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Objectives: The skill of general practitioners (GPs) in performing the insertion/removal of intrauterine devices (IUDs) and contraceptive implants is one of the factors that determines patient's access to these contraceptive devices. In France, GP residents have few opportunities to perform these procedures during their internships. This study aimed to measure the effects of a single short training workshop on the number of residents and supervisors offering these procedures., Study Design: Each participant attended a unique 2-hour session. After a brief didactic review and video presentations, participants received hands-on training in technical procedures (insertion/removal of IUDs and contraceptive implants) using procedural simulators. The evaluation measured the number of GPs offering these procedures before, 1 month after, and 3 months after the workshops., Results: Fourteen sessions were organized from February 2017 to June 2022. Among the 387 residents and 123 supervisors invited, 143 (37.0%) and 56 (45.5%), respectively, participated in this workshop. Of 199 participants, 66.3% completed all questionnaires. There was a significant increase in the number of GPs inserting IUDs by direct method 3 months after training (20.5% vs 9.0%, p = 0.005). GPs providing information to patients about contraceptive implants were significantly higher at 1 month (80.6% vs 64.8%, p = 0.001) but this increase was no longer significant at 3 months (75.0%, p = 0.07). Residents changed their practices more than their supervisors, and women more than men., Conclusions: A short training workshop increased the number of GPs inserting IUDs, influenced by the gender and the number of years practicing., Implications: A single workshop had positive effects on IUD insertion and patient education about contraceptive implants. Repeating several times this training could be an option in the initial and ongoing training of general practitioners. Work on the general practitioners' own feeling of legitimacy in their practice context could also increase the effectiveness of these workshops and the practical implementation of the procedures taught., (Copyright © 2023 Elsevier Inc. All rights reserved.)

As a part of descending pain inhibitory system, orexin (OXs) in the ventral tegmental area (VTA) are implicated in nociceptive responses. The current study aimed to evaluate the role of OX receptors (OXRs) in the VTA in stress-induced analgesia in persistent inflammatory pain. Ninety-nine adult male Wistar rats underwent forced swim stress (FSS) following intra-VTA infusion of various doses of SB334867 or TCS OX2 29 (1, 3, 10, and 30 nmol/0.3 μL) as an OX1R or OX2R antagonist, respectively. The nociceptive threshold was evaluated using the formalin test as an animal model of persistent inflammatory pain. Current results demonstrated FSS as acute stress produced analgesic responses in the persistent inflammatory pain. Moreover, either OX1R or OX2R antagonist infusion in the VTA hindered the FSS-induced analgesia in both early and late phases. The inhibitory effect of SB334768 in the FSS-induced analgesia was stronger than TCS OX2 29 in both early and late phases of the formalin test. Neither SB334768 nor TCS OX2 29 alone affects pain-related behaviors in formalin tests. Intra-VTA microinjection of each treatment could not modify locomotion in rats. The findings suggest that OX1R and OX2R in the VTA are implicated in FSS-induced analgesia mechanisms., (Copyright © 2022 Elsevier Ltd. All rights reserved.)

Background and Objectives: Glioblastoma multiforme (GBM) is the most common and deadly type of primary cancers of the brain and central nervous system in adults. Despite the importance of designing a personalized treatment regimen for the patient, clinical trials prescribe a set of conventional regimens for GBM patients. We propose a computerized framework for designing chemo-radiation therapy (CRT) regimen based on patient characteristics., Methods: An intelligent agent, based on deep reinforcement learning, interacts with a virtual personalized GBM. The proposed deep Q network (DQN) uses a deep neural network to estimate the state - action value function. The algorithm stores agent experiences in a replay memory to be used for training of the deep neural network. Also, the proliferation-invasion model is used to simulate spatiotemporal dynamics of GBM growth and its response to therapeutic agents., Results: Assuming tumor size at the end of the treatment course as a measure of the quality of the treatment regimen, experiments show that the proposed DQN is superior to the Q learning. Also, while the quality of the protocols obtained by the Q learning as well as its convergence speed decreases sharply with the increase in the dimensions of the state-action value function, the DQN is relatively robust against increasing the initial tumor size or lengthening the treatment period., Conclusion: Our results suggest that the optimal personalized treatment regimen may differ from the conventional regimens suggested by clinical trials. Given the scalability of the proposed DQN in designing treatment regimen for real size tumors, as well as its superiority over previous models, it is a suitable tool for designing personalized CRT regimen for GBM patients., (Copyright © 2022 Elsevier Inc. All rights reserved.)

