Modern Trends in Surgical Site Infection Rates for Colorectal Surgery: A National Surgical Quality Improvement Project Study 2013-2020.

BACKGROUND: There are few studies investigating trends in global surgical site infection rates in colorectal surgery in the last decade. OBJECTIVE: This study seeks to describe changes in rates of different surgical site infections from 2013-2020, identify risk factors for SSI occurrence and evaluate the association of minimally invasive surgery and infection rates in colorectal resections. DESIGN: A retrospective analysis of the National Surgical Quality Improvement Program database 2013-2020 identifying patients undergoing open or laparoscopic colorectal resections by procedure codes was performed. Patient demographic information, comorbidities, procedures, and complications data were obtained. Univariable and multivariable logistic regression were performed. SETTING: This was a retrospective study. PATIENTS: A total of 279,730 patients received colorectal resection from 2013 - 2020. MAIN OUTCOME MEASURES: Primary outcome measure was rate of surgical site infection, divided into superficial, deep incisional and organ space infections. RESULTS: There was a significant decrease in rates of superficial infections (p < 0.01) and deep incisional infections (p < 0.01) from 5.9% in 2013 to 3.3% in 2020 and from 1.4% in 2013 to 0.6% in 2020, respectively, but a rise in organ space infections (p < 0.01) from 5.2% in 2013 to 7.1% in 2020. Use of minimally invasive techniques was associated with decreased odds of all surgical site infections compared to open techniques (p < 0.01) in multivariate analysis and adoption of minimally invasive techniques increased from 59% in 2013 to 66% in 2020. LIMITATIONS: Study is limited by retrospective nature and variables available for analysis. CONCLUSIONS: Superficial and deep infection rates have significantly decreased, likely secondary to improved adoption of minimally invasive techniques and infection prevention bundles. Organ space infection rates continue to increase. Additional research is warranted to clarify current recommendations for mechanical bowel prep and oral antibiotic use as well as to study novel interventions to decrease postoperative infection occurrence. See Video Abstract.

Procedural Interventions for Terminally Ill Children - Are We Aiding Palliation?

Objectives: Many children undergo surgery or an invasive procedure during their terminal hospital admission.1 The types of procedures, patients, and the intent of the procedures has not been well defined. Understanding these details may help pediatric surgeons better determine the clinical settings in which certain procedures will not enhance palliation or survival. Methods: A retrospective single institution chart review was performed for patients age 14 days to 18 years with chronic conditions who died while inpatient from 2013-2017. Data was gathered on demographics, primary diagnosis, intubation status, palliative care involvement, duration of hospital stay, length of palliative care involvement, and total number of procedures. Negative binomial regression was used to assess association with number of procedures. Results: 132 children met inclusion criteria. Most children were White and less than one year old. The most common type of diagnosis was cardiac in nature. Children underwent an average of three procedures. 75% were intubated and 77.5% had palliative care involved. Patients who were less than one year old at death were more likely to have been intubated, had longer terminal hospital stays, and had more procedures. Those who were intubated underwent more procedures and had longer hospital stays. Those with longer palliative care involvement had fewer procedures. Conclusions: Children undergo a significant number of surgical procedures during their terminal hospitalization. This may be influenced by age, intubation status, and length of stay. Ongoing study may help refine which procedures may have limited impact on survival in the chronically ill pediatric population.

Non-Nutritive Suck Parameters Measurements Using a Custom Pressure Transducer System.

The non-nutritive suck (NNS) device is a transportable, user-friendly pressure transducer system that quantifies infants' NNS behavior on a pacifier. Recording and analysis of the NNS signal using our system can provide measures of an infant's NNS burst duration (s), amplitude (cmH2O), and frequency (Hz). Accurate, reliable, and quantitative assessment of NNS has immense value in serving as a biomarker for future feeding, speech-language, cognitive, and motor development. The NNS device has been used in numerous research lines, some of which have included measuring NNS features to investigate the effects of feeding-related interventions, characterizing NNS development across populations, and correlating sucking behaviors with subsequent neurodevelopment. The device has also been used in environmental health research to examine how exposures in utero can influence infant NNS development. Thus, the overarching goal in research and clinical utilization of the NNS device is to correlate NNS parameters with neurodevelopmental outcomes to identify children at risk for developmental delays and provide rapid early intervention.

