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Objective: This study aimed to identify a consensus among pharmacy educators regarding relevant social and administrative science (SAS) topic areas and their priorities within pharmacy curricula., Methods: A modified Delphi process was conducted with members of selected American Association of Colleges of Pharmacy affinity groups as the expert panel. A total of 83 potential topic areas across 12 domains were gathered via an informal literature review. Four rounds of electronic surveys were conducted in June 2023, September 2023, January 2024, and March 2024. Questionnaires queried the importance and tiered priority ranking of topics using methodology adapted from the American College of Clinical Pharmacy Pharmacotherapy Didactic Curriculum Toolkit., Results: A total of 147, 140, 139, and 111 respondents participated in each of the 4 rounds, respectively. Approximately two-thirds of respondents were women, with just over half working at public institutions, and had a median of 12 to 15 years of experience in academia. The final list of SAS topics after 4 rounds included 76 topics across 11 domains, with 35 topics (46%) placed in tier 1, 28 topics (37%) in tier 2, and 13 (17%) in tier 3., Conclusion: A tiered prioritization of SAS topics results can assist institutions in curricular mapping and preparation of graduates for pharmacy practice of today and the future., Competing Interests: Declaration of Competing Interest None declared., (Copyright © 2024 American Association of Colleges of Pharmacy. Published by Elsevier Inc. All rights reserved.)

Background: Guided by the tenets of Kolcaba's holistic comfort theory, we developed, implemented, and evaluated a simulated online pediatric advanced practice health center. The Pediatric Comfy Care Clinic (PCCC) was created to enhance person-centered diagnostic reasoning and holistic advanced management skills for family nurse practitioner students., Methods: Our interprofessional team used a standardized approach to online design and development while integrating essential holistic comfort theory concepts for student engagement and assessment of learning. We explored outcomes of pre- and postclinic quizzes and student reflection data using mixed methods., Results: Significant differences (P < .001) were noted in all postpractice quizzes in each affiliated PCCC module with variable student outcomes on graded clinic encounters. Important student perspectives on teaching and learning in the virtual clinic were noted., Conclusion: A comfort theory-driven, simulated, and digitally enhanced virtual clinic is feasible and valuable with important implications for holistic advanced practice., Competing Interests: The authors declare no conflicts of interest., (Copyright © 2024 Wolters Kluwer Health, Inc. All rights reserved.)

Understanding the human milk metabolome can help inform infant nutrition and health. Untargeted metabolomics was used to study breast milk from 31 healthy participants to assess the shared metabolites in milk from participants with various backgrounds and understand how different demographic, health, and environmental factors impact the milk metabolome. Breast milk samples were analyzed by four separate UPLC-MS/MS methods. Metabolite Set Enrichment Analysis was used to study the most and least variable metabolites. The associations between participant factors and the metabolome were assessed with redundancy analyses. Among all 31 participants and between each untargeted UPLC-MS/MS method, 731 metabolites were detected, of which 389 were shared among all participants. Of the shared metabolites, lactose was the least and lactobionate the most variable metabolite. In the biological super pathway analysis, xenobiotics were the most variable metabolites. Infant age, maternal age, number of live births, and pre-pregnancy BMI were associated with the milk metabolome. In conclusion, the most variable metabolites originate from environmental exposures while the well-conserved core metabolites are linked to cell metabolism or are crucial for infant nutrition and osmoregulation. Understanding the variability of the breast milk metabolome can help identify components that are crucial for infant nutrition, growth, and development., (© 2024. The Author(s).)

Background: Diastolic blood pressure (DBP) is suggested as a surrogate for coronary perfusion pressure (CPP) during cardiopulmonary resuscitation. We examined the correlation between DBP and CPP and hypothesized that both would be associated with survival in a pediatric swine model of asphyxial cardiac arrest., Methods: We performed a retrospective, secondary analysis of 102 pediatric swine resuscitations. DBP and CPP were recorded every 30 s during resuscitation. Values were compared between survivors and non-survivors., Results: DBP mirrored CPP in survivors and non-survivors throughout resuscitation and both were associated with survival. Improvements in DBP and CPP after the first epinephrine administration were greater in survivors (DBP: 25.1 ± 3.0 vs. 5.4 ± 0.8 mmHg, p < 0.01; CPP: 24.9 ± 3.2 vs. 4.8 ± 0.9 mmHg, p < 0.01). DBP and CPP after epinephrine administration were highly predictive of survival, with an area under the curve of 0.95 (0.89-1.00) for DBP and 0.90 (0.81-0.99) for CPP. The optimal threshold for DBP was 22.5 mmHg, whereas that for CPP was 14.5 mmHg., Conclusions: DBP and CPP were associated with survival throughout resuscitation, and the response of both to the first epinephrine administration was highly predictive of survival in this model. Clinically, the availability of DBP makes it useful as a target for physiologic feedback during resuscitation., Impact: Diastolic blood pressure (DBP) mirrored coronary perfusion pressure (CPP) throughout prolonged resuscitation in a pediatric model of asphyxial cardiac arrest. Mean DBP and CPP were significantly greater in survivors than in non-survivors both before and after administration of epinephrine. The response of both DBP and CPP to the first dose of epinephrine was highly predictive of return of spontaneous circulation. Given the clinical availability of DBP, these findings support its use as a surrogate for CPP to guide high-quality cardiopulmonary resuscitation in this pediatric swine model., (© 2024. The Author(s), under exclusive licence to the International Pediatric Research Foundation, Inc.)

Background: Daily airway clearance therapy (ACT) is a critical aspect of treatment in cystic fibrosis (CF), but poor adherence is a prominent concern. Identifying factors that might enhance or diminish adherence is a priority for treatment centers. Gratitude, a generalized tendency to notice and appreciate positive facets of experience, is a psychosocial resource that has commanded growing research interest. This longitudinal study examined whether gratitude at baseline was associated with ongoing or persistent ACT adherence over the course of a year., Methods: Trait gratitude was evaluated at baseline using a validated measure, among adults receiving care at a regional CF treatment center. Self-reported adherence to ACT was assessed at baseline, 6 months, and 12 months using the Cystic Fibrosis Treatment Questionnaire. Average age of participants was 27.2 years, 45.5% were women, and 19.7% had severe disease., Results: In multivariable logistic regression models that accounted for disease severity (Forced Expiratory Volume 1 % predicted) and other clinical and demographic variables, individuals with higher baseline gratitude were significantly more likely to demonstrate persistent adherence over the course of the year. Gratitude remained predictive after additionally adjusting for other well-known psychosocial resource variables (social support and emotional well-being)., Conclusion: This is among the first demonstrations that gratitude is associated with persistent self-reported adherence to treatment over time. Findings suggest that gratitude may be important psychosocial resource for adults with CF, as they contend with complex, highly burdensome treatment regimens. Further research is warranted to examine these relationships and their impact on downstream health outcomes., (© 2024. International Society of Behavioral Medicine.)

