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Durable response to chimeric antigen receptor T (CART) cell therapy remains limited in part due to CART cell exhaustion. Here, we investigate the regulation of CART cell exhaustion with three independent approaches including: a genome-wide CRISPR knockout screen using an in vitro model for exhaustion, RNA and ATAC sequencing on baseline and exhausted CART cells, and RNA and ATAC sequencing on pre-infusion CART cell products from responders and non-responders in the ZUMA-1 clinical trial. Each of these approaches identify interleukin (IL)-4 as a regulator of CART cell dysfunction. Further, IL-4-treated CD8 + CART cells develop signs of exhaustion independently of the presence of CD4 + CART cells. Conversely, IL-4 pathway editing or the combination of CART cells with an IL-4 monoclonal antibody improves antitumor efficacy and reduces signs of CART cell exhaustion in mantle cell lymphoma xenograft mouse models. Therefore, we identify both a role for IL-4 in inducing CART exhaustion and translatable approaches to improve CART cell therapy., (© 2024. The Author(s).)

Background: Plasmodium falciparum, the malaria-causing parasite, is a leading cause of infection-induced deaths worldwide. The preferred treatment approach is artemisinin-based combination therapy, which couples fast-acting artemisinin derivatives with longer-acting drugs, such as lumefantrine, mefloquine, and amodiaquine. However, the urgency for new treatments has risen due to the parasite's growing resistance to existing therapies. In this study, a common characteristic of the P. falciparum proteome-stretches of poly-lysine residues, such as those found in proteins related to adhesion and pathogenicity-is investigated for its potential to treat infected erythrocytes., Methods: This study utilizes in vitro culturing of intra-erythrocytic P. falciparum to assess the ability of poly-lysine peptides to inhibit the parasite's growth, measured via flow cytometry of acridine orange-stained infected erythrocytes. The inhibitory effect of many poly-lysine lengths and modifications were tested this way. Affinity pull-downs and mass spectrometry were performed to identify the proteins interacting with these poly-lysines., Results: A single dose of these poly-basic peptides can successfully diminish parasitemia in human erythrocytes in vitro with minimal toxicity. The effectiveness of the treatment correlates with the length of the poly-lysine peptide, with 30 lysine peptides supporting the eradication of erythrocytic parasites within 72 h. PEG-ylation of the poly-lysine peptides or utilizing poly-lysine dendrimers and polymers retains or increases parasite clearance efficiency and bolsters the stability of these potential new therapeutics. Lastly, affinity pull-downs and mass-spectrometry identify P. falciparum's outer membrane proteins as likely targets for polybasic peptide medications., Conclusion: Since poly-lysine dendrimers are already FDA-approved for drug delivery and this study displays their potency against intraerythrocytic P. falciparum, their adaptation as anti-malarial drugs presents a promising new therapeutic strategy for malaria., (© 2024. The Author(s).)

Objectives: To investigate the relationship between preoperative inflammatory markers and recurrence of CIN after loop electrosurgical excision procedure (LEEP)., Methods: A retrospective historical cohort study was conducted at gynecologic oncology unit, Bhumibol Adulyadej Hospital, Royal Thai Air Force, Thailand. Data was collected from medical records of CIN cases from year 2016 to 2021. Inclusion criteria were subjects who were diagnosed of CIN and underwent LEEP with pathologic confirmation and followed up for two years (at 6 months, 1 year, and 2 years). Preoperative complete blood count (CBC) was obtained within one month for calculation as systemic inflammatory values., Results: One hundred and ten cases of CIN were enrolled. Mean age of participants was 48.1 years old. Three-fourths (83/110) of the participants had histological confirmation as CIN2/3. Sixteen (18/110) and twenty (22/110) percentage of cases had recurrence of disease at 1 and 2 years, respectively. Monocytes /lymphocytes ratio (MLR) and systemic inflammation response index (SIRI) could predict recurrence of CIN within 2 years. MLR more than 0.16 and SIRI more than 0.57 gave the sensitivity and negative predictive value (NPV) at percentage of 77.3/ 81.8 and 91.8/ 90.2, respectively. Combination of MLR and SIRI had sensitivity and NPV at 90.5 and 95.4 percent, respectively. MLR and SIRI could not predict marginal involvement, glandular involvement, and LEEP confirmed CIN 2/3., Conclusion: Pretreatment MLR and SIRI were statistically significant in predicting the recurrence in CIN after post LEEP procedure within 2 years follow up.

