Ketamine anaesthesia induces gain enhancement via recurrent excitation in granular input layers of the auditory cortex.

KEY POINTS: Ketamine is a common anaesthetic agent used in research and more recently as medication in treatment of depression. It has known effects on inhibition of interneurons and cortical stimulus-locked responses, but the underlying functional network mechanisms are still elusive. Analysing population activity across all layers within the auditory cortex, we found that doses of this anaesthetic induce a stronger activation and stimulus-locked response to pure-tone stimuli. This cortical response is driven by gain enhancement of thalamocortical input processing selectively within granular layers due to an increased recurrent excitation. Time-frequency analysis indicates a higher broadband magnitude response and prolonged phase coherence in granular layers, possibly pointing to disinhibition of this recurrent excitation. These results further the understanding of ketamine's functional mechanisms, which will improve the ability to interpret physiological studies moving from anaesthetized to awake paradigms and may lead to the development of better ketamine-based depression treatments with lower side effects. ABSTRACT: Ketamine is commonly used as an anaesthetic agent and has more recently gained attention as an antidepressant. It has been linked to increased stimulus-locked excitability, inhibition of interneurons and modulation of intrinsic neuronal oscillations. However, the functional network mechanisms are still elusive. A better understanding of these anaesthetic network effects may improve upon previous interpretations of seminal studies conducted under anaesthesia and have widespread relevance for neuroscience with awake and anaesthetized subjects as well as in medicine. Here, we investigated the effects of anaesthetic doses of ketamine (15 mg kg-1  h-1 i.p.) on the network activity after pure-tone stimulation within the auditory cortex of male Mongolian gerbils (Meriones unguiculatus). We used laminar current source density (CSD) analysis and subsequent layer-specific continuous wavelet analysis to investigate spatiotemporal response dynamics on cortical columnar processing in awake and ketamine-anaesthetized animals. We found thalamocortical input processing within granular layers III/IV to be significantly increased under ketamine. This layer-dependent gain enhancement under ketamine was not due to changes in cross-trial phase coherence but was rather attributed to a broadband increase in magnitude reflecting an increase in recurrent excitation. A time-frequency analysis was indicative of a prolonged period of stimulus-induced excitation possibly due to a reduced coupling of excitation and inhibition in granular input circuits - in line with the common hypothesis of cortical disinhibition via suppression of GABAergic interneurons.

Cognitive function in children with brain tumors in the first year after diagnosis compared to healthy matched controls.

BACKGROUND: Improved survival of children with brain tumors (BTs) has increased focus on ameliorating morbidity. To reduce the risk of progressive cognitive decline, remedial strategies need to be instituted early, based upon accurate appraisal of need, yet few studies have investigated cognition in BT children early post-diagnosis. The study aims were to investigate cognition in children with primary BTs 1, 6, and 12 months post-diagnosis compared with healthy children, exploring the impact of disease and treatment variables. METHODS: Forty-eight children aged 2-16 years with primary BTs, referred to a Regional Neurosurgical Unit over the 2-year study period were eligible for enrollment. The "best friends" model was used to recruit matched controls. Cognition was assessed using age-appropriate Wechsler Intelligence scales; Children's Memory Scale; Test of Everyday Attention for Children, and Wechsler Quicktest. RESULTS: Patients with BTs had significantly reduced performance compared to controls early post-diagnosis in tests of Performance IQ, processing speed, verbal and visual memory, and selective attention. Improved performance over 12 months was seen in patients with BTs although also, for some measures, in controls. Significant deficits in cognitive performance were seen one year post-diagnosis for Verbal IQ; processing speed, visual and verbal immediate memory, and selective attention. Infratentorial site, high tumor grade, hydrocephalus, radiotherapy, and chemotherapy were associated with poorer functioning. CONCLUSION: Early cognitive impairment is present in BT children, sometimes prior to radiotherapy/chemotherapy treatment, and is associated with hydrocephalus, high tumor grade and infratentorial site. Future studies should investigate the role of early rehabilitation in improving cognition.