An examination of the association between infant non-nutritive suck and developmental outcomes at 12 months.

OBJECTIVE: To determine the association between infant non-nutritive suck (NNS) dynamics at 3 months and developmental outcomes at 12 months of age in full-term infants. We hypothesized that infants with more mature NNS at 3 months, as evidence by shorter burst duration, fewer cycles per burst, cycles per minute, higher amplitude, and more bursts, would have higher (better) scores on the developmental outcomes at 12 months. METHODS: This was a prospective study that utilized objective and self-report measures. A five-minute NNS sample was collected from 67 infants (54% male) at 3 months of age (average age 2.99 (0.27) months). At 12 months (average age 11.91 (0.26) months), the Development Profile-3 was administered through caregiver interview. RESULTS: Infant NNS burst duration, cycles per burst, and cycles per minute were significantly negatively associated with the Development Profile-3 cognitive domain and general scores at 12 months. This is consistent with our hypothesis that infants who have more efficient NNS (fewer bursts and cycles) at 3 months would have higher (better) scores on the Development Profile-3 at 12 months. CONCLUSIONS: Findings from this work complement emerging research linking infant NNS with subsequent neurodevelopmental outcomes. This is the first time that these associations have been examined using a quantitative and physiologic-based measure of NNS. These results seem to indicate that specific NNS metrics, which demonstrate maturation of this complex skill, may be useful predictors of neurodevelopment later in life.

Preoperative medically supervised weight loss programs and weight loss outcomes following bariatric surgery - a prospective analysis.

BACKGROUND: Prior to undergoing bariatric surgery, many insurance companies require patients to attend medically supervised weight management visits for 3-6 months to be eligible for surgery. There have been few studies that have looked specifically at the relationship between medically supervised weight management visit attendance and postoperative outcomes, and the current literature reports discrepant findings. OBJECTIVES: This project aimed to better characterize the relationship between preoperative medically supervised weight management visit attendance and postoperative weight loss outcomes by examining weight loss up to 5 years postbariatric surgery, and by stratifying findings according to the type of surgery undergone. SETTING: University Hospital. METHODS: Participants were recruited during presurgical bariatric surgery clinic visits at a bariatric and metabolic weight loss center. As part of standard of care all participants were required to participate in monthly medically supervised weight management visits before surgery. Participants who completed bariatric surgical procedures participated in postsurgical follow-up at 3 weeks, 3 months, 6 months, and then annually for 5 years. Weight outcomes measured were percentage of total weight lost. RESULTS: The results do not indicate a significant association between number of group visits attended and percent total weight loss at 1 month, 3 months, 6 months, 1 year, 2 years, 3 years, 4 years, or 5 years postbariatric surgery. CONCLUSIONS: These data do not suggest a relationship between engagement in a medically supervised weight loss program prior to bariatric surgery and weight loss after surgery in either the short- or the long-term.

Dorsomedial prefrontal hypoexcitability underlies lost empathy in frontotemporal dementia.

