A burden of proof study on alcohol consumption and ischemic heart disease.

Cohort and case-control data have suggested an association between low to moderate alcohol consumption and decreased risk of ischemic heart disease (IHD), yet results from Mendelian randomization (MR) studies designed to reduce bias have shown either no or a harmful association. Here we conducted an updated systematic review and re-evaluated existing cohort, case-control, and MR data using the burden of proof meta-analytical framework. Cohort and case-control data show low to moderate alcohol consumption is associated with decreased IHD risk - specifically, intake is inversely related to IHD and myocardial infarction morbidity in both sexes and IHD mortality in males - while pooled MR data show no association, confirming that self-reported versus genetically predicted alcohol use data yield conflicting findings about the alcohol-IHD relationship. Our results highlight the need to advance MR methodologies and emulate randomized trials using large observational databases to obtain more definitive answers to this critical public health question.

Health effects associated with chewing tobacco: a Burden of Proof study.

Chewing tobacco use poses serious health risks; yet it has not received as much attention as other tobacco-related products. This study synthesizes existing evidence regarding the health impacts of chewing tobacco while accounting for various sources of uncertainty. We conducted a systematic review and meta-analysis of chewing tobacco and seven health outcomes, drawing on 103 studies published from 1970 to 2023. We use a Burden of Proof meta-analysis to generate conservative risk estimates and find weak-to-moderate evidence that tobacco chewers have an increased risk of stroke, lip and oral cavity cancer, esophageal cancer, nasopharynx cancer, other pharynx cancer, and laryngeal cancer. We additionally find insufficient evidence of an association between chewing tobacco and ischemic heart disease. Our findings highlight a need for policy makers, researchers, and communities at risk to devote greater attention to chewing tobacco by both advancing tobacco control efforts and investing in strengthening the existing evidence base.

Health effects associated with exposure to secondhand smoke: a Burden of Proof study.

Despite a gradual decline in smoking rates over time, exposure to secondhand smoke (SHS) continues to cause harm to nonsmokers, who are disproportionately children and women living in low- and middle-income countries. We comprehensively reviewed the literature published by July 2022 concerning the adverse impacts of SHS exposure on nine health outcomes. Following, we quantified each exposure-response association accounting for various sources of uncertainty and evaluated the strength of the evidence supporting our analyses using the Burden of Proof Risk Function methodology. We found all nine health outcomes to be associated with SHS exposure. We conservatively estimated that SHS increases the risk of ischemic heart disease, stroke, type 2 diabetes and lung cancer by at least around 8%, 5%, 1% and 1%, respectively, with the evidence supporting these harmful associations rated as weak (two stars). The evidence supporting the harmful associations between SHS and otitis media, asthma, lower respiratory infections, breast cancer and chronic obstructive pulmonary disease was weaker (one star). Despite the weak underlying evidence for these associations, our results reinforce the harmful effects of SHS on health and the need to prioritize advancing efforts to reduce active and passive smoking through a combination of public health policies and education initiatives.

Health effects associated with exposure to intimate partner violence against women and childhood sexual abuse: a burden of proof study.

The health impacts of intimate partner violence against women and childhood sexual abuse are not fully understood. Here we conducted a systematic review by comprehensively searching seven electronic databases for literature on intimate partner violence-associated and childhood sexual abuse-associated health effects. Following the burden of proof methodology, we evaluated the evidence strength linking intimate partner violence and/or childhood sexual abuse to health outcomes supported by at least three studies. Results indicated a moderate association of intimate partner violence with major depressive disorder and with maternal abortion and miscarriage (63% and 35% increased risk, respectively). HIV/AIDS, anxiety disorders and self-harm exhibited weak associations with intimate partner violence. Fifteen outcomes were evaluated for their relationship to childhood sexual abuse, which was shown to be moderately associated with alcohol use disorders and with self-harm (45% and 35% increased risk, respectively). Associations between childhood sexual abuse and 11 additional health outcomes, such as asthma and type 2 diabetes mellitus, were found to be weak. Although our understanding remains limited by data scarcity, these health impacts are larger in magnitude and more extensive than previously reported. Renewed efforts on violence prevention and evidence-based approaches that promote healing and ensure access to care are necessary.

Effects of elevated systolic blood pressure on ischemic heart disease: a Burden of Proof study.

