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Abstract Traumatic Brain Injury (TBI) induces neuroinflammatory response that can initiate epileptogenesis, which develops into epilepsy. Recently, we identified anti-convulsive effects of naltrexone, a mu-opioid receptor (MOR) antagonist, used to treat drug addiction. While blocking opioid receptors can reduce inflammation, it is unclear if post-TBI seizures can be prevented by blocking MORs. Here, we tested if naltrexone prevents neuroinflammation and/or seizures post-TBI. TBI was induced by a modified Marmarou Weight-Drop (WD) method on 4-week-old C57BL/6J male mice. Mice were placed in two groups: non-telemetry assessing the acute effects or in telemetry monitoring for interictal events and spontaneous seizures both following TBI and naltrexone. Molecular, histological and neuroimaging techniques were used to evaluate neuroinflammation, neurodegeneration and fiber track integrity at 8 days and 3 months post-TBI. Peripheral immune responses were assessed through serum chemokine/cytokine measurements. Our results show an increase in MOR expression, nitro-oxidative stress, mRNA expression of inflammatory cytokines, microgliosis, neurodegeneration, and white matter damage in the neocortex of TBI mice. Video-EEG revealed increased interictal events in TBI mice, with 71% mice developing post-traumatic seizures (PTS). Naltrexone treatment ameliorated neuroinflammation, neurodegeneration, reduced interictal events and prevented seizures in all TBI mice, which makes naltrexone a promising candidate against PTS, TBI-associated neuroinflammation and epileptogenesis in a WD model of TBI.

IntroductionDistinct, disease-associated intracellular miRNA (miR) expression profiles have been observed in peripheral blood mononuclear cells (PBMCs) of systemic lupus erythematous (SLE) patients. Additionally, we have identified novel estrogenic responses in PBMCs from SLE patients and demonstrated that estrogen upregulates toll-like receptor (TLR)7 and TLR8 expression. TLR7 and TLR8 bind viral-derived single-stranded RNA to stimulate innate inflammatory responses, but recent studies have shown that miR-21, mir-29a, and miR-29b can also bind and activate these receptors when packaged and secreted in extracellular vesicles (EVs). The objective of this study was to evaluate the association of EV-encapsulated small RNA species in SLE and examine the therapeutic approach of miR inhibition in humanized mice.MethodsPlasma-derived EVs were isolated from SLE patients and quantified. RNA was then isolated and bulk RNA-sequencing reads were analyzed. Also, PBMCs from active SLE patients were injected into immunodeficient mice to produce chimeras. Prior to transfer, the PBMCs were incubated with liposomal EVs containing locked nucleic acid (LNA) antagonists to miR-21, mir-29a, and miR-29b. After three weeks, blood was collected for both immunophenotyping and cytokine analysis; tissue was harvested for histopathological examination.ResultsEVs were significantly increased in the plasma of SLE patients and differentially expressed EV-derived small RNA profiles were detected compared to healthy controls, including miR-21, mir-29a, and miR-29b. LNA antagonists significantly reduced proinflammatory cytokines and histopathological infiltrates in the small intestine, liver, and kidney, as demonstrated by H&E-stained tissue sections and immunohistochemistry measuring human CD3.DiscussionThese data demonstrate distinct EV-derived small RNA signatures representing SLE-associated biomarkers. Moreover, targeting upregulated EV-encapsulated miR signaling by antagonizing miRs that may bind to TLR7 and TLR8 reveals a novel therapeutic opportunity to suppress autoimmune-mediated inflammation and pathogenesis in SLE.

Background: Much has been written about fathers, fatherhood and premature babies. However, in the South African context, studies about the experiences of fathers having a premature baby are lacking. Aim: This study aimed to explore how South African fathers (n = 10) experience having a premature baby using a descriptive phenomenological approach. Setting: This research study was conducted online using various social media platforms such as WhatsApp, Google Meet and through telephonic conversations. Methods: A descriptive phenomenological approach that allowed for the distillation and elucidation of common core experiences among fathers who had a premature baby. Results: The findings demonstrated that the participants experienced intense fears regarding the survival and well-being of their children. They reported experiencing financial difficulties related to hospital bills and experienced being alienated by hospital institutions. Despite these reported barriers, these fathers were adamant in their resolve to support their children and partners during this challenging time. Conclusion: The experiences of fathers were riddled with fear, uncertainty, ambiguity and alienation, which placed them in very precarious situations when trying to navigate their role in a more sensitive and enlightened way. Having a premature infant calls into question the systems that men are positioned within as these systems to a large extent shape these events and how they are experienced. Contribution: This study is original as no other published studies seem to exist in South Africa that speaks to fathers’ lived experiences of having a premature baby.

Abstract Background DiabetesWise is an unbranded, data‐driven online resource that tailors device recommendations based on preferences and priorities of people with insulin‐requiring diabetes. The objective of this study is to examine whether DiabetesWise increases uptake of diabetes devices, which are empirically supported to improve glycemic and psychosocial outcomes. Methods The sample included 458 participants (Mage = 37.1, SD = 9.73; 66% female; 81% type 1 diabetes) with insulin‐requiring diabetes and minimal diabetes device use at enrollment. Participants used DiabetesWise and completed online surveys. Chi‐square and t tests evaluated requests for a device prescription, receiving a prescription, and starting a new device at 1 and 3 months post use. Baseline predictors of these variables and past use of continuous glucose monitors (CGMs) and changes in diabetes distress post use were also examined. Results Within the first month of interacting with DiabetesWise 19% of participants asked for a prescription for a diabetes device. This rate rose to 31% in the first 3 months. These requests resulted in 16% of the sample starting a new device within the first 3 months. Whereas several factors were associated with prior CGM use, receiving a prescription, and starting a new device, more diabetes distress (t(343) = −3.13, p = .002) was the only factor associated with asking for a prescription. Diabetes distress decreased after interacting with DiabetesWise within 1 month (t(193) = 3.51, p

Brown algae are the main source of polysaccharides such as fucoidan and alginate, which can be used to develop a wide range of bioactive and polymer materials. In this study, sodium alginate and fucoidan were sequentially extracted using thermochemical, microwave, ultrasonic and sub critical water treatments of untreated and ethanol-pre-treated brown algae, Ascophyllum nodosum. Extraction was achieved using a solvent solution consisting of a 1:2 M ratio of choline chloride to glycerol (ChGl) in 70% water (w/w) for initial treatment to extract fucoidan, followed by Na2CO3 treatments for alginate extraction. Microwave extraction was shown to be the most advantageous treatment for alginate extraction, with the greatest biomass extracted (46.2%), purity (33.43% combined mannuronic and guluronic acid content), and molecular weight, whilst indicating an increased bioactive capacity associated with co-extracted polyphenolic content. However, using ChGl for fucoidan extraction resulted in a large fraction of the solvent remaining within the fucoidan. This is evidenced by up to 39% of the fucoidan consisting of glycerol. The extracted alginate has the potential as a bioactive polysaccharide, whilst the fucoidan would require further purification.

