Fundamental processes in sensorimotor learning: Reasoning, refinement, and retrieval.

Motor learning is often viewed as a unitary process that operates outside of conscious awareness. This perspective has led to the development of sophisticated models designed to elucidate the mechanisms of implicit sensorimotor learning. In this review, we argue for a broader perspective, emphasizing the contribution of explicit strategies to sensorimotor learning tasks. Furthermore, we propose a theoretical framework for motor learning that consists of three fundamental processes: reasoning, the process of understanding action-outcome relationships; refinement, the process of optimizing sensorimotor and cognitive parameters to achieve motor goals; and retrieval, the process of inferring the context and recalling a control policy. We anticipate that this '3R' framework for understanding how complex movements are learned will open exciting avenues for future research at the intersection between cognition and action.

Case report: Comprehensive follow-up of a Colombian family carrying a novel MEN1 variant linked to a rare ACTH-producing pancreatic neuroendocrine carcinoma.

Background: Multiple Endocrine Neoplasia type 1 (MEN1) is an autosomal dominant disorder marked by pathogenic variants in the MEN1 tumor suppressor gene, leading to tumors in the parathyroid glands, pancreas, and pituitary. The occurrence of ACTH-producing pancreatic neuroendocrine carcinoma is exceedingly rare in MEN1. Case presentation: This report details a Colombian family harboring a novel MEN1 variant identified through genetic screening initiated by the index case. Affected family members exhibited primary hyperparathyroidism (PHPT) symptoms from their 20s to 50s. Uniquely, the index case developed an ACTH-secreting pancreatic neuroendocrine carcinoma, a rarity in MEN1 syndromes. Proactive screening enabled the early detection of pituitary neuroendocrine tumors (PitNETs) as microadenomas in two carriers, with subsequent surgical or pharmacological intervention based on the clinical presentation. Conclusion: Our findings underscore the significance of cascade screening in facilitating the early diagnosis and individualized treatment of MEN1, contributing to better patient outcomes. Additionally, this study brings to light a novel presentation of ACTH-producing pancreatic neuroendocrine carcinoma within the MEN1 spectrum, expanding our understanding of the disease's manifestations.

Rates of Systemic Therapy for Metastatic Bladder Cancer Are Lower in Unmarried Males and Females.

OBJECTIVE: Systemic therapy is guideline-recommended for metastatic urothelial carcinoma of the urinary bladder (UCUB). Unmarried status represents an important barrier to treatment access in many primaries. The importance of married status is unknown in the context of systemic therapy in metastatic UCUB and was addressed in the current study. METHODS: We relied on the Surveillance, Epidemiology, and End Results database (2004-2020) to identify patients with metastatic UCUB. Univariable and multivariable logistic regression models were fitted to address systemic therapy rates. Additionally, temporal trends were plotted. RESULTS: Overall, 6873 patients with stage IV UCUB were identified. Of those, 4853 (71%) were male. Of males, 2993 (62%) were married vs. 797 (39%) of females. The rates of systemic therapy were 55% in both married males and married females. Married males and females differed from their unmarried counterparts regarding age and race/ethnicity. In males, prior to any adjustment, married status was associated with an odds ratio of 1.46 (P < .001). After adjustment for age and race/ethnicity, the odds ratio increased to 1.73 (P < .001). In females, prior to any adjustment, married status was associated with an odds ratio of 1.94 (P < .001). After adjustment for age and race/ethnicity, the odds ratio decreased to 1.57 (P < .001). CONCLUSION: Unmarried males and unmarried females are significantly exposed to lower access to systemic therapy compared to their married counterparts. In consequence, both unmarried men and unmarried women should be given very careful consideration when use of systemic therapy in metastatic UCUB is contemplated.

An image-based screen for secreted proteins involved in breast cancer G0 cell cycle arrest.

Secreted proteins regulate the balance between cellular proliferation and G0 arrest and therefore play important roles in tumour dormancy. Tumour dormancy presents a significant clinical challenge for breast cancer patients, where non-proliferating, G0-arrested cancer cells remain at metastatic sites, below the level of clinical detection, some of which can re-enter proliferation and drive tumour relapse. Knowing which secreted proteins can regulate entry into and exit from G0 allows us to manipulate their signalling to prevent tumour relapse. To identify novel secreted proteins that can promote breast cancer G0 arrest, we performed a secretome-wide, image-based screen for proteins that increase the fraction of cells in G0 arrest. From a secretome library of 1282 purified proteins, we identified 29 candidates that promote G0 arrest in non-transformed and transformed breast epithelial cells. The assay we have developed can be adapted for use in other perturbation screens in other cell types. All datasets have been made available for re-analysis and our candidate proteins are presented for alternative bioinformatic refinement or further experimental follow up.

