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Purpose To review our experience of concomitant single agent cheoradiotherapy treatment of locally advanced squamous cell carcinoma of the head and neck (SCCHN). Methodology A retrospective cohort study of 56 patients with advanced SCCHN. Patients were eligible for inclusion if they had been treated with primary concurrent chemoradiotherapy for squamous cell carcinoma of the oral cavity (p = 7%), oropharynx (p = 54%), larynx (p = 23%) or hypopharynx (p = 16%) at the Sydney Head and Neck Cancer Institute between 2000 and 2005. Patients treated previously for this disease, or with other agents (such as 5-FU) in combination with cisplatin/carboplatin, were excluded. Treatment was 80 or 100 mg/m2 of cisplatin in weeks 1, 4 and 7 of radiotherapy. Percutaneous endoscopic gastrostomy (PEG) feeding tubes were placed in 86% of patients. Results A 90% initial complete response rate was observed. The Kaplan-Meier 3 year projected overall survival rate was 72% and 3-year disease specific survival was 74%. Eleven percent of the patient cohort underwent salvage surgery while 14% required chemotherapy dose adjustments. Twenty percent of patients required unplanned hospital admission for the management of treatment related toxicity. Conclusion Our study affirms that our overall survival rates and treatment related toxicities, using a concomitant chemoradiotherapy protocol are comparable with other institutions. Our initial clinical response rates may reflect our selection criteria and the low percentage of patients requiring dose adjustments. Our low rate of unplanned hospital admissions may be explained by the routine use of PEG tubes to reduce treatment related complications. [ABSTRACT FROM AUTHOR]

Purpose To prospectively assess the subjective experience of patients and the degree of benefit they felt they gained from attending the Multidisciplinary Head and Neck Clinic (MDHNC). Methodology An internally validated questionnaire of patient responses to their experiences at the MDHNC was implemented prospectively. Data were gathered between May and September 2006. The questionnaire consisted of 36 questions, addressing 3 components of the clinic; before, during and after attendance. Twenty four of 48 questionnaires were completed. Results Patients’ experiences of the clinic were mainly positive. All patients reported feeling adequately informed about both illness and their treatment options. No patients left with unanswered questions. All, but one patient, tolerated the examination well, although 4 patients were unprepared for the number of people present at the clinic. Twenty two patients especially valued the post-clinic discussion with their specialist. Five patients felt that insufficient information about treatment choice was provided to their family. No discrepancy between internal validation questions was recorded. Conclusion Patients expressed a high level of appreciation for the care provided in the multidisciplinary clinic. Contrary to our expectations, patients generally did not mind examination in the presence of a large number of clinicians. Most patients reported particularly valuing the discussion with the treating specialist after the clinic visit. Reducing waiting times, providing clearly written plans for treatment resulting from the clinic, and distributing more information to assist individuals accompanying patients, emerged as target areas for future improvement. [ABSTRACT FROM AUTHOR]

During the COVID-19 pandemic, teachers in the United States, an already at-risk occupation group, experienced new work-related stressors, safety concerns, and work-life challenges, magnifying on-going retention concerns. Integrating the crisis management literature with the unfolding model of turnover, we theorize that leader actions trigger initial employee responses but also set the stage for on-going crisis response that influence changes in teachers' turnover intentions. We apply latent growth curve modelling to test our hypotheses based on a sample of 617 K-12 teachers using nine waves of data, including a baseline survey at the start of the 2020-2021 school year and eight follow-up surveys (2-week lags) through the Fall 2020 semester. In terms of overall adaptation, teachers on average, experienced an increase in work-life balance and a decrease in turnover intentions over the course of the semester. Results also suggest that district and school leadership provide unique and complementary resources, but leader behaviours that shape initial crisis responses do not similarly affect employee responses during crisis, contrary to theory. Instead, teachers' adaptive crisis response trajectories were triggered by continued resource provision over the semester; increasing provision of valued resources (i.e., continued refinement of safety practices) and improvements in work-life balance prevented turnover intentions from spiralling throughout the crisis. Crisis management theory and research should continue to incorporate temporal dynamics and identify factors that contribute to crisis response trajectories, using designs and analyses that allow for examination as crises unfold in real time., Competing Interests: All authors declare no conflict of interest., (© 2022 The British Psychological Society.)

