MIR137 polygenic risk for schizophrenia and ephrin-regulated pathway: Role in lateral ventricles and corpus callosum volume.

Background/Objective. Enlarged lateral ventricle (LV) volume and decreased volume in the corpus callosum (CC) are hallmarks of schizophrenia (SZ). We previously showed an inverse correlation between LV and CC volumes in SZ, with global functioning decreasing with increased LV volume. This study investigates the relationship between LV volume, CC abnormalities, and the microRNA MIR137 and its regulated genes in SZ, because of MIR137's essential role in neurodevelopment. Methods. Participants were 1224 SZ probands and 1466 unaffected controls from the GENUS Consortium. Brain MRI scans, genotype, and clinical data were harmonized across cohorts and employed in the analyses. Results. Increased LV volumes and decreased CC central, mid-anterior, and mid-posterior volumes were observed in SZ probands. The MIR137-regulated ephrin pathway was significantly associated with CC:LV ratio, explaining a significant proportion (3.42 %) of CC:LV variance, and more than for LV and CC separately. Other pathways explained variance in either CC or LV, but not both. CC:LV ratio was also positively correlated with Global Assessment of Functioning, supporting previous subsample findings. SNP-based heritability estimates were higher for CC central:LV ratio (0.79) compared to CC or LV separately. Discussion. Our results indicate that the CC:LV ratio is highly heritable, influenced in part by variation in the MIR137-regulated ephrin pathway. Findings suggest that the CC:LV ratio may be a risk indicator in SZ that correlates with global functioning.

Clusters of 24-hour movement behavior and diet and their relationship with health indicators among youth: a systematic review.

Movement-related behaviors (physical activity [PA], sedentary behavior [SB], and sleep) and diet interact with each other and play important roles in health indicators in youth. This systematic review aimed to investigate how PA, SB, sleep, and diet cluster in youth by biological sex; and to examine which cluster are associated with health indicators. This study was registered in PROSPERO (number: CRD42018094826). Five electronic databases were assessed. Eligibility criteria allowed studies that included youth (aged 19 years and younger), and only the four behaviors {PA, SB, sleep, and diet (ultra-processed foods [UPF]; fruits and vegetables [FV])} analyzed by applying data-based cluster procedures. From 12,719 articles screened; 23 were included. Of these, four investigated children, and ten identified clusters by biological sex. Sixty-six mixed cluster were identified including, 34 in mixed-sex samples, 10 in boys and 11 in girls. The most frequent clusters in mixed-sex samples were "High SB UPF Low Sleep", "Low PA High SB Satisfactory Sleep", and "High PA". The main difference in profiles according to sex was that girls' clusters were characterized by high sleep duration, whereas boys' clusters by high PA. There were a few associations found between cluster types and health indicators, highlighting that youth assigned to cluster types with low PA exhibited higher adiposity. In conclusion, the youth presented a range of clusters of behaviors, typically exhibiting at least one unhealthy behavior. Similar patterns were observed in both sexes with the biggest difference in time of sleep for girls and PA for boys. These findings underscore the importance of intervention strategies targeting multiple behaviors simultaneously to enhance health risk profiles and indicators in children and adolescents.

Neurodevelopmental Outcomes After Late Preterm Antenatal Corticosteroids: The ALPS Follow-Up Study.

Importance: The Antenatal Late Preterm Steroids (ALPS) trial changed clinical practice in the United States by finding that antenatal betamethasone at 34 to 36 weeks decreased short-term neonatal respiratory morbidity. However, the trial also found increased risk of neonatal hypoglycemia after betamethasone. This follow-up study focused on long-term neurodevelopmental outcomes after late preterm steroids. Objective: To evaluate whether administration of late preterm (34-36 completed weeks) corticosteroids affected childhood neurodevelopmental outcomes. Design, Setting, and Participants: Prospective follow-up study of children aged 6 years or older whose birthing parent had enrolled in the multicenter randomized clinical trial, conducted at 13 centers that participated in the Maternal-Fetal Medicine Units (MFMU) Network cycle from 2011-2016. Follow-up was from 2017-2022. Exposure: Twelve milligrams of intramuscular betamethasone administered twice 24 hours apart. Main Outcome and Measures: The primary outcome of this follow-up study was a General Conceptual Ability score less than 85 (-1 SD) on the Differential Ability Scales, 2nd Edition (DAS-II). Secondary outcomes included the Gross Motor Function Classification System level and Social Responsiveness Scale and Child Behavior Checklist scores. Multivariable analyses adjusted for prespecified variables known to be associated with the primary outcome. Sensitivity analyses used inverse probability weighting and also modeled the outcome for those lost to follow-up. Results: Of 2831 children, 1026 enrolled and 949 (479 betamethasone, 470 placebo) completed the DAS-II at a median age of 7 years (IQR, 6.6-7.6 years). Maternal, neonatal, and childhood characteristics were similar between groups except that neonatal hypoglycemia was more common in the betamethasone group. There were no differences in the primary outcome, a general conceptual ability score less than 85, which occurred in 82 (17.1%) of the betamethasone vs 87 (18.5%) of the placebo group (adjusted relative risk, 0.94; 95% CI, 0.73-1.22). No differences in secondary outcomes were observed. Sensitivity analyses using inverse probability weighting or assigning outcomes to children lost to follow-up also found no differences between groups. Conclusion and Relevance: In this follow-up study of a randomized clinical trial, administration of antenatal corticosteroids to persons at risk of late preterm delivery, originally shown to improve short-term neonatal respiratory outcomes but with an increased rate of hypoglycemia, was not associated with adverse childhood neurodevelopmental outcomes at age 6 years or older.

