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.

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.

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.

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.

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.

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.

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.

Efficacy and safety of alirocumab vs ezetimibe in statin-intolerant patients, with a statin rechallenge arm: The ODYSSEY ALTERNATIVE randomized trial.

BACKGROUND: Statin intolerance limits many patients from achieving optimal low-density lipoprotein cholesterol (LDL-C) concentrations. Current options for such patients include using a lower but tolerated dose of a statin and adding or switching to ezetimibe or other non-statin therapies. METHODS: ODYSSEY ALTERNATIVE (NCT01709513) compared alirocumab with ezetimibe in patients at moderate to high cardiovascular risk with statin intolerance (unable to tolerate ≥2 statins, including one at the lowest approved starting dose) due to muscle symptoms. A placebo run-in and statin rechallenge arm were included in an attempt to confirm intolerance. Patients (n = 361) received single-blind subcutaneous (SC) and oral placebo for 4 weeks during placebo run-in. Patients reporting muscle-related symptoms during the run-in were to be withdrawn. Continuing patients were randomized (2:2:1) to double-blind alirocumab 75 mg SC every 2 weeks (Q2W; plus oral placebo), ezetimibe 10 mg/d (plus SC placebo Q2W), or atorvastatin 20 mg/d (rechallenge; plus SC placebo Q2W) for 24 weeks. Alirocumab dose was increased to 150 mg Q2W at week 12 depending on week 8 LDL-C values. Primary end point was percent change in LDL-C from baseline to week 24 (intent-to-treat) for alirocumab vs ezetimibe. RESULTS: Baseline mean (standard deviation) LDL-C was 191.3 (69.3) mg/dL (5.0 [1.8] mmol/L). Alirocumab reduced mean (standard error) LDL-C by 45.0% (2.2%) vs 14.6% (2.2%) with ezetimibe (mean difference 30.4% [3.1%], P < .0001). Skeletal muscle-related events were less frequent with alirocumab vs atorvastatin (hazard ratio 0.61, 95% confidence interval 0.38-0.99, P = .042). CONCLUSIONS: Alirocumab produced greater LDL-C reductions than ezetimibe in statin-intolerant patients, with fewer skeletal-muscle adverse events vs atorvastatin.

Characterization of Autosomal Dominant Hypercholesterolemia Caused by PCSK9 Gain of Function Mutations and Its Specific Treatment With Alirocumab, a PCSK9 Monoclonal Antibody.

BACKGROUND: Patients with PCSK9 gene gain of function (GOF) mutations have a rare form of autosomal dominant hypercholesterolemia. However, data examining their clinical characteristics and geographic distribution are lacking. Furthermore, no randomized treatment study in this population has been reported. METHODS AND RESULTS: We compiled clinical characteristics of PCSK9 GOF mutation carriers in a multinational retrospective, cross-sectional, observational study. We then performed a randomized placebo-phase, double-blind study of alirocumab 150 mg administered subcutaneously every 2 weeks to 13 patients representing 4 different PCSK9 GOF mutations with low-density lipoprotein cholesterol (LDL-C) ≥70 mg/dL on their current lipid-lowering therapies at baseline. Observational study: among 164 patients, 16 different PCSK9 GOF mutations distributed throughout the gene were associated with varying severity of untreated LDL-C levels. Coronary artery disease was common (33%; average age of onset, 49.4 years), and untreated LDL-C concentrations were higher compared with matched carriers of mutations in the LDLR (n=2126) or apolipoprotein B (n=470) genes. Intervention study: in PCSK9 GOF mutation patients randomly assigned to receive alirocumab, mean percent reduction in LDL-C at 2 weeks was 62.5% (P<0.0001) from baseline, 53.7% compared with placebo-treated PCSK9 GOF mutation patients (P=0.0009; primary end point). After all subjects received 8 weeks of alirocumab treatment, LDL-C was reduced by 73% from baseline (P<0.0001). CONCLUSIONS: PCSK9 GOF mutation carriers have elevated LDL-C levels and are at high risk of premature cardiovascular disease. Alirocumab, a PCSK9 antibody, markedly lowers LDL-C levels and seems to be well tolerated in these patients. CLINICAL TRIAL REGISTRATION: URL: http://www.clinicaltrials.gov. Unique Identifier: NCT01604824.

Efficacy and safety of alirocumab as add-on therapy in high-cardiovascular-risk patients with hypercholesterolemia not adequately controlled with atorvastatin (20 or 40 mg) or rosuvastatin (10 or 20 mg): design and rationale of the ODYSSEY OPTIONS Studies.

