Two-sample Mendelian randomization study does not reveal a significant relationship between cytomegalovirus (CMV) infection and autism spectrum disorder.

BACKGROUND: Autism spectrum disorder (ASD) is a neurodevelopmental disorder affecting ~ 2% of children worldwide and is characterized by repetitive, stereotypical behaviours and impaired expressive communication. Cytomegalovirus (CMV) is considered a risk factor for ASD; however, published studies are usually limited by covering too few events and have different conclusions, indicating that the relationship between CMV infection and ASD remains elusive. METHODS: To investigate the association between CMV infection and ASD, we conducted this 2-sample Mendelian randomization (MR) study using genome-wide association studies (GWAS) summary data from FinnGen and the IEU Open GWAS project. RESULTS: Our results showed no significant relationship between all 3 CMV infections (unspecified cytomegaloviral diseases, anti-CMV IgG levels, and maternal CMV) and ASD. CONCLUSIONS: Our results indicate that CMV infection does not significantly increase ASD risk. These results show that the relationship between CMV infection and ASD remains elusive and needs to be further clarified.

Alirocumab in patients with heterozygous familial hypercholesterolaemia undergoing lipoprotein apheresis: the ODYSSEY ESCAPE trial.

AIM: To evaluate the effect of alirocumab on frequency of standard apheresis treatments [weekly or every 2 weeks (Q2W)] in heterozygous familial hypercholesterolaemia (HeFH). METHODS AND RESULTS: ODYSSEY ESCAPE (NCT02326220) was a double-blind study in 62 HeFH patients undergoing regular weekly or Q2W lipoprotein apheresis. Patients were randomly assigned (2:1, respectively) to receive alirocumab 150 mg (n = 41) or placebo (n = 21) Q2W subcutaneously for 18 weeks. From day 1 to week 6, apheresis rate was fixed according to the patient's established schedule; from weeks 7 to 18, apheresis rate was adjusted based on the patient's low-density lipoprotein cholesterol (LDL-C) response in a blinded fashion. Apheresis was not performed when the LDL-C value was ≥30% lower than the baseline (pre-apheresis) value. The primary efficacy endpoint was the rate of apheresis treatments over 12 weeks (weeks 7-18), standardized to number of planned treatments. In the alirocumab group the least square (LS) mean ± SE (95% confidence interval [CI]) per cent change in pre-apheresis LDL-C from baseline at week 6 was -53.7 ± 2.3 (-58.2 to - 49.2) compared with 1.6 ± 3.1 (-4.7 to 7.9) in the placebo group. The primary efficacy endpoint showed statistically significant benefit in favour of alirocumab (Hodges-Lehmann median estimate of treatment difference: 0.75; 95% CI 0.67-0.83; P < 0.0001). Therefore, alirocumab-treated patients had a 0.75 (75%) additional reduction in the standardized rate of apheresis treatments vs. placebo-treated patients. During this period, 63.4% of patients on alirocumab avoided all and 92.7% avoided at least half of the apheresis treatments. Adverse event rates were similar (75.6% of patients on alirocumab vs. 76.2% on placebo). CONCLUSIONS: Lipoprotein apheresis was discontinued in 63.4% of patients on alirocumab who were previously undergoing regular apheresis, and the rate was at least halved in 92.7% of patients. Alirocumab was generally safe and well tolerated.

Effect of a monoclonal antibody to PCSK9 on LDL cholesterol.

