A phase 1 open label study to assess the human mass balance and metabolite profile of 14C-fosmanogepix, a novel Gwt-1 inhibitor in healthy male participants.

Fosmanogepix [FMGX; active form manogepix (MGX)], a novel antifungal, is currently being studied for the treatment of invasive fungal diseases caused by Candida spp., Aspergillus spp., and other rare molds. This Phase 1, single-dose study used 14C-radiolabeled FMGX to determine the disposition and metabolism of FMGX. Ten healthy male participants were enrolled equally into: oral cohort {FMGX 500 mg oral + 3.1 megabecquerel [MBq, 84.0 microcurie (µCi)] 14C} and intravenous (IV) cohort [FMGX 600 mg IV + 3.4 MBq (93.0 µCi) 14C]. At the end of the sampling period (456 h post-dose), 90.2% of radioactivity administered was recovered (46.4% from urine; 43.8% from feces) in oral cohort (82.3% within 240 h), and 82.4% was recovered (42.5% from urine; 39.9% from feces) in IV cohort (76.2% within 264 h), indicating that FMGX elimination occurs via renal and hepatic routes. Radioactivity transformation pathways (oral and IV) indicated multiple major routes of metabolism of FMGX, mainly via MGX, and included oxidation, oxidative deamination, and conjugation. All except one key human plasma metabolite was observed in toxicity species, but its proportion (<10%) in the human area under the curve plasma samples was not of toxicological concern. No deaths, serious, or severe adverse events (AE) were reported, and there were no AE-related withdrawals. The results of this study indicated extensive metabolism of FMGX, with similar key human plasma metabolites observed in the animal studies. The elimination of FMGX was equally through renal and hepatic routes. CLINICAL TRIALS: This study is registered with ClinicalTrials.gov as NCT04804059.

Alabama community pharmacists' knowledge and perceptions regarding fentanyl test strips: A cross-sectional survey.

BACKGROUND: Fentanyl test strips (FTS) are used to detect the presence of fentanyl in other substances, but Alabama pharmacists' opinions regarding FTS provision are unknown. OBJECTIVE: The purpose of this study was to assess the knowledge and perceptions of Alabama pharmacists regarding FTS and factors influencing pharmacists' FTS provision intentions across community pharmacy locations and types. METHODS: An anonymous cross-sectional survey was distributed via email to Alabama pharmacists employed in community (retail) pharmacies. The survey consisted of multiple-choice questions and 5-point Likert-type scales (1 = strongly disagree, 5 = strongly agree) informed by the Theory of Planned Behavior. Primary outcome measures included: knowledge; general attitudes; perceived benefits; perceived barriers; self-efficacy; subjective norms; perceived behavioral control (PBC); and intention regarding FTS provision. Outcomes were characterized using descriptive statistics and differences in scales scores across pharmacy locations (rural vs. urban) and types (corporately-vs. independently-owned) were assessed using Mann-Whitney U tests. Predictors of FTS provision intentions were evaluated using multiple linear regression (alpha=0.05). RESULTS: Respondents (N = 131; 3.82% response rate) were mostly female (64%) and Caucasian (92%). No respondents stocked FTS at their pharmacy and knowledge about FTS was low (mean[SD] knowledge score: 58.7% [15.1]). Despite the existence of perceived barriers (mean [SD] scale score: 3.2 [0.6]), pharmacists' general attitudes (3.4 [0.5]), perceived benefits (3.7 [0.6]), self-efficacy (3.1 [0.8]), and intentions (3.2[0.7]) were positive. While subjective norms were positive (3.5[0.6]), PBC over FTS decision-making was negative (2.7[0.8]). Subjective norms were higher (P = 0.040) and PBC was lower (P < 0.001) amongst corporately-versus independently-owned pharmacies, but no differences existed between rural and urban locations for any measures. Additionally, perceived benefits (ß=0.342, P = 0.002), PBC (ß = 0.133, P = 0.045), and self-efficacy (ß = 0.142, P = 0.034) were positive predictors and perceived barriers (ß = -0.211, P = 0.029) was a negative predictor of intention. CONCLUSION: Alabama community pharmacists have positive attitudes regarding FTS, but future research should focus on strategies to increase PBC and overcome perceived barriers.

