Endothelial dysfunction influences augmented aortic hemodynamic responses to metaboreflex activation in postmenopausal women.

PURPOSE: Postmenopausal women experience augmented aortic hemodynamic responses to isometric handgrip (IHG) exercise and metaboreflex activation post-exercise muscle ischemia (PEMI). Relationships between endothelial function brachial artery flow-mediated dilation (FMD) and aortic stiffness carotid-femoral pulse wave velocity (cfPWV) with aortic pulsatile hemodynamics during IHG and PEMI have not been determined. The relationships between aortic hemodynamic responses to PEMI were evaluated. METHODS: Aortic blood pressure (BP), wave reflection, and pressure of forward (Pf) and backward (Pb) waves were measured using arterial tonometry at rest, IHG at 30% maximal force, and PEMI in 30 (15/group) postmenopausal women with low (≤ 4.5%) and normal (≥ 5.5%) FMD. Hemodynamic responses were analyzed as the change (Δ) from rest to the last minute of IHG and PEMI. RESULTS: Brachial and aortic systolic BP (SBP) responses to IHG were higher in the low vs normal FMD group (P < 0.05). Aortic SBP (Δ20 ± 8 vs Δ11 ± 7 mmHg), pulse pressure (PP) (Δ12 ± 8 vs Δ6 ± 4 mmHg), augmented pressure (AP) (Δ5 ± 3 vs Δ2 ± 2 mmHg), and Pb (Δ6 ± 4 vs Δ3 ± 2 mmHg) responses to PEMI were greater (P < 0.05) in women with low vs. normal FMD. FMD was negatively correlated with aortic SBP, PP, AP, and Pb (P < 0.05) responses to PEMI. cfPWV was not correlated with responses to PEMI. CONCLUSION: Endothelial dysfunction relates to augmented aortic pulsatile load during metaboreflex activation, which may increase cardiovascular risk in postmenopausal women.

Endothelial and exercise vasodilation are reduced in postmenopausal females with obesity versus lean and overweight.

BACKGROUND: Obesity (OB) is highly prevalent in females after menopause, especially visceral adipose tissue (VAT) accumulation which contributes to endothelial dysfunction. The endothelium assists in regulating blood flow (BF) during exercise and is attenuated in females with OB. The purpose of this study was to examine upper and lower limb flow-mediated dilation (FMD) and BF regulation during graded low-intensity submaximal exercises in postmenopausal females with BMI in the lean (LN), overweight (OW) and OB categories. METHODS: Participants were grouped by body mass index (BMI) into LN (BMI 18.5-24.9 kg/m2; n = 11), OW (BMI 25.0-29.9 kg/m2; n = 15), and OB (BMI 30.0-39.9 kg/m2; n = 13). FMD of the brachial (BA-FMD) and superficial femoral arteries (FA-FMD) were assessed. Subsequently, BF and vascular conductance (VC) in the upper (BA-BF and BA-VC) and lower limbs (FA-BF and FA-VC) were measured during separate 3-stage incremental rhythmic handgrip and plantarflexion exercises. RESULTS: Significantly lower FA-FMD (P < 0.05) were seen in OB than LN and OW groups with no differences in BA-FMD. Increases in FA-BF and FA-VC were attenuated during the last stage of plantarflexion exercise at 30% of 1RM in OB (both P < 0.001) compared to LN and OW, while upper-body exercise vasodilation was unchanged. FA-BF and FA-VC during plantarflexion exercise were correlated to FA-FMD (FA-BF: r = 0.423, P = 0.007, FA-VC: r = 0.367, P = 0.021) and BMI (FA-BF: r = -0.386, P = 0.015, FA-VC: r = -0.456, P = 0.004). CONCLUSION: Postmenopausal females with OB have reduced lower-limb endothelial and exercise vasodilator function during submaximal dynamic plantarflexion exercise compared to LN and OW. Our findings indicate that obesity may predict diminished leg endothelial function, BF and VC during exercise in postmenopausal females.

