Pharmacodynamic, prognostic, and predictive biomarkers in severe and critical COVID-19 patients treated with sirukumab.

We examined candidate biomarkers for efficacy outcomes in hospitalized COVID-19 patients who were treated with sirukumab, an IL-6 neutralizing antibody, in a randomized, double-blind, placebo-controlled, phase 2 trial. Between May 2020 and March 2021, 209 patients were randomized (sirukumab, n = 139; placebo, n = 70); 112 had critical COVID-19. Serum biomarkers were evaluated for the pharmacodynamic effect of sirukumab and for their potential prognostic and predictive effect on time to sustained clinical improvement up to Day 28, clinical improvement at Day 28, and mortality at Day 28. The absence of detectable IL-4 increase and smaller increases in CCL13 post-baseline were most significantly associated with better response to sirukumab (versus placebo) treatment for all clinical efficacy outcomes tested, especially in patients with critical COVID-19. These data suggest that patients with critical COVID-19 without detectable sirukumab-induced IL-4 levels are more likely to benefit from sirukumab treatment. ClinicalTrials.gov Identifier: NCT04380961.

Perspectives of non-physician partners on barriers and facilitators to AYA cancer care in Latin America.

BACKGROUND: Cancer is the fourth leading cause of death in adolescents and young adults (AYA) worldwide. Although successful treatment of cancer in AYA has increased in recent years in most of the world, this is not true for many low- and middle-income countries (LMIC) where over 80% of all AYA live. This study investigated the needs of AYA with cancer in parts of Latin America (LATAM) through the perspectives of non-physician health care providers and partners. METHODS: Semi-structured interviews (in Spanish) were conducted with non-physician partners from Mexico, Peru, Central America, and the Caribbean over Zoom. Participants were recruited through previously identified local physicians and international non-physician professionals working in these countries. Transcripts were coded and key themes identified until thematic saturation was reached (Atlas.ti). FINDINGS: Thirty participants representing eight countries were interviewed, providing 1202 min of transcript data. Data were organized into barriers, facilitators, and strategies to improve the delivery of health care for AYA with cancer in LATAM at the patient- (e.g., financial barriers, continued schooling), parent- (e.g., limited medical literacy, advocacy), and hospital-level (e.g., structural barriers, increasing funding). INTERPRETATION: There are many similarities in the barriers and facilitators to AYA care between LATAM and high-income countries (HIC); however, some characteristics are more unique to LATAM, for example, strict age restrictions for pediatric care and abandonment of therapy. As LATAM countries continue to build cancer control programs, there is an opportunity to consider our identified barriers, facilitators, and strategies to address the unique needs of AYA with cancer.

Cerebral salt wasting syndrome in a child with central diabetes insipidus following surgery for recurrent craniopharyngioma: A case report.

Surgical treatment of craniopharyngiomas in children can produce disorders related to water and sodium such as central diabetes insipidus (CDI) and cerebral salt wasting syndrome (CSWS). The combination of both in children is unusually reported in the literature and is associated with high mortality. The management of CSWS is based on fluid therapy. Fludrocortisone is useful in children with CSWS who do not respond to fluid management. The objective of the paper is to describe the case of 6 years and 10 months old male child with hypopituitarism secondary to a craniopharyngioma surgery performed 7 months before, who presented to the emergency department due to recurrent craniopharyngioma. The child presented a combination of CDI and CSWS following surgery for this recurrent tumor. Therapy with fludrocortisone was effective. Pediatric patients as the one of this report can help build the foundation for subsequent systematic reviews or trials.

Loss of biochemical response at any time worsens outcomes in UDCA-treated patients with primary biliary cholangitis.

