Search

Introduction: Lorecivivint (LOR), a CDC-like kinase/dual-specificity tyrosine kinase (CLK/DYRK) inhibitor thought to modulate inflammatory and Wnt pathways, is being developed as a potential intra-articular knee osteoarthritis (OA) treatment. The objective of this trial was to evaluate long-term safety of LOR within an observational extension of two phase 2 trials. Methods: This 60-month, observational extension study (NCT02951026) of a 12-month phase 2a trial (NCT02536833) and 6-month phase 2b trial (NCT03122860) was administratively closed after 36 months as data inferences became limited. Participants received a single intra-articular LOR or placebo (PBO) injection at their parent-trial baseline. The primary outcome was the comparative incidence of serious adverse events (SAEs), with AEs and similar safety measures comprising secondary outcomes. A post hoc baseline-adjusted analysis of covariance (ANCOVA) compared changes from baseline in Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) Pain and Function subscores and medial joint space width (JSW) between LOR 0.07 mg and PBO groups in a subpopulation of participants with unilateral knee pain and widespread pain low enough to allow participants to differentiate their target knee pain. Results: The safety analysis set for the extension study included 495 LOR-treated and 208 control participants, with 409 (82.6%) and 175 (84.1%) remaining at study close, respectively. There were 68 SAEs reported in 38 (5.4%) patients; none were considered treatment-related by investigators. The incidence of AEs was similar between groups. In the post hoc subgroup efficacy analyses, LOR 0.07 mg demonstrated greater mean improvements from baseline compared with PBO in WOMAC pain and function scores out to 12 months post-injection. No between-group differences in medial JSW were observed out to 18 months. Conclusions: LOR appeared generally safe and well tolerated. Efficacy analyses on the subset of completer patients demonstrated durable symptom improvements in WOMAC pain and function for at least 12 months compared to PBO after a single injection of LOR. Clinical Trial Registration Number: NCT02951026. Lay Summary: Knee osteoarthritis (OA) is the most common degenerative joint disease and significantly impairs patients' function and quality of life. Lorecivivint (LOR) is a drug candidate undergoing clinical trials as an injectable treatment for knee OA. It inhibits molecules in joint cells (called CLKs and DYRKs) that regulate inflammatory (affecting pain) and Wnt (affecting cartilage and bone turnover) pathways; abnormalities of both contribute to OA. We report data from patients with knee OA who completed two randomized, placebo (PBO)-controlled trials and who chose to continue to be observed for up to 3 years. They did not receive any new LOR injections but continued to get regular exams and annual X-rays by their clinicians and to report any (new / ongoing) health problems. An analysis was performed matching patients with similar clinical features (especially regarding their knee pain) from both trials, to see if a 0.07 mg dose of LOR was safe and if it affected knee pain and function. LOR appeared to be well tolerated, with few side effects that were similar in number to those receiving the placebo. More patients in the LOR-treated group reported feeling less knee pain and improved function than those in the PBO group; however, because knee x-rays of patients in both LOR and PBO groups showed no worsening of their OA over this time period, the evidence remained inconclusive. The profound need for safe, disease-modifying OA treatments and the encouraging results from this study support the continued development of LOR as a treatment for knee osteoarthritis. [ABSTRACT FROM AUTHOR]

