[Making change: the new principles of the World organization of general medicine (Wonca 2022) and territorial medicine in Italy.] / Realizzare il cambiamento: i nuovi princìpi dell'organizzazione europea della medicina generale (Wonca Europe 2022) e la medicina territoriale in Italia.

The new european declaration "Core values and principles of general practice and family medicine" (Wonca Europe 2022) has been recently issued: which contributions can it provide to the discussion on the future of primary health medicine? And what challenges and changes would it impose in its application to the contexts of medical training, care services and clinical research in Italy? We analyse here the seven principles and values of the new declaration: 1) person-centred care; 2) continuity of care; 3) cooperation in care; 4) community-oriented care; 5) equity in care; 6) science-oriented care; 7) professionalism in care; and through them we reflect on the announced reforms of primary health care (Phc) policy. Indeed, these provide an important basis for a critical discussion regarding the reform of the primary care model, the evolution of the medical training pathway (pre- and post-graduate and therefore towards an adjustment of the specialty pathway of future general practitioners) and research Phc. Considering that the Phc health policies are experiencing a condition of permanent and apparently uncontrollable change, it is well to ask ourselves how and if these values-principles, which are considered fundamental at an international level, will be able to come to life in order to build a new therapeutic trust, specific to general practice and family medicine, both in the professional and disciplinary sphere.

Effect of a biosynthetic bacterial 6-phytase on the digestibility of phosphorus and phytate in midlactating dairy cows.

The effect of a biosynthetic bacterial 6-phytase (PhyG) on the digestibility and excretion of crude protein (CP), phosphorus (P), and phytate-P (PP) in midlactating dairy cows was investigated. Thirty Holstein-Friesians were assigned to three treatments with 10 cows per treatment in a randomized block design. Cows were fed forage (grass and corn silage) provided ad libitum, and a concentrate (without added inorganic phosphate) administered separately in amounts individualized per cow according to milk production, supplemented with phytase according to treatment. The formulated forage-to-concentrate-ratio was ~65%:35%. Dietary treatments comprised the control diet (CON) and CON supplemented with 2,000 (PhyG2,000) or 5,000 (PhyG5,000) phytase units (FTU)/kg DM in the total diet. The experiment comprised an 18-d preperiod for the collection of data to facilitate the allocation of cows to the treatments, followed by a 19-d experimental period comprising a 14-d diet adaptation period and 5 d of twice daily feces collection. Fecal samples were analyzed for the determination of apparent total tract digestibility (ATTD) of chemical constituents in the diet. The ATTD of PP was 92.6% in CON suggesting a high but incomplete degradation of phytate by ruminal microbial phytases. Cows fed PhyG2,000 exhibited increased ATTD of CP and PP [68.4% (2.7% points above CON) and 95.1% (2.5% points above CON), respectively] whilst PhyG5,000 further increased ATTD PP and also increased ATTD P [54.1% (7.8% points above CON)]; ATTD of Ca tended to be increased in PhyG5,000 vs. CON. Linear dose-response relationships were observed for ATTD of DM, CP, P, Ca, and PP. In addition, fecal excretion of P, and PP linearly reduced and that of Ca and CP tended to linearly reduce with increasing PhyG dose level. No difference was observed for DM intake and milk composition was unaffected except for milk protein which tended to be higher in cows fed PhyG5,000 than CON. In summary, the addition of exogenous phytase at 2,000 FTU/kg or higher to diets of lactating dairy cows improved P, PP, Ca, and CP digestibility and reduced fecal excretion of P, PP, and CP in a dose-dependent manner.

Traditionally, it has been believed that dairy cows are able to fully utilize the phosphorus (P) in feed, including that from plant-derived phytate, because of phytase activity of bacteria in the rumen. However, recent data have shown otherwise. This study investigated the effect of a biosynthetic bacterial 6-phytase supplemented to the diets of midlactating dairy cows on the digestibility and excretion of phosphorus and other key nutrients, over a 19-d experimental period. The experimental diets were commercially relevant in composition and low in phosphorus. At either or both of two tested dose levels (2,000 and 5,000 phytase units (FTU) per kilogram DM in the total diet), the exogenous phytase increased the digestibility and reduced fecal excretion of crude protein (CP), total P, and phytate-P compared with a comparable unsupplemented diet. The increases in CP, PP, and P digestibility were phytase-dose dependent. In addition, at the highest dose level, the phytase tended to increase the protein content of milk. The findings indicate that the use of exogenous phytase can improve P and protein utilization in dairy cows and offers an important approach to optimizing nutrient balance and reducing environmental P and nitrogen (N) pollution from dairy farms.