The Health and Environmental Sciences Institute (HESI) is a nonprofit organization dedicated to resolving global health challenges through collaborative scientific efforts across academia, regulatory authorities and the private sector. Collaborative science across non-clinical disciplines offers an important keystone to accelerate the development of safer and more effective medicines. HESI works to address complex challenges by leveraging diverse subject-matter expertise across sectors offering access to resources, data and shared knowledge. In 2008, the HESI Cardiac Safety Committee (CSC) was established to improve public health by reducing unanticipated cardiovascular (CV)-related adverse effects from pharmaceuticals or chemicals. The committee continues to significantly impact the field of CV safety by bringing together experts from across sectors to address challenges of detecting and predicting adverse cardiac outcomes. Committee members have collaborated on the organization, management and publication of prospective studies, retrospective analyses, workshops, and symposia resulting in 38 peer reviewed manuscripts. Without this collaboration these manuscripts would not have been published. Through their work, the CSC is actively addressing challenges and opportunities in detecting potential cardiac failure modes using in vivo, in vitro and in silico models, with the aim of facilitating drug development and improving study design. By examining past successes and future prospects of the CSC, this manuscript sheds light on how the consortium's multifaceted approach not only addresses current challenges in detecting potential cardiac failure modes but also paves the way for enhanced drug development and study design methodologies. Further, exploring future opportunities and challenges will focus on improving the translational predictability of nonclinical evaluations and reducing reliance on animal research in CV safety assessments., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023. Published by Elsevier Inc.)

Objective: Terminal extubation (TE) and terminal weaning (TW) during withdrawal of life-sustaining therapies (WLSTs) have been described and defined in adults. The recent Death One Hour After Terminal Extubation study aimed to validate a model developed to predict whether a child would die within 1 hour after discontinuation of mechanical ventilation for WLST. Although TW has not been described in children, pre-extubation weaning has been known to occur before WLST, though to what extent is unknown. In this preplanned secondary analysis, we aim to describe/define TE and pre-extubation weaning (PW) in children and compare characteristics of patients who had ventilatory support decreased before WLST with those who did not., Design: Secondary analysis of multicenter retrospective cohort study., Setting: Ten PICUs in the United States between 2009 and 2021., Patients: Nine hundred thirteen patients 0-21 years old who died after WLST., Interventions: None., Measurements and Main Results: 71.4% ( n = 652) had TE without decrease in ventilatory support in the 6 hours prior. TE without decrease in ventilatory support in the 6 hours prior = 71.4% ( n = 652) of our sample. Clinically relevant decrease in ventilatory support before WLST = 11% ( n = 100), and 17.6% ( n = 161) had likely incidental decrease in ventilatory support before WLST. Relevant ventilator parameters decreased were F io2 and/or ventilator set rates. There were no significant differences in any of the other evaluated patient characteristics between groups (weight, body mass index, unit type, primary diagnostic category, presence of coma, time to death after WLST, analgosedative requirements, postextubation respiratory support modality)., Conclusions: Decreasing ventilatory support before WLST with extubation in children does occur. This practice was not associated with significant differences in palliative analgosedation doses or time to death after extubation., Competing Interests: Dr. Pringle’s institution received funding from the National Institutes of Health (NIH) (Ul1TR001427); she received support for article research from the NIH. Dr. Winter received support for article research from the LK Whittier Foundation. The remaining authors have disclosed that they do not have any potential conflicts of interest., (Copyright © 2023 by the Society of Critical Care Medicine and Wolters Kluwer Health, Inc. All Rights Reserved.)

The effects of hypothermia on neonatal encephalopathy may vary topographically and cytopathologically in the neocortex with manifestations potentially influenced by seizures that alter the severity, distribution, and type of neuropathology. We developed a neonatal piglet survival model of hypoxic-ischemic (HI) encephalopathy and hypothermia (HT) with continuous electroencephalography (cEEG) for seizures. Neonatal male piglets received HI-normothermia (NT), HI-HT, sham-NT, or sham-HT treatments. Randomized unmedicated sham and HI piglets underwent cEEG during recovery. Survival was 2-7 days. Normal and pathological neurons were counted in different neocortical areas, identified by cytoarchitecture and connectomics, using hematoxylin and eosin staining and immunohistochemistry for RNA-binding FOX-1 homolog 3 (Rbfox3/NeuN). Seizure burden was determined. HI-NT piglets had a reduced normal/total neuron ratio and increased ischemic-necrotic/total neuron ratio relative to sham-NT and sham-HT piglets with differing severities in the anterior and posterior motor, somatosensory, and frontal cortices. Neocortical neuropathology was attenuated by HT. HT protection was prominent in layer III of the inferior parietal cortex. Rbfox3 immunoreactivity distinguished cortical neurons as: Rbfox3-positive/normal, Rbfox3-positive/ischemic-necrotic, and Rbfox3-depleted. HI piglets had an increased Rbfox3-depleted/total neuron ratio in layers II and III compared to sham-NT piglets. Neuronal Rbfox3 depletion was partly rescued by HT. Seizure burdens in HI-NT and HI-HT piglets were similar. We conclude that the neonatal HI piglet neocortex has: (1) suprasylvian vulnerability to HI and seizures; (2) a limited neuronal cytopathological repertoire in functionally different regions that engages protective mechanisms with HT; (3) higher seizure burden, insensitive to HT, that is correlated with more panlaminar ischemic-necrotic neurons in the somatosensory cortex; and (4) pathological RNA splicing protein nuclear depletion that is sensitive to HT. This work demonstrates that HT protection of the neocortex in neonatal HI is topographic and laminar, seizure unmitigating, and restores neuronal depletion of RNA splicing factor.

Welfare metrics have been established for octopuses in the laboratory, but not for octopuses living in the wild. Wild octopuses are constantly exposed to potentially harmful situations, and the ability to assess the welfare status of wild octopuses could provide pertinent information about individuals' health and species' resilience to stressors. Here, we used underwater photos and videos to identify injuries and stress-related behaviors in wild Octopus insularis in a variety of contexts, including interacting with fishermen, interacting with other octopuses and fish, proximity to predators, in den, foraging, and in senescence. We adapted established metrics of octopus welfare from the laboratory to these wild octopuses. In addition to observing all of the stress measures, we also identified two previously unknown measures associated with decreased welfare: (1) a half white eye flash and (2) a half-and-half blotch body pattern. More than half of the individuals analyzed had arm loss, and almost half of the individuals had skin injuries. We also observed that irregular chromatophore expression and abnormal motor coordination were associated with interactions with fishermen. This is the first study to apply measures of welfare from the laboratory to wild octopuses. Our results may also aid in the identification of welfare measures for other wild invertebrates.

Membrane trafficking is essential for sculpting neuronal morphology. The GARP and EARP complexes are conserved tethers that regulate vesicle trafficking in the secretory and endolysosomal pathways, respectively. Both complexes contain the Vps51, Vps52, and Vps53 proteins, and a complex-specific protein: Vps54 in GARP and Vps50 in EARP. In Drosophila, we find that both complexes are required for dendrite morphogenesis during developmental remodeling of multidendritic class IV da (c4da) neurons. Having found that sterol accumulates at the trans-Golgi network (TGN) in Vps54KO/KO neurons, we investigated genes that regulate sterols and related lipids at the TGN. Overexpression of oxysterol binding protein (Osbp) or knockdown of the PI4K four wheel drive (fwd) exacerbates the Vps54KO/KO phenotype, whereas eliminating one allele of Osbp rescues it, suggesting that excess sterol accumulation at the TGN is, in part, responsible for inhibiting dendrite regrowth. These findings distinguish the GARP and EARP complexes in neurodevelopment and implicate vesicle trafficking and lipid transfer pathways in dendrite morphogenesis., (© 2022 O'Brien et al.)