Introduction: Knee osteoarthritis (OA) is a common painful disorder. Intra-articular (IA) corticosteroid injections are frequently prescribed to treat knee pain. Lorecivivint (LOR), a novel IA cdc2-Like Kinase (CLK)/Dual-Specificity Tyrosine Phosphorylation-Regulated Kinase (DYRK) inhibitor thought to modulate Wnt and inflammatory pathways, has appeared safe and demonstrated improved patient-reported outcomes compared with placebo. While LOR is proposed for stand-alone use, in clinical practice, providers might administer LOR in close time proximity to IA corticosteroid. This open-label, parallel-arm, healthy volunteer study assessed potential short-term safety, tolerability and pharmacokinetic (PK) interactions between IA LOR and triamcinolone acetonide (TCA) administered 7 days apart. Methods: Healthy volunteers were randomized to Treatment Sequence 1 (IA 40 mg TCA followed by IA 0.07 mg LOR) or Treatment Sequence 2 (IA 0.07 mg LOR followed by IA 40 mg TCA). Treatment-emergent adverse events (TEAEs) were categorized by "epoch", with epoch 1 spanning from first until second injection, and epoch 2 spanning from second injection until end of study. Plasma PK was assessed pre injection and out to 22 days after to assess PK treatment interaction. Results: A total of 18 TEAEs were reported by 11 (27.5%) of 40 enrolled participants, and there were no serious adverse events. Thirteen TEAEs were reported in Treatment Sequence 1 and five in Treatment Sequence 2, similarly distributed between epochs 1 and 2. In all participants and at all time points, plasma LOR concentrations were below the limit of quantification (0.100 ng/mL). Geometric mean concentrations and PK parameters for TCA were similar between treatment sequences. Conclusion: No safety signals were observed. There were no quantifiable plasma concentrations of LOR in either Treatment Sequence. The PK of TCA was unaffected by previous LOR injection. These results suggest that IA administration of LOR and TCA in close time proximity is unlikely to pose a safety concern. Trial Registration: ClinicalTrials.gov identifier, NCT04598542. Plain Language Summary: Knee osteoarthritis (OA) is a common disorder characterized by pain and loss of function. This clinical trial tested if two different treatments for OA injected into the same knee 1 week apart would impact the safety or exposure of either treatment. The treatments evaluated were an injection of a corticosteroid, triamcinolone acetonide, and a potential OA treatment in development, lorecivivint, a novel small molecule thought to inhibit inflammation and a biological pathway called the Wnt pathway. The amount of either treatment found in circulation was not different when injected before or after the other treatment. The order of injection did not change the safety profile for either agent, suggesting injection of the two agents 1 week apart is unlikely to pose a safety concern. [ABSTRACT FROM AUTHOR]

Objective: To evaluate the regional variation of cost sharing and associations with rheumatoid arthritis (RA) disease burden in the US. Methods: Patients with RA from rheumatology practices in Northeast, South, and West US regions were evaluated. Sociodemographics, RA disease status, and comorbidities were collected, and Rheumatic Disease Comorbidity Index (RDCI) score was calculated. Primary insurance types and copay for office visits (OVs) and medications were documented. Univariable pairwise differences between regions were conducted, and multivariable regression models were estimated to evaluate associations of RDCI with insurance, geographical region, and race. Results: In a cohort of 402 predominantly female, White patients with RA, most received government versus private sponsored primary insurance (40% vs. 27.9%). Disease activity and RDCI were highest for patients in the South region, where copays for OVs were more frequently more than $25. Copays for OVs and medications were less than $10 in 45% and 31.8% of observations, respectively, and more prevalent in the Northeast and West patient subsets than in the South subset. Overall, RDCI score was significantly higher for OV copays less than $10 as well as for medication copays less than $25, both independent of region or race. Additionally, RDCI was significantly lower for privately insured than Medicare individuals (RDCI −0.78, 95% CI [−0.41 to −1.15], P < 0.001) and Medicaid (RDCI −0.83, 95% CI [−0.13 to −1.54], P = 0.020), independent of region and race. Conclusion: Cost sharing may not facilitate optimum care for patients with RA, especially in the Southern regions. More support may be required of government insurance plans to accommodate patients with RA with a high disease burden. [ABSTRACT FROM AUTHOR]

Background: Durable, meaningful symptom responses to intra-articular saline placebo injections are observed in knee osteoarthritis (OA) trials, but it is unclear if these are due to physiological effects. Purpose: To perform a prospective comparison of patient-reported outcome responses among participants with knee OA who underwent intra-articular injection of saline-based placebo or sham (dry needle). Study Design: Randomized controlled trial; Level of evidence, 2. Methods: From a 24-week randomized double-blind trial, participants with moderate to severe knee OA received 2-mL intra-articular injections of saline-based placebo (PBO; 99.45% PBS) or sham (dry needle) to the target knee. Least squares mean differences of changes from baseline to week 24 were compared between the PBO and sham groups for the following: pain Numeric Rating Scale; Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) pain, stiffness, and function; and patient global assessment. Bang Blinding Index was used to evaluate all-group blinding on day 1 and week 24. Results: In total, 116 and 117 participants were randomized to the PBO and sham groups, respectively. Within the full trial population, the mean ± SD age and body mass index were 59.0 ± 8.5 years and 28.97 ± 4.01, respectively. An overall 406 (58.4%) were female, and 394 (57.3%) had Kellgren-Lawrence grade 3 target knee OA. The PBO and sham groups demonstrated clinically meaningful improvements (≥10%) from baseline in all patient-reported outcomes at all time points (ie, weeks 4-24). Mean differences (95% CI) at week 24 between the PBO and sham groups were as follows: pain Numeric Rating Scale, –0.10 (–0.79 to 0.59; P =.78); WOMAC pain, –2.89 (–9.70 to 3.92; P =.40); WOMAC stiffness, –2.37 (–9.37 to 4.63; P =.51); and WOMAC function, –1.39 (–8.06 to 5.29; P =.68). Bang Blinding Index indicated that blinding was maintained. Conclusion: PBO and sham groups demonstrated equivalent patient-reported outcomes at all time points through week 24, suggesting that responses attributed to saline were contextual (ie, to the procedure) and not physiological. Registration: NCT03122860 (ClinicalTrials.gov identifier). [ABSTRACT FROM AUTHOR]

