A hypothalamic novelty signal modulates hippocampal memory.

The ability to recognize information that is incongruous with previous experience is critical for survival. Novelty signals have therefore evolved in the mammalian brain to enhance attention, perception and memory1,2. Although the importance of regions such as the ventral tegmental area3,4 and locus coeruleus5 in broadly signalling novelty is well-established, these diffuse monoaminergic transmitters have yet to be shown to convey specific information on the type of stimuli that drive them. Whether distinct types of novelty, such as contextual and social novelty, are differently processed and routed in the brain is unknown. Here we identify the supramammillary nucleus (SuM) as a novelty hub in the hypothalamus6. The SuM region is unique in that it not only responds broadly to novel stimuli, but also segregates and selectively routes different types of information to discrete cortical targets-the dentate gyrus and CA2 fields of the hippocampus-for the modulation of mnemonic processing. Using a new transgenic mouse line, SuM-Cre, we found that SuM neurons that project to the dentate gyrus are activated by contextual novelty, whereas the SuM-CA2 circuit is preferentially activated by novel social encounters. Circuit-based manipulation showed that divergent novelty channelling in these projections modifies hippocampal contextual or social memory. This content-specific routing of novelty signals represents a previously unknown mechanism that enables the hypothalamus to flexibly modulate select components of cognition.

Epigenetic and transcriptional dysregulation in CD4+ T cells in patients with atopic dermatitis.

Atopic dermatitis (AD) is one of the most common skin disorders among children. Disease etiology involves genetic and environmental factors, with 29 independent AD risk loci enriched for risk allele-dependent gene expression in the skin and CD4+ T cell compartments. We investigated the potential epigenetic mechanisms responsible for the genetic susceptibility of CD4+ T cells. To understand the differences in gene regulatory activity in peripheral blood T cells in AD, we measured chromatin accessibility (an assay based on transposase-accessible chromatin sequencing, ATAC-seq), nuclear factor kappa B subunit 1 (NFKB1) binding (chromatin immunoprecipitation with sequencing, ChIP-seq), and gene expression levels (RNA-seq) in stimulated CD4+ T cells from subjects with active moderate-to-severe AD, as well as in age-matched non-allergic controls. Open chromatin regions in stimulated CD4+ T cells were highly enriched for AD genetic risk variants, with almost half of the AD risk loci overlapping AD-dependent ATAC-seq peaks. AD-specific open chromatin regions were strongly enriched for NF-κB DNA-binding motifs. ChIP-seq identified hundreds of NFKB1-occupied genomic loci that were AD- or control-specific. As expected, the AD-specific ChIP-seq peaks were strongly enriched for NF-κB DNA-binding motifs. Surprisingly, control-specific NFKB1 ChIP-seq peaks were not enriched for NFKB1 motifs, but instead contained motifs for other classes of human transcription factors, suggesting a mechanism involving altered indirect NFKB1 binding. Using DNA sequencing data, we identified 63 instances of altered genotype-dependent chromatin accessibility at 36 AD risk variant loci (30% of AD risk loci) that might lead to genotype-dependent gene expression. Based on these findings, we propose that CD4+ T cells respond to stimulation in an AD-specific manner, resulting in disease- and genotype-dependent chromatin accessibility alterations involving NFKB1 binding.

Human cytomegalovirus mediates APOBEC3B relocalization early during infection through a ribonucleotide reductase-independent mechanism.

The APOBEC3 family of DNA cytosine deaminases comprises an important arm of the innate antiviral defense system. The gamma-herpesviruses Epstein-Barr virus and Kaposi's sarcoma-associated herpesvirus and the alpha-herpesviruses herpes simplex virus (HSV)-1 and HSV-2 have evolved an efficient mechanism to avoid APOBEC3 restriction by directly binding to APOBEC3B and facilitating its exclusion from the nuclear compartment. The only viral protein required for APOBEC3B relocalization is the large subunit of the ribonucleotide reductase (RNR). Here, we ask whether this APOBEC3B relocalization mechanism is conserved with the beta-herpesvirus human cytomegalovirus (HCMV). Although HCMV infection causes APOBEC3B relocalization from the nucleus to the cytoplasm in multiple cell types, the viral RNR (UL45) is not required. APOBEC3B relocalization occurs rapidly following infection suggesting the involvement of an immediate early or early (IE/E) viral protein. In support of this possibility, genetic (IE1 mutant) and pharmacologic (cycloheximide) strategies that prevent the expression of IE/E viral proteins also block APOBEC3B relocalization. In comparison, the treatment of infected cells with phosphonoacetic acid, which interferes with viral late protein expression, still permits A3B relocalization. These results combine to indicate that the beta-herpesvirus HCMV uses an RNR-independent, yet phenotypically similar, molecular mechanism to antagonize APOBEC3B. IMPORTANCE Human cytomegalovirus (HCMV) infections can range from asymptomatic to severe, particularly in neonates and immunocompromised patients. HCMV has evolved strategies to overcome host-encoded antiviral defenses to achieve lytic viral DNA replication and dissemination and, under some conditions, latency and long-term persistence. Here, we show that HCMV infection causes the antiviral factor, APOBEC3B, to relocalize from the nuclear compartment to the cytoplasm. This overall strategy resembles that used by related herpesviruses. However, the HCMV relocalization mechanism utilizes a different viral factor(s) and available evidence suggests the involvement of at least one protein expressed at the early stages of infection. This knowledge is important because a greater understanding of this mechanism could lead to novel antiviral strategies that enable APOBEC3B to naturally restrict HCMV infection.

