The implantable cardioverter-defibrillator (ICD) effectively reduces sudden cardiac death in patients with severe LV dysfunction. Effect of ICD therapy on total mortality in patients on the waiting ...list for cardiac transplantation is still uncertain.
We retrospectively analyzed 854 unselected consecutive patients (ICD therapy, n=102; 11.9%) on the waiting list for cardiac transplantation between January 1992 and March 2000. Actuarial 12-month total mortality rate on the waiting list was 24.2%; sudden cardiac death was the predominant mode of death (66.7% of total deaths). Kaplan-Meier analysis revealed improved survival for ICD (total mortality, 13.2%) compared with non-ICD (total mortality, 25.8%) patients (log rank, P=0.03). No event of sudden death occurred in ICD patients, whereas in non-ICD patients, 12-month sudden death rate was 20.1% (P=0.0001). Nonsudden death rates did not differ between ICD and non-ICD patients (P=0.16). A Cox proportional hazards model demonstrated that absence of an ICD was a powerful independent predictor of total mortality (P=0.02; relative risk, 2.22; 95% confidence interval, 1.16 to 4.17) and sudden cardiac death (P<0.0001; infinite relative risk) on the waiting list.
ICD therapy, because it prevents sudden cardiac death, significantly improves survival on the waiting list for cardiac transplantation. The present study supports the use of ICDs as a bridge to transplantation in patients who are at risk of sudden cardiac death. Prospective randomized trials are needed to evaluate the potential benefit of prophylactic ICD therapy as a bridge to transplantation in all patients on cardiac transplant waiting lists.
Feebly-interacting particles Carenza, Pierluca; Milstead, David A.; Wallisch, Benjamin
The European physical journal. C, Particles and fields,
12/2023, Letnik:
83, Številka:
12
Journal Article
Recenzirano
Odprti dostop
Particle physics today faces the challenge of explaining the mystery of dark matter, the origin of matter over anti-matter in the Universe, the origin of the neutrino masses, the apparent fine-tuning ...of the electro-weak scale, and many other aspects of fundamental physics. Perhaps the most striking frontier to emerge in the search for answers involves new physics at mass scales comparable to familiar matter, below the GeV-scale, or even radically below, down to sub-eV scales, and with very feeble interaction strength. New theoretical ideas to address dark matter and other fundamental questions predict such feebly interacting particles (FIPs) at these scales, and indeed, existing data provide numerous hints for such possibility. A vibrant experimental program to discover such physics is under way, guided by a systematic theoretical approach firmly grounded on the underlying principles of the Standard Model. This document represents the report of the FIPs 2022 workshop, held at CERN between the 17 and 21 October 2022 and aims to give an overview of these efforts, their motivations, and the decadal goals that animate the community involved in the search for FIPs.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
OBJECTIVE:Our objective was to identify patient, study, and site factors associated with assay sensitivity in placebo-controlled neuropathic pain trials.
METHODS:We examined the associations between ...study characteristics and standardized effect size (SES) in a database of 200 publicly available randomized clinical trials of pharmacologic treatments for neuropathic pain.
RESULTS:There was considerable heterogeneity in the SESs among the examined trials. Univariate meta-regression analyses indicated that larger SESs were significantly associated with trials that had 1) greater minimum baseline pain inclusion criteria, 2) greater mean subject age, 3) a larger percentage of Caucasian subjects, and 4) a smaller total number of subjects. In a multiple meta-regression analysis, the associations between SES and minimum baseline pain inclusion criterion and age remained significant.
CONCLUSIONS:Our analyses have examined potentially modifiable correlates of study SES and shown that a minimum pain inclusion criterion of 40 or above on a 0 to 100 scale is associated with a larger SES. These data provide a foundation for investigating strategies to improve assay sensitivity and thereby decrease the likelihood of falsely negative outcomes in clinical trials of efficacious treatments for neuropathic pain.
