Effect of different feeding strategies and dietary fiber levels on energy and protein retention in gestating sows.

The aim of the study was to investigate whether increased inclusion of sugar beet pulp (SBP) alters retention of fat, protein, and energy when backfat (BF) is restored in early- and mid-gestation. In total, 46 sows were fed one of four dietary treatments with increasing inclusion of SBP providing dietary fiber (DF) levels of 119, 152, 185, and 217 g/kg; sows were assigned to one of three feeding strategies (FS; high, medium, and low) depending on BF thickness at mating and again at day 30 for the following month. On days 0, 30, 60, and 108, body weight (BW) and BF thickness were measured and body pools of protein and fat were estimated using the deuterium oxide technique. On days 30 and 60, urine, feces, and blood samples were collected to quantify metabolites, energy, and nitrogen (N) balances. On days 15 and 45, heart rate was recorded to estimate heat energy. At farrowing, total born and weight of the litter were recorded. In early gestation, BW gain (P < 0.01) and body protein retention increased (P < 0.05) with increasing fiber inclusion, while body fat retention increased numerically by 59%. The increase in BF was greatest for sows fed the high FS, intermediate when fed the medium strategy, and negligible for sows fed the lowest FS (P < 0.001). Nitrogen intake, N loss in feces, and N balance increased linearly, whereas N loss in urine tended to decrease with increasing inclusion of fibers in early gestation. Concomitantly, fecal energy output and energy lost as methane increased linearly (P < 0.001), while energy output in urine declined linearly. Total metabolizable energy (ME) intake therefore increased from 36.5 MJ ME/d in the low fiber group to 38.5 MJ ME/d in the high fiber group (P < 0.01). Changing the ME towards more ketogenic energy was expected to favor fat retention rather than protein retention. However, due to increased intake of ME and increased N efficiency with increasing fiber inclusion, the sows gained more weight and protein with increasing fiber inclusion. In conclusion, increased feed intake improved both fat and protein retention, whereas increased DF intake increased protein retention.

Feeding sows sugar beet pulp (SBP) has many known benefits, for example, increased satiety and high fermentability. This study investigates the ability of the sow to utilize energy for fat retention when replacing part of starch with dietary fiber. After a demanding lactation, sows need to restore body fat, and concomitantly avoid excessive protein retention, which will increase energy demand for maintenance and risk of locomotory problems. The hypothesis in this study is that energy from fermented fibers is more efficient for fat retention than dietary starch. In the study, sows had numerically greater fat retention when fed high concentrations of fiber from SBP, but concomitantly sows unintendedly also increased their protein retention, which in turn substantially increased their body weight. Sows were allocated to one of three feeding strategies depending on their body condition score (lean, medium, or fat) in early gestation, and backfat was efficiently restored in most sows within a month. In conclusion, although gestating sows have a high capability to utilize energy from fermentable fiber, they are disposed to protein over fat retention. These aspects need to be addressed in the nutrition of modern genotype sows.

NGS-determined molecular markers and disease burden metrics from ctDNA correlate with PFS in previously untreated DLBCL.

Personalized risk stratification and treatment may help improve outcomes among patients with diffuse large B-cell lymphoma (DLBCL). We developed a next-generation sequencing (NGS)-based method to assess a range of potential prognostic indicators, and evaluated it using pretreatment plasma samples from 310 patients with previously untreated DLBCL from the GOYA trial (NCT01287741). Variant calls and DLBCL subtyping with the plasma-based method were concordant with corresponding tissue-based methods. Patients with a tumor burden greater than the median (p = .003) and non-germinal center B-cell-like (non-GCB) DLBCL (p = .049) had worse progression-free survival than patients with a tumor burden less than the median or GCB DLBCL. Multi-factor assessment combining orthogonal features from a single pretreatment plasma sample has promise as a prognostic indicator in this setting (p = .085). This minimally invasive plasma-based NGS assay could enable comprehensive prognostic assessment of patients in a clinical setting, with greater accessibility than current methods.

Zinc status and indicators of intestinal health in enterotoxigenic Escherichia coli F18 challenged newly weaned pigs fed diets with different levels of zinc.

This study investigated the impact of an enterotoxigenic Escherichia coli (ETEC) F18 challenge on newly weaned pigs when fed one of three Zn levels (150, 1,400, or 2,500 ppm) on performance, Zn status, ETEC shedding, and diarrhea. The ETEC challenge was hypothesized to have a more pronounced negative impact on pigs fed a diet containing 150 ppm Zn compared to 1,400 or 2,500 ppm Zn for 14 d after weaning. The study included 72 ETEC F18 susceptible pigs weaned at ~28 d of age (d 0 of the study). The pigs were distributed according to initial weight and litter to one of the three dietary Zn levels. Half of the pigs were challenged with ETEC on d 1 and 2. The challenge reduced (P ≤ 0.03) feed intake and average daily gain (ADG) during d 3 to 5. Challenged pigs fed 150 ppm Zn had lower (P = 0.01) ADG during d 5 to 7 compared to those fed 1,400 or 2,500 ppm Zn, whereas control pigs' ADG were not affected by dietary Zn content. Challenged pigs fed 150 ppm Zn also showed lower (P < 0.01) fecal dry matter (DM) on d 5 compared to control pigs fed 150 ppm Zn and challenged pigs fed 1,400 or 2,500 ppm Zn. Challenge increased (P < 0.01) ETEC shedding in all groups, but challenged pigs fed 150 ppm Zn showed higher (P ≤ 0.05) fecal shedding of ETEC and toxins than when fed 1,400 or 2,500 ppm. On d 3, C-reactive protein concentration in plasma was lower (P < 0.03) for pigs fed 1,400 and 2,500 compared to 150 ppm Zn. Plasma haptoglobin and pig major acute phase protein were unaffected by dietary Zn content. On d 0, the serum Zn concentration was 586 ±â€…36.6 µg/L, which pigs fed 150 ppm Zn maintained throughout the study. The serum Zn concentration increased (P ≤ 0.07) in pigs fed 1,400 or 2,500 ppm Zn. The challenge decreased (P < 0.01) the serum Zn concentration in pigs fed 2,500 ppm Zn. On d 5 and 7, serum Zn concentration was similar for challenged pigs fed 1,400 and 2,500 ppm Zn, while control pigs fed 2,500 ppm Zn had higher (P < 0.01) serum Zn concentration than 1,400 ppm Zn. On d 7, serum Zn concentration tended (P = 0.08) to be lower for pigs with diarrhea (fecal DM ≤ 18%). In summary, these results indicate that newly weaned pigs fed 150 ppm Zn are more susceptible to ETEC F18 colonization and its adverse consequences such as diarrhea and reduced growth, even though challenge did not increase acute phase proteins.

