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Background The CARD study demonstrated superiority of cabazitaxel over abiraterone/enzalutamide in patients with metastatic castration-resistant prostate cancer (mCRPC) who received prior docetaxel and progressed ≤12 months on the alternative androgen-receptor-targeted agent (ARTA). The objective was to compare characteristics and treatment patterns of patients from a real-world dataset with the CARD population. Methods Real-world data were collected from Medimix Live TrackerTM, a retrospective, global oncology database of healthcare professional-reported electronic patient medical forms (2001–2019), with data from patients from Europe, USA, Brazil and Japan. The database contained patient, tumor and treatment information for 12,140 patients who received ≥1 line of treatment for mCRPC. A CARD-like cohort included patients treated with docetaxel, prior abiraterone/enzalutamide and cabazitaxel. Results A large proportion of patients received ≥2 lines of ARTA (35.1%) with 42% of patients who received a first-line ARTA receiving another ARTA in second line. Of the total patients, 452 were eligible for the CARD-like cohort. Median age of the CARD-like cohort was comparable to CARD (73 vs 70 years). The CARD-like cohort had unfavorable disease characteristics vs CARD: ECOG PS ≥ 2 (45% vs 4.7%); metastasis at diagnosis (46% vs 38%) and Gleason 8–10 (65% vs 57%). More patients in the CARD-like cohort received ARTA before docetaxel (48% vs 39%) and received the first ARTA for >12 months (30% vs 17%) compared with CARD. Despite more patients in the CARD-like cohort receiving the lower 20 mg/m2 dose of cabazitaxel (55% vs 21%), cabazitaxel treatment duration was similar (21.9 vs 22.0 weeks). Conclusions Sequential use of ARTA was frequent. Results indicate the CARD population is reflective of routine clinical practice and duration of response to cabazitaxel was similar in a real-world population.

Background Morbidity and Mortality (M&M) conferences allow clinicians to review adverse events and identify areas for improvement. There are few reports of structured M&M conferences in low- and middle-income countries and no report of collaborative efforts to standardize them. Methods The present study aims to gather general surgeons representing most of Peru’s urban surgical care and, in collaboration, with trauma quality improvement experts develop a M&M conferences toolkit with the expectation that its diffusion impacts their reported clinical practice. Fourteen general surgeons developed a toolkit as part of a working group under the auspices of the Peruvian General Surgery Society. After three years, we conducted an anonymous written questionnaire to follow-up previous observations of quality improvement practices. Results A four-component toolkit was developed: Toolkit component #1: Conference logistics and case selection; Toolkit component #2: Documenting form; Toolkit component #3: Presentation template; and Toolkit component #4: Code of conduct. The toolkit was disseminated to 10 hospitals in 2016. Its effectiveness was evaluated by comparing the results of surveys on quality improvement practices conducted in 2016, before toolkit dissemination (101 respondents) and 2019 (105 respondents). Lower attendance was reported by surgeons in 2019. However, in 2019, participants more frequently described “improve the system” as the perceived objective of M&M conferences (70.5% vs. 38.6% in 2016; p Conclusion We established a toolkit for the national dissemination of a standardized M&M conference. Three years following the initial assessment in Peru, we found similar practice patterns except for increased reporting of “system improvement” as the goal of M&M conferences.

Macrophages are ubiquitously distributed throughout the various tissues of the body and perform many functions including the orchestration of inflammatory responses against pathogens by classically activated M1 macrophages and the regulation of wound healing and tissue remodeling by anti-inflammatory, alternatively activated M2 macrophages. The responsibility for these pleiotropic functions lies in the expression of a myriad of surface receptors unique to given subsets of macrophages. Much of what we know about the function of human macrophage subsets has been gleaned by studying in vitro generated macrophages matured in the presence of GM-CSF or M-CSF and polarized with different cytokines. Oftentimes, culture conditions, such as the type of serum used, the duration of the culture, and the use of polarizing cytokines, vary between studies making direct comparisons difficult. Sample preparation and processing (e.g., Ficoll