ABSTRACTEmerging evidence implicates microbial proteolytic activity in ulcerative colitis (UC), but whether it also plays a role in Crohn’s disease (CD) remains unclear. We investigated the effects of colonizing adult and neonatal germ-free C57BL/6 mice with CD microbiota, selected based on high (CD-HPA) or low fecal proteolytic activity (CD-LPA), or microbiota from healthy controls with LPA (HC-LPA) or HPA (HC-HPA). We then investigated colitogenic mechanisms in gnotobiotic C57BL/6, and in mice with impaired Nucleotide-binding Oligomerization Domain-2 (NOD2) and Protease-Activated Receptor 2 (PAR2) cleavage resistant mice (Nod2−/−; R38E-PAR2 respectively). At sacrifice, total fecal proteolytic, elastolytic, and mucolytic activity were analyzed. Microbial community and predicted function were assessed by 16S rRNA gene sequencing and PICRUSt2. Immune function and colonic injury were investigated by inflammatory gene expression (NanoString) and histology. Colonization with HC-LPA or CD-LPA lowered baseline fecal proteolytic activity in germ-free mice, which was paralleled by lower acute inflammatory cell infiltrate. CD-HPA further increased proteolytic activity compared with germ-free mice. CD-HPA mice had lower alpha diversity, distinct microbial profiles and higher fecal proteolytic activity compared with CD-LPA. C57BL/6 and Nod2−/− mice, but not R38E-PAR2, colonized with CD-HPA had higher colitis severity than those colonized with CD-LPA. Our results indicate that CD proteolytic microbiota is proinflammatory, increasing colitis severity through a PAR2 pathway.

Abstract It is well-established that individuals with autism exhibit atypical functional brain connectivity. However, the role this plays in naturalistic social settings has remained unclear. Atypical patterns may reflect core deficits or may instead compensate for deficits and promote adaptive behavior. Distinguishing these possibilities requires measuring the ‘typicality’ of spontaneous behavior and determining how connectivity relates to it. Thirty-nine male participants (19 autism, 20 typically-developed) engaged in 115 spontaneous conversations with an experimenter during fMRI scanning. A classifier algorithm was trained to distinguish participants by diagnosis based on 81 semantic, affective and linguistic dimensions derived from their use of language. The algorithm’s graded likelihood of a participant's group membership (autism vs. typically-developed) was used as a measure of task performance and compared with functional connectivity levels. The algorithm accurately classified participants and its scores correlated with clinician-observed autism signs (ADOS-2). In support of a compensatory role, greater functional connectivity between right inferior frontal cortex and left-hemisphere social communication regions correlated with more typical language behavior, but only for the autism group. We conclude that right inferior frontal functional connectivity increases in autism during communication reflect a neural compensation strategy that can be quantified and tested even without an a priori behavioral standard.

Abstract Background The experience of expectant parenthood is commensurate of relative angst and nervousness albeit one of overall excitement and joy. However, when the pregnancy is regarded as high-risk, this experience changes dramatically for both parents. While literature on high-risk pregnancies is gaining traction, the focus is predominantly on the mother’s experiences and therefore, a paucity exists in exploring the father’s experiences of a high-risk pregnancy. This study aimed to determine the current extent of literature focusing on father’s experiences of a high-risk pregnancy using a scoping review methodology. Method Nine databases were reviewed using the EBSCOHost metadatabase: Academic Search Complete; APA PsychArticles; CINAHL Plus with full-text; Health Source: Nursing/Academic Edition; MasterFILE Premier; MasterFILE Reference eBook Collection; MEDLINE; SocINDEX with full-text; and eBook Collection. Data was extracted according to the following headings: Authors (including the year of publication); aim of the study; research context; research design; sample characteristics; and key findings. Results Fifteen studies were included in this review. A narrative synthesis was applied within which 4 key themes emerged from the data: (1) The father versus the healthcare professional and the hospital environment; (2) The impact of high-risk pregnancies on fathers; (3) Redefining the role of ‘father’ after experiencing high-risk pregnancy and (4) Focus on fathers: Recommendations for support during high-risk pregnancies. Conclusion The findings of this study highlights the importance of the inclusion of men and fathers in supporting both his partner and (un)born child. The findings further illustrated the long-lasting impact of trauma felt by men which constrained his ability to support his family. A family-centred approach is needed to further support the family and the impact of a high-risk pregnancy on all members within the family unit.

In order to meet mobile cellular users' ever-increasing data demands, today's 4G and 5G wireless networks are designed mainly with the goal of maximizing spectral efficiency. While they have made progress in this regard, controlling the carbon footprint and operational costs of such networks remains a long-standing problem among network designers. This article takes a long view on this problem, envisioning a NextG scenario where the network leverages quantum annealing for cellular baseband processing. We gather and synthesize insights on power consumption, computational throughput and latency, spectral efficiency, operational cost, and feasibility timelines surrounding quantum annealing technology. Armed with these data, we project the quantitative performance targets future quantum annealing hardware must meet in order to provide a computational and power advantage over complementary metal–oxide semiconductor (CMOS) hardware, while matching its whole-network spectral efficiency. Our quantitative analysis predicts, that with 82.32 $\mu$s problem latency and 2.68 M qubits, quantum annealing will achieve a spectral efficiency equal to CMOS while reducing power consumption by 41 kW (45% lower) in a large MIMO base station with 400-MHz bandwidth and 64 antennas, and a 160-kW power reduction (55% lower) using 8.04 M qubits in a centralized radio access network setting with three large MIMO base stations.

Abstract Nanofilamentous bacteriophages (bacterial viruses) are biofunctional, self-propagating, and monodisperse natural building blocks for virus-built materials. Minifying phage-built materials to microscale offers the promise of expanding the range function for these biomaterials to sprays and colloidal bioassays/biosensors. Here, we crosslink half a million self-organized phages as the sole structural component to construct each soft microgel. Through an in-house developed, biologics-friendly, high-throughput template method, over 35,000 phage-built microgels are produced from every square centimetre of a peelable microporous film template, constituting a 13-billion phage community. The phage-exclusive microgels exhibit a self-organized, highly-aligned nanofibrous texture and tunable auto-fluorescence. Further preservation of antimicrobial activity was achieved by making hybrid protein-phage microgels. When loaded with potent virulent phages, these microgels effectively reduce heavy loads of multidrug-resistant Escherichia coli O157:H7 on food products, leading to up to 6 logs reduction in 9 hours and rendering food contaminant free.