Pharmacogenetic variability of tuberculosis biomarkers in native and mestizo Peruvian populations.

In Peru, 29 292 people were diagnosed with tuberculosis in 2022. Although tuberculosis treatments are effective, 3.4%-13% are associated with significant adverse drug reactions, with drug-induced liver injury (DILI) considered the most predominant. Among the first-line antituberculosis drugs, isoniazid is the main drug responsible for the appearance of DILI. In liver, isoniazid (INH) is metabolized by N-acetyltransferase-2 (NAT2) and cytochrome P450 2E1 (CYP2E1). Limited information exists on genetic risk factors associated with the presence of DILI to antituberculosis drugs in Latin America, and even less is known about these factors in the native and mestizo Peruvian population. The aim of this study was to determine the prevalence of NAT2 and CYP2E1 genotypes in native and mestizo population. An analytical cross-sectional analysis was performed using genetic data from mestizo population in Lima and native participants from south of Peru. NAT2 metabolizer was determined as fast, intermediate and slow, and CYP2E1 genotypes were classified as c1/c1, c1/c2 and c2/c2, from molecular tests and bioinformatic analyses. Of the 472 participants, 36 and 6 NAT2 haplotypes were identified in the mestizo and native population, respectively. In mestizo population, the most frequent NAT2*5B and NAT2*7B haplotypes were associated with DILI risk; while in natives, NAT2*5G and NAT2*13A haplotypes were associated with decreased risk of DILI. For CYP2E1, c1/c1 and c1/c2 genotypes are the most frequent in natives and mestizos, respectively. The linkage disequilibrium of NAT2 single nucleotide polymorphisms (SNPs) was estimated, detecting a block between all SNPs natives. In addition, a block between rs1801280 and rs1799929 for NAT2 was detected in mestizos. Despite the limitations of a secondary study, it was possible to report associations between NAT2 and CYP2E alleles with Peruvian native and mestizo by prevalence ratios. The results of this study will help the development of new therapeutic strategies for a Tuberculosis efficient control between populations.

Blood flow restriction training does not negatively alter the mechanical strength or histomorphology of uninjured equine superficial digital flexor tendons.

BACKGROUND: Low load exercise training with blood flow restriction (BFR) has become increasingly used by human physical therapists to prescribe controlled exercise following orthopaedic injury; its effects on the equine superficial digital flexor tendon (SDFT), however, are unknown. OBJECTIVE: To investigate outcomes of pressure specific BFR walking exercise on uninjured equine SDFT biomechanics and histomorphology. STUDY DESIGN: Controlled in vivo experiment. METHODS: Four forelimbs of four horses were exposed to 40 BFR-walk sessions (10-min interval walking) on a treadmill over a 56-day study period with their contralateral forelimbs serving as untreated controls. Similarly, four forelimbs of four control horses were exposed to 40 sham cuff walk sessions. On study Day 56, all horses (n = 8) were humanely euthanised and forelimb SDFTs underwent non-destructive biomechanical testing and corresponding histomorphological analysis. Significance in biomechanical parameters between treatment groups was analysed using a mixed-effects ANOVA with Tukey's post-hoc tests. RESULTS: Statistically significant differences in SDFT stiffness for both first (p = 0.02) and last cycles (p = 0.03) were appreciated within the BFR treated group only, with BFR exposed forelimbs being significantly stiffer than the contralateral unexposed forelimbs. When normalised to cross-sectional area, no significant differences were appreciated among treatment groups in elastic modulus for the first (p = 0.5) or last cycles (p = 0.4). No histological differences were appreciated among treatment groups according to Bonar, Movin, or musculotendinous junction evaluation criteria. MAIN LIMITATIONS: Short-term comparisons were performed in a small sample population without correlation to performance outcome measures. Optimal occlusion percentages and walk protocols remain unknown. CONCLUSIONS: This study demonstrated no negative impact of BFR on mechanical strength of the equine SDFT; however, evidence suggests that BFR results in increased tendon stiffness based on biomechanical testing and subsequent calculations. No consistent detrimental histomorphological changes were seen.

