Impact of the COVID-19 pandemic on hospital episodes for falls and fractures associated with new-onset disability and frailty in England: a national cohort study.

BACKGROUND: Older people with frailty are at risk of harm from immobility or isolation, yet data about how COVID-19 lockdowns affected them are limited. Falls and fractures are easily measurable adverse outcomes correlated with frailty. We investigated whether English hospital admission rates for falls and fractures varied from the expected trajectory during the COVID-19 pandemic, and how these varied by frailty status. METHODS: NHS England Hospital Episode Statistics Admitted Patient Care data were analysed for observed versus predicted outcome rates for 24 January 2020 to 31 December 2021. An auto-regressive integrated moving average time-series model was trained using falls and fracture incidence data from 2013 to 2018 and validated using data from 2019. Models included national and age-, sex- and region-stratified forecasts. Outcome measures were hospital admissions for falls, fractures, and falls and fractures combined. Frailty was defined using the Hospital Frailty Risk Score. RESULTS: 144,148,915 pre-pandemic hospital admissions were compared with 42,267,318 admissions after pandemic onset. For the whole population, falls and fracture rates were below predicted for the first period of national lockdown, followed by a rapid return to rates close to predicted. Thereafter, rates followed expected trends. For people living with frailty, however, falls and fractures increased above expected rates during periods of national lockdown and remained elevated throughout the study period. Effects of frailty were independent of age. CONCLUSIONS: People living with frailty experienced increased fall and fracture rates above expected during and following periods of national lockdown. These remained persistently elevated throughout the study period.

Qualitative interviews to understand methods and systems used to collect ethnicity information in health administrative data sources in England.

Background: This article is one of a series aiming to inform analytical methods to improve comparability of estimates of ethnic health disparities based on different sources. This article explores the quality of ethnicity data and identifies potential sources of bias when ethnicity information is collected in three key NHS data sources. Future research can build on these findings to explore analytical methods to mitigate biases. Methods: Thematic analysis of semi-structured qualitative interviews to explore potential sources of error and bias in the process of collecting ethnicity information across three NHS data sources: General Practice Extraction Service (GPES) Data for Pandemic Planning and Research (GDPPR), Hospital Episode Statistics (HES) and Improving Access to Psychological Therapies (IAPT). The study included feedback from 22 experts working on different aspects of health admin data collection for England (including staff from NHS Digital, IT system suppliers and relevant healthcare service providers). Results: Potential sources of error and bias were identified across data collection, data processing and quality assurance processes. Similar issues were identified for all three sources. Our analysis revealed three main themes which can result in bias and inaccuracies in ethnicity data recorded: data infrastructure challenges, human challenges, and institutional challenges. Conclusions: Findings highlighted that analysts using health admin data should be aware of the main sources of potential error and bias in health admin data, and be mindful that the main sources of error identified are more likely to affect the ethnicity data for ethnic minority groups. Where possible, analysts should describe and seek to account for this bias in their research.

Study protocol for the use of time series forecasting and risk analyses to investigate the effect of the COVID-19 pandemic on hospital admissions associated with new-onset disability and frailty in a national, linked electronic health data setting.