High systolic blood pressure (SBP) is a major risk factor for ischemic heart disease (IHD), the leading cause of death worldwide. Using data from published observational studies and controlled trials, we estimated the mean SBP-IHD dose-response function and burden of proof risk function (BPRF), and we calculated a risk outcome score (ROS) and corresponding star rating (one to five). We found a very strong, significant harmful effect of SBP on IHD, with a mean risk-relative to that at 100 mm Hg SBP-of 1.39 (95% uncertainty interval including between-study heterogeneity 1.34-1.44) at 120 mm Hg, 1.81 (1.70-1.93) at 130 mm Hg and 4.48 (3.81-5.26) at 165 mm Hg. The conservative BPRF measure indicated that SBP exposure between 107.5 and 165.0 mm Hg raised risk by 101.36% on average, yielding a ROS of 0.70 and star rating of five. Our analysis shows that IHD risk was already increasing at 120 mm Hg SBP, rising steadily up to 165 mm Hg and increasing less steeply above that point. Our study endorses the need to prioritize and strengthen strategies for screening, to raise awareness of the need for timely diagnosis and treatment of hypertension and to increase the resources allocated for understanding primordial prevention of elevated blood pressure.

Health effects associated with consumption of unprocessed red meat: a Burden of Proof study.

Characterizing the potential health effects of exposure to risk factors such as red meat consumption is essential to inform health policy and practice. Previous meta-analyses evaluating the effects of red meat intake have generated mixed findings and do not formally assess evidence strength. Here, we conducted a systematic review and implemented a meta-regression-relaxing conventional log-linearity assumptions and incorporating between-study heterogeneity-to evaluate the relationships between unprocessed red meat consumption and six potential health outcomes. We found weak evidence of association between unprocessed red meat consumption and colorectal cancer, breast cancer, type 2 diabetes and ischemic heart disease. Moreover, we found no evidence of an association between unprocessed red meat and ischemic stroke or hemorrhagic stroke. We also found that while risk for the six outcomes in our analysis combined was minimized at 0 g unprocessed red meat intake per day, the 95% uncertainty interval that incorporated between-study heterogeneity was very wide: from 0-200 g d-1. While there is some evidence that eating unprocessed red meat is associated with increased risk of disease incidence and mortality, it is weak and insufficient to make stronger or more conclusive recommendations. More rigorous, well-powered research is needed to better understand and quantify the relationship between consumption of unprocessed red meat and chronic disease.

Health effects associated with smoking: a Burden of Proof study.

As a leading behavioral risk factor for numerous health outcomes, smoking is a major ongoing public health challenge. Although evidence on the health effects of smoking has been widely reported, few attempts have evaluated the dose-response relationship between smoking and a diverse range of health outcomes systematically and comprehensively. In the present study, we re-estimated the dose-response relationships between current smoking and 36 health outcomes by conducting systematic reviews up to 31 May 2022, employing a meta-analytic method that incorporates between-study heterogeneity into estimates of uncertainty. Among the 36 selected outcomes, 8 had strong-to-very-strong evidence of an association with smoking, 21 had weak-to-moderate evidence of association and 7 had no evidence of association. By overcoming many of the limitations of traditional meta-analyses, our approach provides comprehensive, up-to-date and easy-to-use estimates of the evidence on the health effects of smoking. These estimates provide important information for tobacco control advocates, policy makers, researchers, physicians, smokers and the public.

Prevalence and patterns of sensory processing behaviors in a large clinical sample of children with prenatal alcohol exposure.

BACKGROUND: Atypical behavioral responses to sensation are reported in a large proportion of children affected by prenatal alcohol exposure (PAE). Systematic examination of symptoms across the fetal alcohol spectrum in a large clinical sample is needed to inform diagnosis and intervention. AIMS: To describe the prevalence and patterns of atypical sensory processing symptoms in a clinical sample of children with PAE. METHODS: Retrospective analysis of diagnostic clinical data from the University of Washington Fetal Alcohol Syndrome Diagnostic and Prevention Network (FASDPN). Participants were ages 3 through 11 years, had a diagnosis on the fetal alcohol spectrum, and Short Sensory Profile (SSP) assessment. The proportions of children categorized with definite differences on the SSP across selected clinical and demographic features were examined with chi-square analyses. OUTCOMES: The sample consisted of 325 children; 73.2 % had SSP total scores in the definite difference range. Atypical sensory processing symptoms were significantly more prevalent among children with higher reported levels of PAE. The prevalence of atypical symptoms was comparably high across age, levels of diagnostic severity, and other prenatal/postnatal risks. CONCLUSIONS: Results lend support for altered sensory processing as another domain of brain function affected by the teratogenic impact of PAE, guiding clinical work and research.

Listening Difficulties in Children With Fetal Alcohol Spectrum Disorders: More Than a Problem of Audibility.

