Moral cleansing as hypocrisy: When private acts of charity make you feel better than you deserve.

What counts as hypocrisy? Current theorizing emphasizes that people see hypocrisy when an individual sends them "false signals" about his or her morality (Jordan, Sommers, Bloom, & Rand, 2017); indeed, the canonical hypocrite acts more virtuously in public than in private. An alternative theory posits that people see hypocrisy when an individual enjoys "undeserved moral benefits," such as feeling more virtuous than his or her behavior merits, even when the individual has not sent false signals to others (Effron, O'Connor, Leroy, & Lucas, 2018). This theory predicts that acting less virtuously in public than in private can seem hypocritical by indicating that individuals have used good deeds to feel less guilty about their public sins than they should. Seven experiments (N = 3,468 representing 64 nationalities) supported this prediction. Participants read about a worker in a "sin industry" who secretly performed good deeds. When the individual's public work (e.g., selling tobacco) was inconsistent with, versus unrelated to, the good deeds (e.g., anonymous donations to an antismoking cause vs. an antiobesity cause), participants perceived him as more hypocritical, which in turn predicted less praise for his good deeds. Participants also inferred that the individual was using the inconsistent good deeds to cleanse his conscience for his public work, and such moral cleansing appeared hypocritical when it successfully alleviated his guilt. These results broaden and deepen understanding about how lay people conceptualize hypocrisy. Hypocrisy does not require appearing more virtuous than you are; it suffices to feel more virtuous than you deserve. (PsycInfo Database Record (c) 2020 APA, all rights reserved).

Characterizing Reimbursements for Medicare Patients Receiving Endovascular Abdominal Aortic Aneurysm Repair at Vascular Quality Initiative Centers.

BACKGROUND: Endovascular aortic aneurysm repair (EVR) has a major financial impact on health care systems. We characterized reimbursement for index EVR hospitalizations among Medicare beneficiaries having surgery at Vascular Quality Initiative (VQI) centers. METHODS: We linked Medicare claims to VQI clinical registry data for patients undergoing EVR from 2003 to 2015. Analysis was limited to patients fully covered by fee-for-service Medicare parts A and B in the year of their operation and assigned a corresponding diagnosis-related group for EVR. The primary outcome was Medicare's reimbursement for inpatient hospital and professional services, adjusted to 2015 dollars. We performed descriptive analysis of reimbursement over time and univariate analysis to evaluate patient demographics, clinical characteristics, procedural variables, and postoperative events associated with reimbursement. This informed a multilevel regression model used to identify factors independently associated with EVR reimbursement and quantify VQI center-level variation in reimbursement. RESULTS: We studied 9,403 Medicare patients who underwent EVR at VQI centers during the study period. Reimbursements declined from $37,450 ± $9,350 (mean ± standard deviation) in 2003 to $27,723 ± $10,613 in 2015 (test for trend, P < 0.001). For patients experiencing a complication (n = 773; 8.2%), mean reimbursement for EVR was $44,858 ± $23,825 versus $28,857 ± $9,258 for those without complications (P < 0.001). Intestinal ischemia, new dialysis requirement, and respiratory compromise each doubled Medicare's average reimbursement for EVR. After adjusting for diagnosis-related group, several patient-level factors were independently associated with higher Medicare reimbursement; these included ruptured abdominal aortic aneurysm (+$2,372), additional day in length of stay (+$1,275), and being unfit for open repair (+$501). Controlling for patient-level factors, 4-fold variation in average reimbursement was seen across VQI centers. CONCLUSIONS: Reimbursement for EVR declined between 2003 and 2015. We identified preoperative clinical factors independently associated with reimbursement and quantified the impact of different postoperative complications on reimbursement. More work is needed to better understand the substantial variation observed in reimbursement at the center level.

Testing for Meningitis in Febrile Well-Appearing Young Infants With a Positive Urinalysis.

