Ensemble Learning for Breast Cancer Lesion Classification: A Pilot Validation Using Correlated Spectroscopic Imaging and Diffusion-Weighted Imaging.

The main objective of this work was to evaluate the application of individual and ensemble machine learning models to classify malignant and benign breast masses using features from two-dimensional (2D) correlated spectroscopy spectra extracted from five-dimensional echo-planar correlated spectroscopic imaging (5D EP-COSI) and diffusion-weighted imaging (DWI). Twenty-four different metabolite and lipid ratios with respect to diagonal fat peaks (1.4 ppm, 5.4 ppm) from 2D spectra, and water and fat peaks (4.7 ppm, 1.4 ppm) from one-dimensional non-water-suppressed (NWS) spectra were used as the features. Additionally, water fraction, fat fraction and water-to-fat ratios from NWS spectra and apparent diffusion coefficients (ADC) from DWI were included. The nine most important features were identified using recursive feature elimination, sequential forward selection and correlation analysis. XGBoost (AUC: 93.0%, Accuracy: 85.7%, F1-score: 88.9%, Precision: 88.2%, Sensitivity: 90.4%, Specificity: 84.6%) and GradientBoost (AUC: 94.3%, Accuracy: 89.3%, F1-score: 90.7%, Precision: 87.9%, Sensitivity: 94.2%, Specificity: 83.4%) were the best-performing models. Conventional biomarkers like choline, myo-Inositol, and glycine were statistically significant predictors. Key features contributing to the classification were ADC, 2D diagonal peaks at 0.9 ppm, 2.1 ppm, 3.5 ppm, and 5.4 ppm, cross peaks between 1.4 and 0.9 ppm, 4.3 and 4.1 ppm, 2.3 and 1.6 ppm, and the triglyceryl-fat cross peak. The results highlight the contribution of the 2D spectral peaks to the model, and they demonstrate the potential of 5D EP-COSI for early breast cancer detection.

Veterans' Experiences of Support in Managing Comorbid Sleep Apnea and Type 2 Diabetes.

BACKGROUND: Obstructive sleep apnea (OSA) is highly prevalent in patients with Type 2 diabetes, more so in veterans compared with nonveterans. Positive airway pressure is the recommended first-line treatment for OSA. However, adherence to both positive airway pressure and diabetes management regimens can be challenging for older adults. Support from family or friends may improve glucose control or sleep-apnea-related symptoms, yet the evidence is limited when both conditions coexist. OBJECTIVES: This study aimed to describe veterans' experiences of support from family and friends with managing comorbid sleep apnea and Type 2 diabetes. METHODS: We conducted a postal survey of older veterans with OSA and Type 2 diabetes from one healthcare system. Questions include demographic and health-related information, information about sleep apnea and diabetes treatment and education received, related support from family or a friend, perceived benefits of regular positive airway pressure device use on improving sleep health, and perceived benefits of education for family or a friend on sleep apnea and diabetes. Descriptive and bivariate analyses were performed. RESULTS: Of 145 respondents (mean age = 72 years), 43% reported receiving help for Type 2 diabetes from family or a friend. Almost two thirds of the respondents were currently using a positive airway pressure device, of whom 27% received support with device use from family or friends. About one third of veterans perceived family and friends receiving education on treating sleep apnea and diabetes to be very or extremely helpful. Such perceived benefit was higher among those who were married or identified as non-White. Veterans using a positive airway pressure device had lower hemoglobin A1c levels than nonusers. DISCUSSION: Veterans perceived that additional education for the individuals providing support would be beneficial. Future studies could address interventions to increase sleep apnea and Type 2 diabetes knowledge among families and friends of veterans with these comorbid conditions. In addition, patients' adherence to positive airway pressure may be enhanced by support from family and friends.

Stimulus-independent and stimulus-dependent neural networks underpin placebo analgesia responsiveness in humans.

The neural circuits that regulate placebo analgesia responsivity are unknown, although engagement of brainstem pain modulatory regions is likely critical. Here we show in 47 participants that differences are present in neural circuit connectivity's in placebo responders versus non-responders. We distinguish stimulus-independent and stimulus-dependent neural networks that display altered connections between the hypothalamus, anterior cingulate cortex and midbrain periaqueductal gray matter. This dual regulatory system underpins an individual's ability to mount placebo analgesia.

A First Look at Childhood Abuse in Women with Obstructive Sleep Apnea.

