1. In this phase 3 randomized, alteplase-controlled, open-label clinical trial, recombinant human prourokinase (rhPro-UK) was noninferior to controls when used within 4.5 hours of acute ischemic stroke (AIS) symptom onset.
2. There were fewer cases of systemic bleeding in the rhPro-UK group compared to the alteplase group.
Evidence Rating Level: 1 (Excellent)
Intravenous thrombolysis (IVT) within 4.5 hours of AIS symptom onset is first-line therapy, and alteplase is the preferred agent. Prourokinase is a specific plasminogen activator acting on fibrin at the thrombus site, and animal stroke models have demonstrated its associated decreased risk for intracranial hemorrhage (ICH) and systemic bleeding, decreased infarct volume, and reduced neurological deficits with its use. rhPro-UK, recombinant human prourokinase, is already approved in China for the treatment of acute myocardial infarction. It is also more cost-effective than r-tPA. A phase 2 randomized clinical trial (RTC) demonstrated that rhPro-UK was effective when used within 4.5 hours of stroke onset and the current phase 3 trial sought to further study its noninferiority to alteplase in this context. A total of 663 patients were included in the analysis and were sorted into either the rhPro-UK group or the alteplase group in a 1:1 ratio. Cerebral computed tomography (CT) was used as the imaging method. There was no significant difference in the achievement of excellent functional outcomes at 90 days between the two groups (P = .81), nor was there a significant difference in major neurological improvement at 24 hours (P = .49) or 90 days (P = .77). There was no significant difference in all-cause mortality at 90 days (P = .30) between the groups, and rates of symptomatic ICH between the two groups were also similar. However, the alteplase group did demonstrate more systemic bleeding within 90 days (P < .001) when compared to the rhPro-UK group. There were no significant differences in the incidence of serious adverse events or recurrent ischemic stroke within 7 days. Overall, the results of this RCT demonstrate the noninferiority of rhPro-UK compared to alteplase when used within 4.5 hours of AIS onset, presenting a potentially cost-effective alternative in the management of AIS.
Comparative Effectiveness of Anticoagulants in Patients With Cancer-Associated Thrombosis
1. This comparative effectiveness study found that in patients with cancer, direct oral anticoagulants (DOACs) were associated with a decreased risk for venous thromboembolism (VTE) in comparison to low-molecular-weight heparin (LMWH) and warfarin.
2. DOAC use was also associated with a decreased risk of major bleeding compared to LMWH.
Evidence Rating Level: 2 (Good)
Cancer-associated thrombosis (CAT) is a multifactorial-influenced complication owing to an increased risk of VTE recurrence and major bleeding. Current guidelines indicate the use of LMWH for cancer-associated VTE, and warfarin is also a standard treatment modality in community-based oncology practices. However, more recent randomized clinical trials have supported DOACs in the management of cancer-associated VTE treatment. This retrospective cohort comparative effectiveness study analyzed claims-based data from OptumLabs to assess the safety and efficacy of these three anticoagulant classes. Analyses included 5100 adult patients with a primary cancer diagnosis (except skin cancer) who were treated for VTE. DOACs were administered in a 2:1:1 ratio with LMWH and warfarin. The risk of VTE recurrence and all-cause mortality were the main efficacy outcomes, and the primary safety outcomes included the risk of hospitalizations due to significant bleeding. Those receiving LMWH or warfarin demonstrated an increased risk of VTE recurrence compared to those using DOACs (LMWH: HR, 1.47; 95% CI, 1.14-1.90; warfarin: HR, 1.46; 95% CI, 1.13-1.87). Patients receiving LMWH experienced increased risk of all-cause mortality (LMWH: 21.18 per 100 person-years; DOACs: 11.36 per 100 person-years; LMWH vs DOAC: HR: 1.61; 95% CI, 1.15-2.25), hospitalization for major bleeding (HR, 2.27; 95% CI, 1.62-3.20), gastrointestinal (GI) bleeding (LMWH vs DOAC: HR, 1.72; 95% CI, 1.12-2.62), and intracranial bleeding (LMWH vs DOAC: HR, 2.72; 95% CI, 1.24-5.97). Rates of hospitalization for significant bleeds were similar between the DOAC and warfarin groups. The nearly 50% reduction in VTE recurrence rates and two-fold reduction in all-cause mortality in the DOAC group compared to the LMWH group reinforces the general efficacy and safety of DOAC use in this population of interest. Warfarin also remains an option for those with contraindications to DOACs.
