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The circadian stimulus is an important, validated and updated metric that describes the invisible influences of light on the human circadian system explicitly and scientifically. However, an absolute spectral power distribution must be supplied for its computation, which is only measurable by an expensive and complicated spectrometer. This paper proposes an alternative circadian stimulus computation model that is identified as the function CS(z, Ev) for white light sources based on the most common and simplest parameters of illuminance Ev in lux and the chromaticity coordinate z. These parameters are well known and widely used in both colour science and lighting technology. In order to prove the accuracy and availability of the model, an internal validation was performed with the adapted method repeating split data to check the goodness of the model fit. The fitted model achieved a maximum residual of 0.058 in the circadian stimulus quantity (R2 = 0.998). An external validation with the maximum residual of 0.030 (R2 = 0.999) provided stronger evidence for the usability of the model in applications. [ABSTRACT FROM AUTHOR]

Purpose: The "law of diminishing returns" (LODR) in early-onset scoliosis (EOS) is well-known. We hypothesized that previously observed variations between constructs may be related to the lateral distance that each construct lies from the spine. We therefore sought to determine whether the curve magnitude improvement and spinal length gains for distraction-based constructs in EOS are positively correlated with the collinearity of the spine and the convex-sided implant on posteroanterior radiographs., Methods: A prospectively-collected, multicenter EOS registry was queried for all patients who underwent non-fusion, distraction-based instrumentation surgery. Post-index radiographs were graded from 1 to 5 based on amount of overlap between the convex-sided rod and the apical vertebra. Grade 1: convex rod is lateral to convex-sided pedicle; Grade 2: overlaps the convex-sided pedicle; Grade 3: lies between pedicles; Grade 4: overlaps concave-sided pedicle; Grade 5: medial to concave-sided pedicle. ANOVA assessed the correlations between post-index overlap grade and change in (a) curve magnitude and (b) T1-T12 height. Multivariable regression modeling further assessed these associations., Results: 284 patients met all selection criteria and were included. On ANOVA, post-index grade was associated with curve magnitude (p <0.001) and T1-12 height (p = 0.028) change. Better curve correction and height change were associated with higher grade. On regression modeling, curve correction (R = 0.574) and T1-T12 height change (R = 0.339) remained significantly associated with grade when controlling for time, anchor locations, age, underlying diagnosis, and pre-index curve magnitude., Conclusion: More apical overlap by the convex rod was associated with better spinal deformity control and improved height gain., Level of Evidence Iii: Therapeutic., (© 2024. This is a U.S. Government work and not under copyright protection in the US; foreign copyright protection may apply.)

Aim: To better understand the reasons for reduced hospital admissions to a hospital general medicine service during COVID-19 lockdowns., Methods: A statistical model for admission rates to the General Medicine Service at Wellington Hospital, Aotearoa New Zealand, since 2015 was constructed. This model was used to estimate changes in admission rates for transmissible and non-transmissible diagnoses during and following COVID-19 lockdowns for total admissions and various sub-groups., Results: For the 2020 lockdown (n=734 admissions), the overall rate ratio of admissions was 0.71 compared to the pre-lockdown rate. Non-transmissible diagnoses, which constitute 87% of admissions, had an admission rate ratio of 0.77. Transmissible diagnoses, constituting 13% of admissions, had an admission rate ratio of 0.44. Reductions in admissions did not exacerbate existing ethnic disparities in access to health services. The lag in recovery of admission rates was more pronounced for transmissible than non-transmissible diagnoses. The 2021 lockdown (n=105 admissions) followed this pattern, but was of shorter duration with small numbers, and therefore measures were frequently not statistically significant., Conclusions: The biggest relative reduction in hospital admission was due to a reduction in transmissible illness admissions, likely due to COVID-related public health measures. However, the biggest reduction in absolute terms was in non-transmissible illnesses, where hospital avoidance may be associated with increased morbidity or mortality., Competing Interests: Nil., (© PMA.)

Background Context: Etiology of adolescent idiopathic scoliosis (AIS) is still unknown. Prior in vitro research suggests intervertebral disc pathomorphology as a cause for the initiation and progression of the spinal deformity, however, this has not been well characterized in vivo., Purpose: To quantify and compare lumbar disc health and morphology in AIS to controls., Study Design/setting: Cross-sectional study., Methods: All lumbar discs were imaged using a 3T MRI scanner. T2-weighted and quantitative T2* maps were acquired. Axial slices of each disc were reconstructed, and customized scripts were used to extract outcome measurements: Nucleus pulposus (NP) signal intensity and location, disc signal volume, transition zone slope, and asymmetry index. Pearson's correlation analysis was performed between the NP location and disc wedge angle for AIS patients. ANOVAs were utilized to elucidate differences in disc health and morphology metrics between AIS patients and healthy controls. α=0.05., Results: There were no significant differences in disc health metrics between controls and scoliotic discs. There was a significant shift in the NP location towards the convex side of the disc in AIS patients compared to healthy controls, with an associated increase of the transition zone slope on the convex side. Additionally, with increasing disc wedge angle, the NP center migrated towards the convex side of the disc., Conclusions: The present study elucidates morphological distinctions of intervertebral discs between healthy adolescents and those diagnosed with AIS. Discs in patients diagnosed with AIS are asymmetric, with the NP shifted towards the convex side, which was exacerbated by an increased disc wedge angle., Clinical Significance: Investigation of the MRI signal distribution (T2w and T2* maps) within the disc suggests an asymmetric pressure gradient shifting the NP laterally towards the convexity. Quantifying the progression of these morphological alterations during maturation and in response to treatment will provide further insight into the mechanisms of curve progression and correction, respectively., Competing Interests: Declarations of Competing Interests One or more of the authors declare financial or professional relationships on ICMJE-TSJ disclosure forms., (Copyright © 2023 Elsevier Inc. All rights reserved.)

