RuBi-Ruxolitinib: A Photoreleasable Antitumor JAK Inhibitor.

We describe the synthesis and biological testing of ruthenium-bipyridine ruxolitinib (RuBiRuxo), a photoreleasable form of ruxolitinib, a JAK inhibitor used as an antitumoral agent in cutaneous T-cell lymphomas (CTCL). This novel caged compound is synthesized efficiently, is stable in aqueous solution at room temperature, and is photoreleased rapidly by visible light. Irradiation of RuBiRuxo reduces cell proliferation and induces apoptosis in a light- and time-dependent manner in a CTCL cell line. This effect is specific and is mediated by a decreased phosphorylation of STAT proteins. Our results demonstrate the potential of ruthenium-based photocompounds and light-based therapeutic approaches for the potential treatment of cutaneous lymphomas and other pathologies.

A methodology for specific disruption of microtubule polymerization into dendritic spines.

Dendritic spines, the mushroom-shaped extensions along dendritic shafts of excitatory neurons, are critical for synaptic function and are one of the first neuronal structures disrupted in neurodevelopmental and neurodegenerative diseases. Microtubule (MT) polymerization into dendritic spines is an activity-dependent process capable of affecting spine shape and function. Studies have shown that MT polymerization into spines occurs specifically in spines undergoing plastic changes. However, discerning the function of MT invasion of dendritic spines requires the specific inhibition of MT polymerization into spines, while leaving MT dynamics in the dendritic shaft, synaptically connected axons and associated glial cells intact. This is not possible with the unrestricted, bath application of pharmacological compounds. To specifically disrupt MT entry into spines we coupled a MT elimination domain (MTED) from the Efa6 protein to the actin filament-binding peptide LifeAct. LifeAct was chosen because actin filaments are highly concentrated in spines and are necessary for MT invasions. Temporally controlled expression of this LifeAct-MTED construct inhibits MT entry into dendritic spines, while preserving typical MT dynamics in the dendrite shaft. Expression of this construct will allow for the determination of the function of MT invasion of spines and more broadly, to discern how MT-actin interactions affect cellular processes.

A Methodology for Specific Disruption of Microtubules in Dendritic Spines.

Dendritic spines, the mushroom-shaped extensions along dendritic shafts of excitatory neurons, are critical for synaptic function and are one of the first neuronal structures disrupted in neurodevelopmental and neurodegenerative diseases. Microtubule (MT) polymerization into dendritic spines is an activity-dependent process capable of affecting spine shape and function. Studies have shown that MT polymerization into spines occurs specifically in spines undergoing plastic changes. However, discerning the function of MT invasion of dendritic spines requires the specific inhibition of MT polymerization into spines, while leaving MT dynamics in the dendritic shaft, synaptically connected axons and associated glial cells intact. This is not possible with the unrestricted, bath application of pharmacological compounds. To specifically disrupt MT entry into spines we coupled a MT elimination domain (MTED) from the Efa6 protein to the actin filament-binding peptide LifeAct. LifeAct was chosen because actin filaments are highly concentrated in spines and are necessary for MT invasions. Temporally controlled expression of this LifeAct-MTED construct inhibits MT entry into dendritic spines, while preserving typical MT dynamics in the dendrite shaft. Expression of this construct will allow for the determination of the function of MT invasion of spines and more broadly, to discern how MT-actin interactions affect cellular processes.

Development of the Valued Living Questionnaire - Comprehension Support version (VLQ-CS) and validation in adults with acquired brain injury.

