Nevin Manimala

eNeuro. 2021 Nov 2:ENEURO.0194-21.2021. doi: 10.1523/ENEURO.0194-21.2021. Online ahead of print.

ABSTRACT

Studies in animals have demonstrated a strong relationship between cortical and hippocampal activity, and autonomic tone. However, the extent, distribution, and nature of this relationship have not been investigated with intracranial recordings in humans during sleep. Cortical and hippocampal population neuronal firing was estimated from high gamma band activity (HG) from 70 to 110 Hz in local field potentials recorded from 15 subjects (9 females) during non-rapid eye movement (NREM) sleep. Autonomic tone was estimated from heart rate variability (HRV). HG and HRV were significantly correlated in the hippocampus and multiple cortical sites in NREM stages N1-3. The average correlation between HG and HRV could be positive or negative across patients given anatomical location and sleep stage and was most profound in lateral temporal lobe in N3, suggestive of greater cortical activity associated with sympathetic tone. Patient-wide correlation was related to delta band activity (1-4 Hz), which is known to be correlated with high gamma activity during sleep. The percentage of statistically correlated channels was weaker in N1 and N2 as compared to N3, and was strongest in regions that have previously been associated with autonomic processes, such as anterior hippocampus and insula. The anatomical distribution of HRV-HG correlations during sleep did not reproduce those usually observed with PET or fMRI during waking. This study aims to characterize the relationship between autonomic tone and neuronal firing rate during sleep and further studies are needed to investigate finer temporal resolutions, denser coverages, and different frequency bands in both waking and sleep.Significance StatementStudies in animals have shown that the autonomic nervous system sets the operating mode of all the organ systems in the body, including the central nervous system. We show here that high gamma activity in widespread cortical and hippocampal regions is correlated with heart rate variability in humans during sleep. The correlation was especially profound in sites which have previously been associated with autonomic and emotional regulation. The direction of change varied between forebrain locations, indicating the existence of sympathetic and parasympathetic modulating structures. The percentage of correlated channels between autonomic tone and cortical activity was greatest in the deepest stages of slow-wave sleep. Overall, this study characterizes in humans a foundational link in the unity of mind and body.

PMID:34732536 | DOI:10.1523/ENEURO.0194-21.2021

J Neurosci. 2021 Nov 2:JN-RM-1311-21. doi: 10.1523/JNEUROSCI.1311-21.2021. Online ahead of print.

ABSTRACT

Learned associations between stimuli allow us to model the world and make predictions, crucial for efficient behavior; e.g., hearing a siren, we expect to see an ambulance and quickly make way. While there are theoretical and computational frameworks for prediction, the circuit and receptor-level mechanisms are unclear. Using high-density EEG, Bayesian modeling and machine learning, we show that inferred “causal” relationships between stimuli and frontal alpha activity account for reaction times (a proxy for predictions) on a trial-by-trial basis in an audio-visual delayed match-to-sample task which elicited predictions. Predictive beta feedback activated sensory representations in advance of predicted stimuli. Low-dose ketamine, a NMDA receptor blocker – but not the control drug dexmedetomidine – perturbed behavioral indices of predictions, their representation in higher-order cortex, feedback to posterior cortex and pre-activation of sensory templates in higher-order sensory cortex. This study suggests predictions depend on alpha activity in higher-order cortex, beta feedback and NMDA receptors, and ketamine blocks access to learned predictive information.SIGNIFICANCE STATEMENT:We learn the statistical regularities around us, creating associations between sensory stimuli. These associations can be exploited by generating predictions, which enable fast and efficient behavior. When predictions are perturbed, it can negatively influence perception and even contribute to psychiatric disorders such as schizophrenia. Here we show that the frontal lobe generates predictions and sends them to posterior brain areas, to activate representations of predicted sensory stimuli before their appearance. Oscillations in neural activity – alpha and beta waves – are vital for these predictive mechanisms. The drug ketamine blocks predictions and the underlying mechanisms. This suggests that the generation of predictions in the frontal lobe, and the feedback pre-activating sensory representations in advance of stimuli, depend on NMDA receptors.

