Comparative effectiveness of abatacept versus TNF inhibitors in rheumatoid arthritis patients who are ACPA and shared epitope positive.

BACKGROUND: The HLA-DRB1 shared epitope (SE) is a risk factor for the development of rheumatoid arthritis (RA) and the production of anti-citrullinated protein antibodies (ACPAs) in RA patients. Our objective was to examine the real-world effectiveness of abatacept versus tumor necrosis factor inhibitors (TNFi) in patients with RA who were SE and anti-cyclic citrullinated peptide antibody (anti-CCP3) positive. METHODS: Abatacept or TNFi initiators who were SE + and anti-CCP3+ (> 20 U/mL) at or prior to treatment and had moderate or high CDAI score (> 10) at initiation were identified. The primary outcome was mean change in CDAI score over six months. Analyses were conducted in propensity score (PS)-trimmed and -matched populations overall and a biologic-experienced subgroup. Mixed-effects models were used. RESULTS: In the overall PS-trimmed (abatacept, n = 170; TNFi, n = 157) and PS-matched cohorts (abatacept, n = 111; TNFi, n = 111), there were numerically greater improvements in mean change in CDAI between abatacept and TNFi but were not statistically significant. Similar trends were seen for biologic-experienced patients, except that statistical significance was reached for mean change in CDAI in the PS-trimmed cohort (abatacept, 12.22 [95% confidence interval (95%CI) 10.13 to 14.31]; TNFi, 9.28 [95%CI 7.08 to 11.48]; p = 0.045). CONCLUSION: In this real world cohort, there were numerical improvements in efficacy outcomes with abatacept over TNFi in patients with RA who were SE + and ACPA+, similar to results from a clinical trial population The only statistically significant finding after adjusting for covariates was greater improvement in CDAI with abatacept versus TNFi in the bio-experienced PS-trimmed cohort..

Comparative effectiveness of abatacept versus TNF inhibitors in rheumatoid arthritis patients who are ACPA and shared epitope positive

Abstract Background The HLA-DRB1 shared epitope (SE) is a risk factor for the development of rheumatoid arthritis (RA) and the production of anti-citrullinated protein antibodies (ACPAs) in RA patients. Our objective was to examine the real-world effectiveness of abatacept versus tumor necrosis factor inhibitors (TNFi) in patients with RA who were SE and anti-cyclic citrullinated peptide antibody (anti-CCP3) positive. Methods Abatacept or TNFi initiators who were SE + and anti-CCP3+ (> 20 U/mL) at or prior to treatment and had moderate or high CDAI score (> 10) at initiation were identified. The primary outcome was mean change in CDAI score over six months. Analyses were conducted in propensity score (PS)-trimmed and -matched populations overall and a biologic-experienced subgroup. Mixed-effects models were used. Results In the overall PS-trimmed (abatacept, n = 170; TNFi, n = 157) and PS-matched cohorts (abatacept, n = 111; TNFi, n = 111), there were numerically greater improvements in mean change in CDAI between abatacept and TNFi but were not statistically significant. Similar trends were seen for biologic-experienced patients, except that statistical significance was reached for mean change in CDAI in the PS-trimmed cohort (abatacept, 12.22 [95% confidence interval (95%CI) 10.13 to 14.31]; TNFi, 9.28 [95%CI 7.08 to 11.48]; p = 0.045). Conclusion In this real world cohort, there were numerical improvements in efficacy outcomes with abatacept over TNFi in patients with RA who were SE + and ACPA+, similar to results from a clinical trial population The only statistically significant finding after adjusting for covariates was greater improvement in CDAI with abatacept versus TNFi in the bio-experienced PS-trimmed cohort. .

Disease burden among patients with atopic dermatitis treated with systemic therapy for 4-12 months: results from the CorEvitas Atopic Dermatitis Registry.