Study objectives. Women who experienced childhood sexual abuse have higher rates of obesity, a risk factor for obstructive sleep apnea (OSA). We assessed if prior childhood sexual abuse was more common in women with OSA vs. control, with possible mediation by obesity. Methods . We studied 21 women with OSA (age mean±s.d. 59±12 years, body mass index (BMI) 33±8 kg/m 2 , respiratory event index [REI] 25±16 events/hour, Epworth Sleepiness Scale [ESS] 8±5) and 21 women without OSA (age 53±9 years, BMI 25±5 kg/m 2 , REI (in 7/21 women) 1±1 events/hour, ESS 5±3). We evaluated four categories of trauma (general trauma, physical, emotional, and sexual abuse) with the early trauma inventory self-report-short form (ETISR-SF). We assessed group differences in trauma scores with independent samples t-tests and multiple regressions. Parametric Sobel tests were used to model BMI as a mediator for individual trauma scores predicting OSA in women. Results. Early childhood sexual abuse reported on the ETISR-SF was 2.4 times more common in women with vs. without OSA ( p =0.02 for group difference). Other trauma scores were not significantly different between women with and without OSA. However, BMI was a significant mediator ( p =0.02) in predicting OSA in women who experienced childhood physical abuse. Conclusions. Childhood sexual abuse was more common in a group of women with OSA than those without OSA. Additionally, BMI was a mediator for OSA of childhood physical but not sexual abuse. There may be physiological impacts of childhood trauma in women that predispose them to OSA.

Social Media Use and Depression in Older Adults: A Systematic Review.

Social media has become an integral part of everyday life and revolutionized how older adults communicate and interact with others. The aim of the current review was to identify and synthesize quantitative studies addressing the potential relationship between social media use and depression in older adults. Medline, CINAHL, and PsycINFO databases were used to identify studies performed up to July 2020. Keywords identified were depression, social media use, and older adults. A nuanced relationship was revealed between social media use and depression in older adults. There were noted differences in the conceptualization of social media use. The reviewed studies lacked exploration of structural characteristics, examination of content, and quality of interactions in older adults' social media use. Health variables, social factors, and age cohort differences could influence the relationship between social media use and depression. Further studies are needed to enhance the understanding and explore the benefits and potential disadvantages of social media use in older adults. [Research in Gerontological Nursing, 16(2), 97-104.].

Detailed organisation of the human midbrain periaqueductal grey revealed using ultra-high field magnetic resonance imaging.

The midbrain periaqueductal grey (PAG) is a critical region for the mediation of pain-related behavioural responses. Neuronal tract tracing techniques in experimental animal studies have demonstrated that the lateral column of the PAG (lPAG) displays a crude somatotopy, which is thought to be critical for the selection of contextually appropriate behavioural responses, without the need for higher brain input. In addition to the different behavioural responses to cutaneous and muscle pain - active withdrawal versus passive coping - there is evidence that cutaneous pain is processed in the region of the lPAG and muscle pain in the adjacent ventrolateral PAG (vlPAG). Given the fundamental nature of these behavioural responses to cutaneous and muscle pain, these PAG circuits are assumed to have been preserved, though yet to be definitively documented in humans. Using ultra-high field (7-Tesla) functional magnetic resonance imaging we determined the locations of signal intensity changes in the PAG during noxious cutaneous heat stimuli and muscle pain in healthy control participants. Images were processed and blood oxygen level dependant (BOLD) signal changes within the PAG determined. It was observed that noxious cutaneous stimulation of the lip, cheek, and ear evoked maximal increases in BOLD activation in the rostral contralateral PAG, whereas noxious cutaneous stimulation of the thumb and toe evoked increases in the caudal contralateral PAG. Analysis of individual participants demonstrated that these activations were located in the lPAG. Furthermore, we found that deep muscular pain evoked the greatest increases in signal intensity in the vlPAG. These data suggest that the crude somatotopic organization of the PAG may be phyletically preserved between experimental animals and humans, with a body-face delineation capable of producing an appropriate behavioural response based on the location and tissue origin of a noxious stimulus.

Alterations of gray and white matter volumes and cortical thickness in treated HIV-positive patients.

