Implementing code review in the scientific workflow: Insights from ecology and evolutionary biology.

Code review increases reliability and improves reproducibility of research. As such, code review is an inevitable step in software development and is common in fields such as computer science. However, despite its importance, code review is noticeably lacking in ecology and evolutionary biology. This is problematic as it facilitates the propagation of coding errors and a reduction in reproducibility and reliability of published results. To address this, we provide a detailed commentary on how to effectively review code, how to set up your project to enable this form of review and detail its possible implementation at several stages throughout the research process. This guide serves as a primer for code review, and adoption of the principles and advice here will go a long way in promoting more open, reliable, and transparent ecology and evolutionary biology.

Improving the Breast Surgeon's Ergonomic Workload for Nipple-Sparing Mastectomies Using Exercise and Operating Room Positioning Protocol.

BACKGROUND: The objective of this study was to examine whether an exercise program and standardized operating room positioning protocol (EOPP) would improve surgeon muscle workload and/or surgeon perception of mental/physical workload for nipple-sparing mastectomy (NSM). METHODS: This prospective study analyzed muscle workload by EMG of four surgeons performing NSM before and after an EOPP. Surveys were administered assessing surgeon perception of mental/physical workload. EMG data were analyzed using repeated-measures ANOVA, controlling for surgeon, first assistant, duration and difficulty of procedure, left or right side, and sequence of the procedure. RESULTS: A total of 56 NSM cases performed by 3 surgeons were analyzed. One surgeon was excluded because of muscle injury and undergoing active physical therapy during the study period. After implementation of the EOPP, the left (P = 0.005) and right (P = 0.020) upper trapezii muscles had a significant decrease in overall ergonomic workload but there was no significant change in overall ergonomic workload for the bilateral cervical erector spinae, anterior deltoid, and lumbar erector spinae muscle groups. When analyzing muscle group exertion by surgeon, there was significant variability in all muscles except the left cervical erector spinae. Following the EOPP, surgeons reported that the procedures were more physically (P = 0.01) and mentally (P = 0.002) demanding and visualization (P = 0.04) was worse. The breast laterality and sequence did not affect muscle exertion. CONCLUSIONS: An EOPP decreased the overall ergonomic workload of one muscle group for surgeons performing NSM but did not impact surgeon perception of mental/physical workload. Further investigation is needed to improve surgeon ergonomics.

TRPV4 Antagonism Prevents Mechanically Induced Myotonia.

OBJECTIVE: Myotonia is caused by involuntary firing of skeletal muscle action potentials and causes debilitating stiffness. Current treatments are insufficiently efficacious and associated with side effects. Myotonia can be triggered by voluntary movement (electrically induced myotonia) or percussion (mechanically induced myotonia). Whether distinct molecular mechanisms underlie these triggers is unknown. Our goal was to identify ion channels involved in mechanically induced myotonia and to evaluate block of the channels involved as a novel approach to therapy. METHODS: We developed a novel system to enable study of mechanically induced myotonia using both genetic and pharmacologic mouse models of myotonia congenita. We extended ex vivo studies of excitability to in vivo studies of muscle stiffness. RESULTS: As previous work suggests activation of transient receptor potential vanilloid 4 (TRPV4) channels by mechanical stimuli in muscle, we examined the role of this cation channel. Mechanically induced myotonia was markedly suppressed in TRPV4-null muscles and in muscles treated with TRPV4 small molecule antagonists. The suppression of mechanically induced myotonia occurred without altering intrinsic muscle excitability, such that myotonia triggered by firing of action potentials (electrically induced myotonia) was unaffected. When injected intraperitoneally, TRPV4 antagonists lessened the severity of myotonia in vivo by approximately 80%. INTERPRETATION: These data demonstrate that there are distinct molecular mechanisms triggering electrically induced and mechanically induced myotonia. Our data indicates that activation of TRPV4 during muscle contraction plays an important role in triggering myotonia in vivo. Elimination of mechanically induced myotonia by TRPV4 inhibition offers a new approach to treating myotonia. ANN NEUROL 2020;88:297-308.