PURPOSE: Valued living (acting in accordance with personal values) is associated with better outcomes after acquired brain injury (ABI), but its measurement using the Valued Living Questionnaire (VLQ) may not be valid due to comprehension errors relating to structure and content. We aimed to modify the VLQ to improve its accessibility and evaluate construct validity and reliability in an ABI cohort. MATERIALS AND METHODS: Adaptations made in the VLQ - Comprehension Support version (VLQ-CS) used established communication support methods and addressed common comprehension errors. 103 community-dwelling participants (34% female; mean age 52.17, range 19-79) with ABI (66% stroke, 16% TBI, 18% other) completed the VLQ-CS, and measures of convergent (valued living, mood, wellbeing, psychological inflexibility) and divergent validity (subjective memory). Test-retest reliability was evaluated with repeated administrations 6-8 weeks apart for a subset of participants (n = 44), using Intraclass Correlation Coefficients (ICCs). RESULTS: Convergent validity was supported; VLQ-CS scores were positively correlated with measures of valued living (r=.60-.65) and wellbeing (r=.64-.67), and negatively correlated with depression (r=-0.56-.58), anxiety (r=-0.35-.38) and psychological inflexibility (r=-0.37-.41). Divergent validity was marginal (r=-0.29). Test-retest reliability was good for the VLQ-CS Composite score (ICC=.80). CONCLUSIONS: The VLQ-CS shows promise as a valid, reliable measure of valued living post-ABI. Future research should extend to neurotypical and other clinical populations.

Valued living or values-based action is associated with better functional and psychosocial outcomes after acquired brain injury (ABI) and is therefore an important target for intervention.Measurement of valued living needs to be clear, easily understood, and relevant for people with cognitive and communication impairments associated with ABI and other conditions.The Valued Living Questionnaire ­ Comprehension Support version (VLQ-CS) was developed to optimise accessibility and reduce comprehension errors.The VLQ-CS is valid, reliable and fit-for-purpose as a measure of valued living for people with ABI.

Romidepsin and Afatinib Abrogate Jak-Signal Transducer and Activator of Transcription Signaling and Elicit Synergistic Antitumor Effects in Cutaneous T-Cell Lymphoma.

Cutaneous T-cell lymphomas are mature lymphoid neoplasias resulting from the malignant transformation of skin-resident T-cells. A distinctive clinical feature of cutaneous T-cell lymphomas is their sensitivity to treatment with histone deacetylase inhibitors. However, responses to histone deacetylase inhibitor therapy are universally transient and noncurative, highlighting the need for effective and durable drug combinations. In this study, we demonstrate that the combination of romidepsin, a selective class I histone deacetylase inhibitor, with afatinib, an EGFR family inhibitor, induces strongly synergistic antitumor effects in cutaneous T-cell lymphoma models in vitro and in vivo through abrogation of Jak-signal transducer and activator of transcription signaling. These results support a previously unrecognized potential role for histone deacetylase inhibitor plus afatinib combination in the treatment of cutaneous T-cell lymphomas.

Snow depth influences harvest of a boreal ungulate more than socio-economic factors: Implications for food security in a changing climate.

Climate change may affect the ability of hunters to harvest wildlife and, hence, threaten food security of local people. However, few studies have investigated the relative influence of environmental conditions on wildlife harvest rates. We harnessed a 24-year dataset of harvest dates for a boreal ungulate in a region where climate change is having pronounced impacts on snow depth, precipitation, and temperatures to investigate the effect of weather on harvest rates. We used generalized linear models and a model selection framework to examine the influence of weather covariates (snow depth, mean daily temperature, precipitation) and socio-economic factors (gasoline and red meat prices, employment rates, and moose [Alces americanus] harvest) on harvest rates of bison (Bison bison) in Yukon, Canada, at two temporal scales: annual and daily. At an annual scale, snow depth was the only covariate that was important in explaining bison harvest. No socioeconomic variables improved our model beyond the null. At the daily scale, snow depth and mean daily temperature influenced bison harvest rates, with a 1 SD increase resulting in a 14 % and 9 % increase in daily harvest rates, respectively. Increased snow depth facilitates ease of travel in remote, roadless areas by snowmobile to locate bison and truncates movements of bison, resulting in increased harvest rates. Decreased snow depth due to climate change will impact hunter access to boreal ungulates and food security for northern people. More broadly, our data suggests that in some socioecological systems, environmental covariates have a greater influence on wildlife harvest rates than socioeconomic factors and need to be considered in future studies to better understand and predict harvest rates.

