Cost-effectiveness analysis of once-weekly semaglutide vs. once-daily liraglutide administered subcutaneously in patients with overweight and obesity: a decision analysis.

OBJECTIVE: Obesity presents an enduring and multifaceted dilemma that impacts individuals, society, economies, and healthcare systems alike. Glucagon-like peptide-1 (GLP-1) receptor agonists, including liraglutide and semaglutide, have received FDA approval for obesity treatment. This study aims to present a cost-effectiveness analysis to compare the cost and clinical outcomes of semaglutide vs. liraglutide on weight loss in people with overweight and obesity. MATERIALS AND METHODS: A cost-effectiveness analysis was conducted to compare the cost and the clinical outcomes of adding weekly 2.4 mg SC semaglutide vs. daily 3.0 mg SC liraglutide or placebo to physical activity and diet control in overweight and obese patients. A clinical outcome of achieving ≥15% weight loss was chosen. A simple decision analysis model from a third-payer perspective was applied. Drug costs were based on the retail price of the USA market. One-way sensitivity analyses were performed. RESULTS: Results showed that 2.4 mg weekly semaglutide, when added to physical activity and diet control, was the most cost-effective choice in terms of ≥15% weight loss (ICER: $ 7,056/patient/68 weeks). The model was robust against the 50% increase in the unit cost of semaglutide and the 50% decrease in the unit cost of liraglutide, as well as the changes in probabilities by the corresponding 95% confidence intervals across the model. CONCLUSIONS: This cost-effectiveness analysis suggests that employing once-weekly 2.4 mg semaglutide emerges as a remarkably cost-effective option when contrasted with once-daily 3.0 mg liraglutide in patients with overweight and obesity when added to physical activity and diet control.

The correlation of EMT and p53 immunohistochemical markers with cisplatin resistance in muscle invasive bladder cancer patients: A single-centred study.

INTRODUCTION: Although epithelial-mesenchymal transition (EMT) and p53 have been established to play a pivotal role in the aggressiveness of muscle-invasive bladder cancer (MIBC), its pathological correlation to cisplatin treatment in the Malaysian patient cohort is lacking. This study aimed to evaluate the association of EMT markers, e-cadherin, vimentin and actin, as well as tumour suppressor gene, p53, in cisplatin-receiving MIBC patients. MATERIALS AND METHODS: Formalin-fixed paraffinembedded (FFPE) blocks of muscle-invasive bladder cancer patients receiving cisplatin-based chemotherapy between January 2010 to December 2020 were traced. Immunohistochemistry staining was performed on traced blocks using antibodies to e-cadherin, vimentin and actin, and p53. RESULTS: p53 and e-cadherin were stained positive in most cases (p=0.515 and 0.242 respectively), although e-cadherin showed stronger positive expression in pre-cisplatin receiving MIBC cases. All the cases stained negative for actin and vimentin except for faint staining observed in one pre-cisplatin case. CONCLUSION: Although this study does not show a significant correlation between EMT markers and p53 with cisplatin-responsiveness in MIBC patients, the results serve as preliminary findings on the heterogeneous outcomes of molecular staining in the Malaysian MIBC patient cohort.

Delivery of costimulatory blockade to lymph nodes promotes transplant acceptance in mice.

The lymph node (LN) is the primary site of alloimmunity activation and regulation during transplantation. Here, we investigated how fibroblastic reticular cells (FRCs) facilitate the tolerance induced by anti-CD40L in a murine model of heart transplantation. We found that both the absence of LNs and FRC depletion abrogated the effect of anti-CD40L in prolonging murine heart allograft survival. Depletion of FRCs impaired homing of T cells across the high endothelial venules (HEVs) and promoted formation of alloreactive T cells in the LNs in heart-transplanted mice treated with anti-CD40L. Single-cell RNA sequencing of the LNs showed that anti-CD40L promotes a Madcam1+ FRC subset. FRCs also promoted the formation of regulatory T cells (Tregs) in vitro. Nanoparticles (NPs) containing anti-CD40L were selectively delivered to the LNs by coating them with MECA-79, which binds to peripheral node addressin (PNAd) glycoproteins expressed exclusively by HEVs. Treatment with these MECA-79-anti-CD40L-NPs markedly delayed the onset of heart allograft rejection and increased the presence of Tregs. Finally, combined MECA-79-anti-CD40L-NPs and rapamycin treatment resulted in markedly longer allograft survival than soluble anti-CD40L and rapamycin. These data demonstrate that FRCs are critical to facilitating costimulatory blockade. LN-targeted nanodelivery of anti-CD40L could effectively promote heart allograft acceptance.

