Long-term analysis of humoral responses and spike-specific T cell memory to Omicron variants after different COVID-19 vaccine regimens.

Background: The emergence of SARS-CoV-2 variants has raised concerns about the sustainability of vaccine-induced immunity. Little is known about the long-term humoral responses and spike-specific T cell memory to Omicron variants, with specific attention to BA.4/5, BQ.1.1, and XBB.1. Methods: We assessed immune responses in 50 uninfected individuals who received varying three-dose vaccination combinations (2X AstraZeneca + 1X Moderna, 1X AstraZeneca + 2X Moderna, and 3X Moderna) against wild-type (WT) and Omicron variants at eight months post-vaccination. The serum antibody titers were analyzed by enzyme-linked immunosorbent assays (ELISA), and neutralizing activities were examined by pseudovirus and infectious SARS-CoV-2 neutralization assays. T cell reactivities and their memory phenotypes were determined by flow cytometry. Results: We found that RBD-specific antibody titers, neutralizing activities, and CD4+ T cell reactivities were reduced against Omicron variants compared to WT. In contrast, CD8+ T cell responses, central memory, effector memory, and CD45RA+ effector memory T cells remained unaffected upon stimulation with the Omicron peptide pool. Notably, CD4+ effector memory T cells even exhibited a higher proportion of reactivity against Omicron variants. Furthermore, participants who received three doses of the Moderna showed a more robust response regarding neutralization and CD8+ T cell reactions than other three-dose vaccination groups. Conclusion: Reduction of humoral and CD4+ T cell responses against Omicron variants in vaccinees suggested that vaccine effectiveness after eight months may not have sufficient protection against the new emerging variants, which provides valuable information for future vaccination strategies such as receiving BA.4/5 or XBB.1-based bivalent vaccines.

Rituximab induction and reinduction in granulomatosis with polyangiitis and microscopic polyangiitis: A retrospective multicenter study in Taiwan.

OBJECTIVES: This study aimed to investigate the clinical outcomes of granulomatosis with polyangiitis (GPA) and microscopic polyangiitis (MPA) under rituximab induction and reinduction therapy in Taiwan. METHODS: We performed a retrospective study in patients with GPA or MPA receiving rituximab therapy from August 2008 to July 2020 in seven medical centers in Taiwan. The clinical characteristics and outcomes of these patients were analyzed. RESULTS: In total, 53 patients (18 with GPA and 35 with MPA) were included. Kidney involvement (82.9% vs. 22.2%, p < .001) and initial creatinine (3.25 ± 2.37 vs. 1.07 ± 0.82, p < .001) were significantly higher in MPA. Within 24 weeks after the first course of rituximab, there were seven deaths (five due to infection and two due to active disease) in patients with MPA (7/35, 20%) compared to 0 in patients with GPA. Of 33 patients receiving rituximab for kidney involvement, 23 survived and were free from renal replacement therapy at 24 weeks. Their chronic kidney disease (CKD) stages improved in 2 but progressed in 7, while 24 had stable CKD stages. Death or end-stage renal disease (ESRD) was associated with infection and higher initial creatinine. Reinduction therapy for relapse was required in 18 (39.1%) of 46 survivors, which was associated with anti-proteinase 3 (PR3) positive (odds ratio 3.667, p = .049) and younger age with a cutoff of 49.4 (AUC = 0.679, p = .030, sensitivity = 66.67%, specificity = 75%). CONCLUSION: Significant mortality occurred after rituximab induction, especially in patients with MPA. In survivors, age younger than 50 and anti-PR3 positive were associated with the risk of relapse requiring reinduction.

FlgM is required to evade NLRC4-mediated host protection against flagellated Salmonella.

