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Abstract Physiological regulation of transgene expression is a major challenge in gene therapy. Onasemnogene abeparvovec (Zolgensma®) is an approved adeno-associated virus (AAV) vector gene therapy for infants with spinal muscular atrophy (SMA), however, adverse events have been observed in both animals and patients following treatment. The construct contains a native human survival motor neuron 1 (hSMN1) transgene driven by a strong, cytomegalovirus enhancer/chicken β-actin (CMVen/CB) promoter providing high, ubiquitous tissue expression of SMN. We developed a second-generation AAV9 gene therapy expressing a codon-optimized hSMN1 transgene driven by a promoter derived from the native hSMN1 gene. This vector restored SMN expression close to physiological levels in the central nervous system and major systemic organs of a severe SMA mouse model. In a head-to-head comparison between the second-generation vector and a benchmark vector, identical in design to onasemnogene abeparvovec, the 2nd-generation vector showed better safety and improved efficacy in SMA mouse model.

Abstract Small‐cell lung cancer (SCLC) is the most lethal type of lung cancer. Specifically, MYC‐driven non‐neuroendocrine SCLC is particularly resistant to standard therapies. Lurbinectedin was recently approved for the treatment of relapsed SCLC, but combinatorial approaches are needed to increase the depth and duration of responses to lurbinectedin. Using high‐throughput screens, we found inhibitors of ataxia telangiectasia mutated and rad3 related (ATR) as the most effective agents for augmenting lurbinectedin efficacy. First‐in‐class ATR inhibitor berzosertib synergized with lurbinectedin in multiple SCLC cell lines, organoid, and in vivo models. Mechanistically, ATR inhibition abrogated S‐phase arrest induced by lurbinectedin and forced cell cycle progression causing mitotic catastrophe and cell death. High CDKN1A/p21 expression was associated with decreased synergy due to G1 arrest, while increased levels of ERCC5/XPG were predictive of increased combination efficacy. Importantly, MYC‐driven non‐neuroendocrine tumors which are resistant to first‐line therapies show reduced CDKN1A/p21 expression and increased ERCC5/XPG indicating they are primed for response to lurbinectedin–berzosertib combination. The combination is being assessed in a clinical trial NCT04802174.

Purpose: The Ventral Hernia Working Group (VHWG) proposed a ventral hernia grading guideline, primarily supported by expert opinion, recommending biologic mesh placement in high-risk patients. We investigated the relationship between this industry-sponsored guideline and discourse around ventral hernia repair (VHR). Methods: Medline platform from Web of Science's database identified publications "pre-VHWG"(1999-01-01 to 2009-12-31), and "post-VHWG"(2010-01-01 to 2020-12-31) describing VHR and complications or recurrence of VHR with the following comorbidities: COPD, smoking, diabetes, immunosuppression, or obesity. Poisson regression analyzed keyword frequency over time using logarithmically transformed data. Results: Of 1291 VHR publications identified pre-VHWG and 3041 publications identified post-VHWG, 172 (13.3%) and 642 (21.1%) publications respectively included prespecified keywords. The keyword groups "biologic"(IRR 3.39,95%CI1.34-11.4,p = 0.022) and "comorbid"(IRR 1.95, 95%CI1.09-3.74,p = 0.033) significantly increased with frequency after publication of the VHWG. Conclusion: The VHWG publication likely contributed to a focus on comorbidities and biologic mesh in the ensuing literature within the field of VHR. [ABSTRACT FROM AUTHOR]

Along with clinical and laboratory findings, imaging has a significant role in the initial evaluation and treatment follow-up of a wide variety of infectious and non-infectious musculoskeletal (MSK) conditions. The imaging findings of many non-infectious MSK processes, such as inflammatory, metabolic, and degenerative arthropathies, complications of diabetes mellitus, osseous and soft tissue injuries, osteonecrosis, tumors, and tumor-like lesions may be nonspecific and often overlap with those found in MSK infections. In this article, the authors discuss the imaging findings of both frequent and rare mimickers of MSK infections, including potential distinguishing characteristics. [ABSTRACT FROM AUTHOR]

Background: Endoscopic polypectomy could be an appropriate, definitive treatment for pathologic T1 (pT1) colon polyps without high-risk features. Prior studies suggested worse prognosis for proximal versus distal advanced-stage colon cancers following curative treatment. However, there is limited evidence on the prognostic impact of tumor location for pT1s. Patients and methods: This was a retrospective cohort study using the Surveillance, Epidemiology, and End Results database to identify adults with T1NxMx or T1N0-3M0/x colon adenocarcinoma from 2000 to 2019. Results: A total of 3398 patients underwent endoscopic polypectomy (17% proximal) and 28,334 had a partial colectomy (49% proximal) for pT1 adenocarcinoma. Following endoscopic polypectomy, 5-year overall and cancer-specific survival rates were 64% and 91% for proximal versus 83% and 96% for distal polyps, compared with 82% and 95% for proximal versus 88% and 97% for distal tumors after colectomy. In multivariable models, there was a greater difference in overall survival between proximal and distal polyps for those who underwent endoscopic versus surgical resection [hazard ratio (HR) 1.73, 95% confidence interval (CI) 1.49–2.02 vs. HR 1.13, 95% CI 1.08–1.18]. Patients with proximal versus distal polyps who underwent polypectomy also exhibited increased cancer-specific mortality (HR 1.94, 95% CI 1.37–2.75). However, cancer-specific survival variations based on tumor location were no longer observed in patients undergoing partial colectomy (HR 1.09, 95% CI 0.98–1.21). Conclusions: Proximal tumor location was independently associated with worse overall and cancer-specific survival following endoscopic polypectomy. However, after colectomy, the cancer-specific disparity based on tumor laterality was mitigated. These findings suggest that proximal location may be considered a high-risk feature in endoscopic polypectomy. [ABSTRACT FROM AUTHOR]

Background: Pathologic complete response (pCR) after preoperative chemoradiation (nCRT) correlates with improved overall survival for patients with locally advanced rectal cancers (LARCs). Escalation protocols including total neoadjuvant therapy (TNT), which delivers multi-agent chemotherapy and chemoradiation before surgery, are associated with increased complete response rates. However, TNT is not associated with improved overall survival. The authors hypothesized that the route to pCR may be an important predictor of oncologic outcome. Methods: Adults with LARC between 2006 and 2017 were identified in the National Cancer Database. The cohort was limited to those who received neoadjuvant radiation (45–70 Gy) and underwent proctectomy. Results: Of 25,880 patients, 16 % received TNT and 84 % had nCRT followed by either multi-agent (27 %), single-agent (14 %), or no adjuvant chemotherapy (44 %). Overall, 18 % achieved pCR, with higher rates in the TNT cohort than in the nCRT (18 %) or multi-agent (14 %) chemotherapy cohorts. With control for covariates, the OS in the pCR cohort was similar for the patients that received single-agent therapy and those that received multi-agent adjuvant therapy, and superior to the TNT and no adjuvant therapy cohorts. Conversely, among the patients who did not achieve pCR, those who received single-agent chemotherapy had OS comparable with those who had multi-agent adjuvant therapy and TNT, which was better than no adjuvant therapy. Conclusion: Patients achieving pCR after TNT had worse OS than those who had CRT alone, suggesting that the neoadjuvant route by which pCR is achieved is prognostically relevant. Therefore, in the era of neoadjuvant therapy escalation, pCR does not necessarily portend a uniformly favorable prognosis. [ABSTRACT FROM AUTHOR]