CONTEXTO: Exercício de baixa carga com restrição do fluxo sanguíneo (RFS) tem sido cada vez mais utilizado por fisioterapeutas humanos para tratar lesões ortopédicas. Porém, seus efeitos no tendão flexor digital superficial (TFDS) de equinos não é conhecida. OBJETIVOS: O objetivo deste estudo foi investigar o efeito de específicas pressões com RFS durante o passo em cavalos sem lesão no TFDS, por meio de histologia e análise biomecânica. DELINEAMENTO DO ESTUDO: Estudo controlado. MÉTODOS: Quatro membros torácicos de quatro cavalos foram expostos a 40 sessões de RFS durante o passo (10 minutos de caminhada intervalada), ao longo de 56 dias. O membro contralateral foi utilizado como controle. Da mesma forma, quatro membros de quatro cavalos controle foram expostos a 40 sessões simuladas de caminhada com torniquete. No dia 56, todos os cavalos (n = 8) foram eutanasiados, e os TFDS foram submetidos a testes biomecânicos não destrutivos e análise histológica. A significância dos parâmetros biomecânicos entre tratamentos foi analisada utilizando ANOVA de efeitos mistos, seguida pelo teste de Tukey. RESULTADOS: A rigidez do TFDS foi estatisticamente diferente nos primeiros (p = 0.02) e últimos (p = 0.03) ciclos no grupo submetido à RFS, sendo os membros tratados significativamente mais rígidos do que os membros contralaterais não expostos ao tratamento. Quando normalizado para a área transversal, não foi observada diferença significativa entre os grupos de tratamento no módulo de elasticidade para os primeiros (p = 0.5) e últimos (p = 0.4) ciclos. Não foram identificadas diferenças histológicas nos diferentes tipos de tratamento, de acordo com os critérios de avaliação Bonar, Movin e de junção musculo­tendínea. PRINCIPAIS LIMITAÇÕES: Comparações de curto prazo foram realizadas em uma amostra pequena da população, sem correlação com medidas de resultados de desempenho. As porcentagens ideais de oclusão e os protocolos de caminhada permanecem desconhecidos. CONCLUSÕES: Este estudo não demonstrou impacto negativo do RFS na resistência mecânica do TFDS equino; no entanto, as evidências sugerem que a RFS resulta em aumento da rigidez do tendão com base em testes biomecânicos e cálculos subsequentes. Nenhuma alteração histológica prejudicial consistente foi observada.

Biological validation of faecal corticosterone metabolites as a non-invasive stress assessment in translocated California valley quail (Callipepla californica).

US quail species are vulnerable to population declines as a result of climate change, habitat loss and habitat fragmentation, all of which can result in physiological stress. Additionally, population restoration techniques (PRTs), like translocations, also induce stress. Traditional assessments of avian stress hormone levels include capturing and handling birds to extract blood, methods that are inherently stressful and can compound stress analyses. However, the stress hormone corticosterone (CORT) is metabolized from the blood and excreted in faeces as faecal corticosterone metabolites (FCMs). FCMs have been used as a non-invasive measurement of stress hormone levels in a variety of species, but must be validated for each species. The objective of this study was to biologically validate the use of FCMs as a non-invasive measurement of CORT levels in California valley quail (Callipepla californica). Reference and treatment quail were acclimated for 3 weeks in an outdoor aviary. Subsequently, treatment quail were subjected to a simulated 48-h translocation, a common and stress hormone-inducing PRT. Faecal samples were collected every 4 h and processed using an enzyme immunoassay. Mean FCM concentrations of treatment quail (41.50 ± 16.13 ng/g) were higher than reference FCM concentrations (24.07 ± 10.4 ng/g). These results biologically validate the use of FCMs as a non-invasive method to assess CORT levels in California valley quail, demonstrate diurnal variation in quail CORT levels, and confirm that quail translocations are a stress-inducing PRT. Ultimately, this research validates a new non-invasive tool for stress response measurement to advance quail research, management and conservation.

Safety, timing, and outcomes of early post-operative cardiac catheterisation following congenital heart surgery.