At weaning, the immune system of pigs is not fully developed, leaving them more susceptible to infections such as enterotoxigenic Escherichia coli (ETEC) F18. This study investigated the effect of dietary zinc content on newly weaned pigs infected with ETEC in terms of performance, serum zinc status, diarrhea, E. coli shedding, and systemic inflammation markers. Challenged pigs had reduced growth the first 3 d after the challenge when fed 150 ppm dietary Zn compared to non-challenged pigs. Moreover, the challenge increased E. coli fecal shedding and resulted in more liquid feces, and a greater risk of diarrhea in pigs fed 150 ppm zinc compared to 1,400 and 2,500 ppm zinc. The challenge was not able to induce a response in the acute phase proteins. The serum zinc concentration was lowest when feeding 150 ppm, and the ETEC challenge caused a reduction in the serum Zn concentration only when feeding 2,500 ppm zinc. These findings suggest that newly weaned pigs fed 150 ppm zinc are less capable of withstanding an ETEC challenge based on impaired growth performance and increased diarrhea and E. coli shedding.

Minimal Residual Disease Status Predicts Outcome in Patients With Previously Untreated Follicular Lymphoma: A Prospective Analysis of the Phase III GALLIUM Study.

PURPOSE: We report an analysis of minimal residual/detectable disease (MRD) as a predictor of outcome in previously untreated patients with follicular lymphoma (FL) from the randomized, multicenter GALLIUM (ClinicalTrials.gov identifier: NCT01332968) trial. PATIENTS AND METHODS: Patients received induction with obinutuzumab (G) or rituximab (R) plus bendamustine, or cyclophosphamide, doxorubicin, vincristine, prednisone (CHOP) or cyclophosphamide, vincristine, prednisone (CVP) chemotherapy, followed by maintenance with the same antibody in responders. MRD status was assessed at predefined time points (mid-induction [MI], end of induction [EOI], and at 4-6 monthly intervals during maintenance and follow-up). Patients with evaluable biomarker data at diagnosis were included in the survival analysis. RESULTS: MRD positivity was associated with inferior progression-free survival (PFS) at MI (hazard ratio [HR], 3.03 [95% CI, 2.07 to 4.45]; P < .0001) and EOI (HR, 2.25 [95% CI, 1.53 to 3.32]; P < .0001). MRD response was higher after G- versus R-chemotherapy at MI (94.2% v 88.9%; P = .013) and at EOI (93.1% v 86.7%; P = .0077). Late responders (MI-positive/EOI-negative) had a significantly poorer PFS than early responders (MI-negative/EOI-negative; HR, 3.11 [95% CI, 1.75 to 5.52]; P = .00011). The smallest proportion of MRD positivity was observed in patients receiving bendamustine at MI (4.8% v 16.0% in those receiving CHOP; P < .0001). G appeared to compensate for less effective chemotherapy regimens, with similar MRD response rates observed across the G-chemo groups. During the maintenance period, more patients treated with R than with G were MRD-positive (R-CHOP, 20.7% v G-CHOP, 7.0%; R-CVP, 21.7% v G-CVP, 9.4%). Throughout maintenance, MRD positivity was associated with clinical relapse. CONCLUSION: MRD status can determine outcome after induction and during maintenance, and MRD negativity is a prerequisite for long-term disease control in FL. The higher MRD responses after G- versus R-based treatment confirm more effective tumor cell clearance.

Delirium and delirium severity screening in the intensive care-correspondence of screenings tools.