L-Citrulline supplementation attenuates aortic pressure and pressure waves during metaboreflex activation in postmenopausal women.

Postmenopausal women have augmented pressure wave responses to low-intensity isometric handgrip exercise (IHG) due to an overactive metaboreflex (postexercise muscle ischaemia, PEMI), contributing to increased aortic systolic blood pressure (SBP). Menopause-associated endothelial dysfunction via arginine (ARG) and nitric oxide deficiency may contribute to exaggerated exercise SBP responses. L-Citrulline supplementation (CIT) is an ARG precursor that decreases SBP, pulse pressure (PP) and pressure wave responses to cold exposure in older adults. We investigated the effects of CIT on aortic SBP, PP, and pressure of forward (Pf) and backward (Pb) waves during IHG and PEMI in twenty-two postmenopausal women. Participants were randomised to CIT (10 g/d) or placebo (PL) for 4 weeks. Aortic haemodynamics were assessed via applanation tonometry at rest, 2 min of IHG at 30 % of maximal strength, and 3 min of PEMI. Responses were analysed as change (Δ) from rest to IHG and PEMI at 0 and 4 weeks. CIT attenuated ΔSBP (−9 ± 2 v. −1 ± 1 mmHg, P = 0·006), ΔPP (−5 ± 2 v. 0 ± 1 mmHg, P = 0·03), ΔPf (−6 ± 2 v. −1 ± 1 mmHg, P = 0·01) and ΔPb (−3 ± 1 v. 0 ± 1 mmHg, P = 0·02) responses to PEMI v. PL. The ΔPP during PEMI was correlated with ΔPf (r = 0·743, P < 0·001) and ΔPb (r = 0·724, P < 0·001). Citrulline supplementation attenuates the increase in aortic pulsatile load induced by muscle metaboreflex activation via reductions in forward and backward pressure wave amplitudes in postmenopausal women.

Financial Performance is Associated With PPE Shortages in Chain-Affiliated Nursing Homes During the COVID-19 Pandemic: A Longitudinal Study.

Many nursing homes operated at thin profit margins prior to the COVID-19 pandemic. This study examines the role of nursing homes' financial performance and chain affiliation in shortages of personal protection equipment (PPE) during the first year of the COVID-19 pandemic. We constructed a longitudinal file of 79 868 nursing home-week observations from 10 872 unique facilities. We found that a positive profit margin was associated with a 21.0% lower probability of reporting PPE shortages in chain-affiliated nursing homes, but not in non-chain nursing homes. Having adequate financial resources may help nursing homes address future emergencies, especially those affiliated with a multi-facility chain.

Disparities in utilization of preventive health services among Asian young adults in the United States.

Despite the favorable health impacts of preventive services use, young adults remain at a higher risk of not using these services compared with older adults. This study seeks to identify barriers to receiving recommended preventive services among Asian young adults compared to other racial/ethnic young adults. Using 2016-2018 National Health Interview Survey data, this study examined barriers to recommended preventive services among non-Hispanic (NH) Asian young adults aged 18-39 years compared with other racial/ethnic groups in the United States (Total = 25,430; NH Asians = 6.3%). General prevention included fasting blood sugar, cholesterol, blood pressure, and Human Immunodeficiency Virus checkups. We documented information on vaccinations for influenza, pneumonia, tetanus, hepatitis A/B, and female-specific preventive care measures. NH Asian young adults reported blood pressure checkups less often than NH Whites (72.88% vs. 79.92%, p < 0.001). NH Asian young adults were also less likely to report HIV testing than all other racial/ethnic groups (p < 0.001). After controlling for covariates, NH Whites (odds ratio [OR] = 2.00, 95% confidence interval [CI] = 1.60, 2.50), NH Blacks (OR = 1.55, 95% CI = 1.18, 2.02), and other races (OR = 2.40, 95% CI = 1.60, 3.58) were more likely to receive any preventive services than NH Asians. Among those receiving any preventive services, there were no differences between NH Asians and all other racial/ethnic groups in whether they reported receiving relatively more preventive services. Our findings demonstrate that the rates of certain recommended preventive services use were lower among NH Asian young adults. Targeted public health strategies are needed to increase the use of preventive healthcare for racial/ethnic minority young adults.

