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Introduction: We aimed to compare the effectiveness and cost-effectiveness profiles of glucagon-like peptide-1 receptor agonist (GLP-1-RA), sodium-glucose cotransporter 2 inhibitor (SGLT2i), and dipeptidyl peptidase-4 inhibitor (DPP-4i) compared with sulfonylureas and glinides (SU)., Research Design and Methods: Population-based retrospective cohort study based on linked regional healthcare utilization databases. The cohort included all residents in Lombardy aged ≥40 years, treated with metformin in 2014, who started a second-line treatment between 2015 and 2018 with SU, GLP-1-RA, SGLT2i, or DPP-4i. For each cohort member who started SU, one patient who began other second-line treatments was randomly selected and matched for sex, age, Multisource Comorbidity Score, and previous duration of metformin treatment. Cohort members were followed up until December 31, 2022. The association between second-line treatment and clinical outcomes was assessed using Cox proportional hazards models. The incremental cost-effectiveness ratios (ICERs) were calculated and compared between newer diabetes drugs and SU., Results: Overall, 22 867 patients with diabetes were included in the cohort, among which 10 577, 8125, 2893 and 1272 started a second-line treatment with SU, DPP-4i, SGLT2i and GLP-1-RA, respectively. Among these, 1208 patients for each group were included in the matched cohort. As compared with SU, those treated with DPP-4i, SGLT2i and GLP-1-RA were associated to a risk reduction for hospitalization for major adverse cardiovascular events (MACE) of 22% (95% CI 3% to 37%), 29% (95% CI 12% to 44%) and 41% (95% CI 26% to 53%), respectively. The ICER values indicated an average gain of €96.2 and €75.7 each month free from MACE for patients on DPP-4i and SGLT2i, respectively., Conclusions: Newer diabetes drugs are more effective and cost-effective second-line options for the treatment of type 2 diabetes than SUs., Competing Interests: Competing interests: GC received research support from the European Community (EC), the Italian Agency of Drugs (AIFA), and the Italian Ministry of University and Research (MIUR). He took part in a variety of projects that were funded by pharmaceutical companies (ie, Novartis, GSK, Roche, AMGEN and BMS). He also received honoraria as a member of the advisory board to Roche., (© Author(s) (or their employer(s)) 2024. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Competing Interests: Conflict of interest: The Authors declare no potential conflict of interest with respect to the research, authorship and/or publication of this article. The authors declare the following competing interests: AMM, FC, GCo, AG, ML, MMed , MMel, SP, MP, FP, MZ declare no conflict of interest. WM reports holding a fiduciary role in FIMMG, EPCCS and Consulta. EA is an employee of Amgen and reports stock ownership in the company. MB is an employee of Sanofi. GB is an employee of Dephaforum. RC reported receiving consulting fees from MSD Italia, Eli Lilly Italy, Menarini Diagnostics, Roche Diabetes Care Italy, honoraria from Novo Nordisk, Sanofi, Abbott, Mundipharma Farmaceuticals, participation to an advisory boards supported by Boehringer Ingelheim. GCa reported receiving consulting fees from Novartis, Alexion, AstraZeneca, Abbvie, Astellas, Roche, Takeda, Jannsen and Biomarin. ACa reported receiving consulting fees from MSD Italia, Eli Lilly Italy, Menarini Diagnostics, Roche Diabetes Care Italy, honoraria from Novo Nordisk, Sanofi, Abbott, Mundipharma Farmaceuticals, participation to advisory boards supported by Boehringer Ingelheim. ACo reported receiving research grants by AstraZeneca, honoraria from Novo Nordisk, Eli Lilly, Merck Sharp & Dhome, participation on advisory boards supported by Novo Nordisk and Eli Lilly. GD reports stock ownership in Bristol Meyers Squibb. MDG is an employee of Sanofi and reports stock ownership in the company. EP is an employee or Gilead Sciences and reports stock ownership in the company. DS is an employee of Abbvie. VT reported receiving consulting fees from Biogen Italia and grants from FEEM Fondazione Eni Enrico Mattei. EC is an employee of Chiesi Italia.

