Recommendations and guidelines of integrative medicine for COVID-19 care: The APEC project outcome.

This article - Recommendations and Guidelines of Integrative Medicine (IM) for COVID-19 Care - was one of the outcomes from an Asia-Pacific Economic Cooperation (APEC) Project (Integrative Medicine (IM) and COVID -19 Care) during the time between May 2022 and March 2023. With the efforts from care providers, researchers, health policy makers and healthcare administrative leaders among APEC economies, the purpose of this file was to provide comprehensive IM systems for COVID-19 care as recommendations and suggestive guidelines including care methods, tools, procedures, symptom conditions and targets selections, and points need to be considered during care applications. All cited COVID-19 care practices have confirmed their efficacy and usefulness either used alone or combined with conventional medicine. This article provides current useful medical information on IM for COVID-19 care which could benefit APEC economies and world health communities on their healthcare system.

Polycyclic aromatic hydrocarbons and risk of rheumatoid arthritis: a cross-sectional analysis of the National Health and Nutrition Examination Survey, 2007-2016.

OBJECTIVE: While there are several well-established environmental risk factors for rheumatoid arthritis (RA), a paucity of evidence exists linking environmental toxicants with RA prevalence. We aimed to examine the associations between various environmental toxicants and RA among adults in the U.S. general population while adjusting for non-heritable risk factors. DESIGN: Cross-sectional study. SETTING: National Health and Nutrition Examination Survey conducted from 2007 to 2016. PARTICIPANTS: The study included 21 987 adult participants (no RA: 20 569; RA: 1418). Participants were excluded (n=7214) if they did not answer questions related to self-reporting of RA, had another or unknown type of arthritis, or did not have interview or biospecimen data. PRIMARY AND SECONDARY OUTCOME MEASURES: Association between individual toxicants and body burden scores for polycyclic aromatic hydrocarbons (PAH), phthalates and plasticisers (PHTHTEs) metabolites or volatile organic compounds (VOCs) and participant self-reported RA based on multivariable logistic regression models while adjusting for age, sex, urine creatinine, body mass index, smoking, race, education, family poverty income ratio, any vigorous or moderate activity and dietary fibre. RESULTS: While increased prevalence of RA was observed in participants with the highest quartile of various individual PAHs, only 1-hydroxynaphthalene (OR: 1.8 (1.1 to 3.1); p=0.020) remained associated in a fully adjusted model. PAH body burden was found to be associated with RA (Q4 vs Q1, OR: 2.2 (1.09 to 4.2); p=0.028) in a fully adjusted model. Interestingly, after accounting for PAH body burden, smoking was not associated with RA (OR: 1.4 (0.89 to 2.3); p=0.13). A mediation analysis demonstrated that PAH body burden accounted for 90% of the total effect of smoking on RA. PHTHTE and VOC metabolites were not associated with RA in fully adjusted models. CONCLUSIONS AND RELEVANCE: PAHs are associated with RA prevalence, mediate the majority of the effects of smoking on RA, and are associated with RA independent of smoking status.

Patient-Reported Outcomes and the Patient-Reported Outcome Measurement Information System of Functional Medicine Care and Research.

The functional medicine model of care is focused on patient-centered rather than disease-centered care. Patient-centered care incorporates the patient's voice or experience of their condition alongside conventional biological factors to provide a "more complete" account of health. PROMIS Global, an NIH-validated patient-reported outcome (PRO) measure that evaluates the health-related quality of life, can be incorporated within the functional medicine model of care to evaluate self-reported physical, mental and social well-being across various conditions and guide personalized management strategies. Proper incorporation of PROMIS Global into clinical care and research is warranted to expand the available evidence base.

A nutrition and lifestyle-focused shared medical appointment in a resource-challenged community setting: a mixed-methods study.

