Anti-Mullerian Hormone and Fertility Treatment Decisions in Polycystic Ovary Syndrome: A Literature Review.

Anti-Mullerian hormone is a robust marker of ovarian reserve and ovarian response in in vitro fertilisation (IVF). However, its role extends beyond improving the safety of IVF by aiding in choosing appropriate protocols and dosing. This review looks at the value of pre-treatment anti-Mullerian hormone (AMH) value in choosing the appropriate modality of treatment and its predictive ability for the outcomes of such treatment. It briefly addresses the factors that may modulate AMH levels and make clinical decision-making challenging.

Continued versus discontinued oxytocin stimulation in the active phase of labour (CONDISOX): individual management based on artificial intelligence - a secondary analysis.

BACKGROUND: Current guidelines regarding oxytocin stimulation are not tailored to individuals as they are based on randomised controlled trials. The objective of the study was to develop an artificial intelligence (AI) model for individual prediction of the risk of caesarean delivery (CD) in women with a cervical dilatation of 6 cm after oxytocin stimulation for induced labour. The model included not only variables known when labour induction was initiated but also variables describing the course of the labour induction. METHODS: Secondary analysis of data from the CONDISOX randomised controlled trial of discontinued vs. continued oxytocin infusion in the active phase of induced labour. Extreme gradient boosting (XGBoost) software was used to build the prediction model. To explain the impact of the predictors, we calculated Shapley additive explanation (SHAP) values and present a summary SHAP plot. A force plot was used to explain specifics about an individual's predictors that result in a change of the individual's risk output value from the population-based risk. RESULTS: Among 1060 included women, 160 (15.1%) were delivered by CD. The XGBoost model found women who delivered vaginally were more likely to be parous, taller, to have a lower estimated birth weight, and to be stimulated with a lower amount of oxytocin. In 108 women (10% of 1060) the model favoured either continuation or discontinuation of oxytocin. For the remaining 90% of the women, the model found that continuation or discontinuation of oxytocin stimulation affected the risk difference of CD by less than 5% points. CONCLUSION: In women undergoing labour induction, this AI model based on a secondary analysis of data from the CONDISOX trial may help predict the risk of CD and assist the mother and clinician in individual tailored management of oxytocin stimulation after reaching 6 cm of cervical dilation.

Highly Sensitive Near-Field Electrochemical Sensor for In Vivo Monitoring of Respiratory Patterns.

Real-time tracking of respiratory patterns provides noninvasive and quick access for evaluating pathophysiological conditions yet remains challenging due to limited temporal resolution and poor sensitivity to dig out fingerprints of respiratory waveforms. Here, we report an electrochemical sensor for accurately tracing respiratory patterns of small animal models based on the electrochemical impedance mechanism for wireless coupling of a graphdiyne oxide (GYDO)-modified sensing coil chip and a reader coil chip via near-field magnetic induction. In the electrochemical impedance measurement mode, an alternating current is applied through the reader coil chip to perturb proton transport at the GYDO interface of the sensing coil chip. As demonstrated, a high-frequency perturbing condition significantly reduces the interfacial resistance for proton transport by 5 orders of magnitude under 95% relative humidity (RH) and improves the low-humidity responses with a limit of detection down to 0.2% RH, enabling in vivo accurate profiling of respiratory patterns on epileptic rats. The electrochemical impedance coupling system holds great potential for new wireless bioelectronics.

A case of cough syncope diagnosed by the Valsalva maneuver and cough induction test under invasive arterial pressure measurement.

Following the loss of consciousness during the Valsalva maneuver and cough induction test, real-time arterial pressure measurement could clarify the significant blood pressure decrease in a patient with cough syncope.

Induction of hepatic CYP3A4 expression by cholesterol and cholic acid: Alterations of gene expression, microsomal activity, and pharmacokinetics.

Human cytochrome P450 3A4 (CYP3A4) is a drug-metabolizing enzyme that is abundantly expressed in the liver and intestine. It is an important issue whether compounds of interest affect the expression of CYP3A4 because more than 30% of commercially available drugs are metabolized by CYP3A4. In this study, we examined the effects of cholesterol and cholic acid on the expression level and activity of CYP3A4 in hCYP3A mice that have a human CYP3A gene cluster and show human-like regulation of the coding genes. A normal diet (ND, CE-2), CE-2 with 1% cholesterol and 0.5% cholic acid (HCD) or CE-2 with 0.5% cholic acid was given to the mice. The plasma concentrations of cholesterol, cholic acid and its metabolites in HCD mice were higher than those in ND mice. In this condition, the expression levels of hepatic CYP3A4 and the hydroxylation activities of triazolam, a typical CYP3A4 substrate, in liver microsomes of HCD mice were higher than those in liver microsomes of ND mice. Furthermore, plasma concentrations of triazolam in HCD mice were lower than those in ND mice. In conclusion, our study suggested that hepatic CYP3A4 expression and activity are influenced by the combination of cholesterol and cholic acid in vivo.