Coral adaptation to climate change: Meta-analysis reveals high heritability across multiple traits.

Anthropogenic climate change is a rapidly intensifying selection pressure on biodiversity across the globe and, particularly, on the world's coral reefs. The rate of adaptation to climate change is proportional to the amount of phenotypic variation that can be inherited by subsequent generations (i.e., narrow-sense heritability, h2 ). Thus, traits that have higher heritability (e.g., h2  > 0.5) are likely to adapt to future conditions faster than traits with lower heritability (e.g., h2  < 0.1). Here, we synthesize 95 heritability estimates across 19 species of reef-building corals. Our meta-analysis reveals low heritability (h2 < 0.25) of gene expression metrics, intermediate heritability (h2  = 0.25-0.50) of photochemistry, growth, and bleaching, and high heritability (h2  > 0.50) for metrics related to survival and immune responses. Some of these values are higher than typically observed in other taxa, such as survival and growth, while others were more comparable, such as gene expression and photochemistry. There was no detectable effect of temperature on heritability, but narrow-sense heritability estimates were generally lower than broad-sense estimates, indicative of significant non-additive genetic variation across traits. Trait heritability also varied depending on coral life stage, with bleaching and growth in juveniles generally having lower heritability compared to bleaching and growth in larvae and adults. These differences may be the result of previous stabilizing selection on juveniles or may be due to constrained evolution resulting from genetic trade-offs or genetic correlations between growth and thermotolerance. While we find no evidence that heritability decreases under temperature stress, explicit tests of the heritability of thermal tolerance itself-such as coral thermal reaction norm shape-are lacking. Nevertheless, our findings overall reveal high trait heritability for the majority of coral traits, suggesting corals may have a greater potential to adapt to climate change than has been assumed in recent evolutionary models.

Physician Responses to Enhanced Prescription Drug Monitoring Program Profiles.

OBJECTIVE: Many states have begun implementing enhancements to PDMP patient profiles such as summaries or graphics to highlight issues of concern and enhance comprehension. The purpose of this study was to examine how physicians respond to sample enhanced PDMP profiles based on patient vignettes. DESIGN: Brief semistructured interviews with physicians. SETTING: Three national medical conferences for targeted specialties. SUBJECTS: Ninety-three physicians practicing in primary care, emergency medicine, or pain management. METHODS: We presented participants with one of three patient vignettes with corresponding standard and enhanced PDMP profiles and conducted brief interviews. RESULTS: Findings indicated that enhanced profiles could increase ease of comprehension, reduce time burden, and aid in communicating with patients about opioid risks. Physicians also expressed concern about liability for prescribing when the enhanced profile indicates risk and cautioned against any implication that risk warnings should override clinical judgment based on the patient's complete medical history or presenting condition. Physicians emphasized the need for transparency of measures and evidence of validation of risk scores. We found little indication that enhanced profiles would change opioid prescribing decisions, though decisions varied by physician. CONCLUSIONS: Our study underscores the importance of involving prescribers in developing and testing PDMP profile enhancements, as well as providing guidance in the interpretation and clinical use of enhanced profiles. Reduced time burden is an important benefit to consider as the number of states mandating PDMP use increases.

Impact of the RESPOND Toolkit on community pharmacists' opioid safety attitudes, self-efficacy, and knowledge.

