Health-related quality of life following breast reconstruction compared to total mastectomy and breast-conserving surgery among breast cancer survivors: a systematic review and meta-analysis.

The present review evaluated health-related quality of life (HR-QoL) outcomes in surgical breast cancer survivors who received breast reconstruction (BR), breast-conservation surgery (BCS) or mastectomy (M), and whether HR-QoL domains across generic and disease/surgery-specific questionnaires are compatible. Six electronic databases were searched for appropriate observational studies. Standardized scores for different HR-QoL domains in the BR, BCS, and M treatment groups were extracted from each study for the purpose of a meta-analysis. Using Stata version 14.0, a random-effects meta-analysis model was adopted for each outcome variable to estimate the effect size, 95% CI-confidence intervals, and statistical significance. Sixteen of the 18 eligible studies with BR (n = 1474) and BCS (n = 2612) or M (n = 1458) groups were included in the meta-analysis. The BR group exhibited a better physical health (k = 12; 0.1, 95% CI 0.04, 0.24) and body image (k = 12; 0.50, 95% CI 0.10, 0.89) than the M group. However, the two groups exhibited comparable social health (k = 13; 0.1, 95% CI -0.07, 0.37), emotional health (k = 13; -0.08, 95% CI - 0.41, 0.25), global health (k = 7; 0.1, 95% CI - 0.01, 0.27), and sexual health (k =11; 0.2, 95% CI - 0.02,0.57). There was no clear evidence of the superiority of BR to BCS for all the six domains. These results suggest that HR-QoL outcomes in BR and BCS groups are better than the M group. Therefore, women opting for BR or BCS are likely to report fairly better HR-QoL outcomes than M. However, due to the significant heterogeneity observed in most BR versus BCS outcomes, developing a unified questionnaire incorporating both breast/surgery-specific and generic HR-QoL domains is warranted.

Prevalence of Smoking and Provision of Smoking Cessation Advice during Hospitalization

Aim We aimed to determine the prevalence of smoking and smoking cessation advice received by inpatients in Beaumont Hospital and compared results to previous similar studies. Method Cross-sectional survey where we interviewed eligible in-patients over a two-week period. Results 14.8% (30/203) of participants were current smokers, which is lower than the smoking prevalence found by previous studies. The rate of cessation advice delivery was 53.3% (16/30). An increasing socioeconomic gap between smokers and non-smokers over time was found. Discussion There remains limited provision of smoking cessation advice to inpatients.

Radiology reporting of obesity: a survey of patient and clinician attitudes.

AIM: To determine whether obesity information obtained via imaging techniques is desirable for clinicians and patients, and to investigate whether it impacts clinical decision-making. MATERIALS AND METHODS: Parallel surveys were designed to assess patient and clinician attitudes to the medical utility and social stigma of reporting obesity on radiology reports performed for other reasons. RESULTS: Where obesity was noted at medical imaging performed for any reason, clinicians and patients strongly agreed that it should be included in the radiology report (5.9 and 5.8, respectively, on a seven-point preference score ranging from strongly disagree [1] to strongly agree [7]). Clinicians and patients indicated a preference for a quantitative report. Clinicians somewhat disagreed and patients disagreed that a radiology report describing obesity would be considered insulting (3 and 2.1, respectively). Clinicians and patients agreed that they would be more likely to discuss overweight/obesity if it was described in a radiology report (5.3 and 6.1 respectively). Clinicians and patients agreed that radiology reports describing obesity would influence future management/behaviour (4.5 and 6.2, respectively). Clinicians strongly disagreed that they would avoid sending patients for scans if obesity was reported (1.3). Patients also disagreed that including such information on a report would result in imaging avoidance (1.9). CONCLUSION: Both clinicians and patients indicate a clear preference for obesity-related information on radiology reports for examinations performed for any reason. Surveyed attitudes suggest including such information is not considered insulting, and is unlikely to result in avoidance of imaging.

Whole-genome DNA methylation status associated with clinical PTSD measures of OIF/OEF veterans.

