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The California Current System (CCS) has experienced large fluctuations in environmental conditions in recent years that have dramatically affected the biological community. Here we synthesize remotely sensed, hydrographic, and biological survey data from throughout the CCS in 2019–2020 to evaluate how recent changes in environmental conditions have affected community dynamics at multiple trophic levels. A marine heatwave formed in the north Pacific in 2019 and reached the second greatest area ever recorded by the end of summer 2020. However, high atmospheric pressure in early 2020 drove relatively strong Ekman-driven coastal upwelling in the northern portion of the CCS and warm temperature anomalies remained far offshore. Upwelling and cooler temperatures in the northern CCS created relatively productive conditions in which the biomass of lipid-rich copepod species increased, adult krill size increased, and several seabird species experienced positive reproductive success. Despite these conditions, the composition of the fish community in the northern CCS remained a mixture of both warm- and cool-water-associated species. In the southern CCS, ocean temperatures remained above average for the seventh consecutive year. Abundances of juvenile fish species associated with productive conditions were relatively low, and the ichthyoplankton community was dominated by a mixture of oceanic warm-water and cosmopolitan species. Seabird species associated with warm water also occurred at greater densities than cool-water species in the southern CCS. The population of northern anchovy, which has been resurgent since 2017, continued to provide an important forage base for piscivorous fishes, offshore colonies of seabirds, and marine mammals throughout the CCS. Coastal upwelling in the north, and a longer-term trend in warming in the south, appeared to be controlling the community to a much greater extent than the marine heatwave itself.

Alzheimer's disease (AD) is the most common cause of dementia and is classically characterized by two major histopathological abnormalities: extracellular plaques composed of amyloid beta (Aβ) and intracellular hyperphosphorylated tau. Due to the progressive nature of the disease, it is of the utmost importance to develop disease-modifying therapeutics that tackle AD pathology in its early stages. Attenuation of hippocampal hyperactivity, one of the earliest neuronal abnormalities observed in AD brains, has emerged as a promising strategy to ameliorate cognitive deficits and abate the spread of neurotoxic species. This aberrant hyperactivity has been attributed in part to the dysfunction of voltage-gated Na+ (Nav) channels, which are central mediators of neuronal excitability. Therefore, targeting Nav channels is a promising strategy for developing disease-modifying therapeutics that can correct aberrant neuronal phenotypes in early-stage AD. This review will explore the role of Nav channels in neuronal function, their connections to AD pathology, and their potential as therapeutic targets. [ABSTRACT FROM AUTHOR]

Background: Nav1.6 is the most densely expressed sodium channel isoform in the adult brain and is a primary determinant of action potential initiation and propagation due to its subcellular localization at the axon initial segment (AIS). Importantly, it has been shown that the firing frequency and Na+ currents of Nav 1.6 channels in hippocampal neurons are specifically increased by Aβ exposure in a concentration‐dependent manner. Nav1.6 is regulated through its interactions with key auxiliary proteins, notably Glycogen Synthase Kinase 3‐β (GSK3β), which has increased expression in the hippocampus of AD patients as well as peripheral circulating lymphocytes in both MCI and AD patients. We have shown that GSK3β regulates Nav1.6 channel activity through phosphorylation of and direct binding to the Nav1.6's intracellular C‐terminal domain (CTD). Furthermore, genetic silencing of GSK3Ββ significantly decreased both Na+ currents and intrinsic firing compared to controls specifically through Nav1.6, while GSK3Ββ over‐expression or pharmacological disinhibition produced opposing phenotypes. Multiple lines of evidence indicate that hippocampal hyperactivity is present in patients with MCI and early‐stage AD and it is observed that reduction of hippocampal hyperactivity in MCI patients improves cognition and memory performance. We hypothesize that small‐molecule modulation of the Nav1.6:GSK3β PPI interface can counteract hippocampal hyperexcitability and could be used to treat early phases of AD, preventing the onset of cognitive decline. Method: HEK293 cells co‐transfected with WT or mutant Nav1.6 and GSK3β were utilized to interrogate the Nav1.6:GSK3β PPI and screen a series of 50 validated hit compounds using split‐luciferase complementation (LCA). Whole‐cell patch‐clamp electrophysiology was performed in heterologous cells and acute slice preparations to validate GSK3β‐mediated regulation of Nav1.6 activity and evaluate lead compound efficacy. Result: Mutagenesis screening revealed putative interaction sites of the Nav1.6:GSK3β PPI. Counter‐screening of 50 validated hits revealed 5 compounds that inhibit Nav1.6:GSK3β complex assembly at low micromolar concentrations (Figure 1). Compound 5671063, identified from the counter‐screen, exhibits functional modulation of Nav1.6 activity in heterologous cells (Figure 2). Conclusion: The Nav1.6:GSK3β complex is a critical mediator of neuronal activity and represents a novel target for treatment of pathological hippocampal hyperexcitability associated with cognitive decline. [ABSTRACT FROM AUTHOR]

