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BACKGROUND: A proliferation-inducing ligand (APRIL) is implicated in the pathogenesis of IgA nephropathy. Sibeprenlimab is a humanized IgG2 monoclonal antibody that binds to and neutralizes APRIL. METHODS: In this phase 2, multicenter, double-blind, randomized, placebo-controlled, parallel-group trial, we randomly assigned adults with biopsy-confirmed IgA nephropathy who were at high risk for disease progression, despite having received standard-care treatment, in a 1:1:1:1 ratio to receive intravenous sibeprenlimab at a dose of 2, 4, or 8 mg per kilogram of body weight or placebo once monthly for 12 months. The primary end point was the change from baseline in the log-transformed 24-hour urinary protein-to-creatinine ratio at month 12. Secondary end points included the change from baseline in the estimated glomerular filtration rate (eGFR) at month 12. Safety was also assessed. RESULTS: Among 155 patients who underwent randomization, 38 received sibeprenlimab at a dose of 2 mg per kilogram, 41 received sibeprenlimab at a dose of 4 mg per kilogram, 38 received sibeprenlimab at a dose of 8 mg per kilogram, and 38 received placebo. At 12 months, the geometric mean ratio reduction (±SE) from baseline in the 24-hour urinary protein-to-creatinine ratio was 47.2±8.2%, 58.8±6.1%, 62.0±5.7%, and 20.0±12.6% in the sibeprenlimab 2-mg, 4-mg, and 8-mg groups and the placebo group, respectively. At 12 months, the least-squares mean (±SE) change from baseline in eGFR was -2.7±1.8, 0.2±1.7, -1.5±1.8, and -7.4±1.8 ml per minute per 1.73 m2 in the sibeprenlimab 2-mg, 4-mg, and 8-mg groups and the placebo group, respectively. The incidence of adverse events that occurred after the start of administration of sibeprenlimab or placebo was 78.6% in the pooled sibeprenlimab groups and 71.1% in the placebo group. CONCLUSIONS: In patients with IgA nephropathy, 12 months of treatment with sibeprenlimab resulted in a significantly greater decrease in proteinuria than placebo. (Funded by Visterra; ENVISION ClinicalTrials.gov number, NCT04287985; EudraCT number, 2019-002531-29.).
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Anticorpos Monoclonais Humanizados , Glomerulonefrite por IGA , Membro 13 da Superfamília de Ligantes de Fatores de Necrose Tumoral , Adulto , Humanos , Administração Intravenosa , Creatinina/urina , Método Duplo-Cego , Taxa de Filtração Glomerular , Glomerulonefrite por IGA/complicações , Glomerulonefrite por IGA/tratamento farmacológico , Glomerulonefrite por IGA/genética , Proteinúria/tratamento farmacológico , Proteinúria/etiologia , Anticorpos Monoclonais Humanizados/administração & dosagem , Anticorpos Monoclonais Humanizados/efeitos adversos , Anticorpos Monoclonais Humanizados/uso terapêutico , Membro 13 da Superfamília de Ligantes de Fatores de Necrose Tumoral/antagonistas & inibidores , Membro 13 da Superfamília de Ligantes de Fatores de Necrose Tumoral/genética , Imunoglobulina GRESUMO
BACKGROUND: Current diagnoses of urinary tract infection (UTI) by standard urine culture (SUC) has significant limitations in sensitivity, especially for fastidious organisms, and the ability to identify organisms in polymicrobial infections. The significant rate of both SUC "negative" or "mixed flora/contamination" results in UTI cases and the high prevalence of asymptomatic bacteriuria indicate the need for an accurate diagnostic test to help identify true UTI cases. This study aimed to determine if infection-associated urinary biomarkers can differentiate definitive UTI cases from non-UTI controls. METHODS: Midstream clean-catch voided urine samples were collected from asymptomatic volunteers and symptomatic subjects ≥ 60 years old diagnosed with a UTI in a