Salmonella enterica serovar Typhimurium is a leading cause of gastroenteritis worldwide and a deadly pathogen in children, immunocompromised patients, and the elderly. Salmonella induces innate immune responses through the NLRC4 inflammasome, which has been demonstrated to have distinct roles during systemic and mucosal detections of flagellin and non-flagellin molecules. We hypothesized that NLRC4 recognition of Salmonella flagellin is the dominant protective pathway during infection. To test this hypothesis, we used wild-type, flagellin-deficient, and flagellin-overproducing Salmonella to establish the role of flagellin in mediating NLRC4-dependent host resistance during systemic and mucosal infections in mice. We observed that during the systemic phase of infection, Salmonella efficiently evades NLRC4-mediated innate immunity. During mucosal Salmonella infection, flagellin recognition by the NLRC4 inflammasome pathway is the dominant mediator of protective innate immunity. Deletion of flgM results in constitutive expression of flagellin and severely limits systemic and mucosal Salmonella infections in an NLRC4 inflammasome-dependent manner. These data establish that recognition of Salmonella's flagellin by the NLRC4 inflammasome during mucosal infection is the dominant innate protective pathway for host resistance against the enteric pathogen and that FlgM-mediated evasion of the NLRC4 inflammasome enhances virulence and intestinal tissue destruction.

Significant impact of body mass index on the relationship between increased white blood cell count and new-onset diabetes.

An elevated white blood cell (WBC) count has been linked to incident diabetes. WBC count has been positively associated with body mass index (BMI), and elevated BMI has been reported to be a strong predictor of future diabetes. Hence, the association of increased WBC count with the subsequent development of diabetes may be mediated by increased BMI. This study was designed to address this issue. We selected subjects from the 104,451 participants enrolled from 2012 to 2018 in the Taiwan Biobank. We only included those with complete data at baseline and follow-up and those without diabetes at baseline. Finally, 24,514 participants were enrolled in this study. During an average 3.88 years of follow-up, 248 (1.0%) of the participants had new-onset diabetes. After adjusting for demographic, clinical, and biochemical parameters, increased WBC count was associated with new-onset diabetes in all of these participants (p ≤ 0.024). After further adjustment for BMI, the association became insignificant (p = 0.096). In addition, subgroup analysis of 23,430 subjects with a normal WBC count (range: 3500-10500/µl) demonstrated that increased WBC count was significantly associated with new-onset diabetes after adjusting for demographic, clinical, and biochemical parameters (p ≤ 0.016). After further adjustment for BMI, this association was attenuated (p = 0.050). In conclusion, our results showed that BMI had a significant impact on the relationship between increased WBC count and new-onset diabetes in all study participants, and BMI also attenuated the association in those with a normal WBC count. Hence, the association between increased WBC count and the future development of diabetes may be mediated by BMI.

Streptococcus agalactiae pyomyositis in a patient with primary biliary cholangitis: A case report.

Pyomyositis is an uncommon clinical scenario; it is usually associated with predisposing factors, including poorly controlled diabetes mellitus, trauma history, and immunocompromise. We discuss the case of an elderly woman with a 20-year history of diabetes mellitus and remissive breast cancer after modified radical mastectomy and subsequent chemotherapy 28 years previously. The patient presented with severe shoulder pain and gradual swelling. After examination, pyomyositis was diagnosed and debridement surgery was performed. Culture of the wound samples showed the growth of Streptococcus agalactiae. During hospitalization, primary biliary cholangitis (PBC) was diagnosed incidentally, accompanied by poor glycemic control. After treatment with antibiotics for pyomyositis and ursodeoxycholic acid for PBC, the infection resolved in 8 weeks, and her glycemic control was improved after PBC treatment. It is possible that the long-term untreated PBC worsened insulin resistance and aggravated diabetes mellitus in this patient. To the best of our knowledge, this is the first reported case of pyomyositis caused by an unusual pathogen, S. agalactiae, in a patient with newly diagnosed PBC.

Case report: Hemophagocytic lymphohistiocytosis complicated by multiple organ dysfunction syndrome following aseptic encephalitis.

Hemophagocytic lymphohistiocytosis (HLH) is a rare but potentially life-threatening condition caused by excessive immune activation. Secondary HLH is usually triggered by infection, most often from viral infection or malignancy. Here, we present a case of secondary HLH, complicated by multiple organ dysfunction syndrome triggered by critical aseptic encephalitis. A 27-year-old man without any underlying disease presented to our hospital with fever, disturbance of consciousness, and generalized seizures. The patient was diagnosed with aseptic encephalitis with super-refractory status epilepticus. Although antiseizure medications and immunoglobulins were administered, the patient developed multiple organ dysfunction syndrome. HLH was later diagnosed based on hypertriglyceridemia, hyperferritinemia, splenomegaly, cytopenia, and phagocytosis of nucleated cells, as shown by a blood smear of bone marrow aspiration. Treatment with pulse steroid therapy and plasmapheresis was initiated rather than chemotherapy because of the patient's critical condition. However, the patient died of profound shock and multiple organ failure. Diagnosis of HLH is challenging in patients with severe infections because of similar clinical manifestations and laboratory findings. The early recognition of HLH provides patients with the opportunity to receive appropriate treatment, which can lead to increased survival and remission rates.

