Background: Knee osteoarthritis (OA) is the most common form of arthritis in older adults. Knee OA is associated with limitations in physical function. Functional limitations are also associated with another geriatric condition, frailty. Frailty is characterized by reduced strength, endurance and physiological function. Purpose: The primary purpose of this study is to determine if there is a difference in radiographic or symptomatic knee OA severity between non-frail and pre-frail women with knee OA. Secondary objectives include: a) the relationship between radiographic and symptomatic OA severity with serum inflammatory cytokines, and b) if there is a difference in inflammatory cytokines between non-frail and pre-frail women with knee OA. Methods: We included 21 community-dwelling women with knee OA. Frailty was assessed using the Fried Frailty Phenotype. Knee OA severity was characterized by the Kellgren and Lawrence (KL) score and the Knee Injury and Osteoarthritis Outcome Questionnaire (KOOS). Inflammatory cytokines included serum interleukin-6 (IL-6), interleukin-10 (IL-10), tumor necrosis alpha (TNF α) and C reactive protein (CRP). Results: Data from 20 participants (66.1 [9.6] years, BMI 29.7 [4.9] kg/m2, non-frail=55%; pre-frail=45%) were analyzed. Radiographic severity was not different between frailty groups (p= 0.11). There was no difference in symptomatic knee OA severity, measured using the KOOS subscales, between frailty groups (p>0.17). Radiographic OA severity and inflammatory markers were not associated (p>0.30). There was a negative relationship between TNF α and self-reported pain (r=0.26), no relationships between inflammatory cytokines with any other KOOS sub-scales. Lastly, there was no difference in any inflammatory cytokines between non-frail and pre-frail groups. Conclusion: Despite the relatively young age, nearly 50% of our participants were pre-frail. Pre-frailty was unrelated to the severity of the knee OA, or inflammatory cytokines. TNF α may be involved in the experience of pain in these women. While it appears women with knee OA frequently demonstrate pre-frail status, more work is necessary to examine the link between these diseases. / Thesis / Master of Science (MSc) / Arthritis is a chronic disease that has a debilitating effect on the lives of more than 4.6 million Canadians. In 2015, the cumulative economic burden of osteoarthritis was 195.2 billion dollars and is expected to increase significantly in the next two years. Knee osteoarthritis is the most common form of arthritis in older adults. Knee osteoarthritis is associated with increased pain, decreased physical function and decreased quality of life (QOL). In vulnerable older adults increased exhaustion, decreased physical function and muscle loss can increase the risk of developing frailty. Frail older adults are at higher risk of adverse health outcomes such as falls, hospitalization and death. Previous research has shown that older adults with knee OA are at higher risk of developing frailty however, it is not understood what underlying mechanisms increase this risk. This thesis provides fundamental information aimed at understanding potential mechanisms associated with knee osteoarthritis and frailty in women. Our study found that despite their relatively young age, nearly half of the women with knee OA are pre-frail. This data shows that inflammatory cytokines in particular, tumor necrosis factor alpha is related to symptomatic knee osteoarthritis severity in particular, self-reported pain. Overall, early detection of frailty is important when managing this condition. These data suggest that chronic knee pain associated with OA may be a useful trigger for early assessments of frailty in women.

Interleukin-6 (IL-6) and C-reactive protein (CRP) are being used for diagnosis of sepsis. However, studies have reported varying cut-off levels and diagnostic performance. This study aims to investigate the optimal cut-off levels and performance of IL-6 and CRP for the diagnosis of neonatal sepsis. The study was conducted at the University Hospital of Leipzig, Germany from November 2012 to June 2020. A total of 899 neonates: 104 culture proven sepsis, 160 clinical sepsis, and 625 controls were included. Blood culture was performed using BacT/ALERT 3D system. IL-6 and CRP were analyzed by electrochemiluminescent immunoassay and immunoturbidimetric assay, respectively. Data were analyzed using SPSS 20 statistical software. Among neonates with proven sepsis, the optimal cut-off value of IL-6 was 313.5 pg/mL. The optimal cut-off values for CRP in 5 days serial measurements (CRP1, CRP2, CRP3, CRP4, and CRP5) were 2.15 mg/L, 8.01 mg/L, 6.80 mg/L, 5.25 mg/L, and 3.72 mg/L, respectively. IL-6 showed 73.1% sensitivity, 80.2% specificity, 37.6% PPV, and 94.8% NPV. The highest performance of CRP was observed in the second day with 89.4% sensitivity, 97.3% specificity, 94.5% PPV, and 98.3% NPV. The combination of IL-6 and CRP showed increase in sensitivity with decrease in specificity. In conclusion, this study defines the optimal cut-off values for IL-6 and CRP. The combination of IL-6 and CRP demonstrated increased sensitivity. The CRP 2 at cut-off 8.01 mg/L showed the highest diagnostic performance for identification of culture negative clinical sepsis cases. We recommend the combination of IL-6 (≥313.5 pg/mL) and CRP1 (≥2.15 mg/L) or IL-6 (≥313.5 pg/mL) and CRP2 (≥8.01 mg/L) for early and accurate diagnosis of neonatal sepsis. The recommendation is based on increased sensitivity, that is, to minimize the risk of any missing cases of sepsis. The CRP2 alone at cut-off 8.01 mg/L might be used to identify clinical sepsis cases among culture negative sepsis suspected neonates in hospital settings.