Background and Objectives: Glioblastoma multiforme (GBM) is the most common and malignant type of primary brain tumors. Radiation therapy (RT) plus concomitant and adjuvant Temozolomide (TMZ) constitute standard treatment of GBM. Existing models for GBM growth do not consider the effect of different schedules on tumor growth and patient survival. However, clinical trials show that treatment schedule and drug dosage significantly affect patient survival. The goal is to provide a patient calibrated model for predicting survival according to the treatment schedule., Methods: We propose a top-down method based on artificial neural networks (ANN) and genetic algorithm (GA) to predict survival of GBM patients. A feed forward undercomplete Autoencoder network is integrated with the neuro-evolutionary (NE) algorithm in order to extract a compressed representation of input clinical data. The proposed NE algorithm uses GA to obtain optimal architecture of a multi-layer perceptron (MLP). Taguchi L 16 orthogonal design of experiments is used to tune parameters of the proposed NE algorithm. Finally, the optimal MLP is used to predict survival of GBM patients., Results: Data from 8 related clinical trials have been collected and integrated to train the model. From 847 evaluable cases, 719 were used for train and validation and the remaining 128 cases were used to test the model. Mean absolute error of the predictions on the test data is 0.087 months which shows excellent performance of the proposed model in predicting survival of the patients. Also, the results show that the proposed NE algorithm is superior to other existing models in both the mean and variability of the prediction error., (Copyright © 2021 Elsevier Inc. All rights reserved.)

Coronavirus disease 2019 (COVID-19) pandemic has affected more than 40 million people worldwide. Some patients had episodes of symptom recurrence after the first episode of infection with variable intervals. There are multiple issues and hypotheses about re-infection or re-activation of the virus, especially in immunocompromised patients. In this paper, we present details of an individual with a recent history of COVID-19 who proceeded to acute myeloid leukaemia M3 and immunosuppression by chemotherapy, then we review some recently published articles about possible re-infection or re-activation., (© 2020 The Authors.)

Titanium-niobium (Ti-Nb) alloys have great potential for biomedical applications due to their superior biocompatibility and mechanical properties that match closely to human bone. Powder metallurgy is an ideal technology for efficient manufacture of titanium alloys to generate net-shape, intricately featured and porous components. This work reports on the effects of Nb concentrations on sintered Ti-xNb alloys with the aim to establish an optimal composition in respect to mechanical and biological performances. Ti-xNb alloys with 33, 40, 56 and 66 wt% Nb were fabricated from elemental powders and the sintering response, mechanical properties, microstructures and biocompatibility assessed and compared to conventional commercial purity titanium (CPTi). The sintered densities for all Ti-xNb compositions were around 95%, reducing slightly with increasing Nb due to increasing open porosity. Higher Nb levels retarded sintering leading to more inhomogeneous phase and pore distributions. The compressive strength decreased with increasing Nb, while all Ti-xNb alloys displayed higher strengths than CPTi except the Ti-66Nb alloy. The Young's moduli of the Ti-xNb alloys with ≥40 wt% Nb were substantially lower (30-50%) than CPTi. In-vitro cell culture testing revealed excellent biocompatibility for all Ti-xNb alloys comparable or better than tissue culture plate and CPTi controls, with the Ti-40Nb alloy exhibiting superior cell-material interactions. In view of its mechanical and biological performance, the Ti-40Nb composition is most promising for hard tissue engineering applications., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2020 Elsevier Ltd. All rights reserved.)

