Physician-reviewers' perceptions and judgments about quality of care.

OBJECTIVE: Although Peer Review Organizations (PROs) and researchers rely on physicians to assess quality of care, little is known about what physicians think about when they judge quality. We sought to identify features of individual cases that are associated with physicians' judgments. DESIGN: Using 1994 Medicare data, we selected hospitalizations for 1134 beneficiaries in 42 acute care hospitals in California and Connecticut. The sample was enriched with 17 surgical and six medical complications identified using diagnosis and procedure codes. PRO physicians confirmed quality problems using a structured implicit chart review instrument and provided written open-ended comments about each case. We coded physicians' comments for factors presumed to influence judgments about quality. RESULTS: In crude and adjusted comparisons, reviewers questioned quality more frequently in cases with serious or fatal outcomes, technical mishaps and inadequate documentation. Among surgical (but not medical) patients, they were less likely to record poor quality among patients presenting with an acute illness. CONCLUSION: Factors other than the adequacy of key processes of care are associated with physician-reviewers' judgments about quality.

Use of administrative data to find substandard care: validation of the complications screening program.

OBJECTIVE: The use of administrative data to identify inpatient complications is technically feasible and inexpensive but unproven as a quality measure. Our objective was to validate whether a screening method that uses data from standard hospital discharge abstracts identifies complications of care and potential quality problems. DESIGN: This was a case-control study with structured implicit physician reviews. SETTING: Acute-care hospitals in California and Connecticut in 1994. PATIENTS: The study included 1,025 Medicare beneficiaries greater than 265 years of age. METHODS: Using administrative data, we stratified acute-care hospitals by observed-to-expected complication rates and randomly selected hospitals within each state. We randomly selected cases flagged with 1 of 17 surgical complications and 6 medical complications. We randomly selected controls from unflagged cases. MAIN OUTCOME MEASURE: Peer-review organization physicians' judgments about the presence of the flagged complication and potential quality-of-care problems. RESULTS: Physicians confirmed flagged complications in 68.4% of surgical and 27.2% of medical cases. They identified potential quality problems in 29.5% of flagged surgical and 15.7% of medical cases but in only 2.1% of surgical and medical controls. The rate of physician-identified potential quality problems among flagged cases exceeded 25% in 9 surgical screens and 1 medical screen. Reviewers noted several potentially mitigating circumstances that affected their judgments about quality, including factors related to the patients' illness, the complexity of the case, and technical difficulties that clinicians encountered. CONCLUSIONS: For some types of complications, screening administrative data may offer an efficient approach for identifying potentially problematic cases for physician review. Understanding the basis for physicians' judgments about quality requires more investigation.

Does clinical evidence support ICD-9-CM diagnosis coding of complications?

BACKGROUND: Hospital discharge diagnoses, coded by use of the International Classification of Diseases, 9th Revision, Clinical Modification (ICD-9-CM), increasingly determine reimbursement and support quality monitoring. Prior studies of coding validity have investigated whether coding guidelines were met, not whether the clinical condition was actually present. OBJECTIVE: To determine whether clinical evidence in medical records confirms selected ICD-9-CM discharge diagnoses coded by hospitals. RESEARCH DESIGN AND SUBJECTS: Retrospective record review of 485 randomly sampled 1994 hospitalizations of elderly Medicare beneficiaries in Califomia and Connecticut. MAIN OUTCOME MEASURE: Proportion of patients with specified ICD-9-CM codes representing potential complications who had clinical evidence confirming the coded condition. RESULTS: Clinical evidence supported most postoperative acute myocardial infarction diagnoses, but fewer than 60% of other diagnoses had confirmatory clinical evidence by explicit clinical criteria; 30% of medical and 19% of surgical patients lacked objective confirmatory evidence in the medical record. Across 11 surgical and 2 medical complications, objective clinical criteria or physicians' notes supported the coded diagnosis in >90% of patients for 2 complications, 80% to 90% of patients for 4 complications, 70% to <80% of patients for 5 complications, and <70% for 2 complications. For some complications (postoperative pneumonia, aspiration pneumonia, and hemorrhage or hematoma), a large fraction of patients had only a physician's note reporting the complication. CONCLUSIONS: Our findings raise questions about whether the clinical conditions represented by ICD-9-CM codes used by the Complications Screening Program were in fact always present. These findings highlight concerns about the clinical validity of using ICD-9-CM codes for quality monitoring.