OBJECTIVE: The safety of early post-operative cardiac catheterisation has been described following congenital heart surgery. Optimal timing of early post-operative cardiac catheterisation remains uncertain. The aim of this study was to describe the safety of early post-operative cardiac catheterisation and its impact on cardiac ICU and hospital length of stay, duration of mechanical ventilation, and extracorporeal support. METHODS: This single-centre retrospective cohort study compared clinical and outcome variables between "early" early post-operative cardiac catheterisation (less than 72 hours after surgery) and "late" early post-operative cardiac catheterisation (greater than 72 hours after surgery) groups using Chi-squared, Student's t, and log-rank test (or appropriate nonparametric test). RESULTS: In total, 132 patients were included, 22 (16.7%) "early" early post-operative cardiac catheterisation, and 110 (83.3%) "late" early post-operative cardiac catheterisation. Interventions were performed in 63 patients (51.5%), 7 (11.1%) early and 56 (88.9%) late. Complications of catheterisation occurred in seven (5.3%) patients, two early and five late. There were no major complications. Patients in the late group trended towards a longer stay in the cardiac ICU (19 days [7, 62] versus 11.5 days [7.2, 31.5], p = 0.6) and in the hospital (26 days [9.2, 68] versus 19 days [13.2, 41.8], p = 0.8) compared to the earlier group. CONCLUSION: "Early" early post-operative cardiac catheterisation was associated with an overall low rate of complications. Earlier catheterisations trended towards shorter cardiac ICU and hospital length of stays. Earlier catheterisations may lead to earlier recovery for patients not following an expected post-operative course.

Effects of diets supplemented with bioactive peptides on nutrient digestibility, immune cell responsiveness, and fecal characteristics, microbiota, and metabolites of adult cats.

Bioactive peptides (BP) are recognized for their ability to function as antioxidants and maintain lipid stability. They may have positive health effects, including antihypertensive, anti-inflammatory, antimicrobial, osteoprotective, gut health and immunomodulatory properties, but are poorly tested in cats. Our primary objective was to determine the apparent total tract digestibility (ATTD) of BP-containing kibble diets and assess how the fecal characteristics, metabolites, and microbiota were affected in adult cats. Our secondary objective was to test whether BP could impact blood oxidative stress markers and cytokine concentrations following transport stress. Twelve adult cats (4.83±0.37 yr; 4.76±0.14 kg) were used in a replicated 4x4 Latin square design to test four extruded kibble diets: control (no BP), chicken (4% chicken BP), marine1 (2% marine BP), and marine2 (4% marine BP). Each experimental period lasted 28 days, with a 20-day adaptation phase, 5 days for fecal collection, 2 days for blood collection, and 1 day for transport stress testing (driven in vehicle in individual carriers for 45 minutes). Salivary cortisol and blood oxidative stress markers and cytokines were measured after transport. Fecal microbiota data were evaluated using 16S rRNA gene amplicon sequencing and QIIME2. All other data were analyzed using the Mixed Models procedure of SAS, with P<0.05 being considered significant and P<0.10 considered trends. No differences were observed in animal health outcomes, with all cats remaining healthy and serum metabolites remaining within reference ranges. Cats fed the marine2 diet had higher (P<0.05) ATTD of dry matter (84.5% vs. 80.9%) and organic matter (88.3% vs. 85.8%) than those fed the control diet. The ATTD of protein and energy tended to be higher (P<0.10) for cats fed the marine2 diet. Fecal characteristics, metabolites, and bacterial alpha and beta diversity measures were not affected by treatment. However, the relative abundances of six bacterial genera were different (P<0.05) and two bacterial genera tended to be different (P<0.10) across treatments. Treatment did not alter salivary cortisol, blood oxidative stress markers, or blood cytokines after transport stress. Our data suggest that BP inclusion may increase nutrient digestibility and modify fecal microbiota and immune measures. More testing is required, however, to determine whether BP may provide additional benefits to cats.

Rotational spectroscopy of methyl tert-butyl ether with a new Ka band chirped-pulse Fourier transform microwave spectrometer.

