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ABSTRACT: Thanks to improvements in genetics, nutrition, and management, modern dairy cows can still produce large amounts of milk at the end of lactation, with possible negative effects on health and welfare, particularly when milking is stopped abruptly. To limit yield at dry-off, strategies involving different types of dietary restriction have been used worldwide. Thus, we aimed to investigate the effects of a reduced nutrient density at dry-off on milk production, metabolism, the pattern of rumen fermentation, and milk fatty acid profile around dry-off and in the ensuing periparturient period. During the last week before dry-off, 26 Holstein cows were enrolled in pairs according to the expected calving date and either fed ad libitum ryegrass hay (nutrient restricted, NR; 13 cows) or continued to receive lactation diet (control group, CTR; 13 cows). After dry-off, both groups received only grass hay for 7 d, and free access to water was always provided. Blood, milk, and rumen fluid samples were collected from 7 d before dry-off to 28 DIM. Milk production, DMI (during the periparturient period), and rumination times were recorded daily. At dry-off, NR cows had decreased milk yield (−62%) and milk lactose compared with CTR but had higher fat and protein contents. In the subsequent lactation, no significant differences were observed in milk yield and composition. The BCS did not differ between groups during the transition period, but it decreased in NR after dry-off. Before dry-off, NR had decreased glucose, urea, and insulin, but higher creatinine, BHB, and nonesterified fatty acids (NEFA). The day after dry-off, NEFA were lower in NR, but they were higher 7 d after calving. At dry-off, NR had higher rumen pH, lower lactate, urea, and total volatile fatty acid concentrations. Considering volatile fatty acid molar proportions, NR had increased acetate but decreased propionate and butyrate at dry-off. Rumination time dropped 6 d before dry-off in NR and after dry-off in CTR, but no differences were observed in the periparturient period. Milk fatty acid profile revealed a remarkably lower proportion of short-chain fatty acids in NR at dry-off and a higher proportion of medium- and long-chain ones. These results confirmed that decreasing nutrient density reduce milk yield before dry-off. However, metabolism around dry-off was significantly affected, as suggested by plasma, rumen fluid, and milk analyses. Further research is required to investigate the impact of the metabolic effects on the inflammatory response, liver function, and immune system, particularly concerning the mammary gland.

Twelve Holstein (HOL), 9 Brown Swiss (BRO), and 9 Simmental (SIM) dairy cows raised in the same barn and managed identically were enrolled to characterise the responses to the transition period. From −21 to 28 d from calving (DFC), body condition score (BCS) and milk yield were measured, and blood samples were collected to assess plasma biomarkers of metabolism, minerals, liver function, inflammation, and oxidative status. Compared with SIM, HOL and BRO had higher milk yield during the first week of lactation. HOL had the highest milk yield from the second to the fourth week and the lowest BCS at 28 DFC. SIM had the highest BCS and the highest plasma creatinine and P, reflecting a greater attitude to gain muscle mass. Compared with SIM, BRO and HOL had lower plasma fructosamine, indicating reduced glucose availability driven by lactose synthesis. SIM had the mildest acute phase response at the onset of lactation, as suggested by the lowest ceruloplasmin concentration. HOL had the highest cholesterol and paraoxonase concentrations, and the greatest interleukin-1β production by leukocytes following ex-vivo stimulation, suggesting that they had the quickest resolution of the acute phase response due to the fastest immune cell activation. BRO had the highest concentration of reactive oxygen metabolites, ceruloplasmin, bilirubin, glutamate-oxaloacetate transaminase, γ-glutamyl transferase, and β-hydroxybutyrate, and the lowest concentration of paraoxonase, reflecting the strongest activation of leukocytes and the most severe acute phase response. Together, these results highlight different metabolic and inflammatory conditions around calving in the three explored breeds.HIGHLIGHTS Holstein, Brown Swiss, and Simmental are dairy breeds selected for different purposes. These three breeds have different productivity, and metabolic and inflammatory responses during the transition period. Understanding the differences among breeds might improve their management, nutrition, and productivity in commercial dairy farms.