BACKGROUND: Delirium severity scores are gaining acceptance for measuring delirium in the intensive care unit (ICU). OBJECTIVE: The aim of this study was to evaluate the concordance between the Confusion Assessment Method for the intensive care unit (CAM-ICU)-7 and the Intensive Care Delirium Screening Checklist (ICDSC) as delirium severity measurement tools. METHODS: This was a prospective, comparative, observational multicentre study. This study was conducted in 18 Danish ICUs. Delirium was assessed in adult critically ill patients admitted to an ICU with a Richmond Agitation and Sedation Score (RASS) of -2 or above. ICU nurses assessed delirium with randomised paired delirium screening instruments, using the CAM-ICU, the ICDSC, and the CAM-ICU-7. The correlation between the CAM-ICU-7 and the ICDSC severity scores was evaluated for all predefined patient subgroups. RESULTS: A total of 1126 paired screenings were conducted by 127 ICU nurses in 850 patients. The patients' median age was 70 years (interquartile range: 61-77), 40% (339/850) were female, and 54% (457/850) had at least one positive delirium score. Delirium severity ranges (CAM-ICU-7: 0-7; and ICDSC: 0-8) were positively correlated (Pearson's correlation coefficient, r = 0.83; p < 0.0001). The overall agreement between the CAM-ICU-7 and the ICDSC for delirium measurement (CAM-ICU-7: >2, and ICDSC: >3) was substantial (kappa = 0.74), but the agreement decreased to fair (kappa = 0.38) if a patient had a RASS less than 0. CONCLUSIONS: The agreement between the CAM-ICU-7 and the ICDSC for delirium severity measurement was substantial but might be affected by the patient's sedation and agitation level at the time of assessment. IMPLICATIONS FOR PRACTICE: Both CAM-ICU-7 and ICDSC can be implemented for delirium severity measurement. Attention is warranted in both scores if a patient has a RASS of -2.

A comparison of the prognostic performance of the Lugano 2014 and RECIL 2017 response criteria in patients with NHL from the phase III GOYA and GALLIUM trials.

The Lugano 2014 criteria are the standard for response assessment in lymphoma. We compared the prognostic performance of Lugano 2014 and the more recently developed response evaluation criteria in lymphoma (RECIL 2017), which relies primarily on computed tomography and uses unidimensional measurements, in patients with previously untreated diffuse large B-cell lymphoma (DLBCL) and follicular lymphoma (FL) from the phase III GOYA and GALLIUM trials, respectively. Concordance between responses according to the Lugano 2014 and RECIL 2017 criteria was analyzed. Landmark analyses of progression-free survival (PFS) and overall survival (OS) by end of treatment (EOT) and end of induction (EOI) response status according to RECIL 2017 and Lugano 2014 criteria, and prognostic value of response at EOT/EOI were also compared. Overall, 1333 patients were included from GOYA and 502 from GALLIUM. Complete response (CR) status according to RECIL 2017 criteria showed high concordance with complete metabolic response (CMR) status by Lugano 2014 criteria in both GOYA (92.5%) and GALLIUM (92.4%). EOT and EOI CR/CMR status by both criteria was highly prognostic for PFS in GOYA (RECIL 2017 [CR]: hazard ratio [HR], 0.35 [95% confidence interval [CI] 0.26-0.46]; Lugano 2014 [CMR]: HR, 0.35 [95% CI 0.26-0.48]; both p < .0001) and GALLIUM (RECIL 2017 [CR]: HR, 0.35 [95% CI 0.23-0.53]; Lugano 2014 [CMR]: HR, 0.21 [95% CI 0.14-0.31]; both p < .0001). In conclusion, response categorization by RECIL 2017 is similar to that by Lugano 2014 criteria, with high concordance observed. Both were prognostic for PFS and OS.

Determination of the optimal dietary zinc content for pigs between 10 and 30 kg body weight.

The Zn requirement of pigs immediately after weaning is more investigated compared to the Zn requirement in the growth period between 10 and 30 kg. Unabsorbed and excessive dietary Zn is excreted mainly through feces, and spreading pig slurry to fields can cause environmental issues because high levels of Zn can impair plant growth and contribute to the development of antimicrobial resistance genes in microorganisms. Therefore, more precise knowledge of Zn requirements and dietary Zn recommendations is important. The present study investigated the optimal dietary Zn content for 10- to 30-kg pigs. The study used 150 pigs weaned at 28 d of age (day 0) and supplied with 1,474 mg dietary Zn/kg the first 2 wk post-weaning. After 2 wk, pigs were randomly distributed according to body weight (BW; 10.1 ±â€…0.3 kg) and sex, to individually housing, and fed a diet supplemented with either 0, 30, 60, 120, or 240 mg Zn/kg (from ZnO), resulting in total dietary Zn contents of 80, 92, 117, 189, and 318 mg/kg until week 6 post-weaning. BW, feed intake, and fecal scores were recorded, and samples of blood (weeks 2, 3, 5, and 6) and tissues (week 6) were collected. The feed intake, growth, feed efficiency, relative weight of the pancreas and liver, Zn concentration in the liver, and pancreatic digestive enzyme activity were unaffected by dietary Zn content (P > 0.12). The serum Zn level decreased (P < 0.01) by up to 24% from weeks 2 to 3. The serum Zn concentrations in weeks 5 and 6 were similar to in week 2 when 117, 189, and 318 mg Zn/kg were provided, while with 80 and 92 mg Zn/kg the serum Zn concentration was lower (P < 0.01) than in week 2. The serum Zn concentration reached a plateau in weeks 5 and 6, and breakpoints were calculated at 126 ±â€…17 and 102 ±â€…6 mg Zn/kg, respectively. Bone Zn status was greater (P < 0.01) with 189 than 80 mg Zn/kg and a breakpoint was calculated at 137 ±â€…19 mg Zn/kg. According to performance, the Zn requirement for 10- to 30-kg pigs can be fulfilled with 80 mg total Zn/kg, but based on serum and bone Zn status, the optimal total dietary Zn content is 102 to 137 mg/kg. The latter corresponds to a daily Zn intake (requirement) of 103 to 138 mg when calculated from the average feed intake during weeks 3 to 6 (1,005 g/d). Importantly, the presented results are obtained in pigs supplied with 1,474 mg Zn/kg from ZnO the first 2 wk post-weaning and a high level of phytase (1,000 phytase units) in the diet throughout the experiment.

