Anxiety, distress tolerance, and the relationship between complex posttraumatic stress disorder symptoms and alcohol use in veterans.

OBJECTIVES: Little is known about whether distress tolerance and anxiety mediate the relationship between comorbid complex posttraumatic stress disorder (CPTSD) and alcohol use among military veterans. Here, we investigated the contribution of distress tolerance and anxiety on the strength of the CPTSD and alcohol use association. We hypothesized that the impact of a two-factor model of CPTSD derived from subscale scores on the International Trauma Questionnaire (ITQ)-namely ITQ PTSD and ITQ Disturbances in Self Organization (DSO; e.g., issues with affective regulation/self-belief and shame)-on alcohol use severity would be mediated by anxiety but not by distress tolerance. METHODS: Participants included 403 community-dwelling United Kingdom (UK) veterans (91.64% male, Mage = 51.15 years, SD = 12.48) recruited as part of a larger, online study. RESULTS: Findings indicated that the influence of CPTSD symptoms on alcohol use severity was mediated by anxiety, not by distress tolerance, with greater relative impact due to ITQ DSO status than ITQ PTSD status. CONCLUSIONS: We identified the mediational influence of anxiety and distress tolerance on the association between CPTSD subscales and alcohol use in UK veterans. Interventions for anxiety may be adapted for reducing problematic alcohol use and the impact of CPTSD symptoms in veterans with comorbid PTSD and alcohol use disorder.

Cultivation of enteroids from fresh and cryopreserved bovine duodenal tissues.

This study aimed to develop a method for intestinal tissue cryopreservation and resuscitation for enteroid cultivation. Two different types of tissues, fresh duodenal tissues (n = 3, from Angus steers) and duodenal tissues cryopreserved in 90% fetal bovine serum (FBS) and 10% dimethyl sulfoxide (DMSO; n = 3, from Holstein calves), were collected to develop enteroids. Crypts were isolated using 2 mM EDTA/phosphate-buffered saline from both fresh and cryopreserved tissues and embedded in basement membrane extract. Embedded crypts were seeded in a 24-well plate and cultured in IntestiCult Organoid Growth Medium (Mouse) with inhibitors cocktail and Primocin. The upper opening of crypts became sealed, and crypts formed sphere structures (i.e., enteroids) within 24 h. Primary (passage 0) enteroids showed budding crypt domains from d 3 of cultivation at the earliest. After 7 d of cultivation, enteroids were passaged in a new 24-well plate. Fragments from passaged d 7 enteroids also formed sphere structures within 24 h after seeding and showed budding crypt domains from d 3 of cultivation at the earliest. The area of enteroids was measured in each animal during d 1 to 7 in passage 0 and 1, and the area of enteroids derived from both tissues increased during d 1 to 7 in passage 0 and 1. The area increased from d 1 to 7 of cultivation, and the area of passage 1 was greater than that of passage 0. F-actin staining using phalloidin revealed that brush border microvilli were distributed on the luminal side of the enteroids. In conclusion, a cryopreserved solution consisting of FBS and DMSO is useful for cryopreservation and resuscitation of bovine intestine for enteroid cultivation. This method allows researchers to investigate intestinal function and health in the laboratory using enteroids derived from fresh and cryopreserved tissues collected from cattle.

Action slips in food choices: A measure of habits and goal-directed control.