BACKGROUND: In order to address disparities in preventable chronic diseases, we adapted a nutrition and lifestyle-focused shared medical appointment (SMA) program to be delivered in an underserved community setting. The objective was to evaluate a community-based nutrition and lifestyle-focused SMA as it relates to acceptability and health and behavior-related outcomes. METHODS: A mixed-methods study was performed to evaluate pre-post changes in wellness indices, biometrics, self-efficacy, and trust in medical researchers as part of a community-based SMA. To understand program acceptability including barriers and facilitators for implementation and scalability, we conducted two participant focus groups and five stakeholder interviews and used content analysis to determine major themes. RESULTS: Fifteen participants attended 10 weekly sessions. The majority were older adult, African American women. There were pre-post improvements in mean [SD] systolic (-10.5 [7.7] mmHg, p = 0.0001) and diastolic (-4.7 [6.7] mmHg, p = 0.17) blood pressures and weight (-5.7 [6.3] pounds, p = 0.003) at 3 months though these were not significant at 6 months. More individuals reported improvements in health status, daily fruit and vegetable intake, and sleep than at baseline. There were no significant pre-post changes in other wellness indices, self-efficacy, trust in medical researchers, hemoglobin A1c, insulin, or LDL cholesterol. Participants discussed positive health changes as a result of the SMA program, program preferences, and facilitators and barriers to continuing program recommendations in focus groups. SMA implementation was facilitated by clinical staff who adjusted content to a low health literacy group and partnership with a trusted community partner. Sustainability barriers include heavy personnel time and in-kind resources to deliver the program. CONCLUSIONS: Nutrition and lifestyle-focused SMAs in a resource-challenged community setting may be an acceptable intervention for underserved patients.

Patient outcomes and costs associated with functional medicine-based care in a shared versus individual setting for patients with chronic conditions: a retrospective cohort study.

OBJECTIVE: To compare outcomes and costs associated with functional medicine-based care delivered in a shared medical appointment (SMA) to those delivered through individual appointments. DESIGN: A retrospective cohort study was performed to assess outcomes and cost to deliver care to patients in SMAs and compared with Propensity Score (PS)-matched patients in individual appointments. SETTING: A single-centre study performed at Cleveland Clinic Center for Functional Medicine. PARTICIPANTS: A total of 9778 patients were assessed for eligibility and 7323 excluded. The sample included 2455 patients (226 SMAs and 2229 individual appointments) aged ≥18 years who participated in in-person SMAs or individual appointments between 1 March 2017 and 31 December 2019. Patients had a baseline Patient-Reported Outcome Measurement Information System (PROMIS) Global Physical Health (GPH) score and follow-up score at 3 months. Patients were PS-matched 1:1 with 213 per group based on age, sex, race, marital status, income, weight, body mass index, blood pressure (BP), PROMIS score and functional medicine diagnostic category. PRIMARY AND SECONDARY OUTCOME MEASURES: The primary outcome was change in PROMIS GPH at 3 months. Secondary outcomes included change in PROMIS Global Mental Health (GMH), biometrics, and cost. RESULTS: Among 213 PS-matched pairs, patients in SMAs exhibited greater improvements at 3 months in PROMIS GPH T-scores (mean difference 1.18 (95% CI 0.14 to 2.22), p=0.03) and PROMIS GMH T-scores (mean difference 1.78 (95% CI 0.66 to 2.89), p=0.002) than patients in individual appointments. SMA patients also experienced greater weight loss (kg) than patients in individual appointments (mean difference -1.4 (95% CI -2.15 to -0.64), p<0.001). Both groups experienced a 5.5 mm Hg improvement in systolic BP. SMAs were also less costly to deliver than individual appointments. CONCLUSION: SMAs deliver functional medicine-based care that improves outcomes more than care delivered in individual appointments and is less costly to deliver.

The impact of functional medicine on patient-reported outcomes in inflammatory arthritis: A retrospective study.