Empathic function is essential for the well-being of social species. Empathy loss is associated with various brain disorders and represents arguably the most distressing feature of frontotemporal dementia (FTD), a leading form of presenile dementia. The neural mechanisms are unknown. We established an FTD mouse model deficient in empathy and observed that aged somatic transgenic mice expressing GGGGCC repeat expansions in C9orf72, a common genetic cause of FTD, exhibited blunted affect sharing and failed to console distressed conspecifics by affiliative contact. Distress-induced consoling behavior activated the dorsomedial prefrontal cortex (dmPFC), which developed profound pyramidal neuron hypoexcitability in aged mutant mice. Optogenetic dmPFC inhibition attenuated affect sharing and other-directed consolation in wild-type mice, whereas chemogenetically enhancing dmPFC excitability rescued empathy deficits in mutant mice, even at advanced ages when substantial cortical atrophy had occurred. These results establish cortical hypoexcitability as a pathophysiological basis of empathy loss in FTD and suggest a therapeutic strategy.

Dysregulation of PRMT5 in chronic lymphocytic leukemia promotes progression with high risk of Richter's transformation.

Richter's Transformation (RT) is a poorly understood and fatal progression of chronic lymphocytic leukemia (CLL) manifesting histologically as diffuse large B-cell lymphoma. Protein arginine methyltransferase 5 (PRMT5) is implicated in lymphomagenesis, but its role in CLL or RT progression is unknown. We demonstrate herein that tumors uniformly overexpress PRMT5 in patients with progression to RT. Furthermore, mice with B-specific overexpression of hPRMT5 develop a B-lymphoid expansion with increased risk of death, and Eµ-PRMT5/TCL1 double transgenic mice develop a highly aggressive disease with transformation that histologically resembles RT; where large-scale transcriptional profiling identifies oncogenic pathways mediating PRMT5-driven disease progression. Lastly, we report the development of a SAM-competitive PRMT5 inhibitor, PRT382, with exclusive selectivity and optimal in vitro and in vivo activity compared to available PRMT5 inhibitors. Taken together, the discovery that PRMT5 drives oncogenic pathways promoting RT provides a compelling rationale for clinical investigation of PRMT5 inhibitors such as PRT382 in aggressive CLL/RT cases.

Targeting OXPHOS de novo purine synthesis as the nexus of FLT3 inhibitor-mediated synergistic antileukemic actions.

Using a genome-wide CRISPR screen, we identified CDK9, DHODH, and PRMT5 as synthetic lethal partners with gilteritinib treatment in fms-like tyrosine kinase 3 (FLT3)-internal tandem duplication (ITD) acute myeloid leukemia (AML) and genetically and pharmacologically validated their roles in gilteritinib sensitivity. The presence of FLT3-ITD is associated with an increase in anaerobic glycolysis, rendering leukemia cells highly sensitive to inhibition of glycolysis. Supportive of this, our data show the enrichment of single guide RNAs targeting 28 glycolysis-related genes upon gilteritinib treatment, suggesting that switching from glycolysis to oxidative phosphorylation (OXPHOS) may represent a metabolic adaption of AML in gilteritinib resistance. CDK9i/FLT3i, DHODHi/FLT3i, and PRMT5i/FLT3i pairs mechanistically converge on OXPHOS and purine biosynthesis blockade, implying that targeting the metabolic functions of these three genes and/or proteins may represent attractive strategies to sensitize AML to gilteritinib treatment. Our findings provide the basis for maximizing therapeutic impact of FLT3-ITD inhibitors and a rationale for a clinical trial of these novel combinations.

Motivation to Impact: Medical Student Volunteerism in the COVID 19 Pandemic.

