Exaggerated renal sympathetic nerve and pressor responses during spontaneously occurring motor activity in hypertensive rats.

Stimulation of the mesencephalic locomotor region elicits exaggerated sympathetic nerve and pressor responses in spontaneously hypertensive rats (SHR) as compared with normotensive Wistar-Kyoto rats (WKY). This suggests that central command or its influence on vasomotor centers is augmented in hypertension. The decerebrate animal model possesses an ability to evoke intermittent bouts of spontaneously occurring motor activity (SpMA) and generates cardiovascular responses associated with the SpMA. It remains unknown whether the changes in sympathetic nerve activity and hemodynamics during SpMA are altered by hypertension. To test the hypothesis that the responses in renal sympathetic nerve activity (RSNA) and mean arterial pressure (MAP) during SpMA are exaggerated with hypertension, this study aimed to compare the responses in decerebrate, paralyzed SHR, WKY, and normotensive Sprague-Dawley (SD) rats. In all strains, an abrupt increase in RSNA occurred in synchronization with tibial motor discharge (an index of motor activity) and was followed by rises in MAP and heart rate. The centrally evoked increase in RSNA and MAP during SpMA was much greater (306 ± 110%) in SHR than WKY (187 ± 146%) and SD (165 ± 44%). Although resting baroreflex-mediated changes in RSNA were not different across strains, mechanically or pharmacologically induced elevations in MAP attenuated or abolished the RSNA increase during SpMA in WKY and SD but had no effect in SHR. It is likely that the exaggerated sympathetic nerve and pressor responses during SpMA in SHR are induced along a central command pathway independent of the arterial baroreflex and/or result from central command-induced inhibition of the baroreflex.

Mechanisms in clinical practice: use and justification.

While the importance of mechanisms in determining causality in medicine is currently the subject of active debate, the role of mechanistic reasoning in clinical practice has received far less attention. In this paper we look at this question in the context of the treatment of a particular individual, and argue that evidence of mechanisms is indeed key to various aspects of clinical practice, including assessing population-level research reports, diagnostic as well as therapeutic decision making, and the assessment of treatment effects. We use the pulmonary condition bronchiectasis as a source of examples of the importance of mechanistic reasoning to clinical practice.

The evidence that evidence-based medicine omits.

According to current hierarchies of evidence for EBM, evidence of correlation (e.g., from RCTs) is always more important than evidence of mechanisms when evaluating and establishing causal claims. We argue that evidence of mechanisms needs to be treated alongside evidence of correlation. This is for three reasons. First, correlation is always a fallible indicator of causation, subject in particular to the problem of confounding; evidence of mechanisms can in some cases be more important than evidence of correlation when assessing a causal claim. Second, evidence of mechanisms is often required in order to obtain evidence of correlation (for example, in order to set up and evaluate RCTs). Third, evidence of mechanisms is often required in order to generalise and apply causal claims. While the EBM movement has been enormously successful in making explicit and critically examining one aspect of our evidential practice, i.e., evidence of correlation, we wish to extend this line of work to make explicit and critically examine a second aspect of our evidential practices: evidence of mechanisms.

Bayesianism from a philosophical perspective and its application to medicine.

Bayesian philosophy and Bayesian statistics have diverged in recent years, because Bayesian philosophers have become more interested in philosophical problems other than the foundations of statistics and Bayesian statisticians have become less concerned with philosophical foundations. One way in which this divergence manifests itself is through the use of direct inference principles: Bayesian philosophers routinely advocate principles that require calibration of degrees of belief to available non-epistemic probabilities, while Bayesian statisticians rarely invoke such principles. As I explain, however, the standard Bayesian framework cannot coherently employ direct inference principles. Direct inference requires a shift towards a non-standard Bayesian framework, which further increases the gap between Bayesian philosophy and Bayesian statistics. This divergence does not preclude the application of Bayesian philosophical methods to real-world problems. Data consolidation is a key challenge for present-day systems medicine and other systems sciences. I show that data consolidation requires direct inference and that the non-standard Bayesian methods outlined here are well suited to this task.

Utility of standing office blood pressure in detecting hypertension in healthy adults.