Introduction: Established thresholds for patient-reported outcomes (PROs) provide clinically relevant responder data from trials. Lorecivivint (LOR) is an intra-articular (IA) therapy in development for knee osteoarthritis (OA). A post hoc analysis from a phase 2b trial (NCT03122860) determined proportions of LOR responders. Methods: A 24-week, randomized trial of 0.07 mg LOR demonstrated PRO improvements compared with PBO in moderate-to-severe knee OA participants. Participants treated with LOR and PBO achieving 30%/50%/70% improvements at weeks 12 and 24 in Pain Numeric Rating Scale (NRS), WOMAC Pain/Function subscales, Patient Global Assessment (PtGA), and OMERACT-OARSI responder criteria were determined. Odds ratios (ORs) and 95% confidence intervals [CIs] were compared with PBO. Results: There were 115 and 116 participants in the LOR and PBO groups, respectively. For Pain NRS, LOR increased ORs of achieving 30% [week 12, OR = 2.47 (1.45, 4.19), P < 0.001; week 24, OR = 2.37 (1.40, 4.02), P < 0.01] and 50% [week 24, OR = 1.89 (1.11, 3.23), P < 0.05] improvements over baseline. For WOMAC Pain, LOR increased ORs of achieving 30% [week 24, OR = 1.79 (1.06, 3.01), P < 0.05] and 50% [week 12, OR = 1.79 (1.06, 3.03), P < 0.05; week 24, OR = 1.73 (1.02, 2.93), P < 0.05] improvements. For WOMAC Function, LOR increased ORs of achieving 30% [week 12, OR = 1.85 (1.10, 3.12), P < 0.05; week 24, OR = 1.93 (1.14, 3.26), P < 0.05] improvements. For PtGA, LOR increased ORs of achieving 50% [week 12, OR = 2.28 (1.25, 4.16), P < 0.01] improvements. LOR produced numerical increases at the 70% threshold. LOR increased ORs of achieving OMERACT-OARSI responses [week 12, OR = 2.21 (1.29, 3.78); P < 0.01; week 24, OR = 2.57 (1.49, 4.43), P < 0.001] and strict responses [week 12, OR = 2.13 (1.26, 3.61), P < 0.01; week 24, OR = 2.05 (1.21, 3.47), P < 0.01]. Conclusions: LOR (0.07 mg) demonstrated improved PRO threshold responses across single and composite measures of pain, function, and patient global assessment compared with PBO, with benefits sustained to 24 weeks. Plain Language Summary: Lorecivivint (LOR) is a new injectable medicine being studied as a treatment for knee osteoarthritis (OA). An early (phase 2b) trial found participants with moderate-to-severe knee OA receiving LOR on average reported improved pain, function, and reduced impact of OA symptoms over 24 weeks compared with placebo. To consider how likely individuals were to respond to treatment, this study analyzed how many participants per group achieved different percentage levels of symptom improvement. Participants were given a single LOR or placebo injection into their most painful (target) knee at trial initiation. Participants reported their target knee status from day 1 (baseline) to week 24 using pain and function questionnaires. We analyzed the number of participants given 0.07 mg LOR and placebo whose symptom scores improved by 30, 50, and 70% over baseline scores at weeks 12 and 24. Results showed that 0.07 mg LOR treatment produced a higher likelihood beyond chance at week 12 of achieving a 30% improvement in some pain and function scores and a 50% improvement in other symptom scores compared with placebo. Similar 30% and 50% symptom score improvements were found at week 24. More complex scores, combining individual symptom scores into single index measures, also showed improvements beyond chance for 0.07 mg LOR from baseline compared with placebo at weeks 12 and 24. Thus, more participants with knee OA who were treated with 0.07 mg LOR demonstrated long-lasting, meaningful improvements in pain and function compared to those given placebo. [ABSTRACT FROM AUTHOR]