Objective: Volunteerism represents an important mechanism to promote resilience, empathy, and general well-being in medical students, a group that stands to benefit. Medical students report feelings of fatigue, burnout, exhaustion, and stress that correlates with poor academic performance, and significant decline in empathy over the 3rd year of both MD and DO programs. Volunteer motivations have been shown to mediate participant well-being. The relationship between medical student volunteer motivations and specific outcomes during the COVID-19 pandemic has not been addressed. Methods: We characterized features of medical student volunteers during the COVID-19 pandemic in 2020, including volunteering motivation using the Volunteer Functions Inventory, the types of activities in which they participated, and the physical, psychosocial, and emotional outcomes they experienced following volunteering. Results: Altruistic and humanitarian values-centric motivation predicts positive volunteering outcomes including increased resilience, ability to deal with disappointment and loss, and ability to cope with the COVID-19 pandemic. Values-centric motivation also increases volunteer empathy independent of educational stage. Values-centric participants were more likely to select volunteering activities with patient contact, which promotes student empathy and resilience. Conversely, career-centric motivation does not predict positive outcomes. These students are more likely to engage in research-oriented activities. Conclusions: The efficacy of integrating volunteerism into medical school curricula may be limited by professional pressure that manifests as career-oriented motivation. We propose that practical integration should promote altruistic and humanitarian values-centric participant orientation to the volunteering process, which is associated with enhanced recruitment, preservation of empathy, and additional positive volunteering outcomes of interest.

Alternative Practices in Organic Dairy Production and Effects on Animal Behavior, Health, and Welfare.

The number of organic dairy farms has increased because of the increased growth of the organic market, higher organic milk price, and because some consumers prefer to purchase products from less intensive production systems. Best management practices are expected from organic dairy farms to ensure animal health and milk production. Organic dairy producers typically transition from conventional systems to avoid chemicals and pesticides, enhance economic viability, improve the environment, and increase soil fertility. Organic dairy producers respect and promote a natural environment for their animals, is also an important component of animal welfare. Organic producers have few options to mitigate pain in dairy calves. In the United States, therapies to mitigate pain for disbudded organic dairy calves are regulated by the US National Organic Program. Organic producers regularly use naturally derived alternatives for the treatment of health disorders of dairy calves, heifers, and cows. Alternative natural products may provide an option to mitigate pain in organic dairy calves. Despite the reluctance to implement pain alleviation methods, some organic farmers have expressed interest in or currently implement plant-based alternatives. Efficacy studies of alternative remedies for organic livestock are needed to verify that their use improves animal welfare. Non-effective practices represent a major challenge for organic dairy animal welfare. The relationship between humans and animals may be jeopardized during milking because first-lactation cows may exhibit adverse behaviors during the milking process, such as kicking and stomping. The periparturient period is particularly challenging for first-lactation cows. Adverse behaviors may jeopardize animal welfare and reduce safety for humans because stressed heifers may kick off the milking unit, kick at milkers, and display other unwanted behaviors in the milking parlor. This may reduce milking efficiency, overall production, and ultimately reduce the profitability of the dairy farm. Positive animal welfare is a challenging balancing act between the three overlapping ethic concerns. Identifying animal welfare deficits in organic livestock production is the first step in capitalizing on these opportunities to improve welfare.

Older People's Neighborhood Perceptions Are Related to Social and Emotional Loneliness and Mediated by Social Network Type.

BACKGROUND AND OBJECTIVES: Loneliness among older people is a public health issue; however, there is very weak support for the efficacy of individually focused interventions. A public health model, which includes the environmental influence on the formation of social networks and protection from loneliness, and theoretical approaches differentiating between social and emotional loneliness, suggest the importance of neighborhoods in preventing loneliness. This approach was used to test the influence of neighborhood factors on loneliness and the mediating role of social networks. RESEARCH DESIGN AND METHODS: A questionnaire survey of 917 people aged 60-100 years was conducted in one region of Aotearoa/New Zealand to assess loneliness, social network types, social participation, marital status, gender, health, and four aspects of neighborhood perceptions. RESULTS: Social and emotional loneliness scores were regressed on predicted demographic and social variables, followed by perceptions of Housing Satisfaction, Neighborhood Accessibility, Neighborhood Security, and Neighborhood Social Cohesion. Neighborhood variables added significant explanation of variance in both social and emotional loneliness. Mediation tests using PROCESS showed that the effects of all neighborhood variables were mediated by Private-Restricted or Locally Integrated Network types on Social Loneliness only. DISCUSSION AND IMPLICATIONS: These findings highlight the importance of neighborhood factors in relation to feelings of loneliness and the recognition of social network types as mediators of these relationships for social loneliness. The aspects of neighborhoods that prevent loneliness provide directions for planners and prevention programs. Interventions to prevent social loneliness can usefully and practicably focus on the housing and neighborhood environment.