It is important to ensure that the dietary zinc (Zn) content fulfills the Zn requirement of pigs. The unabsorbed proportion of dietary Zn is excreted mainly through feces and supplying pigs with more Zn than they need increases the excretion, which may be an environmental issue. This study investigated the optimal dietary Zn content in 10- to 30-kg pigs. From weaning until 10 kg (the first 2 wk post-weaning) pigs were fed a diet containing 1,474 mg Zn/kg. From the third to the sixth week post-weaning (10- to 30-kg) pigs were fed a basal diet supplemented with either 0, 30, 60, 120, or 240 mg Zn/kg from zinc oxide. Analysis of the five experimental diets showed total Zn contents of 80, 92, 117, 189, and 318 mg/kg. The feed intake, weight gain, and feed efficiency were unaffected by dietary Zn content. The Zn concentration in serum (blood) at the end of the experiment was lowest with 80 and 92 mg total Zn/kg compared to 117, 189, and 318 mg total Zn/kg, which resulted in similar serum Zn concentration. The Zn content in bone was lower at 80 compared to 189 mg total Zn/kg.

Multi-omic analysis of the tumor microenvironment shows clinical correlations in Ph1 study of atezolizumab +/- SoC in MM.

Multiple myeloma (MM) remains incurable, and treatment of relapsed/refractory (R/R) disease is challenging. There is an unmet need for more targeted therapies in this setting; deep cellular and molecular phenotyping of the tumor and microenvironment in MM could help guide such therapies. This phase 1b study (NCT02431208) evaluated the safety and efficacy of the anti-programmed death-ligand 1 monoclonal antibody atezolizumab (Atezo) alone or in combination with the standard of care (SoC) treatments lenalidomide (Len) or pomalidomide (Pom) and/or daratumumab (Dara) in patients with R/R MM. Study endpoints included incidence of adverse events (AEs) and overall response rate (ORR). A novel unsupervised integrative multi-omic analysis was performed using RNA sequencing, mass cytometry immunophenotyping, and proteomic profiling of baseline and on-treatment bone marrow samples from patients receiving Atezo monotherapy or Atezo+Dara. A similarity network fusion (SNF) algorithm was applied to preprocessed data. Eighty-five patients were enrolled. Treatment-emergent deaths occurred in 2 patients; both deaths were considered unrelated to study treatment. ORRs ranged from 11.1% (Atezo+Len cohorts, n=18) to 83.3% (Atezo+Dara+Pom cohort, n=6). High-dimensional multi-omic profiling of the tumor microenvironment and integrative SNF analysis revealed novel correlations between cellular and molecular features of the tumor and immune microenvironment, patient selection criteria, and clinical outcome. Atezo monotherapy and SoC combinations were safe in this patient population and demonstrated some evidence of clinical efficacy. Integrative analysis of high dimensional genomics and immune data identified novel clinical correlations that may inform patient selection criteria and outcome assessment in future immunotherapy studies for myeloma.

Obinutuzumab Versus Rituximab Immunochemotherapy in Previously Untreated iNHL: Final Results From the GALLIUM Study.

The phase III GALLIUM trial assessed the safety and efficacy of obinutuzumab-based versus rituximab-based immunochemotherapy in patients with previously untreated follicular lymphoma (FL) or marginal zone lymphoma (MZL). At the primary analysis, the trial met its primary end point, demonstrating improvement in investigator-assessed progression-free survival (PFS) with obinutuzumab-based versus rituximab-based immunochemotherapy in patients with FL. We report the results of the final analysis in the FL population, with an additional exploratory analysis in the MZL subgroup. Overall, 1202 patients with FL were randomized 1:1 to obinutuzumab- or rituximab-based immunochemotherapy followed by maintenance with the same antibody for up to 2 years. After a median 7.9 (range, 0.0-9.8) years of follow-up, PFS remained improved with obinutuzumab- versus rituximab-based immunochemotherapy, with 7-year PFS rates of 63.4% versus 55.7% (P = 0.006). Time-to-next antilymphoma treatment was also improved (74.1% versus 65.4% of patients had not started their next antilymphoma treatment at 7 y; P = 0.001). Overall survival was similar between the arms (88.5% versus 87.2%; P = 0.36). Irrespective of the treatment received, PFS and OS were higher in patients with a complete molecular response (CMR) versus those with no CMR (P < 0.001). Serious adverse events were reported in 48.9% and 43.4% of patients in the obinutuzumab and rituximab arms, respectively; there was no difference in the rate of fatal adverse events (4.4% and 4.5%, respectively). No new safety signals were reported. These data demonstrate the long-term benefit of obinutuzumab-based immunochemotherapy and confirm its role as a standard-of-care for the first-line treatment of advanced-stage FL, taking into account patient characteristics and safety considerations.

Corrigendum: A westernized diet changed the colonic bacterial composition and metabolite concentration in a dextran sulfate sodium pig model for ulcerative colitis.

[This corrects the article DOI: 10.3389/fmicb.2023.1018242.].

A westernized diet changed the colonic bacterial composition and metabolite concentration in a dextran sulfate sodium pig model for ulcerative colitis.

