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Clinical trials frequently include multiple end points that mature at different times. The initial report, typically based on the primary end point, may be published when key planned co-primary or secondary analyses are not yet available. Clinical Trial Updates provide an opportunity to disseminate additional results from studies, published in JCO or elsewhere, for which the primary end point has already been reported.To assess long-term risk of local tumor regrowth, we report updated organ preservation rate and oncologic outcomes of the OPRA trial (ClinicalTrials.gov identifier: NCT02008656). Patients with stage II/III rectal cancer were randomly assigned to receive induction chemotherapy followed by chemoradiation (INCT-CRT) or chemoradiation followed by consolidation chemotherapy (CRT-CNCT). Patients who achieved a complete or near-complete response after finishing treatment were offered watch-and-wait (WW). Total mesorectal excision (TME) was recommended for those who achieved an incomplete response. The primary end point was disease-free survival (DFS). The secondary end point was TME-free survival. In total, 324 patients were randomly assigned (INCT-CRT, n = 158; CRT-CNCT, n = 166). Median follow-up was 5.1 years. The 5-year DFS rates were 71% (95% CI, 64 to 79) and 69% (95% CI, 62 to 77) for INCT-CRT and CRT-CNCT, respectively (P = .68). TME-free survival was 39% (95% CI, 32 to 48) in the INCT-CRT group and 54% (95% CI, 46 to 62) in the CRT-CNCT group (P = .012). Of 81 patients with regrowth, 94% occurred within 2 years and 99% occurred within 3 years. DFS was similar for patients who underwent TME after restaging (64% [95% CI, 53 to 78]) and patients in WW who underwent TME after regrowth (64% [95% CI, 53 to 78]; P = .94). Updated analysis continues to show long-term organ preservation in half of the patients with rectal cancer treated with total neoadjuvant therapy. In patients who enter WW, most cases of tumor regrowth occur in the first 2 years.

The elements hydrogen, carbon, nitrogen and oxygen are assumed to comprise the bulk of the interiors of the ice giant planets Uranus, Neptune, and sub-Neptune exoplanets. The details of their interior structures have remained largely unknown because it is not understood how the compounds H2O, NH3 and CH4 behave and react once they have been accreted and exposed to high pressures and temperatures. Here we study thirteen H-C-N-O compounds with ab initio computer simulations and demonstrate that they assume a superionic state at elevated temperatures, in which the hydrogen ions diffuse through a stable sublattice that is provided by the larger nuclei. At yet higher temperatures, four of the thirteen compounds undergo a second transition to a novel doubly superionic state, in which the smallest of the heavy nuclei diffuse simultaneously with hydrogen ions through the remaining sublattice. Since this transition and the melting transition at yet higher temperatures are both of first order, this may introduce additional layers in the mantle of ice giant planets and alter their convective patterns.

We explore the structural properties of Mg, MgO, and MgSiO3 liquids from ab initio computer simulations at conditions that are relevant for the interiors of giant planets, stars, shock compression measurements, and inertial confinement fusion experiments. Using path-integral Monte Carlo and density functional theory molecular dynamics, we derive the equation of state of magnesium-rich liquids in the regime of condensed and warm dense matter, with densities ranging from 0.32 to 86.11 g cm−3 and temperatures from 20,000 K to 5 × 108 K. We study the electronic structure of magnesium as a function of density and temperature and the correlations of the atomic motion, finding an unexpected local maximum in the pair correlation functions that emerges at high densities which decreases the coordination number of elemental magnesium and reveals a higher packing. This phenomenon is not observed in other magnesium liquids, which maintain a rather constant coordination number.

BACKGROUND: Older smokers account for the greatest tobacco-related morbidity and mortality in the USA, while quitting smoking remains the single most effective preventive health intervention for reducing the risk of smoking-related illness. Yet, knowledge about patterns of smoking and smoking cessation in older adults is lacking. OBJECTIVE: Assess trends in prevalence of cigarette smoking between 1998 and 2018 and identify patterns and predictors of smoking cessation in US older adults. DESIGN: Retrospective cohort study PARTICIPANTS: Individuals aged 55+ enrolled in the nationally representative Health and Retirement Study, 1998-2018 MAIN MEASURES: Current smoking was assessed with the question: Do you smoke cigarettes now? Quitting smoking was defined as having at least two consecutive waves (between 2 and 4 years) in which participants who were current smokers in 1998 reported they were not currently smoking in subsequent waves. KEY RESULTS: Age-adjusted smoking prevalence decreased from 15.9% in 1998 (95% confidence interval (CI) 15.2, 16.7) to 11.2% in 2018 (95% CI 10.4, 12.1). Among 2187 current smokers in 1998 (mean age 64, 56% female), 56% of those living to age 90 had a sustained period of smoking cessation. Smoking less than 10 cigarettes/day was strongly associated with an increased likelihood of quitting smoking (subdistribution hazard ratio 2.3; 95% CI 1.9, 2.8), compared to those who smoked more than 20 cigarettes/day. CONCLUSIONS: Smoking prevalence among older persons has declined and substantial numbers of older smokers succeed in quitting smoking for a sustained period. These findings highlight the need for continued aggressive efforts at tobacco cessation among older persons.