INTRODUCTION: Older people were at particular risk of morbidity and mortality during COVID-19. Consequently, they experienced formal (externally imposed) and informal (self-imposed) periods of social isolation and quarantine. This is hypothesised to have led to physical deconditioning, new-onset disability and frailty. Disability and frailty are not routinely collated at population level but are associated with increased risk of falls and fractures, which result in hospital admissions. First, we will examine incidence of falls and fractures during COVID-19 (January 2020-March 2022), focusing on differences between incidence over time against expected rates based on historical data, to determine whether there is evidence of new-onset disability and frailty. Second, we will examine whether those with reported SARS-CoV-2 were at higher risk of falls and fractures. METHODS AND ANALYSIS: This study uses the Office for National Statistics (ONS) Public Health Data Asset, a linked population-level dataset combining administrative health records with sociodemographic data of the 2011 Census and National Immunisation Management System COVID-19 vaccination data for England. Administrative hospital records will be extracted based on specific fracture-centric International Classification of Diseases-10 codes in years preceding COVID-19 (2011-2020). Historical episode frequency will be used to predict expected admissions during pandemic years using time series modelling, if COVID-19 had not occurred. Those predicted admission figures will be compared with actual admissions to assess changes in hospital admissions due to public health measures comprising the pandemic response. Hospital admissions in prepandemic years will be stratified by age and geographical characteristics and averaged, then compared with pandemic year admissions to assess more granular changes. Risk modelling will assess risk of experiencing a fall, fracture or frail fall and fracture, if they have reported a positive case of COVID-19. The combination of these techniques will provide insight into changes in hospital admissions from the COVID-19 pandemic. ETHICS AND DISSEMINATION: This study has approval from the National Statistician's Data Ethics Advisory Committee (NSDEC(20)12). Results will be made available to other researchers via academic publication and shared via the ONS website.

Ethnic differences in COVID-19 mortality in the second and third waves of the pandemic in England during the vaccine rollout: a retrospective, population-based cohort study.

BACKGROUND: Ethnic minority groups in England have been disproportionately affected by the COVID-19 pandemic and have lower vaccination rates than the White British population. We examined whether ethnic differences in COVID-19 mortality in England have continued since the vaccine rollout and to what extent differences in vaccination rates contributed to excess COVID-19 mortality after accounting for other risk factors. METHODS: We conducted a retrospective, population-based cohort study of 28.8 million adults aged 30-100 years in England. Self-reported ethnicity was obtained from the 2011 Census. The outcome was death involving COVID-19 during the second (8 December 2020 to 12 June 2021) and third wave (13 June 2021 to 1 December 2021). We calculated hazard ratios (HRs) for death involving COVID-19, sequentially adjusting for age, residence type, geographical factors, sociodemographic characteristics, pre-pandemic health, and vaccination status. RESULTS: Age-adjusted HRs of death involving COVID-19 were elevated for most ethnic minority groups during both waves, particularly for groups with lowest vaccination rates (Bangladeshi, Pakistani, Black African, and Black Caribbean). HRs were attenuated after adjusting for geographical factors, sociodemographic characteristics, and pre-pandemic health. Further adjusting for vaccination status substantially reduced residual HRs for Black African, Black Caribbean, and Pakistani groups in the third wave. Fully adjusted HRs only remained elevated for the Bangladeshi group (men: 2.19 [95% CI 1.72-2.78]; women: 2.12 [1.58-2.86]) and Pakistani men (1.24 [1.06-1.46]). CONCLUSIONS: Lower COVID-19 vaccination uptake in several ethnic minority groups may drive some of the differences in COVID-19 mortality compared to White British. Public health strategies to increase vaccination uptake in ethnic minority groups would help reduce inequalities in COVID-19 mortality, which have remained substantial since the start of the vaccination campaign.

Religious affiliation and COVID-19-related mortality: a retrospective cohort study of prelockdown and postlockdown risks in England and Wales.

BACKGROUND: COVID-19 mortality risk is associated with demographic and behavioural factors; furthermore, religious gatherings have been linked with the spread of COVID-19. We sought to understand the variation in risk of COVID-19-related death across religious groups in England and Wales both before and after the first national lockdown. METHODS: We conducted a retrospective cohort study of usual residents in England and Wales enumerated at the 2011 Census (n=47 873 294, estimated response rate 94%) for risk of death involving COVID-19 using linked death certificates. Cox regression models were estimated to compare risks between religious groups. Time-dependent coefficients were added to the model allowing HRs before and after lockdown period to be estimated separately. RESULTS: Compared with Christians, all religious groups had an elevated risk of death involving COVID-19; the largest age-adjusted HRs were for Muslim and Jewish males at 2.5 (95% CI 2.3 to 2.7) and 2.1 (95% CI 1.9 to 2.5), respectively. The corresponding HRs for Muslim and Jewish females were 1.9 (95% CI 1.7 to 2.1) and 1.5 (95% CI 1.7 to 2.1), respectively. The difference in risk between groups contracted after lockdown. Those who affiliated with no religion had the lowest risk of COVID-19-related death before and after lockdown. CONCLUSION: The majority of the variation in COVID-19 mortality risk was explained by controlling for sociodemographic and geographic determinants; however, those of Jewish affiliation remained at a higher risk of death compared with all other groups. Lockdown measures were associated with reduced differences in COVID-19 mortality rates between religious groups; further research is required to understand the causal mechanisms.