Objective: To evaluate the effect of chair placement on length of time physicians sit during a bedside consultation and patients' satisfaction., Design: Single center, double blind, randomized controlled deception trial., Setting: County hospital in Texas, USA., Participants: 51 hospitalist physicians providing direct care services, and 125 observed encounters of patients who could answer four orientation questions correctly before study entry, April 2022 to February 2023., Intervention: Each patient encounter was randomized to either chair placement (≤3 feet (0.9 m) of patient's bedside and facing the bed) or usual chair location (control)., Main Outcome Measures: The primary outcome was the binary decision of the physician to sit or not sit at any point during a patient encounter. Secondary outcomes included patient satisfaction, as assessed with the Tool to Assess Inpatient Satisfaction with Care from Hospitalists (TAISCH) and the Hospital Consumer Assessment of Healthcare Providers and Systems (HCAHPS) surveys, time in the room, and both physicians' and patients' perception of time in the room., Results: 125 patient encounters were randomized (60 to chair placement and 65 to control). 38 of the 60 physicians in the chair placement group sat during the patient encounter compared with five of the 65 physicians in the control group (odds ratio 20.7, 95% confidence interval 7.2 to 59.4; P<0.001). The absolute risk difference between the intervention and control groups was 0.55 (95% confidence interval 0.42 to 0.69). Overall, 1.8 chairs needed to be placed for a physician to sit. Intervention was associated with 3.9% greater TAISCH scores (effect estimate 3.9, 95% confidence interval 0.9 to 7.0; P=0.01) and 5.1 greater odds of complete scores on HCAHPS (95% confidence interval 1.06 to 24.9, P=0.04). Chair placement was not associated with time spent in the room (10.6 minutes v control 10.6 minutes) nor perception of time in the room for physicians (9.4 minutes v 9.8 minutes) or patients (13.1 minutes v 13.5 minutes)., Conclusion: Chair placement is a simple, no cost, low tech intervention that increases a physician's likelihood of sitting during a bedside consultation and resulted in higher patients' scores for both satisfaction and communication., Trial Registration: ClinicalTrials.gov NCT05250778., Competing Interests: Competing interests: All authors have completed the ICMJE uniform disclosure form at www.icmje.org/disclosure-of-interest/ and declare: no support from any organization for the submitted work; no financial relationships with any organizations that might have an interest in the submitted work in the previous three years; no other relationships or activities that could appear to have influenced the submitted work., (© Author(s) (or their employer(s)) 2019. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Recent advances in methodology have made phosphopeptide analysis a tractable problem for many proteomics researchers. There are now a wide variety of robust and accessible enrichment strategies to generate phosphoproteomes while free or inexpensive software tools for quantitation and site localization have simplified phosphoproteome analysis workflow tremendously. As a research group under the Association for Biomolecular Resource Facilities umbrella, the Proteomics Standards Research Group has worked to develop a multipathway phosphopeptide standard based on a mixture of heavy-labeled phosphopeptides designed to enable researchers to rapidly develop assays. This mixture contains 131 mass spectrometry vetted phosphopeptides specifically chosen to cover as many known biologically interesting phosphosites as possible from seven different signaling networks: AMPK signaling, death and apoptosis signaling, ErbB signaling, insulin/insulin-like growth factor-1 signaling, mTOR signaling, PI3K/AKT signaling, and stress (p38/SAPK/JNK) signaling. Here, we describe a characterization of this mixture spiked into a HeLa tryptic digest stimulated with both epidermal growth factor and insulin-like growth factor-1 to activate the MAPK and PI3K/AKT/mTOR pathways. We further demonstrate a comparison of phosphoproteomic profiling of HeLa performed independently in five labs using this phosphopeptide mixture with data-independent acquisition. Despite different experimental and instrumentation processes, we found that labs could produce reproducible, harmonized datasets by reporting measurements as ratios to the standard, while intensity measurements showed lower consistency between labs even after normalization. Our results suggest that widely available, biologically relevant phosphopeptide standards can act as a quantitative "yardstick" across laboratories and sample preparations enabling experimental designs larger than a single laboratory can perform. Raw data files are publicly available in the MassIVE dataset MSV000090564., Competing Interests: Conflict of interest B. C. S. is a founder and shareholder in Proteome Software, which operates in the field of proteomics. A. J. N. and J. M. R. are employees of Cell Signaling Technology. A. W. H. and B. P. are employees of Thermo Fisher Scientific., (Copyright © 2023 The Authors. Published by Elsevier Inc. All rights reserved.)

Older patients have an increased risk of depression, neglect, and abuse. Studies demonstrate that spiritual and religious coping is important at times of personal crisis, but few studies explore the impact of religion on older persons' experiences of aging, illness, and impending death. This study set out to identify recurring spiritual and clinical themes shared by retirement home residents in the context of a Christian faith-based processing group. A qualitative cohort study of residents over the age of 65 was conducted at a retirement home in Chicago, Illinois. The study consisted of 8 hour-long Scripture-based processing group sessions co-led by a study researcher and the onsite chaplain. Questionnaires were administered to each group and handwritten responses were collected and analyzed to identify recurring clinical and spiritual themes. Ten participants enrolled in the group study. The questionnaire completion rate was 35% (49/140). The most recurring clinical themes included 1) events of death or terminal illness and 2) physical limitations. The most recurring spiritual themes included 1) God's presence and 2) prayer and worship. The most recurring coded theme overall was family. This study provided insight into the spiritual experiences of older Christians in one retirement home community. Increased awareness of the spiritual perspectives of the geriatric population may strengthen the doctor-patient relationship and lead to improvements in clinical care., Competing Interests: The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article., (© Catholic Medical Association 2023.)

Objectives: New Zealand pharmacists have been providing immunisation services since 2011. Literature from other developed countries reports the positive experience of people with community pharmacy immunisation services resulting in expansion of the scope of pharmacy practice. However, there is a dearth of such data in a New Zealand context. Therefore, we aimed to understand patients' experiences with pharmacy immunisation services in New Zealand., Methods: A self-administered questionnaire developed after considering the aims and objectives of the study, and previously published literature was delivered to 14 pharmacies covering a range of socio-economic areas across New Zealand. The survey assessed patients' experiences in a community pharmacy setting and measured their satisfaction using a 5-point Likert scale., Key Findings: Out of the 364 survey participants, 60.7% were female, 76.9% were of European ethnicity and 43.4% belonged to the age group of 45-64 years. Convenience (65.4%) and accessibility (44.8%) were cited as the most common reasons for choosing a community pharmacy to receive vaccinations. Over 90% of the respondents reported that they were satisfied with the pharmacy immunisation services, were vaccinated professionally, would choose a community pharmacy again next time for vaccination and would like to see pharmacists administering other vaccines., Conclusions: The pharmacy immunisation services were highly valued by patients because of the associated convenience and professionalism demonstrated by the pharmacists. A possible expansion of pharmacist-administered vaccination services to a wider range of vaccines will not only improve access to immunisation but will also potentially escalate immunisation rates., (© The Author(s) 2023. Published by Oxford University Press on behalf of the Royal Pharmaceutical Society.)

Objectives: To examine the relationship between neighborhood-level advantage and severe obstructive sleep apnea (OSA) in children., Methods: A retrospective case-control study was conducted on 249 children who underwent adenotonsillectomy and had full-night polysomnography conducted within 6 months prior. Patients were divided into more or less socioeconomically disadvantaged groups using a validated measure, the area deprivation index (ADI). The primary outcomes were the relationship between the apnea-hypopnea index (AHI) and the presence of severe OSA, and the secondary outcome was residual moderate or greater OSA after tonsillectomy., Results: Of the 249 children included in the study, 175 (70.3%) were socially disadvantaged (ADI > 50). The median (interquartile range [IQR]) age was 9.4 (7.3-12.3) years, 129 (51.8%) were male, and the majority were White (151, 60.9%), Black (51, 20.6%), and/or of Hispanic (155, 62.5%) ethnicity. A total of 140 (56.2%) children were obese. The median (IQR) AHI was 8.9 (3.9-20.2). There was no significant difference in the median AHI or the presence of severe OSA between the more and less disadvantaged groups. Severe OSA was found to be associated with obesity (odds ratio [OR] = 3.13, 95% confidence interval [CI] = 1.83-5.34), and residual moderate or greater OSA was associated with older age (OR = 1.20, 95% CI = 1.05-1.38)., Conclusions: The ADI was not significantly associated with severe OSA or residual OSA in this cohort of children. Although more neighborhood-level disadvantage may increase the risk of comorbidities associated with OSA, it was not an independent risk factor in this study., Level of Evidence: Level 4., Competing Interests: The authors declare no conflict of interest., (© 2023 The Authors. Laryngoscope Investigative Otolaryngology published by Wiley Periodicals LLC on behalf of The Triological Society.)