Competing Interests: Conflict of interest: The authors declare no potential conflict of interest with respect to the research, authorship and/or publication of this article. The authors declare the following competing interests.

The debate around unmet clinical need (UCN) is still very much alive. How do we define UCN? How does it influence the definition of clinically relevant outcomes in a therapeutic area? Who defines UCN? What are the consequences of recognizing different grading of UCN? In this paper we will address these questions and finally formulate proposals for the Italian context. The paper is based on a discussion within a panel of experts. This topic is even more stimulating as this work takes place in a historical period which, on the one hand, sees the start of a new course of negotiation rules recently published by AIFA and, on the other hand, poses unprecedented challenges that emerged during the pandemic crisis. The working group formulated suggestions and proposals to further enhance the role of the UCN in decision-making processes, also in the light of the new negotiation procedure, and to help refine the tools for grading the UCN and the value of medicines in the interests of patients and society as a whole.

Competing Interests: Conflict of interest: GA, GA, GB, PC, EC, FD, CLV, MM, WM, AM, AP, WR, FRdM, FS and VT have nothing to declare. AA received personal fees and/or grants from BMS, MSD, Roche, Astra Zeneca, Eli-Lilly, Takeda e Bayer. GWC received personal fees and/or grants from A. Menarini, Alk-Abelló, Allergy Therapeutics, AstraZeneca-Medimmune, Boehringer Ingelheim, Chiesi Farmaceutici, Genentech, Guidotti-Malesci, Glaxo Smith Kline, Hal Allergy, Merck Sharp & Dome, Mundipharma, Novartis, Orion, Sanofi-Aventis, Sanofi Genzyme/Regeneron, Stallergenes-Greer, Uriach Pharma, Teva, Valeas, ViforPharma. GC received personal fees and/or grants from the European Community, AIFA, Ministeri dell’Università e Ricerca (MIUR), Novartis, GSK, Roche, AMGEN, BMS, Roche. APM received personal fees and/or grants from Bayer, Fresenius, Novartis. GM received personal fees and/or grants from Astra Zeneca, Boehringer Ingelheim, Daiichi Sankyo, Medtronic, Menarini, Merck, Novartis, Recordati, Sandoz, Sanofi, Servier. AM received personal fees and/or grants from Ventana, Pierre Fabre, Verily, Abbvie, AstraZeneca, Verseau Therapeutics, Compungen, Myeloid Therapeutics, Third Rock Venture, Imcheck Therapeutics, Ellipses, Novartis, Roche, Macrophage Pharma, Bioveloclta, Merck, Principia, BMS, Johnson & Johnson. Declares commercial interest in Cedarlane Laboratories Ltd, HyCult Biotechnology, eBioscience, Biolegend, ABCAM PIc, Novus Biologicals, Enzo Life, Affymetrix. AR received personal fees and/or grants from Amgen, Pfizer, Sanofi, Novartis, Kite-Gilead, Celgene-BMS, Jazz, Omeros.

Objective: To evaluate the effect of the exposure to "The Original Sound" (TOS), an original track composed of different sounds such as fetal heartbeat, breathing, blood flow, and ambience sounds, specifically created for this study, on physiological stability of preterm infants during a 10-d hospitalization., Methods: Thirty-four preterm infants (32-37 weeks of gestation) were randomized to receive either TOS or environmental noise. TOS was provided for a 20-min period, three times a day, using two speakers and a MP3 player placed in the cradle. Cardiorespiratory and behavioral parameters were recorded., Results: Heart rate in the treated group was positively correlated with TOS exposure, showing a significant reduction on day 2 and lower values during the first day. A decrease in RR is also recorded on day two in the TOS group, although not significant., Conclusion: This study provides preliminary evidence for short-term improvements in the physiological stability of preterm infants using TOS. Future studies are needed to investigate the potential of this non-pharmacological approach and its clinical relevance to postnatal stress management in neonatal intensive care units.