The electroencephalogram (EEG) is a powerful tool for analyzing neural activity in various neurological disorders, both in animals and in humans. This technology has enabled researchers to record the brain’s abrupt changes in electrical activity with high resolution, thus facilitating efforts to understand the brain’s response to internal and external stimuli. The EEG signal acquired from implanted electrodes can be used to precisely study the spiking patterns that occur during abnormal neural discharges. These patterns can be analyzed in conjunction with behavioral observations and serve as an important means for accurate assessment and quantification of behavioral and electrographic seizures. Numerous algorithms have been developed for the automated quantification of EEG data; however, many of these algorithms were developed with outdated programming languages and require robust computational hardware to run effectively. Additionally, some of these programs require substantial computation time, reducing the relative benefits of automation. Thus, we sought to develop an automated EEG algorithm that was programmed using a familiar programming language (MATLAB), and that could run efficiently without extensive computational demands. This algorithm was developed to quantify interictal spikes and seizures in mice that were subjected to traumatic brain injury. Although the algorithm was designed to be fully automated, it can be operated manually, and all the parameters for EEG activity detection can be easily modified for broad data analysis. Additionally, the algorithm is capable of processing months of lengthy EEG datasets in the order of minutes to hours, reducing both analysis time and errors introduced through manual-based processing.

Abstract The World Health Organization has designated Staphylococcus aureus as a global health concern. This designation stems from the emergence of multiple drug‐resistant strains that already account for hundreds of thousands of deaths globally. The development of novel treatment strategies to eradicate S. aureus or mitigate its pathogenic potential is desperately needed. In the effort to develop emerging strategies to combat S. aureus, phage display is uniquely positioned to assist in this endeavor. Leveraging bacteriophages, phage display enables researchers to better understand interactions between proteins and their antagonists. In doing so, researchers have the capacity to design novel inhibitors, biosensors, disinfectants, and immune modulators that can target specific S. aureus strains. In this review, we highlight how phage display can be leveraged to design novel solutions to combat S. aureus. We further discuss existing uses of phage display as a detection, intervention, and prevention platform against S. aureus and provide outlooks on how this technology can be optimized for future applications.

Sound is processed in primate brains along anatomically and functionally distinct streams: this pattern can be seen in both human and non-human primates. We have previously proposed a general auditory processing framework in which these different perceptual profiles are associated with different computational characteristics. In this paper we consider how recent work supports our framework.

Rationale & Objective: Suboptimal care coordination between dialysis facilities and hospitals is an important driver of 30-day hospital readmissions among patients receiving dialysis. We examined whether the introduction of web-based communications platform (“DialysisConnect”) was associated with reduced hospital readmissions. Study Design: Pilot pre-post study. Setting & Participants: A total of 4,994 index admissions at a single hospital (representing 2,419 patients receiving dialysis) during the study period (January 1, 2019-May 31, 2021). Intervention: DialysisConnect was available to providers at the hospital and 4 affiliated dialysis facilities (=intervention facilities) during the pilot period (November 1, 2020-May 31, 2021). Outcomes: The primary outcome was 30-day readmission; secondary outcomes included 30-day emergency department visits and observation stays. Interrupted time series and linear models with generalized estimating equations were used to assess pilot versus prepilot differences in outcomes; difference-in-difference analyses were performed to compare these differences between intervention versus control facilities. Sensitivity analyses included a third, prepilot/COVID-19 period (March 1, 2020-October 31, 2020). Results: There was no statistically significant difference in the monthly trends in the 30-day readmissions pilot versus prepilot periods (−0.60 vs -0.13, P = 0.85) for intervention facility admissions; the difference-in-difference estimate was also not statistically significant (0.54 percentage points, P = 0.83). Similar analyses including the prepilot/COVID-19 period showed that, despite a substantial drop in admissions at the start of the pandemic, there were no statistically significant differences across the 3 periods. The age-, sex-, race-, and comorbid condition-adjusted, absolute pilot versus prepilot difference in readmissions rate was 1.8% (−3.7% to 7.3%); similar results were found for other outcomes. Limitations: Potential loss to follow-up and pandemic effects. Conclusions: In this pilot, the introduction of DialysisConnect was not associated with reduced hospital readmissions. Tailored care coordination solutions should be further explored in future, multisite studies to improve the communications gap between dialysis facilities and hospitals.

The current study examines the potential mediating role of professional identification of school teachers in the relationship between psychological distress and teaching satisfaction. Professional identification is the extent to which an individual identifies with a professional group, including the values, beliefs, and commitment the individual has in relation to the professional group. Professional identification has been linked to negative work outcomes, such as job performance and turnover intentions, as well as to adverse mental health outcomes. In the context of education, professional identification is the extent to which teachers identify with the teaching profession. Participants (N = 355) were school teachers in South Africa who completed the Center for Epidemiological Depression Scale, the Beck Hopelessness Scale, the Professional Identification Scale, and the Teaching Satisfaction Scale. Structural equation analysis showed that professional identification plays a fully mediational role in the relationship between psychological distress and teaching satisfaction. Interventions that strengthen teachers’ identification with the teaching profession should be considered a priority.

BackgroundWe piloted a web-based, provider-driven mobile app (DialysisConnect) to fill the communication and care coordination gap between hospitals and dialysis facilities. ObjectiveThis study aimed to describe the development and pilot implementation of DialysisConnect. MethodsDialysisConnect was developed iteratively with focus group and user testing feedback and was made available to 120 potential users at 1 hospital (hospitalists, advanced practice providers [APPs], and care coordinators) and 4 affiliated dialysis facilities (nephrologists, APPs, nurses and nurse managers, social workers, and administrative personnel) before the start of the pilot (November 1, 2020, to May 31, 2021). Midpilot and end-of-pilot web-based surveys of potential users were also conducted. Descriptive statistics were used to describe system use patterns, ratings of multiple satisfaction items (1=not at all; 3=to a great extent), and provider-selected motivators of and barriers to using DialysisConnect. ResultsThe pilot version of DialysisConnect included clinical information that was automatically uploaded from dialysis facilities, forms for entering critical admission and discharge information, and a direct communication channel. Although physicians comprised most of the potential users of DialysisConnect, APPs and dialysis nurses were the most active users. Activities were unevenly distributed; for example, 1 hospital-based APP recorded most of the admissions (280/309, 90.6%) among patients treated at the pilot dialysis facilities. End-of-pilot ratings of DialysisConnect were generally higher for users versus nonusers (eg, “I can see the potential value of DialysisConnect for my work with dialysis patients”: mean 2.8, SD 0.4, vs mean 2.3, SD 0.6; P=.02). Providers most commonly selected reduced time and energy spent gathering information as a motivator (11/26, 42%) and a lack of time to use the system as a barrier (8/26, 31%) at the end of the pilot. ConclusionsThis pilot study found that APPs and nurses were most likely to engage with the system. Survey participants generally viewed the system favorably while identifying substantial barriers to its use. These results inform how best to motivate providers to use this system and similar systems and inform future pragmatic research in care coordination among this and other populations.

