Agonist-selective activation of individual G-proteins by muscarinic receptors.

Selective activation of individual subtypes of muscarinic receptors is a promising way to safely alleviate a wide range of pathological conditions in the central nervous system and the periphery as well. The flexible G-protein interface of muscarinic receptors allows them to interact with several G-proteins with various efficacy, potency, and kinetics. Agonists biased to the particular G-protein mediated pathway may result in selectivity among muscarinic subtypes and, due to the non-uniform expression of individual G-protein alpha subunits, possibly achieve tissue specificity. Here, we demonstrate that novel tetrahydropyridine-based agonists exert specific signalling profiles in coupling with individual G-protein α subunits. These signalling profiles profoundly differ from the reference agonist carbachol. Moreover, coupling with individual Gα induced by these novel agonists varies among subtypes of muscarinic receptors which may lead to subtype selectivity. Thus, the novel tetrahydropyridine-based agonist can contribute to the elucidation of the mechanism of pathway-specific activation of muscarinic receptors and serve as a starting point for the development of desired selective muscarinic agonists.

Network resources and educational outcomes among Mexican-origin youth.

Despite schooling gains over the last two decades, Mexican-origin adults complete fewer years of schooling than adults from other ethnic backgrounds. Explanations emphasizing network resources suggest Mexican-origin adolescents have social ties that are more likely to be "closed" from adults with experience in higher education-and this, in turn, inhibits the transition to college. In this study, we draw on unusual network data measuring characteristics of students' peers and friends, as well as the socioeconomic background of peers' and friends' parents. We demonstrate that Mexican-origin adolescents are much less likely to have friends whose parents have college educations. 83% of non-Hispanic Asian students and 72% of non-Hispanic white students have nominated friends with college-educated mothers; about half of Mexican-origin students do. These patterns are the result of socioeconomic segregation in social networks both across and within schools. Within schools, we observe that the educational background of friends is predictive of schooling outcomes for non-Mexican students. We find evidence that this network resource shapes non-Mexican students' educational expectations in high school and longer-run completed schooling as adults more so than it shapes the outcomes among Mexican-origin students.

Vaping and E-Cigarette Use in Children and Adolescents: Implications on Perioperative Care From the American Society of Anesthesiologists Committee on Pediatric Anesthesia, Society for Pediatric Anesthesia, and American Academy of Pediatrics Section on Anesthesiology and Pain Medicine.

Electronic cigarettes (e-cigarettes) or vaping use in adolescents has emerged as a public health crisis that impacts the perioperative care of this vulnerable population. E-cigarettes have become the most commonly used tobacco products among youth in the United States. Fruit and mint flavors and additives such as marijuana have enticed children and adolescents. E-cigarette, or vaping, product use-associated lung injury (EVALI) is a newly identified lung disease linked to vaping. Clinical presentation of EVALI can be varied, but most commonly includes the respiratory system, gastrointestinal (GI) tract, and constitutional symptoms. Clinical management of EVALI has consisted of vaping cessation and supportive therapy, including supplemental oxygen, noninvasive ventilation, mechanical ventilation, glucocorticoids, and empiric antibiotics, until infectious causes are eliminated, and in the most severe cases, extracorporeal membrane oxygenation (ECMO). Currently, although there is an insufficient evidence to determine the safety and the efficacy of e-cigarettes for perioperative smoking cessation, EVALI clearly places these patients at an increased risk of perioperative morbidity. Given the relatively recent introduction of e-cigarettes, the long-term impact on adolescent health is unknown. As a result, the paucity of postoperative outcomes in this potentially vulnerable population does not support evidence-based recommendations for the management of these patients. Clinicians should identify "at-risk" individuals during preanesthetic evaluations and adjust the risk stratification accordingly. Our societies encourage continued education of the public and health care providers of the risks associated with vaping and nicotine use and encourage regular preoperative screening and postoperative outcome studies of patients with regard to smoking and vaping use.

Anesthesia for children with complete trisomy 18 (Edwards syndrome): A cohort review of 84 anesthesia encounters in nine patients.

