Observation of the radiative decay of the 229Th nuclear clock isomer.

The radionuclide thorium-229 features an isomer with an exceptionally low excitation energy that enables direct laser manipulation of nuclear states. It constitutes one of the leading candidates for use in next-generation optical clocks1-3. This nuclear clock will be a unique tool for precise tests of fundamental physics4-9. Whereas indirect experimental evidence for the existence of such an extraordinary nuclear state is substantially older10, the proof of existence has been delivered only recently by observing the isomer's electron conversion decay11. The isomer's excitation energy, nuclear spin and electromagnetic moments, the electron conversion lifetime and a refined energy of the isomer have been measured12-16. In spite of recent progress, the isomer's radiative decay, a key ingredient for the development of a nuclear clock, remained unobserved. Here, we report the detection of the radiative decay of this low-energy isomer in thorium-229 (229mTh). By performing vacuum-ultraviolet spectroscopy of 229mTh incorporated into large-bandgap CaF2 and MgF2 crystals at the ISOLDE facility at CERN, photons of 8.338(24) eV are measured, in agreement with recent measurements14-16 and the uncertainty is decreased by a factor of seven. The half-life of 229mTh embedded in MgF2 is determined to be 670(102) s. The observation of the radiative decay in a large-bandgap crystal has important consequences for the design of a future nuclear clock and the improved uncertainty of the energy eases the search for direct laser excitation of the atomic nucleus.

AsIII Selectively Induces a Disorder-to-Order Transition in the Metalloid Binding Region of the AfArsR Protein.

Arsenic is highly toxic and a significant threat to human health, but certain bacteria have developed defense mechanisms initiated by AsIII binding to AsIII-sensing proteins of the ArsR family. The transcriptional regulator AfArsR responds to AsIII and SbIII by coordinating the metalloids with three cysteines, located in a short sequence of the same monomer chain. Here, we characterize the binding of AsIII and HgII to a model peptide encompassing this fragment of the protein via solution equilibrium and spectroscopic/spectrometric techniques (pH potentiometry, UV, CD, NMR, PAC, EXAFS, and ESI-MS) combined with DFT calculations and MD simulations. Coordination of AsIII changes the peptide structure from a random-coil to a well-defined structure of the complex. A trigonal pyramidal AsS3 binding site is formed with almost exactly the same structure as observed in the crystal structure of the native protein, implying that the peptide possesses all of the features required to mimic the AsIII recognition and response selectivity of AfArsR. Contrary to this, binding of HgII to the peptide does not lead to a well-defined structure of the peptide, and the atoms near the metal binding site are displaced and reoriented in the HgII model. Our model study suggests that structural organization of the metal site by the inducer ion is a key element in the mechanism of the metalloid-selective recognition of this protein.

An in vitro method for inducing titan cells reveals novel features of yeast-to-titan switching in the human fungal pathogen Cryptococcus gattii.

Cryptococcosis is a potentially lethal fungal infection of humans caused by organisms within the Cryptococcus neoformans/gattii species complex. Whilst C. neoformans is a relatively common pathogen of immunocompromised individuals, C. gattii is capable of acting as a primary pathogen of immunocompetent individuals. Within the host, both species undergo morphogenesis to form titan cells: exceptionally large cells that are critical for disease establishment. To date, the induction, defining attributes, and underlying mechanism of titanisation have been mainly characterized in C. neoformans. Here, we report the serendipitous discovery of a simple and robust protocol for in vitro induction of titan cells in C. gattii. Using this in vitro approach, we reveal a remarkably high capacity for titanisation within C. gattii, especially in strains associated with the Pacific Northwest Outbreak, and characterise strain-specific differences within the clade. In particular, this approach demonstrates for the first time that cell size changes, DNA amplification, and budding are not always synchronous during titanisation. Interestingly, however, exhibition of these cell cycle phenotypes was correlated with genes associated with cell cycle progression including CDC11, CLN1, BUB2, and MCM6. Finally, our findings reveal exogenous p-Aminobenzoic acid to be a key inducer of titanisation in this organism. Consequently, this approach offers significant opportunities for future exploration of the underlying mechanism of titanisation in this genus.

Correction: An in vitro method for inducing titan cells reveals novel features of yeast-to-titan switching in the human fungal pathogen Cryptococcus gattii.

[This corrects the article DOI: 10.1371/journal.ppat.1010321.].

Tailored Viral-like Particles as Drivers of Medical Breakthroughs.