Brain structural changes in HIV identified by voxel-based morphometry (VBM) alone could arise from a variety of causes that are difficult to distinguish without further information, such as cortical thickness (CT), gyrification index (GI) or sulcal depth (SD). Hence, our goal was to assess these additional metrics in HIV using high-resolution 3D T1-weighted images and investigate if surface-based morphometric (SBM) analysis would reveal significant changes in the gray matter (GM) and white matter (WM) volumes combined with alterations in cortical thickness (CT), gyrification index (GI), sulcal depth (SD). T1-w magnetization-prepared-rapid-acquisition gradient-echo (MP-RAGE) scans were acquired in 27 HIV-infected individuals on antiretroviral therapy (ART) and 15 HIV-uninfected healthy controls using a 3T MRI scanner equipped with a 16-channel head "receive" and a quadrature body "transmit" coil. Voxel-based and surface-based morphometric analyses were performed using the MATLAB based SPM Computational Anatomy Toolbox (CAT12.7(1700)). HIV-infected patients showed significantly altered GM and WM volumes, CT, GI, and SD, in multiple brain regions. This study showed the association of altered GM and WM volumes in local brain regions with the changes in region-wise CT, GI and SD measures of HIV-infected patients, especially in the parahippocampal and middle frontal regions as compared to uninfected healthy controls. The outcome of this study suggests that the findings of VBM may not necessarily indicate the volumetric shrinkage or increase alone, but might also be due to altered CT, GI, or SD. Correlation analysis showed a significantly accelerated gray matter loss with age in HIV-infected individuals compared to uninfected healthy controls.

Adulthood Psychosocial Disadvantages and Risk of Hypertension in U.S. Workers: Effect Modification by Adverse Childhood Experiences.

Hypertension is a key driver of cardiovascular diseases. However, how stressors contribute to the development of hypertension remains unclear. The objective of this study was to examine prospective associations of adverse childhood experiences (ACEs) and adulthood psychosocial disadvantages (APDs) with incident hypertension. Data were from the Mid-life in the United States (MIDUS) study, a national, population-based, prospective cohort study. ACEs were examined via retrospective reports, and APDs including work stress and social isolation were assessed using survey measures. Incident hypertension was defined based on self-reported physician diagnosis. Baseline data were collected in 1995, with follow-up in 2004-2006 and 2013-2014. Cox proportional hazards regression was applied to assess prospective associations of ACEs and APDs with incident hypertension in 2568 workers free from hypertension at baseline. After adjustment for covariates, baseline APDs were associated with increased incident hypertension (aHR and 95% CI = 1.48 [1.09, 2.01]) during a 20-year follow-up, whereas ACEs showed null associations. Moreover, a moderating effect by ACEs was observed-the effect of APDs on risk of hypertension was stronger when ACEs were present (aHR and 95% CI = 1.83 [1.17, 2.86]). These findings underscore the importance of psychosocial stressors as nontraditional risk factors of cardiometabolic disorders.

Alterations in brain structure associated with trigeminal nerve anatomy in episodic migraine.

The pathophysiology of migraine remains to be elucidated. We have recently shown that interictal migraineurs exhibit reduced fractional anisotropy (FA) in the root entry zone of the trigeminal nerve when compared to controls, but it is not known if this altered nerve anatomy is associated with changes within the brainstem or higher cortical brain regions. Diffusion tensor imaging of the brain was used to calculate regional measures of structure, including mean diffusivity (MD), axial diffusivity (AX) and radial diffusivity (RD) in addition to voxel-based morphometry of T1-weighted anatomical images. Linear relationships between trigeminal nerve anatomy (FA) and MD throughout the brainstem and/or higher cortical regions were determined in both controls (n = 31, brainstem; n = 38, wholebrain) and interictal migraineurs (n = 32, brainstem; n = 38, wholebrain). Additionally, within the same brain areas, relationships of AX and RD with nerve FA were determined. We found that in both interictal migraine and control participants, decreasing trigeminal nerve FA was associated with significantly increased MD in brainstem regions including the spinal trigeminal nucleus and midbrain periaqueductal gray matter (PAG), and in higher brain regions such as the hypothalamus, insula, posterior cingulate, primary somatosensory and primary visual (V1) cortices. Whereas, both control and migraineur groups individually displayed significant inverse correlations between nerve FA and MD, in migraineurs this pattern was disrupted in the areas of the PAG and V1, with only the control group displaying a significant linear relationship (PAG controls r = -0.58, p = 0.003; migraineurs r = -0.25, p = 0.17 and V1 controls r = -0.52, p = 0.002; migraineurs r = -0.10, p = 0.55). Contrastingly, we found no gray matter volume changes in brainstem or wholebrain areas. These data show that overall, trigeminal nerve anatomy is significantly related to regional brain structure in both controls and migraineurs. Importantly, the PAG showed a disruption of this relationship in migraineurs suggesting that the anatomy and possibly the function of the PAG is uniquely altered in episodic migraine, which may contribute to altered orofacial pain processing in migraine.