Deformed wing virus (DWV) has long been identified as a critical pathogen affecting honeybees, contributing to colony losses through wing deformities, neurological impairments, and reduced lifespan. Since DWV also affects other pollinators, it poses a significant threat to global pollination networks. While honeybees have been the focal point of DWV studies, emerging research indicates that this RNA virus is not host-specific but rather a generalist pathogen capable of infecting a wide range of insect species, including other bee species such as bumblebees and solitary bees, as well as wasps and ants. This expands the potential impact of DWV beyond honeybees to broader ecological communities. The black imported fire ant, Solenopsis richteri, is an economically important invasive ant species. In this study, we describe deformed wing (DW) symptoms in S. richteri. DW alates were found in three of nine (33%) laboratory colonies. The symptoms ranged from severely twisted wings to a single crumpled wing tip. Additionally, numerous symptomatic alates also displayed altered mobility, ranging from an ataxic gait to an inability to walk. Viral replication of DWV was confirmed using a modified strand-specific RT-PCR. Our results suggest that S. richteri can be an alternative host for DWV, expanding our understanding of DWV as a generalist pathogen in insects. However, additional research is required to determine whether DWV is the etiological agent responsible for DW syndrome in S. richteri. [ABSTRACT FROM AUTHOR]

The World Health Organization has identified antibiotic resistance as one of the three greatest threats to human health. The need for antibiotics is a pressing matter that requires immediate attention. Here, computer-aided drug design is used to develop a structurally unique antibiotic family targeting holo-acyl carrier protein synthase (AcpS). AcpS is a highly conserved enzyme essential for bacterial survival that catalyzes the first step in lipid synthesis. To the best of our knowledge, there are no current antibiotics targeting AcpS making this drug development program of high interest. We synthesize a library of > 700 novel compounds targeting AcpS, from which 33 inhibit bacterial growth in vitro at ≤ 2 μg/mL. We demonstrate that compounds from this class have stand-alone activity against a broad spectrum of Gram-positive organisms and synergize with colistin to enable coverage of Gram-negative species. We demonstrate efficacy against clinically relevant multi-drug resistant strains in vitro and in animal models of infection in vivo including a difficult-to-treat ischemic infection exemplified by diabetic foot ulcer infections in humans. This antibiotic family could form the basis for several multi-drug-resistant antimicrobial programs. Holo-acyl carrier protein synthase (AcpS) is an enzyme that catalyses the first step in lipid synthesis and is essential for bacterial survival, but no current antibiotics targeting AcpS are known. Here, the authors use computer-aided drug design to develop a structurally unique antibiotic family targeting AcpS. [ABSTRACT FROM AUTHOR]

To withstand their internal turgor pressure and external threats, most bacteria have a protective peptidoglycan (PG) cell wall. The growth of this PG polymer relies on autolysins, enzymes that create space within the structure. Despite extensive research, the regulatory mechanisms governing these PG-degrading enzymes remain poorly understood. Here, we unveil a novel and widespread control mechanism of lytic transglycosylases (LTs), a type of autolysin responsible for breaking down PG glycan chains. Specifically, we show that LD-crosslinks within the PG sacculus act as an inhibitor of LT activity. Moreover, we demonstrate that this regulation controls the release of immunogenic PG fragments and provides resistance against predatory LTs of both bacterial and viral origin. Our findings address a critical gap in understanding the physiological role of the LD-crosslinking mode in PG homeostasis, highlighting how bacteria can enhance their resilience against environmental threats, including phage attacks, through a single structural PG modification. The regulatory mechanisms governing peptidoglycan-degrading autolysins remain poorly understood. In this work, Alvarez et al. show that lytic transglycosylase activity is inhibited by LD-crosslinks in Vibrio cholerae and other bacteria, providing resistance against predatory enzymes of both bacterial and viral origin. [ABSTRACT FROM AUTHOR]

While first-generation, spike (S)-based COVID-19 vaccines were effective against early SARS-CoV-2 strains, the rapid evolution of novel Omicron subvariants have substantially reduced vaccine efficacy. As such, broadly protective vaccines against SARS-CoV-2 are needed to prevent future viral emergence. In addition, it remains less clear whether peripheral immunization, especially with mRNA vaccines, elicits effective respiratory immunity. Our group has developed a nucleoside-modified mRNA vaccine expressing the nucleocapsid (N) protein of the ancestral SARS-CoV-2 virus and has tested its use in combination with the S-based mRNA vaccine (mRNA-S). In this study, we examined efficacy of mRNA-N alone or in combination with mRNA-S (mRNA-S+N) against more immune evasive Omicron variants in hamsters. Our data show that mRNA-N alone induces a modest but significant protection against BA.5 and that dual mRNA-S+N vaccination confers complete protection against both BA.5 and BQ.1, preventing detection of virus in the hamster lungs. Analysis of respiratory immune response in mice shows that intramuscular mRNA-S+N immunization effectively induces respiratory S- and N-specific T cell responses in the lungs and in bronchoalveolar lavage (BAL), as well as antigen-specific binding IgG in BAL. Together, our data further support mRNA-S+N as a potential pan-COVID-19 vaccine for broad protection against current and emerging SARS-CoV-2 variants. [ABSTRACT FROM AUTHOR]

Early childhood educators often lack adequate preparation in the delivery of evidence-based practices. However, providing preservice teachers with ongoing implementation support during field-based training experiences may serve to occasion evidence-based practice delivery when they enter the field of early childhood education. Using a concurrent multiple baseline across participants design, this study examined the effectiveness of a multitiered consultation model to increase three early childhood preservice teachers' rates of behavior-specific praise in target and generalization settings. The results indicated all three preservice teachers' rates of behavior-specific praise increased across target and generalization settings, with evidence that praise rates maintained following removal of implementation supports. The results, limitations, and implications for research and practice are described. [ABSTRACT FROM AUTHOR]

