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The author reflects on new technologies in drug development which helps patients to be treated with therapies that have the potential to revolutionize human health. The author states the clinical trial paradigm which allows medical decision making whether the molecule really is promising and warrants moving forward in development. An overview on the complex process of drug development is also offered.

This paper considers the Canadian Tri-Council Policy Statement: Ethical Conduct for Research Involving Humans (TCPS 2) a visionary document when viewed in comparison with the ways ethics review is enacted in New Zealand. New Zealand has unequivocal guidelines for indigenous research. The indigenous guidelines in Chapter 9 of the Canadian document are particularly innovative, in that they prescribe indigenous consultation for some, but not all researchers. In New Zealand, according to the Health Research Council Te Ara Tika guidelines, all research in New Zealand warrants indigenous consultation. This paper suggests that progress around improving the practice of consultation and engagement with Māori could be made if the consultation requirements for mainstream research were to be paper based, and reviewed by an ethics committee without actual expectation of mandatory consultation conditions. On the other hand, Māori centred research should require actual and detailed evidence of consultation that would be tied to an explicit articulation of the mutual understanding of the benefits accruing from this relationship. [ABSTRACT FROM PUBLISHER]

Sickle cell anemia and thalassemia are hemoglobinopathies rarely encountered in the United States. Compounded with congenital heart disease, patients with sickle cell disease (SCD) requiring cardiopulmonary bypass and open-heart surgery represent the proverbial “needle in the haystack”. As such, there is some trepidation on the part of clinicians when these patients present for complex cardiac surgery.SCD is an autosomal, recessive condition that results from a single nucleotide polymorphism in the β-globin gene. Hemoglobin SS molecules (HgbSS) with this point mutation can polymerize under the right conditions, stiffening the erythrocyte membrane and distorting the cellular structure to the characteristic sickle shape. This shape change alters cellular transit through the microvasculature. As a result, circumstances such as hypoxia, hypothermia, acidosis or diminished blood flow can lead to aggregation, vascular occlusion and thrombosis. Chronically, SCD can give rise to multiorgan damage secondary to hemolysis and vascular obstruction.This review and case study details an 11-year-old African-American male with known SCD who presented to the cardiothoracic surgical service with congenital heart disease consisting of an anomalous, intramural right coronary artery arising from the left coronary sinus for surgical consultation and subsequent surgical correction. This case report will include a review of the pathophysiology and current literature regarding preoperative, intraoperative and postoperative management of SCD patients. [ABSTRACT FROM AUTHOR]

Mechanical circulatory support emerged for the pediatric population in the late 1980s as a bridge to cardiac transplantation. The Total Artificial Heart (TAH-t) (SynCardia Systems Inc., Tuscon, AZ) has been approved for compassionate use by the Food and Drug Administration for patients with end-stage biventricular heart failure as a bridge to heart transplantation since 1985 and has had FDA approval since 2004. However, of the 1,061 patients placed on the TAH-t, only 21 (2%) were under the age 18. SynCardia Systems, Inc. recommends a minimum patient body surface area (BSA) of 1.7 m2, thus, limiting pediatric application of this device.This unique case report shares this pediatric institution’s first experience with the TAH-t. A 14-year-old male was admitted with dilated cardiomyopathy and severe biventricular heart failure. The patient rapidly decompensated, requiring extracorporeal life support. An echocardiogram revealed severe biventricular dysfunction and diffuse clot formation in the left ventricle and outflow tract. The decision was made to transition to biventricular assist device. The biventricular failure and clot formation helped guide the team to the TAH-t, in spite of a BSA (1.5 m2) below the recommendation of 1.7m2. A computed tomography (CT) scan of the thorax, in conjunction with a novel three-dimensional (3D) modeling system and team, assisted in determining appropriate fit. Chest CT and 3D modeling following implantation were utilized to determine all major vascular structures were unobstructed and the bronchi were open. The virtual 3D model confirmed appropriate device fit with no evidence of compression to the left pulmonary veins. The postoperative course was complicated by a left lung opacification. The left lung anomalies proved to be atelectasis and improved with aggressive recruitment maneuvers. The patient was supported for 11 days prior to transplantation. Chest CT and 3D modeling were crucial in assessing whether the device would fit, as well as postoperative complications in this smaller pediatric patient. [ABSTRACT FROM PUBLISHER]

Background: Shoulder deformities are common secondary sequelae associated with brachial plexus birth palsy. The aim of the present study was to characterize three-dimensional glenohumeral deformity associated with brachial plexus birth palsy with use of microcomputed tomography scanning in a recently developed animal model.Methods: Brachial plexus birth palsy was produced by a right-sided neurotomy of the C5 and C6 nerve roots in seven five-day-old Sprague-Dawley rats. Microcomputed tomography scanning was performed when the rats were four months of age. Glenoid size, version, and inclination; humeral head size; and acromion-glenoid distance were measured. Normal shoulders of age-matched rats (n = 9) served as controls. Statistical analysis was performed with use of the unpaired two-tailed Student t test.Results: There were significant increases in glenoid retroversion (-7.6° ± 4.9° compared with 3.6° ± 2.1°; p = 0.038) and glenoid inclination (38.7° ± 7.3° compared with 11.2° ± 1.9°; p = 0.015) in the shoulders with simulated brachial plexus birth palsy in comparison with the normal, control shoulders. The glenohumeral joints were more medialized in the joints with simulated brachial plexus birth palsy as reflected by the acromion-glenoid distance measurement; however, the difference was not significant (3.20 ± 0.51 compared with 2.40 ± 0.18 mm; p = 0.12). Although the mean humeral head height and width measurements, on the average, were smaller in the brachial plexus birth palsy shoulders as compared with the normal, control shoulders, only the measurement of humeral head height was significantly different between the two groups (4.25 ± 2.02 compared with 4.97 ± 0.11 mm [p = 0.008] and 3.56 ± 0.27 compared with 4.19 ± 0.17 mm [p = 0.056], respectively).Conclusions: In this animal model, rats with simulated brachial plexus birth palsy developed gross architectural joint distortion characterized by increased glenoid retroversion and inclination. In addition, humeral heads tended to be smaller four months after simulated brachial plexus birth palsy. [ABSTRACT FROM AUTHOR]

Each month, Clinical Pharmacology & Therapeutics focuses on a particular theme. Twice a year, the associate editors, editors, and staff get together to discuss journal business and spend time setting up the calendar of themes. Often, there are no experts among us to take on a particular topic that we have chosen. The consequence is that one or two of us take on the theme and then have a crash course to learn as much as they can about it in order to solicit meaningful articles. This month's theme on rare diseases is such a case. [ABSTRACT FROM AUTHOR]

The purpose of this commentary is to place probability of trial success, or assurance, in the context of decision making in drug development, and to illustrate its properties in an intuitive manner for the readers of Clinical Pharmacology and Therapeutics. The hope is that this will stimulate a dialog on how assurance should be incorporated into a quantitative decision approach for clinical development and trial design that uses all available information. [ABSTRACT FROM AUTHOR]

An introduction is presented in which the editor discusses topics related to men's health within the issue including prostate cancer, mental health disorders, and testicular cancer.