Emerging knowledge suggests that post-traumatic stress disorder (PTSD) pathophysiology is linked to the patients' epigenetic changes, but comprehensive studies examining genome-wide methylation have not been performed. In this study, we examined genome-wide DNA methylation in peripheral whole blood in combat veterans with and without PTSD to ascertain differentially methylated probes. Discovery was initially made in a training sample comprising 48 male Operation Enduring Freedom (OEF)/Operation Iraqi Freedom (OIF) veterans with PTSD and 51 age/ethnicity/gender-matched combat-exposed PTSD-negative controls. Agilent whole-genome array detected ~5600 differentially methylated CpG islands (CpGI) annotated to ~2800 differently methylated genes (DMGs). The majority (84.5%) of these CpGIs were hypermethylated in the PTSD cases. Functional analysis was performed using the DMGs encoding the promoter-bound CpGIs to identify networks related to PTSD. The identified networks were further validated by an independent test set comprising 31 PTSD+/29 PTSD- veterans. Targeted bisulfite sequencing was also used to confirm the methylation status of 20 DMGs shown to be highly perturbed in the training set. To improve the statistical power and mitigate the assay bias and batch effects, a union set combining both training and test set was assayed using a different platform from Illumina. The pathways curated from this analysis confirmed 65% of the pool of pathways mined from training and test sets. The results highlight the importance of assay methodology and use of independent samples for discovery and validation of differentially methylated genes mined from whole blood. Nonetheless, the current study demonstrates that several important epigenetically altered networks may distinguish combat-exposed veterans with and without PTSD.

A community virtual ward model to support older persons with complex health care and social care needs.

BACKGROUND: Globally the older population is increasing rapidly. As a result there is an increase in frail older persons living within the community, with increased risks of a hospital admission and higher mortality and morbidity rates. Due to complexity of care, health care professionals face challenges in providing effective case management and avoiding unplanned admissions to hospital. A community virtual ward (CVW) model was developed to assist health care professionals to support older persons at home during periods of illness and/or functional decline. METHODS: A quantitative observational study was conducted to examine if a CVW model of care reduced unplanned hospital admissions and emergency department (ED) presentations in 54 patients over a 12-month period. The sign-rank test examined matched data on bed days, ED presentations, and unplanned hospital admissions pre- and post-CVW implementation. Other risk factors for admission to hospital were examined using the Mann-Whitney test pre-and post-CVW admission, including falls, living alone, and cognition. Correlations between hospital admission avoidances and unplanned hospital admissions and ED presentations were tested using Spearman's ρ test. RESULTS: There was a reduction in ED presentations post-CVW admission (P<0.001), and median unscheduled admissions were reduced (P=0.001). Those living alone had a lower number of ED presentations (median 0.5, interquartile range 0-1) prior to admission in comparison to those living with a caregiver, with no differences observed during admission to CVW. For those who experienced a fall during CVW admission, the odds ratio (OR) of requiring long-term care doubled for each extra fall (OR =2.24, 95% CI 1.11 to 4.52, P=0.025). Reduced cognition was associated with an increased risk of ED presentations (ρ=0.292, P<0.05) but not associated with increased risks of unplanned hospital admissions (ρ=0.09, P=0.546). There were no significant correlations seen between admission avoidance and the number of unplanned hospital admissions or ED presentations. CONCLUSION: Through an integrated approach to care, a CVW model in the care of older persons can reduce ED presentations and unplanned hospital admissions.

Patient behaviour at the time of stroke onset: a cross-sectional survey of patient response to stroke symptoms.

BACKGROUND AND PURPOSE: Revascularisation treatment with thrombolysis must be initiated within 4.5 h following ischaemic stroke symptom onset. Despite its proven benefits, thrombolysis therapy is underused, with patient delay in presenting to hospital with symptoms identified as the leading barrier. This study aimed to examine help-seeking behaviour at stroke onset, in order to understand delays in accessing acute medical care for stroke symptoms. METHODS: 149 consecutive patients hospitalised with ischaemic stroke were interviewed at 72 h poststroke with the Stroke Awareness Questionnaire and the Response to Symptoms Questionnaire. RESULTS: Sixty per cent of stroke cases presented to the ED within 3.5 h of stroke onset. Knowledge of stroke symptoms and risk factors was poor, with 40% unable to correctly define a stroke. Bystander recognition of symptoms (p=0.03) and bystander initiation of Emergency Medical Services was associated with ED presentation within 3.5 h (p=0.03). CONCLUSIONS: This study provides insights into patient response when a stroke occurs, with the presence and action of others highlighted as critical in fast response to stroke symptoms. Knowledge of stroke warning signs and risk factors was low among stroke survivors. Findings highlight the complexity of changing help-seeking behaviour during stroke onset, and provide directions for public education efforts to reduce prehospital delay.