BACKGROUND: Proprotein convertase subtilisin/kexin 9 (PCSK9), one of the serine proteases, binds to low-density lipoprotein (LDL) receptors, leading to their accelerated degradation and to increased LDL cholesterol levels. We report three phase 1 studies of a monoclonal antibody to PCSK9 designated as REGN727/SAR236553 (REGN727). METHODS: In healthy volunteers, we performed two randomized, single ascending-dose studies of REGN727 administered either intravenously (40 subjects) or subcutaneously (32 subjects), as compared with placebo. These studies were followed by a randomized, placebo-controlled, multiple-dose trial in adults with heterozygous familial hypercholesterolemia who were receiving atorvastatin (21 subjects) and those with nonfamilial hypercholesterolemia who were receiving treatment with atorvastatin (30 subjects) (baseline LDL cholesterol, >100 mg per deciliter [2.6 mmol per liter]) or a modified diet alone (10 subjects) (baseline LDL cholesterol, >130 mg per deciliter [3.4 mmol per liter]). REGN727 doses of 50, 100, or 150 mg were administered subcutaneously on days 1, 29, and 43. The primary outcome for all studies was the occurrence of adverse events. The principal secondary outcome was the effect of REGN727 on the lipid profile. RESULTS: Among subjects receiving REGN727, there were no discontinuations because of adverse events. REGN727 significantly lowered LDL cholesterol levels in all the studies. In the multiple-dose study, REGN727 doses of 50, 100, and 150 mg reduced measured LDL cholesterol levels in the combined atorvastatin-treated populations to 77.5 mg per deciliter (2.00 mmol per liter), 61.3 mg per deciliter (1.59 mmol per liter), and 53.8 mg per deciliter (1.39 mmol per liter), for a difference in the change from baseline of -39.2, -53.7, and -61.0 percentage points, respectively, as compared with placebo (P<0.001 for all comparisons). CONCLUSIONS: In three phase 1 trials, a monoclonal antibody to PCSK9 significantly reduced LDL cholesterol levels in healthy volunteers and in subjects with familial or nonfamilial hypercholesterolemia. (Funded by Regeneron Pharmaceuticals and Sanofi; ClinicalTrials.gov numbers, NCT01026597, NCT01074372, and NCT01161082.).

Discovery of Novel 5,6-Dihydro-4H-pyrido[2,3,4-de]quinazoline Irreversible Inhibitors Targeting Both Wild-Type and A775_G776insYVMA Mutated HER2 Kinases.

HER2 mutations were seen in 4% of non-small-cell lung cancer (NSCLC) patients. Most of these mutations (90%) occur as an insertion mutation within the exon 20 frame, leading to the downstream activation of the PI3K-AKT and RAS/MAPK pathways. However, no targeted therapies have yet been approved worldwide. Here a novel series of highly potent HER2 inhibitors with a pyrido[2,3,4-de]quinazoline core were designed and developed. The derivatives with the pyrido[2,3,4-de]quinazoline core displayed superior efficacy of antiproliferation in BaF3 cells harboring HER2insYVMA mutation compared with afatinib and neratinib. Rat studies showed that 8a and 9a with the newly developed core have good pharmacokinetic properties with an oral bioavailability of 41.7 and 42.0%, respectively. Oral administration of 4a and 10e (30 mg/kg, QD) displayed significant antitumor efficacy in an in vivo xenograft model. We proposed promising strategies for the development of HER2insYVMA mutant inhibitors in this study.

Occurrence and Distribution of Tetrabromobisphenol A and Diversity of Microbial Community Structure in the Sediments of Mangrove.

The occurrence and distribution characteristics of tetrabromobisphenol A (TBBPA) and its relationship with microbial community diversity in different mangrove sediments need further investigation. The results of this study indicated levels of TBBPA in mangrove sediments from the Zhangjiang Estuary (ZJ), Jiulongjiang Estuary (JLJ), and Quanzhou Bay (QZ) in Southeast China ranging from 1.80 to 20.46, 3.47 to 40.77, and 2.37 to 19.83 ng/g dry weight (dw), respectively. Mangrove sediments from JLJ contained higher levels of TBBPA, possibly due to agricultural pollution. A correlation analysis revealed a significant correlation between total organic carbon (TOC), total nitrogen (TN), and TBBPA distribution in ZJ and JLJ mangrove sediments, but not in QZ mangrove sediments. TOC significantly affected the distribution of TBBPA in mangrove sediments, but pH had no effect. High-throughput 16S rRNA gene sequencing showed that Pseudomonadota dominated the sediment bacteria followed by Chloroflexota, Actinobacteota, Bacillota, Acidobacteriota, Bacteroidota, and Aminicenantes in mangrove sediments. Although the microbial community structure of the ZJ, JLJ, and QZ mangrove sediments was similar, the taxonomic profile of their sensitive responders differed markedly. The genus Anaerolinea was dominant in the mangrove sediments and was responsible for the in situ dissipation of TBBPA. Based on redundancy analysis, there was a correlation between TBBPA, TOC, TN, C/N, pH, and microbial community structure at the genus level. Combining TBBPA, TN, and TOC may induce variations in the microbial community of mangrove sediments.