BackgroundAdults aged ≥ 60 years are often underrepresented in atopic dermatitis (AD) clinical trials; age-related comorbidities may impact treatment efficacy and safety.ObjectiveThe aim was to report dupilumab efficacy and safety in patients aged ≥ 60 years with moderate-to-severe AD.MethodsData were pooled from four randomized, placebo-controlled dupilumab trials of patients with moderate-to-severe AD (LIBERTY AD SOLO 1 and 2, LIBERTY AD CAFÉ, and LIBERTY AD CHRONOS) and stratified by age (

PSICHE (NCT05022914) is a prospective trial to test a [68Ga]Ga- PSMA-11 PET/CT imaging tailored strategy. All evaluable patients had biochemical relapse after surgery and underwent centralized [68Ga]Ga-PSMA-11 PET/CT imaging. The treatment was performed according pre-defined criteria. Observation and re-staging at further PSA progression were proposed to patients with negative PSMA and previous postoperative RT. Prostate bed SRT was proposed to all patients with a negative staging or positive imaging within prostate bed. Stereotactic body radiotherapy (SBRT) to all sites of disease was used for all patients with pelvic nodal recurrence (nodal disease

In the hopes of observing the highest-energy neutrinos (E>1 EeV) populating the Universe, both past (RICE, AURA, ANITA) and current (RNO-G, ARIANNA, ARA and TAROGE-M) polar-sited experiments exploit the impulsive radio emission produced by neutrino interactions. In such experiments, rare single event candidates must be unambiguously identified above backgrounds. Background rejection strategies to date primarily target thermal noise fluctuations and also impulsive radio-frequency signals of anthropogenic origin. In this paper, we consider the possibility that ‘fake’ neutrino signals may also be generated naturally via the ‘triboelectric effect.’ This broadly describes any process in which force applied at a boundary layer results in displacement of surface charge, leading to the production of an electrostatic potential difference ΔV. Wind blowing over granular surfaces such as snow can induce such a potential difference, with subsequent coronal discharge. Discharges over timescales as short as nanoseconds can then lead to radio-frequency emissions at characteristic MHz–GHz frequencies. Using data from various past (RICE, AURA, SATRA, ANITA) and current (RNO-G, ARIANNA and ARA) neutrino experiments, we find evidence for such backgrounds, which are generally characterized by: (a) a threshold wind velocity which likely depends on the experimental trigger criteria and layout; for the experiments considered herein, this value is typically O(10 m/s), (b) frequency spectra generally shifted to the low-end of the frequency regime to which current radio experiments are typically sensitive (100–200 MHz), (c) for the strongest background signals, an apparent preference for discharges from above-surface structures, although the presence of more isotropic, lower amplitude triboelectric discharges cannot be excluded.

Abstract The TAROGE-M radio observatory is a self-triggered antenna array on top of the ∼2700 m high Mt. Melbourne in Antarctica, designed to detect impulsive geomagnetic emission from extensive air showers induced by ultra-high energy (UHE) particles beyond 1017 eV, including cosmic rays, Earth-skimming tau neutrinos, and particularly, the “ANITA anomalous events” (AAE) from near and below the horizon. The six AAE discovered by the ANITA experiment have signal features similar to tau neutrinos but that hypothesis is in tension either with the interaction length predicted by Standard Model or with the flux limits set by other experiments. Their origin remains uncertain, requiring more experimental inputs for clarification. The detection concept of TAROGE-M takes advantage of a high altitude with synoptic view toward the horizon as an efficient signal collector, and the radio quietness as well as strong and near vertical geomagnetic field in Antarctica, enhancing the relative radio signal strength. This approach has a low energy threshold, high duty cycle, and is easy to extend for quickly enlarging statistics. Here we report experimental results from the first TAROGE-M station deployed in January 2020, corresponding to approximately one month of livetime. The station consists of six receiving antennas operating at 180-450 MHz, and can reconstruct source directions of impulsive events with an angular resolution of ∼0.3°, calibrated in situ with a drone-borne pulser system. To demonstrate TAROGE-M's ability to detect UHE air showers, a search for cosmic ray signals in 25.3-days of data together with the detection simulation were conducted, resulting in seven identified candidates. The detected events have a mean reconstructed energy of 0.95-0.31+0.46 EeV and zenith angles ranging from 25° to 82°, with both distributions agreeing with the simulations, indicating an energy threshold at about 0.3 EeV. The estimated cosmic ray flux at that energy is 1.2-0.9+0.7 × 10-16 eV-1 km-2 yr-1 sr-1, also consistent with results of other experiments. The TAROGE-M sensitivity to AAEs is approximated by the tau neutrino exposure with simulations, which suggests comparable sensitivity as ANITA's at around 1 EeV energy with a few station-years of operation. These first results verified the station design and performance in a polar and high-altitude environment, and are promising for further discovery of tau neutrinos and AAEs after an extension in the near future.

The TAROGE-M observatory is an autonomous antenna array on the top of Mt. Melbourne (∼2700 m altitude) in Antarctica, designed to detect radio pulses from ultra-high energy (over 1017 eV) air showers coming from near-horizon directions. The targeted sources include cosmic rays, Earth-skimming tau neutrinos, and most of all, the anomalous near-horizon upward-going events of yet unknown origin discovered by ANITA experiments. The detection concept follows that of ANITA: monitoring large area of ice from high-altitude and taking advantage of strong geomagnetic field and quiet radio background in Antarctica, whereas having significantly greater livetime and scalability. The TAROGE-M station, upgraded from its prototype built in 2019, was deployed in January 2020, and consists of 6 log-periodic dipole antennas pointing horizontally with bandwidth of 180-450 MHz. The station is then calibrated with drone-borne transmitter, with which the event reconstruction obtained ∼0.3° angular resolution. The station was then smoothly operating in the following month, with the live time of ∼ 30 days, before interrupted by a power problem, and its online filtering has identified several candidate cosmic-ray events and sent out via satellite communication. In this paper, the instrumentation of the station for polar and high-altitude environment, its radio-locating performance, the preliminary result on cosmic-ray detection, and the future extension plan are presented.

