Κυριακή 10 Ιουλίου 2022

MEK Inhibitors for Neurofibromatosis Type 1 Manifestations: Clinical Evidence and Consensus

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Abstract
The wide variety of clinical manifestations of the genetic syndrome neurofibromatosis type 1 (NF1) are driven by overactivation of the RAS pathway. Mitogen-activated protein kinase kinase inhibitors (MEKi) block downstream targets of RAS. The recent regulatory approvals of the MEKi selumetinib for inoperable symptomatic plexiform neurofibromas in children with NF1 has made it the first medical therapy approved for this indication in the United States, the European Union and elsewhere. Several recently published and ongoing clinical trials have demonstrated that MEKi may have potential benefit for a variety of other NF1 manifestations, and there is broad interest in the field regarding the appropriate clinical use of these agents. In this review, we present the current evidence regarding the use of existing MEKi for a variety of NF1-related manifestations, including tumor (neurofibromas, malignant peripheral nerve sheath tumors, low grade glioma, and juvenile myelomonocytic leukemia) and non-tumor (bone, pain, and neurocognitive) manifestations. We discuss the potential utility of MEKi in related genetic conditions characterized by overactivation of the RAS pathway (RASopathies). In addition, we review practical treatment considerations for the use of MEKi as well as provide consensus recommendations regarding their clinical use from a panel of experts.
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Sound Induced Vibrations Deform the Organ of Corti Complex in the Low-Frequency Apical Region of the Gerbil Cochlea for Normal Hearing

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AbstractHuman speech primarily contains low frequencies. It is well established that such frequencies maximally excite the cochlea near its apex. But, the micromechanics that precede and are involved in this transduction are not well understood. We measured vibrations from the low-frequency, second turn in intact gerbil cochleae using optical coherence tomography (OCT). The data were used to create spatial maps that detail the sound-evoked motions across the sensory organ of Corti complex (OCC). These maps were remarkably similar across animals and showed little variation with frequency or level. We identify four, anatomically distinct, response regions within the OCC: the basilar membrane (BM), the outer hair cells (OHC), the lateral compartment (lc), and the tectorial membrane (TM). Resu...
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Abutment mechanical complications of a Morse taper connection implant system: A 1‐ to 9‐year retrospective study

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Abstract

Background

The fracture of a Morse tapered abutment connection in an osseointegrated implant is one of the most serious mechanical complications, and it is extremely hard to deal with this complication in clinical practice.

Purpose

The aim of this study was to explore the cumulative mechanical complications focus on abutment of a platform switching Morse taper connection implant system after loading, and to perform a retrospective, approximately 1- to 9-year follow-up study to identify the predisposing factors.

Materials and Methods

A total of 495 patients with 945 fitted implants were enrolled in this study with a follow-up from January 2012 to January 2020. The data of mechanical complications of the abutment, including abutment fracture (AF) and abutment screw loosening (ASL), and possible causative factors were extracted and evaluated statistically.

Results

A total of 25 out of 945 (2.65%) cumulative abutment mechanical complications occurred. AF was the most common complication (n = 13, 1.38%), followed by ASL (n = 12, 1.27%). For AF, gender, type of prosthesis, abutment design, and implant diameter were identified as the causative factors. AF was mostly observed in the single crown of males in molar areas, while ASL was more likely to occur on an angled abutment than on a non-angled abutment. Moreover, the abutment with the positioning index (/X) had a higher incidence of fracture than the abutment without the positioning index (C/).

Conclusions

This study shows that the Morse taper connection is a safe abutment connection. AF occurs more frequently within single crowns in molar area of males, especially with the positioning index (/X), while ASL is more likely to occur in an angled abutment.
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Present and future avenues of cell‐based therapy for brain injury: The enteric nervous system as a potential cell source

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Abstract

Cell therapy is a promising strategy in the field of regenerative medicine; however, several concerns limit the effective clinical use, namely a valid cell source. The gastrointestinal tract, which contains a highly organized network of nerves called the enteric nervous system (ENS), is a valuable reservoir of nerve cells. Together with neurons and neuronal precursor cells, it contains glial cells with a well described neurotrophic potential and a newly identified neurogenic one. Recently, enteric glia is looked at as a candidate for cell therapy in intestinal neuropathies. Here, we present the therapeutic potential of the ENS as cell source for brain repair, too. The example of stroke is introduced as a brain injury where cell therapy appears promising. This disease is the first cause of handicap in adults. The therapies developed in recent years allow a partial response to the consequences of the disease. The only prospect of recovery in the chronic phase is currently based on r ehabilitation. The urgency to offer other treatments is therefore tangible. In the first part of the review, some elements of stroke pathophysiology are presented. An update on the available therapeutic strategies is provided, focusing on cell- and biomaterial-based approaches. Following, the ENS is presented with its anatomical and functional characteristics, focusing on glial cells. The properties of these cells are depicted, with particular attention to their neurotrophic and, recently identified, neurogenic properties. Finally, preliminary data on a possible therapeutic approach combining ENS-derived cells and a biomaterial are presented.
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Real‐life impact of tenofovir disoproxil fumarate and entecavir therapy on lipid profile, glucose and uric acid in chronic hepatitis B patients

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Abstract

Background & Aims

The impact of long-term nucleos(t)ide analogs treatment on host metabolism is a concern. Hence, we conducted this study to compare the effect of entecavir (ETV) and tenofovir disoproxil fumarate (TDF) on metabolic parameters among CHB patients.

