Individualized prescribing portraits to reduce inappropriate initiation of opioid analgesics to opioid naïve patients in primary care: Protocol for a randomized controlled trial.

Background Opioid analgesics are frequently initiated for chronic and acute pain despite weak evidence of benefit, although prescribing rates of some analgesics decreased in the context of the epidemic. In some populations, up to a quarter of opioid naïve persons prescribed opioids for non-cancer pain develop prescription opioid use disorder (OUD). Audit and feedback interventions rely on constructive use of routinely collected data to align professional behaviours and clinical practice with best evidence. These interventions have been shown to help reduce inappropriate initiation. However, effectiveness and acceptability of individualized "portraits" of physicians' prescribing patterns, to reduce inappropriate initiation of opioid analgesics to opioid naïve persons, have not been evaluated. Methods REDONNA is a mixed-methods randomized study testing the effectiveness of individualized prescribing Portraits to reduce inappropriate initiation of opioid analgesics. This intervention to improve safety of opioid prescribing in primary care in British Columbia (BC), Canada involves mailing individual prescribing portraits to an 'early group' of 2604 family physicians, followed in 6 months by a mailing to 2553 family physicians in the 'delayed group'. Primary outcome is number of new opioid prescriptions initiated in opioid naïve people, measured using administrative data from a centralized medication monitoring database covering all prescription opioids dispensed from BC community pharmacies. Secondary endpoints will compare prescribing impact between the two groups. A qualitative sub-study will examine feasibility among a purposive sample of physicians and patients. Discussion This trial provides important evidence on the intervention's potential to steer policy and practice on inappropriate opioid analgesics initiation. Trial registration: The study was registered prospectively on 30 March 2020 at the ISRCTN Register (https://www.isrctn.com/ISRCTN34246811).

Corticosteroid signaling at the brain-immune interface impedes coping with severe psychological stress.

The immune system supports brain plasticity and homeostasis, yet it is prone to changes following psychological stress. Thus, it remains unclear whether and how stress-induced immune alterations contribute to the development of mental pathologies. Here, we show that following severe stress in mice, leukocyte trafficking through the choroid plexus (CP), a compartment that mediates physiological immune-brain communication, is impaired. Blocking glucocorticoid receptor signaling, either systemically or locally through its genetic knockdown at the CP, facilitated the recruitment of Gata3- and Foxp3-expressing T cells to the brain and attenuated post-traumatic behavioral deficits. These findings functionally link post-traumatic stress behavior with elevated stress-related corticosteroid signaling at the brain-immune interface and suggest a novel therapeutic target to attenuate the consequences of severe psychological stress.

Silver-doped self-assembling di-phenylalanine hydrogels as wound dressing biomaterials.

Chronic and acute wounds can be quickly contaminated and infected by microorganisms such as bacteria, multi-resistant organisms or fungi. The introduction of silver as anti-microbial agent into wound management has widely been demonstrated to be effective and contribute to wound healing. As a consequence, many approaches and different materials have been employed to synthesize antibacterial silver-hydrogels. In this work the introduction of silver particles into the fibrillar structure of self-assembling aromatic di-phenylalanine derivatives modified with aromatic groups such as 9-fluorenylmethoxycarbonyl is proposed to produce antibacterial wound dressings. Hydrogels doped with increasing amounts of silver were tested and adopted to modify flax textiles. The influence of silver on the structure of hydrogels was studied using light and confocal microscopy, while SEM-EDX allowed the characterization of the hydrogel coating on the surface of the textile substrates as well as the identification and distribution of silver nanoparticles. The antibacterial potential of the treated flax was demonstrated through microbiological tests on Staphylococcus aureus. The combination of the physico-chemical and anti-bacterial properties, together with the ease of preparation of these biomaterials, fulfils the requirement of clinically-effective wound dressings.

Feasibility study for the development of certified reference materials for specific migration testing. Part 1: initial migrant concentration and specific migration.

The paper describes a project with the main objective of developing the know how to produce certified reference materials (CRMs) for specific migration testing. Certification parameters discussed are the initial concentration of the migrant in the polymer (C(P),0) and the specific migration into a food simulant under certain temperature/time conditions. Sixteen preliminary candidate CRMs were defined and produced. The most important polymers (low- and high-density polyethylene (LDPE and HDPE), polypropylene (PP), polystyrene (PS), polyethylene terephtalate (PET), plasticized polyvinyl chloride (PVC), rigid PVC, polyamides (PA)) and additives as well as monomers representing different physicochemical properties as target substances for migration were chosen. The stability and homogeneity of the migrants in the materials were tested and methods for the determination of the certification parameters were developed and validated. > From the 16 materials produced, the six most suitable CRM candidates (LDPE//Irganox 1076/Irgafos 168, LDPE//1,4-diphenyl-1,3-butadiene (DPBD), HDPE//Chimassorb 81/Uvitex OB, PP homo//Irganox 1076/Irgafos 168, HIPS, 1% mineral oil//styrene, PA 6//caprolactam) were selected. The feasibility of CRM production for the six candidate materials was demonstrated and a trial certification exercise was performed with participation of all four partner laboratories. All six materials showed suitable properties for future production as certified reference materials.

