Analysis of neutrophil-to-lymphocyte and platelet-to-lymphocyte ratios as inflammatory biomarkers in chronic kidney disease: impact of parathyroidectomy / Análise das relações neutrófilo/linfócito e plaqueta/linfócito como marcadores inflamatórios na doença renal crônica: impacto da paratireoidectomia

Abstract Introduction: Secondary hyperparathyroidism (SHPT) is one of the causes for inflammation in CKD. We assessed the impact of parathyroidectomy (PTX) on neutrophil-to-lymphocyte (N/L) and platelet-to-lymphocyte (P/L) ratios in SHPT patients. Methods: A total of 118 patients [hemodialysis (HD, n = 81), and transplant recipients (TX, n = 37)] undergoing PTX between 2015 and 2021 were analyzed. Results: There was a significant reduction in calcium and PTH levels in both groups, in addition to an increase in vitamin D. In the HD group, PTX did not alter N/L and P/L ratios. In the TX group, there was a reduction in N/L and P/L ratios followed by a significant increase in total lymphocyte count. Conclusion: N/L and P/L ratios are not reliable biomarkers of inflammation in SHPT patients undergoing PTX. Uremia, which induces a state of chronic inflammation in dialysis patients, and the use of immunosuppression in kidney transplant recipients are some of the confounding factors that prevent the use of this tool in clinical practice.

Resumo Introdução: O hiperparatireoidismo secundário (HPTS) é uma das causas de inflamação na DRC. Avaliamos o impacto da paratireoidectomia (PTX) nas relações neutrófilo/linfócito (N/L) e plaqueta/linfócito (P/L) em pacientes com HPTS. Métodos: Foram analisados 118 pacientes [hemodiálise (HD, n = 81) e transplantados (TX, n = 37)] submetidos à PTX entre 2015 e 2021. Resultados: Houve redução significativa de cálcio e PTH nos dois grupos, além de elevação de vitamina D. No grupo HD, a PTX não mudou as relações N/L e P/L. Já no grupo TX, houve redução nas relações N/L e P/L acompanhadas de elevação significativa do número de linfócitos totais. Conclusão: As relações N/L e P/L não são marcadores fidedignos de inflamação em pacientes com HPTS submetidos à PTX. A uremia, que induz um estado de inflamação crônica em pacientes dialíticos, e o uso de imunossupressão em pacientes transplantados renais são alguns dos fatores de confusão que impedem o uso dessa ferramenta na prática clínica.

Differential Pharmacodynamic Effects on Psoriatic Biomarkers by Guselkumab Versus Secukinumab Correlate with Long-Term Efficacy: An ECLIPSE Substudy.

IL-23 is a cytokine produced by myeloid cells that drives the T helper 17 pathway and plays an essential role in the pathophysiology of plaque psoriasis. IL-23 activation initiates a cascade of cytokines subsequently inducing the expression of many psoriasis-related proteins. This study aimed to better understand the underlying mechanisms driving the differences between IL-23 and IL-17A blockade in patients with psoriasis and their implications for durability of clinical responses. Serum and/or skin biopsies were isolated from patients treated with guselkumab or secukinumab for evaluation of potential biomarkers of pharmacodynamic response to treatment. Guselkumab treatment led to significantly greater reductions of IL-17F and IL-22 serum levels than treatment with secukinumab at weeks 24 and 48, demonstrating sustained regulation of the IL-23/T helper 17 pathway. Analyses of proteomic and transcriptomic profiles of patient sera and skin biopsies demonstrated differential regulation of proteins involved in chemokine, TNF, and relevant immune signaling pathways to a greater degree with guselkumab than with secukinumab treatment. These data provide insights into the differences between the mechanisms and impact of IL-23 and IL-17A blockade in psoriasis, with implications for efficacy observations and treatment paradigms. Trial Registration: The original study was registered at ClinicalTrials.gov (NCT03090100).

Flecainide toxicity-Clinical diagnosis and management of an urgent condition.

Clinical suspicion, clinical presentation, and electrocardiogram can help clinicians diagnose flecainide toxicity. Currently, there are no guidelines for the management of patients with flecainide toxicity. Sodium bicarbonate, lipid emulsion therapy, and extracorporeal life support have been used in this setting. Amiodarone and lidocaine can be used for the management of wide QRS complex tachycardias in hemodynamically stable patients with flecainide toxicity.