Objective: To assess the safety and efficacy of a novel Wnt pathway modulator, lorecivivint (SM04690), for treating pain and inhibiting structural progression in moderately to severely symptomatic knee osteoarthritis (OA). Methods: Subjects in this 52‐week, phase IIa, multicenter, randomized, double‐blind, placebo‐controlled, dose‐ranging trial received a single 2‐ml intraarticular injection of lorecivivint (dose of 0.03 mg, 0.07 mg, or 0.23 mg) or placebo. Efficacy was assessed based on change from baseline on the Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) score subscales for pain and function (scale 0–100 for each) and change from baseline in the radiographic medial joint space width (JSW). Baseline‐adjusted analysis of covariance with multiple imputation was performed separately to evaluate efficacy. This proof‐of‐concept study evaluated the intent‐to‐treat population as well as a prespecified group of subjects with unilateral symptoms of knee OA (designated UNI) and an additional post hoc subgroup of subjects with unilateral symptoms but without widespread pain (designated UNI WP−). Results: In this trial, 455 subjects were randomized to a treatment group. The primary end point, significant improvement in the WOMAC pain score compared with placebo at week 13, was not met by any lorecivivint dose group (mean ± SD change from baseline, −23.3 ± 2.2 in the 0.03 mg group, −23.5 ± 2.1 in the 0.07 mg group, −21.3 ± 2.2 in the 0.23 mg group, and −22.1 ± 2.1 in the placebo group; each P > 0.05 versus placebo). All groups (including placebo) demonstrated clinically meaningful (≥20‐point) improvements from baseline in the WOMAC pain score. The durability of response was evaluated through week 52. In the prespecified UNI group and post hoc UNI WP− group at week 52, treatment with 0.07 mg lorecivivint significantly improved the WOMAC pain score (between‐group difference versus placebo, −8.73, 95% confidence interval [95% CI] −17.44, −0.03 [P = 0.049] and −11.21, 95% CI −20.99, −1.43 [P = 0.025], respectively) and WOMAC function score (between‐group difference versus placebo, −10.26, 95% CI −19.82, −0.69 [P = 0.036] and −13.38, 95% CI −24.33, −2.43 [P = 0.017], respectively). Relative to baseline, the mean change in the medial JSW at week 52 was −0.04 mm in the 0.03 mg cohort, −0.09 mm in the 0.07 mg cohort, −0.16 mm in the 0.23 mg cohort, and −0.14 mm in the placebo cohort; no treatment group achieved a significant change in medial JSW compared with placebo at week 52. In both unilateral symptom subgroups, the 0.07 mg lorecivivint dose significantly increased medial JSW compared with placebo at week 52 (medial JSW 0.39 mm, 95% CI 0.06, 0.72 in the UNI group [P = 0.021] and 0.42 mm, 95% CI 0.04, 0.80 in the UNI WP− group [P = 0.032]). Changes observed in the 0.03 mg and 0.23 mg dose groups were not significantly different from those in the placebo group for any of these measures. Lorecivivint appeared safe and well tolerated. Conclusion: This phase IIa, proof‐of‐concept trial in patients with symptomatic knee OA did not meet its primary end point. Nevertheless, the study identified a target population in whom to evaluate the potential efficacy of lorecivivint for the treatment of knee OA. [ABSTRACT FROM AUTHOR]