OBJECTIVE: Pharmacists are well positioned to reduce risks from opioid-prescribing but often lack resources and training to effectively support these activities. The Resources Encouraging Safe Prescription Opioid and Naloxone Dispensing (RESPOND) Toolkit is an educational package developed to provide community pharmacists with a comprehensive education program and practice resources on prescription drug misuse, prescription drug monitoring programs (PDMPs), and naloxone dispensing. Our objective was to evaluate the effectiveness of the RESPOND Toolkit to improve pharmacists' knowledge and assess changes in pharmacists' attitudes and beliefs toward opioid use disorder (OUD) and PDMPs across a diverse pool of Oregon community pharmacists. METHODS: Pharmacists were recruited using an electronic mailing list of Oregon-licensed pharmacists. Pharmacists were asked to complete a preintervention survey, 3 online educational modules with pre- and post-module quizzes (optional), and a postintervention survey. Data were analyzed using paired t tests, chi-square analyses, and effect size calculations (Cohen's d). RESULTS: A total of 131 pharmacists completed the 3 educational modules and postintervention survey. Respondents were aged 37.6 ± 11.0 (mean ± SD) years and mostly frontline pharmacy staff (n = 86; 65.6%) with 10.5 ± 11.6 years of pharmacy experience. Pharmacists' knowledge and attitudes toward OUD, perceived behavioral control to address OUD, resources to address OUD, and perceptions regarding PDMP-associated difficulties improved significantly as a result of the intervention (all P < 0.001). In addition, 120 pharmacists completed the optional module quizzes, and aggregate knowledge assessment scores improved significantly (P < 0.001). CONCLUSION: The RESPOND Toolkit is an effective and scalable training resource for community pharmacists, with the potential to promote behavioral shifts that support opioid safety among patients. The results demonstrated improved attitudes, knowledge, and perceived behavioral control. Future work on the RESPOND Toolkit should evaluate the effect of implementation on pharmacist clinical activities and dispensing outcomes.

The "Nipple Whipple"?! A Pilot Study to Assess the Ergonomic Effects of Nipple-Sparing Mastectomy.

BACKGROUND: Nipple-sparing mastectomies (NSMs) with reconstruction are believed to be more difficult to perform than skin-sparing mastectomies (SSMs), but there is little quantitative data to support this claim. METHODS: This prospective study analyzed four surgeons performing mastectomies. Electromyography (EMG) electrodes placed on selected muscle groups on each surgeon were used to capture muscle exertion intraoperatively and a percentage of maximum voluntary exertion was calculated (%MVE). Data regarding surgeon demographics, exercise habits, musculoskeletal problems, and surgery-specific workload was collected using a questionnaire. RESULTS: A total of 61 mastectomies were analyzed; 40 were NSM and 21 were SSM/total mastectomies. NSM were considered to be more mentally demanding and physically demanding than SSM (p < 0.001). When the surgeons' EMG data was analyzed as a group, there was a statistically significant difference in %MVE for NSM versus SSM at high muscle activity in bilateral anterior deltoid muscle groups and at average muscle activity for the left anterior deltoid muscle only. At low muscle activity, there was a statistically significant increase in activation for SSM versus NSM in bilateral cervical erector spinae. Repeated measures ANOVA was performed, which showed statistically significant differences at high muscle activity between NSM and SSM in the left cervical erector spinae and bilateral anterior deltoid muscles. CONCLUSIONS: Our pilot study shows that intraoperative EMGs can assess muscle activity for mastectomy operations and show a difference between NSM and SSM. This is the first study to provide quantitative data on muscle strain with NSM.

A novel alarm signal in aquatic prey: Familiar minnows coordinate group defences against predators through chemical disturbance cues.

Animal signalling systems outside the realm of human perception remain largely understudied. These systems consist of four main components: a signalling context, a voluntary signal, receiver responses and resulting fitness benefits to both the signaller and receiver(s). It is often most difficult to determine incidental cues from voluntary signals. One example is chemical disturbance cues released by aquatic prey during predator encounters that may serve to alert conspecifics of nearby risk and initiate tighter shoaling. We aimed to test whether disturbance cues are released incidentally (i.e. as a cue) or are produced voluntarily depending on a specific signalling context such as the audience surrounding the individual, and thus constitute a signal. We hypothesized that if receivers use disturbance cues to communicate risk among themselves, they would produce more (or more potent) disturbance cues when present in a group of conspecifics rather than when they are isolated (presence/absence of an audience) and use disturbance cues more when present alongside familiar rather than unfamiliar conspecifics (audience composition effect). We placed fathead minnows (Pimephales promelas) in groups with familiar fish, unfamiliar fish or as isolated individuals with no audience present, and then simulated a predator chase to evoke disturbance cues. We used bioassays with independent receivers to assess whether the disturbance cues produced differed depending on the signallers' audience. We found evidence of voluntary signalling, as minnows responded to disturbance cues from groups of fish with tighter shoaling while disturbance cues from isolated minnows did not evoke a significant shoaling response (presence/absence audience effect). Receivers also increased shoaling, freezing and dashing more in response to disturbance cues from familiar groups compared to disturbance cues from unfamiliar groups or isolated minnows (audience composition effect). Together, these findings support our hypothesis that disturbance cues are used as an antipredator signal to initiate coordinated group defences among familiar conspecifics involving shoaling, freezing and dashing. This study represents the strongest evidence to date that chemicals released by aquatic prey upon disturbance by predators serve as voluntary signals rather than simply cues that prey have evolved to detect when assessing their risk of predation.

