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International audience; Cancer is still considered a “hopeless case”, besides all of the advancements in oncology research. On the other hand, the naturalproducts, as effective lead molecules, have gained significant interest for research due to the absence of toxic and harmful sideeffects usually associated with conventional treatment methods. Medicinal properties of herbal plants are strongly evidenced intraditionalmedicine fromancient times. In the context above, withaferin A (WA) was identified as the active principle of the plantWithania somnifera, its molecule being reported to have excellent anticancer and tumour inhibition activities in various cell lines.Furthermore, the in silico approaches in the medicinal chemistry ofWA revealed the biological targets and gave momentum forthe research that leads to many amazing pharmacological activities of WA which are not yet explored. This includes a broadspectrum of anticancer actionsmanifested in different organs (breast, pancreas, colon), melanoma and B cell lymphoma, etc. Thisreview is an extensive survey of the most recent anticancer studies reported for WA, along with its mechanism of action anddetails about its in vitro and/or in vivo behaviour.

International audience; In this research, the variations in the chemical composition of the Lavandula angustifolia Mill. essential oil, the Romanian variety Moldoveanca 4, obtained from the same culture, in the same harvesting and extraction conditions, during the years 2016-2018, representing the years 2-4 of culture. Lavandula angustifolia Mill. flowers were supplied from an ecological-crops from N-E Romania and the essential oils were obtained by hydro distillation of freshly harvested flowers. To determine the chemical composition, the essential oil was semi-quantitatively analysed by using gas chromatography coupled with mass spectrometry (GC-MS). In all the samples, 30 organic compounds were identified, linalool and linalyl acetate being in similar concentrations (23.51-27.39% for linalool and 26.60-40.66% for linalyl acetate). Changes in chemical composition were observed in 2017 and 2018. Also, in 2017 was determined an increase in the quantity of linalyl acetate (from 26.60 to 40.66 %), and a slight decrease in linalool content; in 2018, the concentration in linalyl acetate remained approximately the same as in 2017 (38.03 versus 40.66 %) and there was an increase in linalool compared to the previous years (27.39 %, compared to 23.51 % in 2017 and 26.22 % in 2016). The chemical composition of the essential oils obtained from flowers of Lavandula angustifolia L., Moldoveanca 4 variety, showed substantial changes of the chemical profile describing the compounds during the analysed three years, as was determined by GC-MS analyses.

Clostridium difficile infection (CDI) is the most common infectious disease related to antibiotic-associated diarrhoea and is a current leading cause of morbidity/mortality, with substantial consequences for healthcare services and overall public health. Thus, we performed a retrospective epidemiological study of CDI for a long period (8 years), in an infectious hospital located in north-western Romania, which serves an entire county of the country (617,827 inhabitants). From 2011 to 2018, 877 patients were diagnosed with CDI; the mean incidence of this disease was 2.76 cases/10,000 patient-days, with an increasing trend in the annual incidence until 2016, at which point there was a decrease. The most commonly afflicted were patients in the 75–84 age group, observed in winter and spring. The results show that the antibiotics were administered in 679 (77.42%) subjects, within the last 3 months before CDI, statistically significant more than proton-pump inhibitors (PPIs)—128 (14.60%) and antidepressant medications—60 (6.84%), which were administered during the same period (p < 0.001). No medication was reported in 10 (6.84%) cases of CDI, in the last 3 months of the study. The fatality rate attained 4.1%, tripling in 2018 vs. 2011. CDI became a significant public health conundrum that can, nevertheless, be combatted through a judicious use of antibiotics.

Antibiotic sensitivity spectrum of isolated strains differs according to hospital departments, the hospitals themselves, and countries. Discrepancies also exist in terms of antibiotic use and dosage. The aim of the present study is to compare the antibacterial agents, the types of infections, the number and type of pathogens, and the sensitivity to antibiotics used in the Intensive Care Unit (ICU) of the Emergency Clinical County Hospital of Oradea, Romania. Over a one-year period, data were gathered from the pharmacy computer system and medical records of inpatients. WHO Anatomical Therapeutic Chemical (ATC)/defined daily doses (DDD) methodology was used to assess drug administration data, and antibiotic use was expressed as DDD/1000 PD (patient days). The antibiotic susceptibility of isolated strains was expressed through the cumulative antibiogram. The overall consumption of antimicrobial agents was 1247.47 DDD/1000 PD. The most common drugs used were cephalosporins and fluoroquinolones (52.97% of the total). Ceftriaxone was the most commonly used, followed by levofloxacin. Infections of the respiratory and urinary tract were the most frequently diagnosed infections. The most commonly isolated bacteria type was Acinetobacter baumannii (22.12% overall), isolated especially from the respiratory tract and resistant to all the β–lactam antibiotics including carbapenems. Antimicrobials intake at the ICU is much higher compared to medical and surgical wards. After we tested the existence of a possible connection between antibiotic consumption and antibiotic resistance of bacteria, it was revealed that on our sample exists a poor positive association.

International audience; Giardia spp. is the most common intestinal protozoan (causing gastrointestinal illness) and the most frequentcause of parasitic gastroenteritis in humans and animals worldwide. The aim of this study was to highlightnew data in a specific area regarding clinical presentation and epidemiological prevalence over a long periodof time. Patients (a total number of 54,623 patients) admitted in a tertiary center for infectious diseases servinga county for a period of 14 years were tested for infection with Giardia. Positive cases were recorded through analyzing the clinical complaints, the month of incidence and the demographic area from which the patients camefrom. Longitudinal trends have been evaluated. The incidence of giardiasis among the tested patients was 4.47%.A decreasing trend was observed regarding the annual incidence. Patients between the ages of 15 and 44 presented most commonly giardiasis, especially those from urban areas and women. The most common symptomsare loss of appetite (71.24%) and abdominal pain (69.07%). The highest monthly incidence was quoted in July(10.65%), August (10.49%) and June (10.20%). This epidemiological study allows a better knowledge of the infection with Giardia spp. It gives the long-term changes in demographic characteristics of the infected patients in aspecific area and the monthly incidence.

International audience; According to general principles of good practice, adopted at the international level, quality control is a key function in management and not just a simple means of verification. In a clinic or hospital pharmacy, the chief pharmacist has the training and authority to take the control measures necessary to develop and implement an Internal Managerial Control System (IMCS). The present article analyzes and describes the case of the County Hospital of Oradea, Romania, and presents how the IMCS was adopted and integrated. Quality assessment in the health services takesplace via an accreditation process and quality certification, as well as through an internal audit of the hospital pharmacy. The authors report a retrospective and descriptive study carried out from 2012 to 2017, analyzing how current legislative standards are applied. The IMCS in the hospital pharmacy is a dynamic process of continuous transformation, permanently adapted to hospital requirements, achieved under the direction of the chief pharmacist and involving all pharmacy employees, as well as through good coordination practices applied by hospital management. In this specific case, the IMCS features 11 annually updated compliance standards, classed under the headings of work procedures, risk register, job descriptions and staff training. The pharmacy's good practice model for IMCS development, was adopted by all of the hospital's sectors, services and departments.

International audience; Self-medication during pregnancy continues to be an issue in developing countries due topoor medical education. The most commonly used drugs are analgesics, mainlyacetaminophen (paracetamol, APAP) and, to a lesser extent, ketoprofen (KPF). The aim of thestudy was to establish whether there are consequences of accidental use of these two drugsduring early embryogenesis. The experimental study was performed on 30 pregnant whitemice, divided into three groups: a first group to which APAP was administered, a secondgroup to which KPF was administered, and group 3 as a control group. At delivery, the babymice were examined, and after their first parturition, they were taken into study and examinedaccording to the established protocol. Macroscopic and microscopic examinations of the liverand kidney were performed; liver and renal changes were recorded. Regarding the fertility,the number of fetuses born to mothers that were administered APAP and KPF correspondedto the normal values recorded in this species. Microscopic changes that were found in thekidney were as follows: APAP group  necrosis of the urinary tube, vascular congestions andvascular disorders; KPF group  ectasia, especially in the medullary cavity. Microscopichepatic changes showed in the APAP group  vascular congestions, vascular disorders andhemosiderin deposits in the Kupffer cells; in the KPF group were found  discrete vasculardisorders consisting in sinusoidal capillary ectasia and vascular congestions, as well as thepresence of lymphocyte conglomerates. The aforementioned lesions indicate hepatic and renaldistress with variable degrees of severity, but they appear to be reversible (the longer the timefrom the maximum effect of the drug the lower its toxicity).