Developing and Evaluating a School-Based Tobacco and E-Cigarette Prevention Program for Deaf and Hard-of-Hearing Youth.

School-based programs are an important tobacco prevention tool. Yet, existing programs are not suitable for Deaf and Hard-of-Hearing (DHH) youth. Moreover, little research has examined the use of the full range of tobacco products and related knowledge in this group. To address this gap and inform development of a school-based tobacco prevention program for this population, we conducted a pilot study among DHH middle school (MS) and high school (HS) students attending Schools for the Deaf and mainstream schools in California (n = 114). American Sign Language (ASL) administered surveys, before and after receipt of a draft curriculum delivered by health or physical education teachers, assessed product use and tobacco knowledge. Thirty-five percent of students reported exposure to tobacco products at home, including cigarettes (19%) and e-cigarettes (15%). Tobacco knowledge at baseline was limited; 35% of students knew e-cigarettes contain nicotine, and 56% were aware vaping is prohibited on school grounds. Current product use was reported by 16% of students, most commonly e-cigarettes (12%) and cigarettes (10%); overall, 7% of students reported dual use. Use was greater among HS versus MS students. Changes in student knowledge following program delivery included increased understanding of harmful chemicals in tobacco products, including nicotine in e-cigarettes. Post-program debriefings with teachers yielded specific recommendations for modifications to better meet the educational needs of DHH students. Findings based on student and teacher feedback will guide curriculum development and inform next steps in our program of research aimed to prevent tobacco use in this vulnerable and heretofore understudied population group.

Articulation Rate, Pauses, and Disfluencies in Professional Fighters: Potential Speech Biomarkers for Repetitive Head Injury.

OBJECTIVE: As part of a larger study dedicated to identifying speech and language biomarkers of neurological decline associated with repetitive head injury (RHI) in professional boxers and mixed martial artists (MMAs), we examined articulation rate, pausing, and disfluency in passages read aloud by participants in the Professional Athletes Brain Health Study. SETTING: A large outpatient medical center specializing in neurological care. PARTICIPANTS, DESIGN, AND MAIN MEASURES: Passages read aloud by 60 boxers, 40 MMAs, and 55 controls were acoustically analyzed to determine articulation rate (the number of syllables produced per second), number and duration of pauses, and number and duration of disfluencies in this observational study. RESULTS: Both boxers and MMAs differed from controls in articulation rate, producing syllables at a slower rate than controls by nearly half a syllable per second on average. Boxers produced significantly more pauses and disfluencies in passages read aloud than MMAs and controls. CONCLUSIONS: Slower articulation rate in both boxers and MMA fighters compared with individuals with no history of RHI and the increased occurrence of pauses and disfluencies in the speech of boxers suggest changes in speech motor behavior that may relate to RHI. These speech characteristics can be measured in everyday speaking conditions and by automatic recognition systems, so they have the potential to serve as effective, noninvasive clinical indicators for RHI-associated neurological decline.

Developing a novel device, Eggcell, to improve temperature stability during oocyte collection for IVF.

RESEARCH QUESTION: What temperature fluctuations are oocytes exposed to during oocyte retrieval? Can an alternative method of oocyte retrieval be designed to minimize these fluctuations? DESIGN: Mock oocyte retrieval procedures were performed to investigate the change in temperature when the follicular fluid is drained into collection tubes and when the fluid is subsequently poured into dishes to allow identification of the cumulus-oocyte complex (COC). A new device, the Eggcell, has been designed that addresses the problem of these temperature fluctuations. To confirm its safety and demonstrate the clinical applicability of Eggcell, laboratory validation was performed prior to use with human participants (n = 15). RESULTS: Eggcell meets its design specification to provide temperature stability within the physiological range for aspirated follicular fluid. The COC can be successfully retained within the chamber (n = 180) without evidence of loss or damage to the oocytes or compromise of fertilization rate, blastocyst development or clinical outcome. CONCLUSIONS: This study has demonstrated the successful first stages of development of a new medical device. Further studies are needed for comparative evaluation of clinical outcome with standard technology.

