Anal Cancers in Previously Screened Versus Unscreened Patients: Tumor Stage and Treatment Outcomes.

BACKGROUND: Targeted screening programs for patients at high risk for anal squamous-cell carcinoma have been proposed; however, the evidence in support of screening remains unclear. OBJECTIVE: This study aimed to determine whether screening high-risk patients (predominantly those living with HIV) detected squamous-cell carcinoma at an earlier stage compared to the routine practice of not screening. DESIGN: This is a cohort study. SETTINGS: This study was conducted at a quaternary care center in Canada. PATIENTS: Included patients were at least 18 years old with a pathologic diagnosis of invasive anal squamous-cell carcinoma between 2002 and 2022. INTERVENTIONS: Patients diagnosed through a high-risk screening program were compared to those who did not undergo screening. MAIN OUTCOME MEASURES: The primary outcome was clinical stage at presentation, categorized as T1N0M0 vs other. Secondary outcomes included treatments received, treatment failure, and overall survival. RESULTS: A total of 612 patients with anal squamous-cell carcinoma were included, with 26 of those patients diagnosed through a screening program. Patients with screen-detected cancers had greater odds of presenting with T1N0M0 tumors compared to unscreened patients (18 [69.2%] vs 84 [14.3%]; adjusted OR 9.95; 95% CI, 3.95-25.08). A propensity score-matched sensitivity analysis found similar results (OR 11.13; 95% CI, 4.67-26.52). Screened patients had greater odds of treatment with wide local excision alone, as opposed to any combination of chemotherapy, radiation therapy, and surgery (3 [12.5%] vs 18 [3.2%]; OR 4.38; 95% CI, 1.20-16.04). There were no statistically significant differences in treatment failure or overall survival between groups. LIMITATIONS: The small number of screened patients limits the power of the analysis. CONCLUSIONS: Screening for anal squamous-cell carcinoma among high-risk populations detects cancers at an earlier stage. Patients with screen-detected cancers also had a greater likelihood of being candidates for wide local excision alone, which may have spared them the morbidity associated with chemoradiotherapy or abdominoperineal resection. See Video Abstract. CNCERES DE ANO EN PACIENTES PREVIAMENTE DETECTADOS POR CRIBADO VERSUS NO DETECTADOS ESTADIO DEL TUMOR Y RESULTADOS DEL TRATAMIENTO: ANTECEDENTES:Se han propuesto programas de cribado dirigidos a pacientes con alto riesgo de carcinoma anal de células escamosas; sin embargo, la evidencia a favor de la detección sigue sin estar clara.OBJETIVO:Este estudio tuvo como objetivo determinar si el cribado de pacientes de alto riesgo (predominantemente aquellos que viven con el VIH) detectó el carcinoma de células escamosas en una etapa más temprana en comparación con la práctica habitual de no cribado.DISEÑO:Este es un estudio de cohortes.CONFIGURACIÓN:Este estudio se realizó en un centro de atención cuaternaria en Canadá.PACIENTES:Los pacientes incluidos tenían al menos 18 años con un diagnóstico patológico de carcinoma de células escamosas anal invasivo entre 2002 y 2022.INTERVENCIONES:Los pacientes diagnosticados mediante un programa de cribado de alto riesgo se compararon con aquellos que no se sometieron a cribado.PRINCIPALES MEDIDAS DE RESULTADO:El resultado primario fue el estadio clínico en la presentación, categorizado como T1N0M0 versus otro. Los resultados secundarios incluyeron los tratamientos recibidos, el fracaso del tratamiento y la supervivencia general.RESULTADOS:Se incluyeron un total de 612 pacientes con carcinoma anal de células escamosas, con 26 de esos pacientes diagnosticados a través de un programa de cribado. Los pacientes con cánceres detectados mediante cribado tenían mayores probabilidades de presentar tumores T1N0M0 en comparación con los pacientes no cribados (18 [69.2%] frente a 84 [14.3%]; razón de probabilidad ajustada 9.95; intervalo de confianza del 95 % 3.95 -25.08). Un análisis de sensibilidad emparejado por puntaje de propensión encontró resultados similares (odds ratio 11.13; intervalo de confianza del 95% 4.67 -26.52; p < 0.001). Los pacientes examinados tenían mayores probabilidades de recibir tratamiento con escisión local amplia sola, en comparación con cualquier combinación de quimioterapia, radiación y cirugía (3 [12.5%] frente a 18 [3.2%]; razón de probabilidad 4.38; intervalo de confianza del 95 % 1.20 -16.04). No hubo diferencias estadísticamente significativas en el fracaso del tratamiento o la supervivencia global entre los grupos.LIMITACIONES:El pequeño número de pacientes evaluados limita el poder del análisis.CONCLUSIONES:La detección del carcinoma anal de células escamosas entre las poblaciones de alto riesgo detecta los cánceres en una etapa más temprana. Los pacientes con cánceres detectados mediante cribado también tenían una mayor probabilidad de ser candidatos para una escisión local amplia sola, lo que puede haberles evitado la morbilidad asociada con la quimiorradioterapia o la resección abdominoperineal. (Traducción --Dr. Aurian Garcia Gonzalez ).