Photosynthetic response of Chlamydomonas reinhardtii and Chlamydomonas sp. 1710 to zinc toxicity.

Zinc (Zn) is an essential trace element but can lead to water contamination and ecological deterioration when present in excessive amounts. Therefore, investigating the photosynthetic response of microalgae to Zn stress is of great significance. In this study, we assessed the photosynthetic responses of neutrophilic Chlamydomonas reinhardtii and acidophilic Chlamydomonas sp. 1710 to Zn exposure for 96 h. The specific growth rate (µ), chlorophyll-a (Chl-a) content, and chlorophyll fluorescence parameters were determined. The results demonstrated that Chlamydomonas sp. 1710 was much more tolerant to Zn than C. reinhardtii, with the half-maximal inhibitory concentration (IC50) values of 225.4 mg/L and 23.4 mg/L, respectively. The µ and Chl-a content of C. reinhardtii decreased in the presence of 15 mg/L Zn, whereas those of Chlamydomonas sp. 1710 were unaffected by as high as 100 mg/L Zn. Chlorophyll fluorescence parameters indicated that the regulation of energy dissipation, including non-photochemical quenching, played a crucial role in Zn stress resistance for both Chlamydomonas strains. However, in the case of C. reinhardtii, non-photochemical quenching was inhibited by 5 mg/L Zn in the first 48 h, whereas for Chlamydomonas sp. 1710, it remained unaffected under 100 mg/L Zn. Chlamydomonas sp. 1710 also exhibited a 20 times stronger capacity for regulating the electron transfer rate than C. reinhardtii under Zn stress. The light energy utilization efficiency (α) of Chlamydomonas sp. 1710 had the most highly non-linear correlation with µ, indicating the energy utilization and regulation process of Chlamydomonas sp. 1710 was well protected under Zn stress. Collectively, our findings demonstrate that the photosystem of Chlamydomonas sp. 1710 is much more resilient and tolerant than that of C. reinhardtii under Zn stress.

Tertiary lymphoid structures in head and neck squamous cell carcinoma.

Head and neck squamous cell carcinoma (HNSCC) is the sixth most common malignancy worldwide. Smoking, drinking, and human papillomavirus (HPV) infection are the main risk factors. Early-stage patients can benefit from radical surgery, chemotherapy, and radiotherapy, but the prognosis of locally advanced, recurrent, or metastatic patients is poor. Programmed cell death receptor 1 (PD-1) inhibitor significantly prolongs the survival of these patients, but only about 20 % of the population can benefit significantly. Exploring effective predictive indicators of immunotherapy efficacy and new therapeutic targets is necessary. Tertiary lymphoid structure (TLS) is an ectopic lymphoid organ formed in non-lymphoid tissues, which usually occurs in chronic inflammation including autoimmune diseases, infectious diseases, and tumors. The structure and function of TLS are similar to those of secondary lymphoid organs. The existence of TLS is closely related to the favorable prognosis and immune response of patients. This article will review the formation, prognosis, and predictive value of TLS as well as inducing TLS neogenesis in HNSCC.

Asp-tRNAAsn/Glu-tRNAGln amidotransferase A subunit-like amidase mediates the degradation of insecticide flonicamid by Variovorax boronicumulans CGMCC 4969.

