Aim To evaluate the number and nature of reported congenital malformations (CMs) after intrauterine exposure to non-tumour necrosis factor inhibitors (non-TNFis) compared to certolizumab pegol (CZP) Material and methods A retrospective comparative study was conducted in the EudraVigilance (EV) database. EV is a pharmacovigilance database, which can be used for detecting safety signals and generating hypotheses on possible relations between drugs and adverse events. A supposedly safe biologic (CZP) was considered as the reference group. Pregnancy-reports of non-TNFis and CZP were extracted. Odds ratios (ORs) for CMs were calculated for each non-TNFi, versus CZP (quantitative assessment). Then, CM patterns were compared to CZP in consultation with a clinical geneticist (qualitative assessment). Results ORs were not statistically significant except for belimumab and vedolizumab (similar in magnitude). Although qualitative analyses did not show any specific patterns for belimumab but three cases of corpus callosum agenesis (CCA) were identified for vedolizumab (versus null in CZP and other investigated non-TNFis). Two of the CCA cases were associated with other neurological CMs (one cerebral ventriculomegaly with microcephaly and one polymicrogyria). This may indicate that these CCAs are related to undiagnosed genetic alterations or are associated with the underlying maternal disease, although a definite relationship with vedolizumab exposure cannot be ruled out. Conclusion No special safety signal was identified regarding the occurrence of CMs after exposure to non-TNFis, except for vedolizumab. Based on available information, no firm conclusions can be made regarding observed CCAs in the vedolizumab group (it warrants further research)

Primary yolk sac tumor of the liver is very rare and can present as multifocal liver lesions. Multifocal nature may mimic other diagnoses such as hepatocellular carcinoma. Early recognition and therapeutic intervention are important as the prognosis of metastatic yolk sac tumors is poor.

Allergic diseases are allergen-induced immunological disorders characterized by the development of type 2 immunity and IgE responses. The prevalence of allergic diseases has been on the rise alike cardiovascular disease (CVD), which affects arteries of different organs such as the heart, the kidney and the brain. The underlying cause of CVD is often atherosclerosis, a disease distinguished by endothelial dysfunction, fibrofatty material accumulation in the intima of the artery wall, smooth muscle cell proliferation, and Th1 inflammation. The opposed T-cell identity of allergy and atherosclerosis implies an atheroprotective role for Th2 cells by counteracting Th1 responses. Yet, the clinical association between allergic disease and CVD argues against it. Within, we review different phases of allergic pathology, basic immunological mechanisms of atherosclerosis and the clinical association between allergic diseases (particularly asthma, atopic dermatitis, allergic rhinitis and food allergy) and CVD. Then, we discuss atherogenic mechanisms of type 2 immunity and allergic inflammation including acute allergic reactions (IgE, IgG1, mast cells, macrophages and allergic mediators such as vasoactive components, growth factors and those derived from the complement, contact and coagulation systems) and late phase inflammation (Th2 cells, eosinophils, type 2 innate-like lymphoid cells, alarmins, IL-4, IL-5, IL-9, IL-13 and IL-17).