Current guidelines recommend office blood pressures (BP) be taken in a seated position when screening for hypertension (HTN). Seated BP is known to have limited accuracy in detecting high BP, while the utility of standing BP in diagnosing HTN is unknown. We conducted a cross-sectional study to determine the incremental value of standing BP in diagnosing HTN. Seated, standing, and 24-h ambulatory BPs (ABPM) were obtained in adults without known cardiovascular disease, HTN, or BP medication use. Presence of HTN was defined by the 2017 ACC/AHA and the 2023 ESH HTN guidelines based on ABPM. Area under the receiver-operating-characteristic curve (AUROC) was used to evaluate the diagnostic accuracy of seated and standing BP. Sensitivity and specificity of standing BP was determined using cut-offs derived from Youden's Index, while sensitivity and specificity of seated BP was determined using the cut-off of 130/80 mmHg and by 140/90 mmHg. Among 125 participants (mean age 49 ± 17 years; 62% female; 24% Black), 33.6% of them had HTN. Sensitivity and specificity of seated systolic BP (SBP) was 43% and 92%, respectively. Cut-offs selected by Youden's index for standing SBP/diastolic BP (DBP) were 124/81 mmHg according to the 2017 ACC/AHA HTN guidelines, and 123.5/83.5 mmHg according to the 2023 ESH HTN guidelines. Sensitivity and specificity of standing SBP was 71% and 67%, respectively. The AUROC of standing SBP (0.81 [0.71-0.92]) was significantly higher than seated SBP (0.70 [0.49-0.91]), when HTN was defined as average 24-h SBP ≥ 125 mmHg. Moreover, the addition of standing to seated SBP (0.80 [0.68-0.92]) improved HTN detection when compared to seated SBP. These patterns were consistent for both the 2017 ACC/AHA and the 2023 ESH definitions for HTN. In summary, standing BP, alone or in combination with seated BP, outperformed seated BP alone in diagnosing HTN in adults.

Direct Inference and Probabilistic Accounts of Induction.

Schurz (2019, ch. 4) argues that probabilistic accounts of induction fail. In particular, he criticises probabilistic accounts of induction that appeal to direct inference principles, including subjective Bayesian approaches (e.g., Howson 2000) and objective Bayesian approaches (see, e.g., Williamson 2017). In this paper, I argue that Schurz' preferred direct inference principle, namely Reichenbach's Principle of the Narrowest Reference Class, faces formidable problems in a standard probabilistic setting. Furthermore, the main alternative direct inference principle, Lewis' Principal Principle, is also hard to reconcile with standard probabilism. So, I argue, standard probabilistic approaches cannot appeal to direct inference to explicate the logic of induction. However, I go on to defend a non-standard objective Bayesian account of induction: I argue that this approach can both accommodate direct inference and provide a viable account of the logic of induction. I then defend this account against Schurz' criticisms.

The use of mechanistic reasoning in assessing coronavirus interventions.

RATIONALE: Evidence-based medicine (EBM), the dominant approach to assessing the effectiveness of clinical and public health interventions, focuses on the results of association studies. EBM+ is a development of EBM that systematically considers mechanistic studies alongside association studies. AIMS AND OBJECTIVES: To explore examples of the importance of mechanistic evidence to coronavirus research. METHODS: We have reviewed the mechanistic evidence in four major areas that are relevant to the management of COVID-19. RESULTS AND CONCLUSIONS: (a) Assessment of combination therapy for MERS highlights the need for systematic assessment of mechanistic evidence. (b) That hypertension is a risk factor for severe disease in the case of SARS-CoV-2 suggests that altering hypertension treatment might alleviate disease, but the mechanisms are complex, and it is essential to consider and evaluate multiple mechanistic hypotheses. (c) Confidence that public health interventions will be effective requires a detailed assessment of social and psychological components of the mechanisms of their action, in addition to mechanisms of disease. (d) In particular, if vaccination programmes are to be effective, they must be carefully tailored to the social context; again, mechanistic evidence is crucial. We conclude that coronavirus research is best situated within the EBM+ evaluation framework.

The IARC Monographs: Updated Procedures for Modern and Transparent Evidence Synthesis in Cancer Hazard Identification.

The Monographs produced by the International Agency for Research on Cancer (IARC) apply rigorous procedures for the scientific review and evaluation of carcinogenic hazards by independent experts. The Preamble to the IARC Monographs, which outlines these procedures, was updated in 2019, following recommendations of a 2018 expert advisory group. This article presents the key features of the updated Preamble, a major milestone that will enable IARC to take advantage of recent scientific and procedural advances made during the 12 years since the last Preamble amendments. The updated Preamble formalizes important developments already being pioneered in the Monographs program. These developments were taken forward in a clarified and strengthened process for identifying, reviewing, evaluating, and integrating evidence to identify causes of human cancer. The advancements adopted include the strengthening of systematic review methodologies; greater emphasis on mechanistic evidence, based on key characteristics of carcinogens; greater consideration of quality and informativeness in the critical evaluation of epidemiological studies, including their exposure assessment methods; improved harmonization of evaluation criteria for the different evidence streams; and a single-step process of integrating evidence on cancer in humans, cancer in experimental animals, and mechanisms for reaching overall evaluations. In all, the updated Preamble underpins a stronger and more transparent method for the identification of carcinogenic hazards, the essential first step in cancer prevention.