BACKGROUND: Despite treatment advances for inflammatory arthritis, a significant amount of patients fail to achieve remission. Other modifiable factors such as diet, physical activity and environmental exposures may be an important area of focus to help patients achieve disease remission and greater overall health. Functional medicine focuses on these lifestyle factors and may be an important adjunctive therapy. In this study, we examined the impact of functional medicine on patient-reported outcomes in patients with inflammatory arthritis. MATERIALS AND METHODS: In this 12-week, retrospective study, patients with confirmed diagnoses of rheumatoid arthritis (RA) or psoriatic arthritis (PsA) were treated according to guidelines from the American College of Rheumatology for RA or PSA respectively. Those in the functional medicine group underwent a functional medicine program adjunctive to the standard of care. Patient reported outcomes, such as PROMIS (Patient Reported Outcomes Measurement Information System) global physical health, mental health and pain scores were collected at baseline and 12 weeks. Multivariable statistical modeling was used to identify the impact of functional medicine on patient-reported outcomes. RESULTS: 318 patients were screened and 54 patients (mean age 52.9±11.3 years, females 74(67.9%)), were included. Baseline characteristics were similar in both patient groups with the exception of PROMIS global physical health and pain (PROMIS global physical health score 43·2 ± 6·6 and 39·7 ± 8·7 and pain scores of 3·5 ± 1·9 and 5·2 ± 2·7 in the functional medicine group vs. standard of care group respectively). Using multivariable model to account for these differences, patients in the functional medicine group had a statistically significant reduction in pain (0.92, p-value = 0.007) and change in PROMIS physical health score (2·84, p-value = 0.001) as compared to the standard of care. Changes in PROMIS global mental health scores were also significant and were dependent on age and were greatest in those older than 55. LIMITATIONS: Retrospective design, baseline difference in patient reported outcomes. CONCLUSIONS: Functional medicine may have an important role as adjunctive therapy to improve patients' pain, physical and mental health in those who do not see improvement with conventional therapy alone.

Association of the Functional Medicine Model of Care With Patient-Reported Health-Related Quality-of-Life Outcomes.

Importance: The incidence of chronic disease is increasing along with health care-related costs. The functional medicine model of care provides a unique operating system to reverse illness, promote health, and optimize function. The association between this model of care and patient's health-related quality of life (HRQoL) is unknown. Objective: To assess the association between functional medicine and patient-reported HRQoL using Patient-Reported Outcome Measurement Information System (PROMIS) global health measures. Design, Setting, and Participants: A retrospective cohort study was performed to compare 7252 patients aged 18 years or older treated in a functional medicine setting with propensity score (PS)-matched patients in a primary care setting. Sensitivity analyses assessed improvement limited to patients seen at both 6 and 12 months. The study included patients who visited the Cleveland Clinic Center for Functional Medicine or a Cleveland Clinic family health center between April 1, 2015, and March 1, 2017. Main Outcomes and Measures: The primary outcome was change in PROMIS Global Physical Health (GPH) at 6 months. Secondary outcomes included PROMIS Global Mental Health (GMH) at 6 months and PROMIS GPH and GMH at 12 months. The PROMIS GPH and GMH scores were transformed to a T-score from 0 to 100 with a mean of 50. Higher scores indicate a better health-related quality of life. Results: Of the 7252 patients (functional medicine center: 1595; family health center: 5657), 4780 (65.9%) were women; mean (SD) age was 54.1 (16.0) years. At 6 months, functional medicine patients exhibited significantly larger improvements in PROMIS GPH T-score points than were seen in patients treated at a family health center (mean [SD] change, functional medicine center: 1.59 [6.29] vs family health center: 0.33 [6.09], P = .004 in 398 PS-matched pairs). At 12 months, functional medicine patients showed improvement similar to that observed at 6 months; however, comparisons with patients seen at the family health center were not significant. Patients in the functional medicine center with data at both 6 and 12 months demonstrated improvements in PROMIS GPH (mean [SD], 2.61 [6.53]) that were significantly larger compared with patients seen at a family health center (mean [SD], 0.25 [6.54]) (P = .02 in 91 PS-matched pairs). Conclusions and Relevance: In this study, the functional medicine model of care demonstrated beneficial and sustainable associations with patient-reported HRQoL. Prospective studies are warranted to confirm these findings.