Effects of a school-based intervention for urban adolescents with asthma. A controlled trial.

RATIONALE: Asthma prevalence and morbidity are especially elevated in adolescents, yet few interventions target this population. OBJECTIVES: To test the efficacy of Asthma Self-Management for Adolescents (ASMA), a school-based intervention for adolescents and medical providers. METHODS: Three hundred forty-five primarily Latino/a (46%) and African American (31%) high school students (mean age = 15.1 yr; 70% female) reporting an asthma diagnosis, symptoms of moderate to severe persistent asthma, and asthma medication use in the last 12 months were randomized to ASMA, an 8-week school-based intervention, or a wait-list control group. They were followed for 12 months. MEASUREMENTS AND MAIN RESULTS: Students completed bimonthly assessments. Baseline, 6-month, and 12-month assessments were comprehensive; the others assessed interim health outcomes and urgent health care use. Primary outcomes were asthma self-management, symptom frequency, and quality of life (QOL); secondary outcomes were asthma medical management, school absences, days with activity limitations, and urgent health care use. Relative to control subjects, ASMA students reported significantly: more confidence to manage their asthma; taking more steps to prevent symptoms; greater use of controller medication and written treatment plans; fewer night awakenings, days with activity limitation, and school absences due to asthma; improved QOL; and fewer acute care visits, emergency department visits, and hospitalizations. In contrast, steps to manage asthma episodes, daytime symptom frequency, and school-reported absences did not differentiate the two groups. Most results were sustained over the 12 months. CONCLUSIONS: ASMA is efficacious in improving asthma self-management and reducing asthma morbidity and urgent health care use in low-income urban minority adolescents.

Parental perceptions toward digital imaging and telemedicine for retinopathy of prematurity management.

BACKGROUND: Telemedicine is an emerging technology with potential to improve care for retinopathy of prematurity (ROP). This study evaluates parental perceptions about digital imaging and telemedicine for ROP care. METHODS: During a 1-year period, one parent of each infant who underwent wide-field retinal imaging for ROP was given a questionnaire designed to evaluate parental perceptions using a 5-point Likert-type scale. Five items assessed perceptions toward digital retinal imaging, and ten items assessed attitudes toward telemedicine. Construct validity of the questionnaire was examined using factor analysis. Responses were summarized using descriptive and correlational statistics. RESULTS: Forty-two parents participated. Factor analysis extracted two factors explaining 79% of the total variance in digital retinal imaging items (Cronbach's alpha = 0.843), and three factors explaining 63% of the total variance in telemedicine items (Cronbach's alpha = 0.631). Among digital imaging items, the highest mean (+/-SD) score was for "digital pictures of my child's retinopathy should be included in the permanent medical record" (4.4 +/- 0.6), and the lowest was for "digital cameras and computers are reliable" (3.8 +/- 0.8). Among telemedicine items, the highest mean (+/-SD) score was for "technology will improve the quality of medical care for my child" (4.3 +/- 0.6), and the lowest was for "technology will make it harder for a patient and doctor to establish a good relationship" (2.6 +/- 1.1). CONCLUSIONS: Parents reported positive perceptions about telemedical ROP diagnosis, but expressed some preference for face-to-face care. Telemedicine has potential to alter the nature of the patient-physician relationship.

Typical variations of subthalamic electrode location do not predict limb motor function improvement in Parkinson's disease.