Regular physical exercise can decrease the risk for obesity, diabetes, and cardiovascular disease, increase life expectancy, and promote psychological health and neurocognitive functioning. Cross-sectional studies show that cardiorespiratory fitness level (VO 2 max) is associated with enhanced brain health, including improved mood state and heightened cognitive performance. Interventional studies are consistent with these cross-sectional studies, but most have focused on low-fit populations. Few such studies have asked if increasing levels of physical activity in moderately fit people can significantly enhance mood, motivation, and cognition. Therefore, the current study investigated the effects of increasing aerobic exercise in moderately fit individuals on psychological state and cognitive performance. We randomly assigned moderately fit healthy adults, 25-59 years of age, who were engaged in one or two aerobic exercise sessions per week to either maintain their exercise regimen ( n = 41) or increase their exercise regimen (i.e., 4-7 aerobic workouts per week; n = 39) for a duration of 3 months. Both before and after the intervention, we assessed aerobic capacity using a modified cardiorespiratory fitness test, and hippocampal functioning via various neuropsychological assessments including a spatial navigation task and the Mnemonic Similarity Task as well as self-reported measures including the Positive and Negative Affect Scale, Beck Anxiety Inventory, State-Trait Anxiety Inventory, Perceived Stress Scale, Rumination Scale, Eating Disorders Examination, Eating Attitudes Test, Body Attitudes Test, and Behavioral Regulation of Exercise Questionnaire. Consistent with our initial working hypotheses, we found that increasing exercise significantly decreased measures of negative affect, including fear, sadness, guilt, and hostility, as well as improved body image. Further, we found that the total number of workouts was significantly associated with improved spatial navigation abilities and body image as well as reduced anxiety, general negative affect, fear, sadness, hostility, rumination, and disordered eating. In addition, increases in fitness levels were significantly associated with improved episodic memory and exercise motivation as well as decreased stress and disordered eating. Our findings are some of the first to indicate that in middle-aged moderately-fit adults, continuing to increase exercise levels in an already ongoing fitness regimen is associated with additional benefits for both psychological and cognitive health., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Basso, Oberlin, Satyal, O’Brien, Crosta, Psaras, Metpally and Suzuki.)

For more than 100 years, the fruit fly Drosophila melanogaster has been one of the most studied model organisms. Here, we present a single-cell atlas of the adult fly, Tabula Drosophilae , that includes 580,000 nuclei from 15 individually dissected sexed tissues as well as the entire head and body, annotated to >250 distinct cell types. We provide an in-depth analysis of cell type-related gene signatures and transcription factor markers, as well as sexual dimorphism, across the whole animal. Analysis of common cell types between tissues, such as blood and muscle cells, reveals rare cell types and tissue-specific subtypes. This atlas provides a valuable resource for the Drosophila community and serves as a reference to study genetic perturbations and disease models at single-cell resolution.

Background: Recent studies have reported a dysfunctional gut microbiome in breastfed infants. Probiotics have been used in an attempt to restore the gut microbiome; however, colonization has been transient, inconsistent among individuals, or has not positively impacted the host's gut., Methods: This is a 2-year follow-up study to a randomized controlled trial wherein 7-day-old infants received 1.8 × 10 10 colony-forming unit Bifidobacterium longum subsp. infantis (B. infantis) EVC001 (EVC) daily for 21 days or breast milk alone (unsupplemented (UNS)). In the follow-up study, mothers (n = 48) collected infant stool at 4, 6, 8, 10, and 12 months postnatal and completed the health-diet questionnaires., Results: Fecal B. infantis was 2.5-3.5 log units higher at 6-12 months in the EVC group compared with the UNS group (P < 0.01) and this relationship strengthened with the exclusion of infants who consumed infant formula and antibiotics. Infants in the EVC group had significantly higher Bifidobacteriaceae and lower Bacteroidaceae and Lachnospiraceae (P < 0.05). There were no differences in any health conditions between the two groups., Conclusions: Probiotic supplementation with B. infantis within the first month postnatal, in combination with breast milk, resulted in stable colonization that persisted until at least 1 year postnatal., Impact: A dysfunctional gut microbiome in breastfed infants is common in resource-rich nations and associated with an increased risk of immune diseases. Probiotics only transiently exist in the gut without persistent colonization or altering the gut microbiome. This is the first study to show that early probiotic supplementation with B. infantis with breast milk results in stable colonization of B. infantis and improvements to the gut microbiome 1 year postnatal. This study addresses a key gap in the literature whereby probiotics can restore the gut microbiome if biologically selected microorganisms are matched with their specific food in an open ecological niche., (© 2021. The Author(s).)

Candida metapsilosis is a member of the Candida parapsilosis species complex, a group of opportunistic human pathogens. Of all the members of this complex, C. metapsilosis is the least virulent, and accounts for a small proportion of invasive Candida infections. Previous studies established that all C. metapsilosis isolates are hybrids, originating from a single hybridization event between two lineages, parent A and parent B. Here, we use MinION and Illumina sequencing to characterize a C. metapsilosis isolate that originated from a separate hybridization. One of the parents of the new isolate is very closely related to parent A. However, the other parent (parent C) is not the same as parent B. Unlike C. metapsilosis AB isolates, the C. metapsilosis AC isolate has not undergone introgression at the mating type-like locus. In addition, the A and C haplotypes are not fully collinear. The C. metapsilosis AC isolate has undergone loss of heterozygosity with a preference for haplotype A, indicating that this isolate is in the early stages of genome stabilization., (© The Author(s) 2021. Published by Oxford University Press on behalf of Genetics Society of America.)

Aim: To examine the associations between ETCO 2 , ROSC, and chest compression quality markers in paediatric patients during active resuscitation., Methods: This was a single-centre cohort study of data collected as part of an institutional prospective quality initiative improvement program that included all paediatric patients who received chest compressions of any duration from January 1, 2013, through July 10, 2018, in the Johns Hopkins Children's Center. Data was collected from Zoll R Series® defibrillators. Events were included if Zoll data files contained both chest compression and ETCO 2 data. 2,746 minutes corresponding to 143 events were included in the analyses., Results: The median event ETCO 2 for all 143 events was 16.8 [9.3-26.3] mmHg. There was a significant difference in median event ETCO 2 between events that achieved ROSC and those that did not (ROSC: 19.3 [14.4-26.6] vs. NO ROSC: 13.9 [6.6-25.5] mmHg; p < 0.05). When the events were based on patient age, this relationship held in adolescents (ROSC: 18.8 [15.5-22.3] vs. NO ROSC: 9.6 [4.4-15.9] mmHg; p < 0.05), but not in children or infants. Median event ETCO 2 was significantly associated with chest compression rate less than 140 (p < 0.0001) and chest compression fraction 90-100 (p < 0.0001)., Conclusions: This represents the largest collection of ETCO 2 and chest compression data in paediatric patients to date and unadjusted analyses suggests an association between ETCO 2 and ROSC in some paediatric patients., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2021. Published by Elsevier B.V.)