ABSTRACT The majority of Osteosarcoma (OS) patients are treated with a combination of chemotherapy, resection, and limb salvage protocols. These protocols include distraction osteogenesis (DO), which is characterized by direct new bone formation. Cisplatin (CDP) is extensively used for OS chemotherapy and recent studies, using a mouse DO model, have demonstrated that CDP has profound negative effects on bone repair. Recent oncological therapeutic strategies are based on the use of standard cytotoxic drugs plus an assortment of biologic agents. Here we demonstrate that the previously reported CDP-associated inhibition of bone repair can be modulated by the administration of a small molecule p53 inducer (nutlin-3). The effects of nutlin-3 on CDP osteotoxicity were studied using both pre- and post-operative treatment models. In both cases the addition of nutlin-3, bracketing CDP exposure, demonstrated robust and significant bone sparing activity ( p < 0.01-0.001). In addition the combination of nutlin-3 and CDP induced equivalent OS tumor killing in a xenograft model. Collectively, these results demonstrate that the induction of p53 peri-operatively protects bone healing from the toxic effects of CDP, while maintaining OS toxicity. © 2016 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res 34:1716-1724, 2016. [ABSTRACT FROM AUTHOR]

Purpose: Rapid assessment of volume status in children is often difficult. The purpose of this study was to evaluate the feasibility of surgeon-performed ultrasound to assess volume status in patients with hypertrophic pyloric stenosis.Methods: Ultrasounds were performed on admission and before operation. The diameters of the inferior vena cava (IVC) and aorta (Ao) were measured and IVC/Ao ratios were calculated. Electrolytes were measured on admission and repeated if warranted. Logistic regression was used to associate the clinical outcome, defined as CO2 ≤30 mEq/L, with IVC/Ao ratios. Predictive capacity was estimated from the logistic regression for IVC/Ao ratios. Linear regression was used to estimate associations between CO2 values and IVC/Ao ratios.Results: Thirty-one patients were enrolled. The IVC/Ao ratio is highly associated with actual CO2 values (P < 0.001) and the clinical outcome (P = 0.004). For every 0.05 unit increase in IVC/Ao ratio, predicted CO2 decreased 1.1 units. For every 0.05 unit increase in the IVC/Ao ratio, the odds of having a CO2 ≤30 mEq/L increased 48% [OR = 1.48, 95% CI (1.13,1.94)]. Predictive capacity is maximized at an IVC/Ao ratio of 0.75 as 83.9 % of subjects were correctly classified and specificity and PPV = 100%.Conclusions: Surgeon-performed ultrasound to determine IVC/Ao ratio is feasible. An IVC/Ao ratio of 0.75 predicted adequate resuscitation. [ABSTRACT FROM AUTHOR]

ABSTRACT Osteosarcoma (OS) is the most common malignant bone tumor affecting children and adolescents. Many patients are treated with a combination of chemotherapy, resection, and limb salvage protocols. Surgical reconstructions after tumor resection include structural allografts, non-cemented endoprostheses, and distraction osteogenesis (DO), which require direct bone formation. Although cisplatin (CDP) is extensively used for OS chemotherapy, the effects on bone regeneration are not well studied. The effects of CDP on direct bone formation in DO were compared using two dosing regimens and both C57BL/6 (B6) and tumor necrosis factor receptor 1 knockout (TNFR1KO) mice, as CDP toxicity is associated with elevated TNF levels. Detailed evaluation of the five-dose CDP regimen (2 mg/kg/day), demonstrated significant decreases in new bone formation in the DO gaps of CDP treated versus vehicle treated mice ( p < 0.001). Further, no significant inhibitory effects from the five-dose CDP regimen were observed in TNFR1KO mice. The two-dose regimen significantly inhibited new bone formation in B6 mice. These results demonstrate that CDP has profound short term negative effects on the process of bone repair in DO. These data provide the mechanistic basis for modeling peri-operative chemotherapy doses and schedules and may provide new opportunities to identify molecules that spare normal cells from the inhibitory effects of CDP. © 2013 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res 32:464-470, 2014. [ABSTRACT FROM AUTHOR]

Neonatal neurology is a growing subspecialty area. Given the considerable amount of neurologic problems present in the neonatal intensive care unit, a neurologist with expertise in neonates is becoming more important. We sought to evaluate the change in neurologic care in the neonatal intensive care unit at our tertiary care hospital by having a dedicated neonatal neurologist. The period post–neonatal neurologist showed a greater number of neurology consultations (P<.001), number of neurology encounters per patient (P<.001), a wider variety of diagnoses seen, and an increase in the use of video electroencephalography (P=.022), compared to the period pre–neonatal neurologist. The neonatologists expressed appreciation for having a dedicated neurologist available. Standardized protocols for treating hypoxic-ischemic encephalopathy and neonatal seizures were also developed. Overall, by having a neonatal neurologist, neurology became part of the multidisciplinary team providing focused neurologic care to newborns. [ABSTRACT FROM AUTHOR]