Local delivery of cell surface-targeted immunocytokines programs systemic antitumor immunity.

Systemically administered cytokines are potent immunotherapeutics but can cause severe dose-limiting toxicities. To overcome this challenge, cytokines have been engineered for intratumoral retention after local delivery. However, despite inducing regression of treated lesions, tumor-localized cytokines often elicit only modest responses at distal untreated tumors. In the present study, we report a localized cytokine therapy that safely elicits systemic antitumor immunity by targeting the ubiquitous leukocyte receptor CD45. CD45-targeted immunocytokines have lower internalization rates relative to wild-type counterparts, leading to sustained downstream cis and trans signaling between lymphocytes. A single intratumoral dose of αCD45-interleukin (IL)-12 followed by a single dose of αCD45-IL-15 eradicated treated tumors and untreated distal lesions in multiple syngeneic mouse tumor models without toxicity. Mechanistically, CD45-targeted cytokines reprogrammed tumor-specific CD8+ T cells in the tumor-draining lymph nodes to have an antiviral transcriptional signature. CD45 anchoring represents a broad platform for protein retention by host immune cells for use in immunotherapy.

Movement- and Posture-based Measures of Sedentary Patterns and Associations with Metabolic Syndrome in Hispanic/Latino and non-Hispanic Adults.

BACKGROUND: Sedentary behavior has been identified as a significant risk factor for Metabolic Syndrome (MetS). However, it is unclear if the sedentary pattern measurement approach (posture vs. movement) impacts observed associations or if associations differ for Hispanic/Latino communities, who have higher risk of MetS. METHODS: Participants from the Community of Mine (CoM) study (N = 602) wore hip-based accelerometers for 14 days and completed MetS-associated biomarker assessment (triglycerides, blood pressure, fasting glucose, HDL cholesterol, waist circumference). Sedentary patterns were classified using both cutpoints (movement-based) and the Convolutional Neural Network Hip Accelerometer Posture (CHAP) algorithm (posture-based). We used logistic regression to estimate associations between MetS with sedentary patterns overall and stratified by Hispanic/Latino ethnicity. RESULTS: CHAP and cutpoint sedentary patterns were consistently associated with MetS. When controlling for total sedentary time and moderate to vigorous physical activity, only CHAP-measured median sedentary bout duration (OR = 1.15, CI: 1.04, 1.28) was significant. In stratified analysis, CHAP-measured median bout duration and time spent in sedentary bouts ≥ 30 min were each associated with increased odds of MetS, but the respective associations were stronger for Hispanic/Latino ethnicity (OR = 1.71 and 1.48; CI = 1.28-2.31 and 1.12-1.98) than for non-Hispanic/Latino ethnicity (OR = 1.43 and 1.40; CI = 1.10-1.87 and 1.06-1.87). CONCLUSIONS: The way sedentary patterns are measured can impact the strength and precision of associations with MetS. These differences may be larger in Hispanic/Latino ethnic groups and warrants further research to inform sedentary behavioral interventions in these populations.

Perceived childhood family cohesiveness prior to deployment prospectively moderates risk for war-zone psychopathology in theater among deployed U.S. soldiers.

OBJECTIVE: Several studies have demonstrated robust protective effects of childhood family support and cohesiveness on adult stress-related psychopathology. However, there is little evidence regarding the prospective relationship between the perceived childhood family environment and the in-theater emergence of war-zone stress-related psychological symptoms. The present report is from data collected from the Texas Combat PTSD Risk Project, which aims to identify risk and resilience factors at predeployment that predict the subsequent impact of war-zone stressors in terms of psychological symptom emergence in U.S. soldiers deployed to Iraq. METHOD: Soldiers (N = 150) completed a battery of standardized interview and self-report assessments at predeployment, including a measure of perceived childhood family cohesion. Once deployed, soldiers completed monthly web-based self-report assessments of war-zone stressors, posttraumatic stress symptoms, depression, and anxiety. RESULTS: Consistent with predictions, greater perceived childhood family cohesiveness prior to deployment robustly mitigated subsequent in-theater symptoms. However, contrary to predictions, childhood family cohesiveness did not reliably moderate the linkage between war-zone stressors and in-theater symptoms. CONCLUSIONS: Consistent with a wealth of other evidence demonstrating protective stress resilience effects of childhood family cohesion that extend across the lifespan, the present findings suggest they also extend to the war-zone environment among deployed soldiers. (PsycInfo Database Record (c) 2024 APA, all rights reserved).

