Factors regulating arteriolar tone during microvascular growth

Growth of the arteriolar network is accompanied by progressive changes in pressure and flow, and in the metabolic environment to which the arterioles are exposed. This dissertation was carried out to investigate the extent to which mechanisms involved in local blood flow regulation may also change during this growth. We isolated gracilis muscle arterioles from weanling (age 25-26 days) and juvenile (44-66 days) rats, and studied the responsiveness of these vessels to both myogenic and endothelium-dependent stimuli. Overall arteriolar responses to the endothelium-dependent agonists acetylcholine (ACh), A23187, VEGF and simvastatin were not different between age groups. Responses of juvenile arterioles to ACh and simvastatin were significantly reduced by inhibition of nitric oxide synthase or cyclooxygenase, by the hydrogen peroxide scavenger catalase, and by potassium channel inhibition. Responses of weanling arterioles to ACh and simvastatin were unaffected by these treatments, but significantly reduced by heme oxygenase inhibition. Arteriolar growth during juvenile maturation is accompanied by an increase in myogenic responsiveness, possibly because endothelium-derived PGH2 or TXA2 assumes a role in reinforcing myogenic activity over this period. In conclusion, mediators of endothelium-dependent dilation change during growth, with carbon monoxide contributing largely to these responses in young animals, and a combination of nitric oxide, prostanoids and hydrogen peroxide contributing to these responses in older animals. These data suggest that age-dependent differences in the control of vascular tone exist and may have significant implications for the regulation of tissue perfusion

A population pharmacokinetic model to guide clozapine dose selection, based on age, sex, ethnicity, body weight and smoking status

Aims: Guidance on clozapine dosing in treatment-resistant schizophrenia is based largely on data from White young adult males. This study aimed to investigate the pharmacokinetic profiles of clozapine and Ndesmethylclozapine (norclozapine) across the age range, accounting for sex, ethnicity, smoking status, and body weight. Methods: A population pharmacokinetic model, implemented in Monolix, that linked plasma clozapine and norclozapine via a metabolic rate constant, was used to analyse data from a clozapine therapeutic drug monitoring service, 1993–2017. Results: There were 17,787 measurements from 5960 patients (4315 male) aged 18 to 86 years. The estimated clozapine plasma clearance was reduced from 20.2 to 12.0 L h-1 between 20 and 80 years. Model based dose predictions to attain a pre-dose plasma clozapine concentration of 0.35 mg L-1 was 275 (90% prediction interval 125, 625) mg day-1 in a nonsmoking White male weighing 70 kg and aged 40 years. The corresponding predicted dose was increased by 30% in smokers, decreased by 18% in females and was 10% higher and 14% lower in otherwise analogous Afro-Caribbean and Asian patients, respectively. Overall, the predicted dose decreased by 56% between age 20 and 80 years. Conclusion: The large sample size and wide age range of the patients studied allowed precise estimation of dose requirements to attain a pre-dose plasma clozapine concentration of 0.35 mg L-1. The analysis was however limited by the absence of data on clinical outcome and further studies are required to determine optimal pre-dose concentrations specifically in those aged over 65 years

From self-efficacy to imposter syndrome: The intrapersonal traits of surgeons

BACKGROUND: Demographic differences among surgical trainees regarding intrapersonal traits, such as imposter syndrome and assertiveness, have become widely acknowledged. However, many of these characteristics have not been examined in tandem, nor among both trainees and surgeons in practice. This study aimed to address these knowledge gaps. METHODS: This was an anonymous, voluntary survey study comprised of validated measures of (1) self-efficacy, (2) imposter syndrome, (3) assertiveness, (4) perfectionism, and (5) self-rated likeability. A multimodal recruitment strategy was used and surgeons across all subspecialties were eligible for inclusion. RESULTS: A total of 296 participants were included, with 54% identifying as female (n = 161) and 72% between the ages of 25 and 40 years of age (n = 212). Imposter syndrome, assertiveness, and perfectionism scales were normally distributed; self-efficacy and self-rated likeability scales demonstrated slight negative skew. Self-identified male sex was associated with less imposter syndrome (P \u3c 0.001) and perfectionism (P = 0.035) and higher assertiveness (P \u3c 0.001). Imposter syndrome was less common among older age groups (P = 0.001). CONCLUSIONS: Surgeons are a self-efficacious group of perfectionists with widespread variability in imposter syndrome and assertiveness. Female sex and younger age were associated with more imposter syndrome and less assertiveness, highlighting an opportunity for early career coaching

How risky are risk factors? An analysis of prenatal risk factors in patients participating in the congenital upper limb differences registry

