Citations

KIF20A is a critical kinesin for cell division and a promising anti-cancer drug target. The mechanisms underlying its cellular roles remain elusive. Interestingly, unusual coupling between the nucleotide- and microtubule-binding sites of this kinesin-6 has been reported, but little is known about how its divergent sequence leads to atypical motility properties. We present here the first high-resolution structure of its motor domain that delineates the highly unusual structural features of this motor, including a long L6 insertion that integrates into the core of the motor domain and that drastically affects allostery and ATPase activity. Together with the high-resolution cryo-electron microscopy microtubule-bound KIF20A structure that reveals the microtubule-binding interface, we dissect the peculiarities of the KIF20A sequence that influence its mechanochemistry, leading to low motility compared to other kinesins. Structural and functional insights from the KIF20A pre-power stroke conformation highlight the role of extended insertions in shaping the motor's mechanochemical cycle. Essential for force production and processivity is the length of the neck linker in kinesins. We highlight here the role of the sequence preceding the neck linker in controlling its backward docking and show that a neck linker four times longer than that in kinesin-1 is required for the activity of this motor.

Introduction: There is an increasing interest in cold snare endoscopic mucosal resection (CS-EMR), and studies have shown its safety and efficacy for colonic polyps. This meta-analysis aims to assess the safety and efficacy of CS-EMR for the removal of duodenal adenomas. Methods: We conducted a comprehensive literature search of several databases, from inception through February 2023, for studies that addressed outcomes of CS-EMR for nonampullary duodenal adenomas. We used the random-effects model for the statistical analysis. The weighted pooled rates were used to summarize the technical success, polyp recurrence, bleeding, and perforation events. Cochran Q test and I 2 statistics adjudicated heterogeneity. Results: Six studies were included in the analysis. In all, 178 duodenal polyps were resected using CS-EMR. The pooled rates were 95.8% (95% CI 89.1–98.5%, I 2=21.5%) for technical success and 21.2% (95% CI 8.5–43.6%, I 2=78%) for polyp recurrence. With regards to CS-EMR safety, the pooled rates were 4.2% (95% CI 1.6–10.5%, I 2=12%) for immediate bleeding, 3.4% (95% CI 1.5–7.6%, I 2=0%) for delayed bleeding, 2.8% (95% CI 1.1–6.7%, I 2=0%) for perforation, and 2% (95% CL 0.5–7.5%, I 2=0%) for post-polypectomy syndrome. Rates were not significantly different for large adenomas. Three studies reported data on CS-EMR and conventional EMR. Compared with conventional EMR, CS-EMR had lower odds of delayed bleeding, OR 0.11 (CI 0.02–0.62, P value 0.012, I 2=0%). Conclusion: Our findings suggest that CS-EMR is a safe and effective strategy for the resection of nonampullary duodenal adenomas, with an acceptable recurrence rate. Data from larger randomized controlled studies are needed to validate our findings.

With the previous worldwide initial coronavirus disease 2019 (COVID-19) pandemic, a notable rise in spontaneous pneumomediastinum with/without pneumothorax (SPP) has been noted. Most cases were initially reported as complications secondary to barotrauma from mechanical ventilation (MV) with COVID-19. However, with the Delta strain, starting from December 2020, there have been multiple reports of SPP. The SPP is an uncommon complication outside use of assisted ventilation with either noninvasive positive pressure ventilation (NIPPV) or MV. COVID-19 has been linked to higher incidence of SPP without use of NIPPV or MV. We present a series of 5 cases with a polymerase chain reaction–confirmed COVID-19 diagnostic testing whose hospital course was complicated by SPP unrelated to the use of either NIPPV or MV.