Background: Repetitive trauma to the hand is a concern for baseball players. The present study investigated the effects of repetitive trauma and the prevalence of microvascular pathological changes in the hands of minor league professional baseball players. In contrast to previous investigators, we documented the presence of abnormalities in younger, asymptomatic individuals.Methods: Thirty-six baseball players on active minor league rosters underwent a history and physical examination of both hands as well as additional specialized tests, including Doppler ultrasound, a timed Allen test, determination of digital brachial pressure indices, and ring sizing of fingers. Data were compared between gloved hands and throwing hands, hitters and nonhitters, and players at four different positions (catcher [nine subjects], outfielder [seven subjects], infielder [five subjects], and pitcher [fifteen subjects]).Results: Digital brachial indices in the ring fingers of the gloved (p < 0.05) and throwing hands (p < 0.02) of catchers were significantly diminished compared with those in all other players. Doppler testing showed a significantly greater prevalence of abnormal flow in the ulnar artery at Guyon's canal when catchers were compared with other position players (p < 0.01). Doppler abnormalities were significantly more common in the gloved hand compared with the throwing hand (p < 0.05). Seven of nine catchers (and only catchers) were found to have index finger hypertrophy (average change, two ring sizes; p < 0.01); the hypertrophy occurred at the proximal phalanx and the proximal interphalangeal joint of the gloved hand. Catchers had a significantly higher prevalence of subjective hand symptoms (specifically, weakness in the gloved hand) compared with pitchers and infielders/outfielders (44% compared with 7% and 17%, respectively; p < 0.05).Conclusions: Microvascular changes are present in the hands of otherwise healthy professional baseball players in all positions, with a significantly higher prevalence in catchers, prior to the development of clinically important ischemia. Repetitive trauma resulting from the impact of the baseball also leads to digital hypertrophy in the index finger of the gloved hand of catchers. Gloves currently used by professional catchers do not adequately protect the hand from repetitive trauma. [ABSTRACT FROM AUTHOR]

Background: Distal radial fractures with extensive comminution involving the metaphyseal-diaphyseal junction present a major treatment dilemma. Of particular difficulty are those fractures involving the articular surface. One approach is to apply a dorsal 3.5-mm plate extra-articularly from the radius to the third metacarpal, stabilizing the diaphysis and maintaining distraction across the radiocarpal joint.Methods: Twenty-two patients treated with a distraction plate for a comminuted distal radial fracture were included in the study. With use of three limited incisions, a 3.5-mm ASIF plate was applied in distraction dorsally from the radial diaphysis, bypassing the comminuted segment, to the long-finger metacarpal, where it was fixed distally. The articular surface was anatomically reduced and was secured with Kirschner wires or screws. Eleven of the twenty-two fractures were treated with bone-grafting. The plate was removed after fracture consolidation (at an average of 124 days), and wrist motion was initiated. All patients were followed prospectively with use of radiographs, physical examination, and DASH (Disabilities of the Arm, Shoulder and Hand) scores.Results: All fractures united by an average of 110 days. Radiographs showed an average palmar tilt of 4.6 degrees and an average ulnar variance of neutral (0 degrees), whereas loss of radial length averaged 2 mm. Flexion and extension averaged 57 degrees and 65 degrees, respectively, and pronation and supination averaged 77 degrees and 76 degrees , respectively. The average DASH scores were 34 points at six months, 15 points at one year, and 11.5 points at the time of final follow-up (at an average of 24.8 months). According to the Gartland-Werley rating system, fourteen patients had an excellent result, six had a good result, and two had a fair result. Grip strength and the range of motion of the wrist at one year correlated inversely with the proximal extent of fracture comminution into the diaphysis. The duration of plate immobilization did not correlate with the range of motion of the wrist or with the DASH score at one year.Conclusions: The use of a distraction plate combined with reduction of the articular surface and bone-grafting when needed can be an effective technique for treatment of fractures of the distal end of the radius with extensive metaphyseal and diaphyseal comminution. A functional range of motion with minimal disability can be achieved despite a prolonged period of fixation with a distraction plate across the wrist joint. [ABSTRACT FROM AUTHOR]

The purpose of this study was to characterize the effect of potent CYP2D6 inhibition byparoxetine on atomoxetine disposition in extensive metabolizers. This was a single-blind, two-period, sequential studyin 22 healthy individuals. In period 1, 20 mg atomoxetine bid was administered to steady state. In period 2, 20 mg paroxetine was administered qd for 17 days. On days 12 through 17, 20 mg atomoxetine bid were coadministered. Plasma pharmacokinetics of atomoxetine, 4-hydroxyatomoxetine, and N-desmethylatomoxetine was determined at steady state in each treatment period. Plasma pharmacokinetics of paroxetine were determined after the 11th and 17th doses. Paroxetine increased C(ss,max), AUC0-12, and t1/2 of atomoxetine by approximately 3.5-, 6.5-, and 2.5-fold, respectively. After coadministration with paroxetine, increases in N-desmethylatomoxetine and decreases in 4-hydroxyatomoxetine concentrations were observed. No changes in paroxetine pharmacokinetics were observed after coadministration with atomoxetine. It was concluded that inhibition of CYP2D6 by paroxetine markedly affected atomoxetine disposition, resulting in pharmacokinetics similar to poor metabolizers of CYP2D6 substrates. [ABSTRACT FROM AUTHOR]

OBJECTIVE: The most common treatment of soft tissue contusions is ice application (cryotherapy). The physiological basis for this therapy is assumed to be cold-mediated vasoconstriction resulting in decreased edema formation and a reduction in overall morbidity. This proposed mechanism has not been tested. The present research examined the hypothesis that cryotherapy following contusion is effective because it reduces microvascular perfusion and subsequent edema formation. EXPERIMENTAL DESIGN: The microcirculatory responses to contusion were studied with and without cryotherapy in a chronically instrumented rat model. Initial studies evaluated the immediate effects of cryotherapy on arteriolar and venular diameters and microvascular perfusion (using laser Doppler floxmetry). Variables were measured before and immediately after 20 minutes of cryotherapy. Two additional studies monitored the same microvascular parameters longitudinally in four sets of chronically instrumented animals. Groups of rats studied had contusion or sham contusion with ice treatment or no ice treatment. Measurements were performed repeatedly before and after treatment for 24 hours or 96 hours after contusion/sham contusion. RESULTS: The acute microvascular effects of cryotherapy were vasoconstriction and decreased perfusion. However, when cryotherapy was used as a treatment following contusion/sham contusion, there were no long-lasting microvascular effects of cryotherapy either in the presence or absence of contusion. CONCLUSIONS: These results indicate that cryotherapy of striated muscle following contusion does not reduce microvascular diameters or decrease microvascular perfusion. Alternate mechanisms of action for cryotherapy treatment need to be investigated. [ABSTRACT FROM AUTHOR]