The phase 3 ODYSSEY OPTIONS studies (OPTIONS I, NCT01730040; OPTIONS II, NCT01730053) are multicenter, multinational, randomized, double-blind, active-comparator, 24-week studies evaluating the efficacy and safety of alirocumab, a fully human monoclonal antibody targeting proprotein convertase subtilisin/kexin type 9, as add-on therapy in ∼ 650 high-cardiovascular (CV)-risk patients whose low-density lipoprotein cholesterol (LDL-C) levels are ≥100 mg/dL or ≥70 mg/dL according to the CV-risk category, high and very high CV risk, respectively, with atorvastatin (20-40 mg/d) or rosuvastatin (10-20 mg/d). Patients are randomized to receive alirocumab 75 mg via a single, subcutaneous, 1-mL injection by prefilled pen every 2 weeks (Q2W) as add-on therapy to atorvastatin (20-40 mg) or rosuvastatin (10-20 mg); or to receive ezetimibe 10 mg/d as add-on therapy to statin; or to receive statin up-titration; or to switch from atorvastatin to rosuvastatin (OPTIONS I only). At week 12, based on week 8 LDL-C levels, the alirocumab dose may be increased from 75 mg to 150 mg Q2W if LDL-C levels remain ≥100 mg/dL or ≥70 mg/dL in patients with high or very high CV risk, respectively. The primary efficacy endpoint in both studies is difference in percent change in calculated LDL-C from baseline to week 24 in the alirocumab vs control arms. The studies may provide guidance to inform clinical decision-making when patients with CV risk require additional lipid-lowering therapy to further reduce LDL-C levels. The flexibility of the alirocumab dosing regimen allows for individualized therapy based on the degree of LDL-C reduction required to achieve the desired LDL-C level.

Effect of alirocumab, a monoclonal proprotein convertase subtilisin/kexin 9 antibody, on lipoprotein(a) concentrations (a pooled analysis of 150 mg every two weeks dosing from phase 2 trials).

Lipoprotein(a) [Lp(a)] is an independent risk factor for cardiovascular disease, with limited treatment options. This analysis evaluated the effect of a monoclonal antibody to proprotein convertase subtilisin/kexin 9, alirocumab 150 mg every 2 weeks (Q2W), on Lp(a) levels in pooled data from 3 double-blind, randomized, placebo-controlled, phase 2 studies of 8 or 12 weeks' duration conducted in patients with hypercholesterolemia on background lipid-lowering therapy (NCT01266876, NCT01288469, and NCT01288443). Data were available for 102 of 108 patients who received alirocumab 150 mg Q2W and 74 of 77 patients who received placebo. Alirocumab resulted in a significant reduction in Lp(a) from baseline compared with placebo (-30.3% vs -0.3%, p <0.0001). Median percentage Lp(a) reductions in the alirocumab group were of a similar magnitude across a range of baseline Lp(a) levels, resulting in greater absolute reductions in Lp(a) in patients with higher baseline levels. Regression analysis indicated that <5% of the variance in the reduction of Lp(a) was explained by the effect of alirocumab on low-density lipoprotein cholesterol. In conclusion, pooled data from 3 phase 2 trials demonstrate substantive reduction in Lp(a) with alirocumab 150 mg Q2W, including patients with baseline Lp(a) >50 mg/dl. Reductions in Lp(a) only weakly correlated with the magnitude of low-density lipoprotein cholesterol lowering.

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.).

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.

Image analysis for retinopathy of prematurity diagnosis.

PURPOSE: To review findings from the authors' published studies involving telemedicine and image analysis for retinopathy of prematurity (ROP) diagnosis. METHODS: Twenty-two ROP experts interpreted a set of 34 wide-angle retinal images for presence of plus disease. For each image, a reference standard diagnosis was defined from expert consensus. A computer-based system was used to measure individual and linear combinations of image parameters for arteries and veins: integrated curvature (IC), diameter, and tortuosity index (TI). Sensitivity, specificity, and receiver operating characteristic areas under the curve (AUC) for plus disease diagnosis were determined for each expert. Sensitivity and specificity curves were calculated for the computer-based system by varying the diagnostic cutoffs for arterial IC and venous diameter. Individual vessels from the original 34 images were identified with particular diagnostic cutoffs, and combined into composite wide-angle images using graphics editing software. RESULTS: For plus disease diagnosis, expert sensitivity ranged from 0.308-1.000, specificity from 0.571-1.000, and AUC from 0.784 to 1.000. Among computer system parameters, one linear combination had AUC 0.967, which was greater than that of 18 of 22 (81.8%) experts. Composite computer-generated images were produced using the arterial IC and venous diameter values associated with 75% under-diagnosis of plus disease (ie, 25% sensitivity cutoff), 50% under-diagnosis of plus disease (ie, 50% sensitivity cutoff), and 25% under-diagnosis of plus disease (ie, 75% sensitivity cutoff). CONCLUSIONS: Computer-based image analysis has the potential to diagnose severe ROP with comparable or better accuracy than experts, and could provide added value to telemedicine systems. Future quantitative definitions of plus disease might improve diagnostic objectivity.

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.

A brief office intervention is associated with increased days per week of exercise.

OBJECTIVE: We hypothesized that a cardiologist-initiated motivational discussion during a routine general cardiology clinic visit that included an exercise 'contract' signed by the patient, physician and a witness, would increase self-reported days per week of exercise. METHODS: A short-term pilot intervention was provided to forty consecutive general cardiology clinic patients who were enrolled in 2005. They were asked to answer the question "How many days each week do you exercise" prior to the motivational discussion and at routine follow-up. Each participant signed an exercise 'contract' and agreed to exercise for at least 15 min everyday. RESULTS: Participants had an average follow-up of 3.2 (1.7) months. The initial visit mean days of exercise per week were 3.1 (1.9). At follow-up, mean days of exercise per week were 4.0 (1.8), (p=0.04). CONCLUSION: This simple rapid intervention was associated with increased self-reported days per week of exercise.

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.