The First Genome-Wide Association Study for Type 2 Diabetes in Youth: The Progress in Diabetes Genetics in Youth (ProDiGY) Consortium

The prevalence of type 2 diabetes in youth has increased substantially, yet the genetic underpinnings remain largely unexplored. To identify genetic variants predisposing to youth-onset type 2 diabetes, we formed ProDiGY, a multiethnic collaboration of three studies (TODAY, SEARCH, and T2D-GENES) with 3,006 youth case subjects with type 2 diabetes (mean age 15.1 ± 2.9 years) and 6,061 diabetes-free adult control subjects (mean age 54.2 ± 12.4 years). After stratifying by principal component–clustered ethnicity, we performed association analyses on ∼10 million imputed variants using a generalized linear mixed model incorporating a genetic relationship matrix to account for population structure and adjusting for sex. We identified seven genome-wide significant loci, including the novel locus rs10992863 in PHF2 (P = 3.2 × 10⁻⁸; odds ratio [OR] = 1.23). Known loci identified in our analysis include rs7903146 in TCF7L2 (P = 8.0 × 10⁻²⁰; OR 1.58), rs72982988 near MC4R (P = 4.4 × 10⁻¹⁴; OR 1.53), rs200893788 in CDC123 (P = 1.1 × 10⁻¹²; OR 1.32), rs2237892 in KCNQ1 (P = 4.8 × 10⁻¹¹; OR 1.59), rs937589119 in IGF2BP2 (P = 3.1 × 10⁻⁹; OR 1.34), and rs113748381 in SLC16A11 (P = 4.1 × 10⁻⁸; OR 1.04). Secondary analysis with 856 diabetes-free youth control subjects uncovered an additional locus in CPEB2 (P = 3.2 × 10⁻⁸; OR 2.1) and consistent direction of effect for diabetes risk. In conclusion, we identified both known and novel loci in the first genome-wide association study of youth-onset type 2 diabetes.     

Feasibility and delivery of patient-reported outcomes in clinical practice among racially diverse bladder and prostate cancer patients

ObjectiveTo assess the feasibility of enrollment and collecting patient-reported outcome (PRO) data as part of routine clinical urologic care for bladder and prostate cancer patients and examine overall patterns and racial variations in PRO use and symptom reports over time.Subjects/Patients and MethodsWe recruited 76 patients (n = 29 Black and n = 47 White) with prostate or bladder cancer at a single, comprehensive cancer center. The majority of prostate cancer patients had intermediate risk (57%) disease and underwent either radiation or prostatectomy. Over half (58%) of bladder cancer patients had muscle invasive disease and underwent cystectomy.Patients were asked to complete PRO symptom surveys using their preferred mode [web- or phone-based interactive voice response (IVR)]. Symptom summary reports were shared with providers during visits. Surveys were completed at 3 time points and assessed urinary, sexual, gastrointestinal, anxiety/depression, and sleep symptoms. Feasibility of enrollment and survey completion were calculated, and linear mixed effects models estimated differences in outcomes by race and time.ResultsSixty three percent of study participants completed all PRO measures at all 3 time points. Black patients were more likely to select IVR as their survey mode (40% vs. 13%, P < 0.05), and less likely to complete all surveys (55% vs. 74%, P = 0.13). Patients using IVR were also less likely to complete all surveys (41% vs. 69%, P = 0.046).ConclusionsReported preferences for survey mode and completion rates differ by race, which may influence survey completion rates and highlight potential obstacles for equitable implementation of PROs into clinical care.     

Patterns of E-Cigarette Use Among Primary Care Patients at an Urban Community Center

Tobacco use remains the leading cause of preventable disease and death in the US. The number of tobacco products has grown over the past decade. E-cigarette use has increased rapidly in recent years, but patterns and correlates of use have not been thoroughly assessed. We examined relationships among demographic factors, e-cigarette and conventional cigarette use in a large sample (N?=?12,409) of adult patients at a community health center in the Northeastern US. Overall, 13% (N?=?1675) of the sample reported ever using e-cigarettes. In logistic regression models, ever having used e-cigarettes was associated with younger age (ages 18–25; OR?=?3.5, p?<?0.001). Being transgender (OR?=?1.8, p?<?0.001), bisexual (OR?=?1.5, p?<?0.001), un-partnered (OR?=?1.5, p?<?0.001), having a lower income (OR?=?1.6, p?<?0.001) or a high BMI (OR?=?1.4, p?=?0.009) were associated with increased odds of use, whereas being a woman (OR?=?0.7, p?<?0.001) or Black/African American (OR?=?0.7, p?=?0.007) were associated with lower odds of use. Of the participants who reported e-cigarette use, a majority also endorsed current or former use of conventional cigarettes. Individuals who formerly used conventional cigarettes were nearly three times more likely to report daily e-cigarette use than current users. Among primary care patients at a community health center, e-cigarette use was reported by a sizeable portion of the sample. Overall, odds of use were higher in certain patient populations, and individuals who formally used cigarettes were more likely to report e-cigarette use than individuals who currently smoke, suggesting that e-cigarettes may be functioning as a cessation aid or a strategy to reduce conventional cigarette use.