The socially mediated recovery of a fearful fish paired with periodically replaced calm models.

Social learning is an important mechanism for acquiring knowledge about environmental risk. However, little work has explored the learning of safety and how such learning outcomes are shaped by the social environment. Here, we exposed minnows, Pimephales promelas, to a high-risk environment to induce behavioural responses associated with fear (e.g. neophobia). We then used the presence of calm conspecific models (low-risk individuals) to weaken these responses. When observers (individuals from the high-risk environment) and models were paired consistently in a one-on-one setting, the observers showed no recovery (i.e. no weakening of the fear responses), and instead the models indirectly acquired those responses (i.e. a socially transmitted state of fear). However, observers paired with models that were periodically replaced with new calm models showed a significant recovery, and each new model showed diminished socially transmitted fear. We argue that our understanding of predation-related fear and social information transfer can prove fruitful in understanding problems with fear and stress across animal taxa, including among humans who experience post-traumatic stress and secondary trauma. Our findings indicate that the periodic replacement of models can promote fear recovery in observers and reduce socially transmitted fear in models.

Pharmacists' attitudes, knowledge, utilization, and outcomes involving prescription drug monitoring programs: A brief scoping review.

OBJECTIVE: While literature on pharmacists' engagement with prescription drug monitoring programs (PDMPs) is growing, no formal synthesis of findings has been conducted to provide overarching recommendations for research or practice. The objective of this study was to identify and synthesize findings from current literature on community pharmacists' attitudes toward, knowledge of, and registration and utilization behaviors regarding PDMPs. DATA SOURCES: Electronic databases (MEDLINE, PsychINFO, Cochrane Database of Systematic Reviews, Google Scholar, and the Brandeis University PDMP Center of Excellence) and reference lists from relevant manuscripts were searched for relevant English-language manuscripts. Key words used in searches included pharmacist, prescription drug monitoring program, opioid safety, attitudes, knowledge, and utilization. STUDY SELECTION: Papers were included from January 1, 2008 up to October 6, 2017. Three authors independently screened articles for full text review; 2 authors independently conducted full text review for final study selection. Discrepancies were resolved through consensus. DATA EXTRACTION: Data were extracted to an evidence table, coded by topic category, and checked for accuracy. RESULTS: Fifteen manuscripts met inclusion criteria. The studies varied greatly in methodological approach. In general, pharmacists' attitudes and knowledge of PDMPs positively influenced likelihood to register and use their state's program. Targeted training had a substantial impact on knowledge, registration, and utilization. CONCLUSION: Pharmacist-targeted PDMPs and opioid safety training is highly recommended to increase knowledge of and insight into behavioral change.

Trust thy neighbour in times of trouble: background risk alters how tadpoles release and respond to disturbance cues.

In aquatic environments, uninjured prey escaping a predator release chemical disturbance cues into the water. However, it is unknown whether these cues are a simple physiological by-product of increased activity or whether they represent a social signal that is under some control by the sender. Here, we exposed wood frog tadpoles (Lithobates sylvaticus) to either a high or low background risk environment and tested their responses to disturbance cues (or control cues) produced by tadpoles from high-risk or low-risk backgrounds. We found an interaction between risk levels associated with the cue donor and cue recipient. While disturbance cues from low-risk donors did not elicit an antipredator response in low-risk receivers, they did in high-risk receivers. In addition, disturbance cues from high-risk donors elicited a marked antipredator response in both low- and high-risk receivers. The response of high-risk receivers to disturbance cues from high-risk donors was commensurate with other treatments, indicating an all-or-nothing response. Our study provides evidence of differential production and perception of social cues and provides insights into their function and evolution in aquatic vertebrates. Given the widespread nature of disturbance cues in aquatic prey, there may exist a social signalling system that remains virtually unexplored by ecologists.