PURPOSE: Prospective data on the efficacy of a watch-and-wait strategy to achieve organ preservation in patients with locally advanced rectal cancer treated with total neoadjuvant therapy are limited. METHODS: In this prospective, randomized phase II trial, we assessed the outcomes of 324 patients with stage II or III rectal adenocarcinoma treated with induction chemotherapy followed by chemoradiotherapy (INCT-CRT) or chemoradiotherapy followed by consolidation chemotherapy (CRT-CNCT) and either total mesorectal excision (TME) or watch-and-wait on the basis of tumor response. Patients in both groups received 4 months of infusional fluorouracil-leucovorin-oxaliplatin or capecitabine-oxaliplatin and 5,000 to 5,600 cGy of radiation combined with either continuous infusion fluorouracil or capecitabine during radiotherapy. The trial was designed as two stand-alone studies with disease-free survival (DFS) as the primary end point for both groups, with a comparison to a null hypothesis on the basis of historical data. The secondary end point was TME-free survival. RESULTS: Median follow-up was 3 years. Three-year DFS was 76% (95% CI, 69 to 84) for the INCT-CRT group and 76% (95% CI, 69 to 83) for the CRT-CNCT group, in line with the 3-year DFS rate (75%) observed historically. Three-year TME-free survival was 41% (95% CI, 33 to 50) in the INCT-CRT group and 53% (95% CI, 45 to 62) in the CRT-CNCT group. No differences were found between groups in local recurrence-free survival, distant metastasis-free survival, or overall survival. Patients who underwent TME after restaging and patients who underwent TME after regrowth had similar DFS rates. CONCLUSION: Organ preservation is achievable in half of the patients with rectal cancer treated with total neoadjuvant therapy, without an apparent detriment in survival, compared with historical controls treated with chemoradiotherapy, TME, and postoperative chemotherapy.

TAROGE-M is a self-triggered radio antenna array atop the 2700 m high Mt.Melbourne in Antarctica, designed to detect impulsive geomagnetic emission fromextensive air showers induced by ultra-high energy (UHE) particles beyond 0.1EeV, including cosmic rays (CRs), Earth-skimming tau neutrinos, andparticularly, the "ANITA anomalous events" (AAEs) from near and below thehorizon, which origin remains uncertain and requires more experimental inputsfor clarification. The detection concept of TAROGE-M takes advantage of a high altitude withsynoptic view toward the horizon as an efficient signal collector, and theradio quietness as well as strong and near vertical geomagnetic field inAntarctica. This approach has a low energy threshold, high duty cycle, and iseasy to extend for quickly enlarging statistics. Here we report experimentalresults from the first TAROGE-M station deployed in 2020, corresponding to$25.3$-days of livetime. The station consists of six receiving antennasoperating at 180-450 MHz, and can reconstruct source directions with$\sim0.3^\circ$ angular resolution. To demonstrate its ability to detect UHEair showers, a search for CR signals in the data was conducted, resulting inseven identified events. These events have a mean reconstructed energy of$0.95_{-0.31}^{+0.46}$ EeV and zenith angles between $25^\circ-82^\circ$, withboth distributions agreeing with simulations. The estimated CR flux is alsoconsistent with results of other experiments. The TAROGE-M sensitivity to AAEsis approximated by the tau neutrino exposure with simulations, suggestingcomparable sensitivity as ANITA's at $~1$ EeV energy with a few station-yearsof operation. These first results verified the station design and performancein a polar and high-altitude environment, and are promising for furtherdiscovery of tau neutrinos and AAEs after an extension in the near future.

The ARIANNA detector is designed to detect neutrinos with energies above 1017 eV. Due to the similarities in generated radio signals, cosmic rays are often used as test beams for neutrino detectors. Some ARIANNA detector stations are equipped with antennas capable of detecting air showers. Since the radio emission properties of air showers are well understood, and the polarization of the radio signal can be predicted from the arrival direction, cosmic rays can be used as a proxy to assess the reconstruction capabilities of the ARIANNA neutrino detector. We report on dedicated efforts of reconstructing the polarization of cosmic-ray radio pulses. After correcting for difference in hardware, the two stations used in this study showed similar performance in terms of event rate and agreed with simulation. Subselecting high quality cosmic rays, the polarizations of these cosmic rays were reconstructed with a resolution of 2.5° (68% containment), which agrees with the expected value obtained from simulation. A large fraction of this resolution originates from uncertainties in the predicted polarization because of the contribution of the subdominant Askaryan effect in addition to the dominant geomagnetic emission. Subselecting events with a zenith angle greater than 70° removes most influence of the Askaryan emission, and, with limited statistics, we found the polarization uncertainty is reduced to 1.3° (68% containment).

The ARIANNA neutrino detector, located at sea-level on the Ross Ice Shelf, Antarctica, consists of 200 autonomous and independent detector stations separated by 1 kilometer in a uniform triangular mesh, and serves to inform the planning of the future projects. The primary science mission of ARIANNA is to search for sources of neutrinos with energies greater than 1017 eV, complementing the reach of IceCube and other neutrino telescopes that focus on lower energies. An ARIANNA observation of a neutrino source would provide strong insight into the enigmatic sources of cosmic rays. ARIANNA observes the radio emission from high energy neutrino interactions in the Antarctic ice. Among radio based concepts under current investigation, ARIANNA would uniquely survey the vast majority of the southern sky at any instant in time, and an important region of the northern sky, by virtue of its location on the surface of the Ross Ice Shelf at Moore’s Bay. The broad sky coverage is specific to the Moore’s Bay site, providing capabilities to observe explosive sources from unknown directions. The ARIANNA architecture is designed to measure the angular direction to within 4 degrees for every neutrino candidate, which too plays an important role in the pursuit of multi-messenger observations of astrophysical sources. The sea level location reduces the impact of a potentially serious background associated with the cores of cosmic ray air showers striking the ice surface, generating radio pulses which are similar to those expected from neutrino events. Reflecting layers at the bottom or within the ice sheet (which are known to exist in thick ice sheets) might create a troublesome rate of background events, provided the reflection coefficients are large enough, that arrive at the detector from the same directions as neutrinos.