Purpose: To explore distress in the medical profession and how it was highlighted by the ongoing COVID-19 pandemic. The term "orientational distress" was developed to name the experience of a breakdown in the patterns of moral self-understanding and one's capacity to navigate professional responsibilities., Method: The Enhancing Life Research Laboratory at the University of Chicago convened a 5-session online workshop (total 10 hours, May-June 2021) to explore orientational distress and to promote collaboration between academics and physicians. Sixteen participants from Canada, Germany, Israel, and the United States engaged in discussions of the conceptual framework and toolkit to address orientational distress within institutional settings. The tools included 5 dimensions of life, 12 dynamics of life, and the role of counterworlds. Follow-up narrative interviews were transcribed and coded using a consensus-based iterative process., Results: Participants reported that the concept of orientational distress helped explain their professional experiences better than burnout or moral distress. Moreover, participants strongly endorsed the project's supporting thesis that collaborative work on orientational distress and the tools provided in the research laboratory had a specific intrinsic value and provided benefits not found in other support instruments., Conclusions: Orientational distress compromises medical professionals and threatens the medical system. Next steps include the dissemination of materials from the Enhancing Life Research Laboratory to more medical professionals and medical schools. In contrast to burnout and moral injury, the concept of orientational distress may better enable clinicians to understand and more fruitfully navigate the challenges of their professional situations., Competing Interests: Other disclosures: On behalf of all authors, the corresponding author states that there are no conflicts of interest., (Copyright © 2023 by the Association of American Medical Colleges.)

The R-carvedilol enantiomer, present in the racemic mixture of the chiral drug carvedilol, does not bind to the β-adrenergic receptors, but exhibits skin cancer preventive activity. For skin delivery, R-carvedilol-loaded transfersomes were prepared using various ratios of drug, lipids, and surfactants, and characterized for particle size, zeta potential, encapsulation efficiency, stability, and morphology. Transfersomes were compared for in vitro drug release and ex vivo skin penetration and retention. Skin irritation was evaluated by viability assay on murine epidermal cells and reconstructed human skin culture. Single-dose and repeated-dose dermal toxicity was determined in SKH-1 hairless mice. Efficacy was evaluated in SKH-1 mice exposed to single or multiple ultraviolet (UV) radiations. Transfersomes released the drug at a slower rate, but significantly increased skin drug permeation and retention compared with the free drug. The transfersome with a drug-lipid-surfactant ratio of 1:3:0.5 (T-RCAR-3) demonstrated the highest skin drug retention and was selected for further studies. T-RCAR-3 at 100 µM did not induce skin irritation in vitro and in vivo. Topical treatment with T-RCAR-3 at 10 µM effectively attenuated acute UV-induced skin inflammation and chronic UV-induced skin carcinogenesis. This study demonstrates feasibility of using R-carvedilol transfersome for preventing UV-induced skin inflammation and cancer.

Targeted selection-based genome-editing approaches have enabled many fundamental discoveries and are used routinely with high precision. We found, however, that replacement of DBP1 with a common selection cassette in budding yeast led to reduced expression and function for the adjacent gene, MRP51 , despite all MRP51 coding and regulatory sequences remaining intact. Cassette-induced repression of MRP51 drove all mutant phenotypes detected in cells deleted for DBP1 . This behavior resembled the 'neighboring gene effect' (NGE), a phenomenon of unknown mechanism whereby cassette insertion at one locus reduces the expression of a neighboring gene. Here, we leveraged strong off-target mutant phenotypes resulting from cassette replacement of DBP1 to provide mechanistic insight into the NGE. We found that the inherent bidirectionality of promoters, including those in expression cassettes, drives a divergent transcript that represses MRP51 through combined transcriptional interference and translational repression mediated by production of a long undecoded transcript isoform (LUTI). Divergent transcript production driving this off-target effect is general to yeast expression cassettes and occurs ubiquitously with insertion. Despite this, off-target effects are often naturally prevented by local sequence features, such as those that terminate divergent transcripts between the site of cassette insertion and the neighboring gene. Thus, cassette-induced off-target effects can be eliminated by the insertion of transcription terminator sequences into the cassette, flanking the promoter. Because the driving features of this off-target effect are broadly conserved, our study suggests it should be considered in the design and interpretation of experiments using integrated expression cassettes in other eukaryotic systems, including human cells., Competing Interests: EP, CC, ED, LL, JK, MJ, GB No competing interests declared, (© 2022, Powers et al.)

Objective: Physician motivation has been described as the reason, purpose, and force that drives people to pursue their work, and motivating factors include those that are intrinsic or extrinsic to the work. Social forces may contribute to motivational disparities between medical school and actual practice., Methods: A secondary data analysis of two national surveys (medical students and practicing physicians from various specialties) was conducted. Content analysis was performed on open-ended survey items that elicited students' and physicians' responses to meaningful experiences in medicine., Results: In the medical student sample, four themes were identified as factors intrinsic to medicine: role models, clinical experiences, patient interactions, and peer interactions. In total, intrinsic factors comprised 86.5% (193/208) of coded responses. In the practicing physician sample, five themes were identified as factors intrinsic to medicine: difficult patient interactions, conflict with colleagues or staff, meaningful patient interactions, involvement in medical education-research-academia, and medicine as a calling/mission. In total, intrinsic factors comprised 24.0% (140/582) of coded responses., Conclusions: Our findings suggest that the reality of social forces in medicine threatens the ability of practicing physicians to derive meaning from their work, although students and physicians still report intrinsic motivation from establishing meaningful relationships. Further research is needed to explore what strategies enable physicians to wisely navigate the dynamic interactions of intrinsic and extrinsic motivators over various stages of their careers. These strategies could include encouraging reflective spaces in physicians' workplaces that have a specific focus on sustaining intrinsic motivation in medicine.

