Interdisciplinary training program for pediatric cardiorespiratory arrest using rapid cycle deliberate practice: A descriptive cross-sectional study.

BACKGROUND: cardiorespiratory arrest (CRA) is a severe public health concern, and clinical simulation has proven to be a beneficial educational strategy for training on this topic. OBJECTIVE: To describe the implementation of a program for pediatric cardiac arrest care using rapid-cycle deliberate practice (RCDP), the quality of the technique employed, and participants' opinions on the methodology. DESIGN AND SETTING: This descriptive cross-sectional study of pre- and post-performance training in cardiopul monary resuscitation (CPR) techniques and reaction evaluation was conducted in a hospital in São Paulo. METHODS: Multidisciplinary groups performed pediatric resuscitation in a simulated scenario with RCDP mediated by a facilitator. The study sample included professionals working in patient care. During the simulation, the participants were evaluated for their compliance with the CRA care algorithm. Further, their execution of chest compressions was assessed pre- and post-intervention. RESULTS: In total, 302 professionals were trained in this study. The overall quality of CPR measured pre-intervention was inadequate, and only 26% had adequate technique proficiency, whereas it was 91% (P < 0.01) post-intervention. Of the participants, 95.7% responded to the final evaluation and provided positive comments on the method and their satisfaction with the novel simulation. Of these, 88% considered that repetition of the technique used was more effective than traditional simulation. CONCLUSIONS: The RCDP is effective for training multidisciplinary teams in pediatric CPR, with an emphasis on the quality of chest compressions. However, further studies are necessary to explore whether this trend translates to differential performances in practical settings.

Simultaneous integrated boost on pathologic lymph nodes safely improves clinical outcomes compared to sequential boost in locally advanced cervical cancer: a multicenter retrospective study.

Objective: This multicenter study aimed to retrospectively evaluate the impact of high boost simultaneous integrated boost (SIB) to pathologic lymph nodes compared to Sequential boost (Seq) in patients with locally advanced cervical cancer (LACC). Materials and methods: 97 patients with pelvic and/or para-aortic (PAo) node-positive LACC treated by definitive chemoradiation were included. Two groups were analyzed: Sequential boost group and simultaneous integrated boost (SIB) group. Endpoints were Distant Recurrence Free Survival (DRFS), Recurrence Free Survival (RFS), Overall Survival (OS), locoregional pelvic and PAo control and toxicities. Results: 3-years DRFS in SIB and Seq groups was 65% and 31% respectively (log-rank p < 0.001). 3-years RFS was 58% and 26% respectively (log-rank p = 0.009). DRFS prognostic factors in multivariable analysis were SIB, PAo involvement and maximum pelvic node diameter ≥ 2cm. Adenocarcinoma histology and absence of brachytherapy tended to be prognostic factors. SIB provided the best pelvic control at first imaging with 97%. There was no significant difference in terms of toxicities between groups. Conclusions: Nodal SIB seems to be unavoidable in the treatment of node-positive LACC. It provides the best DRFS, RFS and pelvic control without additional toxicity, with a shortened treatment duration.

Evaluating the antimicrobial and anti-biofilm activity of three synthetic antimicrobial Citropin analogs and their ability to fight against Staphylococcus aureus and Staphylococcus pseudintermedius.