The main metabolic product of the pyridinecarboxamide insecticide flonicamid, N-(4-trifluoromethylnicotinyl)glycinamide (TFNG-AM), has been shown to have very high mobility in soil, leading to its accumulation in the environment. Catabolic pathways of flonicamid have been widely reported, but few studies have focused on the metabolism of TFNG-AM. Here, the rapid transformation of TFNG-AM and production of the corresponding acid product N-(4-trifluoromethylnicotinoyl) glycine (TFNG) by the plant growth-promoting bacterium Variovorax boronicumulans CGMCC 4969 were investigated. With TFNG-AM at an initial concentration of 0.86 mmol/L, 90.70 % was transformed by V. boronicumulans CGMCC 4969 resting cells within 20 d, with a degradation half-life of 4.82 d. A novel amidase that potentially mediated this transformation process, called AmiD, was identified by bioinformatic analyses. The gene encoding amiD was cloned and expressed recombinantly in Escherichia coli, and the enzyme AmiD was characterized. Key amino acid residue Val154, which is associated with the catalytic activity and substrate specificity of signature family amidases, was identified for the first time by homology modeling, structural alignment, and site-directed mutagenesis analyses. When compared to wild-type recombinant AmiD, the mutant AmiD V154G demonstrated a 3.08-fold increase in activity toward TFNG-AM. The activity of AmiD V154G was greatly increased toward aromatic L-phenylalanine amides, heterocyclic TFNG-AM and IAM, and aliphatic asparagine, whereas it was dramatically lowered toward benzamide, phenylacetamide, nicotinamide, acetamide, acrylamide, and hexanamid. Quantitative PCR analysis revealed that AmiD may be a substrate-inducible enzyme in V. boronicumulans CGMCC 4969. The mechanism of transcriptional regulation of AmiD by a member of the AraC family of regulators encoded upstream of the amiD gene was preliminarily investigated. This study deepens our understanding of the mechanisms of metabolism of toxic amides in the environment, providing new ideas for microbial bioremediation.

Self-regulated efficient production of L-threonine via an artificial quorum sensing system in engineered Escherichia coli.

Imbalance in carbon flux distribution is one of the most important factors affecting the further increase in the yield of high value-added natural products in microbial metabolic engineering. Meanwhile, the most common inducible expression systems are difficult to achieve industrial-scale production due to the addition of high-cost or toxic inducers during the fermentation process. Quorum sensing system, as a typical model for density-dependent induction of gene expression, has been widely applied in synthetic biology. However, there are currently few reports for efficient production of microbial natural products by using quorum sensing system to self-regulate carbon flux distribution. Here, we designed an artificial quorum sensing system to achieve efficient production of L-threonine in engineered Escherichia coli by altering the carbon flux distribution of the central metabolic pathways at specific periods. Under the combination of switch module and production module, the system was applied to divide the microbial fermentation process into two stages including growth and production, and improve the production of L-threonine by self-inducing the expression of pyruvate carboxylase and threonine extracellular transporter protease after a sufficient amount of cell growth. The final strain TWF106/pST1011, pST1042pr could produce 118.2 g/L L-threonine with a yield of 0.57 g/g glucose and a productivity of 2.46 g/(L· h). The establishment of this system has important guidance and application value for the production of other high value-added chemicals in microorganisms by self-regulation.

Reusable and inductively regenerable magnetic activated carbon for removal of organic micropollutants from secondary wastewater effluents.

This work introduces a new sustainable alternative of powdered activated carbon (PAC) - magnetically harvestable and reusable after regeneration via inductive heating - for the adsorptive removal of organic micropollutants (OMP) from secondary wastewater effluents. For this purpose, two commercial PACs - lignite "L" (1187 m2/g) and coconut "C"-based (1524 m2/g) - were modified with magnetic iron oxide following two different synthesis approaches: infiltration ("infiltr") and surface deposition ("depos") route. The resulting magnetic powdered activated carbons (mPAC) and their precursor PACs were fully characterized before application. The iron oxide content of the modified "L" and "C" samples was ∼30 % and ∼20 %, respectively. Iron oxide gives the PAC beneficial magnetic properties for easy magnetic separation and simultaneously acts as an inductively heatable agent for the carbon regeneration. The infiltrated samples displayed better inductive heating performance and regeneration than their deposited counterparts. Tests with real wastewater showed fast adsorption kinetics of the organic load following the pseudo-second-order kinetic model. Adsorption isotherms were compliant with the Freundlich isotherm model. Sample "L-infiltr" had the best overall adsorption performance throughout 5 reuse cycles when intermediately inductively regenerated (<3 % drop in organics removal per cycle with intermediate regeneration vs. ∼10 % drop per cycle without regeneration). The treated supernatant was additionally tested for 31 representative organic micropollutants and their transformation products (pharmaceuticals, personal care products, industrial chemicals, etc.), where 26 OMPs had consistently high removal (>85 %) throughout 5 cycles with intermediate regeneration and for 28 OMPs the total adsorption efficiency dropped by <5 % after 5 cycles.