Associations of Liver Function Parameters with New-Onset Hyperuricemia in a Large Taiwanese Population Study.

Hyperuricemia is the chief cause of gout and has been linked with hypertension, cardiovascular and renal disease, diabetes and metabolic syndrome. Liver with the highest protein expression of xanthine oxidase, the main enzyme responsible for uric acid formation, is the primary site of uric acid biosynthesis. However, there are few studies that examine the association between liver function and new-onset hyperuricemia. Hence, using the Taiwan Biobank dataset, we aimed to explore the capability of liver function parameters, including gamma-glutamyl transferase, total bilirubin, albumin, alanine aminotransferase and aspartate aminotransferase in association with the subsequent development of hyperuricemia. We analyzed 21,030 participants without hyperuricemia at baseline. Hyperuricemia was defined as a uric acid concentration > 6.0 mg/dL in women or >7.0 mg/dL in men. New-onset hyperuricemia was defined as participants without baseline hyperuricemia having developed hyperuricemia upon subsequent exam. Overall, 1804 (8.6%) of the study subjects developed new-onset hyperuricemia. After multivariable analysis, significant associations were found between the male sex (odds ratio [OR], 4.412; p < 0.001), high values of systolic blood pressure (SBP) (OR, 1.006; p = 0.012), body mass index (BMI) (OR, 1.064; p < 0.001), fasting glucose (OR, 1.005; p < 0.001), triglycerides (OR, 1.001; p = 0.003), uric acid (OR, 5.120; p < 0.001), low values of estimated glomerular filtration rates (eGFR) (OR, 0.995; p < 0.001), total bilirubin (OR, 0.616; p < 0.001) and new-onset hyperuricemia. The cutoff level of total bilirubin, according to the Youden index, of receiver operating characteristic curve for identifying new-onset hyperuricemia was 0.65 mg/dL. Low total bilirubin was defined as ≤0.65 mg/dL. After multivariable analysis, we found a significant association between low total bilirubin level (≤0.65 mg/dL) (OR = 0.806; p < 0.001) and new-onset hyperuricemia. Our present study demonstrated that in addition to male sex, high SBP, BMI, fasting glucose, triglycerides, and uric acid and low eGFR, the serum's total bilirubin levels were negatively associated with new-onset hyperuricemia in a large Taiwanese cohort.

Case report: Vaccine-induced immune thrombotic thrombocytopenia complicated by acute cerebral venous thrombosis and hemorrhage after AstraZeneca vaccines followed by Moderna COVID-19 vaccine booster and surgery.

Vaccine-induced thrombotic thrombocytopenia (VITT) is a well-known complication of adenoviral vector COVID-19 vaccines including ChAdOx1 nCoV-19 (AstraZeneca) and Ad26. COV2.S (Janssen, Johnson & Johnson). To date, only a few cases of mRNA COVID-19 vaccine such as mRNA-1273 (Moderna) or BNT162b2 (Pfizer-BioNTech)-induced VITT have been reported. We report a case of VITT with acute cerebral venous thrombosis and hemorrhage after a booster of mRNA-1273 (Moderna) vaccine in a patient previously vaccinated with two doses of the AstraZeneca vaccine. A 42-year-old woman presented with sudden onset of weakness of the right upper limb with focal seizure. She had received two doses of AstraZeneca vaccines and a booster with Moderna vaccine 32 days before presentation. She had also undergone a laparoscopic myomectomy 12 days previously. Laboratory examinations revealed anemia (9.5 g/dl), thrombocytopenia (31 × 103/µl), and markedly elevated d-dimer (>20.0 mg/L; reference value < 0.5 mg/L). The initial brain computed tomography (CT) was normal, but a repeated scan 10 h later revealed hemorrhage at the left cerebrum. Before the results of the blood smear were received, on suspicion of thrombotic microangiopathy with thrombocytopenia and thrombosis, plasmapheresis and pulse steroid therapy were initiated, followed by intravenous immunoglobulin (1 g/kg/day for two consecutive days) due to refractory thrombocytopenia. VITT was confirmed by positive anti-PF4 antibody and both heparin-induced and PF4-induced platelet activation testing. Clinicians should be aware that mRNA-1273 Moderna, an mRNA-based vaccine, may be associated with VITT with catastrophic complications. Additionally, prior exposure to the AstraZeneca vaccine and surgical procedure could also have precipitated or aggravated autoimmune heparin-induced thrombocytopenia/VITT-like presentation.