Mechanisms underlying the control of responses to predator odours in aquatic prey.

In aquatic systems, chemical cues are a major source of information through which animals are able to assess the current state of their environment to gain information about local predation risk. Prey use chemicals released by predators (including cues from a predator's diet) and other prey (such as alarm cues and disturbance cues) to mediate a range of behavioural, morphological and life-history antipredator defences. Despite the wealth of knowledge on the ecology of antipredator defences, we know surprisingly little about the physiological mechanisms that control the expression of these defensive traits. Here, we summarise the current literature on the mechanisms known to specifically mediate responses to predator odours, including dietary cues. Interestingly, these studies suggest that independent pathways may control predator-specific responses, highlighting the need for greater focus on predator-derived cues when looking at the mechanistic control of responses. Thus, we urge researchers to tease apart the effects of predator-specific cues (i.e. chemicals representing a predator's identity) from those of diet-mediated cues (i.e. chemicals released from a predator's diet), which are known to mediate different ecological endpoints. Finally, we suggest some key areas of research that would greatly benefit from a more mechanistic approach.

Sodium channel slow inactivation as a therapeutic target for myotonia congenita.

OBJECTIVE: Patients with myotonia congenita have muscle hyperexcitability due to loss-of-function mutations in the chloride channel in skeletal muscle, which causes spontaneous firing of muscle action potentials (myotonia), producing muscle stiffness. In patients, muscle stiffness lessens with exercise, a change known as the warmup phenomenon. Our goal was to identify the mechanism underlying warmup and to use this information to guide development of novel therapy. METHODS: To determine the mechanism underlying warmup, we used a recently discovered drug to eliminate muscle contraction, thus allowing prolonged intracellular recording from individual muscle fibers during induction of warmup in a mouse model of myotonia congenita. RESULTS: Changes in action potentials suggested slow inactivation of sodium channels as an important contributor to warmup. These data suggested that enhancing slow inactivation of sodium channels might offer effective therapy for myotonia. Lacosamide and ranolazine enhance slow inactivation of sodium channels and are approved by the US Food and Drug Administration for other uses in patients. We compared the efficacy of both drugs to mexiletine, a sodium channel blocker currently used to treat myotonia. In vitro studies suggested that both lacosamide and ranolazine were superior to mexiletine. However, in vivo studies in a mouse model of myotonia congenita suggested that side effects could limit the efficacy of lacosamide. Ranolazine produced fewer side effects and was as effective as mexiletine at a dose that produced none of mexiletine's hypoexcitability side effects. INTERPRETATION: We conclude that ranolazine has excellent therapeutic potential for treatment of patients with myotonia congenita.

The relationship between obsessive-compulsive symptoms and PARKIN genotype: The CORE-PD study.

BACKGROUND: Few studies have systematically investigated the association between PARKIN genotype and psychiatric co-morbidities of Parkison's disease (PD). PARKIN-associated PD is characterized by severe nigral dopaminergic neuronal loss, a finding that may have implications for behaviors rooted in dopaminergic circuits such as obsessive-compulsive symptoms (OCS). METHODS: The Schedule of Compulsions and Obsessions Patient Inventory (SCOPI) was administered to 104 patients with early-onset PD and 257 asymptomatic first-degree relatives. Carriers of one and two PARKIN mutations were compared with noncarriers. RESULTS: Among patients, carriers scored lower than noncarriers in adjusted models (one-mutation: 13.9 point difference, P = 0.03; two-mutation: 24.1, P = 0.001), where lower scores indicate less OCS. Among asymptomatic relatives, a trend toward the opposite was seen: mutation carriers scored higher than noncarriers (one mutation, P = 0.05; two mutations, P = 0.13). CONCLUSIONS: First, a significant association was found between PARKIN mutation status and obsessive-compulsive symptom level in both PD and asymptomatic patients, suggesting that OCS might represent an early non-motor dopamine-dependent feature. Second, irrespective of disease status, heterozygotes were significantly different from noncarriers, suggesting that PARKIN heterozygosity may contribute to phenotype. © 2014 International Parkinson and Movement Disorder Society.