BACKGROUND: Real-world data on the effectiveness of systemic therapy in atopic dermatitis (AD) are limited. METHODS: Adult patients with AD in the CorEvitas AD registry (2020-2021) who received systemic therapies for 4-12 months prior to enrollment were included based on disease severity: body surface area (BSA) 0%-9% and BSA ≥10%. Demographics, clinical characteristics, and outcomes were assessed using descriptive statistics. Pairwise effect sizes (ES) were used to compare BSA groups. RESULTS: The study included 308 patients (BSA 0%-9%: 246 [80%]; BSA ≥10%: 62 [20%]). Despite systemic therapy, both BSA groups reported the use of additional topical therapy and the presence of lesions at difficult locations. Moderate-to-severe AD (vIGA-AD®) was reported by 11% (BSA 0%-9%) and 66% (BSA ≥10%; ES = 0.56) of patients. Mean disease severity scores: total BSA (2% and 22%; ES = 3.59), EASI (1.1 and 11.1; ES = 2.60), and SCORAD (12.1 and 38.0; ES = 1.99). Mean scores for PROs: DLQI (3.7 and 7.5; ES = 0.75), and peak pruritus (2.2 and 4.5; ES = 0.81). Inadequate control of AD was seen in 27% and 53% of patients (ES = 0.23). CONCLUSIONS: Patients with AD experience a high disease burden despite systemic treatment for 4-12 months. This study provides potential evidence of suboptimal treatment and the need for additional effective treatment options for AD.

This real-world study assessed clinical characteristics and overall disease burden in adult patients with atopic dermatitis (AD) who were receiving systemic therapy for 4­12 months.Patients reported greater involvement of back and anterior trunk, and lesions at difficult locations. Irrespective of body surface area involvement, patients continued to experience inadequate control of AD, varied disease severity, and impact on quality of life.The study provides potential evidence of suboptimal treatment and the need for effective treatment options for the management of AD. Besides clinical outcomes, treating dermatologists and dermatology practitioners should include patient-reported outcomes in routine clinical care to determine the best treatment options for their patients.

A Real-World Effectiveness Study Using a Mobile Application to Evaluate Early Outcomes with Upadacitinib in Rheumatoid Arthritis.

INTRODUCTION: The impact of upadacitinib on rheumatoid arthritis (RA) symptoms was evaluated during the first 12 weeks of treatment via patient-reported outcomes (PROs) using a mobile health application (app). METHODS: Participating rheumatologists from the CorEvitas RA Registry (prospective, observational cohort) recruited patients with RA initiating upadacitinib treatment. A modified version of the ArthritisPower® app was used to collect PROs, including the Routine Assessment of Patient Index Data 3 (RAPID3), duration of morning joint stiffness, and the Patient-Reported Outcomes Measurement Information System (PROMIS)-Fatigue 7a Short Form at baseline and weeks 1-4, 8, and 12. RAPID3 responses over time were assessed using Kaplan-Meier estimation to determine the proportion of patients achieving disease activity improvement and minimal clinically important difference (MCID). Results were analyzed for all patients initiating upadacitinib and a subsample of TNF inhibitor (TNFi)-experienced patients with moderate to severe disease at baseline. RESULTS: A total of 103 patients with RA initiating upadacitinib (62.1% TNFi-experienced) were included. At week 12, 53 patients (51.4%) completed the study and provided PRO data via the app. Among all patients, improvements in RAPID3, pain, morning stiffness, and fatigue were observed at week 1 and were maintained or further improved through week 12. At week 12, 37.5% of patients achieved RAPID3 low disease activity. Starting at week 1, improvements in RAPID3 disease activity category (19.4% of patients) and achievement of MCID (16.3%) were reported, with nearly 50% of patients achieving these outcomes by week 4 (RAPID3 category: 48.8%; MCID: 49.2%) and 60% by week 12 (RAPID3 category: 59.6%; MCID: 59.8%). TNFi-experienced patients generally reported similar outcomes. Patient-reported medication convenience and compliance were generally high. CONCLUSIONS: In this real-world cohort of patients with RA, treatment with upadacitinib was associated with early and significant improvement in RAPID3, pain, morning stiffness, and fatigue regardless of prior TNFi experience. Clinically meaningful improvement in RAPID3 patient-reported disease activity was observed as early as week 1, with continued improvement reported through week 12.

Association Between Baseline Anti-cyclic Citrullinated Peptide Antibodies and 6-Month Clinical Response Following Abatacept or TNF Inhibitor Treatment: A Real-World Analysis of Biologic-Experienced Patients with RA.

