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Background: Typically, the fitness of UK firefighters is assessed via submaximal estimate methods due to the low demands on time, money, expertise and equipment. However, the firefighter-specific validity of such testing in relation to maximum aerobic capacity (V˙O2max) and particularly muscular strength is not well established., Aims: To examine the validity of submaximal methods to estimate V˙O2max and maximal strength in operational firefighters., Methods: Twenty-two full-time operational firefighters (3 female) completed same-day submaximal (Chester Step Test; CST) and maximal (treadmill) assessments of V˙O2max, with a sub-sample of 10 firefighters (1 female) also completing submaximal and maximal back-squat (i.e. one repetition maximum; 1RM) assessments. All participants then completed the Firefighter Simulation Test (FFST) within 2-4 days., Results: CST underestimated actual V˙O2max by 1.4 ml·kg-1·min-1 (~3%), although V˙O2max values were positively correlated (r = 0.61, P < 0.01) and not significantly different. Estimated V˙O2max values negatively correlated with FFST performance (r = -0.42). Predicted 1RM underestimated actual 1RM by ~2%, although these values were significantly correlated (r = 0.99, P < 0.001) and did not significantly differ. The strongest predictive model of FFST performance included age, body mass index, and direct maximal measures of 1RM and V˙O2max., Conclusions: Submaximal back-squat testing offers good validity in estimating maximum firefighter strength without exposure to the fatigue associated with maximal methods. The CST provides a reasonably valid and cost-effective V˙O2max estimate which translates to firefighting task performance, although the error observed means it should be used cautiously when making operational decisions related to V˙O2max benchmarks., (© The Author(s) 2024. Published by Oxford University Press on behalf of the Society of Occupational Medicine.)

Background: Multimorbidity, typically defined as having two or more long-term health conditions, is associated with reduced wellbeing and life expectancy. Understanding the determinants of multimorbidity, including whether they are causal, may help with the design and prioritisation of prevention interventions. This study seeks to assess the causality of education, BMI, smoking and alcohol as determinants of multimorbidity, and the degree to which BMI, smoking and alcohol mediate differences in multimorbidity by level of education., Methods: Participants were 181,214 females and 155,677 males, mean ages 56.7 and 57.1 years respectively, from UK Biobank. We used a Mendelian randomization design; an approach that uses genetic variants as instrumental variables to interrogate causality., Results: The prevalence of multimorbidity was 55.1%. Mendelian randomization suggests that lower education, higher BMI and higher levels of smoking causally increase the risk of multimorbidity. For example, one standard deviation (equivalent to 5.1 years) increase in genetically-predicted years of education decreases the risk of multimorbidity by 9.0% (95% CI: 6.5 to 11.4%). A 5 kg/m 2 increase in genetically-predicted BMI increases the risk of multimorbidity by 9.2% (95% CI: 8.1 to 10.3%) and a one SD higher lifetime smoking index increases the risk of multimorbidity by 6.8% (95% CI: 3.3 to 10.4%). Evidence for a causal effect of genetically-predicted alcohol consumption on multimorbidity was less strong; an increase of 5 units of alcohol per week increases the risk of multimorbidity by 1.3% (95% CI: 0.2 to 2.5%). The proportions of the association between education and multimorbidity explained by BMI and smoking are 20.4% and 17.6% respectively. Collectively, BMI and smoking account for 31.8% of the educational inequality in multimorbidity., Conclusions: Education, BMI, smoking and alcohol consumption are intervenable causal risk factors for multimorbidity. Furthermore, BMI and lifetime smoking make a considerable contribution to the generation of educational inequalities in multimorbidity. Public health interventions that improve population-wide levels of these risk factors are likely to reduce multimorbidity and inequalities in its occurrence., (© 2023. BioMed Central Ltd., part of Springer Nature.)

Community-based group physical activity programs promote exercise opportunities for older people. The aim of this study was to examine the short-term, new participant effect after joining Vitality, a community-based group physical activity program available in the East of England for older adults. Two independent groups of participants were assessed before and after an 8 week period: a group recruited from the 'Vitality' program (VP) (n 15, age: Age = 69.4 ± 6.4 y), and; a non-intervention control (CON) group (n 14, age: 64.5 ± 5.8 y). Assessment outcomes included basic physical health measures, a fitness test battery, and three psychological scales. The VP group recorded statistically significant improvements on the following outcomes: body mass (VP: -1.39 kg/CON: -0.2 kg), body mass index (VP: -1.5 kg/CON: -0.2 kg), 6 min walk (VP: +42.81 m/CON: -0.45 m), 30 s sit-to-stand (VP: -1.7 s/CON: -0.7 s), the chair sit-and-reach (VP: +3.12 cm/CON: +1.90 cm), and the 30 s arm curl test (VP: + 2 reps/CON: +0.9 reps). No significant differences were found with the other outcomes assessed. New members to the Vitality program achieved several physical and functional benefits without regression on any aspects of physical or psychological health.

