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Sean C Blackwell,1 Erin M Sullivan,2 Allison A Petrilla,2 Xian Shen,2 Kathleen A Troeger,3 James D Byrne4 1Department of Obstetrics, Gynecology and Reproductive Sciences, University of Texas Health Sciences Center, Houston, TX, USA; 2Avalere Health, LLC, Health Economics and Outcomes Research, Washington, DC, USA; 3Hologic, Inc., Outcomes Research, Marlborough, MA, USA; 4Department of Obstetrics and Gynecology, Santa Clara Valley Medical Center, San Jose, CA, USA Objectives: To identify pregnant health plan members triaged through the emergency department (ED), including labor and delivery (ELD) units, with symptoms of preterm labor (PTL), and evaluate the use of fetal fibronectin (fFN) testing; and to calculate the rate of hospitalization and timing of delivery in relation to the ED visit. Methods: Retrospective cohort study using Medical Outcomes Research for Effectiveness and Economics Registry®, a national multipayer claims database. A cohort of pregnant women evaluated in an ELD with a diagnosis of PTL from June 2012 through November 2015 was identified. The proportion of women with PTL who received fFN testing was calculated.Results: A total of 23,062 patients met the criteria for inclusion in the study. The rate of fFN testing prior to delivery was 12.0%. Of the 23,062 patients included in the analysis, 75.9% were discharged home. Of those who were discharged from the emergency room, one in five went on to deliver within 3 days and almost 96% of this group was not screened for the presence of fFN. Of the remaining 24.1% of patients admitted to the hospital, 91.3% delivered during their stay. In a sensitivity analysis, the percentage of women who delivered within 3 days of the ELD encounter was lower for women who received fFN testing only (6.6%) versus those who had a history of transvaginal ultrasound (TVUS) only (21.6%). Furthermore, the rate of delivery within 3 days was lowest among patients who had both fFN testing and TVUS (4.7%).Conclusion: The utilization of fFN testing is 12%. The majority of pregnant patients triaged through the ELD with symptomatic PTL do not receive an fFN test. As part of PTL evaluation, fFN testing may identify women at increased risk for preterm delivery and help determine appropriate patient management. Keywords: preterm labor, pregnancy, emergency department, fetal fibronectin testing

Disabled older adults have been shown to be at risk for underutilization of some preventive services relative to able-bodied individuals. The Women's Health and Aging Study surveyed female Medicare enrollees in Baltimore, Maryland, who were among the most disabled community-dwelling women at the start of the study. Longitudinal survey data from the study were used to test for the existence or emergence of racial variation in influenza vaccination rates, for which racial variation has been shown in the general population. The primary analysis, using data on the same women before and after Medicare flu shot coverage began, suggested that influenza vaccination rates increased after Medicare coverage began and that there was no difference by race. A secondary analysis using data on women who were interviewed only after Medicare flu shot coverage began showed some racial variation, although the difference may have been larger prior to coverage. The utilization rate did not approach the Healthy People 2010 target. [ABSTRACT FROM AUTHOR]

Pigtail pleural catheters are becoming more popular because they are a less painful and equally efficacious alternative to the traditional large-bore thoracostomy tube. This report describes the case of a 48-year-old male whose deteriorating condition required the placement of a pigtail pleural catheter for treatment of parapneumonic pleural effusion. He later developed significant complications related to the procedure., Competing Interests: Human subjects: Consent was obtained or waived by all participants in this study. Conflicts of interest: In compliance with the ICMJE uniform disclosure form, all authors declare the following: Payment/services info: All authors have declared that no financial support was received from any organization for the submitted work. Financial relationships: All authors have declared that they have no financial relationships at present or within the previous three years with any organizations that might have an interest in the submitted work. Other relationships: All authors have declared that there are no other relationships or activities that could appear to have influenced the submitted work., (Copyright © 2024, Sullivan et al.)

Purpose: Brain metastases are associated with high morbidity and are often resistant to immune checkpoint inhibitors. We evaluated whether CDK4/6 inhibitor (CDKi) abemaciclib can sensitize intracranial tumors to programmed cell death protein 1 (PD-1) inhibition in mouse models of melanoma and breast cancer brain metastasis., Experimental Design: Treatment response was evaluated in vivo using immunocompetent mouse models of brain metastasis bearing concurrent intracranial and extracranial tumors. Treatment effect on intracranial and extracranial tumor-immune microenvironments (TIME) was evaluated using immunofluorescence, multiplex immunoassays, high-parameter flow cytometry, and T-cell receptor profiling. Mice with humanized immune systems were evaluated using flow cytometry to study the effect of CDKi on human T-cell development., Results: We found that combining abemaciclib with PD-1 inhibition reduced tumor burden and improved overall survival in mice. The TIME, which differed on the basis of anatomic location of tumors, was altered with CDKi and PD-1 inhibition in an organ-specific manner. Combination abemaciclib and anti-PD-1 treatment increased recruitment and expansion of CD8+ effector T-cell subsets, depleted CD4+ regulatory T (Treg) cells, and reduced levels of immunosuppressive cytokines in intracranial tumors. In immunodeficient mice engrafted with human immune systems, abemaciclib treatment supported development and maintenance of CD8+ T cells and depleted Treg cells., Conclusions: Our results highlight the distinct properties of intracranial and extracranial tumors and support clinical investigation of combination CDK4/6 and PD-1 inhibition in patients with brain metastases. See related commentary by Margolin, p. 257., (©2023 American Association for Cancer Research.)

Background: Patient-reported outcomes (PROs) can assess chronic health. The study aims were to pilot a survey through the PEDSnet Healthy Weight Network (HWN), collecting PROs in tertiary care pediatric weight management programs (PWMP) in the United States, and demonstrate that a 50% enrollment rate was feasible; describe PROs in this population; and explore the relationship between child/family characteristics and PROs. Methods: Participants included 12- to 18-year-old patients and parents of 5- to 18-year-olds receiving care at PWMP in eight HWN sites. Patient-Reported Outcomes Measurement Information System (PROMIS ® ) measures assessed global health (GH), fatigue, stress, and family relationships (FR). T-score cut points defined poor GH or FR or severe fatigue or stress. Generalized estimating equations explored relationships between patient/family characteristics and PROMIS measures. Results: Overall, 63% of eligible parents and 52% of eligible children enrolled. Seven sites achieved the goal enrollment for parents and four for children. Participants included 1447 children. By self-report, 44.6% reported poor GH, 8.6% poor FR, 9.3% severe fatigue, and 7.6% severe stress. Multiple-parent household was associated with lower odds of poor GH by parent proxy report [adjusted odds ratio (aOR) 0.69, 95% confidence interval (CI) 0.55-0.88] and poor FR by self-report (aOR 0.36, 95% CI 0.17-0.74). Parents were significantly more likely to report that the child had poor GH and poor FR when a child had multiple households. Conclusions: PROs were feasibly assessed across the HWN, although implementation varied by site. Nearly half of the children seeking care in PWMP reported poor GH, and family context may play a role. Future work may build on this pilot to show how PROs can inform clinical care in PWMP.