Echocardiography was performed at every six months in hypertensives well controlled on metoprolol, 100 mg twice a day. After six months' treatment blood pressure was reduced from 177/110 mm Hg to 147/88 (p less than 0.02). LV wall thickness (septum + posterior wall) was unchanged 2.10 cm (2.14), and a significant drop in cardiac output (CO) to 5.0 l/min (6.1, p less than 0.02) was recorded (pretreatment values in brackets). After 24 months' treatment LV wall thickness was reduced to 1.94 cm (p less than 0.02), total peripheral resistance (TPR) to 17.3 mm Hg/l/min (23.4, p less than 0.02) and CO increased to 6.7 l/min (6.1, n.s.). After six months' treatment, there was thus a drop in BP with a significant drop in CO and unchanged TPR. After 24 months' treatment, however, CO was back to the pretreatment level and the drop in BP was entirely caused by a drop in TPR which was probably secondary to a reduction in the wall thickness of the arterial resistance vessels as judged by the relationship between the reduction in wall thickness in the LV and the reduction in TPR during the treatment.

Purpose: The effects of a low-antigen-content diet (LAC diet) versus a standard normocaloric diet on the signs and symptoms of mixed cryoglobulinemia (MC) were compared in a crossover randomized study., Patients and Methods: The study consisted of 24 outpatients with MC, and was carried out in a 48-week period. After 18 weeks of either the LAC or the placebo diet, patients returned to a totally unrestricted diet for 12 weeks (washout period) and crossed over to the second half of the study for the other 18 weeks., Results: After three weeks of the restricted LAC diet, the cryocrit decreased from 3.5 +/- 3.4% (mean +/- SD) to 2.3 +/- 2.0% (p less than 0.01), and the circulating immune complex levels decreased from 48 +/- 30% to 39 +/- 34% (p less than 0.01). At the same time, the purpura score (p less than 0.05), glutamic pyruvic transaminase level (p less than 0.01), and gamma glutamyl transferase level (p less than 0.001) significantly improved. Splenic reticuloendothelial function, measured as the half-life of heat-damaged autologous red cells, decreased from 41 +/- 21 minutes to 21 +/- 10 minutes (p less than 0.005). In contrast, no significant parallel clinical, biochemical, and immunologic changes occurred in the same patients during the placebo (standard normocaloric) diet., Conclusion: These data show that an LAC diet decreases the amount of circulating immune complexes in MC and can modify certain signs and symptoms of the disease. These effects of the LAC diet may be explained by postulating a functional restoration of the mononuclear phagocytic system.

We studied the hemodynamic mechanism responsible for the antihypertensive effect of indapamide in eight patients with mild essential hypertension. Systemic and pulmonary hemodynamics were measured using direct techniques (right heart catheterization and thermodilution method), before and 7-10 days after oral treatment with indapamide (2.5 mg/day). Indapamide reduced mean arterial blood pressure from 120 +/- 1.6 (mean +/- SE) to 101 +/- 1.4 mm Hg (p less than 0.01), and mean pulmonary artery pressure from 21 +/- 0.59 to 17 +/- 1.05 mm Hg (p less than 0.01). Total peripheral vascular resistance (TPR) and pulmonary vascular resistance were reduced from 36 +/- 0.85 to 29 +/- 0.72 U/m2 (p less than 0.01) and from 4.3 +/- 0.17 to 3.8 +/- 0.18 U/m2 (p less than 0.01), respectively. Indapamide did not change cardiac index (CI) (3,311 +/- 61.6 vs. 3,325 +/- 72.1 ml/min/m2), heart rate (HR) (75 +/- 1.7 vs. 75 +/- 9 beats/min), mean rate of left ventricular ejection index 140 +/- 2.04 vs. 139 +/- 1.99 ml/s/m2, and stroke index (44 +/- 5.6 vs. 43 +/- 5.8 ml/m2). Mean pulmonary wedge pressure decreased from 7 +/- 0.6 to 5 +/- 0.5 mm Hg (p less than 0.05). Body weight, 24-h urinary volume, and hematocrit were unchanged after treatment. We conclude that the hemodynamic mechanism responsible for the antihypertensive action of indapamide is a reduction in TPR without changes in CI and HR.