[How are future family doctors in Italy trained? Pilot descriptive study of Postgraduate Training in General Practice.] / Come si formano i futuri medici di medicina generale in Italia? Studio pilota descrittivo di comparazione dei Corsi di formazione specifica in medicina generale.

INTRODUCTION: General practitioner (GP) training programme involves a complex process. In Italy, unlike in other European countries, there is no national core curriculum for the training of GPs and the three-year specific training course in General Medicine (CSFMG) is not equated as a proper specialty. Furthermore, the quality of the CFSMGs is poorly investigated and data are difficult to find/fragment. The aim of this study is to describe and compare GP tranining from two pilot regions (Lombardy and Lazio). METHODS: The study analysed the white and grey literature. For data collection a descriptive grid was created using the characteristics foreseen by current legislation as comparison indicators; the information came exclusively from official and public written data. RESULTS: The analysis reports indicators: structural-organisational; theoretical activity; practical activity; research/guided study; final thesis. DISCUSSION: The most evident fact that emerges is the lack of available (show the gap), public and official information on the GP training, therefore the description and comparison of the basic indicators in the pilot Regions suffers. A learning model based more on minimum time requirements (time-based learning) than on competences to be acquired (competencies-based learning) is evident. Furthermore, the professional/academic profiles of the lecturers are not available and thus comparable; finally, no information on the training methodologies of the frontal/research sessions can be found. CONCLUSIONS: The limitation to only two Regions and the lack of available data do not allow a comprehensive assessment and it would be useful to extend the study on a national scale. However, there is a clear need for improved transparency and evaluation within the GP's training in different Regions through a periodic monitoring system with specific indicators (quantitative and qualitative). The re-establishment/establishment of an independent national observatory on Training in General Practice would be desirable.

Preference for inorganic sources of magnesium and phosphorus in sheep as a function of need.

We determined whether sheep discriminate among different mineral supplements containing P and Mg and if they modify their selection as a function of the basal diet received. Forty lambs were offered four-way choices among inorganic sources of P and Mg: magnesium oxide in its coarse 1) C-MgO and granular 2) MgO forms and magnesium phosphate: 3) Mag33 (33% Mg and 2.7% P), and 4) MGP (25% Mg and 15% P), and two-way choices between MGP and each of the other minerals, and between MgO and C-MgO (baseline). Subsequently, lambs were randomly assigned to four groups (10 lambs/group) and fed rations such that the levels of Mg and P were low (LMg_LP), adequate (NMg_NP), low in Mg and adequate in P (LMg_NP), or adequate in Mg and low in P (NMg_LP). After 29 d, choice tests (post-deficiency) were repeated. During baseline, lambs ate and preferred Mag33 > C-MgO = MGP > MgO (P < 0.05). This pattern remained during post-deficiency tests, but lambs in LMg_LP and LMg_NP increased their preference for MGP and C-MgO, respectively, whereas lambs in NMg_LP increased their preference for C-MgO and MGP relative to baseline (P < 0.05). The serum concentrations of P and Mg increased after preference tests, and preference for MgO and MGP in low-Mg groups increased as the serum concentration of Mg declined (P < 0.05). Thus, lambs discriminated among different minerals and some groups modified their preferences based on the basal diets received, which rectified mineral imbalances.

General Practitioners' Experiences During the First Phase of the COVID-19 Pandemic in Italy: A Critical Incident Technique Study.

Since February 2020, when coronavirus disease began to spread in Italy, general practitioners (GPs) were called to manage a growing number of health situations. The challenges experienced by Italian GPs remained unrevealed. This study aimed at exploring Italian GPs' care experiences and practices associated with critical incidents during the first wave of the pandemic. A qualitative study design involving the critical incident technique through an online survey was applied. Sociodemographic data and open-ended responses were collected. While participants' characteristics were analyzed through descriptive statistics, qualitative data were thematically analyzed employing the framework method. 149 GPs responded to the survey and 99 participants completed the survey (dropout rate = 33%). Eight themes emerged indicating factors related to the organization of the healthcare system and factors related to the clinical management of patients, that were perceived as impacting on the GPs' care provision. The analysis revealed difficulties in communicating with other local services. This, together with the lack of coordination among services, was reported as a major challenge. Primary care was perceived as having been undervalued and criticalities in the organization of GP courses, led in a bureaucratic fashion, posed at risk some trainees to be infected. The digital technologies adopted for remote patient consultations were seen as useful tools for daily practice helping the GPs to stay emotionally connected with their patients. Besides, the improvement in the GP-patient relationship in terms of solidarity between patients and doctors and compliance to rules, had a positive impact. Moreover, many respondents addressed the importance of professional collaboration and teamwork, in terms of both support in practical issues (to find PPE, diagnostics and guidelines) and emotional support. At the same time, the lack of resources (e.g., PPE, swabs) and of specific guidelines and protocols impacted on the care provision. Our findings suggest that GPs in Italy are at risk of being left behind within the epidemic management. Communication and coordination among services are essential and should be substantially improved, and primary care research should be initiated to collect the context-specific evidence necessary to enhance the system's preparedness to public health emergencies and the quality of primary care services.