Despite the recognized potential of nanoparticles, only a few formulations have progressed to clinical trials, and an even smaller number have been approved by the regulatory authorities and marketed. Virus-like particles (VLPs) have emerged as promising alternatives to conventional nanoparticles due to their safety, biocompatibility, immunogenicity, structural stability, scalability, and versatility. Furthermore, VLPs can be surface-functionalized with small molecules to improve circulation half-life and target specificity. Through the functionalization and coating of VLPs, it is possible to optimize the response properties to a given stimulus, such as heat, pH, an alternating magnetic field, or even enzymes. Surface functionalization can also modulate other properties, such as biocompatibility, stability, and specificity, deeming VLPs as potential vaccine candidates or delivery systems. This review aims to address the different types of surface functionalization of VLPs, highlighting the more recent cutting-edge technologies that have been explored for the design of tailored VLPs, their importance, and their consequent applicability in the medical field.

Lung abscess in a non-compliant patient with Crohn's disease.

A 66-year-old man was admitted to the emergency department due to malaise, fatigue and anorexia for the last 2 weeks. He presented no fever, no respiratory or gastrointestinal symptoms. The patient had been previously diagnosed with Crohn's Disease (CD) (A2L1L4B1 of Montreal Classification) 10 years before, when he presented complaints of watery diarrhea and unexplained weight loss. Despite refusing to start treatment, in the last staging exams performed 5 years before the admission (colonoscopy and magnetic resonance imaging) the patient was in deep remission. Nevertheless, he frequently missed his medical appointments and his disease had not been monitored since then. He denied previous use of corticosteroids, past abdominal surgery or previous CD related hospital admissions. He also denied smoking habits or chronic lung disease.

Pseudomonas aeruginosa increases the susceptibility of Candida albicans to amphotericin B in dual-species biofilms.

BACKGROUND: Biofilms are the leading cause of nosocomial infections and are hard to eradicate due to their inherent antimicrobial resistance. Candida albicans is the leading cause of nosocomial fungal infections and is frequently co-isolated with the bacterium Pseudomonas aeruginosa from biofilms in the cystic fibrosis lung and severe burn wounds. The presence of C. albicans in multispecies biofilms is associated with enhanced antibacterial resistance, which is largely mediated through fungal extracellular carbohydrates sequestering the antibiotics. However, significantly less is known regarding the impact of polymicrobial biofilms on antifungal resistance. RESULTS: Here we show that, in dual-species biofilms, P. aeruginosa enhances the susceptibility of C. albicans to amphotericin B, an effect that was biofilm specific. Transcriptional analysis combined with gene ontology enrichment analysis identified several C. albicans processes associated with oxidative stress to be differentially regulated in dual-species biofilms, suggesting that P. aeruginosa exerts oxidative stress on C. albicans, likely through the secretion of phenazines. However, the mitochondrial superoxide dismutase SOD2 was significantly down-regulated in the presence of P. aeruginosa. Monospecies biofilms of the sod2Δ mutant were more susceptible to amphotericin B, and the susceptibility of these biofilms was further enhanced by exogenous phenazines. CONCLUSIONS: We propose that in dual-species biofilms, P. aeruginosa simultaneously induces mitochondrial oxidative stress, while down-regulating key detoxification enzymes, which prevents C. albicans mounting an appropriate oxidative stress response to amphotericin B, leading to fungal cell death. This work highlights the importance of understanding the impact of polymicrobial interactions on antimicrobial susceptibility.

The HIV-1 Matrix Protein p17 Does Cross the Blood-Brain Barrier.

Human immunodeficiency virus type 1 (HIV-1)-associated neurocognitive disorder (HAND) remains an important neurological manifestation in HIV-1-infected (HIV+) patients. Furthermore, detection of the HIV-1 matrix protein p17 (p17) in the central nervous system (CNS) and its ability to form toxic assemblies in the brain have been recently confirmed. Here, we show for the first time, using both an in vitro blood-brain barrier (BBB) model and in vivo biodistribution studies in healthy mice, that p17 can cross the BBB. There is rapid brain uptake with 0.35% ± 0.19% of injected activity per gram of tissue (IA/g) 2 min after administration, followed by brain accumulation with 0.28% ± 0.09% IA/g after 1 h. The interaction of p17 with chemokine receptor 2 (CXCR2) at the surface of brain endothelial cells triggers transcytosis. The present study supports the hypothesis of a direct role of free p17 in neuronal dysfunction in HAND by demonstrating its intrinsic ability to reach the CNS. IMPORTANCE The percentage of patients affected by HIV-1-associated neurocognitive disorder (HAND) ranges from 30% to 50% of HIV-infected (HIV+) patients. The mechanisms leading to HAND development need to be elucidated, but the roles of secreted viral proteins, chemokines, and proinflammatory molecules appear to be clear. In particular, the blood-brain barrier (BBB) represents a route for entry into the central nervous system (CNS) and thus plays an important role in HAND. Several findings suggest a key role for the HIV-1 matrix protein p17 (p17) as a microenvironmental factor capable of inducing neurocognitive disorders. Here, we show the ability of the p17 to cross the BBB and to reach the CNS, thus playing a crucial role in neuronal dysfunction in HAND.

