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Regorafenib was the first drug to demonstrate a survival benefit as a second-line agent after sorafenib failure in patients with unresectable hepatocellular carcinoma (HCC). Recent studies have shown that its mechanism of action is not only limited to its very broad spectrum of inhibition of angiogenesis, tumor proliferation, spread, and metastasis, but also to its immunomodulatory properties that have favorable effects on the very intricate role that the tumor microenvironment plays in carcinogenesis and tumor growth. In this review, we discuss rationale and evidence supporting regorafenib efficacy in HCC and that led to its approval as a second-line treatment, after sorafenib failure. We also discuss the evidence from clinical practice studies that confirm the results previously achieved in clinical trials. Finally, we analyze the potential role of regorafenib in emerging combined treatment approach with immunotherapy strategies using immune checkpoint blockade and its potential extension to patient categories not included in the registrative study.

This paper aims to identify the relationship between the output-oriented technical efficiency of Italian private hospitals and their ownership structure. Using the one-step Stochastic Frontier Anal...

Circulating cell-free DNA (cfDNA) testing has emerged as an alternative to tumor tissue analyses for the management of metastatic non-small-cell lung cancer (NSCLC) patients. Analysis of cfDNA is a minimally invasive procedure that might better reflect tumor heterogeneity and allows repeated testing over the time. Areas covered: This review article covers the different applications of cfDNA testing in NSCLC: early diagnosis of the disease; detection of minimal residual disease in early lung cancer; identification of predictive and prognostic markers in advanced NSCLC patients; monitoring the response to therapy; assessment of tumor mutation burden. Expert commentary: The use of liquid biopsy is rapidly expanding to different applications. The combination of different circulating biomarkers (cfDNA, protein, miRNA) might improve the sensitivity and specificity of this approach in patients with low tumor burden. cfDNA testing is representing a valid source for molecular profiling in management of metastatic NSCLC patients and is providing important knowledge on tumor heterogeneity. Clinical trials are needed in order to transfer the information deriving from liquid biopsy testing in new therapeutic strategies.

Coxiella burnetii is a gram-negative bacterium able to infect several eukaryotic cells, mainly monocytes and macrophages. It is found widely in nature with ticks, birds, and mammals as major hosts. C. burnetii is also the biological warfare agent that causes Q fever, a disease that has no vaccine or proven chemotherapy available. Considering the current geopolitical context, this fact reinforces the need for discovering new treatments and molecular targets for drug design against C. burnetii. Among the main molecular targets against bacterial diseases reported, the enzyme dihydrofolate reductase (DHFR) has been investigated for several infectious diseases. In the present work, we applied molecular modeling techniques to evaluate the interactions of known DHFR inhibitors in the active sites of human and C. burnetii DHFR (HssDHFR and CbDHFR) in order to investigate their potential as selective inhibitors of CbDHFR. Results showed that most of the ligands studied compete for the binding site of the substrate more effectively than the reference drug trimethoprim. Also the most promising compounds were proposed as leads for the drug design of potential CbDHFR inhibitors.

The activity of the epidermal growth factor receptor (EGFR) antibodies cetuximab and panitumumab in metastatic colorectal carcinoma (mCRC) is significantly limited by molecular mechanisms leading to intrinsic or acquired resistance. The S492R mutation of the EGFR, which is caused by either the 1476C>A or the 1474A>C substitution, interferes with binding to cetuximab but not to panitumumab, and has been detected in mCRC with acquired resistance to cetuximab. Since mechanisms of acquired and intrinsic resistance to EGFR monoclonal antibodies in CRC significantly overlap, we evaluated the frequency of the S492R mutation in a series of KRAS-exon 2 wild-type CRC patients. Genomic DNA was extracted from formalin fixed paraffin embedded (FFPE) tissues that were obtained from 505 systemic therapy-naïve CRC patients. A PCR/sequencing method for the detection of the S492R mutation was developed, by using as positive control a plasmid in which the 1474A>C mutation was generated by site directed mutagenesis. The lowest level of detection of this assay was approximately 10% mutant DNA in a background of wild-type DNA. PCR sequencing analysis revealed no S492R mutations in any of the analyzed 505 CRC specimens. Our findings suggest that the S492R mutation is not involved in primary resistance to cetuximab in CRC. Therefore, patients with mCRC should not be routinely screened for this mutation prior therapy with cetuximab.