Effects of differential overexpression of Bcl-2 on apoptosis, proliferation, and telomerase activity in Jurkat T cells.

The effects of Bcl-2 overexpression on several of its multifunctional characteristics, which include anti-apoptotic properties, impeding of cell proliferation, and telomerase activity, were examined in four Jurkat T cell clones overexpressing different levels of Bcl-2. When treated with anti-Fas or staurosporine, only three of the four clones showed resistance to apoptosis that correlated with the level of Bcl-2 expression. Surprisingly, the clone having no anti-apoptotic characteristic expressed the highest level of Bcl-2. When all the clones were treated with anti-Fas the processing of caspase-2, -3, and -7 but not -8 was inhibited in the resistant clones to a similar extent by the differential overexpression of Bcl-2. However, with staurosporine treatment the processing of all the caspases examined was inhibited to a similar degree by the different levels of Bcl-2 expression in the resistant clones. These results suggest that Bcl-2 blocked Fas-mediated cell death by acting downstream of caspase-8, which is in contrast to staurosporine-induced apoptosis where Bcl-2 is acting upstream of caspase-8. When the anti-proliferative effect of Bcl-2 was examined, a direct correlation between a decrease in cell proliferation and the level of Bcl-2 overexpressed in the clones was observed. The clone overexpressing the greatest amount of Bcl-2 protein, which had no resistance to apoptosis, had the slowest proliferative rate. This suggests that the anti-apoptotic effect of Bcl-2 can be separated from its anti-proliferative effect. The possible effect of overexpression of Bcl-2 on telomerase activity, which is known to control the proliferative capacity of normal cells and cellular senescence, was also determined. Our results suggest that Bcl-2 had no effect on telomerase activity or telomere length in the clones. In summary, our results further suggest that some properties of Bcl-2, such as anti-apoptotic and inhibition of cell proliferation, are individual features of a multifaceted protein.

Prognostic markers of disease activity in Hodgkin's disease.

The erythrocyte sedimentation rate (ESR), liver alkaline phosphatase (ALP), serum copper (Cu) and urinary nucleoside excretion (UNs) have been proposed as independent prognostic markers in Hodgkin's Disease (HD). However, their prognostic value has not satisfactorily been directly compared to recognised clinical prognostic factors. One hundred and sixty-eight patients with HD had the above markers performed prior to initial treatment. At a median follow-up of 10.9 yrs, the predicted 10 year relapse free survival (RFS) and overall survival (OS) for the entire cohort is 64% and 66%, respectively. In general, patients with elevated markers were significantly less likely to achieve CR, remain in CR and survive. However, multivariate analysis revealed this was due to the association of elevated markers with stage and constitutional symptoms. Following therapy, elevated markers were also correlated with evidence of clinically detectable disease. We conclude that although UNs, Cu, ALP and ESR reflect disease activity, they do not provide independent information beyond that of clinical assessment.

Survey of bisphenol a diglycidyl ether (BADGE) in canned foods.

2,2-Bis(4-hydroxyphenyl)propane bis(2,3-epoxypropyl) ether (BADGE) is used in the manufacture of lacquers for coating the inside of food and beverage cans. In June 1996 the EC Scientific Committee for Food temporarily increased the specific migration limit applying to BADGE to 1 mg/kg pending consideration of additional toxicological data. In order to find out if there is migration of BADGE from can coatings into foods, a 'worst case' sampling exercise has been conducted to survey those canned foods where the propensity for migration of BADGE was judged to be highest. The foods surveyed include canned fish in oil, meat and milk and, altogether, BADGE was determined in 181 retail samples. Analysis for BADGE was conducted, in duplicate, by HPLC with fluorescence detection with confirmation of BADGE identity by GC/MS analysis using selected ion monitoring. BADGE was found at levels exceeding 1 mg/kg in seven of the 15 canned anchovy samples and five of the 22 sardine samples purchased during the period September 1995-July 1996. Infrared analysis of the can coatings provided strong evidence that the higher BADGE levels found were associated with use of PVC organosol lacquers, although in some cases cans coated with organosols gave low BADGE results. For canned sardine samples found to contain greater than 0.5 mg/kg BADGE in the total contents, a replicate can was opened and separate analyses performed on the drained fish and the oil. The results clearly showed that BADGE concentrations in the oil were about 20 times higher than in the drained fish. Further samples of canned sardines and anchovies were purchased in June/July 1997 and, in all cases, BADGE levels were found to be below 1 mg/kg. In the other retail canned foods, BADGE was not detectable (DL = 0.02 mg/kg) or detected at concentrations well below the temporary SML of 1 mg/kg.