Preference for inorganic sources of calcium and phosphorus by sheep as a function of need.

We hypothesized that ruminants discriminate among different mineral supplements and modify their selection as a function of need. Forty lambs were offered four-way choices among P, Ca, and Mg sources: monosodium phosphate (MSP), Magnesium phosphate (MGP), Monocalcium phosphate (MCP), and Dicalcium phosphate (DCP); and two-way choices between DCP and the other mineral sources (Baseline). Subsequently, lambs were randomly assigned to four groups (10 lambs/group) and fed rations such that levels of Ca and P were low (LCa_LP), adequate (NCa_NP), low in Ca and adequate in P (LCa_NP), or adequate in Ca and low in P (NCa_LP). Four- and two-way choice tests were repeated (Post-deficiency). During Baseline, lambs ate and preferred MSP > MGP>DCP = MCP (p < .0001), showing that they discriminated among minerals. This pattern remained during four-way Post-deficiency tests, but lambs in LCa_LP, LCa_NP, and NCa_LP showed increased preference for MCP, MGP, and DCP, respectively, relative to other groups and Baseline (p < .05). Some mineral preference also changed in relation to serum concentration of P and Ca. Thus, lambs discriminated among minerals and some groups modified their preferences from Baseline to Post-deficiency choice tests, likely influenced by mineral needs, which in turn contributed to rectify mineral imbalances.

Supplementation with nitrate only modestly affects lipid and glucose metabolism in genetic and dietary-induced murine models of obesity.

To gain a better understanding of how nitrate may affect carbohydrate and lipid metabolism, female wild-type mice were fed a high-fat, high-fructose diet supplemented with either 0, 400, or 800 mg nitrate/kg diet for 28 days. Additionally, obese female db/db mice were fed a 5% fat diet supplemented with the same levels and source of nitrate. Nitrate decreased the sodium-dependent uptake of glucose by ileal mucosa in wild-type mice. Moreover, nitrate significantly decreased triglyceride content and mRNA expression levels of Pparγ in liver and Glut4 in skeletal muscle. Oral glucose tolerance as well as plasma cholesterol, triglyceride, insulin, leptin, glucose and the activity of ALT did not significantly differ between experimental groups but was higher in db/db mice than in wild-type mice. Nitrate changed liver fatty acid composition and mRNA levels of Fads only slightly. Further hepatic genes encoding proteins involved in lipid and carbohydrate metabolism were not significantly different between the three groups. Biomarkers of inflammation and autophagy in the liver were not affected by the different dietary treatments. Overall, the present data suggest that short-term dietary supplementation with inorganic nitrate has only modest effects on carbohydrate and lipid metabolism in genetic and dietary-induced mouse models of obesity.

Antimicrobial promotion of pig growth is associated with tissue-specific remodeling of bile acid signature and signaling.

The spread of bacterial resistance to antimicrobials (AMA) have intensified efforts to discontinue the non-therapeutic use of AMA in animal production. Finding alternatives to AMA, however, is currently encumbered by the obscure mechanism that underlies their growth-promoting action. In this report, we demonstrate that combinations of antibiotics and zinc oxide at doses commonly used for stimulating growth or preventing post-weaning enteritis in pigs converge in promoting microbial production of bile acids (BA) in the intestine. This leads to tissue-specific modifications in the proportion of BA, thereby amplifying BA signaling in intestine, liver, and white adipose tissue (WAT). Activation of BA-regulated pathways ultimately reinforces the intestinal protection against bacterial infection and pathological secretion of fluids and electrolytes, attenuates inflammation in colon and WAT, alters protein and lipid metabolism in liver, and increases the circulating levels of the hormone FGF19. Conceivably, these alterations could spare nutrients for growth and improve the metabolic efficiency of AMA-treated animals. This work provides evidence that BA act as signaling molecules that mediate host physiological, metabolic, and immune responses to the AMA-induced alterations in gut microbial metabolism, eventually permitting the growth-promoting action of AMA. Consequently, BA emerge as a promising target for developing efficacious alternatives to AMA.