AIMS: We developed three new analogs of the antimicrobial peptide (AMP) Citropin 1.1: DAN-1-13, AJP-1-1, and HHX-2-28, and tested their potential antimicrobial and antibiofilm activities against Staphylococcus aureus and S. pseudintermedius. Potential cytotoxic or hemolytic effects were determined using cultured human keratinocytes and erythrocytes to determine their safety. METHODS AND RESULTS: To assess the antimicrobial activity of each compound, minimum inhibitory concentrations (MIC) and minimum bactericidal concentrations (MBC) were determined against methicillin-resistant and methicillin-susceptible strains of S. aureus and S. pseudintermedius. Activity against newly formed and mature biofilms was determined in two clinical isolates using spectrophotometry and scanning electron microscopy (SEM). All three compounds exhibited antimicrobial and bactericidal activity against all studied S. aureus and S. pseudintermedius strains, with MICs ranging from 4-32 µg ml-1 and MBCs ranging from 8-128 µg ml-1. Subinhibitory concentrations of all compounds also showed ant-biofilm activity in the two tested isolates. All compounds exhibited limited cytotoxic and hemolytic activity. CONCLUSIONS: Novel analogs of Citropin 1.1 exhibit antimicrobial and bactericidal activities against S. aureus and S. pseudintermedius isolates and inhibit the biofilm formation of these bacteria.

Chromatin accessibility and epigenetic deoxyribose nucleic acid (DNA) modifications in chronic kidney disease (CKD) osteoblasts: a study of bone and osteoblasts from pediatric patients with CKD.

Maturation defects are intrinsic features of osteoblast lineage cells in CKD patients. These defects persist ex vivo, suggesting that CKD induces epigenetic changes in bone cells. To gain insights into which signaling pathways contribute to CKD-mediated, epigenetically driven, impairments in osteoblast maturation, we characterized RNA expression and DNA methylation patterns by RNA-Seq and MethylationEpic in primary osteoblasts from nine adolescent and young adult dialysis patients with end-stage kidney disease and three healthy references. ATAC-Seq was also performed on a subset of osteoblasts. Bone matrix protein expression was extracted from the iliac crest and evaluated by proteomics. Gene set enrichment analysis was used to establish signaling pathways consistently altered in chromatin accessibility, DNA methylation, and RNA expression patterns. Single genes were suppressed in primary osteoblasts using shRNA and mineralization characterized in vitro. The effect of nuclear factor of activated T cells (NFAT) signaling suppression was also assessed using 3-(4,5-dimethylthiazol-2-yl)-5-(3-carboxymethoxyphenyl)-2-(4-sulfophenyl)-2H-tetrazolium (MTS) incorporation. We found that signaling pathways critical for osteoblast differentiation were strongly downregulated in CKD osteoblasts. Gene set enrichment analysis identified highly significant methylation changes, differential chromatin accessibility, and altered RNA expression in NFAT signaling targets. NFAT inhibition reduced osteoblast proliferation. Combined analysis of osteoblast RNA expression and whole bone matrix composition identified 13 potential ligand-receptor pairs. In summary, epigenetic changes in CKD osteoblasts associate with altered expression of multiple osteoblast genes and signaling pathways. An increase in NFAT signaling may play a role in impaired CKD osteoblast maturation. Epigenetic changes also associate with an altered bone matrix, which may contribute to bone fragility. Further studies are necessary to elucidate the pathways affected by these genetic alterations since elucidating these pathways will be vital to correcting the underlying biology of bone disease in the CKD population.

How different attributes are weighted in professionals' decision-making in Pediatric Dentistry-a protocol for guiding discrete choice experiment focused on shortening the evidence-based practice implementation for dental care.

BACKGROUND: Important evidence has been constantly produced and needs to be converted into practice. Professional consumption of such evidence may be a barrier to its implementation. Then, effective implementation of evidence-based interventions in clinical practice leans on the understanding of how professionals value attributes when choosing between options for dental care, permitting to guide this implementation process by maximizing strengthens and minimizing barriers related to that. METHODS: This is part of a broader project investigating the potential of incorporating scientific evidence into clinical practice and public policy recommendations and guidelines, identifying strengths and barriers in such an implementation process. The present research protocol comprises a Discrete Choice Experiment (DCE) from the Brazilian oral health professionals' perspective, aiming to assess how different factors are associated with professional decision-making in dental care, including the role of scientific evidence. Different choice sets will be developed, either focusing on understanding the role of scientific evidence in the professional decision-making process or on understanding specific attributes associated with different interventions recently tested in randomized clinical trials and available as newly produced scientific evidence to be used in clinical practice. DISCUSSION: Translating research into practice usually requires time and effort. Shortening this process may be useful for faster incorporation into clinical practice and beneficial to the population. Understanding the context and professionals' decision-making preferences is crucial to designing more effective implementation and/or educational initiatives. Ultimately, we expect to design an efficient implementation strategy that overcomes threats and potential opportunities identified during the DCEs, creating a customized structure for dental professionals. TRIAL REGISTRATION: https://osf.io/bhncv .