Background: Avocados are a rich dietary source of monounsaturated fatty acids, carotenoids, and phenolic compounds. Clinical studies have demonstrated that oral consumption of carotenoids improved skin aging. However, no studies have investigated whether oral intake of avocado will reduce skin aging., Objectives: We therefore performed this pilot study to assess whether oral consumption of one avocado daily for 8 weeks can reduce skin aging in healthy overweight women assessing skin physical characteristics and resistance to UVB radiation., Methods: Thirty-nine female participants (age 27-73 years) with Fitzpatrick skin type II-IV were randomly assigned to consume either one avocado daily or continue habitual diet for 8 weeks. Facial skin elasticity, firmness, pigmentation, sebum, and hydration were determined using a cutometer on the forehead and under eye. Minimal erythema dose (MED) was determined by standardized protocol at inner arm., Results: Elasticity and firmness were increased at forehead comparing 8 weeks to baseline in the avocado group. Comparing avocado to control, change in firmness marker from baseline to week 8 indicated a significant increase in forehead skin firmness in the avocado group. We did not observe any change in hydration, pigmentation, sebum, and UVB resistance between the avocado and control group, although changes in melanin and erythema were observed in both groups over time., Conclusions: Our findings suggest that daily oral avocado consumption may lead to enhanced elasticity and firmness of the facial skin in healthy women. Further studies of other skin locations are required to establish the connection between avocado consumption and skin aging., (© 2022 The Authors. Journal of Cosmetic Dermatology published by Wiley Periodicals LLC.)

Objective: To compare closure rates of endoscopic and microscopic tympanoplasty (MT) as influenced by perforation size, perforation location, and graft position., Study Design: Retrospective chart review., Setting: Tertiary university medical center., Patients: Adult patients who underwent tympanoplasty by a fellowship-trained neurotologist from January 2010 to December 2019, had at least 2 months of follow-up, and had a tympanic perforation with no cholesteatoma before surgery., Interventions: Transcanal endoscopic tympanoplasty (ET) or MT., Main Outcome Measures: The primary outcome is postoperative closure of the tympanic membrane perforation as assessed using otomicroscopy at the last follow-up appointment., Results: Two-hundred and eleven patients-98 in the transcanal ET group and 113 in the MT group-were identified. Tympanic membrane closure rates were not significantly different between the ET and MT groups (79.6% and 84.1% respectively; P = 0.473), and further multivariable analysis revealed that closure rates for ET relative to MT had an insignificant odds ratio (0.56; P = 0.144). Similar analyses also found no significant difference between the 2 methods in subsets of perforation size (small, large, subtotal/total), perforation location (anterior, posterior, inferior), and graft position (underlay, overlay)., Conclusions: ET resulted in similar rates of postoperative closure rates compared with the microscopic technique., Competing Interests: Jacob Hunter, Brandon Isaacson, and Walter Kutz are each a member of the editorial board for Otology & Neurotology Open and have been recused from reviewing or making decisions for the manuscript. No other authors have any conflicts of interest to declare., (Copyright © 2022 The Authors. Published by Wolters Kluwer Health, Inc. on behalf of Otology & Neurotology, Inc.)

Acne affects 1 in 10 people globally, often resulting in disfigurement. The disease involves excess production of lipids, particularly squalene, increased growth of Cutibacterium acnes , and a host inflammatory response with foamy macrophages. By combining single-cell and spatial RNA sequencing as well as ultrahigh-resolution Seq-Scope analyses of early acne lesions on back skin, we identified TREM2 macrophages expressing lipid metabolism and proinflammatory gene programs in proximity to hair follicle epithelium expressing squalene epoxidase. We established that the addition of squalene induced differentiation of TREM2 macrophages in vitro, which were unable to kill C. acnes . The addition of squalene to macrophages inhibited induction of oxidative enzymes and scavenged oxygen free radicals, providing an explanation for the efficacy of topical benzoyl peroxide in the clinical treatment of acne. The present work has elucidated the mechanisms by which TREM2 macrophages and unsaturated lipids, similar to their involvement in atherosclerosis, may contribute to the pathogenesis of acne.

The 2021-2026 Strategic Plan of the National Institute of Neurological Disorders and Stroke began with a vision, a mission, and strategic objectives elaborated from within the institute. This plan is a collaborative product of the institute and its many stakeholders, emphasizing cross-cutting operational principles including scientific rigor, communication, workforce culture, and equity., Competing Interests: Declaration of interests The authors declare no competing interests., (Published by Elsevier Inc.)

Background: Little is known about the prevalence of Ancylostoma in dogs in the Caribbean. In view of the number of owned free-roaming and feral dogs within the islands and the ideal subtropical climate for parasite development and environmental survival, Ancylostoma could pose a threat to the health of the dogs as well as a zoonotic risk to people., Methods: To determine whether generalities about Ancylostoma in dogs in the Caribbean could be made and to obtain a better understanding of the prevalence, published (Scielo, Scopus, and PubMed databases) and gray (e.g., student theses, conference presentations) literature was reviewed. Retrieved manuscripts were screened, and relevant data (year, location, dog population, method of diagnosis, positivity rate) were extracted. Data from two dog populations on St. Kitts also were included: a 2014 field study involving dogs with limited veterinary care and data from the Ross University School of Veterinary Medicine's Veterinary Clinic records for 2018-2019., Results: Fourteen manuscripts from the 1950s to 2019, representing ten of the Caribbean islands/countries and the Bahamas, were identified. Methods of diagnosing infection status ranged from simple qualitative or quantitative flotation methods to centrifugation with Sheather's sugar flotation solution or necropsy. Dog populations sampled included stray, owned free-roaming, and owned confined. Reported rates of Ancylostoma infection ranged from 10 to 91%. Studies from the last 10 years indicate positivity rates of 21 to 73%. Ancylostoma positivity rates in the St. Kitts' populations were 61% and 10% for the 2014 and 2018-2019 populations, respectively., Conclusions: There was no indication that hookworm prevalence has changed over time in the Caribbean, and there were no obvious differences between owned and unowned dogs or free-roaming and confined dogs. The data from St. Kitts were on par with positivity rates from the other islands within the last 10 years and reflective of the impact that veterinary care, including anthelmintic treatment, is expected to have on parasites in pets. There is a clear need to expand the available data for the region and improve control programs for Ancylostoma infections to protect both canine and human health., (© 2022. The Author(s).)