Abstract Background A previous study reported that the malaria parasite Plasmodium falciparum enters an altered growth state upon extracellular withdrawal of the essential amino acid isoleucine. Parasites slowed transit through the cell cycle when deprived of isoleucine prior to the onset of S-phase. Methods This project was undertaken to study at higher resolution, how isoleucine withdrawal affects parasite growth. Parasites were followed at regular intervals across an extended isoleucine deprivation time course across the cell cycle using flow cytometry. Results These experiments revealed that isoleucine-deprived parasites never exit the cell cycle, but instead continuously grow at a markedly reduced pace. Moreover, slow growth occurs only if isoleucine is removed prior to the onset of schizogony. After S-phase commenced, the parasite is insensitive to isoleucine depletion and transits through the cell cycle at the normal pace. Conclusions The markedly different response of the parasite to isoleucine withdrawal before or after the onset of DNA replication is reminiscent of the nutrient-dependent G1 cell cycle checkpoints described in other organisms.

Prosody can be defined as the rhythm and intonation patterns spanning words, phrases and sentences. Accurate perception of prosody is an important component of many aspects of language processing, such as parsing grammatical structures, recognizing words, and determining where emphasis may be placed. Prosody perception is important for language acquisition and can be impaired in language-related developmental disorders. However, existing assessments of prosodic perception suffer from some shortcomings. These include being unsuitable for use with typically developing adults due to ceiling effects and failing to allow the investigator to distinguish the unique contributions of individual acoustic features such as pitch and temporal cues. Here we present the Multi-Dimensional Battery of Prosody Perception (MBOPP), a novel tool for the assessment of prosody perception. It consists of two subtests: Linguistic Focus, which measures the ability to hear emphasis or sentential stress, and Phrase Boundaries, which measures the ability to hear where in a compound sentence one phrase ends, and another begins. Perception of individual acoustic dimensions (Pitch and Duration) can be examined separately, and test difficulty can be precisely calibrated by the experimenter because stimuli were created using a continuous voice morph space. We present validation analyses from a sample of 59 individuals and discuss how the battery might be deployed to examine perception of prosody in various populations.

Aromatase Inhibitors (AIs) block estrogen production and improve survival in patients with hormone-receptor-positive breast cancer. However, half of patients develop aromatase-inhibitor-induced arthralgia (AIIA), which is characterized by inflammation of the joints and the surrounding musculoskeletal tissue. To create a platform for future interventional strategies, our objective was to characterize a novel animal model of AIIA. Female BALB/C-Tg(NFκB-RE-luc)-Xen mice, which have a firefly luciferase NFκB reporter gene, were oophorectomized and treated with an AI (letrozole). Bioluminescent imaging showed significantly enhanced NFκB activation with AI treatment in the hind limbs. Moreover, an analysis of the knee joints and legs via MRI showed enhanced signal detection in the joint space and the surrounding tissue. Surprisingly, the responses observed with AI treatment were independent of oophorectomy, indicating that inflammation is not mediated by physiological estrogen levels. Histopathological and pro-inflammatory cytokine analyses further demonstrated the same trend, as tenosynovitis and musculoskeletal infiltrates were detected in all mice receiving AI, and serum cytokines were significantly upregulated. Human PBMCs treated with letrozole/estrogen combinations did not demonstrate an AI-specific gene expression pattern, suggesting AIIA-mediated pathogenesis through other cell types. Collectively, these data identify an AI-induced stimulation of disease pathology and suggest that AIIA pathogenesis may not be mediated by estrogen deficiency, as previously hypothesized.

Abstract Malaria parasites have a complex life cycle that includes specialized stages for transmission between their mosquito and human hosts. These stages are an understudied part of the lifecycle yet targeting them is an essential component of the effort to shrink the malaria map. The human parasite Plasmodium falciparum is responsible for the majority of deaths due to malaria. Our goal was to generate transgenic P. falciparum lines that could complete the lifecycle and produce fluorescent transmission stages for more in-depth and high-throughput studies. Using zinc-finger nuclease technology to engineer an integration site, we generated three transgenic P. falciparum lines in which tdtomato or gfp were stably integrated into the genome. Expression was driven by either stage-specific peg4 and csp promoters or the constitutive ef1a promoter. Phenotypic characterization of these lines demonstrates that they complete the life cycle with high infection rates and give rise to fluorescent mosquito stages. The transmission stages are sufficiently bright for intra-vital imaging, flow cytometry and scalable screening of chemical inhibitors and inhibitory antibodies.

Gene editing following designer nuclease cleavage in the presence of a DNA donor template can revert mutations in disease-causing genes. For optimal benefit, reversion of the point mutation in HBB leading to sickle cell disease (SCD) would permit precise homology-directed repair (HDR) while concurrently limiting on-target non-homologous end joining (NHEJ)-based HBB disruption. In this study, we directly compared the relative efficiency of co-delivery of a novel CRISPR/Cas9 ribonucleoprotein targeting HBB in association with recombinant adeno-associated virus 6 (rAAV6) versus single-stranded oligodeoxynucleotides (ssODNs) to introduce the sickle mutation (GTC or GTG; encoding E6V) or a silent change (GAA; encoding E6optE) in human CD34+ mobilized peripheral blood stem cells (mPBSCs) derived from healthy donors. In vitro, rAAV6 outperformed ssODN donor template delivery and mediated greater HDR correction, leading to both higher HDR rates and a higher HDR:NHEJ ratio. In contrast, at 12–14 weeks post-transplant into recipient, immunodeficient, NOD, B6, SCID Il2rγ−/− Kit(W41/W41) (NBSGW) mice, a ∼6-fold higher proportion of ssODN-modified cells persisted in vivo compared to recipients of rAAV6-modified mPBSCs. Together, our findings highlight that methodology for donor template delivery markedly impacts long-term persistence of HBB gene-modified mPBSCs, and they suggest that the ssODN platform is likely to be most amenable to direct clinical translation. Keywords: sickle cell disease, gene editing, rAAV6, ssODN, homology-directed repair, Crispr/Cas9, hemoglobin disorders, NHEJ versus HDR, in vivo engraftment, NBSGW41 mice, CD34, hematopoietic stem cells, stem cell cures

Elements within the γ-hemoglobin promoters (HBG1 and HBG2) function to bind transcription complexes that mediate repression of fetal hemoglobin expression. Sickle cell disease (SCD) subjects with a 13-bp deletion in the HBG1 promoter exhibit a clinically favorable hereditary persistence of fetal hemoglobin (HPFH) phenotype. We developed TALENs targeting the homologous HBG promoters to de-repress fetal hemoglobin. Transfection of human CD34+ cells with TALEN mRNA resulted in indel generation in HBG1 (43%) and HBG2 (74%) including the 13-bp HPFH deletion (∼6%). Erythroid differentiation of edited cells revealed a 4.6-fold increase in γ-hemoglobin expression as detected by HPLC. Assessment of TALEN-edited CD34+ cells in vivo in a humanized mouse model demonstrated sustained presence of indels in hematopoietic cells up to 24 weeks. Indel rates remained unchanged following secondary transplantation consistent with editing of long-term repopulating stem cells (LT-HSCs). Human γ-hemoglobin expressing F cells were detected by flow cytometry approximately 50% more frequently in edited animals compared to mock. Together, these findings demonstrate that TALEN-mediated indel generation in the γ-hemoglobin promoter leads to high levels of fetal hemoglobin expression in vitro and in vivo, suggesting that this approach can provide therapeutic benefit in patients with SCD or β-thalassemia. Keywords: TALEN, hemoglobinopathy, HBG, hemoglobin, HPFH, SCD, sickle cell disease, thalassemia, gene editing, HSC