Structural bone grafting for glenoid bone loss in primary anatomic total shoulder arthroplasty: a case series and technique report.

Background: Posterior glenoid bone loss in glenohumeral osteoarthritis poses significant challenges in shoulder arthroplasty. Anatomic total shoulder arthroplasty (TSA) with a humeral head autograft to address the glenoid bone deficiency is an option for these difficult cases. Variable results with this procedure are reported in the literature. This article describes the surgical technique of posterior glenoid bone grafting in TSA using a glenoid implant with hybrid fixation and a series of reported patient functional and radiographic outcomes. Methods: A retrospective chart review of cases from 2015 to 2020 by a single surgeon revealed 10 patients who underwent primary TSA with hybrid glenoid component and posterior glenoid bone grafting. Preoperative and postoperative radiographs were assessed for glenoid inclination, glenoid version, acromiohumeral distance, humeral stem status, and glenoid implant status. Functional outcomes were evaluated by range of motion, strength, and patient-reported clinical outcomes (pain and function on a visual analog scale, Disabilities of the Arm, Shoulder, and Hand score, Single Assessment Numeric Evaluation, American Shoulder and Elbow Surgeons score). Complications and reoperations were also evaluated. Results: Average follow-up was 31.4 months, active forward flexion and external rotation improved on average from 105° to 150° and 20° to 60°, respectively (P < .001) and average abduction improved from 100° to 140° (P < .002). At an average of 26.7 months, patients reported assessments (visual analog scale pain and function, Disabilities of the Arm, Shoulder, and Hand score, Single Assessment Numeric Evaluation, American Shoulder and Elbow Surgeons scores) reveal significant (P < .05) improvement in pain and functional outcomes. Radiographically, at 23.0 ± 20.1 months, all patients demonstrated a well-fixed humeral and glenoid component without evidence of lucent lines. The bone graft used in each patient was well unionized and no radiographic complications were reported. No patients underwent revision surgery, and there was one clinical complication reported, which consisted of a suspected rotator cuff injury at follow-up. Conclusion: Hybrid fixation with structural glenoid bone grafting in TSA resulted in excellent outcomes with no evidence of graft or component failure on follow-up radiographs and significantly reduced pain, improved functional scores, and improved active range of motion.

Development of Preliminary Integrated Health Care Clinical Competencies for United States Doctor of Chiropractic Programs: A Modified Delphi Consensus Process.

Background: There has been rapid growth of chiropractors pursuing career opportunities in both public and private hospitals and other integrated care settings. Chiropractors that prosper in integrated care settings deliver patient-centered care, focus on the institutional mission, understand and adhere to organizational rules, and are proficient in navigating complex systems. The Council on Chiropractic Education Accreditation Standards do not outline specific meta-competencies for integrated care clinical training. Objective: The purpose of this study was to develop preliminary integrated health care competencies for DC programs to guide the advancement of clinical chiropractic education. Methods: A systematic literature search was performed. Articles were screened for eligibility and extracted in duplicate. Domains and seed statements were generated from this literature, piloted at a conference workshop, and evaluated via a modified Delphi consensus process. Of 42 invited, 36 chiropractors participated as panelists. Public comment period yielded 20 comments, none resulting in substantive changes to the competencies. Results: Of 1718 citations, 23 articles met eligibility criteria. After 2 modified Delphi rounds, consensus was reached on all competency statements. A total of 78 competency statements were agreed upon, which encompassed 4 domains and 11 subdomains. The 4 domains were: 1) Collaboration, (2) Clinical Excellence, (3) Communication, and (4) Systems Administration. Conclusion: We identified 78 preliminary competencies appropriate for preparing DC students and early career chiropractors for clinical practice in integrated healthcare settings. Educational programs may consider these competencies for curricular design and reform to strengthen DC program graduates for integrated practice, advanced training, and employment.

Race/Ethnicity Affects Access and Survival Differences After Neoadjuvant or Adjuvant Chemotherapy at Radical Cystectomy in Urothelial Carcinoma Patients.