Regional hypothalamic, amygdala, and midbrain periaqueductal gray matter recruitment during acute pain in awake humans: A 7-Tesla functional magnetic resonance imaging study.

Over the past two decades, magnetic resonance imaging (MRI) studies have explored brain activation patterns during acute noxious stimuli. Whilst these human investigations have detailed changes in primarily cortical regions, they have generally not explored discrete changes within small brain areas that are critical in driving behavioural, autonomic, and endocrine responses to pain, such as within subregions of the hypothalamus, amygdala, and midbrain periaqueductal gray matter (PAG). Ultra-high field (7-Tesla) MRI provides enough signal-to-noise at high spatial resolutions to investigate activation patterns within these small brain regions during acute noxious stimulation in awake humans. In this study we used 7T functional MRI to concentrate on hypothalamic, amygdala, and PAG signal changes during acute noxious orofacial stimuli. Noxious heat stimuli were applied in three separate fMRI scans to three adjacent sites on the face in 16 healthy control participants (7 females). Images were processed using SPM12 and custom software, and blood oxygen level dependent signal changes within the hypothalamus, amygdala, and PAG assessed. We identified altered activity within eight unique subregions of the hypothalamus, four unique subregions of the amygdala, and a single region in the lateral PAG. Specifically, within the hypothalamus and amygdala, signal intensity largely decreased during noxious stimulation, and increased in the lateral PAG. Furthermore, we found sex-related differences in discrete regions of the hypothalamus and amygdala. This study reveals that the activity of discrete nuclei during acute noxious thermal stimulation in awake humans.

Baroreflex sensitivity during rest and pressor challenges in obstructive sleep apnea patients with and without CPAP.

INTRODUCTION: Obstructive sleep apnea (OSA) increases sympathetic vasoconstrictor drive and reduces baroreflex sensitivity (BRS), the degree to which blood pressure changes modify cardiac output. Whether nighttime continuous positive airway pressure (CPAP) corrects BRS in the awake state in OSA remains unclear. We assessed spontaneous BRS using non-invasive continuous BP and ECG recordings at rest and during handgrip and Valsalva challenges, maneuvers that increase vasoconstrictor drive with progressively higher BP, in untreated OSA (unOSA), CPAP-treated OSA (cpOSA) and healthy (CON) participants. METHODS: In a cross-sectional study of 104 participants, 34 unOSA (age mean±std, 50.6±14.1years; Respiratory Event Index [REI] 21.0±15.3 events/hour; 22male), 31 cpOSA (49.6±14.5years; REI 23.0±14.2 events/hour; 22male; self-report 4+hours/night,5+days/week,6months), and 39 CON (42.2±15.0years; 17male), we calculated BRS at rest and during handgrip and Valsalva. Additionally, we correlated BP variability (BPV) with BRS during these protocols. RESULTS: BRS in unOSA, cpOSA and CON was, respectively (mean±sdv in ms/mmHg), at rest: 14.8±11.8, 15.8±17.0, 16.1±11.3; during handgrip 13.3±7.6, 12.7±8.4, 16.4±8.7; and during Valsalva 12.7±8.0, 11.5±6.6, 15.1±8.9. BRS was lower in cpOSA than CON for handgrip (p=0.04) and Valsalva (p=0.03). BRS was negatively correlated with BPV in unOSA during Valsalva and handgrip for cpOSA, both R=-0.4 (p=0.02). BRS was negatively correlated with OSA severity (levels: none, mild, moderate, severe) at R=-0.2 (p=0.04,n=104). CONCLUSIONS: As expected, BRS was lower and BPV higher in OSA during the pressor challenges, and disease severity negatively correlated with BRS. In this cross-sectional study, both CPAP-treated (self-reported) and untreated OSA showed reduced BRS, leaving open whether within-person CPAP improves BRS.

Alterations in pain processing circuitries in episodic migraine.

