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Background: The cascade of care, commonly used to assess HIV and hepatitis C (HCV) health service delivery, has limitations in capturing the complexity of individuals' engagement patterns. This study examines the dynamic nature of engagement and mortality trajectories among people with HIV and HCV., Methods: We used data from the Canadian HIV-HCV Co-Infection Cohort, which prospectively follows 2098 participants from 18 centers biannually. Markov multistate models were used to evaluate sociodemographic and clinical factors associated with transitioning between the following states: (1) lost-to-follow-up (LTFU), defined as no visit for 18 months; (2) reengaged (reentry into cohort after being LTFU); (3) withdrawn from the study (ie, moved); (4) death; otherwise remained (5) engaged-in-care., Results: A total of 1809 participants met the eligibility criteria and contributed 12 591 person-years from 2003 to 2022. LTFU was common, with 46% experiencing at least 1 episode, of whom only 57% reengaged. One in 5 (n = 383) participants died during the study. Participants who transitioned to LTFU were twice as likely to die as those who were consistently engaged. Factors associated with transitioning to LTFU included detectable HCV RNA (adjusted hazards ratio [aHR], 1.37; 95% confidence interval [CI], 1.13-1.67), evidence of HCV treatment but no sustained virologic response result (aHR, 1.99; 95% CI, 1.56-2.53), and recent incarceration (aHR, 1.94; 95% CI, 1.58-2.40). Being Indigenous was a significant predictor of death across all engagement trajectories., Interpretation: Disengagement from clinical care was common and resulted in higher death rates. People LTFU were more likely to require HCV treatment highlighting a priority population for elimination strategies., Competing Interests: Potential conflicts of interest. The authors declare the following financial interests: S. S. reports receiving honorariums for participation in ad hoc advisory boards for Novo Nordisk. M. B. K. reports grants for investigator-initiated studies from ViiV Healthcare, AbbVie, and Gilead; and consulting fees from ViiV Healthcare, Merck, AbbVie, and Gilead. J. G. reports receiving honorariums for participation in ad hoc advisory boards for ViiV Gilead and Merck. A. W. reports research grants from ViiV HealthCare, AbbVie, and Gilead Sciences and consulting fees from ViiV Healthcare, AbbVie, Merck, and Gilead Sciences. C. C. reports speaker fees, advisor fees and program support from Gilead Sciences, AbbVie, and ViiV Healthcare. J. C. reports grants for investigator-initiated studies from ViiV Healthcare and Gilead and consulting fees from ViiV Healthcare and Gilead. V. M. L. reports research grant from Merck and Gilead and consulting fee from AbbVie. S. W. reports grants for investigator-initiated studies from ViiV Healthcare, Merck, and Gilead and consulting fees and speaking at CME events for ViiV Healthcare, Merck, Gilead and Jannsen. All other authors report no potential conflicts., (© The Author(s) 2024. Published by Oxford University Press on behalf of Infectious Diseases Society of America.)

Objective: HIV-1 epidemics among MSM remain unchecked despite advances in treatment and prevention paradigms. This study combined viral phylogenetic and behavioural risk data to better understand underlying factors governing the temporal growth of the HIV epidemic among MSM in Quebec (2002-2015)., Methods: Phylogenetic analysis of pol sequences was used to deduce HIV-1 transmission dynamics (cluster size, size distribution and growth rate) in first genotypes of treatment-naïve MSM (2002-2015, n = 3901). Low sequence diversity of first genotypes (0-0.44% mixed base calls) was used as an indication of early-stage infection. Behavioural risk data were obtained from the Montreal rapid testing site and primary HIV-1-infection cohorts., Results: Phylogenetic analyses uncovered high proportion of clustering of new MSM infections. Overall, 27, 45, 48, 53 and 57% of first genotypes within one (singleton, n = 1359), 2-4 (n = 692), 5-9 (n = 367), 10-19 (n = 405) and 20+ (n = 1277) cluster size groups were early infections (<0.44% diversity). Thirty viruses within large 20+ clusters disproportionately fuelled the epidemic, representing 13, 25 and 42% of infections, first genotyped in 2004-2007 (n = 1314), 2008-2011 (n = 1356) and 2012-2015 (n = 1033), respectively. Of note, 35, 21 and 14% of MSM belonging to 20+, 2-19 and one (singleton) cluster groups were under 30 years of age, respectively. Half of persons seen at the rapid testing site (2009-2011, n = 1781) were untested in the prior year. Poor testing propensity was associated with fewer reported partnerships., Conclusion: Addressing the heterogeneity in transmission dynamics among HIV-1-infected MSM populations may help guide testing, treatment and prevention strategies.