Methods

In this real-life retrospective study, 2,030 CHB outpatients treated with ETV or TDF at Nanfang Hospital, China, were included. For treatment-naïve patients, pretreatment and semiannual metabolic parameters were collected. For treatment-experienced patients, metabolic parameters were collected at the first visit. Propensity score matching (PSM) was used to balance the effects of potential confounding factors.

Results

Among 122 treatment-naïve patients and 1908 treatment-experienced patients, ETV-treated patients were older with a higher percentage of metabolic syndrome. After PSM, the characteristics were comparable between the two groups. For treatment-naïve patients, fou r lipid parameters, including total cholesterol (TC), low-density lipoprotein (LDL), high-density lipoprotein and triglyceride levels showed a decreasing trend during the 42-month TDF treatment, while they remained relatively stable or increased during ETV treatment. At month 30, the levels of TC and LDL among TDF-treated patients were significantly lower than those among ETV-treated patients (TC: 4.7 vs. 3.9 mmol/L, p=0.004; LDL: 3.0 vs. 2.4 mmol/L, p=0.009). For treatment-experienced patients, we also observed lower levels of lipid parameters in patients with different durations of TDF treatment. The levels of glucose and uric acid were similar among ETV- and TDF-treated patients.

Conclusion

TDF has a lipid-lowering effect in CHB patients, which provides a basis for the selection of antiviral drugs for aging CHB patients.

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High Levels of C‐reactive protein‐to‐Albumin Ratio (CAR) Are Associated With a Poor Prognosis in Patients With Severe Fever With Thrombocytopenia Syndrome in early stage

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Abstract

Background

C-reactive protein-to-Albumin Ratio (CAR) can be used to assess the prognosis of various diseases. This study aimed to evaluate the relationship between CAR on the prognosis of patients with severe fever with thrombocytopenia syndrome (SFTS).

Methods

This study included 155 SFTS patients from the Public Health Clinical Center of Dalian from January to December 2021. They were divided into survival and deceased groups based on the clinical prognosis. The independent risk factors for poor prognosis of SFTS patients at an early stage were determined by Cox regression. The efficacy of CAR prediction was assessed by the receiver operating characteristic (ROC) curve.

Result

A total of 155 patients were included in this study, with an average age of 61.98±11.70 years, including 77 males and 65 females. The mortality rate of the patients enrolled in this study was 14.19%. Multivariate Cox regression indicated that CAR (HR=2.585, 95% CI 1.405 -4.753, p=0.002) could be an independent predictor for prognosis in SFTS patients at an early stage. CAR had an AUC of 0.781 (95% CI, 0.665-0.898, p=0.000), a cut-off value of 0.57, a sensitivity of 0.77, and a specificity of 0.80, with better predictive efficacy, compared to Neutrophil-to-Lymphocyte Ratio (NLR).

Conclusion

High levels of CAR are associated with poor prognosis in SFTS patients, and CAR can be used as an independent predictor for SFTS patients.

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A seroepidemiological study across age groups before and after the 2010–2011 mumps epidemic in Japan

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Abstract

In Japan, large-scale mumps epidemics recur every 4–6 years because of low vaccination coverage. This study aimed to describe the seroprevalence of mumps in the Japanese population and identify the age groups most affected. The prevalence of anti-mumps antibodies was evaluated based on 1000 serum samples obtained from the Japanese National Serum Reference Bank. These samples consisted of 50 sera for each of 10 different age groups, collected during 2007–2008 (pre-epidemic period) and 2012–2013 (post-epidemic period). Seropositivity was lowest in the 6–11 months subgroup (3% and 0% in pre- and post-epidemic periods, respectively) and highest in the 10–14 years group (66% and 72% in pre- and post-epidemic periods, respectively). A comparison of anti-mumps antibody prevalence throughout the two periods considered revealed a large rise seropositivity among the 2004–2008 birth cohort, using that of the 1–4 years group as representative in the pre-ep idemic period (from 22% in pre- to 58% in post-epidemic periods) (P=0.0002). These results indicate that most people likely gain antibodies to the mumps virus during their childhood, especially during the first epidemic that they experience after their second year of life. Therefore, children should be vaccinated against mumps soon after their first birthday for effective prevention.