The ARIANNA detector is designed to detect neutrinos of energies above 1016 eV. Due to the similarities in generated radio signals, cosmic rays are often used as test beams for neutrino detectors. Some ARIANNA detector stations are equipped with antennas capable of detecting air showers. The radio emission properties of air showers are well understood, and the polarization of the radio signal can be predicted from arrival direction with high precision. For this reason, cosmic rays can be used as a proxy to assess the reconstruction capabilities of the ARIANNA neutrino detector. We report on dedicated efforts of reconstructing the polarization of cosmic-ray radio pulses. A total of 148 cosmic rays are identified from over 90,000 triggered events collected between Nov 21, 2018 and Mar 15, 2019. A cut was put on these events requiring them to have a signal-to-noise (SNR) ratio of at least 4.5 in all upward-facing channels. This was to improve the performance of arrival direction and polarization reconstruction algorithms. Polarization of these cosmic rays were reconstructed with a resolution of 3.5 degrees (68% containment), which agrees with the expected value we obtained from simulation. Furthermore, if we subselect events with zenith angle greater than 70 deg, the contribution to polarization of Askaryan effect is reduced, which reduces the error in the predicted polarization. With limited statistics, we find the polarization uncertainty is reduced to 1.3 deg (68% containment).

High energy neutrinos (E >1017 eV) are detected cost-efficiently via the Askaryan effect in ice, where a particle cascade induced by the neutrino interaction produces coherent radio emission that can be picked up by antennas installed below the surface. A good knowledge of the near surface ice (aka firn) properties is required to reconstruct the neutrino properties. In particular, a continuous monitoring of the snow accumulation (which changes the depth of the antennas) and the index-of-refraction profile are crucial for an accurate determination of the neutrino’s direction and energy. We present an in-situ calibration system that extends the radio detector station with a radio emitter to continuously monitor the firn properties by measuring time differences of direct and reflected (off the surface) signals (D’n’R). We optimized the station layout in a simulation study and quantified the achievable precision. We present 14 months of data of the ARIANNA detector on the Ross Ice Shelf, Antarctica, where a prototype of this calibration system was successfully used to monitor the snow accumulation with unprecedented precision of 1 mm. We explore and test several algorithms to extract the D’n’R time difference from noisy data (including deep learning). This constitutes an in-situ test of the neutrino vertex distance reconstruction using the D’n’R technique which is needed to determine the neutrino energy.

The ARIANNA experiment is a proposed Askaryan detector designed to record radio signals induced by neutrino interactions in the Antarctic ice. Because of the low neutrino flux at high energies, the physics output is limited by statistics. Hence, an increase in sensitivity significantly improves the interpretation of data and offers the ability to probe new parameter spaces. The trigger thresholds are limited by the rate of triggering on unavoidable thermal noise fluctuations. The real-time thermal noise rejection algorithm enables the thresholds to be lowered substantially and increases the sensitivity by up to a factor of two compared to the current ARIANNA capabilities. A deep learning discriminator, based on a Convolutional Neural Network (CNN), is implemented to identify and remove a high percentage of thermal events in real time while retaining most of the neutrino signals. We describe a CNN that runs on the current ARIANNA microcomputer and retains 95% of the neutrino signals at a thermal rejection factor of 105. Finally, the experimental verification from lab measurements are conducted.

A radio-frequency polarization measurement by the ARIANNA surface station was performed using a residual hole from the South Pole Ice Core (SPICEcore) Project. Radio pulses were emitted from a transmitter located down to 1.7 km below the snow surface. After deconvolving the raw signals for the detector response and attenuation from propagation through the ice, the signal pulses show no significant distortion and agree with a reference measurement of the emitter made in an anechoic chamber. The direction to transmitted radio pulse was measured with an angular resolution of 0.37 degree [statistical error]. For polarization, the statistical error of the polarization vector is depth dependent and below 1 degree. In addition, a slowly-varying systematic variation is observed as a function of depth with an rms error of 2.7 degrees. Neither the direction or polarization measurement show a significant offset as a function of depth relative to expectation. We also report on the results of a simulation study of the ARIANNA neutrino direction and energy resolution. The software tool NuRadioMC was used to reconstruct the polarization and viewing angle to determine the neutrino direction. Multiple models of Askaryan radiation and detector sites along with a range of neutrino energies were evaluated. The neutrino space angle resolution was determined to be below 3 degrees, which is comparable to the systematic polarization uncertainty. Therefore it is expected that the polarization resolution, which is the dominant contribution to the neutrino space angle resolution, will be improved in future studies by determining and eliminating systematic effects.

The ARIANNA experiment is an Askaryan detector designed to record radio signals induced by neutrino interactions in the Antarctic ice. Because of the low neutrino flux at high energies (Eν > 1016 eV), the physics output is limited by statistics. Hence, an increase in sensitivity significantly improves the interpretation of data and offers the ability to probe new parameter spaces. The amplitudes of the trigger threshold are limited by the rate of triggering on unavoidable thermal noise fluctuations. We present a real-time thermal noise rejection algorithm that enables the trigger thresholds to be lowered, which increases the sensitivity to neutrinos by up to a factor of two (depending on energy) compared to the current ARIANNA capabilities. A deep learning discriminator, based on a Convolutional Neural Network (CNN), is implemented to identify and remove thermal events in real time. We describe a CNN trained on MC data that runs on the current ARIANNA microcomputer and retains 95% of the neutrino signal at a thermal noise rejection factor of 105, compared to a template matching procedure which reaches only 102 for the same signal efficiency. Then the results are verified in a lab measurement by feeding in generated neutrino-like signal pulses and thermal noise directly into the ARIANNA data acquisition system. Lastly, the same CNN is used to classify cosmic-rays events to make sure they are not rejected. The network classified 102 out of 104 cosmic-ray events as signal.