Predictors of self-esteem were examined in 50 pre-adolescents and adolescents with cerebral palsy. On average, self-esteem was high, although 30% scored below a cut-point for low self-esteem. Self-esteem was bivariately associated with female gender, better physician-assessed functional ability, greater perception of the impact of the disability, and higher perceived parent overprotectiveness. In a multivariate model, only perceived impact of the disability remained significant. [ABSTRACT FROM AUTHOR]

Background: Rural patients suffer higher incidence of and mortality from colorectal cancer. Ensuring high-quality screening is essential to address these disparities., Objective: To investigate whether socioecological determinants of health are associated with colonoscopy quality in rural Alabama., Design: Retrospective review., Setting: Data across three rural hospitals in Alabama from August 2021 to July 2023., Patients: We included adults (≥18 years) who underwent screening or diagnostic colonoscopy and completed a validated survey that measures socioecological determinants of health., Main Outcome Measures: Primary outcomes included bowel preparation quality, cecal intubation, and adenoma detection rate. We linked th e survey responses to these quality metrics to identify factors associated with outcomes. Analyses included the χ 2, Fisher's Exact and Kruskal-Wallis Rank sum tests, with p < 0.05 considered statistically significant., Results: The 84 patients surveyed were 66.7% male, 50.0% Black, and had a median age of 64 years. Optimal bowel preparation was present in 88.0%, 89.3% had successful cecal intubations, and overall adenoma detection rate was 45.8%. Patients with suboptimal bowel preparation described lower rates of internet access (60.0% vs. 87.4%, p < 0.05), more difficulty understanding written information (30.0% vs. 1.4%, p < 0.05) and lacked a sense of responsibility for their health (30.0% vs. 51.4%, p < 0.05) compared to those having optimal bowel preparation. Those with unsuccessful cecal intubations had lower physician-trust (55.6% vs. 73.3%, p < 0.05), while patients with successful cecal intubations were more confident in preventing health-related problems (53.3% vs. 33.3%, p < 0.05) and had a more supportive social environment (72.0% vs. 66.7%, p < 0.05)., Limitations: Retrospective design and small sample size limiting multivariable analyses., Conclusion: In rural Alabama, health literacy, internet access, and physician-trust were associated with low-quality colonoscopy, while a higher patient sense of responsibility and a supportive social environment was associated with higher-quality metrics. These findings identify potential targets for improving colonoscopy quality in rural settings. See Video Abstract., (Copyright © The ASCRS 2024.)

Introduction: Socioecological determinants of health (SEDOHs) influence disparities in surgical outcomes. However, SEDOHs are challenging to measure, limiting our ability to address disparities. Using a validated survey (SEDOH-88), we assessed SEDOHs in three rural communities in Alabama. We hypothesized that SEDOHs would vary significantly across sites but measuring them would be acceptable and feasible., Materials and Methods: This was a retrospective review of a prospectively maintained database involving surgical patients who completed the SEDOH-88 and a secondary survey assessing it's acceptability or feasibility from August 2021 to July 2023. Included patients underwent endoscopic, minimally invasive, or open surgery at three rural hospitals: Demopolis (DM), Alexander City (AC), and Greenville (GV)., Results: The 107 participants comprised 48 (44.9%) from DM, 27 (25.2%) from AC, and 32 (29.9%) from GV, respectively. The median age was 64 y, and 65.6% were female. When comparing DM to AC and GV by individual factors, DM had the largest Black population (78.7 versus 22.2 versus 48.3%, P < 0.001) and more often required help reading hospital materials (20.5 versus 3.7 versus 10.3%, P = 0.007). When comparing DM to AC and GV by structural and environmental factors, DM had more Medicaid enrollees (27.3 versus 3.7 versus 6.9%, P = 0.033) and lacked fresh produce (18.2 versus 25.9 versus 39.3%, P = 0.033) and internet access (63.6 versus 100.0 versus 86.2%, P < 0.001). The SEDOH-88 had an overall 90.9% positive acceptability and feasibility score., Conclusions: SEDOHs varied significantly across rural communities regarding individual (race or health literacy), structural (insurance), and environmental-level factors (nutritious food or internet access). The high acceptability and feasibility of the SEDOH-88 shows it's potential utility in identifying targets for future disparity-reducing interventions., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Background: Surgery is essential for gastrointestinal (GI) cancer treatment. Many patients lack access to surgical care that optimizes outcomes. Scarce availability and/or low accessibility of appropriate resources may be the reason for this, especially in economically disadvantaged areas. This study aimed to investigate providers' and survivors' perspectives on barriers and facilitators to the availability and accessibility of surgical care., Methods: Semistructured interviews informed by surgical disparities and access-to-care conceptual frameworks with purposively selected GI cancer providers and survivors in Alabama and Mississippi were conducted. Survivors were within 3 years of diagnosis of stage I to III esophageal, pancreatic, or colorectal cancer. Transcripts were analyzed using inductive thematic and content analysis techniques. Intercoder agreement was reached at 90 %., Results: The 27 providers included surgeons (n = 11), medical oncologists (n = 2), radiation oncologists (n = 2), a primary care physician (n = 1), nurses (n = 8), and patient navigators (n = 3). This study included 36 survivors with ages ranging from 44 to 87 years. Of the 36 survivors, 21 (58.3 %) were male, and 11 (30.6 %) identified as Black. Responses were grouped into 3 broad categories: (i) transportation/geographic location, (ii) specialized care/testing, and (iii) patient-/provider-related factors. The barriers included lack and cost of transportation, reluctance to travel because of uneasiness with urban centers, low availability of specialized care, overburdened referral centers, provider-related referral biases, and low health literacy. Facilitators included availability of charitable aid, centralizing multidisciplinary care, and efficient appointment scheduling., Conclusion: In the Deep South, barriers and facilitators to the availability and accessibility of GI surgical cancer care were identified at the health system, provider, and patient levels, especially for rural residents. Our data suggest targets for improving the use of surgery in GI cancer care., Competing Interests: Declaration of Competing Interest The authors declare no competing interests., (Copyright © 2024 Society for Surgery of the Alimentary Tract. Published by Elsevier Inc. All rights reserved.)