This article explores the strategic compensation efforts of the Austin Independent School District (AISD) in Texas, which is piloting a system of supports and rewards for teachers and administrators. The article highlights the key components of this system, what it took to put a 4-year pilot program in place, and what results are emerging from this effort. Finally, the authors reflect on what this example says about the challenges of growing, deploying, assessing, and rewarding accomplished teaching in a complex urban school district.

The Palestinian Ministry of Health introduced an essential medicines list (EML) in 2000 to improve rational use of medicines and contain costs. We have examined the effects of the EML in the Palestinian healthcare public sector. We obtained data on prescription patterns for medicines from 3570 prescriptions given during outpatient visits in 17 healthcare facilities in the West Bank from 1997 to 2003. We analyzed the prescriptions to measure rational use. We modeled indicators of rational use as a function of the EML and 16 health center indicator variables. The EML was effective in shifting all prescribing indicators toward standard values. To improve rational medicine use, treatment protocols for the most common diseases and continuous education for medical staff is required.

The demand for global healthcare services is experiencing tremendous growth. US patients are seeking to reduce their expenditures on healthcare through obtaining treatment on an internationally competitive basis. This trend, known as medical tourism, is on the rise, and US legislators and policy makes must be aware of the issues facing American patients. This paper seeks to model factors that influence a patient's decision to seek healthcare services abroad. we develop a two-stage model for medical tourism- the first stage being the evaluation of the foreign country and the second stage choosing the healthcare facility. We argue country-specific characteristics influence the country of choice-including economic condition, political climate, and regulatory policies. We also argue that certain factors- including costs, hospital accreditaion, quality of care, and physician trining- impact the choice of healthcare facility. The model suggests that no one factor is dominant in the decision, but all play a crucial role in choosing healthcare on an international basis. Policy makers must use these factors to evaluate the impact medical tourism will continuw to have on the US healtcare system in order to effectively compete in today's global, consumer-driven healthcare market.

This study investigated the immediate effect of changing mandibular position on the electromyographic (EMG) activity of the masseter (MS), temporalis (TM), sternocleidomastoid (SCM) and trapezius (TR) muscles. Thirty-three (33) asymptomatic subjects (16 males and 17 females), ages 23 to 52 were selected. Surface EMG recordings were obtained for all muscles bilaterally with the mandible in a relaxed open position (relaxed) and during maximal voluntary clenching (fullbite) for the following: a non-repositioning appliance (NONREPOS) and repositioning appliance (REPOS). REPOS significantly reduced EMG activity of all muscles bilaterally during fullbite. During relaxation, reduction in EMG activity was only found for TR bilaterally. NONREPOS decreased the EMG activity bilaterally for TM and TR and unilaterally (left) for MS and SCM during fullbite. During relaxation, NONREPOS decreased muscle activity bilaterally for TR and SCM. A unilateral reduction was found for TM (right). These findings suggest that immediate alterations in mandibular position affect the cranio-cervical system. Both mandibular positions tested lowered the EMG activity of masticatory and cervical muscles in the relaxed and fullbite positions. The trapezius muscle was the most responsive to alterations in mandibular position.

Active robotic filtering is probably the solution for beating heart Totally Endoscopic Coronary Artery Bypass Grafting (TECABG). In this work, we assess the heart motion dynamics by simultaneous use of high-speed imaging of optical markers attached to the heart, ECG signals and ventilator airflow acquisitions. Our goal is to assess the heart motions (shape, velocity, acceleration) in order to be able to make more accurate specifications for a novel, dedicated robot that could follow these motions in real time. Furthermore, using two additional inputs (ECG and airflow), we propose a novel robust prediction algorithm that could be used with a predictive control algorithm to improve the tracking accuracy.