INTRODUCTION: Anti-cyclic citrullinated peptide (anti-CCP) antibodies are associated with poor prognosis in patients with rheumatoid arthritis (RA). Previous data from randomized controlled trials and clinical practice have shown anti-CCP-positive (+) patients had a better response to treatment with abatacept or tumor necrosis factor inhibitor (TNFi) treatment than those who were anti-CCP negative. This study assessed the association between baseline anti-CCP2 [a surrogate for anti-citrullinated protein antibody (ACPA)] concentration and 6-month treatment responses to abatacept or TNFi in patients with RA. METHODS: This real-world analysis included biologic-experienced patients from CERTAIN (Comparative Effectiveness Registry to study Therapies for Arthritis and Inflammatory CoNditions) who initiated abatacept or TNFi, had prior biologic disease-modifying drug exposure and baseline anti-CCP2 concentration/serostatus and serum samples (baseline and 6 months). Baseline demographics and disease characteristics were compared. Change from baseline at 6 months in Clinical Disease Activity Index (CDAI) score and patient-reported outcomes [PROs: pain, fatigue, patient global assessment (PtGA), modified Health Assessment Questionnaire (mHAQ) score], by baseline anti-CCP2 quartile and binary cut-off (> 10-250 and > 250 U/ml), were evaluated separately in the abatacept and TNFi groups using a linear regression model adjusted for age, sex, CDAI/PROs, comorbidity index, and methotrexate use. RESULTS: Included were 138 abatacept and 137 TNFi initiators who were anti-CCP2+. At baseline, there were significant differences between anti-CCP2 quartiles and mean CDAI, swollen joint count 28, C-reactive protein (CRP), Disease Activity Score 28 (CRP), rheumatoid factor (RF), mHAQ and physician global assessment among abatacept initiators, and in mean RF, mHAQ, and PtGA among TNFi initiators. Among abatacept (but not TNFi) initiators, CDAI numerically improved (p = 0.208) and PROs significantly improved (p < 0.05) with increasing baseline anti-CCP2. CONCLUSIONS: In patients treated with abatacept, not TNFi, higher anti-CCP2 concentrations at baseline were associated with numerically greater improvements in CDAI and significant improvements in PROs after 6 months. CLINICAL TRIAL NUMBER: NCT01625650.

Rheumatoid arthritis (RA) is an autoimmune disease ­ a disease that causes the immune system to attack an individual's own body. A key feature of RA is the presence of proteins called autoantibodies in the blood. While antibodies help protect against external threats such as viruses, autoantibodies mistakenly target an individual's own tissues and organs. One type of autoantibody often found in patients with RA is called anti-cyclic citrullinated peptide (anti-CCP). Studies have shown that patients with RA with anti-CCP antibodies may experience worse physical symptoms, function, disease activity, and outcomes than patients with RA without anti-CCP antibodies. Clinical trials suggest that some drugs may be more effective than others at managing symptoms of RA in patients who have anti-CCP in their blood. It is important to study this further to give doctors a sense of how patients respond to drug therapy in the 'real world', without clinical trial constraints. This study examined real-world patient data to see whether the presence of anti-CCP in patients' blood impacted how their RA symptoms responded to treatment with two different drugs: abatacept or a tumor necrosis factor inhibitor (TNFi). This study found that patients with higher levels of anti-CCP at the start of the study, compared with patients with lower levels of anti-CCP, experienced less disease activity and greater improvement in physical function after 6 months of treatment with abatacept. The study found no relationship between anti-CCP and treatment response after 6 months of treatment with a TNFi.

Potential Beneficial Effects of Dietary Protein Supplementation and Exercise on Functional Capacity in a Pilot Study of Individuals with Heart Failure with Preserved Ejection Fraction.

Approximately half of heart failure patients in the US have heart failure with preserved ejection fraction (HFpEF). HFpEF impairs physical performance and thus reduces quality of life. Increasing dietary protein intake can increase lean body mass and physical performance in healthy elderly individuals, but the effect of a high-quality protein supplement, with or without a structured exercise program, has not been investigated in HFpEF patients. Twenty-three obese elderly HFpEF patients with grade 1 or 2 diastolic dysfunction were randomized into three groups: control, protein supplementation alone, and protein plus exercise. Protein supplementation involved providing sufficient whey protein so that total intake was 1.2 g protein/kg/day. The exercise intervention was 2 days of hydrotherapy and 1 day of gym sessions per week under supervision of a fitness expert. Physical parameters and functional tests were performed at baseline and at 12 weeks. Protein supplementation alone failed to improve physical performance. However, when combined with light exercise, there was significant improvement in some (6-minute walk, 10 m walking speed, quadriceps strength), but not all, physical function measurements. The results of this pilot study suggest that further exploration of potential interactive effects between protein supplementation and light exercise in individuals with HFpEF is warranted.