PMID:34732525 | DOI:10.1523/JNEUROSCI.1311-21.2021

BMJ Open. 2021 Nov 3;11(11):e055072. doi: 10.1136/bmjopen-2021-055072.

ABSTRACT

OBJECTIVE: To determine the accuracy of QT measurement in a smartphone-operated, single-lead ECG (1L-ECG) device (AliveCor KardiaMobile 1L).

DESIGN: Cross-sectional, within-patient diagnostic validation study.

SETTING/PARTICIPANTS: Patients underwent a 12-lead ECG (12L-ECG) for any non-acute indication in primary care, April 2017-July 2018.

INTERVENTION: Simultaneous recording of 1L-ECGs and 12L-ECGs with blinded manual QT assessment. OUTCOMES OF INTEREST: (1) Difference in QT interval in milliseconds (ms) between the devices; (2) measurement agreement between the devices (excellent agreement <20 ms and clinically acceptable agreement <40 ms absolute difference); (3) sensitivity and specificity for detection of extreme QTc (short (≤340 ms) or long (≥480 ms)), on 1L-ECGs versus 12L-ECGs as reference standard. In case of significant discrepancy between lead I/II of 12L-ECGs and 1L-ECGs, we developed a correction tool by adding the difference between QT measurements of 12L-ECG and 1L-ECGs.

RESULTS: 250 ECGs of 125 patients were included. The mean QTc interval, using Bazett’s formula (QTcB), was 393±25 ms (mean±SD) in 1L-ECGs and 392±27 ms in lead I of 12L-ECGs, a mean difference of 1±21 ms, which was not statistically different (paired t-test (p=0.51) and Bland Altman method (p=0.23)). In terms of agreement between 1L-ECGs and lead I, QTcB had excellent agreement in 66.9% and clinically acceptable agreement in 93.4% of observations. The sensitivity and specificity of detecting extreme QTc were 0% and 99.2%, respectively. The comparison of 1L-ECG QTcB with lead II of 12L-ECGs showed a significant difference (p=<0.01), but when using a correction factor (+9 ms) this difference was cancelled (paired t-test (p=0.43) or Bland Altman test (p=0.57)). Moreover, it led to improved rates of excellent (71.3%) and clinically acceptable (94.3%) agreement.

CONCLUSION: Smartphone-operated 1L-ECGs can be used to accurately measure the QTc interval compared with simultaneously obtained 12L-ECGs in a primary care population. This may provide an opportunity for monitoring the effects of potential QTc-prolonging medications.

PMID:34732504 | DOI:10.1136/bmjopen-2021-055072

BMJ Open. 2021 Nov 3;11(11):e054954. doi: 10.1136/bmjopen-2021-054954.

ABSTRACT

INTRODUCTION: Heavy drinkers in contact with alcohol services do not routinely have access to testing to establish the severity of potential liver disease. Transient elastography by FibroScan can provide this information. A recent systematic review suggested providing feedback to patients based on markers of liver injury can be an effective way to reduce harmful alcohol intake. This randomised control trial (RCT) aims to establish the feasibility of conducting a larger national trial to test the effectiveness of FibroScan advice and Alcohol Recovery Video Stories (ARVS) in changing high-risk drinking behaviour in community alcohol services common to UK practice.

METHODS AND ANALYSIS: This feasibility trial consists of three work packages (WP). WP1: To draft a standardised script for FibroScan operators to deliver liver disease-specific advice to eligible participants having FibroScan. WP2: To create a video library of ARVS for use in the feasibility RCT (WP3). WP3: To test the feasibility of the trial design, including the FibroScan script and video stories developed in WP1 and WP2 in a one-to-one individual randomised trial in community alcohol services. Semi-structured interviews will be conducted at 6 months follow-up for qualitative evaluation. Outcomes will be measures of the feasibility of conducting a larger RCT. These outcomes will relate to: participant recruitment and follow-up, intervention delivery, including the use of the Knowledge of LIver Fibrosis Affects Drinking trial FibroScan scripts and videos, clinical outcomes, and the acceptability and experience of the intervention and trial-related procedures. Data analysis will primarily be descriptive to address the feasibility aims of the trial. All proposed analyses will be documented in a Statistical Analysis Plan.