Objectives: The few voxel-wise lesion-symptom mapping (VLSM) studies aimed at identifying the anatomy of executive function are limited by the absence of a model and by small populations. Using Trail Making Test (TMT) and verbal fluency and a model of their architectures, our objective was to identify the key structures underlying two major executive processes, set-shifting and strategic word search. Methods: We applied a validated VLSM analysis to harmonized cognitive and imaging data from 2009 ischemic stroke patients as a part of the Meta VCI Map consortium. All contrast analyses used an adjusted threshold with 2000 Freedman–Lane permutations (p ≤ 0.05). Results: The TMT parts A and B were associated with structures involved in visual-spatial processing, the motor system, the frontal lobes, and their subcortical connections. Set-shifting depended on the left dorsomedial frontal region. Both semantic and phonemic fluency tests depended on verbal output abilities and processing speed with similar slopes in different languages. The strategic search process depended on Broca's area, F2 and related tracts, temporal and deep regions. Lastly, the lesion map of set-shifting did not overlap with those of strategic word search processes. Interpretation: Our results identify the anatomical substrates of two main executive processes, revealing that they represent only a specific subpart of previously reported structures. Finally, our results indicate that executive functions depend on several specific, anatomically separable executive processes mainly operating in various parts of the frontal lobes. [ABSTRACT FROM AUTHOR]

In this novel large-scale multiplexed immunofluorescence study we comprehensively characterized and compared layer-specific proteomic features within regions of interest of the widely divergent dorsolateral prefrontal cortex (A46) and primary visual cortex (A17) of adult rhesus monkeys. Twenty-eight markers were imaged in rounds of sequential staining, and their spatial distribution precisely quantified within gray matter layers and superficial white matter. Cells were classified as neurons, astrocytes, oligodendrocytes, microglia, or endothelial cells. The distribution of fibers and blood vessels were assessed by quantification of staining intensity across regions of interest. This method revealed multivariate similarities and differences between layers and areas. Protein expression in neurons was the strongest determinant of both laminar and regional differences, whereas protein expression in glia was more important for intra-areal laminar distinctions. Among specific results, we observed a lower glia-to-neuron ratio in A17 than in A46 and the pan-neuronal markers HuD and NeuN were differentially distributed in both brain areas with a lower intensity of NeuN in layers 4 and 5 of A17 compared to A46 and other A17 layers. Astrocytes and oligodendrocytes exhibited distinct marker-specific laminar distributions that differed between regions; notably, there was a high proportion of ALDH1L1-expressing astrocytes and of oligodendrocyte markers in layer 4 of A17. The many nuanced differences in protein expression between layers and regions observed here highlight the need for direct assessment of proteins, in addition to RNA expression, and set the stage for future protein-focused studies of these and other brain regions in normal and pathological conditions. [ABSTRACT FROM AUTHOR]

Extravehicular activities will play a crucial role in lunar exploration on upcoming Artemis missions and may involve astronauts operating a lunar terrain vehicle (LTV) in a standing posture. This study assessed kinematic response and injury risks using an active muscle human body model (HBM) restrained in an upright posture on the LTV by simulating dynamic acceleration pulses related to lunar surface irregularities. Linear accelerations and rotational displacements of 5 lunar obstacles (3 craters; 2 rocks) over 5 slope inclinations were applied across 25 simulations. All body injury metrics were below NASA's injury tolerance limits, but compressive forces were highest in the lumbar (250–550N lumbar, tolerance: 5300N) and lower extremity (190–700N tibia, tolerance: 1350N) regions. There was a strong association between the magnitudes of body injury metrics and LTV resultant linear acceleration (ρ = 0.70–0.81). There was substantial upper body motion, with maximum forward excursion reaching 375 mm for the head and 260 mm for the chest. Our findings suggest driving a lunar rover in an upright posture for these scenarios is a low severity impact presenting low body injury risks. Injury metrics increased along the load path, from the lower body (highest metrics) to the upper body (lowest metrics). While upper body injury metrics were low, increased body motion could potentially pose a risk of injury from flail and occupant interaction with the surrounding vehicle, suit, and restraint hardware. [ABSTRACT FROM AUTHOR]

There are genetic and environmental risk factors that contribute to the development of cognitive decline in Alzheimer's disease (AD). Some of these include the genetic predisposition of the apolipoprotein E4 genotype, consuming a high-fat diet (HFD), and the female sex. Brain insulin receptor resistance and deficiency have also been shown to be associated with AD and cognitive impairment. Intranasal (INL) insulin enhances cognition in AD, but the response varies due to genotype, diet, and sex. We investigated here the combination of these risk factors in a humanized mouse model, expressing E3 or E4, following a HFD in males and females on cognitive performance and the brain distribution of insulin following INL delivery. The HFD had a negative effect on survival in male mice only, requiring sex to be collapsed. We found many genotype, diet, and genotype x diet effects in anxiety-related tasks. We further found beneficial effects of INL insulin in our memory tests, with the most important findings showing a beneficial effect of INL insulin in mice on a HFD. We found insulin distribution throughout the brain after INL delivery was largely unaffected by diet and genotype, indicating these susceptible groups can still receive adequate levels of insulin following INL delivery. Our findings support the involvement of brain insulin signaling in cognition and highlight continuing efforts investigating mechanisms resulting from treatment with INL insulin. [ABSTRACT FROM AUTHOR]

Background: The use of robotic-assisted total knee arthroplasty (RA-TKA) is gaining traction. There is evidence to suggest that RA-TKA can help to optimize the precision and accuracy of implant positioning and that there may be protective effects on surrounding bony and soft tissues. Yet, there are important differences between the various RA-TKA systems currently on the market. One such newly introduced RA-TKA system uses imageless technology and performs bony cuts with the use of a burr-based device. The learning curve and complications unique to this system have yet to be assessed. Methods: We evaluated 500 consecutive RA-TKA cases using a newly developed burr-based and imageless system which were done by a single surgeon between the months of October 2021 and February 2023. Operative times were recorded and compared to the previous 150 conventional TKA cases allowing for the learning curve to be calculated using the CUSUM method. Intraoperative and postoperative complications were categorically profiled. Results: The learning curve of this RA-TKA system was found to be 6 cases. Intraoperative complications included unintended bony over resection (n = 3), soft tissue injury (n = 2), and robotic system hardware (n = 2) or software (n = 2) malfunction. Postoperative complications consisted of superficial pin site infection (n = 1) and periprosthetic fracture near the pin sites (n = 1). There were no identified cases of prosthetic joint infection, instability events, or wound complications. Conclusions: The learning curve and the complication profile of a newly introduced imageless and burr-based RA-TKA system were described. This information serves to guide surgeons in adopting this technology and can counsel them regarding the potential pitfalls and challenges associated with its integration into practice. The work sheds light on the complexity and learning curve of the recently released imageless burr-based RA-TKA system. This important information is intended to help surgeons accept this cutting-edge technology by providing advice on any errors and difficulties that can occur when integrating it into clinical practice. This information can help surgeons navigate the complexities of integrating this new burr-based robotic technology into knee replacement procedures, enabling them to make well-informed decisions and receive guidance. [ABSTRACT FROM AUTHOR]