BACKGROUND: The precise underlying mechanisms of migraine remain unknown. Although we have previously shown acute orofacial pain evoked changes within the brainstem of individuals with migraine, we do not know if these brainstem alterations are driven by changes in higher cortical regions. The aim of this investigation is to extend our previous investigation to determine if higher brain centers display altered activation patterns and connectivity in migraineurs during acute orofacial noxious stimuli. METHODS: Functional magnetic resonance imaging was performed in 29 healthy controls and 25 migraineurs during the interictal and immediately (within 24-h) prior to migraine phases. We assessed activation of higher cortical areas during noxious orofacial heat stimulation using a thermode device and assessed whole scan and pain-related changes in connectivity. RESULTS: Despite similar overall pain intensity ratings between all three groups, migraineurs in the group immediately prior to migraine displayed greater activation of the ipsilateral nucleus accumbens, the contralateral ventrolateral prefrontal cortex and two clusters in the dorsolateral prefrontal cortex (dlPFC). Reduced whole scan dlPFC [Z + 44] connectivity with cortical/subcortical and brainstem regions involved in pain modulation such as the putamen and primary motor cortex was demonstrated in migraineurs. Pain-related changes in connectivity of the dlPFC and the hypothalamus immediately prior to migraine was also found to be reduced with brainstem pain modulatory areas such as the rostral ventromedial medulla and dorsolateral pons. CONCLUSIONS: These data reveal that the modulation of brainstem pain modulatory areas by higher cortical regions may be aberrant during pain and these alterations in this descending pain modulatory pathway manifests exclusively prior to the development of a migraine attack.

Associations of Smokeless Tobacco Use With Cardiovascular Disease Risk: Insights From the Population Assessment of Tobacco and Health Study.

INTRODUCTION: Cigarette smoking is strongly associated with the development of cardiovascular disease (CVD). However, evidence is limited as to whether smokeless tobacco (ST) use is associated with CVD. AIMS AND METHODS: Using data from 4347 adults in the Population Assessment of Tobacco and Health Study (2013-2014), we compared geometric mean concentrations of CVD-related harm biomarkers and biomarkers of exposure among exclusive ST users and exclusive cigarette smokers-in relation to recent nicotine exposure-and never tobacco users, adjusting for age, sex, race/ethnicity, income, body mass index, and CVD. Biomarker levels among exclusive ST users who were former established cigarette smokers were compared with exclusive cigarette smokers. RESULTS: Compared with cigarette smokers, ST users had significantly higher concentrations of total nicotine equivalents (TNE) but lower concentrations of inflammatory (high-sensitivity C-reactive protein, interleukin-6, intercellular adhesion molecule, fibrinogen) and oxidative stress (8-isoprostane) biomarkers (all p < .05). Biomarker levels among ST users were similar to never smokers. ST users who were former cigarette smokers had lower levels of inflammatory and oxidative stress biomarkers and biomarkers of exposure (cadmium, lead, 1-hydroxypyrene, acrylonitrile, and acrolein), compared with cigarettes smokers (p < .05), despite having higher TNE levels (p < .05). Among cigarette smokers, but not among ST users, inflammatory biomarkers and TNE were highly correlated. CONCLUSIONS: ST use is not associated with increases in biomarkers of CVD-related harm and exposure, compared with never smokers, despite exposure to nicotine at levels higher than those observed among cigarette smokers. These findings support the concept that increases in CVD risk among cigarette smokers is caused primarily by constituents of tobacco smoke other than nicotine. IMPLICATIONS: Despite having higher levels of nicotine and compared with exclusive cigarette smokers, exclusive ST users (including those who were former cigarette smokers) had significantly lower concentrations of inflammatory and oxidative stress biomarkers, comparable to levels observed among never tobacco users. These findings suggest that increases in CVD risk among cigarette smokers is caused primarily by tobacco constituents other than nicotine and that switching to ST is likely associated with lower CVD risk.

Breathing rate variability in obstructive sleep apnea during wakefulness.