Building bridges to outpatient treatment services for post-overdose care via paramedic buprenorphine field initiation.

INTRODUCTION: Despite sustained efforts to reduce opioid-related overdose fatalities, rates have continued to rise. In many areas, overdose response involves emergency medical service (EMS) personnel administering naloxone and transporting patients to the emergency department (ED). However, a substantial number of patients decline transport, and many EDs do not provide medication for opioid use disorder (MOUD). One approach to filling this gap involves delivering MOUD to overdose patients in the field with trained post-overdose EMS teams who can initiate buprenorphine. In this MOUD field initiation pilot program, a trained EMS Community Paramedicine team initiates buprenorphine in the field and links patients to care. The program includes three pathways to treatment with the first designed for EMS to initiate buprenorphine after overdose reversal when the patient is in withdrawal from naloxone; a second pathway initiates buprenorphine after overdose when the patient is not in withdrawal; and a third enables self-referral via a connection to the community EMS team not necessarily related to a recent overdose. METHODS: We conducted a retrospective cohort study of the MOUD field initiation pilot program. Data are from 28 patients who entered care immediately post-overdose initiation of buprenorphine, 21 patients who initiated on buprenorphine while not in naloxone withdrawal, and 37 patients who self-referred to treatment following outreach efforts by paramedicine and peer support professionals. RESULTS: A total of 118 patients initiated buprenorphine during the 12-month study period and 104 (83 %) visited the clinic for their first appointment. Over two thirds (68 %, n = 80) remained engaged in care after 30 days. Retained patients tended to be male, white, uninsured, food insecure, have unstable housing, lack reliable transportation, and report prior involvement with the criminal legal system. CONCLUSION: The initial 12-month period of the pilot program demonstrated the feasibility of initiating buprenorphine at the site of overdose without requiring transport to the ED and offer self-referral pathways for people experiencing barriers to treatment. Specialized EMS can play a critical role in expanding access to MOUD treatment by bridging the gap between overdose and comprehensive community-based care.

A heart transplant center experience with basiliximab induction strategies: A double edged sword?

BACKGROUND: The use of induction immunosuppression for heart transplantation (HT) is debated given the uncertain benefit and potential risks of infection and malignancy. METHODS: This is a retrospective single-center analysis of 475 consecutive HT recipients from 2003 to 2020 grouped by use of induction with basiliximab group (BG) and the no basiliximab group (NBG). Subgroup analysis by era compared pre-2016 standard-basiliximab (BX) induction and 2016-2020 with selective-BX use as part of a calcineurin-inhibitor-sparing regimen. RESULTS: When adjusted for confounders (sex, age, PRA, eGFR), the BG was less likely to have acute cellular rejection (ACR) (OR.42, p < .001), but had more antibody mediated rejection (AMR) (OR 11.7, p < .001) and more cardiac allograft vasculopathy (CAV) (OR 3.8, p = .04). There was no difference between BG and NBG in the incidence of malignancies or infections. When stratified by era (pre-2016 vs. 2016-2020), ACR remained less common in the BG than the NBG (36% vs. 50%, p = .045) groups, while AMR remained more common (9.7 vs. 0% p = .005). There was no significant difference in conditional survival comparing pre-and post-2016 NBG (HR 2.20 (95% CI.75-6.43); however, both pre-2016 BG and post-2016 BG have significantly higher mortality (HR 2.37 [95% CI 1.02-5.50) and HR 2.69 (95% CI 1.08-6.71), p = .045 and.03, respectively]. CONCLUSION: Basiliximab reduces the incidence of ACR but increases the risk of AMR, CAV, and may be associated with increased mortality. Mechanistic studies are needed to describe a potential T-cell-escape mechanism with enhanced humoral immunity.

Thoracic Society of Australia and New Zealand position statement: The safe clinical use of sputum induction for bio-sampling of the lower airways in children and adults.

Sputum induction is widely used in clinical settings for collection of biological samples from the lower airways. However, in recent years sputum induction has been associated with serious adverse events and even death. This position statement was commissioned by the Thoracic Society of Australia and New Zealand to address major adverse events of two deaths associated with sputum induction that have occurred in Australia in 2021, and outlines best practice for the safe use of sputum induction. The statement resulted from systematic literature searches by a multi-disciplinary group including respiratory physicians, nurses and physiotherapists (paediatric and adults focused). Consumers had input to an advanced draft of the position statement. The position statement covers indications for sputum induction, informed consent, scope of practice of personnel administering the procedure, infection control considerations, details about the sputum induction procedure, safety considerations and risk assessment in clinical settings.