Synchronous colorectal liver metastasis: a network meta-analysis review comparing classical, combined, and liver-first surgical strategies.

BACKGROUND: In recent years, the management of synchronous colorectal liver metastasis has changed significantly. Alternative surgical strategies to the classical colorectal-first approach have been proposed. These include the liver-first and combined resections approaches. The objectives of this review were to compare the short- and long-term outcomes for all three approaches. METHODS: A systematic review of comparative studies was performed. Evaluated endpoints included surgical outcomes (5-year overall survival, 30-day mortality, and post-operative complications). Pair-wise and network meta-analysis (NMA) were performed to compare survival outcomes. RESULTS: Eighteen studies were included in this review, reporting on 3,605 patients. NMA and pair-wise meta-analysis of the 5-year overall survival did not show significant difference between the three surgical approaches: combined versus colorectal-first, mean odds ratio (OR) 1.02 (95% CI 0.8-1.28, P = 0.93); liver-first versus colorectal-first, mean OR 0.81 (95% CI 0.53-1.26, P = 0.37); liver-first versus combined, mean OR 0.80 (95% CI 0.52-1.24, P = 0.41). In addition NMA of the 30-day mortality among the three approaches also did not observe statistical difference. Analysis of variance showed that mean post-operative complications of all approaches were comparable (P = 0.51). CONCLUSION: There are considerable differences in the peri-operative management of synchronous CLM patients. This meta-analysis demonstrated no clear statistical surgical outcome or survival advantage towards any of the three approaches.

[Psychosocial Aspects in Cardiac Rehabilitation: From Theory to Practice. A Position Paper From the Cardiac Rehabilitation Section of The European Association of Cardiovascular Prevention and Rehabilitation of the European Society of Cardiology].

A large body of empirical research shows that psychosocial risk factors (PSRFs) such as low socio-economic status, social isolation, stress, type-D personality, depression and anxiety increase the risk of incident coronary heart disease (CHD) and also contribute to poorer health-related quality of life (HRQoL) and prognosis in patients with establishedCHD. PSRFs may also act as barriers to lifestyle changes and treatment adherence and may moderate the effects of cardiac rehabilitation (CR). Furthermore, there appears to be a bidirectional interaction between PSRFs and the cardiovascular system. Stress, anxiety and depression affect the cardiovascular system through immune, neuroendocrine and behavioural pathways. In turn, CHD and its associated treatments may lead to distress in patients, including anxiety and depression. In clinical practice, PSRFs can be assessed with single-item screening questions, standardised questionnaires, or structured clinical interviews. Psychotherapy and medication can be considered to alleviate any PSRF-related symptoms and to enhance HRQoL, but the evidence for a definite beneficial effect on cardiac endpoints is inconclusive. A multimodal behavioural intervention, integrating counselling for PSRFs and coping with illness should be included within comprehensive CR. Patients with clinically significant symptoms of distress should be referred for psychological counselling or psychologically focused interventions and/or psychopharmacological treatment. To conclude, the success of CR may critically depend on the interdependence of the body and mind and this interaction needs to be reflected through the assessment and management of PSRFs in line with robust scientific evidence, by trained staff, integrated within the core CR team.

Does pain mediate or moderate the relationship between physical activity and depressive symptoms in older people? Findings from The Irish Longitudinal Study on Ageing (TILDA).

Background. Depression is an increasing problem in older adults, which is exacerbated by under diagnosis and ineffective treatment options. Broadly speaking, as people age, their levels of regular physical activity (PA) decrease, while their experience of chronic pain increases. PA has been shown to be an effective, yet under-utilised, treatment for depression in this age-cohort although the influence of pain on the relationship between PA and depressive symptoms has not been considered. Methods. Secondary analysis of national data from The Irish Longitudinal Study on Ageing (TILDA, 2011) (n = 8163 participants aged 50 years and older) examined the mediating or moderating role of pain in the relationship between depressive symptoms and PA, and the impact of PA, pain and depressive symptoms on health-care utilisation. Results. Approximately 8.5% TILDA older adults were depressed. No mediating or moderating effects of pain were found in the association between PA and depressive symptoms. Higher levels of PA were found to be independently associated with lower depressive symptoms, while higher levels of pain significantly increased the likelihood of depressive symptoms supporting previous findings. Depressive symptoms and higher levels of pain were also found to significantly increase health-care utilisation. Conclusions. Consistent with previous findings in this field, both PA and pain were found to be independently associated with depressive symptoms in Irish older adults. Furthermore, pain does not play a mediating or moderating role in the relationship between PA and depressive symptoms. Continued support for ongoing initiatives in this area aimed at increasing PA in older adults as a means to improve both physical and mental well-being is advised. The absence of any synergistic effect between PA and pain suggests that clinicians and health service providers should continue to promote PA as a treatment for depression, irrespective of the pain levels of their patients.