In silico-designed vitrification protocols: an approach to improve survival of in vitro produced-bovine embryos.

In brief: In silico predictions validated in this study demonstrate the potential for designing shorter equilibration protocols that improve post-warming re-expansion and hatching rates of D7 and D8 in vitro-produced bovine embryos. Our results benefit the livestock industry by providing a refined and reproducible approach to cryopreserving bovine embryos, which, in addition, could be useful for other mammalian species. Abstract: The cryopreservation of in vitro-produced (IVP) embryos is vital in the cattle industry for genetic selection and crossbreeding programs. Despite its importance, there is no standardized protocol yielding pregnancy rates comparable to fresh embryos. Current approaches often neglect the osmotic tolerance responses to cryoprotectants based on temperature and time. Hereby, we propose improved vitrification methods using shorter dehydration-based protocols. Blastocysts cultured for 7 (D7) or 8 days (D8) were exposed to standard equilibration solution (ES) at 25ºC and 38.5ºC. Optimized exposure times for each temperature and their impact on post-warming re-expansion, hatching rates, cell counts, and apoptosis rate were determined. In silico predictions aligned with in vitro observations, showing original volume recovery within 8 min 30 s at 25ºC or 3 min 40 s at 38.5ºC (D7 blastocysts) and 4 min 25 s at 25ºC and 3 min 15 s at 38.5ºC (D8 blastocysts) after exposure to ES. Vitrification at 38.5ºC resulted in D7 blastocysts re-expansion and hatching rates (93.1% and 38.1%, respectively) comparable to fresh embryos (100.0% and 32.4%, respectively), outperforming the 25ºC protocol (86.2% and 24.4%, respectively; P < 0.05). No differences were observed between D7 and D8 blastocysts using the 38.5ºC protocol. Total cell number was maintained for D7 and D8 blastocysts vitrified at 38.5ºC but decreased at 25ºC (P < 0.05). Apoptosis rates increased post-warming (P < 0.05), except for D8 blastocysts vitrified at 38.5ºC, resembling fresh controls. In conclusion, based on biophysical permeability data, new ES incubation times of 3 min 40 s for D7 blastocysts and 3 min 15 s for D8 blastocysts at 38.5ºC were validated for optimizing vitrification/warming methods for bovine IVP blastocysts.

Colloidal Stability of PFSA-Ionomer Dispersions. Part I. Single-Ion Electrostatic Interaction Potential Energies.

Charged colloidal particles neutralized by a single counterion are increasingly important for many emerging technologies. Attention here is paid specifically to hydrogen fuel cells and water electrolyzers whose catalyst layers are manufactured from a perfluorinated sulfonic acid polymer (PFSA) suspended in aqueous/alcohol solutions. Partially dissolved PFSA aggregates, known collectively as ionomers, are stabilized by the electrostatic repulsion of overlapping diffuse double layers consisting of only protons dissociated from the suspended polymer. We denote such double layers containing no added electrolyte as "single ion". Size-distribution predictions build upon interparticle interaction potential energies from the Derjaguin-Landau-Verwey-Overbeek (DLVO) formalism. However, when only a single counterion is present in solution, classical DLVO electrostatic potential energies no longer apply. Accordingly, here a new formulation is proposed to describe how single-counterion diffuse double layers interact in colloidal suspensions. Part II (Srivastav, H.; Weber, A. Z.; Radke, C. J. Langmuir 2024 DOI: 10.1021/acs.langmuir.3c03904) of this contribution uses the new single-ion interaction energies to predict aggregated size distributions and the resulting solution pH of PFSA in mixtures of n-propanol and water. A single-counterion diffuse layer cannot reach an electrically neutral concentration far from a charged particle. Consequently, nowhere in the dispersion is the solvent neutral, and the diffuse layer emanating from one particle always experiences the presence of other particles (or walls). Thus, in addition to an intervening interparticle repulsive force, a backside osmotic force is always present. With this new construction, we establish that single-ion repulsive pair interaction energies are much larger than those of classical DLVO electrostatic potentials. The proposed single-ion electrostatic pair potential governs dramatic new dispersion behavior, including dispersions that are stable at a low volume fraction but unstable at a high volume fraction and finite volume-fraction dispersions that are unstable with fine particles but stable with coarse particles. The proposed single-counterion electrostatic pair potential provides a general expression for predicting colloidal behavior for any charged particle dispersion in ionizing solvents with no added electrolyte.