Biarylcarbamoylindolines are novel and selective 5-HT(2C) receptor inverse agonists: identification of 5-methyl-1-[[2-[(2-methyl-3-pyridyl)oxy]- 5-pyridyl]carbamoyl]-6-trifluoromethylindoline (SB-243213) as a potential antidepressant/anxiolytic agent.

The evolution, synthesis, and biological activity of a novel series of 5-HT(2C) receptor inverse agonists are reported. Biarylcarbamoylindolines have been identified with excellent 5-HT(2C) affinity and selectivity over 5-HT(2A) receptors. In addition, (pyridyloxypyridyl)carbamoylindolines have been discovered with additional selectivity over the closely related 5-HT(2B) receptor. Compounds from this series are inverse agonists at the human cloned 5-HT(2C) receptor, completely abolishing basal activity in a functional assay. The new series have reduced P450 inhibitory liability compared to a previously described series of 1-(3-pyridylcarbamoyl)indolines (Bromidge et al. J. Med. Chem. 1998, 41, 1598) from which they evolved. Compounds from this series showed excellent oral activity in a rat mCPP hypolocomotion model and in animal models of anxiety. On the basis of their favorable biological profile, 32 (SB-228357) and 40 (SB-243213) have been selected for further evaluation to determine their therapeutic potential for the treatment of CNS disorders such as depression and anxiety.

Model studies on a synthetically facile series of N-substituted phenyl-N'-pyridin-3-yl ureas leading to 1-(3-pyridylcarbamoyl) indolines that are potent and selective 5-HT(2C/2B) receptor antagonists.

A model series of 5-HT2C antagonists have been prepared by rapid parallel synthesis. These N-substituted phenyl-N'-pyridin-3-yl ureas were found to have a range of 5-HT2C receptor affinities and selectivities over the closely related 5-HT2A receptor. Extrapolation of simple SAR, derived from this set of compounds, to the more active but synthetically more complex 1-(3-pyridylcarbamoyl)indoline series allowed us to target optimal substitution patterns and identify potent and selective 5-HT(2C/2B) antagonists.

Novel and selective 5-HT2C/2B receptor antagonists as potential anxiolytic agents: synthesis, quantitative structure-activity relationships, and molecular modeling of substituted 1-(3-pyridylcarbamoyl)indolines.

The synthesis, biological activity, and molecular modeling of a novel series of substituted 1-(3-pyridylcarbamoyl)indolines are reported. These compounds are isosteres of the previously published indole urea 1 (SB-206553) and illustrate the use of aromatic disubstitution as a replacement for fused five-membered rings in the context of 5-HT2C/2B receptor antagonists. By targeting a region of space previously identified as sterically allowed at the 5-HT2C receptor but disallowed at the 5-HT2A receptor, we have identified a number of compounds which are the most potent and selective 5-HT2C/2B receptor antagonists yet reported. 46 (SB-221284) was selected on the basis of its overall biological profile for further evaluation as a novel, potential nonsedating anxiolytic agent. A CoMFA analysis of these compounds produced a model with good predictive value and in addition good qualitative agreement with both our 5-HT2C receptor model and our proposed binding mode for this class of ligands within that model.

The chemistry of Pseudomonic acid. 15. Synthesis and antibacterial activity of a series of 5-alkyl, 5-alkenyl, and 5-heterosubstituted oxazoles.

The synthesis of a range of 5-alkyl, 5-alkenyl, and 5-heterosubstituted 2-(1-normon-2-yl) oxazoles is described. The antibacterial activity was determined as the minimum inhibitory concentration against a range of Gram-positive and Gram-negative organisms using a standard Agar dilution procedure. Compounds possessing an acid functionality directly on, or close to, the ring were found to be of greatly decreased potency, while increasing lipophilicity with greater chain length led to increased potency of these derivatives.

The effect of implantation of osmotic pumps on rat thyroid hormone and testosterone levels in the plasma, an implication for tissue 'S' phase studies.

