Clinical categories of patients and encounter rates in primary health care – a three-year study in defined populations

BACKGROUND: The objective was to estimate the proportion of inhabitants with a diagnosis-registered encounter with a general practitioner, and to elucidate annual variations of clinical categories of patients in terms of their individual comorbidity. METHODS: A three-year retrospective study of encounter data from electronic patient records, with an annual-based application of the Johns Hopkins Adjusted Clinical Groups (ACG) system. Data were retrieved from every patient with a diagnosis-registered encounter with a GP during the period 2001–2003 at 13 publicly managed primary health care centres in Blekinge county, southeastern Sweden, with about 150000 inhabitants. Main outcome measures: Proportions of inhabitants with a diagnosis-registered encounter, and ranges of the annual proportions of categories of patients according to ACGs. RESULTS: The proportion of inhabitants with a diagnosis-registered encounter ranged from about 64.0% to 90.6% for the primary health care centres, and averaged about 76.5% for all inhabitants. In a three-year perspective the average range of categories of patients was about 0.4% on the county level, and about 0.9% on the primary health care centre level. About one third of the patients each year had a constellation of two or more types of morbidity. CONCLUSION: About three fourths of all inhabitants had one or more diagnosis-registered encounters with a general practitioner during the three-year period. The annual variation of categories of patients according to ACGs was small on both the county and the primary health care centre level. The ACG system seems useful for demonstrating and predicting various aspects of clinical categories of patients in Swedish primary health care

Rational Design of Thermodynamic and Kinetic Binding Profiles by Optimizing Surface Water Networks Coating Protein Bound Ligands

A previously studied congeneric series of thermolysin inhibitors addressing the solvent-accessible S₂′ pocket with different hydrophobic substituents showed modulations of the surface water layers coating the protein-bound inhibitors. Increasing stabilization of water molecules resulted in an enthalpically more favorable binding signature, overall enhancing affinity. Based on this observation, we optimized the series by designing tailored P₂′ substituents to improve and further stabilize the surface water network. MD simulations were applied to predict the putative water pattern around the bound ligands. Subsequently, the inhibitors were synthesized and characterized by high-resolution crystallography, microcalorimetry, and surface plasmon resonance. One of the designed inhibitors established the most pronounced water network of all inhibitors tested so far, composed of several fused water polygons, and showed 50-fold affinity enhancement with respect to the original methylated parent ligand. Notably, the inhibitor forming the most perfect water network also showed significantly prolonged residence time compared to the other tested inhibitors

Intensive care unit diaries to help bereaved family members in their grieving process : a systematic review

Background: Intensive care unit diaries are often used to support patients during their psychological recovery. The intensive care unit stay can be upsetting, disturbing and traumatic for both patients and their families especially when the patient does not survive. Aim: To investigate the connection between intensive care unit diaries and the grieving process experienced by family members of adult patients deceased in the intensive care unit. Methods: Systematic literature review according to PRISMA guidelines: PubMed, CINAHL and Cochrane Library were consulted. The Caldwell's framework was used for the quality appraisal. Results: Only six studies examine this topic. The potential benefits of intensive care unit diaries in family members’ bereavement process may be an aid to realise how extremely ill their loved one was, may provide comfort and may help relatives to cope with their loss. Conclusion: The use of intensive care unit diaries to help family members’ bereavement process may be a useful tool but further research is necessary to better understand their role and benefits.

Elucidating the Origin of Long Residence Time Binding for Inhibitors of the Metalloprotease Thermolysin

Kinetic parameters of protein-ligand interactions are progressively acknowledged as valuable information for rational drug discovery. However, a targeted optimization of binding kinetics is not easy to achieve, and further systematic studies are necessary to increase the understanding about molecular mechanisms involved. We determined association and dissociation rate constants for 17 inhibitors of the metalloprotease thermolysin by surface plasmon resonance spectroscopy and correlated kinetic data with high-resolution crystal structures in complex with the protein. From the structure-kinetics relationship, we conclude that the strength of interaction with Asn112 correlates with the rate-limiting step of dissociation. This residue is located at the beginning of a β-strand motif that lines the binding cleft and is commonly believed to align a substrate for catalysis. A reduced mobility of the Asn112 side chain owing to an enhanced engagement in charge-assisted hydrogen bonds prevents the conformational adjustment associated with ligand release and transformation of the enzyme to its open state. This hypothesis is supported by kinetic data of ZF; P; LA, a known pseudopeptidic inhibitor of thermolysin, which blocks the conformational transition of Asn112. Interference with this retrograde induced-fit mechanism results in variation of the residence time of thermolysin inhibitors by a factor of 74 000. The high conservation of this structural motif within the M4 and M13 metalloprotease families underpins the importance of this feature and has significant implications for drug discovery

Price for Opening the Transient Specificity Pocket in Human Aldose Reductase upon Ligand Binding Structural, Thermodynamic, Kinetic, and Computational Analysis

Insights into the thermodynamic and kinetic signature of the transient opening of a protein-binding pocket resulting from accommodation of suitable substituents attached to a given parent ligand scaffold are presented. As a target, we selected human aldose reductase, an enzyme involved in the development of late-stage diabetic complications. To recognize a large scope of substrate molecules, this reductase opens a transient specificity pocket. The pocket-opening step was studied by X-ray crystallography, microcalorimetry, and surface plasmon resonance using a narrow series of 2-carbamoyl-phenoxy-acetic acid derivatives. Molecular dynamics simulations suggest that pocket opening occurs only once an appropriate substituent is attached to the parent scaffold. Transient pocket opening of the uncomplexed protein is hardly recorded. Hydration-site analysis suggests that up to five water molecules entering the opened pocket cannot stabilize this state. Sole substitution with a benzyl group stabilizes the opened state, and the energetic barrier for opening is estimated to be ∼5 kJ/mol. Additional decoration of the pocket-opening benzyl substituent with a nitro group results in a huge enthalpy-driven potency increase; on the other hand, an isosteric carboxylic acid group reduces the potency 1000-fold, and binding occurs without pocket opening. We suggest a ligand induced-fit mechanism for the pocket-opening step, which, however, does not represent the rate-determining step in binding kinetics