Habitual Tea Consumption and Risk of Cataracts: A Longitudinal Study.

We aimed to investigate the association between habitual tea consumption and the risk of developing cataracts in a large community-based cohort study. We prospectively collected volunteers from 29 recruitment centers that were ≧ 55 years old with no history of cataracts at the beginning of the study. There were 12,080 participants with available information in our study and were divided into two groups according to habitual tea consumption; non-tea-drinking and tea-drinking groups. The mean age was 59 years. Compared to the non-tea-drinking group, the tea-drinking group had a significantly lower incidence of developing cataracts (15.5% vs 12.1%) during follow-up of 46 months. In multivariate Cox proportional hazards regression analysis, the relative risk (RR) of incident cataracts was lower in the tea-drinking group than the non-tea-drinking group (RR = 0.848; 95% confidence interval [CI] = 0.751 to 0.957). Participants with ≧ 2 cups per day were associated with almost 16% reduction in the risk of developing cataracts compared with the non-tea-drinking group (RR = 0.844; 95% CI = 0.741 to 0.961). Our study suggests that habitual tea consumption can reduce the incidence of cataracts and raises the possibility that the tea content may slow the progression of cataracts.

KL-6 as a Biomarker of Interstitial Lung Disease Development in Patients with Sjögren Syndrome: A Retrospective Case-Control Study.

Objective: Krebs von den Lungen-6 (KL-6) is expressed on regenerating type II pneumocytes and has been recognized as biomarkers in interstitial lung disease (ILD). We aim to identify the role of the serum KL-6 level in patients with newly diagnosed Sjögren syndrome (SS), as well as the correlation between the immunoassays. Methods: Patients with newly diagnosed SS and receiving HRCT for clinical reason during follow-up were included. Baseline KL-6 level was measured via enzyme-linked immunosorbent assay (ELISA) and latex particle-enhanced turbidimetric immunoassay (LETIA). Results: Of the 39 patients, 21 (53.85%) developed interstitial lung disease (ILD) by the conclusion of the follow-up period. The median time to diagnosis of ILD was 2.24 years (IQR 1.15-4.34) in the ILD group. The median serum KL-6 level, measured using ELISA, was 1232 U/mL (IQR 937-2242) and 764.5 U/mL (IQR 503.25-1035.75) in the ILD group and the non-ILD group, respectively (p = 0.001). The median LETIA for serum KL-6 was 329 U/mL (IQR 235-619) and 245 U/mL (IQR 215.25-291) in the ILD group and the non-ILD group, respectively (p = 0.074). Conclusion: Serum KL-6 levels were higher in newly diagnosed SS patients with ILD diagnosis during follow-up. Thus, the serum KL-6 level can serve as a valuable biomarker to identify hidden ILD in patients with newly diagnosed SS patients. However, the immunoassay procedure may influence the efficacy of the prediction and its clinical association.

Corticosteroid-Induced Liver Injury in Adult-Onset Still's Disease.

Background and Objectives: Adult-onset Still's disease (AOSD) is a rheumatic disease characterized by systemic inflammatory symptoms, including intermittent spiking fever, polyarthritis and a distinctive salmon-colored rash. Corticosteroids are the first-line treatment for AOSD. However, corticosteroids are potentially hepatotoxic in certain cases and may complicate the course of the disease. Materials and Methods: A 29-year-old female suffering from fever of unknown origin for two weeks was diagnosed with AOSD according to Yamaguchi's criteria. She received corticosteroids as the first-line treatment for AOSD and developed acute severe hepatitis. A diagnostic protocol has been performed. Results: Corticosteroid-induced liver injury was confirmed by clinical observation and rechallenge of the drug in this case. The result of liver biopsy also supported the diagnosis. Mycophenolic acid, a disease-modifying antirheumatic drug (DMARD) was chosen as an alternative treatment. AOSD remission was achieved under this treatment after three months. Conclusions: Severe acute hepatitis induced by corticosteroids, although very rare, may be observed in patients with AOSD. Drug-induced liver injury needs to be kept in mind when unexpected acute hepatitis is found. Mycophenolic acid could be a proper substitute medication in these cases.

