Factorial invariance of the Wechsler Intelligence Scale for Children, Fifth Edition, across the UK, US and Australia & New Zealand.

OBJECTIVES: This study examined the factorial invariance of the factor structure of the Wechsler Intelligence Scale for Children, Fifth Edition (WISC-V) across the UK, US and Australia & New Zealand (A&NZ). The factorial equivalence of cognitive assessments should be demonstrated before assuming cross-culture generalizability and interpretations of score comparisons. METHODS: Data were obtained from the UK, US and A&NZ normative standardizations of the WISC-V. The samples consisted of 415 UK, 2200 US and 528 A&NZ children, aged 6-16. Confirmatory factor analysis was applied separately in each sample to establish the baseline model. Next, tests of factorial invariance were undertaken using the recommended hierarchical approach, firstly across the UK and A&NZ samples and then across the UK and US samples. RESULTS: The five-factor first-order scoring model was found to be excellent fit across all three samples independently. Strict factorial invariance of the WISC-V was demonstrated firstly across the UK and A&NZ and secondly the UK and US nationally representative standardization samples. Comparison of latent means found small but significant differences in female children across the UK and A&NZ samples. CONCLUSIONS: Consistent with previous research, these results demonstrate the generality of the WISC-V factor structure across the UK, US and A&NZ. Furthermore, as the WISC-V factor structure aligns with the Cattell-Horn-Carroll (CHC) model of cognitive abilities, the results add further support to the cross-cultural generalizability of the CHC model. Small but significant differences in latent factor scores found across samples support the development and use of local normative data.

Outcomes of Home Emergency Physical Readiness Education for Older Adults.

Emergency preparedness initiatives are a Medicare condition of participation in home healthcare, yet limited evidence on the impact of associated programming is available. The purpose of this exploratory pilot study was to examine the outcomes of an individualized emergency preparedness educational program provided by a physical therapist (PT) in the homes of older adults. The investigators recruited older adults (n = 30) using convenience sampling. An emergency preparedness education module was developed. Demographics, functional and environmental outcome measures, a pre- and post-education confidence survey, and learning outcomes were ascertained and analyzed. Participants reported being female (n = 23), 70 to 79 years (n = 15), and 19 individuals reported 35 different lifetime emergency events. Hearing and vision impairments, inability to change a battery or navigate stairs, and environmental deficits including clutter and poor lighting were identified. Closing bedroom doors at nighttime, functioning carbon monoxide and smoke detectors, creating an evacuation plan, and assembling first aid kits were learning outcomes. Trends toward increased confidence were identified, with statistically significant improvements in the ability to respond to a fire (P = .01), a heat wave (P = .03), and to crawl on hands and knees (P = .05) identified. This study provides emerging evidence that PTs have a role in improving an older adult's confidence to prepare for and respond to an emergency event.

Metatranscriptomic Analysis Reveals Synergistic Activities of Comammox and Anammox Bacteria in Full-Scale Attached Growth Nitrogen Removal System.

Leveraging comammox Nitrospira and anammox bacteria for shortcut nitrogen removal can drastically lower the carbon footprint of wastewater treatment facilities by decreasing aeration energy, carbon, alkalinity, and tank volume requirements while also potentially reducing nitrous oxide emissions. However, their co-occurrence as dominant nitrifying bacteria is rarely reported in full-scale wastewater treatment. As a result, there is a poor understanding of how operational parameters, in particular, dissolved oxygen, impact their activity and synergistic behavior. Here, we report the impact of dissolved oxygen concentration (DO = 2, 4, 6 mg/L) on the microbial community's transcriptomic expression in a full-scale integrated fixed film activated sludge (IFAS) municipal wastewater treatment facility where nitrogen removal is predominantly performed by comammox Nitrospira and anammox bacterial populations. 16S rRNA transcript compositions revealed anammox bacteria and Nitrospira were significantly more active in IFAS biofilms compared to suspended sludge biomass. In IFAS biofilms, anammox bacteria significantly increased hzo expression at lower dissolved oxygen concentrations and this increase was highly correlated with the amoA expression levels of comammox bacteria. Interestingly, the genes involved in nitrite oxidation by comammox bacteria were significantly more upregulated, relative to the genes involved in ammonia oxidation with decreasing dissolved oxygen concentrations. Ultimately, our findings suggest that comammox Nitrospira supplies anammox bacteria with nitrite via ammonia oxidation and that this synergistic behavior is dependent on dissolved oxygen concentrations.