Clinical impact of a multifaceted intervention aimed at decreasing distress in people living with dementia: evaluating the Reconnect program.

Background: To better meet the needs of people living with advanced dementia, Orchard Care Homes, United Kingdom have established an enhanced person focused program, namely the Reconnect program, which provides an enriched psycho-social care to enhance peoples' quality of life and well-being. Here we aimed to review the impact of this program on people living with dementia. Methods: In this study the implementation of the Reconnect program was evaluated for two six-month periods (April-September 2020 and April-September 2021). The focus of this evaluation was on three key interventions: increasing meaningful occupation and engagement; improving pain identification and management, and reducing constipation. The Reconnect program was conducted in a single for-profit care home. It involved residents with complex dementia needs who previously not responded to support in alternative settings or found previous care ineffective in relieving their distress and reducing risks they pose to themselves or others. Results: A total of 24 people participated in the program during this evaluation. We observed a substantial increase in engagement in meaningful activity per person, including an increase of outdoor access to fresh air. Pain management improved as evidenced by more standardized pain assessments using the PainChek system and coverage of people with either regular and/or "when required" pain management. Constipation relief also improved. For the two comparison periods, distress responses per resident reduced from 14.5 to 10.6 events and use of regular pain relief increased from 21.7 to 48.1%. Use of "when required" benzodiazepine halved from 6 months average of 46 to 23.2 doses given. Benzodiazepine dose reductions increased from 13.3 to 31.8%, while cessations increased from 20 to 50%. We also observed a reduction from 76.3 to 56.3% in antipsychotic use. Their dose reductions increased from 8.3 to 40% and drug cessation was made in 30% of people using antipsychotics (compared to the first period in which no medication cessation was observed). A 91.7% reduction (i.e., from 36 to 3 events) in safeguarding events related to behaviors was also observed. Conclusion: Introduction of the Reconnect program, through its interventions focused on meaningful activity engagement, pain management and constipation relief resulted in substantial improvements related to people's distress, safeguarding and psychotropic use.

Influence of fiber type and carbohydrase supplementation on nutrient digestibility, energy and nitrogen balance, and physiology of sows at mid and late gestation.

Carbohydrase supplementation in grow-finish pig diets improves energy, nutrient digestibility, and gastrointestinal function, but their efficacy in gestation diets is understudied. The experimental objective was to evaluate the efficacy of a multicarbohydrase to improve digestion, energetics, and various physiological functions in gestating sows fed soluble and insoluble fiber diets. On day 28 of gestation, 36 sows (186 ±â€…4.6 kg body weight), blocked by parity, were randomly assigned to a 2 × 2 factorial arrangement of dietary treatments (n = 9). Factors included fiber type of insoluble (IF; 20% dried distiller grains with solubles) or soluble fiber (SF; 20% sugar beet pulp) and with (+) or without (-) enzyme (0.05%, Rovabio Advance P10; Adisseo, Antony, France). Diets were fed from days 28 to 109 of gestation at a feeding level of 2.1 kg (SID-Lys 11 g/d and 4.5 net energy-Mcal/d). Two separate 9-d metabolism periods were conducted on days 50 to 59 (mid) and 99 to 108 (late) of gestation. During each period, days 1 to 3 served as an adaptation period, days 4 to 7 total urine and feces were collected (96-h) and followed by a 48-h lactulose-mannitol study. Serum and plasma were collected on days 50 and 99. Data were analyzed as repeated records using a linear mixed model with block as a random effect and fiber type, enzyme, and period and their interactions as fixed effects. Sows fed SF+ had increased serum IL-1ra (Fiber × Enzyme P = 0.035), and IL-2 (Fiber × Enzyme P = 0.042). In the presence of IF, multicarbohydrases increased serum lipopolysaccharide-binding protein, but not when supplemented with SF (Fiber × Enzyme P = 0.028). Circulating IL-8 and TNF-α were decreased in sows fed multicarbohydrases (P < 0.05). Multicarbohydrase supplementation increased the apparent total tract digestibility (ATTD) of gross energy (GE), dry matter, and neutral detergent fiber by 2.8%, 3.4%, and 8.3%, respectively (P < 0.05). Compared to IF-, the ATTD of hemicellulose was 5.3% greater in sows fed IF+ but did not differ from SF- and SF+ (Fiber × Enzyme P = 0.037). Sows fed IF+ had the greatest ATTD of insoluble dietary fiber (Fiber × Enzyme P = 0.011). Sows fed multicarbohydrases excreted less energy in their urine (519 vs. 469 GE kcal/d; Enzyme P = 0.033) and in their feces (985 vs. 900 GE kcal/d; Enzyme P = 0.003). This resulted in an improvement in both digestible energy (Enzyme P < 0.01) and metabolizable energy (Enzyme P = 0.041), irrespective of fiber type. In conclusion, multicarbohydrase supplementation increased the digestibility and energetic contribution of fiber, irrespective of adaptation time or fiber type, but modulation of inflammatory responses was unique to dietary fiber type.