Protein intake distribution pattern does not affect anabolic response, lean body mass, muscle strength or function over 8 weeks in older adults: A randomized-controlled trial.

BACKGROUND & AIMS: In our recent acute metabolic study, we found no differences in the anabolic response to differing patterns of dietary protein intake. To confirm this in a chronic study, we investigated the effects of protein distribution pattern on functional outcomes and protein kinetics in older adults over 8 weeks. METHODS: To determine chronic effects of protein intake pattern at 1.1 g protein/kg/day in mixed meals on lean body mass (LBM), functional outcomes, whole body protein kinetics and muscle protein fractional synthesis rate (MPS) over 8-week respective dietary intervention, fourteen older subjects were randomly divided into either EVEN or UNVEN group. The UNEVEN group (n = 7) consumed the majority of dietary protein with dinner (UNEVEN, 15/20/65%; breakfast, lunch, dinner), while the EVEN group (n = 7) consumed dietary protein evenly throughout the day (EVEN: 33/33/33%). RESULTS: We found no significant differences in LBM, muscle strength, and other functional outcomes between EVEN and UNEVEN before and after 8-week intervention. Consistent with these functional outcomes, we did not find significant differences in the 20-h integrated whole body protein kinetics [net protein balance (NB), protein synthesis (PS), and breakdown (PB)] above basal states and MPS between EVEN and UNEVEN intake patterns. CONCLUSIONS: We conclude that over an 8-week intervention period, the protein intake distribution pattern in mixed meals does not play an important role in determining anabolic response, muscle strength, or functional outcomes. This trial is registered at https://ClinicalTrials.gov as NCT02787889.

Feasibility of Conducting a 6-month long Home-based Exercise Program with Protein Supplementation in Elderly Community-dwelling Individuals with Heart Failure.

OBJECTIVE: Cardiac cachexia is a condition associated with heart failure, particularly in the elderly, and is characterized by loss of muscle mass with or without the loss of fat mass. Approximately 15% of elderly heart failure patients will eventually develop cardiac cachexia; such a diagnosis is closely associated with high morbidity and increased mortality. While the mechanism(s) involved in the progression of cardiac cachexia is incompletely established, certain factors appear to be contributory. Dietary deficiencies, impaired bowel perfusion, and metabolic dysfunction all contribute to reduced muscle mass, increased muscle wasting, increased protein degradation, and reduced protein synthesis. Thus slowing or preventing the progression of cardiac cachexia relies heavily on dietary and exercise-based interventions in addition to standard heart failure treatments and medications. METHODS: The aim of the present study was to test the feasibility of an at-home exercise and nutrition intervention program in a population of elderly with heart failure, in an effort to determine whether dietary protein supplementation and increased physical activity may slow the progression, or prevent the onset, of cardiac cachexia. Frail elderly patients over the age of 55 with symptoms of heart failure from UAMS were enrolled in one of two groups, intervention or control. To assess the effect of protein supplementation and exercise on the development of cardiac cachexia, data on various measures of muscle quality, cardiovascular health, mental status, and quality of life were collected and analyzed from the two groups at the beginning and end of the study period. RESULTS: More than 50% of those who were initially enrolled actually completed the 6-month study. While both groups showed some improvement in their study measures, the protein and exercise group showed a greater tendency to improve than the control group by the end of the six months. CONCLUSION: These findings suggest that with a larger cohort, this intervention may show significant positive effects for elderly patients who are at risk of developing cardiac cachexia.

Hydration health literacy in the elderly.

BACKGROUND: Inadequate hydration in the elderly is associated with increased morbidity and mortality. However, few studies have addressed the knowledge of elderly individuals regarding hydration in health and disease. Gaps in health literacy have been identified as a critical component in health maintenance, and promoting health literacy should improve outcomes related to hydration associated illnesses in the elderly. METHODS: We administered an anonymous survey to community-dwelling elderly (n = 170) to gauge their hydration knowledge. RESULTS: About 56% of respondents reported consuming >6 glasses of fluid/day, whereas 9% reported drinking ≤3 glasses. About 60% of respondents overestimated the amount of fluid loss at which moderately severe dehydration symptoms occur, and 60% did not know fever can cause dehydration. Roughly 1/3 were not aware that fluid overload occurs in heart failure (35%) or kidney failure (32%). A majority of respondents were not aware that improper hydration or changes in hydration status can result in confusion, seizures, or death. CONCLUSIONS: Overall, our study demonstrated that there were significant deficiencies in hydration health literacy among elderly. Appropriate education and attention to hydration may improve quality of life, reduce hospitalizations and the economic burden related to hydration-associated morbidity and mortality.

