Effects of an online mindfulness-based program for parents of children with attention deficit/hyperactivity disorder: a pilot, mixed methods study.

Objectives: Online mindfulness-based program (MBP) for parents and families especially in clinical population is limited. Engagement and significant dropout are major issues in MBP implementation. This pilot study examined the effects of an online mindfulness-based program (MBP) on parents of children with Attention Deficit/Hyperactivity Disorder (ADHD). Methods: A mixed methods study was applied to evaluate the effects of the MBP. A total of 43 parents were recruited and were randomly assigned into intervention group and waitlist control group. The online MBP lasted for 28 days, including 20 psychoeducation videos, homework audio guidance, and four instructor-led online group meetings. Purposive sampling was used to recruit parents who completed the program to share their experiences and suggestions for improving the program in semi-structured online interviews. Results: Quantitative data showed that participants from the online MBP reported a medium to large effect on the reduction of child ADHD symptoms. In semi-structured interviews, participants reported positive experiences in their help seeking intention, and personal changes, such as emotion regulation and quality attention to their children. Participants further made suggestions for improvement. Conclusions: The effect of online MBP is promising, and the program should be conducted. A large scale randomized controlled trial should be conducted to investigate the effects of MBP in clinical populations. Clinical trial registration: ClinicalTrials.gov NCT05480423.

Characterization of Adeno-Associated Virus Capsid Proteins by Microflow Liquid Chromatography Coupled with Mass Spectrometry.

Adeno-associated virus (AAV) has been widely used to treat various human diseases as an important delivery vector for gene therapy due to its low immunogenicity and safety. AAV capsids proteins are comprised of three capsid viral proteins (VP; VP1, VP2, VP3). The capsid proteins play a key role in viral vector infectivity and transduction efficiency. To ensure the safety and efficacy of AAV gene therapy products, the quality of AAV vector capsid proteins during development and production should be carefully monitored and controlled. Microflow liquid chromatography coupled with mass spectrometry provides superior sensitivity and fast analysis capability. It showed significant advantages in the analysis of low- concentration and large numbers of AAV samples. The intact mass of capsid protein can be accurately determined using high-resolution mass spectrometry (MS). And MS also provides highly confident confirmation of sequence coverage and post-translational modifications site identification and quantitation. In this study, we used microflow liquid chromatography-tandem mass spectrometry (LC-MS/MS) for the characterization of AAV2 capsid protein. we obtained nearly 100% sequence coverage of low-concentration AAV2 capsid protein (8 × 1011 GC/mL). More than 30 post-translational modifications (PTMs) sites were identified, the PTMs types included deamidation, oxidation and acetylation. From this study, the proposed microflow LC-MS/MS method provides a sensitive and high throughput approach in the characterization of AAVs and other biological products with low abundance.

Education as a Moderator of Help Seeking Behavior in Subjective Cognitive Decline.

OBJECTIVE: Disparities in Alzheimer disease (AD) and differences in help seeking (HS) across sociodemographic groups warrant public health concern. Research addressing such disparities must shift toward the earliest clinical manifestations of AD to optimize diagnosis, intervention and care planning. Subjective cognitive decline (SCD), a risk state for AD, provides an important context in which to examine sociodemographic-related disparities in HS. PARTICIPANTS AND METHODS: One hundred sixty-seven cognitively healthy older adults (M age =73, M education =16) (26.4% Black, Asian, or "Other") completed SCD questionnaire, HS questions, and mood measures (depression and anxiety). Binary logistic adjusted regressions examined: (a) the association between SCD and HS; and (b) the extent to which education moderated the relationship between SCD and HS. SCD [b = 0.06, SE=0.13, P <0.001, odds ratio=1.06, 95% CI (1.03, 1.08)] and education [b=0.32, SE=0.09, P <0.001, odds ratio=1.37, 95% CI (1.15, 1.64)] were independently associated with HS, with significant interaction between education and SCD on HS [b=0.2, SE=0.01, P =0.01, odds ratio=1.02, 95% CI (1.00, 1.03)]. CONCLUSIONS: Findings elucidate the importance of tailoring SCD-related psychoeducational resources depending on educational background as a preliminary stepping-stone in encouraging HS among older adults who may be at particular risk for developing dementia.