This study evaluated the effects and mechanisms of supplementing multicarbohydrases to gestating sow diets containing either corn-dried distiller grains or sugar beet pulp fibrous co-products. Findings revealed significant energy, dry matter, and fiber digestibility enhancements with carbohydrase supplementation, irrespective of adaptation time. However, the interaction between enzyme supplementation and fiber type led to distinct immune marker responses. Specifically, granulocyte-macrophage colony-stimulating factor, interleukin-1 receptor antagonist, and interleukin-2 responses differed based on the presence of insoluble or soluble fiber. Sows in late gestation have greater nutrient and energy digestibility and altered nitrogen balance relative to day 50 of gestation. These findings highlight the potential benefits of incorporating carbohydrases into gestating sow diets to improve nutrient utilization and metabolic efficiency. Moreover, the study underscores the intricate interplay between enzyme supplementation, adaptation time, dietary fiber characteristics, and immune responses, offering valuable insights into the underlying mechanisms governing sow physiology during gestation and the influence of enzyme supplementation.

An estimation of osteochondrodysplasia prevalence in Australian Scottish Fold cats: a retrospective study using VetCompass Data.

BACKGROUND: All Scottish Fold cats are believed to be affected by osteochondrodysplasia, a painful degenerative joint disorder. This retrospective study aimed to estimate the prevalence of osteochondrodysplasia in Scottish Fold and Scottish Straight cats in Australian veterinary clinics using electronic patient records (EPRs), collected between 1992 and 2018. RESULTS: Consultation events (34,926) in EPRs from veterinary clinics located in New South Wales, Queensland, and Victoria, were collected from 1,131 Scottish Fold and 117 Scottish Shorthair cats. A clinical diagnosis of osteochondrodysplasia was made in 12/1,131 Scottish Fold cats. Additionally, 69 cats were identified with suspected osteochondrodysplasia. Of these, 64 were Scottish Fold and 5 were Scottish Shorthair cats. Male and female cats were equally represented. However, a significant difference was observed for the age clinical signs were first recorded in the EPRs. Cats diagnosed clinically with osteochondrodysplasia were significantly younger (p < 0.0001) compared to cats identified as suspected SFOCD cases. CONCLUSIONS: Findings from this study suggest a relatively low prevalence of clinically diagnosed Scottish Fold osteochondrodysplasia (SFOCD) in the studied Australian Scottish Fold population, with cats generally diagnosed with SFOCD at less than 30 months of age. Further evidence is required to accurately assess the clinical relevance of SFOCD in the Scottish Fold population.

The Association of Cardiovascular and Neurological Comorbidities in Geriatric Patients Sustaining Ocular Trauma.