Pandemic preparedness: why humanities and social sciences matter.

Whilst many lessons were learned from the COVID-19 pandemic, ongoing reflection is needed to develop and maintain preparedness for future outbreaks. Within the field of infectious disease and public health there remain silos and hierarchies in interdisciplinary work, with the risk that humanities and social sciences remain on the epistemological peripheries. However, these disciplines offer insights, expertise and tools that contribute to understanding responses to disease and uptake of interventions for prevention and treatment. In this Perspective, using examples from our own cross-disciplinary research and engagement programme on vaccine hesitancy in South Africa and the United Kingdom (UK), we propose closer integration of expertise, research and methods from humanities and social sciences into pandemic preparedness.

Magnitude and Severity of Anxiety and Risk Factors among Hypertensive Patients Attending Public Hospitals in Arba Minch Town, Ethiopia.

Background: Comorbid anxiety in hypertensive patients yields poor remedy adherence which may additionally restrict treatment choices. Objective: To assess the magnitude and severity of anxiety and risk factors among hypertensive patients attending public hospitals in Arba Minch town, Ethiopia, 2022. Methods: A hospital-based cross-sectional study design was performed from June 1 to July 30/2022. The overall sample size was 336 and a systematic random sampling technique was used to pick out sufferers. Used Epi data version 3.1 for data entry and SPSS version 25 for analysis. Logistic regression analysis was done and variables with p-values less than .25 were taken into multivariable. Statistical significance was declared at a p-value of less than .05 with a 95% confidence interval in the adjusted odds ratio. Result: The magnitude of anxiety among hypertensive patients was 32.1% with 95% CI (26.2%-37.1%). Sex [AOR: 2.25, 95%CI: 1.22-4.13], status of blood pressure [AOR: 0.30, 95%CI: 0.15-0.63], family history of hypertension [AOR: 2.48, 95%CI: 1.20-5.12], family history of mental illness [AOR: 0.19, 95%CI: 0.09-0.39], history of admission [AOR: 5.14, 95%CI: 2.73-9.68], social support status [AOR: 2.96, 95%CI: 1.09-7.97], and current alcohol use [AOR: 0.39, 95%CI: 0.18-0.86] had been notably related. Conclusion: About three in 10 hypertensive patients attending public hospitals in Arba Minch town public hospitals were anxious. Approximately two in 10 hypertensive sufferers had moderate to severe anxiety. Sex, status of blood pressure, family history of hypertension, family history of mental illness, history of admission, social support status, and current alcohol use have been substantially associated with anxiety among hypertensive patients. Therefore, enhancing gender identity, controlling blood pressure, screening and treating a family history of high blood pressure and family history of mental illness, coping with previous admission, improving social help, and cessation of alcohol use might lessen the burden of anxiety among hypertensive sufferers.

Comparison of Patient-Reported Outcomes for Immediate Unrestricted Weightbearing Versus Restricted Rehabilitation Protocols After Osteochondral Allograft Transplantation to the Distal Femur.

