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Draws on interviews with 61 officials in 13 federal agencies to illustrate a framework showing many of the potential uses of evaluation in support of performance management. Suggests 10 actions as opportunities for agency administrators and evaluators to bridge the current gaps between potential and actual uses of evaluation. (Author/SLD)

Background: Implantable cardioverter defibrillators (ICDs) decrease mortality in high-risk patients but can also cause distressing shocks near death. Patients who lack knowledge about their ICDs are more likely to have an active device at the end of life. Many hospice workers lack sufficient knowledge to educate patients about ICDs., Measures: An ICD educational video created for use in a diverse, underserved patient population was shown to hospice workers from two large community hospices and attendees of a regional conference. A validated 10 question survey was given to participants before and after the video., Outcomes: Significant improvement in ICD knowledge scores was seen in all participants (W = 3119.5, P < 0.0001). While doctors and nurses showed higher pretest knowledge, post-test knowledge scores equalized across all participants., Conclusions/lessons Learned: An ICD patient educational video designed for a diverse, underserved patient population effectively improved ICD knowledge to a uniform excellent level for a broad range of hospice workers., (Copyright © 2024 American Academy of Hospice and Palliative Medicine. Published by Elsevier Inc. All rights reserved.)

Background: Studies thus far lacking diversity show many patients with implantable cardioverter defibrillators (ICDs) have poor understanding of ICD functioning, preventing informed decision-making near end of life (EOL)., Objective: To describe knowledge, perceptions, and preferences regarding ICDs among patients nearing EOL in a diverse, safety-net hospital population., Methods: A cross sectional phone survey of patients with ICDs nearing EOL from a safety-net hospital was performed. The survey assessed knowledge, perceptions, and preferences regarding their ICD., Results: Nearly half (46%) of patients falsely believed turning off shocking function would stop the heart, 69% were unaware that disabling ICDs does not require surgery, and 88% said no doctor had ever discussed the option of deactivation of shocking therapy with them., Conclusion: Challenges in health care delivery in a safety-net hospital patient population may result in patients being poorly equipped to align ICD settings with goals of care when nearing EOL.

T cell exhaustion has been associated with poor prognosis in persistent viral infection and cancer. Conversely, in the context of autoimmunity, T cell exhaustion has been favorably correlated with long-term clinical outcome. Understanding the development of exhaustion in autoimmune settings may provide underlying principles that can be exploited to quell autoreactive T cells. Here, we demonstrate that the adaptor molecule Bat3 acts as a molecular checkpoint of T cell exhaustion, with deficiency of Bat3 promoting a profound exhaustion phenotype, suppressing autoreactive T cell-mediated neuroinflammation. Mechanistically, Bat3 acts as a critical mTORC2 inhibitor to suppress Akt function. As a result, Bat3 deficiency leads to increased Akt activity and FoxO1 phosphorylation, indirectly promoting Prdm1 expression. Transcriptional analysis of Bat3 -/- T cells revealed up-regulation of dysfunction-associated genes, concomitant with down-regulation of genes associated with T cell effector function, suggesting that absence of Bat3 can trigger T cell dysfunction even under highly proinflammatory autoimmune conditions., (Copyright © 2021 The Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science. No claim to original U.S. Government Works. Distributed under a Creative Commons Attribution NonCommercial License 4.0 (CC BY-NC).)