ABSTRACT: The cessation of lactation (i.e., dry-off) in dairy cattle is an area of research that has received much focus in recent years. The dry period is necessary to optimize tissue remodeling of the mammary gland, but represents a stressful event, incorporating several changes in daily routine, diet, and metabolism. Moreover, the high milk yields achieved by modern cows in late gestation exacerbate the need for relevant manipulations in the days around dry-off, as excessive accumulation of milk might jeopardize the success of the dry period, with potential negative effects on future lactation. Production levels over 15 kg/d are an additional risk factor for udder health, delay mammary involution, and worsen metabolic stress and inflammatory responses. Furthermore, the pressure to reduce antibiotic usage in farm animals has resulted in increased attention on the dry period, given that historically most dairy cattle were provided prophylactic intramammary antibiotic treatment at dry-off as a means to reduce the risk of intramammary infections in the subsequent lactation. Several strategies have been proposed over the years to cope with these challenges, aiming to gradually reduce milk yield before dry-off, promoting at the same time the start of mammary involution. Among them, the most common are based on feed or nutrient restriction, a decrease in milking frequency, or administration of prolactin inhibitors. These practices have different capacities to reduce milk yield through different mechanisms and entail several implications for udder health, animal welfare, behavior, endocrine status, metabolism, and inflammatory conditions. The present review aims to provide a comprehensive overview of the dry-off phase in high-yielding cows and of the impact of high milk production at dry-off, and to describe possible strategies that might be implemented by farmers and veterinarians to optimize this critical phase in an integrated way.

ABSTRACT: Dairy cows have to face several nutritional challenges during the transition period, and live yeast supplementation appears to be beneficial in modulating rumen activity. In this study, we evaluated the effects of live yeast supplementation on rumen function, milk production, and metabolic and inflammatory conditions. Ten Holstein multiparous cows received either live Saccharomyces cerevisiae (strain Sc47; SCY) supplementation from −21 to 21 d from calving (DFC) or a control diet without yeast supplementation. Feed intake, milk yield, and rumination time were monitored until 35 DFC, and rumen fluid, feces, milk, and blood samples were collected at different time points. Compared with the control diet, SCY had increased dry matter intake (16.7 vs. 19.1 ± 0.8 kg/d in wk 2 and 3) and rumination time postpartum (449 vs. 504 ± 19.9 min/d in wk 5). Milk yield tended to be greater in SCY (40.1 vs. 45.2 ± 1.7 kg/d in wk 5), protein content tended to be higher, and somatic cell count was lower. In rumen fluid, acetate molar proportion was higher and that of propionate lower at 21 DFC, resulting in increased acetate:propionate and (acetate + butyrate):propionate ratios. Cows in the SCY group had lower fecal dry matter but higher acetate and lower propionate proportions on total volatile fatty acids at 3 DFC. Plasma analysis revealed a lower degree of inflammation after calving in SCY (i.e., lower haptoglobin concentration at 1 and 3 DFC) and a likely better liver function, as suggested by the lower γ-glutamyl transferase, even though paraoxonase was lower at 28 DFC. Plasma IL-1β concentration tended to be higher in SCY, as well as Mg and P. Overall, SCY supplementation improved rumen and hindgut fermentation profiles, also resulting in higher dry matter intake and rumination time postpartum. Moreover, the postcalving inflammatory response was milder and liver function appeared to be better. Altogether, these effects also led to greater milk yield and reduced the risk of metabolic diseases.

Abstract Positive effects have been observed as a result of Aloe arborescens supplementation in the dry-off phase in dairy cows. Metabolomic approaches can provide additional information about animal physiology. Thus, we characterized plasma metabolome around dry-off in 12 cows supplemented (AL) or not (CTR) with 10 g/d of lyophilized A. arborescens with an untargeted metabolomic approach. Overall, 1658 mass features were annotated. Regardless of treatment, multivariate statistics discriminated samples taken before and after dry-off. Overall, 490 metabolites were different between late lactation and early dry period, of which 237 were shared between AL and CTR. The most discriminant compounds (pentosidine and luteolin 7-O-glucoside) were related to the more fibrous diet. Pathway analysis indicated that pyrimidine and glycerophospholipid metabolisms were down-accumulated, suggesting reduced rumen microbial activity and liver load. Samples from AL were discriminated from CTR either the day of dry-off or 7 days after. At dry-off, aloin and emodin were the most discriminant metabolites, indicating that Aloe's bioactive compounds were absorbed. Seven days later, 534 compounds were different between groups, and emodin was among the most impacted. Pathway analysis highlighted that glycerophospholipid, pyrimidine, and folate metabolisms were affected. These results might indicate that Aloe has positive effects on liver function and a modulatory effect on rumen fermentation.