Utility of Blood Biomarkers to Predict Marrow Iron Stores in Children.

BACKGROUND: Iron deficiency is common in children with kidney failure, but current guidelines are based on biomarkers of iron stores that may be influenced by inflammation. This is the first study that examined which serum iron indices were associated with stainable marrow iron stores (the gold standard) in this population with kidney failure who underwent bone biopsies. METHODS: This cross-sectional study enrolled 71 clinically stable children and young adults receiving dialysis who underwent bone biopsy for chronic kidney disease-mineral bone disorder between 2007 through 2011. Bone biopsies were stained with Perls' Prussian blue and independently interpreted by a pathologist blinded to participants' iron parameters and clinical status. Marrow staining was scored absent vs. present to facilitate receiver operator curve (ROC) analysis. In ROC analysis, the ability of serum ferritin to detect stainable marrow iron stores was compared with that of transferrin saturation (TSAT), serum hepcidin, and clinical guideline-based iron deficiency cut-offs for serum iron, TSAT, and their combinations. RESULTS: Mean age was 17.2 ± 4.4 years (range 2-28), and 30% of patients were female. Median dialysis vintage was 1.2 (IQR 0.7, 2.0) years, and 56% were supported by peritoneal dialysis. Mean hemoglobin was 12.4 ± 1.7 g/dl, and 35% were receiving iron supplementation at the time of biopsy. Based on the gold standard of depleted marrow iron stores, 46.5% of patients were iron-deficient. As an indicator of marrow iron staining, serum ferritin provided a higher area under the ROC curve than serum hepcidin, TSAT, or clinical guidelines-based evaluation of TSAT + ferritin. CONCLUSIONS: In this cohort of children and young adults with kidney failure, serum ferritin provided the best indication of stainable marrow iron stores, followed by transferrin saturation.

ATF4-dependent increase in mitochondrial-endoplasmic reticulum tethering following OPA1 deletion in skeletal muscle.

Mitochondria and endoplasmic reticulum (ER) contact sites (MERCs) are protein- and lipid-enriched hubs that mediate interorganellar communication by contributing to the dynamic transfer of Ca2+, lipid, and other metabolites between these organelles. Defective MERCs are associated with cellular oxidative stress, neurodegenerative disease, and cardiac and skeletal muscle pathology via mechanisms that are poorly understood. We previously demonstrated that skeletal muscle-specific knockdown (KD) of the mitochondrial fusion mediator optic atrophy 1 (OPA1) induced ER stress and correlated with an induction of Mitofusin-2, a known MERC protein. In the present study, we tested the hypothesis that Opa1 downregulation in skeletal muscle cells alters MERC formation by evaluating multiple myocyte systems, including from mice and Drosophila, and in primary myotubes. Our results revealed that OPA1 deficiency induced tighter and more frequent MERCs in concert with a greater abundance of MERC proteins involved in calcium exchange. Additionally, loss of OPA1 increased the expression of activating transcription factor 4 (ATF4), an integrated stress response (ISR) pathway effector. Reducing Atf4 expression prevented the OPA1-loss-induced tightening of MERC structures. OPA1 reduction was associated with decreased mitochondrial and sarcoplasmic reticulum, a specialized form of ER, calcium, which was reversed following ATF4 repression. These data suggest that mitochondrial stress, induced by OPA1 deficiency, regulates skeletal muscle MERC formation in an ATF4-dependent manner.

