The World Health Organization recommends intermittent preventive treatment in pregnancy (IPTp) with sulfadoxine-pyrimethamine (SP) in African regions with moderate to high malaria transmission. ...However, growing resistance to SP threatens the effectiveness of IPTp-SP, and alternative drugs are needed. This study tested the efficacy, tolerability, and safety of a fixed-dose combination azithromycin-chloroquine (AZCQ; 250 mg AZ/155 mg CQ base) for IPTp relative to IPTp-SP.
A randomized, Phase 3, open-label, multi-center study was conducted in sub-Saharan Africa (Benin, Kenya, Malawi, Tanzania, and Uganda) between October 2010 and November 2013. Pregnant women received 3 IPTp courses with AZCQ (each course: 1,000/620 mg AZCQ QD for 3 days) or SP (each course 1,500/75 mg SP QD for 1 day) at 4- to 8-week intervals during the second and third trimester. Long-lasting insecticide-treated bednets were also provided at enrollment. Study participants were followed up until day 28 post delivery (time window: day 28-42). The primary endpoint was the proportion of participants with sub-optimal pregnancy outcomes (a composite endpoint comprising live-borne neonates with low birth weight LBW, <2,500 g, premature birth <37 weeks, still birth >28 weeks, abortion ≤28 weeks, lost to follow-up prior to observation of pregnancy outcome, or missing birth weight). The study was terminated early after recruitment of 2,891 of the planned 5,044 participants, due to futility observed in a pre-specified 35% interim analysis. In the final intent-to-treat dataset, 378/1,445 (26.2%) participants in the AZCQ and 342/1,445 (23.7%) in the SP group had sub-optimal pregnancy outcomes, with an estimated risk ratio (RR) of 1.11 (95% CI: 0.97, 1.25; p = 0.12). There was no significant difference in the incidence of LBW between treatment groups (57/1138 5.0% in the AZCQ group, 68/1188 5.7% in the SP group, RR 0.87 95% CI: 0.62, 1.23; p = 0.44). IPTp-AZCQ was less well-tolerated in mothers than IPTp-SP. Occurrences of congenital anomalies, deaths, and serious adverse events were comparable in neonates for both groups. Limitations included the open-label design and early study termination.
IPTp-AZCQ was not superior to IPTp-SP in this study and alternatives for IPTp-SP remain to be identified. The proportions of sub-optimal pregnancy outcomes and LBW were lower than expected, which may be linked to insecticide-treated bednet use throughout the study. Reduced incidences of symptomatic malaria infection and peripheral parasitemia in the AZCQ group relative to SP suggest that AZCQ warrants further investigation as an alternative treatment of uncomplicated malaria.
ClinicalTrials.gov (NCT01103063).
Multinational clinical trials are logistically complex and require close coordination between various stakeholders. They must comply with global clinical standards and are accountable to multiple ...regulatory and ethical bodies. In resource-limited settings, it is challenging to understand how to apply global clinical standards to international, national, and local factors in clinical trials, making multiple-level stakeholder engagement an important element in the successful conduct of these clinical trials.
During the planning and implementation of a large multinational clinical trial for intermittent preventive treatment of malaria in pregnancy in resource-limited areas of sub-Saharan Africa, we encountered numerous challenges, which required implementation of a range of engagement measures to ensure compliance with global clinical and regulatory standards. These challenges included coordination with ongoing global malaria efforts, heterogeneity in national regulatory structures, sub-optimal healthcare infrastructure, local practices and beliefs, and perspectives that view healthcare providers with undue trust or suspicion. In addition to engagement with international bodies, such as the World Health Organization, the Malaria in Pregnancy Consortium, the Steve Biko Centre for Bioethics, and the London School of Hygiene and Tropical Medicine, in order to address the challenges just described, Pfizer Inc. and Medicines for Malaria Venture (the "Sponsoring Entities" for these studies) and investigators liaised with national- and district-level stakeholders such as health ministers and regional/local community health workers. Community engagement measures undertaken by investigators included local meetings with community leaders to explain the research aims and answer questions and concerns voiced by the community. The investigators also engaged with family members of prospective trial participants in order to be sensitive to local practices and beliefs.