International audience; Polyphenols are important to human health thus making it interesting and necessary to identify and assess methods for their detection. Gallic acid (GA) is a well-known antioxidant compound, found in tea leaves, various fruits, fruit seeds and in fruit-derived foods and beverages. In this study, to electrochemically detect this compound and assess the potential for GA detection, different analytical conditions at pH values of 5.8, 7 and 8 were tried. Two types of device were used for GA detection: (1) Lazar ORP-146C reduction-oxidation microsensors, coupled with a Jenco device, for estimation of antioxidant capacities of different electroactive media, and (2) screen-printed carbon sensors coupled with a mobile PalmSens device using differential pulse voltammetry (qualitative and quantitative GA determination). These proposed methods were validated by analysing some real samples: wine, green tea, apple juice and serum fortified with GA. Detection was evaluated in terms of specific calibration curves, with low limit of detection (LOD) and limit of quantification (LOQ), low response time, and high sensitivities. The analytical characteristics obtained recommend these methods to be tested on more other types of real samples. Our proposed methods, used in the established conditions of pH, may have further application in other clinical, food or environmental samples analyses in which the results of total antioxidants contents are usually expressed in GA equivalents.

International audience; Stroke is the main cause of disability after age 65, leaving survivors with sequels that require care and recovery treatment lasting years. It is estimated that by the year 2030 this pathology will be leading cause of mortality. To determine the efficacy of Lokomat training combined with neurotrophic medication and balneo-physiotherapeutic treatment in rehabilitation of post-stroke patients, a prospective study of 3 parallel groups was conducted: Group I (n = 22) – Lokomat, balneo-physiotherapy, and Cerebrolysin; Group II (n = 18) – Lokomat associated with balneo-physiotherapy; and Group III (n = 30) – balneo-physiotherapy alone (Control group). Patients were evaluated physically, neurologically, and functionally, according to the evolution of their motor deficiency, spasticity, functional independence and health-related quality of life.Patient improvement is significantly better (p b 0.05) in the group with associated therapies, especially during the first 6 months. Evolution was significantly better in all groups at 12 months than initially (p b 0.05), for all studied parameters and with the best effects in Group I (the three therapies combined). Association of Lokomat training with neurotrophic factors and classic recovery techniques improves the rehabilitationprocess in stroke patients.

Background Stiff left atrial syndrome (SLAS) and pulmonary vein (PV) occlusion are rare yet potentially major life-long complications after radiofrequency ablation for atrial fibrillation. While mostly controlled by medical management, SLAS can progress to refractory congestive heart failure. Treatment of PV stenosis and occlusion remains a challenging problem with ongoing risk for recurrence regardless of techniques employed. Herein we present the case of a now 51-year-old male with acquired PV occlusion and SLAS who, over the course of eleven years, despite multiple interventions, ultimately required heart transplantation. Case presentation After undergoing three radiofrequency catheter procedures for paroxysmal atrial fibrillation (AF), a hybrid ablation was planned due to reappearance of symptomatic AF. Preoperative echocardiography and chest computed tomography (CT) revealed an occlusion of both left PVs. Furthermore, left atrial dysfunction, high pulmonary artery and pulmonary wedge pressures were diagnosed as well as an important reduction of the left atrial volume. The diagnosis of stiff left atrial syndrome was made. Primary surgical repair of the left-sided PVs was performed using a pericardial patch as a tubular neo-vein, combined with cryoablation in the left and right atrium to treat the patient’s arrhythmia. Initial results were favorable, however, after two years the patient experienced progressive restenosis with hemoptysis. Therefore, stenting of the common left PV was performed. Over the years, progressive right heart failure with severe tricuspid regurgitation developed, despite maximal medical therapy, which led to the need for heart transplantation. Conclusion The impact of PV occlusion and SLAS after percutaneous radiofrequency ablation can be lifelong and devastating for the clinical course of the patient. Since the presence of a small left atrium could be an important predictor for SLAS in case of redo ablation, preprocedural imaging should guide the operator to an algorithm of a decision-making containing lesion set, energy source, and safety of re-ablation.

International audience; This article explores the correlation between specific aspects of antibiotic usage, their resistance development, and environmental factors. The indiscriminate use of antibiotics led to environment contamination, selection and spreading of antibiotic-resistant organisms, and alteration of the microbial ecosystems balance. Sociobehavioural environmental factors and changes in the natural environment are major contributors to resistance development. Resistant bacteria strains' isolation in food, water, soil etc. demonstrates the environmental influence on the strains through antibiotics accumulation in the environment. It is difficult to assess the impact of antibiotic consumption on public health and the environment. Reducing irrational consumption, restoring microbial ecosystems, adopting methodologies to control antimicrobial resistance in case of in-hospital infections, implementation of measures included in national/international health policies are the main solutions for this problem.

Targeted radionuclide therapy (TRT) using targeting moieties labeled with α-particle-emitting radionuclides (α-TRT) is an intensely investigated treatment approach as the short range of α-particles allows effective treatment of local lesions and micrometastases. However, profound assessment of the immunomodulatory effect of α-TRT is lacking in literature. Methods: Using flow cytometry of tumors, splenocyte restimulation, and multiplex analysis of blood serum, we studied immunologic responses ensuing from TRT with an antihuman CD20 single-domain antibody radiolabeled with 225Ac in a human CD20 and ovalbumin expressing B16-melanoma model. Results: Tumor growth was delayed with α-TRT and increased blood levels of various cytokines such as interferon-γ, C-C motif chemokine ligand 5, granulocyte-macrophage colony-stimulating factor, and monocyte chemoattractant protein-1. Peripheral antitumoral T-cell responses were detected on α-TRT. At the tumor site, α-TRT modulated the cold tumor microenvironment (TME) to a more hospitable and hot habitat for antitumoral immune cells, characterized by a decrease in protumoral alternatively activated macrophages and an increase in antitumoral macrophages and dendritic cells. We also showed that α-TRT increased the percentage of programmed death-ligand 1 (PD-L1)-positive (PD-L1pos) immune cells in the TME. To circumvent this immunosuppressive countermeasure we applied immune checkpoint blockade of the programmed cell death protein 1-PD-L1 axis. Combination of α-TRT with PD-L1 blockade potentiated the therapeutic effect, however, the combination aggravated adverse events. A long-term toxicity study revealed severe kidney damage ensuing from α-TRT. Conclusion: These data suggest that α-TRT alters the TME and induces systemic antitumoral immune responses, which explains why immune checkpoint blockade enhances the therapeutic effect of α-TRT. However, further optimization is warranted to avoid adverse events.

Oocyte in vitro maturation (IVM) is an assisted reproductive technology with a long and sometimes checked history. It is a minimally invasive technique involving the deliberate collection of immature oocytes from patients that have received no or minimal ovarian stimulation and the culture of oocytes to maturity in vitro, before standard procedures thereafter. Now, IVM is classified as nonexperimental and is primarily indicated for patients with a high antral follicle count, especially patients with polycystic ovaries or polycystic ovary syndrome, as well as for fertility preservation in cancer patients. In the recent past, IVM practice has had a confusing array of clinical protocols and has been slow to adapt to new scientific insights; however, recently, significant advances have been made in IVM culture methods based on new knowledge from animal studies, combined with defining a simple patient treatment protocol. These improvements have led to significant recent progress in IVM practice to the extent that IVM is now routinely practiced in a growing number of centers with specialized expertise around the world.