Introduction: Ulcerative colitis (UC) is characterized by chronic inflammation in the colonic epithelium and has a blurred etiology. A western diet and microbial dysbiosis in the colon were reported to play a role in UC development. In this study, we investigated the effect of a westernized diet, i.e., increasing fat and protein content by including ground beef, on the colonic bacterial composition in a dextran sulfate sodium (DexSS) challenged pig study. Methods: The experiment was carried out in three complete blocks following a 2×2 factorial design including 24 six-week old pigs, fed either a standard diet (CT) or the standard diet substituted with 15% ground beef to simulate a typical westernized diet (WD). Colitis was induced in half of the pigs on each dietary treatment by oral administration of DexSS (DSS and WD+DSS, respectively). Samples from proximal and distal colon and feces were collected. Results and discussion: Bacterial alpha diversity was unaffected by experimental block, and sample type. In proximal colon, WD group had similar alpha diversity to CT group and the WD+DSS group showed the lowest alpha diversity compared to the other treatment groups. There was a significant interaction between western diet and DexSS for beta diversity, based on Bray-Curtis dissimilarly. The westernized diet and DexSS resulted in three and seven differentially abundant phyla, 21 and 65 species, respectively, mainly associated with the Firmicutes and Bacteroidota phyla followed by Spirochaetota, Desulfobacterota, and Proteobacteria. The concentration of short-chain fatty acids (SCFA) was lowest in the distal colon. Treatment had a slight effect on the estimates for microbial metabolites that might have valuable biological relevance for future studies. The concentration of putrescine in the colon and feces and that of total biogenic amines was highest in the WD+DSS group. We conclude that a westernized diet could be a potential risk factor and an exacerbating agent for UC by reducing the abundance of SCFA-producing bacteria, increasing the abundance of pathogens such as Helicobacter trogontum, and by increasing the concentration of microbial proteolytic-derived metabolites in the colon.

Composition of mucus- and digesta-associated bacteria in growing pigs with and without diarrhea differed according to the presence of colonic inflammation.

BACKGROUND: In the pig production, diarrhea can occur during different growth stages including the period 4-16 weeks post weaning, during which a diarrheal outbreak also termed as colitis-complex diarrhea (CCD) can occur and it is distinct from post-weaning diarrhea (1-2 weeks post weaning). We hypothesized that CCD in growing pigs is associated with changes in colonic microbiota composition and fermentation patterns, and the aim of the present observational study was to identify changes in digesta-associated bacteria (DAB) and mucus-associated bacteria (MAB) in the colon of growing pigs with and without diarrhea. A total number of 30 pigs (8, 11, and 12 weeks of age) were selected; 20 showed clinical signs of diarrhea and 10 appeared healthy. Based on histopathological examination of colonic tissues, 21 pigs were selected for further studies and classified as follows: without diarrhea, no colon inflammation (NoDiar; n = 5), with diarrhea, without colonic inflammation (DiarNoInfl; n = 4), and with diarrhea, with colonic inflammation (DiarInfl; n = 12). Composition (based on 16S rRNA gene amplicon sequencing) and fermentation pattern (short-chain fatty acids; SCFA profile) of the DAB and MAB communities were characterized. RESULTS: The DAB showed higher alpha diversity compared to MAB in all pigs, and both DAB and MAB showed lowest alpha diversity in the DiarNoInfl group. Beta diversity was significantly different between DAB and MAB as well as between diarrheal groups in both DAB and MAB. Compared to NoDiar, DiarInfl showed increased abundance of various taxa, incl. certain pathogens, in both digesta and mucus, as well as decreased digesta butyrate concentration. However, DiarNoInfl showed reduced abundance of different genera (mainly Firmicutes) compared to NoDiar, but still lower butyrate concentration. CONCLUSION: Diversity and composition of MAB and DAB changed in diarrheal groups depending on presence/absence of colonic inflammation. We also suggest that DiarNoInfl group was at the earlier stage of diarrhea compared with DiarInfl, with a link to dysbiosis of colonic bacterial composition as well as reduced butyrate concentration, which plays a pivotal role in gut health. This could have led to diarrhea with inflammation due to a dysbiosis, associated with an increase in e.g., Escherichia-Shigella (Proteobacteria), Helicobacter (Campylobacterota), and Bifidobacterium (Actinobacteriota), which may tolerate or utilize oxygen and cause epithelial hypoxia and inflammation. The increased consumption of oxygen in epithelial mucosal layer by infiltrated neutrophils may also have added up to this hypoxia. Overall, the results confirmed that changes in DAB and MAB were associated with CCD and reduced butyrate concentration in digesta. Moreover, DAB might suffice for future community-based studies of CCD.

Influence of fiber-rich coproducts on nutrient and energy digestibility and utilization in sows.