Objective: This study evaluated the association between preoperative education and adherence to downstream components of enhanced recovery programs (ERPs) and surgical outcomes among patients undergoing elective colorectal surgery., Background: ERPs improve outcomes for surgical patients. While preoperative education is an essential component of ERPs, its relationship with other components is unclear., Methods: This was a retrospective cohort study of all ERP patients undergoing elective colorectal surgery from 2019 to 2022. Our institutional ERP database was linked with American College of Surgeons National Surgical Quality Improvement Program data and stratified by adherence to preoperative education. Primary outcomes included adherence to individual ERP components and secondary outcomes included high-level ERP adherence (>70% of components), length of stay (LOS), readmissions, and 30-day complications., Results: A total of 997 patients were included. The mean (SD) age was 56.5 (15.8) years, 686 (57.3%) were female, and 717 (71.9%) were white. On adjusted analysis, patients who received preoperative education (n = 877, 88%) had higher adherence rates for the following ERP components: no prolonged fasting (estimate = +19.6%; P < 0.001), preoperative blocks (+8.0%; P = 0.02), preoperative multimodal analgesia (+18.0%; P < 0.001), early regular diet (+15.9%; P < 0.001), and postoperative multimodal analgesia (+6.4%; P < 0.001). High-level ERP adherence was 13.4% higher ( P < 0.01) and LOS was 2.0 days shorter ( P < 0.001) for those who received preoperative education. Classification and regression tree analysis identified preoperative education as the first-level predictor for adherence to early regular diet, the second-level predictor for LOS, and the third-level predictor for ERP high-level adherence., Conclusion: Preoperative education is associated with adherence to ERP components and improved surgical outcomes., (Copyright © 2024 The Author(s). Published by Wolters Kluwer Health, Inc.)

The first total synthesis of dragocins A-C, remarkable natural products containing an unusual C4' oxidized ribose architecture bridged by a polyhydroxylated pyrrolidine, is presented through a route featuring a number of uncommon maneuvers. Several generations towards the target molecules are presented, including the spectacular failure of a key C-H oxidation on a late-stage intermediate. The final route features rapid, stereocontrolled access to a densely functionalized pyrrolidine and an unprecedented diastereoselective oxidative electrochemical cyclization to forge the hallmark 9-membered ring. Preliminary studies suggest this electrochemical oxidation protocol is generally useful., (© 2024 Wiley‐VCH GmbH.)

Background: No-show visits have serious consequences for patients, providers, and healthcare systems as they lead to delays in care, increased costs, and reduced access to services. Telemedicine has emerged as a promising alternative to in-person visits by reducing travel barriers, but risks exacerbating the digital divide. The aim of this study was to assess the impact of telemedicine (video and phone) at a tertiary care academic center on no-show visits compared to in-person visits., Methods: A retrospective cohort analysis of all weekday clinic visits among in-state adult patients at a single tertiary care center in the southeast from January 2020 to April 2023 was performed. Rates of no-show visits for patients who were seen via phone and video were compared with those who were seen in-person. Demographic and clinical characteristics of these groups were also compared, including age, sex, race/ethnicity, socioeconomic status, and visit type. The primary outcome was the rate of no-show visits for each visit type., Results: Our analysis included 3,105,382 scheduled appointments, of which 81.2% were in-person, 13.4% via video, and 5.4% via phone calls. Compared to in-person visits, phone calls and video visits reduced the odds of no-show visits by 50% (aOR 0.5, CI 0.49-0.51) and 15% (aOR 0.85, CI 0.84-0.86), respectively. Older patients, Black patients, patients furthest from clinic, and patients from counties with the greatest degree of vulnerability and disparities in digital access were more likely to use phone visits. No-shows were more common among non-white, male, and younger patients from counties with lower socioeconomic status., Conclusion: Telemedicine effectively reduced no-show visits. However, limiting telemedicine to video-based visits only exacerbated disparities in access. Phone calls allow historically underserved patients from lower socioeconomic backgrounds to access healthcare and should be included within the definition of telemedicine., Competing Interests: Declaration of conflicting interestsThe author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Background: Increasing social vulnerability, measured by the Social Vulnerability Index, has been associated with worse surgical outcomes. However, less is known about the impact of social vulnerability on patients who underwent colorectal surgery under enhanced recovery programs., Objective: We hypothesized that increasing social vulnerability is associated with worse outcomes before enhanced recovery implementation, but that after implementation, disparities in outcomes would be reduced., Design: Retrospective cohort study using multivariable logistic regression to identify associations of social vulnerability and enhanced recovery with outcomes., Settings: Institutional American College of Surgeons National Surgical Quality Improvement Program database., Patients: Patients undergoing elective colorectal surgery (2010-2020). Enhanced recovery programs were implemented in 2015. Those adhering to 70% or more of enhanced recovery program components were defined as enhanced recovery and all others as nonenhanced recovery., Outcomes: Length of stay, complications, and readmissions., Results: Of 1523 patients, 589 (38.7%) were in the enhanced recovery group, with 625 patients (41%) in the lowest third of the Social Vulnerability Index, 411 (27%) in the highest third. There were no differences in Social Vulnerability Index distribution by the enhanced recovery group. On multivariable modeling, social vulnerability was not associated with increased length of stay, complications, or readmissions in the enhanced recovery group. Black race was associated with increased length of stay in both the nonenhanced recovery (OR 1.2; 95% CI, 1.1-1.3) and enhanced recovery groups (OR 1.2; 95% CI, 1.1-1.4). Enhanced recovery adherence was associated with reductions in racial disparities in complications as the Black race was associated with increased odds of complications in the nonenhanced recovery group (OR 1.9; 95% CI, 1.2-3.0) but not in the enhanced recovery group (OR 0.8; 95% CI, 0.4-1.6)., Limitations: Details of potential factors affecting enhanced recovery program adherence were not assessed and are the subject of current work by this team., Conclusion: High social vulnerability was not associated with worse outcomes among both enhanced recovery and nonenhanced recovery colorectal patients. Enhanced recovery program adherence was associated with reductions in racial disparities in complication rates. However, disparities in length of stay remain, and work is needed to understand the underlying mechanisms driving these disparities. See Video Abstract ., Comprendiendo El Impacto De Los Programas De Recuperacin Mejorada En La Vulnerabilidad Social, La Raza Y Los Resultados De La Ciruga Colorrectal: ANTECEDENTES:El aumento de la vulnerabilidad social medida por el índice de vulnerabilidad social se ha asociado con peores resultados quirúrgicos. Sin embargo, se sabe menos sobre el impacto de la vulnerabilidad social en los pacientes de cirugía colorrectal bajo programas de recuperación mejorados.OBJETIVO:Planteamos la hipótesis de que el aumento de la vulnerabilidad social se asocia con peores resultados antes de la implementación de la recuperación mejorada, pero después de la implementación, las disparidades en los resultados se reducirían.DISEÑO:Estudio de cohorte retrospectivo que utilizó regresión logística multivariable para identificar asociaciones de vulnerabilidad social y recuperación mejorada con los resultados.ESCENARIO:Base de datos institucional del Programa de Mejora Nacional de la Calidad de la Cirugía del American College of Surgeons.PACIENTES:Pacientes sometidos a cirugía colorrectal electiva (2010-2020). Programas de recuperación mejorada implementados en 2015. Aquellos que se adhieren a ≥70% de los componentes del programa de recuperación mejorada definidos como recuperación mejorada y todos los demás como recuperación no mejorada.MEDIDAS DE RESULTADO:Duración de la estancia hospitalaria, complicaciones y reingresos.RESULTADOS:De 1.523 pacientes, 589 (38,7%) estaban en el grupo de recuperación mejorada, con 732 (40,3%) pacientes en el tercio más bajo del índice de vulnerabilidad social, 498 (27,4%) en el tercio más alto, y no hubo diferencias en la distribución del índice vulnerabilidad social por grupo de recuperación mejorada. En el modelo multivariable, la vulnerabilidad social no se asoció con una mayor duración de la estancia hospitalaria, complicaciones o reingresos en ninguno de los grupos de recuperación mejorada. La raza negra se asoció con una mayor duración de la estadía tanto en el grupo de recuperación no mejorada (OR1,2, IC95% 1,1-1,3) como en el grupo de recuperación mejorada (OR1,2, IC95% 1,1-1,4). La adherencia a la recuperación mejorada se asoció con reducciones en las disparidades raciales en las complicaciones, ya que la raza negra se asoció con mayores probabilidades de complicaciones en el grupo de recuperación no mejorada (OR1,9, IC95% 1,2-3,0), pero no en el grupo de recuperación mejorada (OR0,8, IC95% 0,4-1,6).LIMITACIONES:No se evaluaron los detalles de los factores potenciales que afectan la adherencia al programa de recuperación mejorada y son el tema del trabajo actual de este equipo.CONCLUSIÓN:La alta vulnerabilidad social no se asoció con peores resultados entre los pacientes colorrectales con recuperación mejorada y sin recuperación mejorada. Una mayor adherencia al programa de recuperación se asoció con reducciones en las disparidades raciales en las tasas de complicaciones. Sin embargo, persisten disparidades en la duración de la estadía y es necesario trabajar para comprender los mecanismos subyacentes que impulsan estas disparidades. (Traducción-Dr. Felipe Bellolio )., (Copyright © The ASCRS 2023.)