Deep brain stimulation (DBS) of the subthalamic nucleus (STN) is an effective treatment for patients with medically refractory Parkinson's disease (PD). The degree to which the anatomic location of the DBS electrode tip determines the improvement of contralateral limb movement function has not been defined. This retrospective study was performed to address this issue. Forty-two DBS electrode tips in 21 bilaterally implanted patients were localized on postoperative MRI. The postoperative and preoperative planning MRIs were merged with the Stealth FrameLink 4.0 stereotactic planning workstation (Medtronic Inc., Minneapolis, MN, USA) to determine the DBS tip coordinates. Stimulation settings were postoperatively optimized for maximal clinical effect. Patients were videotaped 1 year postoperatively and assessed by a movement disorder neurologist blinded to electrode tip locations. The nine limb-related components of the Unified PD Rating Scale Part III were tabulated to obtain a limb score, and the electrode tip locations associated with the 15 least and 15 greatest limb scores were evaluated. Two-tailed t-tests revealed no significant difference in electrode tip location between the two groups in three-dimensional distance (p=0.759), lateral-medial (x) axis (p=0.983), anterior-posterior (y) axis (p=0.949) or superior-inferior (z) axis (p=0.894) from the intended anatomical target. The range of difference in tip location and limb scores was extensive. Our results suggest that anatomic targeting alone may provide the same clinical efficacy as is achieved by "fine-tuning" DBS placement with microelectrode recording to a specific target.

Retinopathy of prematurity management using single-image vs multiple-image telemedicine examinations.

PURPOSE: To compare performance of single-image vs multiple-image telemedicine examinations for retinopathy of prematurity (ROP) diagnosis. DESIGN: Prospective comparative study. METHODS: A total of 248 eyes from 67 consecutive infants underwent wide-angle retinal imaging by a trained neonatal nurse at 31 to 33 weeks and/or 35 to 37 weeks postmenstrual age (PMA) at a single academic institution. Data were uploaded to a web-based telemedicine system and interpreted by three masked retinal specialists. Diagnoses were provided based on single images, and subsequently on multiple images, from both eyes of each infant. Findings were compared to a reference standard of indirect ophthalmoscopy by a pediatric ophthalmologist. Primary outcome measures were recommended follow-up interval, presence of plus disease, presence of type-2 or worse ROP, and presence of visible peripheral ROP. RESULTS: Among the three graders, mean sensitivity/specificity for detection of infants requiring follow-up in less than one week were 0.85/0.93 by single-image examination and 0.91/0.88 by multiple-image examination at 35 to 37 weeks PMA. Mean sensitivity/specificity for detection of infants with type-2 or worse ROP were 0.82/0.95 by single-image examination and 1.00/0.91 by multiple-image examination at 35 to 37 weeks PMA. Mean sensitivity/specificity for detection of plus disease were 1.00/0.86 by single-image examination and 1.00/0.87 by multiple-image examination at 35 to 37 weeks PMA. There were no statistically-significant intragrader differences between accuracy of single-image and multiple-image telemedicine examinations for detection of plus disease. CONCLUSIONS: Single-image and multiple-image telemedicine examinations perform comparably for determination of recommended follow-up interval and detection of plus disease. This may have implications for development of screening protocols, particularly in areas with limited access to ophthalmic care.

Patient experience in a randomized trial of a weekly progesterone vaginal ring versus a daily progesterone gel for luteal support after in vitro fertilization.

OBJECTIVE: To assess patient experience and convenience of using progesterone vaginal ring (VR) versus vaginal gel for women requiring luteal phase support during in vitro fertilization (IVF). DESIGN: Post hoc analysis of a prospective, randomized, single-blind, multicenter, phase 3 clinical trial. SETTING: Twenty-two U.S. IVF centers. PATIENT(S): Women undergoing IVF (N = 1,297). INTERVENTION(S): Randomization to weekly VR or daily gel the day after egg retrieval for up to 10 weeks, with fresh embryo transfer IVF per site-specific procedures. MAIN OUTCOME MEASURE(S): Patient satisfaction questionnaire completed at final study visit. RESULT(S): In the women who were taking ≥1 dose of either VR (n = 647) or gel (n = 650), >97% reported that learning to use the formulation, remembering to take it at the correct time, and using it as prescribed was "easy" or "somewhat easy." More VR than gel users reported noninterference with daily activity (93.3% vs. 74.7%, P<.001), sexual comfort (80.3% vs. 67.8%, P<.001), and sexual desire (73.8% vs. 61.8%, P<.001), as well as not being bothered during sexual intercourse (66.9% vs. 39.2%, P<.001). More gel than VR users reported no difficulty with application (97.4% vs. 80.9%, P<.001). Among women who had previously used progesterone during IVF, more VR users than gel users preferred their currently assigned treatment to their previous treatment (91.4% vs. 83.0%, P=.03). CONCLUSION(S): Weekly progesterone VR and daily progesterone gel were easy to use, with limited impact on quality of life. Overall, the VR appeared to interfere less with daily life, social activities, and sexual activity although the gel was less difficult or stressful to apply. CLINICAL TRIAL REGISTRATION NUMBER: NCT00615251.