ETHICS AND DISSEMINATION: This trial received favourable ethical approval from the West of Scotland Research Ethics Service (WoSRES) on 20 January 2021, REC reference: 20/WS/0179. Results will be submitted for publication to a peer-reviewed journal.

TRIAL REGISTRATION NUMBER: ISRCTN16922410.

PMID:34732502 | DOI:10.1136/bmjopen-2021-054954

BMJ Open. 2021 Nov 3;11(11):e052944. doi: 10.1136/bmjopen-2021-052944.

ABSTRACT

OBJECTIVES: A key predictor for developing chronic residual pain after total knee or hip arthroplasty (TKA/THA) is sensitisation. Sensitisation can be defined as an ‘increased responsiveness of nociceptive neurons in the nervous system’. Aim of this study is to investigate the effects of preoperative treatment with duloxetine in sensitised knee and hip osteoarthritis (OA) patients on postoperative chronic residual pain up to 1 year after arthroplasty.

SETTING: A multicentre, pragmatic, prospective, randomised clinical trial was conducted in three secondary care hospitals in the Netherlands.

PARTICIPANTS: Patients with primary knee/hip OA who were planned for TKA/THA were screened using the modified painDETECT Questionnaire. Patients whose painDETECT score indicated that sensitisation may be present were eligible for participation. 111 participants were included and randomly assigned 1:1 to an intervention or control group. The intervention group received additional duloxetine treatment, the control group did not receive any additional treatment but was allowed to continue with any pain medication they were already taking.

INTERVENTIONS: Preoperative oral treatment for 7 weeks with 60 mg/day of duloxetine was compared with usual care.

PRIMARY AND SECONDARY OUTCOME MEASURES: Primary outcome measure was pain at 6 months after arthroplasty, assessed with the Pain Subscale of the Knee injury and Osteoarthritis Outcome Score (KOOS) or the Hip disability and Osteoarthritis Outcome Score (HOOS) with a 0-100 scale. Secondary outcome measures were Visual Analogue Scale (VAS), and neuropathic-like pain measured using the modified PainDETECT Questionnaire. Longitudinal data collection included time points directly after duloxetine treatment, 1-day preoperatively, and 6 weeks, 6 months and 12 months postoperatively.

RESULTS: Mean improvement in the KOOS/HOOS pain subscale at 6 months postoperatively was 37 (SD 28.1) in the intervention group and 43 (SD 26.5) in the control group. No statistically significant difference was found in change score 6 months postoperatively between the two groups (p=0.280). 12 patients from the intervention group (21%) discontinued duloxetine due to adverse effects.

CONCLUSIONS: Preoperative targeted treatment with duloxetine in end-stage knee and hip OA patients with sensitisation does not influence postoperative chronic residual pain after TKA/THA.

TRIAL REGISTRATION NUMBER: NTR4744.

PMID:34732491 | DOI:10.1136/bmjopen-2021-052944

BMJ Open. 2021 Nov 3;11(11):e051866. doi: 10.1136/bmjopen-2021-051866.

ABSTRACT

OBJECTIVES: To evaluate the cost-effectiveness of custom-made insoles compared with general practitioner (GP)-led usual care after 26 weeks of follow-up in individuals with plantar heel pain (PHP) from a societal perspective.

DESIGN: Cost-effectiveness analysis of a double-blinded randomised controlled trial.

SETTING: General practice in the Netherlands.

PARTICIPANTS: 116 participants with PHP for at least 2 weeks, aged 18-65 years and presenting to the GP.

INTERVENTIONS: Participants were randomised to GP-led usual care (n=46) or referral to a podiatrist for treatment with a custom-made insole (n=70). Participant randomised to a sham insole (n=69) were excluded from this analysis.

PRIMARY AND SECONDARY OUTCOMES: Outcomes comprised pain during rest and activity, and quality of life. Costs included healthcare and lost productivity costs. Statistical uncertainty was estimated using bootstrapping and presented using cost-effectiveness acceptability curves.