SKF96365 modulates activity of CatSper channels in human sperm.

Exposure of human sperm to progesterone (P4) activates cation channel of sperm (CatSper) channels, inducing an intracellular Ca2+ concentration ([Ca2+]i) transient followed by repetitive [Ca2+]i activity (oscillations), which are believed to be functionally important. We investigated the potential significance of store-operated Ca2+-entry in these oscillations using the inhibitor SKF96365 (30 µM; SKF). Following pre-treatment of human sperm with 3 µM P4, exposure to SKF doubled the proportion of oscillating cells (P = 0.00004). In non-pre-treated cells, SKF had an effect similar to P4, inducing a [Ca2+]i transient in >80% of cells which was followed by oscillations in ≈50% of cells. The CatSper blocker RU1968 (11 µM) inhibited the SKF-induced [Ca2+]i increase and reversibly arrested [Ca2+]i oscillations. Using whole-cell patch clamp, we observed that SKF enhanced CatSper currents by 100% within 30 s, but amplitude then decayed to levels below control over the next minute. When cells were stimulated with P4, CatSper currents were stably increased (by 200%). Application of SKF then returned current amplitude to control level or less. When sperm were prepared in medium lacking bovine serum albumin (BSA), both P4 and SKF induced a [Ca2+]i transient in >95% of cells but the ability of SKF to induce oscillations was greatly reduced (P = 0.0009). We conclude that SKF, similar to a range of small organic molecules, activates CatSper channels, but that a secondary blocking action also occurs, which was detected only during patch-clamp recording. The failure of SKF to induce oscillations when cells were prepared without BSA emphasizes that the drug does not fully mimic the actions of P4.

Organ damage is a major determinant of work productivity impairment in Behçet's Syndrome: a post-hoc analysis of the BODI validation study.

OBJECTIVES: To evaluate the prevalence, magnitude, and potential determinants of work productivity impairment in patients with Behçet's Syndrome (BS), focusing on the role of irreversible organ damage. METHODS: A post-hoc analysis of the BS overall damage index (BODI) prospective validation study was performed. Demographics and clinical features were recorded in all patients. The Work Productivity and Activity Impairment: General Health (WPAI: GH) questionnaire was administered to assess the work limitation and the BODI to measure organ damage. The independent effect of BS features on WPAI: GH outcomes was evaluated by regression analysis. RESULTS: Out of 148 patients, 34.5% were unemployed, with age (OR 1.035) and BODI score (OR 1.313 for 1-unit increase) as the only factors significantly (p< 0.05) associated with the unemployment state. An overall work impairment was reported in about 64.2% of the employed patients. Indeed, 22.7% reported missing work h due to their health (absenteeism), with a mean time loss of 34.4%; whereas 60.2% declared a reduced performance at work because of their health (presenteeism), with a mean productivity impairment of 45.4%. Ocular damage was associated with absenteeism (ß 0.225); female sex (ß 0.260), physician global assessment of disease activity (ß 0.502) and an increased BODI score (ß 0.166 for 1-point increase) with presenteeism; fibromyalgia (ß 0.246), physician global assessment (ß 0.469), and musculoskeletal damage (ß 0.325) with overall work impairment. CONCLUSIONS: Disease activity and organ damage accrual remarkably affect work productivity in BS patients. Achieving remission and preventing damage accrual are crucial and complementary objectives.

Septorhinoplasty and the Late Impact on Olfactory Function: A Review and Meta-analysis.

Septorhinoplasty (SRP) is one of the most commonly performed procedures worldwide. There is a recognized debate about the impact of nasal surgery on olfactory function (OF). The study's objective was to assess the effect of SRP on late postoperative OF. A comprehensive review and meta-analysis were employed to assess OF after SRP. All the integrated studies used objective instruments to quantify OF before and after surgery. A literature search was conducted, and the selected works were evaluated, computed, and finally included in a meta-analysis. The risk of bias was assessed using the NIH Guidance for Evaluating the Quality of Before-After (Pre-Post) Studies with No Control Group. Only the latest follow-up OF measurements provided by each research were considered in the analysis. The 95% confidence interval of the effect magnitude for each study was calculated to elucidate effect sizes. Eleven studies were included in the analysis. Five studies reported late OF improvement (45.5%), five reported no alteration in OF (45.5%), and only one study reported OF impairment after SRP (9%). Some works described a transitory decline in OF shortly following surgery, followed by postoperative improvement. A pooled meta-analysis showed that OF was not significantly altered after SRP (p = 0.10) in the late follow-up. SRP surgery seems to constitute a safe procedure concerning OF in the long term. According to research, OF may deteriorate temporarily after surgery with later improvement, sometimes to higher values than baseline. The anticipated evolution of OF after intervention could be discussed during the preoperative consultation for SRP.