Chimeric antigen receptor T cell (CAR-T) therapy is a promising approach to improve survival for children and adults with relapsed/refractory (r/r) B cell acute lymphoblastic leukemia (B-ALL), but these clinical trials might not be equally accessible to patients of low socioeconomic status (SES) or to patients from racial or ethnic minority groups. We sought to describe the sociodemographic characteristics of pediatric and adolescent and young adult (AYA) patients enrolled in CAR-T clinical trials and to compare these characteristics to those of other patients with r/r B-ALL. We conducted a multicenter retrospective cohort study at 5 pediatric consortium sites to compare the sociodemographic characteristics of patients treated and enrolled in CAR-T trials at their home institution, other patients with r/r B-ALL treated at these sites, and patients referred from an external hospital for CAR-T trials. The patients were age 0 to 27 years with r/r B-ALL treated at 1 of the consortium sites between 2012 and 2018. Clinical and demographic data were collected from the electronic health record. We calculated distance from home to treating institution and assigned SES scores based on census tract. Among the 337 patients treated for r/r B-ALL, 112 were referred from an external hospital to a consortium site and enrolled in a CAR-T trial and 225 were treated primarily at a consortium site, with 34% enrolled in a CAR-T trial. Patients treated primarily at a consortium site had similar characteristics regardless of trial enrollment. Lower proportions of Hispanic patients (37% versus 56%; P = .03), patients whose preferred language was Spanish (8% versus 22%; P = .006), and publicly insured patients (38% versus 65%; P = .001) were referred from an external hospital than were treated primarily at a consortium site and enrolled in a CAR-T trial. Patients who are Hispanic, Spanish-speaking, or publicly insured are underrepresented in referrals from external hospitals to CAR-T centers. External provider implicit bias also may influence referral of these patients. Establishing partnerships between CAR-T centers and external hospital sites may improve provider familiarity, patient referral, and patient access to CAR-T clinical trials., (Copyright © 2023 The American Society for Transplantation and Cellular Therapy. Published by Elsevier Inc. All rights reserved.)

Background: Systemic mastocytosis (SM) is a rare clonal neoplasm driven by KIT D816V and other mutations. Data were collected from the patient perspective on disease burden and included an SM-specific symptom assessment tool., Methods: US adults aged 18 years and older with a self-reported SM diagnosis completed an online TouchStone SM Patient Survey of 100 items, including the 12-item Short-Form Health Survey, the Indolent Systemic Mastocytosis Symptom Assessment Form, and the Work Productivity and Activity Impairment Questionnaire, as well as questions about SM diagnosis, the impact of SM on daily activities, work impairment, and health care use. The results were analyzed using descriptive statistics., Results: Fifty-six individuals completed the survey (89% women; median age, 48 years; mean time since diagnosis, 6.7 years), reporting indolent SM (66%), aggressive SM (9%), smoldering SM (5%), and unknown SM subtype (18%). Over a 1-year recall, respondents reported seeking emergency care for anaphylaxis (30%) and taking three or more prescription medications (52%) for SM. Over one half of patients (54%) reduced their work hours because of SM, and 64% avoided leaving home because of symptoms. A majority of respondents (93%) had experienced ≥10 SM-related symptoms, noting that the most bothersome were anaphylactic episodes (18%), abdominal/stomach pain (16%), diarrhea/loose stools (13%), and fatigue (11%). Whereas an Indolent Systemic Mastocytosis Symptom Assessment Form-derived total symptom score of 28 is used to indicate moderate-to-severe symptoms, the mean total symptom score was 52.7. Mental and physical component summary scores from the 12-item Short-Form Health Survey were below population norms., Conclusions: Patients who were surveyed reported substantial symptom burden and unmet needs because of SM, as evidenced by seeking emergency care and reporting bothersome symptoms, poor quality of life, and reduced work hours and productivity., Lay Summary: The objective of this research was to understand the burden and unmet needs in the rare disease of systemic mastocytosis (SM) to guide future care. Fifty-six patients completed an online survey containing questions about their diagnosis, medications, health care use, quality of life, and SM symptoms. The results demonstrated that SM is associated with severe and burdensome symptoms, anaphylactic events, emergency department visits, use of multiple medications, reduced ability to work, and poor physical and psychological quality of life. These findings suggest the need for future advances to address unmet needs in patients affected by SM., (© 2022 The Authors. Cancer published by Wiley Periodicals LLC on behalf of American Cancer Society.)

Background: Systemic mastocytosis (SM) is a rare clonal neoplasm driven by the KIT D816V mutation and has a broad range of debilitating symptoms. In this study, the authors evaluated SM disease perceptions and management strategies among US health care providers (HCPs)., Methods: Hematologist/oncologist (H/O) HCPs and allergist/immunologist (A/I) HCPs who were treating four or more patients with SM completed an online, 51-item TouchStone HCP Survey, which queried provider characteristics, perceptions of disease burden, and current management. Descriptive analyses by specialty and SM subtype were performed., Results: Of 304 HCPs contacted, 111 (37%) met eligibility criteria, including 51% A/I specialists and 49% H/O specialists. On average, the HCPs had 14 years of practice experience and cared for 20 patients with SM. A/I HCPs saw more patients with nonadvanced SM (78%) compared with H/O HCPs, who saw similar proportions of patients with nonadvanced SM (54%) and advanced SM (46%). HCPs reported testing 75% of patients for the KIT D816V mutation and found an estimated prevalence of 47%. On average, HCPs estimated 8 months between symptom onset and SM diagnosis. HCPs reported that 62% of patients with indolent SM felt depressed or discouraged because of symptoms. In terms of treatment goals for SM, both types of specialists prioritized symptom improvement for nonadvanced SM and improved survival for advanced SM while also prioritizing improving patient quality of life., Conclusions: Both A/I and H/O specialists highlighted unmet needs for patients with SM. The HCPs surveyed reported a lower rate of KIT D816V mutations and a perceived shorter time between symptom onset and SM diagnosis compared with published estimates., Lay Summary: Specialists treating systemic mastocytosis (SM) completed a 51-item questionnaire about their clinical practices and perceptions of disease impact. The study included 111 hematology, oncology, allergy, and immunology physicians. Physicians reported that most patients had nonadvanced disease, yet SM symptoms significantly disrupted their patients' lives. Physicians estimated that SM is diagnosed within months of symptom onset, in contrast with published reports of years' long delays reported by patients with SM. This study identified unmet needs that can inform educational and patient management priorities in this rare disease., (© 2022 The Authors. Cancer published by Wiley Periodicals LLC on behalf of American Cancer Society.)

Objective: Moral distress is increasingly identified as a major problem affecting healthcare professionals, but it is poorly characterized among pediatricians. Our objective was to assess the sources of moral distress in residents and pediatric hospitalist attendings and to examine the association of moral distress with reported burnout., Methods: Cross-sectional survey from January through March 2019 of pediatric residents and hospital medicine attending physicians affiliated with 4 free-standing children's hospitals. Moral distress was measured using the Measure of Moral Distress for Healthcare Professionals (MMD-HP). Burnout was measured using 2 items adapted from the Maslach Burnout Inventory., Results: Respondents included 288 of 541 eligible pediatric residents (response rate: 53%) and 118 of 168 pediatric hospitalists (response rate: 70%; total response rate: 57%). The mean MMD-HP composite score was 93.4 (SD = 42.5). Residents reported significantly higher frequency scores (residents: M = 38.5 vs. hospitalists: M = 33.3; difference: 5.2, 95% confidence interval [CI], 2.9-7.5) and composite scores (residents: M = 97.6 vs hospitalists: M = 83.0; difference:14.6, 95% CI, 5.7-23.5) than hospitalists. The most frequent source of moral distress was "having excessive documentation requirements that compromise patient care," and the most intense source of moral distress was "be[ing] required to work with abusive patients/family members who are compromising quality of care." Significantly higher mean MMD-HP composite scores were observed among participants reporting that they felt burned out at least once per week (M= 114.6 vs M= 82.3; difference: 32.3, 95% CI, 23.5-41.2)., Conclusions: Pediatric residents and hospitalists report experiencing moral distress from a variety of patient-, team-, and system-level sources, and this distress is associated with burnout., (Copyright © 2020 Academic Pediatric Association. Published by Elsevier Inc. All rights reserved.)