Introduction: Patients with cerebral palsy (CP) may receive intrathecal baclofen (ITB) to reduce muscle spasticity and dystonia. It can be challenging to identify the proper dose of ITB, and anecdotally these dosing needs may change after spinal fusion surgery. This study aimed to evaluate the need for changes in ITB dosing following a spinal fusion in pediatric neuromuscular scoliosis (NMS) patients and identify predisposing factors for those changes., Methods: This was a retrospective case-control study of NMS patients with an ITB pump who later received a spinal fusion surgery. Dosing changes and the indications for the changes were postoperatively noted. Demographics, preoperative factors, and surgical factors were evaluated for correlation with dosing changes., Results: A total of 49 patients were included in this study. Most had no change in ITB dose (71.4%), and others required a change that averaged about 10%. Male patients, those with larger pumps, and those that had a longer hospital stay were more likely to require a decrease in dose. Complications were similar between groups. Three catheters were revised during surgery: two continued on the same dose and one required an increase in dose after surgery., Conclusions: Spinal fusion after ITB pump placement is feasible and safe. Most patients did not require dosing changes after spine fusion; however, careful evaluation postoperatively remains prudent., Competing Interests: Conflicts of Interest: The authors declare that there are no relevant conflicts of interest., (Copyright © 2023 The Japanese Society for Spine Surgery and Related Research.)

Background: Congenital myopathies (CMs) are complex conditions often associated with early-onset scoliosis (EOS). The purpose of this study was to investigate radiographic outcomes in CM patients undergoing EOS instrumentation as well as complications. Secondarily, we sought to compare these patients to a population with higher prevalence, cerebral palsy (CP) EOS patients., Methods: This is a retrospective study of a prospectively collected multicenter registry. The registry was queried for EOS patients with growth-sparing instrumentation (vertical expandable prosthetic titanium ribs, magnetically controlled growing rods, traditional growing rod, or Shilla) and a CM or CP diagnosis with minimum 2 years follow-up. Outcomes included major curve magnitude, T1-S1 height, kyphosis, and complications., Results: Sixteen patients with CM were included. Six (37.5%) children with CM experienced 11 complications by 2 years. Mean major curve magnitude for CM patients was improved postoperatively and maintained at 2 years (P<0.01), with no significant increase in T1-S1 height or maximum kyphosis(P>0.05). Ninety-seven patients with CP EOS were included as a comparative cohort. Fewer CP patients required baseline respiratory support compared with CM patients (20.0% vs. 92.9%, P<0.01). Fifty-four (55.7%) CP patients experienced a total of 105 complications at 2 years. There was no evidence that the risk of complication or radiographic outcomes differs between cohorts at 2 years, though CP EOS patients experienced significant improvement in all measurements at 2 years., Conclusions: EOS CM children face a high risk of complication after growing instrumentation, with similar curve correction and risk of complication to CP patients., Level of Evidence: Level III., Competing Interests: The authors declare no conflicts of interest., (Copyright © 2021 Wolters Kluwer Health, Inc. All rights reserved.)

Background: Inadequate treatment of painful conditions in children is a significant and complex problem. The objective of this study was to examine the effect of socioeconomic status on the provision of analgesic medicines at discharge in children treated emergently for a long-bone fracture., Methods: A retrospective review of all patients during a 1-year period with a long-bone fracture treated in 2 urban pediatric emergency departments (EDs) was performed., Results: Eight hundred seventy-three patients were identified who met our inclusion criteria. Sixty percent of patients received a prescription for an opioid-containing medicine, and 22% received a prescription for an over-the-counter analgesic medicine at ED discharge. Socioeconomic status had no effect on opioid analgesic prescriptions at discharge. Patients in the lowest-income group were younger, presented to the ED longer after an injury, were likely nonwhite, and had higher rates of over-the-counter analgesic medicine prescriptions provided at discharge. Higher-income patients were likely white and non-Hispanic, presented to the ED sooner, and were less likely to receive a prescription for a nonopioid analgesic medicine., Conclusions: Socioeconomic status is associated with different nonopioid analgesic prescription patterns in children treated in the ED for a long-bone fracture, but had no effect on opioid analgesic prescriptions., Competing Interests: Disclosure: The authors declare no conflict of interest., (Copyright © 2018 Wolters Kluwer Health, Inc. All rights reserved.)