Background & Aims: Biochemical response to ursodeoxycholic acid (UDCA) therapy is associated with good prognosis in people living with primary biliary cholangitis (PBC). Biochemical response is typically assessed early in disease and it is not known what proportion of patients lose previously attained biochemical response, nor whether this impacts long-term liver transplant (LT)-free survival. Methods: We identified all UDCA-treated patients with PBC from the Canadian Network for Autoimmune Liver disease with biochemical measurements at 1 year, and evaluated their liver biochemistry over time. Inadequate biochemical response was defined as serum alkaline phosphatase ≥1.67x the upper limit of normal or abnormal serum total bilirubin at 1 year of UDCA therapy and all time points thereafter. Multistate Markov models were used to estimate transition rates between biochemical response states and from each state to LT or death. Results were validated in an external cohort (GLOBAL PBC registry). Results: A total of 823 patients from eight centers were included. Mean age at diagnosis was 53 years, 91% were female, 33% had inadequate biochemical response to UDCA at 1 year (n = 269). Patients who retained initial adequate response had lower rates of LT or death compared to patients who subsequently lost response (relative rate 0.102, 95% CI 0.047-0.223). Patients who regained adequate response had lower rates than patients who did not (0.016, 95% CI 0.001-0.568), and patients who lost response once more (0.010, 95% CI 0.001-0.340). Patients who regained adequate response for a third time also had lower rates than patients who did not (0.151, 95% CI 0.040-0.566). Analyses in the GLOBAL PBC registry (n = 2,237) validated these results. Conclusion: Loss of biochemical response at any time is associated with heightened risks of LT or death in people living with PBC. Achievement of biochemical response is an important goal throughout follow-up, regardless of biochemical response profile early in therapy. Impact and implications: Early biochemical response to ursodeoxycholic acid is associated with good prognosis in patients with primary biliary cholangitis (PBC). Our work demonstrates that patients with PBC transition between biochemical response states over time, and that these transitions correspond with changes in risk of liver transplantation or death. Clinicians should re-evaluate risk and optimize treatment decisions for patients with PBC throughout follow-up, regardless of early biochemical response to therapy.

Stability and suitability of housekeeping genes in phlebotomine sand flies.

We investigated gene expression patterns in Lutzomyia and Phlebotomus sand fly vectors of leishmaniases. Using quantitative PCR, we assessed the expression stability of potential endogenous control genes commonly used in dipterans. We analyzed Lutzomyia longipalpis and Phlebotomus papatasi samples from L3 and L4 larval stages, adult sand flies of different sexes, diets, dsRNA injection, and Leishmania infection. Six genes were evaluated: actin, α-tubulin, GAPDH, 60 S ribosomal proteins L8 and L32 (RiboL8 and RiboL32), and elongation factor 1-α (EF1-α). EF1-α was among the most stably expressed along with RiboL8 in L. longipalpis larvae and RiboL32 in adults. In P. papatasi, EF1-α and RiboL32 were the top in larvae, while EF1-α and actin were the most stable in adults. RiboL8 and actin were the most stable genes in dissected tissues and infected guts. Additionally, five primer pairs designed for L. longipalpis or P. papatasi were effective in PCR with Lutzomyia migonei, Phlebotomus duboscqi, Phlebotomus perniciosus, and Sergentomyia schwetzi cDNA. Furthermore, L. longipalpis RiboL32 and P. papatasi α-tubulin primers were suitable for qPCR with cDNA from the other four species. Our research provides tools to enhance relative gene expression studies in sand flies, facilitating the selection of endogenous control for qPCR.

Graphene-based microelectrodes with bidirectional functionality for next-generation retinal electronic interfaces.

Neuroelectronic prostheses are being developed for restoring vision at the retinal level in patients who have lost their sight due to photoreceptor loss. The core component of these devices is the electrode array, which enables interfacing with retinal neurons. Generating the perception of meaningful images requires high-density microelectrode arrays (MEAs) capable of precisely activating targeted retinal neurons. Achieving this precision necessitates the downscaling of electrodes to micrometer dimensions. However, miniaturization increases electrode impedance, which poses challenges by limiting the amount of current that can be delivered, thereby impairing the electrode's capability for effective neural modulation. Additionally, it elevates noise levels, reducing the signal quality of the recorded neural activity. This report focuses on evaluating reduced graphene oxide (rGO) based devices for interfacing with the retina, showcasing their potential in vision restoration. Our findings reveal low impedance and high charge injection limit for microscale rGO electrodes, confirming their suitability for developing next-generation high-density retinal devices. We successfully demonstrated bidirectional interfacing with cell cultures and explanted retinal tissue, enabling the identification and modulation of multiple cells' activity. Additionally, calcium imaging allowed real-time monitoring of retinal cell dynamics, demonstrating a significant reduction in activated areas with small-sized electrodes. Overall, this study lays the groundwork for developing advanced rGO-based MEAs for high-acuity visual prostheses.