Factors Associated With Loss to Follow-Up in Surgical Trials: A Systematic Review and Meta-Analysis.

INTRODUCTION: Loss to follow-up (LTFU) distorts results of randomized controlled trials (RCTs). Understanding trial characteristics that contribute to LTFU may enable investigators to anticipate the extent of LTFU and plan retention strategies. The objective of this systematic review and meta-analysis was to investigate the extent of LTFU in surgical RCTs and evaluate associations between trial characteristics and LTFU. METHODS: MEDLINE, Embase, and PubMed Central were searched for surgical RCTs published between January 2002 and December 2021 in the 30 highest impact factor surgical journals. Two-hundred eligible RCTs were randomly selected. The pooled LTFU rate was estimated using random intercept Poisson regression. Associations between trial characteristics and LTFU were assessed using metaregression. RESULTS: The 200 RCTs included 37,914 participants and 1307 LTFU events. The pooled LTFU rate was 3.10 participants per 100 patient-years (95% confidence interval [CI] 1.85-5.17). Trial characteristics associated with reduced LTFU were standard-of-care outcome assessments (rate ratio [RR] 0.17; 95% CI 0.06-0.48), surgery for transplantation (RR 0.08; 95% CI 0.01-0.43), and surgery for cancer (RR 0.10; 95% CI 0.02-0.53). Increased LTFU was associated with patient-reported outcomes (RR 14.21; 95% CI 4.82-41.91) and follow-up duration ≥ three months (odds ratio 10.09; 95% CI 4.79-21.28). CONCLUSIONS: LTFU in surgical RCTs is uncommon. Participants may be at increased risk of LTFU in trials with outcomes assessed beyond the standard of care, surgical indications other than cancer or transplant, patient-reported outcomes, and longer follow-up. Investigators should consider the impact of design on LTFU and plan retention strategies accordingly.

Hospital learning curves for robot-assisted surgeries: a population-based analysis.

BACKGROUND: Robot-assisted surgery has been rapidly adopted. It is important to define the learning curve to inform credentialling requirements, training programs, identify fast and slow learners, and protect patients. This study aimed to characterize the hospital learning curve for common robot-assisted procedures. STUDY DESIGN: This cohort study, using administrative health data for Ontario, Canada, included adult patients who underwent a robot-assisted radical prostatectomy (RARP), total robotic hysterectomy (TRH), robot-assisted partial nephrectomy (RAPN), or robotic portal lobectomy using four arms (RPL-4) between 2010 and 2021. The association between cumulative hospital volume of a robot-assisted procedure and major complications was evaluated using multivariable logistic models adjusted for patient characteristics and clustering at the hospital level. RESULTS: A total of 6814 patients were included, with 5230, 543, 465, and 576 patients in the RARP, TRH, RAPN, and RPL-4 cohorts, respectively. There was no association between cumulative hospital volume and major complications. Visual inspection of learning curves demonstrated a transient worsening of outcomes followed by subsequent improvements with experience. Operative time decreased for all procedures with increasing volume and reached plateaus after approximately 300 RARPs, 75 TRHs, and 150 RPL-4s. The odds of a prolonged length of stay decreased with increasing volume for patients undergoing a RARP (OR 0.87; 95% CI 0.82-0.92) or RPL-4 (OR 0.77; 95% CI 0.68-0.87). CONCLUSION: Hospitals may adopt robot-assisted surgery without significantly increasing the risk of major complications for patients early in the learning curve and with an expectation of increasing efficiency.