Early brain injury occurs in newborns with congenital heart disease (CHD) placing them at risk for impaired neurodevelopmental outcomes. Predictors for preoperative brain injury have not been well described in CHD newborns. This study aimed to analyze, retrospectively, brain magnetic resonance imaging (MRI) in a heterogeneous group of newborns who had CHD surgery during the first month of life using a detailed qualitative CHD MRI Injury Score, quantitative imaging assessments (regional apparent diffusion coefficient [ADC] values and brain volumes), and clinical characteristics. Seventy-three newborns who had CHD surgery at 8 ± 5 (mean ± SD) days of life and preoperative brain MRI were included; 38 also had postoperative MRI. Thirty-four (34 of 73, 47 %) had at least one type of preoperative brain injury, and 28 of 38 (74 %) had postoperative brain injury. The 5-min APGAR score was negatively associated with preoperative injury, but there was no difference between CHD types. Infants with intraparenchymal hemorrhage, deep gray matter injury, and/or watershed infarcts had the highest CHD MRI Injury Scores. ADC values and brain volumes were not different in infants with different CHD types or in those with and without brain injury. In a mixed group of CHD newborns, brain injury was found preoperatively on MRI in almost 50 %, and there were no significant baseline characteristic differences to predict this early brain injury except 5-min APGAR score. We conclude that all infants, regardless of CHD type, who require early surgery should be evaluated with MRI because they are all at high risk for brain injury. [ABSTRACT FROM AUTHOR]

Background Booster seats reduce mortality and morbidity for young children in car crashes, but use is low, particularly in rural areas. This study targeted rural communities in 4 states using a community sports-based approach. Objective The Strike Out Child Passenger Injury (Strike Out) intervention incorporated education about booster seat use in children ages 4-7 years within instructional baseball programs. We tested the effectiveness of Strike Out in increasing correct restraint use among participating children. Methods Twenty communities with similar demographics from 4 states participated in a nonrandomized, controlled trial. Surveys of restraint use were conducted before and after baseball season. Intervention communities received tailored education and parents had direct consultation on booster seat use. Control communities received only brochures. Results One thousand fourteen preintervention observation surveys for children ages 4-7 years (Intervention Group [I]: N = 511, Control [C]: N = 503) and 761 postintervention surveys (I: N = 409, C: N = 352) were obtained. For 3 of 4 states, the intervention resulted in increases in recommended child restraint use (Alabama +15.5%, Arkansas +16.1%, Illinois +11.0%). Communities in 1 state (Indiana) did not have a positive response (-9.2%). Overall, unadjusted restraint use increased 10.2% in intervention and 1.7% in control communities ( P = .02). After adjustment for each state in the study, booster seat use was increased in intervention communities (Cochran-Mantel-Haenszel odds ratio 1.56, 95% confidence interval [1.16-2.10]). Conclusions A tailored intervention using baseball programs increased appropriate restraint use among targeted rural children overall and in 3 of 4 states studied. Such interventions hold promise for expansion into other sports and populations. [ABSTRACT FROM AUTHOR]

Knecht KR, Alexander ML, Swearingen CJ, Frazier EA. NTproBNP as a marker of rejection in pediatric heart transplant recipients. Abstract: Acute rejection is a major morbidity in heart transplant recipients; diagnosis is difficult, and rejection must often be treated reactively. Various serum biomarkers have been investigated for non-invasive monitoring of the cardiac allograft. NTproBNP is produced by the ventricular myocardium and may increase with evolving rejection allowing earlier diagnosis. Retrospective review of serum NTproBNP levels in pediatric heart transplant recipients has been carried out to evaluate the association with episodes of acute rejection. Repeated measures logistic regression was used to model associations for variables with first rejection and within an individual for change in NTproBNP and first rejection. Odds ratios for rejection risk given an increase in serum NTproBNP were calculated. Correlation of NTproBNP levels with renal function as estimated by modified Schwartz equation was performed to look for confounding. Higher serum NTproBNP level was associated with increased risk of rejection, but intersubject variability was wide. However, increase in an individual subject's serum level showed increased risk of rejection, greater with greater rise. Serum NTproBNP levels appear not greatly affected by renal function. NTproBNP shows promise in surveillance for pediatric heart transplant recipients. The greatest use appears to be in following trends for an individual instead of using an absolute value. [ABSTRACT FROM AUTHOR]