STUDY OBJECTIVES: Obstructive sleep apnea (OSA) is defined by pauses in breathing during sleep, but daytime breathing dysregulation may also be present. Sleep may unmask breathing instability in OSA that is usually masked by behavioral influences during wakefulness. A breath-hold (BH) challenge has been used to demonstrate breathing instability. One measure of breathing stability is breathing rate variability (BRV). We aimed to assess BRV during rest and in response to BH in OSA. METHODS: We studied 62 participants (31 with untreated OSA: respiratory event index [mean ± SD] 20 ± 15 events/h, 12 females, age 51 ± 14 years, body mass index [BMI] 32 ± 8 kg/m2; 31 controls: 17 females, age 47 ± 13 years; BMI 26 ± 4 kg/m2). Breathing movements were collected using a chest belt for 5 minutes of rest and during a BH protocol (60 seconds baseline, 30 seconds BH, 90 seconds recovery, 3 repeats). From the breathing movements, we calculated median breathing rate (BR) and interquartile BRV at rest. We calculated change in BRV during BH recovery from baseline. Group comparisons of OSA vs control were conducted using analysis of covariance with age, sex, and BMI as covariates. RESULTS: We found 10% higher BRV in OSA vs controls (P < .05) during rest. In response to BH, BRV increased 7% in OSA vs 1% in controls (P < .001). Resting BR was not significantly different in OSA and controls, and sex and age did not have any significant interaction effects. BMI was associated with BR at rest (P < .05) and change in BRV with BH (P < .001), but no significant BMI-by-group interaction effect was observed. CONCLUSIONS: The findings suggest breathing instability as reflected by BRV is high in OSA during wakefulness, both at rest and in response to a stimulus. Breathing instability together with high blood pressure variability in OSA may reflect a compromised cardiorespiratory consequence in OSA during wakefulness. CITATION: Pal A, Martinez F, Akey MA, et al. Breathing rate variability in obstructive sleep apnea during wakefulness. J Clin Sleep Med. 2022;18(3):825-833.

Pain Following Endoscopic Foreheadplasty Surgery in Women.

BACKGROUND: Endoscopic foreheadplasty surgery (EFS) is a common procedure; however, little has been reported about the nature or treatment of postoperative headache pain and associated symptoms. OBJECTIVES: The objective of this study was to describe the intensity, quality, location, and duration of headache pain in women following EFS. We also compared post-EFS symptoms with migraine, described medication use and efficacy, and measured emotional and functional outcomes. METHODS: This descriptive study used an observational repeated-measures design. Forty-two women (mean [standard deviation] age, 59.0 [7.9] years) undergoing EFS were prospectively recruited from 12 private cosmetic practices in 3 California counties. Telephone interviews with the Acute Short-Form 12v2 and the Headache Pain Questionnaire were conducted on postoperative days (POD) 1, 3, 7, and 30. RESULTS: On POD 1, 93% reported at least moderate pain and 64% severe pain. Severe pain was characterized as throbbing (71%), sharp (53%), dull (76%), exploding (41%), imploding (53%), continuous (53%), or intermittent (41%) on POD 1. Moderate pain was most frequent on POD 3 (21%) compared to POD 1 (19%), 7 (12%) and 30 (12%). Mild pain predominated on POD 3 (40%) and 7 (40%), with 20% remaining on POD 30. The majority (79%) of post-EFS symptoms included light sensitivity and nausea, and therefore met most International Classification of Headache Disorders criteria for migraine. Analgesic use provided inconsistent relief. Functional and emotional status did not return to baseline throughout the 30-day postoperative period. CONCLUSIONS: Immediately following EFS, most women experience moderate to severe headache pain, despite use of medications. Pain persists in many patients for up to 1 month. Headache is associated with migraine symptoms, including light sensitivity and nausea.

Inspiratory Muscle Training for Obstructive Sleep Apnea: Protocol Development and Feasibility of Home Practice by Sedentary Adults.

Background: Inspiratory muscle training (IMT) may improve respiratory and cardiovascular functions in obstructive sleep apnea (OSA) and is a potential alternative or adjunct treatment to continuous positive airway pressure (CPAP). IMT protocols were originally designed for athletes, however, we found some OSA patients could not perform the exercise, so we aimed for a more OSA-friendly protocol. Our feasibility criteria included (1) participants successfully managing the technique at home; (2) participants completing daily practice sessions and recording data logs; and (3) capturing performance plateaus to determine an optimal length of the intervention. Methods: Five sedentary OSA patients participated in this feasibility study (three men, mean age = 61.6 years, SD = 10.2). Using a digital POWERbreathe K4 or K5 device, participants performed 30 daily inhalations against a resistance set at a percentage of maximum, recalculated weekly. Participants were willing to perform one but not two daily practice sessions. Intervention parameters from common IMT protocols were adapted according to ability and subjective feedback. Some were unable to perform the typically used 75% of maximum inspiratory resistance so we lowered the target to 65%. The technique required some practice; therefore, we introduced a practice week with a 50% target. After an initial 8 weeks, the intervention was open-ended and training continued until all participants demonstrated at least one plateau of inspiratory strength (2 weeks without strength gain). Weekly email and phone reminders ensured that participants completed all daily sessions and logged data in their online surveys. Weekly measures of inspiratory resistance, strength, volume, and flow were recorded. Results: Participants successfully completed the practice and subsequent 65% IMT resistance targets daily for 13 weeks. Inspiratory strength gains showed plateaus in all subjects by the end of 10 weeks of training, suggesting 12 weeks plus practice would be sufficient to achieve and capture maximum gains. Participants reported no adverse effects. Conclusion: We developed and tested a 13-week IMT protocol in a small group of sedentary, untreated OSA patients. Relative to other IMT protocols, we successfully implemented reduced performance requirements, a practice week, and an extended timeframe. This feasibility study provides the basis for a protocol for clinical trials on IMT in OSA.