Migrating partial seizures of infancy: expansion of the electroclinical, radiological and pathological disease spectrum.

Migrating partial seizures of infancy, also known as epilepsy of infancy with migrating focal seizures, is a rare early infantile epileptic encephalopathy with poor prognosis, presenting with focal seizures in the first year of life. A national surveillance study was undertaken in conjunction with the British Paediatric Neurology Surveillance Unit to further define the clinical, pathological and molecular genetic features of this disorder. Fourteen children with migrating partial seizures of infancy were reported during the 2 year study period (estimated prevalence 0.11 per 100,000 children). The study has revealed that migrating partial seizures of infancy is associated with an expanded spectrum of clinical features (including severe gut dysmotility and a movement disorder) and electrographic features including hypsarrhythmia (associated with infantile spasms) and burst suppression. We also report novel brain imaging findings including delayed myelination with white matter hyperintensity on brain magnetic resonance imaging in one-third of the cohort, and decreased N-acetyl aspartate on magnetic resonance spectroscopy. Putaminal atrophy (on both magnetic resonance imaging and at post-mortem) was evident in one patient. Additional neuropathological findings included bilateral hippocampal gliosis and neuronal loss in two patients who had post-mortem examinations. Within this cohort, we identified two patients with mutations in the newly discovered KCNT1 gene. Comparative genomic hybridization array, SCN1A testing and genetic testing for other currently known early infantile epileptic encephalopathy genes (including PLCB1 and SLC25A22) was non-informative for the rest of the cohort.

A COVID-19 Outbreak in a Large Meat-Processing Plant in England: Transmission Risk Factors and Controls.

The meat-processing industry had frequent COVID-19 outbreaks reported worldwide. In May 2021, a large meat-processing plant in the UK had an outbreak affecting 4.1% (63/1541) of workers. A rapid on-site investigation was conducted to understand the virus transmission risk factors and control measures. This included observational assessments of work activities, control measures, real-time environmental measurements and surface microbial sampling. The production night-shift attack rate (11.6%, 44/380) was nearly five times higher than the production day-shift (2.4%, 9/380). Shared work transport was provided to 150 staff per dayshift and 104 per nightshift. Production areas were noisy (≥80 dB(A)) and physical distancing was difficult to maintain. Face visors were mandatory, additional face coverings were required for some activities but not always worn. The refrigeration system continuously recirculated chilled air. In some areas, the mean temperature was as low as 4.5 °C and mean relative humidity (RH) was as high as 96%. The adequacy of ventilation in the production areas could not be assessed reliably using CO2, due to the use of CO2 in the packaging process. While there were challenges in the production areas, the observed COVID-19 control measures were generally implemented well in the non-production areas. Sixty surface samples from all areas were tested for SARS-CoV-2 RNA and 11.7% were positive. Multi-layered measures, informed by a workplace specific risk assessment, are required to prevent and control workplace outbreaks of COVID-19 or other similar respiratory infectious diseases.

Validating expression of beta cell maturation-associated genes in human pancreas development.

The identification of genes associated with human pancreatic beta cell maturation could stimulate a better understanding of normal human islet development and function, be informative for improving stem cell-derived islet (SC-islet) differentiation, and facilitate the sorting of more mature beta cells from a pool of differentiated cells. While several candidate factors to mark beta cell maturation have been identified, much of the data supporting these markers come from animal models or differentiated SC-islets. One such marker is Urocortin-3 (UCN3). In this study, we provide evidence that UCN3 is expressed in human fetal islets well before the acquisition of functional maturation. When SC-islets expressing significant levels of UCN3 were generated, the cells did not exhibit glucose-stimulated insulin secretion, indicating that UCN3 expression is not correlated with functional maturation in these cells. We utilized our tissue bank and SC-islet resources to test an array of other candidate maturation-associated genes, and identified CHGB, G6PC2, FAM159B, GLUT1, IAPP and ENTPD3 as markers with expression patterns that correlate developmentally with the onset of functional maturation in human beta cells. We also find that human beta cell expression of ERO1LB, HDAC9, KLF9, and ZNT8 does not change between fetal and adult stages.