Objective. There are few established diagnostic tools to define non-IgE-mediated food hypersensitivity reactions. Cow milk protein allergy (CMPA) is a multisystem disorder affecting the gastrointestinal, skin, and lower and upper airway systems. This link is frequently missed because of subspecialty evaluation of the multisystem effects individually. The authors hypothesize that a more global evaluation based on a simple scored questionnaire will reveal this link. Methods. Over an 18-month period, children younger than 2 years with non-IgE-mediated CMPA were identified. A symptom questionnaire was developed and scored and also applied to a control population. The prevalence of symptoms in each group was compared and a cumulative score was determined. Symptoms evaluated included gastrointestinal, aerodigestive, lower airway, and skin symptoms. A positive response was scored 1 and a negative response scored 0. Results. Significant differences in prevalence rates between CMPA and control populations were noted, particularly in aerodigestive symptoms. There were marked differences in cumulative score between populations (P < .001). The authors identified a cut-off score at which there was close to 80% sensitivity and 90% specificity for distinguishing CMPA from a control population. Conclusion. A global evaluation of multiple systems can be an important diagnostic tool in determining CMPA in infants. [ABSTRACT FROM PUBLISHER]

Objective Criteria for sonographic diagnosis of monosodium urate (MSU) crystal deposition have been developed, but the interreader reproducibility of this modality is not well established. We therefore assessed agreement using a systematic approach. Methods Fifty male subjects ages 55-85 years were recruited during primary care visits to an urban Veterans Affairs hospital, and were assessed by musculoskeletal ultrasound (US) of the knees and first metatarsophalangeal (MTP) joints to evaluate for the double contour sign and tophi as evidence of MSU crystal deposition. Images were read by 2 blinded rheumatologists trained in musculoskeletal US, and the degree of concordance was determined for individual subjects, total joints, femoral articular cartilage (FAC), and first MTP joints. Subjects were further categorized into 3 diagnostic groups: gout, asymptomatic hyperuricemia (no gout, serum uric acid [UA] ≥6.9 mg/dl), and controls (no gout, serum UA ≤6.8 mg/dl), and reader concordance within these 3 groups was assessed. Results We observed almost perfect agreement between readers for 1) individual subjects (yes/no; n = 50, 100% agreement, κ = 1.000), 2) total joints (n = 200, 99% agreement, κ = 0.942), 3) FAC (n = 100, 99% agreement, κ = 0.942), and 4) first MTP joints (n = 100, 99% agreement, κ = 0.942). Furthermore, findings by side (right/left) and diagnostic group (gout, asymptomatic hyperuricemia, control) showed substantial to almost perfect concordance for all measures. MSU deposition was seen most commonly in gout patients, and deposition was also seen in some subjects with asymptomatic hyperuricemia, but in only 1 control. Conclusion Musculoskeletal US is reliable for detecting MSU deposition in FAC and first MTP joints in gout and asymptomatic hyperuricemia. [ABSTRACT FROM AUTHOR]

Background and Purpose: Ischemic stroke lesion volumes have proven difficult to analyze due to the extremely skewed shape of their underlying distribution. We introduce an extension of generalized linear models, beta regression, as a possible method of modeling extremely skewed distributions as evidenced in ischemic stroke lesion volumes. Methods: The NINDS rt-PA clinical trials measured ischemic stroke lesion volume as a secondary trial outcome. Three-month lesion volumes from these trials were analyzed using beta regression. A multi-variable regression model associating explanatory variables with ischemic stroke lesion volumes was constructed using accepted model building strategies and compared with the previously published volumetric analysis. Results: Beta regression produced a similar model when compared to the previous analysis published by the study group. All previously identified variables of importance were detected in the model building process. The age by treatment interaction described in previous studies was also found in this analysis, confirming the strong effect age has on stroke outcomes. Further, a treatment effect was elicited in terms of odds ratios, yielding a previously unknown quantification of the effect of rt-PA on lesion volumes. Conclusions: Beta regression proved adept in modeling ischemic stroke lesions and offered the interpretation of covariates in terms of odds ratios. Beta regression is seen as a legitimate alternative to analyze ischemic stroke volumes. Copyright © 2011 S. Karger AG, Basel [ABSTRACT FROM AUTHOR]

