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We have created a lung simulation to quantify lung heterogeneity from the results of the inspired sinewave test (IST). The IST is a lung function test that is non-invasive, non-ionising and does not require patients' cooperation. A tidal lung simulation is developed to assess this test and also a method is proposed to calculate lung heterogeneity from IST results. A sensitivity analysis based on the Morris method and linear regression were applied to verify and to validate the simulation. Additionally, simulated emphysema and pulmonary embolism conditions were created using the simulation to assess the ability of the IST to identify these conditions. Experimental data from five pigs (pre-injured vs injured) were used for validation. This paper contributes to the development of the IST. Firstly, our sensitivity analysis reveals that the IST is highly accurate with an underestimation of about 5% of the simulated values. Sensitivity analysis suggested that both instability in tidal volume and extreme expiratory flow coefficients during the test cause random errors in the IST results. Secondly, the ratios of IST results obtained at two tracer gas oscillation frequencies can identify lung heterogeneity (ELV60/ELV180 and Qp60/Qp180). There was dissimilarity between simulated emphysema and pulmonary embolism (p < 0.0001). In the animal model, the control group had ELV60/ELV180 = 0.58 compared with 0.39 in injured animals (p < 0.0001).
T cells rely for their development and function on the correct folding and turnover of proteins generated in response to a broad range of molecular cues. In the absence of the eukaryotic type II chaperonin complex, CCT, T cell activation induced changes in the proteome are compromised including the formation of nuclear actin filaments and the formation of a normal cell stress response. Consequently, thymocyte maturation and selection, and T cell homeostatic maintenance and receptor-mediated activation are severely impaired. In the absence of CCT-controlled protein folding, Th2 polarization diverges from normal differentiation with paradoxical continued IFN-γ expression. As a result, CCT-deficient T cells fail to generate an efficient immune protection against helminths as they are unable to sustain a coordinated recruitment of the innate and adaptive immune systems. These findings thus demonstrate that normal T cell biology is critically dependent on CCT-controlled proteostasis and that its absence is incompatible with protective immunity.
Contrasting the brain imaging features of MOG-antibody disease, with AQP4-antibody NMOSD and multiple sclerosis.
BACKGROUND: Identifying magnetic resonance imaging (MRI) markers in myelin-oligodendrocytes-glycoprotein antibody-associated disease (MOGAD), neuromyelitis optica spectrum disorder-aquaporin-4 positive (NMOSD-AQP4) and multiple sclerosis (MS) is essential for establishing objective outcome measures. OBJECTIVES: To quantify imaging patterns of central nervous system (CNS) damage in MOGAD during the remission stage, and to compare it with NMOSD-AQP4 and MS. METHODS: 20 MOGAD, 19 NMOSD-AQP4, 18 MS in remission with brain or spinal cord involvement and 18 healthy controls (HC) were recruited. Volumetrics, lesions and cortical lesions, diffusion-imaging measures, were analysed. RESULTS: Deep grey matter volumes were lower in MOGAD (p = 0.02) and MS (p = 0.0001), compared to HC and were strongly correlated with current lesion volume (MOGAD R = -0.93, p
Elucidating distinct clinico-radiologic signatures in the borderland between neuromyelitis optica and multiple sclerosis.
BACKGROUND: Separating antibody-negative neuromyelitis optica spectrum disorders (NMOSD) from multiple sclerosis (MS) in borderline cases is extremely challenging due to lack of biomarkers. Elucidating different pathologies within the likely heterogenous antibody-negative NMOSD/MS overlap syndrome is, therefore, a major unmet need which would help avoid disability from inappropriate treatment. OBJECTIVE: In this study we aimed to identify distinct subgroups within the antibody-negative NMOSD/MS overlap syndrome. METHODS: Twenty-five relapsing antibody-negative patients with NMOSD features underwent a prospective brain and spinal cord MRI. Subgroups were identified by an unsupervised algorithm based on pre-selected NMOSD/MS discriminators. RESULTS: Four subgroups were identified. Patients from Group 1 termed "MS-like" (n = 6) often had central vein sign and cortical lesions (83% and 67%, respectively). All patients from Group 2 ("spinal MS-like", 8) had short-segment myelitis and no MS-like brain lesions. Group 3 ("classic NMO-like", 6) had high percentage of bilateral optic neuritis and longitudinally extensive transverse myelitis (LETM, 80% and 60%, respectively) and normal brain appearance (100%). Group 4 ("NMO-like with brain involvement", 5) typically had a history of NMOSD-like brain lesions and LETM. When compared with other groups, Group 4 had significantly decreased fractional anisotropy in non-lesioned tracts (0.46 vs. 0.49, p = 0.003) and decreased thalamus volume (0.84 vs. 0.98, p = 0.04). CONCLUSIONS: NMOSD/MS cohort contains distinct subgroups likely corresponding to different pathologies and requiring tailored treatment. We propose that non-conventional MRI might help optimise diagnosis in these challenging patients.