A full hemostatic repertoire in a complex cirrhotic patient.

A 55-year-old woman with cirrhosis was admitted for acute decompensation caused by portal vein thrombosis. Ten days later, the patient presented melena. Esophagogastroscopy revealed two gastric polyps, both with bleeding stigmata. One of the polyps was removed with a diathermic loop, after adrenalin injection, while in the other the "ligate and let go" technique was applied, after biopsy. A "metallic tulip-bundle" technique, combining through the scope and over-the-scope clips, was applied for hemostasis. This case underlines how the combination of various endoscopic techniques may be useful to manage upper gastrointestinal bleeding, especially in patients with important comorbidities.

Hemostasis of a bleeding inverted colonic diverticulum.

The authors report a case of a 62-year-old male presenting to the emergency department with hematochezia. Urgent colonoscopy revealed numerous diverticula in the sigmoid colon, two of them inverted. Oozing bleeding from a visible vessel was identified on the top of the most distal inverted diverticulum. An over-the-scope clip was released after suction into the transparent cap and successful hemostasis was achieved.

Endoscopic "purse-string" to close a rectal endoscopic submucosal dissection eschar with intentional muscular sectioning.

This case demonstrates the utility of the "purse string" to close large defects and shows that optical diagnosis may have pitfalls in evaluating the invasion of neoplastic lesions, particularly large ones.

Forecast models to predict the demand for endoscopic procedures in a tertiary unit: a prospective validation.

Over the past few decades, there has been an exponential increase in the utilization of endoscopic procedures. Accurately predicting the demand is crucial for effective capacity planning and resource allocation in the endoscopic unit. However, predictive models are not integrated into current endoscopy software. To overcome this limitation, our group used data on the demand in our tertiary unit from 2015 to 2021 (83 months) to develop forecast models using exponential smoothing techniques adjusted for trend and seasonality (derivation phase). These models were recently published at the Revista Española de Enfermedades Digestivas.

Effective submucosal tunneling endoscopic resection (STER) of a giant esophageal leiomyoma.

We report the successful removal of a giant esophageal leiomyoma using submucosal tunneling endoscopic resection in a 37-year-old woman with significant dysphagia.

Are sarcopenia, frailty and malnutrition prognostic markers of liver disease decompensation in the ambulatory setting? - A prospective cohort study.

BACKGROUND: Sarcopenia, frailty and malnutrition are associated with adverse outcomes in liver cirrhosis. Studies assessing the prognostic value of these conditions in ambulatory patients with cirrhosis are scarce. METHODS: A prospective cohort study was conducted, with consecutive inclusion of all patients with cirrhosis observed in the Hepatology outpatient clinic of a Portuguese tertiary centre. At study enrolment, evaluation of muscle mass (ultrasound quadriceps femoris thickness), muscle strength (handgrip dynamometry) and nutritional status (Patient-Generated Subjective Global Assessment Short Form) was held. Follow-up ended upon the occurrence of a composite endpoint, comprising liver decompensation events and liver-related death, or last medical appointment/non-liver related death before the end of the study. The prognostic value of anthropometrical parameters and nutritional status in the composite endpoint was assessed using a multivariate Cox regression analysis, adjusted for several confounders. RESULTS: Ninety patients were enrolled (80% male), with a mean age of 63.5±10.5 years. The median follow-up was 30 (interquartile range 38) weeks, during which 12 patients reached the composite endpoint. These patients presented a lower mean handgrip strength [23.1±6.41 vs 30.3±10.4 Kg, p=0.04], compared to patients who did not reach the composite endpoint. On Cox regression multivariate analysis, however, no independent predictors of the composite endpoint were found, apart from previous decompensation episodes. CONCLUSION: In this study, muscle strength was lower in the group of patients with cirrhosis who presented a liver-related event. Handgrip strength might be a promising tool in the ambulatory setting to identify patients at risk of liver decompensation and liver-related death in the short term.

Diagnostic and therapeutic yields of early capsule endoscopy and device-assisted enteroscopy in the setting of overt GI bleeding: a systematic review with meta-analysis.