Prognostic value of cytogenetic abnormalities in previously untreated patients with non-Hodgkin's lymphoma.

In this study cytogenetic findings have been correlated with prognosis in 78 previously untreated patients with non-Hodgkin's lymphoma (NHL) presenting between 1983 and 1988. The median follow-up was 7 years (range 2-9 years). There was no significant difference in the duration of survival of 33 patients with only abnormal karyotypes, 35 patients with a mixture of normal and abnormal karyotypes (AN) and 10 patients with only normal karyotypes (NN). This was true for the entire group (p = 0.6) as well as for the subsets of diffuse lymphomas (DL) and follicular lymphomas (FL) (p = 0.6 and 0.4, respectively). Monosomy 14 was the only abnormality in the entire group of patients to be associated with a statistically significant difference in survival duration (p = 0.046). Among the FL patients, trisomy 7 (p = 0.046) and trisomy 12 (p = 0.010) were associated with shorter survival. Presence of t(14;18) did not influence survival in the entire group (p = 0.16), nor in any of the histological subgroups. Among the FL patients with t(14;18), presence of additional cytogenetic abnormalities was not associated with a worse outcome. The lack of consistency of results between various studies is likely to be due to several factors and the prognostic significance of karyotypic abnormalities can only be clarified by large prospective studies employing uniform treatment policies.

Treatment of advanced Hodgkin's disease with chemotherapy--comparison of MOPP/ABV hybrid regimen with alternating courses of MOPP and ABVD: a report from the National Cancer Institute of Canada clinical trials group.

PURPOSE: This randomized, prospective trial compares outcomes for patients with advanced Hodgkin's disease treated with mechlorethamine, vincristine, procarbazine, and prednisone (MOPP)/doxorubicin, bleomycin, and vinblastine (ABV) hybrid regimen or alternating MOPP/doxorubicin, bleomycin, vinblastine, and dacarbazine (ABVD). METHODS: Three hundred one patients with advanced Hodgkin's disease were randomized to receive MOPP/ ABV hybrid regimen or alternating MOPP/ABVD after stratification for prior treatment, B symptoms, and treatment center. Eligible patients were either previously untreated and found to have stage IIIB, IVA, or IVB disease or previously treated with wide-field irradiation. Responding patients received a minimum of eight cycles of chemotherapy. Those with residual disease in a localized region received irradiation between the sixth and seventh cycle of treatment. RESULTS: Response rates to the two regimens were similar. Five-year overall survival rates were 81% and 83% for MOPP/ABV hybrid and alternating MOPP/ ABVD, respectively (P = .74; 95% confidence interval [CI] for the difference, -11% to 7%). Five-year failure-free survivals were 71% and 67% for MOPP/ABV hybrid and alternating MOPP/ABVD, respectively (P = .87; 95% CI for the difference, -9% to 17%). Significantly more episodes of febrile neutropenia and stomatitis were observed with the MOPP/ABV hybrid regimen; there was no significant difference in fatal toxicity. Patients with predefined, high-quality partial responses (PR-1s) had results similar to those with complete responses (CRs). Planned subset analysis showed no significant difference in outcome between the two arms of the trial for patients with newly diagnosed disease (5-year failure-free survival rates were 70% for MOPP/ABV hybrid and 59% for alternating MOPP/ABVD; P = .180), but superiority of alternating MOPP/ABVD for patients with prior irradiation (5-year failure-free survival 94% v 73%; P = .017). CONCLUSION: MOPP/ABV hybrid and alternating MOPP/ABVD regimens are equally effective for patients with advanced Hodgkin's disease.

Long-term survival advantage of MACOP-B over CHOP in intermediate-grade non-Hodgkin's lymphoma. The Australian and New Zealand Lymphoma Group.