Purpose: Falls are associated with ocular trauma in the elderly. However, it is unlikely for a fall to cause ocular injury unless there is a disruption in the protective maneuvers that shield the face. We suspect ocular injury may be an early indicator of systemic or neurologic degeneration. This study investigates the 5-year incidence of cardiovascular and neurodegenerative diseases in older patients who sustained ocular or periorbital injuries. Patients and Methods: This was a retrospective cohort study. The study population included 141 patients over the age of 65 who sustained trauma to the eye, orbit, or eyelid between April 2011 and June 2016. The control population included 141 patients with a similar range of comorbidities who received cataract surgery during the same period. The study measured new diagnoses of various disorders during the 5-year period following presentation. Results: There were a total of 180 females and 102 males in the study. The mean ages of the control and subject group were 76 and 81.8, respectively. Of our twelve tested comorbidity types, patients that suffered a periocular trauma were more likely to develop heart failure (p=0.00244), dementia (p=0.00002), Alzheimer's disease (p=0.00087), and vascular disease (p=0.00037). Conclusion: Geriatric patients who sustained ocular and periocular injuries had a greater incidence of heart failure, dementia, Alzheimer's disease, and atherosclerosis diagnoses in the 5-year period following injury. The findings of this study suggest that periocular trauma may be an early indicator of underlying degenerative or systemic disease. Ophthalmologists should ensure proper primary care follow-up in conjunction with recovery from injury.

Two-dimensional modeling of CO2 mineral trapping through the oxalate­carbonate pathway: Influence of the root system model.

Two-dimensional reactive transport models, one with a simplified root system and the other accounting for dynamically evolving root architecture, were constructed to examine the influence of model complexity on capturing the effect of soil-root dynamics relating to the Oxalate Carbonate Pathway (OCP) of the Iroko tree over 170 years. Oxidation of oxalate from fallen tree tissue by soil bacteria enables local soil pH increase, leading to the sequestration of atmospheric carbon in carbonate minerals (calcite) in the shallow soil surrounding the tree. Simulations of both root models corroborate previous one-dimensional models of the OCP focused on Ca and C mass balance, where high weathering rates of Ca-containing silicate minerals in bedrock, along with contributions from groundwater, provided sufficient Ca for precipitation of observed quantities of calcite. Both simulations demonstrate the development of a distinct high pH zone where oxalate is oxidized, Ca accumulates, and calcite precipitates (OCP zone); and a low pH zone where roots collect Ca, later returned to the top soil as calcium oxalate (Total Root Extent/TRE zone) via litterfall. While the extent of OCP zone development near the ground surface was very similar between simulations, differences in localized root water uptake between the two approaches resulted in variation in water and solute transport and influenced the geometry of the OCP zone at depth, with implications for calcite precipitation in the soil. Trends in CO2 and O2 partial pressures in the OCP zone were mirrored in the TRE zone, suggesting linkage between the two zones with regard to gas transport. Near the end of the tree's lifespan, results indicate that soil permeability decreases due to calcite precipitation may limit O2 ingress and availability in the shallow soil, while trapping CO2 released from the oxidation of organics in the shallow soil, with implications for the long-term sustainability of the OCP itself.

Frail Multiple Myeloma Patients Deserve More Than Just a Score.

Frailty is a hot topic in the field of multiple myeloma (MM). Clinicians have realised that frail myeloma patients can struggle with treatment, resulting in dose reductions and treatment discontinuation, which risk shorter progression-free and overall survival. Efforts have focused on the validity of existing frailty scores and on the development of new indices to identify frail patients more accurately. This review article explores the challenges of the existing frailty scores, including the International Myeloma Working Group (IMWG) frailty score, the revised Myeloma Co-morbidity Index (R-MCI), and the Myeloma Risk Profile (MRP). We conclude that the missing link is for frailty scoring to translate into a tool useful in real-world clinical practice. The future of frailty scores lies in their ability to be woven into clinical trials, to create a robust clinical evidence base for treatment selection and dose modification, and also to identify a cohort of patients who merit additional support from the wider MM multidisciplinary team.