Objective: To assess the predictive value of baseline measures of impairment, disability, and quality of life for the timing of initiation of symptomatic treatment in early Parkinson disease (PD). Design: Inception cohort analysis. Setting: Ambulatory population from multiple sites in the United States and Canada. Participants: Four hundred thirteen patients with early, untreated PD who participated in 2 double-blind trials that assessed the potential of experimental drugs to serve as disease-modifying agents in PD. Intervention: Participants were randomized into treatment groups: creatine (n=67), minocycline (n=66), coenzyme Q10( n=71), GPI-1485(n=71), and placebo(n=138). Main Outcome Measure: Time between baseline assessment and need for the initiation of symptomatic treatment for PD. The following baseline variables were assessed for their relation to the main outcome measure, while adjusting for possible treatment effect: sex; age; level of education; race/ethnicity; disease duration; occupational status; and Unified Parkinson Disease Rating Scale (UPDRS), Medical Outcomes Study Short Form Survey, Modified Rankin Scale, Schwab and England Activities of Daily Living Scale, Total Functional Capacity Scale, 39-item Parkinson Disease Questionnaire, and Geriatric Depression Scale scores. Variables reaching statistical threshold in univariate analyses (α=.15) were entered into a multivariable Cox proportional hazards regression modelusing time tosymptomatic treatment as the dependent variable. Results: Approximately half (48.5%) of the participants reached end point within 12 months. Higher baseline impairment and disability, as determined by UPDRS III (motor section), UPDRS II (activities of daily living section, participant rating), and Modified Rankin Scale scores and level of education were independently associated with an earlier need for symptomatic treatment. Conclusions: In early PD, greater impairment and disability and higher level of education are independently associated with an earlier need for symptomatic treatment. [ABSTRACT FROM AUTHOR]

Background Skin cancers among commercial airline pilots have been reported to occur at increased rates in pilot populations worldwide. The reasons for these increases are unclear, but postulated factors include ionizing radiation, circadian disruption and leisure sun exposure. [ABSTRACT FROM PUBLISHER]

Dual‐specificity tyrosine phosphorylation‐regulated kinase‐1A (DYRK1A) is known to phosphorylate the microtubule‐associated tau protein. Overexpression is correlated with tau hyperphosphorylation and neurofibrillary tangle (NFT) formation in Alzheimer's disease (AD). This study assessed the potential of SM07883, an oral DYRK1A inhibitor, to inhibit tau hyperphosphorylation, aggregation, NFT formation, and associated phenotypes in mouse models. Exploratory neuroinflammatory effects were also studied. SM07883 specificity was tested in a kinase panel screen and showed potent inhibition of DYRK1A (IC50 = 1.6 nM) and GSK‐3β (IC50 = 10.8 nM) kinase activity. Tau phosphorylation measured in cell‐based assays showed a reduction in phosphorylation of multiple tau epitopes, especially the threonine 212 site (EC50 = 16 nM). SM07883 showed good oral bioavailability in multiple species and demonstrated a dose‐dependent reduction of transient hypothermia‐induced phosphorylated tau in the brains of wild‐type mice compared to vehicle (47%, p < 0.001). Long‐term efficacy assessed in aged JNPL3 mice overexpressing the P301L human tau mutation (3 mg/kg, QD, for 3 months) exhibited significant reductions in tau hyperphosphorylation, oligomeric and aggregated tau, and tau‐positive inclusions compared to vehicle in brainstem and spinal cord samples. Reduced gliosis compared to vehicle was further confirmed by ELISA. SM07883 was well tolerated with improved general health, weight gain, and functional improvement in a wire‐hang test compared to vehicle‐treated mice (p = 0.048). SM07883, a potent, orally bioavailable, brain‐penetrant DYRK1A inhibitor, significantly reduced effects of pathological tau overexpression and neuroinflammation, while functional endpoints were improved compared to vehicle in animal models. This small molecule has potential as a treatment for AD. [ABSTRACT FROM AUTHOR]