BACKGROUND: The initial publication of the results of the Australian and New Zealand Lymphoma Group (ANZLG) randomized controlled trial comparing MACOP-B and CHOP in patients with intermediate-grade non-Hodgkin's lymphoma (NHL) showed equivalent complete response rates, time to treatment failure, and survival. Here we report the long-term follow-up of the 236 patients entered on that study to determine if there were any long-term advantages or disadvantages associated with MACOP-B. PATIENTS AND METHODS: Two hundred thirty-six eligible patients were randomized between October 1986 and June 1991. The median duration of follow-up has been extended from 3.2 years in our previous publication to 6.5 years. RESULTS: As previously reported, the complete response (CR) rate for MACOP-B and CHOP chemotherapy was 51% and 59%, respectively. The estimated failure-free survival rate for MACOP-B and CHOP patients was 42% and 30%, respectively, at 5 years (P = 0.045) and 37% and 25%, respectively, at 8 year (P = 0.057). The estimated overall survival rate at 5 years was 54% for MACOP-B and 41% for CHOP patients (P = 0.035) and at 8 years was 45% and 36%, respectively (P = 0.16). CONCLUSION: With this extended follow-up, we have shown a long-term survival advantage for MACOP-B chemotherapy over standard CHOP in patients with intermediate-grade non-Hodgkin's lymphoma.

Interaction between a murine myeloma cell line and bone marrow stromal cells.

Intravenous transplantation of an in vitro maintained murine myeloma cell line, 5T33, results in progressive growth in the bone marrow of C57Bl/KaLwRiJ mice. Concurrent with the growth of the tumor in vivo, the bone marrow stromal cells are inhibited, as assayed by their ability to form stromal cell foci and long-term monolayers in vitro. Inhibition of normal mouse marrow stromal cell growth also occurs when 5T33 cells are added to the marrow cells in vitro, and contact between the marrow and 5T33 cells is not necessary to achieve inhibition, indicating secretion of one or more diffusible inhibitory factors.

Post-splenectomy lymphocytosis.

We describe post-splenectomy lymphocytosis (PSL) in 23 patients, a majority (20/23) of whom have undergone splenectomy as a staging procedure for Hodgkin's disease. The absolute lymphocyte count ranged from 4.0 to 8.7 x 10(9)/l. The lymphocytosis was noted 4-242 (median 70) months after splenectomy and persisted almost unchanged in most patients on prolonged follow up (median 50 months). Immunophenotyping of the lymphocytes revealed no monoclonal B cell population.

Vancomycin-resistant Enterococcus faecium sepsis following persistent colonization.

Vancomycin-resistant enterococci have emerged as important nosocomial pathogens and represent a serious threat to patients with impaired host defenses. We describe a patient with leukemia who developed prolonged colonization with vancomycin-resistant Enterococcus faecium and ultimately died of sepsis due to this multidrug-resistant organism. This case report confirms that colonization with vancomycin-resistant enterococci may last indefinitely and that asymptomatic carriage can lead to invasive infection.

Lymphocyte predominant Hodgkin's disease: a clinicopathologic comparative study of histologic and immunophenotypic subtypes.

PURPOSE: To compare the clinicopathologic features of the histologic and immunophenotypic subgroups of lymphocyte predominant Hodgkin's disease. METHODS AND MATERIALS: A retrospective review of 64 patients with lymphocyte predominant Hodgkin's disease treated at the Peter MacCallum Cancer Institute, Melbourne, was performed. Nodular and diffuse histological subtypes were confirmed by review of hematoxylin and eosin paraffin sections. Immunophenotyping with monoclonal antibodies L26 (B-cell origin) and Leu M1 (Hodgkin's phenotype) were available in 36 patients. RESULTS: The estimated freedom from progression and estimated overall survival at 10 years was 74% standard error (SE 5.8%) and 85% (SE 5.2%), non-Hodgkin's respectively. There were no significant differences in freedom from progression or overall survival when nodular and diffuse histology were compared. Similarly the presence of B-cell markers did not influence prognosis. There was only one case of secondary non-Hodgkin's lymphoma. CONCLUSION: Our results are consistent with major reported series displaying no differences between any of the subgroups of lymphocyte predominant Hodgkin's disease.

Association of abnormalities of chromosome 11 with t(14;18) in diffuse non-Hodgkin's lymphoma.