This randomized, double-blind, placebo-controlled, n-of-1 crossover study assessed whether metformin's side effects are reproducible in patients with a history of metformin intolerance. Participants completed up to four cycles of 2 weeks of metformin exposure and 2 weeks of placebo exposure. Participants completed surveys based on the Gastrointestinal Symptom Rating Scale and the Treatment Satisfaction Questionnaire for Medication. The primary hypotheses were that treatment satisfaction would be equal for placebo and metformin and that more than 30% of the study enrollees would be able to adhere to a higher dose of metformin 6 months after participation. Thirteen patients (all women, mean age 52.4 years) enrolled, three of whom were lost to follow-up or were non-adherent to study protocol. Metformin was associated with significantly lower global treatment satisfaction scores compared with placebo (39.58 vs. 53.75, P < .05 ) but participants could not distinguish metformin from placebo and did not report higher rates of gastrointestinal side effects on metformin. Two out of 10 participants adhered to a higher dose of metformin after trial completion. Metformin appears to have barriers to use beyond its classic gastrointestinal side effects., (© 2020 John Wiley & Sons Ltd.)

Introduction: Pediatric septic arthritis (SA) is a condition that can be associated with significant morbidity. Although previous research has been on predictive care pathways, scrutiny of the literature continues to reveal wide differences in the patient evaluation and management. The purpose of this study was to define the differences in joint aspiration for the evaluation of pediatric SA across pediatric tertiary care institutions in the United States., Methods: Surgeons from 18 pediatric tertiary care centers across the United States were surveyed on current institutional practices regarding joint aspiration, laboratory studies, MRI usage, and treatment timing in the evaluation for SA. Responses were recorded by institution and analyzed to generate descriptive statistics., Results: Responses were received from all institutions asked to participate. Overall, joint specific practice variation exists regarding the person completing the aspiration, where the aspiration is performed, utilization of image guidance, and the utilization of anesthesia. Additional areas of variation included the method and calculation of cell count and the routine use of MRI., Discussion: Significant practice variations exist across pediatric tertiary care centers for the evaluation of pediatric SA. Using these data, future prospective studies can be used to unify institutional practices to minimize practice variation and ultimately improve the care delivery to pediatric patients presenting with SA.

Background Immobilization after hip reconstruction in children with cerebral palsy varies according to surgeon preference. The effect of postoperative immobilization on postoperative pain is unknown. Success in achieving hip stability and complications may also differ depending on the immobilization technique utilized. Questions/purposes Using retrospective data, we aimed to evaluate: (a) what effect does postoperative immobilization with hip spica casting versus short leg casts and bar (SLCaB); have on pain and pain management in children with quadriplegic cerebral palsy undergoing femoral and/or pelvic osteotomy? and (b) Do complications and radiographic outcomes differ between those treated postoperatively with hip spica casting and those in short leg casts? Materials and Methods Children with quadriplegic cerebral palsy (GMFCS IV-V, mean age 7.8 years [range: 3-15 years]) undergoing femoral or pelvic osteotomy between 2012 and 2014 in the treatment of spastic hip subluxation were reviewed. Modes of immobilization were compared, between spica casting (n=15) and SLCaB (n=12). Preoperative, perioperative, and postoperative pain was quantified between groups. In-hospital epidural dosage, morphine equivalent dosages (MED), adjunctive medications, early maintenance of radiographic hip stability, and all complications were noted and analyzed. Results Children were more likely to have spica cast immobilization if they were younger. Postoperative pain scores were similar between groups, with comparable patterns of epidural and MED administered during hospitalization. Spica casts were often flared up during hospitalization, but skin ulcers were uncommon and comparable between the two groups. Within 12 months of surgery, more ipsilateral femur fractures were observed distant to implants in the hip spica group, although the incidence of fractures did not meet statistical thresholds. Conclusion Spica casting and SLCaB after neuromuscular hip reconstruction did not show a difference in hip stability, narcotic pain medication usage or complication profile., Competing Interests: The authors have declared that no competing interests exist., (Copyright © 2020, Truong et al.)

Data suggest that nutrient order during a meal significantly impacts postprandial glucose and insulin excursions in type 2 diabetes, while its effects in prediabetes have not been reported. Fifteen participants with prediabetes consumed the same meal on 3 days in random order: carbohydrate first, followed 10 minutes later by protein and vegetables (CF); protein and vegetables first, followed 10 minutes later by carbohydrate (PVF); or vegetables first followed by protein and carbohydrate (VF). Blood was sampled for glucose and insulin measurements at 0, 30, 60, 90, 120, 150 and 180 minutes. Incremental glucose peaks were similarly attenuated by >40% in the PVF and VF meal conditions compared with CF. The incremental area under the curve for glucose was 38.8% lower following the PVF meal order, compared with CF, and postprandial insulin excursions were significantly lower in the VF meal condition compared with CF. The CF meal pattern showed marked glycaemic variability whereas glucose levels were stable in the PVF and VF meal conditions. Food order presents a novel, simple behavioural strategy to reduce glycaemic excursions in prediabetes., (© 2018 John Wiley & Sons Ltd.)