Cylindromatosis drives synapse pruning and weakening by promoting macroautophagy through Akt-mTOR signaling.

The lysine-63 deubiquitinase cylindromatosis (CYLD) is long recognized as a tumor suppressor in immunity and inflammation, and its loss-of-function mutations lead to familial cylindromatosis. However, recent studies reveal that CYLD is enriched in mammalian brain postsynaptic densities, and a gain-of-function mutation causes frontotemporal dementia (FTD), suggesting critical roles at excitatory synapses. Here we report that CYLD drives synapse elimination and weakening by acting on the Akt-mTOR-autophagy axis. Mice lacking CYLD display abnormal sociability, anxiety- and depression-like behaviors, and cognitive inflexibility. These behavioral impairments are accompanied by excessive synapse numbers, increased postsynaptic efficacy, augmented synaptic summation, and impaired NMDA receptor-dependent hippocampal long-term depression (LTD). Exogenous expression of CYLD results in removal of established dendritic spines from mature neurons in a deubiquitinase activity-dependent manner. In search of underlying molecular mechanisms, we find that CYLD knockout mice display marked overactivation of Akt and mTOR and reduced autophagic flux, and conversely, CYLD overexpression potently suppresses Akt and mTOR activity and promotes autophagy. Consequently, abrogating the Akt-mTOR-autophagy signaling pathway abolishes CYLD-induced spine loss, whereas enhancing autophagy in vivo by the mTOR inhibitor rapamycin rescues the synaptic pruning and LTD deficits in mutant mice. Our findings establish CYLD, via Akt-mTOR signaling, as a synaptic autophagy activator that exerts critical modulations on synapse maintenance, function, and plasticity.

Red blood cells differentiated in vitro using sequential liquid and semi-solid culture as a pre-clinical model.

The in vitro erythrocyte differentiation model remains a strong, clinically relevant tool to model erythroid development in normal and disease related hematopoiesis. This model also has application to developing therapeutics for diseases related to red blood cells such as sickle cell anemia where targeting increased expression of fetal hemoglobin has been a major emphasis. Since the original protocol's publication in 2002, many groups have published modified methodologies to address issues in efficiency of maturation and terminal enucleation, as well as in scalability. While all reports have merit and show efficient enucleation, the methodologies used vary widely in technique and cytokine content. Additionally, despite the strengths in these methods, reproducibility of efficient differentiation to the point of differentiation is difficult. To address these limitations, we developed a streamlined process where total PBMCs are first primed using the original liquid culture expansion phase (published in 2002) before being differentiated with minimal input via standardized, commercially purchased semi-solid medium culture pre-supplemented with erythropoietin. Our data show this methodology to produce similar levels of CD235/CD71 positivity as previous methods but with enhanced CD235 solo positivity and evidence of enucleated cells in comparison with other widely used methods. Given the difficulty and wide variation in in vitro differentiation techniques, we present this methodology as a streamlined methodology for production of mature erythroid cells with minimal input using easily purchased reagents.

Effects of Pre-Parturient Iodine Teat Dip Applications on Modulating Aversive Behaviors and Mastitis in Primiparous Cows.