Coproducts from the food and agricultural industries can potentially be used to replace concentrated high-value grain crops in diets for sows. The coproducts are typically high in fiber and with diverse composition. Energy digestibility and utilization are generally high in sows fed fiber-rich feedstuff, but nitrogen digestion and utilization may be compromised. The purpose of this study was to quantify the apparent total tract digestibility (ATTD) of nutrients and utilization of energy and nitrogen in empty nonlactating sows fed with six different fiber-rich coproducts (FRCP). Brewers spent grain (BSG), pea hull (PH), potato pulp (PP), pectin residue (PR), sugar beet pulp (SBP), and seed residue (SR) were mixed into a basal diet (BD) with as high an inclusion level as possible, or the BD was fed solely to eight empty sows in a Youden square incomplete cross-over design. The collection period consisted of a total collection period of 5 d, of which 2 d were in a respiration chamber. The sows had a gross energy (GE) intake between 28.5 and 42.3 MJ/d; greatest for the PH fed sows and lowest for the PP fed sows. The ATTD of dry matter, organic matter, GE, and N did not differ among the BD and the PH and SBP fed sows, while the ATTDs of all nutrients and energy were intermediate for PR and BSG lowest in SR fed sows (P < 0.01). The differences were caused by variation in digestible and metabolizable energy content of the FRCP ingredients, which was lowest for SR, intermediate for PR followed by BSG and greatest for SBP, PP, and PH (P < 0.001). Total heat production (HP) did not differ among treatments but the nonactivity related HP was highest in SR fed sows and lowest in PH and SBP fed sows (P < 0.05). Retention of energy was greatest following the PH and BD (7.42 and 2.19 MJ/d, respectively), intermediate for PP, SBP, and BSG fed sows (-0.22 to -0.69 MJ/d) and lowest for the PR and SR fed sows (-4.26 and -6.17 MJ/d, respectively; P < 0.001). From a sow feeding perspective, SBP and PH have the potential to partly replace high-value grain crops due to high ATTD of all nutrients and because sows can efficiently utilize energy and protein. In contrast, SR and PR show low ATTD of nutrients and energy, thereby compromising the nutritive value. PP and BSG also have the potential to be included in sow diets, but caution should be taken because of compromised N utilization and thereby increased environmental impact.

Coproducts from the food and agricultural industries have the potential to partly substitute grain in diets for empty nonlactating sows. Many coproducts are high in fiber and with diverse fiber composition. Some being easily fermented, while others are more resistant to fermentation giving rise to a large variation in the total tract digestibility and utilization of nutrients and energy. How well fiber-rich coproducts are digested and utilized is poorly understood in sows, but it is important to ensure an optimal energy and protein composition of the feed depending on the physiological stage of the sow. This study aimed to increase knowledge on the digestibility and utilization of six fiber-rich coproducts potentially to be included in the sow's feed. We found pea hulls and sugar beet pulp suitable as grain replacers due to their high total tract digestibility and no negative effects on energy and protein utilization. Potato pulp and brewers spent grain were also well suited. However, caution should be taken in balancing diets because of increased fecal and urine nitrogen output, which will increase environmental impact. Seed and pectin residues primarily serve as gut fill.

Intensive care unit nurses' perception of three different methods for delirium screening: A survey (DELIS-3).

BACKGROUND: Delirium is common in critically ill patients with detrimental effects in terms of increased morbidity, mortality, costs, and human suffering. Delirium detection and management depends on systematic screening for delirium, which can be challenging to implement in clinical practice. OBJECTIVES: The aim of this study was to explore how nurses in the intensive care unit perceived the use of Confusion Assessment Method for the Intensive Care Unit (CAM-ICU), the Confusion Assessment Method for the Intensive Care Unit-7 (CAM-ICU-7), and Intensive Care Delirium Screening Checklist (ICDSC) for delirium screening of patients in the intensive care unit. METHODS: This was a cross-sectional, electronic-based survey of nurses' perceptions of delirium screening with the three different instruments for delirium screening. Nurses were asked to grade their perception of the usability of the three instruments and how well they were perceived to detect delirium and delirium symptom changes on a 1- to 6-point Likert scale. Open questions about perceived advantages and disadvantages of each instrument were analysed using the framework method. RESULTS: One hundred twenty-seven of 167 invited nurses completed the survey and rated the CAM-ICU-7 as faster and easier than the ICDSC, which was more nuanced and reflected changes in the patient's delirium better. Despite being rated as the fastest, easiest, and most used, the CAM-ICU provided less information and was considered inferior to the CAM-ICU-7 and ICDSC. Using familiar instruments made delirium screening easier, but being able to grade and nuance the delirium assessment was experienced as important for clinical practice. CONCLUSIONS: Both the ICDSC and the CAM-ICU-7 were perceived well suited for detection of delirium and reflected changes in delirium intensity. The CAM-ICU was rated as fast and easy but inferior in its ability to grade and nuance the assessment of delirium. Emphasis on clinical meaningfulness and continued education in delirium screening are necessary for adherence to delirium management guidelines.

Influence of four fiber-rich supplements on digestibility of energy and nutrients and utilization of energy and nitrogen in early and mid-gestating sows.

The digestibility of energy and nutrients in fiber-rich diets depends greatly on the fiber source but most data are from studies with growing pigs. The purpose of this study was to investigate the apparent total tract digestibility (ATTD) of nutrients in different fiber-rich diets and to quantify whole-body metabolism and utilization of energy and nitrogen (N) in gestating sows. Four fiber-rich diets based on sugar beet pulp (SBP), soy hulls (SH), palm kernel expellers (PKE), or a mixed fiber (MF) were formulated, with an average daily intake of total fiber (TF) of 471, 507, 651, and 437 g/d, respectively. A total of 48 multiparous sows were stratified by body weight at mating (day 0) and assigned to one of the four diets throughout gestation. Body weight and backfat were measured, and body pools of fat and protein were estimated using the deuterium oxide dilution technique at days 0, 30, and 60. On days 30 and 60, urine and fecal grab samples were obtained. On days 15 and 45, heart rate was measured to estimate total heat production. The ATTD of nutrients differed across treatments (P < 0.001), while in vivo organic matter digestibility deviated with up to ±3.3% units from in vitro enzyme digestibility of organic matter. The ATTD of energy was highly negatively correlated with intake of lignin (P < 0.001), while ATTD of N was highest (negatively) correlated (P < 0.001) with intake of insoluble non-starch polysaccharides (NSP). The ATTD of all nutrients except NSP was lowest in PKE-fed sows and highest, except for N, in sows fed the SBP diet. The ATTD of N was highest in the MF-fed sows and ATTD of NSP was lowest in the MF-fed sows. Sows lost most energy as heat (53% to 72% of gross energy intake), followed by energy in feces (15% to 17%), urine (3% to 4%), and methane (0.5% to 0.9%). Energy for maintenance accounted for the majority of the heat production and the total energy retention was lowest and highest in the SBP- and PKE-fed sows, with a retention of 3.3 and 13.3 MJ/d, respectively (P < 0.001). Sows lost most N through urine, the lowest and highest N loss (relative to intake) was observed in SH- and SBP-fed sows (50% to 63%, respectively), while 14% to 26% was retained as body protein. In conclusion, the fiber-rich diets were utilized efficiently by gestating sows with respect to energy with ATTD values above 82% in all four fiber-rich diets, whereas the high TF content in the diets compromised the N utilization in gestating sows.

