Selective sonographic screening for developmental dysplasia of the hip - increasing trends in late diagnosis.

There are concerns that selective sonographic screening for developmental dysplasia of the hip (DDH) may be suboptimal. Our aim was to test this hypothesis by identifying trends in presentation and surgical treatment in patients with DDH. This is a retrospective review of children born between 1997-2018 who were treated surgically for DDH at our sub- regional paediatric orthopaedic unit. Demographic data, risk factors, age of diagnosis and surgical treatments were analysed. Late diagnosis was defined as greater than 4 months. 103 children (14 male, 89 female) underwent surgery. 93 hips were operated for dislocation and 21 for dysplasia. 13 patients presented with bilateral hip dislocations. The median age at diagnosis was 10 months (95% CI: 4-15). 62/103 (60.2%) were diagnosed late (after 4 months) and the median age for diagnosis in this group was 18.5 months (95% CI: 16-20.5). Significantly more patients were referred late (p=0.0077). The presence of risk factors (breech presentation or family history) was associated with early diagnosis. Over the duration of our study the operation rate per 1000 live births gradually increased, and on Poisson regression analysis there was a statistically significant increasing trend towards late diagnosis in recent years (p=0.0237), which necessitated more aggressive surgical management. In the UK, the current selective sonographic screening programme for DDH has shown a deterioration over the years of this study and this questions its current effectiveness. It appears that the majority of irreducible hip dislocations are diagnosed late, with an increased need for surgical management.

Factors that affect fractured neck of femur outcome: Clinical commissioning groups influence length of stay and discharge destination.

BACKGROUND: The average length of stay (LOS) following a hip fracture in hospitals around the UK has been approximately 20 days in recent years. This can vary between hospitals and there are numerous factors that can affect LOS. We had the impression that LOS varied by Clinical Commissioning Group (CCG) from which the patient originates. The aim of our study was to discover whether the concern was valid, and if so, what the reasons may be. METHODS: We analysed hip fracture data collected at our Trust between September 2008 and December 2014. LOS was compared for each of three CCGs in our Trust's catchment areas, and those patients admitted from outlying CCGs. Sub-analysis was performed by patient age, ASA grade, abbreviated mental test score, procedure type and discharge destination to determine which factors influence LOS. RESULTS: 1847 patients were identified. After excluding deaths, missing data and extreme outliers, 1603 patients were included in the analysis. The median LOS varied from 14.9 to 23.4 days across CCGs. The major reason for this variation was discharge destination. CCGs associated with longer LOS had a significantly higher rate of discharge to the patient's own home, rather than institutional care. This was independent of patient age, mental status, ASA grade and promptness of surgery. CONCLUSION: We have shown that CCGs vary in their performance to aid discharge. This directly influences a Trust's performance on the National Hip Fracture Database. Compared with other hospitals, our results show a poor outcome in terms of length of stay, but much better performance regarding home discharge. We recommend that more emphasis in future be placed on discharge destination than LOS.

Longitudinal assessment of anxiety, depression, and fatigue in people with multiple sclerosis.

OBJECTIVES: No longitudinal studies have concurrently evaluated predictors of anxiety, depression, and fatigue in people with multiple sclerosis (PwMS). This study determined factors that best predicted anxiety, depression, and fatigue in MS patients from a large pool of disease, cognitive, life-event stressor (LES), psychosocial, life-style, and demographic factors. DESIGN: A 2-year prospective longitudinal study evaluated predictors of psychological distress and fatigue in PwMS. METHODS: One hundred and one consecutive participants with MS were recruited from two MS clinics in Sydney, Australia. LES, anxiety, depression, and fatigue were assessed at baseline and at 3-monthly intervals for 2-years. Disease, cognitive, demographic, psychosocial, and life-style factors were assessed at baseline. Patient-reported relapses were recorded and corroborated by neurologists or evaluated against accepted relapse criteria. RESULTS: Depression strongly predicted anxiety and fatigue, and anxiety and fatigue strongly predicted later depression. Psychological distress (i.e. anxiety, depression) was also predicted by a combination of unhealthy behaviours (e.g. drug use, smoking, no exercise, or relaxation) and psychological factors (e.g. low optimism, avoidance coping), similar to the results of community-based studies. However, state-anxiety and fatigue were also predicted by immunotherapy status, and fatigue was also predicted by LES and demographics. CONCLUSIONS: These results suggest that similar factors might underpin psychological distress and fatigue in MS patients and community-well samples, although MS treatment factors may also be important. These results might assist clinicians in determining which MS patients are at greatest risk of developing anxiety, depression, or fatigue.