We report a new, simple instrumental action-slip task, which sets goal-directed action against putative S-R associations. On each training trial, participants were presented with one of two stimuli (blue or green coloured screen). One stimulus (S1) signalled that one joystick response (R1-left or right push) would earn one of two rewards (O1-jellybeans or Pringles points). A second stimulus (S2) signalled a different instrumental relationship (S2:R2-O2). On each test trial, participants were told which outcome could be earnt (O1/O2) on that trial. They were required to withhold responding until the screen changed colour to S1 or S2. On congruent test trials, the stimulus presented (e.g., S1) was associated with the same response (R1) as the outcome available on that trial (O1). On incongruent test trials, in contrast, the outcome (e.g., O1) preceded a stimulus that was associated with a different response (e.g., S2). Hence, in order to obtain the outcome (O1) on incongruent trials, participants were required to suppress any tendency they might have to make the response associated with the stimulus (R2 in response to S2). In two experiments, participants made more errors on incongruent than congruent trials. This result suggests that, on incongruent trials, the stimulus drove responding (e.g., S2 increased R2 responding) in a manner that was inconsistent with goal-directed action (e.g., R1 responding to obtain O1)-an action slip. The results are discussed in terms of popular dual-process theories of instrumental action and a single-process alternative.

Geographical variation in implementation of the Pathways to Comorbidity Care program in Australian drug and alcohol services.

AIM: Comorbid drug and alcohol and mental health disorders are highly prevalent. Significant gaps in service provision make this problem particularly difficult to address in regional Australia. The Pathways to Comorbidity Care (PCC) program was designed to improve management of comorbidity by outpatient drug and alcohol clinicians in New South Wales, Australia. This paper uses the Consolidated Framework for Implementation Research (CFIR) to evaluate variations in implementation outcomes across geographically diverse services. METHODS: Twenty clinicians across three drug and alcohol services from metropolitan, outer metropolitan and regional geographic locations were engaged at multiple levels of influence (directors, managers, clinicians) during the implementation of the multimodal PCC training package. The CFIR guided the development of self-report measures and semi-structured interviews evaluating implementation of the PCC training, and disparities in implementation barriers and facilitators were determined. RESULTS: Metropolitan clinicians identified less barriers than regional clinicians on several intervention characteristics (adaptability, complexity, design quality and packaging), as well as outer setting (peer pressure), inner setting (implementation climate, staff incentives, leadership engagement, available resources) and process (planning, opinion leaders, executing) domains. Regional clinicians evaluated the networks and communications construct more favourably. CONCLUSIONS: Specific barriers identified more strongly by regional clinicians included the importance of communication with local clinicians and leadership about the practicalities of incorporating the approach into routine practice (allocation of time, increased accessibility of implementation team). Metropolitan clinicians provided more favourable evaluations of the package design, implementation climate and specific implementation processes such as a clear and informative implementation plan.

Relationship between clinician-level attributes and implementation outcomes from the Pathways to Comorbidity Care training program.

BACKGROUND: The process of determining the best strategy for increasing the uptake of evidence-based practice might be improved through an understanding of relevant clinician-level factors. The Pathways to Comorbidity Care (PCC) training program (Louie E, et al., J Dual Diagnosis 17:304-12, 2021) aimed to facilitate integrated management of comorbid drug and alcohol and mental disorders amongst drug and alcohol clinicians. We hypothesised that uptake of integrated management of comorbidity following the implementation of the PCC program would be associated with clinician-level: (i) demographics (gender, education, experience), (ii) attitudes (evidence-based practice, therapist manuals, counselling self-efficacy), and (iii) organisational readiness to change. METHODS: Twenty clinicians participated in the 9-month PCC training program. Attitudes towards evidence-based practices and psychotherapist manuals, self-efficacy, and organisational readiness to change, along with demographics, were measured at baseline. At follow-up, change in Comorbidity Practice (CoP) scores related to integrated comorbidity management were obtained using a file audit checklist and categorised into high (at least 60% increase in CoP), medium or low (a decrease of - 20% or less in CoP). Clinician-level characteristics were examined across the implementation categories. RESULTS: There were no significant differences found between implementation groups on sociodemographic variables (p's > 0.30), attitudes to evidence-based practices, attitudes to therapist manuals, and self-efficacy (p's > 0.52). The high implementation group demonstrated significantly higher scores on leadership practices aspect of organisational readiness to change relative to the low and medium implementation group ((F(2, 16) = 3.63, p = 0.05; Cohen's d = .31) but not on the other subscales (p's > 0.07). CONCLUSIONS: Confidence that leadership will play a positive role in the implementation process may improve effectiveness of comorbidity training programs for drug and alcohol clinicians. On the other hand, contrary to our hypothesis, counselling self-efficacy, evidence-based practice attitudes, attitudes towards therapist manuals, gender, education and experience were not distinguishing factors.