In order to monitor the effect of the procedures required to s.c. implant osmotic pumps into rats on plasma thyroid and testosterone hormone levels, male Fischer 344 rats (8-10 weeks old) were divided into six groups of 10 rats and the groups treated in the following manner: (1) controls housed 5 per cage; (2) controls housed individually; (3) animals anaesthetised for surgery and individually housed; (4) anaesthetised, sham operated and individually housed; (5) anaesthetised, s.c. implanted with osmotic pumps containing saline and individually housed; (6) anaesthetised, s.c. implanted with osmotic pumps containing 5-bromo 2-deoxyuridine (BRDU) and individually housed. Four days after performing the surgery the study was terminated and the level of hormones in the plasma determined by radio immunoassay (RIA). Tri-iodothyronine (T3) and thyroxine (T4) plasma levels (free and total) were significantly decreased with each additional step in the procedure used for the s.c. implantation of an osmotic pump containing BRDU, when compared with the individually housed controls. Similarly, testosterone plasma levels were significantly decreased by the s.c. implantation of osmotic pumps, implying a 'stress' response might occur following implantation. These observations might need to be considered by investigators when performing toxicological research which, as part of the study, uses osmotic pumps for the delivery of the nucleotide precursor required for monitoring cells in 'S' phase.

Enzymology in preclinical safety evaluation.

This short paper will briefly discuss the merits of determining plasma enzyme activities in pre-clinical safety evaluation. Emphasis is placed on the value of selecting the appropriate enzymes and collecting blood samples at the appropriate times during the study, so as to gain the maximum amount of diagnostic information. Examples of actual results will be cited to illustrate some of the points. These examples are drawn from the 2 commonly used toxicology species--the laboratory white rat and the beagle--and serve to demonstrate the importance of enzymology in monitoring the progress or resolution of an adverse drug effect.

Synthesis and biological activity of a series of piperazine-2,3-dione containing penicillins and 6 alpha-formamidopenicillins. I. Derivatives substituted at C(5) or C(6) of the piperazine ring.

The synthesis and antibacterial activity of a series of penicillins and 6 alpha-formamidopenicillins containing a C(5) or C(6)-substituted piperazine-2,3-dione moiety in the C(6)-beta-sidechain is described.

Role of testosterone and of its metabolites in regulating gonadotrophin secretion in the Japanese quail.

In the Japanese quail gonadal steroids can depress plasma levels of LH and FSH. Since it is now accepted that testosterone metabolites may be metabolized to the tissue-active forms of the hormone, the in-vitro tissue incubation has been combined with steroid replaement therapy in vivo to investigate the physiological roles of various testosterone metabolites as inhibitory feedback agents on gonadtorophin secretion in quail. After the incubation of quail pituitary glands for 3 h with labelled testosterone four metabolites could be identified; androst-4-ene-3,17-dione, 5 beta-dihydrotestosterone (5 beta-DHT), 5 beta-androstane-3 alpha, 17 beta-diol and 5 alpha-DHT. No 5 alpha-androstane-3 alpha, 17 beta-diol was found. Quantitatively, androstenedione was the major metabolite and converison of testosterone to 5 beta-metabolites was significantly greater than to 5 alpha-androgens. Hypothalamic and hyperstriatal tissues converted testosterone than to 5 alpha-androgens. Hypothalamic and hyperstriatal tissues converted testosterone to androstendione, 5 beta-DHT and 5 beta-androstane-3 alpha, 17 beta-diol but not to 5 alpha-DHT or 5 alpha-androstane-3 alpha, 17 beta-diol. Gonadotrophin secretion was studied in castrated quail after chronic s.c. implantation of steroid-containing silicone elastomer capsules or acute injection i.m. of steroid in ethanol: saline. Irrespecive of the route of administration seven androgens, listed in descending order of potency, reduced the increased levels of plasma LH: testosterone: 5 alpha-DHT; androstenedione; 5 alpha-androstane-3, 17-dione; 5 alpha-androstane-3 alpha, 17 beta-diol; 5 alpha-androstan-3 alpha-ol-17-one; 5 alpha-androstan-3 beta-ol-17-one. No changes in levels of plasma LH were observed after the administration of 5 beta-DHT, 5 alpha-androstane-3 beta,17 beta-diol, 5 beta-androstante-3 alpha, 17 beta-diol, 5 beta-androstane-3, 17-dione, androst-5-ene-3 beta, 17 beta-diol or androst-5-en-3 beta-ol-17-one. Testosterone and oestradiol-17 beta were effective in inhibiting secretion of both LH and FSH in young photostimulated quail and completely blocked testicular growth: 5 alpha-DHT inhibited only the release of LH and testicular growth was unaffected.