Standards of care for occupational asthma: an update.

BACKGROUND: The British Thoracic Society (BTS) Standards of Care (SoC) Committee produced a standard of care for occupational asthma (OA) in 2008, based on a systematic evidence review performed in 2004 by the British Occupational Health Research Foundation (BOHRF). METHODS: BOHRF updated the evidence base from 2004-2009 in 2010. RESULTS: This article summarises the changes in evidence and is aimed at physicians, nurses and other healthcare professionals in primary and secondary care, occupational health and public health and at employers, workers and their health, safety and other representatives. CONCLUSIONS: Various recommendations and evidence ratings have changed in the management of asthma that may have an occupational cause.

A detailed prospective longitudinal assessment of health status in children with brain tumors in the first year after diagnosis.

PURPOSE: To compare health status (HS) in children with brain tumors at 1 (t1), 6 (t6), and 12 (t12) months after diagnosis with "normal" controls. To assess the relationship between parent-report and self-report HS for patients at t12. METHODS: HS was assessed using the Health Utilities Index Mark III parent-report at all time points and self-report at t12. Twenty-nine patients and 32 controls were included in analysis of parent-report, and 21 patients and 22 controls in self-report HS at t12. Nonparametric analyses were used. RESULTS: Patients scored significantly lower than controls for global overall HS at all time points for parent-report and at t12 for self-report (Pmax=0.009). For parent-report, patients scored significantly lower than controls in the attributes of emotion, cognition, and pain at t1 and t6, in ambulation at t1 and in dexterity at t6. At t12, the difference was statistically significant for parent-report cognition only (all P<0.01). No attributes reached significance for self-report at t12. For patients, correlations between parent-report and self-report were good (rs>0.73) for all Health Utilities Index Mark 3 scores with the exception of emotion and pain. CONCLUSION: HS is significantly compromised in children with brain tumors over the first year after diagnosis, but improves with time. Parent-report and self-report differ, and both should be considered in assessing outcomes or defining interventions.

Neuroplastin expression is essential for hearing and hair cell PMCA expression.

Hearing deficits impact on the communication with the external world and severely compromise perception of the surrounding. Deafness can be caused by particular mutations in the neuroplastin (Nptn) gene, which encodes a transmembrane recognition molecule of the immunoglobulin (Ig) superfamily and plasma membrane Calcium ATPase (PMCA) accessory subunit. This study investigates whether the complete absence of neuroplastin or the loss of neuroplastin in the adult after normal development lead to hearing impairment in mice analyzed by behavioral, electrophysiological, and in vivo imaging measurements. Auditory brainstem recordings from adult neuroplastin-deficient mice (Nptn-/-) show that these mice are deaf. With age, hair cells and spiral ganglion cells degenerate in Nptn-/- mice. Adult Nptn-/- mice fail to behaviorally respond to white noise and show reduced baseline blood flow in the auditory cortex (AC) as revealed by single-photon emission computed tomography (SPECT). In adult Nptn-/- mice, tone-evoked cortical activity was not detectable within the primary auditory field (A1) of the AC, although we observed non-persistent tone-like evoked activities in electrophysiological recordings of some young Nptn-/- mice. Conditional ablation of neuroplastin in Nptnlox/loxEmx1Cre mice reveals that behavioral responses to simple tones or white noise do not require neuroplastin expression by central glutamatergic neurons. Loss of neuroplastin from hair cells in adult NptnΔlox/loxPrCreERT mice after normal development is correlated with increased hearing thresholds and only high prepulse intensities result in effective prepulse inhibition (PPI) of the startle response. Furthermore, we show that neuroplastin is required for the expression of PMCA 2 in outer hair cells. This suggests that altered Ca2+ homeostasis underlies the observed hearing impairments and leads to hair cell degeneration. Our results underline the importance of neuroplastin for the development and the maintenance of the auditory system.