Case Report: Anti-neutrophil Cytoplasmic Antibody-Associated Vasculitis With Acute Renal Failure and Pulmonary Hemorrhage May Occur After COVID-19 Vaccination.

The rare and severe adverse effects associated with coronavirus disease of 2019 (COVID-19) vaccination have been under-appreciated, resulting in many instances of inappropriate management. We describe the case of an elderly woman who developed anti-neutrophil cytoplasmic antibody-associated vasculitis with pulmonary renal syndrome approximately 3 weeks after the first dose of COVID-19 mRNA vaccination (Moderna). Her nasopharyngeal polymerase chain reaction test for the COVID-19 RNA virus was negative. Gross hematuria, heavy proteinuria, acute renal failure (serum creatinine up to 6.5 mg/dL), and hemoptysis coupled with a marked increase in serum anti-myeloperoxidase-O antibody were observed. Renal biopsy showed severe vasculitis with pauci-immune crescent glomerulonephritis. The pulmonary hemorrhage was resolved and renal function improved following combined plasma exchange and the administration of systemic steroids and anti-CD20 therapy. The early examination of urinalysis and renal function may be crucial for identifying glomerulonephritis and acute renal failure in susceptible patients after COVID-19 vaccination.

Thymoma-Related Paraneoplastic Syndrome Mimicking Reactive Arthritis.

Background and Objectives: Thymomas are associated with a high frequency of paraneoplastic manifestations. Paraneoplastic syndrome (PNS) with thymoma presents a challenge to clinicians because of the need to decipher the association between the presenting symptoms and the underlying tumor. The condition most commonly noted in patients with PNS with thymoma is myasthenia gravis. Other common autoimmune diseases that may present as PNS include systemic lupus erythematosus, pure red cell aplasia, and Good syndrome. Seventy-six percent of patients with PNS-associated thymoma experience resolution of PNS after curing thymoma. Materials and Methods: A 37-year-old man with a two-month fever accompanied by polyarthritis accidently found thymoma after contrast computed tomography scans of his chest. He accepted Video assisted thoracoscopic surgery with resection of thymoma. Results: Fever and polyarthritis resolved after operation but recurred in five days due to cytomegalovirus viremia, which might be predisposed by previous antibiotics treatment before the diagnosis of thymoma. Conclusion: Patients with a thymoma also have a high frequency of PNS, and the most frequent condition found in patients with PNS-associated thymoma is myasthenia gravis. Fever with polyarthritis has been rarely reported as a symptom of PNS-associated thymoma. Here we reported an unusual case of PNS mimicking reactive arthritis with thymoma, as diagnosed based on the patient's clinical progression, imaging examination, and laboratory tests. The patient died of his comorbidities, and his death may have been related to long-term antibiotic use and consequent intestinal dysbiosis. This challenging case may help to inform clinicians of the need for detailed work-up of fever with unknown origin in the presence of chronic polyarthritis to prevent the overdiagnosis of inflammatory arthritis or rheumatic disease and avoid further comorbidities. Detailed work-up should include the patient's history of infections, inflammation, and malignant or nonmalignant tumors.

MRI contributes to accurate and early diagnosis of non-radiographic HLA-B27 negative axial spondyloarthritis.