Ceruminous gland adenocarcinoma in a domestic Persian-mix cat (Felis catus).

A nine years old Persian-mix female cat has been suffering from recurrent bilateral ceruminous gland adenocarcinoma for many years. Masses were first noticed and resected five years ago, but reoccurred later on two more occasions. The animal has usually experienced distressful ear canal problems in association with these masses. The tumor cellular morphology was reviewed, described and discussed. This article is the first in documenting ceruminous gland adenocarcinoma in a Persian-mix cat in Libya.

What could be the reasons of late diagnosis of breast cancer in Tunisia?

INTRODUCTION: Breast cancer is often diagnosed at a late stage in Tunisia with long delay in time to consultation and to diagnosis. The aim of the study was to identify explanatory factors to delayed diagnosis. METHODS: A case control analytical was performed from January 2013 to December 2014 in the department of Medical Oncology in FarhatHachedUniveristy Hospital.Patients with the diagnosis of ductal breast carcinoma were included in the study.Characteristics of a first group of 200 women with locally advanced or metastatic breast cancer (G1)were compared to a second group of 200 patients with early stage (G2). RESULTS: Median delay in consultation and mean tumor size were significantly more important in group G1 (p<0,001).A low level of schooling, a rural origin, poor socio-economic conditions and no encouragement by the patient relatives do not allow an early diagnosis.Misinterpretation of clinical breast signs was the only explanatory factor related to the system. In multivariate study, a low level of schooling(adjusted OR=2.72; CI 95% [1,65-4,49]), no encouragement by the patient's relatives(adjusted OR=7.86; CI 95% [4,24-14,57])and more than three dependants(adjusted OR=2.49; CI 95% [1,58-3,93]) were the independent factors that could explain the delay in diagnosis. CONCLUSION: Our study confirm the inverse relationship between socio-economic and scholar level and disease stage. Health education campaigns particularly among women with a low schooling level and of rural origin could reduce time for consultation. Promoting continuing medical education could avoid diagnostic errors.

Prenatal stress induces vulnerability to nicotine addiction and alters D2 receptors' expression in the nucleus accumbens in adult rats.

Prenatal stress (PS) can induce several long-lasting behavioral and molecular abnormalities in rats. It can also be considered as a risk factor for many psychiatric diseases like schizophrenia, depression or PTSD and predispose to addiction. In this study, we investigated the effect of prenatal stress on the reinforcing properties of nicotine in the CPP paradigm. Then, we examined the mRNA expression of the D2 dopaminergic receptors using the quantitative real-time PCR technique in the nucleus accumbens (NAcc). We found that prenatally stressed rats exhibited a greater place preference for the nicotine-paired compartment than the control rats. Moreover, we observed an overexpression of the DRD2 gene in adult offspring stressed in utero and a downregulation in the PS NIC group (PS rats treated with nicotine) compared with their control counterparts (C NIC). These data suggest that maternal stress can permanently alter the offspring's addictive behavior and D2 receptors' expression.

Effect of prenatal stress on memory, nicotine withdrawal and 5HT1A expression in raphe nuclei of adult rats.

Maternal distress has often been associated with cognitive deficiencies and drug abuse in rats. This study examined these behavioral effects in offspring of mothers stressed during gestation. To this end, pregnant dams were subjected to daily electric foot shocks during the last 10 days of pregnancy. We measured litter parameters and body weights of the descendants after weaning (21 days) and at adulthood (80 days). Afterwards, prenatally stressed and control rats' performances in the novel object recognition test were compared in order to evaluate their memory while others underwent the Water consumption test to assess the nicotine withdrawal intensity after perinatal manipulations. Meanwhile, another set of rats were sacrificed and 5HT1A receptors' mRNA expression was measured in the raphe nuclei by quantitative Real Time PCR. We noticed no significant influence of maternal stress on litter size and body weight right after weaning. However, control rats were heavier than the stressed rats in adulthood. The results also showed a significant decrease in the recognition score in rats stressed in utero compared to the controls. Moreover, a heightened anxiety symptom was observed in the prenatally stressed offspring following nicotine withdrawal. Additionally, the Real Time PCR method revealed that prenatal stress induced a significant decrease in 5HT1A receptors' levels in the raphe nuclei. Nicotine had a similar effect on these receptors' expression in both nicotine-treated control and prenatally stressed groups. Taken together, these findings suggest that the cognitive functions and drug dependence can be triggered by early adverse events in rats.