Teachers’ work roles and responsibilities have changed dramatically because of the COVID-19 pandemic. These unprecedented changes have the potential to generate role stress and burnout and reduce teachers’ job satisfaction. This study investigated the serial relationship between perceived vulnerability to disease, role stress, burnout, and teaching satisfaction. It was hypothesised that individuals who perceive themselves to be at high risk of contracting COVID-19 would report high role conflict and ambiguity in the workplace, which would in turn lead to high levels of burnout and low satisfaction with teaching. Participants were schoolteachers (N = 355) who completed the Perceived Vulnerability to Disease Questionnaire, the Role Orientation Questionnaire, the Maslach Burnout Inventory, and the Teaching Satisfaction Scale. Path analysis confirmed that perceived vulnerability to disease was associated with role conflict and ambiguity, which was in turn associated with emotional exhaustion, depersonalisation, and low teaching satisfaction. Teachers who appraised themselves as being more vulnerable to contracting COVID-19 experienced greater role stress, which was associated with high levels of burnout and low teaching satisfaction. This study highlights that threat appraisals related to contracting COVID-19 represent an additional job demand and this needs to be matched by job resources that can facilitate coping.

Individuals with congenital amusia have a lifelong history of unreliable pitch processing. Accordingly, they downweight pitch cues during speech perception and instead rely on other dimensions such as duration. We investigated the neural basis for this strategy. During fMRI, individuals with amusia (N = 15) and controls (N = 15) read sentences where a comma indicated a grammatical phrase boundary. They then heard two sentences spoken that differed only in pitch and/or duration cues and selected the best match for the written sentence. Prominent reductions in functional connectivity were detected in the amusia group between left prefrontal language-related regions and right hemisphere pitch-related regions, which reflected the between-group differences in cue weights in the same groups of listeners. Connectivity differences between these regions were not present during a control task. Our results indicate that the reliability of perceptual dimensions is linked with functional connectivity between frontal and perceptual regions and suggest a compensatory mechanism.

ObjectivesGout is the most prevalent inflammatory arthritis. To study the effects of regular physical activity and exercise intensity on inflammation and clinical outcome, we examined inflammatory pathogenesis in an acute model of murine gout and analyzed human gout patient clinical data as a function of physical activity.MethodsNF-κB-luciferase reporter mice were organized into four groups and exercised at 0 m/min (non-exercise), 8 m/min (low-intensity), 11 m/min (moderate-intensity), and 15 m/min (high-intensity) for two weeks. Mice subsequently received intra-articular monosodium urate (MSU) crystal injections (0.5mg) and the inflammatory response was analyzed 15 hours later. Ankle swelling, NF-κB activity, histopathology, and tissue infiltration by macrophages and neutrophils were measured. Toll-like receptor (TLR)2 was quantified on peripheral monocytes/neutrophils by flow cytometry and both cytokines and chemokines were measured in serum or synovial aspirates. Clinical data and questionnaires accessing overall physical activity levels were collected from gout patients.ResultsInjection of MSU crystals produced a robust inflammatory response with increased ankle swelling, NF-κB activity, and synovial infiltration by macrophages and neutrophils. These effects were partially mitigated by low and moderate-intensity exercise. Furthermore, IL-1β was decreased at the site of MSU crystal injection, TLR2 expression on peripheral neutrophils was downregulated, and expression of CXCL1 in serum was suppressed with low and moderate-intensity exercise. Conversely, the high-intensity exercise group closely resembled the non-exercised control group by nearly all metrics of inflammation measured in this study. Physically active gout patients had significantly less flares/yr, decreased C-reactive protein (CRP) levels, and lower pain scores relative to physically inactive patients.ConclusionsRegular, moderate physical activity can produce a quantifiable anti-inflammatory effect capable of partially mitigating the pathologic response induced by intra-articular MSU crystals by downregulating TLR2 expression on circulating neutrophils and suppressing systemic CXCL1. Low and moderate-intensity exercise produces this anti-inflammatory effect to varying degrees, while high-intensity exercise provides no significant difference in inflammation compared to non-exercising controls. Consistent with the animal model, gout patients with higher levels of physical activity have more favorable prognostic data. Collectively, these data suggest the need for further research and may be the foundation to a future paradigm-shift in conventional exercise recommendations provided by Rheumatologists to gout patients.

This paper presents the algorithmic design, experimental evaluation, and very large scale of integration (VLSI) implementation of Geosphere, a depth-first sphere decoder able to provide the exact maximum-likelihood solution in dense (e.g., 64) and very dense (e.g., 256, 1024) quadrature amplitude modulation (QAM) constellations by means of a geometrically inspired enumeration. In general, linear detection methods can be highly effective when the multiple input, multiple output (MIMO) channel is well-conditioned. However, this is not the case when the size of the MIMO system increases and the number of transmit antennas approaches the number of the receive antennas. Via our wireless open access research platform (WARP) testbed implementation, we gather indoor channel traces in order to evaluate the performance gains of sphere detection against zero-forcing and minimum mean-square errors (MMSE) in an actual indoor environment. We show that Geosphere can nearly linearly scale performance with the number of user antennas; in 4 × 4 multi-user MIMO for 256-QAM modulation at 30-dB SNR, there is a 1.7 × gain over MMSE and 2.4 × over zero-forcing and a 14% and 22% respective gain in 2 × 2 systems. In addition, by using a new node labeling-based enumeration technique, low-complexity integer arithmetic, and fine-grained clock gating, we implement for up to 1024-QAM constellations and compare in terms of area, delay, power characteristics, the Geosphere VLSI architecture, and the best-known best-scalable exact ML sphere decoder. Results show that Geosphere is twice as area-efficient and 70% more energy efficient in 1024-QAM. Even for 16-QAM, Geosphere is 13% more area-efficient than the best-known implementation for 16-QAM, and it is at least 80% more area-efficient than the state-of-the-art K-best detectors for 64-QAM.