The objective was to evaluate the effect of TeamSTEPPS on operating room efficiency and patient safety. TeamSTEPPS consisted of briefings attended by all health care personnel assigned to the specific operating room to discuss issues unique to each case scheduled for that day. The operative times, on-time start rates, and turnover times of all cases performed by the urology service during the initial year with TeamSTEPPS were compared to the prior year. Patient safety issues identified during postoperative briefings were analyzed. The mean case time was 12.7 minutes less with TeamSTEPPS (P < .001). The on-time first-start rate improved by 21% with TeamSTEPPS (P < .001). The mean room turnover time did not change. Patient safety issues declined from an initial rate of 16% to 6% at midyear and remained stable (P < 0.001). TeamSTEPPS was associated with improved operating room efficiency and diminished patient safety issues in the operating room. [ABSTRACT FROM AUTHOR]

Due to their sensitivity to climate forcing that may alter their abundance and distribution, small pelagic fish are important ecological indicators of the state of the California Current System. They are schooling, planktivorous fish that provide forage for higher trophic levels. We describe the life cycle histories and patterns of distribution of sardine, anchovy, and mackerel species occupying the waters along the west coast of the Baja California Peninsula (Mexico). The links between the physical and biological forcing and the structure and condition of their habitats, their patterns of movement, productivity, and stock structure (where information is available) are described in relation to the fisheries. We have used the catches as a proxy for the history of the different stocks, while recognizing that fisheries-derived information is biased by the operational scale and only covers areas where fish are available. We have relied mainly on studies of sardines to evaluate the validity of the principal paradigms in fisheries oceanography. We describe how the environment can structure a population by relating an example given by the spatiotemporal variability of the northern and southern stocks of Pacific sardine (Sardinops sagax) and Pacific mackerel (Scomber japonicus) from 2000 to 2014. During this period, the northern stocks showed a marked tendency to contract southwards, as far south as Magdalena Bay, in response to the regional cooling that began in the previous decade. It appears that the combined effects of fishing and climate change may sufficiently alter habitat characteristics so that both the distribution and productivity of a population are shifted. [ABSTRACT FROM AUTHOR]

Background and Purpose: Liposomal bupivacaine is a delayed-release preparation providing up to 72 hours of local analgesia. It costs much more than standard bupivacaine, however. A prospective, randomized, patient-blinded, controlled trial was performed to assess the efficacy of liposomal bupivacaine versus 0.25% bupivacaine when injected into surgical incisions during laparoscopic and robot-assisted urologic surgery. Methods: A total of 206 adults were randomized to receive liposomal bupivacaine or 0.25% bupivacaine. All surgical incisions were injected with liposomal bupivacaine or 0.25% bupivacaine with systematic dosing. The primary outcome was total opioid consumption during the postoperative hospital stay. All opioid doses were converted to morphine equivalents. Secondary end points included pain scores using visual analog pain scales, duration of hospital stay, and the time to first opioid use. A subgroup analysis was performed for renal surgery patients. Results: There was no significant difference in median total opioid use during the hospital stay between those who received liposomal bupivacaine (15 [interquartile range (IQR) 6.7-27] mg) and 0.25% bupivacaine (17.3 [IQR 8.3-30.5] mg) ( P=0.39). Furthermore, pain scores, length of hospital stay, and time to first opioid use did not differ between groups. Subgroup analysis of laparoscopic renal surgery revealed no difference between liposomal bupivacaine and 0.25% bupivacaine. Conclusions: For laparoscopic and robot-assisted urologic surgery, there is no significant difference between liposomal bupivacaine and 0.25% bupivacaine for local analgesia at the incision sites. [ABSTRACT FROM AUTHOR]