We designed a trial to simultaneously address the problems of graft versus host disease (GVHD), infection, and recurrence of malignancy after allogeneic stem cell transplantation. CD34 + stem cell isolation was used to minimize the development of acute and chronic GVHD. Two prophylactic infusions, one combining donor-derived cytomegalovirus, Epstein-Barr virus, and Aspergillus fumigatus specific T-cells and the other comprising donor-derived CD19 directed chimeric antigen receptor (CAR) bearing T-cells, were given 21-28 days after transplant. Two patients were transplanted for acute lymphoblastic leukemia from HLA identical siblings using standard doses of cyclophosphamide and total body irradiation without antilymphocyte globulin. Patients received no post-transplant immune suppression and were given no pre-CAR T-cell lymphodepletion. Neutrophil and platelet engraftment was prompt. Following adoptive T-cell infusions, there was rapid appearance of antigen-experienced CD8 + and to a lesser extent CD4 + T-cells. Tetramer-positive T-cells targeting CMV and EBV appeared rapidly after T-cell infusion and persisted for at least 1 year. CAR T-cell expansion occurred and persisted for up to 3 months. T-cell receptor tracking confirmed the presence of product-derived T-cell clones in blood targeting all three pathogens. Both patients are alive over 3 years post-transplant without evidence of GVHD or disease recurrence. Combining robust donor T-cell depletion with directed T-cell adoptive immunotherapy targeting infectious and malignant antigens permits independent modulation of GVHD, infection, and disease recurrence. The combination may separate GVHD from the graft versus tumor effect, accelerate immune reconstitution, and improve transplant tolerability., (© 2022 The Authors. American Journal of Hematology published by Wiley Periodicals LLC.)

We performed a phase 1 clinical trial to evaluate outcomes in patients receiving donor-derived CD19-specific chimeric antigen receptor (CAR) T cells for B-cell malignancy that relapsed or persisted after matched related allogeneic hemopoietic stem cell transplant. To overcome the cost and transgene-capacity limitations of traditional viral vectors, CAR T cells were produced using the piggyBac transposon system of genetic modification. Following CAR T-cell infusion, 1 patient developed a gradually enlarging retroperitoneal tumor due to a CAR-expressing CD4+ T-cell lymphoma. Screening of other patients led to the detection, in an asymptomatic patient, of a second CAR T-cell tumor in thoracic para-aortic lymph nodes. Analysis of the first lymphoma showed a high transgene copy number, but no insertion into typical oncogenes. There were also structural changes such as altered genomic copy number and point mutations unrelated to the insertion sites. Transcriptome analysis showed transgene promoter-driven upregulation of transcription of surrounding regions despite insulator sequences surrounding the transgene. However, marked global changes in transcription predominantly correlated with gene copy number rather than insertion sites. In both patients, the CAR T-cell-derived lymphoma progressed and 1 patient died. We describe the first 2 cases of malignant lymphoma derived from CAR gene-modified T cells. Although CAR T cells have an enviable record of safety to date, our results emphasize the need for caution and regular follow-up of CAR T recipients, especially when novel methods of gene transfer are used to create genetically modified immune therapies. This trial was registered at www.anzctr.org.au as ACTRN12617001579381., (© 2021 by The American Society of Hematology.)

Purpose: This study investigated the effects of complex-paired and reverse-contrast 10-week training programs on sprint, power, and change-of-direction speed performance of elite academy soccer players., Methods: Seventeen elite academy soccer players each performed assessments of the 10- and 40-m sprint, Abalakov vertical jump, seated medicine-ball throw, and Arrowhead change-of-direction speed test, both prior to and after a twice-weekly 10-week resistance-training program. The participants were randomly split into 2 groups; the complex-paired training group (CPT, n = 9) performed 4 different complex pairs (heavy-resistance exercises paired with plyometric and Olympic lifting-style exercises), with each pair being interspersed with an 8-minute recovery period in line with recommended guidelines. The comparative group-the reverse-contrast training group (RCT, n = 8)-performed the same exercises; however, all of the plyometric and Olympic lifting exercises preceded the heavy-resistance exercises., Results: Both groups achieved postintervention increases in the seated medicine-ball throw test (CPT +1.8% and RCT +1.6%, P < .05), whereas VJ performance improved only in the CPT group (+3.4%, P = .003). No significant improvements were observed in either the 10- and the 40-m sprint or Arrowhead change-of-direction speed test for either group., Conclusions: The CPT experienced a small but significant within-group improvement in jump performance. However, no significant between-groups differences were observed in any of the testing variables postintervention. Subsequently, for academy soccer athletes, the CPT approach did not produce meaningful benefits to performance compared with a more time-efficient reverse-contrast approach.

CD19-specific chimeric antigen receptor (CAR19) T cells, generated using viral vectors, are an efficacious but costly treatment for B cell malignancies. The nonviral piggyBac transposon system provides a simple and inexpensive alternative for CAR19 T cell production. Until now, piggyBac has been plasmid based, facilitating economical vector amplification in bacteria. However, amplified plasmids have several undesirable qualities for clinical translation, including bacterial genetic elements, antibiotic-resistance genes, and the requirement for purification to remove endotoxin. Doggybones (dbDNA) are linear, covalently closed, minimal DNA vectors that can be inexpensively produced enzymatically in vitro at large scale. Importantly, they lack the undesirable features of plasmids. We used dbDNA incorporating piggyBac to generate CAR19 T cells. Initially, expression of functional transposase was evident, but stable CAR expression did not occur. After excluding other causes, additional random DNA flanking the transposon within the dbDNA was introduced, promoting stable CAR expression comparable to that of using plasmid components. Our findings demonstrate that dbDNA incorporating piggyBac can be used to generate CAR T cells and indicate that there is a requirement for DNA flanking the piggyBac transposon to enable effective transposition. dbDNA may further reduce the cost and improve the safety of CAR T cell production with transposon systems., (© 2020 The Authors.)