Background: There is no standardized rehabilitation protocol after osteochondral allograft (OCA) transplantation surgery to the distal femur. The spectrum of recommendations includes restrictions to toe-touch weightbearing (TTWB) for 6 weeks and immediate weightbearing as tolerated (WBAT). Purpose/Hypothesis: The purpose of this study was to compare outcomes for immediate unrestricted WBAT to restricted TTWB after OCA transplantation to the distal femur. It was hypothesized that the immediate WBAT protocol would be noninferior to delayed, restricted TTWB. Study Design: Retrospective cohort study. Methods: A total of 74 patients who underwent press-fit, dowel technique OCA transplantation to the femoral condyle(s) for contained (International Cartilage Repair Society grade 3-4) lesions were identified in the Metrics of Osteochondral Allograft multicenter database: 36 patients (18 women/18 men) who were prescribed TTWB were allocated to the control cohort and 38 patients (21 women/17 men) who were prescribed WBAT were allocated to the test cohort. Baseline characteristics were similar except for larger grafts in test patients (3.4 vs 2.7 cm2; P = .004) and higher body mass index (BMI) in control patients (27.8 vs 24.9 kg/m2; P = .01). Failure rates, final patient-reported outcome (PRO) scores, and PRO score changes from baseline were compared between the cohorts. Multiple regression was used to control for potential confounders and investigate noninferiority using minimal clinically important differences (MCIDs). Results: The mean follow-up was 2 years (range, 1-5 years) in both cohorts. Both cohorts showed significant improvement in all PRO scores, with no significant between-group differences in failure rates, final PRO scores, or PRO changes from baseline. There were 3 cases of failure in each cohort (control cohort: allograft revision [n = 2], debridement [n = 1]; test cohort: chondroplasty [n = 2], conversion to total knee arthroplasty [n = 1]). Regression analysis showed that adjusted differences in final PRO scores based on weightbearing protocol were minor and less than MCIDs when controlling for age, sex, graft size, BMI, and allograft location. Analysis of the MCIDs with respect to the lower bounds of the confidence intervals indicated that WBAT was noninferior to TTWB with a reasonable degree of confidence (range, 84.1%-99.9% confidence). Conclusion: Results indicated that immediate unrestricted WBAT after OCA transplantation to the distal femur was equally safe and effective compared to restricted TTWB.

The Crossing Motor Ulnar Nerve Branch at Elbow.

BACKGROUND AND OBJECTIVES: Cubital tunnel syndrome is the second most common nerve entrapment, and understanding the anatomy is crucial for the success of the nerve release. During ulnar nerve release for cubital tunnel syndrome, a motor branch is frequently encountered crossing anteriorly over the ulnar nerve from its medial/ulnar side proximally to the lateral/radial side distally. Little has been noted about this crossing branch in the literature. In this anatomic study, we sought to characterize this branch further and discuss its potential significance in cubital tunnel release. METHODS: We performed a cadaveric dissection of 48 elbow specimens as if performing a cubital tunnel release. We assessed for the presence of the crossing motor branch of the ulnar nerve and measured the distance from the medial epicondyle to the branch takeoff and to its target of innervation. RESULTS: Of our 48 specimens, 34 (71%) were noted to have a crossing motor branch at the area of compression by the deep flexor carpi ulnaris muscle fascia (common aponeurosis). On average, the distance from the medial epicondyle to the branch origin from the ulnar nerve was 18.2 mm and to the target muscle innervation was 28.4 mm. CONCLUSION: Identifying this branch is important for performing a cubital tunnel release, and awareness of this anatomy during ulnar nerve decompression procedures may help avoid injury to this motor branch.

Implementation of a Secure Firearm Storage Program in Pediatric Primary Care: A Cluster Randomized Trial.

Importance: Increased secure firearm storage can reduce youth firearm injury and mortality, a leading cause of death for children and adolescents in the US. Despite the availability of evidence-based secure firearm storage programs and recommendations from the American Academy of Pediatrics, few pediatric clinicians report routinely implementing these programs. Objective: To compare the effectiveness of an electronic health record (EHR) documentation template (nudge) and the nudge plus facilitation (ie, clinic support to implement the program; nudge+) at promoting delivery of a brief evidence-based secure firearm storage program (SAFE Firearm) that includes counseling about secure firearm storage and free cable locks during all pediatric well visits. Design, Setting, and Participants: The Adolescent and Child Suicide Prevention in Routine Clinical Encounters (ASPIRE) unblinded parallel cluster randomized effectiveness-implementation trial was conducted from March 14, 2022, to March 20, 2023, to test the hypothesis that, relative to nudge, nudge+ would result in delivery of the firearm storage program to an additional 10% or more of the eligible population, and that this difference would be statistically significant. Thirty pediatric primary care clinics in 2 US health care systems (in Michigan and Colorado) were included, excluding clinics that were not the primary site for participating health care professionals and a subset selected at random due to resource limitations. All pediatric well visits at participating clinics for youth ages 5 to 17 years were analyzed. Interventions: Clinics were randomly assigned in a 1:1 ratio to receive either the nudge or nudge+. Main Outcomes and Measures: Patient-level outcomes were modeled to estimate the primary outcome, reach, which is a visit-level binary indicator of whether the parent received both components of the firearm storage program (counseling and lock), as documented by the clinician in the EHR. Secondary outcomes explored individual program component delivery. Results: A total of 47 307 well-child visits (median [IQR] age, 11.3 [8.1-14.4] years; 24 210 [51.2%] male and 23 091 [48.8%] female) among 46 597 children and 368 clinicians were eligible to receive the firearm storage program during the trial and were included in analyses. Using the intention-to-treat principle, a higher percentage of well-child visits received the firearm storage program in the nudge+ condition (49%; 95% CI, 37-61) compared to nudge (22%; 95% CI, 13-31). Conclusions and Relevance: In this study, the EHR strategy combined with facilitation (nudge+) was more effective at increasing delivery of an evidence-based secure firearm storage program compared to nudge alone. Trial Registration: ClinicalTrials.gov Identifier: NCT04844021.