The future of work embodies changes to the workplace, work, and workforce, which require additional occupational safety and health (OSH) stakeholder attention. Examples include workplace developments in organizational design, technological job displacement, and work arrangements; work advances in artificial intelligence, robotics, and technologies; and workforce changes in demographics, economic security, and skills. This paper presents the Centers for Disease Control and Prevention, National Institute for Occupational Safety and Health's Future of Work Initiative; suggests an integrated approach to address worker safety, health, and well-being; introduces priority topics and subtopics that confer a framework for upcoming future of work research directions and resultant practical applications; and discusses preliminary next steps. All future of work issues impact one another. Future of work transformations are contingent upon each of the standalone factors discussed in this paper and their combined effects. Occupational safety and health stakeholders are becoming more aware of the significance and necessity of these factors for the workplace, work, and workforce to flourish, merely survive, or disappear altogether as the future evolves. The future of work offers numerous opportunities, while also presenting critical but not clearly understood difficulties, exposures, and hazards. It is the responsibility of OSH researchers and other partners to understand the implications of future of work scenarios to translate effective interventions into practice for employers safeguarding the safety, health, and well-being of their workers., (© 2020 Wiley Periodicals LLC.)

Network bursts and oscillations are forms of spontaneous activity in cortical circuits that have been described in vivo and in vitro. Searching for mechanisms involved in their generation, we investigated the collective network activity and spike discharge oscillations in cortical slice cultures of neonatal rats, combining multielectrode arrays with patch clamp recordings from individual neurons. The majority of these cultures showed spontaneous collective network activity [population bursts (PBs)] that could be described as neuronal avalanches. The largest of these PBs were followed by fast spike discharge oscillations in the beta to theta range, and sometimes additional repetitive PBs, together forming seizure-like episodes. During such episodes, all neurons showed sustained depolarization with increased spike rates. However, whereas regular-spiking (RS) and fast-spiking (FS) neurons fired during the PBs, only the FS neurons fired during the fast oscillations. Blockade of N-methyl-d-aspartate receptors reduced the depolarization and suppressed both the increased FS neuron firing and the oscillations. To investigate the generation of PBs, we studied the network responses to electrical stimulation. For most of the stimulation sites, the relationship between the stimulated inputs and the evoked PBs was linear. From a few stimulation sites, however, large PBs could be evoked with small inputs, indicating the activation of hub circuits. Taken together, our findings suggests that the oscillations originate from recurrent inhibition in local networks of depolarized inhibitory FS interneurons, whereas the PBs originate from recurrent excitation in networks of RS and FS neurons that is initiated in hub circuits., (© 2012 The Authors. European Journal of Neuroscience © 2012 Federation of European Neuroscience Societies and Blackwell Publishing Ltd.)

In co-cultures of embryonic rat spinal cord slices and skeletal muscle, spinal motoneurons innervate muscle fibres and drive muscle contractions. However, multi-electrode array (MEA) recordings show that muscle contractions often appear in the absence of population activity in the spinal cord networks. Such uncorrelated muscle activity persists when the population bursts in the neuronal networks are prevented by un-coupling the network with the glutamatergic antagonists CNQX and D-APV. By contrast, the uncorrelated muscle activity is fully suppressed by the muscular nicotinic antagonist D-tubocurarine. Together, these findings confirm the previous finding that motoneurons drive muscle fibres in this preparation and suggest that they are intrinsically spiking in the absence of synaptic input. Intracellular recordings from spinal neurons support this suggestion. Analysing the correlated muscle activity, we found that in 15% of the population bursts, muscle activity appears at the beginning or before neuronal activity, suggesting that in these cases motoneurons initiate the population activity. Both the total number of population bursts and the percentage of such bursts that are initiated by muscle activity are reduced by a block of nicotinic receptors. Uncorrelated muscle and neuronal activity is reduced by the gap junction blocker carbenoxolone, suggesting that electrical coupling is involved in the generation of this activity. Together, these findings suggest that intrinsic firing of motoneurons may contribute to the activation of population bursts through cholinergic positive feedback loops in cultured spinal networks.