Association between process measures and mortality in individuals with opioid use disorders.

BACKGROUND: Individuals with opioid use disorders have high rates of mortality relative to the general population. The relationship between treatment process and mortality is unknown. AIM: To examine the association between 7 process measures and 12- and 24-month mortality. METHODS: Retrospective cohort study of patients with opioid use disorders who received care from the Veterans Administration between October 2006 and September 2007. Logistic regression models were used to examine the association between 12 and 24-month mortality and 7 patient-level process measures, while risk-adjusting for patient characteristics. Process measures included quarterly physician visits, any opioid use disorder pharmacotherapy, continuous pharmacotherapy, psychosocial treatment, Hepatitis B/C and HIV screening, and no prescriptions for benzodiazepines or opioids. We conducted sensitivity analyses to examine the robustness of our findings to an unobserved confounder. RESULTS: Among individuals with opioid use disorders, not being prescribed opioids or benzodiazepines, receipt of any psychosocial treatment and quarterly physician visits were significantly associated with lower mortality at both 12 and 24 months, but Hepatitis and HIV screening, and measures related to opioid use disorder pharmacotherapy were not. Sensitivity analyses indicated that the difference in the prevalence of an unobserved confounder would have to be unrealistically large given the observed data, or there would need to be a large effect of the confounder, to render these findings non-significant. CONCLUSIONS AND RELEVANCE: This is the first study to show an association between process measures and mortality in patients with opioid use disorders and provides initial evidence for their use as quality measures.

Association Between Quality Measures and Perceptions of Care Among Patients With Substance Use Disorders.

OBJECTIVE: This study evaluated whether eight quality measures assessing care for patients with a substance use disorder were associated with patient perceptions of their care, including perceived improvement and global rating of behavioral health care. METHODS: Secondary data analyses were conducted of administrative and patient survey data collected as part of a national evaluation of Veterans Health Administration (VHA) mental health and substance use services. Data for patients who received care for substance use disorders during October 2006-September 2007 paid for by the VHA and who participated in a telephone interview about their care (N=2,074) were included. Measures of patient perceptions of care included perceived improvement and global rating of behavioral health care. Eight quality measures based on administrative data assessed initiation and engagement in substance use disorder care, receipt of psychotherapy or psychosocial treatment, and follow-up after hospitalization. Regression models were conducted in which each quality measure predicted each outcome, with analyses adjusting for patient characteristics and functioning. RESULTS: Treatment engagement, two measures of psychotherapy receipt, and psychosocial treatment were significantly associated with perceived improvement, whereas treatment initiation and follow-up after hospitalization (seven and 30 days) were not. Psychotherapy receipt and follow-up after hospitalization (seven and 30 days) were significantly associated with global rating of behavioral health care. CONCLUSIONS: Some quality measures assessing care for substance use disorders were significantly associated with patient perceptions of care. Results provide additional support for these quality measures and suggest that patient perceptions of care are an important outcome in assessing care.

Association Between Process-Based Quality Indicators and Mortality for Patients With Substance Use Disorders.

OBJECTIVE: Substance use disorders (SUDs) are associated with elevated rates of mortality. Little is known about whether receiving appropriate care is associated with lower mortality for patients with SUDs. This study examined the association between the receipt of care for SUDs and subsequent 12- and 24-month mortality. METHOD: This was a retrospective cohort study of veterans who received care for SUDs paid for by the Veterans Health Administration during October 2006- September 2007 (n = 339,966). Logistic regressions were used to examine the association between quality indicators measuring receipt of care and mortality while controlling for patient characteristics and facility service area. RESULTS: There were four quality indicators: SUD treatment initiation, SUD treatment engagement, SUD-related psychosocial treatment, and SUD-related psychotherapy. Outcomes measured were mortality 12 and 24 months after the end of the observation period, through September 2009. Receipt of indicated care ranged from 26.5% to 58.6%, and 12- and 24-month mortality rates were 3% and 6%, respectively. Adjusted odds ratios [95% CI] of 12-month mortality by indicator were: initiation, 0.86 [0.79, 0.93]; engagement, 0.65 [0.58, 0.74]; psychosocial treatment, 0.88 [0.84, 0.92]; and psychotherapy, 0.84 [0.79, 0.89]. For the 24-month mortality outcome, adjusted odds ratios were: initiation, 0.88 [0.84, 0.93]; engagement, 0.78 [0.71, 0.85]; psychosocial treatment, 0.91 [0.88, 0.94]; and psychotherapy, 0.87 [0.83, 0.91]. Results were similar when controlling for facility service area. CONCLUSIONS: Receiving appropriate care is associated with lower mortality for patients with SUDs. Significant overall and within-facility service area associations of quality indicators and mortality support their use in encouraging providers to deliver the indicated care. These indicators should be prioritized above others lacking comparably strong process-outcome associations.