Hospital volume-outcome relationships for robot-assisted surgeries: a population-based analysis.

BACKGROUND: Associations between procedure volumes and outcomes can inform minimum volume standards and the regionalization of health services. Robot-assisted surgery continues to expand globally; however, data are limited regarding which hospitals should be using the technology. STUDY DESIGN: Using administrative health data for all residents of Ontario, Canada, this retrospective cohort study included adult patients who underwent a robot-assisted radical prostatectomy (RARP), total robotic hysterectomy (TRH), robot-assisted partial nephrectomy (RAPN), or robotic portal lobectomy using 4 arms (RPL-4) between January 2010 and September 2021. Associations between yearly hospital volumes and 90-day major complications were evaluated using multivariable logistic regression models adjusted for patient characteristics and clustering at the level of the hospital. RESULTS: A total of 10,879 patients were included, with 7567, 1776, 724, and 812 undergoing a RARP, TRH, RAPN, and RPL-4, respectively. Yearly hospital volume was not associated with 90-day complications for any procedure. Doubling of yearly volume was associated with a 17-min decrease in operative time for RARP (95% confidence interval [CI] - 23 to - 10), 8-min decrease for RAPN (95% CI - 14 to - 2), 24-min decrease for RPL-4 (95% CI - 29 to - 19), and no significant change for TRH (- 7 min; 95% CI - 17 to 3). CONCLUSION: The risk of 90-day major complications does not appear to be higher in low volume hospitals; however, they may not be as efficient with operating room utilization. Careful case selection may have contributed to the lack of an observed association between volumes and complications.

Tungsten-182 evidence for an ancient kimberlite source.

Globally distributed kimberlites with broadly chondritic initial 143Nd-176Hf isotopic systematics may be derived from a chemically homogenous, relatively primitive mantle source that remained isolated from the convecting mantle for much of the Earth's history. To assess whether this putative reservoir may have preserved remnants of an early Earth process, we report 182W/184W and 142Nd/144Nd data for "primitive" kimberlites from 10 localities worldwide, ranging in age from 1,153 to 89 Ma. Most are characterized by homogeneous µ182W and µ142Nd values averaging -5.9 ± 3.6 ppm (2SD, n = 13) and +2.7 ± 2.9 ppm (2SD, n = 6), respectively. The remarkably uniform yet modestly negative µ182W values, coupled with chondritic to slightly suprachondritic initial 143Nd/144Nd and 176Hf/177Hf ratios over a span of nearly 1,000 Mya, provides permissive evidence that these kimberlites were derived from one or more long-lived, early formed mantle reservoirs. Possible causes for negative µ182W values among these kimberlites include the transfer of W with low µ182W from the core to the mantle source reservoir(s), creation of the source reservoir(s) as a result of early silicate fractionation, or an overabundance of late-accreted materials in the source reservoir(s). By contrast, two younger kimberlites emplaced at 72 and 52 Ma and characterized by distinctly subchondritic initial 176Hf/177Hf and 143Nd/144Nd have µ182W values consistent with the modern upper mantle. These isotopic compositions may reflect contamination of the ancient kimberlite source by recycled crustal components with µ182W ≥ 0.

Predictors of Sentinel Lymph Node Metastasis in Patients with Thin Melanoma: An International Multi-institutional Collaboration.