Background: Early-onset scoliosis (EOS) affects roughly 1 to 2 out of 10,000 live births per year. Because this subset of patients has a yet to achieve a majority of their skeletal growth, a number of treatment challenges need to be addressed before surgical intervention. If left untreated, EOS can cause a number of problems throughout the patient's lifespan, particularly in regards to the growth of the thorax and pulmonary development. A wide variety of surgical systems and techniques are available to the treating surgeon., Methods: A review of the orthopaedic literature from 2010 to 2015 relating to pediatric spine growth modulation was performed. Ninety-eight papers were identified and, following exclusion criteria, a total of 31 papers were selected for further review., Results: This paper summarizes the recently published literature regarding growth-friendly spinal implants, the status of their Food and Drug Administration approval labeling as well as the indications, applications, and complications associated with their implementation., Conclusions: There are a growing number of options at the surgeon's disposal when treating patients with EOS. As surgeons, we must continue to be vigilant in our demand for sound clinical evidence as we strive to provide optimal care for our patients. The rapidly advancing field of spinal growth modulation is exciting. More work must be done to further enhance our ability to predictably modulate growth in the pediatric spine.

Schizophrenia is associated with abnormalities in cortical thickness, including both thicker and thinner cortices than controls. Although less reliably than in patients, non-psychotic relatives of schizophrenia patients have also demonstrated both thicker and thinner cortices than controls, suggesting an effect of familial or genetic liability. We investigated cortical thickness in 25 schizophrenia patients, 26 adult non-psychotic first-degree biological relatives, and 23 community controls using the automated program FreeSurfer. Contrary to hypotheses, we found relatives of schizophrenia patients had greater cortical thickness in all lobes compared to patients and controls; however, this finding was not as widespread when compared to controls. In contrast, schizophrenia patients only demonstrated a thinner right fusiform region than controls and relatives. Our finding of greater thickness in adult biological relatives could represent a maladaptive abnormality or alternatively, a compensatory mechanism. Previous literature suggests that the nature of abnormalities in relatives can vary by the age of relatives and change across the developmental period. Abnormalities in patients may depend on lifestyle factors and on current and previous anti-psychotic medication use. Our results speak to the need to study various populations of patients and relatives across the lifespan to better understand different developmental periods and the impact of environmental factors. © 2015 Wiley Periodicals, Inc., (© 2015 Wiley Periodicals, Inc.)

Objective: Post-cardiopulmonary bypass biventricular pacing improves hemodynamics but without clearly defined predictors of response. Based on preclinical studies and prior observations, it was suspected that diastolic dysfunction or pulmonary hypertension is predictive of hemodynamic benefit., Design: Randomized controlled study of temporary biventricular pacing after cardiopulmonary bypass., Setting: Single-center study at university-affiliated tertiary care hospital., Interventions: Patients who underwent bypass with preoperative ejection fraction ≤40% and QRS duration ≥100 ms or double-valve surgery were enrolled. At 3 time points between separation from bypass and postoperative day 1, pacing delays were varied to optimize hemodynamics., Participants: Data from 43 patients were analyzed., Measurements and Main Results: Cardiac output and arterial pressure were measured under no pacing, atrial pacing, and biventricular pacing. Preoperative echocardiograms and pulmonary artery catheterizations were reviewed, and measures of both systolic and diastolic function were compared to hemodynamic response. Early after separation, improvement in cardiac output was positively correlated with pulmonary vascular resistance (R(2) = 0.97, p<0.001), ventricle wall thickness (R(2) = 0.72, p = 0.002)), and E/e', a measure of abnormal diastolic ventricular filling velocity (R(2) = 0.56, p = 0.04). Similar trends were seen with mean arterial pressure. QRS duration and ejection fraction did not correlate significantly with improvements in hemodynamics., Conclusions: There may be an effect of biventricular pacing related to amelioration of abnormal diastolic filling patterns rather than electrical resynchronization in the postoperative state., (Copyright © 2015. Published by Elsevier Inc.)