An Atypical Presentation of Sarcoidosis.

Sarcoidosis is a multisystem disease characterized by non-caseating granulomatous organ infiltration. We describe an atypical presentation of sarcoidosis in a 43-year-old male presenting with fatigue and shortness of breath. He had a preceding history of recurrent venous thromboembolism (VTE), hemolytic anemia, cirrhosis, peripheral neuropathies, and calcium deposition, which pre-dated hypercalcemia; he was later diagnosed with IgA nephropathy. Clinicians should consider sarcoidosis in patients with findings of multisystem disease even without hilar lymphadenopathy or hypercalcemia.

Role of the mechanotransductor PIEZO1 in megakaryocyte differentiation.

From haematopoietic stem cells to megakaryocytes (Mks), cells undergo various mechanical forces that affect Mk differentiation, maturation and proplatelet formation. The mechanotransductor PIEZO1 appears to be a natural candidate for sensing these mechanical forces and regulating megakaryopoiesis and thrombopoiesis. Gain-of-function mutations of PIEZO1 cause hereditary xerocytosis, a haemolytic anaemia associated with thrombotic events. If some functions of PIEZO1 have been reported in platelets, few data exist on PIEZO1 role in megakaryopoiesis. To address this subject, we used an in vitro model of Mk differentiation from CD34+ cells and studied step-by-step the effects of PIEZO1 activation by the chemical activator YODA1 during Mk differentiation and maturation. We report that PIEZO1 activation by 4 µM YODA1 at early stages of culture induced cytosolic calcium ion influx and reduced cell maturation. Indeed, CD41+CD42+ numbers were reduced by around 1.5-fold, with no effects on proliferation. At later stages of Mk differentiation, PIEZO1 activation promoted endomitosis and proplatelet formation that was reversed by PIEZO1 gene invalidation with a shRNA-PIEZO1. Same observations on endomitosis were reproduced in HEL cells induced into Mks by PMA and treated with YODA1. We provide for the first time results suggesting a dual role of PIEZO1 mechanotransductor during megakaryopoiesis.

Doxorubicin-Loaded Ultrasmall Gold Nanoparticles (1.5 nm) for Brain Tumor Therapy and Assessment of Their Biodistribution.

Ultrasmall gold nanoparticles (1.5 nm) were covalently conjugated with doxorubicin (AuDox) and AlexaFluor647 (AuAF647) to assess their biodistribution and their efficiency toward brain tumors (glioblastoma). A thorough characterization by transmission electron microscopy, small-angle X-ray scattering, and differential centrifugal sedimentation confirmed their uniform ultrasmall nature which makes them very mobile in the body. Each nanoparticle carried either 13 doxorubicin molecules (AuDox) or 2.7 AlexaFluor-647 molecules (AuAF647). The firm attachment of the ligands to the nanoparticles was demonstrated by their resilience to extensive washing, followed by centrifugation. The particles easily entered mammalian cells (HeLa, T98-G, brain endothelial cells, and human astrocytes) due to their small size. The intravenously delivered fluorescing AuAF647 nanoparticles crossed the blood-brain barrier with ∼23% accumulation in the brain tumor in an orthotopic U87 brain tumor model in nude mice. This was confirmed by elemental analysis (gold; inductively coupled plasma optical emission spectroscopy) in various organs. The doxorubicin-loaded AuDox nanoparticles inhibited brain tumor growth and prolonged animal survival without adverse side effects. Most of the nanoparticles (84%) had been excreted from the animal after 24 h, indicating a high mobility in the body.

Conversion of Ultrasmall Glutathione-Coated Silver Nanoparticles during Dispersion in Water into Ultrasmall Silver Sulfide Nanoparticles.