Colloidal Stability of PFSA-Ionomer Dispersions Part II: Determination of Suspension pH Using Single-Ion Potential Energies.

Perfluorosulfonic acid (PFSA) ionomers serve a vital role in the performance and stability of fuel-cell catalyst layers. These properties, in turn, depend on the colloidal processing of precursor inks. To understand the colloidal structure of fuel-cell catalyst layers, we explore the aggregation of PFSA ionomers dissolved in water/alcohol solutions and relate the predicted aggregation to experimental measurements of solution pH. Not all side chains contribute to measured pH because of burying inside particle aggregates. To account for the measured degree of dissociation, a new description is developed for how PFSA aggregates interact with each other. The developed single-counterion electrostatic repulsive pair potential from Part I is incorporated into the Smoluchowski collision-based kinetics of interacting aggregates with buried side chains. We demonstrate that the surrounding solvent mixture affects the degree of aggregation as well as the pH of the system primarily through the solution dielectric permittivity, which drives the strength of the interparticle repulsive energies. Successful pH prediction of Nafion ionomer dispersions in water/n-propanol solutions validates the numerical calculations. Nafion-dispersion pH measurements serve as a surrogate for Nafion particle-size distributions. The model and framework can be leveraged to explore different ink formulations.

Songbirds avoid the oxidative stress costs of high blood glucose levels: a comparative study.

Chronically high blood glucose levels (hyperglycaemia) can compromise healthy ageing and lifespan at the individual level. Elevated oxidative stress can play a central role in hyperglycaemia-induced pathologies. Nevertheless, the lifespan of birds shows no species-level association with blood glucose. This suggests that the potential pathologies of high blood glucose levels can be avoided by adaptations in oxidative physiology at the macroevolutionary scale. However, this hypothesis remains unexplored. Here, we examined this hypothesis using comparative analyses controlled for phylogeny, allometry and fecundity based on data from 51 songbird species (681 individuals with blood glucose data and 1021 individuals with oxidative state data). We measured blood glucose at baseline and after stress stimulus and computed glucose stress reactivity as the magnitude of change between the two time points. We also measured three parameters of non-enzymatic antioxidants (uric acid, total antioxidants and glutathione) and a marker of oxidative lipid damage (malondialdehyde). We found no clear evidence for blood glucose concentration being correlated with either antioxidant or lipid damage levels at the macroevolutionary scale, as opposed to the hypothesis postulating that high blood glucose levels entail oxidative costs. The only exception was the moderate evidence for species with a stronger stress-induced increase in blood glucose concentration evolving moderately lower investment into antioxidant defence (uric acid and glutathione). Neither baseline nor stress-induced glucose levels were associated with oxidative physiology. Our findings support the hypothesis that birds evolved adaptations preventing the (glyc)oxidative costs of high blood glucose observed at the within-species level. Such adaptations may explain the decoupled evolution of glycaemia and lifespan in birds and possibly the paradoxical combination of long lifespan and high blood glucose levels relative to mammals.

Dietary restriction and life-history trade-offs: insights into mTOR pathway regulation and reproductive investment in Japanese quail.

Resources are needed for growth, reproduction and survival, and organisms must trade off limited resources among competing processes. Nutritional availability in organisms is sensed and monitored by nutrient-sensing pathways that can trigger physiological changes or alter gene expression. Previous studies have proposed that one such signalling pathway, the mechanistic target of rapamycin (mTOR), underpins a form of adaptive plasticity when individuals encounter constraints in their energy budget. Despite the fundamental importance of this process in evolutionary biology, how nutritional limitation is regulated through the expression of genes governing this pathway and its consequential effects on fitness remain understudied, particularly in birds. We used dietary restriction to simulate resource depletion and examined its effects on body mass, reproduction and gene expression in Japanese quails (Coturnix japonica). Quails were subjected to feeding at 20%, 30% and 40% restriction levels or ad libitum for 2 weeks. All restricted groups exhibited reduced body mass, whereas reductions in the number and mass of eggs were observed only under more severe restrictions. Additionally, dietary restriction led to decreased expression of mTOR and insulin-like growth factor 1 (IGF1), whereas the ribosomal protein S6 kinase 1 (RPS6K1) and autophagy-related genes (ATG9A and ATG5) were upregulated. The pattern in which mTOR responded to restriction was similar to that for body mass. Regardless of the treatment, proportionally higher reproductive investment was associated with individual variation in mTOR expression. These findings reveal the connection between dietary intake and the expression of mTOR and related genes in this pathway.

Continuum Modeling of Porous Electrodes for Electrochemical Synthesis.