Cardiolipin (CL) is an anionic phospholipid mainly located in the inner mitochondrial membrane, where it helps regulate bioenergetics, membrane structure, and apoptosis. Localized, phase-segregated domains of CL are hypothesized to control mitochondrial inner membrane organization. However, the existence and underlying mechanisms regulating these mitochondrial domains are unclear. Here, we first isolated detergent-resistant cardiac mitochondrial membranes that have been reported to be CL-enriched domains. Experiments with different detergents yielded only nonspecific solubilization of mitochondrial phospholipids, suggesting that CL domains are not recoverable with detergents. Next, domain formation was investigated in biomimetic giant unilamellar vesicles (GUVs) and newly synthesized giant mitochondrial vesicles (GMVs) from mouse hearts. Confocal fluorescent imaging revealed that introduction of cytochrome c into membranes promotes macroscopic proteolipid domain formation associated with membrane morphological changes in both GUVs and GMVs. Domain organization was also investigated after lowering tetralinoleoyl-CL concentration and substitution with monolyso-CL, two common modifications observed in cardiac pathologies. Loss of tetralinoleoyl-CL decreased proteolipid domain formation in GUVs, because of a favorable Gibbs-free energy of lipid mixing, whereas addition of monolyso-CL had no effect on lipid mixing. Moreover, murine GMVs generated from cardiac acyl-CoA synthetase-1 knockouts, which have remodeled CL acyl chains, did not perturb proteolipid domains. Finally, lowering the tetralinoleoyl-CL content had a stronger influence on the oxidation status of cytochrome c than did incorporation of monolyso-CL. These results indicate that proteolipid domain formation in the cardiac mitochondrial inner membrane depends on tetralinoleoyl-CL concentration, driven by underlying lipid-mixing properties, but not the presence of monolyso-CL., (© 2018 Pennington et al.)

Mitochondria are the energy-producing organelles within a cell. Furthermore, mitochondria have a role in maintaining cellular homeostasis and proper calcium concentrations, building critical components of hormones and other signaling molecules, and controlling apoptosis. Structurally, mitochondria are unique because they have 2 membranes that allow for compartmentalization. The composition and molecular organization of these membranes are crucial to the maintenance and function of mitochondria. In this review, we first present a general overview of mitochondrial membrane biochemistry and biophysics followed by the role of different dietary saturated and unsaturated fatty acids in modulating mitochondrial membrane structure-function. We focus extensively on long-chain n-3 (ω-3) polyunsaturated fatty acids and their underlying mechanisms of action. Finally, we discuss implications of understanding molecular mechanisms by which dietary n-3 fatty acids target mitochondrial structure-function in metabolic diseases such as obesity, cardiac-ischemia reperfusion injury, obesity, type 2 diabetes, nonalcoholic fatty liver disease, and select cancers.

Cardiac mitochondrial phospholipid acyl chains regulate respiratory enzymatic activity. In several diseases, the rodent cardiac phospholipidome is extensively rearranged; however, whether specific acyl chains impair respiratory enzyme function is unknown. One unique remodeling event in the myocardium of obese and diabetic rodents is an increase in docosahexaenoic acid (DHA) levels. Here, we first confirmed that cardiac DHA levels are elevated in diabetic humans relative to controls. We then used dietary supplementation of a Western diet with DHA as a tool to promote cardiac acyl chain remodeling and to study its influence on respiratory enzyme function. DHA extensively remodeled the acyl chains of cardiolipin (CL), mono-lyso CL, phosphatidylcholine, and phosphatidylethanolamine. Moreover, DHA lowered enzyme activities of respiratory complexes I, IV, V, and I+III. Mechanistically, the reduction in enzymatic activities were not driven by a dramatic reduction in the abundance of supercomplexes. Instead, replacement of tetralinoleoyl-CL with tetradocosahexaenoyl-CL in biomimetic membranes prevented formation of phospholipid domains that regulate enzyme activity. Tetradocosahexaenoyl-CL inhibited domain organization due to favorable Gibbs free energy of phospholipid mixing. Furthermore, in vitro substitution of tetralinoleoyl-CL with tetradocosahexaenoyl-CL blocked complex-IV binding. Finally, reintroduction of linoleic acid, via fusion of phospholipid vesicles to mitochondria isolated from DHA-fed mice, rescued the major losses in the mitochondrial phospholipidome and complexes I, IV, and V activities. Altogether, our results show that replacing linoleic acid with DHA lowers select cardiac enzyme activities by potentially targeting domain organization and phospholipid-protein binding, which has implications for the ongoing debate about polyunsaturated fatty acids and cardiac health., (© 2018 by The American Society for Biochemistry and Molecular Biology, Inc.)

Objectives: Fetal fibronectin (fFN) testing between the 24th and 34th weeks of pregnancy in patients with symptomatic preterm labor (PTL) helps assess the risk of spontaneous preterm birth (sPTB), yet the extent of its use is unknown. We assessed use of fFN testing among Texas Medicaid enrollees with symptomatic PTL and evaluated time to infant delivery and healthcare utilization/costs., Study Design: Retrospective cohort study using medical and pharmacy claims for Texas Medicaid enrollees., Methods: We identified pregnant women triaged through the emergency department (ED) and hospital labor-and-delivery units with symptomatic PTL between January 1, 2012, and May 31, 2015. Patients with fFN testing prior to delivery were propensity score matched 1:1 to patients without fFN testing. Primary outcomes included time to delivery from initial PTL encounter and all-cause maternal healthcare utilization and costs., Results: A total of 29,553 women met the criteria for analysis, of whom 14% had a record of receiving fFN testing. Each matched cohort included 4098 patients. Compared with those who did not, patients who underwent fFN testing had significantly more clinical risk factors (mean [SD]: 1.7 [1.1] vs 1.1 [1.0]; P <.0001) and were less likely to deliver during the initial hospital stay (odds ratio [OR], 0.539; 95% CI, 0.489-0.594), deliver ≤3 days following the hospital/ED encounter (OR, 0.499; 95% CI, 0.452-0.551); and receive their first PTL diagnosis during the initial hospital/ED encounter (OR, 0.598; 95% CI, 0.539-0.665). Patients who had an fFN test, compared with those who did not, had 17.5% higher total costs (P <.0001) during the 5 months prior to delivery, but had gestation lengths 9.4 days longer (24.6 vs 15.2 days) than those without testing., Conclusions: Frequency of fFN testing was low in Texas Medicaid enrollees with symptomatic PTL. Patients with fFN testing had longer gestation periods and were less likely to deliver within ≤3 days of a hospital/ED encounter for PTL. These results support the role of fFN in screening for risk for sPTB among women with symptomatic PTL.

Cardiac phospholipids, notably cardiolipin, undergo acyl chain remodeling and/or loss of content in aging and cardiovascular diseases, which is postulated to mechanistically impair mitochondrial function. Less is known about how diet-induced obesity influences cardiac phospholipid acyl chain composition and thus mitochondrial responses. Here we first tested if a high fat diet remodeled murine cardiac mitochondrial phospholipid acyl chain composition and consequently disrupted membrane packing, supercomplex formation and respiratory enzyme activity. Mass spectrometry analyses revealed that mice consuming a high fat diet displayed 0.8-3.3 fold changes in cardiac acyl chain remodeling of cardiolipin, phosphatidylcholine, and phosphatidylethanolamine. Biophysical analysis of monolayers constructed from mitochondrial phospholipids of obese mice showed impairment in the packing properties of the membrane compared to lean mice. However, the high fat diet, relative to the lean controls, had no influence on cardiac mitochondrial supercomplex formation, respiratory enzyme activity, and even respiration. To determine if the effects were tissue specific, we subsequently conducted select studies with liver tissue. Compared to the control diet, the high fat diet remodeled liver mitochondrial phospholipid acyl chain composition by 0.6-5.3-fold with notable increases in n-6 and n-3 polyunsaturation. The remodeling in the liver was accompanied by diminished complex I to III respiratory enzyme activity by 3.5-fold. Finally, qRT-PCR analyses demonstrated an upregulation of liver mRNA levels of tafazzin, which contributes to cardiolipin remodeling. Altogether, these results demonstrate that diet-induced obesity remodels acyl chains in the mitochondrial phospholipidome and exerts tissue specific impairments of respiratory enzyme activity., (Copyright © 2017 Elsevier Inc. All rights reserved.)