Family members of critically ill patients with COVID-19 have described increased symptoms of Post-Traumatic Stress Disorder (PTSD). Little is known about how these symptoms may change over time.We studied changes in PTSD symptoms in family members of critically ill patients with COVID-19 over 12-months.This prospective, multi-site observational cohort study recruited participants at 12 hospitals in 5 states. Calls were made to participants at 3-4 months, 6-months, and 12-months post-patient admission to the ICU.There were 955 eligible family members, of whom 330 (53.3% of those reached) consented to participate. Complete longitudinal data was acquired for 115 individuals (34.8% of consented). PTSD symptoms were measured by the Impact of Events Scale-6 (IES-6), with a score of ≥10 identifying significant symptoms. At 3-months, the mean IES-6 score was 11.9±6.1 with 63.6% having significant symptoms, decreasing to 32.9% at one year (mean IES-6 score 7.6±5.0). Three clusters of symptom evolution emerged over time: persistent symptoms (34.8%, n=40), recovered symptoms (33.0%, n=38) and non-development of symptoms (32.2%, n=37). While participants identifying as Hispanic demonstrated initially higher adjusted IES-6 scores (2.57 points higher [95% CI: 1.1, 4.1, p =0.001]), they also demonstrated a more dramatic improvement in adjusted scores over time (4.7 greater decrease at 12 months [95% CI: 3.2-6.3, p.001]).One year later, some family members of patients with COVID-19 continue to experience significant symptoms of PTSD. Further studies are needed to better understand how various differences contribute to increased risk for these symptoms.

"Smart"-scales are a new tool for frequent monitoring of weight change as well as weigh-in behavior. These scales give researchers the opportunity to discover patterns in the frequency that individuals weigh themselves over time, and how these patterns are associated with overall weight loss. Our motivating data come from an 18-month behavioral weight loss study of 55 adults classified as overweight or obese who were instructed to weigh themselves daily. Adherence to daily weigh-in routines produces a binary times series for each subject, indicating whether a participant weighed in on a given day. To characterize weigh-in by time-invariant patterns rather than overall adherence, we propose using hierarchical clustering with dynamic time warping (DTW). We perform an extensive simulation study to evaluate the performance of DTW compared to Euclidean and Jaccard distances to recover underlying patterns in adherence time series. In addition, we compare cluster performance using cluster validation indices (CVIs) under the single, average, complete, and Ward linkages and evaluate how internal and external CVIs compare for clustering binary time series. We apply conclusions from the simulation to cluster our real data and summarize observed weigh-in patterns. Our analysis finds that the adherence trajectory pattern is significantly associated with weight loss.

IMPORTANCE: The psychological symptoms associated with having a family member admitted to the intensive care unit (ICU) during the COVID-19 pandemic are not well defined. OBJECTIVE: To examine the prevalence of symptoms of stress-related disorders, primarily posttraumatic stress disorder (PTSD), in family members of patients admitted to the ICU with COVID-19 approximately 90 days after admission. DESIGN, SETTING, AND PARTICIPANTS: This prospective, multisite, mixed-methods observational cohort study assessed 330 family members of patients admitted to the ICU (except in New York City, which had a random sample of 25% of all admitted patients per month) between February 1 and July 31, 2020, at 8 academic-affiliated and 4 community-based hospitals in 5 US states. EXPOSURE: Having a family member in the ICU with COVID-19. MAIN OUTCOMES AND MEASURES: Symptoms of PTSD at 3 months, as defined by a score of 10 or higher on the Impact of Events Scale 6 (IES-6). RESULTS: A total of 330 participants (mean [SD] age, 51.2 [15.1] years; 228 [69.1%] women; 150 [52.8%] White; 92 [29.8%] Hispanic) were surveyed at the 3-month time point. Most individuals were the patients’ child (129 [40.6%]) or spouse or partner (81 [25.5%]). The mean (SD) IES-6 score at 3 months was 11.9 (6.1), with 201 of 316 respondents (63.6%) having scores of 10 or higher, indicating significant symptoms of PTSD. Female participants had an adjusted mean IES-6 score of 2.6 points higher (95% CI, 1.4-3.8; P

Forty-four million US licensed drivers are ≥65 years old and at higher crash risk. Decision-making about stopping or continuing driving is difficult and often involves family and friends. This study examines if decision conflict about changing driving habits is associated between older adult drivers and their study partners (SPs) (i.e., family member or friend). Data were from a multi-site trial assessing a driving decision aid. Decision conflict about stopping or continuing driving for drivers and their SPs were measured with the Decision Conflict Scale (DCS). Dyadic associations between drivers’ and SPs’ DCS scores pre- and post-decision aid implementation were analyzed using an actor-partner interdependence model. Among 228 driver-SP dyads, driver mean (SD) age was 77.1 (5.1) years; 50.0% female; 98.7% non-Hispanic; 94.7% white; and 97.8% urban-dwelling. SPs mean age was 66.1 years (13.9); 65.8% female; 95.6% non-Hispanic; 92.1% white; and commonly the driver’s spouse (54.6%) or adult child (21.1%). Most drivers (71.7%) and SPs (63.3%) had baseline DCS scores < 25 (drivers mean 18.5 (SD 12.3); SPs 20.5 (16.8)), suggesting low decision conflict. DCS was correlated within dyads at baseline (r=0.18, p < 0.01), and baseline DCS was associated with post-decision aid DCS (p < 0.001 for SPs [β=0.73] and drivers [β=0.73]). While SPs’ baseline DCS was not associated with drivers’ post-decision aid DCS, drivers’ baseline DCS and SPs’ post-decision DCS were (β=0.10; p=0.036). Higher decision conflict about driving felt by older drivers is frequently shared by their SPs, in whom decision conflict may persist even after a driving decision aid intervention.