The evaluation of the role of technology in the pathways to comorbidity care implementation project to improve management of comorbid substance use and mental disorders.

In substance use treatment settings, comorbid mental health problems can occur in up to 70% of people. An integrated approach for managing comorbidity, implementing evidence-based intervention in drug and alcohol settings, remains problematic. Technology can help in adopting evidence-based practice to implement effective treatment healthcare pathways. This study sought to examine aspects of tailored portal utilization (barriers and facilitators) by participants taking part in a program aimed at improving the implementation of evidence-based practice for comorbidity management Pathways to Comorbidity Care (PCC). Method: A self-report questionnaire and a semi-structured interview were designed to measure clinician satisfaction with the PCC portal and e-resources throughout a 9-month intervention. An adapted version of the "Non-adoption, Abandonment, Scale-up, Spread and, Sustainability" (NASSS) framework facilitated discussion of the findings. Results: Twenty participants from drug and alcohol services responded to all measures. Facilitators included: (i). clinician acceptance of the portal; (ii). guidance from the clinical supervisor or champion to encourage e-resource use. Barriers included: (i). complexity of the illness (condition); (ii). participants' preference (adopter system) for face-to-face resources and training modes; and, (iii). lack of face-to-face training on how to use the portal (technology and organization). Conclusion: Based on the NASSS framework, we identified several barriers and facilitators of the use of the portal including the complexity of illness, lack of face-to-face training, and clinician preference for training mediums. Recommendations include ongoing organizational support, in-house clinical supervision, and consultation with clinical providers to assist in the development of tailored e-health resources and open training opportunities on how to operate and effectively utilize these resources.

Implementation of a Multi-Modal Training Program for the Management of Comorbid Mental Disorders in Drug and Alcohol Settings: Pathways to Comorbidity Care (PCC).

OBJECTIVES: We aimed to evaluate the impact of the Pathways to Comorbidity Care (PCC) training program for alcohol and other drugs (AOD) clinicians to improve the management of comorbidity. METHODS: A controlled before-and-after study using PCC training was conducted across 6 matched sites in Australia including 35 clinicians. Controls received standard workplace training. PCC training included seminar presentations, workshops conducted by local "clinical champions," individual clinical supervision, and access to an online information portal. We examined (a) identification (screening, assessment) and treatment (treatment, referral) of comorbidity in practice (N = 10 clinical files per clinician), (b) self-efficacy, knowledge, and attitudes of clinicians. RESULTS: Significant improvements were observed in the PCC group but not the control sites with regards to the rate of clinical files showing identification of comorbidity (+50% v -12% change from baseline, respectively; [X2 (1, N = 340) = 35.29, p = .01] with only a trend for improvements in the rate of files demonstrating treatment of comorbidity [X2 (1, N = 340) = 10.45, p = .06]. There were significant improvements in the PCC relative to the control group for clinician self-efficacy, F(1,33) = 6.40, p = .02 and knowledge and attitudes of comorbidity monitoring, F(1,33) = 8.745, p = .01. CONCLUSIONS: The PCC training package may help improve identification of comorbidity, self-efficacy, and attitudes toward screening and monitoring of comorbidity in drug and alcohol settings.

Addition of dietary methionine but not dietary taurine or methyl donors/receivers to a grain-free diet increases postprandial homocysteine concentrations in adult dogs.