Introduction Suicide is the fourth leading cause of death among adolescents and young adults (AYA) (Czyz EK, King CA. J Clin Child Adolesc Psychol.2015;44(1):181-19), and psychiatric disorders are a major contributing factor (WHO Global Health Estimates 2000-2019). Studies focusing on suicidality in Italian inpatients samples are scant. Objectives The present cross-sectional study aimed to define clinical variables associated with suicidality related phenomena in a sample of young inpatients. The main objectives were to assess the prevalence of suicidal ideation and deliberate self-harm in inpatients aged 16–24 years and to determine the relationship between suicidal behaviours and psychiatric disorders. Methods This retrospective study was conducted in a naturalistic setting, at the Psychiatric Inpatient Unit, Perugia Hospital/Local Mental Health Unit 1, from January 2018 to December 2019. Sociodemographic information, clinical history, diagnostic and treatment features were collected. Descriptive and bivariate analyses were performed (p

ABSTRACT: Milk yield and composition are modified by level and chemical characteristics of dietary energy and protein. Those factors determine nutrient availability from a given diet, and once absorbed, they interact with the endocrine system and together determine availability of metabolites to the mammary gland. Four multiparous dairy cows in early lactation and subsequently in late lactation were fed 2 diets for 28 d in a changeover design that provided, within the same stage of lactation, similar amounts of rumen fermentable feed with either high (HS) or low starch (LS). All diets had similar dietary crude protein (15.5% dry matter) and rumen-undegradable protein (∼40% of crude protein) content. Profiles of AA were calculated to be similar to that of casein. On d 28, [1-13C] Leu was infused into one jugular vein with blood samples taken at 0, 2, 4, 6, and 8 h, and cows milked at 0, 2, 4, 5, 6, 7, and 8 h from start of infusion. Isotopic enrichments of plasma Leu, keto-isocaproic acid, and milk casein were determined for calculation of Leu kinetics. Data were subjected to ANOVA using the MIXED procedure of SAS (SAS Institute Inc.), with time as repeated factor and cow as the random effect. Dry matter intake within each stage of lactation was similar between groups. Feeding LS resulted in lower blood glucose and greater ratio of bovine somatotropin to insulin. This response was associated with greater blood concentrations of nonesterified fatty acids and β-hydroxybutyrate, which might have contributed to greater milk fat content in LS-fed cows. Except for His, average concentrations of all AA in blood were higher in late than early lactation. Diet did not alter average plasma concentrations of AA. However, for most of the essential AA (particularly branched-chain), the HS diet led to a marked decrease in concentrations after the forage meal, resulting in significant differences between dietary groups in early lactation. In early-lactating cows fed HS, a greater reduction in plasma concentrations at 8 h relative to pre-feeding values (time zero) was observed for Met, Lys, and His, resulting in decreases of 27.9%, 33.6%, and 38.5%, respectively. A higher bovine somatotropin/insulin ratio in early lactation and in cows fed LS could possibly have led to greater breakdown and, consequently, higher AA flux from peripheral tissues. In LS-fed cows, higher mobilization of body fat and protein was confirmed by the greater body weight loss in both stages of lactation. Higher irreversible loss of [1-13C] Leu in early lactation suggested lower protein retention in peripheral tissues during early compared with late lactation. Milk yield, protein output, and composition were similar between groups at both stages of lactation, whereas milk coagulation was faster (lower curd firming rate) and with higher curd firmness in response to feeding HS in late lactation. Overall, data indicated that rate of carbohydrate fermentability in the rumen can modify the availability of metabolites to the mammary gland and consequently modify milk protein coagulation.

The use of modern prolific lines of rabbit does in intensive production systems leads to an increase in productivity but also causes a rise in several problems related to the does’ health status. Hence, the aim of this study was to investigate the effect of the litter size on the metabolic, inflammatory and plasma amino acid profile in rabbit does. The blood of 30 pregnant does was sampled on the 27th day of pregnancy. The does were retrospectively grouped according to the number of offspring into a high litter size group (HI, does with ≥ 12 kits; n= 16) and a low litter size group (LO, does with ≤ 11 kits; n= 14). Data were subjected to Pearson’s correlation analysis. Further, data were analysed in agreement to a completely randomized design in which the main tested effect was litter size. The linear or quadratic trends of litter size on parameters of interests were post hoccompared by using orthogonal contrasts. In addition, compared with the LO group, the HI group had lower levels of glucose (−5%; P< 0.01), zinc (−19%; P< 0.05), albumin (−6%; P< 0.05) and total cholesterol (−13%; P< 0.07), but the total bilirubin level was higher in the HI group (+14%; P< 0.05). Regarding the plasma amino acids, the HI group had lower concentrations of threonine (−15%), glycine (−16%), lysine (−16%) and tryptophan (−26%) and a higher level of glutamic acid (+43%; P< 0.05) compared with the LO group. The exclusively ketogenic amount of amino acids was lower (P< 0.06) in the HI (55.8 mg/100 ml) does compared with the LO does (56.8 mg/100 ml). These results show that a few days before delivery, rabbit does that gave birth to a higher number of offspring had a metabolic profile and an inflammatory status that was less favourable with respect to does who gave birth to a lower number of offspring. Moreover, the plasma amino acid profile points out that there was an enhanced catabolic condition in the rabbit does with a high number of gestated foetuses; it was likely related to the greater energy demand needed to support the pregnancy and an early inflammatory response.