The decision to stop or continue driving can be challenging for older adults. In a prospective two-arm randomized trial, we sought to test whether an online driving decision aid (DDA) would improve decision quality. We recruited 301 English-speaking licensed drivers, age ≥70 years, without significant cognitive impairment but with ≥1 diagnosis associated with increased likelihood of driving cessation, from clinics associated with study sites in three states. They were randomized to view 1) the online Healthwise® DDA for older adults addressing “Is it time to stop driving?”; or 2) a control condition of web-based information. Our primary outcome was decision conflict as estimated by the Decisional Conflict Scale (DCS; lower scores indicate higher quality). Secondary outcomes were knowledge and decision self-efficacy about driving decisions. We examined differences in post-randomization outcomes by study arm using generalized linear mixed-effects models with adjustment for site and pre-randomization scores. Intervention participants had a lower mean DCS score (12.3 DDA vs 15.2 control; p=0.017) and a higher mean knowledge score (88.9 DDA vs 79.9 control; p=0.038); we found no difference between groups in self-efficacy scores. The DDA had high acceptability; 86.9% of those who viewed it said they would recommend it to others in similar situations.The online Healthwise® DDA decreased decision conflict and increased knowledge in this sample of English-speaking, older adults without significant cognitive impairment. Use of such resources in clinical or community settings may support older adults as they transition from driving to other forms of mobility.

Nonlinear propagation of intense laser pulses in condensed media, including liquid water, is under study in experiments and numerical modeling. Recent simulations reveal previously unknown laser-generated plasma effects on stimulated Raman scattering and four-wave mixing.

Ongoing progress in laser and accelerator technology opens new possibilities in high-field science, notably for the study of the largely unexplored strong-field QED regime where electron-positron pairs can be created directly from light-matter or even light-vacuum interactions. Laserless strategies such as beam-beam collisions have also been proposed with the prospect of pushing strong-field quantum electrodynamics (SFQED) in the nonpertubative regime. Here we report on an original concept to probe strong-field QED by harnessing the interaction between an electron beam and a solid target. When a high-density, ultrarelativistic beam impinges onto an even denser plasma, the beam self fields are reflected at the plasma boundary. In the rest frame of the beam electrons, these fields can exceed the Schwinger field, leading to strong-field QED effects such as quantum nonlinear inverse Compton scattering and nonlinear Breit-Wheeler electron-positron pair creation. We show that such beam-plasma collisions can produce results similar to beam-beam collisions with the advantage of a much simpler experimental setup including the automatic overlap between the beam and the reflected fields. This scenario opens the way to precision studies of strong-field QED, with measurable clear signatures in terms of gamma-ray photon and pair production, and thus is a very promising milestone on the path towards laserless studies of nonperturbative SFQED.

Stimulated Raman scattering is ubiquitous in many high-intensity laser environments. Parametric four-wave mixing between the pump and Raman sidebands can affect the Raman gain, but stringent phase matching requirements and strongly nonlinear dynamics obscure clear understanding of its effects at high laser powers. Here we investigate four-wave mixing in the presence of strong self-focusing and weak ionization at laser powers above the Kerr critical power. Theoretical analysis shows that the plasma generated at focus naturally leads to phase matching conditions suitable for enhanced Raman gain, almost without regard to the initial phase mismatch. Multidimensional nonlinear optical simulations with multiphoton and collisional ionization confirm the enhancement and suggest that it may lead to significantly higher Raman losses in some high-intensity laser environments.

