Inclusion Criteria:

• Group 1: healthy control patients Patients undergoing elective total hip replacement will be eligible for enrollment in Group 1 after written informed consent has been obtained. Only 1 blood sample and 1 fat and muscle biopsy will be taken intra-operatively

Group 2: non-septic, critically ill patients Patients requiring intensive care within 48 hours of admission to hospital from home, for a non-septic/non-inflammatory pathology will be eligible for enrollment in the study after informed agreement has been obtained from the closest family member (see Consent below). At enrolment, Group 2 patients must have received mechanical ventilation commencing within 48 hours of admission to intensive care, should be likely to require mechanical ventilation for at least 48 hours, and must not fulfil the 2001 International Sepsis Definition Conference criteria for severe sepsis or septic shock

Group 3: patients with severe sepsis or septic shock Patients requiring intensive care within 48 hours of admission to hospital from home, and evidence of severe sepsis (organ dysfunction due to infection) or septic shock as defined by the 2001 International Sepsis Definition Conference criteria, will be eligible for enrollment in the study after informed agreement has been obtained from their next-of-kin. Patients with underlying chronic liver disease are excluded from this group, and will be enrolled separately into Group 4.

Group 4: patients with severe sepsis and underlying chronic liver disease Patients requiring intensive care admission, with underlying Child-Pugh Class A or B, biopsy-proven liver cirrhosis, within 24 h of the onset of severe sepsis (organ dysfunction due to infection) or septic shock as defined by the 2001 International Sepsis Definition Conference criteria), will be eligible for enrollment in the study after informed agreement has been obtained from their next-of-kin

Exclusion Criteria:

- Age <18 years

Child-Pugh Class C liver disease

Chronic dialysis-dependent renal failure

Hepatitis B or C infection

Immunosuppression (e.g. haematological malignancy, neutropenia, HIV infection)

Immunosuppressive drug therapy within past 6 months

Patient receiving oral or IV steroid therapy for greater than 1 week, within 6 months prior to ICU admission

Muscle biopsy contraindicated in presence of coagulopathy (INR >2, platelet count < 30,000)*

Next-of-kin declines agreement / patient declines consent

Patient receiving thyroid hormone therapy prior to ICU admission

*This does not exclude enrolment into the study, particularly in the case of Group 4 patients who frequently develop a coagulopathy as part of their underlying liver dysfunction