The origin of rhythm generation in mammalian spinal cord networks is still poorly understood. We have previously proposed that disinhibition-induced rhythms are based on intrinsic firing, recurrent excitation and several mechanisms to de-activate the network. In order to clarify these mechanisms we here investigated spontaneous spike discharge oscillations in rat spinal cord slice cultures using multi-electrode arrays and patch clamp. Episodes of such oscillations at 8.5 Hz spontaneously appeared in the ventral parts of the cultured slices. The rising phase of their initial cycles was entirely based on AMPA/kainate receptor-dependent recurrent excitation. Initial oscillations were changed into persistent activity by bicuculline and other blockers of GABA A, but not by blockers of glycine receptors, suggesting a role for GABAergic synaptic inhibition in network de-activation during oscillation cycles. Blockade of glycine receptors by strychnine caused a prolongation of oscillations and their spreading in the slice, suggesting that these receptors are mainly involved in the spatial and temporal restriction of oscillations. In most cultures, oscillations reappeared under disinhibition after an initial phase of persistent activity. Both spontaneous and disinhibition-induced oscillations were facilitated by riluzole, which enhances fast sodium current inactivation and thus leads to early cessation of firing during strong depolarization (depolarization block). In single cell recordings, episodes of strong depolarization were mostly seen during oscillations induced by disinhibition, but occasionally also during spontaneous oscillations. We conclude that both GABA A-mediated synaptic inhibition and depolarization block contribute to the de-activation of spinal cord networks during oscillation cycles.

We have shown previously that rhythm generation in disinhibited spinal networks is based on intrinsic spiking, network recruitment and a network refractory period following the bursts. This refractory period is based mainly on electrogenic Na/K pump activity. In the present work, we have investigated the role of the persistent sodium current (INaP) in the generation of bursting using patch-clamp and multielectrode array recordings. We detected INaP exclusively in the intrinsic spiking cells. The blockade of INaP by riluzole suppressed the bursting by silencing the intrinsic spiking cells and suppressing network recruitment. The blockade of the persistent sodium current produced a hyperpolarization of the membrane potential of the intrinsic spiking cells, but had no effect on non-spiking cells. We also investigated the involvement of the hyperpolarization-activated cationic current (I(h)) in the rhythmic activity. The bath application of ZD7288, a specific I(h) antagonist, slowed down the rate of the bursts by increasing the interburst intervals. I(h) was present in approximately 70% of the cells, both in the intrinsic spiking cells as well as in the non-spiking cells. We also found both kinds of cells in which I(h) was not detected. In summary, in disinhibited spinal cord cultures, a persistent sodium current underlies intrinsic spiking, which, via recurrent excitation, generates the bursting activity. The hyperpolarization-activated cationic current contributes to intrinsic spiking and modulates the burst frequency.

N-methyl-d-aspartic acid (NMDA) receptors are implicated in fictive locomotion; however, their precise role there is not clear. In cultures of dissociated cells from foetal rat spinal cord, synchronous bursting (but not fictive locomotion) can be induced by disinhibition, which is produced by blocking glycinergic and gamma-aminobutyric acid (GABA)A-dependent synaptic conductances. In this study, we investigate the role of NMDA-R in rhythm generation during disinhibition with multielectrode arrays and patch-clamp. We previously determined that bursting activity is generated by repetitive recruitment of a network through recurrent excitation. Blocking NMDA-R with d(-)-2-amino-5-phosphonopentanoic acid (APV) decreased the burst duration, suggesting a role of such receptors in the maintenance of high network activity during the bursts. In addition, APV reduced burst rate in about a third of the experiments, suggesting a contribution of NMDA-R in network recruitment. When (+/-)-alpha-amino-3-hydroxy-5-methylisoxazole-4-propionic acid hydrate (AMPA)/kainate receptors were blocked with 6-cyano-7-nitroquinoxaline-2,3-dione (CNQX) in the presence of disinhibition, the burst rate was reduced and burst onset was slowed in two-thirds of the experiments. In the remaining experiments, bursting ceased completely with CNQX. Neither APV nor CNQX changed the spatial patterns of activity in the network, suggesting a co-operation of both receptors in rhythm generation. While NMDA alone was not able to create a rhythm, it accelerated bursting in the presence of disinhibition, made it more regular and slowed down network recruitment. These effects were most likely due to the depolarization of the interneurons in the network. We conclude that NMDA-R contribute to rhythm generation in spinal cultures by supporting recurrent excitation and network recruitment and by depolarizing the network.