Health literacy of older adults with musculoskeletal problems: A systematic review.

INTRODUCTION: People with poor Health Literacy (HL) find it difficult to understand medical information in their daily lives, participate in health-related decision making and comply with medical instructions. The physical effects of ageing on the musculoskeletal system have a direct impact on skills related to the management of health problems. Many older adults have limited HL, which impacts their ability to fully engage in their care and their health status. The aim of this study is to conduct a systematic review of the published research regarding the prevalence of low HL and its impact on health outcomes of older adults with musculoskeletal problems. METHODS: In accordance with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) Statement, this review examined all peer-reviewed studies published in English, with specific pre-selected eligibility criteria. RESULTS: The combined searches yielded 1617 records of which 19 articles were eligible for inclusion. The percentage of low HL varied across the studies of this review, ranging from 14% to 67%. In most studies, however, patients with limited HL were about 1/3 of the participants. Patients of lower educational level, male gender, older age, lower income, unemployment and different country of origin had lower HL level. Low HL was also associated with worse health outcomes, especially adherence to treatment, pain, functionality and health status. DISCUSSION: It is of major importance to conduct educational interventions aimed at enhancing HL in this patient group, as these will contribute to the empowerment and the promotion of appropriate health behaviors of these patients.

Sphingosine-1-phosphate-cathelicidin axis plays a pivotal role in the development of cutaneous squamous cell carcinoma.

Cutaneous squamous cell carcinoma (cSCC) is a common skin cancer, caused by mutagenesis resulting from excess ultraviolet radiation or other types of oxidative stress. These stressors also upregulate production of a cutaneous innate immune element, cathelicidin antimicrobial peptide (CAMP), via endoplasmic reticulum (ER) stress-initiated, sphingosine-1-phosphate (S1P) signaling pathway. While CAMP has beneficial antimicrobial activities, it also can be pro-inflammatory and pro-carcinogenic. We addressed whether and how S1P-induced CAMP production leads to cSCC development. Our study demonstrated that: 1) CAMP expression is increased in cSCC cells and skin from cSCC patients; 2) S1P levels are elevated in cSCC cells, while inhibition of S1P production attenuates CAMP-stimulated cSCC growth; 3) exogenous CAMP stimulates cSCC, but not normal human keratinocyte growth; 4) blockade of formyl peptide receptor-like (FPRL) 1 protein, a CAMP receptor, attenuates cSCC growth as well as the growth and invasion of cSCC cells mediated by CAMP into an extracellular matrix-containing fibroblast substrate; 5) Foxp3+ regulatory T cell (which decreases anti-tumor immunity) levels increase in cSCC skin; and 6) CAMP induces ER stress in cSCC cells. Together, the ER stress-S1P-CAMP axis forms a vicious circle, creating a favorable environment for cSCC development, i.e., cSCC growth and invasion impedes anti-cancer immunity.

A 32-channel high-impedance honeycomb-shaped receive array for temporal lobes exploration at 11.7T.