Super-Earths and sub-Neptunes are the most common planet types in our galaxy. A subset of these planets is predicted to be water worlds, bodies that are rich in water and poor in hydrogen gas. The interior structures of water worlds have been assumed to consist of water surrounding a rocky mantle and iron core. In small planets, water and rock form distinct layers with limited incorporation of water into silicate phases, but these materials may interact differently during the growth and evolution of water worlds due to greater interior pressures and temperatures. Here, we use density functional molecular dynamics (DFT-MD) simulations to study the miscibility and interactions of enstatite (MgSiO3), a major end-member silicate phase, and water (H2O) at extreme conditions in water world interiors. We explore pressures ranging from 30 to 120 GPa and temperatures from 500 to 8000 K. Our results demonstrate that enstatite and water are miscible in all proportions if the temperature exceeds the melting point of MgSiO3. Furthermore, we performed smoothed particle hydrodynamics simulations to demonstrate that the conditions necessary for rock-water miscibility are reached during giant impacts between water-rich bodies of 0.7-4.7 Earth masses. Our simulations lead to water worlds that include a mixed layer of rock and water.

The incorporation of omics approaches into symptom science research can provide researchers with information about the molecular mechanisms that underlie symptoms. Most of the omics analyses in symptom science have used a single omics approach. Therefore, these analyses are limited by the information contained within a specific omics domain (e.g., genomics and inherited variations, transcriptomics and gene function). A multi-staged data-integrated multi-omics (MS-DIMO) analysis integrates multiple types of omics data in a single study. With this integration, a MS-DIMO analysis can provide a more comprehensive picture of the complex biological mechanisms that underlie symptoms. The results of a MS-DIMO analysis can be used to refine mechanistic hypotheses and/or discover therapeutic targets for specific symptoms. The purposes of this paper are to: (1) describe a MS-DIMO analysis using "Symptom X" as an example; (2) discuss a number of challenges associated with specific omics analyses and how a MS-DIMO analysis can address them; (3) describe the various orders of omics data that can be used in a MS-DIMO analysis; (4) describe omics analysis tools; and (5) review case exemplars of MS-DIMO analyses in symptom science. This paper provides information on how a MS-DIMO analysis can strengthen symptom science research through the prioritization of functional genes and biological processes associated with a specific symptom.

PurposeCyclin-dependent kinase 4 (CDK4) and CDK6 inhibitors (CDK4/6i) are highly effective against estrogen receptor-positive (ER+)/HER2- breast cancer; however, intrinsic and acquired resistance is common. Elucidating the molecular features of sensitivity and resistance to CDK4/6i may lead to identification of predictive biomarkers and novel therapeutic targets, paving the way toward improving patient outcomes.Experimental designParental breast cancer cells and their endocrine-resistant derivatives (EndoR) were used. Derivatives with acquired resistance to palbociclib (PalboR) were generated from parental and estrogen deprivation-resistant MCF7 and T47D cells. Transcriptomic and proteomic analyses were performed in palbociclib-sensitive and PalboR lines. Gene expression data from CDK4/6i neoadjuvant trials and publicly available datasets were interrogated for correlations of gene signatures and patient outcomes.ResultsParental and EndoR breast cancer lines showed varying degrees of sensitivity to palbociclib. Transcriptomic analysis of these cell lines identified an association between high IFN signaling and reduced CDK4/6i sensitivity; thus an "IFN-related palbociclib-resistance Signature" (IRPS) was derived. In two neoadjuvant trials of CDK4/6i plus endocrine therapy, IRPS and other IFN-related signatures were highly enriched in patients with tumors exhibiting intrinsic resistance to CDK4/6i. PalboR derivatives displayed dramatic activation of IFN/STAT1 signaling compared with their short-term treated or untreated counterparts. In primary ER+/HER2- tumors, the IRPS score was significantly higher in lumB than lumA subtype and correlated with increased gene expression of immune checkpoints, endocrine resistance, and poor prognosis.ConclusionsAberrant IFN signaling is associated with intrinsic resistance to CDK4/6i. Experimentally, acquired resistance to palbociclib is associated with activation of the IFN pathway, warranting additional studies to clarify its involvement in resistance to CDK4/6i.

Any large dataset can be analyzed in a number of ways, and it is possible that the use of different analysis strategies will lead to different results and conclusions. One way to assess whether the results obtained depend on the analysis strategy chosen is to employ multiple analysts and leave each of them free to follow their own approach. Here, we present consensus-based guidance for conducting and reporting such multi-analyst studies, and we discuss how broader adoption of the multi-analyst approach has the potential to strengthen the robustness of results and conclusions obtained from analyses of datasets in basic and applied research.

An older, more diverse population and longer lifespans are major contributors to the anticipated tripling of diabetes prevalence by 2050. Diabetes-related distress affects up to 40% of people with diabetes and may be a higher risk for older adults due to greater prevalence of comorbidities. The objective of the current phenomenological study was to describe how diabetes-related distress might be uniquely experienced by older adults (age ≥65) with type 2 diabetes mellitus (T2DM). Interpretive phenomenology guided the research design and analysis. Everyday life experiences of living with T2DM and elevated diabetes distress were investigated with interpretive interviews. The most prevalent lived experiences were strained relationships with health care providers, guilt, fear, loneliness, and forgetfulness. These experiences created challenges in managing diabetes and increased diabetes-related distress. Improving knowledge regarding the lived experience of older adults with diabetes-related distress may allow health care providers to tailor treatment to this population, thus improving outcomes. [Journal of Gerontological Nursing, 46(3), 37-44.].

An older, more diverse population and longer lifespans are major contributors to the anticipated tripling of diabetes prevalence by 2050. Diabetes-related distress affects up to 40% of people with diabetes and may be a higher risk for older adults due to greater prevalence of comorbidities. The objective of the current phenomenological study was to describe how diabetes-related distress might be uniquely experienced by older adults (age ≥65) with type 2 diabetes mellitus (T2DM). Interpretive phenomenology guided the research design and analysis. Everyday life experiences of living with T2DM and elevated diabetes distress were investigated with interpretive interviews. The most prevalent lived experiences were strained relationships with health care providers, guilt, fear, loneliness, and forgetfulness. These experiences created challenges in managing diabetes and increased diabetes-related distress. Improving knowledge regarding the lived experience of older adults with diabetes-related distress may allow health care providers to tailor treatment to this population, thus improving outcomes. [Journal of Gerontological Nursing, 46(3), 37-44.].