Grain-based ingredients are replaced in part by pulse ingredients in grain-free pet foods. Pulse ingredients are lower in methionine and cysteine, amino acid (AA) precursors to taurine synthesis in dogs. Although recent work has investigated plasma and whole blood taurine concentrations when feeding grain-free diets, supplementation of a grain-free diet with various nutrients involved in the biosynthesis of taurine has not been evaluated. This study aimed to investigate the effects of supplementing a complete grain-free dry dog food with either methionine (MET), taurine (TAU), or methyl donors (choline) and methyl receivers (creatine and carnitine; CCC) on postprandial AA concentrations. Eight healthy Beagle dogs were fed one of the three treatments or the control grain-free diet (CON) for 7 d in a 4 × 4 Latin square design. On day 7, cephalic catheters were placed and one fasted sample (0 min) and a series of nine post-meal blood samples were collected at 15, 30, 60, 90, 120, 180, 240, 300, and 360 min. Data were analyzed as repeated measures using the PROC GLIMMIX function in SAS (Version 9.4). Dogs fed MET had greater plasma and whole blood methionine concentrations from 30 to 360 min after a meal (P < 0.0001) and greater plasma homocysteine concentrations from 60 to 360 min after a meal (P < 0.0001) compared with dogs fed CON, TAU, and CCC. Dogs fed TAU had greater plasma taurine concentrations over time compared with dogs fed CON (P = 0.02) but were not different than dogs fed MET and CCC (P > 0.05). In addition, most AAs remained significantly elevated at 6 h post-meal compared with fasted samples across all treatments. Supplementation of creatine, carnitine, and choline in grain-free diets may play a role in sparing the methionine requirement without increasing homocysteine concentrations. Supplementing these nutrients could also aid in the treatment of disease that causes metabolic or oxidative stress, including cardiac disease in dogs, but future research is required.

Dose-escalated intensity-modulated radiotherapy in patients with locally advanced laryngeal and hypopharyngeal cancers: ART DECO, a phase III randomised controlled trial.

BACKGROUND: Radical (chemo)radiotherapy offers potentially curative treatment for patients with locally advanced laryngeal or hypopharyngeal cancer. We aimed to show that dose-escalated intensity-modulated radiotherapy (DE-IMRT) improved locoregional control. METHODS: We performed a phase III open-label randomised controlled trial in patients with laryngeal or hypopharyngeal cancer (AJCC III-IVa/b, TNM 7). Patients were randomised (1:1) to DE-IMRT or standard dose IMRT (ST-IMRT) using a minimisation algorithm, balancing for centre, tumour site, nodal status and chemotherapy use. DE-IMRT was 67.2 gray (Gy) in 28 fractions (f) to the primary tumour and 56Gy/28f to at-risk nodes; ST-IMRT was 65Gy/30f to primary tumour and 54Gy/30f to at-risk nodes. Suitable patients received 2 cycles of concomitant cisplatin and up to 3 cycles of platinum-based induction chemotherapy. The primary end-point was time to locoregional failure analysed by intention-to-treat analysis using competing risk methodology. FINDINGS: Between February 2011 and October 2015, 276 patients (138 ST-IMRT; 138 DE-IMRT) were randomised. A preplanned interim futility analysis met the criterion for early closure. After a median follow-up of 47.9 months (interquartile range 37.5-60.5), there were locoregional failures in 38 of 138 (27.5%) ST-IMRT patients and 42 of 138 (30.4%) DE-IMRT patients; an adjusted subhazard ratio of 1.16 (95% confidence interval: 0.74-1.83, p = 0.519) indicated no evidence of benefit with DE-IMRT. Acute grade 2 pharyngeal mucositis was reported more frequently with DE-IMRT than with ST-IMRT (42% vs. 32%). No differences in grade ≥3 acute or late toxicity rates were seen. CONCLUSION: DE-IMRT did not improve locoregional control in patients with laryngeal or hypopharyngeal cancer. The trial is registered: ISRCTN01483375.

