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Objective: To determine factors that may lead physicians not to comply with clinical practice guidelines.Design: Retrospective analysis of patients whose physicians were not compliant with discharge recommendations from a prospective, controlled interventional trial of a guideline to reduce hospital length of stay for patients admitted for chest pain.Setting: A large community teaching hospital.Participants: Patients admitted with chest pain who were not discharged according to a practice guideline.Results: 79 (34%) of 230 patients with chest pain classified as being at low risk by concurrent or retrospective review were not discharged by day 3 (the guideline recommendation). Of these 79 patients, 33 (42%) were misclassified at concurrent review (10 were falsely classified as being at high risk and 23 were falsely classified as being at low risk). Of 46 correctly classified patients, 11 (14%) were classified as having noncompliant physicians because of health care system inefficiencies. The status of 7 (9%) patients was changed to high risk between initial classification and potential discharge. For 15 patients (19%), no obvious reason for delayed discharge was found, but they had a higher severity of illness than did low-risk patients discharged according to the guideline as measured by mean time-insensitive predictive instrument scores (41.3% +/- [SD] 14.1% compared with 31.5% +/- 14.3%; P = 0.017). In 13 patients (16%), physicians refused to follow the guideline recommendations.Conclusions: In measuring and attempting to improve physician compliance with a length-of-stay guideline, physician refusal accounts for a small percentage (16%) of noncompliance. Implementation issues, health care system inefficiency, and severity of illness were the predominant reasons why physicians did not comply with guidelines. Our study further supports the principle that clinical practice guidelines should complement rather than be a substitute for physician judgment. [ABSTRACT FROM AUTHOR]

In a retrospective study in an academic, acute-care community hospital, we studied the possible safety and effectiveness of a practice guideline recommending early discharge from the hospital for patients having uncomplicated total knee replacement. Of 206 patients receiving knee replacements, 162 (79%) were classified by the guideline as being at low risk for complications between the 4th and 7th postoperative days. Use of the guideline could have reduced the postoperative length of stay from 7.3 +/- 2.6 days to 4 days for the 112 patients (54%) who became low risk on the 4th postoperative day. Explicit and implicit review of the quality of care determined that 157 patients (96.9%; 95% confidence interval, (92.9%, 99.0%) could have been safely transferred from the acute-care hospital to an appropriate setting when they became classified at low risk between the 4th and 7th postoperative days. Clinical practice guidelines can possibly be used to reduce the postoperative length of acute-care hospital stay for patients having knee replacements. This guideline requires further study in a controlled clinical trial before it can be recommended for use. [ABSTRACT FROM AUTHOR]

Objective: The acceptability, safety, and efficacy of practice guidelines have rarely been evaluated. Moreover, despite the recent development of guidelines and decision aids for patients admitted to coronary care and intermediate care units, few have been tested in clinical practice.Design: A prospective, controlled clinical trial with an alternate-month design.Setting: A large teaching community hospital.Patients: Patients admitted to coronary care and intermediate care units with chest pain who were considered at low risk for complications according to a practice guideline (n = 375).Intervention: Physicians caring for patients with chest pain who were at low risk for complications received concurrent, personalized written and verbal reminders regarding a guideline that recommended a 2-day hospital stay.Results: Use of the practice guideline recommendation with concurrent reminders was associated with a 50% to 69% increase in guideline compliance (P < 0.001) and a decrease in length of stay from 3.54 +/- 4.1 to 2.63 +/- 3.0 days (0.91-day reduction, 95% CI, 0.18 to 1.63; P = 0.02) for all patients with chest pain considered at low risk for complications. The intervention was associated with a total (direct and indirect) cost reduction of $1397 per patient (CI, $176 to $2618; P = 0.03). No significant difference was found in the hospital complication rate between patients admitted to the hospital during control and intervention periods, and no significant difference was noted in complications, patient health status, or patient satisfaction when measured 1 month after hospital discharge.Conclusion: These results suggest that implementation of this practice guideline through concurrent reminders reduced hospital costs for patients with chest pain considered at low risk for complications. Further study of the guideline is warranted. [ABSTRACT FROM AUTHOR]