Interexpert agreement of plus disease diagnosis in retinopathy of prematurity.

OBJECTIVE: To measure agreement of plus disease diagnosis among retinopathy of prematurity (ROP) experts. METHODS: A set of 34 wide-angle retinal photographs from infants with ROP was compiled on a secure Web site and was interpreted independently by 22 recognized ROP experts. Diagnostic agreement was analyzed using 3-level (plus, pre-plus, or neither) and 2-level (plus or not plus) categorizations. RESULTS: In the 3-level categorization, all experts agreed on the same diagnosis in 4 of 34 images (12%), and the mean weighted kappa statistic for each expert compared with all others was between 0.21 and 0.40 (fair agreement) for 7 experts (32%) and between 0.41 and 0.60 (moderate agreement) for 15 experts (68%). In the 2-level categorization, all experts who provided a diagnosis agreed in 7 of 34 images (21%), and the mean kappa statistic for each expert compared with all others was between 0 and 0.20 (slight agreement) for 1 expert (5%), between 0.21 and 0.40 (fair agreement) for 3 experts (14%), between 0.41 and 0.60 (moderate agreement) for 12 experts (55%), and between 0.61 and 0.80 (substantial agreement) for 6 experts (27%). CONCLUSIONS: Interexpert agreement of plus disease diagnosis is imperfect. This may have important implications for clinical ROP management, continued refinement of the international ROP classification system, development of computer-based diagnostic algorithms, and implementation of ROP telemedicine systems.

Telemedical retinopathy of prematurity diagnosis: accuracy, reliability, and image quality.

OBJECTIVE: To prospectively measure accuracy, reliability, and image quality of telemedical retinopathy of prematurity (ROP) diagnosis. METHODS: Two-hundred forty-eight eyes from 67 consecutive infants underwent wide-angle retinal imaging by a trained neonatal nurse at 31 to 33 weeks' and/or 35 to 37 weeks' postmenstrual age (PMA) using a standard protocol. Data were uploaded to a Web-based telemedicine system and interpreted by 3 expert retinal specialist graders who provided a diagnosis (no ROP, mild ROP, type 2 prethreshold ROP, treatment-requiring ROP) and an evaluation of image quality for each eye. Findings were compared with a reference standard of indirect ophthalmoscopy by an experienced pediatric ophthalmologist. RESULTS: At 35 to 37 weeks' PMA, sensitivity and specificity for diagnosis of mild or worse ROP were 0.908 and 1.000 for grader A, 0.971 and 1.000 for grader B, and 0.908 and 0.977 for grader C. Sensitivity and specificity for diagnosis of type 2 prethreshold or worse ROP were 1.000 and 0.943 for grader A, 1.000 and 0.930 for grader B, and 1.000 and 0.851 for grader C. At 35 to 37 weeks' PMA, weighted kappa for intergrader reliability was 0.791 to 0.889, and kappa for intragrader reliability for detection of type 2 prethreshold or worse ROP was 0.769 to 1.000. Image technical quality was rated as "adequate" or "possibly adequate" for diagnosis in 93.3% to 100% of eyes. CONCLUSION: A telemedicine system using nurse-captured retinal images has the potential to improve existing shortcomings of ROP management, particularly at later PMAs.

Use of written treatment plans for asthma by specialist physicians.