Human papillomavirus prevalence and type-distribution, cervical cancer screening practices and current status of vaccination implementation in Russian Federation, the Western countries of the former Soviet Union, Caucasus region and Central Asia.

Limited data are available on the burden of human papillomavirus (HPV) and its associated diseases in the Russian Federation, the Western Countries of the former Soviet Union (Belarus, Republic of Moldova, Ukraine), the Caucasus region and Central Asia (Armenia, Azerbaijan, Georgia, Kazakhstan, Kyrgyzstan, Tajikistan, Turkmenistan, Uzbekistan). Both the incidence and mortality rate of cervical cancer are higher in these countries than in most Western European countries. In this article, we review available data on HPV prevalence and type distribution in women with normal cytology, women from the general population, cervical precancerous lesions and cervical cancer, as well as data on national policies of cervical cancer screening and HPV vaccination initiatives in these countries. Based on scarce data from the 12 countries, the high-risk HPV (hrHPV) prevalence among 5226 women with normal cytology ranged from 0.0% to 48.4%. In women with low-grade cervical lesions, the hrHPV prevalence among 1062 women varied from 29.2% to 100%. HrHPV infection in 565 women with high-grade cervical lesions ranged from 77.2% to 100% and in 464 invasive cervical cancer samples from 89.8% to 100%. HPV16 was the most commonly detected hrHPV genotype in all categories. As the HPV genotype distribution in cervical diseases seems to be similar to that found in Western Europe the implementation of HPV testing in screening programs might be beneficial. Opportunistic screening programs, the lack of efficient call-recall systems, low coverage, and the absence of quality assured cytology with centralized screening registry are major reasons for low success rates of cervical cancer programs in many of the countries. Finally, HPV vaccination is currently not widely implemented in most of the twelve countries mainly due to pricing, availability, and limited awareness among public and health care providers. Country-specific research, organized nationwide screening programs, registries and well defined vaccination policies are needed. This article forms part of a Regional Report entitled "Comprehensive Control of HPV Infections and Related Diseases in the Central and Eastern Europe and Central Asia Region" Vaccine Volume 31, Supplement 7, 2013. Updates of the progress in the field are presented in a separate monograph entitled "Comprehensive Control of HPV Infections and Related Diseases" Vaccine Volume 30, Supplement 5, 2012.

¿Qué espera el clínico del informe radiológico? / What does the clinician expect from the radiological report?

Introduction: The written radiology report is the most relevant component of any radiological examination. Few studies about referring clinicians opinion concerning structure and contents of radiology reports have been conducted. Objective: To investigate which radiology report issues are significant to the clinician. Methodology: One hundred and sixty-four physicians, among surgeons, internists, residents, and general practitioners were surveyed. Results: According to surveyed clinicians the most important element in any radiologic examination is the reporting radiologist (67.7 percent); 93.9 percent of them expect the radiology report to address the referral diagnosis; 95.7 percent expects the report to present a conclusion, whilst 73 percent of referring clinicians consider ultrasonography as the imaging procedure that commonly exhibits more errors. Surgeons, generally understimate radiologists recommendations for complementary studies. Conclusion: An experienced reporting radiologist is considered the most significant element of any imaging procedure. The radiology report should be problem-oriented (answering clinical question), and contain a conclusion, which should begin by answering the clinician s concerns. General practitioners, internists and residents value further studies reccommended by radiologists.

Introducción. El informe es lo más relevante de un examen radiológico. Escasas publicaciones han estudiado la opinión del clínico. Objetivo. Establecer qué aspectos del informe son relevantes para el clínico. Metodología. Se aplicó una encuesta a cirujanos, internistas, residentes y médicos generales. Resultados. Se encuestó a 164 médicos. Al pedir un examen radiológico, lo más relevante (67,7 por ciento) fue el radiólogo informante; 93,9 por ciento considera importante que se haga referencia al diagnóstico de derivación; 95,7 por ciento estima que debe haber conclusión. El 73 por ciento cree que el examen en el que se cometen más errores es la ecotomografía. Los cirujanos son los que menos valoran las recomendaciones de estudios posteriores. Conclusión. El radiólogo que informa es considerado lo más importante en un examen. El informe debe hacer referencia al diagnóstico, tener conclusión, la que debe comenzar respondiendo la inquietud del clínico. Los médicos generales, internistas y residentes valoran que se sugieran estudios complementarios.