Obesity is associated with increased risk for infections and poor responses to vaccinations, which may be due to compromised B cell function. However, there is limited information about the influence of obesity on B cell function and underlying factors that modulate B cell responses. Therefore, we studied B cell cytokine secretion and/or Ab production across obesity models. In obese humans, B cell IL-6 secretion was lowered and IgM levels were elevated upon ex vivo anti-BCR/TLR9 stimulation. In murine obesity induced by a high fat diet, ex vivo IgM and IgG were elevated with unstimulated B cells. Furthermore, the high fat diet lowered bone marrow B cell frequency accompanied by diminished transcripts of early lymphoid commitment markers. Murine B cell responses were subsequently investigated upon influenza A/Puerto Rico/8/34 infection using a Western diet model in the absence or presence of docosahexaenoic acid (DHA). DHA, an essential fatty acid with immunomodulatory properties, was tested because its plasma levels are lowered in obesity. Relative to controls, mice consuming the Western diet had diminished Ab titers whereas the Western diet plus DHA improved titers. Mechanistically, DHA did not directly target B cells to elevate Ab levels. Instead, DHA increased the concentration of the downstream specialized proresolving lipid mediators (SPMs) 14-hydroxydocosahexaenoic acid, 17-hydroxydocosahexaenoic acid, and protectin DX. All three SPMs were found to be effective in elevating murine Ab levels upon influenza infection. Collectively, the results demonstrate that B cell responses are impaired across human and mouse obesity models and show that essential fatty acid status is a factor influencing humoral immunity, potentially through an SPM-mediated mechanism., (Copyright © 2017 by The American Association of Immunologists, Inc.)

Cardiolipin (CL) has a critical role in maintaining mitochondrial inner membrane structure. In several conditions such as heart failure and aging, there is loss of CL content and remodeling of CL acyl chains, which are hypothesized to impair mitochondrial inner membrane biophysical organization. Therefore, this study discriminated how CL content and acyl chain composition influenced select properties of simple and complex mitochondrial mimicking model membranes. We focused on monolayer excess area/molecule (a measure of lipid miscibility), bilayer phase transitions, and microdomain organization. In monolayer compression studies, loss of tetralinoleoyl [(18:2) 4 ] CL content decreased the excess area/molecule. Replacement of (18:2) 4 CL acyl chains with tetraoleoyl [(18:1) 4 ] CL or tetradocosahexaenoyl [(22:6) 4 ] CL generally had little influence on monolayer excess area/molecule; in contrast, replacement of (18:2) 4 CL acyl chains with tetramyristoyl [(14:0) 4 ] CL increased monolayer excess area/molecule. In bilayers, calorimetric studies showed that substitution of (18:2) 4 CL with (18:1) 4 CL or (22:6) 4 CL lowered the phase transition temperature of phosphatidylcholine vesicles whereas (14:0) 4 CL had no effect. Finally, quantitative imaging of giant unilamellar vesicles revealed differential effects of CL content and acyl chain composition on microdomain organization, visualized with the fluorescent probe Texas Red DHPE. Notably, microdomain areas were decreased by differing magnitudes upon lowering of (18:2) 4 CL content and substitution of (18:2) 4 CL with (14:0) 4 CL or (22:6) 4 CL. Conversely, exchanging (18:2) 4 CL with (18:1) 4 CL increased microdomain area. Altogether, these data demonstrate that CL content and fatty acyl composition differentially target membrane physical properties, which has implications for understanding how CL regulates mitochondrial activity and the design of CL-specific therapeutics., (Copyright © 2016 Elsevier B.V. All rights reserved.)

The focus of this study is to examine the effect of cellulose nanocrystals (CNC) on the properties of polylactic acid (PLA) films. The films are fabricated via melt compounding and melt fiber spinning followed by compression molding. Film fracture morphology, thermal properties, crystallization behavior, thermo-mechanical behavior, and mechanical behavior were determined as a function of CNC content using scanning electron microscopy, differential scanning calorimetry, X-ray diffraction, dynamic mechanical analysis, and tensile testing. Film crystallinity increases with increasing CNC content indicating CNC act as nucleating agents, promoting crystallization. Furthermore, the addition of CNC increased the film storage modulus and slightly broadened the glass transition region.

Suicide is the second leading cause of death among persons aged 10-24 years in the United States and accounted for 5,178 deaths in this age group in 2012. Firearm, suffocation (including hanging), and poisoning (including drug overdose) are the three most common mechanisms of suicide in the United States. Previous reports have noted that trends in suicide rates vary by mechanism and by age group in the United States, with increasing rates of suffocation suicides among young persons. To test whether this increase is continuing and to determine whether it varies by demographic subgroups among persons aged 10-24 years, CDC analyzed National Vital Statistics System mortality data for the period 1994-2012. Trends in suicide rates were examined by sex, age group, race/ethnicity, region of residence, and mechanism of suicide. Results of the analysis indicated that, during 1994-2012, suicide rates by suffocation increased, on average, by 6.7% and 2.2% annually for females and males, respectively. Increases in suffocation suicide rates occurred across demographic and geographic subgroups during this period. Clinicians, hotline staff and others who work with young persons need to be aware of current trends in suffocation suicides in this group so that they can accurately assess risk and educate families. Media coverage of suicide incidents and clusters should follow established guidelines to avoid exacerbating risk for "suicide contagion" among vulnerable young persons.* Suicide contagion is a process by which exposure to the suicide or suicidal behavior of one or more persons influences others who are already vulnerable and thinking about suicide to attempt or die by suicide. Early prevention strategies are needed to reduce the likelihood of young persons developing suicidal thoughts and behavior.

Electroencephalogram (EEG) stands out as a highly translational tool for psychiatric research, yet rodent and human EEG are not typically obtained in the same way. In this study we developed a tool to record skull EEG in awake-behaving rats in a similar manner to how human EEG are obtained and then used this technique to test whether acute NMDA receptor antagonism alters rodent EEG signals in a similar manner as in humans. Acute MK-801 treatment elevated gamma power and reduced beta band power, which closely mirrored EEG data from healthy volunteers receiving acute ketamine. To explore the mechanisms behind these oscillatory changes, we examined the effects of GABA-A receptor blockade, finding that picrotoxin (PTX) recapitulated the decrease in sound-evoked beta oscillations observed with acute MK-801, but did not produce changes in gamma band power. Chronic treatment with either PTX or MK-801 did not affect frequency-specific oscillatory activity when tested 24 h after the last drug injection, but decreased total broadband oscillatory power. Overall, this study validated a novel platform for recording rodent EEG and demonstrated similar oscillatory changes after acute NMDA receptor antagonism in both humans and rodents, suggesting that skull EEG may be a powerful tool for further translational studies.

Background: The auditory steady-state response, which measures the ability of neural ensembles to entrain to rhythmic auditory stimuli, has been used in human electroencephalogram studies to assess sensory processing and electrical oscillatory deficits. Patients with schizophrenia show a deficit in auditory steady-state response at 40 Hz, and therefore this may be a useful biomarker to study this disorder., Methods: We used auditory steady-state response recordings from the primary auditory cortex, hippocampus, and vertex electroencephalogram sites in awake behaving rats to determine whether pharmacological impairment of excitatory or inhibitory neurotransmission mimics auditory steady-state response abnormalities in schizophrenia., Results: We found the most robust response to auditory stimuli in the primary auditory cortex, in line with previous studies suggesting this region is the primary generator of the auditory steady-state response in humans. Acute MK-801 (0.1mg/kg i.p.) increased primary auditory cortex intertrial coherence during auditory steady-state response at 20 and 40 Hz. Chronic MK-801 (21-day exposure at this daily dose) had no significant effect on 40-Hz auditory steady-state response. Furthermore, we found no effect of acute or chronic picrotoxin (a GABA-A antagonist) on intertrial coherence., Conclusions: Our data indicate that acute N-methyl-d-aspartate receptor antagonism increases synchronous activity in the primary auditory cortex in a frequency-specific manner, supporting the widely held view that acute N-methyl-d-aspartate antagonism augments gamma oscillations. Thus, rodent auditory steady-state response could be a valuable method to study the cortical ability to support synchronous activity at specific frequencies., (© The Author 2015. Published by Oxford University Press on behalf of CINP.)