     

Social HMOs and Other Capitated Arrangements for Children with Special Health Care Needs

Objective: Children with special health care needs are increasingly enrolling in managed care arrangements. However, existing managed care organizations, including traditional HMOs, are often poorly suited for caring for this population. In the adult health care area, new managed care entities, called Social HMOs (S/HMO) and Programs for the All-inclusive Care for the Elderly (PACE), have been created to integrate health and health-related services for chronically ill and disabled adults. We describe these models and assess their potential for serving children with special health care needs. Method: We reviewed the literature on managed care for children with special health care needs and evaluation findings from the S/HMO and PACE models for the elderly. Results: Evaluations of the S/HMO and PACE models have yielded mixed findings. Some of the more positive accomplishments include lower use and expenditures for long-term care services compared to other demonstration projects, greater integration of primary care physicians in decision making concerning long-term care, and improved management of transitions between care levels. On the negative side, start-up has been slow, prospective members have been hesitant to enroll, intermittent and sometimes frequent operating deficits have emerged, no discernible positive effects on health or social outcomes are apparent, and no significant overall savings have emerged. Conclusions: With mixed results so far, caution is required in applying these or similar models for vulnerable child populations. However, given the inadequacies of traditional managed care for this population, we believe experimentation with new models of care that integrate health and health-related services is important. Such experimentation should be fostered only to the extent that the models are carefully designed and then implemented in a manner that protects the interests of children with special health care needs.     

Transfer of liposomal drug carriers from the blood to the peritoneal cavity of normal and ascitic tumor-bearing mice

Summary Previously we have demonstrated that the L1210 antitumor activity of liposomal doxorubicin increased significantly as the size of the liposomal carrier was reduced from 1.0 to 0.1 m. It is demonstrated herein that empty and drug-loaded small (0.1-m diameter) liposomes accumulate efficiently into the peritoneal cavity of normal and ascitic L1210 tumor-bearing animals following i.v. administration. In normal mice injected with 100 nm DSPC/chol liposomal doxorubicin (drug-to-lipid ratio of 0.2; wt/wt) approximately 2.8 g drug could be recovered from the peritoneal cavity following peritoneal lavage at 24 h. Although this represents only 0.7% of the injected doxorubicin dose, this level of drug is 2 orders of magnitude greater than that achieved following administration of an equivalent dose of free drug (20 mg/kg). The drug levels achieved within the peritoneal cavity are dependent on the physical characteristics (size, drug-to-lipid ratio and lipid composition) of the liposomes employed. Optimal delivery is obtained employing 100 nm DSPC/chol liposomal doxorubicin, a vesicle system that is known to retain entrapped drug following i.v. administration and exhibits extended circulation lifetimes. Analysis of drug and liposome distribution within the peritoneal cavity of normal mice indicates that as much as 50% of the measured doxorubicin and liposomal lipid is cell-associated. Flow cytometric analysis of the peritoneal cells demonstrated that cell-associated doxorubicin resides almost exclusively within resident peritoneal macrophages. The increased delivery of doxorubicin to the peritoneal cavity of normal mice following i.v. administration of small (0.1-m) liposomal doxorubicin is correlated with a pronounced (>90%) and prolonged (>14-day) suppression of resident peritoneal cells. Liposomal drug accumulation increased dramatically in animals with an established L1210 ascitic tumor. More than 5% of the injected dose was found in the peritoneal cavity of these animals 24 h after treatment with DSPC/chol liposomal doxorubicin as compared with a value of 0.03% of the injected dose achieved with free drug. It is proposed that accumulation of liposomes into the peritoneal cavity of normal and tumor-bearing mice may serve as a useful model for characterizing factors mediating the transfer of liposomes from the vascular compartment to extravascular sites.     