How much energy and nutrients a pig can use from the feed depends greatly on the feed ingredients, feed level, and the physiological stage of the animal. Fibers are of great interest because they can improve health and welfare of pigs and co-products from the food and agriculture industries are among the most interesting. The ability to degrade different fiber sources and utilize energy and nutrients are poorly understood in gestating sows, but highly important when formulating the feed composition. The hypothesis was that sugar beet pulp was superior to the other three fiber-rich sources investigated: soy hulls, palm kernel expellers, or a mix of fibers, with respect to intake and utilization of energy and nutrients. We did not find sugar beet pulp to be particularly superior with respect to energy (fermentation or utilization), whereas utilization of nitrogen was highest for sugar beet pulp but compromised in the three other diets depending on fiber sources.

Safety and efficacy of atezolizumab with rituximab and CHOP in previously untreated diffuse large B-cell lymphoma.

Rituximab plus cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP) is the current standard therapy for patients with diffuse large B-cell lymphoma (DLBCL) and is curative in ∼60% of patients. Atezolizumab is a humanized immunoglobulin G1 monoclonal antibody that targets programmed death-ligand 1 and has previously shown antitumor activity in several tumor types. In a phase 1b/2 trial (NCT02596971), we evaluated the safety and efficacy of atezolizumab in combination with R-CHOP (atezo-R-CHOP; for 6-8 cycles) in patients with previously untreated DLBCL. Patients achieving a complete response (CR) at the end of induction received consolidation therapy with atezolizumab on day 1 of each 21-day cycle for an additional 17 cycles. Overall, 42 patients with DLBCL were included in this analysis. The primary endpoint, CR rate at the end of induction, as assessed by an independent review committee (modified Lugano 2014 criteria), was 77.5% (95% confidence interval [CI], 64.0-87.7; n = 40). Investigator-assessed progression-free survival and overall survival at 3 years were 77.4% (95% CI, 59.7-88.0) and 87.2% (95% CI, 71.9-94.5), respectively. All treated patients experienced ≥1 adverse event (AE; 32 patients [76.2%] had grade 3-4 AE). One patient had a fatal AE (unconfirmed progressive multifocal leukoencephalopathy) that was considered related to atezolizumab and rituximab, and 17 patients (40.5%) experienced atezolizumab-related AEs of special interest. In previously untreated patients with DLBCL, atezo-R-CHOP demonstrated encouraging clinical efficacy and a safety profile consistent with the known toxicities of the individual drugs. This trial was registered at www.clinicaltrials.gov as #NCT02596971.

Risk Factors for and Outcomes of Follicular Lymphoma Histological Transformation at First Progression in the GALLIUM Study.

BACKGROUND: Although advanced­stage follicular lymphoma (FL) is considered incurable, survival has improved with the introduction of the anti-CD20 antibodies, rituximab (R) and obinutuzumab (G). However, FL can undergo histological transformation (HT) to a more aggressive disease, and a validated model for predicting HT risk is not yet available. PATIENTS AND METHODS: We assessed HT incidence, risk factors and outcomes in the phase III, GALLIUM study evaluating R- or G-chemotherapy in patients with previously untreated, advanced-stage FL (ClinicalTrials.gov NCT01332968). HT rates were assessed by repeat tumour biopsy at disease progression or relapse, at the investigator's discretion. RESULTS: Of 1202 patients enrolled, 315 (26.2%) experienced progressive disease; 46 (14.6%) had a biopsy at first progression, 40 of whom had biopsy-confirmed HT. HT risk factors were male sex (subdistribution hazard ratio [sHR], 2.21; 95% confidence interval [CI], 1.16-4.20), elevated baseline serum lactate dehydrogenase (sHR, 3.97; 95% CI, 2.03-7.76), and elevated baseline serum ß2-microglobulin (sHR, 1.96; 95% CI, 1.02-3.79). Patients with HT at first progression had poorer post-progression survival than those with relapsed FL (2-year rate: 55.9% vs. 83.1%). Relapse with HT occurred earlier than FL relapse (median time from randomisation: 0.8 vs. 2.3 years). CONCLUSION: HT was a low-frequency event associated with poor survival outcomes in the GALLIUM study. Male sex and elevated baseline levels of serum LDH and B2M were significant risk factors for HT. Further research is required to develop validated prognostic indices for HT risk and guide treatment decisions.

