Longitudinal Outcomes of GastroIntestinal symptoms in Canada (LOGIC): key factors for an effective patient retention in observational studies.

BACKGROUND: Longitudinal Outcomes of GastroIntestinal symptoms in Canada (LOGIC) is an ongoing study on irritable bowel syndrome (IBS) treatment patterns and health outcomes in routine Canadian clinical practice. Advancements in understanding IBS, a chronic multifaceted GI disorder, may be possible through methodical observational studies. The objective of this paper is to describe site recruitment techniques and extensive subject follow-up methodology used to facilitate a high return rate of questionnaires from this population-based study of subjects with IBS. METHODS: Invitation letters along with protocol synopses and preliminary site assessment questionnaires were faxed to potential sites across Canada. There were 1,556 subjects enrolled in this study from general practitioner sites (GP) and specialist sites (SP) in Canada. Subjects were compensated for the return of questionnaires reporting symptoms, quality of life, productivity, healthcare and resource utilization at baseline, Month 1, 3, 6, 9, and 12. Upon the return of questionnaires, subjects received thank you cards which included a reminder of the next questionnaire's due date. If subject questionnaires were not received within 2 weeks after the due date, the subjects received a reminder letter in the mail. RESULTS: The methodology in the LOGIC study allowed for a high patient questionnaire return rate (89%) through extensive subject reminders and follow-up. Subject participation throughout the study was not found to be linked to study site size or type (GP or SP). CONCLUSION: Questionnaire based observational studies may benefit from focusing resources on increasing questionnaire return rates to effectively maintain data reliability and also reduce non-response bias.

Symptomatic and health status outcomes in the Canadian randomized MAC treatment trial (CTN010). Canadian HIV Trials Network Protocol 010 Study Group.

Our objective was to compare the effect of 2 regimens for treatment of Mycobacterium avium complex (MAC) bacteraemia in an HIV-positive population on symptoms and health status outcomes using a substudy of an open-label randomized controlled trial. The study was conducted in 24 hospital-based human immunodeficiency virus (HIV) clinics in 16 Canadian cities. Patients had HIV infection and MAC bacteraemia and were given either rifampin 600 mg, ethambutol 15 mg/kg daily, clofazimine 100 mg daily and ciprofloxacin 750 mg twice daily (4-drug arm) or rifabutin 600 mg daily (amended to 300 mg daily in mid-trial), ethambutol 15 mg/kg daily and clarithromycin 1000 mg twice daily (3-drug arm). The primary health status outcome was the change on the 8-item symptom subscale of the Medical Outcome Study (MOS)-HIV Health Survey adapted for MAC. Changes on other MOS-HIV subscales and on the Karnofsky score were also evaluated. Patients on the 3-drug arm had better outcomes on the MOS-HIV symptom subscale at 16 weeks (P=0.06), with statistically significant differences restricted to night sweats and fever and chills (P < 0.001). The proportion of patients improving on the symptom subscale relative to baseline was 55% on the 3-drug arm and 40% on the 4-drug arm. Patients on the 3-drug arm also had better Karnofsky score at 16 weeks (P < 0.001) and better outcomes on the social function, mental health, energy/fatigue, health distress and cognitive function subscales of the MOS-HIV. The 3-drug arm is superior to the 4-drug arm in terms of impact on MAC-associated symptoms, functional status and other aspects of health status.

A randomized trial of N-acetylcysteine for prevention of trimethoprim-sulfamethoxazole hypersensitivity reactions in Pneumocystis carinii pneumonia prophylaxis (CTN 057). Canadian HIV Trials Network 057 Study Group.

Hydroxylamine derivatives of sulfamethoxazole may be the reactive metabolites that cause adverse reactions to trimethoprim-sulfamethoxazole (TMP-SMX). The increased frequency of reactions observed in HIV-positive individuals is hypothesized to be due to systemic glutathione deficiency and a decreased ability to scavenge these metabolites. Two hundred and thirty-eight patients were randomized to receive or not receive N-acetylcysteine (3 g of the 20% liquid solution) 1 hour before each dose of TMP-SMX (trimethoprim 80 mg, sulfamethoxazole 400 mg) twice daily, which was initiated as primary Pneumocystis carinii pneumonia prophylaxis. Forty-five patients had to discontinue TMP-SMX within 2 months because of fever, rash, or pruritus including 25 of 102 patients (25%) who were receiving TMP-SMX alone and 20 of 96 patients (21%) who were randomized to TMP-SMX and N-acetylcysteine. The difference between treatment groups is 4% (95% confidence interval [CI]: -16%, +9%). No independent association was found with the hypersensitivity reaction and age, gender, race, HIV risk factor, prior AIDS, concurrent use of fluconazole, or baseline CD4. N-acetylcysteine at a dose of 3 g twice daily could not be shown to prevent TMP-SMX hypersensitivity reactions in patients with HIV infection.

Activin and follistatin as local regulators in the human ovary.

There is increasing evidence that activin may act as an autocrine/paracrine regulator of ovarian functions. Activin subunit mRNAs as well as activin immunoreactivities have been detected in the human ovary. Activin alters granulosa cell proliferation and steroidogenesis. The effect of activin is most likely mediated through specific receptors as mRNAs encoding several forms of activin receptors, namely ActR-I, ActR-IB, ActR-II and ActR-IIB are found in the preovulatory follicles as well as in cultured granulosa-luteal cells. Activin-binding protein, follistatin (FS), is also produced in the human ovary. In addition to neutralizing the effect of activin on steroid production, FS on its own also enhances estradiol production, an effect similar to that seen after activin treatment. These findings strongly suggest that activin and FS are important local regulators of steroidogenesis in the human ovary.

Stimulation of progesterone secretion by recombinant follistatin-288 in human granulosa cells.

The effects of recombinant human follistatin (follistatin-288) on basal and hCG-stimulated progesterone secretion were examined in cultured human granulosa cells. Follistatin increased progesterone secretion in a dose-dependent manner. However, follistatin did not augment hCG- or cAMP-stimulated progesterone secretion. Time-course analysis revealed that follistatin increased progesterone secretion after 24 h of incubation. Follistatin also enhanced basal, but not hCG-stimulated, 20 alpha-hydroxyprogesterone accumulation, indicating that the increase in progesterone accumulation was not due to a blockade of the 20 alpha-hydroxylase metabolic pathway. In the presence of the phosphodiesterase inhibitor isobutylmethylxanthine, follistatin significantly increased intracellular cAMP accumulation to levels comparable to those induced by 1 IU/ml hCG. These results provide the first evidence of a stimulatory action of follistatin on progestin secretion in the human ovary, which is accompanied by an increased accumulation of intracellular cAMP levels. Follistatin may well be another potential regulator of steroid hormone production in human granulosa cells during the periovulatory period.