Post-operative pain management by nurses in an intensive care unit: a best practice implementation project.

INTRODUCTION: Post-operative pain is the most prevalent type of acute pain. Nurses are the health care professionals who most frequently assess pain, as well as evaluating the patient's response to pain management treatment and monitoring for the occurrence of adverse events. Thus, to improve outcomes and quality of care, the interventions used by nurses should be based on best practices. OBJECTIVES: The aim of this project was to implement best practices in post-operative pain management in an intensive care unit. METHODS: This evidence implementation project was conducted in a hospital for the surgical treatment of orthopedic diseases and trauma. The project followed the JBI evidence implementation framework. The project used JBI PACES software as well as JBI's Getting Research into Practice (GRiP) audit and feedback tools to develop eight audit criteria for the baseline and follow-up audits. RESULTS: The baseline audit showed that criteria 3 and 6 had low compliance, with few patients having documented plans and goals, and receiving multimodal analgesia in the ICU, respectively. Criteria 7 and 8, which assessed the use of opioids and follow-up by a pain specialist, revealed compliance of 60% and 50%, respectively. Criterion 3 improved from 0% to 20%. Criteria 6, 7, and 8 also improved, rising to 30%, 22.8%, and 50%, respectively. CONCLUSION: The project improved compliance with best practices in post-operative pain management. Further studies are needed to ensure the project's long-term sustainability.

ATF4 expression in thermogenic adipocytes is required for cold-induced thermogenesis in mice via FGF21-independent mechanisms.

In brown adipose tissue (BAT), short-term cold exposure induces the activating transcription factor 4 (ATF4), and its downstream target fibroblast growth factor 21 (FGF21). Induction of ATF4 in BAT in response to mitochondrial stress is required for thermoregulation, partially by increasing FGF21 expression. In the present study, we tested the hypothesis that Atf4 and Fgf21 induction in BAT are both required for BAT thermogenesis under physiological stress by generating mice selectively lacking either Atf4 (ATF4 BKO) or Fgf21 (FGF21 BKO) in UCP1-expressing adipocytes. After 3 days of cold exposure, core body temperature was significantly reduced in ad-libitum-fed ATF4 BKO mice, which correlated with Fgf21 downregulation in brown and beige adipocytes, and impaired browning of white adipose tissue. Conversely, despite having reduced browning, FGF21 BKO mice had preserved core body temperature after cold exposure. Mechanistically, ATF4, but not FGF21, regulates amino acid import and metabolism in response to cold, likely contributing to BAT thermogenic capacity under ad libitum-fed conditions. Importantly, under fasting conditions, both ATF4 and FGF21 were required for thermogenesis in cold-exposed mice. Thus, ATF4 regulates BAT thermogenesis under fed conditions likely in a FGF21-independent manner, in part via increased amino acid uptake and metabolism.

Mitochondrial Dynamics, Diabetes, and Cardiovascular Disease.

Mitochondria undergo repeated cycles of fusion and fission that regulate their size and shape by a process known as mitochondrial dynamics. Numerous studies have revealed the importance of this process in maintaining mitochondrial health and cellular homeostasis, particularly in highly metabolically active tissues such as skeletal muscle and the heart. Here, we review the literature on the relationship between mitochondrial dynamics and the pathophysiology of type 2 diabetes and cardiovascular disease (CVD). Importantly, we emphasize divergent outcomes resulting from downregulating distinct mitochondrial dynamics proteins in various tissues. This review underscores compensatory mechanisms and adaptive pathways that offset potentially detrimental effects, resulting instead in improved metabolic health. Finally, we offer a perspective on potential therapeutic implications of modulating mitochondrial dynamics proteins for treatment of diabetes and CVD.