INTRODUCTION: It is unknown whether race/ethnicity affects access and/or survival after neoadjuvant (NAC) or adjuvant chemotherapy (ADJ) at radical cystectomy (RC). We addressed these knowledge gaps. MATERIAL AND METHODS: Within the Surveillance, Epidemiology, and End Results database (2007-2020), we identified NAC candidates (T2-T4N0M0) and ADJ candidates (T3-T4 and/or N1-3). We focused on the four most prevalent race/ethnicities: Caucasians, Hispanics, African American (AA), and Asian/Pacific Islanders (API). Multivariable logistic regression models (MLR) tested access to NAC and ADJ. Subsequently, within NAC-exposed patients, survival analyses consisting of Kaplan-Meier plots and multivariable Cox regression models addressed CSM according to race/ethnicity were fitted. We repeated the same methodology in ADJ-exposed patients. RESULTS: In 6418 NAC candidates, NAC was administered in 1011 (19.0%) Caucasians, 88 (21.0%) Hispanics, 65 (17.0%) AA, and 53 (18.0%) API. In MLR, AA exhibited lower access rates to NAC (OR 0.83, p = 0.04). In NAC-exposed patients, AA independently predicted higher CSM (HR 1.3, p < 0.001) and API independently predicted lower CSM (HR 0.83, p = 0.03). Similarly, in 5195 ADJ candidates, ADJ was administered to 1387 (33.0%) Caucasians, 100 (28.0%) Hispanics, 105 (29.0%) AA, and 90 (37.0%) API. In MLR, AA (OR 68, p = 0.003) and Hispanics (OR 0.69, p = 0.004) exhibited lower access rates to ADJ. In ADJ-exposed patients, AA independently predicted lower CSM (HR 1.32, p < 0.001), while API showed better CSM (HR 0.82, p = 0.01). CONCLUSION: Relative to Caucasians, AA are less likely to receive either NAC or ADJ. Moreover, relative to Caucasians, AA exhibit higher CSM even when treated with either NAC or ADJ.

Development of a Modular Cryo-Transfer Station for the Side-Entry Transmission Electron Microscope†.

Cryo-transfer stations are essential tools in the field of cryo-electron microscopy, enabling the safe transfer of frozen vitreous samples between different stages of the workflow. However, existing cryo-transfer stations are typically configured for only the two most popular sample holder geometries and are not commercially available for all electron microscopes. Additionally, they are expensive and difficult to customize, which limits their accessibility and adaptability for research laboratories. Here, we present a new modular cryo-transfer station that addresses these limitations. The station is composed entirely of 3D-printed and off the shelf parts, allowing it to be reconfigured to a fit variety of microscopes and experimental protocols. We describe the design and construction of the station and report on the results of testing the cryo-transfer station, including its ability to maintain cryogenic temperatures and transfer frozen vitreous samples as demonstrated by vibrational spectroscopy. Our findings demonstrate that the cryo-transfer station performs comparably to existing commercial models, while offering greater accessibility and customizability. The design for the station is open source to encourage other groups to replicate and build on this development. We hope that this project will increase access to cryo-transfer stations for researchers in a variety of disciplines with nonstandard equipment.

Dos and don'ts to optimize transnasal aerosol drug delivery in clinical practice.

INTRODUCTION: Transnasal aerosol drug delivery has become widely accepted for treating acutely ill infants, children, and adults. More recently aerosol administration to wider populations receiving high and low-flow nasal oxygen has become common practice. AREAS COVERED: Skepticism of insufficient aerosol delivery to the lungs has been tempered by multiple in vitro explorations of variables to optimize delivery efficiency. Additionally, clinical studies demonstrated comparable clinical responses to orally inhaled aerosols. This paper provides essential clinical guidance on how to improve transnasal aerosol delivery based on device-, settings-, and drug-related optimization to serve as a resource for educational initiatives and quality enhancement endeavors at healthcare institutions. EXPERT OPINION: Transnasal aerosol delivery is proliferating worldwide, but indiscriminate use of excessive-high flows, poor selection and placement of aerosol devices and circuits can greatly reduce aerosol delivery and efficacy, potentially compromising treatment to acute and critically ill patients. Attention to these details can improve inhaled dose by an order of magnitude, making the difference between effective treatment and the progression to more invasive ventilatory support, with greater inherent risk and cost. These revelations have prompted specific recommendations for optimal delivery, driving advancements in aerosol generators, formulations, and future device designs to administer aerosols and maximize treatment effectiveness.

Adverse In-Hospital Outcomes after Radical Prostatectomy in Leukemia History Patients.