RESULTS: Participants in the custom-made insole group experienced statistically significant more pain during activity at 26 weeks than participants in the usual care group (overall effect 1.06; 95% CI 0.36 to 1.75). There were no significant differences between groups in other outcomes. Total societal costs in the custom-made insole group were non-significantly higher than in the usual care group (mean difference €376; 95% CI -€1775 to €2038). The intervention with custom-made insoles was dominated by usual care by the GP (ie, more expensive and less effective) for pain during activity and quality of life outcomes. For the outcome pain at rest, the intervention was more expensive and more effective than usual care. However, the maximum probability of cost-effectiveness was only 0.59 at very high ceiling ratios.

CONCLUSIONS: These findings show that that custom-made insoles are not cost-effective in comparison with GP-led usual care. Clinicians should be reserved in prescribing custom-made insoles for PHP as a primary intervention.

TRIAL REGISTRATION NUMBER: NTR5346.

PMID:34732484 | DOI:10.1136/bmjopen-2021-051866

BMJ Open. 2021 Nov 3;11(11):e049568. doi: 10.1136/bmjopen-2021-049568.

ABSTRACT

INTRODUCTION: Robust randomised trial data have shown that routine preoperative (pre-op) testing for cataract surgery patients is inappropriate. While guidelines have discouraged testing since 2002, cataract pre-op testing rates have remained unchanged since the 1990s. Given the challenges of reducing low-value care despite strong consensus around the evidence, innovative approaches are needed to promote high-value care. This trial evaluates the impact of an interdisciplinary electronic health record (EHR) intervention that is informed by behavioural economic theory.

METHODS AND ANALYSIS: This pragmatic randomised trial is being conducted at UCLA Health between June 2021 and June 2022 with a 12-month follow-up period. We are randomising all UCLA Health physicians who perform pre-op visits during the study period to one of the three nudge arms or usual care. These three nudge alerts address (1) patient harm, (2) increased out-of-pocket costs for patients and (3) psychological harm to the patients related to pre-op testing. The nudges are triggered when a physician starts to order a pre-op test. We hypothesise that receipt of a nudge will be associated with reduced pre-op testing. The primary outcome will be the change in the percentage of patients undergoing pre-op testing at 12 months. Secondary outcomes will include the percentage of patients undergoing specific categories of pre-op tests (labs, EKGs, chest X-rays (CXRs)), the efficacy of each nudge, same-day surgery cancellations and cost savings.

ETHICS AND DISSEMINATION: The study protocol was approved by the institutional review board of the University of California, Los Angeles as well as a nominated Data Safety Monitoring Board. If successful, we will have created a tool that can be disseminated rapidly to EHR vendors across the nation to reduce inappropriate testing for the most common low-risk surgical procedures in the country.

TRIAL REGISTRATION NUMBER: ClinicalTrials.gov identifier: NCT04104256.

PMID:34732478 | DOI:10.1136/bmjopen-2021-049568

BMJ Open. 2021 Nov 3;11(11):e047190. doi: 10.1136/bmjopen-2020-047190.

ABSTRACT

INTRODUCTION: One of the known risk factors for fall incidents is the use of specific medications, fall-risk-increasing drugs (FRIDs). However, to date, there is uncertainty related to the effectiveness of deprescribing as a single intervention in falls prevention. Thus, a comprehensive update of the literature focusing on all settings in which older people receive healthcare and all deprescribing interventions is warranted to enhance the current knowledge.

METHODS AND ANALYSIS: This systematic review protocol follows the Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines. A systematic search was performed in Cochrane Central Register of Controlled Trials, MEDLINE, Embase and PsycINFO (2 November 2020). We will also search in trial registers. We will include randomised controlled trials, in which any deprescribing intervention is compared with usual care and reports falls as an outcome. Both title and abstract screening and full-text screening will be done by two reviewers. The Cochrane Collaboration revised tool of Risk of Bias will be applied to perform risk of bias assessment. We will categorise the results separately for every setting. If a group of sufficiently comparable studies will be identified, we will perform a meta-analysis applying random effects model. We will investigate heterogeneity using a combination of visual inspection of the forest plot along with consideration of the χ² test and the I² statistic results. We have prespecified several subgroup and sensitivity analyses.