Accuracy of an artificial intelligence algorithm for detecting moderate-to-severe vertebral compression fractures on abdominal and thoracic computed tomography scans / Acurácia de um algoritmo de inteligência artificial na detecção de fraturas compressivas moderadas a graves na tomografia computadorizada abdominal e torácica

Abstract Objective: To describe the accuracy of HealthVCF, a software product that uses artificial intelligence, in the detection of incidental moderate-to-severe vertebral compression fractures (VCFs) on chest and abdominal computed tomography scans. Materials and Methods: We included a consecutive sample of 899 chest and abdominal computed tomography scans of patients 51-99 years of age. Scans were retrospectively evaluated by the software and by two specialists in musculoskeletal imaging for the presence of VCFs with vertebral body height loss > 25%. We compared the software analysis with that of a general radiologist, using the evaluation of the two specialists as the reference. Results: The software showed a diagnostic accuracy of 89.6% (95% CI: 87.4-91.5%) for moderate-to-severe VCFs, with a sensitivity of 73.8%, a specificity of 92.7%, and a negative predictive value of 94.8%. Among the 145 positive scans detected by the software, the general radiologist failed to report the fractures in 62 (42.8%), and the algorithm detected additional fractures in 38 of those scans. Conclusion: The software has good accuracy for the detection of moderate-to-severe VCFs, with high specificity, and can increase the opportunistic detection rate of VCFs by radiologists who do not specialize in musculoskeletal imaging.

Resumo Objetivo: Descrever a acurácia do software HealthVCF na detecção incidental de fraturas compressivas de corpos vertebrais moderadas a graves em exames de tomografia computadorizada do tórax e abdome. Materiais e Métodos: Foram incluídos 899 exames consecutivos de pacientes com idades entre 51 e 99 anos. As imagens foram retrospectivamente avaliadas pelo software e por dois radiologistas especializados em musculoesquelético que investigaram fraturas compressivas de corpos vertebrais com perda da altura somática > 25%. A análise comparativa foi realizada entre o software e um radiologista geral, usando a avaliação do especialista como referência. Resultados: O software apresentou uma acurácia de 89,6% (IC 95%: 87,4-91,5%) para fraturas compressivas moderadas a graves, com sensibilidade de 73,8%, especificidade de 92,7% e valor preditivo negativo de 94,8%. Entre as 145 tomografias positivas detectadas pelo software, o radiologista geral deixou de relatar as fraturas em 62 (42,8%) e o algoritmo detectou fraturas adicionais em 38 dessas tomografias. Conclusão: O software possui boa acurácia na detecção de fraturas compressivas moderadas a graves, com alta especificidade, podendo aumentar a taxa de detecção oportunística dessas fraturas por radiologistas não especializados em musculoesquelético.

The stingless bee Trigona spinipes (Hymenoptera: Apidae) is at risk from a range of insecticides via direct ingestion and trophallactic exchanges.

BACKGROUND: The stingless bee, Trigona spinipes, is an important pollinator of numerous native and cultivated plants. Trigona spinipes populations can be negatively impacted by insecticides commonly used for pest control in crops. However, this species has been neglected in toxicological studies. Here we observed the effects of seven insecticides on the survival of bees that had fed directly on insecticide-contaminated food sources or received insecticides via trophallactic exchanges between nestmates. The effects of insecticides on flight behavior were also determined for the compounds considered to be of low toxicity. RESULTS: Imidacloprid, spinosad and malathion were categorized as highly toxic to T. spinipes, whereas lambda-cyhalothrin, methomyl and chlorfenapyr were of medium to low toxicity and interfered with two aspects of flight behavior evaluated here. Chlorantraniliprole was the only insecticide tested here that had no significant effect on T. spinipes survival, although it did interfere with one aspect of flight capacity. A single bee that had ingested malathion, spinosad or imidacloprid, could contaminate three, four and nineteen other bees, respectively via trophallaxis, resulting in the death of the recipients. CONCLUSION: This is the first study to evaluate the ecotoxicology of a range of insecticides that not only negatively affected T. spinipes survival, but also interfered with flight capacity, a very important aspect of pollination behavior. The toxicity of the insecticides was observed following direct ingestion and also via trophallactic exchanges between nestmates, highlighting the possibility of lethal effects of these insecticides spreading throughout the colony, reducing the survival of non-foraging individuals. © 2023 Society of Chemical Industry.