Analysis of Sialic Acid Linkage in N-Linked Glycopeptides Using Liquid Chromatography-Electron-Activated Dissociation Time-of-Flight Mass Spectrometry.

Herein, we report a novel liquid chromatography coupled with tandem mass spectrometry method to characterize N-acetylneuraminic acid (Neu5Ac, Sa) linkage in N-linked glycans in glycopeptides with no sialic acid derivatization. First, we established a separation in reversed-phase high-performance liquid chromatography (HPLC) using a higher formic acid concentration in the mobile phases, which separated the N-glycopeptides depending on the Sa linkage. We also demonstrated a novel characterization method of Sa linkages in N-glycopeptides using electron-activated dissociation. We found that hot electron capture dissociation using an electron beam energy higher than 5 eV cleaved glycosidic bonds in glycopeptides, resulting in each glycosidic bond in the antennas being broken on both sides of the oxygen atom. Such glycosidic bond cleavage at the reducing end (C-type ion) showed the difference in Sa linkages between Sa-Gal, Gal-GlcNAc, and GlcNAc-Man. We proposed a rule to characterize the Sa linkages using the Sa-Gal products. This method was applied to N-glycopeptides in tryptic fetuin digest separated by an optimized reversed-phase HPLC. We successfully identified a number of isomeric glycoforms in the glycopeptides with different Sa links, whose peptide backbones were also simultaneously sequenced by hot ECD.

The Effects of a Mindfulness-Based Family Psychoeducation Intervention for the Caregivers of Young Adults with First-Episode Psychosis: A Randomized Controlled Trial.

OBJECTIVE: In this study, we investigated the effects of a mindfulness-based family psychoeducation (MBFPE) program on the mental-health outcomes of both caregivers and young adults with first-episode psychosis with an onset in the past three years through a multi-site randomized controlled trial. We also studied the outcomes of three potential mediating effects of interpersonal mindfulness, expressed emotions, and non-attachment on the program. METHOD: We randomly assigned 65 caregivers of young adults with psychosis to MBFPE (n = 33) or an ordinary family psychoeducation (FPE) program (n = 32); among them, 18 young adults in recovery also participated in the evaluation of outcomes. RESULTS: Intent-to-treat analyses were conducted. No significant time × group interaction effects of MBFPE and FPE programs were found in any of the caregivers' outcomes. However, the young adults with psychosis reported higher levels of recovery after the MBFPE program than after the ordinary FPE program (F = 8.268, p = 0.012, d = 1.484). They also reported a larger reduction in over-involvement of their caregivers (F = 4.846, p = 0.044, d = 1.136), showing that MBFPE had a superior effect to FPE in promoting recovery and reducing over-involvement. CONCLUSIONS: A brief psychoeducation program may not reduce the burden on or improve the mental-health outcome of caregivers of individuals with recent-onset psychosis. However, integrating mindfulness into a conventional family psychoeducation program may reduce the expressed emotions of caregivers, especially over-involvement. Further studies should explore how psychoeducation programs can reduce the impact of psychosis on family through sustainable effects in terms of reducing their burden and expressed emotions, using a rigorous study and adequate sample size.

Localization of Multiple O-Linked Glycans Exhibited in Isomeric Glycopeptides by Hot Electron Capture Dissociation.

We describe a method to obtain a comprehensive profile of multiple glycosylations in glycopeptide isoforms. We detected a wide range of abundances of various O-glycoforms in isomeric glycopeptides using hot electron capture dissociation (hot ECD) in liquid chromatography-tandem mass spectrometry. To capture low abundant glycosylated species, a prototype of a ZenoTOF 7600 system incorporating an efficient electron-activated dissociation device to perform hot ECD was operated in targeted or scheduled high-resolution multiple reaction monitoring workflows. In addition, Zeno trap pulsing was activated to enhance the sensitivity of the time-of-flight mass spectrometer. Sixty-nine O-glycopeptides of the long O-glycopeptides in tryptic bovine fetuin digest were obtained with a relative abundance range from 100 to 0.2%, which included sialylated glycans with Neu5Ac and Neu5Gc.