Curvafix: A novel implant for pelvic fragility fractures.

Fragility fractures of the pelvis are a frequently encountered injury in orthopedic practice. These injuries occur in patients with diminished bone density secondary to low energy mechanisms. This injury is associated with increased mortality and decreased quality of life. These fractures have been treated conservatively and with open or percutaneous surgical fixation. This case report illustrates the use of the Curvafix, a novel intramedullary implant used to treat a patient with a pelvic fragility fracture.

Improving Time to Stat Intravenous Antibiotic Administration: An 8-Year Quality Initiative.

BACKGROUND AND OBJECTIVES: Prompt antibiotics have been shown to improve outcomes in pediatric sepsis, which continues to be a leading cause of death in children. We describe the quality improvement (QI) efforts of a single academic children's hospital to improve antibiotic timeliness. METHODS: Using the electronic health record, we report time from order to the administration of stat intravenous (IV) antibiotics from 2012 to 2020 using statistical process control charts. We describe QI interventions initiated over the study period. These include the formation of a Pediatric Sepsis Committee, routine use of automated dispensing machines for stat IV antibiotics, creation of sepsis order sets, manual and automated sepsis screening implementation, participation in national sepsis QI collaboratives, creation of difficult intravenous access guidelines, and an automated notification system for charge nurses. As a balancing measure, we assessed stat IV antibiotic use normalized to total emergency department visits and inpatient days. RESULTS: Multiple quality improvement interventions were initiated and sustained under the direction of the hospital Pediatric Sepsis Committee. We improved our stat IV antibiotics given within 1 hour of order from 33% in 2012 to 77% in 2019 and maintained this through the end of the study period in July 2020. CONCLUSIONS: By using a multipronged quality improvement approach, we demonstrated consistent and sustained improvement in the timely administration of stat IV antibiotics over an 8-year period at our institution. Further study is needed to assess whether this is associated with reduced length of stay or improved survival in children with sepsis.

Characterization and Function of Cryopreserved Bone Marrow from Deceased Organ Donors: A Potential Viable Alternative Graft Source.

Despite the readily available graft sources for allogeneic hematopoietic cell transplantation (alloHCT), a significant unmet need remains in the timely provision of suitable unrelated donor grafts. This shortage is related to the rarity of certain HLA alleles in the donor pool, nonclearance of donors owing to infectious disease or general health status, and prolonged graft procurement and processing times. An alternative hematopoietic progenitor cell (HPC) graft source obtained from the vertebral bodies (VBs) of deceased organ donors could alleviate many of the obstacles associated with using grafts from healthy living donors or umbilical cord blood (UCB). Deceased organ donor-derived bone marrow (BM) can be preemptively screened, cryogenically banked for on-demand use, and made available in adequate cell doses for HCT. We have developed a good manufacturing practice (GMP)-compliant process to recover and cryogenically bank VB-derived HPCs from deceased organ donor (OD) BM. Here we present results from an analysis of HPCs from BM obtained from 250 deceased donors to identify any substantial difference in composition or quality compared with HPCs from BM aspirated from the iliac crests of healthy living donors. BM from deceased donor VBs was processed in a central GMP facility and packaged for cryopreservation in 5% DMSO/2.5% human serum albumin. BM aspirated from living donor iliac crests was obtained and used for comparison. A portion of each specimen was analyzed before and after cryopreservation by flow cytometry and colony-forming unit potential. Bone marrow chimerism potential was assessed in irradiated immunocompromised NSG mice. Analysis of variance with Bonferroni correction for multiple comparisons was used to determine how cryopreservation affects BM cells and to evaluate indicators of successful engraftment of BM cells into irradiated murine models. The t test (with 95% confidence intervals [CIs]) was used to compare cells from deceased donors and living donors. A final dataset of complete clinical and matched laboratory data from 226 cryopreserved samples was used in linear regressions to predict outcomes of BM HPC processing. When compared before and after cryopreservation, OD-derived BM HPCs were found to be stable, with CD34+ cells maintaining high viability and function after thawing. The yield from a single donor is sufficient for transplantation of an average of 1.6 patients (range, 1.2 to 7.5). CD34+ cells from OD-derived HPCs from BM productively engrafted sublethally irradiated immunocompromised mouse BM (>44% and >67% chimerism at 8 and 16 weeks, respectively). Flow cytometry and secondary transplantation confirmed that OD HPCs from BM is composed of long-term engrafting CD34+CD38-CD45RA-CD90+CD49f+ HSCs. Linear regression identified no meaningful predictive associations between selected donor-related characteristics and OD BM HPC quality or yield. Collectively, these data demonstrate that cryopreserved BM HPCs from deceased organ donors is potent and functionally equivalent to living donor BM HPCs and is a viable on-demand graft source for clinical HCT. Prospective clinical trials will soon commence in collaboration with the Center for International Blood and Marrow Research to assess the feasibility, safety, and efficacy of Ossium HPCs from BM (ClinicalTrials.gov identifier NCT05068401).