Educating Future Physicians in Nutritional Science and Practice: The Time Is Now.

The need to educate and train future physicians about nutrition and wellness has become increasingly apparent in the past decade. A rising incidence of chronic health conditions with a nutrition background (e.g., obesity, cardiovascular disease, type 2 diabetes) has led to an even greater need for nutrition educational content in medical school curricula so that physicians may counsel patients regarding their lifestyle factors. This review provides an overview of the successful development and integration of a nutrition thread in a 5-year medical school curriculum. Based on a survey conducted in our medical school program, students beginning medical school are lacking formal nutrition education, as only 8% arrived with some form of exposure. Despite this, nearly 85% of these medical students recognized that nutrition education is necessary in their training, and 70% state that the nutrition education they have received has influenced the way they care for patients. Key teaching points Physicians are faced with rising incidence of chronic health conditions that have a nutritional risk factor Physician self-care including optimal nutrition to support resilience is gaining importance. Nutrition education in medical schools is inadequate to address these rising needs. Implementing a comprehensive nutrition curricula that addresses personal wellness strategies, basic science concepts related to nutrition, and diagnosis and management of diseases that can be modified by or are related to nutrition as a topic thread that is woven throughout all years of the curriculum highlights the importance of nutrition in health and disease.

Diet and lifestyle recommendations for the treatment of chronic cough and chronic disease.

Chronic cough, possibly due to toxicant exposure, may be improved by using a low-risk nutrition-centred strategy. A 71-year-old man experiencing chronic cough for the past 25 years presented to the Cleveland Clinic. In recent years, the patient's cough had increased in frequency and intensity despite pulmonary interventions. The patient's social history revealed exposures as a foundry worker to dimethylethylamine and triethylamine two known respiratory irritants. The patient was placed on a nutrition programme (nutrient dense, low glycaemic index and anti-inflammatory), encouraged to use a sauna each day and placed on nutraceutical supplementation that supports liver detoxification, digestive health and inflammation reduction. Over the course of approximately 1 year, the patient experienced improvement in his cough despite the discontinuation of formal, intensive pulmonary therapy. The patient also experienced weight loss, lower blood pressure and glycaemic status improvement, as well as decreased fatigue and increased energy.

Function of phosphoenolpyruvate carboxykinase in mammary gland epithelial cells.

Previously, we have shown that Pck1 expression in mammary gland adipocytes and white adipose tissue maintains triglyceride stores through glyceroneogenesis, and these lipids were used for synthesis of milk triglycerides during lactation. Reduced milk triglycerides during lactation resulted in patterning of the newborn for insulin resistance. In this study, the role of Pck1 in mammary gland epithelial cells was analyzed. The developmental expression of Pck1 decreased in isolated mouse mammary gland epithelial cells through development and during lactation. Using HC11, a clonal mammary epithelial cell line, we found that both Janus kinase 2 signal transducers and activators of transcription 5 and the AKT pathways contributed to the repression of Pck1 mRNA by prolactin. These pathways necessitate three accessory factor regions of the Pck1 promoter for repression by prolactin. Using [U-(13)C(6)]glucose, [U-(13)C(3)]pyruvate, and [U-(13)C(3)]glycerol in HC11 cells, we determined that Pck1 functions in the pathway for the conversion of gluconeogenic precursors to glucose and contributes to glycerol-3-phosphate synthesis through glyceroneogenesis. Therefore, Pck1 plays an important role in both the mammary gland adipocytes and epithelial cells during lactation.

Titanium particles activate toll-like receptor 4 independently of lipid rafts in RAW264.7 murine macrophages.