Electron Impact Excitation of Ions from Organics on Singly Protonated Peptides with and without Post-Translational Modifications.

We report on the dissociation of singly protonated peptides by electrons using electron-activated dissociation (EAD), which comprises electron impact excitation of ions from organics (EIEIO), electronic-excitation dissociation (EED), and electron ionization dissociation (EIoD). Various singly protonated peptides were dissociated using a recently reported fast EAD device. The dissociation can be induced through two pathways: (i) vibrational dissociation similar to collision-activated dissociation (CAD, or collision-induced dissociation, CID) by relaxation from a molecular electronic excited state to high vibrational states; and (ii) radical-induced dissociation where molecular electronic excitation is followed by homolytic cleavage. EAD is complementary to CAD as additional molecular information can be obtained; e.g., fragile PTM moieties, such as glycosylation and sulfation, can be localized. Simultaneously, the energetic production of radical z• fragments enables Leu and Ile discrimination, like in a hot ECD process. Using the fast EAD device, LC-EIEIO-time-of-flight mass spectrometry was applied to a tryptic monoclonal antibody digest containing short singly protonated peptides.

Multi-attribute method based characterization of antibody drug conjugates (ADC) at the intact and subunit levels.

Antibody-drug conjugates (ADCs) represent an important class of new biopharmaceutical modalities. ADCs are highly complex and heterogeneous molecules, potentially containing numerous product-related structures, that can contribute to the quality, efficacy and safety of the product. To keep up with product life cycle related changes, wide-range and targeted characterization of product quality attributes (PQA) are of high demand. Multi-attribute methods (MAM) can screen numerous PQAs in a parallel fashion including product properties as well as product and process-related impurities. MAM is usually based on a bottom-up approach relying on the enzymatic digestion of the protein into peptides prior to mass spectrometry (MS). However, this processing workflow can result in considerable information loss, such as the drug distribution profile of an antibody-drug conjugate. Therefore, complementary MAM approaches, based on subunit and intact mass analyses, are necessary approaches offering the advantage of product identity confirmation, quantification of the different conjugated species and monitoring the drug-to-antibody ratio at the same time. In this work we introduce a high throughput MS based attribute tracking method for ADC characterization at the intact and subunit levels by simultaneously monitoring multiple PQAs. The workflow includes sample preparation and MS instrument suitability testing for heterogeneous lysine-linked ADCs, software solutions for routine PQAs tracking, method repeatability and an easy data review fitting perfectly into high throughput analyses. As methionine oxidation is one of the modifications that should be closely monitored at any step of process development, an important application to oxidative stress evaluation using forced degradation demonstrated the applicability of the workflow.

Use of a Real-Time Locating System for Contact Tracing of Health Care Workers During the COVID-19 Pandemic at an Infectious Disease Center in Singapore: Validation Study.

BACKGROUND: In early 2020, coronavirus disease (COVID-19) emerged and spread by community and nosocomial transmission. Effective contact tracing of potentially exposed health care workers is crucial for the prevention and control of infectious disease outbreaks in the health care setting. OBJECTIVE: This study aimed to evaluate the comparative effectiveness of contact tracing during the COVID-19 pandemic through the real-time locating system (RTLS) and review of the electronic medical record (EMR) at the designated hospital for COVID-19 response in Singapore. METHODS: Over a 2-day study period, all admitted patients with COVID-19, their ward locations, and the health care workers rostered to each ward were identified to determine the total number of potential contacts between patients with COVID-19 and health care workers. The numbers of staff-patient contacts determined by EMR reviews, RTLS-based contact tracing, and a combination of both methods were evaluated. The use of EMR-based and RTLS-based contact tracing methods was further validated by comparing their sensitivity and specificity against self-reported staff-patient contacts by health care workers. RESULTS: Of 796 potential staff-patient contacts (between 17 patients and 162 staff members), 104 (13.1%) were identified by both the RTLS and EMR, 54 (6.8%) by the RTLS alone, and 99 (12.4%) by the EMR alone; 539 (67.7%) were not identified through either method. Compared to self-reported contacts, EMR reviews had a sensitivity of 47.2% and a specificity of 77.9%, while the RTLS had a sensitivity of 72.2% and a specificity of 87.7%. The highest sensitivity was obtained by including all contacts identified by either the RTLS or the EMR (sensitivity 77.8%, specificity 73.4%). CONCLUSIONS: RTLS-based contact tracing showed higher sensitivity and specificity than EMR review. Integration of both methods provided the best performance for rapid contact tracing, although technical adjustments to the RTLS and increasing user compliance with wearing of RTLS tags remain necessary.