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Deriving prognostic significance from a molecular subtype model of laryngeal carcinoma

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Abstract

Background

This study explored whether laryngeal carcinoma could be divided into different subtypes based on molecular differences using a molecular subtype-prediction model.

Methods

We extracted data from the Cancer Genome Atlas and Gene Expression Omnibus databases and then performed unsupervised cluster analysis to identify discrete molecular subtypes of laryngeal carcinoma. Significance analysis of microarrays was performed to detect differentially expressed genes for each subtype, and gene set enrichment analysis and the GenCliP3 software were used to label gene functions and identify key pathways.

Results

We categorized 126 patients into C1 and C2 molecular subtypes associated with pathologic grade. The C2 subtype appeared more aggressive, with a worse prognosis. The most significant enrichment pathway of the C2 subtype was the Hedgehog pathway, and GLI1 was a core gene.

Conclusions

Laryngeal carcinoma can be divided into two subtypes based on differences in molecular expression, which could identify key molecules associated with prognosis.
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Influence of supplement administration of omega‐3 on the subcutaneous tissue response of endodontic sealers in Wistar Rats

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Abstract

Aim

Natural substances such as omega-3 have been used in the medical field due to their numerous properties and, in particular, modulating effect on the systemic and local inflammatory processes. Thus, this study evaluated the influence of omega-3 supplementation on the subcutaneous tissue response of endodontic sealers in Wistar Rats.

Methodology

Polyethylene tubes were implanted in the subcutaneous tissue of 48 animals (one empty for control and three filled with Sealapex, AH Plus or Endofill). The animals were treated with omega-3 (TO) or water (TW). Treatments started 15 days before implantation until euthanasia. After 5, 15 and 30 days (n=8), animals were euthanized and polyethylene tubes and surrounding tissue were removed and processed for histological analysis. The inflammatory reaction was analysed by Haematoxylin and Eosin stain and immunolabeling for IL-6 and TNF-α. The collagen maturity was analysed by picrosirius red stain and calcium deposition by von Kossa stain and polarized light. Results were statistically analysed (p<0.05).

Results

Among TW sealers groups, Endofill evoked a more intense inflammatory infiltrate compared with AH Plus and control in the 30-day period (p=0.009). However, in TO sealers groups, there was no difference among the sealers and control in all periods (p>0.05). Comparing each sealer as a function of the supplementation with water or omega-3, there are differences for Endofill (p=0.001) and Sealapex (p=0.005) in the 30-day period, presenting lower inflammatory infiltrate in the animals treated with omega 3. A higher percentage of immature fibres was observed at 15 and 30 days in the TO group, compared with TW group (p<0.05). The deposition of calcium particles was observed only by Sealapex in all periods, despite the supplementation procedure.

Conclusions

Omega-3 supplementation influence the tissue reactions of endodontic sealers, modulating inflammation, the immunolabeling of IL-6 and TNF-α, the repair process and it does not interfere with calcium deposition.
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The efficacy and safety of combined administration of intravenous and intra‐articular tranexamic acid in total knee arthroplasty: An update meta‐analysis

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The efficacy and safety of combined administration of intravenous and intra-articular tranexamic acid in total knee arthroplasty: An update meta-analysis

Ten studies provided total blood loss data, seven of which used tourniquet and three of which did not use tourniquet. The pooled results showed that total blood loss in combined TXA group was significantly less than that in IV or IA TXA alone group.


Abstract

What is known and objective

This study was performed to compare the efficacy and safety of combined administration of intravenous (IV) and intra-articular (IA) tranexamic acid (TXA) with IV or IA TXA alone in total knee arthroplasty (TKA).

Methods

PubMed, Embase, Cochrane Library and Web of Science were searched for randomized controlled trials (RCTs) in July 2021. Total blood loss, transfusion rate, postoperative haemoglobin drop, drain output, deep venous thrombosis (DVT) and pulmonary embolism (PE) were pooled. Data were analyzed using Stata 14.0 software. The study protocol was registered with PROSPERO, number CRD42020186654.

Results

Ten RCTs involving 1306 patients were included. Combined TXA group provided lower total blood loss (SMD -0.47; 95% CI −0.64 to −0.30; p < 0.001), postoperative haemoglobin drop (SMD −0.47; 95% CI −0.60 to −0.33; p < 0.001) and drain output (SMD −0.50; 95% CI −0.71 to −0.29; p = 0.009) compared with IV or IA TXA alone group. No significant difference was found in terms of transfusion rate (OR 0.53; 95% CI 0.23 to 1.23; p = 0.137) and DVT (OR 0.55; 95% CI 0.18 to 1.68; p = 0.293). PE data was provided by all 10 studies, but PE only occurred in one patient in IV TXA alone group.

What is new and conclusion

Combined administration of IV and IA TXA was relatively more effective in reducing total blood loss, transfusion rate, postoperative haemoglobin drop, and drain output after TKA. TXA may not increase the risk of DVT/PE, but it also needs to be monitored in clinical application.
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