What components are important for effective healthcare alliance governance? Findings from a modified Delphi study in New Zealand

Alliance governance is a form of governance developed in industry settings and more recently applied to healthcare. The core idea behind alliance governance is to involve the many stakeholders in the system to collaboratively develop a joint programme that promotes an integrated and whole of systems approach to care. Little is known about the model in healthcare, nor what those involved in an alliance should be focused upon. Using a modified Delphi method, this research presents a set of components that research participants agreed should underpin development of an effective alliance governance arrangement.These characteristics include a systems perspective—a truly shared governance protocol based on a shared vision and a common purpose; performance measurement—collecting and using real-time data that depicts the realities of an end-to-end system to establish better and more achievable goals based on alliance performance; a relational perspective to promote trust, respect and collaboration amongst alliance members, who historically have been competing for contracts and resources; structural changes that enable and promote a shared governance system; and, finally, equity and inclusion to ensure a diverse alliance which promotes diversity of ideas, and involvement of all stakeholders in the decision making process. This research is relevant to policymakers seeking to develop effective alliance-type arrangements as well as to those involved in the practice of alliance governance.     

Modulation of oral squamous cell carcinoma incidence in rats via diet and a novel calcium channel antagonist

An unexpected dose related increase in oral squamous cell carcinomas was observed in a standard 2-year carcinogenicity study with a novel calcium channel blocker, in which Wistar rats received daily doses of 0, 1.5, 7, 20, or 40 mg/kg of the compound mixed with a standard diet containing fibers from barley. This finding was associated with an increased incidence of severe (destructive) periodontitis and the formation of oro-nasal fistulae at the 2 highest doses. Five assays of the compound for genotoxicity were negative indicating that a genotoxic effect was highly improbable. To investigate the underlying pathogenic mechanisms a second 2-year study in the same strain of rats was initiated and the influence of the diet and/or a possible local irritancy by the drug was assessed. In this second study the compound was administered by oral gavage at daily doses of 0, 7, or 40 mg/kg (later reduced to 20 mg/kg due to systemic intolerance) to rats maintained either on the standard diet or on a low fiber diet assumed to be less aggressive in terms of inducing periodontal lesions. Dose dependent gingival overgrowth (a class-related effect) was observed in the incisor and molar teeth area of all treated groups but was independent of the diet used. No oral tumors were found in the standard diet or low fiber diet controls and all treatment groups fed the low fiber diet, whereas in the high-dose group fed the standard diet a total of 8 oral squamous cell carcinomas were detected in association with an increased incidence of severe periodontitis. These results indicate that the increased incidence of squamous cell carcinomas observed upon chronic administration of the compound is not due to a direct tumorigenic effect of the drug. Tumor formation is attributable to severe periodontal disease favored by the diet and class related gingival overgrowth.     

Cytotoxic properties of a new synthetic demethylpodophyllotoxin derivative,BN 58705, against human tumor cell lines

The in vitro cytotoxic properties of a newly synthesized demethylpodophyllotoxin derivative, 4-o-butanoyl-4-demethylpodophyllotoxin (BN 58705), were determined by using several human tumor cell lines of different histological origin and of different sensitivity to conventional chemotherapeutic drugs (Adriamycin andcis-diammine-dichloride platinum). BN 58705 is shown to be cytotoxic against various human tumor cell lines as assessed by the MTT assay. Furthermore, BN 58705 is shown to be cytotoxic against several drug-resistant tumor cell lines. BN 58705 is cytotoxic at concentrations 100- to 1000-fold lower than those of Adriamycin orcis-diammine-dichloride platinum required to achieve similar cytotoxicity. BN 58705 did not mediate DNA fragmentation of target cells, whereas the epipodophyllotoxin-like etoposide induced DNA cleavage by stabilizing the DNA-enzyme intermediate. Like vinca alkaloids, BN 58705 induced a block in the mitotic phase of the cell cycle. By comparison, BN 58705 exerted a stronger cytotoxic activity in vitro than did either etoposide, an epipodophyllotoxin, or vincristine, a vinca alkaloid. When BN 58705 was applied in vivo in mice, it resulted in low toxicity (50% lethal dose, 150 mg/kg). These results demonstrate than BN 58705 is cytotoxic to drug-resistant human tumor cell lines and is manyfold more potent than conventional drugs. The cytotoxic potency and low toxicity of BN 58705 are important criteria to establish its potential chemotherapeutic efficacy in vivo.Abbreviations cpm counts per minute - BN 58705 4-o-butanoyl-4-demethylpodophyllotoxin - MTT 3-(4,5-dimethyl-thiazoyl-2-yl)-2,5-diphenyl-tetrazolium bromide - OD optical density - TRIS TRIS (hydroxymethyl) aminomethane - EDTA ethylenediaminetetraacetic acid - FITC fluoresceinisothiocyanate - PI propidium iodide This work was supported by a grant from Institut Henri Beaufour, France     