Objective: To determine whether providing private practitioners with triage criteria for their low-risk chest pain patients would safely enhance bed utilization efficiency in coronary and intermediate care units.Design: Prospective, controlled, interventional trial using an alternate month study design.Setting: A large teaching community hospital.Patients: Cohort of 404 low-risk patients with chest pain for whom a diagnosis of myocardial infarction has been excluded and who have not sustained complications, required interventions, or developed unstable comorbidity.Interventions: During intervention months, private practitioners caring for low-risk patients in the coronary and intermediate care units were contacted 24 hours after admission. Physicians were informed that the transfer of low-risk patients to nonmonitored beds could probably be done safely, based on the results of a pilot study. The practitioner had the option of agreeing to or deferring patient transfer. During control months, physicians were not contacted in this way.Measurements and Main Results: Use of the triage criteria by private practitioners reduced lengths of stay in the intermediate and coronary care units by 36% and 53%, respectively. Bed availability increased by 744 intermediate and 372 coronary care unit bed-days per year. Charges decreased by $2.6 million per year and profits improved by $390,000 per year. There were not significant differences in complications between control and intervention patients and in no case (95% CI, 0% to 1.6%) did the triage criteria adversely affect quality of care.Conclusions: The early transfer triage criteria may be a safe and efficacious decision aid for improving bed utilization in intermediate and coronary care units. In addition, this study shows the feasibility of and potential benefits from applying practice guidelines at a community hospital. [ABSTRACT FROM AUTHOR]

Background: Diet largely impacts the gut microbiota, and may affect mental and somatic health via the gut-brain axis. As such, the relationship between diet and the microbiota in Bipolar Disorder (BD) could be of importance, but has not been studied before. The aim was therefore to assess whether dietary quality is associated with the gut microbiota diversity in patients with recently diagnosed BD, and whether changes occur in dietary quality and microbiota diversity during their first year of treatment., Methods: Seventy recently (<1 year) diagnosed patients with BD were included in the "Bipolar Netherlands Cohort" (BINCO), and a total of 45 participants were assessed after one year. A 203-item Food Frequency Questionnaire (FFQ) data yielded the Dutch Healthy index (DHD-15), and the microbiota composition and diversity of fecal samples were characterized by 16S rRNA gene amplicon sequencing at baseline and 1-year follow-up. Associations and changes over time were analyzed using multivariate regression analyses and t-tests for paired samples., Results: Included patients had a mean age of 34.9 years (SD ± 11.2), and 58.6 % was female. Alpha diversity (Shannon diversity index), richness (Chao1 index) and evenness (Pielou's Evenness Index) were positively associated with the DHD-15 total score, after adjustment for sex, age and educational level (beta = 0.55; P < 0.001, beta = 0.39; P = 0.024, beta = 0.54; P = 0.001 respectively). The positive correlations were largely driven by the combined positive effect of fish, beans, fruits and nuts, and inverse correlations with alcohol and processed meats. No significant changes were found in DHD-15 total score, nor in microbiota diversity, richness and evenness indexes during one year follow-up and regular treatment., Conclusion: A healthy and varied diet is associated with the diversity of the microbiota in BD patients. Its potential consequences for maintaining mood stability and overall health should be studied further., Competing Interests: Declaration of competing interest All authors declare no conflict of interest., (Copyright © 2024 The Authors. Published by Elsevier B.V. All rights reserved.)

Distractibility determines the propensity to have one's attention captured by irrelevant information; it relies on a balance between voluntary and involuntary attention. We report a cross-sectional study that uses the competitive attention test to characterize patterns of attention across the adult life span from 21 to 86 years old. Several distractibility components were measured in 186 participants distributed within seven age groups. Results indicate that distractibility components follow distinct trajectories with aging: Voluntary orienting remains stable from 21 to 86 years old, sustained attention decreases after 30 years old, distraction progressively increases between 26 and 86 years old, and impulsivity is lower in older compared to younger adults. Increased distractibility in older age thus seems to result from a dominance of involuntary over voluntary attention processes, whose detrimental effect on performance is partly compensated by enhanced motor control. (PsycInfo Database Record (c) 2023 APA, all rights reserved).