Background: Almonds are a rich source of phenolic and polyphenolic compounds, which have antioxidant activity. In vitro and in vivo studies have demonstrated that topical application of almond oil and almond skin extract reduces UVB-induced photoaging. Ultraviolet-B (UVB) protection by oral almond consumption has not been previously studied in humans., Objectives: To investigate whether oral almond consumption can increase resistance to UVB radiation and reduce skin aging in healthy Asian women., Methods: Thirty-nine female participants (18-45 years) with Fitzpatrick skin type II-IV were randomly assigned to consume either 1.5 oz of almonds or 1.8 oz of pretzels daily for 12 weeks. Minimal erythema dose (MED) was determined using a standardized protocol, which determined the minimal radiation needed to induce erythema on the inner arm following UVB exposure. Facial skin texture was evaluated by two dermatologists using the Clinician's Erythema Assessment scale and Allergan Roughness scale. Facial melanin index, hydration, sebum, and erythema were determined using a cutometer., Results: The MED was increased in the subjects consuming almonds compared to the control group consuming pretzels. There were no differences noted between the groups consuming almonds versus pretzels in Allergan roughness, melanin, hydration, or sebum on facial skin., Conclusions: Our findings suggest that daily oral almond consumption may lead to enhanced protection from UV photodamage by increasing the MED., (© 2021 The Authors. Journal of Cosmetic Dermatology published by Wiley Periodicals LLC.)

Cognitive function impairment due to high altitude exposure has been reported with some contradictory results regarding the possible selective cognitive domain involvement. We prospectively evaluated in 36 lowlanders, exposed for 3 consecutive days to an altitude of 3,269 m, specific cognitive abilities (attention, processing speed, and decision-making) required to safely explore the mountains, as well as to work at altitude. We simultaneously monitored the physiological parameters. Our study provides evidence of a reduced processing speed in lowlanders when exposed to altitude in the first 24 h. There was a fairly quick recovery since this impairment was no more detectable after 36 h of exposure. There were no clinically relevant effects on decision-making, while psychomotor vigilance was unaffected at altitude except for individuals with poor sleep. Significant changes were seen in physiological parameters (increased heart rate and reduced peripheral oxygen saturation). Our results may have practical implications, suggesting that individuals should practice prudence with higher ascent when performing risky activities in the first 24-36 h, even at altitudes below 3,500 m, due to an impairment of the cognitive performance that could worsen and lead to accidents., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Falla, Papagno, Dal Cappello, Vögele, Hüfner, Kim, Weiss, Weber, Palma, Mrakic-Sposta, Brugger and Strapazzon.)

Importance: A substantial number of patients discharged to skilled nursing facilities (SNFs) after heart failure (HF) hospitalization experience regression in function or do not improve. Delirium is one of few modifiable risk factors in this patient population. Therefore, understanding the role of delirium in functional recovery may be useful for improving outcomes., Objective: To assess the association of delirium with 30-day functional improvement in patients discharged to SNFs after HF hospitalization., Design, Setting, and Participants: This retrospective cohort study included patients hospitalized for HF in 129 US Department of Veterans Affairs hospitals who were discharged to SNFs from October 1, 2010, to September 30, 2015. Data were analyzed from June 14 to December 18, 2020., Exposures: Delirium, as determined by the Minimum Data Set (MDS) 3.0 Confusion Assessment Method, with dementia as a covariate, determined via International Classification of Diseases, Ninth Revision (ICD-9) coding., Main Outcomes and Measures: The difference between admission and 30-day MDS 3.0 Activities of Daily Living (ADL) scores., Results: A total of 20 495 patients (mean [SD] age, 78 [10.3] years; 78.9% White; and 97% male) were included in the analysis. Of the total sample, 882 patients (4.3%) had delirium on an SNF admission. The mean (SD) baseline ADL score on admission to SNF was significantly worse among patients with delirium than without (18.3 [4.7] vs 16.1 [5.2]; P < .001; d = 0.44.). On the 30-day repeated assessment, mean (SD) function (ADL scores) improved for both patients with delirium (0.6 [2.9]) and without delirium (1.8 [3.6]) (P < .001; d = -0.38). In the multivariate adjusted model, delirium was associated with statistically significant lower ADL improvement (difference in ADL score, -1.07; 95% CI, -1.31 to -0.83; P < .001)., Conclusions and Relevance: In this retrospective cohort study, patients with HF discharged to SNFs with delirium were less likely to show improvement in function compared with patients without delirium. Findings suggest a potential need to reexamine how and when health care professionals assess delirium in HF patients throughout their hospitalization and SNF course. Identifying and treating delirium for HF patients earlier in their care trajectory may play an important role in improving care and long-term functional outcomes in this population. Future research is warranted to further investigate the association between delirium and functional recovery for HF and other patient populations.

Background: Efforts have begun to characterize the ethical and professional issues encountered by medical students in their clinical years. By applying previously identified taxonomies to a national sample of medical students, this study seeks to develop generalizable insights that can inform professional identity formation across various clerkships and medical institutions., Methods: In a national survey of medical students, participants answered an open-ended survey item that asked them to describe a clinical experience involving an ethical or professional issue. We conducted a content analysis with these responses using the Kaldjian taxonomy of ethical and professionalism themes in medical education through an iterative, consensus-building process. Noting the emerging virtues-based approach to ethics and professionalism, we also reexamined the data using a taxonomy of virtues., Results: The response rate to this survey item was 144 out of 499 eligible respondents (28.9%). All 144 responses were successfully coded under one or more themes in the original taxonomy of ethical and professional issues, resulting in a total of 173 coded responses. Professional duties was the most frequently coded theme (29.2%), followed by Communication (26.4%), Quality of care (18.8%), Student-specific issues of moral distress (16.7%), Decisions regarding treatment (16.0%), and Justice (13.2%). In the virtues taxonomy, 180 total responses were coded from the 144 original responses, and the most frequent virtue coded was Wisdom (23.6%), followed by Respectfulness (20.1%) and Compassion or Empathy (13.9%)., Conclusions: Originally developed from students' clinical experiences in one institution, the Kaldjian taxonomy appears to serve as a useful analytical framework for categorizing a variety of clinical experiences faced by a national sample of medical students. This study also supports the development of virtue-based programs that focus on cultivating the virtue of wisdom in the practice of medicine.

Mutations in GBA1, the gene mutated in Gaucher disease, are a common genetic risk factor for Parkinson disease, although the penetrance is low. We performed [ 18 F]-fluorodopa positron emission tomography studies of 57 homozygous and heterozygous GBA1 mutation carriers (15 with parkinsonism) and 98 controls looking for early indications of dopamine loss using voxelwise analyses to identify group differences in striatal [ 18 F]-fluorodopa uptake (K i ). Forty-eight subjects were followed longitudinally. Cross-sectional and longitudinal comparisons of K i and K i change found significant effects of Parkinson disease. However, at baseline and over time, striatal [ 18 F]-fluorodopa uptake in mutation carriers without parkinsonism did not significantly differ from controls. ANN NEUROL 2020;87:652-657., (© 2020 American Neurological Association.)