Total parenteral nutrition during acute pancreatitis: Clinical experience with 156 Patients

Over a 3-year period, 156 of 815 patients admitted to a single institution with acute pancreatitis received total parenteral nutrition (TPN) for 2,572 patient days. Seventy had simple acute pancreatitis (group I) and 86 (group II) developed local complex disease (pseudocyst, abscess, or necrotic gland). In groups I and II, respectively, days without oral intake (NPO) were 13.6±1.5 (SEM) and 24.0±2.1 (p<0.005), hospital days were 19.8±1.7 and 35.8±3.2 (p<0.005), and duration of TPN was 10.9 ±1.0 and 21.0±2.3 days (p<0.005). Thirty-three patients in group I and 53 in group II required exogenous insulin. Alteration of standard formulas was necessary in 87 patients, but cessation of therapy was necessary in only one instance. Twenty catheters were removed for suspected sepsis with only 3 confirmed cases. Fat-based formulas were well tolerated in 15% of patients. During TPN, body weight rose from 95.0±2.4% to 97.4±4.3% of ideal in group I and remained at 90.5±1.8% in group II. Albumin rose from 3.36±0.10 to 3.50±0.08 g/dl in group I and from 3.01±0.07 to 3.35±0.07 g/dl in group II. The entire cohort differed from 10 randomly chosen patients who did not receive TPN in terms of days NPO (2.8±0.3) and hospital days (5.5±0.6). Variables associated with prolongation of hospital stay and time NPO were number of prognostic criteria, local complex disease, and underlying chronic pancreatitis only in select groups. We conclude that during acute pancreatitis, TPN can be administered safely but with careful monitoring and we recommend early aggressive therapy in the subgroups noted above and when underlying malnutrition exists. In the borderline patient, TPN may be administered by peripheral vein until the severity of disease is manifest.

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Resumen En el curso de un período de 3 años, 156 de 815 pacientes hospitalizados en una sola institución por pancreatitis aguda recibieron nutrición parenteral total (NPT) durante 2,572 paciente-días. Setenta presentaban pancreatitis aguda simple (grupo I) y 86 (grupo II) desarrollaron enfermedad local complicada (pseudoquiste, absceso, o necrosis de la glándula). Las siguientes fueron las características de los grupos I y II, respectivamente: días sin ingesta oral (NPO) 13.6±1.5 (SEM) y 24.0±2.1 (p<0.005), días de hospitalización: 19.8±1.7 y 35.8±3.2 (p<0.005), y duración de la NPT: 10.9±1.0 y 21.0 ±2.3 días (p<0.005). Trienta y tres pacientes en el grupo I y 53 en el grupo II requirieron insulina exógena. Se requirió alterar la fórmula estándar en 87 pacientes, pero sólo fue necesario cesar la terapia en un caso. Veinte catéteres fueron retirados por sospecha de sepsis, pero sólo en 3 se confirmó. Las fórmulas a base de grasa fueron bien toleradas en 15% de los pacientes. En el curso de la NPT el peso corporal ascendió de 95.0±2.4% a 97.4±4.3% del peso ideal en el grupo I y se mantuvo a un 90.5±1.8% en el grupo II. La albúmina ascendió de 3.36±0.10 a 3.50±0.8 g/dl en el grupo I y de 3.01±0.07 a 3.35±0.07 g/dl en el grupo II. Toda la cohorte se diferenció de un grupo de 10 pacientes escogidos al azar que no recibieron NPT en términos del número de días NPO (2.8±0.3) y de días de hospitalización (5.5±0.6). Las variables que aparecieron asociadas con prolongación de la hospitalización y el tiempo NPO fueron el número de criterios de pronóstico, la enfermedad complicada, y la presencia de pancreatitis crónica subyacente sólo en grupos seleccionados. Nuestra conclusión es que en el curso de la pancreatitis aguda, la NPT puede ser administrada con seguridad pero bajo monitoría cuidadosa, y recomendamos terapia agresiva precoz en los subgrupos anotados anteriormente y cuando exista mal nutrición concomitante. En el paciente limitrofe se puede administrar la NPT por vía periférica hasta cuando la gravedad de la enfermedad se haga manifiesta.