Heifers and their human handlers are at risk for decreased welfare during the early lactation period. This experiment investigated pre-parturient teat dipping and parlor acclimation to reduce mastitis and aversive behaviors in early lactation heifers. Three weeks prior to calving, heifers were randomly assigned to receive either: (1) a weekly 1.0% iodine-based teat dip in the parlor (trained; n = 37) or (2) no treatment (control; n = 30). For the first 3 days of lactation, heifers were milked twice daily, and treatment-blinded handlers assessed behaviors and clinical mastitis. Aseptic quarter milk samples were collected within 36 h of calving and analyzed for pathogens. Control heifers had (OR ± SE) 2.2 ± 0.6 times greater (p < 0.01) odds of kicking during milking. Trained heifers had (OR ± SE) 1.7 ± 0.4 times greater (p = 0.02) odds of being very calm during milking, while control heifers had 2.2 ± 0.8 and 3.8 ± 2.1 times greater (p < 0.04) odds of being restless and very restless or hostile during milking, respectively. Quarters of control heifers had (OR ± SE) 5.4 ± 3.4 greater (p < 0.01) odds of intramammary Staphylococcus aureus infection, yet clinical mastitis was similar among treatments. The results indicate that teat dipping in the parlor weekly for 3 weeks before calving may alleviate some aversive milking behaviors and protect against early lactation S. aureus intramammary infections.

Evaluation of an herbal therapy to alleviate acute pain and stress of disbudded dairy calves under organic management.

The objective of this experiment was to evaluate a herbal therapy used in place of standard synthetic analgesia to mitigate disbudding pain of dairy calves. For this experiment, 54 calves were randomly assigned to one of three treatments: 1) local anesthetic lidocaine given as a cornual nerve block before cautery disbudding (AD); 2) sham disbudding (SD); or 3) herbal tincture (Dull It, Dr. Paul's Lab, Mazomanie, WI) composed of white willow (Salix alba L.) bark, St. John's wort (Hypericum perforatum L.), chamomile (Matricaria recutita L.), arnica (Arnica montana L.), and fennel (Foeniculum vulgare Mill.) administered orally before and after cautery disbudding (TD). Behaviors were assessed during disbudding, and behaviors and blood plasma cortisol concentrations were assessed following disbudding. Tail wag, head movement, forcing ahead, and kick rates recorded during disbudding were similar among treatments. When averaged across the 360-min observation period following disbudding, injury-directed behavioral rates of head jerks, head shakes, horn bud scratches, and head rubs were greater (P ≤ 0.03) for calves in the AD group than calves in the SD group, calves in the TD group had greater (P < 0.01) horn bud scratch and head rub rates compared to calves in the SD group, and calves in the AD group had a greater (P < 0.01) horn bud scratch rate than calves in the TD group. Calves in the AD group took 1.6 [95% confidence interval (CI) = 1.0 to 2.4, P = 0.03] times longer to lie down after disbudding compared to calves in the TD group. Serum cortisol concentrations were greater (P ≤ 0.01) for calves in the TD group compared to calves in the SD group at 10, 30, and 90 min after disbudding. At 30 min after disbudding, calves in the AD group had 5.8 ng/mL (95% CI = -1.1 to 12.7 ng/mL, P = 0.02) greater serum cortisol compared to calves in the SD group, while calves in the TD group had 14.3 ng/mL (95% CI = 1.5 to 27.1 ng/mL, P < 0.01) greater serum cortisol than calves in the AD group. In conclusion, neither the local anesthetic lidocaine nor the orally administered herbal tincture attenuated both acute injury-directed behaviors and blood plasma cortisol concentrations in disbudded calves, and the tincture was clearly less effective at mitigating cortisol; therefore, additional analgesic may be required to properly manage disbudding pain effectively.

Effects of Outdoor Stocking Density on Growth, Feather Damage and Behavior of Slow-Growing Free-Range Broilers.