In mid- to late-nineteenth-century Paris, walking emerged as a significant pictorial theme, especially among Impressionist painters, who depicted not just the flâneur but also everyday pedestrian practices in the remodeled city. The history of writing about walking insists on its coherent intertwining of body, mind, and vision. That context reveals how the paintings exploit that integrated triad of faculties, complicating our sense of Impressionist practice as primarily optical. Cast as flâneurs, those painters evoke the walking experience with a phenomenological acuity that belies the prevailing notion of the flâneur as noteworthy chiefly for his gaze.

This randomized, double-blind study was designed to evaluate the effectiveness of the topical cream Theraflex-TMJ (NaBob/Rx, San Mateo, CA) in patients with masseter muscle pain and temporomandibular joint (TMJ) pain. Fifty-two subjects (5 males and 47 females) were instructed to apply a cream over the afflicted masseter muscle(s) or over the jaw joint(s) twice daily for two weeks. Theraflex-TMJ cream was used by the experimental group, while a placebo cream was used by the control group. The means of pain ratings were calculated prior to the application of the cream (baseline), after ten days of tx (period 1), and 15 days of tx (period 2) days of treatment and five days after stopping the treatment (follow-up). There was a significant decrease in reported pain levels from baseline in the experimental group for period 1 (p0.01), period 2 (p0.001), and follow-up (p0.01). For the control group, no significant differences were found between the different time periods (p0.05). There was evidence of minor side effects such as skin irritation and/or burning on the site of the application in two subjects in the experimental as well as two subjects in the control groups. The data strongly suggest that Theraflex-TMJ topical cream is safe and effective for reducing pain in the masseter muscle and the temporomandibular joint.

This randomized double-blind study evaluated the effectiveness of pulsed radio frequency energy therapy (PRFE) in patients with temporomandibular joint arthralgia. Forty subjects (age range 22 to 55 yrs.) were assigned randomly into two equal groups: (1) Experimental group received PRFE using the Energex unit (Energex, Inc. Emerson, New Jersey) and (2) Control group received PRFE placebo treatment using a sham device. Both groups received six applications to the TMJ area over two weeks. Data were analyzed for the following times: baseline, first and second follow-up visits. Numerical Rating Scale scores for TMJ pain showed a significant reduction over time for the experimental group (mean = 6.13 to 3.05, p0.001). There was also a significant effect for the controls (mean = 5.35 to 4.20, p = 0.01). The effect for experimental subjects was a mean reduction of 3.07 versus 1.15 for controls. The significant reduction in controls was attributed to the placebo effect. The experimental group showed a significant increase in mouth opening (mean = 34.95 to 41.70 mm, p = 0.002), right lateral movement (mean = 7.85 to 10.80 mm, p = 0.001) and left lateral movement (mean = 7.65 to 10.85 mm, p0.0001). No significant (p0.1) change in the control group occurred for mouth opening (mean = 38.50 to 39.65 mm), right lateral movement (mean = 8.60 to 8.75 mm) and left lateral movement (mean = 8.50 to 8.80 mm). No side effects were reported during the treatment and the two week follow-up. These results suggest strongly that PRFE is a safe and effective treatment for TMJ arthralgia as well as for increasing mandibular range of motion.