Background: Pelvic injuries in young children are rare, and it has been difficult to establish clinical guidelines to assist providers in managing blunt pelvic trauma, especially in non-Level 1 trauma centers., Objective: Our aim was to describe the relationship among clinical findings, mechanism of injury, and the radiographic resources utilized in children with pelvic fractures presenting to a non-Level 1 trauma center., Methods: A retrospective review of patients with a pelvic fracture treated in two urban pediatric Level 3 emergency departments was performed., Results: Between 2001 and 2010, a total of 208 patients were identified. Avulsion/iliac wing fractures were the most common fractures (58.7%), and sports-related injuries were the most common mechanism of injury (50.0%). Children with sports-related injuries were more likely to sustain an avulsion fracture (p<0.001), less likely to have a computed tomography scan obtained in the emergency department (p<0.001), and less likely to have an associated injury (p<0.001) than other children. Children struck by a motor vehicle (p<0.001) or involved in a motor vehicle accident (p<0.001) were more likely to receive a computed tomography scan (p<0.001) and have associated head and extremity injuries (p<0.001). Mechanism of injury was associated with abnormal computed tomography scans. Nearly all patients were treated nonoperatively (98.1%) and no deaths were reported in this study., Conclusions: Patterns of injury, based on mechanism of injury, have been reported to assist the assessment and management of children with minor pelvic injuries., (Copyright © 2014 Elsevier Inc. All rights reserved.)

Introduction: Complete reporting assists readers in confirming the methodological rigor and validity of findings and allows replication. The reporting quality of observational functional magnetic resonance imaging (fMRI) studies involving clinical participants is unclear., Objectives: We sought to determine the quality of reporting in observational fMRI studies involving clinical participants., Methods: We searched OVID MEDLINE for fMRI studies in six leading journals between January 2010 and December 2011.Three independent reviewers abstracted data from articles using an 83-item checklist adapted from the guidelines proposed by Poldrack et al. (Neuroimage 2008; 40: 409-14). We calculated the percentage of articles reporting each item of the checklist and the percentage of reported items per article., Results: A random sample of 100 eligible articles was included in the study. Thirty-one items were reported by fewer than 50% of the articles and 13 items were reported by fewer than 20% of the articles. The median percentage of reported items per article was 51% (ranging from 30% to 78%). Although most articles reported statistical methods for within-subject modeling (92%) and for between-subject group modeling (97%), none of the articles reported observed effect sizes for any negative finding (0%). Few articles reported justifications for fixed-effect inferences used for group modeling (3%) and temporal autocorrelations used to account for within-subject variances and correlations (18%). Other under-reported areas included whether and how the task design was optimized for efficiency (22%) and distributions of inter-trial intervals (23%)., Conclusions: This study indicates that substantial improvement in the reporting of observational clinical fMRI studies is required. Poldrack et al.'s guidelines provide a means of improving overall reporting quality. Nonetheless, these guidelines are lengthy and may be at odds with strict word limits for publication; creation of a shortened-version of Poldrack's checklist that contains the most relevant items may be useful in this regard.

Environmental conditions can influence the physiology of marine organisms and have important implications for their reproductive performance and capacity to supply new recruits. This study examined the seasonal reproductive patterns of the coral Montipora capitata in habitats exposed to different sedimentation regimes. Although M. capitata is a main reef-building coral in the Hawaiian Archipelago, little is known about the gametogenic cycle and reproductive ecology of this important species. Our results indicate that gamete production in M. capitata is a resilient process; no differences in gamete development or fecundity were observed among sites with very different sedimentation regimes. The gametogenic cycle of M. capitata lasts between 10 and 11 months, with spawning occurring over 3-5 months during warmer months (May-September). Oocytes were found throughout the year, but spermatocysts were only found April-August. The largest increases in oocyte size occurred during February to May, the months when solar radiation increased rapidly. The largest variation in oocyte sizes was found during July and August; during this period individual colonies contained mature oocytes for immediate spawning and new oocytes being formed for spawning the next year. The capacity of M. capitata to reproduce in areas with high sedimentation is an interesting finding highlighting the potential of the species for acclimatization, adaptation, or both. Despite this optimistic finding, the management of terrestrial runoff and the restoration of habitat quality for corals remains a top priority to ensure the renewal and maintenance of coral populations.

Neurobiological mechanisms underlying the development of major depressive disorder (MDD) may differ depending on age-of-onset. Our aim was to compare patients who differ in age-of-onset, while controlling for illness duration, and number of depressive episodes. By directly comparing early-(EOD) and late-onset (LOD) patients, we examined whether age-of-onset is associated with changes in the extent or spatial pattern of cortical thickness. Cross-sectional comparison of cortical thickness in EOD vs. LOD. Age-of-onset was determined based on self-report, with EOD defined as onset prior to age 25. Reduced cortical thickness in the dorsal-lateral prefrontal cortex (DLPFC), pre- and postcentral gyrus, and the lingual gyrus were found in EOD compared to healthy controls (p<0.001). In linear regression models controlling for number of episodes, illness duration, severity, and sex, differences (at p<0.001) were found between EOD and LOD in the bilateral posterior cingulate, parahippocampal gyri, right precuneus, lingual, and fusiform gyri, but not the DLPFC. EOD is associated with greater disturbances in cortical thickness than LOD, even when duration of illness and other factors are controlled. These results provide novel insights on how development of depression is differentiated by age., (© 2013 Published by Elsevier Ireland Ltd.)