We examined the sensitivity of the neurons in the mouse inferior colliculus (IC) to the interaural time differences (ITD) conveyed in the sound envelope. Utilizing optogenetic methods, we compared the responses to the ITD in the envelope of identified glutamatergic and GABAergic neurons. More than half of both cell types were sensitive to the envelope ITD, and the ITD curves were aligned at their troughs. Within the physiological ITD range of mice (±50 μs), the ITD curves of both cell types had a higher firing rate when the contralateral envelope preceded the ipsilateral envelope. These results show that the circuitry to process ITD persists in the mouse despite its lack of low-frequency hearing. The sensitivity of IC neurons to ITD is most likely to be shaped by the binaural interaction of excitation and inhibition in the lateral superior olive., (Copyright © 2019 Elsevier B.V. All rights reserved.)

Clinical trials of CD19-specific chimeric antigen receptor (CAR19) T cells have demonstrated remarkable efficacy against relapsed and refractory B cell malignancies. The piggyBac transposon system offers a less complex and more economical means for generating CAR19 T cells compared to viral vectors. We have previously optimized a protocol for the generation of CAR19 T cells using the piggyBac system, but we found that CAR19 T cells had poor in vivo efficacy and persistence, probably due to deleterious FcγR interactions with the CAR's IgG1 Fc-containing spacer domain. We therefore designed three CD19-specifc CARs that lacked the IgG1 Fc region, and we incorporated combinations of CD28 or 4-1BB transmembrane and co-stimulatory domains. PiggyBac-generated CAR19 T cells expressing these re-designed constructs all demonstrated reactivity in vitro specifically against CD19 + cell lines. However, those combining CD28 transmembrane and co-stimulatory domains showed CD4 predominance and inferior cytotoxicity. At high doses, CAR19 T cells were effective against B-ALL in a xenograft mouse model, regardless of co-stimulatory domain. At diminishing doses, 4-1BB co-stimulation led to greater potency and persistence of CAR19 T cells, and it provided protection against B-ALL re-challenge. Production of potent CAR T cells using piggyBac is simple and cost-effective, and it may enable wider access to CAR T cell therapy., (Copyright © 2018 The American Society of Gene and Cell Therapy. All rights reserved.)

GABAergic neurons in the inferior colliculus (IC) play a critical role in auditory information processing, yet their responses to sound are unknown. Here, we used optogenetic methods to characterize the response properties of GABAergic and presumed glutamatergic neurons to sound in the IC. We found that responses to pure tones of both inhibitory and excitatory classes of neurons were similar in their thresholds, response latencies, rate-level functions, and frequency tuning, but GABAergic neurons may have higher spontaneous firing rates. In contrast to their responses to pure tones, the inhibitory and excitatory neurons differed in their ability to follow amplitude modulations. The responses of both cell classes were affected by their location regardless of the cell type, especially in terms of their frequency tuning. These results show that the synaptic domain, a unique organization of local neural circuits in the IC, may interact with all types of neurons to produce their ultimate response to sound. SIGNIFICANCE STATEMENT Although the inferior colliculus (IC) in the auditory midbrain is composed of different types of neurons, little is known about how these specific types of neurons respond to sound. Here, for the first time, we characterized the response properties of GABAergic and glutamatergic neurons in the IC. Both classes of neurons had diverse response properties to tones but were overall similar, except for the spontaneous activity and their ability to follow amplitude-modulated sound. Both classes of neurons may compose a basic local circuit that is replicated throughout the IC. Within each local circuit, the inputs to the local circuit may have a greater influence in determining the response properties to sound than the specific neuron types., (Copyright © 2017 the authors 0270-6474/17/378952-13$15.00/0.)

Background: Crown-heel length (CHL) measurement is influenced by technique, training, experience and subject cooperation. We investigated whether extending one or both of an infant's legs affects the precision of CHL taken using an infantometer. The influence of staff training and infant cooperation were also examined., Methods: CHL was measured in children (aged 2), infants (aged 1) and newborns, by extending one or both legs. The subject's level of cooperation was recorded. Mean differences were compared using Student's t-test; intra- and inter-observer variability were assessed using Bland-Altman plots with 95 % limits of agreement. Intra- and inter-observer technical errors of measurement (TEMs) were also calculated., Results: Measuring CHL in newborns using only one leg resulted in significantly longer measurements. Across all groups, there was less inter-observer variability using both legs; 95 % limits of agreement were lower and TEMs smaller. Larger measurement differences were seen if children were uncooperative., Conclusions: This study supports measuring CHL with both legs extended. The two-leg technique reduces variability and increases precision by allowing the measurer to control better the position and movements of the infant's body.

Objective: To describe patterns in maternal gestational weight gain (GWG) in healthy pregnancies with good maternal and perinatal outcomes., Design: Prospective longitudinal observational study., Setting: Eight geographically diverse urban regions in Brazil, China, India, Italy, Kenya, Oman, United Kingdom, and United States, April 2009 to March 2014., Participants: Healthy, well nourished, and educated women enrolled in the Fetal Growth Longitudinal Study component of the INTERGROWTH-21(st) Project, who had a body mass index (BMI) of 18.50-24.99 in the first trimester of pregnancy., Main Outcome Measures: Maternal weight measured with standardised methods and identical equipment every five weeks (plus/minus one week) from the first antenatal visit (<14 weeks' gestation) to delivery. After confirmation that data from the study sites could be pooled, a multilevel, linear regression analysis accounting for repeated measures, adjusted for gestational age, was applied to produce the GWG values., Results: 13,108 pregnant women at <14 weeks' gestation were screened, and 4607 met the eligibility criteria, provided consent, and were enrolled. The variance within sites (59.6%) was six times higher than the variance between sites (9.6%). The mean GWGs were 1.64 kg, 2.86 kg, 2.86 kg, 2.59 kg, and 2.56 kg for the gestational age windows 14-18(+6) weeks, 19-23(+6) weeks, 24-28(+6) weeks, 29-33(+6) weeks, and 34-40(+0) weeks, respectively. Total mean weight gain at 40 weeks' gestation was 13.7 (SD 4.5) kg for 3097 eligible women with a normal BMI in the first trimester. Of all the weight measurements, 71.7% (10,639/14,846) and 94.9% (14,085/14,846) fell within the expected 1 SD and 2 SD thresholds, respectively. Data were used to determine fitted 3rd, 10th, 25th, 50th, 75th, 90th, and 97th smoothed GWG centiles by exact week of gestation, with equations for the mean and standard deviation to calculate any desired centiles according to gestational age in exact weeks., Conclusions: Weight gain in pregnancy is similar across the eight populations studied. Therefore, the standards generated in this study of healthy, well nourished women may be used to guide recommendations on optimal gestational weight gain worldwide., (Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://group.bmj.com/group/rights-licensing/permissions.)