BACKGROUND AND OBJECTIVES: To determine factors associated with cerebrospinal fluid (CSF) testing in febrile young infants with a positive urinalysis and assess the probability of delayed diagnosis of bacterial meningitis in infants treated for urinary tract infection (UTI) without CSF testing. METHODS: We performed a retrospective cohort study using data from the Reducing Excessive Variability in Infant Sepsis Evaluation quality improvement project. A total of 20 570 well-appearing febrile infants 7 to 60 days old presenting to 124 hospitals from 2015 to 2017 were included. A mixed-effects logistic regression was conducted to determine factors associated with CSF testing. Delayed meningitis was defined as a new diagnosis of bacterial meningitis within 7 days of discharge. RESULTS: Overall, 3572 infants had a positive urinalysis; 2511 (70.3%) underwent CSF testing. There was wide variation by site, with CSF testing rates ranging from 64% to 100% for infants 7 to 30 days old and 10% to 100% for infants 31 to 60 days old. Factors associated with CSF testing included: age 7 to 30 days (adjusted odds ratio [aOR]: 4.6; 95% confidence interval [CI]: 3.8-5.5), abnormal inflammatory markers (aOR: 2.2; 95% CI: 1.8-2.5), and site volume >300 febrile infants per year (aOR: 1.8; 95% CI: 1.2-2.6). Among 505 infants treated for UTI without CSF testing, there were 0 (95% CI: 0%-0.6%) cases of delayed meningitis. CONCLUSIONS: There was wide variation in CSF testing in febrile infants with a positive urinalysis. Among infants treated for UTI without CSF testing (mostly 31 to 60-day-old infants), there were no cases of delayed meningitis within 7 days of discharge, suggesting that routine CSF testing of infants 31 to 60 days old with a positive urinalysis may not be necessary.

AMG 176, a Selective MCL1 Inhibitor, Is Effective in Hematologic Cancer Models Alone and in Combination with Established Therapies.

The prosurvival BCL2 family member MCL1 is frequently dysregulated in cancer. To overcome the significant challenges associated with inhibition of MCL1 protein-protein interactions, we rigorously applied small-molecule conformational restriction, which culminated in the discovery of AMG 176, the first selective MCL1 inhibitor to be studied in humans. We demonstrate that MCL1 inhibition induces a rapid and committed step toward apoptosis in subsets of hematologic cancer cell lines, tumor xenograft models, and primary patient samples. With the use of a human MCL1 knock-in mouse, we demonstrate that MCL1 inhibition at active doses of AMG 176 is tolerated and correlates with clear pharmacodynamic effects, demonstrated by reductions in B cells, monocytes, and neutrophils. Furthermore, the combination of AMG 176 and venetoclax is synergistic in acute myeloid leukemia (AML) tumor models and in primary patient samples at tolerated doses. These results highlight the therapeutic promise of AMG 176 and the potential for combinations with other BH3 mimetics. SIGNIFICANCE: AMG 176 is a potent, selective, and orally bioavailable MCL1 inhibitor that induces a rapid commitment to apoptosis in models of hematologic malignancies. The synergistic combination of AMG 176 and venetoclax demonstrates robust activity in models of AML at tolerated doses, highlighting the promise of BH3-mimetic combinations in hematologic cancers.See related commentary by Leber et al., p. 1511.This article is highlighted in the In This Issue feature, p. 1494.

CDK12-mediated transcriptional regulation of noncanonical NF-κB components is essential for signaling.

Members of the family of nuclear factor κB (NF-κB) transcription factors are critical for multiple cellular processes, including regulating innate and adaptive immune responses, cell proliferation, and cell survival. Canonical NF-κB complexes are retained in the cytoplasm by the inhibitory protein IκBα, whereas noncanonical NF-κB complexes are retained by p100. Although activation of canonical NF-κB signaling through the IκBα kinase complex is well studied, few regulators of the NF-κB-inducing kinase (NIK)-dependent processing of noncanonical p100 to p52 and the subsequent nuclear translocation of p52 have been identified. We discovered a role for cyclin-dependent kinase 12 (CDK12) in transcriptionally regulating the noncanonical NF-κB pathway. High-content phenotypic screening identified the compound 919278 as a specific inhibitor of the lymphotoxin ß receptor (LTßR), and tumor necrosis factor (TNF) receptor superfamily member 12A (FN14)-dependent nuclear translocation of p52, but not of the TNF-α receptor-mediated nuclear translocation of p65. Chemoproteomics identified CDK12 as the target of 919278. CDK12 inhibition by 919278, the CDK inhibitor THZ1, or siRNA-mediated knockdown resulted in similar global transcriptional changes and prevented the LTßR- and FN14-dependent expression of MAP3K14 (which encodes NIK) as well as NIK accumulation by reducing phosphorylation of the carboxyl-terminal domain of RNA polymerase II. By coupling a phenotypic screen with chemoproteomics, we identified a pathway for the activation of the noncanonical NF-κB pathway that could serve as a therapeutic target in autoimmunity and cancer.