The ability to monitor anti-tumor CD8+ T cell responses in the blood has tremendous therapeutic potential. Here, we used paired single-cell RNA and TCR sequencing to detect and characterize "tumor-matching" (TM) CD8+ T cells in the blood of mice with MC38 tumors or melanoma patients using the TCR as a molecular barcode. TM cells showed increased activation compared with nonmatching T cells in blood and were less exhausted than matching cells in tumors. Importantly, PD-1, which has been used to identify putative circulating anti-tumor CD8+ T cells, showed poor sensitivity for identifying TM cells. By leveraging the transcriptome, we identified candidate cell surface markers for TM cells in mice and patients and validated NKG2D, CD39, and CX3CR1 in mice. These data show that the TCR can be used to identify tumor-relevant cells for characterization, reveal unique transcriptional properties of TM cells, and develop marker panels for tracking and analysis of these cells., Competing Interests: Disclosures:   K. Tsai reported personal fees from Regeneron, grants from Array/Pfizer, grants from Replimune, and grants from Oncosec outside the submitted work. M. Rosenblum reported other from TRex Bio and other from Sitryx Bio outside the submitted work. A. Daud reported grants from Merck, grants from BMS, other from Trex, grants from Pfizer, grants from Incyte, grants from Xencor, grants from Roche, and grants from Novartis during the conduct of the study as well as grants from Oncosec outside the submitted work. A. Sharpe reported grants from NIH R01 CA229851, grants from NIH U54 CA224088, grants from NIH P01 56299, and grants from NIH P01 39671 during the conduct of the study; personal fees from Surface Oncology, personal fees from Sqz Biotech, personal fees from Selecta, personal fees from Monopteros, personal fees from Elstar, personal fees from Elpiscience, grants from Novartis, grants from Roche, grants from Merck, grants from Ipsen, grants from UCB, and grants from Quark Ventures outside the submitted work. In addition, A. Sharpe had a patent number 7,432,059 with royalties paid (Roche, Merck, Bristol-Myers-Squibb, EMD-Serono, Boehringer-Ingelheim, AstraZeneca, Leica, Mayo Clinic, Dako and Novartis), a patent number 7,722,868 with royalties paid (Roche, Merck, Bristol-Myers-Squibb, EMD-Serono, Boehringer-Ingelheim, AstraZeneca, Leica, Mayo Clinic, Dako and Novartis), a patent number 8,652,465 licensed (Roche), a patent number 9,457,080 licensed (Roche), a patent number 9,683,048 licensed (Novartis), a patent number 9,815,898 licensed (Novartis), a patent number 9,845,356 licensed (Novartis), a patent number 10,202,454 licensed (Novartis), a patent number 10,457,733 licensed (Novartis), a patent number 9,580,684 issued (none), a patent number 9,988,452 issued (none), and a patent number 10,370,446 issued (none); A. Sharpe is on the scientific advisory boards for the Massachusetts General Cancer Center, Program in Cellular and Molecular Medicine at Boston Children's Hospital, and the Human Oncology and Pathogenesis Program at Memorial Sloan Kettering Cancer Center and is a scientific editor for the Journal of Experimental Medicine. M. Singer reported personal fees from Guardant Health outside the submitted work. No other disclosures were reported., (© 2021 Pauken et al.)

Immune checkpoint blockade (ICB) is efficacious in many diverse cancer types, but not all patients respond. It is important to understand the mechanisms driving resistance to these treatments and to identify predictive biomarkers of response to provide best treatment options for all patients. Here we introduce a resection and response-assessment approach for studying the tumor microenvironment before or shortly after treatment initiation to identify predictive biomarkers differentiating responders from nonresponders. Our approach builds on a bilateral tumor implantation technique in a murine metastatic breast cancer model (E0771) coupled with anti-PD-1 therapy. Using our model, we show that tumors from mice responding to ICB therapy had significantly higher CD8 + T cells and fewer Gr1 + CD11b + myeloid-derived suppressor cells (MDSCs) at early time points following therapy initiation. RNA sequencing on the intratumoral CD8 + T cells identified the presence of T cell exhaustion pathways in nonresponding tumors and T cell activation in responding tumors. Strikingly, we showed that our derived response and resistance signatures significantly segregate patients by survival and associate with patient response to ICB. Furthermore, we identified decreased expression of CXCR3 in nonresponding mice and showed that tumors grown in Cxcr3 -/- mice had an elevated resistance rate to anti-PD-1 treatment. Our findings suggest that the resection and response tumor model can be used to identify response and resistance biomarkers to ICB therapy and guide the use of combination therapy to further boost the antitumor efficacy of ICB., Competing Interests: Competing interest statement: R.K.J. received an honorarium from Amgen; consultant fees from Merck, Pfizer, SPARC, and SynDevRx; owns equity in Enlight and SynDevRx; and serves on the scientific advisory board of Accurius Therapeutics and boards of trustees of Tekla Healthcare Investors, Tekla Life Sciences Investors, Tekla Healthcare Opportunities Fund, and Tekla World Healthcare Fund. Neither any reagent nor any funding from these organizations was used in this study. A.H.S. has patents on the PD-1 pathway licensed by Roche/Genentech and Novartis, consults for Novartis, is on the scientific advisory boards for Surface Oncology, Sqz Biotech, Elstar Therapeutics, Elpiscience, Selecta, and Monopteros, and has research funding from Merck, Novartis, Roche, and Quark Ventures. R.K.J. and D.A.T. are co-authors on a 2020 Cold Spring Harbor Laboratory meeting report., (Copyright © 2020 the Author(s). Published by PNAS.)