Background: Although disparities in surgical outcomes are well-documented, our understanding of how socioecological factors drive these disparities remains limited. Comprehensive and efficient assessment tools are needed. This study's objective was to develop and assess the acceptability and feasibility of a comprehensive tool evaluating socioecological determinants of health in patients requiring colorectal surgery., Methods: In the first phase, a comprehensive socioecological determinant of health assessment tool was developed. A review of validated socioecological health evaluation instruments was conducted, and a 2-step modified Delphi method addressed the length, clarity, appropriateness, and redundancy of each instrument. A comprehensive tool was then finalized. In the second phase, the tool was tested for acceptability and feasibility in adult patients requiring colorectal surgery using a theory-guided framework at 3 Alabama hospitals. Relationships between survey responses and measures of acceptability and feasibility were evaluated using results from initial pilot tests of the survey., Results: In Phase 1, a modified Delphi process led to the development of a comprehensive tool that included 31 socioecological determinants of health (88 questions). Results of acceptability and feasibility were globally positive (>65%) for all domains. Overall, 83% of participants agreed that others would have no trouble completing the survey, 90.4% of respondents reported the survey was not burdensome, 97.6% of patients reported having enough time to complete the survey, and 80.9% agreed the survey was well-integrated into their appointment., Conclusion: An 88-item assessment tool measuring 31 socioecological determinants of health was developed with high acceptability and feasibility for patients who required colorectal surgery. This work aids in the development of research needed to understand and address surgical disparities., (Copyright © 2023 Elsevier Inc. All rights reserved.)

Given the exponentially aging population and rising life expectancy in the United States, surgeons are facing a challenging frail population who may require surgery but may not qualify based on their general fitness. There is an urgent need for greater awareness of the importance of frailty measurement and the implementation of universal assessment of frail patients into clinical practice. Pairing risk stratification with stringent protocols for prehabilitation and minimally invasive surgery and appropriate enhanced recovery protocols could optimize and condition frail patients before, during, and immediately after surgery to mitigate postoperative complications and consequences on patient function and quality of life. In this paper, highlights from the 2022 Society for Surgery of the Alimentary Tract State-of-the-Art Session on frailty in surgery are presented. This work aims to improve the understanding of the impact of frailty on patients and the methods used to augment the outcomes for frail patients during their surgical experience., (Copyright © 2023 Society for Surgery of the Alimentary Tract. Published by Elsevier Inc. All rights reserved.)

Background: Canine cognitive dysfunction (CCD) is a neurodegenerative disease that is difficult to diagnose, as its clinical signs are similar to those of other age-related conditions. The experience of caring for a senior dog with or without CCD is not well described., Methods: Data were collected via an online survey. Using a mixed methods design, the level of CCD and burden of care were measured using validated tools, and open-ended questions gathered qualitative data. A general linear model showed the factors associated with guardian burden of care., Results: Sixteen percent of guardians experienced a clinically significant burden of care. Factors associated with burden of care included severity of CCD, sleep location, guardian employment, household size, dog age, guardian age and the dog taking medication. Few dogs with CCD were prescribed CCD medications to ameliorate clinical signs. Euthanasia, strong attachment mitigating burden and the complexities of caregiving were themes presented by guardians., Limitations: Measures are based on self-reports and as such the usual limitations apply., Conclusions: The burden of caring for an older dog is greater if they have CCD. More attention to the treatment of senior dogs, including medications to reduce clinical signs of CCD, could improve the welfare of older dogs and decrease the clinical burden experienced by guardians., (© 2023 The Authors. Veterinary Record published by John Wiley & Sons Ltd on behalf of British Veterinary Association.)

Cardiovascular disease (CVD) is largely preventable, and the leading cause of death for men and women. Though women have increased life expectancy compared to men, there are marked sex disparities in prevalence and risk of CVD-associated mortality and dementia. Yet, the basis for these and female-male differences is not completely understood. It is increasingly recognized that heart and brain health represent a lifetime of exposures to shared risk factors (including obesity, hyperlipidemia, diabetes, and hypertension) that compromise cerebrovascular health. We describe the process and resources for establishing a new research Center for Women's Cardiovascular and Brain Health at the University of California, Davis as a model for: (1) use of the cy pres principle for funding science to improve health; (2) transdisciplinary collaboration to leapfrog progress in a convergence science approach that acknowledges and addresses social determinants of health; and (3) training the next generation of diverse researchers. This may serve as a blueprint for future Centers in academic health institutions, as the cy pres mechanism for funding research is a unique mechanism to leverage residual legal settlement funds to catalyze the pace of scientific discovery, maximize innovation, and promote health equity in addressing society's most vexing health problems., (© The Author(s) 2024.)

Prior analysis of intact and modified protein forms (proteoforms) of KRAS4B isolated from cell lines and tumor samples by top-down mass spectrometry revealed the presence of novel posttranslational modifications (PTMs) and potential evidence of context-specific KRAS4B modifications. However, low endogenous proteoform signal resulted in ineffective characterization, making it difficult to visualize less abundant PTMs or perform follow-up PTM validation using standard proteomic workflows. The NCI RAS Initiative has developed a model system, whereby KRAS4B bearing an N-terminal FLAG tag can be stably expressed within a panel of cancer cell lines. Herein, we present a method for combining immunoprecipitation with complementary proteomic methods to directly analyze N-terminally FLAG-tagged KRAS4B proteoforms and PTMs. We provide detailed protocols for FLAG-KRAS4B purification, proteoform analysis by targeted top-down LC-MS/MS, and validation of abundant PTMs by bottom-up LC-MS/MS with example results., (© 2024. The Author(s), under exclusive license to Springer Science+Business Media, LLC, part of Springer Nature.)