Fast gadolinium-based contrast agent challenge test searching for an alternative contrast mediaTo the Editor,Gadolinium-based contrast agents (GBCA) are used in contrast-enhanced magnetic resonance imaging. Hypersensitivity reactions (HSR) to GBCA are scarce, with an incidence of 0.07% and a recurrence rate of 30%, being urticaria the most common presentation (91%), with 0.52/10000 of severe reactions reported1. Recommendation of an alternative GBCA without checking tolerance is dangerous, due to high cross-reactivity between them2. Moreover, premedication is not enough1, showing an overall rate of breakthrough reactions of 39%3.Allergy studies to achieve a safe recommendation in HSR to GBCA have been performed. Negative predictive value of skin-tests to GBCA has been estimated in 84%1. Therefore, more than 10% of patients could react using an alternative negative skin-tested GBCA, and thus, good tolerance to GBCA should be confirmed through a drug challenge-test (DCT)4. These tests are usually performed at graded administrations, and with observation periods between doses1,5. However, since GBCA is usually given as a bolus during radiologic exams, DCT at slow rates cannot be extrapolated to further administrations. Trying to avoid this limitation, we study the tolerance of an alternative GBCA, by means of a fast DCT, approaching the infusion rates used in clinical practice.In accordance with the safety warnings to avoid linear GBCA, we have only used the macrocyclic drugs gadobutrol (Gb) and gadoteric acid (Ga). After obtaining signed informed consent from the patients, skin pricktests (SPT) with undiluted macrocyclic GBCA commercial solutions were done. When SPT at 20 min yielded negative results, intradermal tests (IDT) with 1:10 dilutions were performed, with subsequent readings at both 20 min and 24 hours.A fast DCT with negative skin-tested GBCA was then performed, following our methodology to study HSR to iodinated contrast media, previously described elsewhere6. Doses were 0.2 mg/kg for Ga and 0.1 mg/kg for Gb. First, one third of the total dose of Ga was administered at a rate of 120 cc/hour and, immediately after, the remaining 2/3 at 80 cc/hour. In case of Gb, infusion rates were half those of Ga, i.e., 1/3 at 60 cc/hour and 2/3 at 40 cc/hour. Total infusion time was 8 minutes for both of them. Well-tolerated GBCA was finally recommended for subsequent examinations, and its tolerance was recorded if it was used later.Study results of sixteen patients that were enrolled are summarized in Table 1. They were 12 women and 4 men, with median age of 45.5 years (range 28-73). Adverse reactions to GBCA were immediate in 13 patients (12 urticaria or exanthema, and 1 anaphylaxis), and delayed exanthema in the remaining 3. Gb was involved in 11 reactions, and unknown GBCA in the other 5. Most of the patients (14/16) had been previously exposed to GBCA.Median delay to perform the allergy study was 10 months (range 2-72 months). All skin-tests were negative, except in one patient who showed an immediate positive SPT to Gb, which had been the GBCA involved in the adverse reaction. In our study, we have estimated a negative predictive value of skintests to GBCA of 89%. DCT were negative in 14 patients (12 with Ga, and 2 with Gb). Finally, 15 out of 16 patients had an alternative GBCA, avoiding the use of premedication. In fact, tolerance has been confirmed in 7 of them in subsequent examinations.Safety of our protocol has been confirmed because our 2 positive DCT showed only mild reactions (delayed exanthema and immediate urticarial, both with Ga), and also by including a patient with previous anaphylaxis to GBCA.Here we present a prospective protocol to identify a safe alternative GBCA, including DCT at high infusion rates. Further studies will be necessary on this item/to check this.

This is an invited commentary. I did not think abstracts were required for commentaries.

Background and Purpose: New remedies are required for the treatment of diabetic neuropathic pain (DNP) due to insufficient efficacy of available therapies. Here, we used chemogenetic approaches combined with in vivo pharmacology to elucidate the role of BLA astrocytes in DNP pathogenesis and provide new insights into DNP therapeutic strategies. Experimental Approach: A streptozotocin-induced DNP model was established. Designer receptors exclusively activated by designer drugs (DREADDs) were used to regulate the activity of astrocytes. Mechanical hyperalgesia was assessed using the electronic von Frey test. Anxiety-like behaviors were detected by open field and elevated plus maze tests. Astrocytic activity was detected by immunofluorescence, and cytokine content was determined by ELISA. Key Results: BLA astrocytes were regulated by DREADDs, and inhibition of BLA astrocytes attenuated mechanical allodynia and anxiety-like behavior in DNP rats. Contrastively, temporary activation of BLA astrocytes induced allodynia without anxious behavior in naive rats. In addition, we found that koumine alleviates mechanical allodynia and anxiety-like behavior in DNP rats, inhibits the activation of BLA astrocytes and suppresses the inflammatory response. Furthermore, persistent activation of BLA astrocytes by chemogenetic mimics chronic pain, and koumine can alleviate its pain hypersensitivity and anxiety-like behavior. Conclusion and Implications: DREADDs bidirectionally regulate the activity of BLA astrocytes, which proves for the first time the role of BLA astrocytes activation in the pathogenesis of DNP and represents a novel therapeutic strategy for DNP. Koumine ameliorated DNP, perhaps by inhibiting the activation of BLA astrocytes and reveal KM as a potential candidate for treating DNP.