Cloacal gland of the Japanese quail: androgen dependence and metabolism of testosterone.

A cloacal gland complex whose growth and development is androgen-dependent exists in the Japanese quail. In-vitro incubation studies of the cloacal gland using 4-14C-labelled testosterone as substrate allowed the positive identification of five metabolites: androstenedione, 5 beta-dihydrotestosterone (5 beta-DHT), 5 beta-androstane-3 alpha, 17 beta-diol, 5 alpha-DHT and 5 alpha -androstane-3 alpha, 17 beta-diol. More polar metabolites, not yet chemically identified, were detected in trace amounts. Androstenedione appeared to be the main testosterone metabolite in immature birds while in mature birds on long daylengths testosterone was preferentially metabolized to 5 alpha-DHT. This change may have been in response to the higher levels of plasma steroids found in mature birds. When various testosterone metabolites, contained in silicone elastomer capsules, were implanted s.c. into castrated birds maintained on a photostimulatory light regime, 5 alpha-DHT, 5 alpha-androstane-3,17-dione, androstenedione and 5 alpha-androstan-3 alpha-ol-17-one were shown to be equipotent with testosterone in stimulating the development of the cloacal gland. 5 alpha-Androstane-3 alpha, 17 beta-diol and 5 alpha-androstan-3 beta-ol-17-one stimulated some growth while 5 beta-DHT, 5 alpha-androstane-3 beta, 17 beta-diol, 5 alpha-androstane-3 alpha, 17 beta-diol, 5 beta-androstane-3,17-dione, androst-5-en-3 beta-ol-17-one and androst-5-ene-3 beta, 17 beta-diol were completely ineffective.

The neuroendocrine control of gonadotrophin release in the Japanese quail. III. The role of the tuberal and anterior hypothalamus in the control of ovarian development and ovulation.

Reproduction in the Japanese quail (Coturnix coturnix japonica), as in many other species, is controlled by the length of the daily photoperiod. The present experiments have investigated the neuroendocrine regulation of both the photoperiodically induced 'tonic' gonadotrophin secretion, which causes the development and maintenance of the ovary, and the 'cyclic' surge release of luteinizing hormone (LH), which stimulates ovulation. Areas within the anterior and tuberal hypothalamus were destroyed by means of electrolytic lesions while a small knife was used to isolate, to various degrees, the tuberal hypothalamus. Information was obtained on the regulation of 'tonic' and 'cyclic' secretion of gonadotrophin by using immature and mature laying females, respectively. The results indicate that the neuroendocrine regulation of photoperiodically induced gonadotrophin secretion in immature quail appears to be controlled by two discrete hypothalamic centres, the infundibular nuclear complex (i.n.c.) and the preoptic region (po.r.). The supraoptic region (so.r.) appears to have no influence on photoperiodically induced ovarian development. Deafferentation reveals that afferents from the anterior hypothalamus enter the tuberal region in a diffuse manner from both anterior and lateral directions. As in the developing animals, destruction of either the i.n.c. or the po.r. in mature birds results in a complete block to 'tonic' gonadotrophin release and to regression of the ovaries. When the supraoptic region is destroyed, the 'cyclic' ovulatory surge of LH is blocked and a polyfollicular syndrome ensues in which the ovaries, still under the influence of 'tonic' gonadotrophin release, grow to a very large size, but no ovulation takes place. An intramuscular injection of progesterone stimulates a release of LH in both untreated mature females and in sham-operated females, but not in so.r.-lesioned birds. Priming these lesioned females with oestrogen and progesterone restores, in some birds, the ability to respond positively to progesterone stimulation.

Possible priming effect of luteinizing hormone releasing hormone on the anterior pituitary gland in the Japanese quail and the stimulation of secretion of follicle-stimulating hormone.

After the i.m. injection of 10 micrograms synthetic LH releasing hormone (LH-RH) into Japanese quail the levels of LH and FSH in plasma rose significantly within 2 min. The increased level of LH declined rapidly but that of FSH was maintained for the duration of the experiment. To determine whether the anterior pituitary gland is primed by LH-RH a double injection schedule was adopted. It would appear that, while endogenous LH-RH may prime the avian pituitary gland slightly, synthetic LH-RH is ineffective.