Chirped-pulse Fourier transform microwave (CP-FTMW) spectroscopy is a powerful tool for performing broadband gas-phase rotational spectroscopy, and its applications include discovery of new molecules, complex mixture analysis, and exploration of fundamental molecular physics. Here we report the development of a new Ka band (26.5-40 GHz) CP-FTMW spectrometer that is equipped with a pulsed supersonic expansion source and a heated reservoir for low-volatility samples. The spectrometer is built around a 150 W traveling wave tube amplifier and has an instantaneous bandwidth that covers the entire Ka band spectral range. To test the performance of the spectrometer, the rotational spectrum of methyl tert-butyl ether (MTBE), a former gasoline additive and environmental pollutant, has been measured for the first time in this spectral range. Over 1000 spectroscopic transitions have been measured and assigned to the vibrational ground state and a newly-identified torsionally excited state; all transitions were fit using the XIAM program to a root-mean-square deviation of 22 kHz. The spectrum displays internal rotation splitting, nominally forbidden transitions, and an intriguing axis-switching effect between the ground and torsionally excited state that is a consequence of MTBE's extreme near-prolate nature. Finally, the sensitivity of the spectrometer enabled detection of all singly-substituted 13C and 18O isotopologues in natural abundance. This set of isotopic spectra allowed for a partial r0 structure involving the heavy atoms to be derived, resolving a structural discrepancy in the literature between previous microwave and electron diffraction measurements.

Characterization of peer support services for substance use disorders in 11 US emergency departments in 2020: findings from a NIDA clinical trials network site selection process.

INTRODUCTION: Emergency departments (ED) are incorporating Peer Support Specialists (PSSs) to help with patient care for substance use disorders (SUDs). Despite rapid growth in this area, little is published regarding workflow, expectations of the peer role, and core components of the PSS intervention. This study describes these elements in a national sample of ED-based peer support intervention programs. METHODS: A survey was conducted to assess PSS site characteristics as part of site selection process for a National Institute on Drug Abuse (NIDA) Clinical Trials Network (CTN) evaluating PSS effectiveness, Surveys were distributed to clinical sites affiliated with the 16 CTN nodes. Surveys were completed by a representative(s) of the site and collected data on the PSS role in the ED including details regarding funding and certification, services rendered, role in medications for opioid use disorder (MOUD) and naloxone distribution, and factors impacting implementation and maintenance of ED PSS programs. Quantitative data was summarized with descriptive statistics. Free-text fields were analyzed using qualitative content analysis. RESULTS: A total of 11 surveys were completed, collected from 9 different states. ED PSS funding was from grants (55%), hospital funds (46%), peer recovery organizations (27%) or other (18%). Funding was anticipated to continue for a mean of 16 months (range 12 to 36 months). The majority of programs provided "general recovery support (81%) Screening, Brief Intervention, and Referral to Treatment (SBIRT) services (55%), and assisted with naloxone distribution to ED patients (64%). A minority assisted with ED-initiated buprenorphine (EDIB) programs (27%). Most (91%) provided services to patients after they were discharged from the ED. Barriers to implementation included lack of outpatient referral sources, barriers to initiating MOUD, stigma at the clinician and system level, and lack of ongoing PSS availability due to short-term grant funding. CONCLUSIONS: The majority of ED-based PSSs were funded through time-limited grants, and short-term grant funding was identified as a barrier for ED PSS programs. There was consistency among sites in the involvement of PSSs in facilitation of transitions of SUD care, coordination of follow-up after ED discharge, and PSS involvement in naloxone distribution.

Effects of a novel dental chew on oral health outcomes, halitosis, and microbiota of adult dogs.

Halitosis in dogs is an initial indication of periodontitis, highlighting its significance as a vital marker for underlying problems. Moreover, the oral microbial population has a significant influence on periodontal disease. Measuring the oral microbiota may be used in addition to breath odor, dental plaque, and gingivitis scoring to assess the impact of dental chews on oral health. In this study, we aimed to determine the differences in breath odor, oral health outcomes, and oral microbiota of adult dogs consuming a novel dental chew compared with control dogs consuming only a diet. Twelve healthy adult female beagle dogs were used in a crossover design study. Treatments (n = 12/group) included: diet only (control) or the diet + a novel dental chew. Each day, one chew was provided 4 h after mealtime. On days 1, 7, 14, 21, and 27, breath samples were analyzed for total volatile sulfur compound concentrations using a halimeter. On day 0 of each period, teeth were cleaned by a veterinary dentist blinded to treatments. Teeth were scored for plaque, calculus, and gingivitis by the same veterinary dentist on day 28 of each period. After scoring, subgingival and supragingival plaque samples were collected for microbiota analysis using Illumina MiSeq. All data were analyzed using SAS (version 9.4) using the Mixed Models procedure, with P < 0.05 being significant. Overall, the dental chews were well accepted. Dogs consuming the dental chews had lower calculus coverage, thickness, and scores, lower gingivitis scores, and less pocket bleeding than control dogs. Breath volatile sulfur compounds were lower in dogs consuming the dental chews. Bacterial alpha-diversity analysis demonstrated that control dogs had higher bacterial richness than dogs fed dental chews. Bacterial beta-diversity analysis demonstrated that samples clustered based on treatment. In subgingival and supragingival plaque, control dogs had higher relative abundances of potentially pathogenic bacteria (Pelistega, Desulfovibrio, Desulfomicrobium, Fretibacterium, Helcococcus, and Treponema) and lower relative abundances of genera associated with oral health (Neisseria, Actinomyces, and Corynebacterium). Our results suggest that the dental chew tested in this study may aid in reducing periodontal disease risk in dogs by beneficially shifting the microbiota population and inhabiting plaque buildup.