Barriers and Facilitators to the Implementation of the Pathways to Comorbidity Care (PCC) Training Package for the Management of Comorbid Mental Disorders in Drug and Alcohol Settings.

Background: We have previously reported that the Pathways to Comorbidity Care (PCC) training program for alcohol and other drug (AOD) clinicians improved identification of comorbidity, self-efficacy, and attitudes toward screening and monitoring of comorbidity. We aimed to identify barriers and facilitators of implementation of the PCC training program in drug and alcohol settings. Methods: The PCC training program was implemented across 6 matched sites in Australia as per (1), and 20 clinicians received training. PCC training included seminar presentations, workshops conducted by local "clinical champions," individual clinical supervision, and access to an online information portal. We examined barriers and facilitators of implementation according to the Consolidated Framework for Implementation Research. Results: Barriers included inner setting (e.g., allocated time for learning) and characteristics of individuals (e.g., resistance). Facilitators included intervention characteristics (e.g., credible sources), inner setting (e.g., leadership), and outer setting domains (e.g., patient needs). Clinical champions were identified as an important component of the implementation process. Conclusions: Barriers included limited specific allocated time for learning. A credible clinical supervisor, strong leadership engagement and an active clinical champion were found to be facilitators of the PCC training program.

The clinical obesity maintenance model: a structural equation model.

PURPOSE: Theoretical research on the psychological underpinnings of weight management is limited. Recently, the clinical obesity maintenance model (COMM) proposed a theoretical conceptualisation of salient psychological and neuropsychological mechanisms maintaining weight management issues. The current study aimed to empirically test the COMM and elucidate the results in the context of recent empirical findings. METHODS: Participants (N = 165) were recruited from university and community settings in Australia. The sample consisted of adults with normal weight (n = 41), overweight (n = 40), and obesity (n = 84). Participants completed self-report questionnaires and a brief neuropsychological test. Structural equation modelling was used to estimate the associations between the hypothesised variables of the COMM and evaluate the model fit. RESULTS: Findings suggested acceptable to good model fit. Furthermore, several direct effects were found. First, cognitive flexibility directly affected eating habit strength. Second, eating habit strength directly affected eating beliefs. Third, eating beliefs directly affected emotion dysregulation. Fourth, emotion dysregulation directly affected depression and binge eating with depression partially mediating this relationship. Finally, depression directly affected binge eating. CONCLUSION: This was the first study to empirically test the COMM. Overall, findings provide preliminary support for the COMM as a psychological model of weight management and highlight the underlying psychological and neuropsychological mechanisms that may contribute to weight management issues. As this study examined a simplified version of the COMM, future research should continue evaluating this model and consider incorporating these components into more holistic weight management models to improve long-term treatment outcomes. LEVEL OF EVIDENCE: V, cross-sectional descriptive study.

COVID-19 and the agri-food system in the United States and Canada.

Agri-food supply chains in North America have become remarkably efficient, supplying an unprecedented variety of items at the lowest possible cost. However, the initial stages of the COVID-19 pandemic and the near-total temporary loss of the foodservice distribution channel, exposed a vulnerability that many found surprising. Instead of continued shortages, however, the agri-food sector has since moved back to near normal conditions with prices and production levels similar to those typically observed in years prior to the pandemic. Ironically, the specialization in most food supply chains designed for "just-in-time" delivery to specific customers with no reserve capacity, which led to the initial disruptions, may have also been responsible for its rapid rebound. A common theme in assessing the impacts across the six commodities examined is the growing importance of understanding the whole supply chain. Over the longer term, a continuation of the pandemic could push the supply chain toward greater consolidation of firms and diversification of products given the increasing option value of maintaining flexibility. Other structural changes will be felt through input markets, most notably labour, as the trend toward greater automation will continue to accelerate as a response to meeting concerns about a consistent supply of healthy and productive workers. The economic fall out from the pandemic may lead to greater concentration in the sector as some firms are not able to survive the downturn and changes in consumer food buying behaviour, including movement toward online shopping and enhanced demand for attributes associated with resiliency, such as local. On the other hand, online shopping may provide opportunities for small producers and processors to shorten supply chains and reach customers directly. In the long term, COVID-19 impacts on global commerce and developing country production are more uncertain and could influence poverty reduction. While COVID-19's impacts on North American agriculture should have minimal effect on the Sustainable Development Goals (SDGs) through food prices, the ongoing global trends in trade and agribusiness accelerated by the pandemic are relevant for achievement of the SDGs.