Different forms of plasticity are known to play a critical role in the processing of information about sound. Here, we report a novel neural plastic response in the inferior colliculus, an auditory center in the midbrain of the auditory pathway. A vigorous, long-lasting sound-evoked afterdischarge (LSA) is seen in a subpopulation of both glutamatergic and GABAergic neurons in the central nucleus of the inferior colliculus of normal hearing mice. These neurons were identified with single unit recordings and optogenetics in vivo. The LSA can continue for up to several minutes after the offset of the sound. LSA is induced by long-lasting, or repetitive short-duration, innocuous sounds. Neurons with LSA showed less adaptation than the neurons without LSA. The mechanisms that cause this neural behavior are unknown but may be a function of intrinsic mechanisms or the microcircuitry of the inferior colliculus. Since LSA produces long-lasting firing in the absence of sound, it may be relevant to temporary or chronic tinnitus or to some other aftereffect of long-duration sound.

This study aimed to determine the effect of plyometric training (PT) when added to habitual gymnastic training (HT) on handspring vault (HV) performance variables. Twenty youth female competitive gymnasts (Age: 12.5 ± 1.67 y) volunteered to participate and were randomly assigned to two independent groups. The experimental plyometric training group (PTG) undertook a six-week plyometric program, involving two additional 45 min PT sessions a week, alongside their HT, while the control group (CG) performed regular HT only. Videography was used (120 Hz) in the sagittal plane to record both groups performing three HVs for both the baseline and post-intervention trials. Furthermore, participants completed a countermovement jump test (CMJ) to assess the effect of PT on functional power. Through the use of Quintic biomechanics software, significant improvements (P < 0.05) were found for the PTG for run-up velocity, take-off velocity, hurdle to board distance, board contact time, table contact time and post-flight time and CMJ height. However, there were no significant improvements on pre-flight time, shoulder angle or hip angle on the vault for the PTG. The CG demonstrated no improvement for all HV measures. A sport-specific PT intervention improved handspring vault performance measures and functional power when added to the habitual training of youth female gymnasts. The additional two hours plyometric training seemingly improved the power generating capacity of movement-specific musculature, which consequently improved aspects of vaulting performance. Future research is required to examine the whether the improvements are as a consequence of the additional volume of sprinting and jumping activities, as a result of the specific PT method or a combination of these factors.

The inferior colliculus (IC) is the first integration center of the auditory system. After the transformation of sound to neural signals in the cochlea, the signals are analyzed by brainstem auditory nuclei that, in turn, transmit this information to the IC. However, the neural circuitry that underlies this integration is unclear. This review consists of two parts: one is about the cell type which is likely to integrate sound information, and the other is about a technique which is useful for studying local circuitry. Large GABAergic (LG) neurons receive dense excitatory axosomatic terminals that originate from the lower brainstem auditory nuclei as well as local IC neurons. Dozens of axons coming from both local and lower brainstem neurons converge on a single LG soma. Excitatory neurons in IC can innervate many nearby LG somata in the same fibrodendritic lamina. The combination of local and ascending inputs is well suited for auditory integration. LG neurons are one of the main sources of inhibition in the medial geniculate body (MGB). LG neurons and the tectothalamic inhibitory system are present in a wide variety of mammalian species. This suggests that the circuitry of excitatory and inhibitory tectothalamic projections may have evolved earlier than GABAergic interneurons in the MGB, which are found in fewer species. Cellular-level functional imaging provides both morphological and functional information about local circuitry. In the last part of this review, we describe an in vivo calcium imaging study that sheds light on the functional organization of the IC.

The inferior colliculus (IC), the midbrain component of the auditory pathway, integrates virtually all inputs from the auditory brainstem. These are a mixture of excitatory and inhibitory ascending inputs, and the inhibitory transmitters include both gamma-aminobutyric acid (GABA) and glycine (GLY). Although the presence of these inhibitory inputs is well established, their relative location in the IC is not, and there is little information on the mouse. Here, we study the distribution of glutamic acid decarboxylase (GAD)67 and GLY transporter 2 (T2) in axonal terminals to better understand the relative contributions of these inputs. Large-scale mosaic composite images of immunohistochemistry sections of rat and mice were used to isolate the signals related to the concentrations of these axonal terminals in the tissue, and the ratio of GLYT2/GAD67 in each pixel was calculated. GLYT2 was seen only in the central nucleus of the IC (ICC), whereas GAD67 was seen throughout the IC. The map of the GAD67 and GLYT2 axonal distribution revealed a gradient that runs from ventrolateral to dorsomedial along the axis of the laminae of the ICC and perpendicular to the tonotopic axis. Although anatomically different, both the mouse and the rat had relatively more GAD67 dorsomedially in the ICC and relatively more GLYT2 ventrolaterally. This organization of GABA and GLY inputs may be related to functional zones with different properties in ICC that are based, in part, on different sets of inhibitory inputs to each zone., (© 2015 Wiley Periodicals, Inc.)