Towards clinical application of pronuclear transfer to prevent mitochondrial DNA disease.

Mitochondrial DNA (mtDNA) mutations are maternally inherited and are associated with a broad range of debilitating and fatal diseases. Reproductive technologies designed to uncouple the inheritance of mtDNA from nuclear DNA may enable affected women to have a genetically related child with a greatly reduced risk of mtDNA disease. Here we report the first preclinical studies on pronuclear transplantation (PNT). Surprisingly, techniques used in proof-of-concept studies involving abnormally fertilized human zygotes were not well tolerated by normally fertilized zygotes. We have therefore developed an alternative approach based on transplanting pronuclei shortly after completion of meiosis rather than shortly before the first mitotic division. This promotes efficient development to the blastocyst stage with no detectable effect on aneuploidy or gene expression. After optimization, mtDNA carryover was reduced to <2% in the majority (79%) of PNT blastocysts. The importance of reducing carryover to the lowest possible levels is highlighted by a progressive increase in heteroplasmy in a stem cell line derived from a PNT blastocyst with 4% mtDNA carryover. We conclude that PNT has the potential to reduce the risk of mtDNA disease, but it may not guarantee prevention.

Understanding Veteran Suicide Risk and Mitigation Strategies During the COVID-19 Pandemic.

U.S. Veterans experience a significantly higher risk for suicide compared to the general population. Understanding the challenges associated with coronavirus disease 2019 (COVID-19) enables providers to mitigate the risk of suicide among Veterans. Evidence supports access and utilization of U.S. Department of Veterans Affairs (VA) mental health services as they are a protective factor associated with lower suicide rates. During the ongoing COVID-19 pandemic, the VA has worked to further decrease deaths by suicide in the Veteran population by rapid expansion of current interventions and implementation of new evidence-based interventions. These interventions include mental health and coaching applications, consistent use of measurement-based care across multiple disciplines, and greater use of telehealth services. Through these efforts, despite increased risk for suicide due to additional stressors from COVID-19, suicide rates among Veterans are decreasing. [Journal of Psychosocial Nursing and Mental Health Services, 60(12), 25-29.].

Could mindfulness-based cognitive therapy prevent a lifelong recurrent course of depression or anxiety by addressing key mechanisms of vulnerability in high-risk adolescents?

We explore the potential of mindfulness-based cognitive therapy, a skills-based intervention that provides participants with sustainable tools for adaptive responses to stress and negative mood, for the large group of young people with depression or anxiety who only partially or briefly respond to currently available first-line interventions.

Patterns of narrative discourse in early recovery following severe Traumatic Brain Injury.

Primary Objective: To investigate the nature and patterns of narrative discourse impairment in people with severe Traumatic Brain Injury (TBI) during early recovery.Methods and Procedures: A single image picture description task was administered to 42 participants with severe TBI at 3 and 6-months post-injury. The same task was administered to 37 control participants. Discourse samples were analyzed with measures of productivity, informativeness and story organization. The performance of people with TBI was compared with the control group at both 3 and 6 months, and the performance of the participants with TBI was also compared across the two time points. Individual patterns of performance were also examined.Results: Inferential analyses revealed significant differences between the control group and the group with TBI on informativeness at both time points and  number of complete episodes at 3 months, but no significant differences for productivity measures. There was no significant change for the group with TBI between 3 and 6 months. However, individual improvement over time was observed.Conclusions: People with TBI have discourse difficulties early post TBI that are also present at 6-months post-injury. In order to understand longer-term discourse recovery, it is necessary to examine participant patterns over further time points on this narrative task.

Moving Toward Non-transcription based Discourse Analysis in Stable and Progressive Aphasia.