BACKGROUND: Trisomy 18 or Edwards syndrome is the second most common aneuploidy with a prevalence between 1/3000 and 1/10 000 live births. The syndrome encompasses malformations of the central nervous, cardiac, respiratory, gastrointestinal, and genitourinary systems. Trisomy 18 carries a poor prognosis with 90% of patients not surviving beyond 1 year of age; however, the current trend toward more aggressive supportive care may prolong survival. The limited anesthesia literature highlights the abnormal airway anatomy but generally describes uneventful airway management and perioperative course. AIM: Our goal was to review all anesthesia encounters recorded for eleven trisomy 18 patients treated at Children's Wisconsin during the study period to explore the frequency of anesthesia encounters and to improve our understanding of the perioperative risks. METHODS: We performed a retrospective chart review of all patients with trisomy 18 who were treated at our institution between 2012 and 2017. Records were screened for anesthesia encounters, perioperative critical events and complications, enrollment in palliative care, code status, and time of death. RESULTS: Eleven children were identified. Children were born between 2001 and 2016. Two children never required anesthesia care. Nine patients had a total of 84 anesthesia encounters for 121 surgical or diagnostic procedures or emergent intubations. Critical events and perioperative complications included difficult mask ventilation (n = 7), difficult intubation (n = 15), and mechanical or pharmacological cardiopulmonary resuscitation (n = 6). Five patients presented with difficult peripheral intravenous access. One patient died in the immediate postoperative period. On five occasions, patients required emergent intubation outside of the operating room. CONCLUSION: Difficult airway management and respiratory compromise were critical concerns during the perioperative period in our patient population, and the inability to ventilate could lead to cardiorespiratory arrest. This case series provides a comprehensive, longitudinal view of complete trisomy 18 patients in the perioperative period and adds information for counseling families and care providers.

E-cigarette, or Vaping, Product Use-Associated Lung Injury-Lessons Learned: A Case Series.

E-cigarette, or vaping, product use has been declared an epidemic, and a new disease has emerged from their use. We describe 4 patients with significant acute lung injury related to e-cigarette use who underwent bronchoscopy and bronchoalveolar lavage. All cases posed anesthetic challenges, including increased airway reactivity, hypoxia, increasing oxygen requirements, and, in 2 severe cases, the need for continued postprocedural mechanical ventilatory support. It is imperative that all members of the treating team are aware of the disproportionate risk of respiratory complications to anticipate the possible need for increased postprocedural respiratory support.

Impaired lung function following e-cigarette or vaping product use associated lung injury in the first cohort of hospitalized adolescents.

BACKGROUND: Beginning June 2019, Children's Wisconsin was the first hospital to identify a cohort of adolescent patients hospitalized with symptoms likely associated with e-cigarette use. Our report adds to the growing literature describing the radiographic, gross and cytopathologic bronchoscopic findings, and short-term lung function outcomes in this cohort of adolescents with e-cigarette or vaping product use associated lung injury (EVALI). METHODS: We present 15 adolescents hospitalized from June to September, 2019 with confirmed EVALI. We abstracted data from inpatient hospitalization and first outpatient pulmonary clinic visit. RESULTS: There were 15 patients (11 male, 12 White) with a mean age of 17.1 years. All patients presented with subacute pulmonary, gastrointestinal and constitutional complaints. Diagnostic workup was guided by the Centers for Disease Control criteria for confirmed EVALI case surveillance. Flexible bronchoscopy was performed in 13/15 patients with 10/13 demonstrating gross pathologic abnormalities. Seven of 15 patients required intensive care and 2 met criteria for pediatric Acute Respiratory Distress Syndrome. Patients had dramatic improvement with systemic glucocorticoid therapy and 14/15 were discharged on room air. Eleven patients were seen as outpatients. Despite 11/11 patients reporting resolved or improved symptoms, 7/11 had abnormalities on pulmonary function testing. We initiated inhaled corticosteroids for 5/11 patients and 4/11 patients remained on their corticosteroid wean. CONCLUSIONS AND RELEVANCE: We report short-term outcomes of the first cohort of adolescent patients hospitalized with EVALI. An association is observed between clinical improvement and treatment with systemic corticosteroids. However, residual airway reactivity or diffusion abnormalities persisted when patients were re-evaluated in the short-term period (mean 4.5 weeks).

Low VWF levels in children and lack of association with bleeding in children undergoing tonsillectomy.