With recent advances proving that effective inhibition of KRAS is possible, there have been significant efforts made to develop inhibitors of specific mutant alleles. Here we describe a detailed protocol that employs homogeneous time-resolved fluorescence (HTRF) to identify compounds acting on KRAS signaling in malignant cell lines. This method allows for high-throughput, cell-based screens of large compound libraries for the development of RAS-targeted therapeutics., (© 2024. The Author(s), under exclusive license to Springer Science+Business Media, LLC, part of Springer Nature.)

Background: Delta-8 tetrahydrocannabinol (THC) is a psychoactive cannabinoid found in small amounts naturally in the cannabis plant; it can also be synthetically produced in larger quantities from hemp-derived cannabidiol. Most states permit the sale of hemp and hemp-derived cannabidiol products; thus, hemp-derived delta-8 THC products have become widely available in many state hemp marketplaces, even where delta-9 THC, the most prominently occurring THC isomer in cannabis, is not currently legal. Health concerns related to the processing of delta-8 THC products and their psychoactive effects remain understudied., Objective: The goal of this study is to implement a novel topic modeling approach based on transformers, a state-of-the-art natural language processing architecture, to identify and describe emerging trends and topics of discussion about delta-8 THC from social media discourse, including potential symptoms and adverse health outcomes experienced by people using delta-8 THC products., Methods: Posts from January 2008 to December 2021 discussing delta-8 THC were isolated from cannabis-related drug forums on Reddit (Reddit Inc), a social media platform that hosts the largest web-based drug forums worldwide. Unsupervised topic modeling with state-of-the-art transformer-based models was used to cluster posts into topics and assign labels describing the kinds of issues being discussed with respect to delta-8 THC. Results were then validated by human subject matter experts., Results: There were 41,191 delta-8 THC posts identified and 81 topics isolated, the most prevalent being (1) discussion of specific brands or products, (2) comparison of delta-8 THC to other hemp-derived cannabinoids, and (3) safety warnings. About 5% (n=1220) of posts from the resulting topics included content discussing health-related symptoms such as anxiety, sleep disturbance, and breathing problems. Until 2020, Reddit posts contained fewer than 10 mentions of delta-8-THC for every 100,000 cannabis posts annually. However, in 2020, these rates increased by 13 times the 2019 rate (to 99.2 mentions per 100,000 cannabis posts) and continued to increase into 2021 (349.5 mentions per 100,000 cannabis posts)., Conclusions: Our study provides insights into emerging public health concerns around delta-8 THC, a novel substance about which little is known. Furthermore, we demonstrate the use of transformer-based unsupervised learning approaches to derive intelligible topics from highly unstructured discussions of delta-8 THC, which may help improve the timeliness of identification of emerging health concerns related to new substances., (©Brandi Patrice Smith, Brooke Hoots, Lara DePadilla, Douglas R Roehler, Kristin M Holland, Daniel A Bowen, Steven A Sumner. Originally published in the Journal of Medical Internet Research (https://www.jmir.org), 21.12.2023.)

Adefovir based acyclic nucleoside phosphonates were previously shown to modulate bacterial and, to a certain extent, human adenylate cyclases (mACs). In this work, a series of 24 novel 7-substituted 7-deazaadefovir analogues were synthesized in the form of prodrugs. Twelve analogues were single-digit micromolar inhibitors of Bordetella pertussis adenylate cyclase toxin with no cytotoxicity to J774A.1 macrophages. In HEK293 cell-based assays, compound 14 was identified as a potent (IC 50  = 4.45 μM), non-toxic, and selective mAC2 inhibitor (vs. mAC1 and mAC5). Such a compound represents a valuable addition to a limited number of small-molecule probes to study the biological functions of individual endogenous mAC isoforms., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 Elsevier Ltd. All rights reserved.)

Two epoxidation catalysts, one of which consists of two VANOL ligands and an aluminum and the other that consists of two VANOL ligands and a boron, were compared. Both catalysts are highly effective in the catalytic asymmetric epoxidation of a variety of aromatic and aliphatic aldehydes with diazoacetamides, giving high yields and excellent asymmetric inductions. The aluminum catalyst is effective at 0 °C and the boron catalyst at -40 °C. Although both the aluminum and boron catalysts of ( R )-VANOL give very high asymmetric inductions (up to 99% ee), they give opposite enantiomers of the epoxide. The mechanism, rate- and enantioselectivity-determining step, and origin of enantiodivergence are evaluated using density functional theory calculations., Competing Interests: Complete contact information is available at: https://pubs.acs.org/10.1021/acscatal.3c03929 The authors declare no competing financial interest.

More than ever the welfare of horses in equestrian sport is in the spotlight. In response to this scrutiny, one peak body, the Federation Equestre Internationale (FEI) has created an Equine Ethics and Wellbeing Commission to protect their sport's longevity. However, for welfare-based strategies to be successful, the conceptualisation of horse welfare must align across various stakeholders, including the general public. The value-laden nature of welfare makes agreement on its definition, even among scientists, difficult. Given little is known about how equestrians conceptualise horse welfare, we interviewed 19 Australian amateur equestrians using a semi-structured format. Systems thinking and the Five Domains Model provided the theoretical framework and informed our methods. Using reflexive thematic analysis, three themes were identified: (1) good horse welfare is tangible; (2) owners misinterpret unwanted horse behaviour; and (3) equestrians publicly minimise horse welfare issues but are privately concerned. Our results highlight participants' conceptualisations of horse welfare do not align with the Five Domains Model; participants' ideal of prioritising horse welfare does not align with their practice; and there is inconsistency between what participants share publicly and what they think privately about horse welfare. These findings can inform the development of programmes to improve ridden horse welfare throughout the horse industry. As a starting point, programmes that provide a safe space for equestrians to explore their private horse welfare concerns, and programmes that build a partnership mindset to facilitate knowledge exchange between all stakeholders are needed., Competing Interests: None., (© The Author(s) 2023.)