Impact of water flow rate on finishing pig performance.

A survey of 23 South Dakota pork producers in 2019 reported that 68% of the waterers in finishing barns had water flow rates above the recommended rate of 500-1,000 mL/min. The objective of the two studies was to determine the impact of water flow rate on finishing pig performance in the summer months. Study 1 used a total of 396 pigs in two groups in a 77-day trial (35.0 to 104.3 kg BW) with 6 pigs/pen and 1 cup waterer/pen. Study 2, conducted in a commercial style barn, used a total of 1,227 pigs in an 84-day trial (60.9 to 117.4 kg BW) with 26 pigs/pen and 2 cup waters/pen. Pens were assigned to one of three water flow rates (high, medium, low) based on the 3-hole settings of the water nipples (2.0, 1.0, and 0.8 mm; n = 22 and 16 pens/treatment for Study 1 and 2, respectively). Room temperature, outside temperature and relative humidity were recorded daily for both studies. In Study 1, water disappearance was recorded daily, and individual pen water flow rates were recorded every two weeks. At every diet phase change (26 ±â€…2.6 days), feed disappearance and individual pig body weights were recorded. Water flow rates averaged 1856 ±â€…188, 906 ±â€…214, 508 ±â€…100 mL/min for high, medium, and low flow settings, respectively. In Study 2, individual pen water flow rate, water disappearance, BW, and feed disappearance were recorded every two weeks. Water flow rates averaged 1115 ±â€…98, 906 ±â€…209, and 605 ±â€…203 mL/min for high, medium, and low flow settings, respectively. In both studies, there were no differences in final BW, cumulative ADG, or G:F. Due to the variability of water flow rate within a setting, data was further analyzed using regression with flow rate as the independent variable. Apart from average daily water disappearance (adj. R 2 = 0.87), there was a low relationship between pig performance and water flow rate (adj. R 2 < 0.09). The low R 2 values associated with pig performance and the high association with water disappearance suggests that water flow rate above current recommendations has little impact on finishing pig performance but does contribute to water wastage and its associated costs.

Comparison of Time-to-Surgery and Outcomes in Transferred Vs Non-Transferred Open Globe Injuries.