von Willebrand disease is a common bleeding disorder, but diagnosis can be difficult in young children who have not had bleeding challenges. We sought to evaluate the correlation between bleeding and von Willebrand factor (VWF) levels in children undergoing surgical challenge with tonsillectomy. Children ages 0 to 18 undergoing tonsillectomy without a personal or family history of bleeding were enrolled prospectively following informed consent and institutional review board approval. VWF levels were obtained at the time of surgery. VWF antigen (VWF:Ag) and VWF activity (VWF:GPIbM) were tested via enzyme-linked immunosorbent assay. Bleeding score was calculated using the International Society of Hematology bleeding assessment tool (BAT). Surgical and postoperative bleeding were determined using questionnaires filled out by the surgeon and patient/family. A total of 1399 subjects were enrolled with evaluable data, with a median age of 5 years. The median VWF:Ag was 85 IU/dL and the median VWF:GPIbM was 100 U/dL. Median BAT for the entire population was 0, including those with postoperative bleeding. There was no difference in VWF level between those who experienced postoperative bleeding and those who did not, with median VWF:Ag 85 vs 85 (P = .89) and mean VWF:GPIbM 98 vs 100 (P = .5). Interestingly, there was a difference in VWF levels with age, with median VWF:Ag 81 for those younger than 3 years, 82 for those 3 to 6 years, 90 for those 7 to 10 years, and 100 for those 11 to 18 years. A similar trend was noted for VWF:GPIbM. Of the 2 to 6 year olds, 5% had VWF:Ag <50, which would meet criteria for low VWF, but only 1.8% had an abnormal BAT at study entry and only 2.5% bled after surgery. Only 1 subject with low VWF had an elevated postoperative BAT >2. These data suggest that low VWF levels do not correlate with bleeding in children undergoing tonsillectomy. In addition, VWF levels outside the adult normal range in young children may be more common than previously thought and do not necessarily predict surgical bleeding.

Familism and the Hispanic Health Advantage: The Role of Immigrant Status.

It is well known that Hispanic immigrants exhibit better physical and mental health than their U.S.-born counterparts. Scholars theorize that stronger orientations toward the family, also known as familism, could contribute to this immigrant advantage. Yet, little work directly tests whether familial attitudes may be responsible for the favorable health of foreign-born Hispanics. We investigate this possibility using biomarkers, anthropometrics, and mental health assessments from the Hispanic Community Health Study/Study of Latinos (N = 4,078). Results demonstrate that the relationship between familial attitudes and health vary depending on the outcome assessed. While Hispanics with strong attitudes toward familial support have fewer symptoms of depression and anxiety, those who report high referent familism display worse mental health outcomes. We find little evidence that familism is linked to physical health or that immigrant generation moderates the relationship of interest. Our results challenge assumptions that familism is responsible for the comparably better health of foreign-born Hispanics.

Investigating Health Selection Within Mexico and Across the US Border.

Despite acquiring lower levels of attainment and earnings, Mexican immigrants exhibit favorable health outcomes relative to their native-born counterparts. And while scholars attempt to reconcile this so-called paradoxical relationship with a variety of theoretical and empirical approaches, patterns of selective migration continue to receive considerable attention. The present study contributes to the literature on health selection by extending the healthy migrant hypothesis in a number of ways. First, we rely on a unique combination of data sets to assess whether the healthy are disproportionately more likely to migrate. We use the latest wave of the Mexican Family Life Survey and the 2013 Migrante Study, a survey that is representative of Mexican-born persons who are actively migrating through Tijuana. Pooling these data also allow us to differentiate between internal and US-bound migrants to shed light on their respective health profiles. Results provide modest support for the healthy migrant hypothesis. Although those who report better overall health are more likely to migrate, we find that the presence of certain chronic conditions increases migration risk. Our findings also suggest that internal migrants are healthier than those traveling to the US, though this is largely because those moving within Mexico reflect a younger and more educated population. This study takes an important step in uncovering variation across migrant flows and highlights the importance of the timing at which health is measured in the migration process.

Moving Beyond Salmon Bias: Mexican Return Migration and Health Selection.

Despite having lower levels of education and limited access to health care services, Mexican immigrants report better health outcomes than U.S.-born individuals. Research suggests that the Mexican health advantage may be partially attributable to selective return migration among less healthy migrants-often referred to as "salmon bias." Our study takes advantage of a rare opportunity to observe the health status of Mexican-origin males as they cross the Mexican border. To assess whether unhealthy migrants are disproportionately represented among those who return, we use data from two California-based studies: the California Health Interview Survey; and the Migrante Study, a survey that samples Mexican migrants entering and leaving the United States through Tijuana. We pool these data sources to look for evidence of health-related return migration. Results provide mixed support for salmon bias. Although migrants who report health limitations and frequent stress are more likely to return, we find little evidence that chronic conditions and self-reported health are associated with higher probabilities of return. Results also provide some indication that limited health care access increases the likelihood of return among the least healthy. This study provides new theoretical considerations of return migration and further elucidates the relationship between health and migration decisions.

The Effect(s) of Teen Pregnancy: Reconciling Theory, Methods, and Findings.