Physician Preferences Surrounding Urinary Tract Infection Management in Neonates.

OBJECTIVES: Variability exists in the treatment of neonates with urinary tract infection (UTI), potentially reflecting an overuse of resources. A cross-sectional vignette survey was designed to examine variability in physician preferences for intravenous (IV) antibiotic duration, genitourinary imaging, and prophylactic antibiotics and to evaluate drivers of resource use. METHODS: The survey was administered to a random sample of pediatricians through the American Medical Association's Physician Masterfile. Respondents were provided with a case vignette of a 2-week-old neonate with a febrile UTI and asked to indicate preferences for IV antibiotic duration and rank drivers of this decision. Respondents were also asked whether they would obtain a voiding cystourethrogram (VCUG) and, regardless of preference, randomly presented with a normal result or bilateral grade II vesicoureteral reflux. The survey was delivered electronically to facilitate skip logic and randomization. RESULTS: A total of 279 surveys were completed. Preference for total IV antibiotic duration differed significantly (P < .001) across specialty, with a median duration of 2 days for general pediatricians/hospitalists, 7 days for neonatologists, and 5 days for infectious disease pediatricians. For the 47% (n = 131) who did not want a VCUG, 24/61 (39%) wanted prophylactic antibiotics when presented with grade II vesicoureteral reflux (P < .001). CONCLUSIONS: Subspecialty status appeared to be the most influential driver of IV antibiotic duration in the treatment of UTI. A substantial proportion of pediatricians who initially expressed a preference against ordering a VCUG wished to prescribe prophylactic antibiotics when results were abnormal, which suggests that even unwanted diagnostic test results drive treatment decisions.

Discovery and in Vivo Evaluation of the Potent and Selective PI3Kδ Inhibitors 2-((1S)-1-((6-Amino-5-cyano-4-pyrimidinyl)amino)ethyl)-6-fluoro-N-methyl-3-(2-pyridinyl)-4-quinolinecarboxamide (AM-0687) and 2-((1S)-1-((6-Amino-5-cyano-4-pyrimidinyl)amino)ethyl)-5-fluoro-N-methyl-3-(2-pyridinyl)-4-quinolinecarboxamide (AM-1430).

Optimization of the potency and pharmacokinetic profile of 2,3,4-trisubstituted quinoline, 4, led to the discovery of two potent, selective, and orally bioavailable PI3Kδ inhibitors, 6a (AM-0687) and 7 (AM-1430). On the basis of their improved profile, these analogs were selected for in vivo pharmacodynamic (PD) and efficacy experiments in animal models of inflammation. The in vivo PD studies, which were carried out in a mouse pAKT inhibition animal model, confirmed the observed potency of 6a and 7 in biochemical and cellular assays. Efficacy experiments in a keyhole limpet hemocyanin model in rats demonstrated that administration of either 6a or 7 resulted in a strong dose-dependent reduction of IgG and IgM specific antibodies. The excellent in vitro and in vivo profiles of these analogs make them suitable for further development.

Discovery and in vivo evaluation of (S)-N-(1-(7-fluoro-2-(pyridin-2-yl)quinolin-3-yl)ethyl)-9H-purin-6-amine (AMG319) and related PI3Kδ inhibitors for inflammation and autoimmune disease.

The development and optimization of a series of quinolinylpurines as potent and selective PI3Kδ kinase inhibitors with excellent physicochemical properties are described. This medicinal chemistry effort led to the identification of 1 (AMG319), a compound with an IC50 of 16 nM in a human whole blood assay (HWB), excellent selectivity over a large panel of protein kinases, and a high level of in vivo efficacy as measured by two rodent disease models of inflammation.

Lithium as an adjunct to radioactive iodine for the treatment of hyperthyroidism: a systematic review and meta-analysis.