This study used the random forest algorithm to predict outcomes of intramuscular psoas lengthening as part of a single event multi-level surgery in patients with cerebral palsy. Data related to preoperative medical history, physical exam, and instrumented three-dimensional gait analysis were extracted from a historic database in a motion analysis center. Data from 800 limbs of patients with diplegic cerebral palsy were analyzed. An index quantifying the overall deviation in pelvic tilt and hip flexion was used to define outcome categories. The random forest algorithm was used to derive criteria that predicted the outcome of a limb. The criteria were applied to limbs that underwent psoas lengthening with outstanding results (accuracy=.78, sensitivity=.82, specificity=.73). The criteria were then validated using an extended retrospective case-control design. Case limbs met the criteria and underwent psoas lengthening. Control limbs met the criteria, but did not undergo psoas lengthening. Over-treated limbs failed the criteria and underwent psoas lengthening. Other-treated limbs failed the criteria and did not undergo psoas lengthening. The rate of good outcomes among Cases exceeded that observed among controls (82% vs. 60%, relative risk=1.37), and far exceeded that observed in Over-treated limbs (27%). Other-treated limbs had good outcomes 52% of the time. Application of the criteria in the future is estimated to increase the overall rate of good pelvis-hip outcomes from 58% to 72% among children with diplegia who undergo single-event multi-level surgery (SEMLS)., (Copyright © 2012 Elsevier B.V. All rights reserved.)

Objectives: To systematically summarize the randomized trial evidence regarding the relative effectiveness of cognitive behavioural therapy (CBT) in patients with depression in receipt of disability benefits in comparison to those not receiving disability benefits., Data Sources: All relevant RCTs from a database of randomized controlled and comparative studies examining the effects of psychotherapy for adult depression (http://www.evidencebasedpsychotherapies.org), electronic databases (MEDLINE, EMBASE, PSYCINFO, AMED, CINAHL and CENTRAL) to June 2011, and bibliographies of all relevant articles. STUDY ELIGIBILITY CRITERIA, PARTICIPANTS AND INTERVENTION: Adult patients with major depression, randomly assigned to CBT versus minimal/no treatment or care-as-usual., Study Appraisal and Synthesis Methods: Three teams of reviewers, independently and in duplicate, completed title and abstract screening, full text review and data extraction. We performed an individual patient data meta-analysis to summarize data., Results: Of 92 eligible trials, 70 provided author contact information; of these 56 (80%) were successfully contacted to establish if they captured receipt of benefits as a baseline characteristic; 8 recorded benefit status, and 3 enrolled some patients in receipt of benefits, of which 2 provided individual patient data. Including both patients receiving and not receiving disability benefits, 2 trials (227 patients) suggested a possible reduction in depression with CBT, as measured by the Beck Depression Inventory, mean difference [MD] (95% confidence interval [CI]) = -2.61 (-5.28, 0.07), p = 0.06; minimally important difference of 5. The effect appeared larger, though not significantly, in those in receipt of benefits (34 patients) versus not receiving benefits (193 patients); MD (95% CI) = -4.46 (-12.21, 3.30), p = 0.26., Conclusions: Our data does not support the hypothesis that CBT has smaller effects in depressed patients receiving disability benefits versus other patients. Given that the confidence interval is wide, a decreased effect is still possible, though if the difference exists, it is likely to be small.

The novel coinhibitory receptor BTLA may have a regulatory role in maintaining peripheral tolerance; however, its role in autoimmune diabetes is unknown. In this study, we show that anti-BTLA mAb 6F7 selectively depleted pathogenic B and CD4+ T(H) cells; enhanced the proportion of cells with the forkhead box p3+ PD-1+CD4+ regulatory T phenotype; and increased the production of potentially protective (IL-10) and detrimental (IL-2, IFN-gamma) cytokines in NOD mice. As interactions between BTLA and PD-1 coinhibitory pathways have been described in the cardiac allograft model, we also investigated if these pathways may have significant interaction in autoimmune diabetes. Anti-BTLA inhibited anti-PD-1-potentiated total IL-12 (p40+p70) production, suggesting the possibility that anti-BTLA may have a greater effect in the setting of anti-PD-1-triggered diabetes. To test this, NOD mice at 4 and 10 weeks of age were treated with anti-BTLA mAb, anti-PD-1 mAb, both mAb, or isotype control and were monitored for diabetes development. Although anti-BTLA mAb delayed diabetes onset significantly in 10- but not 4-week-old NOD mice, anti-BTLA mAb attenuated anti-PD-1-induced diabetes in both age groups. Hence, strategies targeting BTLA+ lymphocytes or therapies enhancing the BTLA-negative cosignal may prove valuable in treating autoimmune diabetes.