Access to pasture is a main benefit of free-range broiler housing systems, yet the level of outdoor stocking density on broiler animal welfare remains unsettled. The growth, feather damage, pasture ranging and behaviors were assessed for 150 mixed-sex, slow-growing Freedom Rangers from 5 to 11 weeks of age of with free access to either a high outdoor stocking density pasture (0.5 m2 per bird) or a low outdoor stocking density pasture (2.5 m2 per bird). The probability (mean, 95% CI) of tail feather damage was greater for the high-density (23.1%, 16.3 to 31.7%) compared to the low-density group (11.9%, 7.1 to 19.3%). The percent of observations resulting in sunbathing and aggressive attacks (i.e., pecking and fighting behaviors) were greater for the high-density (1.0%, 0.6 to 1.8% and 0.5%, 0.2 to 1.3%, respectively) compared to the low-density group (0.3%, 0.1 to 0.7% and 0.1%, 0.0 to 0.4%, respectively). Furthermore, an interaction between treatment and age indicated that birds in the high-density group displayed greater stretching (during weeks 7 to 10) and panting (during weeks 6 and 9). Results of this study suggest that additional outdoor pasture space may be positively associated with broiler welfare.

Association between early postpartum rumination time and peak milk yield in dairy cows.

Limited information is available on the relationship between rumination time (RT) in the early postpartum period and milk production later in lactation. Therefore, the objectives of this study were to (1) investigate the association of change in RT and average RT during the immediate postpartum period with peak milk yield (PMY) in dairy cows, and (2) determine the best model based on days in milk (DIM) to evaluate this association. Cows from 33 free-flow automatic milking system farms were included in this study, where retrospective milk production and RT data were collected for 12 mo. Cows were categorized by parity number into parity 1 (P1, n = 1,538), parity 2 (P2, n = 1,354), or parity ≥3 (P3+, n = 1,770). For each cow, PMY was identified as the highest daily milk yield up to 180 DIM for P1 and 120 DIM for P2 and P3+ cows. Five change in RT variables and 5 average RT variables were created corresponding to the first 2 to 6 DIM. Change in RT variables were the slope coefficients for change in RT/d related to DIM = 1 extracted from simple linear regressions, and average RT variables were the arithmetic mean RT. Five models analyzing PMY and corresponding variables calculated over the first 2 to 6 DIM had fixed effects of average RT, change in RT, parity, average RT × parity interaction, change in RT × parity interaction, and a random intercept for farm. Peak milk yield occurred at (median) 75, 44, and 46 DIM for P1, P2, and P3+, respectively. Overall PMY was (mean ± standard deviation) 54 ± 11 kg and it increased as parity increased. A positive association was found between change in RT and PMY, and average RT and PMY for P2 and P3+ cows in all 5 models corresponding to the first 2 to 6 DIM, indicating that greater average RT and quicker increase in RT after calving are associated with greater PMY for multiparous cows. Although the model including all 6 DIM had the greatest accuracy, results indicated that rumination data collected over the first 2 DIM may also provide adequate information for the association of average RT and change in RT with PMY in P2 and P3+ cows. For each 100 min/d increase in change in RT over the first 6 DIM, PMY increased by 4.3 (95% confidence interval: 2.2-6.3) and 4.8 (95% confidence interval: 3.2-6.5) kg for P2 and P3+ cows, respectively. Peak milk yield increased by 2.3 (95% CI: 1.7-2.8) and 2.2 (95% confidence interval: 1.7-2.6) kg for each 100 min increase in average RT over the first 6 DIM for P2 and P3+ cows, respectively. No association was observed between rumination behaviors and PMY for P1 cows. Results from this study indicate that the length of time for multiparous cows to achieve a stable RT in the early postpartum period combined with average RT during the same period may be useful in predicting their overall lactation milk production.

Targeting DNA Damage Repair Functions of Two Histone Deacetylases, HDAC8 and SIRT6, Sensitizes Acute Myeloid Leukemia to NAMPT Inhibition.