The aim of this study was to investigate the metabolic and biochemical changes in plasma that occur in the reproductive rabbit doe close to the parturition, as well as if the number of offspring affects the metabolism and the health status of the doe. At −3, 4 and 12 days from parturition (–D3, D4, and D12, respectively) nine rabbit does at their third parity from a commercial hybrid line (HYPLUS PS 19) selected for high prolificacy were weighted and blood was collected for a wide inflammometabolic profile. According to the number of offspring the does were retrospectively divided in two groups: high litter size group (HI; n=5) and low litter size group (LO; n=4). BW was higher (P

UNLABELLED: Molecular modifiers of KRASG12C inhibitor (KRASG12Ci) efficacy in advanced KRASG12C-mutant NSCLC are poorly defined. In a large unbiased clinicogenomic analysis of 424 patients with non-small cell lung cancer (NSCLC), we identified and validated coalterations in KEAP1, SMARCA4, and CDKN2A as major independent determinants of inferior clinical outcomes with KRASG12Ci monotherapy. Collectively, comutations in these three tumor suppressor genes segregated patients into distinct prognostic subgroups and captured ∼50% of those with early disease progression (progression-free survival ≤3 months) with KRASG12Ci. Pathway-level integration of less prevalent coalterations in functionally related genes nominated PI3K/AKT/MTOR pathway and additional baseline RAS gene alterations, including amplifications, as candidate drivers of inferior outcomes with KRASG12Ci, and revealed a possible association between defective DNA damage response/repair and improved KRASG12Ci efficacy. Our findings propose a framework for patient stratification and clinical outcome prediction in KRASG12C-mutant NSCLC that can inform rational selection and appropriate tailoring of emerging combination therapies. SIGNIFICANCE: In this work, we identify co-occurring genomic alterations in KEAP1, SMARCA4, and CDKN2A as independent determinants of poor clinical outcomes with KRASG12Ci monotherapy in advanced NSCLC, and we propose a framework for patient stratification and treatment personalization based on the comutational status of individual tumors. See related commentary by Heng et al., p. 1513. This article is highlighted in the In This Issue feature, p. 1501.

Six dairy cows received 3 treatments after morning meal, in a double Latin square design. Treatments were ACTH challenge (SYN), hoof trimming (TRIM) and saline (CTR). Measurements included: plasma cortisol and metabolic profile during the 24 h after treatments; the rate of digesta passage, faecal dry matter and pH. Both acute stress situations vs CTR caused a rapid and similar rise in plasma cortisol (P

To study the relationships between in vitro NDF or true dry matter digestibility (NDFD and IVTDMD) and forage fibre content, 95 alfalfa samples from 5 cultivars grown in 3 different locations and from different cuts were analysed for fibre fractions and evaluated for NDFD and IVTDMD. NDFD was mainly influenced by order of cut and age of the fields. The multifoliate cultivar controlled did not appear to differ for fibre composition and NDFD from the other ones. Fibre fractions contents explained a large part of the difference in NDFD and IVTDMD, and no significant differences in this relationships appeared for first-cut vs. aftermath forage. The best predictive equation of NDFD from fibre factions was: NDFD = 73.61 -0.62 * NDF (% DM) – 56.33 * ADL/NDF (R2=0.39). Variations in fibre content and quality do not completely explain differences in NDFD suggesting the interference of other factors that are worth to be better studied.

High environmental temperature induces physiological stress in rabbits leading to production losses, also because of their quite poor thermoregulation ability. Some consequences of heat stress affect digestive system functions, with impaired appetite, growth and feed conversion, but also with increased disease incidence. These effects can also reflect on the levels of some blood metabolites. Relatively few experimental works are available on the effects of high environmental temperature on the rabbit metabolic profile reared in commercial farms. The aim of this study was to study, in separate experiments, the effects of “fresh” spring and of “hot” summer temperatures on rabbits performance with particular attention to the behaviour of some metabolic parameters and of some aspects of the functionality of the digestive system.