Seasonal influenza-associated intensive care unit admission and death in tropical Singapore, 2011-2015.

BACKGROUND: Seasonal influenza can cause severe illness leading to intensive care unit (ICU) admission and death. OBJECTIVE: To define the clinical and epidemiological features of severe seasonal influenza infection and factors associated with mortality. STUDY DESIGN: A retrospective review was conducted on all patients with laboratory-confirmed influenza infection who were either admitted into the ICU or died in the two largest tertiary hospitals in Singapore from 2011-2015. RESULTS: Of 520 patients included in our study, 423 (81.3%) had influenza A infection and the rest with influenza B. Of patients with influenza A infection, 70.0% (296/423) were subtyped, of whom 24.0% (71/296) had A/H1N1pdm2009 and 76.0% (225/296) had A/H3N2. The median age of patients was 72 years (IQR 61-82). Males constituted 53.1% (276/520). Median Charlson comorbidity index score was 1 (IQR 0-3). About 70% had physical or radiological evidence of pneumonia upon admission. In-hospital mortality was 58.1% (302/520). On multiple logistic regression analysis, factors positively associated with mortality were age ≥65 years (adjusted odds ratio, aOR = 3.64, 95%CI 2.21-5.99, p < 0.001), malignancy (aOR = 2.53, 95%CI 1.12-5.73; p = 0.026), and hypoalbuminemia (aOR = 2.16, 95%CI 1.26-3.73; p = 0.005), while antiviral therapy (aOR = 0.33, 95%CI 0.17-0.63; p < 0.001) and ventilation (aOR = 0.23, 95% CI 0.13-0.39; p < 0.001) were negatively associated. CONCLUSIONS: Patients with severe seasonal influenza infection were characterized by advanced age, hypoalbuminemia and presence of pneumonia on admission. Age ≥65 years, malignancy, and hypoalbuminemia were associated with increased mortality, and antiviral therapy and ventilation with decreased mortality.

Clinical and microbiological characteristics of non-tuberculous mycobacteria diseases in Singapore with a focus on pulmonary disease, 2012-2016.

BACKGROUND: Information on non-tuberculosis mycobacterial (NTM) diseases remains limited in Singapore and other Southeast Asian countries. This study aimed to delineate epidemiological and clinical features of pulmonary NTM disease. METHODS: A retrospective review was performed on all NTM isolates identified in Singapore General Hospital from 2012 to 2016 using the 2007 ATS/IDSA diagnostic criteria. RESULTS: A total of 2026 NTM isolates from 852 patients were identified. M. abscessus-chelonae group (1010, 49.9%) was the most commonly isolated and implicated in pulmonary NTM disease. Pulmonary cases (352, 76%) had the highest prevalence among patients diagnosed with NTM diseases (465/852, 54.6%) with no gender difference. Male patients were older (68.5 years, P = 0.014) with a higher incidence of chronic obstructive pulmonary disease (COPD) (23.6%, P < 0.001) and recurrent cough with phlegm production (51.6%, P = 0.035). In contrast, more female patients had bronchiectasis (50%, P < 0.001) and haemoptysis (37.6%, P = 0.042). Age and COPD were associated with multiple NTM species isolation per patient. CONCLUSIONS: M. abscessus-chelonae group was the commonest NTM species isolated in Singapore. Pulmonary NTM infection has the highest frequency with male and female patients associated with a higher incidence of COPD and bronchiectasis respectively. Age and COPD were associated with multiple NTM species isolation per patient.