CAR (chimeric antigen receptor) T cell therapy has shown clinical success in treating hematological malignancies, but its treatment of solid tumors has been limited. One major challenge is on-target, off-tumor toxicity, where CAR T cells also damage normal tissues that express the targeted antigen. To reduce this detrimental side-effect, Boolean-logic gates like AND-NOT gates have utilized an inhibitory CAR (iCAR) to specifically curb CAR T cell activity at selected nonmalignant tissue sites. However, the strategy seems inefficient, requiring high levels of iCAR and its target antigen for inhibition. Using a TROP2-targeting iCAR with a single PD1 inhibitory domain to inhibit a CEACAM5-targeting CAR (CEACAR), we observed that the inefficiency was due to a kinetic delay in iCAR inhibition of cytotoxicity. To improve iCAR efficiency, we modified three features of the iCAR-the avidity, the affinity, and the intracellular signaling domains. Increasing the avidity but not the affinity of the iCAR led to significant reductions in the delay. iCARs containing twelve different inhibitory signaling domains were screened for improved inhibition, and three domains (BTLA, LAIR-1, and SIGLEC-9) each suppressed CAR T function but did not enhance inhibitory kinetics. When inhibitory domains of LAIR-1 or SIGLEC-9 were combined with PD-1 into a single dual-inhibitory domain iCAR (DiCARs) and tested with the CEACAR, inhibition efficiency improved as evidenced by a significant reduction in the inhibitory delay. These data indicate that a delicate balance between CAR and iCAR signaling strength and kinetics must be achieved to regulate AND-NOT gate CAR T cell selectivity.

In vowel discrimination, commonly found discrimination patterns are directional asymmetries where discrimination is faster (or easier) if differing vowels are presented in a certain sequence compared to the reversed sequence. Different models of speech sound processing try to account for these asymmetries based on either phonetic or phonological properties. In this study, we tested and compared two of those often-discussed models, namely the Featurally Underspecified Lexicon (FUL) model (Lahiri and Reetz, 2002) and the Natural Referent Vowel (NRV) framework (Polka and Bohn, 2011). While most studies presented isolated vowels, we investigated a large stimulus set of German vowels in a more naturalistic setting within minimal pairs. We conducted an mismatch negativity (MMN) study in a passive and a reaction time study in an active oddball paradigm. In both data sets, we found directional asymmetries that can be explained by either phonological or phonetic theories. While behaviorally, the vowel discrimination was based on phonological properties, both tested models failed to explain the found neural patterns comprehensively. Therefore, we additionally examined the influence of a variety of articulatory, acoustical, and lexical factors (e.g., formant structure, intensity, duration, and frequency of occurrence) but also the influence of factors beyond the well-known (perceived loudness of vowels, degree of openness) in depth via multiple regression analyses. The analyses revealed that the perceptual factor of perceived loudness has a greater impact than considered in the literature and should be taken stronger into consideration when analyzing preattentive natural vowel processing., 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 Riedinger, Nagels, Werth and Scharinger.)

Metastatic castration-resistant prostate cancer (CRPC) is the primary cause of prostate cancer-specific mortality. Defining new mechanisms that can predict recurrence and drive lethal CRPC is critical. Here, we demonstrate that localized high-risk prostate cancer and metastatic CRPC, but not benign prostate tissues or low/intermediate-risk prostate cancer, express high levels of nuclear Notch homolog 1, translocation-associated (Notch1) receptor intracellular domain. Chronic activation of Notch1 synergizes with multiple oncogenic pathways altered in early disease to promote the development of prostate adenocarcinoma. These tumors display features of epithelial-to-mesenchymal transition, a cellular state associated with increased tumor aggressiveness. Consistent with its activation in clinical CRPC, tumors driven by Notch1 intracellular domain in combination with multiple pathways altered in prostate cancer are metastatic and resistant to androgen deprivation. Our study provides functional evidence that the Notch1 signaling axis synergizes with alternative pathways in promoting metastatic CRPC and may represent a new therapeutic target for advanced prostate cancer., Competing Interests: The authors declare no conflict of interest.

Efficient and adequate generation of deoxyribonucleotides is critical to successful DNA repair. We show that ataxia telangiectasia mutated (ATM) integrates the DNA damage response with DNA metabolism by regulating the salvage of deoxyribonucleosides. Specifically, ATM phosphorylates and activates deoxycytidine kinase (dCK) at serine 74 in response to ionizing radiation (IR). Activation of dCK shifts its substrate specificity toward deoxycytidine, increases intracellular dCTP pools post IR, and enhances the rate of DNA repair. Mutation of a single serine 74 residue has profound effects on murine T and B lymphocyte development, suggesting that post-translational regulation of dCK may be important in maintaining genomic stability during hematopoiesis. Using [(18)F]-FAC, a dCK-specific positron emission tomography (PET) probe, we visualized and quantified dCK activation in tumor xenografts after IR, indicating that dCK activation could serve as a biomarker for ATM function and DNA damage response in vivo. In addition, dCK-deficient leukemia cell lines and murine embryonic fibroblasts exhibited increased sensitivity to IR, indicating that pharmacologic inhibition of dCK may be an effective radiosensitization strategy.