Enteral tube feeding for individuals with cystic fibrosis: Cystic Fibrosis Foundation evidence-informed guidelines.

Nutrition is integral to the care of individuals with cystic fibrosis (CF). Better nutritional status is associated with improved pulmonary function. In some individuals with CF, enteral tube feeding can be useful in achieving optimal nutritional status. Current nutrition guidelines do not include detailed recommendations for enteral tube feeding. The Cystic Fibrosis Foundation convened an expert panel to develop enteral tube feeding recommendations based on a systematic review of the evidence and expert opinion. These guidelines address when to consider enteral tube feeding, assessment of confounding causes of poor nutrition in CF, preparation of the patient for placement of the enteral feeding tube, management of the tube after placement and education about enteral feeding. These recommendations are intended to guide the CF care team, individuals with CF, and their families through the enteral tube feeding process.

Association Between Quality Measures and Mortality in Individuals With Co-Occurring Mental Health and Substance Use Disorders.

IMPORTANCE: Individuals with co-occurring mental and substance use disorders have increased rates of mortality relative to the general population. The relationship between measures of treatment quality and mortality for these individuals is unknown. OBJECTIVE: To examine the association between 5 quality measures and 12- and 24-month mortality. DESIGN, SETTING AND PARTICIPANTS: Retrospective cohort study of patients with co-occurring mental illness (schizophrenia, bipolar disorder, post-traumatic stress disorder and major depression) and substance use disorders who received care for these disorders paid for by the Veterans Administration between October 2006 and September 2007. Logistic regression models were used to examine the association between 12 and 24-month mortality and 5 patient-level quality measures, while risk-adjusting for patient characteristics. Quality measures included receipt of psychosocial treatment, receipt of psychotherapy, treatment initiation and engagement, and a measure of continuity of care. We also examined the relationship between number of diagnosis-related outpatient visits and mortality, and conducted sensitivity analyses to examine the robustness of our findings to an unobserved confounder. MAIN OUTCOMES MEASURE: Mortality 12 and 24 months after the end of the observation period. RESULTS: All measures except for treatment engagement at 24 months were significantly associated with lower mortality at both 12 and 24 months. At 12 months, receiving any psychosocial treatment was associated with a 21% decrease in mortality; psychotherapy, a 22% decrease; treatment initiation, a 15% decrease, treatment engagement, a 31% decrease; and quarterly, diagnosis-related visits a 28% decrease. Increasing numbers of visits were associated with decreasing mortality. Sensitivity analyses indicated that the difference in the prevalence of an unobserved confounder would have to be unrealistically large given the observed data, or there would need to be a large effect of an unobserved confounder, to render these findings non-significant. CONCLUSIONS AND RELEVANCE: This is the first study to show an association between process-based quality measures and mortality in patients with co-occurring mental and substance use disorders, and provides initial support for the predictive validity of the measures. By devising strategies to improve performance on these measures, health care systems may be able to decrease the mortality of this vulnerable population.

The anabolic response to a meal containing different amounts of protein is not limited by the maximal stimulation of protein synthesis in healthy young adults.