Few studies have addressed use of written treatment plans (WTPs) for asthma by specialist physicians. The purpose of this study is to characterize the attitudes, beliefs, and self-reported practice behaviors regarding asthma WTP use among specialist physicians. Structured interviews were conducted with pulmonologists and allergists who provide direct patient asthma care in two New York City medical centers. The interview covered five areas: (1) demographic information; (2) experiences with WTPs; (3) reported clinical practice behaviors; (4) factors influencing use of WTPs; and (5) physician-patient communication. Forty-five physicians were eligible to participate in the study. Sixty-eight percent of physicians treated adult patients while 32% were pediatric specialists. Forty-four physicians completed interviews, (response rate of 98%). Eighty-six percent indicated they use WTPs with at least some of their patients (71% of their patients had received a plan from them). Most reported handwriting plans on a blank piece of paper (66%). Most plans were symptom-based (47%) or combined symptoms with peak flow measurement (50%). Most plans supported patient autonomy. More than 80% of physicians believe the use of a WTP improves patient outcomes. The results suggest that asthma specialists in this survey utilize WTPs more frequently than reported in other studies. Physicians encourage patient autonomy and believe asthma self-management by patients improves their outcomes. Controlled studies of the efficacy of asthma management plans are needed to assess the impact of WTPs as used in clinical practice.

Organizational climate and occupational health outcomes in hospital nurses.

OBJECTIVE: The objective of this study was to determine relationships between organizational climate (OC) factors and occupational health outcomes (lost workdays, musculoskeletal injury, blood and body fluid exposures, injuries, and burnout) among hospital-based nurses. METHODS: Measures were obtained through a self-administered, anonymous survey distributed in 13 New York City hospitals. Multivariate models appropriate for clustered data were developed. These analyses controlled for nurse and employment characteristics. Independent effects of OC factors were examined. RESULTS: Surveys from 2047 predominantly registered nurses were obtained (response rate 50%). More than 75% reported lost workdays due to illness in the previous 4-month period and over one third reported experiencing some type of injury. OC factors were independently associated with injuries and measures of burnout (P < or = 0.05). CONCLUSIONS: OC is significantly associated with the health and well-being of hospital nurses.

Plus disease in retinopathy of prematurity: pilot study of computer-based and expert diagnosis.

PURPOSE: To measure accuracy of plus disease diagnosis by recognized experts in retinopathy of prematurity (ROP), and to conduct a pilot study examining performance of a computer-based image analysis system, Retinal Image multiScale Analysis (RISA). METHODS: Twenty-two ROP experts independently interpreted a set of 34 wide-angle retinal images for presence of plus disease. A reference standard diagnosis based on expert consensus was defined for each image. Images were analyzed by the computer-based system using individual and linear combinations of system parameters for arterioles and venules: integrated curvature (IC), diameter, and tortuosity index (TI). Sensitivity, specificity, and receiver operating characteristic areas under the curve (AUC) for plus disease diagnosis compared with the reference standard were determined for each expert, as well as for the computer-based system. RESULTS: Expert sensitivity ranged from 0.308 to 1.000, specificity ranged from 0.571 to 1.000, and AUC ranged from 0.784 to 1.000. Among individual computer system parameters, venular IC had highest AUC (0.853). Among all computer system parameters, the linear combination of arteriolar IC, arteriolar TI, venular IC, venular diameter, and venular TI had highest AUC (0.967), which was greater than that of 18 (81.8%) of 22 experts. CONCLUSIONS: Accuracy of ROP experts for plus disease diagnosis is imperfect. A computer-based image analysis system has potential to diagnose plus disease with high accuracy. Further research involving RISA system parameter cut-off values from this study are required to fully validate performance of this computer-based system compared with that of human experts.

Accuracy and reliability of remote retinopathy of prematurity diagnosis.