Purpose: Modern trauma care has reduced mortality but poor long-term outcomes with low follow-up rates are common with limited recommendations for improvements. The aim of this study was to describe the impact of severe injury on the health-related quality of life, specifically characterise the non-responder population and to identify modifiable predictors of poorer outcomes. Methods: Five-year (2012–2016) prospective cohort study was performed at a level 1 trauma centre. Baseline Short-Form Health Survey (SF36) was collected at admission, and at 6 and 12 months postinjury together with demographics, injury mechanism and severity, psychosocial wellbeing, and return to work capacity. Results: Of the 306 consecutive patients [age 52 ± 17 years, male 72%, ISS 21 (17, 29), mortality 5%], 195 (64%) completed questionnaires at baseline, and at 12 months. Preinjury physical health scores were above the general population (53.1 vs. 50.3, p < 0.001) and mental health component was consistent with the population norms (51.7 vs. 52.9, p = 0.065). One year following injury, both physical health (13.2, 95% CI 14.8, 11.6) and mental health scores (6.0, 95% CI 8.1, 3.8) were significantly below age- and sex-adjusted preinjury baselines. Non-responders had similar ISS but with a lower admission GCS, and were more likely to be younger, and without comorbidities, employment, or university education. Conclusion: Contrary to their better than population norm preinjury health status, polytrauma patients remain functionally impaired at least 1 year after injury. The identified high risk for non-responding group needs more focused efforts for follow-up. A fundamentally different approach is required in polytrauma research which identify modifiable predictors of poor long-term outcomes. [ABSTRACT FROM AUTHOR]

Purpose: To examine outcomes of oocyte retrievals completed by Reproductive Endocrinology and Infertility (REI) fellows versus faculty physicians. Methods: This retrospective cohort study examined patients who underwent oocyte retrievals at Mayo Clinic from July 15, 2009, to December 15, 2016. The primary outcome was the oocyte retrieval rate (ORR) calculated per retrieval as the number of oocytes retrieved per follicles aspirated. The Wilcoxon signed-rank test was used to compare follicle and oocyte counts and ORR between fellows and faculty during the same bilateral retrieval. Results: The study cohort included the first bilateral retrieval from 845 unique patients completed by 11 fellows and seven faculty. The median ORR was not statistically different for fellows and faculty (0.79 versus 0.80, p = 0.46). To assess for a learning curve, the outcomes of seven fellows who completed at least 80 retrievals in their first year were examined as four chronologically ordered sets of 20. When these sets were compared to the faculty physician mean ORR, no significant differences were found (p-values of 0.69, 0.69, 0.81, and 0.81, respectively). Conclusion: There were no significant differences in oocyte retrieval rates between fellows versus faculty over a 7-year period, with no significant learning curve observed. These findings suggest that fellows possess the requisite skills for successful oocyte retrieval upon entering REI fellowship following their OB/GYN residency. However, this does not diminish the critical role of comprehensive fellowship training and close supervision, especially in initial and complex cases. [ABSTRACT FROM AUTHOR]

Providing safe and informed healthcare for sexual and gender minority (SGM) individuals with cancer is stymied by the lack of sexual orientation and gender identity (SOGI) data reliably available in health records and by insufficient training for staff. Approaches that support institutional learning, especially around sensitive topics, are essential for hospitals seeking to improve practices impacting patient safety and research. We engineered annual institutional retreats to identify and unify stakeholders, promote awareness of gaps and needs, identify initiatives, minimize redundant projects, and coordinate efforts that promote improvements in SGM cancer care, education, and research. The 2022 and 2023 retreats employed a 4-h hybrid format allowing virtual and in-person engagement. Retreat organizers facilitated small-group discussions for brainstorming among participants. We performed descriptive statistics from retreat evaluations. The retreats engaged 104 attendees from distinct departments and roles. Participants expressed robust satisfaction, commending the retreat organization and content quality. Notably, the first retreat yielded leadership endorsement and funding for a Quality Improvement pilot to standardize SOGI data collection and clinical staff training. The second retreat provided a platform for updates on focused efforts across the institution and for receiving direction regarding national best practices for SGM care and research. We report the processes and outcomes of institution-wide retreats, which served as a platform for identifying gaps in organizational healthcare practices and research for SGM individuals with cancer. The strategies described herein may be readily scaled at other cancer hospitals seeking to learn and enact system-wide practice changes that support the needs of SGM patients and families. [ABSTRACT FROM AUTHOR]

This paper examines the study space preferences of college students in their respective university colleges. The study utilized principles of visual ethnography to collect participatory photographic data. Student participants completed three tasks, a demographic survey, participant-supplied photographs, and an exit interview. We recruited from the Colleges of Architecture and Education and Human Development 60 participants who captured their preferred study spaces in their colleges and adjacent areas through photographic evidence. Grounded theory and qualitative coding were applied to analyze and create preliminary code themes from the visual and textual data to further evaluate student study preferences. The authors discovered that there were differences, and sometimes similarities, of space availability between the colleges, patterns of semesterly inhabiting behavior and transient movement, and organic ability for collaboration. [ABSTRACT FROM AUTHOR]

Motor neuron disease (MND) is a rapidly progressive condition traditionally assessed using a questionnaire to evaluate physical function, the revised amyotrophic lateral sclerosis functional rating scale (ALSFRS-R). Its use can be associated with poor sensitivity in detecting subtle changes over time and there is an urgent need for more sensitive and specific outcome measures. The ActiGraph GT9X is a wearable device containing multiple sensors that can be used to provide metrics that represent physical activity. The primary aim of this study was to investigate the initial suitability and acceptability of limb-worn wearable devices to group of people with MND in Scotland. A secondary aim was to explore the preliminary associations between the accelerometer sensor data within the ActiGraph GT9X and established measures of physical function. 10 participants with MND completed a 12-week schedule of assessments including fortnightly study visits, both in-person and over videoconferencing software. Participants wore the device on their right wrist and right ankle for a series of movements, during a 6-min walking test and for a period of 24-h wear, including overnight. Participants also completed an ALSFRS-R and questionnaires on their experience with the devices. 80% of the participants found wearing these devices to be a positive experience and no one reported interference with daily living or added burden. However, 30% of the participants experienced technical issues with their devices. Data from the wearable devices correlated with established measures of physical function. [ABSTRACT FROM AUTHOR]

Purpose: To examine the differential effect of non- and anthracycline-based chemotherapy on fatigue over 12 months post-diagnosis among breast cancer survivors. Methods: This study is based on a prospective Wake Forest NCI Community Oncology Research Program (NCORP) multicenter cohort study (WF-97415) of women with stage I to III breast cancer and non-cancer controls. Analyses compared those: 1) receiving, or 2) not receiving anthracycline chemotherapy, 3) receiving aromatase inhibitors (AIs) without chemotherapy, with 4) a comparator group without a history of cancer. In-person clinic assessments were conducted at: baseline (prior to chemotherapy or start of AI therapy), and 3 and 12 months after baseline. The Functional Assessment of Chronic Illness Therapy-Fatigue scale was the primary outcome. Estimated least squares means by group using mixed models with a random subject effect, fixed effects of time and group, and the interaction between time and group was used to compare groups across time, controlling for age, comorbidities, and treatment variables. Results: Among 284 women (mean age = 53.4 years, sd 11.9 years), there was a significant (p < 0.0001) group by time interaction, with a sharp increase in fatigue at 3 months in the two chemotherapy groups in comparison to the non-chemotherapy and non-cancer controls. The two chemotherapy groups did not significantly differ in fatigue at any time point. Conclusion: Women with breast cancer who receive non- or anthracycline-based chemotherapy experience similar trends in and levels of fatigue within the first year of treatment and greater fatigue than women receiving AIs alone or women without breast cancer. [ABSTRACT FROM AUTHOR]