Recommendations for standards of monitoring during anaesthesia and recovery 2021: Guideline from the Association of Anaesthetists.
This guideline updates and replaces the 5th edition of the Standards of Monitoring published in 2015. The aim of this document is to provide guidance on the minimum standards for monitoring of any patient undergoing anaesthesia or sedation under the care of an anaesthetist. The recommendations are primarily aimed at anaesthetists practising in the UK and Ireland, but it is recognised that these guidelines may also be of use in other areas of the world. Minimum standards for monitoring patients during anaesthesia and in the recovery phase are included. There is also guidance on monitoring patients undergoing sedation and during transfer. There are new sections specifically discussing capnography, sedation and regional anaesthesia. In addition, the indications for processed electroencephalogram and neuromuscular monitoring have been updated.
The absolute number of never events is used by UK regulators to help assess hospital safety performance, without account of hospital workload. We applied funnel plots, as an established means of taking workload into account, to published never event data for 151 acute Trusts in NHS England, matched to finished consultant episodes for 3 years, 2017-2020. Trusts with excess event rates should have the most never events if absolute number is a valid way to judge performance. The absolute number of never events was correlated with workload (r2 = 0.51, p
Apathy in small vessel cerebrovascular disease is associated with deficits in effort-based decision making
Abstract Patients with small vessel cerebrovascular disease frequently suffer from apathy, a debilitating neuropsychiatric syndrome, the underlying mechanisms of which remain to be established. Here we investigated the hypothesis that apathy is associated with disrupted decision making in effort-based decision making, and that these alterations are associated with abnormalities in the white matter network connecting brain regions that underpin such decisions. Eighty-two patients with MRI evidence of small vessel disease were assessed using a behavioural paradigm as well as diffusion weighted MRI. The decision-making task involved accepting or rejecting monetary rewards in return for performing different levels of physical effort (hand grip force). Choice data and reaction times were integrated into a drift diffusion model that framed decisions to accept or reject offers as stochastic processes approaching a decision boundary with a particular drift rate. Tract-based spatial statistics were used to assess the relationship between white matter tract integrity and apathy, while accounting for depression. Overall, patients with apathy accepted significantly fewer offers on this decision-making task. Notably, while apathetic patients were less responsive to low rewards, they were also significantly averse to investing in high effort. Significant reductions in white matter integrity were observed to be specifically related to apathy, but not to depression. These included pathways connecting brain regions previously implicated in effort-based decision making in healthy people. The drift rate to decision parameter was significantly associated with both apathy and altered white matter tracts, suggesting that both brain and behavioural changes in apathy are associated with this single parameter. On the other hand, depression was associated with an increase in the decision boundary, consistent with an increase in the amount of evidence required prior to making a decision. These findings demonstrate altered effort-based decision making for reward in apathy, and also highlight dissociable mechanisms underlying apathy and depression in small vessel disease. They provide clear potential brain and behavioural targets for future therapeutic interventions, as well as modelling parameters that can be used to measure the effects of treatment at the behavioural level.
Long-term symptoms of polyneuropathy in breast and colorectal cancer patients treated with and without adjuvant chemotherapy.