BACKGROUND: Radioactive iodine (RAI) is commonly used in the treatment of hyperthyroidism but is not uniformly successful. Lithium increases thyroidal iodine retention without reducing iodide uptake, increasing the radiation dose to the thyroid when administered with RAI. Although these actions suggest that adjuvant lithium may increase the efficacy of RAI, its role as an adjunct to RAI remains contentious. OBJECTIVE: To evaluate the safety and efficacy of adding lithium to RAI to treat hyperthyroidism. METHODS: Relevant studies were identified by a search of Medline and the Cochrane Central Register of Controlled Trials. To be included, a study had to be a controlled trial comparing the effect of RAI alone to RAI with lithium in the treatment of hyperthyroidism. Relevant data were extracted and meta-analyses were performed. RESULTS: Of the 75 identified studies, 6 met the inclusion criteria; 4 of these studies were interventional and 2 were observational trials. Meta-analysis of the observational trials (N = 851), both of which were retrospective cohort studies, showed significant improvement in the primary outcome (i.e., cure rate) with adjunctive lithium (odds ratio [OR], 1.92; 95% confidence interval [CI], 1.24 to 2.96). The combined interventional trials (N = 485) also showed an improvement in cure rate, but the difference did not reach statistical significance (OR, 1.28; 95% CI, 0.85 to 1.91). Adjunctive lithium reduced time to cure and blunted thyroid hormone excursions after RAI. Lithium-related side effects were infrequent and usually mild. CONCLUSION: The observational trials demonstrated significant improvement in the cure rate of hyperthyroidism when lithium is added to RAI. The improvements shown in the interventional trials did not reach statistical significance due to the effect of a single, large negative trial.

Discovery of AMG 232, a potent, selective, and orally bioavailable MDM2-p53 inhibitor in clinical development.

We recently reported the discovery of AM-8553 (1), a potent and selective piperidinone inhibitor of the MDM2-p53 interaction. Continued research investigation of the N-alkyl substituent of this series, focused in particular on a previously underutilized interaction in a shallow cleft on the MDM2 surface, led to the discovery of a one-carbon tethered sulfone which gave rise to substantial improvements in biochemical and cellular potency. Further investigation produced AMG 232 (2), which is currently being evaluated in human clinical trials for the treatment of cancer. Compound 2 is an extremely potent MDM2 inhibitor (SPR KD = 0.045 nM, SJSA-1 EdU IC50 = 9.1 nM), with remarkable pharmacokinetic properties and in vivo antitumor activity in the SJSA-1 osteosarcoma xenograft model (ED50 = 9.1 mg/kg).

Diagnostic accuracy retrospectively of electrocardiographic findings and cancer history for tamponade in patients determined to have pericardial effusion by transthoracic echocardiogram.

Unexpected pericardial effusions are often found by frontline providers who perform computed tomography. To study the hypothesis that electrocardiographic findings and whether cancer is known or suspected importantly change the likelihood of tamponade for such providers, all unique patients with moderate or large pericardial effusions determined by transthoracic echocardiography during a 6-year period were retrospectively identified. Electrocardiograms were evaluated by blinded investigators for electrical alternans (total and QRS), low voltage (limb leads only, precordial leads only, and both), and tachycardia (>100 QRS complexes/min). Medical records were reviewed to determine whether cancer was known or suspected and whether tamponade was diagnosed. Tamponade was present in 66 patients (27% of 241) with moderate or large pericardial effusions. No tachycardia lowered the odds of tamponade the most (likelihood ratio 0.4, 95% confidence interval 0.3 to 0.6) but by a degree less than any single diagnostic element increased it when present. The combined presence of all 3 electrocardiographic findings and cancer increased the odds of tamponade 63-fold (likelihood ratio 63, 95% confidence interval 33 to 150), whereas their combined absence decreased the odds only fivefold (likelihood ratio 0.2, 95% confidence interval 0.2 to 0.3). In conclusion, electrocardiography findings and cancer rule in tamponade better than they rule it out. Combining these diagnostic elements improves their discriminatory power but not sufficiently enough to rule out tamponade in patients with moderate or large pericardial effusions.

Organ donation among undocumented hispanic immigrants: an assessment of knowledge and attitudes.