Background: Little evidence supports use of chlorhexidine gluconate (CHG) baths to reduce health care-associated infections, including central catheter-associated bloodstream infections in infants less than 2 months old., Objective: To describe the safety of biweekly CHG baths in infants less than 2 months old by measuring blood levels of CHG, liver and renal function, skin reactions, and adverse events., Methods: Study participants received twice-weekly 2% CHG baths, weekly blood tests, and twice-daily skin assessments. Adverse events were monitored., Results: Ten infants 36 to 48 weeks' postmenstrual age with central venous catheters admitted to the neonatal or cardiac intensive care unit were enrolled before the study was closed by the Food and Drug Administration. The 9 patients contributing data had 83 CHG exposures; 31 CHG levels were analyzed. All patients had evidence of CHG absorption. Seven patients had CHG levels of 100 ng/mL or greater. Findings did not support accumulation of CHG but did show evidence of higher absorption than previously reported. Results of liver and renal function studies remained within reference limits. No patient had any adverse events, including skin reactions., Conclusions: Although no adverse events were observed, our patients had evidence of CHG absorption. The effects of this absorption remain unknown. More research is needed to determine safe blood levels of CHG in infants less than 2 months of age., (©2019 American Association of Critical-Care Nurses.)

In vitro and animal studies have demonstrated that topical application and oral consumption of pomegranate reduces UVB-induced skin damage. We therefore investigated if oral pomegranate consumption will reduce photodamage from UVB irradiation and alter the composition of the skin microbiota in a randomized controlled, parallel, three-arm, open label study. Seventy-four female participants (30-45 years) with Fitzpatrick skin type II-IV were randomly assigned (1:1:1) to 1000 mg of pomegranate extract (PomX), 8 oz of pomegranate juice (PomJ) or placebo for 12 weeks. Minimal erythema dose (MED) and melanin index were determined using a cutometer (mexameter probe). Skin microbiota was determined using 16S rRNA sequencing. The MED was significantly increased in the PomX and PomJ group compared to placebo. There was no significant difference on phylum, but on family and genus level bacterial composition of skin samples collected at baseline and after 12 week intervention showed significant differences between PomJ, PomX and placebo. Members of the Methylobacteriaceae family contain pigments absorbing UV irradiation and might contribute to UVB skin protection. However, we were not able to establish a direct correlation between increased MED and bacterial abundance. In summary daily oral pomegranate consumption may lead to enhanced protection from UV photodamage.

Nutritional deficiencies, including deficiencies of vitamin B12, copper, and vitamin C, may result in cytopenias and hematologic symptoms. Early recognition of these deficiencies is imperative for prompt treatment and improvement in hematologic and other manifestations. We describe 5 cases which illustrate the hematologic manifestations of nutritional deficiencies and challenges to initial diagnosis and management. Supplementation of the deficient vitamin or micronutrient in all of these cases resulted in rapid resolution of cytopenias, hemorrhage, and other associated hematologic symptoms. We also review other nutritional deficiencies that manifest with hematologic symptoms and compile recommendations on treatment and expected time to response.

While previous studies have considered medical student burnout and resilience at discrete points in students' training, few studies examine how stressors and resilience-building factors can emerge before, and during, medical school. Our study focuses on students' life stories to comprehensively identify factors contributing to student wellbeing. We performed a secondary analysis of life-story interviews with graduating fourth year medical students. These interviews were originally conducted in 2012 as part of the Project on the Good Physician, and then re-analyzed, focusing on student wellbeing. Respondents were encouraged to identify turning points in their life stories. De-identified transcripts were then coded using a consensus-based iterative process. 17 of 21 respondents reported feeling burned out at least once during medical school. Students identified three major stressors: negative role models, difficult rotations, and the United States Medical Licensing Examination Step 1. Two "motivational stressors"-financial concerns and personal life events-emerged as sources of stress that also motivated students to persevere. Finally, students identified four factors-positive role models, support networks, faith and spirituality, and passion-that helped them reframe stressors, making the struggle seem more worthwhile. These findings suggest that a life-story approach can add granularity to current understandings of medical student wellbeing. Initiatives to reduce stress and burnout should extend beyond the immediate medical school context and consider how past challenges might become future sources of resilience. This study also provides an example of secondary analysis of qualitative data, an approach which could be useful to future research in medical education.

Background: As the demand for cosmetic treatments increases, it is important for dermatology residents to be educated about and achieve proficiency in dermatologic cosmetic procedures., Objective: To assess dermatology residents' educational exposure to cosmetic dermatology., Materials and Methods: An anonymous 18-question survey was sent electronically to 1,266 dermatology residents requesting information about cosmetic dermatology training during residency., Results: Two hundred sixty-eight residents responded to the survey (21% response rate). Most residents receive didactic instruction (94%) and hands-on training (91%) on cosmetic dermatology topics during residency. Survey participants in residency programs perceived as supportive of cosmetic dermatology training are more frequently provided lectures (70% vs 31%, p < .001) and procedural training (100% vs 69%, p < .001) in cosmetic dermatology as compared to residents in unsupportive programs. Eighty-nine percent of respondents reported hands-on training as the most effective method for developing proficiency in cosmetic procedures., Conclusion: Providing safe and competent patient care should serve as the impetus for expanding cosmetic dermatology education and training for residents.