Evidential Proximity, Independence, and the evaluation of carcinogenicity.

This paper analyses the methods of the International Agency for Research on Cancer (IARC) for evaluating the carcinogenicity of various agents. I identify two fundamental evidential principles that underpin these methods, which I call Evidential Proximity and Independence. I then show, by considering the 2018 evaluation of the carcinogenicity of styrene and styrene-7,8-oxide, that these principles have been implemented in a way that can lead to inconsistency. I suggest a way to resolve this problem: admit a general exception to Independence and treat the implementation of Evidential Proximity more flexibly where this exception applies. I show that this suggestion is compatible with the general principles laid down in the 2019 version of IARC's methods guide, its Preamble to the Monographs.

Justifying the principle of indifference.

This paper presents a new argument for the Principle of Indifference. This argument can be thought of in two ways: as a pragmatic argument, justifying the principle as needing to hold if one is to minimise worst-case expected loss, or as an epistemic argument, justifying the principle as needing to hold in order to minimise worst-case expected inaccuracy. The question arises as to which interpretation is preferable. I show that the epistemic argument contradicts Evidentialism and suggest that the relative plausibility of Evidentialism provides grounds to prefer the pragmatic interpretation. If this is right, it extends to a general preference for pragmatic arguments for the Principle of Indifference, and also to a general preference for pragmatic arguments for other norms of Bayesian epistemology.

Intervention and Identifiability in Latent Variable Modelling.

We consider the use of interventions for resolving a problem of unidentified statistical models. The leading examples are from latent variable modelling, an influential statistical tool in the social sciences. We first explain the problem of statistical identifiability and contrast it with the identifiability of causal models. We then draw a parallel between the latent variable models and Bayesian networks with hidden nodes. This allows us to clarify the use of interventions for dealing with unidentified statistical models. We end by discussing the philosophical and methodological import of our result.

The use of mechanistic evidence in drug approval.

The role of mechanistic evidence tends to be under-appreciated in current evidence-based medicine (EBM), which focusses on clinical studies, tending to restrict attention to randomized controlled studies (RCTs) when they are available. The EBM+ programme seeks to redress this imbalance, by suggesting methods for evaluating mechanistic studies alongside clinical studies. Drug approval is a problematic case for the view that mechanistic evidence should be taken into account, because RCTs are almost always available. Nevertheless, we argue that mechanistic evidence is central to all the key tasks in the drug approval process: in drug discovery and development; assessing pharmaceutical quality; devising dosage regimens; assessing efficacy, harms, external validity, and cost-effectiveness; evaluating adherence; and extending product licences. We recommend that, when preparing for meetings in which any aspect of drug approval is to be discussed, mechanistic evidence should be systematically analysed and presented to the committee members alongside analyses of clinical studies.

Exercise-induced decrease in insular cortex rCBF during postexercise hypotension.

UNLABELLED: The insular cortex (IC), a region of the brain involved in blood pressure (BP) modulation, shows decreases in regional cerebral blood flow (rCBF) during postexercise hypotension (PEH). PURPOSE: To determine whether changes in IC neural activity were caused by prior exercise or by changes in BP, this investigation compared patterns of rCBF during periods of hypotension, which was induced by prior exercise (i.e., PEH) and sodium nitroprusside (SNP) infusion and a cold pressor (CP), to restore BP. METHODS: Ten subjects were studied on three different days with randomly assigned conditions: i) resting baseline; ii) PEH; and iii) SNP-induced hypotension (matched to the PEH BP decrease). Data were collected for heart rate (HR) and mean BP, and rCBF was assessed using single-photon emission computed tomography (SPECT) as an index of brain activation. RESULTS: Using ANOVA across conditions, there were differences (P<0.05; mean +/- SD) from baseline during PEH for HR (+12 +/- 3 bpm) and mean BP (-8 +/- 2 mm Hg) and during SNP-induced hypotension (HR = +15 +/- 4 bpm; MBP = -9 +/- 2 mm Hg), with no differences between PEH and SNP. After exercise, there were decreases (P<0.05) in the leg sensorimotor area, anterior cingulate, and the right and left inferior thalamus, right inferior insula, and left anterior insular regions. During SNP-induced hypotension, there were significant increases in the right and left inferior thalamus and the right and left inferior anterior IC. CP during PEH increased BP and IC activity. CONCLUSIONS: Data show that reductions in IC neural activity are not caused by acute BP decreases. Findings suggest that exercise can lead to a temporary decrease in IC neural activity, which may be a significant neural factor contributing to PEH.