Impacts of ocean warming on echinoderms: A meta-analysis.

Rising ocean temperatures are threatening marine species and populations worldwide, and ectothermic taxa are particularly vulnerable. Echinoderms are an ecologically important phylum of marine ectotherms and shifts in their population dynamics can have profound impacts on the marine environment. The effects of warming on echinoderms are highly variable across controlled laboratory-based studies. Accordingly, synthesis of these studies will facilitate the better understanding of broad patterns in responses of echinoderms to ocean warming. Herein, a meta-analysis incorporating the results of 85 studies (710 individual responses) is presented, exploring the effects of warming on various performance predictors. The mean responses of echinoderms to all magnitudes of warming were compared across multiple biological responses, ontogenetic life stages, taxonomic classes, and regions, facilitated by multivariate linear mixed effects models. Further models were conducted, which only incorporated responses to warming greater than the projected end-of-century mean annual temperatures at the collection sites. This meta-analysis provides evidence that ocean warming will generally accelerate metabolic rate (+32%) and reduce survival (-35%) in echinoderms, and echinoderms from subtropical (-9%) and tropical (-8%) regions will be the most vulnerable. The relatively high vulnerability of echinoderm larvae to warming (-20%) indicates that this life stage may be a significant developmental bottleneck in the near-future, likely reducing successful recruitment into populations. Furthermore, asteroids appear to be the class of echinoderms that are most negatively affected by elevated temperature (-30%). When considering only responses to magnitudes of warming representative of end-of-century climate change projections, the negative impacts on asteroids, tropical species and juveniles were exacerbated (-51%, -34% and -40% respectively). The results of these analyses enable better predictions of how keystone and invasive echinoderm species may perform in a warmer ocean, and the possible consequences for populations, communities and ecosystems.

Upregulation of the CaV 1.1-ryanodine receptor complex in a rat model of critical illness myopathy.

The processes that trigger severe muscle atrophy and loss of myosin in critical illness myopathy (CIM) are poorly understood. It has been reported that muscle disuse alters Ca(2+) handling by the sarcoplasmic reticulum. Since inactivity is an important contributor to CIM, this finding raises the possibility that elevated levels of the proteins involved in Ca(2+) handling might contribute to development of CIM. CIM was induced in 3- to 5-mo-old rats by sciatic nerve lesion and infusion of dexamethasone for 1 wk. Western blot analysis revealed increased levels of ryanodine receptor (RYR) isoforms-1 and -2 as well as the dihydropyridine receptor/voltage-gated calcium channel type 1.1 (DHPR/Ca(V) 1.1). Immunostaining revealed a subset of fibers with elevation of RYR1 and Ca(V) 1.1 that had severe atrophy and disorganization of sarcomeres. These findings suggest increased Ca(2+) release from the sarcoplasmic reticulum may be an important contributor to development of CIM. To assess the endogenous functional effects of increased intracellular Ca(2+) in CIM, proteolysis of α-fodrin, a well-known target substrate of Ca(2+)-activated proteases, was measured and found to be 50% greater in CIM. There was also selective degradation of myosin heavy chain relative to actin in CIM muscle. Taken together, our findings suggest that increased Ca(2+) release from the sarcoplasmic reticulum may contribute to pathology in CIM.

Neuropsychological Profile of Parkin Mutation Carriers with and without Parkinson Disease: The CORE-PD Study.

