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Filarial worms cause multiple debilitating diseases in millions of people worldwide, including river blindness. Currently available drugs reduce transmission by killing larvae (microfilariae), but there are no effective cures targeting the adult parasites (macrofilaricides) which survive and reproduce in the host for very long periods. To identify effective macrofilaricides, we carried out phenotypic screening of a library of 2121 approved drugs for clinical use against adult Brugia pahangi and prioritized the hits for further studies by integrating those results with a computational prioritization of drugs and associated targets. This resulted in the identification of 18 hits with anti-macrofilaricidal activity, of which two classes, azoles and aspartic protease inhibitors, were further expanded upon. Follow up screening against Onchocerca spp. (adult Onchocerca ochengi and pre-adult O. volvulus) confirmed activity for 13 drugs (the majority having IC50 < 10 μM), and a counter screen of a subset against L. loa microfilariae showed the potential to identify selective drugs that prevent adverse events when co-infected individuals are treated. Stage specific activity was also observed. Many of these drugs are amenable to structural optimization, and also have known canonical targets, making them promising candidates for further optimization that can lead to identifying and characterizing novel anti-macrofilarial drugs.

PURPOSE This trial assessed the utility of applying tumor DNA sequencing to treatment selection for patients with advanced, refractory cancer and somatic mutations in one of four signaling pathways by comparing the efficacy of four study regimens that were either matched to the patient's aberrant pathway (experimental arm) or not matched to that pathway (control arm). MATERIALS AND METHODS Adult patients with an actionable mutation of interest were randomly assigned 2:1 to receive either (1) a study regimen identified to target the aberrant pathway found in their tumor (veliparib with temozolomide or adavosertib with carboplatin [DNA repair pathway], everolimus [PI3K pathway], or trametinib [RAS/RAF/MEK pathway]), or (2) one of the same four regimens, but chosen from among those not targeting that pathway. RESULTS Among 49 patients treated in the experimental arm, the objective response rate was 2% (95% CI, 0% to 10.9%). One of 20 patients (5%) in the experimental trametinib cohort had a partial response. There were no responses in the other cohorts. Although patients and physicians were blinded to the sequencing and random assignment results, a higher pretreatment dropout rate was observed in the control arm (22%) compared with the experimental arm (6%; P = .038), suggesting that some patients may have had prior tumor mutation profiling performed that led to a lack of participation in the control arm. CONCLUSION Further investigation, better annotation of predictive biomarkers, and the development of more effective agents are necessary to inform treatment decisions in an era of precision cancer medicine. Increasing prevalence of tumor mutation profiling and preference for targeted therapy make it difficult to use a randomized phase II design to evaluate targeted therapy efficacy in an advanced disease setting.

Stereotactic radiosurgery (SRS) involves the delivery of a highly conformal ablative dose of radiation to both benign and malignant targets. This has traditionally been accomplished in a single fraction; however, fractionated approaches involving five or fewer treatments have been delivered for larger lesions, as well as lesions in close proximity to radiosensitive structures. The clinical utilization of SRS has overwhelmingly involved photon-based sources via dedicated radiosurgery platforms (e.g., Gamma Knife® and Cyberknife®) or specialized linear accelerators. While photon-based methods have been shown to be highly effective, advancements are sought for improved dose precision, treatment duration, and radiobiologic effect, among others, particularly in the setting of repeat irradiation. Particle-based techniques (e.g., protons and carbon ions) may improve many of these shortcomings. Specifically, the presence of a Bragg Peak with particle therapy at target depth allows for marked minimization of distal dose delivery, thus mitigating the risk of toxicity to organs at risk. Carbon ions also exhibit a higher linear energy transfer than photons and protons, allowing for greater relative biological effectiveness. While the data are limited, utilization of proton radiosurgery in the setting of brain metastases has been shown to demonstrate 1-year local control rates >90%, which are comparable to that of photon-based radiosurgery. Prospective studies are needed to further validate the safety and efficacy of this treatment modality. We aim to provide a comprehensive overview of clinical evidence in the use of particle therapy-based radiosurgery.

Background. Intraoperative fluid management may affect the outcome after kidney transplantation. However, the amount and type of fluid administered, and monitoring techniques vary greatly between institutions and there are limited prospective randomized trials and meta-analyses to guide fluid management in kidney transplant recipients. Methods. Members of the American Society of Anesthesiologists (ASA) committee on transplantation reviewed the current literature on the amount and type of fluids (albumin, starches, 0.9% saline, and balanced crystalloid solutions) administered and the different monitors used to assess fluid status, resulting in this consensus statement with recommendations based on the best available evidence. Results. Review of the current literature suggests that starch solutions are associated with increased risk of renal injury in randomized trials and should be avoided in kidney donors and recipients. There is no evidence supporting the routine use of albumin solutions in kidney transplants. Balanced crystalloid solutions such as Lactated Ringer are associated with less acidosis and may lead to less hyperkalemia than 0.9% saline solutions. Central venous pressure is only weakly supported as a tool to assess fluid status. Conclusions. These recommendations may be useful to anesthesiologists making fluid management decisions during kidney transplantation and facilitate future research on this topic.