Intense laser interactions in condensed optical media are under study at NRL for several Navy applications, including remote undersea laser acoustic generation and advanced micromachining. We have developed models and simulation codes for nonlinear propagation and interactions in water. Our modeling includes the effects of stimulated Raman scattering (SRS), optical Kerr effect, parametric four-wave mixing (FWM) and nonlinear coupling involving pump, Stokes and anti-Stokes waves, multiphoton and collisional ionization, plasma refraction, diffraction and dispersion. 1 , 2 Our models are incorporated into the SNOPROP 2D axisymmetric nonlinear propagation and interaction simulation code (open-source, in Python). 3 , 4 Our modeling simulations showed good agreement with recent nonlinear propagation experiments. 1 Both our model and code can be used for a variety of condensed dielectric optical media.

As the world continues to fight the coronavirus pandemic caused by SARS‐CoV‐2, we are gaining valuable insights by comparing this virus to other human coronaviruses such as SARS‐CoV and MERS‐CoV that have also caused outbreaks. Coronaviruses infect many animal species, but disease severity varies between strains. Viral accessory proteins are generally implicated in increased infectivity, pathogenicity, and virulence. The accessory protein open reading frame 8 (ORF8), although not essential for viral replication, appears to play a critical role in disease severity by inhibiting multiple pathways of the immune response. Furthermore, the ORF8 gene is found within a highly variable portion of the genome, increasing the possibility of dangerous mutant forms arising. Structure‐based design of therapeutics holds great promise for effective targeting of such rapidly evolving threats. Thus, we designed physical models and computer representations of ORF8, based on the published structure 7JTL, to better evaluate the structural features responsible for viral pathogenicity. ORF8 exists as a homodimer held together by amino acid residues that interact through hydrophobic interactions, hydrogen bonding, a salt bridge, and a disulfide bond. These interactions occur in a region referred to as the covalent interface. Another interface, referred to as the noncovalent interface, exists between separate homodimers and results in oligomerization. The homodimers in the oligomer are held together by an intermolecular beta sheet that is stabilized by an extensive hydrophobic surface. These two dimerization interfaces are unique to SARS‐CoV‐2 and have been proposed to be involved in the protein's ability to evade and suppress the host immune response. The computer and physical representations allow for better visualization of the ORF8 structure to evaluate the role of the multimeric structure. ORF8 has been found to interact with various host proteins, including Interleukin‐17 Receptor A (IL17RA), a pro‐inflammatory cytokine. To further corroborate the existence of this interaction and to better understand the role oligomerization might play in pathogenicity, we assessed the possible interactions of ORF8 (7JTL) and IL17RA (5N9B) through theoretical modeling using available tools such as HDOCK. A better understanding of these inter‐subunit interactions may improve our understanding of the unique mechanism the virus uses to evade the immune system and may be instrumental in the development of effective therapeutics.

To report a case of a patient with overlapping posterior reversible encephalopathy syndrome (PRES) and reversible cerebral vasoconstriction syndrome (RCVS), and review the existing literature emphasizing the pathophysiological overlap of these two entities.We conducted a literature search in electronic database PubMed identifying studies reporting the overlap of PRES and RCVS.PRES and RCVS are two increasingly recognized entities that share similar clinical and imaging features. PRES is characterized by vasogenic edema predominantly in the parieto-occipital regions, associated with acute onset of neurological symptoms including encephalopathy, seizures, headaches, and visual disturbances. RCVS is characterized by reversible segmental and multifocal vasoconstriction of the cerebral arteries and classically presents with thunderclap headache, with or without associated focal neurological deficits and seizures. PRES is frequently associated with uncontrolled hypertension but can also be seen in the setting of renal failure, exposure to cytotoxic agents, or pre-eclampsia. RCVS is often triggered by exposure to vasoactive agents, postpartum state, or immunosuppression. We report a case of a patient presenting with vision changes and hemiparesis, and found to have extensive cytotoxic and vasogenic edema involving the cortex and subcortical white matter on brain imaging. These changes were primarily noted in the parieto-occipital and brainstem regions, along with features of reversible vasculopathy on vascular imaging suggestive of coexisting PRES and RCVS.PRES and RCVS share precipitating factors, clinical and radiological features, and frequently co-exist, suggesting a common pathophysiological mechanism related to reversible dysregulation of cerebral vasculature, endothelial dysfunction, and breakdown of the blood-brain barrier.