Lung cancer is the most common non-AIDS defining cancer among people living with HIV (PLWH), but there is a paucity of data regarding the efficacy and toxicity of radiotherapy and systemic regimens, including immunotherapy, in the treatment of these patients. In order to answer this question, we have performed a systematic search of the literature in Ovid Medline until March 17, 2022. We included 21 publications, enrolling 513 PLWH with non-small cell lung cancer (NSCLC), mostly male (75-100%), (ex-)smokers (75-100%) and with stage III-IV at diagnosis (65-100%). The overall response rate (ORR) to chemotherapy (n = 186 patients, mostly receiving platinum-based regimens) was highly variable (17 %-83 %), with a substantial hematological toxicity. ORR varied between 13 % and 50 % with single-agent immunotherapy (n = 68), with median overall survival between 9 and 11 months and a very acceptable toxicity profile, in line with studies in the HIV non-infected population. All five patients receiving tyrosine kinase inhibitors (TKIs; gefitinib or erlotinib) showed a partial response and long overall survival. Yet, combination of TKIs with antiretroviral therapy using pharmacological boosters, such as ritonavir, should be avoided. Radiotherapy was evaluated among 42 patients, showing high ORR (55 %-100 %), but 18 % of patients had a pneumonitis. This systematic review shows that radiotherapy and systemic therapy are effective and safe among PLWH with controlled infection diagnosed with NSCLC. Nonetheless, most reports were small and heterogeneous and larger studies are needed to confirm these encouraging findings. Moreover, clinical trials should not restrict the inclusion of PLWH, as more data is needed regarding the long-term efficacy and safety of treatments among this underserved population, especially of immunotherapy.

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To analyse the impact of the COVID-19 pandemic on women experiencing motherhood in the areas of perception, adaptation and assessment of the pandemic situation. Material and method: A qualitative study was conducted using semi-structured interviews. The interviews were conducted in a group of 25 women aged 22-41 who gave birth during the pandemic. Most of the respondents live in the city with more than 500,000 inhabitants, and have a higher education. In most cases, the research material was collected by means of face to face interviews, and in the case of 9 women, using remote techniques. Results: The results do not demonstrate a decreased interest in motherhood during the COVID-19 pandemic. Most of the respondents had planned their pregnancy and complied with the sanitary regime. Online prenatal education turned out to be a good solution for the study group at the time of restrictions. The number of antenatal visits was not increased as compared to previous pregnancies. Five respondents were considering a homebirth. The respondents complained of reduced well-being, which resulted in the recurrence of depressive moods. Most concerns were related to the reliability of tele-counselling and the availability of the doctor and partner during childbirth. Conclusions: The analysis of the respondents’ answers leads to the conclusion that the COVID-19 pandemic had a significant influence on the mental state of women giving birth at that time. The most difficult aspect for the respondents was the prohibition of giving birth in the presence of family, no mental support and feeling lonely both during the pregnancy and after childbirth at the time of quarantine. The COVID-19 pandemic did not have a significant effect on the perception of motherhood by women or on their reproduction plans.

Multiple myeloma (MM) remains an incurable haematological malignancy despite substantial advances in therapy. Hypoxic bone marrow induces metabolic rewiring in MM cells contributing to survival and drug resistance. Therefore, targeting metabolic pathways may offer an alternative treatment option. In this study, we repurpose two FDA-approved drugs, syrosingopine and metformin. Syrosingopine was used as a dual inhibitor of monocarboxylate transporter 1 and 4 (MCT1/4) and metformin as an inhibitor for oxidative phosphorylation (OXPHOS). Anti-tumour effects were evaluated for single agents and in combination therapy. Survival and expression data for MCT1/MCT4 were obtained from the Total Therapy 2, Mulligan, and Multiple Myeloma Research Foundation cohorts. Cell death, viability, and proliferation were measured using Annexin V/7-AAD, CellTiterGlo, and BrdU, respectively. Metabolic effects were assessed using Seahorse Glycolytic Rate assays and LactateGlo assays. Differential protein expression was determined using western blotting, and the SUnSET method was implemented to quantify protein synthesis. Finally, the syngeneic 5T33MMvv model was used for in vivo analysis. High-level expression of MCT1 and MCT4 both correlated with a significantly lower overall survival of patients. Lactate production as well as MCT1/MCT4 expression were significantly upregulated in hypoxia, confirming the Warburg effect in MM. Dual inhibition of MCT1/4 with syrosingopine resulted in intracellular lactate accumulation and reduced cell viability and proliferation. However, only at higher doses (>10 μm) was syrosingopine able to induce cell death. By contrast, combination treatment of syrosingopine with metformin was highly cytotoxic for MM cell lines and primary patient samples and resulted in a suppression of both glycolysis and OXPHOS. Moreover, pathway analysis revealed an upregulation of the energy sensor p-AMPKα and more downstream a reduction in protein synthesis. Finally, the combination treatment resulted in a significant reduction in tumour burden in vivo. This study proposes an alternative combination treatment for MM and provides insight into intracellular effects.

Validated in vitro assays for testing non-genotoxic carcinogenic potential of chemicals are currently not available. Consequently, the two-year rodent bioassay remains the gold standard method for the identification of these chemicals. Transcriptomic and proteomic analyses have provided a comprehensive understanding of the non-genotoxic carcinogenic processes, however, functional changes induced by effects at transcriptional and translational levels have not been addressed. The present study was set up to test a number of proposed in vitro biomarkers of non-genotoxic hepatocarcinogenicity at the functional level using a translational 3-dimensional model. Spheroid cultures of human hepatocytes and stellate cells were exposed to 5 genotoxic carcinogenic, 5 non-genotoxic carcinogenic, and 5 non-carcinogenic chemical compounds and assessed for oxidative stress, mitochondrial dysfunction, endoplasmic reticulum stress, apoptosis, and inflammation. The spheroid model could capture many of these events triggered by the genotoxic carcinogenic chemicals, particularly aflatoxin B1 and hydroquinone. Nonetheless, no clear distinction could be made between genotoxic and non-genotoxic hepatocarcinogenicity. Therefore, spheroid cultures of human liver cells may be appropriate in vitro tools for mechanistic investigation of chemical-induced hepatocarcinogenicity, however, these mechanisms and their read-outs do not seem to be eligible biomarkers for detecting non-genotoxic carcinogenic chemicals.

Helicobacter pylori (H. pylori) infection causes chronic gastritis, peptic ulcers and gastric cancer. Although H. pylori prevalence is decreasing worldwide, regional variations exist in Europe, with the lowest infection prevalence in Northern Europe, and the highest in Eastern and Southern Europe (1). Changes in the treatment recommendations and the increasing available evidence have justified the implementation of new recommendations since last Belgian consensus in 1998 (2). Several non-H. pylori Helicobacter species (NH.PYLORI-H), colonizing the stomach of domestic animals, also have the ability to cause gastric disease in humans, although to a lesser extent. These zoonotic NH. PYLORIH are not the subject of the current recommendations.

BACKGROUND: Limited data on the real-world safety and efficacy of leadless pacemakers (LPMs) post-transvenous lead extraction (TLE) are available. OBJECTIVE: The purpose of this study was to assess the long-term safety and effectiveness of LPMs following TLE in comparison with LPMs de novo implantation. METHODS: Consecutive patients who underwent LPM implantation in 12 European centers joining the International LEAdless PacemakEr Registry were enrolled. The primary end point was the comparison of LPM-related complication rate at implantation and during follow-up (FU) between groups. Differences in electrical performance were deemed secondary outcomes. RESULTS: Of the 1179 patients enrolled, 15.6% underwent a previous TLE. During a median FU of 33 (interquartile range 24-47) months, LPM-related major complications and all-cause mortality did not differ between groups (TLE group: 1.6% and 5.4% vs de novo group: 2.2% and 7.8%; P = .785 and P = .288, respectively). Pacing threshold (PT) was higher in the TLE group at implantation and during FU, with very high PT (>2 V@0.24 ms) patients being more represented than in the de novo implantation group (5.4% vs 1.6 %; P = .004). When the LPM was deployed at a different right ventricular (RV) location than the one where the previous transvenous RV lead was extracted, a lower proportion of high PT (>1-2 V@0.24 ms) patients at implantation, 1-month FU, and 12-month FU (5.9% vs 18.2%, P = .012; 3.4% vs 12.9%, P = .026; and 4.3% vs 14.5%, P = .037, respectively) was found. CONCLUSION: LPMs showed a satisfactory safety and efficacy profile after TLE. Better electrical parameters were obtained when LPMs were implanted at a different RV location than the one where the previous transvenous RV lead was extracted.