PURPOSE: The newly operational 11.7T Iseult scanner provides an improved global SNR in the human brain. This gain in SNR can be pushed even further locally by designing region-focused dense receive arrays. The temporal lobes are particularly interesting to neuroscientists as they are associated with language and concept recognition. Our main goal was to maximize the SNR in the temporal lobes and provide high-acceleration capabilities for fMRI studies. METHODS: We designed and developed a 32-channel receive array made of non-overlapped hexagonal loops. The loops were arranged in a honeycomb pattern and targeted the temporal lobes. They were placed on a flexible neoprene cap closely fitting the head. A new stripline design with a high impedance was proposed and applied for the first time at 11.7T. Specific homebuilt miniaturized low-impedance preamplifiers were directly mounted on the loops, providing preamplifier decoupling in a compact and modular design. Using an anatomical phantom, we experimentally compared the SNR and parallel imaging performance of the region-focused cap to a 32-channel whole-brain receive array at 11.7T. RESULTS: The experimental results showed a 1.7-time higher SNR on average in the temporal lobes compared to the whole brain receive array. The g-factor is also improved when undersampling in the antero-posterior and head-foot directions. CONCLUSION: A significant SNR boost in the temporal lobes was demonstrated at 11.7T compared to the whole-brain receive array. The parallel imaging capabilities were also improved in the temporal lobes in some acceleration directions.

An Ultrasensitive Molecularly Imprinted Point-Of-Care Electrochemical Sensor for Detection of Glial Fibrillary Acidic Protein.

Accurate assessment of neurological disease through monitoring of biomarkers has been made possible using the antibody-based assays. But these assays suffer from expensive development of antibody probes, reliance on complicated equipments, and high maintenance costs. Here, using the novel reduced graphene oxide/polydopamine-molecularly imprinted polymer (rGO/PDA-MIP) as the probe layer, a robust electrochemical sensing platform is demonstrated for the ultrasensitive detection of glial fibrillary acidic protein (GFAP), a biomarker for a range of neurological diseases. A miniaturized integrated circuit readout system is developed to interface with the electrochemical sensor, which empowers it with the potential to be used as a point-of-care (POC) diagnostic tool in primary clinical settings. This innovative platform demonstrated good sensitivity, selectivity, and stability, with imprinting factor evaluated as 2.8. A record low limit-of-detection (LoD) is down to 754.5 ag mL-1, with a wide dynamic range from 1 to 106 fg mL-1. The sensing platform is validated through the analysis of GFAP in clinical plasma samples, yielding a recovery rate range of 81.6-108.8% compared to Single Molecule Array (Simoa). This cost-effective and user-friendly sensing platform holds the potential to be deployed in primary and resource-limited clinical settings for the assessment of neurological diseases.

PTH may predict early mortality in incident patients on hemodialysis: results from a large cohort.

PURPOSE: Parathyroid hormone (PTH) is merit as a risk factor for mortality in patients with chronic kidney disease in prevalent hemodialysis patients in a U shape. Most studies, however, do not focus on incident patients and those who died within the first 90 days of therapy. We evaluated PTH as a risk factor for mortality in a large cohort population in Brazil. METHODS: This is an observational cohort study that included 4317 adult patients who initiated hemodialysis between July 1st, 2012 and June 30, 2017. The main outcome was all-cause mortality. Fine-gray sub-distribution hazard models were used to evaluate survival in the presence of a competing event (kidney transplant). RESULTS: Median PTH levels of 252 (118, 479) pg/mL. There were 331 deaths during the first 90 days of therapy (6.7%), 430 in a 1-year follow-up (10.7%) and 1282 (32%) during the 5-year study period. Deaths according to PTH < 150, 150-600 and > 600 pg/mL corresponded to 38.1%, 33.0% and 28.5%, respectively (p < 0.001). In an adjusted model, patients who started dialysis with PTH < 150 pg/mL had a higher mortality risk within the first 90 days, but not in 1 year and 5 years after starting dialysis. Analyses in a subset of patients with a repeated PTH in 1 year (N = 1954) showed that although persistent PTH low levels (< 150 pg/mL) at 1 year were significantly associated with all-cause mortality, this result was not sustained after multiple adjustments. CONCLUSION: PTH < 150 pg/mL confers a high mortality risk in the first 90 days of dialysis. If this result reflects poor nutritional conditions, it deserves further investigations.

The hepatitis C virus envelope protein complex is a dimer of heterodimers.