Effect of Low-Dose Progesterone on Glycemic Metabolism, Morphology and Function of Adipose Tissue and Pancreatic Islets in Diet-Induced Obese Female Mice.

BACKGROUND: Obesity is a worldwide concern due to its global rapid expansion and remarkable impact on individual's health by predisposing to several other diseases. About twice as many women as men suffer from severe obesity and, in fact, there are stages in a woman's life when weight gain and adiposity can result in greater damage to health. For example, obesity triples the chance of a woman developing gestational diabetes. Many hormones promote the metabolic adaptations of pregnancy, including progesterone, whose role in female obesity is still not well known despite being involved in many physiological and pathological processes. METHODS: Here we investigated whether progesterone treatment at low dose can worsen the glucose metabolism and the morpho functional aspects of adipose tissue and pancreas in obese females. Mice were assigned into four groups: normocaloric diet control (NO-CO), high-fat and -fructose diet control (HFF-CO), normocaloric diet plus progesterone (NO-PG) and high-fat and -fructose diet plus progesterone (HFF-PG) for 10 weeks. Infusion of progesterone (0.25 mg/kg/day) was done by osmotic minipump in the last 21 days of protocol. RESULTS: Animals fed a hypercaloric diet exhibited obesity with increased body weight (p < 0.0001), adipocyte hypertrophy (p < 0.0001), hyperglycemia (p = 0.03), and glucose intolerance (p = 0.001). HFF-CO and HFF-PG groups showed lower adiponectin concentration (p < 0.0001) and glucose-stimulated insulin secretion (p = 0.03), without differences in islet size. Progesterone attenuated glucose intolerance in the HFF-PG group (p = 0.03), however, did not change morphology or endocrine function of adipose tissue and pancreatic islets. CONCLUSIONS: Taken together, our results showed that low dose of progesterone does not worsen the effects of hypercaloric diet in glycemic metabolism, morphology and function of adipose tissue and pancreatic islets in female animals. These results may improve the understanding of the mechanisms underlying the pathogenesis of obesity in women and eventually open new avenues for therapeutic strategies and better comprehension of the interactions between progesterone effects and obesity.

The roles of FGF21 and GDF15 in mediating the mitochondrial integrated stress response.

Various models of mitochondrial stress result in induction of the stress-responsive cytokines fibroblast growth factor 21 (FGF21) and growth differentiation factor 15 (GDF15). This is an adaptive mechanism downstream of the mitochondrial integrated stress response frequently associated with improvements in systemic metabolic health. Both FGF21 and GDF15 have been shown to modulate energy balance and glucose homeostasis, and their pharmacological administration leads to promising beneficial effects against obesity and associated metabolic diseases in pre-clinical models. Furthermore, endogenous upregulation of FGF21 and GDF15 is associated with resistance to diet-induced obesity (DIO), improved glucose homeostasis and increased insulin sensitivity. In this review, we highlight several studies on transgenic mouse models of mitochondrial stress and will compare the specific roles played by FGF21 and GDF15 on the systemic metabolic adaptations reported in these models.

GDF15 is required for cold-induced thermogenesis and contributes to improved systemic metabolic health following loss of OPA1 in brown adipocytes.