Clinical success with poly (ADP-ribose) polymerase inhibitors (PARPi) is impeded by inevitable resistance and associated cytotoxicity. Depletion of Amplified in Liver Cancer 1 (ALC1), a chromatin-remodeling enzyme, can overcome these limitations by hypersensitizing BReast CAncer genes 1/2 (BRCA1/2) mutant cells to PARPi. Here, we demonstrate that PARPi hypersensitivity upon ALC1 loss is reliant on its role in promoting the repair of chromatin buried abasic sites. We show that ALC1 enhances the ability of the abasic site processing enzyme, Apurinic/Apyrimidinic endonuclease 1 (APE1) to cleave nucleosome-occluded abasic sites. However, unrepaired abasic sites in ALC1-deficient cells are readily accessed by APE1 at the nucleosome-free replication forks. APE1 cleavage leads to fork breakage and trapping of PARP1/2 upon PARPi treatment, resulting in hypersensitivity. Collectively, our studies reveal how cells overcome the chromatin barrier to repair abasic lesions and uncover cleavage of abasic sites as a mechanism to overcome limitations of PARPi. Loss of Amplified in Liver Cancer 1 (ALC1) has been shown to confer PARP inhibitor hypersensitivity in BRCA-mutant cells. Here, the authors show that in ALC1-deficient BRCA-mutant cells, APE1 cleaves abasic sites at the forks resulting in DNA breaks and thereby enhances PARP inhibitor sensitivity. [ABSTRACT FROM AUTHOR]

The impacts of tropical cyclones (TCs) on Southeast Asia's coastlines are acute due to high population densities in low-lying coastal environments. However, the trajectories of TCs are uncertain in a warming climate. Here, we assess >64,000 simulated TCs from the nineteenth century to the end of the twenty-first century for both moderate- and high-emissions scenarios. Results suggest changes to TC trajectories in Southeast Asia, including: (1) poleward shifts in both genesis and peak intensification rates; (2) TC formation and fastest intensification closer to many coastlines; (3) increased likelihoods of TCs moving most slowly over mainland Southeast Asia; and (4) TC tracks persisting longer over land. In the cities of Hai Phong (Vietnam), Yangon (Myanmar), and Bangkok (Thailand), these variations result in future increases in both peak TC intensity and TC duration compared to historical TCs. [ABSTRACT FROM AUTHOR]

Genome-wide association studies (GWAS) are often underpowered due to small effect sizes of common single nucleotide polymorphisms (SNPs) on phenotypes and extreme multiple testing thresholds. The most common approach for increasing statistical power is to increase sample size. We propose an alternative strategy of redefining case-control outcomes into ordinal case-subthreshold-asymptomatic variables. While maintaining the clinical case threshold, we subdivide controls into two groups: individuals who are symptomatic but do not meet the clinical criteria for diagnosis (subthreshold) and individuals who are effectively asymptomatic. We conducted a simulation study to examine the impact of effect size, minor allele frequency, population prevalence, and the prevalence of the subthreshold group on statistical power to detect genetic associations in three scenarios: a standard case-control, an ordinal, and a case-asymptomatic control analysis. Our results suggest the ordinal model consistently provides the greatest statistical power while the case-control model the least. Power in the case-asymptomatic control model reflects the case-control or ordinal model depending on the population prevalence and size of the subthreshold category. We then analyzed a major depression phenotype from the UK Biobank to corroborate our simulation results. Overall, the ordinal model improves statistical power in GWAS consistent with increasing the sample size by approximately 10%. [ABSTRACT FROM AUTHOR]

Periodontitis affects billions of people worldwide. To address relationships of periodontal niche cell types and microbes in periodontitis, we generated an integrated single-cell RNA sequencing (scRNAseq) atlas of human periodontium (34-sample, 105918-cell), including sulcular and junctional keratinocytes (SK/JKs). SK/JKs displayed altered differentiation states and were enriched for effector cytokines in periodontitis. Single-cell metagenomics revealed 37 bacterial species with cell-specific tropism. Fluorescence in situ hybridization detected intracellular 16 S and mRNA signals of multiple species and correlated with SK/JK proinflammatory phenotypes in situ. Cell-cell communication analysis predicted keratinocyte-specific innate and adaptive immune interactions. Highly multiplexed immunofluorescence (33-antibody) revealed peri-epithelial immune foci, with innate cells often spatially constrained around JKs. Spatial phenotyping revealed immunosuppressed JK-microniches and SK-localized tertiary lymphoid structures in periodontitis. Here, we demonstrate impacts on and predicted interactomics of SK and JK cells in health and periodontitis, which requires further investigation to support precision periodontal interventions in states of chronic inflammation. Here, Easter et al. generate a single-cell atlas of human periodontium including sulcular and junctional keratinocytes. Cell-cell communication analysis is used to predict keratinocyte-specific immune cell interactions. [ABSTRACT FROM AUTHOR]

The impacts of thermal treatment on the precipitate morphology and oxidation behavior of a dual-phase (FCC + L12) multi-principal element alloy (MPEA), Ni45Co17Cr14Fe12Al7Ti5, was studied at 1000 °C via isothermal and cyclic testing. Thermogravimetric analysis and subsequent characterization revealed that smaller precipitates had an increased capacity to form protective sub-surface oxide layers which mitigated total mass gain. The smaller-precipitate-containing samples exhibited a decrease in thickness of the primary Cr2O3 scale and parabolic growth rate. Mechanistically this behavior is believed to stem from the increased growth rate of initial Al2O3 nuclei and decreased inter-precipitate spacing which results in faster lateral diffusion and agglomeration. [ABSTRACT FROM AUTHOR]

People's lived experiences of distress are complex, personal, and vary widely across cultures. So, too, do the terms and expressions people use to describe distress. This variation presents an engaging challenge for those doing intercultural work in transcultural psychiatry, global mental health, and psychological anthropology. This article details the findings of a study of common distress terminology among 63 Kannada-speaking Hindu women living in Mysuru, the second largest city in the state of Karnataka, South India. Very little existing scholarship focuses on cultural adaptation for speakers of Dravidian languages like Kannada; this study aims to fill this gap and support greater representation of this linguistic family in research on mental health, idioms of distress, and distress terminology. Between 2018 and 2019, we conducted a 3-phase study consisting of interviews, data reduction, and focus group discussions. The goal was to produce a non-exhaustive list of common Kannada distress terms that could be used in future research and practice to translate and culturally adapt mental health symptom scales or other global mental health tools. [ABSTRACT FROM AUTHOR]