Background: Patients with cirrhosis are known to experience sleep disturbance, which negatively impacts health-related quality of life., Objective: To assess the prevalence and predictors of sleep disturbance before and after liver transplantation (LT)., Methods: Both pre- and post-LT patients were administered the Basic Nordic Sleep Questionnaire. The primary outcome was overall sleep satisfaction; the secondary outcomes were sleep latency and sleep duration., Results: Eighty-three patients participated pre-LT and 273 post-LT. Overall, participants having completed both pre- and post-LT questionnaires reported satisfactory sleep 61% of the time before LT and 65% of the time after LT. However, on review of all questionnaires, patients with alcoholic liver disease (ETOH) experienced dramatically less sleep disturbance (OR 0.13 [95% CI 0.03 to 0.60]) post-LT, whereas those with hepatitis C remained without improvement (OR 0.90 [95% CI [0.38 to 2.15]). On logistic regression, patients with ETOH had statistically less sleep satisfaction pre-LT (OR 5.8 [95% CI 1.0 to 40.5]) and significantly better sleep satisfaction post-LT (OR 0.50 [95% CI 0.20 to 1.00]) compared with those with hepatitis C. In addition, both ETOH and other conditions had significantly better sleep latency than hepatitis C patients., Conclusions: Sleep parameters for patients who undergo LT for hepatitis C do not improve following LT as much as they do in patients transplanted for ETOH. Following LT, patients transplanted for ETOH are significantly more satisfied with their sleep than those transplanted for hepatitis C. Physicians should address and manage sleep quality after LT, so as to ultimately improve quality of life.

Background: Clozapine remains the antipsychotic of choice for people who, having met the criteria for a diagnosis of schizophrenia or a related psychotic disorder, do not respond adequately to other antipsychotic medications. Utilization rates appear highly variable across jurisdictions, with an overall tendency toward underuse. This paper describes patterns of clozapine use in the province of Québec, Canada., Methods: Individuals with a diagnosis of schizophrenia were identified using linked government medical claims and hospitalization records for 2003 and 2004. Linked data on their filled prescriptions in 2004 were then used to determine clozapine-use rates at the level of the province, the region, and the hospital at which individuals received most of their services. Individual predictors of clozapine use were identified using logistic regression., Results: Only 6.7% of the 29,155 individuals identified with schizophrenia received clozapine for six months or longer in 2004. Utilization rates ranged from 3.9 to 9.0% among regions with 1,000 or more people with schizophrenia. Over 8% of 61 hospitals did not prescribe clozapine at all. People with schizophrenia taking clozapine experienced 3.4 fewer days of hospitalization per year than those not taking clozapine-representing a cost offset of about $1,800 per year. Medication costs were higher, however, by about $3,000 per year., Conclusions: Given the increasingly clear benefits of clozapine for people who do not respond to other antipsychotics, measures to increase access to clozapine for people who can benefit from it are likely to be cost effective and are urgently needed.

Standard statistical analyses of randomized controlled trials with partially missing outcome data often exclude valuable information from individuals with incomplete follow-up. This may lead to biased estimates of the intervention effect and loss of precision. We consider a randomized trial with a repeatedly measured outcome, in which the value of the outcome on the final occasion is of primary interest. We propose a modelling strategy in which the model is successively extended to include baseline values of the outcome, then intermediate values of the outcome, and finally values of other outcome variables. Likelihood-based estimation of random effects models is used, allowing the incorporation of data from individuals with some missing outcomes. Each estimated intervention effect is free of non-response bias under a different missing-at-random assumption. These assumptions become more plausible as the more complex models are fitted, so we propose using the trend in estimated intervention effects to assess the nature of any non-response bias. The methods are applied to data from a trial comparing intensive case management with standard case management for severely psychotic patients. All models give similar estimates of the intervention effect and we conclude that non-response bias is likely to be small.