Combined Citrulline and Glutathione Supplementation Improves Endothelial Function and Blood Pressure Reactivity in Postmenopausal Women.

Postmenopausal women (PMW) may experience endothelial dysfunction associated with arginine (ARG) deficiency relative to asymmetric dimethylarginine (ADMA) caused by oxidative stress. Endothelial dysfunction contributes to increased blood pressure (BP) responsiveness to sympathoexcitation induced by the cold pressor test (CPT). We investigated the effects of citrulline alone (CIT) and combined with the antioxidant glutathione (CIT+GSH) on vascular function. Forty-four healthy PMW were randomized to CIT (6 g), CIT+GSH (2 g + 200 mg: Setria®) or placebo (PL) for 4 weeks. Brachial artery flow-mediated dilation (FMD), aortic stiffness (pulse wave velocity, PWV), brachial and aortic BP reactivity to CPT, and serum fasting blood glucose (FBG), ARG, and ARG/ADMA ratio were measured. Baseline FBG was higher in CIT+GSH vs. PL. FMD increased after CIT+GSH vs. PL (p < 0.05). CIT and CIT+GSH increased ARG/ADMA (p < 0.05), but did not affect aortic PWV. CIT+GSH attenuated the brachial and aortic systolic BP and mean arterial pressure (MAP) responses to CPT vs. PL and CIT (p < 0.05). The improvements in FMD were related to baseline FMD (r = -0.39, p < 0.05) and aortic MAP response to CPT (r = -0.33, p < 0.05). This study showed that CIT+GSH improved FMD and attenuated systolic BP and MAP reactivity in PMW. Although CIT increased ARG/ADMA, it did not improve FMD in healthy PMW.

Non-pharmacological Management of Non-productive Chronic Cough in Adults: A Systematic Review.

Background: Chronic cough is a common reason for medical referral and its prevalence is on the rise. With only one pharmaceutical therapy currently under review for the treatment of refractory chronic cough, exploring non-pharmacological chronic cough management therapies is important. This systematic review summarizes the effectiveness of non-pharmacological chronic cough therapies in adults with non-productive refractory chronic cough or cough due to chronic respiratory diseases. Methods: We searched Medline, Embase, Cochrane, CINAHL, and Scopus from inception to September 2021. Randomized controlled trials published in English, Portuguese, or French, and examining the effects of non-pharmacological therapies in adults with chronic non-productive cough (>8 weeks; <2 teaspoons sputum) were included. Mean differences, medians, and odds ratios were calculated as appropriate. Results: 16,546 articles were identified and six articles representing five unique studies were included. Studies evaluated 228 individuals with refractory chronic cough or chronic cough due to a chronic respiratory disease [162 women (71%); 52 ± 11 to 61 ± 8 years old]. Obstructive sleep apnea was the only chronic respiratory disease studied. Non-pharmacological therapies included education, cough suppression, breathing techniques, mindfulness, and continuous positive airway pressure. When standing alone, non-pharmacological cough therapies improved cough-specific health related quality of life when not associated with interventions (mean diff MD 1.53 to 4.54), cough frequency (MD 0.59 95%CI 0.36 to 0.95), and voice outcomes (MD 0.3 to 1) when compared to control interventions. Conclusion: The evidence of non-pharmacological therapies for non-productive chronic cough is limited. Existing studies reflect the heterogeneity in study design, sample size, and outcome measures. Thus, clinical recommendations for using the most effective interventions remain to be confirmed.