Metabolism-based isolation of invasive glioblastoma cells with specific gene signatures and tumorigenic potential.

BACKGROUND: Glioblastoma (GBM) is a highly aggressive brain tumor with rapid subclonal diversification, harboring molecular abnormalities that vary temporospatially, a contributor to therapy resistance. Fluorescence-guided neurosurgical resection utilizes the administration of 5-aminolevulinic acid (5-ALA) generating individually fluorescent tumor cells within a background population of non-neoplastic cells in the invasive tumor region. The aim of the study was to specifically isolate and interrogate the invasive GBM cell population using a novel 5-ALA-based method. METHODS: We have isolated the critical invasive GBM cell population by developing 5-ALA-based metabolic fluorescence-activated cell sorting. This allows purification and study of invasive cells from GBM without an overwhelming background "normal brain" signal to confound data. The population was studied using RNAseq, real-time PCR, and immunohistochemistry, with gene targets functionally interrogated on proliferation and migration assays using siRNA knockdown and known drug inhibitors. RESULTS: RNAseq analysis identifies specific genes such as SERPINE1 which is highly expressed in invasive GBM cells but at low levels in the surrounding normal brain parenchyma. siRNA knockdown and pharmacological inhibition with specific inhibitors of SERPINE1 reduced the capacity of GBM cells to invade in an in vitro assay. Rodent xenografts of 5-ALA-positive cells were established and serially transplanted, confirming tumorigenicity of the fluorescent patient-derived cells but not the 5-ALA-negative cells. CONCLUSIONS: Identification of unique molecular features in the invasive GBM population offers hope for developing more efficacious targeted therapies compared to targeting the tumor core and for isolating tumor subpopulations based upon intrinsic metabolic properties.

The role of clinical champions in facilitating the use of evidence-based practice in drug and alcohol and mental health settings: A systematic review.

Background: The dissemination and adoption of research into clinical practice in health care settings is a complex and challenging process. Clinical champions have been increasingly used in health care to facilitate the implementation and adoption of evidence-based practice and to overcome organizational barriers. In relation to substance use and mental health disorders, translation of new evidence into practice is an ongoing challenge. The utilization of a clinical champion to motivate staff to implement evidence-based practice in these settings may improve treatment quality and reduce the burden of disease. We thus aimed to conduct a systematic review to examine the role and efficacy of clinical champions in the drug and alcohol and mental health settings. Methods: We conducted a systematic literature search (1980-present) using the following databases: PubMed and PsycINFO. Additional studies were identified using reference searches of relevant reviews. Results: Thirteen separate studies were included in the final review. Clinical champions were typically selected rather than emergent, including clinical staff members engaging in a professional clinical role (e.g., physicians, psychologists, social workers). Training provided for these roles was often not stated. Clinical champions assisted with faster initiation and persistence in the application of novel interventions, facilitating overcoming system barriers, and enhanced staff engagement and motivation. Conclusions: In the substance use and mental health field, clinical champions appear to be an important component to facilitating practice changes. Future studies should provide specific details regarding attributes and training and also examine the relevant combination of personal characteristics and training sufficient to facilitate implementation of evidence-based practice in drug and alcohol and mental health settings. Plain language abstract: Treatment delivery in drug and alcohol and mental health settings may not always be based on best available evidence. Organizational context and individual factors are important in determining whether new practices will be adopted. Passive approaches such as websites or treatment manuals do not necessarily lead to change in practice. The clinical champion model has been shown to be effective in aiding implementation of evidence-based practice in health care settings. However, there is limited evidence evaluating its use in drug and alcohol and mental health settings. The current review aims to synthesize and evaluate the use of clinical champions in implementation research in drug and alcohol and mental health settings. We found that clinical champions were typically clinical staff members engaging in a professional clinical role. Training provided for these roles was often limited. Clinical champions may assist with faster initiation and persistence in the application of novel interventions, facilitating overcoming system barriers, and enhanced staff engagement and motivation.