Purpose: It is widely accepted in the field of ophthalmology that closure of open globes within 24 hours of the injury results in the best visual outcomes. This study investigates the time-to-surgery and visual outcomes of open globe injury patients in North Carolina that were transferred to our institution before receiving surgical intervention as compared to those that were not transferred. Patients and methods: This is a retrospective cohort study using data from UNC Hospitals trauma registry. Demographics, time of injury, final clinical outcomes, time to surgical intervention, and transfer history were extracted and analyzed. The study population includes open globe injury patients of all ages that were seen and treated at our institution from 2005 to 2020. Patients were divided based on transfer history. The transfer group consisted of patients who were transferred from an outside hospital to our tertiary care facility for surgical treatment. The non-transfer group consisted of patients who arrived at our tertiary care facility directly after injury. Results: In total, 238 open globe injuries were evaluated. Of those, 197 were transferred and 41 were not transferred. Compared to non-transfer patients, transfer patients had longer delays between injury and surgery, between presentation at the initial ED and surgery, and between injury and arrival at the tertiary care center. On average, the delay between injury and surgical intervention was 3 hours and 51 minutes longer for transfer patients compared to non-transfer patients. Eight patients in the transfer group were delayed >24 hours due to inter-hospital transfer. Additionally, transfer patients on average suffered from poorer final visual acuities, with an average final visual acuity of 1.84 logMAR in the transfer group and 1.35 logMAR in the non-transfer group. Conclusion: Our study found that inter-hospital transfer leads to significant delays in primary closure of open globe injuries. Injuries that were transferred to a tertiary care center before receiving surgical intervention on average resulted in worse final visual acuities.

Pharmacologic Inhibition of NT5C2 Reverses Genetic and Nongenetic Drivers of 6-MP Resistance in Acute Lymphoblastic Leukemia.

Low-intensity maintenance therapy with 6-mercaptopurine (6-MP) limits the occurrence of acute lymphoblastic leukemia (ALL) relapse and is central to the success of multiagent chemotherapy protocols. Activating mutations in the 5'-nucleotidase cytosolic II (NT5C2) gene drive resistance to 6-MP in over 35% of early relapse ALL cases. Here we identify CRCD2 as a first-in-class small-molecule NT5C2 nucleotidase inhibitor broadly active against leukemias bearing highly prevalent relapse-associated mutant forms of NT5C2 in vitro and in vivo. Importantly, CRCD2 treatment also enhanced the cytotoxic activity of 6-MP in NT5C2 wild-type leukemias, leading to the identification of NT5C2 Ser502 phosphorylation as a novel NT5C2-mediated mechanism of 6-MP resistance in this disease. These results uncover an unanticipated role of nongenetic NT5C2 activation as a driver of 6-MP resistance in ALL and demonstrate the potential of NT5C2 inhibitor therapy for enhancing the efficacy of thiopurine maintenance therapy and overcoming resistance at relapse. SIGNIFICANCE: Relapse-associated NT5C2 mutations directly contribute to relapse in ALL by driving resistance to chemotherapy with 6-MP. Pharmacologic inhibition of NT5C2 with CRCD2, a first-in-class nucleotidase inhibitor, enhances the cytotoxic effects of 6-MP and effectively reverses thiopurine resistance mediated by genetic and nongenetic mechanisms of NT5C2 activation in ALL. This article is highlighted in the In This Issue feature, p. 2483.

Interactions between tall oatgrass invasion and soil nitrogen cycling.

Increases in nitrogen (N) inputs to the biosphere can exacerbate the introduction and spread of invasive non-native plant species. Often, with elevated soil N levels, invasive plants establish and further enrich soil N pools, changing overall ecosystem function. This study examined the relationship between soil N cycling and an increasingly prevalent, invasive plant species, tall oatgrass (Arrhenatherum elatius subsp. elatius), in foothills ecosystems between the Colorado Rocky Mountains and the Denver-Boulder Metropolitan area-similar to many Western US grasslands and woodlands. It focused on investigating differences in soil N transformations, inorganic N pools, and vegetation characteristics across invaded and uninvaded plots at three sites in two seasons (summer and autumn). There was a statistically significant effect of invasion on rates of net N mineralization, but it was dependent on site and season (p = 0.046). Site had a statistically significant effect on soil moisture and aboveground biomass C:N (p < 0.04). The interactions of invasion x site were statistically significant for ammonium pools (p < 0.03). These findings suggest that A. elatius invasion can be associated with accelerated N cycling, but that the nature of the relationship differs by location and season in the foothills. More broadly, this study contributes to determining how the N cycle is shifting in grassland ecosystems subject to increasing pressures from anthropogenic change.