We previously reported that mice lacking the protein optic atrophy 1 (OPA1 BKO) in brown adipose tissue (BAT) display induction of the activating transcription factor 4 (ATF4), which promotes fibroblast growth factor 21 (FGF21) secretion as a batokine. FGF21 increases metabolic rates under baseline conditions but is dispensable for the resistance to diet-induced obesity (DIO) reported in OPA1 BKO mice (Pereira et al., 2021). To determine alternative mediators of this phenotype, we performed transcriptome analysis, which revealed increased levels of growth differentiation factor 15 (GDF15), along with increased protein kinase R (PKR)-like endoplasmic reticulum kinase (PERK) levels in BAT. To investigate whether ATF4 induction was mediated by PERK and evaluate the contribution of GDF15 to the resistance to DIO, we selectively deleted PERK or GDF15 in OPA1 BKO mice. Mice with reduced OPA1 and PERK levels in BAT had preserved ISR activation. Importantly, simultaneous deletion of OPA1 and GDF15 partially reversed the resistance to DIO and abrogated the improvements in glucose tolerance. Furthermore, GDF15 was required to improve cold-induced thermogenesis in OPA1 BKO mice. Taken together, our data indicate that PERK is dispensable to induce the ISR, but GDF15 contributes to the resistance to DIO, and is required for glucose homeostasis and thermoregulation in OPA1 BKO mice by increasing energy expenditure.

Sclerostin, Osteocytes, and Wnt Signaling in Pediatric Renal Osteodystrophy.

The pathophysiology of chronic kidney disease-mineral and bone disorder (CKD-MBD) is not well understood. Specific factors secreted by osteocytes are elevated in the serum of adults and pediatric patients with CKD-MBD, including FGF-23 and sclerostin, a known inhibitor of the Wnt signaling pathway. The molecular mechanisms that promote bone disease during the progression of CKD are incompletely understood. In this study, we performed a cross-sectional analysis of 87 pediatric patients with pre-dialysis CKD and post-dialysis (CKD 5D). We assessed the associations between serum and bone sclerostin levels and biomarkers of bone turnover and bone histomorphometry. We report that serum sclerostin levels were elevated in both early and late CKD. Higher circulating and bone sclerostin levels were associated with histomorphometric parameters of bone turnover and mineralization. Immunofluorescence analyses of bone biopsies evaluated osteocyte staining of antibodies towards the canonical Wnt target, ß-catenin, in the phosphorylated (inhibited) or unphosphorylated (active) forms. Bone sclerostin was found to be colocalized with phosphorylated ß-catenin, which suggests that Wnt signaling was inhibited. In patients with low serum sclerostin levels, increased unphosphorylated "active" ß-catenin staining was observed in osteocytes. These data provide new mechanistic insight into the pathogenesis of CKD-MBD and suggest that sclerostin may offer a potential biomarker or therapeutic target in pediatric renal osteodystrophy.

Immunomodulation with romiplostim as a second-line strategy in primary immune thrombocytopenia: The iROM study.

Thrombopoietin receptor agonists (TPO-RAs) stimulate platelet production, which might restore immunological tolerance in primary immune thrombocytopenia (ITP). The iROM study investigated romiplostim's immunomodulatory effects. Thirteen patients (median age, 31 years) who previously received first-line treatment received romiplostim for 22 weeks, followed by monitoring until week 52. In addition to immunological data, secondary end-points included the sustained remission off-treatment (SROT) rate at 1 year, romiplostim dose, platelet count and bleedings. Scheduled discontinuation of romiplostim and SROT were achieved in six patients with newly diagnosed ITP, whereas the remaining seven patients relapsed. Romiplostim dose titration was lower and platelet count response was stronger in patients with SROT than in relapsed patients. In all patients, regulatory T lymphocyte (Treg) counts increased until study completion and the counts were higher in patients with SROT. Interleukin (IL)-4, IL-9 and IL-17F levels decreased significantly in all patients. FOXP3 (Treg), GATA3 (Th2) mRNA expression and transforming growth factor-ß levels increased in patients with SROT. Treatment with romiplostim modulates the immune system and possibly influences ITP prognosis. A rapid increase in platelet counts is likely important for inducing immune tolerance. Better outcomes might be achieved at an early stage of autoimmunity, but clinical studies are needed for confirmation.