COVID-19 and silent hypoxemia in a minimal closed-loop model of the respiratory rhythm generator.

Silent hypoxemia, or "happy hypoxia," is a puzzling phenomenon in which patients who have contracted COVID-19 exhibit very low oxygen saturation ( SaO 2 < 80%) but do not experience discomfort in breathing. The mechanism by which this blunted response to hypoxia occurs is unknown. We have previously shown that a computational model of the respiratory neural network (Diekman et al. in J Neurophysiol 118(4):2194-2215, 2017) can be used to test hypotheses focused on changes in chemosensory inputs to the central pattern generator (CPG). We hypothesize that altered chemosensory function at the level of the carotid bodies and/or the nucleus tractus solitarii are responsible for the blunted response to hypoxia. Here, we use our model to explore this hypothesis by altering the properties of the gain function representing oxygen sensing inputs to the CPG. We then vary other parameters in the model and show that oxygen carrying capacity is the most salient factor for producing silent hypoxemia. We call for clinicians to measure hematocrit as a clinical index of altered physiology in response to COVID-19 infection.

Safe Fall Recovery Education for Older Adults.

High fall rates among older adults in combination with prolonged time on the floor after a fall have created an urgent need to preventatively address fall recovery strategies. The purpose of this study is to describe the outcomes of a novel safe fall recovery (SFR) educational module provided by physical therapists to older adults in their homes. A pre- and post-test descriptive study used a convenience sample to recruit 30 adults (≥65 years). A baseline assessment and SFR in-home education were provided. Pre- and post-education measures included the Steps for Safe Fall Recovery (Steps for SFR) tool, the Activity Specific Balance Confidence (ABC) scale, and a fall confidence survey. The Wilcoxon matched-pairs signed-rank test determined significance (P < .05). Participants were age 77.2 (6.8) years and 20 females. Eight reported a fall during the prior year. Statistically significant improvements were identified in the Steps to SFR tool (P = .001), the ABC scale (P = .004), and the fall recovery confidence survey (P = .001). Integration of an SFR educational intervention delivered to an older adult population in their home demonstrated improved safety and confidence to recover from a fall.

Characteristics of healthcare personnel with SARS-CoV-2 infection: 10 emerging infections program sites in the United States, April 2020-December 2021.

BACKGROUND: Understanding characteristics of healthcare personnel (HCP) with SARS-CoV-2 infection supports the development and prioritization of interventions to protect this important workforce. We report detailed characteristics of HCP who tested positive for SARS-CoV-2 from April 20, 2020 through December 31, 2021. METHODS: CDC collaborated with Emerging Infections Program sites in 10 states to interview HCP with SARS-CoV-2 infection (case-HCP) about their demographics, underlying medical conditions, healthcare roles, exposures, personal protective equipment (PPE) use, and COVID-19 vaccination status. We grouped case-HCP by healthcare role. To describe residential social vulnerability, we merged geocoded HCP residential addresses with CDC/ATSDR Social Vulnerability Index (SVI) values at the census tract level. We defined highest and lowest SVI quartiles as high and low social vulnerability, respectively. RESULTS: Our analysis included 7,531 case-HCP. Most case-HCP with roles as certified nursing assistant (CNA) (444, 61.3%), medical assistant (252, 65.3%), or home healthcare worker (HHW) (225, 59.5%) reported their race and ethnicity as either non-Hispanic Black or Hispanic. More than one third of HHWs (166, 45.2%), CNAs (283, 41.7%), and medical assistants (138, 37.9%) reported a residential address in the high social vulnerability category. The proportion of case-HCP who reported using recommended PPE at all times when caring for patients with COVID-19 was lowest among HHWs compared with other roles. CONCLUSIONS: To mitigate SARS-CoV-2 infection risk in healthcare settings, infection prevention, and control interventions should be specific to HCP roles and educational backgrounds. Additional interventions are needed to address high social vulnerability among HHWs, CNAs, and medical assistants.