Phase Ia Study of Anti-NaPi2b Antibody-Drug Conjugate Lifastuzumab Vedotin DNIB0600A in Patients with Non-Small Cell Lung Cancer and Platinum-Resistant Ovarian Cancer.

PURPOSE: This phase I trial assessed the safety, tolerability, and preliminary antitumor activity of lifastuzumab vedotin (LIFA), an antibody-drug conjugate of anti-NaPi2b mAb (MNIB2126A) and a potent antimitotic agent (monomethyl auristatin E). PATIENTS AND METHODS: LIFA was administered to patients with non-small cell lung cancer (NSCLC) and platinum-resistant ovarian cancer (PROC), once every 3 weeks, by intravenous infusion. The starting dose was 0.2 mg/kg in this 3+3 dose-escalation design, followed by cohort expansion at the recommended phase II dose (RP2D). RESULTS: Overall, 87 patients were treated at doses between 0.2 and 2.8 mg/kg. The MTD was not reached; 2.4 mg/kg once every 3 weeks was selected as the RP2D based on overall tolerability profile. The most common adverse events of any grade and regardless of relationship to study drug were fatigue (59%), nausea (49%), decreased appetite (37%), vomiting (32%), and peripheral sensory neuropathy (29%). Most common treatment-related grade ≥3 toxicities among patients treated at the RP2D (n = 63) were neutropenia (10%), anemia (3%), and pneumonia (3%). The pharmacokinetic profile was dose proportional. At active doses ≥1.8 mg/kg, partial responses were observed in four of 51 (8%) patients with NSCLC and 11 of 24 (46%) patients with PROC per RECIST. All RECIST responses occurred in patients with NaPi2b-high by IHC. The CA-125 biomarker assessed for patients with PROC dosed at ≥1.8 mg/kg showed 13 of 24 (54%) had responses (≥50% decline from baseline). CONCLUSIONS: LIFA exhibited dose-proportional pharmacokinetics and an acceptable safety profile, with encouraging activity in patients with PROC at the single-agent RP2D of 2.4 mg/kg.

Oversupplying metabolizable protein in late gestation for beef cattle: effects on prepartum BW, ruminal fermentation, nitrogen balance, and skeletal muscle catabolism.