Background: The hypothesis of an effect by thiazolidinedione on leukemia cells was proposed 2 decades ago, but there is little clinical evidence regarding its efficacy. We evaluated the safety and efficacy of adding pioglitazone to standard induction chemotherapy in patients with acute myeloid leukemia (AML)., Patients and Methods: In this randomized clinical trial, newly diagnosed AML patients were randomized to 1 of 2 groups. Patients in both groups received cytarabine (100 mg/m 2 per day for 7 days) and daunorubicin (60 mg/m 2 per day for 3 days). Patients in the pioglitazone group additionally received oral pioglitazone (45 mg per day). The 2 groups were compared according to remission rate, laboratory findings, and adverse events during treatment., Results: Forty patients were evaluated, 20 patients in each group. The complete remission rate was 20% more in the pioglitazone group compared to the control group (P = .202). Complications due to pioglitazone discontinuation were observed in 2 cases. The mean serum alanine aminotransferase in the fourth treatment week was significantly more in pioglitazone group compared to the control group (65.5 vs. 33.6 mg/dL, P = .039). The mean serum creatinine in all treatment phases was significantly higher in the pioglitazone group compared to the control group (P < .05). There were no significant differences between the 2 groups regarding other laboratory findings (P > .05)., Conclusion: Adding pioglitazone to cytarabine and daunorubicin increased the remission rate in AML patients compared to control subjects. Although this difference in remission rate between the 2 groups was not statistically significant, it could be important in the clinical setting. Pioglitazone may provide benefits as an adjuvant therapy for AML patients without causing serious adverse events., (Copyright © 2019 Elsevier Inc. All rights reserved.)

Orexins are produced in the restricted regions of the lateral hypothalamus (LH). However, orexinergic receptors and projections are localized in wide regions like nucleus accumbens, ventral tegmental area, periaqueductal gray area and spinal cord which are involved in the pain modulation. This study was carried out to investigate the effects of intrathecal administration of orexin-1 receptor antagonist (SB-334867) in the spinal antinociception induced by intra-LH administration of carbachol (cholinergic receptor agonist) in both early and late phases of pain related behaviors in formalin test. In this study, pain-related behaviors (pain scores) were evaluated using the formalin test during 5-min block intervals for a 60-min period in seventy male Wistar rats were given SB-334867 (3, 10, 30 and 100 μM/10 μl) or vehicle (DMSO 12%; 10 μl) intrathecally following intra-LH administration of carbachol (250 nM/rat). Our data showed that intra-LH injection of carbachol attenuated the formalin-induced biphasic pain responses, and intrathecal administration of SB-334867 dose-dependently decreased LH stimulation-induced antinociceptive responses during both phases. Moreover, administration of different doses of SB-334867 during the early phase were more effective than those during the late phase. The antinociceptive role of orexinergic system in the formalin test through a neural pathway from the LH to the spinal cord provides evidence that orexins can be useful in therapeutic targets for pain relief., (Copyright © 2018 Elsevier Ltd. All rights reserved.)

The effect of chemical composition on microstructure and tensile properties of a series of low modulus Ti-Nb-Cu-Ni-Al alloys was studied. These alloys consist of primary micrometer-sized β-Ti dendrites surrounded by intermetallic phases. The morphology of the intermetallic phases is strongly affected by composition. Due to the composite microstructure, the alloys exhibit a low Young's modulus (77-84GPa) together with a high yield strength of about 1000MPa as well as moderate tensile ductility. The results demonstrate that complete substitution of Al by Ti reduces the Young's modulus by 5%. Increasing Nb content at the expense of Ti causes a significant improvement of tensile ductility., (Copyright © 2016 Elsevier Ltd. All rights reserved.)