Despite the high prevalence of alcoholic liver disease, its identification and characterization remain poor, especially in early stages such as alcoholic fatty liver disease and alcoholic steatohepatitis. This latter implies diagnostic difficulties, few therapeutic options and unclear mechanisms of action. To elucidate the metabolic alterations and pinpoint affected biochemical pathways, alcoholic steatohepatitis was simulated in vitro by exposing HepaRG cells to ethanol (IC10, 368 mM) and tumor necrosis factor alpha (TNF-α, 50 ng/mL) for 24 h. This combined exposure was compared to solely ethanol-exposed as well as -nonexposed cells. Four different metabolomics platforms were used combining liquid chromatography, high-resolution mass spectrometry and drift tube ion mobility to elucidate both intracellular and extracellular metabolic alterations. Some of the key findings include the influence of TNF-α in the upregulation of hepatic triglycerides and the downregulation of hepatic phosphatidylethanolamines and phosphatidylcholines. S-Adenosylmethionine showed to play a central role in the progression of alcoholic steatohepatitis. In addition, fatty acyl esters of hydroxy fatty acid (FAHFA)-containing triglycerides were detected for the first time in human hepatocytes and their alterations showed a potentially important role during the progression of alcoholic steatohepatitis. Ethoxylated phosphorylcholine was identified as a potential new biomarker of ethanol exposure.

BACKGROUND: It is unclear whether the patatin-like phospholipase domain-containing protein 3 (PNPLA3) rs738409 C-to-G single nucleotide polymorphism, resulting in the substitution of isoleucine to methionine at position 148 (I148M), impedes regression of hepatic steatosis when treating non-alcoholic fatty liver disease (NAFLD). OBJECTIVES: Investigate if carriage of the PNPLA3 148M allele affects the anti-steatotic efficacy of all possible anti-NAFLD interventions, identify gaps in current knowledge and provide guidance for individual treatment. METHODS: Research available in public databases was searched up to 13 November 2022. Studies were included if a treatment in NAFLD patients decreased hepatic steatosis in the pooled patient group or a PNPLA3 I148M polymorphism subgroup (II/IM/MM). The risk of bias was assessed using the Cochrane Risk-Of-Bias 2 Tool and the Newcastle-Ottawa Scale. RESULTS: Moderate evidence indicates that NAFLD patients homozygous for the PNPLA3 148M allele benefit less or not at all from omega-3 carboxylic acids to decrease liver fat, while the PNPLA3 148I allele shows moderate benefit. Low evidence suggests that interventions employing lifestyle changes are more effective to reduce liver fat in NAFLD patients homozygous for the PNPLA3 148M allele compared to patients with wild-type PNPLA3. CONCLUSIONS: NAFLD patients homozygous for the PNPLA3 148M allele might not benefit from omega-3 carboxylic acids to reduce hepatic steatosis in contrast to patients with wild-type PNPLA3. Instead, patients with two PNPLA3 148M alleles should be especially advised to adopt lifestyle changes. Genotyping for PNPLA3 I148M should be encouraged in therapeutic studies for NAFLD. REGISTRATION NUMBER (PROSPERO): CRD42022375028.

STUDY QUESTION Can early pregnancies be accurately and cost-effectively diagnosed and managed using a new medical computerized tool? SUMMARY ANSWER Compared to the standard clinical approach, retrospective implementation of the new medical software in a gynaecological emergency unit was correlated with more accurate diagnosis and more cost-effective management. WHAT IS KNOWN ALREADY Early pregnancy complications are responsible for a large percentage of consultations, mostly in emergency units, with guidelines becoming complex and poorly known/misunderstood by practitioners. STUDY DESIGN, SIZE, DURATION A total of 780 gynaecological emergency consultations (446 patients), recorded between November 2018 and June 2019 in a tertiary university hospital, were retrospectively encoded in a new medical computerized tool. The inclusion criteria were a positive hCG test result, ultrasonographical visualization of gestational sac, and/or embryo corresponding to a gestational age of 14 weeks or less. Diagnosis and management suggested by the new computerized tool are named eDiagnoses, while those provided by a gynaecologist member of the emergency department staff are called medDiagnoses. PARTICIPANTS/MATERIALS, SETTING, METHODS Usability was the primary endpoint, with accuracy and cost reduction, respectively, as secondary and tertiary endpoints. Identical eDiagnoses/medDiagnoses were considered as accurate. During follow-up visits, if the updated eDiagnoses and medDiagnoses became both identical to a previously discrepant eDiagnosis or medDiagnosis, this previous eDiagnosis or medDiagnosis was also considered as correct. Four double-blinded experts reviewed persistent discrepancies, determining the accurate diagnoses. eDiagnoses/medDiagnoses accuracies were compared using McNemar’s Chi square test, sensitivity, specificity, and predictive values. MAIN RESULTS AND THE ROLE OF CHANCE Only 1 (0.1%) from 780 registered medical records lacked data for full encoding. Out of the 779 remaining consultations, 675 eDiagnoses were identical to the medDiagnoses (86.6%) and 104 were discrepant (13.4%). From these 104, 60 reached an agreement during follow-up consultations, with 59 medDiagnoses ultimately changing into the initial eDiagnoses (98%) and only one discrepant eDiagnosis turning later into the initial medDiagnosis (2%). Finally, 24 remained discrepant at all subsequent checks and 20 were not re-evaluated. Out of these 44, the majority of experts agreed on 38 eDiagnoses (86%) and 5 medDiagnoses (11%, including four twin pregnancies whose twinness was the only discrepancy). No majority was reached for one discrepant eDiagnosis/medDiagnosis (2%). In total, the accuracy of eDiagnoses was 99.1% (675 + 59 + 38 = 772 eDiagnoses out of 779), versus 87.4% (675 + 1 + 5 = 681) for medDiagnoses (P LIMITATIONS, REASONS FOR CAUTION The retrospective study design is a limitation. Some observed improvements with the medical software could derive from the encoding by a rested and/or more experienced physician who had a better ultrasound interpretation. This software cannot replace clinical and ultrasonographical skills but may improve the compliance to published guidelines. WIDER IMPLICATIONS OF THE FINDINGS This medical computerized tool is improving. A new version considers diagnosis and management of multiple pregnancies with their specificities (potentially multiple locations, chorioamnionicity). Prospective evaluations will be required. Further developmental steps are planned, including software incorporation into ultrasound devices and integration of previously published predictive/prognostic factors (e.g. serum progesterone, corpus luteum scoring). STUDY FUNDING/COMPETING INTEREST(S) No external funding was obtained for this study. F.B. and D.G. created the new medical software. TRIAL REGISTRATION NUMBER NCT03993015

Aims The multielectrode radiofrequency balloon catheter (RFB) has been developed to achieve safe and effective pulmonary vein isolation (PVI) for atrial fibrillation (AF) ablation. This single-centre study aimed to evaluate the midterm clinical outcome and predictors of single-shot PVI with the novel RFB. Methods and results All consecutive patients with symptomatic paroxysmal or persistent AF undergoing first-time PVI with the RFB were prospectively included. Clinical and procedural parameters were systematically collected. The primary safety endpoint was defined as any major periprocedural complications. The primary efficacy endpoint consisted of freedom from any atrial tachyarrhythmias (ATas) lasting >30 s during the follow-up after a 3-month blanking period. Persistent single-shot PVI was defined as PVI achieved with a single RFB application without acute reconnection. A total of 104 consecutive patients (mean age 64.3 ± 11.4 years, 56.7% males) were included. 15 patients (14.4%) presented with persistent AF. The procedure time was 59.0 min with a dwell time of 20.0 min. One major complication occurred in one patient. At a mean follow-up of 10.1 ± 5.3 months, freedom from ATas was 82.9%. ATas occurred in 14 patients, 11/69 patients (15.9%) with paroxysmal AF and 3/13 (23.1%) with persistent AF. The best cut-offs to predict persistent single-shot PVI were impedance drop >19.2 Ω [area under the receiver operator characteristic curve (AUC) 0.74] and temperature rise >11.1° C (AUC 0.77). Conclusion In a large cohort of patients undergoing PVI with the RFB, the complication rate was 1%. At a mid-term follow-up of 10.1 ± 5.3 months, freedom from ATas was 82.9%. Specific cut-offs of impedance drop and temperature rise may be useful to predict persistent single-shot isolation.