Child-related determinants of health-related quality of life in children with brain tumours 1 year after diagnosis.

OBJECTIVES: Infratentorial tumour site and health-related quality of life (HRQL) 1 month after diagnosis have been shown to predict HRQL 1 year after diagnosis in children with brain tumours. This study aimed to identify additional early child-related determinants of parent- and child-report HRQL. METHODS: Longitudinal prospective study. Semi-structured interviews took place approximately 1 and 12 months after diagnosis. HRQL was measured using the self- and parent-report Pediatric Quality of Life Scales (PedsQL 4.0) Total Scale Score and Health Utilities Index Mark 3 (HUI3) multi-attribute utility function. Child variables included performance and verbal IQ, general memory, selective attention executive function, behaviour problems, adaptive behaviour, symptoms of depression and anxiety and event related anxiety. Univariate analyses were used to identify potential early predictors of HRQL. Regression analysis was then used to identify the most important determinants of HRQL at 1 year. RESULTS: Thirty-five patients completed the 12-month interviews. Multivariate analysis showed infratentorial tumour site remained an important determinant of HRQL 1 year after diagnosis. Infratentorial tumour site and selective attention at 1 month generally best predicted poor self- and parent-report HRQL at 12 months. Adaptive behaviour and performance IQ may be important. CONCLUSION: Selective attention and infratentorial tumour site are most important in predicting both parent- and self-report HRQL at 1 year after diagnosis. Larger prospective studies are needed to confirm these findings. Cognitive remediation or/and pharmacological intervention, particularly aimed at children with infratentorial tumours may improve attention and subsequently HRQL and both merit further investigation.

Agreement in diagnosing occupational asthma by occupational and respiratory physicians who report to surveillance schemes for work-related ill-health.

OBJECTIVES: To assess diagnostic agreement for occupational asthma, and to identify case and rater characteristics associated with this diagnosis. METHODS: Summaries of possible occupational asthma cases were sent to 104 occupational and respiratory physicians. Raters assigned likelihood scores (0-100%) of occupational asthma based on case histories (phase 1), and on histories plus investigative procedures (phase 2). Interclass correlation coefficients were calculated as statistical measures of reliability for occupational asthma scores. Comparisons between mean scores were assessed for statistical significance using tests based on multilevel models. RRs were calculated to summarise effects of raters' demographics, and of supplying investigative procedures information. RESULTS: Occupational asthma scores showed limited agreement within each group of (occupational or respiratory) physicians, but scores were not systematically different. The difference between mean overall scores was 2.1% (52.1% occupational physicians; 50.0% respiratory physicians) in phase 1 (95% CI -2.6 to 6.8, p=0.37). In phase 2, mean overall scores were 46.1% (occupational physicians) and 41.5% (respiratory physicians); the difference in mean overall scores was 4.6% (95% CI -3.5 to 12.5, p=0.27). Raters with General Medical Council registration > or =1986 were more likely to give a positive occupational asthma diagnosis. In phase 2, male raters were more likely to label cases as occupational asthma than female raters (RR 4.5, 95% CI 3.3 to 6.0). CONCLUSIONS: The RR of a positive occupational asthma diagnosis was unaffected by clinical specialty. Further work on why physicians consider cases to be occupational asthma will assist better diagnosis and prevention of this disease.

Family, demographic and illness-related determinants of HRQL in children with brain tumours in the first year after diagnosis.