Mechanism and properties of positive allosteric modulation of N-methyl-d-aspartate receptors by 6-alkyl 2-naphthoic acid derivatives.

The theory that N-methyl-d-aspartate receptor (NMDAR) hypofunction is responsible for the symptoms of schizophrenia is well supported by many pharmacological and genetic studies. Accordingly, positive allosteric modulators (PAMs) that augment NMDAR signaling may be useful for treating schizophrenia. Previously we have identified several NMDAR PAMs containing a carboxylic acid attached to naphthalene, phenanthrene, or coumarin ring systems. In this study, we describe several functional and mechanistic properties of UBP684, a 2-naphthoic acid derivative, which robustly potentiates agonist responses at each of the four GluN1a/GluN2 receptors and at neuronal NMDARs. UBP684 increases the maximal l-glutamate/glycine response while having minor subunit-specific effects on agonist potency. PAM binding is independent of agonist binding, and PAM activity is independent of membrane voltage, redox state, and the GluN1 exon 5 N-terminal insert. UBP684 activity is, however, markedly pH-dependent, with greater potentiation occurring at lower pHs and inhibitory activity at pH 8.4. UBP684 increases channel open probability (Po) and slows receptor deactivation time upon removal of l-glutamate, but not glycine. The structurally related PAM, UBP753, reproduced most of these findings, but did not prolong agonist removal deactivation time. Studies using cysteine mutants to lock the GluN1 and GluN2 ligand-binding domains (LBDs) in the agonist-bound states indicate that PAM potentiation requires GluN2 LBD conformational flexibility. Together, these findings suggest that UBP684 and UBP753 stabilize the GluN2 LBD in an active conformation and thereby increase Po. Thus, UBP684 and UBP753 may serve as lead compounds for developing agents to enhance NMDAR activity in disorders associated with NMDAR hypofunction.

Antagonists reversibly reverse chemical LTD induced by group I, group II and group III metabotropic glutamate receptors.

Metabotropic glutamate (mGlu) receptors are implicated in many neurological and psychiatric diseases and are the targets of therapeutic agents currently in clinical development. Their activation has diverse effects in the central nervous system (CNS) that includes an involvement in synaptic plasticity. We previously reported that the brief exposure of hippocampal slices to dihydroxyphenylglycine (DHPG) can result in a long-term depression (LTD) of excitatory synaptic transmission. Surprisingly, this LTD could be fully reversed by mGlu receptor antagonists in a manner that was itself fully reversible upon washout of the antagonist. Here, 15 years after the discovery of DHPG-LTD and its reversible reversibility, we summarise these initial findings. We then present new data on DHPG-LTD, which demonstrates that evoked epileptiform activity triggered by activation of group I mGlu receptors can also be reversibly reversed by mGlu receptor antagonists. Furthermore, we show that the phenomenon of reversible reversibility is not specific to group I mGlu receptors. We report that activation of group II mGlu receptors in the temporo-ammonic pathway (TAP) and mossy fibre pathway within the hippocampus and in the cortical input to neurons of the lateral amygdala induces an LTD that is reversed by LY341495, a group II mGlu receptor antagonist. We also show that activation of group III mGlu8 receptors induces an LTD at lateral perforant path inputs to the dentate gyrus and that this LTD is reversed by MDCPG, an mGlu8 receptor antagonist. In conclusion, we have shown that activation of representative members of each of the three groups of mGlu receptors can induce forms of LTD than can be reversed by antagonists, and that in each case washout of the antagonist is associated with the re-establishment of the LTD. This article is part of the Special Issue entitled 'Glutamate Receptor-Dependent Synaptic Plasticity'.