Quantum simulation of the bosonic Kitaev chain.

Superconducting quantum circuits are a natural platform for quantum simulations of a wide variety of important lattice models describing topological phenomena, spanning condensed matter and high-energy physics. One such model is the bosonic analog of the well-known fermionic Kitaev chain, a 1D tight-binding model with both nearest-neighbor hopping and pairing terms. Despite being fully Hermitian, the bosonic Kitaev chain exhibits a number of striking features associated with non-Hermitian systems, including chiral transport and a dramatic sensitivity to boundary conditions known as the non-Hermitian skin effect. Here, using a multimode superconducting parametric cavity, we implement the bosonic Kitaev chain in synthetic dimensions. The lattice sites are mapped to frequency modes of the cavity, and the in situ tunable complex hopping and pairing terms are created by parametric pumping at the mode-difference and mode-sum frequencies, respectively. We experimentally demonstrate important precursors of nontrivial topology and the non-Hermitian skin effect in the bosonic Kitaev chain, including chiral transport, quadrature wavefunction localization, and sensitivity to boundary conditions. Our experiment is an important first step towards exploring genuine many-body non-Hermitian quantum dynamics.

Characteristics of Patients With Initial Clostridioides difficile Infection (CDI) That Are Associated With Increased Risk of Multiple CDI Recurrences.

Background: Because interventions are available to prevent further recurrence in patients with recurrent Clostridioides difficile infection (rCDI), we identified predictors of multiple rCDI (mrCDI) in adults at the time of presentation with initial CDI (iCDI). Methods: iCDI was defined as a positive C difficile test in any clinical setting during January 2018-August 2019 in a person aged ≥18 years with no known prior positive test. rCDI was defined as a positive test ≥14 days from the previous positive test within 180 days after iCDI; mrCDI was defined as ≥2 rCDI. We performed multivariable logistic regression analysis. Results: Of 18 829 patients with iCDI, 882 (4.7%) had mrCDI; 437 with mrCDI and 7484 without mrCDI had full chart reviews. A higher proportion of patients with mrCDI than without mrCDI were aged ≥65 years (57.2% vs 40.7%; P < .0001) and had healthcare (59.1% vs 46.9%; P < .0001) and antibiotic (77.3% vs 67.3%; P < .0001) exposures in the 12 weeks preceding iCDI. In multivariable analysis, age ≥65 years (adjusted odds ratio [aOR], 1.91; 95% confidence interval [CI], 1.55-2.35), chronic hemodialysis (aOR, 2.28; 95% CI, 1.48-3.51), hospitalization (aOR, 1.64; 95% CI, 1.33-2.01), and nitrofurantoin use (aOR, 1.95; 95% CI, 1.18-3.23) in the 12 weeks preceding iCDI were associated with mrCDI. Conclusions: Patients with iCDI who are older, on hemodialysis, or had recent hospitalization or nitrofurantoin use had increased risk of mrCDI and may benefit from early use of adjunctive therapy to prevent mrCDI. If confirmed, these findings could aid in clinical decision making and interventional study designs.

Septic Arthritis of the Sternoclavicular Joint.

Introduction: Sternoclavicular joint (SCJ) septic arthritis is a rare but rapidly fatal joint infection. Without proper medical or surgical management, it can progress to osteomyelitis, chest wall abscess, mediastinitis, or myositis. Case Report: A 57-year-old male with a past history of intravenous drug use presented to the emergency department (ED) with chest tenderness of one week duration. Vital signs were unremarkable, and exam was notable for tender, raised right SCJ without any fluctuance. On point-of-care ultrasound we noted fluid collection and capsular distention along the SCJ, which aided in rapidly diagnosing septic arthritis. The patient was immediately started on antibiotics and taken to the operating room for excision and debridement. Conclusion: While computed tomography is routinely used in the emergency department for diagnosing septic arthritis, ultrasound offers a rapid and safe alternative for diagnosis.