In this study, we aimed to determine the effects of a novel dental chew on the breath odor, oral health outcomes, and oral microbiota of dogs. Healthy adult dogs were used in a crossover design study to test a diet only (control) or the diet plus a novel dental chew. Each day, one chew was provided 4 h after mealtime. Breath samples were analyzed over time and teeth were scored for plaque, calculus, and gingivitis by a veterinary dentist on day 28 of each period. After scoring, subgingival and supragingival plaque samples were collected for microbiota analysis. Dogs consuming dental chews had lower calculus coverage, thickness, and scores, lower gingivitis scores, and less pocket bleeding than control dogs. Breath volatile sulfur compounds were lower in dogs consuming dental chews. Bacterial alpha-diversity was higher in control dogs than in dogs fed dental chews. Bacterial beta-diversity analysis demonstrated sample clustering based on treatment. Control dogs had higher relative abundances of potentially pathogenic bacteria and lower relative abundances of genera associated with oral health. Our results suggest that the dental chew tested may aid in reducing periodontal disease risk in dogs by beneficially shifting microbiota and inhabiting plaque buildup.

Glucocorticoid receptor and specificity protein 1 (Sp1) or Sp3, but not the antibiotic Mithramycin A, stimulates human alphaherpesvirus 1 (HSV-1) replication.

Following acute human alphaherpesvirus 1 (HSV-1) infection of oral-facial mucosal surfaces, sensory neurons in trigeminal ganglia (TG) are important sites for life-long latency. Neurons in the central nervous system, including brainstem, also harbor viral genomes during latency. Periodically, certain cellular stressors trigger reactivation from latency, which can lead to recurrent HSV-1 disease: herpes labialis, herpes stromal keratitis, and encephalitis for example. Activation of the glucocorticoid receptor (GR) by stressful stimuli enhances HSV-1 gene expression, replication, and explant-induced reactivation. GR and certain stress-induced Krüppel like factors (KLF) cooperatively transactivate cis-regulatory modules (CRM) that drive expression of viral transcriptional regulatory proteins (ICP0, ICP4, and ICP27). These CRMs lack GR response elements (GRE); however, specificity protein 1 (Sp1) binding sites are crucial for GR and KLF15 or KLF4 mediated transactivation. Hence, we tested whether Sp1 or Sp3 regulate viral replication and transactivation of the ICP0 promoter. During early stages of explant-induced reactivation from latency, the number of Sp3+ TG neurons were significantly higher relative to TG from latently infected mice. Conversely, Sp1+ TG neurons were only increased in females, but not male mice, during explant-induced reactivation. Sp1 siRNA significantly reduced HSV-1 replication in cultured mouse (Neuro-2A) and monkey (CV-1) cells. Mithramycin A, an antibiotic that has anti-tumor activity preferentially interacts with GC-rich DNA, including Sp1 binding sites, significantly reduced HSV-1 replication indicating it has antiviral activity. GR and Sp1 or Sp3 transactivated the HSV-1 ICP0 promoter in Neuro-2A and CV-1 cells confirming these transcription factors enhance viral replication and gene expression.

The common marmoset as a translational model of age-related osteoarthritis.

Age-related osteoarthritis (OA) is a degenerative joint disease characterized by pathological changes in nearly every intra- and peri-articular tissue that contributes to disability in older adults. Studying the etiology of age-related OA in humans is difficult due to an unpredictable onset and insidious nature. A barrier in developing OA modifying therapies is the lack of translational models that replicate human joint anatomy and age-related OA progression. The purpose of this study was to determine whether the common marmoset is a faithful model of human age-related knee OA. Semi-quantitative microCT scoring revealed greater radiographic OA in geriatric versus adult marmosets, and the age-related increase in OA prevalence was similar between marmosets and humans. Quantitative assessments indicate greater medial tibial cortical and trabecular bone thickness and heterogeneity in geriatric versus adult marmosets which is consistent with an age-related increase in focal subchondral bone sclerosis. Additionally, marmosets displayed an age-associated increase in synovitis and calcification of the meniscus and patella. Histological OA pathology in the medial tibial plateau was greater in geriatric versus adult marmosets driven by articular cartilage damage, proteoglycan loss, and altered chondrocyte cellularity. The age-associated increase in medial tibial cartilage OA pathology and meniscal calcification was greater in female versus male geriatric marmosets. Overall, marmosets largely replicate human OA as evident by similar 1) cartilage and skeletal morphology, 2) age-related progression in OA pathology, and 3) sex differences in OA pathology with increasing age. Collectively, these data suggest that the common marmoset is a highly translatable model of the naturally occurring, age-related OA seen in humans.