OBJECTIVE: To determine the accuracy and reliability of retinopathy of prematurity (ROP) diagnosis using remote review of digital images by 3 masked ophthalmologist readers. METHODS: An atlas was compiled of 410 retinal photographs from 163 eyes of 64 low-birth-weight infants taken using a wide-angle digital fundus camera. All the images were independently reviewed by 3 readers, and the diagnosis in each eye was classified into 1 of 4 ordinal categories: no ROP, mild ROP, type 2 prethreshold ROP, or ROP requiring treatment. Findings were compared with a reference standard of dilated indirect ophthalmoscopy with scleral depression performed by an experienced pediatric ophthalmologist. RESULTS: Sensitivities/specificities of the diagnosis of any ROP were 0.845/0.910 for the first reader, 0.816/0.955 for the second reader, and 0.864/0.493 for the third reader. Sensitivities/specificities of the diagnosis of ROP requiring treatment were 0.850/0.960 for the first reader, 0.850/0.973 for the second reader, and 0.900/0.953 for the third reader. When ROP was classified into ordinal categories, the overall weighted kappa for interreader reliability was 0.743. Intrareader reliability for detection of low-risk prethreshold ROP or worse was 100% for all readers. CONCLUSION: The accuracy, interreader reliability, and intrareader reliability of remote diagnosis of clinically relevant ROP based on digital imaging are substantial.

Using school staff to establish a preventive network of care to improve elementary school students' control of asthma.

School-based asthma interventions delivered by nonschool staff have been successful but are limited in their reach because of the cost and effort of bringing in outside educators and their inability to establish improved communication about asthma between schools, families, and primary care providers (PCPs). To address these problems, Columbia University and the New York City Department of Education and the New York City Department of Health and Mental Hygiene undertook a randomized controlled trial to test the efficacy of a comprehensive school-based asthma program. In this intervention, school nurses were trained to facilitate the establishment of a preventive network of care for children with asthma by coordinating communications and fostering relationships between families, PCPs, and school personnel. PCPs also received training regarding asthma management. There was limited support for this model. While case detection helped nurses identify additional students with asthma and nurses increased the amount of time spent on asthma-related tasks, PCPs did not change their medical management of asthma. Few improvements in health outcomes were achieved. Relative to controls, 12-months posttest intervention students had a reduction in activity limitations due to asthma (-35% vs -9%, p < .05) and days with symptoms (26% vs 39%, p = .06). The intervention had no impact on the use of urgent health care services, school attendance, or caregiver's quality of life. There were also no improvements at 24-months postintervention. We faced many challenges related to case detection, training, and implementing preventive care activities, which may have hindered our success. We present these challenges, describe how we coped with them, and discuss the lessons we learned.

Efficacy and safety of adding alirocumab to rosuvastatin versus adding ezetimibe or doubling the rosuvastatin dose in high cardiovascular-risk patients: The ODYSSEY OPTIONS II randomized trial.

OBJECTIVE: To compare lipid-lowering efficacy of adding alirocumab to rosuvastatin versus other treatment strategies (NCT01730053). METHODS: Patients receiving baseline rosuvastatin regimens (10 or 20 mg) were randomized to: add-on alirocumab 75 mg every-2-weeks (Q2W) (1-mL subcutaneous injection via pre-filled pen); add-on ezetimibe 10 mg/day; or double-dose rosuvastatin. Patients had cardiovascular disease (CVD) and low-density lipoprotein cholesterol (LDL-C) ≥70 mg/dL (1.8 mmol/L) or CVD risk factors and LDL-C ≥100 mg/dL (2.6 mmol/L). In the alirocumab group, dose was blindly increased at Week 12 to 150 mg Q2W (also 1-mL volume) in patients not achieving their LDL-C target. Primary endpoint was percent change in calculated LDL-C from baseline to 24 weeks (intent-to-treat). RESULTS: 305 patients were randomized. In the baseline rosuvastatin 10 mg group, significantly greater LDL-C reductions were observed with add-on alirocumab (-50.6%) versus ezetimibe (-14.4%; p < 0.0001) and double-dose rosuvastatin (-16.3%; p < 0.0001). In the baseline rosuvastatin 20 mg group, LDL-C reduction with add-on alirocumab was -36.3% compared with -11.0% with ezetimibe and -15.9% with double-dose rosuvastatin (p = 0.0136 and 0.0453, respectively; pre-specified threshold for significance p < 0.0125). Overall, ∼80% alirocumab patients were maintained on 75 mg Q2W. Of alirocumab-treated patients, 84.9% and 66.7% in the baseline rosuvastatin 10 and 20 mg groups, respectively, achieved risk-based LDL-C targets. Treatment-emergent adverse events occurred in 56.3% of alirocumab patients versus 53.5% ezetimibe and 67.3% double-dose rosuvastatin (pooled data). CONCLUSIONS: The addition of alirocumab to rosuvastatin provided incremental LDL-C lowering versus adding ezetimibe or doubling the rosuvastatin dose.