BACKGROUND: Rhabdomyosarcoma (RMS) is an aggressive malignancy, and 20% of children present with metastases at diagnosis. Patients presenting with disseminated disease very occasionally have no clear evidence of a primary tumor mass. Since these patients have rarely been investigated, we report on a series of patients with RMS and unknown primary tumor site registered in the MTS 2008 protocol (October 2008 - December 2016) coordinated by the European pediatric Soft tissue sarcoma Study Group. METHODS: Patients were administered 9 cycles of induction chemotherapy, and 48 weeks of maintenance chemotherapy. Surgery and/or radiotherapy was planned after the first assessment of tumor response, and implemented after six cycles of chemotherapy. If feasible, radiotherapy to all sites of metastasis was recommended. RESULTS: We identified 10 patients with RMS and unknown primary site, most of them adolescents (median age 15.8 years, range 4.6-20.4). Nine had fusion-positive alveolar RMS. Multiple organ involvement was identified in 7 patients, 2 only had bone marrow disease, and 1 only had leptomeningeal dissemination. All patients were given chemotherapy, 4 were irradiated, and none had surgery. Three patients underwent allogeneic bone marrow transplantation. At the time of this analysis, only 2 patients are alive in complete remission: 1 had received radiotherapy; and 1 had a bone marrow transplant. CONCLUSIONS: RMS with unknown primary tumor occurs mainly in adolescents and is typically fusion-positive alveolar. Radiotherapy may be important, but survival is poor and patients should be offered enrollment in investigational trials.

This is an invited commentary and does not need a commentary.

By taking Sugeno-derivative into account, firstly, we investigate the existence of solutions to the initial value problems (IVP) of first-order differential equations with respect to non-additive measure (more precisely, distorted Lebesgue measure). It particularly occurs in the mathematical modeling of biology. We begin by expressing the differential equation in terms of ordinary derivative and the derivative with respect to the distorted Lebesgue measure. Then, by using the fixed point theorem on cones, we construct an operator and prove the existence of positive increasing solutions on cones in semi-order Banach spaces. In addition, we also use Picard’s-Lindel\”of theorem to prove the existence and uniqueness of the solution of the equation. Second, we investigate the existence of a solution to the boundary value problem (BVP) on cones with integral boundary conditions of a mix-order differential equation with respect to non-additive measures. Moreover, the Krasnoselskii fixed point theorem is also applied to both BVP and IVP and obtains at least one positive increasing solution. Examples with graphs are provided to validate the results.

Calcium (Ca 2+) is an important second messenger in plants. The activation of Ca 2+ signaling cascades is critical in the activation of adaptive processes in response to perceived environmental stimuli, including biotic stresses. The colonization of roots by the plant growth promoting endophyte Serendipita indica involves the increase of cytosolic Ca 2+ levels in Arabidopsis thaliana. In this study, we investigated transcriptional changes in Arabidopsis roots during symbiosis with S. indica. RNA-seq profiling disclosed the significant induction of CALCINEURIN B-LIKE 7 ( CBL7) during early- and later phases of the interaction. Consistent with the transcriptomics analysis, reverse genetic evidence and yeast two-hybrid studies highlighted the functional relevance of CBL7 and tested the involvement of a CBL7-CBL-INTERACTING PROTEIN KINASE 13 (CIPK13) signaling pathway in the establishment of the mutualistic relationship that promotes plant growth. The loss-of-function of CBL7 abolished the growth promoting effect of S. indica and affected the colonization of the root by the fungus. The subsequent transcriptomics analysis of cbl7 revealed the involvement of this Ca 2+ sensor in activating plant defense responses. Furthermore, we report on the contribution of CBL7 to potassium transport in Arabidopsis. Triggered by the differential expression of a small number of K + channels/transporter genes, we analyzed K + contents in wild-type and cbl7 plants and observed a significant accumulation of K + in root of cbl7 plants, while shoot tissues demonstrated K + depletion. Taken together, our work associates CBL7 with an important role in the mutual interaction between Arabidopsis and S. indica and links the CBL7 Ca 2+ receptor protein to K + transport.