The cognitive profile of early onset Parkinson's disease (EOPD) has not been clearly defined. Mutations in the parkin gene are the most common genetic risk factor for EOPD and may offer information about the neuropsychological pattern of performance in both symptomatic and asymptomatic mutation carriers. EOPD probands and their first-degree relatives who did not have Parkinson's disease (PD) were genotyped for mutations in the parkin gene and administered a comprehensive neuropsychological battery. Performance was compared between EOPD probands with (N = 43) and without (N = 52) parkin mutations. The same neuropsychological battery was administered to 217 first-degree relatives to assess neuropsychological function in individuals who carry parkin mutations but do not have PD. No significant differences in neuropsychological test performance were found between parkin carrier and noncarrier probands. Performance also did not differ between EOPD noncarriers and carrier subgroups (i.e., heterozygotes, compound heterozygotes/homozygotes). Similarly, no differences were found among unaffected family members across genotypes. Mean neuropsychological test performance was within normal range in all probands and relatives. Carriers of parkin mutations, whether or not they have PD, do not perform differently on neuropsychological measures as compared to noncarriers. The cognitive functioning of parkin carriers over time warrants further study.

Quantitative Electroencephalography as a Biomarker for Cognitive Dysfunction in Parkinson's Disease.

Background: Quantitative electroencephalography (qEEG) has been suggested as a biomarker for cognitive decline in Parkinson's disease (PD). Objective: Determine if applying a wavelet-based qEEG algorithm to 21-electrode, resting-state EEG recordings obtained in a routine clinical setting has utility for predicting cognitive impairment in PD. Methods: PD subjects, evaluated by disease stage and motor score, were compared to healthy controls (N = 20 each). PD subjects with normal (PDN, MoCA 26-30, N = 6) and impaired (PDD, MoCA ≤ 25, N = 14) cognition were compared. The wavelet-transform based time-frequency algorithm assessed the instantaneous predominant frequency (IPF) at 60 ms intervals throughout entire recordings. We then determined the relative time spent by the IPF in the four standard EEG frequency bands (RTF) at each scalp location. The resting occipital rhythm (ROR) was assessed using standard power spectral analysis. Results: Comparing PD subjects to healthy controls, mean values are decreased for ROR and RTF-Beta, greater for RTF-Theta and similar for RTF-Delta and RTF-Alpha. In logistic regression models, arithmetic combinations of RTF values [e.g., (RTF-Alpha) + (RTF-Beta)/(RTF-Delta + RTF-Theta)] and RTF-Alpha values at occipital or parietal locations are most able to discriminate between PD and controls. A principal component (PC) from principal component analysis (PCA) using RTF-band values in all subjects is associated with PD status (p = 0.004, ß = 0.31, AUC = 0.780). Its loadings show positive contribution from RTF-Theta at all scalp locations, and negative contributions from RTF-Beta at occipital, parietal, central, and temporal locations. Compared to cognitively normal PD subjects, cognitively impaired PD subjects have lower median RTF-Alpha and RTF-Beta values, greater RTF-Theta values and similar RTF-Delta values. A PC from PCA using RTF-band values in PD subjects is associated with cognitive status (p = 0.002, ß = 0.922, AUC = 0.89). Its loadings show positive contributions from RTF-Theta at all scalp locations, negative contributions from RTF-Beta at central locations, and negative contributions from RTF-Delta at central, frontal and temporal locations. Age, disease duration and/or sex are not significant covariates. No PC was associated with motor score or disease stage. Significance: Analyzing standard EEG recordings obtained in a community practice setting using a wavelet-based qEEG algorithm shows promise as a PD biomarker and for predicting cognitive impairment in PD.

The mechanism underlying transient weakness in myotonia congenita.

In addition to the hallmark muscle stiffness, patients with recessive myotonia congenita (Becker disease) experience debilitating bouts of transient weakness that remain poorly understood despite years of study. We performed intracellular recordings from muscle of both genetic and pharmacologic mouse models of Becker disease to identify the mechanism underlying transient weakness. Our recordings reveal transient depolarizations (plateau potentials) of the membrane potential to -25 to -35 mV in the genetic and pharmacologic models of Becker disease. Both Na+ and Ca2+ currents contribute to plateau potentials. Na+ persistent inward current (NaPIC) through NaV1.4 channels is the key trigger of plateau potentials and current through CaV1.1 Ca2+ channels contributes to the duration of the plateau. Inhibiting NaPIC with ranolazine prevents the development of plateau potentials and eliminates transient weakness in vivo. These data suggest that targeting NaPIC may be an effective treatment to prevent transient weakness in myotonia congenita.