Electrochemical synthesis possesses substantial promise to utilize renewable energy sources to power the conversion of abundant feedstocks to value-added commodity chemicals and fuels. Of the potential system architectures for these processes, only systems employing 3-D structured porous electrodes have the capacity to achieve the high rates of conversion necessary for industrial scale. However, the phenomena and environments in these systems are not well understood and are challenging to probe experimentally. Fortunately, continuum modeling is well-suited to rationalize the observed behavior in electrochemical synthesis, as well as to ultimately provide recommendations for guiding the design of next-generation devices and components. In this review, we begin by presenting an historical review of modeling of porous electrode systems, with the aim of showing how past knowledge of macroscale modeling can contribute to the rising challenge of electrochemical synthesis. We then present a detailed overview of the governing physics and assumptions required to simulate porous electrode systems for electrochemical synthesis. Leveraging the developed understanding of porous-electrode theory, we survey and discuss the present literature reports on simulating multiscale phenomena in porous electrodes in order to demonstrate their relevance to understanding and improving the performance of devices for electrochemical synthesis. Lastly, we provide our perspectives regarding future directions in the development of models that can most accurately describe and predict the performance of such devices and discuss the best potential applications of future models.

IGF-1 induces sex-specific oxidative damage and mortality in a songbird.

The insulin-like growth factor 1 (IGF-1) is a pleiotropic hormone that regulates essential life-history traits and is known for its major contribution to determining individual ageing processes. High levels of IGF-1 have been linked to increased mortality and are hypothesised to cause oxidative stress. This effect has been observed in laboratory animals, but whether it pertains to wild vertebrates has not been tested. This is surprising because studying the mechanisms that shape individual differences in lifespan is important to understanding mortality patterns in populations of free-living animals. We tested this hypothesis under semi-natural conditions by simulating elevated IGF-1 levels in captive bearded reedlings, a songbird species with an exceptionally fast pace of life. We subcutaneously injected slow-release biodegradable microspheres loaded with IGF-1 and achieved a systemic 3.7-fold increase of the hormone within the natural range for at least 24 h. Oxidative damage to lipids showed marked sexual differences: it significantly increased the day after the manipulation in treated males and returned to baseline levels four days post-treatment, while no treatment effect was apparent in females. Although there was no overall difference in survival between the treatment groups, high initial (pre-treatment) IGF-1 and low post-treatment plasma malondialdehyde levels were associated with enhanced survival prospects in males. These results suggest that males may be more susceptible to IGF-1-induced oxidative stress than females and quickly restoring oxidative balance may be related to fitness. IGF-1 levels evolve under opposing selection forces, and natural variation in this hormone's level may reflect the outcome of individual optimization.

SARS-CoV-2 Inactivation on Hard Non-porous Airplane Cabin Material Surfaces was Limited After Exposure to Far UV-C (222 nm) Radiation.

AIMS: To test the efficacy of 222 nm Far UV-C for surface disinfection of SARS-CoV-2 on inanimate surfaces from airplane cabins. METHODS AND RESULTS: Two far ultraviolet (UV-C) irradiation light systems were evaluated for disinfection of SARS-CoV-2. Materials used for carriers (test surfaces) included polished stainless steel and used airplane materials including seatbelt latches, window dust covers, sidewall laminates, and tray tables. CONCLUSIONS: While demonstrating reasonable efficacy under some experimental conditions, the data indicated that 222 nm Far UV-C disinfection alone does not reliably provide a 3 log10 or 99.9% reduction of SARS-CoV-2 on inanimate surfaces from an airplane cabin. An Ushio (Cypress, CA) 1.7" x 2.3" Care222® 12W 222nm BI lamp module tested in triplicate at a low (⁓ 1.5 mJ cm-2), medium (⁓ 3.0 mJ cm-2), and high (⁓ 6 to 9 mJ cm-2) fluence did not provide a ≥ 3 log10 or 99.9% reduction of SARS-CoV-2. The reduction of SARS-CoV-2 was greatest on stainless steel. The result was a log10 reduction of 2.83, 1.33, 2.58, and 2.21 logs for virus samples containing saline, saline with 2.5 mg BSA, saline with 0.25 mg BSA, and artificial saliva respectively at a dosage of 5 to 9 mJ cm-2. The log10 reduction of SARS-CoV-2 in saline with 2.5 mg bovine serum albumin was lowest with 1.33 for stainless steel, 0.93 for belt latch, and 0.61 for tray table at a dosage of 5 to 6 mJ cm-2.The second UV lighting system tested was a prototype mobile wand with a built-in short-pass filtered krypton-chloride cylindrical lamp. One pass of the wand over a tray holding carriers inoculated with SARS-CoV-2 in artificial saliva at a rate of approximately 1 foot (1') per second (sec) exposed the carriers to 7.3 mJ cm-2. The log10 reductions determined for the single pass were 2.97, 3.75, 1.78, 1.91, and 1.28 logs for stainless steel, belt latch, dust cover, sidewall, and tray table respectively. Two passes of the wand generated 17.2 mJ cm-2 and resulted in log10 reductions of 4.04, 3.74, 4.24, 3.68, and 1.66 logs for stainless steel, belt latch, dust cover, sidewall, and tray table respectively. The combination of higher fluence from multiple passes of the wand, the close proximity (10 cm wand to the carrier), the exposure to elevated temperatures up to 35°C, and ozone from the bulb being blown directly onto the carriers contributed to effective viral inactivation on all surfaces except the airplane tray table. The impact of temperature and ozone on viral inactivation should be determined for future testing of the 222 nm UV-C wand.