Induction of Hepatocellular Carcinoma in Conventional Domestic Swine Using N-Diethylnitrosamine and Phenobarbital.

Purpose: Large animal models are still used in many studies because of their likeness to humans. It has not been documented that regular-sized conventional farm-breed pigs, generally bred for meat production, can be used to generate hepatocellular carcinoma (HCC) animal models. The goal of this study was to investigate how N-diethylnitrosamine (DENA) and phenobarbital (PB) together can generate HCC in ordinary farmed pigs. Materials and Methods: Conventional domestic swine (Sus scrofa domesticus) were used. DENA 15 mg/kg was intraperitoneally injected weekly for 12 weeks, while PB tablets (4 mg/kg) were also administered through food for 16 weeks. Blood testing and ultrasonography evaluation were performed to monitor the progress. Subsequently, computed tomography was conducted in cases with suspected nodules, followed by histopathological examination to confirm the diagnosis. Results: Ten swine (seven males, three females; age: 2 months; weight: 9-15 kg) were included in the study and followed up for 25 months; nine were experimental, and one was control for ethical considerations. The maximum weight of animals during this study reached 162-228 kg. The weight gain seen in the intervention swine was predominantly lower than that documented in the control. The laboratory analysis revealed no notable abnormalities in liver function markers but did demonstrate statistically significant changes in urea (p = 0.028) and creatinine (p = 0.003) levels. Ultrasonography and computed tomography showed multiple liver nodules with characteristics resembling HCC. Serial imaging screening and more extended observations revealed that all animals eventually developed tumors. Histopathological confirmation at 15-22 weeks post-induction revealed that all intervened swine developed multiple nodules of well-differentiated HCC and some with hepatic angiosarcoma. Conclusion: This study successfully generated HCC in conventional domestic swine with a DENA and PB combination. This investigation required at least 15 months to develop tumors. This model will be beneficial for future investigations of HCC in large animals.

Efficient induction and rapid identification of haploid grains in tetraploid wheat by editing genes TtMTL and pyramiding anthocyanin markers.

Doubled haploid (DH) technology provides an effective way to generate homozygous genetic and breeding materials over a short period of time. We produced three types of homozygous TtMTL gene-edited mutants (mtl-a, mtl-b, and mtl-ab) by CRISPR/Cas9 in durum wheat. PCR restriction enzymes and sequencing confirmed that the editing efficiency was up to 53.5%. The seed-setting rates of the three types of mutants ranged from 20% to 60%. Abnormal grain phenotypes of kernel, embryo, and both embryo and endosperm abortions were observed in the progenies of the mutants. The average frequency of embryo-less grains was 25.3%. Chromosome counting, guard cell length, and flow cytometry confirmed that the haploid induction rate was in the range of 3%-21% in the cross- and self-pollinated progenies of the mtl mutants (mtl-a and mtl-ab). Furthermore, we co-transformed two vectors, pCRISPR/Cas9-MTL and pBD68-(ZmR + ZmC1), into durum wheat, to pyramide Ttmtl-edited mutations and embryo-specifically expressed anthocyanin markers, and developed a homozygous durum haploid inducer with purple embryo (DHIPE). Using DHIPE as the male parent to be crossed with the wild-type Kronos, the grains with white embryos were identified as haploid, while the grains with purple embryos were diploid. These findings will promote the breeding of new tetraploid wheat varieties.

Advanced direct torque control based on neural tree controllers for induction motor drives.

This paper introduces a novel direct torque control approach based on the decision tree (T-DTC), employing artificial neural networks that are effectively trained to enhance accuracy and robustness. The main objective of T-DTC is the substantial reduction of flux and torque ripples inherent in the conventional DTC, ensuring effective control of the induction motor. The conventional hysteresis controllers for stator flux and electromagnetic torque are replaced by two advanced controllers named M5 Prime model trees. Additionally, the traditional switching table is substituted with a novel decision tree table utilizing the classifier algorithm 4.5. The effectiveness of the proposed T-DTC strategy is demonstrated through simulation in MATLAB/Simulink and validated in real-time using an HIL platform based on OPAL-RT OP 5600 and Virtex 6 FPGA ML605. The results obtained demonstrate a notable improvement compared to existing techniques in the literature.