C-reactive protein (CRP), a humoral component of the innate immune system with important functions in host-defense, is extensively used as a sensitive biomarker of systemic inflammation. During inflammation, hepatocyte-derived CRP rises dramatically in the blood due to increased interleukin-6 (IL-6) levels. Reliable detection of CRP in saliva, instead of blood, would offer advantages regarding sampling procedure and availability but using saliva as a diagnostic body fluid comes with challenges. The aims of this study were to evaluate associations between salivary CRP, total protein levels in saliva and serum CRP. Furthermore, we examined associations with plasma IL-6, body mass index (BMI), tobacco smoking and age. Salivary CRP was investigated by ELISA in 107 middle-aged participants from the general population. We employed spectrophotometric determination of total protein levels. Correlation analyses were used for associations of salivary CRP with serum CRP (turbidimetry), plasma IL-6 (Luminex®), BMI and smoking habits. Salivary median CRP was 68% higher (p=0.009), and total protein levels were 167% higher (p<0.0001), in morning compared to evening saliva. The correlation coefficients between serum and salivary CRP were low to moderate, but stronger for evening than morning saliva. Plasma IL-6 correlated significantly with serum CRP (rs=0.41, p<0.01), but not with morning or evening salivary CRP. Non-smokers showed 103% higher salivary CRP levels (p=0.015), whereas serum CRP was independent of smoking status. As opposed to CRP in serum, salivary CRP was not associated with BMI. Salivary CRP was 90% higher among the age interval 60–69 years compared to subjects aged 45–59 (p=0.02) while serum CRP levels did not differ between the age groups. In conclusion, CRP in saliva did not straightforwardly reflect serum concentrations. This raises questions regarding adequate reflection of biological events. The pronounced diurnal salivary CRP pattern accentuates the importance of standardizing the time-point of sampling.

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Sowohl FMS als auch PA stehen mit einem veränderten systemischen Zytokinprofil in Zusammenhang. Die chronisch unterschwellige Entzündung, die bei PA vorliegt, gilt als Bindeglied für die Entwicklung von den bei PA bekannten anderen Komorbiditäten. In dieser Studie wurde der Zusammenhang zwischen PA und FMS hinsichtlich systemischer Entzündungsparameter und der Auswirkung auf die Symptomschwere der jeweiligen Erkrankungen geprüft. Hierfür wurden 143 Frauen untersucht, davon 24 FMS-Patientinnen, 46 FMSPatientinnen mit PA, 44 PA-Patientinnen und 29 Gesunde. Es wurden demografische Daten erhoben und Fragebögen zur Einschätzung depressiver Symptome (ADS), der gesundheitsbezogenen Lebensqualität (SF-12) und bei den FMS-Patientinnen zusätzlich der FIQ zur Einschätzung der FMS-Symptomschwere verwendet. Die Serumkonzentrationen von IL-6, TNF-a, IL-17A, IL-10 und IL-18 wurden mittels ELLA Immunoassay bestimmt. Die FMS-Patientinnen mit PA und PA-Patientinnen zeigten im Median signifikant höhere IL-6 Serumkonzentrationen als Gesunde. Zusätzlich wiesen die PA-Patientinnen signifikant erhöhte TNF-a-Werte auf. Bei den FMS-Patientinnen wurden im Vergleich zu den Gesunden keine signifikant erhöhten Zytokinspiegel festgestellt. Auch waren bei den FMS-Patientinnen mit PA keine signifikant höheren Zytokinspiegel im Vergleich zu den FMS-Patientinnen oder PA-Patientinnen zu beobachten. Die FMS-Gruppe mit PA wies im Gruppenvergleich eine höhere Analgesie-Medikation auf. Es gab keinen Unterschied des FIQ, der FMS-Schweregrad wurde nicht durch das Vorhandensein einer PA beeinflusst. Trotz dieser Ergebnisse ist eine Assoziation zwischen beiden Erkrankungen weiterhin möglich. Das Vorliegen einer PA als Komorbidität sollte daher in FMS-Studien und in der FMS-Therapie berücksichtigt werden. Es sind weitere Forschungsarbeiten nötig, um den Zusammenhang beider Erkrankungen eindeutig belegen zu können. / FMS as well as PA are associated with an altered systemic cytokine profile. The chronic low-grade inflammation in PA is linked to the development of other known comorbidities of PA. This study examined the relationship between PA and FMS in terms of systemic inflammatory parameters and their impact on the severity of symptoms in both diseases. 143 women were examined, including 24 FMS patients, 46 FMS patients with PA, 44 PA patients, and 29 healthy controls. Demographic data were collected, and questionnaires were used to assess depressive symptoms (ADS), health-related quality of life (SF-12) and the FIQ to evaluate the severity of FMS symptoms in FMS patients. Serum concentrations of IL-6, TNF-α, IL-17A, IL-10, and IL-18 were determined using the ELLA immunoassay. FMS patients with PA and PA patients show significantly higher median IL-6 serum concentrations compared to healthy individuals. Additionally, PA patients had significantly elevated TNF-α levels compared to healthy controls. No significantly increased cytokine levels were observed in FMS patients compared to healthy controls. Furthermore, FMS patients with PA did not exhibit significantly higher cytokine levels compared to either FMS or PA patients. The FMS group with PA had a higher use of analgesic medication in group comparisons. There was no difference in the FIQ of FMS patients with and without PA. The severity of FMS was not influenced by the presence of PA. Despite these findings, an association between both diseases remains possible. Therefore, the presence of PA as a comorbidity should be considered in FMS studies and therapy. Further research is needed to clearly establish the connection between both conditions.

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