PURPOSE: Nicotinamide phosphoribosyltransferase (NAMPT) inhibitors (NAMPTi) are currently in development, but may be limited as single-agent therapy due to compound-specific toxicity and cancer metabolic plasticity allowing resistance development. To potentially lower the doses of NAMPTis required for therapeutic benefit against acute myeloid leukemia (AML), we performed a genome-wide CRISPRi screen to identify rational disease-specific partners for a novel NAMPTi, KPT-9274. EXPERIMENTAL DESIGN: Cell lines and primary cells were analyzed for cell viability, self-renewal, and responses at RNA and protein levels with loss-of-function approaches and pharmacologic treatments. In vivo efficacy of combination therapy was evaluated with a xenograft model. RESULTS: We identified two histone deacetylases (HDAC), HDAC8 and SIRT6, whose knockout conferred synthetic lethality with KPT-9274 in AML. Furthermore, HDAC8-specific inhibitor, PCI-34051, or clinical class I HDAC inhibitor, AR-42, in combination with KPT-9274, synergistically decreased the survival of AML cells in a dose-dependent manner. AR-42/KPT-9274 cotreatment attenuated colony-forming potentials of patient cells while sparing healthy hematopoietic cells. Importantly, combined therapy demonstrated promising in vivo efficacy compared with KPT-9274 or AR-42 monotherapy. Mechanistically, genetic inhibition of SIRT6 potentiated the effect of KPT-9274 on PARP-1 suppression by abolishing mono-ADP ribosylation. AR-42/KPT-9274 cotreatment resulted in synergistic attenuation of homologous recombination and nonhomologous end joining pathways in cell lines and leukemia-initiating cells. CONCLUSIONS: Our findings provide evidence that HDAC8 inhibition- or shSIRT6-induced DNA repair deficiencies are potently synergistic with NAMPT targeting, with minimal toxicity toward normal cells, providing a rationale for a novel-novel combination-based treatment for AML.

Efficacy of Broilers as a Method of Face Fly (Musca autumnalis De Geer) Larva Control for Organic Dairy Production.

The objective of this study was to evaluate Freedom-Ranger broiler chickens as a method to control face fly (Musca autumnalis De Geer) larvae in cow dung pats on pasture. Ninety-nine pats in three replicates were inoculated with first-instar larvae and exposed to one of four treatment conditions for 3 to 4 days: (1) an environment-controlled greenhouse (GH); (2) pasture without broilers (NEG); (3) pasture with 25 broilers stocked at a low density of 2.5 m2 of outdoor area per broiler (LOW); and (4) pasture with 25 broilers stocked at a high density of 0.5 m2 of outdoor area per broiler (HIGH). Broiler behaviors and weather conditions were recorded twice daily. Survival rates of larvae (mean, 95% CI) were similar for pats in the NEG (4.4%, 2-9%), LOW (5.6%, 3-11%), and HIGH (3.2%, 2-7%) groups, and was greatest for larvae reared in the GH (54.4%, 36-72%) group compared to all other groups. The proportion of broilers observed pasture ranging was 14.0% (6-28%) but was negatively related to solar radiation. Broilers were never observed foraging in pats. Results indicate that use of broilers may not be an effective method for controlling larvae of dung pat breeding flies.

The impact of acute beta-hydroxy-beta-methylbutyrate (HMB) ingestion on glucose and insulin kinetics in young and older men.

Insulin resistance (IR) is a key feature in the development of numerous metabolic diseases. The cornerstone for treatment for IR remains diet and exercise, however these have poor rates of adherence. Beta-hydroxy-beta-methylbutyrate (HMB) is a nutraceutical with contentious effects on IR in animal models. The aim of this study was to evaluate the impact of acute HMB on IR in humans during an oral glucose tolerance test (OGTT). Young and older male volunteers underwent two 75 g OGTT with or without 3 g HMB. In young men, HMB significantly reduced the insulin area-under-the-curve (AUC), with no difference in glucose AUC, resulting in a numerical increase in the Cederholm index of insulin sensitivity. In older men, HMB had no effect on insulin or glucose responses. In conclusion, acute HMB may improve IR following a glucose load in young men; however, this does not appear to be sustained into older age.