The objective of the study was to determine the effect of oversupplying MP during late gestation on maternal BW, ruminal fermentation, nitrogen balance, and skeletal muscle catabolism. Crossbred Hereford heifers (n = 24) were assigned to a control treatment designed to meet MP requirements (CON) or a treatment providing 133% of the MP requirement (HMP). Heifers were individually fed their treatment from day -55 ± 3 relative to parturition and DMI was summarized by week. BW was measured on day -55 ± 3, -41 ± 3, -27 ± 3, and -8 ± 3. Ruminal digesta samples were collected on day -34 ± 5 and -15 ± 4 for short-chain fatty acid and ammonia-N (NH3-N) concentration. Plasma was collected the day prior to ruminal digesta samples and analyzed for plasma urea-N. Nitrogen balance was measured over a 6-d period starting on day -34 ± 4 and -15 ± 4. Following completion of the N balance periods, muscle biopsies were collected from the longissimus dorsi and analyzed for abundance of proteins relating to skeletal muscle catabolism. Data were analyzed as a randomized complete block (date of parturition) design with repeated measures using the MIXED procedure of SAS. Heifers fed HMP increased conceptus-corrected BW by a greater magnitude than CON at day -8 relative to -55 and -41 (treatment × day, P < 0.01). DMI increased (P < 0.01) by 18% on week -2 compared to -8, but then decreased (P < 0.01) by 8.0% for week -1. N-intake, apparent N digestion, N excretion, and N retention (g/d) were all greater (P < 0.01) for HMP heifers than CON but did not differ when expressed as a proportion of N intake. Ruminal NH3-N decreased (treatment × day, P < 0.01) as parturition approached for HMP (10.1 to 8.6 mg/dL); whereas, NH3-N was not affected for CON (1.0 to 1.3 mg/dL). Consequently, plasma urea-N was greater (P < 0.01) for HMP heifers (15.0 vs. 7.5 mg/dL). Heifers fed HMP had improved (P < 0.01) DM, OM, and NDF digestibility relative to CON heifers. The abundance of calpastatin was greater (P = 0.03) and calpain tended to be greater (P = 0.085) for CON cows compared to HMP. Feeding greater quantities of MP during late gestation may improve ruminal fermentation, N balance, and improve BW gain prepartum.

Oversupplying metabolizable protein in late gestation for beef cattle: effects on postpartum ruminal fermentation, blood metabolites, skeletal muscle catabolism, colostrum composition, milk yield and composition, and calf growth performance.

The objective of the study was to determine whether oversupplying MP prepartum affects postpartum cow BW, colostrum composition, milk production and composition, protein catabolism in the dam, and calf growth. Crossbred Hereford heifers were individually fed a control treatment designed to meet MP requirements (CON; n = 10) or 133% of the MP requirement (HMP; n = 11) from day -55 ± 4 until parturition. All cows were provided a common postpartum diet. Cow BW was measured on days 7 ± 1, 14 ± 2, 28 ± 3, 57 ± 4, 82 ± 5, and 111 ± 3 relative to parturition. DMI and ruminal pH were measured daily and summarized by week until day 33. Milk yield was estimated based on a 12-h two-quarter milk yield on days 7 ± 1, 12 ± 1, 28 ± 3, 33 ± 3, 70 ± 3, and 112 ± 3. Urine samples were collected from cows over a 6-d period starting on days 7 ± 1 and 28 ± 3 and the composited samples were analyzed for 3-methylhistidine (3-MH) and creatinine. Muscle samples were collected from cows on day 13 ± 1 while calf muscle samples were collected on days 2 and 111 ± 3 of age. Muscle samples from cows were analyzed for markers of protein catabolism, and calf muscle samples were analyzed for genes regulating cell growth and differentiation. Data were analyzed as a randomized complete block design using the MIXED procedure of SAS accounting for repeated measures when necessary. Postpartum BW did not differ (P ≥ 0.30) by treatment, day, or the interaction of treatment and day (T × D), but rump fat decreased (P = 0.011) as lactation progressed. DMI decreased during weeks 2 and 3 compared to 1 and 4, whereas ruminal pH was less during weeks 2, 3, and 4 relative to week 1. Colostrum fat concentration was less (P = 0.003) for HMP than CON; but, milk production was not affected by treatment. Milk yield was greatest from days 7 to 33 and decreased thereafter (P < 0.01). Urinary 3-MH and the 3-MH:creatinine ratio did not differ by treatment, day, or the T × D (P ≥ 0.22) interaction, nor was there a difference (P ≥ 0.13) in the abundance of catabolic proteins. Calf growth was not affected by treatment, but HMP calves had greater expression (T × D, P = 0.05) of PPARG while PKM expression increased for CON calves (T × D, P = 0.04) at day 111 compared to their expression at day 2. Overfeeding MP during late gestation does not improve postpartum indicators of N balance or maternal muscle turnover but may alter colostrum composition and calf gene expression at weaning.