Direct oral anticoagulants (DOACs) are increasingly used and are an important cornerstone in antithrombotic therapy. Adverse drug reactions (ADRs) such as bleedings have only partially been investigated during clinical trials. The primary goal was to analyse pharmacovigilance data based on spontaneous reports of gastrointestinal (GI) bleedings with DOACs reported to EudraVigilance. A second goal was to compare GI safety profiles between DOACs based on these signals. All DOAC related GI bleedings mentioned in individual case safety reports (ICSRs) from 2012 till 2017 in the European Economic Area were classified in four GI categories based on the reported site of occurrence of the haemorrhage. Age group and gender of the patient, seriousness and ADR outcome, and the reporter's qualification were assessed per category and per DOAC. Disproportionality analyses were performed to evaluate whether or not the reported ADRs were more prevalent with a given DOAC. ICSRs were bleeding-related in about half of the cases (n = 28,992/53,471). Of these bleedings, >25% was GI-related. Most patients experiencing GI bleedings were between 65 and 85 years old, with no obvious differences between men and women. Stomach, ulcer-related duodenal, and rectal bleedings were the most reported GI bleedings with a fatal outcome in 5.8%, 7.5%, and 9.8% of the cases for rivaroxaban, apixaban, and dabigatran, respectively. The disproportionality data suggest that dabigatran is more frequently involved in GI bleeding events than the other DOACs. DOACs were significantly associated with GI bleedings. Although the data should be interpreted with caution, it seems that dabigatran was associated more often than other DOACs with GI bleedings based on the analysis of spontaneous pharmacovigilance reports.

Background: Acetazolamide inhibits proximal tubular sodium reabsorption and improved decongestion in the ADVOR (Acetazolamide in Decompensated Heart Failure with Volume Overload) trial. It remains unclear whether the decongestive effects of acetazolamide differ across the spectrum of left ventricular ejection fraction (LVEF). Methods: This is a prespecified analysis of the randomized, double-blind, placebo-controlled ADVOR trial that enrolled 519 patients with acute heart failure (HF), clinical signs of volume overload (eg, edema, pleural effusion, or ascites), NTproBNP (N-terminal pro-B-type natriuretic peptide) >1000 ng/L, or BNP (B-type natriuretic peptide) >250 ng/mL to receive intravenous acetazolamide (500 mg once daily) or placebo in addition to standardized intravenous loop diuretics (twice that of the oral home maintenance dose). Randomization was stratified according to LVEF (≤40% or >40%). The primary end point was successful decongestion, defined as the absence of signs of volume overload within 3 days from randomization without the need for mandatory escalation of decongestive therapy because of poor urine output. Results: Median LVEF was 45% (25th to 75th percentile; 30% to 55%), and 43% had an LVEF ≤40%. Patients with lower LVEF were younger and more likely to be male with a higher prevalence of ischemic heart disease, higher NTproBNP, less atrial fibrillation, and lower estimated glomerular filtration rate. No interaction on the overall beneficial treatment effect of acetazolamide to the primary end point of successful decongestion (OR, 1.77 [95% CI, 1.18-2.63]; P =0.005; all P values for interaction >0.401) was found when LVEF was assessed per randomization stratum (≤40% or >40%), or as HF with reduced ejection fraction, HF with mildly reduced ejection fraction, and HF with preserved ejection fraction, or on a continuous scale. Acetazolamide resulted in improved diuretic response measured by higher cumulative diuresis and natriuresis and shortened length of stay without treatment effect modification by baseline LVEF (all P values for interaction >0.160). Conclusions: When added to treatment with loop diuretics in patients with acute decompensated HF, acetazolamide improves the incidence of successful decongestion and diuretic response, and shortens length of stay without treatment effect modification by baseline LVEF. Registration: URL: https://www.clinicaltrials.gov ; Unique identifier: NCT03505788.

Background & Aims: HEV genotype (gt) 3 infections are prevalent in high-income countries and display a wide spectrum of clinical presentations. Host - but not viral - factors are reported to be associated with worse clinical outcomes.Methods: Demographic, clinical, and biochemical data laboratory-confirmed HEV infections (by PCR and/or a combination of IgM and IgG serology) at the Belgian National Reference Centre between January 2010 and June 2018 were collected using stand-ardised case report forms. Genotyping was based on HEV open reading frame 2 sequences. Serum CXCL10 levels were measured by a magnetic bead-based assay. H&E staining was performed on liver biopsies.Results: A total of 274 HEV-infected individuals were included. Subtype assignment was possible for 179/218 viraemic cases, confirming gt3 as dominant with an almost equal representation of clades abchijklm and efg. An increased hospitalisation rate and higher peak serum levels of alanine aminotransferase, bilirubin, and alkaline phosphatase were found in clade efg-infected in-dividuals in univariate analyses. In multivariable analyses, clade efg infections remained more strongly associated with severe disease presentation than any of the previously identified host risk factors, being associated with a 2.1-fold higher risk of hos-pitalisation (95% CI 1.1-4.4, p = 0.034) and a 68.2% higher peak of bilirubin levels (95% CI 13.3-149.9, p = 0.010), independently of other factors included in the model. In addition, acute clade efg infections were characterised by higher serum CXCL10 levels (p = 0.0005) and a more pronounced liver necro-inflammatory activity (p = 0.022). Conclusions: In symptomatic HEV gt3 infections, clade efg is associated with a more severe disease presentation, higher serum CXCL10 levels, and liver necro-inflammatory activity, irrespective of known host risk factors.Clinical Trial Registration: The protocol was submitted to clinicaltrials.gov (NCT04670419).(c) 2022 European Association for the Study of the Liver. Published by Elsevier B.V. All rights reserved. This study is a retrospective analysis of routinely collected data, within the Belgian National Reference Centre (NRC) programme funded by the National Institute for Health and Disability Insurance (RIZIV-INAMI, Belgium). TV is supported by a senior clinical investigator grant of the Research Foundation Flanders (FWO) (number 18B2821N, Belgium). JS and NH acknowledge funding from the European Research Council (ERC) Horizon 2020 research and innovation program (grant agreement 682540 — TransMID, European Union). The funding sources did not have any role in study design, in the collection, analysis, and interpretation of data, in the manuscript writing, or in the decision to submit the paper for publication. We thank Harry Dalton for helpful discussions on the national data collection and clinical outcome analysis and Christophe Conrad for his help in collecting patients data. The authors also especially thank all physicians from the following centres who participated in the study: Algemeen Ziekenhuis Alma, Eeklo; Algemeen Medisch Laboratorium, Antwerpen; Algemeen Stedelijk Ziekenhuis, Aalst; Algemeen Ziekenhuis Delta, Roeselare; Algemeen Ziekenhuis Delta, Torhout; Algemeen Ziekenhuis Nikolaas, Sint-Niklaas; Algemeen Ziekenhuis Sint-Elisabeth, Zottegem; Algemeen Ziekenhuis, Turnhout; Centre Hospitalier Universitaire Brugmann, Brussels; Centre Hospitalier de l’Ardenne, Libramont; Hôpital de Braine-l’Alleud-Waterloo, Braine-l’Alleud; Hôpital Delta, Brussels; Centre Hospitalier de Mouscron, Mouscron; Centre Hospitalier Régional Haute Senne, Soignies; Centre Hospitalier Epicura, Hornu; Centre Hospitalier Universitaire de Liège, Liège; Centre Hospitalier de la Wallonie Picarde, Tournai; Clinique CHC, Waremme; Grand Hôpital de Charleroi, Charleroi; Gasthuiszusters Antwerpen, Antwerpen; Hôpital Princesse Paola, Marche-en-Famenne; Hôpital Iris Sud, Brussels; Instituut voor Tropische Geneeskunde, Antwerpen; Hôpital de Jolimont, La Louvière; Centre Hospitalier de Jolimont, Lobbes; Centre Hospitalier de Jolimont, Nivelles; Centre Hospitalier de Jolimont, Tubize; Eurofins Labo Van Poucke, Kortrijk; Medisch Labo Medina, Dendermonde; Algemeen Ziekenhuis Maria Middelares, Gent; Ziekenhuis Netwerk Antwerpen Middelheim, Antwerpen; Cliniques Universitaires Saint-Luc, Brussels; Centre Hospitalier Universitaire UCL, Dinant; Centre Hospitalier Universitaire UCL, Namur; Centre Hospitalier Universitaire de MontGodinne, Yvoir; Clinique Saint-Luc, Bouge; Clinique Notre-Dame de Grâce, Gosselies; Sint-Andriesziekenhuis, Tielt; Algemeen Ziekenhuis West, Veurne; Algemeen Ziekenhuis Sint Blasius, Dendermonde; Algemeen Ziekenhuis SintJan, Brugge; Klinik Sankt-Joseph, Sankt-Vith; Algemeen Ziekenhuis SintLucas, Gent; Algemeen Ziekenhuis Sint-Maarten, Mechelen; Centre Hospitalier Universitaire Saint-Pierre, Brussels; Sint-Trudo Ziekenhuis, Sint-Truiden; Centre Hospitalier Universitaire Tivoli, La Louvière; Hôpital Erasme – Cliniques Universitaires de Bruxelles, Brussels; Universitair Ziekenhuis Antwerpen, Antwerpen; Universitair Ziekenhuis Gent, Gent; Cassiman David, Laleman Wim, Van Malenstein Hannah, Verslype Chris and Van der Merwe Schalk from Universitair Ziekenhuis Leuven, Leuven; Virga Jesse Ziekenhuis, Hasselt; Universitair Ziekenhuis Brussel, Brussels; Jan Yperman Ziekenhuis, Ieper.