Elderly patients with acute myeloid leukaemia (AML) have a poor prognosis with standard chemotherapy. Two elderly AML patients treated with infusion of family-derived partially human leukocyte antigen (HLA)-matched peripheral blood stem cells following each cycle of chemotherapy entered morphological complete remission without graft versus host disease or major toxicity. Our results support this as a non-toxic approach for inducing a graft versus leukaemia effect in patients not suitable for allogeneic transplantation. Additional resources required for donor assessment and harvest may be reduced by using banked partially HLA-matched mononuclear cells from unrelated donors., (© 2014 The Authors; Internal Medicine Journal © 2014 Royal Australasian College of Physicians.)

As evidence-based programs become disseminated, understanding the degree to which they are implemented with fidelity is crucial. This study tested the validity of fidelity ratings made by observers versus those made by teachers. We hypothesized that teachers' reports about fidelity would have a positivity bias when compared to observers' reports. Further, we hypothesized that there would generally be low correspondence between teachers' and observers' ratings of fidelity. We examined teachers' and observers' ratings as they were related to mediating variables targeted for change by the intervention. Finally, we examined the role that years of teaching experience played in achieving fidelity. Eighteen teachers and four research assistants participated in this project as raters. Teachers made video recordings of their implementation of All Stars and completed fidelity assessment forms. Trained observers independently completed parallel forms for 215 sampled classroom sessions. Both teachers and observers rated adherence, quality of delivery, attendance, and participant engagement. Teachers made more positive fidelity ratings than did observers. With the exception of ratings for attendance, teachers and observers failed to agree on fidelity ratings. Observers' ratings were significantly related to students' pretest assessments of targeted program mediators. That observers' ratings were related to students' pretest scores, suggests it is easier to teach well when students are predisposed to program success. Teachers' ratings were infrequently related to mediators, but when they were, the relationship was counterintuitive. Experienced teachers taught with greater fidelity than novice teachers. While possibly inflated and inaccurate, gathering fidelity assessments from teachers may sensitize them to issues of fidelity as a result of requiring form completion. Assessing fidelity through observers' ratings of video recordings has significant merit. As a longterm investment in improving prevention outcomes, policy makers should consider requiring both teacher and observer fidelity assessments as essential components of evaluation.

There is a need to standardize methods for assessing fidelity and adaptation. Such standardization would allow program implementation to be examined in a manner that will be useful for understanding the moderating role of fidelity in dissemination research. This article describes a method for collecting data about fidelity of implementation for school-based prevention programs, including measures of adherence, quality of delivery, dosage, participant engagement, and adaptation. We report about the reliability of these methods when applied by four observers who coded video recordings of teachers delivering All Stars, a middle school drug prevention program. Interrater agreement for scaled items was assessed for an instrument designed to evaluate program fidelity. Results indicated sound interrater reliability for items assessing adherence, dosage, quality of teaching, teacher understanding of concepts, and program adaptations. The interrater reliability for items assessing potential program effectiveness, classroom management, achievement of activity objectives, and adaptation valences was improved by dichotomizing the response options for these items. The item that assessed student engagement demonstrated only modest interrater reliability and was not improved through dichotomization. Several coder pairs were discordant on items that overall demonstrated good interrater reliability. Proposed modifications to the coding manual and protocol are discussed., (© The Author(s) 2013.)

This article presents results from a study that evaluated an online message system designed to improve the delivery of prevention programs. We conducted a quasi-experimental study with 32 agencies and schools that implemented substance use prevention programs and examined differences between the comparison and intervention groups. We also examined the impact of dosage of the message system by comparing results among three groups of teachers: non-users, low users, and high users. Results for norm setting were marginally significant, such that teachers within the agencies assigned to the intervention condition scored higher on their understanding of norm setting at posttest compared to teachers within comparison agencies, after controlling for pretest knowledge scores and demographic items. In the model examining impact of dosage, high users of the intervention scored significantly higher on self-reported understanding of their program, quality of delivery, and program effectiveness compared to non-users. Low users of the intervention reported significantly higher quality of delivery compared to non-users.

Purpose: To be effective, evidence-based programs should be delivered as prescribed. This suggests that adaptations that deviate from intervention goals may limit a program's effectiveness. This study examines the impact that number and quality of adaptations have on substance use outcomes., Design: We examined 306 video recordings of teachers delivering 'All Stars', a middle school drug prevention program. Multiple observers coded each recording, noting the number and type of adaptation each teacher made. Each adaptation was given a valence rating. Adaptations that were deleterious to program goals received negative valence ratings; positive ratings were given for adaptations that were likely to facilitate achievement of program goals; neutral ratings were given to adaptations that were expected to have neither a positive nor negative impact on program goals., Findings: All teachers made adaptations. Teachers were consistent across time in the types of adaptations they made, suggesting each teacher has a personalized style of adapting. Those who made few adaptations, and whose average adaptation was rated as being positive had a higher percentage of students who remained non-drug users. In contrast, teachers who made many adaptations, whether their average valence rating was positive, neutral or negative, failed to have as many students remain non-drug users. Measures of fidelity, including quality of delivery and teacher understanding were related to valence of adaptations, with better performance related to making positive adaptations., Practical Implications: Through training and supervision, teachers should be guided and encouraged to follow programs directions, making few adaptations and ensuring that adaptations that are made advance the goals of intervention. Programs should define acceptable and unacceptable ways they may be adapted., Value: This study provides significant evidence about the challenges that face disseminated evidence-based programs.