PURPOSE: Risk factors for congenital upper limb differences (CoULDs) are often studied at the general population level. The CoULD registry provides a unique opportunity to study prenatal risk factors within a large patient sample. METHODS: All patients enrolled between June 2014 and March 2020 in the prospective CoULD registry, a national multicenter database of patients diagnosed with a CoULD, were included in the analysis. We analyzed self-reported, prenatal risk factors, including maternal smoking, alcohol use, recreational drug use, prescription drug use, gestational diabetes mellitus (GDM), and gestational hypertension. The outcome measures included comorbid medical conditions, proximal involvement of limb difference, bilateral involvement, and additional orthopedic conditions. Multivariable logistic regression was used to analyze the effect of the risk factors, controlling for sex and the presence of a named syndrome. RESULTS: In total, 2,410 patients were analyzed, of whom 72% (1,734) did not have a self-reported risk factor. Among the 29% (676) who did have at least 1 risk factor, prenatal maternal prescription drug use was the most frequent (376/2,410; 16%). Maternal prescription drug use was associated with increased odds of patient medical comorbidities (odds ratio [OR] = 1.43, CONCLUSIONS: Most caregivers (72%) did not report a risk factor during enrollment. However, reporting a risk factor was associated with patient medical and orthopedic comorbidities. Of note, GDM alone significantly increased the odds of both these outcome measures along with proximal limb differences. These findings highlight the ill-defined etiology of CoULDs but suggest that prenatal risk factors, especially GDM, are associated with a higher degree of morbidity. TYPE OF STUDY/LEVEL OF EVIDENCE: Prognostic III

Association of radial longitudinal deficiency and thumb hypoplasia: An update using the CoULD registry

BACKGROUND: Deficiency of the radial aspect of the forearm and hand is the most common congenital longitudinal deficiency of the upper limb. Radial longitudinal deficiency is associated with several named syndromes. The purpose of the present study was to explore patterns of radial longitudinal deficiency and thumb hypoplasia in syndromes and to examine the severity of these differences across various syndromes. METHODS: Data were collected from the Congenital Upper Limb Differences (CoULD) registry. Congenital differences are classified in the registry with use of the Oberg-Manske-Tonkin (OMT) classification system. Diagnosis of a syndrome by a physician as noted in the CoULD registry was recorded. Thumb deficiency and radial deficiency were classified according to the modified versions of the Blauth criteria and the Bayne and Klug criteria, respectively. RESULTS: We identified 259 patients with 383 affected limbs with radial deficiency. Eighty-three of these patients had a diagnosed syndrome. The severity of radial deficiency was correlated with the severity of thumb deficiency. The Kendall tau coefficient indicated significant correlation between radial severity and thumb severity (tau = 0.49 [95% confidence interval = 0.40 to 0.57]; p \u3c 0.05). Subjects with a syndrome were twice as likely to have bilateral deficiency and 2.5 times more likely to have both radial and thumb deficiency compared with subjects without a syndrome. Subjects with VACTERL syndrome (vertebral defects, anal atresia, cardiac anomalies, tracheoesophageal fistula, renal anomalies, and limb defects) had patterns of thumb and radial deficiency similar to the general cohort, whereas subjects with Holt-Oram syndrome, TAR (thrombocytopenia absent radius) syndrome, and Fanconi anemia demonstrated varied presentations of thumb and radial deficiency. CONCLUSIONS: The present study investigated the characteristics of patients with radial longitudinal deficiency and thumb hypoplasia. Our results support the findings of previous research correlating the severity of radial deficiency with the severity of thumb deficiency. Furthermore, we identified characteristic features of patients with radial longitudinal deficiency and associated syndromes

The black-white suicide paradox: Possible effects of misclassification

This research addresses the paradox that the crude and age-adjusted suicide rates of United States blacks are less than half those of whites despite similar risks. Upper and lower limits for true suicide rates are estimated to assess the potential for differential suicide misclassification by race. Construction of these two rate scenarios respectively incorporate one or all of the three cause-of-death categories identified in the literature as most prone to obscure suicides: injury of undetermined intent and unintentional poisonings and drownings. The data source is the US Centers for Disease Control and Prevention's Web-based Injury Statistics Query and Reporting System, and the observation period is 1999-2002. We found that as in the official rates, the racial suicide gap persists within the lower and upper limit scenarios. However, there is marked shrinkage under the upper limit scenario. That scenario even generates rate crossovers for males ages 45-54 years and females ages 85 years and older. Suicide data appear relatively more deficient for black females than for black males. Racial data disparities are minimal for youth and young adults, and maximal for middle-aged males and the oldest and younger middle-aged females. Results strongly indicate greater susceptibility of medico-legal authorities to misclassify black suicides than white suicides. To demystify the racial suicide paradox, research is needed on medical histories and other biographical information that are accessible by the authorities in equivocal cases. To meet the standards of evidence-based medicine and public health, high-quality suicide data are an imperative for risk group delineation; risk factor identification; policy formulation; program planning, implementation, and evaluation; and ultimately, effective prevention.United States Suicide Race Gender Health inequalities Validity