Belgium has one of the highest numbers of COVID-19 cases per 1 million inhabitants. The pandemic has led to significant societal changes with repercussions on sleep and on mental health. We aimed to investigate the effect of the first and the second wave of COVID-19 on the sleep of the Belgian populationWe launched two online questionnaires, one during the first lockdown (7240 respondents) and one during the second (3240 respondents), to test differences in self-reported clinical insomnia (as measured by the Insomnia Severity Index) and sleep habits during the two lockdowns in comparison with the pre-COVID period. The number of persons with clinical insomnia rose during the first lockdown (19.22%) and further during the second (28.91%) in comparison with pre-lockdown (7.04-7.66%). Bed and rise times were delayed and there was an increased time in bed and sleep onset latency. There was further a decrease in total sleep time and in sleep efficiency during both confinements. The prevalence of clinical insomnia quadrupled during the second wave in comparison with the pre-lockdown situation. Sleep habits were most altered in the younger population, indicating a greater risk for this group to develop a sleep-wake rhythm disorder.

The robotic platform can overcome technical difficulties associated with laparoscopic colon surgery. Transitioning from laparoscopic right colectomy with extracorporeal anastomosis (ECA) to robotic right colectomy with intracorporeal anastomosis (ICA) is associated with a learning phase. This study aimed at determining the length of this learning phase and its associated morbidity. We retrospectively analyzed all laparoscopic right colectomies with ECA (n = 38) and robotic right colectomies with ICA (n = 67) for (pre)malignant lesions performed by a single surgeon between January 2014 and December 2020. CUSUM-plot analysis of total procedure time was used for learning curve determination of robotic colectomies. Non-parametric tests were used for statistical analysis. Compared to laparoscopy, the learning phase robotic right colectomies (n = 35) had longer procedure times (p

PURPOSE: The aim of the present study was to evaluate the role of ejection fraction (EF), left ventricular (LV) global longitudinal strain (LVGLS) and global constructive work (GCW) as prognostic variables in patients with cardiac amyloidosis (CA). METHODS: CA patients were retrospectively identified between 2015 and 2021 at a tertiary care hospital. Comprehensive clinical, biochemical, and imaging evaluation including two-dimensional (2D) echocardiography with myocardial work (MW) analysis was performed. A clinical combined endpoint was defined as all-cause mortality and heart failure readmission. RESULTS: 70 patients were followed for 16 (7-37) months and 37 (52.9%) reached the combined endpoint. Patient with versus without clinical events had a significantly lower LVEF (40.71% vs. 48.01%, p = 0.039), LVGLS (-9.26 vs. -11.32, p = 0.034) and GCW (1034.47mmHg% vs. 1424.86mmHg%, p = 0.011). Multivariable analysis showed that LVEF ( odds ratio (OR): 0.904; 95% confidence interval (CI): 0.839-0.973, p = 0.007), LVGLS ( OR: 0.620; 95% CI: 0.415-0.926, p = 0.020) and GCW ( OR: 0.995; 95% CI: 0.990-0.999, p = 0.016) were significant predictors of outcome, but the model including GCW had the best discriminative ability to predict the combined endpoint (C-index = 0.888). A GCW less than 1443mmHg% was able to predict the clinical endpoint with a sensitivity of 94% and a specificity of 64% (Area under the curve (AUC): 0.771 (95% CI: 0.581-0.961; p = 0.005)). CONCLUSION: In CA patients, GCW may be of additional prognostic value to LVEF and GLS in predicting heart failure hospitalization and all-cause mortality.

In Belgium, from June 1st 2018 on, a renewed reim- bursement for hip arthroplasty implants was launched and from January 1st 2019 on, a lump sum covering doctors’ fees for “low variable patients”, was introduced. We investigated the impact of both reimbursement systems on the funding of a University Hospital in Belgium. All patients from the UZ Brussel with a severity of illness score of one or two whom had an elective total hip replacement implanted between January 1st and May 31st 2018, were included retrospectively. We compared their invoicing data to those of patients operated in the same period but one year later. Moreover, we simulated the invoicing data of both groups as if they had been operated in the other period. Overall, we compared invoicing data of 41 patients before and 30 after the introduction of both renewed reimbursement systems. After the introduction of both new laws, we noted a loss of funding per patient and per intervention between 46.8€ and 753.5€ for a single room and, between 105.5€ and 1877.7€ for a double room. We noted the highest loss in the subcategory “physicians’ fees”. The renewed reimbursement system is not “budget neutral”. In time, the new system can lead to an optimization of care, but it can also lead to a progressive decrease of funding if future fees and implant reimbursements would be aligned towards the national mean. More- over, we fear the new financing system could affect the quality of care and/or result in the selection of profitable patients.

It is well established that human pluripotent stem cells (hPSCs) can acquire genetic and epigenetic changes during culture in vitro. Given the increasing use of hPSCs in research and therapy and the vast expansion in the number of hPSC lines available for researchers, the International Society for Stem Cell Research has recognized the need to reassess quality control standards for ensuring the genetic integrity of hPSCs. Here, we summarize current knowledge of the nature of recurrent genetic and epigenetic variants in hPSC culture, the methods for their detection, and what is known concerning their effects on cell behavior in vitro or in vivo. We argue that the potential consequences of low-level contamination of cell therapy products with cells bearing oncogenic variants are essentially unknown at present. We highlight the key challenges facing the field with particular reference to safety assessment of hPSC-derived cellular therapeutics.