Background: It is crucial for physicians to understand the roles of occupational therapy (OT) and physical therapy (PT) to ensure accurate patient referrals and to optimize patient care. Unfortunately, medical students often do not receive sufficient education or interprofessional opportunities regarding OT and PT services., Objective: To evaluate the impact of an educational workshop on medical students' familiarity with the roles of OT and PT and on their confidence in referring to these therapy services., Methods: Thirty-seven fourth-year medical students participated in a 2-hour workshop focused on the roles and benefits of OT and PT. After the didactic portion, students were given case scenarios relevant to their chosen specialty to discuss roles of OT and PT specific to their case., Main Outcome Measurements: The students completed before and after surveys that assessed perceived knowledge and students' perspectives on the value of the work¬shop., Level of Evidence: 3 (case-control study)., Results: From before to after the workshop, the students showed significant improvements in their familiarity with OT and PT and in their confidence to appropriately make a referral to these services., Conclusions: The tailored curriculum hosted in a workshop format improved students' knowledge regarding the role and services of OT and PT as well as their confidence in making accurate referrals.

Akt plays a major role in tumorigenesis and the development of specific Akt inhibitors as effective cancer therapeutics has been challenging. Here, we report the identification of a highly specific allosteric inhibitor of Akt through a FRET-based high-throughput screening, and characterization of its inhibitory mechanism. Out of 373,868 compounds screened, 4-phenylquinolin-2(1H)-one specifically decreased Akt phosphorylation at both T308 and S473, and inhibited Akt kinase activity (IC 50  = 6 µM) and downstream signaling. 4-Phenylquinolin-2(1H)-one did not alter the activity of upstream kinases including PI3K, PDK1, and mTORC2 as well as closely related kinases that affect cell proliferation and survival such as SGK1, PKA, PKC, or ERK1/2. This compound inhibited the proliferation of cancer cells but displayed less toxicity compared to inhibitors of PI3K or mTOR. Kinase profiling efforts revealed that 4-phenylquinolin-2(1H)-one does not bind to the kinase active site of over 380 human kinases including Akt. However, 4-phenylquinolin-2(1H)-one interacted with the PH domain of Akt, apparently inducing a conformation that hinders S473 and T308 phosphorylation by mTORC2 and PDK1. In conclusion, we demonstrate that 4-phenylquinolin-2(1H)-one is an exquisitely selective Akt inhibitor with a distinctive molecular mechanism, and a promising lead compound for further optimization toward the development of novel cancer therapeutics.

Intramuscular hemangioma is a rare but important cause of pain and potentially decreased performance in athletes. These benign tumors occur more often in the lower extremity and usually present during the first three decades of life. Symptomatic intramuscular hemangiomas usually present with pain and swelling, which often worsen with activity. Diagnosis can be difficult, resulting in frustration and prolonged activity limitations for these patients. Magnetic resonance imaging and clinical findings can often suggest the diagnosis. Recommended treatment is usually wide total excision, but there are certain cases in which excision is not possible. In difficult areas such as the hands or feet, a sclerosing agent can be injected into the hemangioma to reduce the size of the hemangioma, decrease pain, and improve function.

Objective: To analyze whether a corticosteroid injection in combination with rehabilitation early in the course of lateral epicondylitis (LE) alters the outcome up to 6 months after injection compared with a control injection and rehabilitation., Design: Randomized, controlled, double-blind study., Setting: Sports medicine center in a tertiary care center., Participants: Subjects with a diagnosis of LE whose symptoms had been present less than 4 weeks were included. Subjects were recruited by word of mouth and through advertising. The 39 subjects who were recruited were 18 to 65 years old., Interventions: 19 subjects were randomized to receive rehabilitation and a sham injection, and 20 were randomized to receive rehabilitation and a corticosteroid injection. At 4 and 8 weeks, they were reevaluated and their treatment programs were modified, if indicated., Main Outcome Measures: Outcome measurements were performed at baseline, 4 weeks, 8 weeks, and 6 months, and included a functional pain questionnaire and a visual analogue pain scale. Painless grip strength on the affected side and maximal grip strength bilaterally were measured at baseline, 4 weeks, and 8 weeks., Results: There were no significant differences in outcome between the two groups with the exception of an improvement in the visual analogue pain scale in the corticosteroid group from 8 weeks to 6 months. Outcome measurements in both groups improved significantly over time; more than 80% of subjects reported improvements from baseline to 6 months for all scales., Conclusion: A corticosteroid injection does not provide a clinically significant improvement in the outcome of LE, and rehabilitation should be the first line of treatment in patients with a short duration of symptoms.