Infections with Tuberculosis (TB)-causing agents of the Mycobacterium tuberculosis complex threaten human, livestock, and wildlife health globally due to the high capacity to cross trans-species boundaries. Tuberculosis is a cryptic disease characterized by prolonged, sometimes lifelong subclinical infections, complicating disease monitoring. Consequently, our understanding of infection risk, disease progression, and mortality across species affected by TB remains limited. The TB agent Mycobacterium suricattae was first recorded in the late 1990s in a wild population of meerkats inhabiting the Kalahari in South Africa and has since spread considerably, becoming a common cause of meerkat mortality. This offers an opportunity to document the epidemiology of naturally spreading TB in a wild population. Here, we synthesize more than 25 years-worth of TB reporting and social interaction data across 3,420 individuals to track disease spread, and quantify rates of TB social exposure, progression, and mortality. We found that most meerkats had been exposed to the pathogen within eight years of first detection in the study area, with exposure reaching up to 95% of the population. Approximately one quarter of exposed individuals progressed to clinical TB stages, followed by physical deterioration and death within a few months. Since emergence, 11.6% of deaths were attributed to TB, although the true toll of TB-related mortality is likely higher. Lastly, we observed marked variation in disease progression among individuals, suggesting inter-individual differences in both TB susceptibility and resistance. Our results highlight that TB prevalence and mortality could be higher than previously reported, particularly in species or populations with complex social group dynamics. Long-term studies, such as the present one, allow us to assess temporal variation in disease prevalence and progression and quantify exposure, which is rarely measured in wildlife. Long-term studies are highly valuable tools to explore disease emergence and ecology, and study host-pathogen co-evolutionary dynamics in general, and its impact on social mammals.

Understanding ageing and the diversity of life histories is a cornerstone in biology. Telomeres, the protecting caps of chromosomes, are thought to be involved in ageing, cancer risks and to modulate life-history strategies. They shorten with cell division and age in somatic tissues of most species, possibly limiting lifespan. The resource allocation trade-off hypothesis predicts that short telomeres have thus co-evolved with early reproduction, proactive behaviour and reduced lifespan: a fast Pace-of-Life Syndrome (POLS). Conversely, since short telomeres may also reduce the risks of cancer, the anti-cancer hypothesis advances that they should be associated with slow POLS. Conclusion on which hypothesis best supports the role of telomeres as mediators of life-history strategies is hampered by a lack of study on wild short-lived vertebrates, apart from birds. Using seven years of data on wild Eastern chipmunks Tamias striatus, we highlighted that telomeres elongate with age and do not limit lifespan in this species. Furthermore, short telomeres correlated with a slow POLS in a sex-specific way. Females with short telomeres had a delayed age at first breeding and a lower fecundity rate than females with long telomeres, whereas those differences were not recorded in males. Our findings support most predictions adapted from the anti-cancer hypothesis, but none of those made under the resource allocation trade-off hypothesis. Results are in line with an increasing body of evidence suggesting that other evolutionary forces than resource allocation trade-offs shape the diversity of telomere length in adult somatic cells and the relationships between telomeres and life-histories.