Disinhibition reliably induces regular synchronous bursting in networks of spinal interneurons in culture as well as in the intact spinal cord. We have combined extracellular multisite recording using multielectrode arrays with whole cell recordings to investigate the mechanisms involved in bursting in organotypic and dissociated cultures from the spinal cords of embryonic rats. Network bursts induced depolarization and spikes in single neurons, which were mediated by recurrent excitation through glutamatergic synaptic transmission. When such transmission was blocked, bursting ceased. However, tonic spiking persisted in some of the neurons. In such neurons intrinsic spiking was suppressed following the bursts and reappeared in the intervals after several seconds. The suppression of intrinsic spiking could be reproduced when, in the absence of fast synaptic transmission, bursts were mimicked by the injection of current pulses. Intrinsic spiking was also suppressed by a slight hyperpolarization. An afterhyperpolarization following the bursts was found in roughly half of the neurons. These afterhyperpolarizations were combined with a decrease in excitability. No evidence for the involvement of synaptic depletion or receptor desensitization in bursting was found, because neither the rate nor the size of spontaneous excitatory postsynaptic currents were decreased following the bursts. Extracellular stimuli paced bursts at low frequencies, but failed to induce bursts when applied too soon after the last burst. Altogether these results suggest that bursting in spinal cultures is mainly based on intrinsic spiking in some neurons, recurrent excitation of the network and auto-regulation of neuronal excitability.

Rat spinal networks generate a spontaneous rhythmic output directed to motoneurons under conditions of increased excitation or of disinhibition. It is not known whether these differently induced rhythms are produced by a common rhythm generator. To investigate the generation and the propagation of rhythmic activity in spinal networks, recordings need to be made from many neurons simultaneously. Therefore extracellular multisite recording was performed in slice cultures of embryonic rat spinal cords grown on multielectrode arrays. In these organotypic cultures most of the spontaneous neural activity was nearly synchronized. Waves of activity spread from a source to most of the network within 35-85 ms and died out after a further 30-400 ms. Such activity waves induced the contraction of cocultured muscle fibres. Several activity waves could be grouped into aperiodic bursts. Disinhibition with bicuculline and strychnine or increased excitability with high K(+) or low Mg(2+) solutions could induce periodic bursting with bursts consisting of one or several activity waves. Whilst the duration and period of activity waves were similar for all protocols, the duration and period of bursts were longer during disinhibition than during increased excitation. The sources of bursting activity were mainly situated ventrally on both sides of the central fissure. The pathways of network recruitment from one source were variable between bursts, but they showed on average no systematic differences between the protocols. These spatiotemporal similarities under conditions of increased excitation and of disinhibition suggest a common spinal network for both types of rhythmic activity.

Locomotion in vertebrates is controlled by central pattern generators in the spinal cord. The roles of specific network architecture and neuronal properties in rhythm generation by such spinal networks are not fully understood. We have used multisite recording from dissociated cultures of embryonic rat spinal cord grown on multielectrode arrays to investigate the patterns of spontaneous activity in randomised spinal networks. We were able to induce similar patterns of rhythmic activity in dissociated cultures as in slice cultures, although not with the same reliability and not always with the same protocols. The most reliable rhythmic activity was induced when a partial disinhibition of the network was combined with an increase in neuronal excitability, suggesting that both recurrent synaptic excitation and neuronal excitability contribute to rhythmogenesis. During rhythmic activity, bursts started at several sites and propagated in variable ways. However, the predominant propagation patterns were independent of the protocol used to induce rhythmic activity. When synaptic transmission was blocked by CNQX, APV, strychnine and bicuculline, asynchronous low-rate activity persisted at approximately 50% of the electrodes and approximately 70% of the sites of burst initiation. Following the bursts, the activity in the interval was transiently suppressed below the level of intrinsic activity. The degree of suppression was proportional to the amount of activity in the preceding burst. From these findings we conclude that rhythmic activity in spinal cultures is controlled by the interplay of intrinsic neuronal activity and recurrent excitation in neuronal networks without the need for a specific architecture.