This study assessed the maxillomandibular relationship in temporomandibular disorders (TMD) patients, before and after short-term, flat plane bite plate therapy. It was of interest to determine the incidence and degree of mandibular deviation in a group of TMD patients and whether the mandible would shift to the midline and consequently affect reported symptoms. Seventeen female and three male subjects (age range 19-60) were included in the study. Thirteen subjects were diagnosed with myofascial pain while seven were diagnosed as exhibiting disk displacement with reduction (Research Diagnostic Criteria). After taking impressions for these subjects, casts were fabricated and mounted. Maxillomandibular relationship was evaluated by the Denar Centric Check system (Anaheim, CA). The maxillary and mandibular labial frena were used as a reference to evaluate mandibular shift. Symptom questionnaires were used to assess temporomandibular joint pain and clicking. All subjects exhibited deviation (12 subjects to the right and 8 subjects to the left) prior to bite plate therapy. After flat plane bite plate therapy, the mandibular position of all subjects shifted toward the labial frenum midline position. Based on the Binomial test, the shift was significant (p < 0.001). Measurements on the Centric Check system showed a significant movement of both condyles in the anterio-posterior plane as well as the vertical plane. There was also significant reduction in TMJ pain and clicking (p < 0.01). The results support the hypothesis that the balanced position of the mandible is with frena aligned. When occlusal obstructions are eliminated, the mandible will drift to this position.

The present work is focused on the computational analysis of evaporative film cooling, in connection with an experimental campaign carried out at the University of Pisa by the EFFE facility ( E xperiments on F alling F ilm E vaporation). The aim of the study is to contribute to the understanding of the heat and mass transfer mechanisms involved in the problem and to check the possibility of making use of a multipurpose commercial computational fluid dynamics (CFD) code for simulating mass transfer phenomena of interest in the nuclear field. After a description of the assumptions adopted in the mathematical formulation of the problem, the governing equations and the boundary conditions implemented in the code are briefly reported. In particular, the method used to evaluate the mass transfer through the interface is described. Then, the calculated results are analyzed and a comparison with experimental data is made. The improvement in the cooling capabilities of the heated plate due to evaporation with resp...

This study was designed to compare the effectiveness of a passive jaw motion device, the Therabite, and wooden tongue depressors (WTD), in patients with temporomandibular joint and muscle disorders, who did not improve after manual manipulation of the mandible and flat bite plane therapy. Forty-three patients were enrolled in the study and were classified as joint or muscle groups according to the Research Diagnostic Criteria for TMD. Twenty-four were assigned to the joint group, and 19 patients were assigned to the muscle group. The patients were assigned at random to three treatment subgroups: 1. passive jaw motion device therapy (Therabite); 2. wooden tongue depressors therapy (WTD); and 3. control group. All subjects received flat bite plane appliance therapy throughout the treatment period. Mandibular range of motion was measured for maximum opening (MO), right and left lateral (Rt. Lateral, Lt. Lateral) and protrusive (Pr) movements. Pain level was also assessed at the beginning and at the end of the treatment. The results suggested that a passive jaw motion device is effective in increasing range of motion in both groups of temporomandibular disorder patients, joint (intracapsular) and muscle (extracapsular). It also appears to decrease pain in patients with temporomandibular disorders. Pain was relieved to a greater degree in the muscle group than the joint group.

This study compared the peak isometric strength of the cervical flexors in deep bite temporomandibular dysfunction (TMD) patients while biting in four bite positions: habitual occlusion, edge-to-edge, lateral shift and retruded. These values were then compared to those of the same subjects' bite positions elevated to a functional criterion (maximum isometric strength of the deltoid muscles). The mean height increase was 2.4 mm with a range of 1.5–3.8 mm. Fifteen of eighteen deep bite subjects met an inclusionary criterion, at least 13.3 Newtons (N) stronger cervical muscle strength with mandible relaxed open than habitual bite. Peak strength biting edge-to-edge was significantly greater than biting in habitual occlusion. Strength was found to increase significantly when biting in each of four mandibular positions when the bite was elevated to the functional criterion. The greatest strength was obtained from elevated habitual and edge-to-edge positions. The findings are of clinical significance, su...