Background: The Omicron (lineage B.1.1.529) variant of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) was first reported in Wales, UK on 3rd December 2021. The aim of the study was to describe the first 1000 cases of the Omicron variant by demographic, vaccination status, travel and severe outcome status and compare this to contemporaneous cases of the Delta variant. Methods: Testing, typing and contact tracing data were collected by Public Health Wales and analysis undertaken by the Communicable Disease Surveillance Centre (CDSC). Risk ratios for demographic factors and symptoms were calculated comparing Omicron cases to Delta cases identified over the same time period. Results: By 14th December 2021, 1000 cases of the Omicron variant had been identified in Wales. Of the first 1000, just 3% of cases had a prior history of travel revealing rapid community transmission. A higher proportion of Omicron cases were identified in individuals aged 20-39 and most cases were double vaccinated (65.9%) or boosted (15.7%). Age adjusted analysis also revealed that Omicron cases were less likely to be hospitalised (0.4%) or report symptoms (60.8%). Specifically a significant reduction was observed in the proportion of Omicron cases reporting anosmia (8.9%). Conclusion: Key findings include a lower risk of anosmia and a reduced risk of hospitalisation in the first 1000 Omicron cases compared to co-circulating Delta cases. We also identify that existing measures for travel restrictions to control importations of new variants identified outside the UK did not prevent the rapid ingress of Omicron within Wales.

Although sporadic Creutzfeldt Jakob disease is always fatal and no accepted treatment is currently available. Moreover, prevalence of COVID-19 in the same patient makes management protocol difficult and prognosis worse.

Aim: Although there is a high risk of gastrointestinal (GI) bleeding in the elderly, few studies have quantified the impact of risk factors on GI complications in elderly nonsteroidal anti-inflammatory drug (NSAID) users. This study aimed to develop and validate a risk prediction score to identify high-risk elderly patients using NSAID for severe GI complications. Methods: We used the following two Korean claims datasets: customized data with an enrollment period 2016–2017 for model development, and the sample data in 2019 for external validation. We conducted a nested case-control study for model development and validation. NSAID users were identified as the elderly (≥ 65 years) who received NSAIDs for more than 30 days. Patients who experienced serious GI complications, defined as hospitalizations or emergency department visits, were diagnosed with GI bleeding or perforation. We derived a model using logistic regression and cross-validation. Results: In the external validation cohort, we identified 372 cases from 254,551 patients. We identified 8,176 cases and 81,760 controls with a 1:10 matched follow-up period in the derivation cohort. In the external validation cohort, we identified 372 cases from 254,551 patients. The risk predictors were high-dose NSAIDs, NSAID type, complicated GI ulcer history, male sex, concomitant gastroprotective agents, relevant co-medications, severe renal disease, and cirrhosis. Area under the receiver operating characteristic curves was 0.77 (95% confidence interval, 0.75–0.80) in the external validation dataset. Conclusion: The prediction model may be a useful tool for reducing the risk of serious GI complications by identifying high-risk elderly patients.

Myocardial wall thickness is one of the crucial parameters affecting the lesion formation produced by radiofrequency current (RF) delivering. Knowing the tissue characterization is critical for improving the durability of the RF lesion. A novel dielectric based method (KODEX-EPD) has been developed for measuring the tissue thickness at the catheter-tissue interface. The authors of this study report for the first time the tissue characterization (i.e. atrial wall thickness) of the cavo-tricuspid isthmus in a series of patients undergoing common atrial flutter ablation, showing a higher thickness close to the tricuspid valve as compared to the inferior vena cava. This can affect the outcome of ablation

Lipschütz’s ulcers (LU) are rare entities, which occur mostly in non-sexually active young women. UL appear to be associated with infectious conditions such as Epstein-Barr virus or cytomegalovirus. We report a case that revealed that SARS-CoV-2 infection could be considered a trigger event for the appearance of acute vulvar ulceration.

To report two cases of suprachoroidal hemorrhage (SCH) during otherwise uncomplicated phacoemulsification, in whom COVID-19 was documented with PCR about one month before the surgery.