Recombination in bdelloid rotifer genomes: asexuality, transfer and stress.

Bdelloid rotifers constitute a class of microscopic animals living in freshwater habitats worldwide. Several strange features of bdelloids have drawn attention: their ability to tolerate desiccation and other stresses, a lack of reported males across the clade despite centuries of study, and unusually high numbers of horizontally acquired, non-metazoan genes. Genome sequencing is transforming our understanding of their lifestyle and its consequences, while in turn providing wider insights about recombination and genome organisation in animals. Many questions remain, not least how to reconcile apparent genomic signatures of sex with the continued absence of reported males, why bdelloids have so many horizontally acquired genes, and how their remarkable ability to survive stress interacts with recombination and other genomic processes.

Vector integration and fate in the hemophilia dog liver multiple years after AAV-FVIII gene transfer.

ABSTRACT: Gene therapy using adeno-associated virus (AAV) vectors is a promising approach for the treatment of monogenic disorders. Long-term multiyear transgene expression has been demonstrated in animal models and clinical studies. Nevertheless, uncertainties remain concerning the nature of AAV vector persistence and whether there is a potential for genotoxicity. Here, we describe the mechanisms of AAV vector persistence in the liver of a severe hemophilia A dog model (male = 4, hemizygous; and female = 4, homozygous), more than a decade after portal vein delivery. The predominant vector form was nonintegrated episomal structures with levels correlating with long-term transgene expression. Random integration was seen in all samples (median frequency, 9.3e-4 sites per cell), with small numbers of nonrandom common integration sites associated with open chromatin. No full-length integrated vectors were found, supporting predominant episomal vector-mediated long-term transgene expression. Despite integration, this was not associated with oncogene upregulation or histopathological evidence of tumorigenesis. These findings support the long-term safety of this therapeutic modality.

What is the Long-term Wear of a 5-Mrad Highly Crosslinked Polyethylene Liner? A 14-year RSA Study.

BACKGROUND: Lower doses of irradiation (≤ 5 Mrad) during the manufacture of highly crosslinked polyethylene acetabular liners may result in less crosslinking and an increased wear rate. Radiostereometric analysis (RSA) studies have found that wear of more highly irradiated highly crosslinked polyethylene liners (7 to 10 Mrad) decreases at longer-term follow-up compared with earlier reports of the same cohorts. Although wear of 5-Mrad irradiated liners appears to increase at midterm follow-up, it is unclear whether that remains true at longer follow-up. QUESTIONS/PURPOSES: We asked: (1) In patients who underwent THA with a 5-Mrad highly crosslinked polyethylene liner, what is the wear rate evaluated with RSA during the first 14 years? (2) Does the wear rate decrease after 6 years in situ? METHODS: This is a brief follow-up of prior RSA studies performed at 2 and 6 years. We prospectively reviewed the longer-term wear rate in 13 patients who underwent primary THAs with the same design of a 5-MRad irradiated crosslinked acetabular liner and a 28-mm cobalt-chromium articulation. Of the initial 30 patients who were enrolled, 13 (43%) were available at the 14-year timepoint; nine patients had died, 1 patient had withdrawn, 1 had an intraoperative fracture, 3 patients were too infirm to have radiographs, 2 had no baseline RSA radiographs, and 1 had poor-quality RSA images. Tantalum markers were inserted during surgery, and all patients had RSA radiographic examinations at 1 week, 6 months, and 1, 2, 6, and 14 years postoperatively. RESULTS: The mean ± standard deviation proximal, 2D, and 3D wear rates calculated between 1 year and 14 years were 0.019 ± 0.013 mm, 0.022 ± 0.015 mm, and 0.025 ± 0.019 mm per year, respectively. No patient had proximal 2D or 3D wear rates exceeding 0.06 mm per year. An increasing wear rate over time was measured for proximal and 2D wear rates between 6 and 14 years (0.024 and 0.030 mm per year) compared with that between 1 and 6 years (0.008 and 0.010 mm per year; p = 0.03). CONCLUSION: The proximal, 2D, and 3D wear of a highly crosslinked polyethylene liner produced using 5-Mrad radiation remains low in the longer-term. With the small numbers available in a long-term RSA study such as this, we confirmed that the wear rate did not decrease at longer-term follow-up, unlike previous RSA studies of more highly irradiated highly crosslinked polyethylene liners. Nevertheless, the wear rate remains very low and below the threshold typically associated with the development of osteolysis (0.1 mm/year of wear). This should provide assurance to orthopaedic surgeons monitoring patients with this 5-Mrad irradiated liner in situ, while providing useful information to manufacturers of future highly crosslinked polyethylene liners. LEVEL OF EVIDENCE: Level IV therapeutic study.