BACKGROUND: The aim of this study was to assess chemotherapy-induced polyneuropathy (CIPN) 5 years after adjuvant chemotherapy in patients with breast and colorectal cancer. The association of CIPN with quality of life, anxiety, and depression was analyzed. METHODS: Of a set of 100 patients with breast cancer and of 74 with colorectal cancer who had undergone surgery and adjuvant chemotherapy in 2011-2012, 80 and 52 patients alive, respectively, were included together with two reference groups of 249 breast cancer patients and 83 colorectal cancer patients who had undergone surgery only. All patients were sent a questionnaire on alcohol consumption, smoking habits, comorbidity, medicine consumption, and oxaliplatin-specific questions, as well as the Michigan Neuropathy Screening Instrument questionnaire (MNSIq), the Douleur Neuropathique 4 Questions (DN4q), the EQ-5D, and the Hospital Anxiety and Depression Scale. Possible polyneuropathy was defined as the presence of numbness and/or tingling in the feet, secondly as a score of ≥4 on the MNSIq. Possible painful polyneuropathy was defined as pain in both feet and a score ≥3 on the DN4q. RESULTS: The prevalence of possible polyneuropathy defined by numbness and/or tingling in the feet was 38.8% (28.1-50.3) after adjuvant docetaxel and 57.7% (43.2-71.3) after adjuvant oxaliplatin, with no significant difference from a previous 1-year follow-up (P >.35). Fewer had possible polyneuropathy as defined by the MNSIq. Patients with possible polyneuropathy after adjuvant chemotherapy reported significantly lower quality of life than patients treated with surgery only. CONCLUSION: Symptoms of polyneuropathy following adjuvant docetaxel and oxaliplatin persist 5 years after treatment and affect quality of life negatively.
The aim of this study was to evaluate the presence and characterization of chemotherapy-induced neuropathy (CIPN) and neuropathic pain 5 years after adjuvant chemotherapy with docetaxel or oxaliplatin. Patients from an ongoing prospective study, who had received adjuvant chemotherapy with docetaxel or oxaliplatin in 2011 to 2012 were invited to participate. The patients underwent a thorough examination with interview, neurological examination, questionnaires, assessment tools, nerve conduction studies (NCS), quantitative sensory testing, MScan motor unit number estimation (MUNE), and corneal confocal microscopy (CCM). Patients were divided into no, possible, probable, and confirmed CIPN. Out of the 132 eligible patients, 63 agreed to participate: 28 had received docetaxel and 35 had received oxaliplatin. Forty-one percent had confirmed CIPN, 34% possible or probable CIPN, and 22% did not have CIPN. The CIPN was characterized mainly by sensory nerve fiber loss, with a more pronounced large fiber than small fiber loss but also some motor fiber loss identified on NCS and MUNE. In general, patients had mild neuropathy with relatively low scores on assessment tools and no association with mood and quality of life. CCM was not useful as a diagnostic tool. Of the patients with probable or confirmed CIPN, 30% experienced pain, which was most often mild, but still interfered moderately with daily life in 20% to 25% and was associated with lower quality of life. In conclusion CIPN was confirmed in 41% 5 years after chemotherapy. The neuropathy was generally mild, but in patients with neuropathic pain it was associated with lower quality of life.
BACKGROUND: Negative beliefs about the self, including low self-compassion, have been identified as a putative causal factor in the occurrence of paranoia. Therefore, improving self-compassion may be one route to reduce paranoia. AIMS: To assess the feasibility, acceptability, and potential clinical effects of a brief compassionate imagery intervention for patients with persecutory delusions. METHOD: Twelve patients with persecutory delusions received an individual four-session compassionate imagery intervention. Assessments of self-concept and paranoia were completed before treatment, immediately after treatment, and at 1-month follow-up. A qualitative study exploring participants' experiences of the treatment was also completed. RESULTS: Twelve out of 14 eligible patients referred to the study agreed to take part. All participants completed all therapy sessions and assessments. Post-treatment, there were improvements in self-compassion (change score -0.64, 95% CI -1.04, -0.24, d = -1.78), negative beliefs about the self (change score 2.42, 95% CI -0.37, 5.20, d = 0.51), and paranoia (change score 10.08, 95% CI 3.47, 16.69, d = 0.61). There were no serious adverse events. Three themes emerged from the qualitative analysis: 'effortful learning', 'seeing change' and 'taking it forward'. Participants described a process of active and effortful engagement in therapy which was rewarded with positive changes, including feeling calmer, gaining clarity, and developing acceptance. CONCLUSION: This uncontrolled feasibility study indicates that a brief compassionate imagery intervention for patients with persecutory delusions is feasible, acceptable, and may lead to clinical benefits.