Adherent pathogen-associated molecular patterns (PAMPs) act through toll-like receptor 2 (TLR2) and TLR4 to increase the biological activity of orthopedic wear particles in cell culture and animal models of implant loosening. This study tested whether this is dependent on TLR association with lipid rafts as reported for the response to soluble TLR ligands. For this purpose, RAW264.7 murine macrophages were activated by exposure to titanium particles with adherent PAMPs, soluble lipopolysaccharide (LPS), soluble lipotecichoic acid (LTA), or heat-killed bacteria that had been extensively washed to remove soluble PAMPs. Lipid rafts were isolated by two independent methods and the location of TLR4 and TLR2 was analyzed by Western blotting. The cognate TLRs associated with lipid rafts when the macrophages were activated with soluble LPS and LTA but not after stimulation with either titanium particles with adherent PAMPs or heat-killed bacteria. The lipid raft disruptor, methyl-ß-cyclodextrin, dose-dependently inhibited TNF-α release in response to LPS but had no affect on TNF-α release in response to titanium particles with adherent PAMPs. We conclude, therefore, that titanium particles with adherent PAMPs and heat-killed bacteria activate TLR2 and TLR4 in macrophages without inducing either TLR to associate with lipid rafts. These results have important implications for the mechanisms of orthopedic implant loosening as well the mechanisms for TLR activation in other inflammatory situations.

Bacterial pathogen-associated molecular patterns stimulate biological activity of orthopaedic wear particles by activating cognate Toll-like receptors.

Aseptic loosening of orthopaedic implants is induced by wear particles generated from the polymeric and metallic components of the implants. Substantial evidence suggests that activation of Toll-like receptors (TLRs) may contribute to the biological activity of the wear particles. Although pathogen-associated molecular patterns (PAMPs) produced by Gram-positive bacteria are likely to be more common in patients with aseptic loosening, prior studies have focused on LPS, a TLR4-specific PAMP produced by Gram-negative bacteria. Here we show that both TLR2 and TLR4 contribute to the biological activity of titanium particles with adherent bacterial debris. In addition, lipoteichoic acid, a PAMP produced by Gram-positive bacteria that activates TLR2, can, like LPS, adhere to the particles and increase their biological activity, and the increased biological activity requires the presence of the cognate TLR. Moreover, three lines of evidence support the conclusion that TLR activation requires bacterially derived PAMPs and that endogenously produced alarmins are not sufficient. First, neither TLR2 nor TLR4 contribute to the activity of "endotoxin-free" particles as would be expected if alarmins are sufficient to activate the TLRs. Second, noncognate TLRs do not contribute to the activity of particles with adherent LPS or lipoteichoic acid as would be expected if alarmins are sufficient to activate the TLRs. Third, polymyxin B, which inactivates LPS, blocks the activity of particles with adherent LPS. These results support the hypothesis that PAMPs produced by low levels of bacterial colonization may contribute to aseptic loosening of orthopaedic implants.

Phosphoenolpyruvate carboxykinase (Pck1) helps regulate the triglyceride/fatty acid cycle and development of insulin resistance in mice.

The aim of this study was to investigate the role of the cytosolic form of phosphoenolpyruvate carboxykinase (Pck1) in the development of insulin resistance. Previous studies have shown that the roles of Pck1 in white adipose tissue (WAT) in glyceroneogenesis and reesterification of free fatty acids (FFA) to generate triglyceride are vital for the prevention of diabetes. We hypothesized that insulin resistance develops when dysregulation of Pck1 occurs in the triglyceride/fatty acid cycle, which regulates lipid synthesis and transport between adipose tissue and the liver. We examined this by analyzing mice with a deletion of the PPARgamma binding site in the promoter of Pck1 (PPARE(-/-)). This mutation reduced the fasting Pck1 mRNA expression in WAT in brown adipose tissue (BAT). To analyze insulin resistance, we performed hyperinsulinemic-euglycemic glucose clamp analyses. PPARE(-/-) mice were profoundly insulin resistant and had more FFA and glycerol released during the hyperinsulinemic-euglycemic clamp compared with wild-type mice (WT). Finally, we analyzed insulin secretion in isolated islets. We found a 2-fold increase in insulin secretion in the PPARE(-/-) mice at 16.7 mM glucose. Thus, the PPARE site in the Pck1 promoter is essential for maintenance of lipid metabolism and glucose homeostasis and disease prevention.