Aim: To evaluate an algorithm that uses an end-tidal carbon dioxide (ETCO 2 ) target of ≥ 30 torr to guide specific changes in chest compression rate and epinephrine administration during cardiopulmonary resuscitation (CPR) in paediatric swine., Methods: Swine underwent asphyxial cardiac arrest followed by resuscitation with either standard or ETCO 2 -guided algorithm CPR. The standard group received chest compressions at a rate of 100/min and epinephrine every 4 min during advanced life support consistent with the American Heart Association paediatric resuscitation guidelines. In the ETCO 2 -guided algorithm group, chest compression rate was increased by 10 compressions/min for every minute that the ETCO 2 was < 30 torr, and the epinephrine administration interval was decreased to every 2 min if the ETCO 2 remained < 30 torr. Short-term survival and physiologic data during active resuscitation were compared., Results: Short-term survival was significantly greater in the ETCO 2 -guided algorithm CPR group than in the standard CPR group (16/28 [57.1%] versus 4/28 [14.3%]; p  = 0.002). Additionally, the algorithm group had higher predicted mean ETCO 2 , chest compression rate, diastolic and mean arterial pressure, and myocardial perfusion pressure throughout resuscitation. Swine in the algorithm group also exhibited significantly greater improvement in diastolic and mean arterial pressure and cerebral perfusion pressure after the first dose of epinephrine than did those in the standard group. Incidence of resuscitation-related injuries was similar in the two groups., Conclusions: Use of a resuscitation algorithm with stepwise guidance for changes in the chest compression rate and epinephrine administration interval based on a goal ETCO 2 level improved survival and intra-arrest hemodynamics in this porcine cardiac arrest model., (© 2021 The Author(s).)

Cerebral hypoxia-ischemia (HI) compromises the proteasome in a clinically relevant neonatal piglet model. Protecting and activating proteasomes could be an adjunct therapy to hypothermia. We investigated whether chymotrypsin-like proteasome activity differs regionally and developmentally in the neonatal brain. We also tested whether neonatal brain proteasomes can be modulated by oleuropein, an experimental pleiotropic neuroprotective drug, or by targeting a proteasome subunit gene using recombinant adeno-associated virus-9 (AAV). During post-HI hypothermia, we treated piglets with oleuropein, used AAV-short hairpin RNA (shRNA) to knock down proteasome activator 28γ (PA28γ), or enforced PA28γ using AAV-PA28γ with green fluorescent protein (GFP). Neonatal neocortex and subcortical white matter had greater proteasome activity than did liver and kidney. Neonatal white matter had higher proteasome activity than did juvenile white matter. Lower arterial pH 1 h after HI correlated with greater subsequent cortical proteasome activity. With increasing brain homogenate protein input into the assay, the initial proteasome activity increased only among shams, whereas HI increased total kinetic proteasome activity. OLE increased the initial neocortical proteasome activity after hypothermia. AAV drove GFP expression, and white matter PA28γ levels correlated with proteasome activity and subunit levels. However, AAV proteasome modulation varied. Thus, neonatal neocortical proteasomes can be pharmacologically activated. HI slows the initial proteasome performance, but then augments ongoing catalytic activity. AAV-mediated genetic manipulation in the piglet brain holds promise, though proteasome gene targeting requires further development.

Individuals with cystic fibrosis (CF) face a challenging disease, and depression is a significant concern. Many patients draw on religious/spiritual resources to assist them in managing the demands of chronic illness; however, these coping efforts rarely have been evaluated among adults with CF. This longitudinal study examined relationships between distinct types of positive and negative religious/spiritual coping at baseline (assessed with the RCOPE) and depression screening outcomes 12 month later (assessed with the Hospital Anxiety and Depression Scale). In logistic regression analyses controlling for disease severity (FEV 1 % predicted), lower likelihood of depression caseness at 12 months was predicted by higher general religiousness at baseline, greater use of benevolent religious reappraisal coping, greater use of spiritual connection coping, and lower spiritual discontent. Results suggest that distinct aspects religious/spiritual coping have differential associations with subsequent depression outcomes. Findings extend prior research to an important, understudied medical population, and address a clinically meaningful outcome., (© 2021. The Author(s), under exclusive licence to Springer Science+Business Media, LLC part of Springer Nature.)

Our cells are comprised of billions of proteins, lipids, and other small molecules packed into their respective subcellular organelles, with the daunting task of maintaining cellular homeostasis over a lifetime. However, it is becoming increasingly evident that organelles do not act as autonomous discrete units but rather as interconnected hubs that engage in extensive communication through membrane contacts. In the last few years, our understanding of how these contacts coordinate organelle function has redefined our view of the cell. This review aims to present novel findings on the cellular interorganelle communication network and how its dysfunction may contribute to aging and neurodegeneration. The consequences of disturbed interorganellar communication are intimately linked with age-related pathologies. Given that both aging and neurodegenerative diseases are characterized by the concomitant failure of multiple cellular pathways, coordination of organelle communication and function could represent an emerging regulatory mechanism critical for long-term cellular homeostasis. We anticipate that defining the relationships between interorganelle communication, aging, and neurodegeneration will open new avenues for therapeutics., (© 2021 Petkovic et al.; Published by Cold Spring Harbor Laboratory Press.)

Candida tropicalis is a human pathogen that primarily infects the immunocompromised. Whereas the genome of one isolate, C. tropicalis MYA-3404, was originally sequenced in 2009, there have been no large-scale, multi-isolate studies of the genetic and phenotypic diversity of this species. Here, we used whole genome sequencing and phenotyping to characterize 77 isolates of C. tropicalis from clinical and environmental sources from a variety of locations. We show that most C. tropicalis isolates are diploids with approximately 2-6 heterozygous variants per kilobase. The genomes are relatively stable, with few aneuploidies. However, we identified one highly homozygous isolate and six isolates of C. tropicalis with much higher heterozygosity levels ranging from 36-49 heterozygous variants per kilobase. Our analyses show that the heterozygous isolates represent two different hybrid lineages, where the hybrids share one parent (A) with most other C. tropicalis isolates, but the second parent (B or C) differs by at least 4% at the genome level. Four of the sequenced isolates descend from an AB hybridization, and two from an AC hybridization. The hybrids are MTLa/α heterozygotes. Hybridization, or mating, between different parents is therefore common in the evolutionary history of C. tropicalis. The new hybrids were predominantly found in environmental niches, including from soil. Hybridization is therefore unlikely to be associated with virulence. In addition, we used genotype-phenotype correlation and CRISPR-Cas9 editing to identify a genome variant that results in the inability of one isolate to utilize certain branched-chain amino acids as a sole nitrogen source., Competing Interests: The authors have declared that no competing interests exist.