1. This large observational, cross-sectional study found that increases in “proinflammatory” microbes Escherichia coli and Ruminococcus gnavus and reductions in beneficial microbes such as Faecalibacterium prausnitzii and Roseburia intestinalis in patients with inflammatory arthritis (rheumatoid arthritis (RA), ankylosing spondylitis (AS), and psoriatic arthritis (PsA)).
2. Hemoglobin concentrations and variation in inflammatory markers also had implications for vitamin B salvaging and biosynthesis, iron sequestration, and folic acid metabolism in the inflammatory arthritis group.
Evidence Rating Level: 2 (Good)
Previous studies have established specific changes to the microbiome in those with inflammatory bowel disease (IBD), type 1 diabetes (T1D), and other inflammatory conditions. Thus, establishing a further pattern of intestinal microbiome alterations in inflammatory conditions could support early disease detection, prevention, or even therapies. The current study analyzed the metagenomes of stool samples from 440 adults from multiple centres across the UK. Of these, 219 were healthy controls or diagnosed with noninflammatory joint pain, and the rest were diagnosed with either RA, PsA, or AS. Blood samples were also collected from those with inflammatory conditions to assess for CRP, RF, anti-CPC, HLA-B27 genotype, full blood count, and liver function. First, patient diagnosis explained 1.6% of taxonomic microbial profiles and 2.3% of functional microbial profile changes. E. coli and R. gnavus, previously suggested “proinflammatory” microbes, were more abundant in those with an inflammatory arthritic condition (P values 0.006 and 0.003, respectively). Several Streptococcus species normally found in the oral cavity, such as S. mutans, S. vestibularis, S. salivarius, and Bifidobacterium dentium, were more abundant in the intestinal microbiome of those with inflammatory arthritis. Beneficial microbes such as F. prausnitzii and R. intestinalis were found to be less abundant in the gut microbiomes of those with RA and AS, which is a result also found in studies related to IBD. Interestingly, Prevotella copri, which has been implicated as a potential RA disease trigger, was not significantly different in this study’s inflammatory arthritis group. The study went further, analyzing other associated functional changes in those with altered microbiomes. It was found that patients’ hemoglobin concentrations and levels of inflammation were associated with impaired vitamin B biosynthesis and salvage pathways. Patients in the inflammatory arthritis group and with higher CRP levels also demonstrated changes in folic acid metabolism and increased iron sequestration, with the latter most impacted by Eubacterium rectale in this study. Several of the taxa-level changes observed align with previous studies assessing the microbiomes of patients with IBD, T1D, and other metabolic conditions. Whether these gut microbiome alterations are causal of inflammatory conditions or a by-product of them remains unclear. There are complex interactions and underlying mechanisms that may mediate these changes which should be elucidated in future studies.
1. Current caffeine consumption was associated with decreased striatal dopamine transporter (DAT) availability in the caudate and putamen of Parkinson’s disease (PD) patients compared with healthy controls (HC). HC current consumers also demonstrated decreased DAT availability compared to former and never consumers.
2. These results also indicate that the effects of caffeine on DAT availability may fade or disappear after cessation of caffeine consumption.