Purpose We evaluated the combination of talimogene laherparepvec plus ipilimumab versus ipilimumab alone in patients with advanced melanoma in a phase II study. To our knowledge, this was the first randomized trial to evaluate addition of an oncolytic virus to a checkpoint inhibitor. Methods Patients with unresectable stages IIIB to IV melanoma, with no more than one prior therapy if BRAF wild-type, no more than two prior therapies if BRAF mutant, measurable/injectable disease, and without symptomatic autoimmunity or clinically significant immunosuppression were randomly assigned 1:1 to receive talimogene laherparepvec plus ipilimumab or ipilimumab alone. Talimogene laherparepvec treatment began in week 1 (first dose, ≤ 4 mL × 10 6 plaque-forming units/mL; after 3 weeks, ≤ 4 mL × 10 8 plaque-forming units/mL every 2 weeks). Ipilimumab (3 mg/kg every 3 weeks; up to four doses) began week 1 in the ipilimumab alone arm and week 6 in the combination arm. The primary end point was objective response rate evaluated by investigators per immune-related response criteria. Results One hundred ninety-eight patients were randomly assigned to talimogene laherparepvec plus ipilimumab (n = 98), or ipilimumab alone (n = 100). Thirty-eight patients (39%) in the combination arm and 18 patients (18%) in the ipilimumab arm had an objective response (odds ratio, 2.9; 95% CI, 1.5 to 5.5; P = .002). Responses were not limited to injected lesions; visceral lesion decreases were observed in 52% of patients in the combination arm and 23% of patients in the ipilimumab arm. Frequently occurring adverse events (AEs) included fatigue (combination, 59%; ipilimumab alone, 42%), chills (combination, 53%; ipilimumab alone, 3%), and diarrhea (combination, 42%; ipilimumab alone, 35%). Incidence of grade ≥ 3 AEs was 45% and 35%, respectively. Three patients in the combination arm had fatal AEs; none were treatment related. Conclusion The study met its primary end point; the objective response rate was significantly higher with talimogene laherparepvec plus ipilimumab versus ipilimumab alone. These data indicate that the combination has greater antitumor activity without additional safety concerns versus ipilimumab.

Key Points: Bronchopulmonary dysplasia is a disease of extreme prematurity that occurs when the immature lung is exposed to gas ventilation. We designed a novel 'artificial womb' system for supporting extreme premature lambs (called EXTEND) that obviates gas ventilation by providing oxygen via a pumpless arteriovenous circuit with the lamb submerged in sterile artificial amniotic fluid. In the present study, we compare different arteriovenous cannulation strategies on EXTEND, including carotid artery/jugular vein (CA/JV), carotid artery/umbilical vein (CA/UV) and umbilical artery/umbilical vein (UA/UV). Compared to CA/JV and CA/UV cannulation, UA/UV cannulation provided significantly higher, physiological blood flows to the oxygenator, minimized flow interruptions and supported significantly longer circuit runs (up to 4 weeks). Physiological circuit blood flow in UA/UV lambs made possible normal levels of oxygen delivery, which is a critical step toward the clinical application of artificial womb technology., Abstract: EXTEND (EXTra-uterine Environment for Neonatal Development) is a novel system that promotes physiological development by maintaining the premature lamb in a sterile fluid environment and providing gas exchange via a pumpless arteriovenous oxygenator circuit. During the development of EXTEND, different cannulation strategies evolved with the aim of improving circuit flow. The present study examines how different cannulation strategies affect EXTEND circuit haemodynamics in extreme premature lambs. Seventeen premature lambs were cannulated at gestational ages 105-117 days (term 145-150 days) and supported on EXTEND for up to 4 weeks. Experimental groups were distinguished by cannulation strategy: carotid artery outflow and jugular vein inflow (CA/JV; n = 4), carotid artery outflow and umbilical vein inflow (CA/UV; n = 5) and double umbilical artery outflow and umbilical vein inflow (UA/UV; n = 8). Circuit flows and pressures were measured continuously. As we transitioned from CA/JV to CA/UV to UA/UV cannulation, mean duration of circuit run and weight-adjusted circuit flows increased (P < 0.001) and the frequency of flow interruptions declined (P < 0.05). Umbilical vessels generally accommodated larger-bore cannulas, and cannula calibre was directly correlated with circuit pressures and indirectly correlated with flow:pressure ratio (a measure of post-membrane resistance). We conclude that UA/UV cannulation in fetal lambs on EXTEND optimizes circuit flow dynamics and flow stability and also supports circuit flows that closely approximate normal placental flow., (© 2018 The Authors. The Journal of Physiology © 2018 The Physiological Society.)

Studies of the human skin microbiome suggest that Propionibacterium acnes strains may contribute differently to skin health and disease. However, the immune phenotype and functions of T helper type 17 (Th17) cells induced by healthy (P H ) versus acne (P A ) skin-associated P. acnes strains are currently unknown. We stimulated peripheral blood mononuclear cells from healthy donors and observed that P A strains induce higher IL-17 levels than P H strains. We next generated P H and P A strain-specific Th17 clones and show that P. acnes strains induce Th17 cells of varied phenotype and function that are stable in the presence of IL-2 and IL-23. Although P H - and P A -specific clones expressed similar levels of LL-37 and DEFB4, only P H -specific clones secreted molecules sufficient to kill P. acnes. Furthermore, electron microscopic studies showed that supernatants derived from activated P H and not P A -specific clones exhibited robust bactericidal activity against P. acnes, and complete breaches in the bacterial cell envelope were observed. This antimicrobial activity was independent of IL-26, because both natural IL-26 released by Th17 clones and rhIL-26 lacked antimicrobial potency against P. acnes. Overall, our data suggest that P. acnes strains may differentially modulate the CD4 + T-cell responses, leading to the generation of Th17 cells that may contribute to either homeostasis or acne pathogenesis., (Copyright © 2017 The Authors. Published by Elsevier Inc. All rights reserved.)

Background: Acne vulgaris is a disease of the pilosebaceous unit characterized by increased sebum production, hyperkeratinization, and immune responses to Propionibacterium acnes (PA). Here, we explore a possible mechanism by which a lipid receptor, G2A, regulates immune responses to a commensal bacterium., Objective: To elucidate the inflammatory properties of G2A in monocytes in response to PA stimulation. Furthermore, our study sought to investigate pathways by which lipids modulate immune responses in response to PA., Methods: Our studies focused on monocytes collected from human peripheral blood mononuclear cells, the monocytic cell line THP-1, and a lab strain of PA. Our studies involved the use of enzyme-linked immunosorbent, Western blot, reverse transcription polymerase chain reaction, small interfering RNA (siRNA), and microarray analysis of human acne lesions in the measurements of inflammatory markers., Results: G2A gene expression is higher in acne lesions compared to normal skin and is inducible by the acne therapeutic, 13-cis-retinoic acid. In vitro , PA induces both the Toll-like receptor 2-dependent expression of G2A as well as the production of the G2A ligand, 9-hydroxyoctadecadienoic acid, from human monocytes. G2A gene knockdown through siRNA enhances PA stimulation of interleukin (IL)-6, IL-8, and IL-1β possibly through increased activation of the ERK1/2 MAP kinase and nuclear factor kappa B p65 pathways., Conclusion: G2A may play a role in quelling inflammatory cytokine response to PA, revealing G2A as a potential attenuator of inflammatory response in a disease associated with a commensal bacterium., Competing Interests: CONFLICTS OF INTEREST: The authors have nothing to disclose.