INTRODUCTION: Leukemia history affects some radical prostatectomy (RP) patients. Although its prevalence and effect as an adverse risk factor are well known in cardiac surgery, the number of RP patients with a leukemia history, as well as their rate of adverse in-hospital outcomes, are unknown. METHODS: We identified RP patients (National Inpatient Sample 2000-2019), stratified according to the presence or absence of a leukemia history. Descriptive analyses, propensity score matching (PSM, ratio 1:10), and multivariable logistic regression models were used. RESULTS: Of 259,939 RP patients, 416 (0.2%) had a leukemia history. Their proportion increased from 0.1 to 0.2% covering the study span (p < 0.01). Leukemia history patients were older (median age, 64 vs. 62 years, p < 0.001). After PSM for age, insurance status, ethnicity, pelvic lymph node dissection, and Charlson Comorbidity Index, leukemia history RP patients exhibited higher rates of acute kidney injury (<2.6 vs. 0.9%; Odds Ratio [OR] 2.0, p = 0.02), more frequently underwent dialysis (3.6 vs. 1.9%; OR 1.9, p = 0.03), and more frequently had a length of stay exceeding one week (4.8 vs. 2.5%; OR 2.0, p = 0.006). CONCLUSIONS: Although leukemia history RP patients are rare, their numbers have increased. Renal complications and extended hospital stays are more frequent in those individuals.

Differences in life expectancy of adrenocortical carcinoma patients vs. age­ and sex-matched population controls.

PURPOSE: To quantify to what extent the 5-year overall survival (OS) of adrenocortical carcinoma (ACC) patients differs from age- and sex-matched population-based controls, especially when stage is considered. METHODS: We relied on the Surveillance, Epidemiology, and End Results database (2004-2020) to identify newly diagnosed (2004-2014) ACC patients. Subsequently, we compared OS between ACC patients relative to simulated age- and sex-matched controls (Monte Carlo simulation), according to Social Security Administration Life Tables (2004-2020). RESULTS: Of all 742 ACC patients, 301 (41%) harbored localized stage, 173 (23%) locally advanced stage, and 268 (36%) metastatic stage. At 5-years follow-up, ACC patients' OS was 33%. After stratification for stage, the 5-years OS was 55 vs. 31 vs. 8% in localized, locally advanced, and metastatic stages, respectively. Conversely, after Monte Carlo simulation of age- and sex-matched controls, OS at five-years was 93% in the entire simulated cohort vs. 94% in the simulated localized cohort vs. 92 and 92% in locally advanced and metastatic stage, respectively. The resulting differences in OS between ACC patients and age- and sex-matched population-based controls were 60 vs. 39 vs. 61 vs. 84% respectively in the overall cohort vs. localized vs. locally advanced vs. metastatic stage. CONCLUSION: The most pronounced life expectancy detriment (84%) was recorded in metastatic ACC followed by locally advanced ACC patients (61%). Unfortunately, even in patients with localized ACC, life expectancy was 39% lower than that of the general population. Therefore, regardless of stage, ACC diagnosis results in a very pronounced detriment in life expectancy relative to the general population.

Tumor-localized interleukin-2 and interleukin-12 combine with radiation therapy to safely potentiate regression of advanced malignant melanoma in pet dogs.

PURPOSE: Interleukin-2 and -12 cytokines have potent anti-cancer activity, but suffer a narrow therapeutic window due to off-tumor immune cell activation. Engineering cytokines with the ability to bind and associate with tumor collagen after intratumoral injection potentiated response without toxicity in mice, and was previously safe in pet dogs with sarcoma. Here we sought to test the efficacy of this approach with in dogs with advanced melanoma. EXPERIMENTAL DESIGN: This study examined fifteen client-owned dogs with histologically- or cytologically-confirmed malignant melanoma who received a single 9 Gray fraction of radiation therapy, followed by six cycles of combined collagen-anchored IL-2 and IL-12 therapy Q2W. Cytokine dosing followed a 3+3 dose escalation design, with the initial cytokine dose chosen from prior evaluation in canine sarcomas. No exclusion criteria for tumor stage or metastatic burden, age, weight, or neuter status were applied for this trial. RESULTS: Median survival regardless of tumor stage or dose level was 256 days and 10/13 (76.9%) dogs that completed treatment had CT-measured tumor regression at the treated lesion. In dogs with metastatic disease, 8/13 (61.5%) dogs had partial responses across their combined lesions, evidence of locoregional response. Profiling by Nanostring of treatment-resistant dogs revealed that B2m loss was predictive of poor response to this therapy. CONCLUSIONS: Collectively, these results confirm the ability of locally administered tumor-anchored cytokines to potentiate responses at regional disease sites when combined with radiation. This evidence supports the clinical translation of this approach and highlights the utility of comparative investigation in canine cancers.