Relationship between stress and relapse in multiple sclerosis: Part I. Important features.

OBJECTIVE: The aim of this two-year prospective study was to examine the relationship between multiple aspects of life-event stress and relapse in multiple sclerosis (MS) patients. BACKGROUND: Few studies have defined the critical features of this life-event stress; for example, stressor duration, frequency, severity, disease-dependency, valency, or stressor constructs, such as the propensity to cause emotional distress/threat or the frustration of life goals. METHODS: 101 consecutive participants with MS were recruited from two MS clinics in Sydney, Australia. Stressful life events were assessed at study-entry and at three-monthly intervals for two years. Patient-reported relapses were recorded and corroborated by neurologists or evaluated against accepted relapse criteria. RESULTS: Acute events, but not chronic difficulties (CDs), predicted relapse occurrence: acute stressor frequency counts predicted greater relapse risk, along with low disability score (EDSS) and being male. We also confirmed the bi-directional stress-illness hypothesis: stressors predicted relapse, and relapse separately predicted stressors. CONCLUSIONS: Life-event stress impacts to a small degree on MS relapse. The number and not the severity of acute stressors are most important; chronic stressors do not predict later relapse. Males and those with early stage disease are also at greater risk of relapse. MS patients should be encouraged to reduce acute stressors during times of high stress, and feel reassured that disease-related chronic stressors do not increase their relapse risk.

Relationship between stress and relapse in multiple sclerosis: Part II. Direct and indirect relationships.

OBJECTIVE: The aim of this two-year prospective study was to determine which factors were: (i) directly related and/or (ii) indirectly related to multiple sclerosis (MS) relapse. These factors included life-event stressors, disease, demographic, psychosocial and lifestyle factors. BACKGROUND: Relatively little attention has been paid to the role of non-clinical relapse predictors (other than stressful life-events) in MS, or factors that indirectly impact on the stress-relapse relationship. METHODS: A total of 101 consecutive participants with MS were recruited from two MS clinics in Sydney, Australia. Stressful life-events, depression, anxiety and fatigue were assessed at study-entry and at three-monthly intervals for two years. Disease, demographic, psychosocial and lifestyle factors were assessed at baseline. Patient-reported relapses were recorded and corroborated by neurologists or evaluated against accepted relapse criteria. RESULTS: MS relapse was predicted by acute stressor frequency counts, coping responses that utilized social support, and being born in Australia, but not by chronic stressors, disease, demographic, psychosocial or lifestyle factors. No factors were found to indirectly impact on the stress relapse relationship. CONCLUSIONS: The number rather than severity of stressors was most important in relation to MS relapse risk, along with coping responses that utilized social support, suggesting that MS patients should avoid situations that are likely to generate multiple stressors or which provide few avenues for social support.

Flash photolysis study of ligand binding by modified myoglobins at low temperatures.

The CO-binding kinetics of myoglobin containing proto-, meso- and deutero-hemes were studied by flash photolysis over the temperature range 50-300 K. Results recorded over a large dynamic range of time (microseconds to many seconds) reveal processes that are non-exponential in time and multiphasic. The data are explained by a model in which the CO molecule must surmount four barriers in migrating from the solvent to the heme iron. At least two of these barriers have heights that vary from one molecule to another. Varying the nature of the heme group affects mainly the innermost of these barriers and, to a lesser degree, the second-outermost barrier.

The effect of mitochondrial energization on cytochrome c oxidase kinetics as measured at low temperatures. I. The reaction with carbon monoxide.

The kinetics of CO binding by the cytochrome c oxidase of pigeon heart mitochondria were studied as a function of membrane energization at temperatures from 180 to 280 degrees K in an ethylene glycol/water medium. Samples energized by ATP showed acceleration of CO binding compared to those untreated or uncoupled by carbonylcyanide p-trifluoromethyoxyphenylhydrazone but only at relatively low temperatures and high CO concentrations. Experiments using samples in a "mixed valency" (partially oxidized) state showed that the acceleration of ligand binding is not due to the formation of a partially oxidized state via reverse electron transport. It is concluded that in the deenergized state one CO molecule can be closely associated with the cytochrome a3 heme site without actually being bound to the heme iron; in the energized state, two or more ligand molecules can occupy this intermediate position. The change in the apparent ligand capacity of a region near the heme iron in response to energization is evidence for an interaction between cytochrome oxidase and the ATPase system. Furthermore, these results suggest a control mechanism for O2 binding.