Effect of electrical and chemical (activation versus inactivation) stimulation of the infralimbic division of the medial prefrontal cortex in rats with chronic neuropathic pain.

Neuropathic pain (NP) represents a complex disorder with sensory, cognitive, and emotional symptoms. The medial prefrontal cortex (mPFC) takes critical regulatory roles and may change functionally and morphologically during chronic NP. There needs to be a complete understanding of the neurophysiological and psychopharmacological bases of the NP phenomenon. This study aimed to investigate the participation of the infralimbic division (IFL) of the mPFC in chronic NP, as well as the role of the N-methyl-D-aspartic acid receptor (NMDAr) in the elaboration of chronic NP. Male Wistar rats were submitted to the von Frey and acetone tests to assess mechanical and cold allodynia after 21 days of chronic constriction injury (CCI) of the sciatic nerve or Sham-procedure ("false operated"). Electrical neurostimulation of the IFL/mPFC was performed by low-frequency stimuli (20 µA, 100 Hz) applied for 15 s by deep brain stimulation (DBS) device 21 days after CCI. Either cobalt chloride (CoCl2 at 1.0 mM/200 nL), NMDAr agonist (at 0.25, 1.0, and 2.0 nmol/200 nL) or physiological saline (200 nL) was administered into the IFL/mPFC. CoCl2 administration in the IFL cortex did not alter either mechanical or cold allodynia. DBS stimulation of the IFL cortex decreased mechanical allodynia in CCI rats. Chemical stimulation of the IFL cortex by an NMDA agonist (at 2.0 nmol) decreased mechanical allodynia. NMDA at any dose (0.25, 1.0, and 2.0 nmol) reduced the flicking/licking duration in the cold test. These findings suggest that the IFL/mPFC and the NMDAr of the neocortex are involved in attenuating chronic NP in rats.

All the might of the osteocyte: emerging roles in chronic kidney disease.

Osteocytes are the most abundant type of bone cell and play crucial roles in bone health. Osteocytes sense mechanical stress and orchestrate osteoblasts and osteoclasts to maintain bone density and strength. Beyond this, osteocytes have also emerged as key regulators of organ crosstalk, and they function as endocrine organs via their roles in secreting factors that mediate signaling within their neighboring bone cells and in distant tissues. As such, osteocyte dysfunction has been associated with the bone abnormalities seen across a spectrum of chronic kidney disease. Specifically, dysregulated osteocyte morphology and signaling have been observed in the earliest stages of chronic kidney disease and have been suggested to contribute to kidney disease progression. More important, US Food and Drug Administration-approved inhibitors of osteocytic secreted proteins, such as fibroblast growth factor 23 and sclerostin, have been used to treat bone diseases. The present mini review highlights new research that links dysfunctional osteocytes to the pathogenesis of chronic kidney disease mineral and bone disorder.

Oligosymptomatic long-term carriers of SARS-CoV-2 display impaired innate resistance but increased high-affinity anti-spike antibodies.

The vast spectrum of clinical features of COVID-19 keeps challenging scientists and clinicians. Low resistance to infection might result in long-term viral persistence, but the underlying mechanisms remain unclear. Here, we studied the immune response of immunocompetent COVID-19 patients with prolonged SARS-CoV-2 infection by immunophenotyping, cytokine and serological analysis. Despite viral loads and symptoms comparable to regular mildly symptomatic patients, long-term carriers displayed weaker systemic IFN-I responses and fewer circulating pDCs and NK cells at disease onset. Type 1 cytokines remained low, while type-3 cytokines were in turn enhanced. Of interest, we observed no defects in antigen-specific cytotoxic T cell responses, and circulating antibodies displayed higher affinity against different variants of SARS-CoV-2 Spike protein in these patients. The identification of distinct immune responses in long-term carriers adds up to our understanding of essential host protective mechanisms to ensure tissue damage control despite prolonged viral infection.