Changes in supraspinal activation patterns following robotic locomotor therapy in motor-incomplete spinal cord injury.

OBJECTIVES: Body weight-supported treadmill training (BWSTT) is a task-specific rehabilitation strategy that enhances functional locomotion in patients following spinal cord injury (SCI). Supraspinal centers may play an important role in the recovery of over-ground locomotor function in patients with motor-incomplete SCI. The purpose of this study was to evaluate the potential for supraspinal reorganization associated with 12 weeks of robotic BWSTT using functional magnetic resonance imaging (fMRI). METHODS: Four men with motor-incomplete SCI participated in this study. Time since onset ranged from 14 weeks to 48 months post-SCI injury. All subjects were trained with BWSTT 3 times weekly for 12 weeks. This training was preceded and followed by fMRI study of supraspinal activity during a movement task. Testing of locomotor disability included the Walking Index for Spinal Cord Injury (WISCI II) and over-ground gait speed. RESULTS: All subjects demonstrated some degree of change in the blood-oxygen-level-dependent (BOLD) signal following BWSTT. fMRI results demonstrated greater activation in sensorimotor cortical regions (S1, S2) and cerebellar regions following BWSTT. CONCLUSIONS: Intensive task-specific rehabilitative training, such as robotic BWSTT, can promote supraspinal plasticity in the motor centers known to be involved in locomotion. Furthermore, improvement in over-ground locomotion is accompanied by an increased activation of the cerebellum.

Academic incentives for students can increase participation in and effectiveness of a physical activity program.

The authors sought to determine whether a greater academic incentive would improve the effectiveness and student adherence to a 12-week voluntary exercise program designed to decrease students' percentage of body fat. They randomly assigned 210 students to 1 of 2 groups with different academic reward structures. The group with the greater reward structure showed better exercise adherence and lost more body fat than those without the additional incentive. These findings suggest that an academic incentive can increase overall student adherence to a voluntary exercise program and can boost the effectiveness of the program in a university environment. The findings also have potential implications for on-campus promotion of physical activity.

The BCoS cognitive profile screen: Utility and predictive value for stroke.

OBJECTIVE: We examined the utility of the Birmingham Cognitive Screen (BCoS) in discriminating cognitive profiles and recovery of function across stroke survivors. BCoS was designed for stroke-specific problems across 5 cognitive domains: (a) controlled and spatial attention, (b) language, (c) memory, (d) number processing, and (e) praxis. METHOD: On the basis of specific inclusion criteria, this cross-section observational study analyzed cognitive profiles of 657 subacute stroke patients, 331 of them reassessed at 9 months. Impairments on 32 measures were evaluated by comparison with 100 matched healthy controls. Measures of affect, apathy, and activities of daily living were also taken. Between-subjects group comparisons of mean performance scores and impairment rates and within-subject examination of impairment rates over time were conducted. Logistic regressions and general linear modeling were used for multivariate analysis of domain-level effects on outcomes. RESULTS: Individuals with repeated stroke experienced significantly less cognitive recovery at 9 months than those with a first stroke despite similar initial level of cognitive performance. Individuals with left hemisphere lesions performed more poorly than those with right hemisphere lesions, but both groups showed similar extent of recovery at 9 months. BCoS also revealed lesion-side-specific deficits and common areas of persistent problems. Functional outcome at 9 months correlated with domain-level deficits in controlled attention, spatial attention, and praxis over and above initial dependency and concurrent levels of affect and apathy. CONCLUSION: The study demonstrates how BCoS can identify differential cognitive profiles across patient groups. This can potentially help predict outcomes and inform rehabilitation.

Can relaxation lower metaboreflex-mediated blood pressure elevations?