L-cysteine ethylester reverses the adverse effects of morphine on breathing and arterial blood-gas chemistry while minimally affecting antinociception in unanesthetized rats.

L-cysteine ethylester (L-CYSee) is a membrane-permeable analogue of L-cysteine with a variety of pharmacological effects. The purpose of this study was to determine the effects of L-CYSee on morphine-induced changes in ventilation, arterial-blood gas (ABG) chemistry, Alveolar-arterial (A-a) gradient (i.e., a measure of the index of alveolar gas-exchange), antinociception and sedation in male Sprague Dawley rats. An injection of morphine (10 mg/kg, IV) produced adverse effects on breathing, including sustained decreases in minute ventilation. L-CYSee (500 µmol/kg, IV) given 15 min later immediately reversed the actions of morphine. Another injection of L-CYSee (500 µmol/kg, IV) after 15 min elicited more pronounced excitatory ventilatory responses. L-CYSee (250 or 500 µmol/kg, IV) elicited a rapid and prolonged reversal of the actions of morphine (10 mg/kg, IV) on ABG chemistry (pH, pCO2, pO2, sO2) and A-a gradient. L-serine ethylester (an oxygen atom replaces the sulfur; 500 µmol/kg, IV), was ineffective in all studies. L-CYSee (500 µmol/kg, IV) did not alter morphine (10 mg/kg, IV)-induced sedation, but slightly reduced the overall duration of morphine (5 or 10 mg/kg, IV)-induced analgesia. In summary, L-CYSee rapidly overcame the effects of morphine on breathing and alveolar gas-exchange, while not affecting morphine sedation or early-stage analgesia. The mechanisms by which L-CYSee modulates morphine depression of breathing are unknown, but appear to require thiol-dependent processes.

Potential underreporting of treated patients using a Clostridioides difficile testing algorithm that screens with a nucleic acid amplification test.

OBJECTIVE: Patients tested for Clostridioides difficile infection (CDI) using a 2-step algorithm with a nucleic acid amplification test (NAAT) followed by toxin assay are not reported to the National Healthcare Safety Network as a laboratory-identified CDI event if they are NAAT positive (+)/toxin negative (-). We compared NAAT+/toxin- and NAAT+/toxin+ patients and identified factors associated with CDI treatment among NAAT+/toxin- patients. DESIGN: Retrospective observational study. SETTING: The study was conducted across 36 laboratories at 5 Emerging Infections Program sites. PATIENTS: We defined a CDI case as a positive test detected by this 2-step algorithm during 2018-2020 in a patient aged ≥1 year with no positive test in the previous 8 weeks. METHODS: We used multivariable logistic regression to compare CDI-related complications and recurrence between NAAT+/toxin- and NAAT+/toxin+ cases. We used a mixed-effects logistic model to identify factors associated with treatment in NAAT+/toxin- cases. RESULTS: Of 1,801 cases, 1,252 were NAAT+/toxin-, and 549 were NAAT+/toxin+. CDI treatment was given to 866 (71.5%) of 1,212 NAAT+/toxin- cases versus 510 (95.9%) of 532 NAAT+/toxin+ cases (P < .0001). NAAT+/toxin- status was protective for recurrence (adjusted odds ratio [aOR], 0.65; 95% CI, 0.55-0.77) but not CDI-related complications (aOR, 1.05; 95% CI, 0.87-1.28). Among NAAT+/toxin- cases, white blood cell count ≥15,000/µL (aOR, 1.87; 95% CI, 1.28-2.74), ≥3 unformed stools for ≥1 day (aOR, 1.90; 95% CI, 1.40-2.59), and diagnosis by a laboratory that provided no or neutral interpretive comments (aOR, 3.23; 95% CI, 2.23-4.68) were predictors of CDI treatment. CONCLUSION: Use of this 2-step algorithm likely results in underreporting of some NAAT+/toxin- cases with clinically relevant CDI. Disease severity and laboratory interpretive comments influence treatment decisions for NAAT+/toxin- cases.