Note: Parameter-independent bounding of the stochastic Michaelis-Menten steady-state intrinsic noise variance.

Using the (slow-scale) linear noise approximation, we give parameter-independent bounds to the substrate and product intrinsic noise variance for the stochastic Michaelis-Menten approximation at steady state.

Adjusted prognostic association of depression following myocardial infarction with mortality and cardiovascular events: individual patient data meta-analysis.

BACKGROUND: The association between depression after myocardial infarction and increased risk of mortality and cardiac morbidity may be due to cardiac disease severity. AIMS: To combine original data from studies on the association between post-infarction depression and prognosis into one database, and to investigate to what extent such depression predicts prognosis independently of disease severity. METHOD: An individual patient data meta-analysis of studies was conducted using multilevel, multivariable Cox regression analyses. RESULTS: Sixteen studies participated, creating a database of 10 175 post-infarction cases. Hazard ratios for post-infarction depression were 1.32 (95% CI 1.26-1.38, P<0.001) for all-cause mortality and 1.19 (95% CI 1.14-1.24, P<0.001) for cardiovascular events. Hazard ratios adjusted for disease severity were attenuated by 28% and 25% respectively. CONCLUSIONS: The association between depression following myocardial infarction and prognosis is attenuated after adjustment for cardiac disease severity. Still, depression remains independently associated with prognosis, with a 22% increased risk of all-cause mortality and a 13% increased risk of cardiovascular events per standard deviation in depression z-score.

Characterizing the biological traits and life history of Acanthopagrus (Sparidae) hybrid complexes: implications for conservation and management.

This study examined the spatio-temporal reproductive patterns, population structure, maturity and growth of Acanthopagrus hybrid complexes, which comprise mainly black bream Acanthopagrus butcheri and the hybrids they form with yellowfin bream Acanthopagrus australis, in two Australian estuaries (Coila and Brou Lakes, NSW). There were no differences between pure A. butcheri and hybrids in terms of their population structure, growth and maturity, suggesting that these two breeds have similar life histories and may therefore be managed as single, naturally cohesive units. Sexual variation in size structure was only observed for the complex in Coila Lake. Although there was significant variation in age structure between estuaries, both complexes exhibited dominance of only a few year classes indicating episodic recruitment and high fishing mortality. Acanthopagrus eggs occurred in higher numbers within upstream creek habitats compared to lake habitats, thereby highlighting the need to protect these spawning habitats. Although maturity in the complexes was not influenced by gender or estuary, differences in growth were detected between the genders and estuaries.

Importance of characteristics and modalities of physical activity and exercise in defining the benefits to cardiovascular health within the general population: recommendations from the EACPR (Part I).

Over the last decades, more and more evidence is accumulated that physical activity (PA) and exercise interventions are essential components in primary and secondary prevention for cardiovascular disease. However, it is less clear whether and which type of PA and exercise intervention (aerobic exercise, dynamic resistive exercise, or both) or characteristic of exercise (frequency, intensity, time or duration, and volume) would yield more benefit in achieving cardiovascular health. The present paper, as the first of a series of three, will make specific recommendations on the importance of these characteristics for cardiovascular health in the population at large. The guidance offered in this series of papers is aimed at medical doctors, health practitioners, kinesiologists, physiotherapists and exercise physiologists, politicians, public health policy makers, and the individual member of the public. Based on previous and the current literature, recommendations from the European Association on Cardiovascular Prevention and Rehabilitation are formulated regarding type, volume, and intensity of PA and exercise.

Importance of characteristics and modalities of physical activity and exercise in the management of cardiovascular health in individuals with cardiovascular risk factors: recommendations from the EACPR. Part II.