The NMDA receptor as a target for cognitive enhancement.

NMDA receptors (NMDARs) play an important role in neural plasticity including long-term potentiation and long-term depression, which are likely to explain their importance for learning and memory. Cognitive decline is a major problem facing an ageing human population, so much so that its reversal has become an important goal for scientific research and pharmaceutical development. Enhancement of NMDAR function is a core strategy toward this goal. In this review we indicate some of the major ways of potentiating NMDAR function by both direct and indirect modulation. There is good evidence that both positive and negative modulation can enhance function suggesting that a subtle approach correcting imbalances in particular clinical situations will be required. Excessive activation and the resultant deleterious effects will need to be carefully avoided. Finally we describe some novel positive allosteric modulators of NMDARs, with some subunit selectivity, and show initial evidence of their ability to affect NMDAR mediated events. This article is part of a Special Issue entitled 'Cognitive Enhancers'.

Different NMDA receptor subtypes mediate induction of long-term potentiation and two forms of short-term potentiation at CA1 synapses in rat hippocampus in vitro.

Potentiation at synapses between CA3 and the CA1 pyramidal neurons comprises both transient and sustained phases, commonly referred to as short-term potentiation (STP or transient LTP) and long-term potentiation (LTP), respectively. Here, we utilized four subtype-selective N-methyl-d-aspartate receptor (NMDAR) antagonists to investigate whether the induction of STP and LTP is dependent on the activation of different NMDAR subtypes. We find that the induction of LTP involves the activation of NMDARs containing both the GluN2A and the GluN2B subunits. Surprisingly, however, we find that STP can be separated into two components, the major form of which involves activation of NMDARs containing both GluN2B and GluN2D subunits. These data demonstrate that synaptic potentiation at CA1 synapses is more complex than is commonly thought, an observation that has major implications for understanding the role of NMDARs in cognition.

A novel anti-epileptic agent, perampanel, selectively inhibits AMPA receptor-mediated synaptic transmission in the hippocampus.

Perampanel is a non-competitive AMPA receptor antagonist that is under development as an anti-epileptic therapy. Although it is known to reduce calcium flux mediated by AMPA receptors in cultured cortical neurons, there are no studies of its selectivity in synaptic transmission in more intact systems. In the present study using hippocampal slices, perampanel (0.01-10 µM) has been tested on pharmacologically isolated synaptic responses mediated by AMPA, NMDA or kainate receptors. Perampanel reduced AMPA receptor-mediated excitatory postsynaptic field potentials (f-EPSPs) with an IC(50) of 0.23 µM and a full block at 3 µM. This compares with an IC(50) of 7.8 µM for GYKI52466 on these responses. By contrast, perampanel at 10 µM had no effect on responses mediated by NMDA or kainate receptors, which were completely blocked by 30 µM D-AP5 and 10 µM NBQX respectively. The concentrations of perampanel required to reduce AMPA receptor-mediated responses are not dissimilar to those in plasma following anti-convulsant doses and are consistent with AMPA receptor antagonism being its primary mode of action.

Quantal analysis reveals a functional correlation between presynaptic and postsynaptic efficacy in excitatory connections from rat neocortex.