Intraoperative Transpedicular Onyx Injection to Reduce Vascularity of a Thoracic Hemangiopericytoma After Unsuccessful Preoperative Endovascular Embolization: a Technical Report.

BACKGROUND AND IMPORTANCE: Hemangiopericytoma is a rare vascular tumor with central nervous system involvement representing only 1% of central nervous system tumors. They rarely affect the vertebral column. Complete surgical resection is the treatment of choice for hemangiopericytoma given their high rates of local recurrence. However, the high vascularity of such tumors with the risk of massive bleeding during surgery represents a significant challenge to surgeons. Therefore, preoperative endovascular embolization via the transarterial route has been advocated. CLINICAL PRESENTATION: In the current study, we present a case of a T12 hemangiopericytoma that was managed by a 2-stage surgical resection, with the use of intraoperative transpedicular onyx injection to reduce intraoperative blood loss following an unsuccessful trial of preoperative endovascular embolization. CONCLUSION: Preoperative endovascular embolization is not feasible in some cases due to the location of the segmental or radiculomedullary arteries in relation to tumor feeders and, rarely, small size of these arterial feeders. Percutaneous injection of onyx is an option. In this case report, we discuss direct intraoperative injection via a transpedicular route as a safe and effective method for decreasing the vascularity of some lesions and improving intraoperative blood loss.

Prognostic factors for mortality due to pneumonia among adults from different age groups in Singapore and mortality predictions based on PSI and CURB-65.

INTRODUCTION: Pneumonia is associated with considerable mortality. However, there is limited information on age-specific prognostic factors for death from pneumonia. METHODS: Patients hospitalised with a diagnosis of pneumonia through the emergency department were stratified into three age groups: 18-64 years, 65-84 years and ≥ 85 years. Multivariate logistic regression and receiver operating characteristic curve analyses were conducted to evaluate prognostic factors for mortality and the performance of pneumonia severity scoring tools for mortality prediction. RESULTS: A total of 1,902 patients were enrolled (18-64 years: 614 [32.3%]; 65-84 years: 944 [49.6%]; ≥ 85 years: 344 [18.1%]). Mortality rates increased with age (18-64 years: 7.3%; 65-84 years: 16.1%; ≥ 85 years: 29.7%; p < 0.001). Malignancy and tachycardia were prognostic of mortality among patients aged 18-64 years. Male gender, malignancy, congestive heart failure and eight other parameters reflecting acute disease severity were associated with mortality among patients aged 65-84 years. For patients aged ≥ 85 years, altered mental status, tachycardia, blood urea nitrogen, hypoxaemia, arterial pH and pleural effusion were significantly predictive of mortality. The Pneumonia Severity Index (PSI) was more sensitive than CURB-65 (confusion, uraemia, respiratory rate ≥ 30 per minute, low blood pressure, age ≥ 65 years) for mortality prediction across all age groups. CONCLUSION: The predictive effect of prognostic factors for mortality varied among patients with pneumonia from the different age groups. PSI performed significantly better than CURB-65 for mortality prediction, but its discriminative power decreased with advancing age.

Differential response to exercise in claudin-low breast cancer.

Exposure to exercise following a breast cancer diagnosis is associated with reductions in the risk of recurrence. However, it is not known whether breast cancers within the same molecular-intrinsic subtype respond differently to exercise. Syngeneic mouse models of claudin-low breast cancer (i.e., EO771, 4TO7, and C3(1)SV40Tag-p16-luc) were allocated to a uniform endurance exercise treatment dose (forced treadmill exercise) or sham-exercise (stationary treadmill). Compared to sham-controls, endurance exercise treatment differentially affected tumor growth rate: 1- slowed (EO771), 2- accelerated (C3(1)SV40Tag-p16-luc), or 3- was not affected (4TO7). Differential sensitivity of the three tumor lines to exercise was paralleled by effects on intratumoral Ki-67, Hif1-α, and metabolic programming. Inhibition of Hif1-α synthesis by the cardiac glycoside, digoxin, completely abrogated exercise-accelerated tumor growth in C3(1)SV40Tag-p16-luc. These results suggest that intratumoral Hif1-α expression is an important determinant of claudin-low breast cancer adaptation to exercise treatment.