We have determined whole body protein kinetics, i.e., protein synthesis (PS), breakdown (PB), and net balance (NB) in human subjects in the fasted state and following ingestion of ~40 g [moderate protein (MP)], which has been reported to maximize the protein synthetic response or ~70 g [higher protein (HP)] protein, more representative of the amount of protein in the dinner of an average American diet. Twenty-three healthy young adults who had performed prior resistance exercise (X-MP or X-HP) or time-matched resting (R-MP or R-HP) were studied during a primed continuous infusion of l-[(2)H5]phenylalanine and l-[(2)H2]tyrosine. Subjects were randomly assigned into an exercise (X, n = 12) or resting (R, n = 11) group, and each group was studied at the two levels of dietary protein intake in random order. PS, PB, and NB were expressed as increases above the basal, fasting values (mg·kg lean body mass(-1)·min(-1)). Exercise did not significantly affect protein kinetics and blood chemistry. Feeding resulted in positive NB at both levels of protein intake: NB was greater in response to the meal containing HP vs. MP (P < 0.00001). The greater NB with HP was achieved primarily through a greater reduction in PB and to a lesser extent stimulation of protein synthesis (for all, P < 0.0001). HP resulted in greater plasma essential amino acid responses (P < 0.01) vs. MP, with no differences in insulin and glucose responses. In conclusion, whole body net protein balance improves with greater protein intake above that previously suggested to maximally stimulating muscle protein synthesis because of a simultaneous reduction in protein breakdown.

Acute ingestion of citrulline stimulates nitric oxide synthesis but does not increase blood flow in healthy young and older adults with heart failure.

To determine if age-associated vascular dysfunction in older adults with heart failure (HF) is due to insufficient synthesis of nitric oxide (NO), we performed two separate studies: 1) a kinetic study with a stable isotope tracer method to determine in vivo kinetics of NO metabolism, and 2) a vascular function study using a plethysmography method to determine reactive hyperemic forearm blood flow (RH-FBF) in older and young adults in the fasted state and in response to citrulline ingestion. In the fasted state, NO synthesis (per kg body wt) was ∼ 50% lower in older vs. young adults and was related to a decreased rate of appearance of the NO precursor arginine. Citrulline ingestion (3 g) stimulated de novo arginine synthesis in both older [6.88 ± 0.83 to 35.40 ± 4.90 µmol · kg body wt(-1) · h(-1)] and to a greater extent in young adults (12.02 ± 1.01 to 66.26 ± 4.79 µmol · kg body wt(-1) · h(-1)). NO synthesis rate increased correspondingly in older (0.17 ± 0.01 to 2.12 ± 0.36 µmol · kg body wt(-1) · h(-1)) and to a greater extent in young adults (0.36 ± 0.04 to 3.57 ± 0.47 µmol · kg body wt(-1) · h(-1)). Consistent with the kinetic data, RH-FBF in the fasted state was ∼ 40% reduced in older vs. young adults. However, citrulline ingestion (10 g) failed to increase RH-FBF in either older or young adults. In conclusion, citrulline ingestion improved impaired NO synthesis in older HF adults but not RH-FBF, suggesting that factors other than NO synthesis play a role in the impaired RH-FBF in older HF adults, and/or it may require a longer duration of supplementation to be effective in improving RH-FBF.

Quantity of dietary protein intake, but not pattern of intake, affects net protein balance primarily through differences in protein synthesis in older adults.

To examine whole body protein turnover and muscle protein fractional synthesis rate (MPS) following ingestions of protein in mixed meals at two doses of protein and two intake patterns, 20 healthy older adult subjects (52-75 yr) participated in one of four groups in a randomized clinical trial: a level of protein intake of 0.8 g (1RDA) or 1.5 g·kg(-1)·day(-1) (∼2RDA) with uneven (U: 15/20/65%) or even distribution (E: 33/33/33%) patterns of intake for breakfast, lunch, and dinner over the day (1RDA-U, 1RDA-E, 2RDA-U, or 2RDA-E). Subjects were studied with primed continuous infusions of L-[(2)H5]phenylalanine and L-[(2)H2]tyrosine on day 4 following 3 days of diet habituation. Whole body protein kinetics [protein synthesis (PS), breakdown, and net balance (NB)] were expressed as changes from the fasted to the fed states. Positive NB was achieved at both protein levels, but NB was greater in 2RDA vs. 1RDA (94.8 ± 6.0 vs. 58.9 ± 4.9 g protein/750 min; P = 0.0001), without effects of distribution on NB. The greater NB was due to the higher PS with 2RDA vs. 1RDA (15.4 ± 4.8 vs. -18.0 ± 8.4 g protein/750 min; P = 0.0018). Consistent with PS, MPS was greater with 2RDA vs. 1RDA, regardless of distribution patterns. In conclusion, whole body net protein balance was greater with protein intake above recommended dietary allowance (0.8 g protein·kg(-1)·day(-1)) in the context of mixed meals, without demonstrated effects of protein intake pattern, primarily through higher rates of protein synthesis at whole body and muscle levels.