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Résumé Pendant une période de 3 ans, 156 des 815 patients admis pour pancréatite aiguë ont reçu une alimentation parentérale totale (APT), soit en tout 2,572 jours patient. Soixante dix patients (groupe I) avaient une pancréatite simple et 86 (groupe II) avaient aussi une maladie locale complexe (pseudokyste, abcès ou nécrose du pancréas). La durée du jeûne était respectivement de 13.6±1.5 (ET) et de 24.0±2.1 (p<0.005), la durée moyenne de séjour était respectivement de 19.8±1.7 et de 35.8 ±3.2 (p<0.005) alors que la durée d'APT était respectivement de 10.9±1.0 et de 21.0±2.3 jours (p<0.005). Trente-trois patients dans le groupe I et 53 dans le groupe II avaient besoin d'insuline exogène. Un changement dans la formule standard a été nécessaire chez 87 patients mais l'APT n'a du être arrêté complètement que chez un patient seul. Vingt cathéters ont été enlevés avec suspicion de sepsis, confirmée cependant dans 3 cas seulement. Les compositions à base de lipides ont été bien tolérées chez 15% des patients. Pendant l'APT, le poids du corps s'est élevé de 95.0±2.4% à 97.4±4.3% du poids idéal chez les patients du groupe I et est resté à 90.5±1.8% chez ceux du groupe II. L'albumine s'est élevée de 3.36±0.10 à 3.50 ±0.08 g/dl dans le groupe I et de 3.01±0.07 à 3.35±0.07 g/dl dans le groupe II. La durée du jeûne (2.8±0.3) et la durée moyenne de séjour (5.5±0.6) de l'ensemble des patients différaient de ces mêmes données chez 10 autres patients choisis au hasard. Les facteurs associés avec un séjour hospitalier prolongé et sans alimentation orale étaient le nombre de critères pronostiques, l'existence de complications locales, et de pancréatite chronique sous-jacente chez certains patients. Nous concluons que pendant la pancréatite aiguë, l'APT peut être administrée sans danger sous contrôle permanent et nous conseillons un traitement agressif et précoce dans le sous groupe mentionné plus haut ou quand existe un état de nutrition déficient. Chez le patient limite, on peut se contenter d'APT par une veine périphérique tant que des signes de gravité ne se manifestent pas.

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Presented at the Société Internationale de Chirurgie in Toronto, Ontario, Canada, September, 1989.     

Nonlinear Binding of Valproic Acid (VPA) and E-Δ2-Valproic Acid to Rat Plasma Proteins

The binding characteristics of valproic acid (VPA) and its pharmacologically active monounsaturated metabolite, E-²-VPA, to rat plasma proteins were compared. The plasma free fraction was determined by a rapid equilibrium procedure, which minimizes the interfering effects of nonesterified fatty acids liberated by in vitro lipolysis. Nonlinear binding behavior was observed with both compounds over their respective pharmacologic concentration range. Multiple binding-site models were invoked to explain the binding isotherm. The 2-unsaturated compound has a much higher affinity for the rat plasma proteins (mainly albumin) than its saturated precursor. The equilibrium association constants for the high- and intermediate-affinity sites were more than an order of magnitude higher with E-²-VPA than with VPA (10⁴–10⁶ versus 10³ M ^–1). This difference in binding affinity was also reflected by a lower plasma free fraction for E-²-VPA compared with VPA (<<10 versus >20% at total concentrations of less than 100 µg/ml). A more pronounced dose- and concentration-dependent variation in the distribution and clearance kinetics is predicted for the 2-unsaturated analogue compared to VPA. Also, the structural dependency in plasma protein binding observed with these branched-chain fatty acids may provide insights into the mechanism of interaction between fatty acyl molecules and albumin.     