Diagnostic Performance of Node Reporting and Data System Magnetic Resonance Imaging Score in Detecting Metastatic Cervical Lymph Nodes of Nasopharyngeal Carcinoma.

Background: The Node Reporting and Data System (Node-RADS) is a recently proposed classification system for the categorization of lymph nodes in radiological images. This study was conducted to retrospectively evaluate the diagnostic accuracy of the Node-RADS score for metastatic cervical lymph nodes on magnetic resonance imaging (MRI) of patients with nasopharyngeal carcinoma (NPC). Methods: We retrospectively analyzed cervical lymph nodes of NPC cases. Two radiologists independently evaluated each lymph node on the MRI scans using Node-RADS. Interobserver agreement between 2 radiologists for Node-RADS score assessment was evaluated by linear weighted kappa statistics. The correlation between metastasis and the Node-RADS score of each lymph node was analyzed using multivariate regression analysis. To investigate the diagnostic performance of the Node-RADS score, we further conducted receiver operating characteristic curve analysis. Correspondently, the sensitivity, specificity, positive predictive value, and negative predictive value of each different cutoff (>1, >2, >3, and >4) were computed. Results: In all, 119 patients with NPC were assessed, including 203 cervical lymph nodes consisting of 140 (69%) of 203 metastatic and 63 (31%) of 203 benign. The kappa agreement between the 2 readers for the Node-RADS score was 0.863 (95% CI = 0.830-0.897, P < .001). Node-RADS score on MRI scan was shown to be an independent predictive factor of lymph node metastasis after multivariate regression analysis (odds ratio [OR] = 6.745, 95% CI = 3.964-11.474, P < .001). Node-RADS achieved an area under the curve (AUC) of 0.950 (95% CI = 0.921-0.979) in diagnosing metastatic lymph nodes. When Node-RADS >2 was identified as the best cutoff based on balanced values, the sensitivity and positive predictive value were 0.92 and 0.94, respectively. Conclusions: Our study suggests that the Node-RADS score has high accuracy in predicting NPC cervical lymph node metastasis. Nevertheless, this conclusion requires confirmation in a larger cohort of patients with NPC.

Low-dose Initiation of Buprenorphine/naloxone for the Management of Chronic Non-cancer Pain in Patients on Long-term Opioid Therapy: A Case Series.

Background: Buprenorphine may provide superior analgesia to full opioid agonist therapy and reverse the effects of opioid-induced hyperalgesia, while having a favorable safety profile and fewer adverse effects, in chronic non-cancer pain treatment. Low-dose initiation of buprenorphine is a useful strategy for patients on long-term opioid therapy because it avoids the need for moderate opioid withdrawal required for traditional buprenorphine initiations. However, there are few published reports of low-dose initiation regimens in the setting of chronic pain. Aims: The aim of the study was to describe a case series of individuals living with chronic pain who were transitioned from long-term full opioid agonist therapy onto sublingual buprenorphine/naloxone using low-dose initiation regimens. Methods: This study is a retrospective case series that included all patients who received care at an outpatient chronic pain clinic and were scheduled for low-dose initiation of buprenorphine/naloxone between March 2020 and December 2022. Data were collected through a retrospective review of electronic medical records and results were analyzed using descriptive statistics. Results: Eighteen patients underwent transitions from their baseline opioids onto buprenorphine/naloxone using a low-dose initiation regimen. Of those patients, 17 successfully completed the initiation (94.44%), 12 experienced adverse effects during the initiation (66.67%), with only one patient requiring treatment discontinuation, and all adverse effects resolved once maintenance doses of buprenorphine/naloxone were established. The mean Clinical Global Impression-Improvement score after initiation was 2 (1-5). Conclusion: Low-dose initiation is an effective approach to transition patients with chronic non-cancer pain from long-term opioid therapy to buprenorphine/naloxone without major complications or worsening pain.