Evidence Rating Level: 2 (Good)
As the most commonly consumed psychostimulant worldwide, research on caffeine consumption is extensive. One area of the literature has demonstrated its neuroprotective effects in preventing Parkinson’s Disease (PD). Caffeine acts as an adenosine receptor antagonist to boost dopamine release and is thought to induce a secondary reduction in the activity of a protein called the dopamine transporter (DAT), which regulates the reuptake and neurotransmission of dopamine. Studies have demonstrated that the loss of dopaminergic neurons in PD may result in decreased DAT signalling, but this has not yet been studied in the nigrostriatal pathways of humans. Data were analyzed from participants registered in the ongoing Parkinson’s Progression Markers Initiative (PPMI) study. A total of 138 PD patients and 75 healthy controls (HC) were included. Participants completed questionnaires regarding coffee consumption and were either current coffee consumers, former consumers, or never consumers. They also underwent a battery of tests assessing baseline clinical status. DAT images were obtained through singe-photon emission computed tomography (SPECT) imaging. PD patients had lower availability of DAT in all striatal regions compared to the HC (p < .001). Within the PD group, the caudate seemed to be implicated most in DAT availability reduction, with current coffee consumers in the PD group having lower DAT availability in the caudate than those who were former consumers (p = .01) and never consumers (p = .022). Cups consumed per day were also negatively correlated with DAT availability in the caudates of PD patients who were current consumers (r = -0.219, p = .047). For the HC subgroups, analyses showed that current coffee consumption resulted in significantly less DAT availability than the former consumers (p = .022). Current coffee consumption was overall an independent predictor of decreased DAT availability in the caudate, both for PD and HC patients (p = .003). This study is the first to detect a decrease in striatal DAT availability in current consumers of coffee but not those who are former consumers and never consumed coffee. This suggests that the effects of caffeine on striatal DAT may be reversible after cessation of coffee consumption. However, although caffeine consumption resulted in decreased DAT availability in healthy controls, its consumption also resulted in increased dopamine levels, whereas in PD, a decrease in DAT availability is coupled with a decrease in striatal dopaminergic neurons. This study therefore provides in vivo evidence of caffeine’s benefit in PD pathologies. Limitations of this study included a lack of control for some lifestyle factors that may impact dopaminergic levels, as well as a lack of standardization related to the most recent cup of coffee consumed before SPECT imaging.
1. This 4-arm, cluster randomized controlled superiority trial found that the use of menstrual cups reduced the incidence of bacterial vaginosis (BV) and increased the abundance of L. crispatus in the vaginal microbiome (VMB).
2. There was no significant difference in the incidence of sexually transmitted infections (STI) incidence between the control and menstrual cup groups.
Evidence Rating Level: 1 (Excellent)
The literature demonstrates that inadequate management of menstruation with poor-quality products can contribute to an increased incidence of reproductive tract infections. An increasingly common, cost-effective, and more sustainable alternative to single-use feminine hygiene products is the menstrual cup, a medical-grade silicone chamber that is inserted into the vagina to capture menstrual blood. The current analysis, nested within a larger 30-month, multicentre randomized controlled trial, sought to assess the impact of menstrual cup use on several parameters of reproductive tract health, including the incidence of BV and STIs, as well as concentrations of Lactobacillus crispatus, a beneficial microbe in preventing BV, in the VMB. Participants included 422 girls aged 14 to 16 years from 6 schools who completed tablet-based surveys on demographics, menstrual health management practices, and sexual health practices, as well as baseline STI and BV testing. Three schools were randomized to the menstrual cup-only arm, and 3 schools to the control arm. The menstrual cup group demonstrated a 26% decreased risk of developing BV, as well as 37% increased odds of optimal VMB community state types (OR 1.37 [95% CI 1.06 to 1.75]), and a 3.95% higher abundance of L. crispatus in comparison to controls at 30-month follow up. Only when adjusting for confounding variables, there was a statistically significant decrease in STI incidence for menstrual cup users (adjusted RR 0.77 [95% CI, 0.62 to 0.95]). Crude analyses did not yield this finding, however. Overall, this study shows promise for menstrual cups in reducing the incidence of BV and optimizing the VMB. Future studies should be conducted to generalize these findings to other global settings and age groups.
Image: PD
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