therapy for ANCA vasculitis to the conditions where invasive candidal infections including nephritis need to be considered.

Petawatt Laser Guiding and Electron Beam Acceleration to 8 GeV in a Laser-Heated Capillary Discharge Waveguide.

Guiding of relativistically intense laser pulses with peak power of 0.85 PW over 15 diffraction lengths was demonstrated by increasing the focusing strength of a capillary discharge waveguide using laser inverse bremsstrahlung heating. This allowed for the production of electron beams with quasimonoenergetic peaks up to 7.8 GeV, double the energy that was previously demonstrated. Charge was 5 pC at 7.8 GeV and up to 62 pC in 6 GeV peaks, and typical beam divergence was 0.2 mrad.

Density characterization of discharged gas-filled capillaries through common-path two-color spectral-domain interferometry.

Electrically discharged plasma structures, typically several centimeters in length and sub-millimeter in diameter, have been applied to guide laser pulses in laser plasma accelerators and to focus ion and relativistic electron beams in compact, radially symmetric transport configurations. Knowledge of the on-axis plasma density is critical. Traditional density interferometry has been ineffective for these laser-machined structures, while group velocity delay (GVD) techniques involve combining two laser paths with corresponding alignment complexities and stability sensitivities. Here the GVD technique is advanced to a common-path two-color interferometer configuration performed in the spectral domain of a broad-bandwidth femtosecond laser. Multi-shot tracking of the phase is not required, and the common path assures improved stability. This in situ technique was validated on 15 mm long plasma structures, measuring electron densities of 1017-1018 cm-3 for various fill pressures.

Multistage Coupling of Laser-Wakefield Accelerators with Curved Plasma Channels.

Multistage coupling of laser-wakefield accelerators is essential to overcome laser energy depletion for high-energy applications such as TeV-level electron-positron colliders. Current staging schemes feed subsequent laser pulses into stages using plasma mirrors while controlling electron beam focusing with plasma lenses. Here a more compact and efficient scheme is proposed to realize the simultaneous coupling of the electron beam and the laser pulse into a second stage. A partly curved channel, integrating a straight acceleration stage with a curved transition segment, is used to guide a fresh laser pulse into a subsequent straight channel, while the electrons continue straight. This scheme benefits from a shorter coupling distance and continuous guiding of the electrons in plasma while suppressing transverse beam dispersion. Particle-in-cell simulations demonstrate that the electron beam from a previous stage can be efficiently injected into a subsequent stage for further acceleration while maintaining high capture efficiency, stability, and beam quality.

Observation of the Self-Modulation Instability via Time-Resolved Measurements.

Self-modulation of an electron beam in a plasma has been observed. The propagation of a long (several plasma wavelengths) electron bunch in an overdense plasma resulted in the production of multiple bunches via the self-modulation instability. Using a combination of a radio-frequency deflector and a dipole spectrometer, the time and energy structure of the self-modulated beam was measured. The longitudinal phase space measurement showed the modulation of a long electron bunch into three bunches with an approximately 200 keV/c amplitude momentum modulation. Demonstrating this effect is a breakthrough for proton-driven plasma accelerator schemes aiming to utilize the same physical effect.

Suppression of Beam Hosing in Plasma Accelerators with Ion Motion.

Mitigation of the beam hose instability in plasma-based accelerators is required for the realization of many applications, including plasma-based colliders. The hose instability is analyzed in the blowout regime including plasma ion motion, and ion motion is shown to suppress the hose instability by inducing a head-to-tail variation in the focusing force experienced by the beam. Hence, stable acceleration in plasma-based accelerators is possible, while, by use of proper bunch shaping, minimizing the energy spread and preserving the transverse beam emittance.

Plasma channel undulator excited by high-order laser modes.

The possibility of utilizing plasma undulators and plasma accelerators to produce compact ultraviolet and X-ray sources, has attracted considerable interest for a few decades. This interest has been driven by the great potential to decrease the threshold for accessing such sources, which are mainly provided by a few dedicated large-scale synchrotron or free-electron laser (FEL) facilities. However, the broad radiation bandwidth of such plasma devices limits the source brightness and makes it difficult for the FEL instability to develop. Here, using multi-dimensional particle-in-cell (PIC) simulations, we demonstrate that a plasma undulator generated by the beating of a mixture of high-order laser modes propagating inside a plasma channel, leads to a few percent radiation bandwidth. The strength of the undulator can reach unity, the period can be less than a millimeter, and the number of undulator periods can be significantly increased by a phase locking technique based on the longitudinal tapering. Polarization control of such an undulator can be achieved by appropriately choosing the phase of the modes. According to our results, in the fully beam loaded regime, the electron current in the plasma undulator can reach 0.3 kA level, making such an undulator a potential candidate towards a table-top FEL.