Elevated HbA1c is not associated with reoperation following arthroscopic rotator cuff repair in patients with diabetes mellitus.

BACKGROUND: Hyperglycemia is a known risk factor for tendon degeneration due to oxidative stresses from production of advanced glycosylation end products. In patients with diabetes mellitus (DM), analysis of glycated hemoglobin (HbA1c) provides a 3-month window into a patient's glucose control. No guidelines exist for ideal preoperative HbA1c and glucose control prior to arthroscopic rotator cuff repair. This study evaluated if a critical HbA1c level is associated with reoperation following arthroscopic rotator cuff repair. METHODS: We retrospectively evaluated patients with DM who underwent primary arthroscopic rotator cuff repair from January 2014 to December 2018 at a single institution. Patients required a preoperative HbA1c within 3 months of surgery. Medical records were queried to evaluate for reoperation and identify the subsequent procedures performed. Univariate statistical analysis was performed to assess factors associated with reoperation (P < .05 considered significant). Threshold, area under the curve (AUC), analysis was performed to assess if a critical HbA1c value was associated with reoperation. RESULTS: A total of 402 patients met inclusion criteria. Patients had an average age of 65.5 years (range 40-89) at time of surgery; 244 (60.6%) patients were male; and average body mass index was 32.96 ± 5.81. Mean HbA1c was 7.36 (range 5.2-12). Thirty-three patients (8.2%) underwent subsequent reoperation. Six patients (1.5%) underwent capsular release and lysis of adhesions, 20 patients (5.0%) underwent a revision rotator cuff surgery, combination revision rotator cuff repair and lysis of adhesions, graft-augmented revision repair, or superior capsular reconstruction, and 7 patients (1.7%) underwent revision to reverse shoulder arthroplasty (1.7%). There were no cases of reoperation for infection. On AUC analysis, no critical HbA1c value was identified to predispose to reoperation. Interestingly, elevated preoperative American Society of Anesthesiologists (ASA) physical status classification score (2.8 vs. 2.28, P = .001) was associated with a higher reoperation rate. DISCUSSION: In patients with DM, preoperative HbA1c is not a predictive factor for surgical failure requiring reoperation. Stable glycemic control is important to a patient's overall health and may play a role in minimizing postoperative medical complications, but an elevated preoperative HbA1c should not be a strict surgical contraindication for arthroscopic rotator cuff repair. In patients with DM, an elevated ASA score is associated with an increased rate of subsequent reoperation; diabetic patients should be counseled accordingly.

Effect of vitamin E-enhanced highly cross-linked polyethylene on wear rate and particle debris in anatomic total shoulder arthroplasty: a biomechanical comparison to ultrahigh-molecular-weight polyethylene.

BACKGROUND: Particle-induced osteolysis resulting from polyethylene wear remains a source of implant failure in anatomic total shoulder designs. Modern polyethylene components are irradiated in an oxygen-free environment to induce cross-linking, but reducing the resulting free radicals with melting or heat annealing can compromise the component's mechanical properties. Vitamin E has been introduced as an adjuvant to thermal treatments. Anatomic shoulder arthroplasty models with a ceramic head component have demonstrated that vitamin E-enhanced polyethylene show improved wear compared with highly cross-linked polyethylene (HXLPE). This study aimed to assess the biomechanical wear properties and particle size characteristics of a novel vitamin E-enhanced highly cross-linked polyethylene (VEXPE) glenoid compared to a conventional ultrahigh-molecular-weight polyethylene (UHMWPE) glenoid against a cobalt chromium molybdenum (CoCrMo) head component. METHODS: Biomechanical wear testing was performed to compare the VEXPE glenoid to UHMWPE glenoid with regard to pristine polyethylene wear and abrasive endurance against a polished CoCrMo alloy humeral head in an anatomic shoulder wear-simulation model. Cumulative mass loss (milligrams) was recorded, and wear rate calculated (milligrams per megacycle [Mc]). Under pristine wear conditions, particle analysis was performed, and functional biologic activity (FBA) was calculated to estimate particle debris osteolytic potential. In addition, 95% confidence intervals for all testing conditions were calculated. RESULTS: The average pristine wear rate was statistically significantly lower for the VEXPE glenoid compared with the HXLPE glenoid (0.81 ± 0.64 mg/Mc vs. 7.00 ± 0.45 mg/Mc) (P < .05). Under abrasive wear conditions, the VEXPE glenoid had a statistically significant lower average wear rate compared with the UHMWPE glenoid comparator device (18.93 ± 5.80 mg/Mc vs. 40.47 ± 2.63 mg/Mc) (P < .05). The VEXPE glenoid demonstrated a statistically significant improvement in FBA compared with the HXLPE glenoid (0.21 ± 0.21 vs. 1.54 ± 0.49 (P < .05). CONCLUSIONS: A new anatomic glenoid component with VEXPE demonstrated significantly improved pristine and abrasive wear properties with lower osteolytic particle debris potential compared with a conventional UHMWPE glenoid component. Vitamin E-enhanced polyethylene shows early promise in shoulder arthroplasty components. Long-term clinical and radiographic investigation needs to be performed to verify if these biomechanical wear properties translate to diminished long-term wear, osteolysis, and loosening.