In a previous paper, as the first of a series of three on the importance of characteristics and modalities of physical activity (PA) and exercise in the management of cardiovascular health within the general population, we concluded that, in the population at large, PA and aerobic exercise capacity clearly are inversely associated with increased cardiovascular disease risk and all-cause and cardiovascular mortality and that a dose­response curve on cardiovascular outcome has been demonstrated in most studies. More and more evidence is accumulated that engaging in regular PA and exercise interventions are essential components for reducing the severity of cardiovascular risk factors, such as obesity and abdominal fat, high BP, metabolic risk factors, and systemic inflammation. However, it is less clear whether and which type of PA and exercise intervention (aerobic exercise, dynamic resistive exercise, or both) or characteristic of exercise (frequency, intensity, time or duration, and volume) would yield more benefit for each separate risk factor. The present paper, therefore, will review and make recommendations for PA and exercise training in the management of cardiovascular health in individuals with cardiovascular risk factors. The guidance offered in this series of papers is aimed at medical doctors, health practitioners, kinesiologists, physiotherapists and exercise physiologists, politicians, public health policy makers, and individual members of the public. Based on previous and the current literature overviews, recommendations from the European Association on Cardiovascular Prevention and Rehabilitation are formulated regarding type, volume, and intensity of PA and regarding appropriate risk evaluation during exercise in individuals with cardiovascular risk factors.

Modular closed-loop control of diabetes.

Modularity plays a key role in many engineering systems, allowing for plug-and-play integration of components, enhancing flexibility and adaptability, and facilitating standardization. In the control of diabetes, i.e., the so-called "artificial pancreas," modularity allows for the step-wise introduction of (and regulatory approval for) algorithmic components, starting with subsystems for assured patient safety and followed by higher layer components that serve to modify the patient's basal rate in real time. In this paper, we introduce a three-layer modular architecture for the control of diabetes, consisting in a sensor/pump interface module (IM), a continuous safety module (CSM), and a real-time control module (RTCM), which separates the functions of insulin recommendation (postmeal insulin for mitigating hyperglycemia) and safety (prevention of hypoglycemia). In addition, we provide details of instances of all three layers of the architecture: the APS© serving as the IM, the safety supervision module (SSM) serving as the CSM, and the range correction module (RCM) serving as the RTCM. We evaluate the performance of the integrated system via in silico preclinical trials, demonstrating 1) the ability of the SSM to reduce the incidence of hypoglycemia under nonideal operating conditions and 2) the ability of the RCM to reduce glycemic variability.

A hierarchy of distress and invariant item ordering in the General Health Questionnaire-12.

BACKGROUND: Invariant item ordering (IIO) is defined as the extent to which items have the same ordering (in terms of item difficulty/severity - i.e. demonstrating whether items are difficult [rare] or less difficult [common]) for each respondent who completes a scale. IIO is therefore crucial for establishing a scale hierarchy that is replicable across samples, but no research has demonstrated IIO in scales of psychological distress. We aimed to determine if a hierarchy of distress with IIO exists in a large general population sample who completed a scale measuring distress. METHODS: Data from 4107 participants who completed the 12-item General Health Questionnaire (GHQ-12) from the Northern Ireland Health and Social Wellbeing Survey 2005-6 were analysed. Mokken scaling was used to determine the dimensionality and hierarchy of the GHQ-12, and items were investigated for IIO. RESULTS: All items of the GHQ-12 formed a single, strong unidimensional scale (H=0.58). IIO was found for six of the 12 items (H-trans=0.55), and these symptoms reflected the following hierarchy: anhedonia, concentration, participation, coping, decision-making and worthlessness. LIMITATIONS: The cross-sectional analysis needs replication. CONCLUSIONS: The GHQ-12 showed a hierarchy of distress, but IIO is only demonstrated for six of the items, and the scale could therefore be shortened. Adopting brief, hierarchical scales with IIO may be beneficial in both clinical and research contexts.

A survey of the prevalence of smoking and smoking cessation advice received by inpatients in a large teaching hospital in Ireland.

BACKGROUND: The adverse effects of smoking are well documented and it is crucial that this modifiable risk factor is addressed routinely. Professional advice can be effective at reducing smoking amongst patients, yet it is not clear if all hospital in-patient smokers receive advice to quit. AIMS: To explore smoking prevalence amongst hospital in-patients and smoking cessation advice given by health professionals in a large university teaching hospital. METHODS: Interviews were carried out over 2 weeks in February 2011 with all eligible in-patients in Beaumont Hospital. RESULTS: Of the 205 patients who completed the survey, 61% stated they had been asked about smoking by a healthcare professional in the past year. Only 44% of current/recent smokers stated they had received smoking cessation advice from a health professional within the same timeframe. CONCLUSIONS: Interventions to increase rates of healthcare professional-provided smoking cessation advice are urgently needed.