Developmental regulation of the intestinal FGF19 system in domestic pigs.

Fibroblast growth factor-19 (FGF19) is an emerging endocrine factor involved in the regulation of bile acid homeostasis and energy metabolism in rodents and humans. In pigs, however, the FGF19 system remains largely unexplored. This study was designed to investigate the developmental regulation of the FGF19 system in domestic pigs. Samples of intestinal sections, liver, and plasma were collected from 24 pigs ( n = 6) at four developmental stages (birth, preweaning, postweaning, and adulthood). In the intestine, expression of the farnesoid X receptor (FXR) and FGF19 showed a congruent time- and region-dependent regulation, beginning soon after birth to achieve maximal expression in ileum during adulthood. The same temporal pattern was followed by the circulating concentration of FGF19, and these changes were accompanied by a time-related increase in the ileal proportion of bile acids that potently activate FXR. Conversely, genes belonging to the FGF19 signaling machinery achieved maximal expression in the small intestine at birth to decrease sharply afterward. In the liver, gene expression of FGF19 receptors and enzymes involved in bile acid biosynthesis paralleled after-birth changes in plasma concentration of this enterokine and attained a maximum during postweaning when plasma FGF19 was the lowest. Although detectable at birth, the hepatic expression of genes belonging to the bile acid-FXR-FGF19 pathway was low before the onset of enteral feeding. In summary, the porcine FGF19 system is present from birth, operative before the onset of enteral feeding, and regulated in a temporal and section-specific manner. NEW & NOTEWORTHY Fibroblast growth factor-19 (FGF19) is an emerging endocrine factor. The domestic pig is a translational model of value in biomedical research. We show for the first time that in pigs the intestinal FGF19 system is present from birth, operative before the onset of enteral feeding, and regulated in a temporal and section-specific manner. This work identifies pigs as a suitable model for investigating the implications of FGF19 signaling within and beyond the gut-liver axis.

Olive oil bioactives protect pigs against experimentally-induced chronic inflammation independently of alterations in gut microbiota.

Subclinical chronic inflammation (SCI) is associated with impaired animal growth. Previous work has demonstrated that olive-derived plant bioactives exhibit anti-inflammatory properties that could possibly counteract the growth-depressing effects of SCI. To test this hypothesis and define the underlying mechanism, we conducted a 30-day study in which piglets fed an olive-oil bioactive extract (OBE) and their control counterparts (C+) were injected repeatedly during the last 10 days of the study with increasing doses of Escherichia coli lipopolysaccharides (LPS) to induce SCI. A third group of piglets remained untreated throughout the study and served as a negative control (C-). In C+ pigs, SCI increased the circulating concentration of interleukin 1 beta (p < 0.001) and decreased feed ingestion (p < 0.05) and weight gain (p < 0.05). These responses were not observed in OBE animals. Although intestinal inflammation and colonic microbial ecology was not altered by treatments, OBE enhanced ileal mRNA abundance of tight and adherens junctional proteins (p < 0.05) and plasma recovery of mannitol (p < 0.05) compared with C+ and C-. In line with these findings, OBE improved transepithelial electrical resistance (p < 0.01) in TNF-α-challenged Caco-2/TC-7 cells, and repressed the production of inflammatory cytokines (p < 0.05) in LPS-stimulated macrophages. In summary, this work demonstrates that OBE attenuates the suppressing effect of SCI on animal growth through a mechanism that appears to involve improvements in intestinal integrity unrelated to alterations in gut microbial ecology and function.

Cromolyn-mediated improvement of intestinal barrier function is associated with enhanced piglet performance after weaning.