Purpose Data from standardized caregiver questionnaires indicate that children with fetal alcohol spectrum disorders (FASDs) frequently exhibit atypical auditory behaviors, including reduced responsivity to spoken stimuli. Another body of evidence suggests that prenatal alcohol exposure may result in auditory dysfunction involving loss of audibility (i.e., hearing loss) and/or impaired processing of clearly audible, "suprathreshold" sounds necessary for sound-in-noise listening. Yet, the nexus between atypical auditory behavior and underlying auditory dysfunction in children with FASDs remains largely unexplored. Method To investigate atypical auditory behaviors in FASDs and explore their potential physiological bases, we examined clinical data from 325 children diagnosed with FASDs at the University of Washington using the FASD 4-Digit Diagnostic Code. Atypical behaviors reported on the "auditory filtering" domain of the Short Sensory Profile were assessed to document their prevalence across FASD diagnoses and explore their relationship to reported hearing loss and/or central nervous system measures of cognition, attention, and language function that may indicate suprathreshold processing deficits. Results Atypical auditory behavior was reported among 80% of children with FASDs, a prevalence that did not vary by FASD diagnostic severity or hearing status but was positively correlated with attention-deficit/hyperactivity disorder. In contrast, hearing loss was documented in the clinical records of 40% of children with fetal alcohol syndrome (FAS; a diagnosis on the fetal alcohol spectrum characterized by central nervous system dysfunction, facial dysmorphia, and growth deficiency), 16-fold more prevalent than for those with less severe FASDs (2.4%). Reported hearing loss was significantly associated with physical features characteristic of FAS. Conclusion Children with FAS but not other FASDs may be at a particular risk for hearing loss. However, listening difficulties in the absence of hearing loss-presumably related to suprathreshold processing deficits-are prevalent across the entire fetal alcohol spectrum. The nature and impact of both listening difficulties and hearing loss in FASDs warrant further investigation.

Neural Switch Asymmetry in Feature-Based Auditory Attention Tasks.

Active listening involves dynamically switching attention between competing talkers and is essential to following conversations in everyday environments. Previous investigations in human listeners have examined the neural mechanisms that support switching auditory attention within the acoustic featural cues of pitch and auditory space. Here, we explored the cortical circuitry underlying endogenous switching of auditory attention between pitch and spatial cues necessary to discern target from masker words. Because these tasks are of unequal difficulty, we expected an asymmetry in behavioral switch costs for hard-to-easy versus easy-to-hard switches, mirroring prior evidence from vision-based cognitive task-switching paradigms. We investigated the neural correlates of this behavioral switch asymmetry and associated cognitive control operations in the present auditory paradigm. Behaviorally, we observed no switch-cost asymmetry, i.e., no performance difference for switching from the more difficult attend-pitch to the easier attend-space condition (P→S) versus switching from easy-to-hard (S→P). However, left lateral prefrontal cortex activity, correlated with improved performance, was observed during a silent gap period when listeners switched attention from P→S, relative to switching within pitch cues. No such differential activity was seen for the analogous easy-to-hard switch. We hypothesize that this neural switch asymmetry reflects proactive cognitive control mechanisms that successfully reconfigured neurally-specified task parameters and resolved competition from other such "task sets," thereby obviating the expected behavioral switch-cost asymmetry. The neural switch activity observed was generally consistent with that seen in cognitive paradigms, suggesting that established cognitive models of attention switching may be productively applied to better understand similar processes in audition.

Evidence for cue-independent spatial representation in the human auditory cortex during active listening.

Few auditory functions are as important or as universal as the capacity for auditory spatial awareness (e.g., sound localization). That ability relies on sensitivity to acoustical cues-particularly interaural time and level differences (ITD and ILD)-that correlate with sound-source locations. Under nonspatial listening conditions, cortical sensitivity to ITD and ILD takes the form of broad contralaterally dominated response functions. It is unknown, however, whether that sensitivity reflects representations of the specific physical cues or a higher-order representation of auditory space (i.e., integrated cue processing), nor is it known whether responses to spatial cues are modulated by active spatial listening. To investigate, sensitivity to parametrically varied ITD or ILD cues was measured using fMRI during spatial and nonspatial listening tasks. Task type varied across blocks where targets were presented in one of three dimensions: auditory location, pitch, or visual brightness. Task effects were localized primarily to lateral posterior superior temporal gyrus (pSTG) and modulated binaural-cue response functions differently in the two hemispheres. Active spatial listening (location tasks) enhanced both contralateral and ipsilateral responses in the right hemisphere but maintained or enhanced contralateral dominance in the left hemisphere. Two observations suggest integrated processing of ITD and ILD. First, overlapping regions in medial pSTG exhibited significant sensitivity to both cues. Second, successful classification of multivoxel patterns was observed for both cue types and-critically-for cross-cue classification. Together, these results suggest a higher-order representation of auditory space in the human auditory cortex that at least partly integrates the specific underlying cues.