Glutamate is the main excitatory neurotransmitter in the auditory system, but associations between glutamatergic neuronal populations and the distribution of their synaptic terminations have been difficult. Different subsets of glutamatergic terminals employ one of three vesicular glutamate transporters (VGLUT) to load synaptic vesicles. Recently, VGLUT1 and VGLUT2 terminals were found to have different patterns of organization in the inferior colliculus, suggesting that there are different types of glutamatergic neurons in the brainstem auditory system with projections to the colliculus. To positively identify VGLUT-expressing neurons as well as inhibitory neurons in the auditory brainstem, we used in situ hybridization to identify the mRNA for VGLUT1, VGLUT2, and VIAAT (the vesicular inhibitory amino acid transporter used by GABAergic and glycinergic terminals). Similar expression patterns were found in subsets of glutamatergic and inhibitory neurons in the auditory brainstem and thalamus of adult rats and mice. Four patterns of gene expression were seen in individual neurons. 1) VGLUT2 expressed alone was the prevalent pattern. 2) VGLUT1 coexpressed with VGLUT2 was seen in scattered neurons in most nuclei but was common in the medial geniculate body and ventral cochlear nucleus. 3) VGLUT1 expressed alone was found only in granule cells. 4) VIAAT expression was common in most nuclei but dominated in some. These data show that the expression of the VGLUT1/2 and VIAAT genes can identify different subsets of auditory neurons. This may facilitate the identification of different components in auditory circuits., (© 2010 Wiley-Liss, Inc.)

Distinct pathways carry monaural and binaural information from the lower auditory brainstem to the central nucleus of the inferior colliculus (ICC). Previous anatomical and physiological studies suggest that differential ascending inputs to regions of the ICC create functionally distinct zones. Here, we provide direct evidence of this relationship by combining recordings of single unit responses to sound in the ICC with focal, iontophoretic injections of the retrograde tracer Fluoro-Gold at the physiologically characterized sites. Three main patterns of anatomical inputs were observed. One pattern was identified by inputs from the cochlear nucleus and ventral nucleus of the lateral lemniscus in isolation, and these injection sites were correlated with monaural responses. The second pattern had inputs only from the ipsilateral medial and lateral superior olive, and these sites were correlated with interaural time difference (ITD)-sensitive responses to low frequency (<500 Hz). A third pattern had inputs from a variety of olivary and lemniscal sources, notably the contralateral lateral superior olive and dorsal nucleus of the lateral lemniscus. These were correlated with high-frequency ITD sensitivity to complex acoustic stimuli. These data support the notion of anatomical regions formed by specific patterns of anatomical inputs to the ICC. Such synaptic domains may represent functional zones in ICC.

Classroom behavior management interventions have been used successfully with drug prevention programs to prevent subsequent antisocial behavior and substance use among youth. This article presents results from implementation of the All Stars Challenge, a classroom-based behavior management component to a drug prevention program for fifth graders. Risk ratings for shyness and lack of awareness of social norms among high-risk students who received the All Stars Challenge were reduced compared with fifth graders who did not receive the intervention. In contrast, physical and social aggressivity among low-risk students who received the program increased when compared to similar control students.

The inferior colliculus (IC) is unique, having both glutamatergic and GABAergic projections ascending to the thalamus. Although subpopulations of GABAergic neurons in the IC have been proposed, criteria to distinguish them have been elusive and specific types have not been associated with specific neural circuits. Recently, the largest IC neurons were found to be recipients of somatic terminals containing vesicular glutamate transporter 2 (VGLUT2). Here, we show with electron microscopy that VGLUT2-positive (VGLUT2(+)) axonal terminals make axosomatic synapses on IC neurons. These terminals contain only VGLUT2 even though others in the IC have VGLUT1 or both VGLUT1 and 2. We demonstrate that there are two types of GABAergic neurons: larger neurons with VGLUT2(+) axosomatic endings and smaller neurons without such endings. Both types are present in all subdivisions of the IC, but larger GABAergic neurons with VGLUT2(+) axosomatic terminals are most prevalent in the central nucleus. The GABAergic tectothalamic neurons consist almost entirely of the larger cells surrounded by VGLUT2(+) axosomatic endings. Thus, two types of GABAergic neurons in the IC are defined by different synaptic organization and neuronal connections. Larger tectothalamic GABAergic neurons are covered with glutamatergic axosomatic synapses that could allow them to fire rapidly and overcome a slow membrane time constant; their axons may be the largest in the brachium of the IC. Thus, large GABAergic neurons could deliver IPSPs to the medial geniculate body before EPSPs from glutamatergic IC neurons firing simultaneously.

This study aimed to identify the effect of plyometric training (PT), when added to habitual training (HT) regimes, on swim start performance. After the completion of a baseline competitive swim start, 22 adolescent swimmers were randomly assigned to either a PT (n = 11, age: 13.1 +/- 1.4 yr, mass: 50.6 +/- 12.3 kg, stature: 162.9 +/- 11.9 cm) or an HT group (n = 11, age: 12.6 +/- 1.9 yr, mass: 43.3 +/- 11.6 kg, stature: 157.6 +/- 11.9 cm). Over an 8-week preseason period, the HT group continued with their normal training program, whereas the PT group added 2 additional 1-hour plyometric-specific sessions, incorporating prescribed exercises relating to the swimming block start (SBS). After completion of the training intervention, post-training swim start performance was reassessed. For both baseline and post-trials, swim performance was recorded using videography (50 Hz Canon MVX460) in the sagital plane of motion. Through the use of Silicon Coach Pro analysis package, data revealed significantly greater change between baseline and post-trials for PT when compared with the HT group for swim performance time to 5.5 m (-0.59 s vs. -0.21 s; p < 0.01) and velocity of take-off to contact (0.19 ms vs. -0.07 ms; p < 0.01). Considering the practical importance of a successful swim start to overall performance outcome, the current study has found that inclusion of suitable and safely implemented PT to adolescent performers, in addition to HT routines, can have a positive impact on swim start performance.