Differential Interferon Signaling Regulation and Oxidative Stress Responses in the Cerebral Cortex and Cerebellum Could Account for the Spatiotemporal Pattern of Neurodegeneration in Niemann-Pick Disease Type C.

Niemann-Pick disease type C (NPC) is a fatal neurodegenerative condition caused by genetic mutations of the NPC1 or NPC2 genes that encode the NPC1 and NPC2 proteins, respectively, which are believed to be responsible for cholesterol efflux from late-endosomes/lysosomes. The pathogenic mechanisms that lead to neurodegeneration in NPC are not well understood. There are, however, well-defined spatiotemporal patterns of neurodegeneration that may provide insight into the pathogenic process. For example, the cerebellum is severely affected from early disease stages, compared with cerebral regions, which remain relatively spared until later stages. Using a genome-wide transcriptome analysis, we have recently identified an aberrant pattern of interferon activation in the cerebella of pre-symptomatic Npc1-/- mice. Here, we carried out a comparative transcriptomic analysis of cerebral cortices and cerebella of pre-symptomatic Npc1-/- mice and age-matched controls to identify differences that may help explain the pathological progression within the NPC brain. We report lower cerebral expression of genes within interferon signaling pathways, and significant differences in the regulation of oxidative stress, compared with the cerebellum. Our findings suggest that a delayed onset of interferon signaling, possibly linked to lower oxidative stress, may account for the slower onset of cerebral cortical pathology in the disease.

How do babies roll? Identifying the coordinated movements of infant rolling through video compared to laboratory techniques.

BACKGROUND: Rolling is an important developmental milestone for infants where identifying the coordinated movement patterns could facilitate the early identification of motor development delays. Current methods for identifying coordinated movements of rolling are limited to a laboratory setting and not feasible for clinicians. OBJECTIVE: To develop video-based methods in which six coordinated movements, previously defined through motion capture, can be identified through video alone. METHODS: Forty-five videos of sixteen healthy infants achieving a roll were used to develop the video-based methodology and twenty-four videos had corresponding motion capture data used for validation. Four raters comprised of researchers and a clinician identified rolling coordination using the new video-based methods. A Fleiss' Kappa statistical test determined the inter- and intra-rater reliability of agreement for the new methodology and compared it to motion capture. RESULTS: The comparison of the motion capture and video-based methods resulted in substantial agreement. The video-based methods inter- and intra-rater reliability were substantial and almost perfect, respectively. CONCLUSIONS: We developed reliable methodology to accurately identify the coordinated movements of infant rolling using only 2D video. This methodology will allow researchers to reliably define coordinated movements of infants through video alone and may assist clinicians in identifying possible motor development delays and disorders.

Increased Rates of Late Periprosthetic Fractures in Larger Hydroxyapatite-Coated Cementless Stems: Are Collared Stems a Better Alternative for Total Hip Arthroplasty?