Variability of environmental sound levels: An observational study from a general adult intensive care unit in the UK
Background Intensive care units are significantly louder than WHO guidelines recommend. Patients are disturbed by activities around them and frequently report disrupted sleep. This can lead to slower recovery and long-term health problems. Environmental sound levels are usually reported as LAeq24, a single daily value that reflects mean sound levels over the previous 24-h period. This may not be the most appropriate measure for intensive care units (ICUs) and other similar areas. Humans experience sound in context, and disturbance will vary according to both the individual and acoustic features of the ambient sounds. Loudness is one of a number of measures that approximate the human perception of sound, taking into account tone, duration, and frequency, as well as volume. Typically sounds with higher frequencies, such as alarms, are perceived as louder and more disturbing. Methods Sound level data were collected from a single NHS Trust hospital general adult intensive care unit between October 2016 and May 2018. Summary data (mean sound levels (LAeq) and corresponding Zwicker calculated loudness values) were subsequently analysed by minute, hour, and day. Results The overall mean LAeq24 across the study duration was 47.4 dBA. This varied by microphone location. We identified a clear pattern to sound level fluctuations across the 24-h period. Weekends were significantly quieter than weekdays in statistical terms but this reduction of 0.2 dB is not detectable by human hearing. Peak loudness values over 90 dB were recorded every hour. Conclusions Perception of sound is sensitive to the environment and individual characteristics and sound levels in the ICU are location specific. This has implications for routine environmental monitoring practices. Peak loudness values are consistently between 90 and 100 dB. These may be driven by alarms and other sudden high-frequency sounds, leading to more disturbance than LAeq24 sound levels suggest. Addressing sounds with high loudness values may improve the ICU environment more than an overall reduction in the 24-h mean decibel value.
AbstractThe major anti-hypertensive (AHT) drug classes have been associated with differential risks of psychiatric disorders. However, existing data are limited largely to depression, and confounding variables have not always been controlled for. We sought to fill the evidence gap, using TriNetX Analytics, an electronic health records network. Amongst 58.6 million patients aged 18–90 years, patients prescribed a calcium channel blocker (CCB) were compared with those taking a diuretic, angiotensin-converting enzyme inhibitor (ACEI), angiotensin receptor blocker (ARB), or β-blocker. Cohorts were propensity score-matched for age, sex, race, and blood pressure. Over a 2-year exposure period, we measured the incidence and risk ratio of a first diagnosis (ICD-10 codes), or a recurrence, of psychotic, affective, and anxiety disorders, as well as substance use disorders and sleep disorders. Cohort sizes ranged from 33,734 to 322,814. CCBs were associated with a lower incidence of psychotic, affective, and anxiety disorders than β-blockers (risk ratios 0.69–0.99) and a higher incidence than ARBs (risk ratios 1.04–2.23) for both first and recurrent diagnoses. Comparisons of CCBs with ACEIs or diuretics showed smaller risk ratios that varied between disorders, and between first episode and recurrence. AHT classes were also associated with the incidence of substance use and sleep disorders. Results remained largely unchanged after more extensive cohort matching for additional potential confounders. In a secondary analysis, a comparison between ARBs and ACEIs showed lower rates of psychotic, affective, and substance use disorders with ARBs, but higher risks of anxiety and sleep disorders. In conclusion, AHT classes are differentially associated with the incidence of psychiatric disorders. ARBs show the most advantageous profile and β-blockers the least. The apparent beneficial effects of ARBs merit further study.