Objective: To study the prevalence and management of shattered kidney and to evaluate if the new description of "loss of identifiable renal anatomy" in the 2018 American Association for the Surgery of Trauma (AAST) organ injury scale (OIS) would improve the ability to predict bleeding control interventions., Methods: We used high-grade renal trauma data from 21 Level-1 trauma centers from 2013 to 2018. Initial CT scans were reviewed to identify shattered kidneys, defined as a kidney having ≥3 parenchymal fragments displaced by blood or fluid on cross-sectional imaging. We further categorized patients with shattered kidney in two models based on loss of identifiable renal parenchymal anatomy and presence or absence of vascular contrast extravasation (VCE). Bleeding interventions were compared between the groups., Results: From 861 high-grade renal trauma patients, 41 (4.8%) had shattered kidney injury. 25 (61%) underwent a bleeding control intervention including 18 (43.9%) nephrectomies and 11 (26.8%) angioembolizations. 18 (41%) had shattered kidney with "loss of identifiable parenchymal renal anatomy" per 2018 AAST OIS (model-1). 28 (68.3%) had concurrent VCE (model-2). Model-2 had a statistically significant improvement in area under the curve over model-1 in predicting bleeding interventions (0.75 vs 0.72; P = .01)., Conclusion: Shattered kidney is associated with high rates of active bleeding, urinary extravasation, and interventions including nephrectomy. The definition of shattered kidney is vague and subjective and our definition might be simpler and more reproducible. Loss of identifiable renal anatomy per the 2018 AAST OIS did not provide better distinction for bleeding control interventions over presence of VCE., Competing Interests: Declaration of Competing Interest None of the authors have any conflicts of interest., (Copyright © 2023 Elsevier Inc. All rights reserved.)

Introduction: Enhanced recovery programs (ERPs) reduce racial disparities in surgical outcomes for general colorectal surgery populations. It is unclear, however, if disparities in IBD populations are impacted by ERPs., Methods: Retrospective study comparing IBD patients undergoing major elective colorectal operations before (2006-2014) and after (2015-2021) ERP implementation using ACS-NSQIP data. The primary outcome of length of stay (LOS) was analyzed by negative binomial regression, and secondary outcomes (complications and readmissions) by logistic regression., Results: Of 466 IBD patients, 47% were pre-ERP and 53% were ERP patients. In multivariable analysis stratified by ERP period, Black race was associated with increased odds of complications in the pre-ERP (OR 3.6, 95%CI 1.4-9.3) and ERP groups (OR 3.1 95%CI 1.3-7.6). Race was not a predictor of LOS or readmission in either group. High social vulnerability was associated with increased odds of readmission pre-ERP (OR 15.1, 95%CI 2.1-136.3), but this disparity was mitigated under ERPs (OR 1.4, 95%CI 0.4-5.6)., Conclusion: While ERPs mitigated some disparities by social vulnerability, racial disparities persist in IBD populations even under ERPs. Further work is needed to achieve surgical equity for IBD patients., Competing Interests: Declaration of competing interest The authors have no additional conflict of interest to disclose other than the funding sources listed below., (Copyright © 2023. Published by Elsevier Inc.)

Purpose: To investigate management trends for American Association for the Surgery of Trauma (AAST) grade V renal trauma with focus on non-operative management., Methods: We used prospectively collected data as part of the Multi-institutional Genito-Urinary Trauma Study (MiGUTS). We included patients with grade V renal trauma according to the AAST Injury Scoring Scale 2018 update. All cases submitted by participating centers with radiology images available were independently reviewed to confirm renal trauma grade. Management was classified as expectant, conservative (minimally invasive, endoscopic or percutaneous procedures), or operative (renal-related surgery)., Results: Eighty patients were included, 25 of whom had complete imaging and had independent confirmation of AAST grade V renal trauma. Median age was 35 years (Interquartile range (IQR) 25-50) and 23 (92%) had blunt trauma. Ten patients (40%) were managed operatively with nephrectomy. Conservative management was used in nine patients (36%) of which six received angioembolization and three had a stent or drainage tube placed. Expectant management was followed in six (24%) patients. Transfusion requirements were progressively higher with groups requiring more aggressive treatment, and injury characteristics differed significantly across management groups in terms of hematoma size and laceration size. Vascular contrast extravasation was more likely in operatively managed patients though a statistically significant association was not found., Conclusion: Successful use of nonoperative management for grade V injuries is used for a substantial subset of patients. Lower transfusion requirement and less severe injury radiologic phenotype appear to be important characteristics delineating this group., (© 2023. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Background: Although specific social determinants of health have been associated with disparities in surgical outcomes, there exists a gap in knowledge regarding the mechanisms of these associations. Gaining perspectives from multiple socioecological levels can help elucidate these mechanisms. Our study aims to identify social determinants of health that act as barriers or facilitators to surgical care among colorectal surgery stakeholders., Methods: We recruited participants representing 5 socioecological levels: patients (individual); caregivers/surgeons (interpersonal); and leaders in hospitals (organizational), communities (community), and government (policy). Patients participated in focus groups, and the remaining participants underwent individual interviews. Semistructured interview guides were used to explore barriers and facilitators to surgical care at each socioecological level. Transcripts were analyzed by 3 coders in an inductive thematic approach with content analyses. The intercoder agreement was 93%., Results: Six patient focus groups (total n = 18) and 12 key stakeholder interviews were conducted. The mean age of patients was 54.7 years, 66% were Black, and 61% were female. The most common diseases were colorectal cancer (28%), inflammatory bowel disease (28%), and diverticulitis (22%). Key social determinants of health impacting surgical care emerged at each level: individual (clear communication, mental stress), interpersonal (provider communication and trust, COVID-related visitation restrictions), organizational (multiple forms of contact, quality educational materials, scheduling systems, discrimination), community (community and family support and transportation), and policy (charity care, patient advocacy organizations, insurance coverage)., Conclusion: Key social determinants of health-impacting care among colorectal surgery patients emerged at each socioecological level and may provide targets for interventions to reduce surgical disparities., (Copyright © 2023 Elsevier Inc. All rights reserved.)

During May 10-December 31, 2022, a total of 29,980 confirmed and probable † U.S. monkeypox (mpox) cases were reported to CDC, predominantly in cisgender adult men reporting recent same-gender sexual partners (1). Urban-rural differences in health (2) and diagnosis of HIV (3,4) and other sexually transmitted infections (5) are well documented nationally. This report describes urban-rural differences in mpox incidence (cases per 100,000 population) among persons aged 15-64 years, by gender and race and ethnicity. Urbanicity was assessed using the 2013 National Center for Health Statistics (NCHS) Urban-Rural Classification Scheme for Counties (2). Substantial differences in incidence by urbanicity, gender, and race and ethnicity were observed; most (71.0%) cases occurred in persons residing in large central urban areas. Among the cases in large central urban areas, most (95.7%) were in cisgender men. The overall incidence of mpox in the United States was 13.5 per 100,000 persons aged 15-64 years and peaked in August in both urban and rural areas. Among cisgender men, incidence in rural areas was approximately 4% that in large central urban areas (risk ratio [RR] = 0.04). Among cisgender women, incidence in rural areas was approximately 11% that in large central urban areas (RR = 0.11). In both urban and rural areas, incidence among non-Hispanic Black or African American (Black) and Hispanic or Latino (Hispanic) persons was consistently higher than that among non-Hispanic White (White) persons; RRs between Black and White persons were highest in rural areas. Support and maintenance of mpox surveillance and prevention efforts including vaccinations should focus on urban areas with the highest incidence of mpox during the 2022 outbreak; however, surveillance and prevention efforts should include all genders, persons of color, and persons residing in both urban and rural areas who are at increased risk for mpox., Competing Interests: All authors have completed and submitted the International Committee of Medical Journal Editors form for disclosure of potential conflicts of interest. Siobhán O’Connor reports patent applications for kits and methods for determining physiologic levels, ranges of hemoglobin, and disease state, unrelated to the current work. No other potential conflicts of interest were disclosed.