Alirocumab in patients with heterozygous familial hypercholesterolemia undergoing lipoprotein apheresis: Rationale and design of the ODYSSEY ESCAPE trial.

BACKGROUND: Many patients with heterozygous familial hypercholesterolemia (HeFH) fail to reach optimal low-density lipoprotein cholesterol (LDL-C) levels with available lipid-lowering medications, including statins, and require treatment using alternative methods such as lipoprotein apheresis. OBJECTIVE: To evaluate the efficacy of alirocumab 150 mg every 2 weeks (Q2W) compared with placebo in reducing the frequency of lipoprotein apheresis treatments in patients with HeFH. METHODS: ODYSSEY ESCAPE is a randomized, double-blind, placebo-controlled, parallel-group, 18-week, phase 3 study being conducted in the United States and Germany. ODYSSEY ESCAPE will evaluate the efficacy and safety of alirocumab in approximately 63 adults with HeFH undergoing regular weekly (QW; for ≥4 weeks) or Q2W (for ≥8 weeks) lipoprotein apheresis. Patients will be randomly assigned (2:1, respectively) to receive alirocumab 150 mg subcutaneously Q2W or placebo subcutaneously Q2W (both in 1-mL injections) for 18 weeks. From day 1 to week 6, the apheresis frequency will be fixed to the individual patient's established schedule (QW or Q2W); thereafter, apheresis will be performed according to the LDL-C value at that visit: apheresis will not be performed when the LDL-C value is ≥30% lower than the baseline pre-apheresis LDL-C value. The primary end point is the frequency of apheresis treatments over a 12-week period starting at week 7. DISCUSSION: The ODYSSEY ESCAPE trial will determine whether alirocumab reduces the frequency of lipoprotein apheresis in patients with HeFH.

Subthalamic stimulation for Parkinson disease: determination of electrode location necessary for clinical efficacy.

OBJECT: Deep brain stimulation (DBS) of the subthalamic nucleus (STN) performed using intraoperative microelectrode recording (MER) to adjust electrode placement has become a widely used treatment for patients with advanced Parkinson disease (PD). Few studies have been conducted to examine the location of implanted electrodes relative to the intended target, and even fewer have been undertaken to investigate the degree to which variations in the location of these electrodes impacts their clinical efficacy. This study was performed to examine these issues. METHODS: The authors located 52 bilaterally implanted DBS electrode tips on postoperative magnetic resonance (MR) images obtained in 26 consecutive patients. Postoperative and preoperative planning MR images were merged to determine the DBS electrode tip coordinates relative to the midcommissural point. Surgical records listed the intended target coordinates for each DBS electrode tip. Clinical outcome assessment included the Unified PD Rating Scale (UPDRS) motor score at 1 year, standardized questionnaires, and routine follow-up visits. The mean difference between electrode tip location and intended target for all 52 electrodes was less than 2 mm in all axes. Only one electrode was farther than 3 mm from the intended target, and this was the only electrode that had to be replaced due to lack of clinical efficacy (lack of tremor suppression); its reimplantation 4 mm more medially provided excellent tremor control. High correlation coefficients indicate that the MR imaging analysis accurately determined the anatomical location of the electrode tips. Blinded videotape reviews of UPDRS motor scores comparing effects of stimulation in patients who were "on" and "off" medication identified subgroups in whom there was minimal and maximal stimulation response. Patients in these subgroups had no differences between the MR imaging-determined actual electrode tip location and its intended location. Similarly, improvements of dyskinesias and severity of symptoms encountered during the wearing-off period for the drug did not correlate with variations of electrode tip location. CONCLUSIONS: The findings in this study lead the authors to suggest that a DBS electrode placed anywhere within a 6-mm-diameter cylinder centered at the presumed middle of the STN (based on stereotactic atlas coordinates) provides similar clinical efficacy. Future studies may be warranted to evaluate prospectively the degree to which MER modification of the anatomically and/or image-determined target improves clinical efficacy of DBS electrodes.