CD4+CD25+ regulatory T cells (TRegs) are critical for the acquisition of peripheral allograft tolerance. However, it is unclear whether TRegs are capable of mediating alloantigen-specific suppressive ...effects and, hence, contributing to the specificity of the tolerant state. In the current report we have used the ABM TCR transgenic (Tg) system, a C57BL/6-derived strain in which CD4+ T cells directly recognize the allogeneic MHC-II molecule I-A(bm12), to assess the capacity of TRegs to mediate allospecific effects. In these mice, 5-6% of Tg CD4+ T cells exhibit conventional markers of the TReg phenotype. ABM TRegs are more effective than wild-type polyclonal TRegs at suppressing effector immune responses directed against I-A(bm12) alloantigen both in vitro and in vivo. In contrast, they are incapable of suppressing responses directed against third-party alloantigens unless these are expressed in the same allograft as I-A(bm12). Taken together, our results indicate that in transplantation, TReg function is dependent on TCR stimulation, providing definitive evidence for their specificity in the regulation of alloimmune responses.
Research conducted to evaluate abuse deterrence should include studies assessing: (1) abuse liability, (2) the likelihood that opioid abusers will find methods to circumvent the deterrent properties ...of the formulation, (3) measures of misuse and abuse in randomized clinical trials involving pain patients with both low risk and high risk of abuse, and (4) postmarketing epidemiological studies.
Opioids are essential to the management of pain in many patients, but they also are associated with potential risks for abuse, overdose, and diversion. A number of efforts have been devoted to the development of abuse-deterrent formulations of opioids to reduce these risks. This article summarizes a consensus meeting that was organized to propose recommendations for the types of clinical studies that can be used to assess the abuse deterrence of different opioid formulations. Because of the many types of individuals who may be exposed to opioids, an opioid formulation will need to be studied in several populations using various study designs to determine its abuse-deterrent capabilities. It is recommended that the research conducted to evaluate abuse deterrence should include studies assessing: (1) abuse liability, (2) the likelihood that opioid abusers will find methods to circumvent the deterrent properties of the formulation, (3) measures of misuse and abuse in randomized clinical trials involving pain patients with both low risk and high risk of abuse, and (4) postmarketing epidemiological studies.
Multiparous Holstein cows at six universities were utilized to examine effects of ruminally protected methionine and lysine on lactational performance. Three hundred and four cows began the study; ...259 cows were included in the production analysis. Following a 21-d standardization period, cows received a basal diet of corn silage and ground corn supplemented with one of five dietary treatments, which were supplements of soybean meal or corn gluten meal, the latter with zero and three combinations of protected methionine and lysine (methionine; methionine and lysine; methionine and double (2×) lysine). Treatment effects were evaluated during early, mid, late, and total lactation (22 to 112, 113 to 224, 225 to 280, and 22 to 280 d post-partum respectively). On a DM basis, ratios of forage to concentrate (50:50, 60:40, and 70:30) increased, and dietary CP (16.0, 14.5, and 13.0%) decreased during the three periods of lactation. Amount of amino acid supplementation also decreased (15, 12, and 9 g/d methionine; 20, 16, and 12 g/d lysine; and 40, 32, and 24 g/d 2× lysine) with period of lactation. Actual and least squares means for milk, FCM, and milk protein yields were greater for soybean than for corn gluten meal during early, mid, and total lactation. In addition, these variables responded linearly to lysine in early lactation. Response to lysine was quadratic during mid and total lactation for these variables. Differences in nutrient intake explained production responses to protein sources but not to lysine. Serum amino acid responses primarily reflected differences in dietary protein source and rumen-protected amino acid.
Skin but not vascularized cardiac allografts from B6.H-2bm12 mice are acutely rejected by C57BL/6 recipients in response to the single class II MHC disparity. The underlying mechanisms preventing ...acute rejection of B6.H-2bm12 heart allografts by C57BL/6 recipients were investigated. B6.H-2bm12 heart allografts induced low levels of alloreactive effector T cell priming in C57BL/6 recipients, and this priming was accompanied by low-level cellular infiltration into the allograft that quickly resolved. Recipients with long-term-surviving heart allografts were unable to reject B6.H-2bm12 skin allografts, suggesting potential down-regulatory mechanisms induced by the cardiac allografts. Depletion of CD25+ cells from C57BL/6 recipients resulted in 15-fold increases in alloreactive T cell priming and in acute rejection of B6.H-2bm12 heart grafts. Similarly, reconstitution of B6.Rag(-/-) recipients with wild-type C57BL/6 splenocytes resulted in acute rejection of B6.H-2bm12 heart grafts only if CD25+ cells were depleted. These results indicate that acute rejection of single class II MHC-disparate B6.H-2bm12 heart allografts by C57BL/6 recipients is inhibited by the emergence of CD25+ regulatory cells that restrict the clonal expansion of alloreactive T cells.
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