The distinction between pre- or postsynaptic expression of synaptic plasticity is difficult to make, unless the postsynaptic receptors can be investigated in isolation. We have studied single synaptic contacts in dissociated cultures of rat hippocampus. The reaction of postsynaptic receptor assemblies to the induction of synaptic plasticity was measured and compared with changes in the rate of spontaneous miniature excitatory postsynaptic currents (mEPSCs), which can reflect changes in the transmitter release mechanism. The response of a receptor assembly to locally applied exogenous glutamate was measured before and after synchronized application of glutamate and a train of postsynaptic depolarizations ('pairing'). Pairing induced a variety of changes: (i) the majority of the receptor assemblies showed no change in their response to glutamate before and after pairing; (ii) the postsynaptic current due to exogenous glutamate showed a rapid increase in five out of 26 cases. This was not due to changes in the single channel conductance; (iii) the rate of mEPSCs increased, if it had previously been below 25 Hz; (iv) the rate of mEPSCs decreased, if it had previously been above 25 Hz. Effects 2 and 3 were blocked by antagonists of NMDA receptors. These findings provide direct evidence for an increase of the number of glutamate receptors at a subset of the investigated postsynaptic sites during synaptic potentiation.

The cytoarchitecture of a spinal cord - dorsal root ganglion - skeletal muscle tissue coculture system was investigated at the level of the light microscope using a number of different staining techniques. In these cultures central synapses between dorsal root ganglion (DRG) cells and interneurons in the ventral spinal cord and between DRG cells and motoneurons were visualized by parvalbumin immunostaining and by intracellular horseradish peroxidase (HRP) filling of DRG cells. Skeletal muscle fibres regenerated in vitro first into multinucleated myotubes, and around day 8 in vitro into well differentiated muscle fibres with regular cross-striation. At the same time newly formed motor endplates could be visualized using acetylcholinesterase staining. The axons of motoneurons could be traced retrogradely by local application of HRP to the regenerated muscle fibres. The motor axons sometimes gave off collaterals reminiscent of Renshaw collaterals at about 300 microm from the axon hillock. Intracellular filling to motoneurons with HRP revealed that only a minority of the motoneurons within a culture had reached their appropriate target. Comparing the dendrograms of the motoneurons which had innervated muscles to those which had not suggested that motoneurons innervating muscle tissue had more complex dendritic trees and larger somata than those which did not innervate muscle tissue. Peripheral neurites of parvalbumin-immunoreactive DRG cells coiling around regenerated muscle fibres could be demonstrated in these cultures. These probably correspond to that part of the sensory muscle spindle apparatus which developed in vivo. However, only a few of the several hundred DRG cells found in every culture were parvalbumin-immunoreactive, suggesting that the actual number of Ia and II afferents within the population of DRG cells in culture is very small. This study demonstrates that all the neural elements necessary for the segmental spinal reflexes develop and can be maintained for several weeks in vitro.

Electrical properties of motoneurons, muscle fibres and dorsal root ganglion (DRG) cells were studied in an organotypic coculture of embryonic rat spinal cord, dorsal root ganglia and skeletal muscle. The motoneurons were identified by their morphology and position in culture. Their size and input conductance were significantly larger than those of spinal interneurons. Intracellular current injection evoked action potentials in all motoneurons, but only evoked stable repetitive firing patterns in some. Excitability was correlated to somatic size and the rate of spontaneous excitatory input. It is suggested that the somatic growth and the increase in excitability is regulated by the excitatory afferents. The motoneurons showed spontaneous excitatory and inhibitory postsynaptic potentials and action potentials which disappeared with the application of various agents known to inhibit excitability or excitatory synaptic transmission. Excitatory and inhibitory postsynaptic potentials (EPSPs and IPSPs respectively) were distinguished by their shape, reversal potential and pharmacology. IPSPs could be depolarizing or hyperpolarizing in different cells. A higher percentage of cells with hyperpolarizing IPSPs was found in older cultures and in the presence of skeletal muscle, suggesting a reversal of the polarity of IPSPs with development. The spontaneous muscle contractions observed in the cultures could be due either to innervation, spontaneous oscillations of the membrane potential, or electrical coupling between neighbouring fibres. A small percentage of DRG cells showed spontaneous action potentials, all of which were found in cultures with spontaneous muscle contractions. The electrical stimulation of DRG afferents evoked mono- and polysynaptic EPSPs in motoneurons, endplate potentials and muscle contractions. The stimulation of the ventral horns evoked endplate potentials and muscle contractions via mono- or polysynaptic pathways. Together these results indicate that appropriate and functional contacts were established in the culture between myotubes and DRG cells, between DRG cells and motoneurons, and between motoneurons and muscle fibres.