2 Minute Medicine Rewind May 25, 2026
Validation of 2 Syncope Risk Scores and Comparison With Physician Risk Estimation
1. The Canadian Syncope Risk Score (CSRS) and FAINT score are effective at identifying which adult patients presenting to the emergency department (ED) are at low risk for short-term adverse outcomes.
Evidence Rating Level: 2 (Good)
Syncope and presyncope account for 2-3% of all ED visits, with approximately 10% of these patients having serious underlying conditions such as arrhythmia, myocardial infarction, structural heart disease, pulmonary embolism, or severe hemorrhage. Previous studies showed that as many as one-third to one-half of these conditions were not identified during ED evaluation, leading to the development of tools such as the CSRS and FAINT score. This prospective, observational, multicenter cohort study performed external validation of these two scores in a United States population. Participants included adults aged 40 years or older presenting with syncope or presyncope who did not have a serious diagnosis identified during their ED visit. The study population had 1263 patients (mean [SD] age, 64.8 [13.1] years; 53.5% female). CSRS and FAINT scores were calculated for each patient, and physicians were asked to provide an unstructured estimate of the risk of the patient experiencing a serious adverse outcome within 30 days, collected as single values from 0% to 100%. The primary outcomes were identical to those in the original CSRS and FAINT studies. The primary outcome for FAINT was a serious cardiac outcome (death, significant cardiac arrhythmia, acute myocardial infarction, new serious structural heart disease, or a significant cardiac intervention) within 30 days of the ED visit. The primary outcome for CSRS was a serious cardiac or non-cardiac outcome (serious cardiac outcomes listed above in addition to aortic dissection, pulmonary embolism, severe hemorrhage, subarachnoid hemorrhage, cerebellar stroke, and other serious conditions causing syncope (including sepsis) and procedural interventions for the treatment of syncope) within 30 days of the ED visit. Of the 1263 patients, 74 (5.9%) had a serious adverse outcome, and 62 (4.9%) had a serious cardiac outcome. The CSRS area under the receiver operating characteristic curve (AUROC) was 0.72 (95% CI, 0.67-0.78). A low-risk score (CSRS <0) had a sensitivity of 91.9% (95% CI, 85.7%-98.1%) and an NPV of 97.5% (95% CI, 96.4%-98.8%). The FAINT score AUROC for a serious cardiac outcome was 0.76 (95% CI, 0.71-0.81). A low-risk score (FAINT = 0) had a sensitivity of 96.7% (95% CI, 92.4%-100%) and an NPV of 98.8% (95% CI, 98.0%-99.7%). The FAINT score, but not the CSRS, was more sensitive than physician-estimated risk (difference, 18.7%; 95% CI, 6.8%-30.6%; P = .002). While the CSRS and FAINT scores identified patients at low risk for adverse outcomes, only the FAINT score outperformed physicians at identifying patients at low risk for serious cardiac outcomes.
1. Incorporating procalcitonin-guided decision making in the management of neonatal late-onset sepsis significantly reduced the duration of antibiotic treatment without increasing mortality.