The Periptychidae, an extinct group of archaic ungulates (‘condylarths’), were the most speciose eutherian mammals in the earliest Paleocene of North America, epitomizing mammalian ascendency after the Cretaceous–Paleogene (K–Pg) mass extinction. Although periptychids are mostly known from fragmentary gnathic remains, the Corral Bluffs area within the Denver Basin, Colorado, has yielded numerous exceptionally well-preserved mammalian fossils, including periptychids, from the earliest Paleocene. Here we describe a partial cranium and articulated dentaries plus an additional unassociated dentary fragment of a small-bodied (~273–455 g) periptychid from ca. 610 thousand years after the K–Pg mass extinction (Puercan 2 North American Land Mammal ‘age’) at Corral Bluffs. Based on these new fossils we erect Militocodon lydae gen. et sp. nov. The dentition of M. lydae exhibits synapomorphies that diagnose the Conacodontinae, but it is plesiomorphic relative to Oxyacodon, resembling putatively basal periptychids like Mimatuta and Maiorana in several dental traits. As such, we interpret M. lydae as a basal conacodontine. Its skull anatomy does not reveal clear periptychid synapomorphies and instead resembles that of arctocyonids and other primitive eutherians. M. lydae falls along a dental morphocline from basal periptychids to derived conacodontines, which we hypothesize reflects a progressive, novel modification of the hypocone to enhance orthal shearing and crushing rather than grinding mastication. The discovery and thorough descriptions and comparisons of the partial M. lydae skull represent an important step toward unraveling the complex evolutionary history of periptychid mammals. [ABSTRACT FROM AUTHOR]

Purpose: Although traumatic rhabdomyolysis (TR) is shown to be associated with acute kidney injury (AKI), there are no large prospective epidemiological studies, interventional trials, official guidelines outlining the appropriate investigation, monitoring, and treatment on this poorly understood condition. We aimed to establish the contemporary epidemiology and describe current practices for TR to power future higher quality studies. We hypothesised that investigation and monitoring occur in an ad hoc fashion. Material and methods: We conducted a 1-year retrospective cohort study of all patients > 16 years of age, with an ISS > 12 and, admitted to a level 1 trauma centre. Demographics, initial vital signs, admission laboratory values, and daily creatinine kinase (CK) values were collected. The primary outcome was TR (defined by CK > 5000 IU), secondary outcomes included AKI (KDIGO criteria), mortality, multiple organ failure, length of stay, and need for renal replacement therapy (RRT). Results: 586 patients met inclusion criteria and 15 patients (2.56%) developed TR. CK testing occurred in 78 (13.1%) patients with 29 (37.7%) of these having values followed until downtrending. AKI occurred in 63 (10.8%) patients within the entire study population. Among those with TR, nine (60%) patients developed AKI. Patients with TR had higher ISS (median 29 vs 18) and mortality (26.7% vs 8.9%). Discussion: Whilst TR appears rare without liberal screening, it is strongly associated with AKI. Given the poor outcomes, standardised monitoring, and liberal testing of CK could be justified in trauma patients with higher injury severity. This epidemiological data can help to define study populations and power future multicentre prospective studies on this infrequent yet morbid condition. [ABSTRACT FROM AUTHOR]

Objective: To better understand the current state of musculoskeletal fellowship program directors and identify opportunities for formal training that could increase job satisfaction, provide a broader knowledge base for mentoring/advising trainees and increase diversity in musculoskeletal radiology. Materials and methods: Eighty-one fellowship program directors who signed the Fellowship Match Memorandum of Understanding with the Society of Skeletal Radiology were sent a survey with questions about demographics, career, background, and training both for musculoskeletal radiology and for the fellowship director role. Results: A 57/81 (70%) of program directors responded, representing 27 different states with a range of 1–9 fellowship positions. Nearly half are in their forties (48%) with most identifying as White (67%) followed by Asian (30%). The majority are male (72%) with over half (60%) remaining at the institution where they completed prior training. Over half plan to change roles within 5 years and do not feel adequately compensated. Top qualities/skills identified as important for the role include effective communication, being approachable, and clinical excellence. Other than clinical excellence, most do not report formal training in skills identified as important for the role. Conclusions: Given the high amount of interaction with trainees, program directors play a key role in the future of our subspecialty. The low diversity among this group, the lack of formal training, and the fact that most do not feel adequately compensated could limit mentorship and recruitment. Program directors identified effective communication, organizational/planning skills, and conflict resolution as the top skills they would benefit from formal training. [ABSTRACT FROM AUTHOR]

This study explored school psychologists' practices in the areas of developing behavior intervention plans (BIPs), conducting functional behavior assessments (FBAs), and behavioral consultation. Practitioners were asked to rate their level of confidence in the implementation with fidelity of the last BIP they developed. Relationships between these practices and school psychologists' confidence levels were examined. Data were collected from a national sample of practitioners (n = 179). Overall, results suggest that school district supports, being mindful of potential barriers to implementation, certain components of the FBA process, and adhering to best practices in behavioral consultation can have substantial positive impacts on a school psychologist's confidence in the treatment integrity and maintenance of BIPs over time. Implications for practice are discussed. [ABSTRACT FROM AUTHOR]

Interleukin 22 (IL-22) has a non-redundant role in immune defence of the intestinal barrier1–3. T cells, but not innate lymphoid cells, have an indispensable role in sustaining the IL-22 signalling that is required for the protection of colonic crypts against invasion during infection by the enteropathogen Citrobacter rodentium4 (Cr). However, the intestinal epithelial cell (IEC) subsets targeted by T cell-derived IL-22, and how T cell-derived IL-22 sustains activation in IECs, remain undefined. Here we identify a subset of absorptive IECs in the mid–distal colon that are specifically targeted by Cr and are differentially responsive to IL-22 signalling. Major histocompatibility complex class II (MHCII) expression by these colonocytes was required to elicit sustained IL-22 signalling from Cr-specific T cells, which was required to restrain Cr invasion. Our findings explain the basis for the regionalization of the host response to Cr and demonstrate that epithelial cells must elicit MHCII-dependent help from IL-22–producing T cells to orchestrate immune protection in the intestine.The murine enteropathogen Citrobacter rodentium targets a specific subset of absorptive intestinal epithelial cells in the mid–distal colon, which stimulate T cells to produce sustained IL-22 signals to mitigate further spread of the pathogen. [ABSTRACT FROM AUTHOR]

Previously, we demonstrated that prebiotics may provide a complementary strategy for increasing calcium (Ca) absorption in adolescents which may improve long-term bone health. However, not all children responded to prebiotic intervention. We determine if certain baseline characteristics of gut microbiome composition predict prebiotic responsiveness. In this secondary analysis, we compared differences in relative microbiota taxa abundance between responders (greater than or equal to 3% increase in Ca absorption) and non-responders (less than 3% increase). Dual stable isotope methodologies were used to assess fractional Ca absorption at the end of crossover treatments with placebo, 10, and 20 g/day of soluble corn fiber (SCF). Microbial DNA was obtained from stool samples collected before and after each intervention. Sequencing of the 16S rRNA gene was used to taxonomically characterize the gut microbiome. Machine learning techniques were used to build a predictive model for identifying responders based on baseline relative taxa abundances. Model output was used to infer which features contributed most to prediction accuracy. We identified 19 microbial features out of the 221 observed that predicted responsiveness with 96.0% average accuracy. The results suggest a simplified prescreening can be performed to determine if a subject's bone health may benefit from a prebiotic. Additionally, the findings provide insight and prompt further investigation into the metabolic and genetic underpinnings affecting calcium absorption during pubertal bone development. [ABSTRACT FROM AUTHOR]