Although teenage mothers have lower educational attainment and earnings than women who delay fertility, causal interpretations of this relationship remain controversial. Scholars argue that there are reasons to predict negative, trivial, or even positive effects, and different methodological approaches provide some support for each perspective. We reconcile this ongoing debate by drawing on two heuristics: (1) each methodological strategy emphasizes different women in estimation procedures, and (2) the effects of teenage fertility likely vary in the population. Analyses of the Child and Young Adult Cohorts of the National Longitudinal Survey of Youth (N = 3,661) confirm that teen pregnancy has negative effects on most women's attainment and earnings. More striking, however, is that effects on college completion and early earnings vary considerably and are most pronounced among those least likely to experience an early pregnancy. Further analyses suggest that teen pregnancy is particularly harmful for those with the brightest socioeconomic prospects and who are least prepared for the transition to motherhood.

The potential utility of urinary biomarkers for risk prediction in combat casualties: a prospective observational cohort study.

INTRODUCTION: Traditional risk scoring prediction models for trauma use either anatomically based estimations of injury or presenting vital signs. Markers of organ dysfunction may provide additional prognostic capability to these models. The objective of this study was to evaluate if urinary biomarkers are associated with poor outcomes, including death and the need for renal replacement therapy. METHODS: We conducted a prospective, observational study in United States Military personnel with traumatic injury admitted to the intensive care unit at a combat support hospital in Afghanistan. RESULTS: Eighty nine patients with urine samples drawn at admission to the intensive care unit were studied. Twelve patients subsequently died or needed renal replacement therapy. Median admission levels of urinary cystatin C (CyC), interleukin 18 (IL-18), L-type fatty acid binding protein (LFABP) and neutrophil gelatinase-associated lipocalin (NGAL) were significantly higher in patients that developed the combined outcome of death or need for renal replacement therapy. Median admission levels of kidney injury molecule-1 were not associated with the combined outcome. The area under the receiver operating characteristic curves for the combined outcome were 0.815, 0.682, 0.842 and 0.820 for CyC, IL-18, LFABP and NGAL, respectively. Multivariable regression adjusted for injury severity score, revealed CyC (OR 1.97, 95 % confidence interval 1.26-3.10, p = 0.003), LFABP (OR 1.92, 95 % confidence interval 1.24-2.99, p = 0.004) and NGAL (OR 1.80, 95 % confidence interval 1.21-2.66, p = 0.004) to be significantly associated with the composite outcome. CONCLUSIONS: Urinary biomarker levels at the time of admission are associated with death or need for renal replacement therapy. Larger multicenter studies will be required to determine how urinary biomarkers can best be used in future prediction models.

Social mobility in the context of fathering: the intergenerational link in parenting among co-resident fathers.

Intergenerational transmissions extend across a number of family-related behaviors, including marriage timing, fertility, and divorce. Surprisingly, few studies investigate the link between the fathering men experience and the fathering they ultimately engage in. I use data on the grandfathers and fathers of the 2001 U.S. birth cohort - measured in the Early Childhood Longitudinal Study (N=4050) - to test whether men's perception of the parenting they received influences their subsequent paternal self-assessments and behaviors. I find a nonlinear association between experiencing warm fathering and men's self-assessed parenting quality and stress. Men with particularly warm fathers are more likely to report being good fathers themselves. Those who report having the harshest fathers also exhibit better paternal self-perceptions and lower stress. Perceptions of paternal warmth show similar associations with men's fathering engagement. This research sheds light on the significance of family dynamics and how a legacy of fathering may contribute to inequality.

Social networkers' attitudes toward direct-to-consumer personal genome testing.

PURPOSE: This study explores social networkers' interest in and attitudes toward personal genome testing (PGT), focusing on expectations related to the clinical integration of PGT results. METHODS: An online survey of 1,087 social networking users was conducted to assess 1) use and interest in PGT; 2) attitudes toward PGT companies and test results; and 3) expectations for the clinical integration of PGT. Descriptive statistics were calculated to summarize respondents' characteristics and responses. RESULTS: Six percent of respondents have used PGT, 64% would consider using PGT, and 30% would not use PGT. Of those who would consider using PGT, 74% report they would use it to gain knowledge about disease in their family. 34% of all respondents consider the information obtained from PGT to be a medical diagnosis. 78% of those who would consider PGT would ask their physician for help interpreting test results, and 61% of all respondents believe physicians have a professional obligation to help individuals interpret PGT results. CONCLUSION: Respondents express interest in using PGT services, primarily for purposes related to their medical care and expect physicians to help interpret PGT results. Physicians should therefore be prepared for patient demands for information and counsel on the basis of PGT results.