BACKGROUND: Consideration of sentinel lymph node biopsy (SLNB) is recommended for patients with T1b melanomas and T1a melanomas with high-risk features; however, the proportion of patients with actionable results is low. We aimed to identify factors predicting SLNB positivity in T1 melanomas by examining a multi-institutional international population. METHODS: Data were extracted on patients with T1 cutaneous melanoma who underwent SLNB between 2005 and 2018 at five tertiary centers in Europe and Canada. Univariable and multivariable logistic regression analyses were performed to identify predictors of SLNB positivity. RESULTS: Overall, 676 patients were analyzed. Most patients had one or more high-risk features: Breslow thickness 0.8-1 mm in 78.1% of patients, ulceration in 8.3%, mitotic rate > 1/mm2 in 42.5%, Clark's level ≥ 4 in 34.3%, lymphovascular invasion in 1.4%, nodular histology in 2.9%, and absence of tumor-infiltrating lymphocytes in 14.4%. Fifty-three patients (7.8%) had a positive SLNB. Breslow thickness and mitotic rate independently predicted SLNB positivity. The odds of positive SLNB increased by 50% for each 0.1 mm increase in thickness past 0.7 mm (95% confidence interval [CI] 1.05-2.13) and by 22% for each mitosis per mm2 (95% CI 1.06-1.41). Patients who had one excised node (vs. two or more) were three times less likely to have a positive SLNB (3.6% vs. 9.6%; odds ratio 2.9 [1.3-7.7]). CONCLUSIONS: Our international multi-institutional data confirm that Breslow thickness and mitotic rate independently predict SLNB positivity in patients with T1 melanoma. Even within this highly selected population, the number needed to diagnose is 13:1 (7.8%), indicating that more work is required to identify additional predictors of sentinel node positivity.

Tungsten isotopic evidence for disproportional late accretion to the Earth and Moon.

Characterization of the hafnium-tungsten systematics ((182)Hf decaying to (182)W and emitting two electrons with a half-life of 8.9 million years) of the lunar mantle will enable better constraints on the timescale and processes involved in the currently accepted giant-impact theory for the formation and evolution of the Moon, and for testing the late-accretion hypothesis. Uniform, terrestrial-mantle-like W isotopic compositions have been reported among crystallization products of the lunar magma ocean. These observations were interpreted to reflect formation of the Moon and crystallization of the lunar magma ocean after (182)Hf was no longer extant-that is, more than about 60 million years after the Solar System formed. Here we present W isotope data for three lunar samples that are more precise by a factor of ≥4 than those previously reported. The new data reveal that the lunar mantle has a well-resolved (182)W excess of 20.6 ± 5.1 parts per million (±2 standard deviations), relative to the modern terrestrial mantle. The offset between the mantles of the Moon and the modern Earth is best explained by assuming that the W isotopic compositions of the two bodies were identical immediately following formation of the Moon, and that they then diverged as a result of disproportional late accretion to the Earth and Moon. One implication of this model is that metal from the core of the Moon-forming impactor must have efficiently stripped the Earth's mantle of highly siderophile elements on its way to merge with the terrestrial core, requiring a substantial, but still poorly defined, level of metal-silicate equilibration.

Origin and Age of Metal Veins in Canyon Diablo Graphite Nodules.

Previous studies attributed the origin of metal veins penetrating graphite nodules in the Canyon Diablo IAB main group iron meteorite to condensation from vapor or melting of host metal. Abundances of 16 siderophile elements measured in kamacite within vein and host meteorite are most consistent with an origin by melting of the host metal followed by fractional crystallization of the liquid. The presence of the veins within graphite nodules may be explained by impact, as peak shock temperatures, and thus the most likely areas to undergo metal melting, are at metal-graphite interfaces. The origin of the veins is constrained by Re-Os chronometry to have occurred early (>4 Ga) in Solar System history.

Tungsten Isotopes in Planets.

The short-lived Hf-W isotope system has a wide range of important applications in cosmochemistry and geochemistry. The siderophile behavior of W, combined with the lithophile nature of Hf, makes the system uniquely useful as a chronometer of planetary accretion and differentiation. Tungsten isotopic data for meteorites show that the parent bodies of some differentiated meteorites accreted within 1 million years after Solar System formation. Melting and differentiation on these bodies took ~1-3 million years and was fueled by decay of 26Al. The timescale for accretion and core formation increases with planetary mass and is ~10 million years for Mars and >34 million years for Earth. The nearly identical 182W compositions for the mantles of the Moon and Earth are difficult to explain in current models for the formation of the Moon. Terrestrial samples with ages spanning ~4 billion years reveal small 182W variations within the silicate Earth, demonstrating that traces of Earth's earliest formative period have been preserved throughout Earth's history.

Rapid effects of terrestrial alteration on highly siderophile elements in the Sutter's Mill meteorite.