Neonatal hypoxia-ischemia (HI) causes white matter injury that is not fully prevented by therapeutic hypothermia. Adjuvant treatments are needed. We compared myelination in different piglet white matter regions. We then tested whether oleuropein (OLE) improves neuroprotection in 2- to 4-day-old piglets randomized to undergo HI or sham procedure and OLE or vehicle administration beginning at 15 minutes. All groups received overnight hypothermia and rewarming. Injury in the subcortical white matter, corpus callosum, internal capsule, putamen, and motor cortex gray matter was assessed 1 day later. At baseline, piglets had greater subcortical myelination than in corpus callosum. Hypothermic HI piglets had scant injury in putamen and cerebral cortex. However, hypothermia alone did not prevent the loss of subcortical myelinating oligodendrocytes or the reduction in subcortical myelin density after HI. Combining OLE with hypothermia improved post-HI subcortical white matter protection by preserving myelinating oligodendrocytes, myelin density, and oligodendrocyte markers. Corpus callosum and internal capsule showed little HI injury after hypothermia, and OLE accordingly had minimal effect. OLE did not affect putamen or motor cortex neuron counts. Thus, OLE combined with hypothermia protected subcortical white matter after HI. As an adjuvant to hypothermia, OLE may subacutely improve regional white matter protection after HI., (© 2020 American Association of Neuropathologists, Inc. All rights reserved.)

Background: Cardiac arrest (CA) is the most common cause of acute neurologic insult in children. Many survivors have significant neurocognitive deficits at 1 year of recovery. Epoxyeicosatrienoic acids (EETs) are multifunctional endogenous lipid signaling molecules that are involved in brain pathobiology and may be therapeutically relevant. However, EETs are rapidly metabolized to less active dihydroxyeicosatrienoic acids by soluble epoxide hydrolase (sEH), limiting their bioavailability. We hypothesized that sEH inhibition would improve outcomes after CA in an infant swine model. Male piglets (3-4 kg, 2 weeks old) underwent hypoxic-asphyxic CA. After resuscitation, they were randomized to intravenous treatment with an sEH inhibitor (TPPU, 1 mg/kg; n = 8) or vehicle (10% poly(ethylene glycol); n = 9) administered at 30 min and 24 h after return of spontaneous circulation. Two sham-operated groups received either TPPU (n = 9) or vehicle (n = 8). Neurons were counted in hematoxylin- and eosin-stained sections from putamen and motor cortex in 4-day survivors., Results: Piglets in the CA + vehicle groups had fewer neurons than sham animals in both putamen and motor cortex. However, the number of neurons after CA did not differ between vehicle- and TPPU-treated groups in either anatomic area. Further, 20% of putamen neurons in the Sham + TPPU group had abnormal morphology, with cell body attrition and nuclear condensation. TPPU treatment also did not reduce neurologic deficits., Conclusion: Treatment with an sEH inhibitor at 30 min and 24 h after resuscitation from asphyxic CA does not protect neurons or improve acute neurologic outcomes in piglets.

Individuals with cystic fibrosis (CF) are confronted by a range of difficult physical and psychosocial sequelae. Gratitude has drawn growing attention as a psychosocial resource, but it has yet to be examined among adults with CF. The current investigation evaluated longitudinal associations between trait gratitude and subsequent outcomes from depression screening 12 months later, adjusting for disease severity (FEV 1 % predicted) and other significant clinical or demographic covariates. Participants were 69 adult CF patients recruited from a regional adult treatment center. They completed a validated measure of gratitude (Gratitude Questionnaire-6) at baseline and a screening measure of depression (Hospital Anxiety and Depression Scale) at 12-month follow-up. In a logistic regression analysis controlling for disease severity, higher levels of baseline gratitude were associated with reduced likelihood of depression caseness at 12 months (OR .83, 95% CI .73-.91, p = .001). Gratitude remained predictive after adjusting for other psychosocial resource variables (i.e., perceived social support and positive reframing coping). Findings offer an initial indication of the potential salutary role of dispositional gratitude in an understudied clinical population.

Draft genomes of several Kazachstania species, a large group of ascomycetous budding yeasts, have been recently published. However, there is none yet available for pathogenic species from the K. telluris clade, including K. telluris sensu stricto, an opportunistic yeast that has been isolated from various niches and human clinical samples. Here we provide the first draft genome sequence of the strain K. telluris CBS 16338, that we isolated from forest soil in Ireland.

Centromeres of Candida albicans form on unique and different DNA sequences but a closely related species, Candida tropicalis , possesses homogenized inverted repeat (HIR)-associated centromeres. To investigate the mechanism of centromere type transition, we improved the fragmented genome assembly and constructed a chromosome-level genome assembly of C. tropicalis by employing PacBio sequencing, chromosome conformation capture sequencing (3C-seq), chromoblot, and genetic analysis of engineered aneuploid strains. Further, we analyzed the 3D genome organization using 3C-seq data, which revealed spatial proximity among the centromeres as well as telomeres of seven chromosomes in C. tropicalis . Intriguingly, we observed evidence of inter-centromeric translocations in the common ancestor of C. albicans and C. tropicalis . Identification of putative centromeres in closely related Candida sojae , Candida viswanathii and Candida parapsilosis indicates loss of ancestral HIR-associated centromeres and establishment of evolutionary new centromeres (ENCs) in C. albicans . We propose that spatial proximity of the homologous centromere DNA sequences facilitated karyotype rearrangements and centromere type transitions in human pathogenic yeasts of the CUG-Ser1 clade., Competing Interests: KG, YC, RM, SM, BT, CO, GB, AS, KS No competing interests declared, (© 2020, Guin et al.)

Centromeres pose an evolutionary paradox: strongly conserved in function but rapidly changing in sequence and structure. However, in the absence of damage, centromere locations are usually conserved within a species. We report here that isolates of the pathogenic yeast species Candida parapsilosis show within-species polymorphism for the location of centromeres on two of its eight chromosomes. Its old centromeres have an inverted-repeat (IR) structure, whereas its new centromeres have no obvious structural features but are located within 30 kb of the old site. Centromeres can therefore move naturally from one chromosomal site to another, apparently spontaneously and in the absence of any significant changes in DNA sequence. Our observations are consistent with a model in which all centromeres are genetically determined, such as by the presence of short or long IRs or by the ability to form cruciforms. We also find that centromeres have been hotspots for genomic rearrangements in the C. parapsilosis clade., (© 2020 Ola et al.; Published by Cold Spring Harbor Laboratory Press.)

Background: Current pediatric resuscitation guidelines suggest that resuscitators using an advanced airway deliver 8-10 breaths per minute while carefully avoiding excessive ventilation. In the intraoperative setting, having a dedicated ventilation rescuer may be difficult because of limited personnel. Continuing pressure-controlled mechanical ventilation during resuscitation for intraoperative cardiac arrest reduces personnel needed and the risk of hyperventilation but might risk hypoventilation during chest compression delivery., Aims: To determine whether the use of pressure-controlled mechanical ventilation at prearrest settings provides normoxia and normocarbia during resuscitation from cardiac arrest., Methods: We retrospectively analyzed combined data from preclinical randomized controlled trials. Two-week-old swine (3-4 kg) underwent asphyxia-induced cardiac arrest. Animals were resuscitated with periods of basic and advanced life support. During resuscitation, pressure-controlled mechanical ventilation was delivered at the prearrest respiratory rate, peak inspiratory pressure, and positive end-expiratory pressure. Arterial blood gases were measured prearrest, at 11 minutes of asphyxia, and at 8 and 20 minutes of cardiopulmonary resuscitation., Results: Piglets (n = 154) received pressure-controlled mechanical ventilation before and during cardiopulmonary resuscitation with a peak inspiratory pressure of 14-15 cm H 2 O, positive end-expiratory pressure of 4 cm H 2 O, 20 breaths/minute, and an inspiratory:expiratory ratio of 1:2. During asphyxia, the arterial blood gas showed the expected severe hypercarbia and hypoxia. Continuing pressure-controlled mechanical ventilation using prearrest parameters and increasing the FiO 2 to 1.0 returned the PaCO 2 to prearrest levels and slightly increased the partial pressure of arterial oxygen at 8 and 20 minutes of cardiopulmonary resuscitation., Conclusion: In this piglet model of resuscitation from asphyxial arrest, pressure-controlled mechanical ventilation during cardiopulmonary resuscitation at the prearrest ventilator settings with an FiO 2 of 1.0 provides adequate oxygenation and restores normocarbia. Clinical investigation is warranted to determine the benefits of continuing pressure-controlled mechanical ventilation at prearrest parameters during pediatric cardiopulmonary resuscitation., (© 2020 John Wiley & Sons Ltd.)