Cytogenetic studies of non-Hodgkin's lymphomas (NHL) have revealed a nonrandom translocation, t(14;18)(q32;q21), to be strongly correlated with follicular histology. In our recent study of 149 cases of NHL, 68 cases had a t(14;18). Forty-four of these were follicular and 24 diffuse. In the majority of cases (90%) there were additional chromosome abnormalities, which were analyzed to determine whether any were specifically associated with diffuse histology. Chromosome 11 abnormalities occurring together with the t(14;18) were found to be present in 17/68 cases; 14/17 (82%) were diffuse and 3/17 (18%) were follicular NHL. Thus, 14/24 (58%) of all diffuse lymphomas with t(14;18) had an abnormality of chromosome 11 compared to only 3/44 (7%) of follicular lymphomas, suggesting that the addition of an abnormality of chromosome 11 to a t(14;18) karyotype is associated with diffuse histology.

Selection of patients for randomised trials: a study based on the MACOP-B vs CHOP in NHL study.

BACKGROUND: Selection of patients for a clinical trial is affected by awareness of the existence of the trial, interest in the study question and clinical practices and views of the clinicians. AIMS: To investigate the selectivity that may have occurred at Peter MacCallum Cancer Institute (PMCI) during the ANZ Lymphoma Group trial of MACOP-B vs CHOP in non-Hodgkin's lymphoma (NHL). METHODS: NHL patients at PMCI in the study period were assessed against the trial's eligibility criteria. Comparisons were made between eligible (except for consent) non-trial patients and all patients actually randomised into the trial. RESULTS: Of 497 patients presenting during the trial period, 320 (64%) did not meet the specified eligibility criteria, 102 (21%) were unsuitable on other grounds (age and medical) and 75 (15%) were eligible. Of those eligible, 43 (57%) were entered into the trial and 32 (43%) were not. Four non-trial patients had inappropriate application of eligibility criteria and 13 unknown reason. Eligible non-trial patients were similar to trial patients in most patient and tumour characteristics and overall survival. Significantly more non-trial patients had higher stage disease (p = 0.02). More non-trial patients had lower grade histology, but this was not significant. CONCLUSIONS: Physician selectivity occurred with respect to patient entry, but trial and non-trial patients were similar in most characteristics. Eligibility criteria should specify that patients can withstand all trial drugs and patient availability for treatment and follow-up. PMCI trial accural could have been up to 33% greater. These results suggest the trial accrual period could have been 25% shorter. Patient entry into this trial by PMCI clinicians compared favourably with other centres.

Randomized comparison of MACOP-B with CHOP in patients with intermediate-grade non-Hodgkin's lymphoma. The Australian and New Zealand Lymphoma Group.

PURPOSE: To compare complete response rates, time to failure, survival, and toxicity for patients with intermediate-grade non-Hodgkin's lymphoma (NHL) treated with cyclophosphamide, doxorubicin, vincristine, and prednisolone (CHOP) versus those treated with a regimen consisting of methotrexate, doxorubicin, cyclophosphamide, vincristine, prednisolone, and bleomycin (MACOP-B), in a multicenter, randomized controlled trial performed by 22 centers of the Australian and New Zealand Lymphoma Group (ANZLG). PATIENTS AND METHODS: Between October 1986 and June 1991, 304 patients were randomized, of whom 236 were eligible for analysis. Eligibility criteria included diffuse small cleaved-cell, diffuse mixed small- and large-cell, follicular large-cell, diffuse large-cell, and large-cell immunoblastic, stages I bulky or II to IV. RESULTS: There was no significant difference in complete response rates (51% for MACOP-B v 59% for CHOP), failure-free survival, or overall survival in the two treatment arms. The rate of death of MACOP-B patients relative to CHOP patients was estimated to be 0.91 (P = .64) when stratified by prognostic group. There were no significant differences between the two regimens in any of the prognostic subgroups. Toxicity was significantly more severe with MACOP-B, particularly cutaneous toxicity, stomatitis, and gastrointestinal ulceration. The average relative dose-intensity (RDI) of MACOP-B was 0.91 and of CHOP was 0.90, indicating good dose delivery in this multicenter group setting. CONCLUSION: CHOP chemotherapy produced results equivalent to those of MACOP-B in patients with intermediate-grade NHL and with significantly fewer toxic complications. Despite relatively poor results in some patient subgroups, CHOP remains the standard chemotherapy for this disease, against which all new regimens should be compared.

Secondary myelodysplastic syndrome following bone marrow transplantation: report of two cases.

We report two cases of secondary myelodysplastic syndrome (SMDS) which followed successful treatment of a primary malignancy with high-dose chemotherapy supported by reinfusion of autologous stem cells. The SMDS was diagnosed 24 months and 40 months, respectively, following autografting. Both patients lived for 7 months after the diagnosis of SMDS. Our cases support the view that there is an increased risk of SMDS/acute leukemia following autologous marrow transplantation.