International audience; BackgroundCutaneous leishmaniasis (CL) is a vector-borne parasitic disease caused by protozoa of the genus Leishmania. In Morocco, CL is a public health problem mainly caused by Leishmania major and Leishmania tropica, which are responsible for zoonotic and anthroponotic CL, respectively. Macrophages are the primary cells infected by Leishmania parasites and their capacity to produce nitric oxide (NO) is of critical importance for parasite elimination. To our knowledge, the role of NO on autochthonous infections has never been investigated before. In this study, we evaluated in vitro the capacity of autochthonous primary dermotropic strains of L. major and L. tropica to modulate NO production by J774-macrophages and determine the sensitivity of both species to exogenous NO.MethodsThe infectivity of the J774 cell line was analyzed by optical microscopy. NO production by macrophages was measured by the Griess method. The sensitivity to NO by the two strains was assessed by the MTT assay using NO donors.ResultsOur results show that the percentage of infected macrophages and the average number of parasites per macrophage were similar for L. major and L. tropica strains. While L. tropica significantly inhibited NO production induced by LPS and IFN-γ stimulation in J774 macrophages, L. major did not affect it. However, soluble Leishmania antigens (SLAs) from both autochthonous primary strains significantly inhibited the production of NO by J774-macrophages in a dose-dependent manner. Finally, our results demonstrated that promastigotes and amastigotes from both strains are sensitive to SNAP NO donor in a dose-dependent manner, although L. tropica demonstrated an increased sensitivity.ConclusionsOur results suggest a differential ability of L. major and L. tropica strains to modulate the capacity of macrophages to produce NO. The increased ability of L. tropica to inhibit NO production by macrophages might come as a necessity due to its higher sensitivity to NO donor. Our results provide one explanation for the tendency of L. tropica to cause chronic lesions and may contribute to the different physiopathology of CL in Morocco.

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While multi-drug combinations and continuous treatment have become standard for multiple myeloma, the disease remains incurable. Repurposing drugs that are currently used for other indications could provide a novel approach to improve the therapeutic efficacy of standard multiple myeloma treatments. Here, we assessed the anti-tumor effects of cardiac drugs called β-blockers as a single agent and in combination with commonly used anti-myeloma therapies. Expression of the β 2-adrenergic receptor correlated with poor survival outcomes in patients with multiple myeloma. Targeting the β 2-adrenergic receptor (β 2AR) using either selective or non-selective β-blockers reduced multiple myeloma cell viability, and induced apoptosis and autophagy. Blockade of the β 2AR modulated cancer cell metabolism by reducing the mitochondrial respiration as well as the glycolytic activity. These effects were not observed by blockade of β 1-adrenergic receptors. Combining β 2AR blockade with the chemotherapy drug melphalan or the proteasome inhibitor bortezomib significantly increased apoptosis in multiple myeloma cells. These data identify the therapeutic potential of β 2AR-blockers as a complementary or additive approach in multiple myeloma treatment and support the future clinical evaluation of non-selective β-blockers in a randomized controlled trial.

OBJECTIVE: Does the dose or type of gonadotropin affect the reproductive outcomes of poor responders undergoing IVF in a modified natural cycle (MNC-IVF)? STUDY DESIGN: This is a retrospective cohort study including patients attending a tertiary referral University Hospital from 1st January 2017 until 1st March 2020. All predicted poor responders (Poseidon groups 3 and 4) who underwent MNC-IVF in our center were included. Mild ovarian stimulation (rFSH/uFSH/hp-hMG) was started when a follicle with a mean diameter of 12-14 mm was observed on ultrasound scan; GnRH antagonist was added from the next day onwards. Mature oocytes were inseminated using ICSI. RESULTS: In total 484 patients undergoing 1398 cycles were included. Mean (SD) age and serum AMH were 38.2 (3.7) years and 0.28 (0.26) ng/ml, respectively. The daily dose of gonadotropins was either

Heterogeneity of dose distribution has been shown at different spatial scales in diagnostic nuclear medicine. In cancer treatment using new radiopharmaceuticals with alpha-particle emitters, it has shown an extensive degree of dose heterogeneity affecting both tumour control and toxicity of organs at risk. This review aims to provide an overview of generalized internal dosimetry in nuclear medicine and highlight the need of consideration of the dose heterogeneity within organs at risk. The current methods used for patient dosimetry in radiopharmaceutical therapy are summarized. Bio-distribution and dose heterogeneities of alpha-particle emitting pharmaceutical 223Ra (Xofigo) within bone tissues are presented as an example. In line with the strategical research agendas of the Multidisciplinary European Low Dose Initiative (MELODI) and the European Radiation Dosimetry Group (EURADOS), future research direction of pharmacokinetic modelling and dosimetry in patient radiopharmaceutical therapy are recommended.

Abstract Raised blood pressure (BP) is the leading cause of preventable death in the world. Yet, its global prevalence is increasing, and it remains poorly detected, treated, and controlled in both high- and low-resource settings. From the perspective of members of the International Society of Hypertension based in all regions, we reflect on the past, present, and future of hypertension care, highlighting key challenges and opportunities, which are often region-specific. We report that most countries failed to show sufficient improvements in BP control rates over the past three decades, with greater improvements mainly seen in some high-income countries, also reflected in substantial reductions in the burden of cardiovascular disease and deaths. Globally, there are significant inequities and disparities based on resources, sociodemographic environment, and race with subsequent disproportionate hypertension-related outcomes. Additional unique challenges in specific regions include conflict, wars, migration, unemployment, rapid urbanization, extremely limited funding, pollution, COVID-19-related restrictions and inequalities, obesity, and excessive salt and alcohol intake. Immediate action is needed to address suboptimal hypertension care and related disparities on a global scale. We propose a Global Hypertension Care Taskforce including multiple stakeholders and societies to identify and implement actions in reducing inequities, addressing social, commercial, and environmental determinants, and strengthening health systems implement a well-designed customized quality-of-care improvement framework.

Background: Frailty and hypertension are interrelated, but it remains unclear whether this relationship is modified by antihypertensive drugs. Methods and results: A systematic review of PubMed and Web of Science databases was performed to review the influence of hypertension management on preventing the occurrence or progression of frailty in older people aged 65 and over. Studies providing information on this association regardless of the study setting, or definition of hypertension and frailty were included. Among the initial 2298 articles identified, 7 were included in the review. Three observational studies assessed the association between frailty and hypertension. Two of them reported no relationship between Aldosterone Antagonists use and frailty prevention. No relationship between BP and incidence frailty after adjustment for hypertension treatment was observed in two other articles. An indirect relationship was reported in the RCTs included. Higher AT11RaAb levels (control group), can lead to a generalized weakness/frailty risk shown by a decrease in grip strength (r = –0.57, p < 0.005) and walking speed (r = – 0.47, p < 0.005). No significant differences between int-hypertensive intervention and control were observed in frailty status after a 12-weeks follow-up after applying three different frailty measurement tools in the other RCT. Conclusions: Based on the results of this systematic review we conclude that BP and frailty occur together but whether the treatment with anti-hypertensive drugs modifies this relationship remains unclear and needs to be further investigated.

A hibernoma is a rare benign soft tissue tumor which may occur in the whole body. In the head and neck region, it occurs only sporadically and is difficult to distinguish clinically and on imaging from malignant tumors. It typically presents as a slow-growing, mobile, non-sensitive mass. Our case report describes an atypical presentation of a hibernoma with sudden onset of swelling in the left neck and dysphagia symptoms in a 16-year-old girl. One week later, a superinfection was noted with discharge of pus. A magnetic resonance imaging (MRI) showed a cystic solid mass, but no definitive diagnosis could be made. Therefore, surgical excision of the mass was performed which proved to be a hibernoma on anatomopathological examination. Whole-body MRI did not show similar lesions in other locations to the head and neck region. A hibernoma should be included in the differential diagnosis in patients presenting with a mass in the head and neck region. It is important to differentiate between benign and malignant tumors since the treatment differs. MRI is the imaging of choice and surgical excision is curative. To our knowledge, this is the first description of a hibernoma with an additional rare abscess formation, making the diagnosis even more difficult.