Ultrasmall silver nanoparticles (2 nm) were prepared by reduction with sodium borohydride (NaBH4) and stabilized by the ligand glutathione (a tripeptide: glycine-cysteine-glutamic acid). NMR spectroscopy and optical spectroscopy (UV and fluorescence) revealed that these particles initially consist of silver nanoparticles and fluorescing silver nanoclusters, both stabilized by glutathione. Over time, the silver nanoclusters disappear and only the silver nanoparticles remain. Furthermore, the capping ligand glutathione eliminates hydrogen sulfide (H2S) from the central cysteine and is released from the nanoparticle surface as tripeptide glycine-dehydroalanine-glutamic acid. Hydrogen sulfide reacts with the silver core to form silver sulfide. After four weeks in dispersion at 4 °C, this process is completed. These processes cannot be detected by transmission electron microscopy (TEM), small-angle X-ray scattering (SAXS), or differential centrifugal sedimentation (DCS) as these methods cannot resolve the mixture of nanoparticles and nanoclusters or the nature of the nanoparticle core. X-ray photoelectron spectroscopy showed the mostly oxidized state of the silver nanoparticle core, Ag(+I), both in freshly prepared and in aged silver nanoparticles. These results demonstrate that ultrasmall nanoparticles can undergo unnoticed changes that considerably affect their chemical, physical, and biological properties. In particular, freshly prepared ultrasmall silver nanoparticles are much more toxic against cells and bacteria than aged particles because of the presence of the silver clusters.

Design, synthesis, and in vitro biological evaluation of meta-sulfonamidobenzamide-based antibacterial LpxH inhibitors.

New antibacterial compounds are urgently needed, especially for infections caused by the top-priority Gram-negative bacteria that are increasingly difficult to treat. Lipid A is a key component of the Gram-negative outer membrane and the LpxH enzyme plays an important role in its biosynthesis, making it a promising antibacterial target. Inspired by previously reported ortho-N-methyl-sulfonamidobenzamide-based LpxH inhibitors, novel benzamide substitutions were explored in this work to assess their in vitro activity. Our findings reveal that maintaining wild-type antibacterial activity necessitates removal of the N-methyl group when shifting the ortho-N-methyl-sulfonamide to the meta-position. This discovery led to the synthesis of meta-sulfonamidobenzamide analogs with potent antibacterial activity and enzyme inhibition. Moreover, we demonstrate that modifying the benzamide scaffold can alter blocking of the cardiac voltage-gated potassium ion channel hERG. Furthermore, two LpxH-bound X-ray structures show how the enzyme-ligand interactions of the meta-sulfonamidobenzamide analogs differ from those of the previously reported ortho analogs. Overall, our study has identified meta-sulfonamidobenzamide derivatives as promising LpxH inhibitors with the potential for optimization in future antibacterial hit-to-lead programs.

"A stratified pathway to stent-free reperfusion: Selecting suitable patients in ST-elevation myocardial infarction".

BACKGROUND: The DANAMI-3 DEFER study demonstrated that deferring stent implantation in ST-elevation myocardial infarction (STEMI) is safe, although not superior to immediate stenting. It is possible that an individualized revascularization strategy in STEMI, achieved through appropriate patient selection, could be feasible and effective. METHODS: This prospective, non-randomized study included 198 patients with STEMI who underwent primary percutaneous coronary intervention (PCI) between October 2019 and November 2021. Patients were assigned to either the deferred stenting (DS) group (n = 19) or the control group (C) undergoing immediate stenting (n = 179) based on a multimodal approach integrating coronary angiography, intravascular imaging, physiological assessments, and clinical judgment. The primary endpoints included all-cause mortality and major adverse cardiac and cerebrovascular events (MACCE). RESULTS: The DS group showed a significantly lower rate of stent implantation (10.5 % vs. 97.7 %, p < 0.001) and a higher use of thrombus aspiration (89.5 % vs. 30.7 %, p < 0.001) and glycoprotein IIb/IIIa inhibitors (31.6 % vs. 6.7 %, p < 0.001) compared to the C group. No significant differences were observed between the groups in terms of all-cause mortality (5.3 % vs. 8.9 %, p = 0.59) or MACCE (10.5 % vs. 8.4 %, p = 0.71). CONCLUSIONS: This study demonstrates the feasibility of implementing individualized reperfusion strategies in STEMI within a real-world clinical setting. The findings, while limited by the study design, generate valuable hypotheses that warrant further investigation to refine patient selection criteria and optimize outcomes.

Surgical treatment of giant penile and scrotal lymphedema after syphilitic infection. Case report.