Feedback inhibition by horizontal cells regulates rod and cone photoreceptor calcium channels that control their release of the neurotransmitter glutamate. This inhibition contributes to synaptic gain control and the formation of the center-surround antagonistic receptive fields passed on to all downstream neurons, which is important for contrast sensitivity and color opponency in vision. In contrast to the plasmalemmal GABA transporter found in non-mammalian horizontal cells, there is evidence that the mechanism by which mammalian horizontal cells inhibit photoreceptors involves the vesicular release of the inhibitory neurotransmitter GABA. Historically, inconsistent findings of GABA and its biosynthetic enzyme, L-glutamate decarboxylase (GAD) in horizontal cells, and the apparent lack of surround response block by GABAergic agents diminished support for GABA's role in feedback inhibition. However, the immunolocalization of the vesicular GABA transporter (VGAT) in the dendritic and axonal endings of horizontal cells that innervate photoreceptor terminals suggested GABA was released via vesicular exocytosis. To test the idea that GABA is released from vesicles, we localized GABA and GAD, multiple SNARE complex proteins, synaptic vesicle proteins, and Cav channels that mediate exocytosis to horizontal cell dendritic tips and axonal terminals. To address the perceived relative paucity of synaptic vesicles in horizontal cell endings, we used conical electron tomography on mouse and guinea pig retinas that revealed small, clear-core vesicles, along with a few clathrin-coated vesicles and endosomes in horizontal cell processes within photoreceptor terminals. Some small-diameter vesicles were adjacent to the plasma membrane and plasma membrane specializations. To assess vesicular release, a functional assay involving incubation of retinal slices in luminal VGAT-C antibodies demonstrated vesicles fused with the membrane in a depolarization- and calcium-dependent manner, and these labeled vesicles can fuse multiple times. Finally, targeted elimination of VGAT in horizontal cells resulted in a loss of tonic, autaptic GABA currents, and of inhibitory feedback modulation of the cone photoreceptor Cai, consistent with the elimination of GABA release from horizontal cell endings. These results in mammalian retina identify the central role of vesicular release of GABA from horizontal cells in the feedback inhibition of photoreceptors.

BackgroundPatients with lung cancer (LC) report lower quality of life (QoL) and higher levels of psychological distress compared with other cancer populations. Lung cancer stigma (LCS) may in part explain these findings.AimWe investigated the prevalence of patient-perceived lung cancer stigma (LCS) and its relationships to symptom burden/severity, depression, and deficits in health-related quality of life (HR-QoL).MethodsIn this descriptive, observational, and cross-sectional study, 201 participants were sent questionnaires. These included the Cataldo Lung Cancer Stigma Scale (CLCSS), the Lung Cancer Symptom Scale, the Centre for Epidemiologic Studies-Depression Scale, and the Quality of Life Inventory.ResultsParticipants were on average 69 years old, 52% women, 95% ever smokers, and 18.5% current smokers. The mean total CLCSS score was 53.1 (SD = 14.1; range = 31-94). LCS was significantly correlated with younger age (P

BackgroundPatients with lung cancer (LC) report lower quality of life (QoL) and higher levels of psychological distress compared with other cancer populations. Lung cancer stigma (LCS) may in part explain these findings.AimWe investigated the prevalence of patient-perceived lung cancer stigma (LCS) and its relationships to symptom burden/severity, depression, and deficits in health-related quality of life (HR-QoL).MethodsIn this descriptive, observational, and cross-sectional study, 201 participants were sent questionnaires. These included the Cataldo Lung Cancer Stigma Scale (CLCSS), the Lung Cancer Symptom Scale, the Centre for Epidemiologic Studies-Depression Scale, and the Quality of Life Inventory.ResultsParticipants were on average 69 years old, 52% women, 95% ever smokers, and 18.5% current smokers. The mean total CLCSS score was 53.1 (SD = 14.1; range = 31-94). LCS was significantly correlated with younger age (P

BackgroundAn older, more diverse population and longer life spans are major contributors to the anticipated tripling of Type 2 diabetes prevalence by 2050. Diabetes-related distress affects up to 40% of people diagnosed with Type 2 diabetes and may be a greater risk for older adults due to greater prevalence of comorbidities.ObjectiveThe objective of this phenomenological study was to describe how diabetes-related distress in older adults (≥65 years) with Type 2 diabetes might be uniquely experienced.MethodsParticipants were recruited using convenience sampling and snowball sampling. Interpretive phenomenology guided the research design and analysis. With interpretive interviews, we investigated the everyday health, symptoms, and life experiences of living with Type 2 diabetes and elevated diabetes distress.ResultsAmong the older adults in this study, the most prevalent symptoms were fatigue, hypoglycemia, diarrhea, pain, loss of balance, and falling. These diabetes-related symptoms led to substantial loss of independence, decreased quality of life, and constrained social lives due to restricted activities.DiscussionDiabetes-related distress presents with some unique symptoms and responses in older adults. Improving knowledge regarding the symptom experience of older adults with diabetes-related distress may allow healthcare providers to tailor treatment and thus improve outcomes for older adults struggling with diabetes.

