Building a Stronger Instrument in an Observational Study of Perinatal Care for Premature Infants

An instrument is a random nudge toward acceptance of a treatment that affects outcomes only to the extent that it affects acceptance of the treatment. Nonetheless, in settings in which treatment assignment is mostly deliberate and not random, there may exist some essentially random nudges to accept treatment, so that use of an instrument might extract bits of random treatment assignment from a setting that is otherwise quite biased in its treatment assignments. An instrument is weak if the random nudges barely influence treatment assignment or strong if the nudges are often decisive in influencing treatment assignment. Although ideally an ostensibly random instrument is perfectly random and not biased, it is not possible to be certain of this; thus a typical concern is that even the instrument might be biased to some degree. It is known from theoretical arguments that weak instruments are invariably sensitive to extremely small biases; for this reason, strong instruments are preferred. The strength of an instrument is often taken as a given. It is not. In an evaluation of effects of perinatal care on the mortality of premature infants, we show that it is possible to build a stronger instrument, we show how to do it, and we show that success in this task is critically important. We also develop methods of permutation inference for effect ratios, a key component in an instrumental variable analysis

Drug design and synthesis of first in class PDZ1 targeting NHERF1 inhibitors as anticancer agents

Targeted approaches aiming at modulating NHERF1 activity, rather than its overall expression, would be preferred to preserve the normal functions of this versatile protein. We focused our attention on the NHERF1/PDZ1 domain that governs its membrane recruitment/displacement through a transient phosphorylation switch. We herein report the design and synthesis of novel NHERF1 PDZ1 domain inhibitors. These compounds have potential therapeutic value when used in combination with antagonists of β-catenin to augment apoptotic death of colorectal cancer cells refractory to currently available Wnt/β-catenin-targeted agents

Integrated Geomatic Techniques for Georeferencing and Reconstructing the Position of Underground Archaeological Sites: The Case Study of the Augustus Sundial (Rome)

A large part of the archaeological remains still to be discovered and excavated are not in remote and depopulated areas of the earth but are often beneath urban centres that have buried them with centuries of debris and later constructions. Excavating in these contexts is much more complex than digging in rural or sparsely inhabited areas because of the constraints imposed by existing buildings and infrastructure. It should also be considered that within an urbanised area, any archaeological remains are concentrated in the subsoil of the historic centre, which is, therefore, often surmounted by buildings that are more recent than the remains but historical as well, and thus, of considerable value and vulnerability. For this reason, an archaeological excavation in an urban area must be preceded by a real feasibility study, where the potential risks for the structures above are minimised and accurately quantified. In many situations, as in the case under study, the discovery of a small segment of a structure is the only clue to reconstruct the development of the remaining part still to be excavated, which may stretch tens or hundreds of metres away from the measurable part. As a consequence, an error of a few centimetres in the survey of the excavated part can lead to errors of metres in estimating the positions of the far parts still to be excavated, and this, in many cases, as in the one under study, must absolutely be avoided. In practice, high-precision geomatic surveys, in support of the archaeological and historical interpretation of the observable structures, will help to establish the exact locations to possibly continue the excavations, helping the accurate planning of the excavation itself. Here, we have shown how the various techniques, compared to each other, have made it possible to reconstruct the location of a short stretch (less than 7 metres) of the Emperor Augustus' Sundial, the only currently visible evidence of a scientific instrument of imposing dimensions (tens of metres in length and height) that served to define some of the characteristics of the calendar that we still use today. The portion of the sundial currently observable, according to the most reliable hypotheses, is located approximately at one end of a structure and extends for several tens of metres. The accurate positioning of the observable parts in a geodetic reference system will enable to identify with certainty the possible areas in which excavation may continue and will also allow to accurately reconstruct the principle of operation of the sundial through an approach that could be defined as "reverse engineering" of the scientific instrument itself. The aim of this work is to study and thus define the combination and integration of existing geomatic techniques for this specific field of applicatio

Cantor type functions in non-integer bases

Cantor's ternary function is generalized to arbitrary base-change functions in non-integer bases. Some of them share the curious properties of Cantor's function, while others behave quite differently

KERATOCONUS AND EPI-OFF CORNEAL CROSS-LINKING BY RIBOFLAVIN-ULTRAVIOLET TYPE A: INDICATIONS AND RATIONAL OF EMPLOYMENT

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T.E.A. Study: three-day ertapenem versus three-day Ampicillin-Sulbactam.