Taphrina betulina is the ascomycete yeast that causes the formation of witches' brooms in birch trees. Here, we report the first draft genome sequence of T. betulina , from strain UCD315, isolated from soil in Ireland. The genome is haploid and 12.5 Mb long., (Copyright © 2019 Heneghan et al.)

Management of infections in patients with cystic fibrosis (CF) presents challenges for healthcare providers, including the eradication of initial acquisition, treatment of acute exacerbations, and chronic infection with suppressive therapy. Inhaled antimicrobial therapy for infections in patients with CF has been used in these capacities, often in an effort to achieve optimal concentrations in sputum for antimicrobial efficacy while mitigating potential toxicities associated with systemic therapy. Unfortunately, there are few commercially available products formulated for inhalation, resulting in the off-label use of other formulations, such as intravenous products, administered via nebulization. This review aims to examine the evidence supporting the efficacy of these off-label formulations for management of acute and chronic infections associated with CF, as well as adverse effects associated with their use., (© 2019 Wiley Periodicals, Inc.)

Symmetrospora coprosmae is a red yeast from the subphylum Pucciniomycotina in the phylum Basidiomycota. Here, we present the first genome sequence of S. coprosmae strain UCD350, from an isolate collected from soil in Ireland. The genome size is 20.2 Mb., (Copyright © 2019 Almasoud et al.)

We sequenced two isolates of Kazachstania servazzii , UCD13 and UCD335, from soil in Ireland. Heterozygosity in these diploid genomes differs 19-fold between the two strains. Most currently available K. servazzii genome sequences come from Korean kimchi isolates, so our data will facilitate analysis of diversity in this species., (Copyright © 2019 Faherty et al.)

Aim: To examine the relationship between survival and diastolic blood pressure (DBP) throughout resuscitation from paediatric asphyxial cardiac arrest., Methods: Retrospective, secondary analysis of 200 swine resuscitations. Swine underwent asphyxial cardiac arrest and were resuscitated with predefined periods of basic and advanced life support (BLS and ALS, respectively). DBP was recorded every 30 s. Survival was defined as 20-min sustained return of spontaneous circulation (ROSC)., Results: During BLS, DBP peaked between 1-3 min and was greater in survivors (20.0 [11.3, 33.3] mmHg) than in non-survivors (5.0 [1.0, 10.0] mmHg; p < 0.001). After this transient increase, the DBP in survivors progressively decreased but remained greater than that of non-survivors after 10 min of resuscitation (9.0 [6.0, 13.8] versus 3.0 [1.0, 6.8] mmHg; p < 0.001). During ALS, the magnitude of DBP change after the first adrenaline (epinephrine) administration was greater in survivors (22.0 [16.5, 36.5] mmHg) than in non-survivors (6.0 [2.0, 11.0] mmHg; p < 0.001). Survival rate was greater when DBP improved by ≥26 mmHg after the first dose of adrenaline (20/21; 95%) than when DBP improved by ≤10 mmHg (1/99; 1%). The magnitude of DBP change after the first adrenaline administration correlated with the timetoROSC (r = -0.54; p < 0.001)., Conclusions: Survival after asphyxial cardiac arrest is associated with a higher DBP throughout resuscitation, but the difference between survivors and non-survivors was reduced after prolonged BLS. During ALS, response to adrenaline administration correlates with survival and time to ROSC. If confirmed clinically, these findings may be useful for titrating adrenaline during resuscitation and prognosticating likelihood of ROSC. Institutional Protocol Numbers: SW14M223 and SW17M101., (Copyright © 2019 Elsevier B.V. All rights reserved.)

Atlantic haddock (Melanogrammus aeglefinus) is a commercially important species of gadoid fish. In the North Sea, their main spawning areas are located close to the northern continental slope. Eggs and larvae drift with the current across the North Sea. However, fish larvae of many taxa can orient at sea using multiple external cues, including the Earth's magnetic field. In this work, we investigated whether haddock larvae passively drift or orient using the Earth's magnetic field. We observed the behavior of 59 and 102 haddock larvae swimming in a behavioral chamber deployed in the Norwegian North Sea and in a magnetic laboratory, respectively. In both in situ and laboratory settings, where the magnetic field direction was modified, haddock larvae significantly oriented toward the northwest. We conclude that haddock larvae orientation at sea is guided by a magnetic compass mechanism. These results have implications for retention and dispersal of pelagic haddock larvae., (Copyright © 2019 The Author(s). Published by Elsevier Inc. All rights reserved.)

Background and Purpose: Motivational interviewing (MI) is a patient-centered method of communicating that can be used to improve medication adherence. However, it can be difficult to teach and learn. This paper describes the creation of a stand-alone introductory MI module for second-year pharmacy students and its transformation to a module intended to reinforce content after the addition of a new MI-based course in the first year. It compares student competence in MI skills between the two modules (introductory versus reinforcement)., Educational Activity and Setting: In 2012 and 2013, an introductory MI module was delivered to second year pharmacy students. In 2014, a course grounded in MI principles was introduced in the first year of the curriculum, with the module in the second year modified to reinforce those principles. All second-year students' MI skills were assessed with an objective structured clinical examination (OSCE) case. Overall case scores and individual item scores were compared before and after the addition of the course using assessment data from two years before and after the change., Findings: Overall case scores (81.9% vs. 86.9%, p = 0.001) significantly improved after the introduction of the new course. Items related to MI skills also improved significantly. Scores for general communication items were not different., Summary: After the introduction of the new MI-based first-year course, students performed better on items specifically related to MI in an OSCE case. This model can serve as a useful example of how to introduce MI skills and reinforce these skills later in the curriculum., (Copyright © 2019 Elsevier Inc. All rights reserved.)