Penile and scrotal lymphedema is characterized by an abnormal retention of fluid in the subcutaneous tissue of the penis and scrotum, due to a deficiency in lymphatic drainage, causing edema, pain, dysuria and sexual dysfunction. The present report describes a patient with a giant penile and scrotal lymphedema after syphilitic infection, treated by excision of all the compromised skin and subcutaneous cellular tissue, with primary reconstruction with partial skin autograft and flap rotation. Literature review showed good functional results (erections and ejaculation) with the use of techniques that resected the skin and subcutaneous tissue and reconstructed the penis using skin grafts. This report can help in the differential diagnosis of lymphedema in the external genitalia and presents an aesthetical and functional reconstructive approach, showing the versatility and applicability of the graft and the fasciocutaneous flap of the thigh in this topography.

Lipid-Based Gels for Delivery of 3-O-Ethyl L-Ascorbic acid in Topical Applications.

This study explores the incorporation of 10% 3-O-ethyl L-ascorbic acid (ETVC), a derivative of vitamin C, into two lipid gel systems: a hydrogel (HG) consisting exclusively of lipids and water and a bigel (BG) combining the hydrogel with an oleogel made from olive oil and beeswax. We investigated the ETVC release profiles from both materials using synthetic membranes and measured their permeation through porcine skin in vitro. Additionally, the interaction of these lipid gel systems with the stratum corneum (SC) was determined. Results from the release study indicate that the BG exhibited slower ETVC release compared to the HG. The permeation experiments showed that the presence of lipids in the formulations enhanced ETVC retention in the skin. The HG delivered a higher amount to the SC, while the BG achieved greater retention in the epidermis. This difference is attributed to the different lipophilic nature of each material. The structural analysis of SC lipids revealed that the organization of surface lipids remained unaltered by the application of the gels. Finally, an in vitro efficacy test in porcine skin using methylene blue indicated that our ETVC gels exhibited antioxidant activity. These findings provide valuable insights into the potential of lipid-based gels for topical applications.

Hepatic immune regulation and sex disparities.

Chronic liver disease is a major cause of morbidity and mortality worldwide. Epidemiology, clinical phenotype and response to therapies for gastrointestinal and liver diseases are commonly different between women and men due to sex-specific hormonal, genetic and immune-related factors. The hepatic immune system has unique regulatory functions that promote the induction of intrahepatic tolerance, which is key for maintaining liver health and homeostasis. In liver diseases, hepatic immune alterations are increasingly recognized as a main cofactor responsible for the development and progression of chronic liver injury and fibrosis. In this Review, we discuss the basic mechanisms of sex disparity in hepatic immune regulation and how these mechanisms influence and modify the development of autoimmune liver diseases, genetic liver diseases, portal hypertension and inflammation in chronic liver disease. Alterations in gut microbiota and their crosstalk with the hepatic immune system might affect the progression of liver disease in a sex-specific manner, creating potential opportunities for novel diagnostic and therapeutic approaches to be evaluated in clinical trials. Finally, we identify and propose areas for future basic, translational and clinical research that will advance our understanding of sex disparities in hepatic immunity and liver disease.

Efficacy and safety of infliximab in patients with autoimmune hepatitis.

BACKGROUND AND AIMS: A limited number of drugs are used as standard or alternative therapies in autoimmune hepatitis (AIH). No specific recommendations are available for patients failing to respond to these therapies. We analyzed the efficacy and safety of infliximab in patients with AIH. APPROACH AND RESULTS: We performed a retrospective study of 42 patients with AIH who received infliximab at 21 liver centers in 12 countries. Patients were categorized according to the reason for infliximab therapy. Patients in group 1 (n=20) had failed standard, second-line (mycophenolate mofetil and 6-mercaptopurine) or third-line (tacrolimus or cyclosporine) therapy. In group 2 (n=22), infliximab was given for treatment of concomitant extrahepatic autoimmune diseases. Patients received a median of 17 (range: 3-104) infliximab infusions. Complete biochemical response (CR) was achieved or maintained in 33 (78%) patients during infliximab therapy. In group 1, infliximab induced CR in 11 of 20 (55%) patients. In group 2, 16 patients with CR prior to infliximab maintained remission, and the remaining 6 patients with active AIH (5 on standard and 1 on both second-line and third-line therapy) showed CR following infliximab therapy. Infliximab led to CR in 75% (6/8) of nonresponders to second-line and in 46% (6/13) of failing third-line therapy. Overall, 65% (17/26) of the patients with active AIH achieved CR on infliximab. Infliximab was discontinued in 3 patients of group 1. One patient had a severe allergic reaction and 2 developed anti-infliximab autoantibodies. CONCLUSIONS: Our study suggests that infliximab may be an effective and safe rescue therapy in AIH.