Measurement of communication ability at the discourse level holds promise for predicting how well persons with stable (e.g., stroke-induced), or progressive aphasia navigate everyday communicative interactions. However, barriers to the clinical utilization of discourse measures have persisted. Recent advancements in the standardization of elicitation protocols and the existence of large databases for development of normative references have begun to address some of these barriers. Still, time remains a consistently reported barrier by clinicians. Non-transcription based discourse measurement would reduce the time required for discourse analysis, making clinical utilization a reality. The purpose of this article is to present evidence regarding discourse measures (main concept analysis, core lexicon, and derived efficiency scores) that are well suited to non-transcription based analysis. Combined with previous research, our results suggest that these measures are sensitive to changes following stroke or neurodegenerative disease. Given the evidence, further research specifically assessing the reliability of these measures in clinical implementation is warranted.

A Compendium of Core Lexicon Checklists.

Core Lexicon (CoreLex) is a relatively new approach assessing lexical use in discourse. CoreLex examines the specific lexical items used to tell a story, or how typical lexical items are compared with a normative sample. This method has great potential for clinical utilization because CoreLex measures are fast, easy to administer, and correlate with microlinguistic and macrolinguistic discourse measures. The purpose of this article is to provide clinicians with a centralized resource for currently available CoreLex checklists, including information regarding development, norms, and guidelines for use.

Can Script Training Improve Narrative and Conversation in Aphasia across Etiology?

Script training is an effective treatment of stable (e.g., stroke-induced) and progressive aphasia of varying severities and subtypes. The theoretical underpinnings of script training are discussed and include fluency-inducing conditions, speech shadowing, principles of neuroplasticity, and automatization. Script training outcomes are reviewed, with a focus on discourse in persons with stable aphasia (PWSAs) and in persons with primary progressive aphasia (PWPPAs). PWSAs and PWPPAs are able to acquire and maintain short scripted monologues or conversational dialogues, with some evidence of generalization to untrained topics and settings. Advances in both technology and access have enriched script training protocols, so they now range from no-tech written script approaches to high-tech audiovisual support and avatars. Advances in audio and/or visual support promote large amounts of practice of less errorful whole-message language processing during a fluent language inducing condition. With enough practice, users decrease reliance on supports and independently produce scripted content. Script training can be delivered in a variety of settings (individual, group, telepractice), lends itself well to homework programs, and is in accordance with the principles of neuroplasticity for neurorehabilitation. Incorporating script training into therapy programming is advantageous throughout aphasia recovery following brain injuries such as stroke. It is also beneficial for persons with progressive disease for prophylaxis, remediation, and compensation. Recommendations for implementing script training in clinical practice and future research directions are presented.

Response of cyanobacteria and phytoplankton abundance to warming, extreme rainfall events and nutrient enrichment.

Cyanobacterial blooms are an increasing threat to water quality and global water security caused by the nutrient enrichment of freshwaters. There is also a broad consensus that blooms are increasing with global warming, but the impacts of other concomitant environmental changes, such as an increase in extreme rainfall events, may affect this response. One of the potential effects of high rainfall events on phytoplankton communities is greater loss of biomass through hydraulic flushing. Here we used a shallow lake mesocosm experiment to test the combined effects of: warming (ambient vs. +4°C increase), high rainfall (flushing) events (no events vs. seasonal events) and nutrient loading (eutrophic vs. hypertrophic) on total phytoplankton chlorophyll-a and cyanobacterial abundance and composition. Our hypotheses were that: (a) total phytoplankton and cyanobacterial abundance would be higher in heated mesocosms; (b) the stimulatory effects of warming on cyanobacterial abundance would be enhanced in higher nutrient mesocosms, resulting in a synergistic interaction; (c) the recovery of biomass from flushing induced losses would be quicker in heated and nutrient-enriched treatments, and during the growing season. The results supported the first and, in part, the third hypotheses: total phytoplankton and cyanobacterial abundance increased in heated mesocosms with an increase in common bloom-forming taxa-Microcystis spp. and Dolichospermum spp. Recovery from flushing was slowest in the winter, but unaffected by warming or higher nutrient loading. Contrary to the second hypothesis, an antagonistic interaction between warming and nutrient enrichment was detected for both cyanobacteria and chlorophyll-a demonstrating that ecological surprises can occur, dependent on the environmental context. While this study highlights the clear need to mitigate against global warming, oversimplification of global change effects on cyanobacteria should be avoided; stressor gradients and seasonal effects should be considered as important factors shaping the response.