Contexte: La buprénorphine peut offrir une analgésie supérieure à celle d'un traitement par agonistes opioïdes complet et inverser les effets de l'hyperalgésie induite par les opioïdes, tout en présentant un profil d'innocuité favorable et moins d'effets indésirables dans le traitement de la douleur chronique non cancéreuse. L'initiation à faible dose de la buprénorphine est une stratégie utile pour les patients sous traitement opioïde à long terme, car elle évite le besoin de sevrage des opioïdes modéré nécessaire pour les traitements traditionnels à base de buprénorphine. Cependant, il existe peu de rapports publiés sur les régimes d'initiation à faible dose dans le cadre de la douleur chronique.Objectifs: L'objectif de cette étude était de décrire une série de cas d'individus vivant avec une douleur chronique qui sont passés d'un traitement opioïde complet à long terme à un traitement par buprénorphine sublinguale/naloxone en ayant recours à des régimes d'initiation à faible dose.Méthodes: Cette étude est une série de cas rétrospective incluant tous les patients pris en charge dans une clinique externe de traitement de la douleur chronique et pour lesquels un schéma d'initiation à faible dose de buprénorphine/naloxone a été programmé entre mars 2020 et décembre 2022. Les données ont été collectées par le biais d'un examen rétrospectif des dossiers médicaux électroniques et les résultats ont été analysés à l'aide de statistiques descriptives.Résultats: Dix-huit patients ont fait la transition des opioïdes de base à la buprénorphine/naloxone en utilisant un régime d'initiation à faible dose. Parmi ces patients, 17 ont terminé l'initiation avec succès (94,44 %), 12 ont présenté des effets indésirables pendant l'initiation (66,67 %) et un seul patient a dû interrompre son traitement. Tous les effets indésirables ont disparu une fois les doses d'entretien de buprénorphine/naloxone établies. Le score d'impression clinique globale-amélioration moyen après le début du traitement était de 2 (1-5).Conclusion: L'initiation à faible dose est une approche efficace pour faire passer les patients souffrant de douleur chronique non cancéreuse d'un traitement opioïde à long terme à la buprénorphine/naloxone sans complications majeures ni aggravation de la douleur.

Novel insights into phage biology of the pathogen Clostridioides difficile based on the active virome.

The global pathogen Clostridioides difficile is a well-studied organism, and researchers work on unraveling its fundamental virulence mechanisms and biology. Prophages have been demonstrated to influence C. difficile toxin expression and contribute to the distribution of advantageous genes. All these underline the importance of prophages in C. difficile virulence. Although several C. difficile prophages were sequenced and characterized, investigations on the entire active virome of a strain are still missing. Phages were mainly isolated after mitomycin C-induction, which does not resemble a natural stressor for C. difficile. We examined active prophages from different C. difficile strains after cultivation in the absence of mitomycin C by sequencing and characterization of particle-protected DNA. Phage particles were collected after standard cultivation, or after cultivation in the presence of the secondary bile salt deoxycholate (DCA). DCA is a natural stressor for C. difficile and a potential prophage-inducing agent. We also investigated differences in prophage activity between clinical and non-clinical C. difficile strains. Our experiments demonstrated that spontaneous prophage release is common in C. difficile and that DCA presence induces prophages. Fourteen different, active phages were identified by this experimental procedure. We could not identify a definitive connection between clinical background and phage activity. However, one phage exhibited distinctively higher activity upon DCA induction in the clinical strain than in the corresponding non-clinical strain, although the phage is identical in both strains. We recorded that enveloped DNA mapped to genome regions with characteristics of mobile genetic elements other than prophages. This pointed to mechanisms of DNA mobility that are not well-studied in C. difficile so far. We also detected phage-mediated lateral transduction of bacterial DNA, which is the first described case in C. difficile. This study significantly contributes to our knowledge of prophage activity in C. difficile and reveals novel aspects of C. difficile (phage) biology.

Early neural specification of stem cells is mediated by a set of SOX2-dependent neural-associated enhancers.

SOX2 is a transcription factor involved in the regulatory network maintaining the pluripotency of embryonic stem cells in culture as well as in early embryos. In addition, SOX2 plays a pivotal role in neural stem cell formation and neurogenesis. How SOX2 can serve both processes has remained elusive. Here, we identified a set of SOX2-dependent neural-associated enhancers required for neural lineage priming. They form a distinct subgroup (1,898) among 8,531 OCT4/SOX2/NANOG-bound enhancers characterized by enhanced SOX2 binding and chromatin accessibility. Activation of these enhancers is triggered by neural induction of wild-type cells or by default in Smad4-ablated cells resistant to mesoderm induction and is antagonized by mesodermal transcription factors via Sox2 repression. Our data provide mechanistic insight into the transition from the pluripotency state to the early neural fate and into the regulation of early neural versus mesodermal specification in embryonic stem cells and embryos.