AbstractBackgroundNimodipine improves outcomes following aneurysmal subarachnoid hemorrhage (aSAH) and current guidelines suggest that patients with aSAH receive nimodipine for 21 days. Patients with no difficulty swallowing will swallow the whole capsules or tablets; otherwise, nimodipine liquid must be drawn from capsules, tablets need to be crushed, or the commercially available liquid product be used to facilitate administration through an enteral feeding tube (FT). It is not clear whether these techniques are equivalent. The goal of the study was to determine if different nimodipine formulations and administration techniques were associated with the safety and effectiveness of nimodipine in aSAH.MethodsThis was a retrospective multicenter observational cohort study conducted in 21 hospitals across North America. Patients admitted with aSAH and received nimodipine by FT for ≥3 days were included. Patient demographics, disease severity, nimodipine administration, and study outcomes were collected. Safety end points included the prevalence of diarrhea and nimodipine dose reduction or discontinuation secondary to blood pressure reduction. Predictors of the study outcomes were analyzed using regression modeling.ResultsA total of 727 patients were included. Administration of nimodipine liquid product was independently associated with higher prevalence of diarrhea compared to other administration techniques/formulations (Odds ratio [OR] 2.28, 95% confidence interval [CI] 1.41–3.67, p‐value = 0.001, OR 2.76, 95% CI 1.37–5.55, p‐value = 0.005, for old and new commercially available formulations, respectively). Bedside withdrawal of liquid from nimodipine capsules prior to administration was significantly associated with higher prevalence of nimodipine dose reduction or discontinuation secondary to hypotension (OR 2.82, 95% CI 1.57–5.06, p‐value = 0.001). Tablet crushing and bedside withdrawal of liquid from capsules prior to administration were associated with increased odds of delayed cerebral ischemia (OR 6.66, 95% CI 3.48–12.74, p‐value <0.0001 and OR 3.92, 95% CI 2.05–7.52, p‐value <0.0001, respectively).ConclusionsOur findings suggest that enteral nimodipine formulations and administration techniques might not be equivalent. This could be attributed to excipient differences, inconsistency and inaccuracy in medication administration, and altered nimodipine bioavailability. Further studies are needed.

AbstractBackgroundHistory and physical examination are key features to narrow the differential diagnosis of central versus peripheral causes in patients presenting with acute vertigo. We conducted a systematic review and meta‐analysis of the diagnostic test accuracy of physical examination findings.MethodsThis study involved a patient–intervention–control–outcome (PICO) question: (P) adult ED patients with vertigo/dizziness; (I) presence/absence of specific physical examination findings; and (O) central (ischemic stroke, hemorrhage, others) versus peripheral etiology. Grading of Recommendations, Assessment, Development, and Evaluations (GRADE) was assessed.ResultsFrom 6309 titles, 460 articles were retrieved, and 43 met the inclusion criteria: general neurologic examination—five studies, 869 patients, pooled sensitivity 46.8% (95% confidence interval [CI] 32.3%–61.9%, moderate certainty) and specificity 92.8% (95% CI 75.7%–98.1%, low certainty); limb weakness/hemiparesis—four studies, 893 patients, sensitivity 11.4% (95% CI 5.1%–23.6%, high) and specificity 98.5% (95% CI 97.1%–99.2%, high); truncal/gait ataxia—10 studies, 1810 patients (increasing severity of truncal ataxia had an increasing sensitivity for central etiology, sensitivity 69.7% [43.3%–87.9%, low] and specificity 83.7% [95% CI 52.1%–96.0%, low]); dysmetria signs—four studies, 1135 patients, sensitivity 24.6% (95% CI 15.6%–36.5%, high) and specificity 97.8% (94.4%–99.2%, high); head impulse test (HIT)—17 studies, 1366 patients, sensitivity 76.8% (64.4%–85.8%, low) and specificity 89.1% (95% CI 75.8%–95.6%, moderate); spontaneous nystagmus—six studies, 621 patients, sensitivity 52.3% (29.8%–74.0%, moderate) and specificity 42.0% (95% CI 15.5%–74.1%, moderate); nystagmus type—16 studies, 1366 patients (bidirectional, vertical, direction changing, or pure torsional nystagmus are consistent with a central cause of vertigo, sensitivity 50.7% [95% CI 41.1%–60.2%, moderate] and specificity 98.5% [95% CI 91.7%–99.7%, moderate]); test of skew—15 studies, 1150 patients (skew deviation is abnormal and consistent with central etiology, sensitivity was 23.7% [95% CI 15%–35.4%, moderate] and specificity 97.6% [95% CI 96%–98.6%, moderate]); HINTS (head impulse, nystagmus, test of skew)—14 studies, 1781 patients, sensitivity 92.9% (95% CI 79.1%–97.9%, high) and specificity 83.4% (95% CI 69.6%–91.7%, moderate); and HINTS+ (HINTS with hearing component)—five studies, 342 patients, sensitivity 99.0% (95% CI 73.6%–100%, high) and specificity 84.8% (95% CI 70.1%–93.0%, high).ConclusionsMost neurologic examination findings have low sensitivity and high specificity for a central cause in patients with acute vertigo or dizziness. In acute vestibular syndrome (monophasic, continuous, persistent dizziness), HINTS and HINTS+ have high sensitivity when performed by trained clinicians.