Background: Intra-abdominal infections are one of the most common infections encountered by a general surgeon. However, despite this prevalence, standardized guidelines outlining the proper use of antibiotic therapy are poorly defined due to a lack of clinical trials investigating the ideal duration of antibiotic treatment. The aim of this study is to compare the efficacy and safety of a three-day treatment regimen of Ampicillin-Sulbactam to that of a three-day regimen of Ertapenem in patients with localized peritonitis ranging from mild to moderate severity. Methods: This study is a prospective, multi-center, randomized investigation performed in the Department of General, Emergency, and Transplant Surgery of St. Orsola-Malpighi University Hospital in Bologna, Italy. Discrete data were analyzed using the Chi-squared and Fisher exact tests. Differences between the two study groups were considered statistically significant for p-values less than 0.05. Results: 71 patients were treated with Ertapenem and 71 patients were treated with Ampicillin-Sulbactam. The two groups were comparable in terms of age and gender as well as the site of abdominal infection. Post-operative infection was identified in 12 patients: 10 with wound infections and 2 with intra-abdominal infections. In the Ertapenem group, 69 of the 71 patients (97%) were treated successfully, while the therapy failed in 2 cases (3%). Therapy failures were more frequent in the Unasyn group, amounting to 10 of 71 cases (p = 0.03). Conclusion: According to these preliminary findings, the authors conclude that a three-day Ertapenem treatment regimen is the most effective antibiotic therapy for patients with localized intra-abdominal infections ranging from mild to moderate severity

Cytoreductive Surgery (CRS) and HIPEC for Advanced Ovarian Cancer with Peritoneal Metastases: Italian PSM Oncoteam Evidence and Study Purposes

Ovarian cancer is the eighth most common neoplasm in women with a high mortality rate mainly due to a marked propensity for peritoneal spread directly at diagnosis, as well as tumor recurrence after radical surgical treatment. Treatments for peritoneal metastases have to be designed from a patient’s perspective and focus on meaningful measures of benefit. Hyperthermic intraperitoneal chemotherapy (HIPEC), a strategy combining maximal cytoreductive surgery with regional chemotherapy, has been proposed to treat advanced ovarian cancer. Preliminary results to date have shown promising results, with improved survival outcomes and tumor regression. As knowledge about the disease process increases, practice guidelines will continue to evolve. In this review, we have reported a broad overview of advanced ovarian cancer management, and an update of the current evidence. The future perspectives of the Italian Society of Surgical Oncology (SICO) are discussed conclusively

PRMT5-Selective Inhibitors Suppress Inflammatory T Cell Responses and Experimental Autoimmune Encephalomyelitis

In the autoimmune disease multiple sclerosis and its animal model, experimental autoimmune encephalomyelitis (EAE), expansion of pathogenic, myelin-specific Th1 cell populations drives active disease; selectively targeting this process may be the basis for a new therapeutic approach. Previous studies have hinted at a role for protein arginine methylation in immune responses, including T cell–mediated autoimmunity and EAE. However, a conclusive role for the protein arginine methyltransferase (PRMT) enzymes that catalyze these reactions has been lacking. PRMT5 is the main PRMT responsible for symmetric dimethylation of arginine residues of histones and other proteins. PRMT5 drives embryonic development and cancer, but its role in T cells, if any, has not been investigated. In this article, we show that PRMT5 is an important modulator of CD4+ T cell expansion. PRMT5 was transiently upregulated during maximal proliferation of mouse and human memory Th cells. PRMT5 expression was regulated upstream by the NF-κB pathway, and it promoted IL-2 production and proliferation. Blocking PRMT5 with novel, highly selective small molecule PRMT5 inhibitors severely blunted memory Th expansion, with preferential suppression of Th1 cells over Th2 cells. In vivo, PRMT5 blockade efficiently suppressed recall T cell responses and reduced inflammation in delayed-type hypersensitivity and clinical disease in EAE mouse models. These data implicate PRMT5 in the regulation of adaptive memory Th cell responses and suggest that PRMT5 inhibitors may be a novel therapeutic approach for T cell–mediated inflammatory disease

A novel oral micellar fenretinide formulation with enhanced bioavailability and antitumour activity against multiple tumours from cancer stem cells

Background: An increasing number of anticancer agents has been proposed in recent years with the attempt to overcome treatment-resistant cancer cells and particularly cancer stem cells (CSC), the major culprits for tumour resistance and recurrence. However, a huge obstacle to treatment success is the ineffective delivery of drugs within the tumour environment due to limited solubility, short circulation time or inconsistent stability of compounds that, together with concomitant dose-limiting systemic toxicity, contribute to hamper the achievement of therapeutic drug concentrations. The synthetic retinoid Fenretinide (4-hydroxy (phenyl)retinamide; 4-HPR) formerly emerged as a promising anticancer agent based on pre-clinical and clinical studies. However, a major limitation of fenretinide is traditionally represented by its poor aqueous solubility/bioavailability due to its hydrophobic nature, that undermined the clinical success of previous clinical trials. Methods: Here, we developed a novel nano-micellar fenretinide formulation called bionanofenretinide (Bio-nFeR), based on drug encapsulation in an ion-pair stabilized lipid matrix, with the aim to raise fenretinide bioavailability and antitumour efficacy. Results: Bio-nFeR displayed marked antitumour activity against lung, colon and melanoma CSC both in vitro and in tumour xenografts, in absence of mice toxicity. Bio-nFeR is suitable for oral administration, reaching therapeutic concentrations within tumours and an unprecedented therapeutic activity in vivo as single agent. Conclusion: Altogether, our results indicate Bio-nFeR as a novel anticancer agent with low toxicity and high activity against tumourigenic cells, potentially useful for the treatment of solid tumours of multiple origin