Cell population modelling describes intrinsic heterogeneity: a case study for hematopoietic stem cells.

The control of stem cell properties during in vitro expansion is of paramount importance for their clinical use. According to Food and Drug Administration (FDA) guidelines, phenotypic heterogeneity is a critical aspect influencing therapeutic response. Even if the authors ability to reduce heterogeneity were limited, the sources from which it arises should be well understood for safe clinical applications. The aim of this work was to describe theoretically the intrinsic cell population heterogeneity that is present even when cells are cultured in a perfectly homogeneous environment. A bivariate population balance model is developed to account for the heterogeneity in the number of receptors and receptor-ligand complexes per cell, and is coupled with a ligand conservation equation. As a case study, the model is applied to the hematopoietic stem cell expansion, considering the c-Kit receptor and stem cell factor pair. Results show the dependence of intrinsic heterogeneity from ligand concentration and the kinetics of its administration. By tracking the cell generations within the total population, the authors highlight intra- and an inter-generational contributions to total population heterogeneity. In terms of dimensionless variables, intrinsic heterogeneity is dependent on the ratio of the characteristic time of cell division to that needed by a newborn cell to reach its single-cell steady state. [Includes supplementary material].

Development of a multi-parametric model predictive control algorithm for insulin delivery in type 1 diabetes mellitus using clinical parameters.

A multi-parametric model predictive control (mpMPC) algorithm for subcutaneous insulin delivery for individuals with type 1 diabetes mellitus (T1DM) that is computationally efficient, robust to variations in insulin sensitivity, and involves minimal burden for the user is proposed. System identification was achieved through impulse response tests feasible for ambulatory conditions on the UVa/Padova simulator adult subjects with T1DM. An alternative means of system identification using readily available clinical parameters was also investigated. A safety constraint was included explicitly in the algorithm formulation using clinical parameters typical of those available to an attending physician. Closed-loop simulations were carried out with daily consumption of 200 g carbohydrate. Controller robustness was assessed by subject/model mismatch scenarios addressing daily, simultaneous variation in insulin sensitivity and meal size with the addition of Gaussian white noise with a standard deviation of 10%. A second-order-plus-time-delay transfer function model fit the validation data with a mean (coefficient of variation) root-mean-square-error (RMSE) of 26 mg/dL (19%) for a 3 h prediction horizon. The resulting control law maintained a low risk Low Blood Glucose Index without any information about carbohydrate consumption for 90% of the subjects. Low-order linear models with clinically meaningful parameters thus provided sufficient information for a model predictive control algorithm to control glycemia. The use of clinical knowledge as a safety constraint can reduce hypoglycemic events, and this same knowledge can further improve glycemic control when used explicitly as the controller model. The resulting mpMPC algorithm was sufficiently compact to be implemented on a simple electronic device.

Distribution-based sensitivity metric for highly variable biochemical systems.

Classical sensitivity analysis is routinely used to identify points of fragility or robustness in biochemical networks. However, intracellular systems often contain components that number in the thousands to tens or less and consequently motivate a stochastic treatment. Although methodologies exist to quantify sensitivities in stochastic models, they differ substantially from those used in deterministic regimes. Therefore it is not possible to tell whether observed differences in sensitivity measured in deterministic and stochastic elaborations of the same network are the result of methodology or model form. The authors introduce here a distribution-based methodology to measure sensitivity that is equally applicable in both regimes, and demonstrate its use and applicability on a sophisticated mathematical model of the mouse circadian clock that is available in both deterministic and stochastic variants. The authors use the method to produce sensitivity measurements on both variants. They note that the rank-order sensitivity of the clock to parametric perturbations is extremely well conserved across several orders of magnitude. The data show that the clock is fragile to perturbations in parameters common to the cellular machinery ('global' parameters) and robust to perturbations in parameters that are clock-specific ('local' parameters). The sensitivity measure can be used to reduce the model from its original 73 ordinary differential equations (ODEs) to 18 ODEs and to predict the degree to which parametric perturbation can distort the phase response curve of the clock. Finally, the method is employed to evaluate the effect of transcriptional and translational noise on clock function. [Includes supplementary material].