The ease with which programs can be delivered may impact sustainability, fidelity, and ultimately program effectiveness in a dissemination environment. This paper presents results from a study examining the ability of technological enhancements to make it easier for teachers to deliver All Stars, an evidence-based drug prevention program. These enhancements were designed to save time for teachers, produce improvements in quality of delivery, and provide features to increase students' involvement. Results of a randomized field trial revealed that teachers who used the enhancements found it easier to implement key program components compared to facilitators who taught the program as usual. Teachers in the technology-enhanced condition reduced the time required to complete otherwise time-consuming tasks. They also reported the ability to deliver more of the program, although they also reported more modifications and omitted activities within sessions when compared to teachers who delivered the program as usual. Moreover, teachers' attitudes about the program improved after their experience with the enhancements, the vast majority wishing to continue to use them in the future. Results suggest that modest gains in quality of program delivery can be expected when online applications designed to make tasks easier can be adopted by prevention service providers. On the other hand, enhancements that require special skill sets regarding computer-based methods may provide no clear benefit.

The inferior colliculus (IC) is the major component of the auditory midbrain and contains three major subdivisions: a central nucleus, a dorsal cortex, and a lateral cortex (LC). Discrepancies in the nomenclature and parcellation of the LC in the rat and cat seem to imply different, species-specific functions for this region. To establish a comparable parcellation of the LC for both rat and cat, we investigated its histochemistry and inputs. In both species, the deep lateral cortex is marked by a transition between the nicotinamide adenine dinucleotide phosphate-diaphorase (NADPH-d) rich superficial cortex and a cytochrome oxidase (CO) rich central nucleus. In both species, focal injections of anterograde tracers in the cochlear nucleus at sites of known best frequency produced bands of labeled inputs in two different subdivisions of the IC. A medial band of axons terminated in the central nucleus, while shorter bands were located laterally and oriented nearly perpendicularly to the medial bands. In the rat, these lateral bands were located in the third, deepest layer of the lateral (external) cortex. In the cat, the bands were located in a region that was previously ascribed to the central nucleus, but now considered to belong to the third, deepest layer of the LC, the ventrolateral nucleus. In both species, the LC inputs had a tonotopic organization. In view of this parallel organization, we propose a common parcellation of the IC for rat and cat with a new nomenclature. The deep layer of the LC, previously referred to as layer 3 in the rat, is designated as the 'ventrolateral nucleus' of the LC, making it clear that this region is thought to be homologous with the ventrolateral nucleus in the cat. The similar organization of the LC implies that this subdivision of the IC has similar functions in cats and rats.

Purpose: To examine the impact of various patient, disease, and treatment characteristics on outcome in patients treated with neoadjuvant hormone therapy (NAHT) and external-beam radiation therapy (EBRT) for clinically localized, high-risk prostate adenocarcinoma (initial prostate-specific antigen [PSA] level >20, Gleason score 8-10 or Stage > or = T3)., Methods and Materials: A retrospective chart review was conducted on 407 patients treated between 1991 and 2001 with NAHT and EBRT for high-risk prostate cancer. The effect of tumor (PSA level, Gleason score, and T stage) and treatment (NAHT duration, total-hormone duration, preradiation PSA) characteristics on rates of biochemical disease-free survival (bDFS), prostate cancer-specific survival, and overall survival were examined., Results: Median follow-up time was 78 months (range: 5-140 months). Actuarial bDFS at 5 years was 52% (95% confidence interval [CI], 46% to 57%) for the entire group. On multivariate analysis, initial PSA level (p = 0.004), Gleason score (p = 0.005), and preradiation PSA level (p < 0.001) were predictive of bDFS, whereas age, T stage, duration of NAHT, and duration of total hormone therapy were not predictive of outcomes. Gleason score and preradiation PSA level were also predictive of prostate cancer-specific survival rates., Conclusion: Improved bDFS in patients with high-risk prostate cancer was associated with lower initial PSA level, lower Gleason score, and lower preradiation PSA level. The duration of NAHT did not have an impact on outcomes, but the preradiation PSA was an important predictor of bDFS in high-risk patients.

The major excitatory, binaural inputs to the central nucleus of the inferior colliculus (ICC) are from two groups of neurons with different functions-the ipsilateral medial superior olive (MSO) and the contralateral lateral superior olive (LSO). A major inhibitory, binaural input emerges from glycinergic neurons in the ipsilateral LSO. To determine whether these inputs converge on the same postsynaptic targets in the ICC, two different anterograde tracers were injected in tonotopically matched areas of the MSO and the LSO on the opposite side in the same animal. The main findings were that the boutons from MSO axons terminated primarily in the central and caudal parts of the ICC laminae but that contralateral LSO terminals were concentrated more rostrally and on the ventral margins of the MSO inputs. In contrast, the ipsilateral LSO projection converged with the MSO inputs and was denser than the contralateral LSO projection. Consistent with this finding, retrograde transport experiments showed that the very low-frequency areas of the ICC with dense MSO inputs also received inputs from greater numbers of ipsilateral LSO neurons than from contralateral LSO neurons. The results suggest that different binaural pathways through the low-frequency ICC may be formed by the segregation of excitatory inputs to ICC from the MSO and the contralateral LSO. At the same time, the ipsilateral LSO is a major inhibitory influence in the target region of the MSO. These data support the concept that each frequency-band lamina in the ICC may comprise several functional modules with different combinations of inputs., (Copyright 2004 Wiley-Liss, Inc.)