Purpose: Not all natural killer (NK) cells are equally cytotoxic against leukemia because of differences in receptor gene content and surface expression. We correlated NK cell genotype and phenotype at diagnosis of childhood acute lymphoblastic leukemia (ALL) with minimal residual disease (MRD) after induction chemotherapy., Experimental Design: The NK cells and leukemia blasts of 244 patients were analyzed at diagnosis by killer-cell immunoglobulin-like receptor (KIR) typing and immunophenotyping. The results were correlated statistically with postinduction MRD status., Results: The odds of being MRD positive in patients with KIR telomeric (Tel)-A/B genotype were 2.85 times the odds in those with Tel-A/A genotype (P = 0.035). MRD-positive patients were more likely to have KIR2DL5A (P = 0.006) and expressed less activating receptor NKp46 and FASL on their NK cells (P = 0.0074 and P = 0.029, respectively). The odds of being MRD positive increased by 2.01-fold for every percentage increase in NK cells expressing KIR2DL1 in the presence of HLA-C2 ligand (P = 0.034). The quantity of granzyme B inhibitor PI-9 in the leukemia blasts was greater in patients who were MRD positive (P = 0.038). Collectively, five NK cell-related factors (Tel-B-associated KIR2DL5A, NKp46, FASL, granzyme B, and PI-9) are strongly associated with MRD positivity at the end of induction with 100% sensitivity and 80% specificity., Conclusions: Our data support the hypothesis that NK cells with a strong effector phenotype in the setting of decreased leukemia resistance are associated with better leukemia control., (©2014 American Association for Cancer Research.)

Activities of the enzymes involved in cellular respiration are markedly influenced by the composition of the phospholipid environment of the inner mitochondrial membrane. Contrary to previous suppositions, we show that fusion of mitochondria isolated from healthy cardiac muscle with cardiolipin or dioleoylphosphatidylcholine results in a 2-6-fold reduction in the activity of complexes I, II, and IV. The activity of complex III was unaffected by increased phospholipid levels. Phospholipid content had an indiscriminate yet detrimental effect on the combined activities of complexes I+III and II+III. These results have strong implications for therapeutic lipid replacement strategies, in which phospholipid modification of the mitochondria is proposed to enhance mitochondrial function.

Background: There are no standardized diagnostic or treatment guidelines for patients with advanced unilateral retinoblastoma., Materials and Methods: Patients with advanced unilateral retinoblastoma were prospectively treated after enucleation using a risk-based protocol. Patients were assigned to low risk (LR), intermediate risk (IR), or high risk (HR) based on pathology. LR patients underwent observation. IR patients received 4 courses of chemotherapy with vincristine, doxorubicin, and cyclophosphamide (VDC). In the HR group, patients received 3 courses of VDC alternating with 3 courses of vincristine, carboplatin, and etoposide (VCE) and irradiation when indicated., Results: Fifty patients with advanced unilateral retinoblastoma were treated (LR, n=36; IR, n=7; HR, n=7). All eyes were Reese-Ellsworth group V. All bone scans (n=81), lumbar punctures (n=16), and bone marrow aspirates (n=16) were negative. Chemotherapy was well tolerated. Grades 3/4 hematologic toxicities were seen in all patients; grades 3/4 nonhematologic toxicities were seen in half the patients. Only one patient in the HR group received radiation therapy. All patients were alive at the time of analysis with no signs of disease recurrence. Median follow-up was 3.4 years (range, 0.8 to 6.4 y)., Conclusions: Patients with nonmetastatic unilateral retinoblastoma undergoing primary enucleation can be cured with a graduated intensity approach based on pathology.

Background: Patients with müllerian agenesis may be at an increased risk of ovarian torsion due to the absence of the utero-ovarian ligament and the fact that the ovary is not tethered to a fixed and relatively non-mobile structure, the uterus., Case: We report a case of a 14-year-old female with abdominal pain who had a physical examination suggestive of müllerian agenesis. Imaging was non-diagnostic and demonstrated an abdominal mass. Emergent surgery revealed ovarian torsion., Summary and Conclusion: We present this case of ovarian torsion and müllerian agenesis, in order to highlight the association and to review potential risk factors., (Published by Elsevier Inc.)

The pathways by which Merkel cell polyomavirus (MCV) infection contributes to the formation of Merkel cell carcinomas are important for understanding the pathogenesis of these cancers. We hypothesized that MCV T antigen suppresses normal responses to ultraviolet radiation (UVR)-induced DNA damage. An MCV-infected cell line (MKL-1) exhibited UVR hypersensitivity, impaired repair of DNA lesions and cell cycle arrest after UVR, as well as reduced levels of the DNA damage recognition protein, XPC. When ectopically expressed in uninfected UISO cells, mutant but not wild-type T antigen resulted in loss of repair of UVR-induced cyclobutane pyrimidine dimers and reductions in XPC, p53 and p21 levels, whereas both wild-type and mutant T antigen inhibited cell cycle arrest after UVR. Similarly, only mutant T antigen in normal fibroblasts inhibited DNA repair and XPC expression, while both mutant and wild-type T antigens produced cell cycle dysregulation. Wild-type T antigen expression produced large T, 57 kT and small T antigens while mutant T antigen was only detectable as a truncated large T antigen protein. Expression of wild-type large T antigen but not small T antigen inhibited the G1 checkpoint in UISO cells, but neither wild-type large T nor small T antigens affected DNA repair, suggesting that large T antigen generates cell cycle defects, and when mutated may also impair DNA repair. These results indicate that T antigen expression by MCV can inhibit key responses to UVR-induced DNA damage and suggest that progressive MCV-mediated abrogation of genomic stability may be involved in Merkel cell carcinogenesis., (Copyright © 2012 UICC.)

Translational studies are becoming more common in schizophrenia research. The past couple of decades witnessed the emergence of novel ideas regarding schizophrenia pathophysiology that originated from both human and animal studies. The findings that glutamate and gamma-aminobutyric acid transmission are affected in the disease led to the hypothesis of altered inhibitory neurotransmission as critical for cognitive deficits and to an exploration of novel therapeutic approaches aimed at restoring excitation-inhibition balance. Much is to be done yet to elucidate the ultimate mechanisms by which excitation and inhibition are affected in this disorder; a comprehensive translational effort is necessary to address what may cause altered GABA function, for example. Here, we present an overview of the excitation-inhibition imbalance hypothesis in schizophrenia and discuss ongoing efforts aimed at determining whether cortical inhibitory interneurons are affected by oxidative stress during development.

Background: Studies using community-based breastfeeding counselors (CBBCs) have repeatedly shown positive impact on breastfeeding initiation, exclusivity and duration, particularly among low-income mothers. To date, there has not been a comprehensive study to determine the impact of CBBC attributes such as educational background and training, on the type of care that CBBCs provide., Methods: This was a cross-sectional study of a convenience sample of CBBCs to ascertain the influence of counselor education and type of training on type of support and proficiency of CBBCs in communities across the United States. Invitations to participate in this online survey of CBBCs were e-mailed to program coordinators of the Special Supplemental Nutrition Program for Women, Infants, and Children (WIC), La Leche League, and other community-based health organizations, who in turn invited and encouraged their CBBCs to participate. Descriptive analysis was used to describe participants (N = 847), while bivariate analysis using χ2 test was used to examine the differences between CBBC education, training received and breastfeeding support skills used. Multivariate logistic regression was used to assess the independent determinants of specific breastfeeding support skills., Results: The major findings from the research indicate that overall, educational attainment of CBBCs is not a significant predictor for the curriculum used in their training and type of support skills used during counseling sessions, but initial training duration was positively associated with the use of many breastfeeding support skills. Another major influence of counselor support to clients is the type of continuing education they receive after their initial training, with higher likelihood of use of desirable support skills associated with counselors continuing their breastfeeding education at conferences or trainings away from their job sites., Conclusions: Our results show that different programs use different training curricula to train their CBBCs varying in duration and content. Counselor education is not a significant predictor of the type of training they receive. Continuing breastfeeding education is a significant determinant of type of counseling techniques used with clients. Further research is therefore needed to critically examine the content of the various training curricula of CBBC programs. This may show a need for a standardized training curriculum for all CBBC programs worldwide to make CBBCs more proficient and efficient, ensuring successful and optimum breastfeeding experiences for mothers and their newborns.