Coatings offer a means to control nanoparticle (NP) size, regulate dissolution, and mitigate runoff when added to crops through soil. Simultaneously, coatings can enhance particle binding to plants and provide an additional source of nutrients, making them a valuable component to existing nanoparticle delivery systems. Here, the surface functionalization of metal and metal-oxide nanoparticles to inhibit aggregation and preserve smaller agglomerate sizes for enhanced transport to the rooting zone and improved uptake in plants is reviewed. Coatings are classified by type and by their efficacy to mitigate agglomeration in soils with variable pH, ionic concentration, and natural organic matter profiles. Varying degrees of success have been reported using a range of different polymers, biomolecules, and inorganic surface coatings. Advances in zwitterionic coatings show the best results for maintaining nanoparticle stability in solutions even under high salinity and temperature conditions, whereas coating by the soil component humic acid may show additional benefits such as promoting dissolution and enhancing bioavailability in soils. Pre-tuning of NP surface properties through exposure to select natural organic matter, microbial products, and other biopolymers may yield more cost-effective nonagglomerating metal/metal-oxide NPs for soil applications in agriculture.

Background: In vivo quantification of choroidal neovascularization (CNV) based on noninvasive optical coherence tomography (OCT) examination and in vitro choroidal flatmount immunohistochemistry stained of CNV currently were used to evaluate the process and severity of age-related macular degeneration (AMD) both in human and animal studies. This study aimed to investigate the correlation between these two methods in murine CNV models induced by subretinal injection. Methods: CNV was developed in 20 C57BL6/j mice by subretinal injection of adeno-associated viral delivery of a short hairpin RNA targeting sFLT-1 (AAV.shRNA.sFLT-1), as reported previously. After 4 weeks, CNV was imaged by OCT and fluorescence angiography. The scaling factors for each dimension, x, y, and z (μm/pixel) were recorded, and the corneal curvature standard was adjusted from human (7.7) to mice (1.4). The volume of each OCT image stack was calculated and then normalized by multiplying the number of voxels by the scaling factors for each dimension in Seg3D software (University of Utah Scientific Computing and Imaging Institute, available at http://www.sci.utah.edu/cibc-software/seg3d.html). Eighteen mice were prepared for choroidal flatmounts and stained by CD31. The CNV volumes were calculated using scanning laser confocal microscopy after immunohistochemistry staining. Two mice were stained by Hematoxylin and Eosin for observing the CNV morphology. Results: The CNV volume calculated using OCT was, on average, 2.6 times larger than the volume calculated using the laser confocal microscopy. The correlation statistical analysis showed OCT measuring of CNV correlated significantly with the in vitro method (R 2 =0.448, P = 0.001, n = 18). The correlation coefficient for CNV quantification using OCT and confocal microscopy was 0.693 (n = 18, P = 0.001). Conclusions: There is a fair linear correlation on CNV volumes between in vivo and in vitro methods in CNV models induced by subretinal injection. The result might provide a useful evaluation of CNV both for the studies using CNV models induced by subretinal injection and human AMD studies.

ABSTRACT The target of rapamycin complex 1 (TORC1) pathway is a highly conserved signaling pathway across eukaryotes that integrates nutrient and stress signals to regulate the cellular growth rate and the transition into and maintenance of dormancy. The majority of the pathway’s components, including the central TOR kinase, have been lost in the apicomplexan lineage, and it is unknown how these organisms detect and respond to nutrient starvation in its absence. Plasmodium falciparum encodes a putative ortholog of the RNA polymerase (Pol) III repressor Maf1, which has been demonstrated to modulate Pol III transcription in a TOR-dependent manner in a number of organisms. Here, we investigate the role of P. falciparum Maf1 (PfMaf1) in regulating RNA Pol III expression under conditions of nutrient starvation and other stresses. Using a transposon insertion mutant with an altered Maf1 expression profile, we demonstrated that proper Maf1 expression is necessary for survival of the dormancy-like state induced by prolonged amino acid starvation and is needed for full recovery from other stresses that slow or stall the parasite cell cycle. This Maf1 mutant is defective in the downregulation of pre-tRNA synthesis under nutrient-limiting conditions, indicating that the function of Maf1 as a stress-responsive regulator of structural RNA transcription is conserved in P. falciparum. Recent work has demonstrated that parasites carrying artemisinin-resistant K13 alleles display an enhanced ability to recover from drug-induced growth retardation. We show that one such artemisinin-resistant line displays greater regulation of pre-tRNA expression and higher survival upon prolonged amino acid starvation, suggesting that overlapping, PfMaf1-associated pathways may regulate growth recovery from both artemisinin treatment and amino acid starvation. IMPORTANCE Eukaryote organisms sense changes in their environment and integrate this information through signaling pathways to activate response programs to ensure survival. The TOR pathway is a well-studied signaling pathway found throughout eukaryotes that is known to integrate a variety of signals to regulate organismal growth in response to starvation and other stresses. The human malaria parasite Plasmodium falciparum appears to have lost the TOR pathway over the course of evolution, and it is unclear how the parasite modulates its growth in response to starvation and drug treatment. Here, we show that Maf1, a protein regulated by TOR in other eukaryotes, plays an important role in maintaining the parasite’s viability in the face of starvation and other forms of stress. This suggests that PfMaf1 is a component of a yet-to-be-described nutrient and stress response pathway.

Increasing demand for large-scale synthesis of in vitro transcribed (IVT) mRNA is being driven by the increasing use of mRNA for transient gene expression in cell engineering and therapeutic applications. An important determinant of IVT mRNA potency is the 3′ polyadenosine (poly(A)) tail, the length of which correlates with translational efficiency. However, present methods for generation of IVT mRNA rely on templates derived from circular plasmids or PCR products, in which homopolymeric tracts are unstable, thus limiting encoded poly(A) tail lengths to ≃120 base pairs (bp). Here, we have developed a novel method for generation of extended poly(A) tracts using a previously described linear plasmid system, pJazz. We find that linear plasmids can successfully propagate poly(A) tracts up to ≃500 bp in length for IVT mRNA production. We then modified pJazz by removing extraneous restriction sites, adding a T7 promoter sequence upstream from an extended multiple cloning site, and adding a unique type-IIS restriction site downstream from the encoded poly(A) tract to facilitate generation of IVT mRNA with precisely defined encoded poly(A) tracts and 3′ termini. The resulting plasmid, designated pEVL, can be used to generate IVT mRNA with consistent defined lengths and terminal residue(s).

This paper examines the use of jazz in contemporary American film and television soundtracks. Through processes of cultural signification, jazz music frequently maps racialized meaning onto the narrative. Often, a “black” jazz aesthetic signifies social and sexual deviance, while a “white” jazz aesthetic signifies elegance and high-culture. Such associations reinforce racial boundaries and essentialist stereotypes by perpetuating a dichotomy in which “blackness” figures as culturally dangerous (e.g. sexually deviant, unrestrained, threatening, and low-class) and “whiteness” as elite and culturally superior (e.g. civilized, educated, and high-class). To demonstrate this, the soundtracks of Anthony Minghella’s The Talented Mr. Ripley (1999); Ryan Murphy and Brad Falchuk’s American Horror Story: Coven (2013); and, Howard Gordon and Alex Gansa’s Homeland (2011) are examined. These examples are then compared to Spike Lee’s Do The Right Thing (1989), a film featuring sympathetic representations of African American identity. In Lee’s film, jazz challenges—rather than reinforces—racial discourse; a characteristic likely linked to Lee’s background as an African American with parents involved in the arts, black literature, and jazz composition. By comparing Lee’s alternative use of jazz to the preceding examples, it is argued that the use of the genre in film and television soundtracks as a stereotyping device reflects racial biases prominent in contemporary culture.