Myotonia is a neuromuscular condition that causes problems with the relaxation of muscles following voluntary movements. One type of myotonia is Becker disease, also called recessive myotonia congenita. This is a genetic condition that causes muscle stiffness as a result of involuntary muscle activity. Patients may also suffer transient weakness for a few seconds or as long as several minutes after initiating a movement. The cause of these bouts of temporary weakness is still unclear, but there are hints that it could be linked to the muscle losing its excitability, the ability to respond to the stimuli that make it contract. However, this is at odds with findings that show that muscles in Becker disease are hyperexcitable. Muscle excitability depends on the presence of different concentrations of charged ions (positively charged sodium, calcium and potassium ions and negatively charged chloride ions) inside and outside of each muscle cells. These different concentrations of ions create an electric potential across the cell membrane, also called the 'membrane potential'. When a muscle cell gets stimulated, proteins on the cell membrane known as ion channels open. This allows the flow of ions between the inside and the outside of the cell, which causes an electrical current that triggers muscle contraction. To better understand the causes behind this muscle weakness, Myers et al. used mice that had either been genetically manipulated or given drugs to mimic Becker disease. By measuring both muscle force and the electrical currents that drive contraction, Myers et al. found that the mechanism underlying post-movement weakness involved a transient change in the concentrations of positively charged ions inside and outside the cells. Further experiments showed that proteins that regulate the passage of both sodium and calcium in and out of the cell ­ called sodium and calcium channels ­ contributed to this change in concentration. In addition, Myers et al. discovered that using a drug called ranolazine to stop sodium ions from entering the cell eliminated transient weakness in live mice. These findings suggest that in Becker disease, muscles cycle rapidly between being hyperexcited or not able to be excited, and that targeting the flow of sodium ions into the cell could be an effective treatment to prevent transient weakness in myotonia congenita. This study paves the way towards the development of new therapies to treat Becker disease as well as other muscle ion channel diseases with transient weakness such as periodic paralysis.

Development and pilot of a prescription drug monitoring program and communication intervention for pharmacists.

BACKGROUND: Pharmacists' role in addressing the opioid crisis continues to expand, but lack of training specifically related to standardized prescription drug monitoring program (PDMP) use and communication strategies for provider and patient interactions remains a significant issue. We developed the Resources Encouraging Safe Prescription Opioid and Naloxone Dispensing (RESPOND) Toolkit to enhance community pharmacists' understanding of their role in addressing opioid safety; improve integration of PDMP into daily workflow; and enhance communication between pharmacists, prescribers, and patients. OBJECTIVE: To describe the development of RESPOND Toolkit and summarize findings from initial pilot testing. METHODS: RESPOND development was informed by focus groups with patients, prescribers, and pharmacists and an external advisory committee. Materials developed include a patient screening & communication algorithm, a provider communication checklist and an online continuing education course with three distinct modules. The RESPOND Toolkit was pilot tested in six community pharmacies in Oregon across two 6-month intervention phases. Pilot data collection included a pre-post intervention survey, pre-post knowledge assessment quizzes within the online course, and post-intervention semi-structured interviews. Interview feedback informed revisions after each phase to shape the final content, flow, and delivery of RESPOND. RESULTS: Sixteen of 21 pharmacists completed the online training, revealing a large, significant effect on knowledge gain across the three training modules (pre-score 57, post-score 84; p < 0.001; Cohen's d = 1.85). Of these participants, 10 also completed the baseline and post intervention survey and showed non-significant moderate improvements in knowledge, perceived behavioral control, and self-efficacy to address opioid safety issues. CONCLUSION: The RESPOND Toolkit has promise as an effective and scalable approach to providing community pharmacist-tailored training, especially in the areas of effective communication and workflow integration, to promote behavioral shifts supporting opioid safety for patients. Further development and testing in a larger sample is warranted.