BACKGROUND: Undocumented immigrants can donate their organs, but lack access to organ transplantation.This challenges foundational principles of organ donation: fairness and informed consent. Little is known about undocumented immigrants' knowledge of barriers to their access to organ transplantation or how this might affect their decision to donate their organs. METHODS: The study was performed in an urban, university-affiliated, safety-net hospital.We interviewed hospitalized patients who self-identified as undocumented immigrants and were unaware of having any contraindication to organ donation (for example, cancer). We first recorded their demographic characteristics and knowledge and attitudes regarding organ donation. We then assessed the effects of informing participants about limits to their access to organ transplants on their willingness to donate. RESULTS: This group of 59 uninsured Hispanic immigrants had adequate knowledge about organ donation. Participants were suspicious about inequality within the medical system, but most were willing to donate their organs (74 percent). Most participants (74 percent) were aware that they would have to pay to receive an organ, but they dramatically underestimated the out-of-pocket expenses.Yet willingness to donate their organs was unaffected by participants being explicitly informed of the low likelihood that they would be able to afford to receive an organ transplant. CONCLUSIONS: Despite being well informed about the organ donation system, undocumented Hispanic immigrants underestimate the costs and overestimate their likelihood of receiving an organ. Even when they are given this information, they remain willing to donate their own organs.

An expeditious synthesis of the MDM2-p53 inhibitor AM-8553.

The development of the structurally complex MDM2/p53 inhibitor AM-8553 was impeded by the low yield of the initial synthesis. A second generation synthesis is described that features a Noyori dynamic kinetic resolution, a highly diastereoselective allylation, and a novel oxazoline-assisted piperidinone forming reaction to provide AM-8553 in 35.6% yield and 11 steps.

Design of 1-piperazinyl-4-arylphthalazines as potent Smoothened antagonists.

The Hedgehog (Hh) signaling pathway regulates cell proliferation and differentiation in developing tissues, and abnormal activation of the Hh pathway has been linked to several tumor subsets. As a transducer of Hh signaling, the GPCR-like protein Smoothened (Smo) is a promising target for disruption of unregulated Hh signaling. A series of 1-amino-4-arylphthalazines was developed as potent and orally bioavailable inhibitors of Smo. A representative compound from this class demonstrated significant tumor volume reduction in a mouse medulloblastoma model.

Total hip and total knee replacement: postoperative nursing management.

Patients having total hip replacement (THR) or total knee replacement (TKR) surgery require skilled nursing care in order to recover from surgery and anaesthesia. The first part of this article will outline the key nursing management issues during the postoperative stage of recovery. The second part will consider the longer term recovery, including the risk of THR dislocation and failure of the prosthesis due to loosening or infection. The role of the nurse in primary and secondary care in monitoring and identifying complications will be highlighted. This is the second of two articles on nursing care for patients undergoing THR or TKR surgery. The first article (Lucas, 2008) looked at preoperative nursing care.

Total hip and total knee replacement: preoperative nursing management.

Total hip replacement (THR) and total knee replacement (TKR) surgery are carried out for the relief of hip or knee pain, usually caused by osteoarthritis. This is the first of two articles on THR and TKR. It will outline the different types of replacement used in lower limb joint replacement surgery. Preparation of patients for surgery requires attention to physical, psychological and social factors and these are explored in detail. The organization of services along the patient pathway to ensure comprehensive preparation is considered and the nursing role highlighted. The second article, to be published in the next issue, will discuss recovery and rehabilitation from THR and TKR surgery.

Preparing patients for hip and knee replacement surgery.

This article considers the pre-operative physical, psychological and social factors that affect the outcomes of patients undergoing total hip and total knee replacement surgery. The implications for patient assessment before surgery are discussed and suggestions made about how interventions can be tailored so that patients' needs are met.

Treatment options for patients with osteoarthritis of the knee.

Knee osteoarthritis (OA) affects many older people and may result in pain and loss of function in the knee. The article explores the wide spectrum of treatments available, including education, exercise, pharmacological agents and surgery. The evidence for these treatments is examined so that nurses have a knowledge base on which to build their practice. The importance of individual patient characteristics and available resources when deciding on treatment options is emphasized. The article is intended to be of use for both acute and primary care nurses who care for patients with knee OA.

Nursing management issues in hip and knee replacement surgery.

Total hip replacement (THR) and total knee replacement (TKR) are carried out for the relief of pain in hip or knee joints usually caused by osteoarthritis. Such replacements last for 10-15 years and therefore many nurses will care for patients with a THR/TKR even if that is not the primary reason for the patient seeking care. The different types of THR/TKR and how patients can be prepared for surgery are discussed. The major long-term complications of loosening or dislocation of the components of the THR/TKR and of infection are explored and the presenting symptoms are highlighted. The article is intended to be useful not only for orthopaedic nurses but also for nurses generally.