Abstract A 40-yr-old male with no significant past medical history presented with sudden onset right-sided retro-orbital headache associated with vision loss after a session of strenuous exercise. Initial assessment with noncontrast head computed tomography at the local emergency department revealed a right sided occipital intracranial hemorrhage (ICH). On arrival the patient ad a left quadrantopsia with Glasgow Coma Scale of 15 and an ICH score of 0. A computed tomographic angiography showed a high density 6 × 9 mm vascular lesion associated with 2 tortuous vessels. Cerebral angiography revealed a right sided dural arteriovenous fistula, Cognard Type IV, with arterial feeders arising from dural branches of the right vertebral artery, the posterior division of the right middle meningeal artery and meningeal branches distal to the neuromeningeal trunk of the left ascending pharyngeal artery. 1 Four days after the ICH event the patient was treated with endovascular Onyx embolization of the fistula, through a transradial approach. Immediate angiographic assessment showed complete obliteration of the dAVF. The patient was discharged home and recovered his visual field deficit over 3 mo. The following operative video includes a discussion of the endovascular technique and treatment nuances associated with the transarterial management of a dural arteriovenous fistula. Patient consent was given prior to the procedure and consent and approval for this operative video was waived due to the retrospective nature of this manuscript and the anonymized video material.

Abstract Wide-necked aneurysms often pose challenges for distal access to the distal vasculature. This 64-yr-old woman without neurological deficits presented with atypical headaches of gradual onset. MRI revealed a large, symptomatic, unruptured carotid terminus aneurysm incorporating the origin of both the middle (MCA) and anterior cerebral arteries (ACA). Its wide neck created significant risks to coil prolapse and parent vessel compromise, risking stroke. With other options of higher risks, we recommended an around-the-world technique. Standard transfemoral access was used to the right internal carotid artery (ICA) with a 6F-Shuttle sheath and intracranial carotid with a 6F-Sofia distal access catheter. With dual-microcatheter access, 1 catheter was placed in the aneurysm dome, a second in the MCA for stent placement. Advancing the wire around the aneurysm first formed a loop from the lateral to medial wall for access to the MCA. The microcatheter was then advanced around the wire into the MCA, keeping the loop within the dome. With the loop's distal tip anchored, the distal end of the stent was deployed and anchored into the MCA. Both pitfalls (ie, lack of sufficient distal access, collapse of stent device during deployment) were resolved using a balloon catheter. With the balloon positioned and inflated as the anchor, the wire and catheter were pulled together. The loop in the aneurysm's dome straightened out across the neck, the stent was advanced into the MCA, and coiling proceeded. A large neck remnant had partially closed on 6-mo follow-up angiogram. Patient consented to undergo the procedure. Illustrations in video published/printed with permission from Mayfield Clinic.

Abstract Sidewall aneurysm treatment often requires complex management strategies. These can include advanced clipping techniques or stent-assisted coiling techniques. Endovascular coiling alone has been associated with high recurrence rates and is often not feasible. 1-4 Flow-diversion embolization has recently become a standard of care for many aneurysms, demonstrating high occlusion rates. 4,5 However, the third generation of coil-assist stents can be delivered with 0.0165” microcatheters, being an ideal adjunct to manage this group of aneurysms in more distal locations. In this video, a 16-yr-old teenager with Parry-Romberg syndrome and congenital adrenal hyperplasia had an incidental finding of a 6.5-mm sidewall aneurysm arising off the angular branch of the left middle cerebral artery, found during the work-up of complex partial seizures. The patient consented to the procedure. Due to his young age and aneurysm size, a decision was made to treat the aneurysm through an endovascular approach. Under general anesthesia, a transfemoral approach was carried out using a 6-French short sheath. A 6-French guiding catheter was left in the distal cervical left internal carotid artery; a 0.0165” microcatheter was used to first deploy a 3.0 × 15 mm Neuroform Atlas stent, completely covering the length of the aneurysm. Then, the stent was traversed with the microcatheter to coil the aneurysm. Follow-up cerebral angiogram confirmed complete occlusion of the aneurysm.

Substantial gaps remain in the evidence base for prenatal tobacco use interventions among Indigenous women. Using a cluster randomized controlled trial (RCT), the Healthy Pregnancies Project evaluated a community-level intervention for Alaska Native (AN) women in rural western Alaska. Sixteen villages were randomly assigned to usual care (control, n = 8 villages) or usual care plus a community-level intervention delivered by local AN “Native Sisters” (n = 8 villages). Outcomes were tobacco use rate at delivery and at 2 and 6 months postpartum, with biochemical confirmation obtained at 6 months. The program had high reach, enrolling 73% of all eligible women screened. Of the 352 participants, 67% used tobacco at baseline. No significant differences emerged between study groups on follow-up in tobacco use rates. More intervention than control participants made a quit attempt at 2 months postpartum (70% vs. 51%, respectively, p = 0.012). Participants in both study groups reported the program helped to raise awareness of healthy pregnancies in the study villages. This trial supports the reach of a community-level intervention, but not its efficacy for reducing tobacco use during pregnancy or postpartum. Efforts to sustain early quit attempts appear warranted. The community involvement, and reported impact on raising awareness of the importance of healthy pregnancies, supports the value of the research program in this community.