Trends and outcomes of outpatient total shoulder arthroplasty after its removal from CMS's inpatient-only list.

BACKGROUND: In January 2021, the US Medicare program approved reimbursement of outpatient total shoulder arthroplasties (TSA), including anatomic and reverse TSAs. It remains unclear whether shifting TSAs from the inpatient to outpatient setting has affected clinical outcomes. Herein, we describe the rate of outpatient TSA growth and compare inpatient and outpatient TSA complications, readmissions, and mortality. METHODS: Medicare fee-for-service claims for 2019-2022Q1 were analyzed to identify the trends in outpatient TSAs and to compare 90-day postoperative complications, all-cause hospital readmissions, and mortality between outpatients and inpatients. Outpatient cases were defined as those discharged on the same day of the surgery. To reduce the COVID-19 pandemic's impact and selection bias, we excluded 2020Q2-Q4 data and used propensity scores to match 2021-2022Q1 outpatients with inpatients from the same period (the primary analysis) and from 2019-2020Q1 (the secondary analysis), respectively. We performed both propensity score-matched and -weighted multivariate analyses to compare outcomes between the two groups. Covariates included sociodemographics, preoperative diagnosis, comorbid conditions, the Hierarchical Condition Category risk score, prior year hospital/skilled nursing home admissions, annual surgeon volume, and hospital characteristics. RESULTS: Nationally, the proportion of outpatient TSAs increased from 3% (619) in 2019Q1 to 22% (3456) in 2021Q1 and 38% (6778) in 2022Q1. A total of 55,166 cases were identified for the primary analysis (14,540 outpatients and 40,576 inpatients). Overall, glenohumeral osteoarthritis was the most common indication for surgery (70.8%), followed by rotator cuff pathology (14.6%). The unadjusted rates of complications (1.3 vs 2.4%, P < .001), readmissions (3.7 vs 6.1%, P < .001), and mortality (0.2 vs 0.4%, P = .024) were significantly lower among outpatient TSAs than inpatient TSAs. Using 1:1 nearest matching, 12,703 patient pairs were identified. Propensity score-matched multivariate analyses showed similar rates of postoperative complications, hospital readmissions, and mortality between outpatients and inpatients. Propensity score-weighted multivariate analyses resulted in similar conclusions. The secondary analysis showed a lower hospital readmission rate in outpatients (odds ratio: 0.8, P < .001). CONCLUSIONS: There has been accelerated growth in outpatient TSAs since 2019. Outpatient and inpatient TSAs have similar rates of postoperative complication, hospital readmission, and mortality.

Racial and Gender Disparities in Utilization of Outpatient Total Shoulder Arthroplasties.

BACKGROUND: Utilization in outpatient total shoulder arthroplasties (TSAs) has increased significantly in recent years. It remains largely unknown whether utilization of outpatient TSA differs across gender and racial groups. This study aimed to quantify racial and gender disparities both nationally and by geographic regions. METHODS: 168,504 TSAs were identified using Medicare fee-for-service (FFS) inpatient and outpatient claims data and beneficiary enrollment data from 2020 to 2022Q4. The percentage of outpatient cases, defined as cases discharged on the same day of surgery, was evaluated by racial and gender groups and by different census divisions. A multivariate logistics regression model controlling for patient socio-demographic information (white vs. non-white race, age, gender, and dual eligibility for both Medicare and Medicaid), hierarchical condition category (HCC) score, hospital characteristics, year fixed effects, and patient residency state fixed effects was performed. RESULTS: The TSA volume per 1000 beneficiaries was 2.3 for the White population compared to 0.8, 0.6 and 0.3 for the Black, Hispanic, and Asian population, respectively. A higher percentage of outpatient TSAs were in White patients (25.6%) compared to Black patients (20.4%) (p < 0.001). The Black TSA patients were also younger, more likely to be female, more likely to be dually eligible for Medicaid, and had higher HCC risk scores. After controlling for patient socio-demographic characteristics and hospital characteristics, the odds of receiving outpatient TSAs were 30% less for Black than the White group (OR 0.70). Variations were observed across different census divisions with South Atlantic (0.67, p < 0.01), East North Central (0.56, p < 0.001), and Middle Atlantic (0.36, p < 0.01) being the four regions observed with significant racial disparities. Statistically significant gender disparities were also found nationally and across regions, with an overall odds ratio of 0.75 (p < 0.001). DISCUSSION: Statistically significant racial and gender disparities were found nationally in outpatient TSAs, with Black patients having 30% (p < 0.001) fewer odds of receiving outpatient TSAs than white patients, and female patients with 25% (p < 0.001) fewer odds than male patients. Racial and gender disparities continue to be an issue for shoulder arthroplasties after the adoption of outpatient TSAs.