The role of alpha-agonists in glaucoma therapy

alpha-Agonists are a relatively old class of medications, the topical use of which lowers eye pressure. Clonidine was introduced for this use in 1966, brimonidine in 1974, and apraclonidine in 1978. Initial short-term attempts to use clonidine were complicated by problems with systemic hypotension. Apraclonidine is more polar and less lipophilic than clonidine. This probably allows less penetration into both the posterior segment of the eye and systemic circulation, allowing for an excellent therapeutic index. The prophylactic use of apraclonidine (1% and 0.5%) has dramatically changed the safety profile for many anterior segment laser procedures, cataract surgery, and vitrectomy. The role of alpha-agonists in the chronic treatment of glaucoma is still uncertain. Potential benefits of additional lowering of intraocular pressure must be weighed against the following potential disadvantages: tachyphalaxsis, posterior segment vasoconstriction, psychologic depression and fatigue, syncope and systemic hypotension, and a topical allergy-like syndrome.     

Labor market conditions and employment of the mentally ill

BACKGROUND: The mental health services literature includes assertions that workers with mental illness are at earlier risk of unemployment than other workers when the economy contracts. This possibility is important for several reasons. One is that such a phenomenon would support the argument that the lives of mentally ill persons are made unnecessarily stressful by the stigma of mental illness. Another is that the phenomenon could distort comparisons of the effectiveness of programs designed to prepare persons with severe mental illness for work. Despite its importance, the assertion that severely mentally ill workers are at early risk of unemployment has never been empirically tested. AIMS OF THE STUDY: We aim to test the hypothesis that unemployment among persons with severe mental illness (SMI) increases before job loss among other workers. METHODS: We test the hypothesis by applying Granger causality methods to time-series data collected in two communities in the United States (i.e., Concord and Manchester, NH) over 131 weeks beginning on 12 May 1991. RESULTS: We find no relationship between job loss in the labor market and the likelihood that persons with SMI will be unemployed. DISCUSSION: We speculate that persons with SMI participate in the secondary labor market and that their employment status is unlikely to be well described by data gathered in the primary labor market. This implies that widely available measures of labor market status, which are designed to describe the primary labor market, cannot be used to improve the evaluation of programs intended to prepare the mentally ill for work. We also discuss the possibility that persons with SMI may have needs that are better met by the secondary than by the primary labor market. CONCLUSIONS: The intuition that workers with severe mental illness are affected earlier than other workers by labor market contraction may not be correct. We infer that persons with severe mental illness may participate in the secondary labor market about which we know relatively little. We cannot, therefore, easily adjust program evaluations to disentangle intervention effects from those, if any, of the labor market.     

Human phase I vaccine trials of 3 recombinant asexual stage malaria antigens with Montanide ISA720 adjuvant

Two phase I vaccine trials were conducted to test the immunogenicity and safety of a vaccine containing three recombinant malaria antigens from the asexual stage of Plasmodium falciparum. The three antigens are a fragment of MSP1 (190LCS.T3); MSP2 and a portion of RESA and were formulated in Montanide ISA720 adjuvant. These trials investigated the dose response of each antigen for eliciting both antibody and T-cell responses and the immunogenicity of a mixture of the antigens compared with the antigens injected separately. All three antigens elicited both antibody and T-cell responses. Strong T-cell responses were observed with 190LCS.T3 and RESA with stimulation indices exceeding 100 for peripheral blood leucocytes in some individuals. The antibody responses were generally weak. The human antibody responses observed with MSP2 in Montanide ISA720 were not significantly different from those obtained in an earlier trial which used MSP2 with alum as the adjuvant. No antigenic competition was observed: volunteers receiving a mixture of antigens had similar responses to those receiving the three antigens at separate sites. Tenderness and pain at the injection site were common over the first few days following immunization. In some volunteers, especially those receiving the highest doses tested, there was a delayed reaction at the injection site with pain and swelling occurring approximately 10 days after injection.