Although insulin independence is maintained in most islet recipients at 1 yr after transplant, extended follow-up has revealed that many patients will eventually require insulin therapy. Previous studies have shown that islet autografts are prone to chronic failure in large animals and humans, suggesting that nonimmunological events contribute to islet graft functional decay. Early intervention with therapies that promote graft stability should provide a measurable benefit over time. In this study, the efficacy of the long-acting glucagon-like peptide-1 analog liraglutide was explored in a porcine marginal mass islet autograft transplant model. Incubation with liraglutide enhanced porcine islet survival and function after prolonged culture. Most vehicle-treated (83%) and liraglutide-treated (80%) animals became insulin independent after islet autotransplantation. Although liraglutide therapy did not improve insulin independence rates or blood glucose levels after transplant, a significant increase in insulin secretion and acute-phase insulin response was observed in treated animals. Surprisingly, no evidence for deterioration of graft function was observed in any of the transplanted animals over more than 18 months of follow-up despite significant weight gain; in fact, an enhanced response to glucose developed over time even in control animals. Histological analysis showed that intraportally transplanted islets remained highly insulin positive, retained alpha-cells, and did not form amyloid deposits. This study demonstrates that marginal mass porcine islet autografts have stable long-term function, even in the presence of an increasing metabolic demand. These results are discrepant with previous large animal studies and suggest that porcine islets may be resistant to metabolic failure.

Currently, lifelong immune suppression regimens are required for solid organ and cellular transplantation and carry significant increased risk of infection, malignancy, and toxicity. For non-life-saving procedures such as islet transplantation, the risk/benefit ratio of lifelong immunosuppression versus benefit from transplantation requires even more careful balance. The search for specific agents to modulate the immune system without chronic immunosuppression is important for the broad application of islet transplantation. The T-cell immunoglobulin mucin (TIM) family is a distinct group of coreceptors that are differentially expressed on T(H)1 and T(H)2 cells, and have the potential to regulate both cytotoxic and humoral immune responses. Completed murine studies demonstrate Tim pathways may be important in the regulation of tolerance to self (auto), harmless (allergic), and transplant (allo) antigen; however, the potential impact of targeting Tim coreceptors has yet to be fully explored in transplantation tolerance induction or autoimmune disease. The current review examines the impact of Tim coreceptor targeting as an emerging therapeutic option for regulating autoimmune diseases and prevention of allograft rejection.

The novel coinhibitory receptor B and T lymphocyte attenuator (BTLA) has been implicated in the regulation of autoimmune and may potentially play a role in alloimmune responses. An anti-BTLA monoclonal antibody has been reported to prolong fully major histocompatibility complex-mismatched cardiac allograft survival, and we test the hypothesis that anti-BTLA monoclonal antibody PJ196 may synergize with cytotoxic T lymphocyte antigen-4 immunoglobulin (CTLA4Ig) costimulatory blockade in islet transplantation. We investigated the potential of PJ196, and show that it did not deplete BTLA expressing cells, but it caused down-regulation of BTLA on the surface of lymphocytes and accumulation of cells with regulatory phenotype at the graft site, promoting islet allograft acceptance together with CTLA4Ig. The combination of BTLA coinhibitory modulation and CTLA4Ig costimulatory blockade may be an effective adjunctive strategy for inducing long-term allograft survival.

Currently, lifelong immune suppression regimens are required for solid organ and cellular transplantation and carry significant increased risk of infection, malignancy, and toxicity. For non-life-saving procedures such as islet transplantation, the risk/benefit ratio of lifelong immunosuppression versus benefit from transplantation requires even more careful balance. The search for specific agents to modulate the immune system without chronic immunosuppression is important for the broad application of islet transplantation. The T-cell immunoglobulin mucin (TIM) family is a distinct group of coreceptors that are differentially expressed on T H 1 and T H 2 cells, and have the potential to regulate both cytotoxic and humoral immune responses. Completed murine studies demonstrate Tim pathways may be important in the regulation of tolerance to self (auto), harmless (allergic), and transplant (allo) antigen; however, the potential impact of targeting Tim coreceptors has yet to be fully explored in transplantation tolerance induction or autoimmune disease. The current review examines the impact of Tim coreceptor targeting as an emerging therapeutic option for regulating autoimmune diseases and prevention of allograft rejection.

Background: Despite recent progress in clinical islet transplantation, the cumulative world experience remains small. Optimizing protection of islets throughout the isolation, purification, and peritransplant period remains critical to outcome. We herein investigate the potential detrimental impact of maintaining islets in a pelleted state for periods preceding implantation. We hypothesize that periods of islet compaction lead to impairment if islet function in vivo., Methods: In this study, 250-islet marginal mass transplants were conducted in the BALB/c syngeneic mouse model using islets either preincubated as an islet pellet or suspended in culture during the 30 min immediately preceding transplant. Nonfasting blood glucose, intraperitoneal glucose tolerance test, graft histology, and graft insulin content were all used to monitor graft function up to four weeks posttransplant., Results: Maintaining islets in a compact pellet for 30 min prior to transplantation significantly reduces the proportion of transplant recipients that achieve normoglycemia (from 100% to 38%, P=0.026) and increases the proportion of apoptotic beta-cells., Conclusion: Our findings confirm that damage induced by sustained islet compaction results in poor graft outcome in mice. These findings raise concerns relating to potential damage to human islets prior to clinical transplantation, and this will be explored in further studies.