Dual-phase (18)F-fluorocholine PET/CT to detect locoregional recurrence of prostate cancer: comparison between each time point of imaging and a summation scan.

OBJECTIVES: Prostate carcinoma is a major health problem, and routine imaging shows only modest results in detecting and restaging clinically localized prostate cancer recurrence. Recent studies have shown promise of radiolabeled analogues of choline for positron emission tomography (PET) scans in patients of biochemical recurrence and that sequentially incremental Fluorocholine (FCH) uptake is associated with malignancy, whereas decreasing tracer activity suggests a benign aetiology. However, this pattern of tracer uptake has not been fully validated, and no standardized (18)F-Fluorocholine ((18)F-FCH) scan protocol is in place yet. This study aimed to better define the role of dual-phase (18)F-FCH PET/computed tomography (CT) imaging using retrospective masked reading focusing on detection of locoregional recurrence/metastasis in patients with biochemical failure after definitive local primary treatment. METHODS: A total of 32 subjects were enrolled during the period 04/2010 to 05/2014 with histologically proven prostate cancer that was treated with curative intent and had biochemical recurrence. Early scans and delayed imaging of the pelvis were graded separately by blinded readers. Final evaluation using the combination of information from dual-phase studies as a "summation scan" was also performed. Maximum standardized uptake value was computed using regions of interest constructed over focal hyperactivity. Calculations were performed using Statistical Product and Service Solutions, Version 20 for Windows. A composite reference consisting of histopathology, correlation with other imaging, or serum prostate specific antigen (PSA) trend with clinical follow-up of at least 6months was used to determine the true disease status of the patient. RESULTS: Early-phase pelvis imaging sensitivity and specificity were calculated to be 73.1% and 90.9%, respectively. Late-phase pelvis imaging sensitivity and specificity were 80.8% and 100%, respectively. Summation scan sensitivity and specificity were 76.9% and 100%, respectively. The odds ratio of having recurrent disease with an uptrend of SUVmax on dual-phase imaging was 33.3. The optimal cutoff value of PSA was 1.85ng/mL with 80% sensitivity and 62.5% specificity. CONCLUSIONS: Single late-phase FCH PET/CT imaging is a reliable scan modality which can detect sites of disease at low levels of PSA which still fulfil the criteria of biochemical recurrence. This will allow clinicians to identify sites for potential biopsy or start locoregional treatment.

The Art of Intraoperative Glioma Identification.

A major dilemma in brain-tumor surgery is the identification of tumor boundaries to maximize tumor excision and minimize postoperative neurological damage. Gliomas, especially low-grade tumors, and normal brain have a similar color and texture, which poses a challenge to the neurosurgeon. Advances in glioma resection techniques combine the experience of the neurosurgeon and various advanced technologies. Intraoperative methods to delineate gliomas from normal tissue consist of (1) image-based navigation, (2) intraoperative sampling, (3) electrophysiological monitoring, and (4) enhanced visual tumor demarcation. The advantages and disadvantages of each technique are discussed. A combination of these methods is becoming widely accepted in routine glioma surgery. Gross total resection in conjunction with radiation, chemotherapy, or immune/gene therapy may increase the rates of cure in this devastating disease.

Case report: Intra-procedural aneurysm rupture during endovascular treatment causing immediate, transient angiographic vasospasm.