Background: Enhanced recovery programs (ERPs) improve outcomes, but over 20 % of patients fail ERP and the contribution of social vulnerability is unknown. This study aimed to characterize the association between social vulnerability and ERP adherence and failure., Methods: This was a retrospective cohort study of colorectal surgery patients between 2015 and 2020 utilizing ACS-NSQIP data. Patients who failed ERP (LOS > 6 days) were compared to patients not failing ERP. The CDC's social vulnerability index (SVI) was used to assess social vulnerability., Result: 273 of 1191 patients (22.9 %) failed ERP. SVI was a significant predictor of ERP failure (OR 4.6, 95 % CI 1.3-16.8) among those with >70 % ERP component adherence. SVI scores were significantly higher among patients non-adherent with 3 key ERP components: preoperative block (0.58 vs. 0.51, p < 0.01), early diet (0.57 vs. 0.52, p = 0.04) and early foley removal (0.55 vs. 0.50, p < 0.01)., Conclusions: Higher social vulnerability was associated with non-adherence to 3 key ERP components as well as ERP failure among those who were adherent with >70 % of ERP components. Social vulnerability needs to be recognized, addressed, and included in efforts to further improve ERPs., Key Message: Social vulnerability is associated with non-adherence to enhanced recovery components and ERP failure among those with high ERP adherence. Social vulnerability needs to be addressed in efforts to improve ERPs., Competing Interests: The authors have no additional conflict of interest to disclose other than the funding sources listed below., (© 2023 The Authors.)

Carbonate rocks provide unique and valuable sedimentary archives for secular changes in Earth's physical, chemical, and biological processes. However, reading the stratigraphic record produces overlapping, nonunique interpretations that stem from the difficulty in directly comparing competing biological, physical, or chemical mechanisms within a common quantitative framework. We built a mathematical model that decomposes these processes and casts the marine carbonate record in terms of energy fluxes across the sediment-water interface. Results showed that physical, chemical, and biological energy terms across the seafloor are subequal and that the energetic dominance of different processes varies both as a function of environment (e.g., onshore vs. offshore) as well as with time-varying changes in seawater chemistry and with evolutionary changes in animal abundance and behavior. We applied our model to observations from the end-Permian mass extinction-a massive upheaval in ocean chemistry and biology-revealing an energetic equivalence between two hypothesized drivers of changing carbonate environments: a reduction in physical bioturbation increased carbonate saturation states in the oceans. Early Triassic occurrences of 'anachronistic' carbonates-facies largely absent from marine environments after the Early Paleozoic-were likely driven more by reduction in animal biomass than by repeated perturbations to seawater chemistry. This analysis highlighted the importance of animals and their evolutionary history in physically shaping patterns in the sedimentary record via their impact on the energetics of marine environments.

Improving pediatric therapeutic development is a mission of universal importance among health authorities, pharmaceutical companies, academic institutions, and healthcare professionals. Following the passage of legislation in the United States and Europe, we witnessed the most significant advancement yet in pediatric data generation, resulting in added pediatric use information to almost 700 product labels. Tools to accelerate generation of data for the pediatric population are available for use today, and when utilized in accordance with current practices and laws, these tools could increase the amount and timeliness of pediatric information available for clinicians and patients. If we utilize the current laws that allow regulators to incentivize and require evidence generation, apply extrapolation, and utilize modeling and simulation, as well as including adolescents in the pivotal studies alongside adults as appropriate, two strategic goals could be achieved by 2030: (1) reduce the time to pediatric approval by 50%, and (2) renew pediatric labeling information for 15 priority pediatric drugs without patent and/or exclusivity., (© 2022. The Drug Information Association, Inc.)

Due to the declining number of scientifically trained physicians and increasing demand for high-quality literature, our institution pioneered a seven-year Physician Scientist Training Program (PSTP) to provide research-oriented residents the knowledge and skills for a successful academic career. The present study sought to identify orthopaedic surgeons with MD/PhD degrees, residency programs with dedicated research tracks, and to assess the effectiveness of the novel seven-year program in training prospective academic orthopaedic surgeons. Surgeons with MD/PhD degrees account for 2.3% of all 3,408 orthopaedic faculty positions in U.S. residency programs. During the last 23 years, our PSTP residents produced 752 peer-reviewed publications and received $349,354 from 23 resident-authored extramural grants. Eleven of our seven-year alumni practice orthopaedic surgery in an academic setting. The seven-year PSTP successfully develops clinically trained surgeon scientists with refined skills in basic science and clinical experimental design, grant proposals, scientific presentations, and manuscript preparation. (Journal of Surgical Orthopaedic Advances 31(3):144-149, 2022).

Economic evaluation studies the costs and outcomes of two or more alternative activities to estimate the relative efficiency of each course of action. Economic evaluation is both important and necessary in the management of speech and language issues. Economic evaluation can help focus attention on interventions that provide value for improving population health. The purpose of this article is to introduce readers to fundamental economic concepts. Readers are also introduced to common issues when conducting economic evaluations and how to address them in practice., Competing Interests: None declared., (Thieme. All rights reserved.)

Objective: To determine whether trauma patients managed by an admitting or consulting service with a high proportion of physicians exhibiting patterns of unprofessional behaviors are at greater risk of complications or death., Summary Background Data: Trauma care requires high-functioning interdisciplinary teams where professionalism, particularly modeling respect and communicating effectively, is essential., Methods: This retrospective cohort study used data from 9 level I trauma centers that participated in a national trauma registry linked with data from a national database of unsolicited patient complaints. The cohort included trauma patients admitted January 1, 2012 through December 31, 2017. The exposure of interest was care by 1 or more high-risk services, defined as teams with a greater proportion of physicians with high numbers of patient complaints. The study outcome was death or complications within 30 days., Results: Among the 71,046 patients in the cohort, 9553 (13.4%) experienced the primary outcome of complications or death, including 1875 of 16,107 patients (11.6%) with 0 high-risk services, 3788 of 28,085 patients (13.5%) with 1 high-risk service, and 3890 of 26,854 patients (14.5%) with 2+ highrisk services (P < 0.001). In logistic regression models adjusting for relevant patient, injury, and site characteristics, patients who received care from 1 or more high-risk services were at 24.1% (95% confidence interval 17.2% to 31.3%; P < 0.001) greater risk of experiencing the primary study outcome., Conclusions: Trauma patients who received care from at least 1 service with a high proportion of physicians modeling unprofessional behavior were at an increased risk of death or complications., Competing Interests: The authors report no conflicts of interest., (Copyright © 2022 Wolters Kluwer Health, Inc. All rights reserved.)