Anti-CD20-atezolizumab-polatuzumab vedotin in relapsed/refractory follicular and diffuse large B-cell lymphoma.

PURPOSE: New therapies are needed for relapsed/refractory (R/R) B-cell non-Hodgkin lymphoma. This phase 1b, open-label trial evaluated two anti-CD20-based triplet combinations. METHODS: Patients with R/R follicular lymphoma (FL; n = 13) were treated with obinutuzumab, atezolizumab, and polatuzumab vedotin (G-atezo-pola; 1.4 mg/kg/1.8 mg/kg) and patients with R/R diffuse large B-cell lymphoma (DLBCL; n = 23) received rituximab (R)-atezo-pola. The primary efficacy endpoint was complete response (CR) at end of induction (EOI) by PET-CT (investigator assessed; modified Lugano 2014 criteria). Safety endpoints were also assessed. RESULTS: 13 FL patients were treated and evaluable for safety; 2/23 DLBCL patients did not receive treatment and were not included in the safety population. Median observation time was 23.3 and 5.7 months in the FL and DLBCL cohorts, respectively. At EOI, CR rates in FL patients treated with G-atezo-pola at pola doses of 1.4 mg/kg (N = 3) and 1.8 mg/kg (N = 7) were 33% and 14%, respectively. In DLBCL patients receiving R-atezo-pola, the CR rate at EOI was 13%. In the FL cohort, 62% of patients experienced a grade 3-5 adverse event (AE; including two deaths) and 31% developed a serious AE (SAE). In DLBCL patients, R-atezo-pola was associated with a lower incidence of grade 3-5 AEs (24%; one death) and SAEs (10%). In both cohorts, the most common grade 3-5 AEs were hematologic toxicities. CONCLUSION: Based on these safety issues, considered as related specifically to G-atezo-pola, and limited efficacy, no further development of either combination is planned. TRIAL REGISTRATION: NCT02729896; Date of registration: April 6, 2016.

Bioavailability of Different Zinc Sources in Pigs 0-3 Weeks Post-Weaning.

The bioavailability of dietary zinc (Zn) in pigs may differ according to the Zn source and is affected by other components in the diet. The aim was to determine the biomarkers of Zn bioavailability (apparent total tract digestibility of Zn and serum Zn status) following six different sources of added Zn and their effect on the performance and faecal consistency score in piglets 0-3 weeks after weaning on day 28. The sources of Zn were Zn oxide (ZnO), Zn sulfate (ZnSO4), porous ZnO, Zn-glycinate, amino acid-bound Zn and hydroxy covalent-bound Zn added at 100 mg/kg (ZnO and ZnSO4 also added at 1000 mg/kg), in a total of eight treatments (n = 12/treatment). Pigs were individually housed, and titanium dioxide was included as an indigestible marker in the feed. The digestibility of Zn on day 14 post-weaning was negative for all six Zn sources at 100 mg Zn/kg, indicating insufficient Zn supply. The digestibility of Zn differed according to the Zn source, but the digestibility of Zn from ZnO and ZnSO4 did not differ between processed inorganic or chelated organic sources of Zn. However, the differences in Zn digestibility between Zn sources were not reflected as differences in the serum Zn status, feed intake, gain or probability of diarrhoea.

Review on Preventive Measures to Reduce Post-Weaning Diarrhoea in Piglets.

In many countries, medical levels of zinc (typically as zinc oxide) are added to piglet diets in the first two weeks post-weaning to prevent the development of post-weaning diarrhoea (PWD). However, high levels of zinc constitute an environmental polluting agent, and may contribute to the development and/or maintenance of antimicrobial resistance (AMR) among bacteria. Consequently, the EU banned administering medical levels of zinc in pig diets as of June 2022. However, this may result in an increased use of antibiotic therapeutics to combat PWD and thereby an increased risk of further AMR development. The search for alternative measures against PWD with a minimum use of antibiotics and in the absence of medical levels of zinc has therefore been intensified over recent years, and feed-related measures, including feed ingredients, feed additives, and feeding strategies, are being intensively investigated. Furthermore, management strategies have been developed and are undoubtedly relevant; however, these will not be addressed in this review. Here, feed measures (and vaccines) are addressed, these being probiotics, prebiotics, synbiotics, postbiotics, proteobiotics, plants and plant extracts (in particular essential oils and tannins), macroalgae (particularly macroalgae-derived polysaccharides), dietary fibre, antimicrobial peptides, specific amino acids, dietary fatty acids, milk replacers, milk components, creep feed, vaccines, bacteriophages, and single-domain antibodies (nanobodies). The list covers measures with a rather long history and others that require significant development before their eventual use can be extended. To assess the potential of feed-related measures in combating PWD, the literature reviewed here has focused on studies reporting parameters of PWD (i.e., faeces score and/or faeces dry matter content during the first two weeks post-weaning). Although the impact on PWD (or related parameters) of the investigated measures may often be inconsistent, many studies do report positive effects. However, several studies have shown that control pigs do not suffer from diarrhoea, making it difficult to evaluate the biological and practical relevance of these improvements. From the reviewed literature, it is not possible to rank the efficacy of the various measures, and the efficacy most probably depends on a range of factors related to animal genetics and health status, additive doses used, composition of the feed, etc. We conclude that a combination of various measures is probably most recommendable in most situations. However, in this respect, it should be considered that combining strategies may lead to additive (e.g., synbiotics), synergistic (e.g., plant materials), or antagonistic (e.g., algae compounds) effects, requiring detailed knowledge on the modes of action in order to design effective strategies.