Autoaggressive T cells directed against insulin secreting pancreatic beta-cells mediate the development of type 1 diabetes. Islet transplantation offers superior glycemic control over exogenous insulin, but chronic immunosuppression limits its broad application. Pathogenic T cells are also important in allograft rejection. Inducing and maintaining antigen-specific peripheral T-cell tolerance toward beta-cells is an attractive strategy to prevent autoimmune disease, and to facilitate treatment of diabetes with islet allografts without long-term immunosuppression. Recent efforts have focused on blocking costimulatory T-cell signals for tolerance induction. Although costimulatory blockade can prolong graft survival, true immunological tolerance remains elusive. Costimulatory signals may even be required for the maintenance of peripheral tolerance. The discovery of novel coinhibitory T-cell pathways, including CTLA-4, PD-1, and BTLA, offers an alternative approach. Stimulating negative T cell cosignals alone or in combination may help induce tolerance. The focus of this review is to summarize the strategies directed at turning off the immune response by exploiting these negative cosignaling pathways in tolerance induction in islet transplantation. Activating several coinhibitory pathways together may be synergistic in preventing pathogenic T-cell responses. Tolerance induction will likely rely on understanding the balance of positive and negative signals affecting the state of T-cell activation.

More than 500 patients with type 1 diabetes mellitus have now received islet transplants at over 50 institutions worldwide in the past 5 years. Rates of insulin independence at 1 year with current protocols are impressive. However, inexorable decay of islet function over time indicates that there are many opportunities for improvement. Improved control of glycosylated hemoglobin and reduced risk of recurrent hypoglycemia are seen as important benefits of islet transplantation, irrespective of the status regarding insulin independence. For the use of islet transplantation to expand it is essential that the donor-to-recipient ratio be reliably reduced to 1 : 1. Enormous opportunities lie ahead for the development of successful living donor islet transplantation, single donor protocols, improved engraftment, islet proliferation in vitro and in the recipient, alternative islet sources, and novel tolerizing drugs. With these emerging opportunities, islet transplantation may expand to include more patients with type 1 diabetes, including children, and will not be restricted to the most unstable forms of the disease, as it is today.

While the field of islet transplantation has evolved over the past 30 years and exponential progress and increase in clinical activity has occurred during the past 5 years, it is clear that major challenges still remain, particularly in understanding why islet function seems to decay over time. High one-year rates of insulin independence, and high 5-year rates of partial islet function (with C-peptide secretion and protection from hypoglycemia) are now routine. Improved control of glycated HbA1c and reduced risk of recurrent hypoglycemia are benefits of islet transplantation irrespective of the status of insulin independence. If complete and sustained freedom from insulin is the primary objective, it is clear that whole pancreas transplantation still offers far superior metabolic reserve. However, the less interventional nature of islet infusion and avoidance of major surgery are advantages of islet transplantation over whole pancreas strategies. While the anti-rejection drugs available today may have had an acceptable safety profile in most islet transplant recipients, the drug-related and dose-limiting side effects have proved to be a challenge in some patients. Current islet-alone transplantation requires lifelong immunosuppression and is limited to patients with recurrent severe hypoglycemia and severe labile diabetes. More effective treatments are needed to control both acute rejection and recurrent autoimmunity. Remarkable opportunities lie ahead for improved islet survival, better engraftment and the possibility of expansion of islet mass both in culture and possibly within the patient after transplantation. Living-donor islet transplantation offers one option to expand the available donor supply, but remains controversial because of the potential for diabetes induction or other morbidities in a healthy donor. The development of less toxic immunosuppression and perhaps immunological tolerance will one day also have a huge impact on this field. Alternative tissue sources from either xenogenic sources or stem cells will ultimately solve the challenge of limited donor supply.

Opioid ligands may exert antinociception through receptors expressed on peripheral afferent axons. Whether local opioid receptors might attenuate neuropathic pain is uncertain. In this work, we examined the function and expression of local mu opioid receptors (MORs) associated with the chronic constriction injury (CCI) model of sciatic neuropathic pain in rats. Low-dose morphine or its carrier were percutaneously superfused over the CCI site with the injector blinded to the identity of the injectate. Morphine, but not its carrier, and not equimolar systemic doses of morphine reversed thermal hyperalgesia in a dose-related, naloxone-sensitive fashion. Moreover, analgesia was conferred at both 48 hours and 14 days after CCI, times associated with very different stages of nerve repair. Equimolar local DAGO ([D-Ala2, N-Me-Phe4, Gly5-(ol)] enkephalin), a selective MOR ligand, provided similar analgesia. Local morphine also attenuated mechanical allodynia. MOR protein was expressed in axonal endbulbs of Cajal just proximal to the injury site, in aberrantly regenerating small axons in the epineurial sheath around the CCI site and in residual small axons distal to the CCI lesion. Sensory neurons ipsilateral to CCI had an increase in the proportion of neurons expressing MOR. We suggest that local MOR expressed in axons may be exploited to modulate some forms of neuropathic pain.