At many central synapses, the presynaptic bouton and postsynaptic density are structurally correlated. However, it is unknown whether this correlation extends to the functional properties of the synapses. To investigate this, we made recordings from synaptically coupled pairs of pyramidal neurons in rat visual cortex. The mean peak amplitude of EPSPs recorded from pairs of L2/3 neurons ranged between 40 microV and 2.9 mV. EPSP rise times were consistent with the majority of the synapses being located on basal dendrites; this was confirmed by full anatomical reconstructions of a subset of connected pairs. Over a third of the connections could be described using a quantal model that assumed simple binomial statistics. Release probability (P(r)) and quantal size (Q), as measured at the somatic recording site, showed considerable heterogeneity between connections. However, across the population of connections, values of P(r) and Q for individual connections were positively correlated with one another. This correlation also held for inputs to layer 5 pyramidal neurons from both layer 2/3 and neighboring layer 5 pyramidal neurons, suggesting that during development of cortical connections presynaptic and postsynaptic strengths are dependently scaled. For 2/3 to 2/3 connections, mean EPSP amplitude was correlated with both Q and P(r) values but uncorrelated with N, the number of functional release sites mediating the connection. The efficacy of a cortical connection is thus set by coordinated presynaptic and postsynaptic strength.

Synaptic strength at the thalamocortical input to layer IV neonatal barrel cortex is regulated by protein kinase C.

Long-term synaptic plasticity is an important mechanism underlying the development of cortical circuits in a number of brain regions. In barrel cortex NMDA receptor (NMDAR)-dependent long-term potentiation (LTP) and long-term depression (LTD) play a critical role in the development and experience-dependent plasticity of the topographical map of the rodent whiskers. However, the mechanisms underlying the induction and expression of these forms of plasticity are poorly characterised. Here we investigate the role of PKC in the regulation of synaptic strength in neonatal barrel cortex using patch-clamp recordings in brain slices. We demonstrate that PKC activity tonically maintains AMPA receptor-mediated transmission at thalamocortical synapses, and that basal transmission can be potentiated by PKC activation using postsynaptic infusion of phorbol ester. Furthermore, we show that induction of NMDAR-dependent LTP requires PKC activity. These findings demonstrate that PKC is required for the regulation of transmission at thalamocortical synapses, the major ascending sensory input to barrel cortex. Thalamocortical inputs in barrel cortex only express LTP during the first postnatal week during a critical period for experience-dependent plasticity in layer IV. Therefore, the requirement for PKC in LTP suggests an important role for this kinase in the development of the barrel cortex sensory map.

Differential roles of NR2A and NR2B-containing NMDA receptors in LTP and LTD in the CA1 region of two-week old rat hippocampus.

The role of NMDA receptors in the induction of long-term potentiation (LTP) and long-term depression (LTD) is well established but which particular NR2 subunits are involved in these plasticity processes is still a matter of controversy. We have studied the effects of subtype selective NMDA receptor antagonists on LTP induced by high frequency stimulation (100 Hz for 1s) and LTD induced by low frequency stimulation (1 Hz for 15 min) in the CA1 region of hippocampal slices from 14 day old Wistar rats. Against recombinant receptors in HEK293 cells NVP-AAM077 (NVP) was approximately 14-fold selective for NR2A vs NR2B receptors, whilst Ro 25-6981 (Ro) was highly selective for NR2B receptors. On NMDA receptor-mediated EPSCs from Schaffer collaterals in CA1 neurones, NVP and Ro both reduced the amplitude but differentially affected the time constant of decay. The data are compatible with the selective effect of NVP (0.1 microM) and Ro (4 microM) on native NR2A and NBR2B receptors, respectively. NVP reduced both LTP and LTD whereas Ro reduced only LTP. Thus, LTP was reduced by 63% at 0.1 microM NVP and almost completely at 0.4 microM whereas 5 microM Ro reduced LTP by 45%. These data are consistent with a role for both NR2A and NR2B in the induction of LTP, under our experimental conditions. In comparison, LTD was unaffected by Ro (5 microM) even in the presence of a glutamate uptake inhibitor threo-beta-benzylaspartic acid (TBOA) to increase the concentration of glutamate at NR2B containing receptors. NVP (0.2-0.4 microM), however, produced a concentration dependent inhibition of LTD which was complete at 0.4 microM. The lack of effect of 0.1 microM NVP on LTD contrasts with its marked effect on LTP and raises the possibility that different NVP-sensitive NR2 subunit-containing NMDA receptors are required for LTP and LTD in this preparation.