The effectiveness of low-molecular weight heparin CY 216 in the prophylaxis of fatal pulmonary embolism in patients undergoing general surgery was assessed in a multicentre, double-blind, randomized, clinical trial against placebo. A total of 4,498 patients aged over 40 undergoing general surgery were enrolled in the 18 centres which took part in the trial. Patients received a single daily subcutaneous injection of 7,500 anti-Xa units I.C. of CY 216 or placebo two hours before surgery, 12 hours after the initial injection and then daily for at least seven days. A post-mortem examination had to be carried out in every patient who died. The two groups of patients were well-matched for age, sex, type of disease, site and duration of operation as well as for incidence of risk factors which could predispose to the development of thromboembolism. Twenty-six deaths were recorded and validated: eight (0.36%) in the CY 216 group and 18 (0.80%) in the placebo group (p less than 0.05). At the post-mortem examination, carried out in 23 patients (88.5%), two deaths were found to be directly due to pulmonary embolism (0.09%) in the CY 216 group and four (0.18%) in the placebo group. Pulmonary embolism contributed to death in four other placebo-treated patients. Pulmonary or extrapulmonary thromboembolism was a significantly less frequent direct cause of death (p less than 0.05) in the CY 216 group (two pulmonary embolisms) than in the placebo group (four pulmonary embolisms, one acute myocardial infarction, one disseminated intravascular coagulation, two ischemic cerebral strokes).(ABSTRACT TRUNCATED AT 250 WORDS)

The antihypertensive efficacy of a serotonin-receptor antagonist, ketanserin, was compared with that of a well-established antihypertensive drug, metoprolol, and their cardiac and forearm hemodynamic effects were investigated using echocardiography and bidimensional pulsed Doppler flowmetry, respectively. Twenty hypertensive subjects completed a double-blind, cross-over, randomized study using ketanserin and metoprolol. Two 5-week courses with ketanserin or metoprolol were preceded by a placebo period; the total duration of the study was 15 weeks. Despite a comparable efficacy in reducing systolic and diastolic blood pressure (about 10% of the basal value), the two drugs showed quite different effects on forearm hemodynamics. Ketanserin increased forearm blood flow and induced a significant decrease in forearm vascular resistance (from 141 +/- 16 to 75 +/- 11 mm Hg/mL/sec, P less than .01). Furthermore, this treatment was able to improve brachial artery compliance (from 1.89 +/- .3 to 3.2 +/- .3 cm4/dyne 10(-7), P less than .01). On the contrary, metoprolol did not modify forearm hemodynamics. Both drugs did not significantly modify cardiac performance, as evaluated by left ventricle circumferential fiber shortening. Cardiac output was increased by ketanserin (from 5.9 +/- .3 to 6.6 +/- .5 L/min, P less than .05) and fell during treatment with metoprolol (from 5.9 +/- .4 to 4.9 +/- .3 L/min P less than .01). Thus, the two drugs reduce blood pressure through different hemodynamic mechanisms and the effects of ketanserin on systemic and peripheral circulation seem more favorable.

The effects of thermal processing on plasma glucose and insulin responses in healthy subjects were examined. Fourteen volunteers, after being tested with a glucose load, were randomly administered a test meal, consisting of an amount of rice, calculated to yield the same quantity of glucose, used for the glucose tolerance test (70 g). Rice (90 g, raw) was cooked in two different manners: (a) boiled in salted water and (b) baked for 10 min at 160 degrees C after boiling as in the first test. A clear difference in viscosity and in in vitro hydrolytic rates between the two rice items could be established, whereas the plasma glucose and insulin responses in the volunteers differed to a smaller extent. In particular the 60-min incremental area for glucose was significantly lower in the case of baked rice, compared to boiled rice. These findings suggest that thermal processing of complex carbohydrates may differently affect glycemic responses in man.