Summary: Non-pharmacological therapies, such as whole-food interventions, are gaining interest as potential approaches to prevent and/or treat low bone mineral density (BMD) in postmenopausal women. Previously, prune consumption preserved two-dimensional BMD at the total hip. Here we demonstrate that prune consumption preserved three-dimensional BMD and estimated strength at the tibia. Purpose: Dietary consumption of prunes has favorable impacts on areal bone mineral density (aBMD); however, more research is necessary to understand the influence on volumetric BMD (vBMD), bone geometry, and estimated bone strength. Methods: This investigation was a single center, parallel arm 12-month randomized controlled trial (RCT; NCT02822378) to evaluate the effects of 50 g and 100 g of prunes vs. a Control group on vBMD, bone geometry, and estimated strength of the radius and tibia via peripheral quantitative computed tomography (pQCT) in postmenopausal women. Women (age 62.1 ± 5.0yrs) were randomized into Control (n = 78), 50 g Prune (n = 79), or 100 g Prune (n = 78) groups. General linear mixed effects (LME) modeling was used to assess changes over time and percent change from baseline was compared between groups. Results: The most notable effects were observed at the 14% diaphyseal tibia in the Pooled (50 g + 100 g) Prune group, in which group × time interactions were observed for cortical vBMD (p = 0.012) and estimated bone strength (SSI; p = 0.024); all of which decreased in the Control vs. no change in the Pooled Prune group from baseline to 12 months/post. Conclusion: Prune consumption for 12 months preserved cortical bone structure and estimated bone strength at the weight-bearing tibia in postmenopausal women. [ABSTRACT FROM AUTHOR]

Background: Scalp cooling is an increasingly recognized non-pharmacologic approach to minimize chemotherapy-induced alopecia (CIA). Several commercially available machine-based and manual scalp cooling systems are available; however, literature reports of effectiveness are highly variable. The purpose of this study was to determine real-world tolerability and subjective effectiveness of a manual cold capping system in minimizing CIA across a variety of patient race and hair types. This study was a single-institution review of outcomes from manual cold capping. Methods: We identified retrospective cohort of adult patients who presented to discuss cold capping between January 14, 2019, and March 31, 2022. Data collected from medical records included demographics, decision to pursue/continue cold capping, diagnoses, chemotherapy regimens, hair characteristics (length, thickness, coarseness, type), and subjective perception of percentage of hair retained. Those with successful vs. unsuccessful cold capping (≥ 50% vs. < 50% of hair retained) were compared based on the patient-level factors of interest. Findings: A total of 100 patients initiated cold capping during the study period, and 95% of them completed cold capping. The majority of patients who started cold capping completed it. The median-reported percentage of hair maintained was 75%, and 82/89 (92.1% of patients) had favorable results, defined as ≥ 50% of hair retained. The only patient-level factor associated with favorable response was chemotherapy regimen, with fewer patients receiving doxorubicin-containing regimens having successful hair retention compared to other chemotherapy types (71.4% successful results vs. 95.7% for those receiving paclitaxel-containing regimens and 96.6% for those receiving docetaxel-containing regimens (p = 0.018). There was no difference in success based on patient race/ethnicity or hair characteristics. Interpretation: The overall effectiveness (92.1%) in this study is consistent to higher than many literature reports. One possible reason for the high success in our cohort is compliance with cold capping protocols, meaning applying the cap in the appropriate manner and wearing the cap for the prescribed durations, which may impact effectiveness. [ABSTRACT FROM AUTHOR]

Early JWST observations have uncovered a population of red sources that might represent a previously overlooked phase of supermassive black hole growth1–3. One of the most intriguing examples is an extremely red, point-like object that was found to be triply imaged by the strong lensing cluster Abell 2744 (ref. 4). Here we present deep JWST/NIRSpec observations of this object, Abell2744-QSO1. The spectroscopy confirms that the three images are of the same object, and that it is a highly reddened (AV ≃ 3) broad emission line active galactic nucleus at a redshift of zspec = 7.0451 ± 0.0005. From the width of Hβ (full width at half-maximum = 2,800 ± 250 km s−1), we derive a black hole mass of M BH = 4 − 1 + 2 × 1 0 7 M ⊙ . We infer a very high ratio of black-hole-to-galaxy mass of at least 3%, an order of magnitude more than that seen in local galaxies5 and possibly as high as 100%. The lack of strong metal lines in the spectrum together with the high bolometric luminosity (Lbol = (1.1 ± 0.3) × 1045 erg s−1) indicate that we are seeing the black hole in a phase of rapid growth, accreting at 30% of the Eddington limit. The rapid growth and high black-hole-to-galaxy mass ratio of Abell2744-QSO1 suggest that it may represent the missing link between black hole seeds6 and one of the first luminous quasars7.JWST/NIRSpec observations of Abell2744-QSO1 show a high black-hole-to-host mass ratio in the early Universe, which indicates that we are seeing the black hole in a phase of rapid growth, accreting at 30% of the Eddington limit. [ABSTRACT FROM AUTHOR]

Targeted protein degradation is an emerging strategy for the elimination of classically undruggable proteins. Here, to expand the landscape of targetable substrates, we designed degraders that achieve substrate selectivity via recognition of a discrete peptide and glycan motif and achieve cell-type selectivity via antigen-driven cell-surface binding. We applied this approach to mucins, O-glycosylated proteins that drive cancer progression through biophysical and immunological mechanisms. Engineering of a bacterial mucin-selective protease yielded a variant for fusion to a cancer antigen-binding nanobody. The resulting conjugate selectively degraded mucins on cancer cells, promoted cell death in culture models of mucin-driven growth and survival, and reduced tumor growth in mouse models of breast cancer progression. This work establishes a blueprint for the development of biologics that degrade specific protein glycoforms on target cells. Targeted protein degradation of cell-surface glycoproteins suppresses cancer in mice. [ABSTRACT FROM AUTHOR]