Neurons in the medial superior olive encode interaural temporal disparity, and their receptive fields indicate the location of a sound source in the azimuthal plane. It is often assumed that the projections of these neurons transmit the receptive field information about azimuth from point to point, much like the projections of the retina to the brain transmit the position of a visual stimulus. Yet this assumption has never been verified. Here, we use physiological and anatomical methods to examine the projections of the medial superior olive to the inferior colliculus for evidence of a spatial topography that would support transmission of azimuthal receptive fields. The results show that this projection does not follow a simple point-to-point topographical map of receptive field location. Thus, the representation of sound location along the azimuth in the inferior colliculus most likely relies on a complex, nonlinear map.

This study investigated the control of sensory inputs during the performance of an inverted-pendulum balancing task. Experiments were conducted to examine modulation of proprioceptive inputs during balance tasks of varying difficulty. It was hypothesized that proprioceptive inputs to both spinal and cortical levels would be facilitated during a challenged balance task. In contrast, during challenged balance control, results revealed task-specific facilitation of sensory inputs to the cortex and inhibition of the spinal reflex pathway. Observations of increased transmission of proprioceptive inputs to the cortex and decreased transmission at the spinal level suggest that the cortex plays an important role in challenged balance, whereas the role for the spinal stretch reflex appears to be less important.

The gain of somatosensory afferent paths from the lower limb to the cerebral cortex was investigated during the acquisition of one target location during plantar flexion. Sensory gain was measured as the magnitude of somatosensory evoked potentials (SEPs) following electrical stimulation of a peripheral nerve in the lower limb, and was recorded from the scalp. We hypothesized gain attenuation of SEPs from sensory paths serving the limb segment responsible for target acquisition. SEP gain was studied as subjects plantar flexed about the anide to a target that was 15 degrees beyond the occurrence of a cutaneous stimulus (cue) to the lateral border of the foot. The "cue" was either fixed in one location or could appear at one of three positions in space. SEP gain was tested during practice and with task acquisition. Electroencephalographic (EEG) recordings were made of primary and secondary complexes of cortical SEPs from sural and tibial nerve stimulation, with 30-40 samples averaged per subject-condition. Electromyographic (EMG) records were made of soleus muscle H-reflexes and M-waves. Target acquisition was recorded as percent correct hits. The results showed significant attenuation in sural and tibial nerve primary SEPs with task acquisition when the cue was fixed or varied in movement space (P<0.05). Secondary SEPs from tibial nerve followed this pattern. Spinal H-reflexes only attenuated with movement per se. We conclude that the CNS preferentially reduces the cerebral inflow of sensory information once such a motor task has been successfully acquired.

The time course and extent of attentional shifts associated with compensatory balancing reactions were explored using a novel dual-task paradigm. Seated subjects performed a continuous visuomotor tracking task with the hand while the feet simultaneously balanced an inverted pendulum. The pendulum was randomly perturbed, evoking compensatory balance reactions. Changes in tracking performance were held to reflect attentional shifts. Discrete deviation in visuomotor tracking, typically a pause in tracking, began on average 235 ms after the onset of the balance reaction (TA EMG; average latency 90 ms). Such pauses lasted on average 600 ms, although additional errors in tracking lasted up to 9 s following the perturbation. The findings reveal evidence of dynamic shifts in attention associated with distinct phases of compensatory balance control. The initial phase appears to be triggered automatically, whereas later phases involve varying degrees of attentional resources.

The laminar organization of the central nucleus of inferior colliculus includes layers of axons that may be important in shaping the responses of neurons. Depending on their source, some layered axons are afferents that are superimposed and terminate on the same postsynaptic neurons, while other layered afferents, such as those from the ipsilateral and contralateral lateral superior olive, terminate side-by-side. The specific pattern of convergence may dictate which populations of axons are presynaptic to layered disc-shaped neurons in the central nucleus. We compared the distribution of afferent axons from the dorsal cochlear nucleus and the lateral superior olive to the contralateral inferior colliculus in the cat. Injection sites in cochlear nucleus and superior olive were physiologically characterized by extracellular recordings of single and multiple units in response to monaural and binaural acoustic stimulation. Two separate injections were made in each case, and both injection sites contained units with overlapping best frequencies. Biotinylated dextran, fluorescent dextran, 3H-leucine, and wheat germ agglutinin conjugated to horseradish peroxidase were used as anterograde tracers. The present results show that layered axons from the dorsal cochlear nucleus and lateral superior olive are superimposed in part of the contralateral central nucleus. Both projections were arranged in rostro-caudally oriented axonal layers that converged in the ventral part of the central nucleus. However, in the dorsal part of the central nucleus, the same layer of axons from the dorsal cochlear nucleus did not terminate with afferents from the lateral superior olive. Within the overlapping layers in the ventral central nucleus, the overlap of axons from the dorsal cochlear nucleus and the lateral superior olive was uniform except for small patches that were usually smaller than the dendritic fields of disc-shaped neurons. These data suggest that the layers may create specific functional zones in the central nucleus of the inferior colliculus. One zone may contain neurons with binaural responses that combine the properties of the inputs from the contralateral lateral superior olive and the dorsal cochlear nucleus. A second zone may contain inputs from the cochlear nucleus but lack those of the lateral superior olive.