ETHICS AND DISSEMINATION: Ethics approval is not applicable for this study since no original data will be collected. The results will be disseminated through peer-reviewed publication and conference presentations. Furthermore, this systematic review will inform the recommendations of working group of polypharmacy and FRIDs of the anticipated World’s Falls Guidelines.

PROSPERO REGISTRATION NUMBER: CRD42020218231.

PMID:34732476 | DOI:10.1136/bmjopen-2020-047190

BMJ Open. 2021 Nov 3;11(11):e046271. doi: 10.1136/bmjopen-2020-046271.

ABSTRACT

OBJECTIVE: To assess the association between the physical activity level and the built environment by accessibility, microinfrastructure and security in Latin America (LA).

DESIGN: We conducted a multicentre cross-sectional study to collect physical activity and built environment data. The levels of physical activity were calculated through the International Physical Activity Questionnaire survey. Using the Neighbourhood Environment Walkability Scale-Abbreviated, characteristics of the built environment were measured through three domains: accessibility, microinfrastructure and security. To estimate the association of the built environment and physical activity, we used mixed effects logistic regression analysis. In addition, likelihood ratio test to account for clustered effect within countries and/or cities was used.

SETTING: Eight countries in LA.

PARTICIPANTS: Adults aged 15-65 years (n=9218) living in urban areas and consented to participate of the Latin American Study of Nutrition and Health.

RESULTS: Most of the population in LA had access to a grocery store (97.2%), public transport stop (91.5%) and children’s playground (81.6%). Metropolitan parks were more accessible in Ecuador (59.8%) and Colombia (59.2%) than in Venezuela (33.5%). Individuals located within 20 min of walking from sport facilities or children’s playground areas were more likely to perform moderate-to-high physical activity OR 1.20 (95% CI 1.06 to 1.36) and OR 1.25 (95% CI 1.02 to 1.53), respectively. Only 14.5% of the population from the region considered that their neighbourhood had an adequate design for walking or cycling. Likewise, among adults living in LA, only 39.75% had the perception of living in a safe neighbourhood.

CONCLUSIONS: This multicentre study shows that currently, LA built environment does not promote physical activity in the region. Our findings provide the rationale to push forward, at regional and national levels, policies and interventions that will help to achieve a safe, healthy and friendly built environment to encourage participation in active recreation and sports in leisure time.

TRIAL REGISTRATION NUMBER: NCT02226627.

PMID:34732475 | DOI:10.1136/bmjopen-2020-046271

Endocrinol Metab (Seoul). 2021 Oct;36(5):1069-1077. doi: 10.3803/EnM.2021.1119. Epub 2021 Oct 28.

ABSTRACT

BACKGROUND: Positive fecal immunochemical test (FIT) results have been recently suggested as a risk factor for systemic inflammation. Diabetes induces inflammation in the gastrointestinal tract via several ways. We investigated the association between FIT results and the incidence of diabetes.

METHODS: A total of 7,946,393 individuals aged ≥50 years from the National Cancer Screening Program database who underwent FIT for colorectal cancer (CRC) screening from 2009 to 2012 were enrolled. The primary outcome was newly diagnosed diabetes based on the International Classification of Disease 10th revision codes and administration of anti-diabetic medication during the follow-up period.

RESULTS: During a mean follow-up of 6.5 years, the incidence rates of diabetes were 11.97, 13.60, 14.53, and 16.82 per 1,000 personyears in the FIT negative, one-positive, two-positive, and three-positive groups, respectively. The hazard ratios (HRs) for the incidence of diabetes were 1.14 (95% confidence interval [CI], 1.12 to 1.16; HR, 1.21; 95% CI, 1.16 to 1.27; and HR, 1.40; 95% CI, 1.28 to 1.55) in the one-positive, two-positive, and three-positive FIT groups compared with the FIT negative group, respectively. The effect was consistent in individuals with normal fasting blood glucose (adjusted HR 1.55 vs. 1.14, P for interaction <0.001).

CONCLUSION: Positive FIT results were associated with a significantly higher risk of diabetes, suggesting that the FIT can play a role not only as a CRC screening tool, but also as a surrogate marker of systemic inflammation; thus, increasing the diabetes risk.

PMID:34731934 | DOI:10.3803/EnM.2021.1119