BACKGROUND: Cementless hip stems are widely used for total hip arthroplasty (THA) and have demonstrated excellent survivorship. This study aimed to investigate the effects of stem size and calcar collars on rates of revision due to periprosthetic fracture. METHODS: All primary THA procedures recorded by the Australian Orthopaedic Association National Joint Replacement Registry (AOANJRR) from September 1999 to December 2021 for a diagnosis of osteoarthritis using a single cementless hip stem with modern bearings were included. The primary outcome measure was revision due to periprosthetic fracture. Stems were divided into 2 groups for comparison, large (size 14 to 20) and small-medium (6 to 13). A subanalysis was performed for collared stems. A total of 59,518 primary THA procedures were included. RESULTS: The cumulative percent revision for periprosthetic fracture was significantly higher for large stems compared to small-medium stems (hazard ratio [HR] = 1.57 [95% confidence interval {CI} 1.18, 2.09] P = .002). Furthermore, collared stems had significantly lower revision rates due to late periprosthetic fracture compared to collarless variants (2 week + HR = 4.55 [95% CI 3.23, 6.42], P < .001). Large collarless stems were found to have greater revision rates due to fracture compared to small-medium collarless stems (HR = 1.55 [95% CI 1.13, 2.12] P = .006), but no difference was found between collared groups (HR = 1.37 [95% CI 0.68, 2.78] P = .382). CONCLUSION: Large cementless hip stems have a higher rate of revision due to periprosthetic fracture compared to small-medium stems. Using a collared stem reduces the rate of periprosthetic fracture.

A highly efficient transgene knock-in technology in clinically relevant cell types.

Inefficient knock-in of transgene cargos limits the potential of cell-based medicines. In this study, we used a CRISPR nuclease that targets a site within an exon of an essential gene and designed a cargo template so that correct knock-in would retain essential gene function while also integrating the transgene(s) of interest. Cells with non-productive insertions and deletions would undergo negative selection. This technology, called SLEEK (SeLection by Essential-gene Exon Knock-in), achieved knock-in efficiencies of more than 90% in clinically relevant cell types without impacting long-term viability or expansion. SLEEK knock-in rates in T cells are more efficient than state-of-the-art TRAC knock-in with AAV6 and surpass more than 90% efficiency even with non-viral DNA cargos. As a clinical application, natural killer cells generated from induced pluripotent stem cells containing SLEEK knock-in of CD16 and mbIL-15 show substantially improved tumor killing and persistence in vivo.

Neurological Effects of Repeated Blast Exposure in Special Operations Personnel.

Exposure to blast overpressure has been a pervasive feature of combat-related injuries. Studies exploring the neurological correlates of repeated low-level blast exposure in career "breachers" demonstrated higher levels of tumor necrosis factor alpha (TNFα) and interleukin (IL)-6 and decreases in IL-10 within brain-derived extracellular vesicles (BDEVs). The current pilot study was initiated in partnership with the U.S. Special Operations Command (USSOCOM) to explore whether neuroinflammation is seen within special operators with prior blast exposure. Data were analyzed from 18 service members (SMs), inclusive of 9 blast-exposed special operators with an extensive career history of repeated blast exposures and 9 controls matched by age and duration of service. Neuroinflammation was assessed utilizing positron emission tomography (PET) imaging with [18F]DPA-714. Serum was acquired to assess inflammatory biomarkers within whole serum and BDEVs. The Blast Exposure Threshold Survey (BETS) was acquired to determine blast history. Both self-report and neurocognitive measures were acquired to assess cognition. Similarity-driven Multi-view Linear Reconstruction (SiMLR) was used for joint analysis of acquired data. Analysis of BDEVs indicated significant positive associations with a generalized blast exposure value (GBEV) derived from the BETS. SiMLR-based analyses of neuroimaging demonstrated exposure-related relationships between GBEV, PET-neuroinflammation, cortical thickness, and volume loss within special operators. Affected brain networks included regions associated with memory retrieval and executive functioning, as well as visual and heteromodal processing. Post hoc assessments of cognitive measures failed to demonstrate significant associations with GBEV. This emerging evidence suggests neuroinflammation may be a key feature of the brain response to blast exposure over a career in operational personnel. The common thread of neuroinflammation observed in blast-exposed populations requires further study.