High level galectin-1 expression results in cancer cell evasion of the immune response, increased tumour survival and aggressive metastases. Using a galectin-1 polyclonal antibody, high levels of galectin-1 protein were shown to be expressed by breast cancer cells established from FVB/N MMTV-c-neu mice as well as by the B16F10 melanoma cell line. In mixed lymphocyte cultures using tumour cells as antigenic stimulators, addition of recombinant galectin-1 dose-dependently inhibited lymphocyte production. Disaccharides were identified that inhibited galectin-1 function and increased growth and activation of CD8(+) CTL's killing cancer cells. X-ray crystallographic structures of human galectin-1 in complex with inhibitory disaccharides revealed their mode of binding. Combining galectin-blocking carbohydrates as adjuvants with vaccine immunotherapy in vivo to promote immune responses significantly decreased tumour progression and improved the outcomes for tumour challenged mice. This is the first report showing that suitably selected galectin-1 blocking disaccharides will act as adjuvants promoting vaccine stimulated immune responses against tumours in vivo., (Crown Copyright © 2010. Published by Elsevier Ireland Ltd. All rights reserved.)

Objectives: We examined the rate of acute myocardial infarction (AMI) deaths in Massachusetts before and after the implementation of a comprehensive smoke-free workplace law in July 2004., Methods: We used Poisson regression models to examine the impact of the state law in cities and towns with and without previous local smoking bans and the effect of the local laws for the period of 1999 through 2006., Results: The AMI mortality rate decreased by 7.4% (95% confidence interval [CI] = 3.3%, 11.4%) after implementation of the state law. The state ban had an impact in cities and towns with no prior local smoking ban (9.2% decrease; P < .001) but not cities and towns with a prior local smoking ban. However, there was a nonsignificant 4.9% (95% CI = -5.0%, 13.9%) decrease associated with the local smoking ban that preceded the effect of the state ban. The effect of the state ban was modest (-1.6%) in the first 12 months after implementation but much larger after the first 12 months (-18.6%; P < .001)., Conclusions: Comprehensive statewide smoke-free workplace laws in Massachusetts were associated with an estimated 270 fewer AMI deaths per year. These results add to the evidence suggesting that smoke-free air laws are associated with lower rates of AMI.

Drug seeking and the vulnerability to relapse occur when individuals are exposed to an environment with sensory cues in which drug taking has occurred. Memory formation is thought to require plasticity in synaptic circuits, and so we examined whether the memory for a drug-paired environment correlates with changes in the synaptic circuits of the basolateral amygdala (BLA), in which emotional learning is a recognized phenomenon. We used amphetamine (AMPH) as the unconditioned stimulus in the conditioned place preference (CPP) paradigm. Rats were conditioned with 1.0 mg/kg AMPH and tested, drug free, 72 h after the last conditioning session. Controls included a saline-conditioned group and a home cage AMPH injection group, whose exposure to the CPP apparatus was delayed by 4 h, long enough to clear the AMPH from the brain. We counted excitatory synapses in the BLA using the electron microscope and the physical disector design (stereology). Rats that expressed AMPH CPP had an increase in excitatory synapses compared with controls. Excitatory synaptic activity was measured using in vivo intracellular recordings from the BLA in anesthetized rats. We found that AMPH CPP, but not drug alone, increased measures of synaptic drive, including the frequency of synaptic events, and the paired-pulse ratio of synaptic inputs to BLA pyramidal neurons. The in vivo findings suggest that the increase in BLA neuronal excitatory drive reflects the change in excitatory synapse number. Thus, context-drug associations are accompanied by structural and functional plasticity in the BLA, findings that have important implications for drug-seeking behavior.

Objectives: We assessed the prospective impact of individual, social-normative, and policy predictors of quit attempts and smoking cessation among Massachusetts adults., Methods: We interviewed a representative sample of current and recent smokers in Massachusetts by telephone in 2001 through 2002 and then again twice at 2-year intervals. The unit of analysis was the 2-year transition from wave 1 to wave 2 and from wave 2 to wave 3. Predictors of quit attempts and abstinence of longer than 3 months were analyzed using multilevel analysis. Predictors included individual, social-normative, and policy factors., Results: Multivariate analyses of 2-year transitions showed that perceptions of strong antismoking town norms were predictive of abstinence (odds ratio = 2.06; P < .01). Household smoking bans were the only policy associated with abstinence, but smoking bans at one's worksite were significant predictors of quit attempts., Conclusions: Although previous research showed a strong relation between local policy and norms, we found no observable, prospective impact of local policy on smoking cessation over 2 years. Our findings provide clear support for the importance of strong antismoking social norms as a facilitator of smoking cessation.

Rationale: The affective aspects of D: -amphetamine (AMPH) may be mediated, in part, by cocaine- and amphetamine-regulated transcript (CART) peptides in the basolateral amygdala (BLA). The formation of context-drug associations produces either conditioned place preference (CPP) or conditioned place aversion (CPA)., Objectives: The aim of the present study was to determine whether intra-BLA infusions of CART 55-102 are either rewarding or aversive and modulate AMPH reward., Materials and Methods: Rats were implanted with bilateral cannulae in the BLA, were subjected to place conditioning, and were tested for CPP or CPA. Rats were conditioned with either intra-BLA infusions of artificial cerebral spinal fluid or one of three dose of CART 55-102 (1, 2, or 4 microg/side), intra-BLA infusions of a subrewarding dose of CART 55-102 (1 microg/side) plus injections of a subrewarding dose of AMPH (0.1 mg/kg, i.p.), or intra-BLA infusions of an aversive dose of CART 55-102 (4 microg/side) plus injections of a rewarding dose of AMPH (1.0 mg/kg, i.p.)., Results: Intra-BLA infusions of 2 microg/side CART 55-102 produced CPP, 4 microg/side produced CPA, and 1 microg/side produced neither CPP nor CPA. Intra-BLA infusions of a subrewarding dose of CART 55-102 (1 microg/side) plus injections of a subrewarding dose of AMPH (0.1 mg/kg, i.p.) produced CPP. Intra-BLA infusions of an aversive dose of CART 55-102 (4 microg/side) plus injections of a rewarding dose of AMPH (1.0 mg/kg, i.p.) produced neither CPP nor CPA., Conclusions: Both the affective properties of intra-BLA CART 55-102 and its ability to either facilitate or block AMPH reward are dose dependent.

Thermotolerance involves more than life or death. Investigating the complexity of this trait will aid identification of its genetic contributors. We examined variation in thermally stressed walking behavior and performance in natural Drosophila melanogaster strains and strains mutant for the heat shock protein Hsp70, to determine which aspects of locomotion are affected by heat shock and genotype. We developed software for the large-scale capture, analysis, and visualization of locomotion, and determined: (1) Heat shock and thermal pretreatment significantly and differentially impact fly locomotor behavior and performance. (2) Stressed locomotion traits vary extensively among natural strains. (3) Interactions among treatments, strains, and traits are substantial and often counterintuitive. (4) Hsp70 overexpressing flies are faster and more basally thermoprotected in performance than Hsp70 null flies, but null flies are more unidirectional. (5) Natural variation in most stressed locomotion traits exceeds that caused by Hsp70 mutation, reveals uncoupling between thermoprotection of behavior and performance, and suggests significant genetic variation for trait-specific modifiers of thermotolerance.