Evidence Rating Level: 1 (Excellent)
Late-onset neonatal sepsis, defined as sepsis occurring after 72 hours of life, is a common neonatal disease. However, the optimal duration of antimicrobial therapy is not well established, and there is a growing body of literature on the risks of prolonged antibiotic exposure in newborns. Procalcitonin has been incorporated into clinical algorithms to reduce antibiotic duration without increasing mortality in critically ill patients. It is unclear if procalcitonin levels can be used to guide antibiotic use in late-onset neonatal sepsis. This prospective, multicentre, randomised, open-label intervention trial included newborns in neonatal intensive care units of postconceptional age 24-45 weeks and after 4 days of life, with suspected or proven late-onset sepsis (defined as onset three days after birth,17 and for whom the treating physician had planned to continue antibiotic treatment beyond 48 hours’ duration). 513 patients were randomized to procalcitonin-guided treatment (n = 248; median (IQR) gestational age at inclusion, 31.0 (28.9-34.0) weeks; median (IQR) number of days of life at inclusion, 14.0 (10.0-24.0) days; 47.2% female) or usual care (n = 256; median (IQR) gestational age at inclusion, 31.3 (29.1-33.6) weeks; median (IQR) number of days of life at inclusion, 13.0 (9.0-23.0) days; 45.3% female). In the procalcitonin group, patients had procalcitonin concentration measured at randomisation and then every two days. If the concentration was 0.5 µg/L or lower, physicians were encouraged to discontinue antibiotics. The median duration of antibiotic treatment was significantly shorter in the procalcitonin-guided group versus the usual care group (median (IQR) 8 (5.0-12.0) days vs. 10 (8.0-13.0) days; absolute difference −2.0 (IQR −3.8 to −1.0), P<0.001). There were six (2.4%) deaths in the procalcitonin-guided group and ten (3.9%) in the usual care group (absolute difference −1.5% (95% CI −5.0% to 1.8%), below the prescribed non-inferiority margin of 3%. Overall, the use of procalcitonin significantly reduced the duration of antibiotic treatment in neonatal late-onset sepsis without increasing mortality or serious adverse events.
Phase 1 randomized trial of HS-10353, a novel GABA(A) positive allosteric modulator for treatment of major depressive disorder
1. H3-10353, a novel GABAA positive allosteric modulator, is safe and well-tolerated in healthy patients and those with major depressive disorder (MDD), and demonstrated some therapeutic benefits in a phase 1 clinical trial.
Evidence Rating Level: 1 (Excellent)
Although there are numerous classes of medications for depression, these treatments result in remission in only 40% of MDD patients and are accompanied by a range of side effects. MDD patients have been found to have lower levels of γ-aminobutyric acid (GABA), representing a target for novel antidepressants. Brexanolone and zuranolone, positive allosteric modulators of GABAA receptors, have been approved for post-partum depression and MDD. HS-10353 is a novel GABAA receptor activator that demonstrated good tolerability in animal toxicology studies. The Phase 1 trial of HS-10353 comprised a single ascending dose (SAD) component and a multiple ascending dose (MAD) component. The SAD part included healthy volunteers aged 18 to 45 years who were randomized 3:1 to receive one dose of HS-10353 or placebo in 6 dose cohorts (2, 6, 15, 30, 45, and 55 mg). The MAD component included patients aged 18-65 years diagnosed with MDD who were randomized 3:1 to receive HS-10353 or placebo once daily for 7 days in 4 dose cohorts (15, 30, 50, and 65 mg). Forty-eight healthy participants (HS-10353, n = 36, mean [SD] age 26.8 [4.7] years, 36.1% female; placebo, n = 12, mean [SD] age 26.3 [4.0] years, 50.0% female); and forty-eight MDD participants (HS-10353, n = 36, mean [SD] age 35.0 [12.6] years, 52.8% female; placebo, n = 12, mean [SD] age 27.4 [8.8] years, 50.0% female) completed the study. All doses were well tolerated, with no adverse events leading to dose adjustment. The incidence of adverse events was not dose-dependent, and no significant differences were observed in adverse event rates between the HS-10353 and placebo groups. There was a significant difference in Hamilton Depression Rating Scale (HAM-D17) scores in patients treated with HS-10353 50 mg compared with placebo (absolute difference: -4.7; 95% CI: -8.9 to -0.5), but not with other dosages.
1. 1 litre polyethylene glycol with ascorbate (1L-PEG-Asc) showed superior bowel cleansing efficacy compared to 2 litre polyethylene glycol with ascorbate (2L-PEG-Asc) in adult patients undergoing colonoscopy for colorectal cancer (CRC) screening.