Stimulation of macrophage TNFalpha production by orthopaedic wear particles requires activation of the ERK1/2/Egr-1 and NF-kappaB pathways but is independent of p38 and JNK.

Bone loss that causes aseptic loosening of orthopedic implants is initiated by pro-inflammatory cytokines produced by macrophages in response to implant-derived wear particles. MAPK and NF-kappaB signaling pathways are activated by the particles; however, it is not clear which of the signaling pathways are important for the initial response to the wear particles and which are only involved at later steps in the process, such as osteoclast differentiation. Here, we show that the ERK1/2, p38, JNK, and NF-kappaB pathways are rapidly activated by the wear particles but that only the ERK1/2 and NF-kappaB pathways are required for the initial response to the wear particles, which include increases in TNFalpha promoter activity, TNFalpha mRNA expression, and secretion of TNFalpha protein. Moreover, ERK1/2 activation by wear particles is also required for increased expression of the transcription factor Egr-1 as well as Egr-1's ability to bind to and activate the TNFalpha promoter. These results, together with our previous studies of the PI3K/Akt pathway, demonstrate that wear particles coordinately activate multiple signaling pathways and multiple transcription factors to stimulate production of pro-inflammatory cytokines, such as TNFalpha. The current study also demonstrates that the signaling pathways are activated to a much greater extent by wear particles with adherent endotoxin than by "endotoxin-free" wear particles. These results, together with those demonstrating the requirement for ERK1/2/Egr-1 and NF-kappaB, show that activation of these signaling pathways is responsible for the ability of adherent endotoxin to potentiate cytokine production, osteoclast differentiation, and bone loss induced by wear particles.

Inhibition of the PI3K-Akt signaling pathway reduces tumor necrosis factor-alpha production in response to titanium particles in vitro.

BACKGROUND: Wear debris contributes to implant loosening after total joint arthroplasty, and few advances have been made in our ability to inhibit the biological response to wear particles. Bacterial endotoxins augment the effects of wear particles in vitro and in vivo. The cytokine, tumor necrosis factor-alpha (TNF-alpha), is produced by macrophages in response to bacterial endotoxins and wear particles, and it increases osteoclast activity resulting in bone resorption and implant loosening. The phosphoinositol-3-kinase (PI3K)-Akt intracellular signal transduction pathway contributes to cytokine production in response to soluble endotoxin. We investigated the role of the PI3K-Akt pathway in the production of TNF-alpha in response to wear particles with adherent endotoxin and so-called endotoxin-free wear particles. METHODS: Cultured RAW264.7 murine macrophages were incubated with titanium particles with adherent endotoxin or with endotoxin-free titanium particles in the presence and absence of specific inhibitors of PI3K (LY294002) or Akt (SH-5). Akt activation was assessed with use of Western blot. TNF-alpha production was measured with use of enzyme-linked immunosorbent assay. Cytotoxicity was determined by measuring lactic dehydrogenase release. RESULTS: Titanium particles with adherent endotoxin increased Akt activation, whereas endotoxin-free titanium particles did not. The PI3K inhibitor reduced TNF-alpha production by 70% in response to titanium with adherent endotoxin without increasing cytotoxicity. Similarly, the Akt inhibitor reduced TNF-alpha production by 83% in response to titanium particles with adherent endotoxin without increasing cytotoxicity. High concentrations of endotoxin-free titanium particles resulted in a small delayed increase in TNF-alpha production that was completely blocked by the PI3K inhibitor. CONCLUSIONS: Inhibition of the PI3K-Akt pathway reduces macrophage TNF-alpha production in response to titanium particles with adherent endotoxin and endotoxin-free particles in vitro.