BackgroundAn older, more diverse population and longer life spans are major contributors to the anticipated tripling of Type 2 diabetes prevalence by 2050. Diabetes-related distress affects up to 40% of people diagnosed with Type 2 diabetes and may be a greater risk for older adults due to greater prevalence of comorbidities.ObjectiveThe objective of this phenomenological study was to describe how diabetes-related distress in older adults (≥65 years) with Type 2 diabetes might be uniquely experienced.MethodsParticipants were recruited using convenience sampling and snowball sampling. Interpretive phenomenology guided the research design and analysis. With interpretive interviews, we investigated the everyday health, symptoms, and life experiences of living with Type 2 diabetes and elevated diabetes distress.ResultsAmong the older adults in this study, the most prevalent symptoms were fatigue, hypoglycemia, diarrhea, pain, loss of balance, and falling. These diabetes-related symptoms led to substantial loss of independence, decreased quality of life, and constrained social lives due to restricted activities.DiscussionDiabetes-related distress presents with some unique symptoms and responses in older adults. Improving knowledge regarding the symptom experience of older adults with diabetes-related distress may allow healthcare providers to tailor treatment and thus improve outcomes for older adults struggling with diabetes.

In the last 20 years, the United States has made stunning progress reducing the rate of adult smoking. However, the smallest reduction is among older adults. Compared to younger smokers, older smokers are more likely to be lower socioeconomic status (SES), have several tobacco related comorbidities, and are less likely to be treated for tobacco addiction yet, in tobacco policy, they are not considered a marginalized group. The tobacco industry's interest in older smokers contrasts with the lack of interest shown by tobacco control. A double whammy is a set of two bad events or situations that have an effect at the same time. The purposes of this article are to use the health disparity paradigm to (a) discuss the "double whammy" of marginalization by tobacco control and valuation by the tobacco industry on the health of older smokers and (b) provide strategies to promote health equity for older smokers.

In the last 20 years, the United States has made stunning progress reducing the rate of adult smoking. However, the smallest reduction is among older adults. Compared to younger smokers, older smokers are more likely to be lower socioeconomic status (SES), have several tobacco related comorbidities, and are less likely to be treated for tobacco addiction yet, in tobacco policy, they are not considered a marginalized group. The tobacco industry's interest in older smokers contrasts with the lack of interest shown by tobacco control. A double whammy is a set of two bad events or situations that have an effect at the same time. The purposes of this article are to use the health disparity paradigm to (a) discuss the "double whammy" of marginalization by tobacco control and valuation by the tobacco industry on the health of older smokers and (b) provide strategies to promote health equity for older smokers.

BackgroundMany health conditions perceived to be contagious, dangerous or incurable, or resulting in clearly visible signs, share a common attribute - an association with stigma and discrimination. While the etiology of stigma may differ between conditions and, sometimes, cultural settings, the manifestations and psychosocial consequences of stigma and discrimination are remarkably similar. However, the vast majority of studies measuring stigma or addressing stigma through interventions employ a disease-specific approach.Main bodyThe current paper opposes this siloed approach and advocates a generic concept of 'health-related stigma' in both stigma measurement and stigma interventions. Employing a conceptual model adapted from Weiss, the current paper demonstrates the commonalities among several major stigmatized conditions by examining how several stigma measurement instruments, such as the Social Distance Scale, Explanatory Model Interview Catalogue, Internalized Stigma of Mental Illness, and Berger stigma scale, and stigma reduction interventions, such as information-based approaches, contact with affected persons, (peer) counselling, and skills building and empowerment, were used successfully across a variety of conditions to measure or address stigma. The results demonstrate that 'health-related stigma' is a viable concept with clearly identifiable characteristics that are similar across a variety of stigmatized health conditions in very diverse cultures.ConclusionA more generic approach to the study of health-related stigma opens up important practical opportunities - cross-cutting measurement and intervention tools are resource saving and easier to use for personnel working with multiple conditions, allow for comparison between conditions, and recognize the intersectionality of many types of stigma. Further research is needed to build additional evidence demonstrating the advantages and effectiveness of cross-condition approaches to stigma measurement and interventions.

BackgroundMany health conditions perceived to be contagious, dangerous or incurable, or resulting in clearly visible signs, share a common attribute - an association with stigma and discrimination. While the etiology of stigma may differ between conditions and, sometimes, cultural settings, the manifestations and psychosocial consequences of stigma and discrimination are remarkably similar. However, the vast majority of studies measuring stigma or addressing stigma through interventions employ a disease-specific approach.Main bodyThe current paper opposes this siloed approach and advocates a generic concept of 'health-related stigma' in both stigma measurement and stigma interventions. Employing a conceptual model adapted from Weiss, the current paper demonstrates the commonalities among several major stigmatized conditions by examining how several stigma measurement instruments, such as the Social Distance Scale, Explanatory Model Interview Catalogue, Internalized Stigma of Mental Illness, and Berger stigma scale, and stigma reduction interventions, such as information-based approaches, contact with affected persons, (peer) counselling, and skills building and empowerment, were used successfully across a variety of conditions to measure or address stigma. The results demonstrate that 'health-related stigma' is a viable concept with clearly identifiable characteristics that are similar across a variety of stigmatized health conditions in very diverse cultures.ConclusionA more generic approach to the study of health-related stigma opens up important practical opportunities - cross-cutting measurement and intervention tools are resource saving and easier to use for personnel working with multiple conditions, allow for comparison between conditions, and recognize the intersectionality of many types of stigma. Further research is needed to build additional evidence demonstrating the advantages and effectiveness of cross-condition approaches to stigma measurement and interventions.