Sensitivity to an Illusion of Sound Location in Human Auditory Cortex.

Human listeners place greater weight on the beginning of a sound compared to the middle or end when determining sound location, creating an auditory illusion known as the Franssen effect. Here, we exploited that effect to test whether human auditory cortex (AC) represents the physical vs. perceived spatial features of a sound. We used functional magnetic resonance imaging (fMRI) to measure AC responses to sounds that varied in perceived location due to interaural level differences (ILD) applied to sound onsets or to the full sound duration. Analysis of hemodynamic responses in AC revealed sensitivity to ILD in both full-cue (veridical) and onset-only (illusory) lateralized stimuli. Classification analysis revealed regional differences in the sensitivity to onset-only ILDs, where better classification was observed in posterior compared to primary AC. That is, restricting the ILD to sound onset-which alters the physical but not the perceptual nature of the spatial cue-did not eliminate cortical sensitivity to that cue. These results suggest that perceptual representations of auditory space emerge or are refined in higher-order AC regions, supporting the stable perception of auditory space in noisy or reverberant environments and forming the basis of illusions such as the Franssen effect.

Tuning to Binaural Cues in Human Auditory Cortex.

Interaural level and time differences (ILD and ITD), the primary binaural cues for sound localization in azimuth, are known to modulate the tuned responses of neurons in mammalian auditory cortex (AC). The majority of these neurons respond best to cue values that favor the contralateral ear, such that contralateral bias is evident in the overall population response and thereby expected in population-level functional imaging data. Human neuroimaging studies, however, have not consistently found contralaterally biased binaural response patterns. Here, we used functional magnetic resonance imaging (fMRI) to parametrically measure ILD and ITD tuning in human AC. For ILD, contralateral tuning was observed, using both univariate and multivoxel analyses, in posterior superior temporal gyrus (pSTG) in both hemispheres. Response-ILD functions were U-shaped, revealing responsiveness to both contralateral and­to a lesser degree­ipsilateral ILD values, consistent with rate coding by unequal populations of contralaterally and ipsilaterally tuned neurons. In contrast, for ITD, univariate analyses showed modest contralateral tuning only in left pSTG, characterized by a monotonic response-ITD function. A multivoxel classifier, however, revealed ITD coding in both hemispheres. Although sensitivity to ILD and ITD was distributed in similar AC regions, the differently shaped response functions and different response patterns across hemispheres suggest that basic ILD and ITD processes are not fully integrated in human AC. The results support opponent-channel theories of ILD but not necessarily ITD coding, the latter of which may involve multiple types of representation that differ across hemispheres.

Monaural and binaural contributions to interaural-level-difference sensitivity in human auditory cortex.

Whole-brain functional magnetic resonance imaging was used to measure blood-oxygenation-level-dependent (BOLD) responses in human auditory cortex (AC) to sounds with intensity varying independently in the left and right ears. Echoplanar images were acquired at 3 Tesla with sparse image acquisition once per 12-second block of sound stimulation. Combinations of binaural intensity and stimulus presentation rate were varied between blocks, and selected to allow measurement of response-intensity functions in three configurations: monaural 55-85 dB SPL, binaural 55-85 dB SPL with intensity equal in both ears, and binaural with average binaural level of 70 dB SPL and interaural level differences (ILD) ranging ±30 dB (i.e., favoring the left or right ear). Comparison of response functions equated for contralateral intensity revealed that BOLD-response magnitudes (1) generally increased with contralateral intensity, consistent with positive drive of the BOLD response by the contralateral ear, (2) were larger for contralateral monaural stimulation than for binaural stimulation, consistent with negative effects (e.g., inhibition) of ipsilateral input, which were strongest in the left hemisphere, and (3) also increased with ipsilateral intensity when contralateral input was weak, consistent with additional, positive, effects of ipsilateral stimulation. Hemispheric asymmetries in the spatial extent and overall magnitude of BOLD responses were generally consistent with previous studies demonstrating greater bilaterality of responses in the right hemisphere and stricter contralaterality in the left hemisphere. Finally, comparison of responses to fast (40/s) and slow (5/s) stimulus presentation rates revealed significant rate-dependent adaptation of the BOLD response that varied across ILD values.