Peptide-based hydrogels represent promising systems for the sustained release of different types of drugs, ranging from small molecules to biologicals. Aiming at subcutaneous injection, which is a desirable parenteral administration route, especially for biologicals, we herein focus on physically crosslinked systems possessing thixotropic behaviour. The purpose of this study was to evaluate the in vitro and in vivo properties of hydrogels based on the amphipathic hexapeptide H-FQFQFK-NH2, which served as the lead sequence. Upon doubling the length of this peptide, the dodecapeptide H-FQFQFKFQFQFK-NH2 gave a significant improvement in terms of hydrogel’s in vivo stability post-injection, as monitored by nuclear SPECT/CT imaging. This increased hydrogel stability also led to a more prolonged in vivo release of encapsulated peptide cargoes. Even though no direct link with the mechanical properties of the hydrogels before injection can be made, an important effect of the subcutaneous medium was noticed in post invivo injection measurements. The results were validated for a therapeutically relevant analgesic peptide using the hot-plate test as an acute pain model. Gratifyingly, it was confirmed that elongation of the hydrogelator sequence induced more extended antinociceptive effects. Altogether, this simple structural modification of the hydrogelating peptide could provide a basis for reaching longer durations of action upon use of these soft biomaterials.

Biomedical science is rapidly developing in terms of more transparency, openness and reproducibility of scientific publications. This is even more important for all studies that are based on results from basic semen examination. Recently two concordant documents have been published: the 6th edition of the WHO Laboratory Manual for the Examination and Processing of Human Semen, and the International Standard ISO 23162:2021. With these tools, we propose that authors should be instructed to follow these laboratory methods in order to publish studies in peer-reviewed journals, preferable by using a checklist as suggested in an Appendix to this article.

Previous studies have shown that differences in experimental design factors may alter the potency of genotoxic compounds in in vitro genotoxicity tests. Most of these studies used traditional statistical methods based on the lowest observed genotoxic effect levels, whereas more appropriate methods, such as the benchmark dose (BMD) approach, are now available to compare genotoxic potencies under different test conditions. We therefore investigated the influence of two parameters, i.e. cell type and exposure duration, on the potencies of two known genotoxicants [aflatoxin B1 and ethyl methanesulfonate (EMS)] in the in vitro micronucleus (MN) assay and comet assay (CA). Both compounds were tested in the two assays using two cell types (i.e. CHO-K1 and TK6 cells). To evaluate the effect of exposure duration, the genotoxicity of EMS was assessed after 3 and 24 h of exposure. Results were analyzed using the BMD covariate approach, also referred to as BMD potency ranking, and the outcome was compared with that of more traditional statistical methods based on lowest observed genotoxic effect levels. When comparing the in vitro MN results obtained in both cell lines with the BMD covariate approach, a difference in potency was detected only when EMS exposures were conducted for 24 h, with TK6 cells being more sensitive. No difference was observed in the potency of both EMS and aflatoxin B1 in the in vitro CA using both cell lines. In contrast, EMS was more potent after 24 h exposure compared with a 3 h exposure under all tested conditions, i.e. in the in vitro MN assay and CA in both cell lines. Importantly, for several of the investigated factors, the BMD covariate method could not be used to confirm the differences in potencies detected with the traditional statistical methods, thus highlighting the need to evaluate the impact of experimental design factors with adequate approaches.

Background and purpose: Head and neck cancer (HNC) patients experiencing anatomical changes during their radiotherapy (RT) course may benefit from adaptive RT (ART). We investigated the sensitivity of an electronic portal imaging device (EPID)-based in-vivo dosimetry (EIVD) system to detect patients that require ART and identified its limitations. Materials and methods: A retrospective study was conducted for 182 HNC patients: laryngeal cancer without elective lymph nodes (group A), postoperative RT (group B) and primary RT including elective lymph nodes (group C). The effect of anatomical changes on the dose distribution and volumetric changes was quantified. The receiver operating characteristic curve was used to obtain the optimal cut-off value for the gamma passing rate (%GP) with a dose difference of 3% and a distance to agreement of 3 mm. Results: Fifty HNC patients receiving ART were analyzed: 1 in group A, 10 in group B and 39 in group C. Failed fractions (FFs) occurred in 1/1, 6/10 and 23/39 cases before ART in group A, B and C respectively. In the four cases in group B without FFs, only minor dosimetric changes were observed. One of the cases in group C without FFs had significant dosimetric changes (false negative). Three cases received ART because of clinical reasons that cannot be detected by EIVD. The optimal cut-off value for the %GP was 95%/95.2% for old/new generation machines respectively. Conclusion: EIVD combined with 3D imaging techniques can be synergistic in the detection of anatomical changes in HNC patients who benefit from ART.

INTRODUCTION: Minimal invasive Robotic Assisted Cochlear Implant Surgery (RACIS) is a keyhole surgery by definition. It is therefore not possible to visualize the electrode array during insertion in the scala tympani. Hitherto, surgeons visualised the round window via the external auditory canal by folding over the tympanic membrane. However, the opening of a tympanomeatal flap is not minimal invasive and is especially in conventional cochlear implantation surgery not even necessary. Here we prove that image guided and robot assisted surgery can also allow correct electrode array insertion without opening the tympanomeatal flap. AIM: The aim is to report the first experience of robotic cochlear implantation surgery fully based on image guided surgery and without the opening of a tympanomeatal flap for electrode array insertion. INTERVENTION: RACIS with a straight flexible lateral wall electrode. PRIMARY OUTCOME MEASUREMENTS: Electrode cochlear insertion depth with RACIS and autonomous inner ear access withfull electrode insertion of a flexible lateral wall electrode array. SECONDARY OUTCOME MEASUREMENTS: The audiological outcome in terms of mean hearing thresholds. CONCLUSION: After a series of 33 cases and after fine-tuning the insertion angles and yet another new version of planning software to depict the round window approach, a new clinical routine for inserting electrodes fully based on image guided surgery without opening a tympanomeatal flap was developed in robotic-assisted cochlear implant surgery.

AIMS: This systematic review and meta-analysis evaluates the additional effect of exercise to hypocaloric diet on body weight, body composition, glycaemic control and cardio-respiratory fitness in adults with overweight or obesity and type 2 diabetes. METHODS: Embase, Medline, Web of Science and Cochrane Central databases were evaluated, and 11 studies were included. Random-effects meta-analysis was performed on body weight and measures of body composition and glycaemic control, to compare the effect of hypocaloric diet plus exercise with hypocaloric diet alone. RESULTS: Exercise interventions consisted of walking or jogging, cycle ergometer training, football training or resistance training and duration varied from 2 to 52 weeks. Body weight and measures of body composition and glycaemic control decreased during both the combined intervention and hypocaloric diet alone. Mean difference in change of body weight (-0.77 kg [95% CI: -2.03; 0.50]), BMI (-0.34 kg/m 2 [95% CI: -0.73; 0.05]), waist circumference(-1.42 cm [95% CI: -3.84; 1.00]), fat-free mass (-0.18 kg [95% CI: -0.52; 0.17]), fat mass (-1.61 kg [95% CI: -4.42; 1.19]), fasting glucose (+0.14 mmol/L [95% CI: -0.02; 0.30]), HbA 1c (-1 mmol/mol [95% CI: -3; 1], -0.1% [95% CI: -0.2; 0.1]) and HOMA-IR (+0.01 [95% CI: -0.40; 0.42]) was not statistically different between the combined intervention and hypocaloric diet alone. Two studies reported VO 2max and showed significant increases upon the addition of exercise to hypocaloric diet. CONCLUSIONS: Based on limited data, we did not find additional effects of exercise to hypocaloric diet in adults with overweight or obesity and type 2 diabetes on body weight, body composition or glycaemic control, while cardio-respiratory fitness improved.

Heavily calcified arterial lesions are difficult to treat in an endovascular manner with conventional techniques due to limited arterial compliance. Intravascular lithotripsy offers a novel minimally invasive therapeutic option through endovascular emission of acoustic waves, fracturing calcium deposits and facilitating lesion dilation. We present the case of a successful application of the Shockwave intravascular lithotripsy system (IVL®, Shockwave Medical Inc) in a heavily calcified stenosis of the right renal artery in a patient with a coral reef aorta.