Brainstem Mechanisms of Pain Modulation: A within-Subjects 7T fMRI Study of Placebo Analgesic and Nocebo Hyperalgesic Responses.

Pain perception can be powerfully influenced by an individual's expectations and beliefs. Although the cortical circuitry responsible for pain modulation has been thoroughly investigated, the brainstem pathways involved in the modulatory phenomena of placebo analgesia and nocebo hyperalgesia remain to be directly addressed. This study used ultra-high-field 7 tesla functional MRI (fMRI) to accurately resolve differences in brainstem circuitry present during the generation of placebo analgesia and nocebo hyperalgesia in healthy human participants (N = 25, 12 male). Over 2 successive days, through blinded application of altered thermal stimuli, participants were deceptively conditioned to believe that two inert creams labeled lidocaine (placebo) and capsaicin (nocebo) were acting to modulate their pain relative to a third Vaseline (control) cream. In a subsequent test phase, fMRI image sets were collected while participants were given identical noxious stimuli to all three cream sites. Pain intensity ratings were collected and placebo and nocebo responses determined. Brainstem-specific fMRI analysis revealed altered activity in key pain modulatory nuclei, including a disparate recruitment of the periaqueductal gray (PAG)-rostral ventromedial medulla (RVM) pathway when both greater placebo and nocebo effects were observed. Additionally, we found that placebo and nocebo responses differentially activated the parabrachial nucleus but overlapped in engagement of the substantia nigra and locus coeruleus. These data reveal that placebo and nocebo effects are generated through differential engagement of the PAG-RVM pathway, which in concert with other brainstem sites likely influences the experience of pain by modulating activity at the level of the dorsal horn.SIGNIFICANCE STATEMENT Understanding endogenous pain modulatory mechanisms would support development of effective clinical treatment strategies for both acute and chronic pain. Specific brainstem nuclei have long been known to play a central role in nociceptive modulation; however, because of the small size and complex organization of the nuclei, previous neuroimaging efforts have been limited in directly identifying how these subcortical networks interact during the development of antinociceptive and pro-nociceptive effects. We used ultra-high-field fMRI to resolve brainstem structures and measure signal change during placebo analgesia and nocebo hyperalgesia. We define overlapping and disparate brainstem circuitry responsible for altering pain perception. These findings extend our understanding of the detailed organization and function of discrete brainstem nuclei involved in pain processing and modulation.

Stress in obstructive sleep apnea.

People with obstructive sleep apnea (OSA) often have psychological symptoms including depression and anxiety, which are commonly treated with anti-depression or anti-anxiety interventions. Psychological stress is a related symptom with different intervention targets that may also improve mental state, but this symptom is not well characterized in OSA. We therefore aimed to describe stress in relation to other psychological symptoms. We performed a prospective cross-sectional study of 103 people, 44 untreated OSA (mean ± s.d. age: 51.2 ± 13.9 years, female/male 13/31) and 57 healthy control participants (age: 46.3 ± 13.8 years, female/male 34/23). We measured stress (Perceived Stress Scale; PSS), excessive daytime sleepiness (Epworth Sleepiness Scale; ESS), depressive symptoms (Patient Health Questionnaire; PHQ-9), and anxiety symptoms (General Anxiety Disorder; GAD-7). We compared group means with independent samples t-tests and calculated correlations between variables. Mean symptom levels were higher in OSA than control, including PSS (mean ± s.d.: OSA = 15.3 ± 6.9, control = 11.4 ± 5.5; P = 0.002), GAD-7 (OSA = 4.8 ± 5.0, control = 2.1 ± 3.9; P = 0.02), PHQ-9 (OSA = 6.9 ± 6.1, control = 2.6 ± 3.8; P = 0.003) and ESS (OSA = 8.1 ± 5.3, control = 5.0 ± 3.3; P = 0.03). Similar OSA-vs-control differences appeared in males, but females only showed significant differences in PHQ-9 and ESS, not PSS or GAD-7. PSS correlated strongly with GAD-7 and PHQ-9 across groups (R = 0.62-0.89), and moderately with ESS. Perceived stress is high in OSA, and closely related to anxiety and depressive symptoms. The findings support testing stress reduction in OSA.