PURPOSE: Relaxation can lower resting blood pressure, and this investigation sought to determine whether relaxation could reduce mean blood pressure (MBP) elevations produced by postexercise circulatory occlusion (PECO). METHODS: Sixteen volunteers trained with relaxation and were able to decrease MBP at rest by at least 5 mm Hg within 2 min. Subjects performed four tests assigned randomly: i). rest with cuff occlusion, ii). rest and cuff occlusion with relaxation, iii). hand-grip exercise followed by PECO rest with cuff occlusion, and iv) hand-grip exercise followed by PECO with relaxation. Data for HR and MBP were collected using a Finapres; ratings of relaxation and discomfort from cuff occlusion were obtained using a 1- to 10-unit scale. Stroke volume (SV) and HR were collected from six subjects to calculate cardiac output and total peripheral conductance (TPC). Dependent variables were compared using an ANOVA. RESULTS: HR (mean +/-SD) was lower during both relaxation conditions as compared with control (-7 +/- 4 bpm vs -2 +/- 3 bpm; P< 0.05). The MBP was reduced during relaxation alone (-6 +/- 3.7 mm Hg; < 0.05) but not during PECO with relaxation. The rating of relaxation was higher during relaxation (6.8 +/- 1.3 units) versus control (3.5 +/- 1.2 units), but ratings were not different between relaxation conditions. Ratings of discomfort were higher during PECO ( P< 0.05). Relaxation did not significantly alter CO or SV (N= 6). During relaxation alone, TPC was increased (0.046 +/- 0.001 vs 0.049 +/- 0.002 L.min.mm Hg; P< 0.05). However, TPC was significantly increased during PECO with relaxation. CONCLUSIONS: These findings suggest that although relaxation can affect cardiovascular regulation and lower HR and MBP at rest, this central signal cannot lower reflex increases in blood pressure originating from a peripheral metabolic stimulus.

Autonomic dysfunction in muscular dystrophy: a theoretical framework for muscle reflex involvement.

Muscular dystrophies are a heterogeneous group of genetically inherited disorders whose most prominent clinical feature is progressive degeneration of skeletal muscle. In several forms of the disease, the function of cardiac muscle is likewise affected. The primary defect in this group of diseases is caused by mutations in myocyte proteins important to cellular structure and/or performance. That being stated, a growing body of evidence suggests that the development of autonomic dysfunction may secondarily contribute to the generation of skeletal and cardio-myopathy in muscular dystrophy. Indeed, abnormalities in the regulation of both sympathetic and parasympathetic nerve activity have been reported in a number of muscular dystrophy variants. However, the mechanisms mediating this autonomic dysfunction remain relatively unknown. An autonomic reflex originating in skeletal muscle, the exercise pressor reflex, is known to contribute significantly to the control of sympathetic and parasympathetic activity when stimulated. Given the skeletal myopathy that develops with muscular dystrophy, it is logical to suggest that the function of this reflex might also be abnormal with the pathogenesis of disease. As such, it may contribute to or exacerbate the autonomic dysfunction that manifests. This possibility along with a basic description of exercise pressor reflex function in health and disease are reviewed. A better understanding of the mechanisms that possibly underlie autonomic dysfunction in muscular dystrophy may not only facilitate further research but could also lead to the identification of new therapeutic targets for the treatment of muscular dystrophy.

Pre-admission factors and utilization of tutoring services in health professions educational programs.

Pre-admission factors tend to serve as indicators of student success in health professions educational programs, but less is known about the effects that academic assistance programs have on student success. This study sought to determine whether specific pre-admission factors could help to identify students who may require academic support during their health professions education. This retrospective analysis aimed to identify differences in pre-admission variables between those students requiring tutoring and a matched sample of students who did not require tutoring. One-way ANOVA was used to assess differences for dependent variables-age, cumulative GPA (cGPA), science GPA (sGPA), verbal graduate record examination (GRE) score, quantitative GRE score, analytical GRE score and combined GRE score, community college hours, average credit hours per semester, and highest semester credit hour load-across three groups of students who received no tutoring (NT 0 hrs), some tutoring (ST <8 hrs), and more tutoring (MT >8 hrs). Total GRE and average semester hours differentiated NT from ST from MT (p<0.05). A linear regression model with these pre-admission factors found only four of the independent variables to be significant (r2=0.41; p<0.05) in predicting hours of tutoring: quantitative GRE, sGPA, cGPA and average semester hours taken. The combination of lower GRE scores and lighter average semester course load were most predictive of the need for academic assistance as defined by hours of tutoring. While the value of the GRE in admissions processes is generally accepted, the average semester hour load in college can also provide important information regarding academic preparation and the need for tutoring services.