Purpose: To evaluate the cost effectiveness of minimally invasive therapy relative to medical (alpha-blocker) therapy and transurethral resection (TURP) for patients with moderate to severe symptoms of benign prostatic hyperplasia (BPH)., Methods: We constructed a decision-analytic Markov model for a hypothetical cohort of 65-year-old men with moderate to severe BPH symptoms. Microwave thermotherapy was selected to represent minimally invasive treatment. Cost-effectiveness analysis was performed with 25 health states using the 3 treatments, 5 short-term clinical events, and 17 possible long-term outcomes. Each health state had an associated cost and utility. Quality of life (QoL) and utility estimates were obtained by interviewing 13 men with BPH symptoms using the standard gamble reference methods. Patients were classified as risk averse (RA) or non-risk averse (NRA) on the basis of their attitudes to risk. We calculated the incremental cost effectiveness of microwave thermotherapy relative to medical therapy and TURP over 5 years after treatment initiation. Event probabilities were obtained from the literature, a consensus panel, and published randomized clinical trials., Results and Conclusions: The utility values generated were internally consistent and externally valid for a hypothetical cohort of 10,000 RA patients. Microwave thermotherapy was preferred by the NRA group, while medical therapy was preferred by the RA group. Surgery was least preferred by both groups. Microwave thermotherapy had a small incremental cost but improved QoL in comparison with medical therapy. Microwave thermotherapy had a higher utility and lower cost than TURP and thus was dominant over TURP. This analytical method can be applied to evaluate the cost effectiveness of any BPH therapy.

We compared medical resource use and costs among rheumatoid arthritis (RA) patients receiving alternative disease-modifying antirheumatic drugs (DMARDs). The cohort study used data from a managed care organization. Health plan members who were prescribed DMARD therapy for at least 2 consecutive months, were age 18 years or older, had at least 6 months of DMARD-free enrollment prior to the first DMARD, and had a diagnosis of RA before or during the first month of DMARD were eligible. Median duration of initial DMARD therapy was 10 months overall: 11 months for hydroxychloroquine (n = 252), 15 months for methotrexate (n = 185), 5 months for sulfasalazine (n = 49), and 5 months for other mono/combination therapy (n = 85) (p < 0.0001). The average monthly cost of care was $853, of which $294 (34%) was for RA-coded medical services. In multivariate analyses, monthly RA-coded costs varied significantly by initial DMARD. RA costs and duration of initial therapy varied significantly by initial DMARD.

Objectives: To evaluate the cost effectiveness of transurethral microwave thermotherapy relative to medical therapy (alpha-blocking agents) and transurethral resection of the prostate (TURP) for patients with moderate-to-severe benign prostatic hyperplasia (BPH) symptoms., Methods: A cost-effectiveness analysis was performed from the societal perspective for a hypothetical cohort of 65-year-old men with moderate-to-severe BPH symptoms. We calculated the incremental cost effectiveness of thermotherapy relative to medical therapy and TURP during 5 years after treatment initiation. Event probabilities were obtained from published reports, a consensus panel, and the Targis System (Urologix) randomized clinical trial. Costs were estimated using the national Medicare reimbursement schedules. Costs are reported in 1999 U.S. dollars. Total thermotherapy procedure costs were estimated at $2629. Quality-of-life and utility estimates were obtained by interviewing 13 patients with moderate-to-severe BPH symptoms. On the basis of their risk attitudes, patients were classified into risk-averse or non-risk-averse groups. The costs and health effects were discounted at 3% annually., Results: In a hypothetical cohort of 10,000 non-risk-averse patients who were candidates for all three modalities, the 5-year costs were highest for patients undergoing TURP and lowest for those receiving medical therapy ($7334 and $6294, respectively). The thermotherapy group exhibited the highest 5-year utility value (53.52 quality-adjusted life-months). Compared with medical therapy, thermotherapy resulted in an additional 0.23 quality-adjusted life-months, with an incremental cost of $741. This yielded an incremental cost per quality-adjusted life-year gained of $38,664 for thermotherapy compared with medical therapy. Thermotherapy had a higher utility (difference of 1.71 quality-adjusted life-months) and lower cost (difference of $299) compared with TURP and thus was dominant over TURP. The results were similar for a hypothetical cohort of 10,000 risk-averse patients., Conclusions: From a societal perspective, thermotherapy appears to be a reasonable and cost-effective alternative to both medical and surgical treatment. However, the actual treatment decision should be based on multiple factors, only one of which is cost effectiveness.

Objectives: To present the method used to evaluate the cost effectiveness, from the societal perspective, of transurethral microwave thermotherapy relative to medical therapy (alpha-blocking agents) and transurethral resection of the prostate (TURP) for a hypothetical cohort of 65-year-old men with moderate-to-severe benign prostatic hyperplasia (BPH) symptoms., Methods: We constructed a decision-analytic Markov model with 25 health states describing the 3 treatments, 5 short-term clinical events, and 17 possible long-term outcomes. Each health state had an associated cost and utility. Utility weights, reflecting an individual's preference for a specific health outcome, range from 0, indicating death, to 100, indicating perfect health. Utility estimates were obtained by interviewing 13 men with moderate-to-severe BPH symptoms using the standard gamble preference measurement technique. On the basis of their risk attitudes, the patients were classified as risk averse or non-risk averse. The rates of remission, temporary and permanent adverse events, retreatment, and mortality were obtained from the Targis System (Urologix) randomized clinical trial, published reports, and a consensus panel. The costs during the 5 years after treatment initiation were estimated using national Medicare reimbursement schedules. The costs are reported in 1999 U.S. dollars., Results: Eliciting utility values from patients with BPH was feasible and generated internally consistent and externally valid measures. In the non-risk-averse group, the utility value for significant remission, moderate remission, no remission, and worsening BPH symptoms without an adverse event was 99.1, 97.1, 94.4, and 87.3, respectively. As expected, the risk-averse individuals (n = 6) exhibited higher utility values than those in the non-risk-averse group (n = 7). In the non-risk-averse group, thermotherapy was the preferred treatment, and in the risk-averse group, medical therapy was preferred. In both groups, TURP was the least preferred therapy. The initial thermotherapy procedure costs without complications were estimated at $2629, and the initial TURP procedure costs without complications were estimated at $4597. Time-dependent probabilities were developed to reflect treatment durability., Conclusions: The resulting model parameters appear to be suitable for evaluating the cost effectiveness of thermotherapy relative to medical therapy and TURP in 65-year-old men with moderate-to-severe BPH symptoms.

Objective: To identify costs among rheumatoid arthritis (RA) patients receiving alternative disease-modifying antirheumatic drug (DMARD) therapies., Methods: Using managed care organization data, we identified members who (a) were prescribed any DMARD therapy for two consecutive months between July 1993 and February 1998, (b) were aged > or = 18 years, (c) had > or = 6 months of DMARD-free enrollment prior to the first DMARD, and (d) had a diagnosis of RA., Results: The average age of the cohort (n = 571) was 51 years, and 70% were women. Mean duration of enrollment following initiation of DMARD therapy (observation period) was 19.5 months; 28.8% of patients switched DMARD regimens. The average monthly cost of care was $853, of which $294 (34%) was for RA-coded medical services. Monthly RA-coded costs varied by DMARD: hydroxychloroquine $227 (n = 252), methotrexate $340 (n = 185); sulfasalazine $233 (n = 49), and other mono/combination therapy $425 (n = 85) (P = 0.001)., Conclusion: Costs of RA-coded care in patients receiving DMARDs are low and vary by DMARD.