The 187Re-187Os isotopic systematics of many bulk chondrites plot well beyond analytical uncertainties of a primordial isochron. Limited variations in 187Os/188Os, coupled with large variations in Re/Os ratios among chondrites, suggest that this apparently open-system behavior is a result of the comparatively recent gain or loss of Re and/or Os. In order to assess whether or not rapid alteration in the terrestrial environment could be responsible for open-system behavior in chondrites, four pieces of the Sutter's Mill meteorite were examined for Os isotopic systematics and abundances of highly siderophile elements. Pieces SM1 and SM2 were collected prior to a rain event, within 2 days of the fall. Pieces SM51 and SM53 were collected after a rain event. There are significant but minor relative and absolute variations in the abundances of the highly siderophile elements, as well as 187Os/188Os among the four pieces. Rhenium-Os isotopic data for SM1 and SM2 plot within analytical uncertainties of a primordial isochron, while powders made from SM51 and SM53 do not. These results suggest that interactions with rain caused some redistribution of Re, and to a lesser extent Os, within small pieces of the meteorite. Thus, Re-Os isotopic systematics of

High-precision analysis of 182W/184W and 183W/184W by negative thermal ionization mass spectrometry: Per-integration oxide corrections using measured 18O/16O.

Here we describe a new analytical technique for the high-precision measurement of 182W/184W and 183W/184W using negative thermal ionization mass spectrometry (N-TIMS). We improve on the recently reported method of Trinquier et al. (2016), which described using Faraday cup collectors coupled with amplifiers utilizing 1013 Ω resistors to continuously monitor the 18O/16O of WO3 - and make per-integration oxide corrections. In our study, we report and utilize a newly measured oxygen mass fractionation line, as well as average 17O/16O and 18O/16O, which allow for more accurate per-integration oxide interference corrections. We also report a Faraday cup and amplifier configuration that allows 18O/16O to be continuously monitored for WO3 - and ReO3 -, both of which are ionized during analyses of W using Re ribbon. The long-term external precision of 182W/184W is 5.7 ppm and 3.7 ppm (2SD) when mass bias corrected using 186W/184W and 186W/183W, respectively. For 183W/184W mass bias is corrected using 186W/184W, yielding a long-term external precision of 6.6 ppm. An observed, correlated variation in 182W/184W and 183W/184W, when mass bias corrected using 186W/184W, is most likely the result of Faraday cup degradation over months-long intervals.

Early inner solar system origin for anomalous sulfur isotopes in differentiated protoplanets.

Achondrite meteorites have anomalous enrichments in (33)S, relative to chondrites, which have been attributed to photochemistry in the solar nebula. However, the putative photochemical reactions remain elusive, and predicted accompanying (33)S depletions have not previously been found, which could indicate an erroneous assumption regarding the origins of the (33)S anomalies, or of the bulk solar system S-isotope composition. Here, we report well-resolved anomalous (33)S depletions in IIIF iron meteorites (<-0.02 per mil), and (33)S enrichments in other magmatic iron meteorite groups. The (33)S depletions support the idea that differentiated planetesimals inherited sulfur that was photochemically derived from gases in the early inner solar system (<∼2 AU), and that bulk inner solar system S-isotope composition was chondritic (consistent with IAB iron meteorites, Earth, Moon, and Mars). The range of mass-independent sulfur isotope compositions may reflect spatial or temporal changes influenced by photochemical processes. A tentative correlation between S isotopes and Hf-W core segregation ages suggests that the two systems may be influenced by common factors, such as nebular location and volatile content.

High-Precision Tungsten Isotopic Analysis by Multicollection Negative Thermal Ionization Mass Spectrometry Based on Simultaneous Measurement of W and (18)O/(16)O Isotope Ratios for Accurate Fractionation Correction.