Abstract Background Bedside measurement of lung volume may provide guidance in the personalised setting of respiratory support, especially in patients with the acute respiratory distress syndrome at risk of ventilator-induced lung injury. We propose here a novel operator-independent technique, enabled by a fibre optic oxygen sensor, to quantify the lung volume available for gas exchange. We hypothesised that the continuous measurement of arterial partial pressure of oxygen (PaO2) decline during a breath-holding manoeuvre could be used to estimate lung volume in a single-compartment physiological model of the respiratory system. Methods Thirteen pigs with a saline lavage lung injury model and six control pigs were studied under general anaesthesia during mechanical ventilation. Lung volumes were measured by simultaneous PaO2 rate of decline (VPaO2) and whole-lung computed tomography scan (VCT) during apnoea at different positive end-expiratory and end-inspiratory pressures. Results A total of 146 volume measurements was completed (range 134 to 1869 mL). A linear correlation between VCT and VPaO2 was found both in control (slope = 0.9, R2 = 0.88) and in saline-lavaged pigs (slope = 0.64, R2 = 0.70). The bias from Bland–Altman analysis for the agreement between the VCT and VPaO2 was − 84 mL (limits of agreement ± 301 mL) in control and + 2 mL (LoA ± 406 mL) in saline-lavaged pigs. The concordance for changes in lung volume, quantified with polar plot analysis, was − 4º (LoA ± 19°) in control and − 9° (LoA ± 33°) in saline-lavaged pigs. Conclusion Bedside measurement of PaO2 rate of decline during apnoea is a potential approach for estimation of lung volume changes associated with different levels of airway pressure.
Chronic insomnia is associated with subjective daytime cognitive dysfunction, but objective corroborative data are often lacking. In this study, we use Perceptual Load Theory to objectively assess distractibility in participants with insomnia ( N = 23) compared with age- and sex-matched controls ( N = 23). Following overnight supervised sleep observation, all participants completed a selective attention task which varied in the level of perceptual load and distractor congruency. The insomnia group was found to be more distracted than controls, whereas their selective attention mechanism appeared to be intact, with reduced distractor processing under high load for both groups. Insomnia symptom severity was positively correlated with participant distractibility. These findings suggest that there are insomnia-related daytime cognitive impairments that are likely to arise from compromised cognitive control rather than an ineffective selective attention mechanism. This task may be clinically useful in assessing daytime impairments, and potentially treatment response, in those with insomnia.
Human sensory neurons derived from pluripotent stem cells for disease modelling and personalized medicine.
In this concise Mini-Review we will summarize ongoing developments of new techniques to study physiology and pathophysiology of the peripheral sensory nervous system in human stem cell derived models. We will focus on recent developments of reprogramming somatic cells into induced pluripotent stem cells, neural differentiation towards neuronal progenitors and human sensory neurons. We will sum up the high potential of this new technique for disease modelling of human neuropathies with a focus on genetic pain syndromes, such as gain- and loss-of-function mutations in voltage-gated sodium channels. The stem cell derived human sensory neurons are used for drug testing and we will summarize their usefulness for individualized treatment identification in patients with neuropathic pain. The review will give an outlook on potential application of this technique as companion diagnostics and for personalized medicine.
Paranoia and Grandiosity in the General Population: Differential Associations With Putative Causal Factors.
Worry, negative self-beliefs, and sleep disturbance have been identified as contributory factors to the onset, maintenance, and severity of paranoia. We tested the specificity of these contributory factors to paranoia compared to grandiosity, a different type of delusional ideation. Data were used from 814 adults from the Nathan Kline Institute-Rockland (NKI-Rockland) study, a general population dataset. Paranoid and grandiose delusional ideation was assessed using the Peters Delusions Inventory (PDI-21) and correlated with self-reported worry (n = 228), negative self-beliefs (n = 485), and sleep quality (n = 655). Correlations were compared using Fisher's r-to-z transform to examine whether the magnitude of relationships differed by delusion type. Paranoia was significantly associated with worry, negative self-belief, and sleep quality. Grandiosity demonstrated significantly weaker relationships with worry and negative self-beliefs. Relationships with sleep quality were similar. We replicate previous reports that worry, negative self-beliefs and sleep quality are associated with paranoid ideation in the general population. We extend these findings by demonstrating that these contributory factors, particularly worry and negative self-beliefs, are associated with paranoid ideation to a greater extent than grandiosity. This suggests a degree of specificity of contributory factors to different types of delusional thinking, supporting the pursuit of specific psychological models and treatments for each delusion type.