Saturation of the Hosing Instability in Quasilinear Plasma Accelerators.

The beam hosing instability is analyzed theoretically for a witness beam in the quasilinear regime of plasma accelerators. In this regime, the hosing instability saturates, even for a monoenergetic bunch, at a level much less than standard scalings predict. Analytic expressions are derived for the saturation distance and amplitude and are in agreement with numerical results. Saturation is due to the natural head-to-tail variations in the focusing force, including the self-consistent transverse beam loading.

Measured Emittance Dependence on the Injection Method in Laser Plasma Accelerators.

Single-shot, charge-dependent emittance measurements of electron beams generated by a laser plasma accelerator (LPA) reveal that shock-induced density down-ramp injection produces beams with normalized emittances a factor of 2 smaller than beams produced via ionization injection. Such a comparison is made possible by the tunable LPA setup, which allows electron beams with nearly identical central energy and peak spectral charge density to be produced using the two distinct injection mechanisms. Parametric measurements of this type are essential for the development of LPA-based applications which ultimately require high charge density and low emittance.

Organ preservation in rectal cancer - Challenges and future strategies.

Neoadjuvant radiochemotherapy with subsequent total mesorectal excision is the standard of care for locally advanced rectal cancer. While this multimodal strategy has decreased local recurrences rates below 5%, long-term morbidities are considerable in terms of urinary, sexual or bowel functioning. At the same time approximately 10-20% of patients have no evidence of residual tumour in their surgical specimen. Pioneering studies from Brazil have suggested that surgery can safely be omitted in carefully selected patients with a clinical complete response after radiochemotherapy. Although confirmatory studies showed similar results, challenges in terms of optimizing radiochemotherapy for organ-preservation, appropriate selection of patients for non-operative management and the safety of this approach remain. The present review will summarize the current data on organ-preservation in rectal cancer and discuss the challenges that need to be addressed in future trials.

Multistage coupling of independent laser-plasma accelerators.

Laser-plasma accelerators (LPAs) are capable of accelerating charged particles to very high energies in very compact structures. In theory, therefore, they offer advantages over conventional, large-scale particle accelerators. However, the energy gain in a single-stage LPA can be limited by laser diffraction, dephasing, electron-beam loading and laser-energy depletion. The problem of laser diffraction can be addressed by using laser-pulse guiding and preformed plasma waveguides to maintain the required laser intensity over distances of many Rayleigh lengths; dephasing can be mitigated by longitudinal tailoring of the plasma density; and beam loading can be controlled by proper shaping of the electron beam. To increase the beam energy further, it is necessary to tackle the problem of the depletion of laser energy, by sequencing the accelerator into stages, each powered by a separate laser pulse. Here, we present results from an experiment that demonstrates such staging. Two LPA stages were coupled over a short distance (as is needed to preserve the average acceleration gradient) by a plasma mirror. Stable electron beams from a first LPA were focused to a twenty-micrometre radius--by a discharge capillary-based active plasma lens--into a second LPA, such that the beams interacted with the wakefield excited by a separate laser. Staged acceleration by the wakefield of the second stage is detected via an energy gain of 100 megaelectronvolts for a subset of the electron beam. Changing the arrival time of the electron beam with respect to the second-stage laser pulse allowed us to reconstruct the temporal wakefield structure and to determine the plasma density. Our results indicate that the fundamental limitation to energy gain presented by laser depletion can be overcome by using staged acceleration, suggesting a way of reaching the electron energies required for collider applications.

Multi-Scale Entrainment of Coupled Neuronal Oscillations in Primary Auditory Cortex.

Earlier studies demonstrate that when the frequency of rhythmic tone sequences or streams is task relevant, ongoing excitability fluctuations (oscillations) of neuronal ensembles in primary auditory cortex (A1) entrain to stimulation in a frequency dependent way that sharpens frequency tuning. The phase distribution across A1 neuronal ensembles at time points when attended stimuli are predicted to occur reflects the focus of attention along the spectral attribute of auditory stimuli. This study examined how neuronal activity is modulated if only the temporal features of rhythmic stimulus streams are relevant. We presented macaques with auditory clicks arranged in 33 Hz (gamma timescale) quintets, repeated at a 1.6 Hz (delta timescale) rate. Such multi-scale, hierarchically organized temporal structure is characteristic of vocalizations and other natural stimuli. Monkeys were required to detect and respond to deviations in the temporal pattern of gamma quintets. As expected, engagement in the auditory task resulted in the multi-scale entrainment of delta- and gamma-band neuronal oscillations across all of A1. Surprisingly, however, the phase-alignment, and thus, the physiological impact of entrainment differed across the tonotopic map in A1. In the region of 11-16 kHz representation, entrainment most often aligned high excitability oscillatory phases with task-relevant events in the input stream and thus resulted in response enhancement. In the remainder of the A1 sites, entrainment generally resulted in response suppression. Our data indicate that the suppressive effects were due to low excitability phase delta oscillatory entrainment and the phase amplitude coupling of delta and gamma oscillations. Regardless of the phase or frequency, entrainment appeared stronger in left A1, indicative of the hemispheric lateralization of auditory function.