INTRODUCTION: Cerebral vasospasm is a major cause of delayed ischemic cerebral injury, typically occurring 3-14 days after subarachnoid hemorrhage (SAH). Ultra-early vasospasm is defined as angiographic vasospasm observed within 48 h of SAH onset. Immediate vasospasm at the time of aneurysmal rupture has been suspected, but has not been previously reported. We describe a case of immediate, transient vasospasm following intra-procedural aneurysmal rupture. METHODS: A 55-year-old woman presented with SAH from a ruptured anterior communicating artery aneurysm. Subsequent coil embolization was complicated by an intra-procedural rupture following placement of the initial coil. A follow-up angiogram obtained after 9 min demonstrated moderate-to-severe vasospasm in the A2 segments of both anterior cerebral arteries. RESULTS: A repeat angiogram 20 min later demonstrated complete resolution of the vasospasm. The aneurysm was successfully obliterated with coil embolization. Post-procedure, the patient manifested no clinical vasospasm and made a good neurological recovery. CONCLUSION: We document a case of ultra-early cerebral vasospasm that occurred immediately after an intra-procedural aneurysmal rupture. Catheter-induced vasospasm from mechanical manipulation of extracranial vasculature is well described. However, immediate vasospasm related to extravascular blood has never before been reported. This finding suggests that extravascular blood can have a local direct effect (presumably mechanical) on cerebral blood vessels, and may be an important mechanism for vasospasm.

Correlation between electrophysiological properties, morphological maturation, and olig gene changes during postnatal motor tract development.

This study investigated electrophysiological and histological changes as well as alterations of myelin relevant proteins of descending motor tracts in rat pups. Motor-evoked potentials (MEPs) represent descending conducting responses following stimulation of the motor cortex to responses being elicited from the lower extremities. MEP responses were recorded biweekly from postnatal (PN) week 1 to week 9 (adult). MEP latencies in PN week 1 rats averaged 23.7 ms and became shorter during early maturation, stabilizing at 6.6 ms at PN week 4. During maturation, the conduction velocity (CV) increased from 2.8 ± 0.2 at PN week 1 to 35.2 ± 3.1 mm/ms at PN week 8. Histology of the spinal cord and sciatic nerves revealed progressive axonal myelination. Expression of the oligodendrocyte precursor markers PDGFRα and NG2 were downregulated in spinal cords, and myelin-relevant proteins such as GalC, CNP, and MBP increased during maturation. Oligodendrocyte-lineage markers Olig2 and MOG, expressed in myelinated oligodendrocytes, peaked at PN week 3 and were downregulated thereafter. A similar expression pattern was observed in neurofilament M/H subunits that were extensively phosphorylated in adult spinal cords but not in neonatal spinal cords, suggesting an increase in axon diameter and myelin formation. Ultrastructural morphology in the ventrolateral funiculus (VLF) showed axon myelination of the VLF axons (99.3%) at PN week 2, while 44.6% were sheathed at PN week 1. Increased axon diameter and myelin thickness in the VLF and sciatic nerves were highly correlated to the CV (rs > 0.95). This suggests that MEPs could be a predicator of morphological maturity of myelinated axons in descending motor tracts.

Clinical trial risk in Non-Hodgkin's lymphoma: endpoint and target selection.

PURPOSE: To quantify the clinical trial risk of new drug development in Non-Hodgkin's lymphoma (NHL). Risk estimates for this disease have not been reported before. METHODS: We undertook a retrospective review of clinical trials in (NHL) in four subtypes to compare the success rate with the industry average. Our inclusion criteria required that a drug must initiate its phase I trial in one of the four NHL subtypes between 1998 and June 2008 in the US. In addition, clinical trials of new drug candidates that pertain to four subtypes of NHL were retrieved from clinicaltrial.gov. Drug candidates that did not meet these criteria were excluded from the study. RESULTS: The overall success rate (8-11%) was significantly lower than the industry standard (17%). Overall survival (OS) as a secondary outcome appeared more predictive than primary endpoints that were surrogate, of overall success. Further, targeted therapies appear more successful in these lymphoma sub-types than broad acting drugs. CONCLUSION: Clinical trial risk in NHL, with an 89% failure rate reported here, may be reduced by basing decisions on OS secondary endpoints and biologic drugs.