Evidence Rating Level: 1 (Excellent)
Colonoscopy is a highly effective procedure for CRC screening and has been shown to reduce CRC mortality. High-quality preoperative bowel cleansing is associated with higher polyp detection and cecal intubation rates. Inadequate bowel cleansing also increases the risk of procedural difficulties and is associated with increased risk of post-colonoscopy colorectal cancer deaths. There are numerous types of bowel preparation, with higher volume solutions resulting in nausea, vomiting, bloating, and abdominal distention. It is thought these side effects can lead to reduced adherence and subsequent inferior cleansing. Previous trials have shown 1L-PEG-Asc to be non-inferior to (2L-PEG-Asc), Moviprep®. However, no studies have assessed whether 1L-PEG-Asc is superior. This randomized, single-centre, superiority trial included patients aged 50-74 years with a positive fecal immunochemical test (FIT) test scheduled for screening colonoscopy. 1275 patients were randomized to receive 1L-PEG-Asc (n = 615; mean [SD] age, 63.0 [8] years; 50.9% female) or 2L-PEG-Asc (n = 628; mean [SD] age, 62.9 [8] years; 47.8% female). Mean Boston Bowel Preparation Scale (BBPS) scores were significantly higher in the 1L-PEG-Asc group compared to the 2L-PEG-Asc group (right 2.54 vs. 2.30, p <0.001; transverse 2.60 vs. 2.36, p <0.001; left 2.63 vs. 2.39, p <0.001). The 1L-PEG-Asc group had higher rates of adequate preparation (BPPS ≥ 2 in each segment; 92.2% vs 86.1%, p<0.001) and excellent preparation (BPPS = 3 in each segment; 59.2% vs 43.8%, p<0.001). There were no significant differences in lesion detection rates. Nausea (57.4% vs. 46.6%, p<0.001) and vomiting (13.9% vs. 8.7%, p=0.006) were more frequent in the 1L-PEG-Asc group. However, a significantly greater proportion of patients were willing to repeat bowel preparation with 1L-PEG-Asc compared to 2L-PEG-Asc (82% vs. 76%, p=0.009). Overall, 1L-PEG-Asc showed greater bowel cleansing efficacy and willingness to use it again despite greater rates of side effects.
Systemic Glucocorticoid Immunosuppression and Survival Among Immune Checkpoint Inhibitor Recipients
1. Exposure to systemic glucocorticoid immunosuppression (gsISP) close to immune checkpoint inhibitor (ICI) initiation was associated with worse overall survival (OS).
Evidence Rating Level: 2 (Good)
The introduction of ICIs has caused a dramatic shift in the management of several types of cancers and has led to improved OS in many cancers. However, the relationship between ICI effectiveness and immunosuppression with concurrent use of glucocorticoids, used for inflammatory symptoms or pre-existing autoimmune diseases, remains unclear. Specifically, the impact of the timing and duration of gsISP on ICI effectiveness has not been evaluated. This retrospective cohort study therefore sought to examine the association between timing and duration of gsISP on the OS of cancer patients treated with ICIs. 39,258 patients (mean[SD] age, 64.7[13.0] years; 46.4% female) from the United States with cancer treated with ICIs were included in the analysis. These patients were derived from two cohorts: the first included patients from Massachusetts General Hospital, Brigham and Women’s Hospital, and Dana-Farber Cancer Institute (MGBD cohort), while the second were derived from the TriNetX database. From the MGBD cohort, exposure to gsISP within 1 year of ICI initiation was associated with worse OS. Specifically, the worst OS was observed when gsISP exposure was within 1 month of ICI initiation (time ratio [TR], 0.49 [95% CI, 0.45-0.54]). Further, increased doses of gsISP were associated with worse OS, with a 19% (95% CI, 11%-28%) reduction in OS at 5 mg or more daily up to a 37% (95% CI, 25%-52%) reduction at 60 mg or more daily. Overall, this study found that exposure to gsISP close to ICI initiation was associated with worse overall survival.
Image: PD
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