Purpose: As narrative medicine interventions are integrated increasingly into medical practice, growing evidence indicates benefits for healthcare professionals. Presently, the prevalence and impact of narrative medicine interventions in the field of oncology remain unknown. This systematic review synthesizes published data on narrative medicine interventions in oncology and reports current knowledge on feasibility, acceptability, and impact on cancer care professionals. Methods: Following PRISMA guidelines, we searched Ovid Medline, Embase, Scopus, Web of Science, Cochrane, and ClinicalTrials.gov databases from inception through February 2024. Eligible articles were published in English and contained original data on feasibility, acceptability, and/or impact of a narrative medicine intervention for oncology professionals. Database searches identified 2614 deduplicated articles, from which 50 articles were identified for full-text assessment and 11 articles met inclusion criteria. Two additional articles were identified through manual review of references. Results: Thirteen articles described 12 unique narrative medicine interventions targeting cancer care professionals. All studies described their respective interventions as feasible, acceptable, and impactful for participants. Interventions involved writing, reading, reflection, and other narrative-based strategies. Standardized validated tools evaluated outcomes including burnout, empathy expression, secondary trauma, quality of humanistic care, and well-being. Participants reported appreciation of opportunities for reflection, perspective sharing, and bearing witness, which they perceived to strengthen wellness and community. Conclusion: Narrative medicine interventions are feasible and acceptable and may bolster oncology clinicians’ functioning across domains. Multi-site, prospective, randomized studies are needed to investigate the broader impact of narrative medicine interventions and advance the science of narrative medicine in oncology. Trial registration: ClinicalTrials.gov Identifier: CRD42022369432 [ABSTRACT FROM AUTHOR]

Liver diseases, including NAFLD, are a growing worldwide health concern. Currently, there is a lack of suitable in vitro models that sustain basic primary human hepatocyte (PHH) morphology and functionality while supporting presentation of disease-associated phenotypic characteristics such as lipid accumulation and inflammasome activation. In TruVivo, an all-human triculture system (hTCS), basic metabolic functions were characterized in PHHs isolated from normal or diseased livers during two-weeks of culture. Decreases in albumin and urea levels and CYP3A4 activity were seen in diseased-origin PHHs compared to normal PHHs along with higher CYP2E1 expression. Positive expression of the macrophage markers CD68 and CD163 were seen in the diseased PHH preparations. Elevated levels of the pro-inflammatory cytokines IL-6 and MCP-1 and the fibrotic markers CK-18 and TGF-β were also measured. Gene expression of FASN, PCK1, and G6PC in the diseased PHHs was decreased compared to the normal PHHs. Further characterization revealed differences in lipogenesis and accumulation of intracellular lipids in normal and diseased PHHs when cultured with oleic acid and high glucose. TruVivo represents a promising new platform to study lipogenic mechanisms in normal and diseased populations due to the preservation of phenotypic differences over a prolonged culture period. [ABSTRACT FROM AUTHOR]

For students with severe or complex challenging behavior, incorporating hypothesis testing as a component of functional behavior assessment (FBA) is often warranted. Several hypothesis testing strategies (i.e., functional analysis, antecedent analysis, concurrent operant analysis) can confirm whether and how features of a student's environment impact their behavior to then inform effective intervention. Yet practitioners have limited guidance on how to select and individualize best-fit strategies for a given student and context. We developed a decision tool for behavior specialists and classroom teachers to collaboratively plan and implement individualized hypothesis testing strategies for students whose initial FBA was inconclusive. We piloted this tool with 12 practitioner teams and students, aiming to (a) identify which assessment strategies were indicated based on practitioner responses; (b) evaluate whether indicated assessments produced conclusive results; and (c) explore practitioner perceptions of the individualized assessment process. The most commonly indicated hypothesis testing strategy was functional analysis. Across teams, one or more hypothesis was successfully confirmed on the first or second assessment iteration. The assessment process was perceived positively by practitioners. Yet they reported feeling ill-equipped to complete the process independently, highlighting important next steps for training and technical assistance work. [ABSTRACT FROM AUTHOR]

Additive manufacturing brings inspection issues for quality assurance of final parts because non-destructive testing methods are faced with shape complexity, size, and high surface roughness. Thus, to drive additive manufacturing forward, advanced non-destructive testing methods are required. Methods based on resonant ultrasound spectroscopy (RUS) can take on all the challenges that come with additive manufacturing. Indeed, these full body inspection methods are adapted to shape complexity, to nearly any size, and to high degrees of surface roughness. Furthermore, they are easy to implement, fast and low cost. In this paper, we present the benefit of a resonant ultrasound spectroscopy method, combined with a statistical analysis through Z score implementation, to classify supposedly identical parts, from a batch comprised of several individual builds. We also demonstrate that the inspection can be further accelerated and automated, to make the analysis operator independent, whether the analysis of the resonant ultrasound spectroscopy data is performed supervised or unsupervised with machine learning algorithms. [ABSTRACT FROM AUTHOR]

MVA-based monovalent eastern equine encephalitis virus (MVA-BN-EEEV) and multivalent western, eastern, and Venezuelan equine encephalitis virus (MVA-BN-WEV) vaccines were evaluated in the cynomolgus macaque aerosol model of EEEV infection. Macaques vaccinated with two doses of 5 × 108 infectious units of the MVA-BN-EEEV or MVA-BN-WEV vaccine by the intramuscular route rapidly developed robust levels of neutralizing antibodies to EEEV that persisted at high levels until challenge at day 84 via small particle aerosol delivery with a target inhaled dose of 107 PFU of EEEV FL93-939. Robust protection was observed, with 7/8 animals receiving MVA-BN-EEEV and 100% (8/8) animals receiving MVA-BN-WEV surviving while only 2/8 mock vaccinated controls survived lethal challenge. Complete protection from viremia was afforded by both vaccines, with near complete protection from vRNA loads in tissues and any pathologic evidence of central nervous system damage. Overall, the results indicate both vaccines are effective in eliciting an immune response that is consistent with protection from aerosolized EEEV-induced disease. [ABSTRACT FROM AUTHOR]

The identification of sources driving cosmic reionization, a major phase transition from neutral hydrogen to ionized plasma around 600–800 Myr after the Big Bang1–3, has been a matter of debate4. Some models suggest that high ionizing emissivity and escape fractions (fesc) from quasars support their role in driving cosmic reionization5,6. Others propose that the high fesc values from bright galaxies generate sufficient ionizing radiation to drive this process7. Finally, a few studies suggest that the number density of faint galaxies, when combined with a stellar-mass-dependent model of ionizing efficiency and fesc, can effectively dominate cosmic reionization8,9. However, so far, comprehensive spectroscopic studies of low-mass galaxies have not been done because of their extreme faintness. Here we report an analysis of eight ultra-faint galaxies (in a very small field) during the epoch of reionization with absolute magnitudes between MUV ≈ −17 mag and −15 mag (down to 0.005L⋆ (refs. 10,11)). We find that faint galaxies during the first thousand million years of the Universe produce ionizing photons with log[ξion (Hz erg−1)] = 25.80 ± 0.14, a factor of 4 higher than commonly assumed values12. If this field is representative of the large-scale distribution of faint galaxies, the rate of ionizing photons exceeds that needed for reionization, even for escape fractions of the order of 5%. An analysis of eight ultra-faint galaxies during the epoch of reionization with absolute magnitudes between −17 mag and −15 mag shows that most of the photons that reionized the Universe come from dwarf galaxies. [ABSTRACT FROM AUTHOR]