BACKGROUND: Previous work showed that weaning stress causes gut barrier dysfunction partly by triggering the release of corticotropin releasing factor (CRF) and thereby inducing the degranulation of intestinal mast cell (MC). This study investigated the hypothesis that attenuating the weaning-induced activation of the CRF-MC axis via administration of a MC stabilizing agent (cromolyn) may improve gut permeability and piglet performance after weaning. RESULTS: To test the hypothesis twenty piglets were weaned (20 ± 1.0 d of age; 6.4 ± 0.4 kg of BW) and injected intraperitoneally with saline (control, n = 10) or 20 mg/kg BW of sodium cromolyn (cromolyn, n = 10) at - 0.5, 8 and 16 h relative to weaning. Piglets were housed individually and fed ad libitum a pre-starter diet from one to 15 d post-weaning followed by a starter diet until the end of the study on d 36. Cromolyn improved intestinal permeability as indicated by the reduced recovery of cobalt and mannitol in plasma samples. Cromolyn treated pigs consumed more feed (369 vs. 313 g/d; P < 0.009), gained more BW (283 vs. 238 g/d; P < 0.006), and grew more efficiently (0.60 vs. 0.40; P < 0.042) than their control counterparts. As a result, cromolyn treated pigs were 1.4 kg heavier than those in the control group by d 36 after weaning (16.5 vs. 17.9 kg; P < 0.002). CONCLUSIONS: In agreement with our hypothesis, present data indicate that the cromolyn-mediated improvement of intestinal permeability is associated with enhanced pig performance after weaning.

Bile acid mediated effects on gut integrity and performance of early-weaned piglets.

BACKGROUND: Early weaning (EW) results in a transient period of impaired integrity of the intestinal mucosa that may be associated with reduced plasma concentration of glucagon-like peptide-(GLP) 2. We have previously shown that intragastric infusion of chenodeoxycholic acid (CDC) increases circulating GLP-2 in early-weaned piglets. The aim of this study was to expand previous work to establish whether feeding piglets a cereal-based diet supplemented with CDC can improve gut integrity and animal performance immediately after EW. A cohort of 36 piglets weaned at 20 days of age, 6.2 ± 0.34 kg of body weight (BW) were randomly assigned (n = 18) to receive a standard prestarter diet or the same diet supplemented with 60 mg of CDC per kg of initial BW for ad libitum intake until day 14 postweaning. Thereafter, all pigs were fed the same untreated starter diet for 21 days until the end of the study on day 35. On days 1, 7 and 14 blood samples were collected from 6 pigs per treatment to measure plasma GLP-2. On day 15, 6 pigs per treatment were euthanized to obtain intestinal tissue samples for later histological and gene expression analyses. RESULTS: Supplementing the diet with CDC tended to increase plasma GLP-2 (P < 0.07; 39 %) and the weight of the large intestine (P < 0.10; 11 %), and increased ileal crypt depth (P < 0.04; 15 %) after 14 days of treatment exposure. Although feed intake and BW gain were not affected by treatments, feeding CDC induced the expression of the cytokines TNF-α (P < 0.02; 1.9 fold), IL-6 (P < 0.01; 2.4 fold), and IL-10 (P < 0.006; 2.2 fold) and the tight junctional protein ZON-1 (P < 0.02; 1.5 fold) in the distal small intestine. CONCLUSIONS: This study showed that the oral administration of CDC to early-weaned pigs has the potential to improve the protection of the intestinal mucosa independently of relevant changes in gut growth.

Bile acids induce glucagon-like peptide 2 secretion with limited effects on intestinal adaptation in early weaned pigs.

Early weaning is a stressful event characterized by a transient period of intestinal atrophy that may be mediated by reduced secretion of glucagon-like peptide (GLP) 2. We tested whether enterally fed bile acids or plant sterols could increase nutrient-dependent GLP-2 secretion and improve intestinal adaptation in weanling pigs. During the first 6 d after weaning, piglets were intragastrically infused once daily with either deionized water (control), chenodeoxycholic acid (CDC; 60 mg/kg body weight), or ß-sitoesterol (BSE; 100 mg/kg body weight). Infusing CDC increased plasma GLP-2 (P < 0.05) but did not affect plasma GLP-1 and feed intake. The intestinal expression of glucagon-like peptide 2 receptor, sodium-dependent bile acid transporter, farnesoid X receptor, and guanosine protein-coupled bile acid receptor genes were not affected by CDC treatment. The intragastric administration of CDC did not alter the weight and length of the intestine, yet increased the activation of caspase-3 in ileal villi (P < 0.02) and the expression of interleukin 6 (P < 0.002) in the jejunum. In contrast, infusing BSE did not affect any of the variables that were measured. Our results show that the enteral administration of the bile acid CDC potentiates the nutrient-induced secretion of endogenous GLP-2 in early-weaned pigs. Bile acid-enhanced release of GLP-2, however, did not result in improved intestinal growth, morphology, or inflammation during the postweaning degenerative phase.