A Preoperative Risk Assessment Tool for Predicting Adverse Outcomes among Total Shoulder Arthroplasty Patients.

BACKGROUND: With the increased utilization of Total Shoulder Arthroplasty (TSA) in the outpatient setting, understanding the risk factors associated with complications and hospital readmissions becomes a more significant consideration. Prior developed assessment metrics in the literature either consisted of hard-to-implement tools or relied on postoperative data to guide decision-making. This study aimed to develop a preoperative risk assessment tool to help predict the risk of hospital readmission and other postoperative adverse outcomes. METHODS: We retrospectively evaluated the 2019-2022(Q2) Medicare fee-for-service inpatient and outpatient claims data to identify primary anatomic or reserve TSAs and to predict postoperative adverse outcomes within 90 days post-discharge, including all-cause hospital readmissions, postoperative complications, emergency room visits, and mortality. We screened 108 candidate predictors, including demographics, social determinants of health, TSA indications, prior 12-month hospital and skilled nursing home admissions, comorbidities measured by hierarchical conditional categories, and prior orthopedic device-related complications. We used two approaches to reduce the number of predictors based on 80% of the data: 1) the Least Absolute Shrinkage and Selection Operator (LASSO) logistic regression and 2) the machine-learning-based cross-validation approach, with the resulting predictor sets being assessed in the remaining 20% of the data. A scoring system was created based on the final regression models' coefficients, and score cutoff points were determined for low, medium, and high-risk patients. RESULTS: A total of 208,634 TSA cases were included. There was a 6.8% hospital readmission rate with 11.2% of cases having at least one postoperative adverse outcome. Fifteen covariates were identified for predicting hospital readmission with the area under the curve (AUC) of 0.70, and 16 were selected to predict any adverse postoperative outcome (AUC=0.75). The LASSO and machine learning approaches had similar performance. Advanced age and a history of fracture due to orthopedic devices are among the top predictors of hospital readmissions and other adverse outcomes. The score range for hospital readmission and an adverse postoperative outcome was 0 to 48 and 0 to 79, respectively. The cutoff points for the low, medium, and high-risk categories are 0-9, 10-14, ≥15 for hospital readmissions, and 0-11, 12-16, ≥17 for the composite outcome. CONCLUSION: Based on Medicare fee-for-service claims data, this study presents a preoperative risk stratification tool to assess hospital readmission or adverse surgical outcomes following TSA. Further investigation is warranted to validate these tools in a variety of diverse demographic settings and improve their predictive performance.

ED diagnosis of peritoneal carcinomatosis.

PURPOSE: The goal of our study was to better characterize new CT diagnoses of peritoneal carcinomatosis (PC) in the ED, and to evaluate how to best identify the primary lesion. Prompt identification of the source of the carcinomatosis may allow for the patient to receive early initial care from the correct clinical service. METHODS: All new CT cases of PC-like appearance identified on CT in the ED from January 2017 through July 2020. Each report and corresponding medical record were manually reviewed. Patient demographics, presence/absence of intravenous contrast, source organ predicted by the radiologist in the CT scan report, pathologic diagnosis, and amount of ascites were tabulated. Chi-tests were used to test the statistical significance of differences between groups. RESULTS: Of the 131 CT cases of new PC-like appearance which received workup, 108 cases had pathologically proven PC and 23 cases had no underlying malignancy yielding a positive predictive value for actual PC of 82%. The most common cause of new PC in women was gynecological (66%), and in men was of GI tract origin (57%). Concordance between radiologist prediction and final pathology was higher with intravenous contrast (58%) compared to without contrast (40%); although this difference was not statistically significant (p = 0.19). A moderate or large amount of ascites was found in more than half of GYN primaries and in adenocarcinoma of unknown primary and there was a statistically significant difference in amount of ascites between cancer primaries (p = 0.01). CONCLUSION: A PC-like appearance on CT in the ED will likely be in patients with known malignancy, but of the new cases, there is a high PPV for it to represent new peritoneal carcinomatosis. Gynecological and GI malignancies are the most common cause in women and men, respectively, and this may help in focusing the radiologist's search pattern. Usage of intravenous contrast may help in identifying a primary lesion, and the presence of high-volume ascites should suggest a GYN primary or adenocarcinoma of unknown primary when there is no other obvious primary lesion.

Resetting our expectations for parasites and their effects on species interactions: a meta-analysis.