Determination of the (182)W/(184)W ratio to a precision of ± 5 ppm (2σ) is desirable for constraining the timing of core formation and other early planetary differentiation processes. However, WO3(-) analysis by negative thermal ionization mass spectrometry normally results in a residual correlation between the instrumental-mass-fractionation-corrected (182)W/(184)W and (183)W/(184)W ratios that is attributed to mass-dependent variability of O isotopes over the course of an analysis and between different analyses. A second-order correction using the (183)W/(184)W ratio relies on the assumption that this ratio is constant in nature. This may prove invalid, as has already been realized for other isotope systems. The present study utilizes simultaneous monitoring of the (18)O/(16)O and W isotope ratios to correct oxide interferences on a per-integration basis and thus avoid the need for a double normalization of W isotopes. After normalization of W isotope ratios to a pair of W isotopes, following the exponential law, no residual W-O isotope correlation is observed. However, there is a nonideal mass bias residual correlation between (182)W/(i)W and (183)W/(i)W with time. Without double normalization of W isotopes and on the basis of three or four duplicate analyses, the external reproducibility per session of (182)W/(184)W and (183)W/(184)W normalized to (186)W/(183)W is 5-6 ppm (2σ, 1-3 µg loads). The combined uncertainty per session is less than 4 ppm for (183)W/(184)W and less than 6 ppm for (182)W/(184)W (2σm) for loads between 3000 and 50 ng.

New high-speed centre of mass method incorporating background subtraction for accurate determination of fluorescence lifetime.

We demonstrate an implementation of a centre-of-mass method (CMM) incorporating background subtraction for use in multifocal fluorescence lifetime imaging microscopy to accurately determine fluorescence lifetime in live cell imaging using the Megaframe camera. The inclusion of background subtraction solves one of the major issues associated with centre-of-mass approaches, namely the sensitivity of the algorithm to background signal. The algorithm, which is predominantly implemented in hardware, provides real-time lifetime output and allows the user to effectively condense large amounts of photon data. Instead of requiring the transfer of thousands of photon arrival times, the lifetime is simply represented by one value which allows the system to collect data up to limit of pulse pile-up without any limitations on data transfer rates. In order to evaluate the performance of this new CMM algorithm with existing techniques (i.e. rapid lifetime determination and Levenburg-Marquardt), we imaged live MCF-7 human breast carcinoma cells transiently transfected with FRET standards. We show that, it offers significant advantages in terms of lifetime accuracy and insensitivity to variability in dark count rate (DCR) between Megaframe camera pixels. Unlike other algorithms no prior knowledge of the expected lifetime is required to perform lifetime determination. The ability of this technique to provide real-time lifetime readout makes it extremely useful for a number of applications.

High-precision molybdenum isotope analysis by negative thermal ionization mass spectrometry.

Procedures for the separation, purification, and high-precision analysis of mass-independent isotopic variations in molybdenum (Mo) using negative thermal ionization mass spectrometry are reported. Separation and purification of Mo from silicate and metal matrices are achieved using a two-stage anion exchange chromatographic procedure. Molybdenum is ionized as the MoO3 - species using a double filament assembly. The MoO3 - ion beams are collected using Faraday cup detectors equipped with a mixed array of amplifiers utilizing 1011 and 1012 Ω resistors, which allows for in situ measurement and correction of oxygen isobars. The long-term external reproducibility of 97Mo/96Mo, the most precisely measured Mo isotope ratio, is ±5.4 ppm (2SD), based on the repeated analyses of the Alfa Aesar Specpure ® Mo plasma standard and using 98Mo/96Mo for fractionation correction. The long-term external reproducibilities of 92Mo/96Mo, 94Mo/96Mo, 95Mo/96Mo, and 100Mo/96Mo are ±107, 37, 23, and 32 ppm (2SD), respectively. With this precision, smaller differences in Mo isotopic compositions can be resolved than have been previously possible.

Early formation of evolved asteroidal crust.

Mechanisms for the formation of crust on planetary bodies remain poorly understood. It is generally accepted that Earth's andesitic continental crust is the product of plate tectonics, whereas the Moon acquired its feldspar-rich crust by way of plagioclase flotation in a magma ocean. Basaltic meteorites provide evidence that, like the terrestrial planets, some asteroids generated crust and underwent large-scale differentiation processes. Until now, however, no evolved felsic asteroidal crust has been sampled or observed. Here we report age and compositional data for the newly discovered, paired and differentiated meteorites Graves Nunatak (GRA) 06128 and GRA 06129. These meteorites are feldspar-rich, with andesite bulk compositions. Their age of 4.52 +/- 0.06 Gyr demonstrates formation early in Solar System history. The isotopic and elemental compositions, degree of metamorphic re-equilibration and sulphide-rich nature of the meteorites are most consistent with an origin as partial melts from a volatile-rich, oxidized asteroid. GRA 06128 and 06129 are the result of a newly recognized style of evolved crust formation, bearing witness to incomplete differentiation of their parent asteroid and to previously unrecognized diversity of early-formed materials in the Solar System.