Low-temperature flash photolysis studies of cytochrome oxidase and its environment.

The CO-binding kinetics of cytochrome a3, in isolated, detergent-solubilized cytochrome oxidase have been studied by flash photolysis over wide ranges of CO concentration and temperature. The results strongly suggest that CO has an intermediate bound state in its path to the final bound state at the heme iron. In the temperture range 230-273 K in frozen aqueous solutions, the recombination rates depend upon CO concentration; at low CO concentrations the kinetics are biphasic. The rate of the faster process depends upon the detergent concentration, that of the slower process upon the salt concentration. In addition, the faster process depends upon the amount of CO photodissociated. It is concluded that the cytochrome oxidase molecules are aggregated in regions that contain detergent and possibly some lipids. The regions retain considerable fluid character well below the macroscopic freezing point of the solution. The faster phase of the recombination is interpreted as the rebinding of CO molecules that remain in the fluid region after photodissociation. The slower phase would then be due to the migration of some dissociated CO out into surrounding frozen solvent. The non-Arrhenius behavior of both phase probably represents partial melting of the medium; preliminary NMR measurements of mobile protons support this hypothesis. Many of the kinetic features described here are also seen in mitochondria; thus the detergent-solubilized cytochrome oxidase may be a useful model system for the ligand-binding behavior of the enzyme in the mitochondrial membrane.

Study of cytochrome oxidase co-binding site using low-temperature flash photolysis.

Flash photolysis has been used to study the kinetics of CO-binding to the heme alpha isolated cytochrome oxidase. Experiments performed over the range 185-295 degrees K with various CO concentrations have revealed significant deviations from the Arrhenius relationship between rate and temperature. These findings can be explained by a model in which the heme site is considered to have three regions between which CO can move; only from the innermost one can binding to the heme iron take place. The relative enthalpies and entropies of the three regions are calculated.

Cytochrome P450cam and its complexes. Mössbauer parameters of the heme iron.

Mössbauer spectroscopy has been used to study the heme iron in various states of cytochrome P450cam from the camphor-hydroxylating system of the bacterium Pseudomonas putida. Native, camphor-free P450cam contains low-spin ferric iron, part of which (approx. 50-70%) is converted to the high-spin ferric state upon addition of camphor. The Mössbauer spectra of the camphor-free enzyme (S equals 1/2) and of the high-spin component (S equals 5/2) of the camphor complex have been successfully simulated using a model based on crystal-field theory and simple convalency considerations. The native low-spin ferric state of P450cam forms a complex with 2-phenylimidazole, with small changes in the g values and Mössbauer spectra. These changes can be accounted for consistently in the crystal-field model referred to above. The addition of putidaredoxin to the camphor-complexed, oxidized P450cam decreases the intensity of the high-spin component and changes its quadrupole splitting. The reduced form of P450cam contrins high-spin ferrous iron, both in the presence and absence of camphor. The complex of reduced P450cam with molecular oxygen is diamagnetic and has a combination of quadrupole splitting and isomer shift that is unusual for a ferrous complex, but strongly resembles that of oxyhemoglobin. These results are compatible with the bound superoxide, Fe3+-O-2, model proposed for oxyhemoglobin (Weiss, J. J. (1964) Nature 202, 83-84). Reduced P450cam and its complexes, oxyP450cam-CO, are all found to be analogous in some respects to the corresponding hemoglobin complexes.

Study of an oxygenated heme complex in frozen solution by Mössbauer emission spectroscopy.

We have used Mössbauer emission spectroscopy to study an oxygenated heme complex, produced in a frozen solution by nuclear decay from the isomorphous (57)Co-labeled compound. The Mössbauer parameters agree with those obtained by Mössbauer absorption spectroscopy of oxyhemoglobin. Thus, a nonprotein environment for iron can duplicate the unique oxyhemoglobin Mössbauer spectrum. The electronic structure of the heme iron in oxyhemoglobin is not significantly influenced by the protein environment. Mössbauer emission spectroscopy can be useful in the investigation of heme proteins.