urology specialty setting. Microbial identification and density were assessed using a multiplex PCR/pooled antibiotic susceptibility test (M-PCR/P-AST) and SUC. Three biomarkers [neutrophil gelatinase-associated lipocalin (NGAL), and Interleukins 8 and 1ß (IL-8, and IL-1ß)] were also measured via enzyme-linked immunosorbent assay (ELISA). Definitive UTI cases were defined as symptomatic subjects with a UTI diagnosis and positive microorganism detection by SUC and M-PCR, while definitive non-UTI cases were defined as asymptomatic volunteers. RESULTS: We observed a strong positive correlation (R2 > 0.90; p < 0.0001) between microbial density and the biomarkers NGAL, IL-8, and IL-1ß for symptomatic subjects. Biomarker consensus criteria of two or more positive biomarkers had sensitivity 84.0%, specificity 91.2%, positive predictive value 93.7%, negative predictive value 78.8%, accuracy 86.9%, positive likelihood ratio of 9.58, and negative likelihood ratio of 0.17 in differentiating definitive UTI from non-UTI cases, regardless of non-zero microbial density. NGAL, IL-8, and IL-1ß showed a significant elevation in symptomatic cases with positive microbe identification compared to asymptomatic cases with or without microbe identification. Biomarker consensus exhibited high accuracy in distinguishing UTI from non-UTI cases. CONCLUSION: We demonstrated that positive infection-associated urinary biomarkers NGAL, IL-8, and IL-1ß, in symptomatic subjects with positive SUC and/or M-PCR results was associated with definitive UTI cases. A consensus criterion with ≥ 2 of the biomarkers meeting the positivity thresholds showed a good balance of sensitivity (84.0%), specificity (91.2%), and accuracy (86.9%). Therefore, this biomarker consensus is an excellent supportive diagnostic tool for resolving the presence of active UTI, particularly if SUC and M-PCR results disagree.
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Interleucina-8 , Infecções Urinárias , Humanos , Pessoa de Meia-Idade , Lipocalina-2 , Consenso , Curva ROC , Infecções Urinárias/diagnóstico , Biomarcadores , Sensibilidade e EspecificidadeRESUMO
BACKGROUND: This study aimed to determine the incidence and prevalence of immunoglobulin A nephropathy (IgAN) in Europe based on high-quality data from national registries. METHODS: IgAN incidences were obtained from a literature review of European studies of national kidney biopsy registry data in which IgAN diagnosis was biopsy-verified using contemporary techniques. Studies were eligible for the main analysis if published from 1990 to 2020. IgAN point prevalence was defined as the annual IgAN incidence multiplied by the estimated duration of disease. Incidence and prevalence estimates were made for three pooled populations: (i) patients of all ages; (ii) pediatric patients; and (iii) elderly patients. RESULTS: Across 10 European countries, the estimated annual IgAN incidence was 0.76 per 100 000 in patients of all ages. The corresponding pooled IgAN point prevalence was 2.53 per 10 000 (95% confidence interval: 2.51-2.55), ranging from 1.14 per 10 000 in Spain to 5.98 per 10 000 in Lithuania. Applied to 2021 population estimates, the number of expected prevalent IgAN cases was 47 027 across all 10 countries and ranged from 577 in Estonia to 16 645 in Italy. Among pediatric patients, IgAN incidence was 0.20 per 100 000 children and IgAN point prevalence was 0.12 per 10 000 children. Among elderly patients, IgAN incidence was 0.30 per 100 000 and IgAN point prevalence was 0.36 per 10 000. CONCLUSIONS: Based on high-quality data from European national registries, IgAN point prevalence was estimated at 2.53 per 10 000 in patients of all ages. Prevalence was considerably lower in pediatric and elderly populations.