Optimal phototransduction requires separation of the avascular photoreceptor layer from the adjacent vascularized inner retina and choroid. Breakdown of peri-photoreceptor vascular demarcation leads to retinal angiomatous proliferation or choroidal neovascularization, two variants of vascular invasion of the photoreceptor layer in age-related macular degeneration (AMD), the leading cause of irreversible blindness in industrialized nations. Here we show that sFLT-1, an endogenous inhibitor of vascular endothelial growth factor A (VEGF-A), is synthesized by photoreceptors and retinal pigment epithelium (RPE), and is decreased in human AMD. Suppression of sFLT-1 by antibodies, adeno-associated virus-mediated RNA interference, or Cre/lox-mediated gene ablation either in the photoreceptor layer or RPE frees VEGF-A and abolishes photoreceptor avascularity. These findings help explain the vascular zoning of the retina, which is critical for vision, and advance two transgenic murine models of AMD with spontaneous vascular invasion early in life.

BACKGROUND:According to the body-specificity hypothesis, people with different bodily characteristics should form correspondingly different mental representations, even in highly abstract conceptual domains. In a previous test of this proposal, right- and left-handers were found to associate positive ideas like intelligence, attractiveness, and honesty with their dominant side and negative ideas with their non-dominant side. The goal of the present study was to determine whether 'body-specific' associations of space and valence can be observed beyond the laboratory in spontaneous behavior, and whether these implicit associations have visible consequences. METHODOLOGY AND PRINCIPAL FINDINGS:We analyzed speech and gesture (3012 spoken clauses, 1747 gestures) from the final debates of the 2004 and 2008 US presidential elections, which involved two right-handers (Kerry, Bush) and two left-handers (Obama, McCain). Blind, independent coding of speech and gesture allowed objective hypothesis testing. Right- and left-handed candidates showed contrasting associations between gesture and speech. In both of the left-handed candidates, left-hand gestures were associated more strongly with positive-valence clauses and right-hand gestures with negative-valence clauses; the opposite pattern was found in both right-handed candidates. CONCLUSIONS:Speakers associate positive messages more strongly with dominant hand gestures and negative messages with non-dominant hand gestures, revealing a hidden link between action and emotion. This pattern cannot be explained by conventions in language or culture, which associate 'good' with 'right' but not with 'left'; rather, results support and extend the body-specificity hypothesis. Furthermore, results suggest that the hand speakers use to gesture may have unexpected (and probably unintended) communicative value, providing the listener with a subtle index of how the speaker feels about the content of the co-occurring speech.

Introduction: Approximately 30% to 50% of hospital discharge antimicrobials are inappropriate. Limited data exist on approaches to improve antimicrobial prescribing practices at the time of discharge from a community hospital. Objective : To assess the impact of a comprehensive pharmacist-led antimicrobial stewardship intervention at discharge., Methods: We conducted a quasi-experimental, pre-post study. A biphasic intervention took place on 2 medicine units from November 2019 to May 2020 at a community hospital. Baseline data were collected, followed by prescriber education on antimicrobial stewardship to both units (education phase). Next, a pharmacist-led intervention took place on one unit (intervention phase). The primary outcome was composite appropriateness of an oral antimicrobial prescribed to an adult at the time of discharge, defined by narrow spectrum of activity, dosing, and duration of therapy. The primary outcome was assessed using Fisher exact test., Results: Baseline composite appropriateness was 30% (n = 12) on the control unit and 30.8% (n = 20) on the intervention unit. From baseline to posteducation, no significant change in composite appropriateness was found on the control (30% to 26.7%, P = 0.256) or intervention (30.8% to 19.4%, P = 0.09) unit. There was no significant difference between the education to intervention phase (26.7% vs 35%, P = 0.254) on the control unit. On the intervention unit, a significant difference in composite appropriateness was found from the education to intervention phase (19.4% vs 47.8%, P = 0.017)., Conclusion and Relevance: A pharmacist-led intervention improved appropriateness of oral antimicrobials prescribed at discharge. One-time education was insufficient for improving antimicrobial stewardship.

Background: Penicillin allergy is one of the most frequent self-reported allergies; however, only about 10% of reported allergies are accurate. Objectives: Through the creation of a continuing pharmacy education (CPE) activity, we sought to assess knowledge gaps and comfort levels in the management of penicillin allergies. Methods: A 1-hour enduring-content CPE activity was offered as an interactive course from September 20, 2019, to September 20, 2020. Participants completed 3 surveys (pre-survey, post-survey, and follow-up survey). Participants were pharmacists and pharmacy technicians who completed, at a minimum, the activity and both pre- and post-surveys. The primary outcome was the percentage of participants scoring >80% on knowledge-based questions on the post-survey compared with the pre-survey. Secondary outcomes included pre-post comparisons on knowledge-based questions, participants' self-report of an allergy, and comfort levels dispensing cephalosporins in a patient with a self-reported penicillin allergy. Results: A total of 389 participants completed the CPE activity, with 176 included for analysis. Significantly more participants scored >80% on knowledge-based questions on the post-survey compared with the pre-survey (71.6% vs 22.7%, P < .001). There was no significant difference between the percentage of participants scoring >80% on the post-survey and the follow-up survey (71.6% vs 65%, P = .119). The majority of participants (74%) felt comfortable dispensing a cephalosporin in a patient with a penicillin allergy on the pre-survey, with similar percentages on the post- and follow-up surveys (77% and 90%, respectively). Conclusion: A targeted continuing education program improved overall knowledge, which was sustained for up to 2 months., Competing Interests: Declaration of Conflicting Interests: The author(s) declared the following potential conflicts of interest with respect to the research, authorship, and/or publication of this article: SHD: has served on the advisory boards for Shionogi Pharmaceuticals and Theratechnologies.CMB: Advisory Board: Merck Pharmaceuticals; Speaker’s Bureau: Merck Pharmaceuticals; Grant Funding: ALK Abello, Inc, and Merck Pharmaceuticals.PBB: receives consultation fees from Kedrion Biopharma; content developer and CE provider for programs funded by Eli Lilly.EBC: serves on the advisory board for Theratechnologies and on the speakers’ bureau of Paratek Pharmaceuticals.JCC: serves on the speaker’s bureau for Allergan and has served on the advisory board for AcelRx Pharmaceuticals.BMJ: serves on the speaker’s bureau or has consulted for Allergan/Abbvie, Tetraphase/La Jolla, Merck, Melinta, and Paratek, and has received grant funding from Merck and ALK Abello.PJH: serves on the Continuing Pharmacy Education Commission for the Accreditation Council for Pharmacy Education (ACPE). The views expressed in this work only represent the authors’ views and do not necessarily represent the views of ACPE.EWC, FD, JAK, KRS, and JLW: have nothing to disclose., (© The Author(s) 2021.)