Fifty-eight million individuals worldwide are affected by chronic hepatitis C virus (HCV) infection, a primary driver of liver cancer for which no vaccine is available1. The HCV envelope proteins E1 and E2 form a heterodimer (E1/E2), which is the target for neutralizing antibodies2. However, the higher-order organization of these E1/E2 heterodimers, as well as that of any Hepacivirus envelope protein complex, remains unknown. Here we determined the cryo-electron microscopy structure of two E1/E2 heterodimers in a homodimeric arrangement. We reveal how the homodimer is established at the molecular level and provide insights into neutralizing antibody evasion and membrane fusion by HCV, as orchestrated by E2 motifs such as hypervariable region 1 and antigenic site 412, as well as the organization of the transmembrane helices, including two internal to E1. This study addresses long-standing questions on the higher-order oligomeric arrangement of Hepacivirus envelope proteins and provides a critical framework in the design of novel HCV vaccine antigens.

Two +ssRNA mycoviruses cohabiting the fungal cultivar of leafcutter ants.

Leafcutter ants are dominant herbivores in the Neotropics and rely on a fungus (Leucoagaricus gongylophorus) to transform freshly gathered leaves into a source of nourishment rather than consuming the vegetation directly. Here we report two virus-like particles that were isolated from L. gongylophorus and observed using transmission electron microscopy. RNA sequencing identified two +ssRNA mycovirus strains, Leucoagaricus gongylophorus tymo-like virus 1 (LgTlV1) and Leucoagaricus gongylophorus magoulivirus 1 (LgMV1). Genome annotation of LgTlV1 (7401 nt) showed conserved domains for methyltransferase, endopeptidase, viral RNA helicase, and RNA-dependent RNA polymerase (RdRp). The smaller genome of LgMV1 (2636 nt) contains one open reading frame encoding an RdRp. While we hypothesize these mycoviruses function as symbionts in leafcutter farming systems, further study will be needed to test whether they are mutualists, commensals, or parasites.

Colony stimulating factor 1 receptor (Csf1r) expressing cell ablation in mafia (macrophage-specific Fas-induced apoptosis) mice alters monocyte landscape and atherosclerotic lesion characteristics.

Macrophage infiltration and accumulation in the atherosclerotic lesion are associated with plaque progression and instability. Depletion of macrophages from the lesion might provide valuable insights into plaque stabilization processes. Therefore, we assessed the effects of systemic and local macrophage depletion on atherogenesis. To deplete monocytes/macrophages we used atherosclerosis-susceptible Apoe- /- mice, bearing a MaFIA (macrophage-Fas-induced-apoptosis) suicide construct under control of the Csf1r (CD115) promotor, where selective apoptosis of Csf1r-expressing cells was induced in a controlled manner, by administration of a drug, AP20187. Systemic induction of apoptosis resulted in a decrease in lesion macrophages and smooth-muscle cells. Plaque size and necrotic core size remained unaffected. Two weeks after the systemic depletion of macrophages, we observed a replenishment of the myeloid compartment. Myelopoiesis was modulated resulting in an expansion of CSF1Rlo myeloid cells in the circulation and a shift from Ly6chi monocytes toward Ly6cint and Ly6clo populations in the spleen. Local apoptosis induction led to a decrease in plaque burden and macrophage content with marginal effects on the circulating myeloid cells. Local, but not systemic depletion of Csf1r+ myeloid cells resulted in decreased plaque burden. Systemic depletion led to CSF1Rlo-monocyte expansion in blood, possibly explaining the lack of effects on plaque development.

LIANA+ provides an all-in-one framework for cell-cell communication inference.

The growing availability of single-cell and spatially resolved transcriptomics has led to the development of many approaches to infer cell-cell communication, each capturing only a partial view of the complex landscape of intercellular signalling. Here we present LIANA+, a scalable framework built around a rich knowledge base to decode coordinated inter- and intracellular signalling events from single- and multi-condition datasets in both single-cell and spatially resolved data. By extending and unifying established methodologies, LIANA+ provides a comprehensive set of synergistic components to study cell-cell communication via diverse molecular mediators, including those measured in multi-omics data. LIANA+ is accessible at https://github.com/saezlab/liana-py with extensive vignettes ( https://liana-py.readthedocs.io/ ) and provides an all-in-one solution to intercellular communication inference.