BACKGROUND: Nonradiographic axial spondyloarthropathies (nr-axSpA) are diagnosed by the absence of radiographic sacroiliitis and the presence of bone marrow edema (BME) on magnetic resonance imaging (MRI). According to the classification criteria of the international Assessment of Spondyloarthritis Society (ASAS), structural changes to sacroiliac joints (SIJs) on MRI cannot be used as criteria in the absence of BME. However, less than half the Asian patients with clinically active axSpA show BME. The incidence of human leukocyte antigen (HLA)-B27 is low in Asian populations, which makes it more difficult to identify nr-axSpA. We used MRI to evaluate the structural damage to SIJs in patients with nr-axSpA with and without BME with the aim of identifying the best methodology for accurate diagnosis, especially in populations with less common BME and HLA-B27. METHODS: One hundred three patients with inflammatory back pain were included in this prospective study. No patient's radiograph met the definition of positive modified New York criteria. BME and structural damage to SIJ including sclerosis and erosion were assessed independently on coronal and axial short-tau inversion recovery and T1-weighted spin echo MRI scans by two well-trained musculoskeletal radiologists using the Spondyloarthritis Research Consortium of Canada (SPARCC) score. Demographics of patients were collected. Disease characteristics and structural damage were analyzed in patients with and without BME on SIJ MRI. Receiver operating characteristic (ROC) curve analysis was used to assess the diagnostic performance of structural damage. RESULTS: All individuals in the cohort had at least one abnormal finding on SIJ MRI, including BME or structural damage; 36 of 103 patients had BME. We identified a significant positive correlation between SPARCC scores and severe erosion assessed by focal joint space widening (fJSW) (p = 0.001) in these 36 patients. Fifty-eight of the 103 enrolled patients fulfilled the ASAS criteria for nr-axSpA in the either absence or presence of BME. Of these 58 patients, 57 and 19 had erosions or fJSW, respectively, and the presence of BME was significantly correlated with fJSW (phi score of 0.319 and p = 0.015). We demonstrated a significant positive correlation between fJSW and either the presence or the severity of BME in patients with nr-axSpA who met the ASAS definition. There was a positive correlation between BME and fJSW across the whole study cohort (phi score of 0.389; p < 0.001). The area under the ROC curve (AUC) for fJSW on SIJ MRI was 0.736, p < 0.001. In both HLA-B27-positive and -negative groups, BME was more common in the presence of fJSW (phi scores of 0.370 and 0.377, p = 0.018 and 0.003, respectively) and SPARCC scores were higher in patients with fJSW (p < 0.001 and p = 0.005). We also identified a positive correlation between fJSW and BME in patients with nr-axSpA and normal serum levels of C-reactive protein (phi score of 0.362 and p = 0.001). CONCLUSION: Structural damage detected on SIJ MRI, sclerosis, erosions and fJSW may be present in patients without detectable inflammation on SIJ MRI. However, fJSW is significantly correlated with the severity of inflammation seen on SIJ MRI, which contributes to the accurate diagnosis of nr-axSpA, and it could be used as an alternative diagnostic test for nr-axSpA in the general population, especially for those who do not carry the HLA-B27 gene, Asian patients without BME, or patients with normal serum inflammatory biomarkers.

Quality of Life among Community-Dwelling Middle-Aged and Older Adults: Function Matters More than Multimorbidity.

OBJECTIVES: Quality of life stands for the comprehensive assessment for health conditions and the central concerns in the seniors' care. The inter-relationship between health-related quality of life (HRQoL) and multimorbidity among community-dwelling healthy older adults remains uncertain. METHODS: Data of 1839 participants from the I-Lan Longitudinal Aging Study were excerpted for analysis. Functional status and HRQoL were measured by the Functional Autonomy Measurement System and the Chinese version of 12-item Short-Form Health Survey version 2. Poor HRQoL was defined as lowest quintile of physical and mental components summaries (PCS and MCS). Multivariable linear and logistic regression analysis were applied to explore associations between variables of interest. RESULTS: Adjusted for potential confounders, multivariable linear regression showed that multimorbidity and functional impairment were negatively associated with PCS (ß coefficients -1.8 vs. -8.4) and MCS (ß coefficients -1.9 vs. -4.8). Logistic regression affirmed similar associations that the odds of being poor HRQoL were 1.6 (95% CI 1.1-2.2) for multimorbidity, and 5.4 (95% CI 2.8-10.3) for functional impairment in PCS; 1.9 (95% CI 1.4-2.6) for multimorbidity and 6.0 (95%CI 3.2-11.5) for functional impairment in MCS. Adjusted for depressive symptoms and cognitive performance, functional impairment was significantly associated with poor physical component (OR:4.68, 95% CI: 0.35-19.34, p<0.001) and mental component in HRQoL (OR:2.4, 95% CI: 1.1-5.5, p=0.032), but the associations were insignificant in multimorbidity. CONCLUSIONS: Findings from the study strengthened the importance of functional performance on HRQoL among community-living middle-aged and older adults, which is essential in community health promotion activities and health service programs.