Rethinking Thin-Layer Chromatography for Screening Technetium-99m Radiolabeled Polymer Nanoparticles.

Thin-layer chromatography (TLC) is commonly employed to screen technetium-99m labeled polymer nanoparticle batches for unreduced pertechnetate and radio-colloidal impurities. Although this method is widely accepted, our findings applying radiolabeled PLGA/PLA-PEG nanoparticles underscore its lack of transferability between different settings and its limitations as a standalone quality control tool. While TLC profiles may appear similar for purified and radiocolloid containing nanoparticle formulations, their in vivo behavior can vary significantly, as demonstrated by discrepancies between TLC results and single-photon emission computed tomography (SPECT) and biodistribution data. This highlights the urgent need for a case-by-case evaluation of TLC methods for each specific nanoparticle type. Our study revealed that polymeric nanoparticles cannot be considered analytically uniform entities in the context of TLC analysis, emphasizing the complex interplay between nanoparticle composition, radiolabeling conditions, and subsequent biological behavior.

A Survey of United States Transplant Center Donation After Circulatory Death Kidney Transplant Practices in the Modern Era.

BACKGROUND: The mismatch between the number of patients awaiting kidney transplantation and the supply of donor organs has contributed to the increase in kidney transplantation from donors after circulatory death (DCD). Persistently long waiting times have led the transplant community to continue to explore the use of expanded- criteria DCD kidneys. In parallel, advances in organ preservation strategies have contributed to an overall increase in DCD organ transplantation and are altering the transplant landscape. Some of these techniques may improve kidney allograft outcomes and affect how DCD kidneys are used. We aimed to better understand practices in accepting DCD kidney offers in the modern era. METHODS: Directors of 196 US kidney transplant centers were emailed a link to an online survey over a 5-week period. RESULTS: Forty-eight out of the 364 directors (13%) responded, with all United Network for Organ Sharing regions represented. Definitions of warm ischemia time (WIT) used in DCD kidney evaluation varied widely among the respondents. The maximum total WIT limit varied, with 19 (39.6%) <60-minute responses, followed by 16 (33%) <90-minute responses, and 10 (20.8%) <120-minute responses. CONCLUSIONS: Despite increasing DCD kidney transplantation volumes in the United States, there are no standardized procurement biopsy practices, organ procurement organization preoperative protocols, or consensus definition or limits of WIT. Agreement on terminology may facilitate rapid clinical communication, efficiency of organ allocation and utilization, recording of data, research, and improvements in policy.

Maternal posture-physiology interactions in human pregnancy: a narrative review.

There are several well-known medical conditions in which posture and gravity interact with natural history, including pregnancy. In this review, we provide a comprehensive overview of interactions between maternal posture and maternal physiology and pathophysiology at rest during pregnancy. We conducted a systematic literature search of the MEDLINE database and identified 644 studies from 1991 through 2021, inclusive, that met our inclusion criteria. We present a narrative review of the resulting literature and highlight discrepancies, research gaps, and potential clinical implications. We organize the results by organ system and, commencing with the neurological system, proceed in our synthesis generally in the craniocaudal direction, concluding with the skin. The circulatory system warranted our greatest and closest consideration-literature concerning the dynamic interplay between physiology (heart rate, stroke volume, cardiac output, blood pressure, and systemic vascular resistance), pathophysiology (e.g., hypertension in pregnancy), and postural changes provide an intricate and fascinating example of the importance of the subject of this review. Other organ systems discussed include respiratory, renal, genitourinary, gastrointestinal, abdominal, and endocrine. In addition to summarizing the existing literature on maternal posture-physiology interactions, we also point out gaps and opportunities for further research and clinical developments in this area. Overall, our review provides both insight into and relevance of maternal posture-physiology interactions vis à vis healthcare's mission to improve health and wellness during pregnancy and beyond.