Menopause influences aortic pulse pressure and pressure wave responses to metaboreflex activation in women.

OBJECTIVE: Postmenopausal women (post-MW) have greater risk of heart failure due to aortic pulsatile overload on the left ventricle associated with increased backward wave pressure (Pb). Post-MW have exaggerated peripheral blood pressure (BP) response to exercise mediated by metaboreflex (postexercise muscle ischemia [PEMI]) overactivation. Increased forward wave pressure (Pf) and Pb are determinants of aortic pulse pressure (PP) during isometric handgrip exercis (IHG) in young adults. We hypothesized that aortic PP and pressure wave responses to PEMI are augmented in nonhypertensive post-MW compared with premenopausal women (pre-MW). METHODS: Aortic BP, Pf, Pb, and reflection magnitude were assessed at rest and during IHG and PEMI by applanation tonometry in 15 pre-MW and 16 post-MW. RESULTS: Aortic systolic BP during PEMI similarly increased in both groups. The increase in diastolic BP was lower in post-MW (post-MW Δ6 ± 2 vs pre-MW Δ11 ± 2 mm Hg, P < 0.05). Aortic PP (post-MW Δ8 ± 2 vs pre-MW Δ3 ± 2), Pf (post-MW Δ6 ± 1 vs pre-MW Δ0 ± 1), and Pb (post-MW Δ5 ± 1 vs pre-MW Δ2 ± 1) augmented during PEMI in post-MW ( P < 0.05 for all), but not in pre-MW. Reflection magnitude increased during PEMI only in pre-MW (pre-MW Δ7 ± 2 vs post-MW Δ-1 ± 2, P < 0.05) due to concurrent increases in Pf and Pb in post-MW. CONCLUSIONS: Even in nonhypertensive postmenopausal women, increases in Pf and Pb and decrease in aortic DBP are important factors that contribute to the augmented aortic PP response to PEMI.

Effects of L-Citrulline Supplementation on Endothelial Function and Blood Pressure in Hypertensive Postmenopausal Women.

Aging and menopause are associated with decreased nitric oxide bioavailability due to reduced L-arginine (L-ARG) levels contributing to endothelial dysfunction (ED). ED precedes arterial stiffness and hypertension development, a major risk factor for cardiovascular disease. This study investigated the effects of L-citrulline (L-CIT) on endothelial function, aortic stiffness, and resting brachial and aortic blood pressures (BP) in hypertensive postmenopausal women. Twenty-five postmenopausal women were randomized to 4 weeks of L-CIT (10 g) or placebo (PL). Serum L-ARG, brachial artery flow-mediated dilation (FMD), aortic stiffness (carotid-femoral pulse wave velocity, cfPWV), and resting brachial and aortic BP were assessed at 0 and 4 weeks. L-CIT supplementation increased L-ARG levels (Δ13 ± 2 vs. Δ−2 ± 2 µmol/L, p < 0.01) and FMD (Δ1.4 ± 2.0% vs. Δ−0.5 ± 1.7%, p = 0.03) compared to PL. Resting aortic diastolic BP (Δ−2 ± 4 vs. Δ2 ± 5 mmHg, p = 0.01) and mean arterial pressure (Δ−2 ± 4 vs. Δ2 ± 6 mmHg, p = 0.04) were significantly decreased after 4 weeks of L-CIT compared to PL. Although not statistically significant (p = 0.07), cfPWV decreased after L-CIT supplementation by ~0.66 m/s. These findings suggest that L-CIT supplementation improves endothelial function and aortic BP via increased L-ARG availability.

Acute Citrulline Blunts Aortic Systolic Pressure during Exercise and Sympathoactivation in Hypertensive Postmenopausal Women.