Evaluating the effects of hypoxic storage on platelet function and health using a novel storage system.

BACKGROUND: Thousands of units of whole blood (WB) and blood components are transfused daily to treat trauma patients. Improved methods for blood storage are critical to support trauma-related care. The Hemanext ONE® system offers a unique method for hypoxic storage of WB, with successfully demonstrated storage of clinically viable RBCs. This work evaluated the system for the storage of WB, focusing on platelet health and function. STUDY DESIGN AND METHODS: WB was collected from healthy donors and processed through the Hemanext ONE® system. Hemoglobin oxygen saturation (HbSO2) levels of WB were depleted to 10%, 20%, or 30% of total HbSO2 and then stored in PVC bags sealed in oxygen-impermeable bags (except for normoxic control) with samples collected on days 1, 7, and 14 post-processing. Flow cytometry assessed the activation and apoptosis of platelets. Clot dynamics were assessed based on aggregometry and thromboelastography assays, as well as thrombin generation using a calibrated-automated thrombogram method. RESULTS: Hypoxic storage conditions were maintained throughout the storage period. Hypoxia triggered increased lactate production, but pH changes were negligible compared to normoxic control. Storage at 10% HbSO2 had a significant impact on platelet function, resulting in increased activation and reduced clot formation and aggregation. These effects were less significant at 20% and 30% HbSO2. DISCUSSION: This study indicates that platelets are sensitive to hypoxic storage and suffer significant metabolic and functional deterioration when stored at or below 10% HbSO2.

Cancer patients with clonal hematopoiesis die from primary malignancy or comorbidities despite higher rates of transformation to myeloid neoplasms.

BACKGROUND: The occurrence of somatic mutations in patients with no evidence of hematological disorders is called clonal hematopoiesis (CH). CH, whose subtypes include CH of indeterminate potential and clonal cytopenia of undetermined significance, has been associated with both hematologic cancers and systemic comorbidities. However, CH's effect on patients, especially those with concomitant malignancies, is not fully understood. METHODS: We performed a retrospective evaluation of all patients with CH at a tertiary cancer center. Patient characteristics, mutational data, and outcomes were collected and analyzed. RESULTS: Of 78 individuals included, 59 (76%) had a history of cancer and 60 (77%) had moderate to severe comorbidity burdens. DNMT3A, TET2, TP53, and ASXL1 were the most common mutations. For the entire cohort, the 2-year overall survival rate was 79% (95% CI: 70, 90), while the median survival was not reached. Of 20 observed deaths, most were related to primary malignancies (n = 7, 35%), comorbidities (n = 4, 20%), or myeloid neoplasms (n = 4, 20%). Twelve patients (15%) experienced transformation to a myeloid neoplasm. According to the clonal hematopoiesis risk score, the 3-year transformation rate was 0% in low-risk, 15% in intermediate-risk (p = 0.098), and 28% in high-risk (p = 0.05) patients. By multivariate analysis, transformation was associated with variant allele frequency ≥0.2 and hemoglobin <10 g/dL. CONCLUSIONS: In a population including mostly cancer patients, CH was associated with comorbidities and myeloid transformation in patients with higher mutational burdens and anemia. Nevertheless, such patients were less likely to die of their myeloid neoplasm than of primary malignancy or comorbidities.

Distribution of Cronartium x flexili, an interspecific hybrid of two fungal tree rust pathogens, in subalpine forest ecosystems of western USA.

Interspecific hybridization plays a key role in the evolution of novel fungal pathogens, and when it occurs between native and invasive species, can lead to potentially serious consequences. In this study, we examined the temporal and spatial distribution of a recently detected hybrid (Cronartium x flexili) of two tree pathogens, invasive to North America Cronartium ribicola and native Cronartium comandrae. In total, 726 and 1452 aecia from 178 Pinus contorta ssp. latifolia and 357 Pinus flexilis trees were collected from 26 sites in four national forests in 2019-2021. Using morphological and molecular analyses, 71 aecia collected from 25 P. flexilis trees had intermediate morphology and contained heterozygous SNPs in two genomic regions. Population analyses revealed the presence of multiple hybrid genotypes randomly distributed among sites and years. No aecia from P. contorta ssp. latifolia were identified as hybrids suggesting unidirectional gene flow from native C. comandrae to invasive C. ribicola. Aeciospores from 2 hybrid aecia produced urediniospores on Ribes nigrum. Overall, these results suggest that, even though low in frequency, C. x flexili is persistent in the region and has pathogenic potential. Hybrid expansion into the large range of susceptible pines could have cascading impacts on forest health.