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Glomerulonefrite por IGA , Idoso , Criança , Humanos , Biópsia , Europa (Continente)/epidemiologia , Glomerulonefrite por IGA/epidemiologia , Glomerulonefrite por IGA/patologia , Incidência , Prevalência , AdultoRESUMO
Standard urine culture (SUC) is the current standard method for confirmation of a urinary tract infection (UTI). SUC identifies microorganisms in urine samples and semi-quantifies these as colony-forming units (CFUs) ml-1. In contrast, quantitative multiplex polymerase chain reaction (q-MPCR) is a culture-independent assay in which the microbes are quantified by targeting genomic sequences and reported as cells ml-1, calculated from copies ml-1. Using serial dilutions within the 104-105 cells ml-1 range, the usual reporting range of SUC, this study compared the quantification results based on SUC and q-MPCR for four uropathogens with the control hemocytometer counts. The results revealed a linear relationship and a 1:1 correlation between the q-MPCR and SUC results. Additional q-MPCR quantification of 36 uropathogenic non-fastidious and fastidious bacteria and yeast indicated a reproducible linear correlation in a 1:1 manner with the control counts over a range of cell densities (103-106 cells ml-1). The results confirm that the quantifications by q-MPCR in cells ml-1 and by SUC in CFUs ml-1 are comparable and answer to the lingering question of how the results of these two methods correlate. Moreover, q-MPCR provided accurate quantification of various microorganisms over wider cell density ranges without the time required for microbial growth.
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Reação em Cadeia da Polimerase Multiplex , Infecções Urinárias , Humanos , Reação em Cadeia da Polimerase Multiplex/métodos , Sensibilidade e Especificidade , Infecções Urinárias/diagnóstico , Infecções Urinárias/microbiologia , Urinálise/métodos , Bactérias/genéticaRESUMO
OBJECTIVE: The aim of the study was to identify indicated homeopathic remedies based on the clinical characteristics of coronavirus disease 2019 (COVID-19) patients in India. METHODS: In this retrospective, cohort study, confirmed COVID-19 patients admitted at a COVID Health Centre in New Delhi between April 29 and June 17, 2020 were given conventional and homeopathic treatment. Patients were grouped into mild, moderate or severe categories of disease. Their symptomatologic profiles were analyzed to identify indicated homeopathic medicines. RESULTS: A total of 196 COVID-19 patients were admitted. One hundred and seventy-eight patients had mild symptoms; eighteen patients had moderate symptoms; no patients with severe symptoms were included as they were referred to tertiary care centers with ventilatory support. The mean age of patients with mild symptoms was significantly lower (38.6 years; standard deviation or SD ± 15.8) compared with patients in the moderate category (66.0 years; SD ± 9.09). The most important symptoms identified were fever (43.4%), cough (47.4%), sore throat (29.6%), headache (18.4%), myalgia (17.9%), fatigue (16.8%), chest discomfort (13.8%), chills (12.6%), shortness of breath (11.2%) and loss of taste (10.2%). Twenty-eight homeopathic medicines were prescribed, the most frequently indicated being Bryonia alba (33.3%), Arsenicum album (18.1%), Pulsatilla nigricans (13.8%), Nux vomica (8%), Rhus toxicodendron (7.2%) and Gelsemium sempervirens (5.8%), in 30C potency. CONCLUSION: Data from the current study reveal that Arsenicum album, Bryonia alba, Pulsatilla nigricans, Nux vomica, Rhus toxicodendron and Gelsemium sempervirens are the most frequently indicated homeopathic medicines. A randomized controlled clinical trial based on this finding is the next step.