Objectives: To determine the effect of the duration of asphyxial arrest on the survival benefit previously seen with end-tidal CO2-guided chest compression delivery., Design: Preclinical randomized controlled study., Setting: University animal research laboratory., Subjects: Two-week-old swine., Interventions: After either 17 or 23 minutes of asphyxial arrest, animals were randomized to standard cardiopulmonary resuscitation or end-tidal CO2-guided chest compression delivery. Standard cardiopulmonary resuscitation was optimized by marker, monitor, and verbal feedback about compression rate, depth, and release. End-tidal CO2-guided delivery used adjustments to chest compression rate and depth to maximize end-tidal CO2 level without other feedback. Cardiopulmonary resuscitation for both groups proceeded from 10 minutes of basic life support to 10 minutes of advanced life support or return of spontaneous circulation., Measurements and Main Results: After 17 minutes of asphyxial arrest, mean end-tidal CO2 during 10 minutes of cardiopulmonary resuscitation was 18 ± 9 torr in the standard group and 33 ± 15 torr in the end-tidal CO2 group (p = 0.004). The rate of return of spontaneous circulation was three of 14 (21%) in the standard group rate and nine of 14 (64%) in the end-tidal CO2 group (p = 0.05). After a 23-minute asphyxial arrest, neither end-tidal CO2 values (20 vs 26) nor return of spontaneous circulation rate (3/14 vs 1/14) differed between the standard and end-tidal CO2-guided groups., Conclusions: Our previously observed survival benefit of end-tidal CO2-guided chest compression delivery after 20 minutes of asphyxial arrest was confirmed after 17 minutes of asphyxial arrest. The poor survival after 23 minutes of asphyxia shows that the benefit of end-tidal CO2-guided chest compression delivery is limited by severe asphyxia duration.

Background: Airway clearance therapy (ACT) is a core component of daily treatment for cystic fibrosis (CF). However, surprisingly little is known about sustained or persistent use of ACT over time among adults with CF. This longitudinal study examined persistent adherence to ACT over 12 months and its modifiable predictors, drawing on aspects of Social Cognitive Theory and the Theory of Planned Behavior., Methods: Subjects were drawn from a regional CF center in the southern United States. Predictor variables evaluated at baseline included self-efficacy for ACT (ie, self-confidence in overcoming barriers), outcome expectations (ie, perceived necessity of ACT and concerns about its disruptive effects), and subjective norms (ie, perceptions of being influenced by others). The Cystic Fibrosis Treatment Questionnaire (CFTQ) was used to assess self-reported adherence to ACT at baseline, at 6 months, and at 12 months., Results: The mean age of subjects was 27.2 ± 9.1 y, and mean FEV 1 % predicted was 65.5 ± 24.8. Forty-six percent of subjects reported persistent use of ACT (classified as adherent at all assessment periods). In bivariate analyses, all social cognitive predictor variables assessed at baseline were significantly related to persistent adherence (all P < .03), except subjective norms. In logistic regression analyses that modeled the effects of these predictors simultaneously while controlling for FEV 1 %, fewer baseline concerns about ACT (odds ratio = 0.82, 95% CI 0.69-0.99) and greater self-efficacy (odds ratio = 1.09, 95% CI 1.01-1.18) remained significant independent predictors., Conclusions: This longitudinal study addresses an important gap in the literature regarding adherence to ACT over time (12 mo) in a routine clinical setting. Persistent adherence was problematic. As anticipated, social cognitive variables (self-confidence and perceived concerns) predicted self-reported persistence, and these may represent practical targets for intervention., Competing Interests: The authors have disclosed no conflicts of interest., (Copyright © 2019 by Daedalus Enterprises.)

Illumina sequencing has revolutionized yeast genomics, with prices for commercial draft genome sequencing now below $200. The popular SPAdes assembler makes it simple to generate a de novo genome assembly for any yeast species. However, whereas making genome assemblies has become routine, understanding what they contain is still challenging. Here, we show how graphing the information that SPAdes provides about the length and coverage of each scaffold can be used to investigate the nature of an assembly, and to diagnose possible problems. Scaffolds derived from mitochondrial DNA, ribosomal DNA, and yeast plasmids can be identified by their high coverage. Contaminating data, such as cross-contamination from other samples in a multiplex sequencing run, can be identified by its low coverage. Scaffolds derived from the bacteriophage PhiX174 and Lambda DNAs that are frequently used as molecular standards in Illumina protocols can also be detected. Assemblies of yeast genomes with high heterozygosity, such as interspecies hybrids, often contain two types of scaffold: regions of the genome where the two alleles assembled into two separate scaffolds and each has a coverage level C , and regions where the two alleles co-assembled (collapsed) into a single scaffold that has a coverage level 2 C Visualizing the data with Coverage- vs. -Length (CVL) plots, which can be done using Microsoft Excel or Google Sheets, provides a simple method to understand the structure of a genome assembly and detect aberrant scaffolds or contigs. We provide a Python script that allows assemblies to be filtered to remove contaminants identified in CVL plots., (Copyright © 2019 Douglass et al.)

Therapeutic hypothermia is the standard of clinical care for moderate neonatal hypoxic-ischemic encephalopathy. We investigated the independent and interactive effects of hypoxia-ischemia (HI) and temperature on neuronal survival and injury in basal ganglia and cerebral cortex in neonatal piglets. Male piglets were randomized to receive HI injury or sham procedure followed by 29 h of normothermia, sustained hypothermia induced at 2 h, or hypothermia with rewarming during fentanyl-nitrous oxide anesthesia. Viable and injured neurons and apoptotic profiles were counted in the anterior putamen, posterior putamen, and motor cortex at 29 h after HI injury or sham procedure. Terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL) identified genomic DNA fragmentation to confirm cell death. Though hypothermia after HI preserved viable neurons in the anterior and posterior putamen, hypothermia prevented neuronal injury in only the anterior putamen. Hypothermia initiated 2 h after injury did not protect against apoptotic cell death in either the putamen or motor cortex, and rewarming from hypothermia was associated with increased apoptosis in the motor cortex. In non-HI shams, sustained hypothermia during anesthesia was associated with neuronal injury and corresponding viable neuron loss in the anterior putamen and motor cortex. TUNEL confirmed increased neurodegeneration in the putamen of hypothermic shams. Anesthetized, normothermic shams did not show abnormal neuronal cytopathology in the putamen or motor cortex, thereby demonstrating minimal contribution of the anesthetic regimen to neuronal injury during normothermia. We conclude that the efficacy of hypothermic protection after HI is region specific and that hypothermia during anesthesia in the absence of HI may be associated with neuronal injury in the developing brain. Studies examining the potential interactions between hypothermia and anesthesia, as well as with longer durations of hypothermia, are needed., (© 2019 S. Karger AG, Basel.)