Cytogenetic and Molecular Associations with Outcomes in Higher-Risk Myelodysplastic Syndromes Treated with Hypomethylating Agents plus Venetoclax.

PURPOSE: Hypomethylating agents (HMA) combined with venetoclax are an emerging therapeutic strategy for higher-risk myelodysplastic syndromes (HR-MDS). The cytogenetic and molecular factors associated with outcomes with this combination for HR-MDS are incompletely understood. EXPERIMENTAL DESIGN: We pooled patient data from 3 prospective trials evaluating HMA-venetoclax in HR-MDS to study associations between cytogenetic and molecular factors and overall response rate (ORR), overall survival (OS), and event-free survival (EFS). The Kaplan-Meier method was used to estimate time-to-event endpoints. Univariate and multivariate analyses using logistic regression (for ORR) or the Cox proportional hazards model (for OS and EFS) were used to identify associations between clinical, cytogenetic, and molecular factors and outcomes. RESULTS: A total of 80 patients (52 HMA-naïve, 28 HMA-failure) were included. ORR was 90% in HMA-naïve and 57% in HMA-failure. Median OS was 28.2 and 8.3 months in HMA-naïve and HMA-failure, respectively. Median EFS was 17.9 and 5.5 months in HMA-naïve and HMA-failure, respectively. In addition, 24/52 (46%) of the HMA-naïve and 3/28 (11%) of the HMA-failure patients proceeded to allogeneic stem cell transplantation (SCT). Factors associated with inferior outcomes were prior HMA failure, complex cytogenetics, trisomy 8, TP53 mutations, and RAS pathway mutations. Mutations in RNA splicing, DNA methylation, and ASXL1 appeared favorable. Blast percentage was not predictive of outcomes. CONCLUSIONS: Knowledge of cytogenetic and molecular alterations may help identify which patients with HR-MDS benefit the most from venetoclax.

Arterial blood gas measurements are different for brachycephalic and nonbrachycephalic dogs acclimatized to an altitude of 1,535 meters.

OBJECTIVE: To define reference intervals (RIs) for arterial blood gas (aBG) measurements in healthy, nonsedated, dolichocephalic, and mesocephalic (nonbrachycephalic) dogs at approximately 1,535 m above sea level and compare these findings with healthy, nonsedated, brachycephalic dogs living at the same altitude. ANIMALS: 120 adult nonbrachycephalic dogs and 20 adult brachycephalic dogs. METHODS: Cases were prospectively enrolled from October 2021 to June 2022. Dogs were enrolled from the community or after presentation for wellness examinations or minor injuries including lacerations, nail injuries, and lameness. Physical examinations and systolic blood pressure (sBP) measurements were obtained before blood sample collection. Arterial blood was collected from the dorsal pedal artery or femoral artery. After data collection, brachycephalic dogs underwent pre- and postexercise tolerance assessments. RESULTS: The mean and RI values for arterial pH (7.442; 7.375 to 7.515), partial pressure of oxygen in arterial blood (Pao2; 78.3; 59.2 to 92.7 mm Hg), partial pressure of carbon dioxide in arterial blood (Paco2; 28.0; 21.5 to 34.4 mm Hg), saturation of arterial oxygen (Sao2; 98.4; 84.3% to 101.4%), HCO3 (18.9; 14.9 to 22.4 mmol/L), concentration of total hemoglobin (ctHb; 17.5; 13.4 to 21.1 g/dL), and sBP (133; 94 to 180 mm Hg) were established for healthy nonbrachycephalic dogs at 1,535-m altitude. All aBG measurements were statistically and clinically different from those previously reported for dogs at sea level. Brachycephalic dogs had significantly lower Pao2 and Sao2 (P = .0150 and P = .0237, respectively) and significantly higher ctHb (P = .0396) compared to nonbrachycephalic dogs acclimatized to the same altitude; the nonbrachycephalic RIs were not transferable to the brachycephalic dogs for Pao2. CLINICAL RELEVANCE: This study represents the first collation of aBG measurements for healthy nonbrachycephalic dogs acclimatized to an altitude of 1,535 m. Additionally, this study identified differences in arterial oxygenation measurements between brachycephalic and nonbrachycephalic dogs. RIs in brachycephalic dogs need to be established.