Time-resolved multifocal multiphoton microscope for high speed FRET imaging in vivo.

Imaging the spatiotemporal interaction of proteins in vivo is essential to understanding the complexities of biological systems. The highest accuracy monitoring of protein-protein interactions is achieved using Förster resonance energy transfer (FRET) measured by fluorescence lifetime imaging, with measurements taking minutes to acquire a single frame, limiting their use in dynamic live cell systems. We present a diffraction limited, massively parallel, time-resolved multifocal multiphoton microscope capable of producing fluorescence lifetime images with 55 ps time-resolution, giving improvements in acquisition speed of a factor of 64. We present demonstrations with FRET imaging in a model cell system and demonstrate in vivo FLIM using a GTPase biosensor in the zebrafish embryo.

Efficient mixing of the solar nebula from uniform Mo isotopic composition of meteorites.

The abundances of elements and their isotopes in our Galaxy show wide variations, reflecting different nucleosynthetic processes in stars and the effects of Galactic evolution. These variations contrast with the uniformity of stable isotope abundances for many elements in the Solar System, which implies that processes efficiently homogenized dust and gas from different stellar sources within the young solar nebula. However, isotopic heterogeneity has been recognized on the subcentimetre scale in primitive meteorites, indicating that these preserve a compositional memory of their stellar sources. Small differences in the abundance of stable molybdenum isotopes in bulk rocks of some primitive and differentiated meteorites, relative to terrestrial Mo, suggest large-scale Mo isotopic heterogeneity between some inner Solar System bodies, which implies physical conditions that did not permit efficient mixing of gas and dust. Here we report Mo isotopic data for bulk samples of primitive and differentiated meteorites that show no resolvable deviations from terrestrial Mo. This suggests efficient mixing of gas and dust in the solar nebula at least to 3 au from the Sun, possibly induced by magnetohydrodynamic instabilities. These mixing processes must have occurred before isotopic fractionation of gas-phase elements and volatility-controlled chemical fractionations were established.

New implications for the origin of the IAB main group iron meteorites and the isotopic evolution of the noncarbonaceous (NC) reservoir.

The origin of the IAB main group (MG) iron meteorites is explored through consideration of 182W isotopic compositions, thermal modeling of 26Al decay, and mass independent (nucleosynthetic) Mo isotopic compositions of planetesimals formed in the noncarbonaceous (NC) protosolar isotopic reservoir. A refined 182W model age for the meteorites Campo del Cielo, Canyon Diablo, and Nantan suggests that the IAB-MG parent body underwent some form of metal-silicate segregation as early as 5.3 ± 0.4 Myr after calcium-aluminum rich inclusion (CAI) formation or as late as 13.8 ± 1.4 Myr after CAI formation. If melting of the IAB-MG occurred prior to 7 Myr after CAI formation, it was likely driven by 26Al decay for a parent body radius >40 km. Otherwise, additional heat from impact is required for melting metal this late in Solar System history. If melting was partially or wholly the result of internal heating, a thermal model of 26Al decay heat production constrains the accretion age of the IAB-MG parent body to ~1.7 ± 0.4 Myr after CAI formation. If melting was, instead, dominantly caused by impact heating, thermal modeling suggests the parent body accreted more than 2 Myr after CAI formation. Comparison of Mo mass independent isotopic compositions of the IAB-MG to other NC bodies with constrained accretion ages suggests that the Mo isotopic composition of the NC reservoir changed with time, and that the IAB-MG parent body accreted between 2 to 3 Myr after CAI formation, thus requiring an origin by impact. The relationship between nucleosynthetic Mo isotopic compositions and accretion ages of planetesimals from the NC reservoir suggests that isotopic heterogeneity developed from either addition of s-process material to, or removal of coupled r-/p-process material from the NC reservoir.