Engagement in Psychotherapy Improves Outcomes for Veterans.

The longstanding partnership between the Birmingham Veterans Affairs Medical Center (BVAMC) and the University of Alabama at Birmingham School of Nursing inspired the establishment of one of the country's first psychiatric-mental health nurse practitioner (PMHNP) residencies and subsequent formation of a Resident Continuity Clinic (RCC). Within the RCC, PMHNP residents deliver evidence-based care that is informed by measurement-based care (MBC) to improve patient outcomes and reduce time to recovery. Determined by the BVAMC Institutional Review Board to be a quality improvement project, PMHNP residents administered the Patient Stress Questionnaire (PSQ), a MBC tool that uses four independently validated screening tools to measure the behavioral health symptoms of depression, anxiety, trauma, and alcohol use. Additional clinical variables of interest included patient use of illicit substances, participation in psychotherapy, and use of psychotropic medications. PSQ scores were reviewed retrospectively via descriptive statistics and nonparametric tests. Analysis demonstrated statistically significant improvements in depression and anxiety. Data also revealed that patients engaged in psychotherapy demonstrated greater improvements on all PSQ screening tools compared to patients not involved in psychotherapy. The results reinforce the value of MBC in psychiatric care and highlight the importance of engaging Veterans in psychotherapy to improve outcomes. [Journal of Psychosocial Nursing and Mental Health Services, 57(6), 30-38.].

Cortical disconnection of the ipsilesional primary motor cortex is associated with gait speed and upper extremity motor impairment in chronic left hemispheric stroke.

Advances in neuroimaging have enabled the mapping of white matter connections across the entire brain, allowing for a more thorough examination of the extent of white matter disconnection after stroke. To assess how cortical disconnection contributes to motor impairments, we examined the relationship between structural brain connectivity and upper and lower extremity motor function in individuals with chronic stroke. Forty-three participants [mean age: 59.7 (±11.2) years; time poststroke: 64.4 (±58.8) months] underwent clinical motor assessments and MRI scanning. Nonparametric correlation analyses were performed to examine the relationship between structural connectivity amid a subsection of the motor network and upper/lower extremity motor function. Standard multiple linear regression analyses were performed to examine the relationship between cortical necrosis and disconnection of three main cortical areas of motor control [primary motor cortex (M1), premotor cortex (PMC), and supplementary motor area (SMA)] and motor function. Anatomical connectivity between ipsilesional M1/SMA and the (1) cerebral peduncle, (2) thalamus, and (3) red nucleus were significantly correlated with upper and lower extremity motor performance (P ≤ 0.003). M1-M1 interhemispheric connectivity was also significantly correlated with gross manual dexterity of the affected upper extremity (P = 0.001). Regression models with M1 lesion load and M1 disconnection (adjusted for time poststroke) explained a significant amount of variance in upper extremity motor performance (R2  = 0.36-0.46) and gait speed (R2  = 0.46), with M1 disconnection an independent predictor of motor performance. Cortical disconnection, especially of ipsilesional M1, could significantly contribute to variability seen in locomotor and upper extremity motor function and recovery in chronic stroke. Hum Brain Mapp 39:120-132, 2018. © 2017 Wiley Periodicals, Inc.

Effects of multiple stressors on cyanobacteria abundance vary with lake type.