BACKGROUND: An older, more diverse population and longer life spans are major contributors to the anticipated tripling of Type 2 diabetes prevalence by 2050. Diabetes-related distress affects up to 40% of people diagnosed with Type 2 diabetes and may be a greater risk for older adults due to greater prevalence of comorbidities. OBJECTIVE: The objective of this phenomenological study was to describe how diabetes-related distress in older adults (≥65 years) with Type 2 diabetes might be uniquely experienced. METHODS: Participants were recruited using convenience sampling and snowball sampling. Interpretive phenomenology guided the research design and analysis. With interpretive interviews, we investigated the everyday health, symptoms, and life experiences of living with Type 2 diabetes and elevated diabetes distress. RESULTS: Among the older adults in this study, the most prevalent symptoms were fatigue, hypoglycemia, diarrhea, pain, loss of balance, and falling. These diabetes-related symptoms led to substantial loss of independence, decreased quality of life, and constrained social lives due to restricted activities. DISCUSSION: Diabetes-related distress presents with some unique symptoms and responses in older adults. Improving knowledge regarding the symptom experience of older adults with diabetes-related distress may allow healthcare providers to tailor treatment and thus improve outcomes for older adults struggling with diabetes.

ContextPain may be a potentially modifiable risk factor for expensive and burdensome emergency department (ED) visits near the end of life for older adults with dementia.ObjectivesThe objective of this study was to assess the effect of pain and unmet need for pain management on ED visits in the last month of life in older adults with dementia.MethodsThis is a mortality follow-back study of older adults with dementia in the National Health and Aging Trends Study who died between 2012 and 2014, linked to Medicare claims.ResultsTwo hundred eighty-one National Health and Aging Trends Study decedents with dementia met criteria (mean age 86 years, 61% female, 81% white). Fifty-seven percent had at least one ED visit in the last month of life, and 46.5% had an ED visit that resulted in a hospital admission. Almost three out of four (73%) of decedents experienced pain in the last month of life, and 10% had an unmet need for pain management. After adjustment for age, gender, race, educational attainment, income, comorbidities, and impairment in activities of daily living, pain was not associated with increased ED use in the last month of life (adjusted incident rate ratio 0.87, 95% CI 0.64-1.17). However, decedents with unmet need for pain management had an almost 50% higher rate of ED visits in the last month of life than those without unmet needs (adjusted incident rate ratio 1.46, 95% CI 1.07-1.99).ConclusionAmong older adults with dementia, unmet need for pain management was associated with more frequent ED visits in the last month of life.

BackgroundBy 2030, the Sub-Saharan African region is projected to be the epicenter of the tobacco epidemic. While smoking prevalence is currently low among women ( 94%); however, specific knowledge of associated health-risks was limited. More than 96% perceived female tobacco use as socially unacceptable. At the same time, more than 70% were able to name potential benefits of using tobacco for both personal consumption and non-personal use. Respondents reported greater experimentation with khat versus tobacco and 73% reported that their religion significantly influenced their tobacco-related attitudes. Overall, there were higher reports of exposure to anti-tobacco (70%) versus pro-tobacco (49%) messaging, in the last 30 days.ConclusionsThe high level of awareness of health risks associated with tobacco use and SHS exposure and the high exposure to anti-tobacco messaging are community-level strengths that can proactively be built on to prevent the projected disease burden associated with tobacco. Findings have implications for the development of contextualized gender-specific tobacco control interventions, particularly in relation to the promotion of smoke-free homes.

ContextPain may be a potentially modifiable risk factor for expensive and burdensome emergency department (ED) visits near the end of life for older adults with dementia.ObjectivesThe objective of this study was to assess the effect of pain and unmet need for pain management on ED visits in the last month of life in older adults with dementia.MethodsThis is a mortality follow-back study of older adults with dementia in the National Health and Aging Trends Study who died between 2012 and 2014, linked to Medicare claims.ResultsTwo hundred eighty-one National Health and Aging Trends Study decedents with dementia met criteria (mean age 86 years, 61% female, 81% white). Fifty-seven percent had at least one ED visit in the last month of life, and 46.5% had an ED visit that resulted in a hospital admission. Almost three out of four (73%) of decedents experienced pain in the last month of life, and 10% had an unmet need for pain management. After adjustment for age, gender, race, educational attainment, income, comorbidities, and impairment in activities of daily living, pain was not associated with increased ED use in the last month of life (adjusted incident rate ratio 0.87, 95% CI 0.64-1.17). However, decedents with unmet need for pain management had an almost 50% higher rate of ED visits in the last month of life than those without unmet needs (adjusted incident rate ratio 1.46, 95% CI 1.07-1.99).ConclusionAmong older adults with dementia, unmet need for pain management was associated with more frequent ED visits in the last month of life.

IntroductionOlder Chinese Americans often defer end-of-life care discussions. Researchers sought to explore how to engage older Chinese Americans and their families in end-of-life care discussions and to understand the optimal timing to initiate such discussions.MethodsIndividual, semistructured interviews were conducted with 14 community-dwelling older Chinese Americans, 9 adult children, and 7 clinicians. The data were collected and analyzed using focused ethnographic methodology.ResultsOlder Chinese Americans and their families would discuss end-of-life care when introduced at "optimal times," which included after-triggering events (e.g., death of loved ones, fall accidents), changes in health status, or advanced age.DiscussionAdult children are not expected to initiate end-of-life care discussions with their parents. Thus, culturally congruent health care that could better engage Chinese Americans in such discussions would be optimized by having clinicians proactively assess their patients' readiness and initiate such discussion at optimal times.

INTRODUCTION:Older Chinese Americans often defer end-of-life care discussions. Researchers sought to explore how to engage older Chinese Americans and their families in end-of-life care discussions and to understand the optimal timing to initiate such discussions. METHODS:Individual, semistructured interviews were conducted with 14 community-dwelling older Chinese Americans, 9 adult children, and 7 clinicians. The data were collected and analyzed using focused ethnographic methodology. RESULTS:Older Chinese Americans and their families would discuss end-of-life care when introduced at "optimal times," which included after-triggering events (e.g., death of loved ones, fall accidents), changes in health status, or advanced age. DISCUSSION:Adult children are not expected to initiate end-of-life care discussions with their parents. Thus, culturally congruent health care that could better engage Chinese Americans in such discussions would be optimized by having clinicians proactively assess their patients' readiness and initiate such discussion at optimal times.