Extracellular calcium regulates postsynaptic efficacy through group 1 metabotropic glutamate receptors.

Bursts of synaptic transmission are known to induce transient depletion of Ca2+ within the synaptic cleft. Although Ca2+ depletion has been shown to lower presynaptic release probability, effects on the postsynaptic cell have not been reported. In this study, we show that physiologically relevant reductions in extracellular Ca2+ lead to a decrease in synaptic strength between synaptically coupled layer 2/3 cortical pyramidal neurons. Using quantal analysis and mEPSP analysis, we demonstrate that a lowered extracellular Ca2+ produces a reduction in the postsynaptic quantal size in addition to its known effect on release probability. An elevated Mg2+ level can prevent this reduction in postsynaptic efficacy at subphysiological Ca2+ levels. We show that the calcium-dependent effect on postsynaptic quantal size is mediated by group 1 metabotropic glutamate receptors, acting via CaMKII (Ca2+/calmodulin-dependent protein kinase II) and PKC. Therefore, physiologically relevant changes in extracellular Ca2+ can regulate information transfer at cortical synapses via both presynaptic and postsynaptic mechanisms.

Rapid, activity-dependent plasticity in timing precision in neonatal barrel cortex.

Developing neuronal networks acquire the ability to precisely time events, a key feature required for information processing. In the barrel cortex, encoding of information requires a high-precision temporal code with a resolution of approximately 5 ms; however, it is not known what process drives the maturation in timing precision. Here, we report that long-term potentiation (LTP) at thalamocortical synapses in the neonatal layer IV barrel cortex produces a dramatic improvement in the timing of neuronal output and synaptic input. LTP strongly reduces the latency and variability of synaptically evoked action potentials, improving the fidelity of timing to within that predicted to be required for adult sensory processing. Such changes in timing also occur during development in the neonate. LTP also reduces the summation of EPSPs shortening the window for coincidence detection for synaptic input. In contrast to these reliable effects, LTP produced only a modest and variable change in synaptic efficacy. Thus, our findings suggest that the primary role of this form of neonatal LTP is for the acquisition of timing precision and the refinement of coincidence detection, rather than an increase in synaptic strength. Therefore, neonatal thalamocortical LTP may be a critical prerequisite for the maturation of information processing in the barrel cortex.

Developmental changes in AMPA and kainate receptor-mediated quantal transmission at thalamocortical synapses in the barrel cortex.

During the first week of life, there is a shift from kainate to AMPA receptor-mediated thalamocortical transmission in layer IV barrel cortex. However, the mechanisms underlying this change and the differential properties of AMPA and kainate receptor-mediated transmission remain essentially unexplored. To investigate this, we studied the quantal properties of AMPA and kainate receptor-mediated transmission using strontium-evoked miniature EPSCs. AMPA and kainate receptor-mediated transmission exhibited very different quantal properties but were never coactivated by a single quantum of transmitter, indicating complete segregation to different synapses within the thalamocortical input. Nonstationary fluctuation analysis showed that synaptic AMPA receptors exhibited a range of single-channel conductance (gamma) and a strong negative correlation between gamma and functional channel number, indicating that these two parameters are reciprocally regulated at thalamocortical synapses. We obtained the first estimate of gamma for synaptic kainate receptors (<2 pS), and this primarily accounted for the small quantal size of kainate receptor-mediated transmission. Developmentally, the quantal contribution to transmission of AMPA receptors increased and that of kainate receptors decreased. No changes in AMPA or kainate quantal amplitude or in AMPA receptor gamma were observed, demonstrating that the developmental change was attributable to a decrease in the number of kainate synapses and an increase in the number of AMPA synapses contributing to transmission. Therefore, we demonstrate fundamental differences in the quantal properties for these two types of synapse. Thus, the developmental switch in transmission will dramatically alter information transfer at thalamocortical inputs to layer IV.