AIMS: To evaluate the relationship between parent- and child-report Health-Related Quality of Life (HRQL) and demographic, tumour and family variables in children with a brain tumour in the first year after diagnosis and to identify determinants of HRQL at 12 months. PROCEDURE: Longitudinal prospective study: Semi-structured interviews took place approximately 1, 6 and 12 months after diagnosis. HRQL was measured using the self- and parent-report PedsQL 4.0 Total Scale Score. Tumour and treatment variables considered included tumour site and grade, hydrocephalus at diagnosis, chemotherapy and radiotherapy. Family variables included measures of family function, family support and family stress, the primary carer's coping strategies and symptoms of depression and anxiety. Univariate analyses were used at all three time points, and to identify potential early predictors of HRQL at 1 year. Regression analysis was then used to identify the most important determinants of HRQL at 1 year. RESULTS: Thirty-five patients completed the 12-month interviews. There were consistent significant negative correlations between concurrent family impact of illness and parent and self-report HRQL, and positive correlations between concurrent family support and parent-report HRQL. Treatment with radio- or chemotherapy correlated with child-report HRQL only at some time points. Multivariate analysis showed infratentorial tumour site, and poor HRQL at 1 month best predicted poor self- and parent-report HRQL at 12 months. CONCLUSION: Children with infratentorial tumours and poor HRQL early after diagnosis tend to have poor HRQL at 1 year. While family factors are important modulators of concurrent HRQL, they do not appear important in predicting HRQL.

Sensitization to wheat flour and enzymes and associated respiratory symptoms in British bakers.

RATIONALE: Current literature suggests that flour exposed workers continue to be at risk of allergic sensitization to flour dust and respiratory ill health. OBJECTIVES: A cross-sectional study of 225 workers currently potentially exposed to flour dust in British bakeries was performed to identify predictors of sensitization to wheat flour and enzymes. RESULTS: Work-related nasal irritation was the most commonly reported symptom (28.9%) followed by eye irritation (13.3%) and work-related cough or chest tightness (both 10.2%). Work-related chest tightness was significantly associated (OR 7.9, 1.3-46.0) with co-sensitization to wheat flour and any added enzyme. Working at a bakery with inadequate control measures was not a risk factor for reporting work-related respiratory symptoms (OR 1.3, 0.4-3.7). Fifty-one workers were atopic and 23 (14%) were sensitized to workplace allergens. Atopy was the strongest predictive factor (OR 18.4, 5.3-64.3) determining sensitization. Current versus never smoking (OR 4.7, 1.1-20.8) was a significant risk factor for sensitization to wheat flour or enzymes in atopic workers only, corrected for current level and duration of exposure. This effect was not seen in non-atopic workers (OR 1.9, 0.2-17.9). Evidence of sensitization to less commonly encountered allergens was also seen to Aspergillus niger derived cellulase, hemicellulase and xylanase mix, in addition to glucose oxidase and amyloglucosidase mix. CONCLUSIONS: The combination of health surveillance and exposure control in this population has been insufficient to prevent clinically significant workplace sensitization. Smoking may pose an additional risk factor for sensitization in atopic workers. Am. J. Ind. Med. 52:133-140, 2009.

Management of occupational health risks in small-animal veterinary practices.

BACKGROUND: Small-animal work is a major element of veterinary practice in the UK and may be hazardous, with high levels of work-related injuries and ill-health reported in Australia and USA. There are no studies addressing the management of occupational health risks arising from small-animal work in the UK. AIMS: To investigate the sources of health and safety information used and how health and safety and 12 specific occupational health risks are managed by practices. METHODS: A cross-sectional postal survey of all small-animal veterinary practices in Hampshire. A response was mandatory as this was a Health & Safety Executive (HSE) inspection activity. RESULTS: A total of 118 (100%) practices responded of which 93 were eligible for inclusion. Of these, 99 and 86%, respectively, were aware of the Royal College of Veterinary Surgeons (RCVS) practice standards and had British Small Animal Veterinary Association (BSAVA) staff members, while only 51% had previous contact with HSE (publications, advice and visit). Ninety per cent had health and safety policies, but only 31% had trained responsible staff in health and safety. Specific health hazards such as occupational allergens and computer use were relatively overlooked both by practices and the RCVS/BSAVA guidance available in 2002. CONCLUSIONS: Failings in active health risk management systems could be due to a lack of training to ensure competence in those with responsibilities. Practices rely on guidance produced by their professional bodies. Current RCVS guidance, available since 2005, has remedied some previous omissions, but further improvements are recommended.