Since Zika virus (ZIKV) was detected in Brazil in 2015, it has spread explosively across the Americas and has been linked to increased incidence of microcephaly and Guillain-Barré syndrome (GBS). In one year, it has infected over 500,000 people (suspected and confirmed cases) in 40 countries and territories in the Americas. Along with recent epidemics of dengue (DENV) and chikungunya virus (CHIKV), which are also transmitted by Aedes aegypti and Ae. albopictus mosquitoes, the emergence of ZIKV suggests an ongoing intensification of environmental and social factors that have given rise to a new regime of arbovirus transmission. Here, we review hypotheses and preliminary evidence for the environmental and social changes that have fueled the ZIKV epidemic. Potential drivers include climate variation, land use change, poverty, and human movement. Beyond the direct impact of microcephaly and GBS, the ZIKV epidemic will likely have social ramifications for women's health and economic consequences for tourism and beyond., Competing Interests: The authors have declared that no competing interests exist.

Background: Acne vulgaris is one of the three most common cutaneous disorders, affecting approximately 50 million people in the US and many more throughout the world., Objective: We designed a pilot program to explore how patients may interact with cell phone technology to supplement medical care beyond patient reminders that would encompass education, interaction, and data capturing., Methods: Twenty-four patients completed a 3-month study in which participants received daily text message reminders for the first 2 weeks of the study, then once weekly thereafter, to take their oral medication or apply topical therapy either once or twice daily., Results: Over a 3-month time period, patients become less responsive to text message reminders over time. Our survey data demonstrated a very high satisfaction with the program, helping patients follow their acne treatment recommendations (mean score 4.31 out of 5) and results demonstrated the mobile application device was easy to use (mean score 4.56 out of 5)., Limitations: Small sample size of the patient population., Conclusion: Patients find this approach acceptable and helpful, and it is a viable method for counseling patients. Based on our results, for future randomized controlled studies, we suggest maximizing messaging during the first month of therapy.

Introduction Demand for dermatologic services in safety net hospitals, which disproportionately serve patients with darker coloured skin, is growing. Teledermatology has the potential to increase access and improve outcomes, but studies have yet to demonstrate the reliability of teledermatology for all Fitzpatrick skin types. Methods We assessed the reliability of teledermatologists' diagnoses and management recommendations for store-and-forward teledermatology in patients with lightly pigmented (Fitzpatrick skin types I-III) versus darkly pigmented (Fitzpatrick skin types IV-VI) skin, when compared to in-person diagnosis and management decisions. This prospective study enrolled 232 adult patients, presenting with new, visible skin complaints in a Los Angeles county dermatology clinic. Forty-seven percent of patients were Fitzpatrick skin types I-III, and 53% were Fitzpatrick skin types IV-VI. Results Percent concordance for the identical primary diagnosis was 53.2% in lighter (Fitzpatrick I-III) skin types and 56.0% in darker (Fitzpatrick IV-VI) skin types. There was no statistically significant difference in concordance rates between lighter and darker skin types for primary diagnosis. Concordance rates for diagnostic testing, clinic-based therapy, and treatments were similar in both groups of Fitzpatrick skin types. Discussion These results suggest that teledermatology is reliable for the diagnosis and management of patients with all Fitzpatrick skin types.

Propionibacterium acnes is a skin commensal bacterium that contributes to the development of acne vulgaris and other infections. Recent work revealed that P. acnes clinical isolates can be classified into distinct phylotypes, several of which have associations with healthy skin or acne. We sought to determine if these phylotypes induce different immunological responses and express protein factors that may contribute to their disease associations. We found that acne-associated P. acnes phylotypes induced 2- to 3-fold higher levels of IFN-γ and IL-17 in peripheral blood mononuclear cells compared with healthy phylotypes. On the other hand, P. acnes phylotypes associated with healthy skin induced 2- to 4-fold higher levels of IL-10. Comparative proteomic analysis of P. acnes phylotypes revealed a differential expression of several proteins, including an adhesion protein that was expressed at least 10-fold higher in acne-associated phylotypes and a cell surface hydrolase expressed in all phylotypes except those associated with healthy skin. Taken together, our data provide insight into how specific P. acnes phylotypes influence immune responses and the pathogenesis of acne., (Copyright © 2016 The Authors. Published by Elsevier Inc. All rights reserved.)

Purpose: This trial assessed the efficacy and safety of docetaxel monotherapy or docetaxel in combination with ramucirumab (vascular endothelial growth factor receptor 2 antibody) or icrucumab (vascular endothelial growth factor receptor 1 antibody) after progression during or within 12 months of platinum-based regimens for patients with locally advanced or metastatic urothelial carcinoma., Patients and Methods: Patients were randomly assigned (1:1:1) to receive docetaxel 75 mg/m(2) intravenously (IV) on day 1 of a 3-week cycle (arm A), docetaxel 75 mg/m(2) IV plus ramucirumab 10 mg/kg IV on day 1 of a 3-week cycle (arm B), or docetaxel 75 mg/m(2) IV on day 1 plus icrucumab 12 mg/kg IV on days 1 and 8 of a 3-week cycle (arm C). Treatment continued until disease progression or unacceptable toxicity. The primary end point was investigator-assessed progression-free survival (PFS)., Results: A total of 140 patients were randomly assigned and treated in arms A (n = 45), B (n = 46), or C (n = 49). PFS was significantly longer in arm B compared with arm A (median, 5.4 months; 95% CI, 3.1 to 6.9 months v 2.8 months; 95% CI, 1.9 to 3.6 months; stratified hazard ratio, 0.389; 95% CI, 0.235 to 0.643; P = .0002). Arm C did not experience improved PFS compared with arm A (1.6 months; 95% CI, 1.4 to 2.9; stratified hazard ratio, 0.863; 95% CI, 0.550 to 1.357; P = .5053). The most common grade 3 or worse adverse events (arms A, B, and C) were neutropenia (36%, 33%, and 39%), fatigue (13%, 30%, and 20%), febrile neutropenia (13%, 17%, and 6.1%), and anemia (6.7%, 13%, and 14%, respectively)., Conclusion: The addition of ramucirumab to docetaxel met the prespecified efficacy end point for prolonging PFS in patients with locally advanced or metastatic urothelial carcinoma receiving second-line treatment and warrants further investigation in the phase III setting., (© 2016 by American Society of Clinical Oncology.)