Objective: To determine whether a lumbar support improves trunk repositioning error (RE), an aspect of proprioception., Design: RE was measured with and without a lumbar support., Setting: Outpatient clinic., Participants: Twenty subjects with chronic low back pain (LBP) and 20 control subjects., Interventions: Subjects wore the lumbar support for 2 hours and then testing was repeated., Main Outcome Measures: Standing with legs and pelvis immobilized, subjects moved to a predetermined target position and then attempted to replicate the position. The 3-dimensional position of the trunk was measured with a 3Space Tracker. RE was calculated as the absolute difference between the actual target position and the subject-perceived target position. Testing was performed with and without a lumbar support both before and after wearing the support for 2 hours., Results: In subjects with LBP, RE was significantly lower with a support in flexion, extension, and right lateral bending. In control subjects, RE was significantly lower when wearing the support in left bending only, and RE was significantly higher in control subjects after wearing the support for 2 hours., Conclusion: A lumbar support improves trunk RE. In subjects with LBP, this result was significant in the sagittal plane and in right lateral bending, whereas in control subjects, it was significant only in left lateral bending., (Copyright 2001 by the American Congress of Rehabilitation Medicine and the American Academy of Physical Medicine and Rehabilitation)

Study Design: Repositioning error of the trunk was tested in 20 subjects with chronic low back pain and in 20 control subjects. The 3Space Tracker (Polhemus, Colchester, VT), a device that measures three-dimensional position in space, was used to determine the subject's trunk position., Objectives: To determine whether repositioning error is different in subjects with chronic low back pain than in control subjects., Summary of Background Data: Proprioception allows the body to maintain proper orientation during static and dynamic activities. In peripheral joint injuries, researchers have demonstrated a loss of some aspects of proprioception and improvement in outcome with retraining. Although the components of proprioception in subjects with low back pain have not been well studied, it is thought that these persons lose some elements of proprioception that can be measured in a quantifiable way. If so, then rehabilitation to improve these deficits is important. In this pilot study, one aspect of proprioception, repositioning error, was examined., Methods: The subjects attempted to replicate target positions of the trunk in flexion, extension, lateral bending, and lateral rotation. Repositioning error was calculated as the absolute difference between the actual and the subject-replicated target positions., Results: No significant difference was found in repositioning error between the control subjects and the persons with chronic low back pain., Conclusions: Because proprioception is complex and entails the use of many afferent receptors, it is difficult to measure any one afferent deficiency discretely. The authors believe that this study, in which one aspect of proprioception was measured in an indirect manner, provides important background information on low back position sense. Further studies analyzing aspects of proprioception in subjects with low back pain are recommended.

Objective: To determine if an attachable silver-impregnated cuff is effective in reducing subclavian hemodialysis catheter-related infections., Design: Prospective, randomized, nonblinded study., Setting: Community teaching hospital., Patients: One hundred one acute and chronic renal failure patients requiring subclavian venipuncture and catheterization. After randomization, 47 patients underwent subclavian catheterization with a silver-impregnated cuff (Ag-CC), and 54 patients had routine catheter (RC) placements., Measurements: Multiple presumed predictor variables for catheter-related infections, exit site infection rate, bacteremia rates, and semiquantitative cultures of all catheters.

The timed-stands test (TST) is a simple measure of lower extremity strength which correlates with age in healthy people. We validated the TST as a functional assessment tool against other measurements of functional capacity and comorbidity in 147 patients with rheumatoid arthritis (RA) or other chronic diseases. The TST was significantly impacted by RA disease activity and by comorbidity. Age affected TST only in patients without arthritis or life threatening disease. TST is a simple, reproducible measure of lower extremity function that was valid in this patient population.

Two brothers were found to have an unusual congenital syndrome of lymphedema, pulmonary lymphagiectasia, hypoparthyroidism, hereditary nephropathy, prolapsing mitral valve, and other somatic abnormalities.

One hundred sixteen subclavian hemodialysis catheter placements in 88 patients were prospectively evaluated for catheter-related infections. Semiquantitative culture techniques and a rigid infection control protocol were used. The overall catheter colonization rate was 21.6% and catheter-associated bacteremia occurred in 9.4%. Catheters removed from febrile patients had much higher colonization (48.3%) and bacteremia (34.5%) rates. In a randomized study comparing infection rates in catheters tunneled subcutaneously or not tunneled, there was no significant difference in the incidence of infection. Catheters inserted over a guidewire to replace clotted or malfunctioning catheters were not associated with higher infection rates.

Analysis of 55 positive tests of a total of 300 tests by conventional criteria revealed that 125I-fibrinogen provides useful information early enough for clinical management. Of the tests which were ultimately interpreted as positive by conventional criteria, at least one was positive at 3-4 hours in 67% of the tests and 98% of the tests were positive at 24 hours after the administration of 125I-fibrinogen. A 20% difference between contralateral identical locations of the legs and a 20% difference between adjacent locations of the ipsilateral leg were found with almost equal frequency in the positive tests, whereas a 20% increase at the same location was less sensitive. The 125I-fibrogen uptake test is a simple and accurate technique for early diagnosis of active thrombophlebitis.