Background: Neuronal cell loss contributes to the pathology of acute and chronic neurodegenerative diseases, including Alzheimer's disease (AD). It remains crucial to identify molecular mechanisms sensitizing neurons to various insults and cell death. To date, the multifunctional, autophagy-related protein Beclin 1 has been shown to be both necessary and sufficient for neuronal integrity in neurodegenerative models associated with protein aggregation. Interestingly, besides its role in cellular homeostasis, Beclin 1 has also been ascribed a role in apoptosis. This makes it critical to elucidate whether Beclin 1 regulates neuronal death and survival across neurodegenerative conditions independent of protein clearance. Here, we provide experimental evidence for a direct functional link between proteolytic cleavage of Beclin 1 and apoptotic neuronal cell loss in two independent models of neurodegeneration in vivo., Methods: Proteolytic cleavage of Beclin 1 was characterized in lysates of human AD brain samples. We developed viral tools allowing for the selective neuronal expression of the various Beclin 1 forms, including Beclin 1 cleavage products as well as a cleavage-resistant form. The effect of these Beclin 1 forms on survival and integrity of neurons was examined in models of acute and chronic neurodegeneration in vitro and in vivo. Markers of neuronal integrity, neurodegeneration and inflammation were further assessed in a Kainic acid-based mouse model of acute excitotoxic neurodegeneration and in a hAPP-transgenic mouse model of AD following perturbation of Beclin 1 in the susceptible CA1 region of the hippocampus., Results: We find a significant increase in caspase-mediated Beclin 1 cleavage fragments in brain lysates of human AD patients and mimic this phenotype in vivo using both an excitotoxic and hAPP-transgenic mouse model of neurodegeneration. Surprisingly, overexpression of the C-terminal cleavage-fragment exacerbated neurodegeneration in two distinct models of degeneration. Local inhibition of caspase activity ameliorated neurodegeneration after excitotoxic insult and prevented Beclin 1 cleavage. Furthermore, overexpression of a cleavage-resistant form of Beclin 1 in hippocampal neurons conferred neuroprotection against excitotoxic and Amyloid beta-associated insults in vivo., Conclusions: Together, these findings indicate that the cleavage state of Beclin 1 determines its functional involvement in both neurodegeneration and neuroprotection. Hence, manipulating the cleavage state of Beclin 1 may represent a therapeutic strategy for preventing neuronal cell loss across multiple forms of neurodegeneration.

Background Neurological deficits in hypoxic-ischemic encephalopathy, even with therapeutic hypothermia, are partially attributed to white matter injury. We theorized that proteasome insufficiency contributes to white matter injury. Methods and Results Neonatal piglets received hypoxia-ischemia ( HI ) or sham procedure with normothermia, hypothermia, or hypothermia+rewarming. Some received a proteasome activator drug (oleuropein) or white matter-targeted, virus-mediated proteasome knockdown. We measured myelin oligodendrocyte glycoprotein, proteasome subunit 20S (P20S), proteasome activity, and carbonylated and ubiquitinated protein levels in white matter and cerebral cortex. HI reduced myelin oligodendrocyte glycoprotein levels regardless of temperature, and myelin oligodendrocyte glycoprotein loss was associated with increased ubiquitinated and carbonylated protein levels. Ubiquitinated and carbonyl-damaged proteins increased in white matter 29 hours after HI during hypothermia to exceed levels at 6 to 20 hours. In cortex, ubiquitinated proteins decreased. Ubiquitinated and carbonylated protein accumulation coincided with lower P20S levels in white matter; P20S levels also decreased in cerebral cortex. However, proteasome activity in white matter lagged behind that in cortex 29 hours after HI during hypothermia. Systemic oleuropein enhanced white matter P20S and protected the myelin, whereas proteasome knockdown exacerbated myelin oligodendrocyte glycoprotein loss and ubiquitinated protein accumulation after HI . At the cellular level, temperature and HI interactively affected macroglial P20S enrichment in subcortical white matter. Rewarming alone increased macroglial P20S immunoreactivity, but this increase was blocked by HI . Conclusions Oxidized and ubiquitinated proteins accumulate with HI -induced white matter injury. Proteasome insufficiency may drive this injury. Hypothermia did not prevent myelin damage, protect the proteasome, or preserve oxidized and ubiquitinated protein clearance after HI .

Background The American Heart Association recommends use of physiologic feedback when available to optimize chest compression delivery. We compared hemodynamic parameters during cardiopulmonary resuscitation in which either end-tidal carbon dioxide ( ETCO 2 ) or diastolic blood pressure ( DBP ) levels were used to guide chest compression delivery after asphyxial cardiac arrest. Methods and Results One- to 2-week-old swine underwent a 17-minute asphyxial-fibrillatory cardiac arrest followed by alternating 2-minute periods of ETCO 2 -guided and DBP -guided chest compressions during 10 minutes of basic life support and 10 minutes of advanced life support. Ten animals underwent resuscitation. We found significant changes to ETCO 2 and DBP levels within 30 s of switching chest compression delivery methods. The overall mean ETCO 2 level was greater during ETCO 2 -guided cardiopulmonary resuscitation (26.4±5.6 versus 22.5±5.2 mm Hg; P=0.003), whereas the overall mean DBP was greater during DBP -guided cardiopulmonary resuscitation (13.9±2.3 versus 9.4±2.6 mm Hg; P=0.003). ETCO 2 -guided chest compressions resulted in a faster compression rate (149±3 versus 120±5 compressions/min; P=0.0001) and a higher intracranial pressure (21.7±2.3 versus 16.0±1.1 mm Hg; P=0.002). DBP -guided chest compressions were associated with a higher myocardial perfusion pressure (6.0±2.8 versus 2.4±3.2; P=0.02) and cerebral perfusion pressure (9.0±3.0 versus 5.5±4.3; P=0.047). Conclusions Using the ETCO 2 or DBP level to optimize chest compression delivery results in physiologic changes that are method-specific and occur within 30 s. Additional studies are needed to develop protocols for the use of these potentially conflicting physiologic targets to improve outcomes of prolonged cardiopulmonary resuscitation.

Medication reconciliation is an important aspect of a patient's care process that is ideally performed by clinical pharmacists. Despite literature supporting this process in other patient populations, cystic fibrosis (CF) lacks research in this area. To address this, we designed a retrospective, multi-centered, non-controlled, cross-sectional study at four CF Foundation-accredited centers in the United States to evaluate the medication reconciliation process for adult and pediatric CF patients by documenting the number of home medications reconciled by clinical pharmacists and the number of patients with home medications that did not align with the current CF guidelines published in 2013. There were 105 adult patients and 72 pediatric patients included in the study analysis with a mean number of medications reconciled by clinical pharmacists of 17.4 (standard deviation (SD) 6.7) for adults and 13 (SD 4.6) for pediatric patients. The mean number of discrepancies from guidelines per patient was 1.61 (SD 1.2) for adult patients and 0.63 (SD 0.9) for pediatric patients. Pharmacists play an essential role in identifying and managing medication interactions and further research is necessary to investigate pharmacist impact on medication reconciliation.

Background and Purpose: Patient-centered communication (PCC) skills are critical to the practice of pharmacy. A gap analysis of the communication content of our curriculum revealed inadequate coverage of several competencies recommended by a National Association of Chain Drug Stores Foundation - National Community Pharmacy Association - Accreditation Council for Pharmacy Education joint task force report: "support patient behavior change through skills such as motivational interviewing", "demonstrate compassion and empathy for patients", and "solve adherence challenges created by low health literacy"., Educational Activity and Setting: A required PCC course, heavily grounded in motivational interviewing principles, was introduced into the spring of the first professional year to address the identified curricular gaps. Activities and assessments in additional semesters were added to further develop these skills and provide accountability., Findings: The course addressed the curricular gaps and was well-received by students. Students demonstrated competency in a role-play setting including improved proficiency between role-play activities. Reflections from a community pharmacy introductory pharmacy practice experience (IPPE) demonstrate that students perceived an ability to use the skills in practice., Discussion and Summary: This course has been successfully established as an introduction to PCC concepts and skills for first professional year pharmacy students. Use of the skills during a community pharmacy IPPE illustrates that the class functions as a foundation on which to further develop these skills throughout the remaining didactic and experiential curricula., (Copyright © 2018. Published by Elsevier Inc.)