A series of Ti-7Fe-xNb (x=0, 1, 4, 6, 9, 11 wt.%) alloys was designed and cast to investigate the β→α″ martensitic phase transformation, β phase stability, the resulting microstructure and mechanical properties. Phase analysis revealed that only Ti-7Fe-11Nb alloy shows a single body-centred cubic β phase microstructure while the others are comprised of β and orthorhombic α″ phases. Moreover, Nb addition up to 11 wt.% enhances the stability and volume fraction of β phase in the microstructure, hence reducing the propensity of the alloy system to form α″ phase during quenching. Compressive yield strength and hardness of the alloys are (985-1847) MPa and (325-520) Hv respectively. Additionally, Ti-7Fe-11Nb possesses the lowest Young's modulus (84 GPa) and the highest deformability (42% strain) among the designed alloys due to the single β phase microstructure. This high deformability is also corroborated by the large plastic deformation zone underneath the Vickers indenter. In contrast, the fractured surfaces of Ti-7Fe and Ti-7Fe-1Nb alloys after compressive tests mostly contain shallow dimples, verifying their low ductility. The good combination of mechanical properties obtained for Ti-7Fe-11Nb renders it more desirable than commonly used CP-Ti and Ti-6Al-4V materials and makes it a promising candidate for biomedical application., (Copyright © 2015 Elsevier B.V. All rights reserved.)

A proportion of healthy siblings of multiple sclerosis (MS) patients have an oligoclonal immunological reaction in their cerebrospinal fluid (CSF) termed the "MS oligoclonal trait". The CSF levels of the major myelin glycosphingolipid sulfatide and serum antibodies against the glycosphingolipids sulfatide and galactosylceramide were recently reported to be increased in MS patients. We studied the levels of these substances in pairs of 46 patients and their 46 healthy siblings and 50 unrelated healthy blood donors (HBD). The sulfatide concentration in CSF was assayed by thin layer chromatography and immunostaining, and the concentration of galactosylceramide by densitometry after thin layer chromatography. Anti-glycosphingolipid antibody levels were assayed by ELISA. In the healthy siblings, the CSF sulfatide concentrations were markedly increased (p<0.001, age adjusted p=0.025), and the serum IgM anti-GalCer antibodies were increased in healthy siblings compared with HBD (p=0.02). The increased sulfatide or antibody levels did not co-segregate with the "MS oligoclonal trait" or the HLA-DR15 phenotype. In conclusion, a proportion of healthy siblings of MS patients have increased CSF sulfatide and anti-glycosphingolipid antibody levels, which may, analogous to the "MS oligoclonal trait", constitute an "MS glycosphingolipid endophenotype". Endophenotypes could potentially simplify the genetics of complex disorders., (Copyright © 2013 Elsevier B.V. All rights reserved.)

Acetyl-CoA synthetase (AceCS) provides acetyl-CoA for different physiological processes, such as fatty acid and cholesterol synthesis, as well as the citric acid cycle. We show here that the cytosolic isoform of this enzyme, AceCS1, is expressed during mouse development. In the embryonic stage E9.5 AceCS1 transcripts localize in the cephalic region. At E10.5 the cephalic expression intensifies and transcripts appear also in the spinal cord and in the dorsal root ganglions. During organogenesis AceCS1 is expressed in the liver from E11.5. The AceCS1 gene is expressed also in the testes from E12.5 onwards and expression localizes in the interstitial Leydig cells. In the ovaries, expression is transient and AceCS1 transcripts are detected from E13.5 to E15.5 in the ovarian interstitial component. In the kidneys AceCS1 transcripts appear in a subset of the renal tubules at E16.5 and remains in these structures in newborns. Hence, expression of AceCS1 is developmentally regulated suggesting a role for AceCS1 during embryogenesis.