The role of SPARC in the TRAMP model of prostate carcinogenesis and progression.

SPARC (Secreted Protein Acidic and Rich in Cysteine), is a matricellular glycoprotein that is produced by tumor and/or neighboring stroma. In human prostate cancer, SPARC immunoreactivity is highest in metastatic lesions but distinct contributions of tumoral and stromal SPARC to tumorigenesis and progression are unclear. To determine the role of SPARC in primary prostate tumorigenesis, we crossed SPARC-null (SP(-/-)) with TRAMP (Transgenic Adenocarcinoma of Mouse Prostate) mice. TRAMP(+)/SP(-/-) mice exhibited accelerated cancer development and progression. Compared to their TRAMP(+)/SP(-/-) counterparts, TRAMP(+)/SP(+/+) tumors had fewer proliferating cells, and decreased cyclins A and D1 with increased p21(Cip) and p27(Kip). Similar effects on proliferation and cell-cycle regulators were observed in human prostate cancer cell lines, transiently transfected with pSPARC. TRAMP(+)/SP(-/-) tumors exhibited decreased stromal collagen, enhanced matrix metalloproteinase activity and increased vascular endothelial growth factor, proinflammatory cytokines. To determine the contribution of stromal SPARC, we evaluated subcutaneous tumor growth of TRAMP cell lines in syngeneic SP(+/+) and SP(-/-) mice. Enhanced growth, decreased stromal collagen and increased proteolysis were noted in SP(-/-) mice. Our findings demonstrate that both tumor and stromal SPARC are limiting for primary prostate tumorigenesis and progression, through effects on the cell cycle and the creation of a less favorable tumor microenvironment.

Selective release of the flexor origin with transfer of flexor carpi ulnaris in cerebral palsy.

Transfer of flexor carpi ulnaris combined with selective release of the flexor pronator origin was undertaken in 35 patients with hemiplegic cerebral palsy for a pronation flexion deformity of the forearm, hand and wrist. The patients were divided into four groups depending on the severity of the deformity, the surgical procedure recommended, potential hand function and prognosis. The procedure reduces the power of wrist and finger flexion by release of the flexor pronator origin, and reinforces the strength of extension and supination of the wrist by transfer of flexor carpi ulnaris. After a mean follow-up of four years the appearance of the hand and forearm improved in all patients. None lost movement and all gained improved mobility of the forearm, wrist and hand. There was no overcorrection.

Osteotomy of the tibia for correction of complex deformity.

Twenty complex tibial deformities due to anterior poliomyelitis in 18 patients were corrected by a modified O'Donoghue osteotomy. This technique allowed correction of the deformity in three planes. This was achieved by widening the rectangular window distally to correct both rotation and valgus and by trimming the anterior edges of the step cuts to correct flexion deformity. An above-knee cast was applied for eight to 13 weeks and the patients followed up for a mean of 3.2 years. One of the 18 patients developed delayed union because of fracture of the medial limb of the step cut. The results showed excellent correction of the three-plane deformity and there was no recurrence. This method of osteotomy is a safe and simple procedure which does not require internal fixation and allows correction of torsional and angular deformity.

Aislamiento y caracterización de cepas vínicas de saccharomyces cerevisiae del valle de Casablanca (Chile) / Isolation and characterization of wine strains saccharomyces cerevisiae from the valley of Casablanca (Chile)

Se aislaron cepas vínicas nativas de uvas procedentes del valle de Casablanca, región productora de vinos de calidad, mediante fermentación natural del mosto en presencia de metabisulfito de potasio como agente selectivo. Los análisis morfológicos y fisiológicos realizados, a partir de colonias aisladas obtenidas del mosto al término del proceso de fermentación, permitieron establecer que, aproximadamente, un 90 porciento de ellas correspondían a cepas de levaduras ascosporógenas de saccharomyces cerevisiae. Además, al determinar el fenotipo "killer" de estas cepas, se encontró que un 40 porciento de ellas eran productoras de toxina "killer". Las evaluaciones enológicas practicadas a un subconjunto de estas cepas, presentaron propiedades similares a cepas vínicas comerciales de s. cerevisiae. La caracterización molecular de éstas, mediante electroforesis de campo pulsado, permitió establecer la presencia de, al menos, cuatro diferentes cariotipos electroforéticos, con un tamaño estimado del genoma nuclear entre los 13.000 a los 21.000 kb

Camptothecin and minor-groove binder hybrid molecules: synthesis, inhibition of topoisomerase I, and anticancer cytotoxicity in vitro.