Despite the ubiquitous nature of parasitism, how parasitism alters the outcome of host-species interactions such as competition, mutualism and predation remains unknown. Using a phylogenetically informed meta-analysis of 154 studies, we examined how the mean and variance in the outcomes of species interactions differed between parasitized and non-parasitized hosts. Overall, parasitism did not significantly affect the mean or variance of host-species interaction outcomes, nor did the shared evolutionary histories of hosts and parasites have an effect. Instead, there was considerable variation in outcomes, ranging from strongly detrimental to strongly beneficial for infected hosts. Trophically-transmitted parasites increased the negative effects of predation, parasites increased and decreased the negative effects of interspecific competition for parasitized and non-parasitized heterospecifics, respectively, and parasites had particularly strong negative effects on host species interactions in freshwater and marine habitats, yet were beneficial in terrestrial environments. Our results illuminate the diverse ways in which parasites modify critical linkages in ecological networks, implying that whether the cumulative effects of parasitism are considered detrimental depends not only on the interactions between hosts and their parasites but also on the many other interactions that hosts experience.

Brain-specific heterozygous loss-of-function of ATP2A2, endoplasmic reticulum Ca2+ pump responsible for Darier's disease, causes behavioral abnormalities and a hyper-dopaminergic state.

A report of a family of Darier's disease with mood disorders drew attention when the causative gene was identified as ATP2A2 (or SERCA2), which encodes a Ca2+ pump on the endoplasmic reticulum (ER) membrane and is important for intracellular Ca2+ signaling. Recently, it was found that loss-of-function mutations of ATP2A2 confer a risk of neuropsychiatric disorders including depression, bipolar disorder and schizophrenia. In addition, a genome-wide association study found an association between ATP2A2 and schizophrenia. However, the mechanism of how ATP2A2 contributes to vulnerability to these mental disorders is unknown. Here, we analyzed Atp2a2 heterozygous brain-specific conditional knockout (hetero cKO) mice. The ER membranes prepared from the hetero cKO mouse brain showed decreased Ca2+ uptake activity. In Atp2a2 heterozygous neurons, decays of cytosolic Ca2+ level were slower than control neurons after depolarization. The hetero cKO mice showed altered behavioral responses to novel environments and impairments in fear memory, suggestive of enhanced dopamine signaling. In vivo dialysis demonstrated that extracellular dopamine levels in the NAc were indeed higher in the hetero cKO mice. These results altogether indicate that the haploinsufficiency of Atp2a2 in the brain causes prolonged cytosolic Ca2+ transients, which possibly results in enhanced dopamine signaling, a common feature of mood disorders and schizophrenia. These findings elucidate how ATP2A2 mutations causing a dermatological disease may exert their pleiotropic effects on the brain and confer a risk for mental disorders.

G1/S Cell Cycle Induction by Epstein-Barr Virus BORF2 Is Mediated by P53 and APOBEC3B.

Herpesvirus lytic infection causes cells to arrest at the G1/S phase of the cell cycle by poorly defined mechanisms. In a prior study using fluorescent ubiquitination-based cell cycle indicator (FUCCI) cells that express fluorescently tagged proteins marking different stages of the cell cycle, we showed that the Epstein-Barr virus (EBV) protein BORF2 induces the accumulation of G1/S cells, and that BORF2 affects p53 levels without affecting the p53 target protein p21. We also found that BORF2 specifically interacted with APOBEC3B (A3B) and forms perinuclear bodies with A3B that prevent A3B from mutating replicating EBV genomes. We now show that BORF2 also interacts with p53 and that A3B interferes with the BORF2-p53 interaction, although A3B and p53 engage distinct surfaces on BORF2. Cell cycle analysis showed that G1/S induction by BORF2 is abrogated when either p53 or A3B is silenced or when an A3B-binding mutant of BORF2 is used. Furthermore, silencing A3B in EBV lytic infection increased cell proliferation, supporting a role for A3B in G1/S arrest. These data suggest that the p53 induced by BORF2 is inactive when it binds BORF2, but is released and induces G1/S arrest when A3B is present and sequesters BORF2 in perinuclear bodies. Interestingly, this mechanism is conserved in the BORF2 homologue in HSV-1, which also re-localizes A3B, induces and binds p53, and induces G1/S dependent on A3B and p53. In summary, we have identified a new mechanism by which G1/S arrest can be induced in herpesvirus lytic infection. IMPORTANCE In lytic infection, herpesviruses cause cells to arrest at the G1/S phase of the cell cycle in order to provide an optimal environment for viral replication; however, the mechanisms involved are not well understood. We have shown that the Epstein-Barr virus BORF2 protein and its homologue in herpes simplex virus 1 both induce G1/S, and do this by similar mechanisms which involve binding p53 and APOBEC3B and induction of p53. Our study identifies a new mechanism by which G1/S arrest can be induced in herpesvirus lytic infection and a new role of APOBEC3B in herpesvirus lytic infection.