Mindfulness effects on lifestyle behavior and blood pressure: A randomized controlled trial.

BACKGROUND AND AIMS: HTN affects nearly 50% of U.S. adults and is the leading modifiable cardiovascular risk factor. A healthy diet and exercise can improve BP control, but adherence to these interventions is low. We tested whether a multimodal mind-body program, Mindful Awareness Practices (MAP) could improve BP and lifestyle behaviors associated with HTN when compared to a Health Promotion Program (HPP). METHODS: Adults with BP >120/80 were randomized to MAP or HPP. Outcome measurements of BP, self-reported diet, and exercise were analyzed with intent-to-treat group comparisons using repeated measures linear mixed models. RESULTS: There was an MAP-HPP between-group difference in interactions of time-by-systolic BP (P = 0.005) and time-by-diastolic BP (P = .003). The mean drops in SBP from baseline to week 13 for the MAP group was 19 mm Hg (138 ± 15 mm Hg-119 ± 6 mm Hg) compared to 7 mm Hg (134 ± 18 mm Hg-127 ± 22 mm Hg) in the HPP group. Similarly, a greater reduction in DBP was observed in the MAP group compared to the HPP group, 12 mm Hg (89 mm Hg ± 11-77 ± 7 mm Hg) and 1 mm Hg (81 ± 16 mm Hg-80 ± 18 mm Hg), respectively. Mediational analysis of the MAP group showed the total effect of mindfulness practice minutes on SBP with indirect effect (ab) of -.057 was significant, resulting in a 40% lower SBP for total effect (c) compared to direct (c') effect alone. The mediational model suggests MAP has a modest positive influence on participants initiating lifestyle behavior change, which partially explains the greater reduction in BP by the MAP group. CONCLUSION: Our findings suggest a multimodal mind-body program involving mindfulness practice may improve BP control in adults with HTN.

Which came first, obstructive sleep apnoea or hypertension? A retrospective study of electronic records over 10 years, with separation by sex.

OBJECTIVES: Obstructive sleep apnoea (OSA) is a risk factor for hypertension (HTN), but the clinical progression of OSA to HTN is unclear. There are also sex differences in prevalence, screening and symptoms of OSA. Our objective was to estimate the time from OSA to HTN diagnoses in females and males. DESIGN: Retrospective analysis of electronic health records (EHR) over 10 years (2006-2015 inclusive). SETTING: University of California Los Angeles (UCLA) Health System in Los Angeles, California, USA. PARTICIPANTS: 4848 patients: females n=2086, mean (SD) age=52.8 (13.2) years; males n=2762, age=53.8 (13.5) years. These patients were selected from 1.6 million with diagnoses in the EHR who met these criteria: diagnoses of OSA and HTN; in long-term care defined by ambulatory visits at least 1 year prior and 1 year subsequent to the first OSA diagnosis; no diagnosis of OSA or HTN at intake; and a sleep study performed at UCLA. PRIMARY AND SECONDARY OUTCOME MEASURES: The primary outcome measure in each patient was time from the first diagnosis of OSA to the first diagnosis of HTN (OSA to HTN days). Since HTN and OSA are progressive disorders, a secondary measure was the relationship between OSA to HTN time and age (OSA to HTN=ß1×Age+ß0). RESULTS: The median (lower and upper quartiles) days from OSA to HTN were: all -532 (-1439, -3); females -610 (-1579, -42); and males -451 (-1358, 0). Older age in both sexes was associated with less time to a subsequent HTN diagnosis or more time from a prior HTN diagnosis (ß1 days/year: all -16.9, females -18.3, males -15.9). CONCLUSIONS: HTN was on average diagnosed years prior to OSA, with a longer separation in females. Our findings are consistent with underscreening of OSA, more so in females than males. Undiagnosed OSA may delay treatment for the sleep disorder and perhaps affect the development and progression of HTN.