The synthesis, characterization, inhibitory activity against topoisomerase I, and biological evaluation of a series of 14 camptothecin derivatives of polypyrrolecarboxamide (lexitropsin) conjugates of two structural classes: (A) camptothecin-NHCO-lexitropsin 44-51 and (B) camptothecin-CONH-lexitropsin 38-43 are described. All 16 compounds tested, 14 conjugates plus two functionalized camptothecin controls, inhibit topoisomerase I in the concentration range 1.12-16.6 microM that divide into three distinct categories based on activity. The most active enzyme inhibitors belong to structure class A with either cationic dimethylaminium or neutral amide end groups. Generally class B conjugates are less effective in inhibiting topoisomerase I. Cytotoxic potencies of the drugs was tested against four representative human tumor cell lines: SKOV3, SKLVB, HT29, and KB. All 16 drugs gave measurable IC50 values against the KB cell line and fell into two categories with IC50 values of 0.049-0.66 microM (largely structure class B) and 1.0-48 microM (largely class A). Thus the class B conjugates, while less potent against the enzyme, contain two of the most potent drugs, 38 and 39, against KB cell lines. In contrast, in the case of the cell lines SKOV3 and HT29 there was a general correlation between the better topoisomerase inhibitors and their cell cytotoxicities.

Design, synthesis and topoisomerase II inhibition activity of 4'-demethylepipodophyllotoxin-lexitropsin conjugates.

The design and synthesis of 4'-demethylepipodophyllotoxin-lexitropsin conjugates capable of inhibiting the actions of topoisomerase II are described. Siteselective topoisomerase II cleavage was observed in the presence of the new inhibitors, as determined by DNA sequencing. Additional topoisomerase II cleavage sites were observed with the new compounds that seem to be characteristic of the minor groove-binding lexitropsin moieties. Compound 17, having three pyrrole units in its binding moiety, exhibited distinct topoisomerase-mediated sites of cleavage at positions 4258, 4257, 4255 and 4247 of the pBR322 DNA fragment. These results demonstrate that conjugation with minor groove-binding moieties can alter or increase the number of topoisomerase II-induced cleavable sites and contribute to our understanding of the cytostatic activity of these compounds against KB cancer cell lines.

Immunohistochemical study of the distribution of endocrine cells in the gastrointestinal tract of the lesser mouse deer (Tragulus javanicus).

The occurrence and distribution of endocrine cells in the gastrointestinal tract of the lesser mouse deer, Tragulus javanicus, were studied immunohistochemically. Fourteen types of endocrine cells immunoreactive for serotonin, somatostatin, enteroglucagon, pancreatic glucagon, bovine pancreatic polypeptide (BPP), gastrin, substance P, motilin, gastric inhibitory polypeptide (GIP), cholecystokinin (CCK), methionine-enkephalin-Arg6-Gly7-Leu8 (MENK-8), secretin, neurotensin, peptide tyrosine tyrosine (PYY) and chromogranin were revealed. Chromogranin-, serotonin-, somatostatin- and enteroglucagon-immunoreactive cells were detected in all regions examined, while pancreatic glucagon-immunoreactive cells, except in the proper gastric gland region, were not found in other regions of the gastrointestinal tract. Few BPP-immunoreactive cells in either the proper gastric gland or pyloric gland regions and abundant gastrin-immunoreactive cells in the pyloric gland region were observed. Restricted distributions of substance P-, GIP-, gastrin-, motilin-, CCK-, MENK-8-, secretin-, neurotensin- and BPP-immunoreactive cells in the small intestine, and BPP-, substance P-, PYY- and motilin-immunoreactive cells in the large intestine were noted. The important findings include the presence of BPP-immunoreactive cells in the abomasum, pancreatic glucagon-immunoreactive cells in the proper gastric gland region, and substance P- and motilin-immunoreactive cells in the large intestine. It is suggested that the distribution pattern of gut endocrine cells in the lesser mouse deer is more similar to that in the pig than in the domestic ruminants so far reported.