Background: We compared patterns of medical resource utilization and costs among patients receiving a serotonin-norepinephrine reuptake inhibitor (venlafaxine), one of the selective serotonin reuptake inhibitors (SSRIs), one of the tricyclic agents (TCAs), or 1 of 3 other second-line therapies for depression., Method: Using claims data from a national managed care organization, we identified patients diagnosed with depression (ICD-9-CM criteria) who received second-line antidepressant therapy between 1993 and 1997. Second-line therapy was defined as a switch from the first class of antidepressant therapy observed in the data set within 1 year of a diagnosis of depression to a different class of antidepressant therapy. Patients with psychiatric comorbidities were excluded., Results: Of 981 patients included in the study, 21% (N = 208) received venlafaxine, 34% (N = 332) received an SSRI, 19% (N = 191) received a TCA, and 25% (N = 250) received other second-line antidepressant therapy. Mean age was 43 years, and 72% of patients were women. Age, prescriber of second-line therapy, and prior 6-month expenditures all differed significantly among the 4 therapy groups. Total, depression-coded, and non-depression-coded 1-year expenditures were, respectively, $6945, $2064, and $4881 for venlafaxine; $7237, $1682, and $5555 for SSRIs; $7925, $1335, and $6590 for TCAs; and $7371, $2222, and $5149 for other antidepressants. In bivariate analyses, compared with TCA-treated patients, venlafaxine- and SSRI-treated patients had significantly higher depression-coded but significantly lower non-depression-coded expenditures. Venlafaxine was associated with significantly higher depression-coded expenditures than SSRIs. However, after adjustment for potential confounding covariables in multivariate analyses, only the difference in depression-coded expenditures between SSRI and TCA therapy remained significant., Conclusion: After adjustment for confounding patient characteristics, 1-year medical expenditures were generally similar among patients receiving venlafaxine, SSRIs, TCAs, and other second-line therapies for depression. Observed differences in patient characteristics and unadjusted expenditures raise questions as to how different types of patients are selected to receive alternative second-line therapies for depression.

Selective rubella vaccination of schoolgirls commenced in 1971 and was followed by a significant reduction in congenital rubella. Infant vaccination with MMR was introduced in 1989 to interrupt circulation of the virus in young children, and in 1994/95 the adolescent school based rubella vaccination program was changed to MMR for both boys and girls. This report reviews the epidemiology of rubella and congenital rubella between 1992 and 1997 using reports to the National Notifiable Diseases Surveillance System (NNDSS) and the Australian Paediatric Surveillance Unit (APSU). Notification rates for rubella exceeded 20 per 100,000 in 1992, 1993 and 1995 and declined to 7.2 per 100,000 in 1997. Sixty-one per cent of notifications occurred between September and December and 68% occurred in males. The incidence rate in males aged 15-22 years peaked at 152.6 per 100,000 in 1995 reflecting the lack of immunisation in this cohort. From 1993 to 1997, 19 children were reported with congenital rubella syndrome, representing 1 in 67,000 live births. Of these, 17 had multiple defects (4 died) and 2 had deafness only. There were also 5 infants with congenital rubella infection but no defects. Australia's rate of congenital rubella syndrome exceeded that of the United Kingdom and the United States of America but this may be partly attributable to differences in reporting practices. The impact of changing the second dose of MMR vaccine to 4 years of age in 1998 will require careful monitoring.

Expression cloning from a cDNA library prepared from a mutant CHO cell line with Golgi-specific resistance to Brefeldin A (BFA) identified a novel 206-kD protein with a Sec7 domain termed GBF1 for Golgi BFA resistance factor 1. Overexpression of GBF1 allowed transfected cells to maintain normal Golgi morphology and grow in the presence of BFA. Golgi- enriched membrane fractions from such transfected cells displayed normal levels of ADP ribosylation factors (ARFs) activation and coat protein recruitment that were, however, BFA resistant. Hexahistidine-tagged-GBF1 exhibited BFA-resistant guanine nucleotide exchange activity that appears specific towards ARF5 at physiological Mg2+concentration. Characterization of cDNAs recovered from the mutant and wild-type parental lines established that transcripts in these cells had identical sequence and, therefore, that GBF1 was naturally BFA resistant. GBF1 was primarily cytosolic but a significant pool colocalized to a perinuclear structure with the beta-subunit of COPI. Immunogold labeling showed highest density of GBF1 over Golgi cisternae and significant labeling over pleiomorphic smooth vesiculotubular structures. The BFA-resistant nature of GBF1 suggests involvement in retrograde traffic.

Objective: An analysis of administrative and claims data was performed to compare the resource use and costs to a managed-care organisation of venlafaxine, a serotonin and norepinephrine reuptake inhibitor (SNRI), versus tricyclic antidepressant (TCA) therapy, after switching from a selective serotonin reuptake inhibitor (SSRI)., Design: One-year costs and frequencies of all medical services, and of services coded for depression, were compared between patients who received venlafaxine and TCA therapy as second-line therapy using bivariate and multivariate statistical analyses., Setting: Data were obtained from 9 individual health plans with more than 1.1 million covered lives affiliated with a national managed-care organisation., Patients and Participants: Health plan members were included if they had a diagnosis of depression between July 1993 and February 1997. They also had to have at least 2 months of prescriptions for SSRI therapy followed by at least 2 months of venlafaxine or TCA therapy, and continuous enrollment in the plan from at least 6 months prior to 12 months following initiation of venlafaxine or TCA therapy. 188 patients who received venlafaxine and 172 patients who received TCAs met the inclusion criteria., Main Outcome Measures and Results: Patients who received TCAs were slightly but significantly older (43 vs 40 years) than venlafaxine recipients and, during 6 months prior to initiating therapy, had significantly higher mean costs coded for depression ($US451 vs $US311) and costs not coded for depression ($US4500 vs $US2090). Psychiatrists prescribed a significantly higher proportion of venlafaxine than TCA prescriptions (46.3 vs 25.0%). Prior to adjusting for confounding characteristics, during 12 months following initiation of therapy, mean depression-coded costs were significantly higher for venlafaxine than TCA recipients ($US1948 vs $US1396) and mean costs not coded for depression were significantly lower ($US4595 vs $US6677). Overall costs were not significantly different ($US6543 for venlafaxine vs $US8073 for TCA). Significant cost differences were observed with primary care physicians as initial prescribers of second-line therapy but not with psychiatrists. However, costs between the 2 groups were similar after adjusting for confounding variables, including prior 6-month costs and initial prescriber of second-line therapy., Conclusions: Payer costs are similar among patients receiving venlafaxine and TCA therapy following SSRI therapy. Higher costs of venlafaxine pharmacotherapy relative to TCA therapy may be offset by lower costs of other medical services. Differences in prescribing patterns and costs between primary care physicians and psychiatrists warrant further investigation.

Objective: Amyotrophic lateral sclerosis (ALS) is a fatal, degenerative neuromuscular disease characterised by a progressive loss of voluntary motor activity. Recombinant human insulin-like growth factor I (rhIGF-I) has been shown to be useful in treating ALS. The purpose of this study was to examine the cost effectiveness of rhIGF-I therapy in patients who have ALS., Design: We performed a cost-effectiveness analysis from the societal perspective on 177 patients who received treatment with rhIGF-I or placebo in a North American randomised clinical trial. We estimated the incremental cost-effectiveness ratio of rhIGF-I using resource utilisation and functional status measurements from the clinical trial. Costs were estimated from 1996 US Medicare reimbursement schedules. Utility weights were elicited from ALS healthcare providers using the standard gamble technique., Main Outcome Measures and Results: The overall cost per quality-adjusted life-year (QALY) gained for rhIGF-I therapy compared with placebo was $US67,440. For the subgroups of patients who were progressing rapidly or were in earlier stages of disease at enrolment, rhIGF-I cost $US52,823 and $US43,197 per QALY gained, respectively., Conclusions: Treatment with rhIGF-I is most cost effective in ALS patients who are either in earlier stages of the disease or progressing rapidly. The cost effectiveness of rhIGF-I therapy compares favourably with treatments for other chronic progressive diseases.