Health related quality of life in the first year after diagnosis in children with brain tumours compared with matched healthy controls; a prospective longitudinal study.

This paper compares parent- and self-report health-related quality of life (HRQL) in children aged 2-16 years with brain tumours, one, six and twelve months after diagnosis with matched normal controls. HRQL was assessed using the PedsQL generic core scales. 37 tumour patients and 42 controls were included in analysis of parent-report, and 27 patients and 31 controls in self-report HRQL. Parent-report scores were significantly lower in patients than controls for all PedsQL scores at all time points (max p=0.002). Differences in self-report PedsQL between patients and controls were variable. The relationship between self- and parent-report in patients and controls was inconsistent; varied over time; and did not consistently correlate with parental depressive symptoms, suggesting parents and their children do not regard HRQL in a similar way. Prospective, longitudinal assessment of HRQL is important, but should be supplemented with other outcome measures such as health status and behaviour in this population.

Variability in the diagnosis of occupational asthma and implications for clinical practice.

PURPOSE OF REVIEW: The purpose of this review is to provide a summary of recent evidence relating to occupational asthma diagnosis. RECENT FINDINGS: Recent evidence suggests that whilst prolonged asthmagen exposure worsens the prognosis, many steps in the diagnostic process are problematic for workers with possible occupational asthma. Certain workers suffer delay prior to specialist assessment, and assessment itself may be of variable quality. Emerging evidence suggests that whilst experts agree about certain aspects of case assessment, there is still likely to be variation in clinical practice. Implications of this variation for the workers assessed are relatively under researched. SUMMARY: Future research needs to focus not only on improving diagnostic testing, but also on improving consistency and agreement over diagnosis.

Occupational asthma: an assessment of diagnostic agreement between physicians.

OBJECTIVES: To investigate the levels of agreement between expert respiratory physicians when making a diagnosis of occupational asthma. METHODS: 19 cases of possible occupational asthma were identified as part of a larger national observational cohort. A case summary for each case was then circulated to 12 physicians, asking for a percentage likelihood, from the supplied information, that this case represented occupational asthma. The resulting probabilities were then compared between physicians using Spearman's rank correlation and Cohen's kappa coefficients. RESULTS: Agreement between the 12 physicians for all 19 cases was generally good as assessed by Spearman's rank correlation. For all 66 physician-physician interactions, 45 were found to correlate significantly at the 5% level. The agreement assessed by kappa analysis was more variable, with a median kappa value of 0.26, (range -0.2 to +0.76), although 7 of the physicians agreed significantly (p<0.05) with >or=5 of their colleagues. Only in one case did the responses for probability of occupational asthma all exceed the "on balance" 50% threshold, although 12 of the 19 cases had an interquartile range of probabilities not including 50%, implying "on balance" agreement. The median probability values for each physician (all assessing the identical 19 cases) varied from 20% to 70%. Factors associated with a high probability rating were the presence of a positive serial peak expiratory flow Occupation Asthma SYStem (OASYS)-2 chart, and both the presence of bronchial hyper-reactivity and significant change in reactivity between periods of work and rest. CONCLUSIONS: Despite the importance of the diagnosis of occupational asthma and reasonable physician agreement, certain variations in diagnostic assessment were seen between UK expert centres when assessing paper cases of possible occupational asthma. Although this may in part reflect the absence of a normal clinical consultation, a more unified national approach to these patients is required.