The effect on isometric strength of the shoulders and limbs while biting in habitual occlusion, on a bite-elevating appliance and on a placebo appliance was analyzed. Twenty female volunteer patients, presenting with temporomandibular pain dysfunction syndrome and obvious loss of vertical dimension, served as subjects. All were weaker to the manual application of the isometric Deltoid Press (IDP) when biting, as opposed to maintaining the mandible in an unsupported rest position. Two intraoral appliances were fabricated for each subject: a bite-elevating appliance (BEA) set by a functional criterion of peak strength to the IDP and a placebo appliance which did not interfere with occlusion but was "set" with a mock IDP procedure. Testing was carried out by the Neuromuscular Research Testing Laboratory of the Neurology Department of Tufts New England Medical Center. Testing was independent of the dentist who fabricated and set the appliances. A standard neuromuscular test with the Maximal Voluntary Isometric Contraction apparatus was used to assess strength of right and left shoulder, elbow and knee flexion and extension as is routinely performed with all neuromuscular disease patients. Twelve strength tests were carried out for each of three conditions: 1. Baseline-biting in habitual occlusion; 2. Elevated-biting on the BEA; and 3. Placebo-biting with the placebo appliance inserted. The order of conditions 2 and 3 was counterbalanced without knowledge of the subjects. Twelve repeated measures ANOVAs (each subject as their own control) were conducted for each of the 12 strength measures. All F-tests indicated a significant main effect for treatment differences (p < 0.0001). Mean strength biting on the BEA was consistantly greater (p < 0.001) than Baseline or Placebo strength. Baseline and Placebo condition were equivalent. These findings confirmed previous observations at this TMD Center: individuals with loss of vertical dimension of occlusion respond to a bite raising appliance by increased isometric-strength.

From the late 1970s until the early 1990s, there have been several reports of improved appendage muscle strength and athletic performance. Much of the criticism of using a mouthguard alone or in conjunction with a splint, such as a mandibular orthopedic repositioning appliance (MORA), to enhance athletic performance has been aimed at study designs, controls, periods of time, double blindness, and the placebo effect. Although it would appear that designing a study which pleases both clinician and researcher would be a difficult task, studies have been performed that do meet the "gold standard." The results favor the premise that jaw repositioning can enhance appendage muscular strength and athletic performance. Studies performed during the mid-1980s, and to which the scientific community refers to continually, on closer examination are flawed.

The effect on isometric strength of biting on three intraoral devices and habitual occlusion was analyzed. Only subjects who showed a relative weakness to the Isometric Deltoid Press (IDP) when biting as opposed to maintaining the mandible in an unsupported rest position were included in the study. Both in the original 35 subjects and the 23 subjects returning on the second day, performance wearing the appliance set by a functional criterion of peak strength (locking) to the IDP was significantly greater than wearing a placebo appliance and a bite raising appliance that deflected the mandible 1 mm to the left. Strength biting on the appliance set by a functional criterion was significantly greater than all these conditions. Strength biting in habitual trials that were matched with the deflection condition was found to be significantly greater than that biting in the placebo condition. It was concluded that a relationship does exist between bite and isometric strength. Previous speculation about th...

The original clinical observations and research in the area of bite and strength enhancement studied individuals with obvious malocclusion and a subject population with mixed occlusions. An increase in isometric strength was obtained when biting on a K-MORA, an intraoral device that supports a mandibular position determined by a functional criterion. The criterion is a locking response to the Isometric Deltoid Press, a muscle challenge used by kinesiologists. Rather than replication with improved design, subsequent research (1) employed different mandibular positions based on therapeutic, electrical impulse or structural criteria; (2) tested mainly isokinetic strength; (3) referred to "strength" without qualification, implying more generalization than the findings actually allowed; (4) criticized and rejected positive findings by attributing strength increase to the placebo effect even though in no instance has the placebo effect been demonstrated in this field. Considering published and unpublished research on isometric strength and the irrelevance of many studies that found no difference in isokinetic strength, it is concluded that it is most probable that isometric strength is increased by the K-MORA in mixed populations.