BACKGROUND AND AIMS: Small-bowel capsule endoscopy (SBCE) and device-assisted enteroscopy (DAE) are essential in obscure GI bleeding (OGIB) management. However, the best timing for such procedures remains unknown. This meta-analysis aimed to compare, for the first time, diagnostic and therapeutic yields, detection of active bleeding and vascular lesions, recurrent bleeding, and mortality of "early" versus "nonearly" SBCE and DAE. METHODS: MEDLINE, ScienceDirect, and Cochrane Central Register of Controlled Trials were searched to identify studies comparing early versus nonearly SBCE and DAE. Random-effects meta-analysis was performed; reporting quality was assessed. RESULTS: From 1974 records, 39 were included (4825 patients). Time intervals for the early approach varied, within 14 days in SBCE and 72 hours in DAE. The pooled diagnostic and therapeutic yields of early DAE were superior to those of SBCE (7.97% and 20.89%, respectively; P < .05). The odds for active bleeding (odds ratio [OR], 5.09; I2 = 53%), positive diagnosis (OR, 3.99; I2 = 45%), and therapeutic intervention (OR, 3.86; I2 = 67%) were higher in the early group for SBCE and DAE (P < .01). Subgroup effects in diagnostic yield were only identified for the early group sample size. Our study failed to identify differences when studies were classified according to time intervals for early DAE (I2 < 5%), but the analysis was limited because of a lack of data availability. Lower recurrent bleeding in early SBCE and DAE was observed (OR, .40; P < .01; I2 = 0%). CONCLUSIONS: The role of small-bowel studies in the early evaluation of OGIB is unquestionable, impacting diagnosis, therapeutic intervention, and prognosis. Comparative studies are still needed to identify optimal timing.

Gastroesophageal Reflux Disease Diagnosis by New Consensus in Clinical Practice: The Additional Value of Mean Basal Impedance.

BACKGROUND: Recently, Lyon consensus and ROME IV were published as there was a need to create a more objective evaluation for gastroesophageal reflux disease (GERD) in order to better predict treatment outcomes. However, with classical pH-impedance measures, some patients would still have diagnostic uncertainty, and new metrics, such as mean nocturnal basal impedance (MNBI), have emerged to corroborate with GERD diagnosis. The aim of the present study was to describe the prevalence of GERD, functional heartburn (FH), reflux hypersensitivity (RH), and undetermined diagnosis using current consensuses and to evaluate if MNBI could be considered a supportive measure for the diagnosis of GERD. METHODS: Patients who underwent pH-multichannel intraluminal impedance (MII-pH) for suspected GERD between 2013 and 2018 were included. Subjects with previous diagnosis of GERD (e.g., esophagitis grade C or D according to Los Angeles classification, Barrett's esophagus, or peptic stricture), atypical symptoms, major esophageal motor disorder, eosinophilic esophagitis, or under proton pump inhibitor were excluded from the analysis. RESULTS: We included 75 patients. The prevalence of GERD, FH, RH and undetermined diagnosis was 44%, 14.7%, 12%, and 29.3%, respectively. MNBI was lower in patients with GERD (GERD: 1,307.5 ± 817.9 Ω vs. FH: 3,039.6 ± 1,040.8 Ω, RH: 2,617.1 ± 1,342.2 Ω, undetermined: 2,351.9 ± 1,018.2, p < 0.001), although it was similar between patients with FH and RH (p = 0.44) or between undetermined diagnosis and FH/RH (p = 0.15). More patients with a GERD diagnosis had a MNBI under 2,292 Ω (GERD: 93.9% vs. non-GERD: 31.7%, p < 0.001). CONCLUSION: In our study, using MII-pH criteria, less than half of the patients had a GERD diagnosis. MNBI showed additional value as another metric for the diagnosis of GERD.

Safe urodynamic practices in times of COVID-19: What can be accomplished and what can be added?

AIM: To present feedback, after applying national and international urodynamic study (UDS) recommendations for safe practice during the COVID-19 pandemic. METHODS: We created a checklist to assess the feasibility of performing UDS recommendations for safe practice during the COVID-19 pandemic from the first week of May 2021 to the last week of July 2021. RESULTS: One hundred patients were analyzed during the study period. We observed that all preventive recommendations for the steps that precede UDS could be followed in full. However, some guidelines for performing the exam were not feasible in all patients. We have successfully adopted other safety measures for all patients. CONCLUSIONS: The COVID-19 pandemic will likely persist for several more years. We believe that continuous improvement, revision, and updating of existing protocols and guidelines for the safe practice of UDS in times of COVID-19, as we propose in this study, should be encouraged.