OBJECTIVES Since its inception, skeletally based paleodemographic research has emphasized the utility of biocultural models for interpreting the dynamic relationship between the sociocultural and ecological forces accompanying demographic transitions and shaping populations' health and well-being. While the demographic transition associated with the Neolithic Revolution has been a common focus in bioarcheology, the present study analyzes human skeletal remains from a large 19th century cemetery in central Indiana to examine population dynamics during the second demographic transition, a period generally characterized by decreasing fertility rates and improvements in life expectancy. This study demonstrates the potential to methodologically identify regional variations in the timing and interactions between broad-scale socioeconomic changes and technological advancements that characterized the time period through observed changes in survivorship and fertility based on age-at-death distributions. MATERIALS AND METHODS This study uses three temporally distinct samples (AD 1827-1869; 1870-1889; 1890-1935) from the Bethel Cemetery (n = 503). Kaplan-Meier survival analyses with a log- rank tests are utilized to evaluate survivorship and mortality over time. Next, Cox proportional hazard analyses are employed to examine the interaction between sex and time as covariates. Finally, the D0-14/D ratio is applied to estimate fertility for each of the three temporally bounded cohorts. RESULTS The Kaplan-Meier survival analyses and Cox proportional hazard modeling revealed statistically significant differences in survivorship between the three time periods. Age-specific mortality rates are reduced among adult female and male age classes in this rural community over the course of the 19th and early 20th centuries, resulting in the increasing life expectancies associated with the second demographic transition. While mortality in early adulthood was common during the first time period and decreases thereafter, sex was not identified as a meaningful covariate. The proportion of juveniles in the three temporal samples indicate that fertility rates were higher than national averages for the better part of the 19th century and subsequently declined around the turn of 20th century for this community. CONCLUSIONS The results indicate temporal differences between the three periods, demonstrating increased survivorship and decreased mortality and fertility over time. These findings corroborate two key features of the second demographic transition characterized by the move from high rates of both fertility and mortality to reduced rates and a general easing of demographic pressures. The observed trends likely reflect improvements in health, coinciding the industrial advance and economic development within and around Indianapolis. While the socioeconomic factors characterizing the Industrial Revolution drove demographic shifts that parallel an equally important epidemiological transition, potential regional differences are discussed to highlight variability in the timing of demographic transitions. The paleodemographic methods utilized in this study demonstrate improved accuracy and efficacy, which ultimately advances researchers' potential to disentangle population-specific socioeconomic factors that may contribute to asymmetrical experiences of health and mortality.

Sources of high-energy photons have important applications in almost all areas of research. However, the photon flux and intensity of existing sources is strongly limited for photon energies above a few hundred keV. Here we show that a high-current ultrarelativistic electron beam interacting with multiple submicrometer-thick conducting foils can undergo strong self-focusing accompanied by efficient emission of gamma-ray synchrotron photons. Physically, self-focusing and high-energy photon emission originate from the beam interaction with the near-field transition radiation accompanying the beam-foil collision. This near field radiation is of amplitude comparable with the beam self-field, and can be strong enough that a single emitted photon can carry away a significant fraction of the emitting electron energy. After beam collision with multiple foils, femtosecond collimated electron and photon beams with number density exceeding that of a solid are obtained. The relative simplicity, unique properties, and high efficiency of this gamma-ray source open up new opportunities for both applied and fundamental research including laserless investigations of strong-field QED processes with a single electron beam., Comment: 17 pages, 11 figures, matches published article

Mesa Verse National Park, located in southwestern Colorado, honors the cultural significance of the fantastic cliff dwellings of the Ancestral Pueblo people, who lived in the area from AD 600 to 1300. Originally these native peoples lived on top of the mesa, but began building structures into the cliffside in the first half of the 12th century. This ancient development area includes single-room structures all the way up to larger villages with more than 150 rooms. Spruce Tree House is the third-largest and best-preserved cliff dwelling in the Park. It was constructed about 800 years ago in a naturally formed alcove, cut into the Cliff House Sandstone formation. The Spruce Tree House alcove measures about 216 ft wide by 89 ft deep. The alcove is located across a deep, narrow canyon from the Park museum and is a very popular tourist destination.

We present a new water phase synthesis method for lead sulfide colloidal quantum dots, and test their applicability for use in photovoltaics. The quantum dots are synthesized inside ferritin protein shells (PbS-FTN). Our synthesis method is simpler than what has previously been reported for PbS-FTN quantum dots, namely we demonstrate that the synthesizing reaction can be run in an aerobic environment and with a Pb:S ratio of 1:1. Protection from photocorrosion is demonstrated by comparing the time evolution of photoluminescence from PbS-FTN with that of non-ferritin PbS quantum dots. In the photovoltaic testing, we use a dye-sensitized solar cell scheme with PbS-FTN as the dye and test several methods to adsorb PbS-FTN to the mesoporous TiO2 layer which is coated on the solar cell anodes. The highest performing cell shows an efficiency of 0.29% using the drop casting method.