Blooms of cyanobacteria are a current threat to global water security that is expected to increase in the future because of increasing nutrient enrichment, increasing temperature and extreme precipitation in combination with prolonged drought. However, the responses to multiple stressors, such as those above, are often complex and there is contradictory evidence as to how they may interact. Here we used broad scale data from 494 lakes in central and northern Europe, to assess how cyanobacteria respond to nutrients (phosphorus), temperature and water retention time in different types of lakes. Eight lake types were examined based on factorial combinations of major factors that determine phytoplankton composition and sensitivity to nutrients: alkalinity (low and medium-high), colour (clear and humic) and mixing intensity (polymictic and stratified). In line with expectations, cyanobacteria increased with temperature and retention time in five of the eight lake types. Temperature effects were greatest in lake types situated at higher latitudes, suggesting that lakes currently not at risk could be affected by warming in the future. However, the sensitivity of cyanobacteria to temperature, retention time and phosphorus varied among lake types highlighting the complex responses of lakes to multiple stressors. For example, in polymictic, medium-high alkalinity, humic lakes cyanobacteria biovolume was positively explained by retention time and a synergy between TP and temperature, while in polymictic, medium-high alkalinity, clear lakes only retention time was identified as an explanatory variable. These results show that, although climate change will need to be accounted for when managing the risk of cyanobacteria in lakes, a "one-size fits-all" approach is not appropriate. When forecasting the response of cyanobacteria to future environmental change, including changes caused by climate and local management, it will be important to take this differential sensitivity of lakes into account.

A mutation in the heptad repeat 2 domain of MFN2 in a large CMT2A family.

Dominant mutations in MFN2 cause a range of phenotypes, including severe, early-onset axonal neuropathy, "classical CMT2," and late-onset axonal neuropathies. We report a large family with an axonal polyneuropathy, with clinical onset in the 20s, followed by slow progression.

Mechanoelectrical transduction in chondrocytes.

Cartilage tissue lines the joints of mammals, helping to lubricate joint movement and distribute mechanical loads. This tissue is comprised of isolated cells known as chondrocytes which are embedded in an extracellular matrix. Chondrocytes produce and maintain the cartilage by sensing and responding to changing mechanical loads. Mechanosensitive ion channels have been implicated in chondrocyte mechanotransduction and recent studies have shown that both PIEZO1 and TRPV4 can be activated by mechanical stimuli in these cells. The 2 channels mediate separate but overlapping mechanoelectrical transduction pathways, PIEZO1 in response to stretch and substrate deflections and TRPV4 in response to substrate deflections alone. These distinct pathways of mechanoelectrical transduction suggest a mechanism by which chondrocytes can distinguish between different stimuli that arise in their complex mechanical environment.

Concise reviews: Assisted reproductive technologies to prevent transmission of mitochondrial DNA disease.

While the fertilized egg inherits its nuclear DNA from both parents, the mitochondrial DNA is strictly maternally inherited. Cells contain multiple copies of mtDNA, each of which encodes 37 genes, which are essential for energy production by oxidative phosphorylation. Mutations can be present in all, or only in some copies of mtDNA. If present above a certain threshold, pathogenic mtDNA mutations can cause a range of debilitating and fatal diseases. Here, we provide an update of currently available options and new techniques under development to reduce the risk of transmitting mtDNA disease from mother to child. Preimplantation genetic diagnosis (PGD), a commonly used technique to detect mutations in nuclear DNA, is currently being offered to determine the mutation load of embryos produced by women who carry mtDNA mutations. The available evidence indicates that cells removed from an eight-cell embryo are predictive of the mutation load in the entire embryo, indicating that PGD provides an effective risk reduction strategy for women who produce embryos with low mutation loads. For those who do not, research is now focused on meiotic nuclear transplantation techniques to uncouple the inheritance of nuclear and mtDNA. These approaches include transplantation of any one of the products or female meiosis (meiosis II spindle, or either of the polar bodies) between oocytes, or the transplantation of pronuclei between fertilized eggs. In all cases, the transferred genetic material arises from a normal meiosis and should therefore, not be confused with cloning. The scientific progress and associated regulatory issues are discussed.