Argon laser trabeculoplasty--the possibility for antiglaucoma treatment

The current role of argon laser trabeculoplasty in the treatment of open angle glaucoma is still open discussion. To evaluate the effectiveness of ALT we performed a study on 36 patients followed for 2 years. We noted a success rate of 61.11% after 2 years and noticed that the success rate decreased in time. ALT should be considered as an intermediate therapy in the management of open angle glaucoma, after drug therapy has failed and before filtering surgery is performed.     

Effects of air pollutants on the oxidative metabolism and phagocytic capacity of pulmonary alveolar macrophages

Isolated rabbit pulmonary alveolar macrophages were found to be a convenient biological model system, relevant for studies of the toxicity of air pollutants. The phagocytic capacity and the oxygen consumption were used as test parameters and studied simultaneously on the same cells. The toxicity of extracts of airborne particles (phi less than 15 microns) collected in urban and rural areas was investigated and compared to a cigarette-smoke condensate. An extract of particles from a car tunnel was found to be the most toxic air sample, inhibiting phagocytosis as well as respiration of the macrophages at a concentration representing 5 m3 air/ml cell suspension. A corresponding sample collected on a roof of a five-storied building in the central area of a city (population 600,000) was found to inhibit phagocytosis but did not affect respiration. Further investigations revealed that one effect of the "tunnel" extract could be explained as an uncoupling of the mitochondrial respiratory control. Compared to the cigarette-smoke condensate, the toxicity of the air samples was infinitesimal.     

Combination chemotherapy with cisplatin, bleomycin, and methotrexate in patients with advanced head and neck cancer

Twenty-six patients with advanced head and neck cancer, 22 of whom had failed prior surgery and/or radiotherapy, were treated with a combination regimen of cis-diamminedichloroplatinum II, bleomycin, and methotrexate. There were no complete responses. Nine patients achieved a partial response (35%). Three of the four (75%) patients without prior therapy achieved a partial response while only 6 of the 22 patients (27%) with prior surgery and/or radiation therapy obtained a partial response. The median response duration was 3 months. Patients with a partial response did not live significantly longer than those who did not live significantly longer than those who did not respond. Toxic reactions were frequent: there were three episodes of sepsis secondary to leukopenia and two cases of bleomycin pulmonary toxicity. Mucositis was noted in 40% and nausea and vomiting in 60% of patients. We conclude that this triple-drug regimen has little value in the treatment of patients with advanced squamous cell carcinoma of the head and neck who have failed prior surgery and radiotherapy.     

Objective acoustic and aerodynamic measures of breathiness in paralytic dysphonia

This study was designed to determine which objective acoustic or aerodynamic parameters allowed a homogeneous group of patients with unilateral vocal fold paralysis (UVFP) to be distinguished from an age-matched and smoking-matched control group and to search for linear correlations between the objective parameters and the subjective breathiness ratings. Eight patients with recent-onset UVFP and 12 controls were prospectively studied. The acoustic parameters measured for the vowel /a/ at a comfortable frequency and intensity were: jitter, shimmer, harmonics-to-noise ratio, cepstral peak prominence, the difference between the levels of the first two harmonics and the relative energy above 6 kHz. Aerodynamic parameters included the mean flow rate during a sustained /a/ and intraoral pressure during the production of the phoneme /pi/. The long-term average spectrum was calculated for 40 s of text, and the relative average energies in four frequency bands were compared. Six judges rated a mid-/a/ sample using a five-parameter scale with four levels of severity. Nonparametric statistical analysis revealed significant differences ( P<.05) between the UVFP group and the control group for 14 of the 19 parameters studied. Correlations between the objective parameters and perceived breathiness differed in the two groups. Correlations were not always as expected as based on previous literature reports. These measurements provided an objective qualification of voice in patients with UVFP and successfully distinguished them from the normal controls. The objective acoustic and aerodynamic measurements had generally low linear correlations with breathiness ratings in the control group. Higher correlations were seen in the UVFP group, in which breathiness was best correlated with airflow measurements.     

Use of radiolabeled antibodies in the treatment of childhood acute leukemia

Abstract: Despite advances in therapy for acute leukemia, relapse continues to be the major cause of treatment failure. Hematopoietic stem cell transplant can rescue some patients after relapse, but the ability to escalate the intensity of preparative regimens is limited by toxicity to normal organs. Radiolabeled monoclonal antibodies against hematopoietic antigens have emerged as an alternative to deliver targeted supplemental radiation to sites of leukemic involvement while relatively sparing normal organs. This paper will review the rationale for using this approach, our current experience with radiolabeled anti-CD45 antibody, and the potential challenges encountered in treating children with radiolabeled antibodies.