PURPOSE: Hypertensive postmenopausal women (PMW) have exaggerated exercise systolic blood pressure (SBP) due to impaired functional sympatholysis. l-Citrulline (CIT) supplementation attenuates aortic SBP responses to cold pressor test (CPT)-induced vasoconstriction in young men. We hypothesized that acute CIT ingestion would attenuate aortic SBP and leg hemodynamic responses during exercise and CPT (EX + CPT). METHODS: Fifteen hypertensive PMW (61 ± 7 yr) were randomly assigned to consume either 6 g of CIT or placebo (PL) separated by a minimum 3-d washout phase. Brachial and aortic blood pressure, femoral artery blood flow (FBF), and vascular conductance (FVC) were measured at rest and during 5 min of unilateral plantarflexion exercise with a CPT applied during minutes 4 and 5. RESULTS: No differences between conditions were found in FBF, FVC, and brachial and aortic blood pressure at rest and during exercise alone. Changes in brachial SBP (CIT vs PL, 29 ± 12 vs 40 ± 10 mm Hg) and mean arterial pressure (CIT vs PL, 21 ± 10 vs 33 ± 11 mm Hg), and aortic SBP (CIT vs PL, 27 ± 11 vs 38 ± 9 mm Hg) and mean arterial pressure (CIT vs PL, 23 ± 9 vs 33 ± 11 mm Hg) to EX + CPT were lower in the CIT versus PL condition (P < 0.05). FBF, FVC, and functional sympatholysis (%ΔFVC) were not significantly different between conditions. CONCLUSIONS: Acute CIT ingestion attenuated aortic SBP response to exercise and cold-induced sympathetic activation that may prevent left ventricle overload in hypertensive PMW.

Combined L-Citrulline Supplementation and Slow Velocity Low-Intensity Resistance Training Improves Leg Endothelial Function, Lean Mass, and Strength in Hypertensive Postmenopausal Women.

Hypertension is highly prevalent in postmenopausal women. Endothelial dysfunction is associated with hypertension and the age-related decreases in muscle mass and strength. L-citrulline supplementation (CIT) and slow velocity low-intensity resistance training (SVLIRT) have improved vascular function, but their effect on muscle mass is unclear. We investigated whether combined CIT and SVLIRT (CIT + SVLIRT) would have additional benefits on leg endothelial function (superficial femoral artery flow-mediated dilation (sfemFMD)), lean mass (LM), and strength in hypertensive postmenopausal women. Participants were randomized to CIT (10 g/day, n = 13) or placebo (PL, n = 11) alone for 4 weeks and CIT + SVLIRT or PL + SVLIRT for another 4 weeks. sfemFMD, leg LM and muscle strength were measured at 0, 4, and 8 weeks. CIT increased sfemFMD after 4 weeks (CIT: Δ1.8 ± 0.3% vs. PL: Δ−0.2 ± 0.5%, p < 0.05) and 8 weeks (CIT + SVLIRT: Δ2.7 ± 0.5% vs. PL + SVLIRT: Δ−0.02 ± 0.5, p = 0.003). Leg LM improved after CIT + SVLIRT compared to PL + SVLIRT (Δ0.49 ± 0.15 kg vs. Δ0.07 ± 0.12 kg, p < 0.05). Leg curl strength increased greater with CIT + SVLIRT compared to PL + SVLIRT (Δ6.9 ± 0.9 kg vs. Δ4.0 ± 1.0 kg, p < 0.05). CIT supplementation alone improved leg endothelial function and when combined with SVLIRT has additive benefits on leg LM and curl strength in hypertensive postmenopausal women.

Risk of fracture in antidepressant users with concurrent use of benzodiazepines: A self-controlled case-series analysis.