We have studied the activity of recombinant human tumor necrosis factor (rHuTNF) on six different human tumor xenografts derived from primary breast and bowel tumors and maintained by passage in nude mice. When 5 micrograms rHuTNF was given daily intratumorally to mice with established (approximately, 0.5 cm) tumors, total tumor regression was observed by 3-4 weeks in three of six xenograft lines. In a further two lines tumor stasis or significant slowing of growth was seen. This antitumor action was not accompanied by any consistent macroscopic change in the tumor such as necrosis, but histological examination revealed tumor cell degeneration and a large peritumoral infiltration of host inflammatory cells after 4-7 days therapy. In contrast to these data, little effect was seen when the same dose of rHuTNF was administered i.p. to nude mice bearing these tumors. In only two of six lines was any significant slowing of tumor growth seen. A 5-fold increase in the i.p. dose resulted in improved activity on only one of two xenograft lines tested. Efficacy of the i.p. rHuTNF dose could, however, be enhanced by simultaneous administration of human interferon, alpha or gamma. No obvious signs of toxicity were observed at all rHuTNF doses administered and weights of control and treated mice at the end of the experiments were comparable.

Human lymphoblastoid interferon strongly increased the anti-tumor activity of suboptimal doses of two commonly used anti-cancer drugs, cyclophosphamide and Adriamycin, on a human breast tumor xenograft growing in nude mice. A combination of human lymphoblastoid interferon with either of these agents caused regression and in some cases total disappearance of tumors at doses of drug and interferon that, used singly, were capable only of inhibiting tumor growth. The combined therapy also resulted in a greatly increased survival. Studies with interferon and cyclophosphamide indicated that the antitumor activity was greatest when the two agents were administered simultaneously rather than sequentially.

The mechanism of increased antitumor activity when human lymphoblastoid interferon [HuIFN-alpha(Ly)] and the drugs cyclophosphamide and Adriamycin are used in combination on a human tumor xenograft in nude mice has been investigated. HuIFN-alpha(Ly) did not affect hepatic levels of the drug-metabolizing enzymes cytochrome P-450 or the glutathione S-transferases. In contrast, mouse interferon caused significant and differential changes in the isozymic forms of these enzymes. However, addition of mouse interferon to the HuIFN-alpha(Ly)/cyclophosphamide or Adriamycin combinations had no effect on the final result, and did not increase the toxicity of the combination therapy. These data provide evidence that the increased activity of the combination therapy is due to effects on the tumor rather than on the host. Further studies showed significant perturbations in the tumor cell cycle after in vivo combination therapy. Cyclophosphamide caused an accumulation in G2 and the addition of HuIFN-alpha(Ly), which alone caused little change in cycle distribution, delayed this G2 block and strongly increased the number of cells in S phase. A similar, although less pronounced, effect was seen with HuIFN-alpha(Ly)/Adriamycin therapy. The increase in S phase seen in combined therapy may account for the synergy seen.

Relationships between calcium of blood plasma and measurements of the electrocardiogram QT interval corrected for heart rate and interval from Q to the apex of T corrected for heart rate were investigated in six dairy cows. Calcium was varied by infusing 4.7% solution of ethylenediaminetetra-acetic acid disodium salt to induce hypocalcemia, followed by treatment with calcium borogluconate. The within-cow regressions of the intervals on calcium in plasma were significant in all four electrocardiogram leads (leads I, aVF, SIII, and SaVF). These regressions differed between cows in these same leads. Correlation coefficients between calcium and the intervals were consistently larger than --.94 in lead SIII in all cows. When the results from four of the cows similar in age and breed were analyzed separately, regression coefficients between individual cows were not significantly different. However, intervals adjusted for calcium in plasma differed between cows.

We have studied the activity of recombinant human gamma-interferon and recombinant human tumor necrosis factor alpha against four human ovarian cancer i.p. xenografts OS, LA, HN, and DO derived from primary tumor material. In the OS xenograft all control mice died by 42 days and therapy starting 7 days after tumor cell injection with 5 X 10(4) units recombinant human gamma-interferon or 1 microgram recombinant human tumor necrosis factor alpha alone had no significant effect on cumulative survival in three separate experiments. However, a combination of the two agents resulted in 85% cumulative survival at 150 days. This combination therapy also significantly increased survival of mice treated as late as 21 days after tumor cell injection. In the LA xenograft (where control mice were all dead by 23 days) therapy with either agent alone, or a combination, more than doubled survival time of mice. In the HN xenograft all control mice were dead at 22 days whereas either therapy alone or in combination gave +85% cumulative survival at 100 days. In a fourth xenograft, DO, survival of mice in the combination therapy group was significantly increased. Thus these two biological therapies, alone or in combination, show significant activity against human ovarian cancer cells.