It is now known that amputation results in reorganization of central motor pathways, but the mechanism for the changes is unclear. One possibility is alteration of the excitability of the alpha motoneurons. We studied motor reorganization and excitability of alpha motoneurons to Ia input in 6 subjects with unilateral lower limb amputation. A Cadwell MES-10 stimulator was used to deliver transcranial magnetic stimuli through a circular coil centered on the sagittal axis 4 cm anterior to Cz and through an 8-shaped coil positioned over scalp locations 1 cm apart along the coronal axis. Surface EMG was recorded bilaterally from quadriceps femoris, the first muscle immediately proximal to the site of amputation. Excitability of the spinal alpha motoneuron pool to Ia afferents was assessed by determining the ratio of the maximal H reflex to the maximal M response (H/M ratio) elicited in the quadriceps femoris. Stimuli of equal intensity delivered to optimal scalp positions recruited a larger percentage of the alpha motoneuron pool in muscles ipsilateral to the stump than in those contralateral to the stump (P less than 0.01). Mean onset latencies of motor evoked potentials were shorter in ipsilateral muscles than in contralateral muscles (P less than 0.01). Muscles ipsilateral to the stump showed a trend toward activation from a larger number of scalp positions than those contralateral to the stump (P = 0.06). There was no difference in the quadriceps H/M ratios (7.2% ipsilateral vs. 10.9% contralateral). The absence of changes in the excitability of the alpha motoneuron pool in the presence of motor reorganization targeting muscles proximal to the stump suggests that reorganization occurs proximal to the alpha motoneuron level.

Magnetic stimulation is a painless, non-invasive technique which allows an alternative method for testing cranial nerves which were previously inaccessible. We compared the latency of muscle responses obtained by electrical stimulation of the facial nerve at the cerebello-pontine angle (CPA) to high intensity transcranial magnetic stimulation (TMS) in 6 dogs. Evoked muscle response from the levator nasolabialis during electrical stimulation had a mean latency of 6.24 +/- 0.42 msec, compared with a mean of latency of 6.13 +/- 0.50 msec obtained by magnetic stimulation. Orbicularis oculi had a mean latency of 3.65 +/- 0.34 msec compared with a mean latency of 3.53 +/- 0.36 msec for magnetic stimulation. This suggests that high intensity TMS results in direct activation of the facial nerve as it exits the brain-stem in dogs. This observation is in accord with previous clinical studies that magnetic stimulation results in activation of the intracranial segment of the facial nerve in man.

Central delay time (CD) has been estimated for activation of limb muscles by electrical or transcranial magnetic coil (TMC) stimulation of motor cortex and ventral root outflow. In the present study, we used surface electrical stimulation of the motor cortex of the right hemisphere to produce evoked compound muscle action potentials (CMAP) from the contralateral orbicularis oris (o.r.), and orbicularis oculi (o.c.), in dogs. Monopolar electrical stimulation of the facial nerve at the cerebello-pontine (CP) angle yielded CMAP activation of ipsilateral facial muscles. These latencies when subtracted from those obtained by direct cortical stimulation established CD for activation of the seventh cranial nerve. Preliminary data with single pulse magnetic stimulation at high outputs (greater than 80%) revealed CMAP with onset latencies similar to the direct facial nerve stimulation at the CP angle by electrical means.

Previous studies have shown various platinum containing compounds to be effective anti-tumor agents in man and animals. Many of these compounds have also been shown to be effective inhibitors of bacterial DNA, RNA and protein synthesis. Data is presented here which compares the inhibitory effectiveness of a number of recently synthesized platinum compounds toward the inhibition of the synthesis of DNA, RNA and protein in Escherichia coli. We also compared the effectiveness of these compounds toward the inhibition of bacterial growth. Some of these new derivatives appear to be nearly 3-fold more potent than the more thoroughly studied cis-diamminedichloroplatinum(II) (cis-PDD) and trans-diamminedichloroplatinum(II) (trans-PDD).