Smooth pursuit inhibition reveals audiovisual enhancement of fast movement control.

The sudden onset of a visual object or event elicits an inhibition of eye movements at latencies approaching the minimum delay of visuomotor conductance in the brain. Typically, information presented via multiple sensory modalities, such as sound and vision, evokes stronger and more robust responses than unisensory information. Whether and how multisensory information affects ultra-short latency oculomotor inhibition is unknown. In two experiments, we investigate smooth pursuit and saccadic inhibition in response to multisensory distractors. Observers tracked a horizontally moving dot and were interrupted by an unpredictable visual, auditory, or audiovisual distractor. Distractors elicited a transient inhibition of pursuit eye velocity and catch-up saccade rate within ∼100 ms of their onset. Audiovisual distractors evoked stronger oculomotor inhibition than visual- or auditory-only distractors, indicating multisensory response enhancement. Multisensory response enhancement magnitudes were equal to the linear sum of responses to component stimuli. These results demonstrate that multisensory information affects eye movements even at ultra-short latencies, establishing a lower time boundary for multisensory-guided behavior. We conclude that oculomotor circuits must have privileged access to sensory information from multiple modalities, presumably via a fast, subcortical pathway.

Biomarkers for Immune Checkpoint Inhibitors in Renal Cell Carcinoma.

Immune checkpoint inhibitor (ICI) therapy has revolutionized renal cell carcinoma treatment. Patients previously thought to be palliative now occasionally achieve complete cures from ICI. However, since immunotherapies stimulate the immune system to induce anti-tumor immunity, they often lead to adverse autoimmunity. Furthermore, some patients receive no benefit from ICI, thereby unnecessarily risking adverse events. In many tumor types, PD-L1 expression levels, immune infiltration, and tumor mutation burden predict the response to ICI and help inform clinical decision making to better target ICI to patients most likely to experience benefits. Unfortunately, renal cell carcinoma is an outlier, as these biomarkers fail to discriminate between positive and negative responses to ICI therapy. Emerging biomarkers such as gene expression profiles and the loss of pro-angiogenic proteins VHL and PBRM-1 show promise for identifying renal cell carcinoma cases likely to respond to ICI. This review provides an overview of the mechanistic underpinnings of different biomarkers and describes the theoretical rationale for their use. We discuss the effectiveness of each biomarker in renal cell carcinoma and other cancer types, and we introduce novel biomarkers that have demonstrated some promise in clinical trials.

Responding to changes in the unregulated drug supply: the need for a dynamic approach to drug checking technologies.

Drug checking services provide individuals who use drugs with the ability to test samples of their drugs for the presence of highly potent substances. However, there has been recent concern about whether the existing repertoire of point-of-care drug checking technologies, such as immunoassay strips and Fourier-transform infrared spectroscopy (FTIR), are adequate in identifying substances in the unregulated drug supply. Carfentanil and nitazene opioids, substances that are even more potent than fentanyl in vitro, have been found in the unregulated supply in North America and pose a challenge to our existing drug checking strategy. For example, etizolam has recently permeated the unregulated drug supply in North America, and has demonstrated the ability to evade point-of-care drug checking technologies. In response to the incessantly changing nature of the unregulated supply, we argue that drug checking technologies and service delivery models must continuously adapt alongside constantly changing drug markets. We provide two examples of emerging technologies, paper spray-mass spectrometry and surface-enhanced Raman spectroscopy, which address many of the shortcomings of existing technologies. For both technologies, we discuss their feasibility, where they can be offered, their advantages, and how they address gaps in our existing technologies. We contend that these technologies, and other emerging technologies, can be integrated into a future approach to drug checking that flexibly uses different technologies and service delivery methods to adapt to changes in the drug supply.

The arteriovenous fistula and the history of a forgotten pioneer.

Objective: The radiocephalic arteriovenous fistula (AVF), first introduced by Dr Kenneth Charles Appell, allowed for the provision of hemodialysis for patients with chronic kidney disease (CKD) and remains a reliable method for vascular access today. The purpose of this study is to review the contributions that led to the development of the AVF. We describe the work of Dr Appell, whose procedure bypassed the need for repeated cannulation in achieving vascular access, transforming the management of patients with dialysis-dependent CKD. Methods: A literature search was conducted by searching "arteriovenous fistula," "history of surgery," "hemodialysis," "vascular access," "chronic kidney disease," "repeated cannulation," and "Kenneth Charles Appell" on PubMed, Embase, and Web of Science. Only articles written in English were considered. Results: Before the arteriovenous fistula, glass cannulae were used for vascular access, beginning with Abel's "vividiffusion" apparatus in animals and Haas's experimental dialysis on humans. The use of glass cannulae was continued by Kolff, who transitioned from venipuncture needles to glass cannulae. However, these attempts were complicated by thrombosis, excessive bleeding related to heparin use, and damage to vascular access sites from repeated cannulation. Arteriovenous shunts, using polytetrafluoroethylene tubing, were an improvement from previous attempts at vascular access, but were prone to local bleeding, shunt occlusion, phlebitis, cellulitis, and rarely lasted more than a few months. To address these challenges, Dr Appell created an upper extremity AVF, allowing for the provision of maintenance dialysis without externalized devices, repeated cannulation, and extensive anticoagulant administration. Despite Dr Appell's vision and pioneering contributions to vascular surgery, he has received little credit for his work. Conclusions: The enormous contribution by Dr Appell in the development of the AVF that transformed the modern management of patients with CKD is recognized in this review of the history of vascular access surgery for hemodialysis.