OBJECTIVE: Despite the fracture risk associated with both antidepressant (AD) medication and benzodiazepines (BDZs), they are commonly prescribed simultaneously. However, studies elucidating the effects of concurrent use of BDZs and ADs on the risk fracture are scant. The objective of this study was to evaluate the risk of fracture associated with concurrent use of BDZs in AD users, using a self-controlled case-series analysis. METHODS: A self-controlled case-series analysis, in which the participants act as their own control, was conducted using the Korean National Health Insurance Service-National Sample Cohort database (2002-2015). We studied AD users who were prescribed BDZs and diagnosed with a fracture. The risk periods were subdivided into consecutive periods (1-30, 31-60, and > 60 days) after receiving a BDZ. A 2-week pre-exposure period and a 2-week post-exposure period were also included. The incidence rate ratio (IRR) was estimated after adjusting for age and use of co-medications. RESULTS: A total of 3020 patients were identified during the study period. There was an increased fracture risk in the first 30 days following BDZ use (IRR: 1.88, 95% confidence interval [CI] 1.66-2.12), in the 31-60-day period (1.73, 95% CI 1.48-2.02), and beyond the 60-day period (IRR: 1.68, 95% CI 1.47-1.91). The risks of fracture were greater in men and older patients. CONCLUSION: The concomitant use of BDZs and ADs was related to a significant increase in fracture risk. AD users should be aware of the fracture risk with concomitant BDZ use, especially for first-time BDZ users and for elderly patients.

Risk of Fractures in Older Adults with Chronic Non-cancer Pain Receiving Concurrent Benzodiazepines and Opioids: A Nested Case-Control Study.

OBJECTIVE: The aim of this study was to investigate the relationship between the concurrent use of benzodiazepines and opioids and the risk of fractures in older patients with chronic non-cancer pain. METHODS: Patients with osteoarthritis or low back pain (≥ 65 years of age) included in the Korean National Health Insurance Service-National Sample Cohort database of Korea and with an incident diagnosis of hip, humeral, or forearm fracture between 2011 and 2015 were identified as cases. For each case, four controls were matched for age (within 5 years), sex, and year of cohort entry. We estimated the adjusted odds ratios (aORs) and 95% confidence intervals (CIs) for fractures associated with concurrent use of benzodiazepines and opioids using a conditional logistic regression analysis, adjusting for comorbidities and comedications. RESULTS: The aOR (95% CI) for the concurrent use of benzodiazepines and opioids was 1.45 (1.22-1.71), compared with those of non-use within 30 days before the index date. The aOR was 1.65 (1.22-2.23) in patients who were continuously receiving benzodiazepines and were newly initiated with concurrent opioids. The aORs for concurrent use were 1.95 (1.39-2.74) and 1.27 (1.03-1.56) in the case of hip fracture and forearm fracture, respectively. CONCLUSION: The concurrent use of benzodiazepines and opioids was associated with an increased risk of fractures in older patients with chronic non-cancer pain. Therefore, patients continuously receiving benzodiazepines in whom opioids are newly initiated need careful monitoring, and such combined therapy should be limited to the shortest duration possible.

Change Point Analysis for Detecting Vaccine Safety Signals.

It is important to detect signals of abrupt changes in adverse event reporting in order to notice public safety concerns and take prompt action, especially for vaccines under national immunization programs. In this study, we assessed the applicability of change point analysis (CPA) for signal detection in vaccine safety surveillance. The performances of three CPA methods, namely Bayesian change point analysis, Taylor's change point analysis (Taylor-CPA), and environmental time series change point detection (EnvCpt), were assessed via simulated data with assumptions for the baseline number of events and degrees of change. The analysis was validated using the Korea Adverse Event Reporting System (KAERS) database. In the simulation study, the Taylor-CPA method exhibited better results for the detection of a change point (accuracy of 96% to 100%, sensitivity of 7% to 100%, specificity of 98% to 100%, positive predictive value of 25% to 85%, negative predictive value of 96% to 100%, and balanced accuracy of 53% to 100%) than the other two CPA methods. When the CPA methods were applied to reports of syncope or dizziness following human papillomavirus (HPV) immunization in the KAERS database, Taylor-CPA and EnvCpt detected a change point (Q2/2013), which was consistent with actual public safety concerns. CPA can be applied as an efficient tool for the early detection of vaccine safety signals.