Background and Purpose: A novel teaching collaborative for acute care medicine advanced pharmacy practice experiences (APPEs) was formed by five faculty preceptors. The primary goal of the collaborative model was to ensure that acute care medicine APPEs provided students with opportunities to achieve Accreditation Council of Pharmacy Education Standards 2016, including strengthening students' ability to be practice- and team-ready., Educational Activity and Setting: The collaborative model included group discussions, video modules, patient cases, journal scans, and case presentations among student pharmacists completing an adult or pediatric acute care APPE. Anonymous, voluntary pre-/post-surveys were completed by a cohort of students who participated in the collaborative model from May 2018 to April 2019. Survey questions assessed student-perceived ability/confidence related to interprofessional (IP) relationships and decision-making skills for adult and pediatric patients, as well as value of activities., Findings: From the cohort of 67 students, 54 pre-survey and 45 post-survey responses were obtained. Post-rotation, students showed an increase in confidence to practice pharmacy on an IP team (39% vs. 100%, P < .001). Significant increases were also found for therapeutic decision-making regarding antibiotics, anticoagulants, and pharmacokinetics for adult and pediatric patients. Among students completing the post-survey, video modules were the most valued component of the model., Summary: A collaborative APPE model resulted in consistent increases in student-perceived ability and confidence related to care of adult and pediatric patients. This APPE model could be adapted within different care settings and pharmacy curricula., Competing Interests: Declaration of Competing Interest None., (Copyright © 2021 Elsevier Inc. All rights reserved.)

Paget-Schroetter syndrome (PSS) is a rare syndrome that typically develops in young, healthy males subjected to repetitive overhead motions resulting in compression and thrombosis of the subclavian vein. This "effort thrombosis" typically occurs acutely in patients with specific anatomic variations within the thoracic outlet and is treated by a combination of surgical and pharmacologic interventions. There is a paucity of literature regarding this syndrome, particularly surrounding pharmacotherapy, and in the treatment of pediatric patients. This case report documents the pharmacologic treatment of a 17-year-old, male, baseball player with confirmed PSS. Apixaban was selected as the anticoagulant therapy of choice following the determination of its safety and anticipated efficacy for this pediatric patient. Upon admission, anticoagulation was initiated with intravenous heparin and transitioned to warfarin for 1 dose. On day 2, the patient was discharged with apixaban 10 mg twice daily for 7 days, followed by 5 mg twice daily. One week later, he underwent catheter-directed thrombectomy, followed by thoracic outlet decompression with resection of the first rib. Apixaban therapy was continued for 10 weeks after the procedure to diminish the risk of any further thrombotic events. This pediatric patient with PSS was successfully treated with apixaban in conjunction with surgical management. Treatment with apixaban resulted in continued resolution of thrombus after follow-up, with no complications reported thereafter. Further research is needed to definitively determine the safety and efficacy of apixaban for the use of pediatric anticoagulation, particularly in upper extremity deep vein thrombosis., Competing Interests: Disclosure. The authors declare no conflicts or financial interest in any product or service mentioned in the manuscript, including grants, equipment, medications, employment, gifts, and honoraria. The authors (MMM, JAK, SMT) had full access to all patient information in this report and take responsibility for the integrity and accuracy of the report., (Copyright. Pediatric Pharmacy Association. All rights reserved. For permissions, email: mhelms@pediatricpharmacy.org 2021.)

Objectives: Urinary tract infections (UTIs) caused by extended-spectrum β-lactamase (ESBL)-producing Enterobacteriaceae are resistant to many conventional therapies, including third-generation cephalosporins. Carbapenems are considered first-line agents for ESBL infections, but their use is associated with increased multidrug resistance and should be reserved when absolutely necessary. Because of the increased rates of UTIs caused by ESBL-producing organisms and incidence of carbapenem resistance, safe and effective alternatives to carbapenems are needed. This study was conducted to evaluate the outcomes associated with the treatment of ESBL UTIs with noncarbapenem antibiotics., Methods: A retrospective cohort study of adults with ESBL UTIs was conducted at a community hospital. Patients were categorized as those receiving definitive carbapenem therapy and those receiving definitive noncarbapenem therapy. Calculated measurements included infection-related mortality, length of hospital stay, and duration of definitive antibiotic therapy. Microbiological failure was assessed as a secondary outcome. Data on the safety of antibiotic therapy were not collected. P < 0.05 was considered significant., Results: Fifty patients met inclusion criteria for the study, divided evenly between the two cohorts. No statistical differences were observed for length of hospital stay ( P = 0.601), duration of therapy ( P = 0.398), or rate of microbiological failure between the groups ( P = 0.115)., Conclusions: Noncarbapenems did not demonstrate significant differences compared with carbapenems in the treatment of adults with ESBL UTIs. In certain patient populations, noncarbapenems that demonstrate in vitro activity may be appropriate for UTIs caused by ESBL-producing organisms.

Objective: To assess the relative validity of the latest version of the Scottish Collaborative Group (SCG) FFQ (version 6.6) in adults living in Scotland., Design: A cross-sectional validation study. Participants completed the self-administered, 169-item SCG FFQ followed by a 7 d, non-weighed food diary. Energy and energy-adjusted macronutrients and micronutrients were examined for relative validity through Spearman's correlation, the percentage of classification into thirds of intake, Cohen's weighted kappa (κ w) and Bland-Altman analysis., Setting: General population living in Scotland., Subjects: Ninety-six adults aged 18-65 years., Results: Spearman's correlation coefficients ranged from 0·21 (retinol) to 0·71 (Mg). A median of 52 % of adults were correctly classified into thirds of intake (range: 42 % (PUFA, MUFA and Fe) to 64 % (percentage energy from carbohydrates)) and 8 % were grossly misclassified into opposite thirds of intake (range: 3 % (carbohydrates, percentage energy from carbohydrates) to 19 % (thiamin)). Values of κ w ranged between 0·20 (PUFA, β-carotene) to 0·55 (percentage energy from carbohydrates). In the Bland-Altman analysis, the smallest limits of agreement, when expressed as a percentage of the mean intake from the FFQ and food diary, were seen for the main macronutrients carbohydrates, fat and protein., Conclusions: As in the previous validation study more than 10 years ago, the FFQ gave higher estimates of energy and most nutrients than the food diary, but after adjustment for energy intake the FFQ could be used in place of non-weighed food diaries for most macronutrients and many micronutrients in large-scale epidemiological studies.