Voltage-gated Na+ (Nav) channels are the primary molecular determinant of the action potential. Among the nine isoforms of the Nav channel α subunit that have been described (Nav1.1-Nav1.9), Nav1.1, Nav1.2, and Nav1.6 are the primary isoforms expressed in the central nervous system (CNS). Crucially, these three CNS Nav channel isoforms display differential expression across neuronal cell types and diverge with respect to their subcellular distributions. Considering these differences in terms of their localization, the CNS Nav channel isoforms could represent promising targets for the development of targeted neuromodulators. However, current therapeutics that target Nav channels lack selectivity, which results in deleterious side effects due to modulation of off-target Nav channel isoforms. Among the structural components of the Nav channel α subunit that could be pharmacologically targeted to achieve isoform selectivity, the C-terminal domains (CTD) of Nav channels represent promising candidates on account of displaying appreciable amino acid sequence divergence that enables functionally unique protein–protein interactions (PPIs) with Nav channel auxiliary proteins. In medium spiny neurons (MSNs) of the nucleus accumbens (NAc), a critical brain region of the mesocorticolimbic circuit, the PPI between the CTD of the Nav1.6 channel and its auxiliary protein fibroblast growth factor 14 (FGF14) is central to the generation of electrical outputs, underscoring its potential value as a site for targeted neuromodulation. Focusing on this PPI, we previously developed a peptidomimetic derived from residues of FGF14 that have an interaction site on the CTD of the Nav1.6 channel. In this work, we show that whereas the compound displays dose-dependent effects on the activity of Nav1.6 channels in heterologous cells, the compound does not affect Nav1.1 or Nav1.2 channels at comparable concentrations. In addition, we show that the compound correspondingly modulates the action potential discharge and the transient Na+ of MSNs of the NAc. Overall, these results demonstrate that pharmacologically targeting the FGF14 interaction site on the CTD of the Nav1.6 channel is a strategy to achieve isoform-selective modulation, and, more broadly, that sites on the CTDs of Nav channels interacted with by auxiliary proteins could represent candidates for the development of targeted therapeutics. [ABSTRACT FROM AUTHOR]

Voltage-gated Na+ (Nav) channels are a primary molecular determinant of the action potential (AP). Despite the canonical role of the pore-forming α subunit in conferring this function, protein–protein interactions (PPI) between the Nav channel α subunit and its auxiliary proteins are necessary to reconstitute the full physiological activity of the channel and to fine-tune neuronal excitability. In the brain, the Nav channel isoforms 1.2 (Nav1.2) and 1.6 (Nav1.6) are enriched, and their activities are differentially regulated by the Nav channel auxiliary protein fibroblast growth factor 14 (FGF14). Despite the known regulation of neuronal Nav channel activity by FGF14, less is known about cellular signaling molecules that might modulate these regulatory effects of FGF14. To that end, and building upon our previous investigations suggesting that neuronal Nav channel activity is regulated by a kinase network involving GSK3, AKT, and Wee1, we interrogate in our current investigation how pharmacological inhibition of Wee1 kinase, a serine/threonine and tyrosine kinase that is a crucial component of the G2-M cell cycle checkpoint, affects the Nav1.2 and Nav1.6 channel macromolecular complexes. Our results show that the highly selective inhibitor of Wee1 kinase, called Wee1 inhibitor II, modulates FGF14:Nav1.2 complex assembly, but does not significantly affect FGF14:Nav1.6 complex assembly. These results are functionally recapitulated, as Wee1 inhibitor II entirely alters FGF14-mediated regulation of the Nav1.2 channel, but displays no effects on the Nav1.6 channel. At the molecular level, these effects of Wee1 inhibitor II on FGF14:Nav1.2 complex assembly and FGF14-mediated regulation of Nav1.2-mediated Na+ currents are shown to be dependent upon the presence of Y158 of FGF14, a residue known to be a prominent site for phosphorylation-mediated regulation of the protein. Overall, our data suggest that pharmacological inhibition of Wee1 confers selective modulatory effects on Nav1.2 channel activity, which has important implications for unraveling cellular signaling pathways that fine-tune neuronal excitability. [ABSTRACT FROM AUTHOR]

Percutaneous cholecystostomy (PC) tube insertion has been shown to be an effective treatment of acute cholecystitis (AC) as a temporary step to subsequent laparoscopic cholecystectomy (LC). However, the optimal time gap between PC implantation and LC has not been identified. Adult patients who underwent PC followed by LC for the treatment of AC between 2016 and 2020 were retrospectively reviewed and analyzed. One hundred twelve patients, consisting of 59.8% males, were included and received LC after a median of 65 [48 - 96.5] days following the PC placement. No deaths or reoperations occurred within 30 days, but 16 (14.3%) patients were readmitted, and 16 (14.3%) required subsequent reintervention. Although a longer interval between PC and LC had no effect on perioperative outcomes, it was associated with considerably longer intensive care unit (ICU) stay. According to these findings, patients may benefit from early LC following PC for the treatment of AC. [ABSTRACT FROM AUTHOR]

Tandem cuff artificial urinary sphincter (AUS) is a well-accepted treatment modality for refractory urinary incontinence following prostatectomy. We present a unique case of a 60-year-old male who experienced spontaneous urethral perforation between tandem AUS cuffs following a strong valsalva maneuver. The patient was treated with immediate AUS explant and transcorporal single cuff placement several months later.