Engagement with key stakeholders at international and national levels enabled the Sponsoring Entities to address challenges by aligning the study design with the requirements of health and regulatory agencies and to understand and address healthcare infrastructure needs prior to trial initiation. Local stakeholder engagement, including community members, study participants, and family enabled the investigators to address challenges by ensuring that study design and conduct were adapted to local considerations and ensuring accurate information about the study aims was shared with the public.
ClinicalTrials.gov, ID: NCT01103063 . Registered on 7 April 2010.
Abstract Background Source control, any procedure used to control the source of a major infection, is critical to the resolution of intra-abdominal infections. We sought to characterize whether ...surgeons agree on methods of source control for patients who had persistent infection despite initial surgical treatment and antimicrobials. Methods We analyzed source control decisions in a trial comparing tigecycline with imipenem in the treatment of intra-abdominal infections for patients who were clinical failures and had persistent abdominal infections after treatment with antibiotics and undergoing source control. Results We found that source control agreement was least among patients who had Acute Physiology and Chronic Health Evaluation (APACHE) II scores greater than 15 (κ = −.17, P = .533) and those with complicated appendicitis (κ = .08, P = .446). There was excellent agreement in the source control decisions for perforation (κ = .76, P = 0.002) and diverticulitis (κ = 1.00, P = .005). Conclusions Agreement on source control is lacking on more severely ill patients and those with complicated appendicitis. These data should be used to seek optimal management for these conditions and to minimize variability in future clinical trials of intra-abdominal infection.
Firearm-related injuries and deaths are an endemic problem in the US, posing a burden on the healthcare system with significant social and economic consequences. As front-line care providers for ...these patients, neurosurgeons are both knowledgeable about these injuries and credible messengers in the public discussion of ways to reduce firearm injuries. The purpose of this study was to explore US-based neurosurgeons' views and behaviors regarding firearms to understand and define a potential role for neurosurgical organizations in advocacy efforts to reduce firearm death and injuries.
The authors conducted an anonymous survey of US neurosurgeons using the American Association of Neurological Surgeons (AANS) member database from April to June 2023. The 22-question survey included questions related to firearm ownership, personal views on firearms, and support for both general and policy-specific advocacy efforts to reduce firearm deaths and injuries.
The survey response rate was 20.7%, with 1568 of the 7587 members invited completing the survey. The survey completion rate was 93.4%, with 1465 of the 1568 surveys completed and included in this analysis. The majority of respondents were male (raw: 81.7%; weighted 81.1%), White (raw: 69.7%; weighted 70.2%), and older than 50 years (raw: 56.2%; weighted: 54%). Most respondents reported treating patients with firearm injuries (raw: 83.3%; weighted: 82%), 85.5% (weighted: 85.1%) had used a firearm, and 42.4% (weighted: 41.5%) reported owning a firearm. Overall, 78.8% (weighted: 78.7%) of respondents felt that organized neurosurgery should participate in advocacy efforts. When examining individual policies, those that restrict the acquisition of firearms garnered the support of at least 65% of respondents, while nonrestrictive policies were supported by more than 75% of respondents. Free-text responses provided insight into both motivations for and objections to organizational advocacy.
The majority of US-based neurosurgeons support involvement in advocacy efforts to reduce firearm deaths and injuries. Themes expressed by members both supporting and objecting to advocacy provide insight into approaches that could ensure broad support. Neurosurgical organizations such as the AANS and Congress of Neurological Surgeons may use the results of this survey to make informed decisions regarding involvement in advocacy efforts on behalf of their membership to lessen the burden of firearm injury in the US.
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