Detecting Stealth Dark Matter Directly through Electromagnetic Polarizability.

We calculate the spin-independent scattering cross section for direct detection that results from the electromagnetic polarizability of a composite scalar "stealth baryon" dark matter candidate, arising from a dark SU(4) confining gauge theory-"stealth dark matter." In the nonrelativistic limit, electromagnetic polarizability proceeds through a dimension-7 interaction leading to a very small scattering cross section for dark matter with weak-scale masses. This represents a lower bound on the scattering cross section for composite dark matter theories with electromagnetically charged constituents. We carry out lattice calculations of the polarizability for the lightest "baryon" states in SU(3) and SU(4) gauge theories using the background field method on quenched configurations. We find the polarizabilities of SU(3) and SU(4) to be comparable (within about 50%) normalized to the stealth baryon mass, which is suggestive for extensions to larger SU(N) groups. The resulting scattering cross sections with a xenon target are shown to be potentially detectable in the dark matter mass range of about 200-700 GeV, where the lower bound is from the existing LUX constraint while the upper bound is the coherent neutrino background. Significant uncertainties in the cross section remain due to the more complicated interaction of the polarizablity operator with nuclear structure; however, the steep dependence on the dark matter mass, 1/m(B)(6), suggests the observable dark matter mass range is not appreciably modified. We briefly highlight collider searches for the mesons in the theory as well as the indirect astrophysical effects that may also provide excellent probes of stealth dark matter.

Active Plasma Lensing for Relativistic Laser-Plasma-Accelerated Electron Beams.

Compact, tunable, radially symmetric focusing of electrons is critical to laser-plasma accelerator (LPA) applications. Experiments are presented demonstrating the use of a discharge-capillary active plasma lens to focus 100-MeV-level LPA beams. The lens can provide tunable field gradients in excess of 3000 T/m, enabling cm-scale focal lengths for GeV-level beam energies and allowing LPA-based electron beams and light sources to maintain their compact footprint. For a range of lens strengths, excellent agreement with simulation was obtained.

Pulse evolution and plasma-wave phase velocity in channel-guided laser-plasma accelerators.

The self-consistent laser evolution of an intense, short-pulse laser exciting a plasma wave and propagating in a preformed plasma channel is investigated, including the effects of pulse steepening and energy depletion. In the weakly relativistic laser intensity regime, analytical expressions for the laser energy depletion, pulse self-steepening rate, laser intensity centroid velocity, and phase velocity of the plasma wave are derived and validated numerically.

Determination of the efficacy of EVICEL™ on blood loss in orthopaedic surgery after total knee replacement: study protocol for a randomised controlled trial.

BACKGROUND: After total knee replacement, overall blood loss is often underestimated, although it exceeds the visible blood loss caused by bleeding into the tissues or into the joint. The use of fibrin sealants during surgery has been suggested to reduce perioperative blood loss and transfusion rates and may be beneficial for patient recovery and the postoperative function of the joint. METHODS/DESIGN: This will be a single-centre, single-blinded, randomised controlled trial with a parallel design, for which 68 patients undergoing total knee replacement will be recruited and followed up at 3, 6 and 12 months; 34 will be control patients who will receive the standard orthopaedic surgery treatment (electrocoagulation), and the other 34 will receive the same treatment plus 5 ml EVICEL™ applied during surgery and used according to the manufacturer's instructions. The primary objective is to test the null hypothesis that the effect of EVICEL™ for controlling haemostasis and reducing postoperative blood loss in patients undergoing total knee replacement is not superior to the use of electrocoagulation alone. The secondary objective is to show that EVICEL™ reduces the need for transfusion, increases range of motion, improves clinical outcome and wound healing, and reduces the need for analgesics. The tertiary objective is to show that EVICEL™ reduces the costs of total knee replacement treatment. DISCUSSION: So far, studies on the effect of fibrin sealants in total knee replacement have delivered inconsistent and ambivalent results, indicating that there is still a need for high-evidence studies as proposed in the presented study protocol. TRIAL REGISTRATION: German registration number DRKS00007564; date of registration: 26 November 2014.