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COVID-19/terapia , Fitoterapia , Adulto , Idoso , Arsenicais/uso terapêutico , Bryonia , Estudos de Coortes , Feminino , Gelsemium , Homeopatia , Humanos , Índia , Masculino , Pessoa de Meia-Idade , Extratos Vegetais/uso terapêutico , Pulsatilla , Estudos Retrospectivos , Índice de Gravidade de Doença , Strychnos nux-vomica , ToxicodendronRESUMO
BACKGROUND: Pituitary adenomas are common benign tumors of the pituitary gland with an overall estimated prevalence of 16.7%. As per the revised World Health Organization (WHO) classification, these tumors are identified by their histological subtypes and are designated by their pituitary cell lineage instead of the hormone they produce. The lactotroph adenoma is the most common subtype of hormone-producing pituitary adenoma. Surgery is the mainstay of treatment, but complications are encountered. So far, there is no reported study evaluating individualized homeopathic intervention in pituitary adenoma in peer-reviewed journals. METHODS: This case study describes a case of functional lactotroph microadenoma with history of failed surgical treatment and heavy intrasellar hemorrhage occurring during the surgery. Phosphorus was prescribed as an individualized homeopathic medicine on the basis of symptoms-hemorrhagic complication during surgical procedure and aggravation of headache thereafter. RESULTS: There was a marked subjective improvement along with complete tumor regression, as evidenced by repeat magnetic resonance imaging scans. The Modified Naranjo Criteria total score was +10 out of a possible +13, providing some evidence to attribute the clinical outcome with the homeopathic intervention. CONCLUSION: This case study reconfirms the association between increased frequency of headaches and pituitary hemorrhage among cases of lactotroph adenoma. It also suggests that individualized homeopathic treatment may be helpful in pituitary adenomas with increased risk of complications such as intrasellar hemorrhage.
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Homeopatia/métodos , Materia Medica/uso terapêutico , Fósforo/uso terapêutico , Neoplasias Hipofisárias/tratamento farmacológico , Prolactinoma/tratamento farmacológico , Adulto , Feminino , Humanos , Imageamento por Ressonância Magnética , Neoplasias Hipofisárias/diagnóstico por imagem , Neoplasias Hipofisárias/cirurgia , Prolactinoma/diagnóstico por imagem , Prolactinoma/cirurgiaRESUMO
BACKGROUND: Trimethoprim-sulfamethoxazole (TMP-SMX) is the drug of choice for anti-Pneumocystis jirovecii pneumonia (PcP) prophylaxis in kidney transplant recipients (KTR). Post-transplant management balances preventing PcP with managing TMP-SMX-related adverse effects. TMP-SMX dose reduction addresses adverse effects but its implications to incident PcP are unclear. METHODS: We performed a retrospective review of all patients transplanted between 2011 and 2015 prescribed daily single strength TMP-SMX for twelve months post-transplantation as PcP prophylaxis. Actual TMP-SMX dose and duration, adverse effects, number of dose reductions and reasons, and PcP events were captured. Multivariate logistic regression analyses for risk factors associated with dose reduction were performed. RESULTS: Of 438 KTR, 233 (53%) maintained daily TMP-SMX and 205 (47%) sustained ≥1 dose reduction, with the point prevalence of a reduced dose regimen being between 18 and 25%. Median duration for daily TMP-SMX was 8.45/12 months, contributing 4137 patient-months daily TMP-SMX and 1110 patient-months with a reduced dose. PcP did not occur in any patients. There were 84 documented dose reductions for hyperkalemia and 102 for leukopenia, with 12 and 7 patients requiring TMP-SMX cessation. In multivariate analysis, a living donor transplant protected against hyperkalemia (Odds Ratio 0.46, 95% CI 0.26-0.83, p < 0.01) while acute rejection risked leukopenia (Odds Ratio 3.31, 95% CI 1.39-7.90, p = 0.006). CONCLUSIONS: TMP-SMX dose reduction is frequent in the first post-transplant year but PcP does not occur. To limit the need for TMP-SMX dose reduction due to adverse effects, a clinical trial comparing daily to thrice weekly single strength TMP-SMX in de-novo KTR is justified.
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Antibioticoprofilaxia/efeitos adversos , Transplante de Rim/métodos , Pneumonia por Pneumocystis/prevenção & controle , Combinação Trimetoprima e Sulfametoxazol/administração & dosagem , Adulto , Idoso , Idoso de 80 Anos ou mais , Antibioticoprofilaxia/métodos , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Pneumocystis carinii/patogenicidade , Pneumonia por Pneumocystis/tratamento farmacológico , Estudos Retrospectivos , Transplantados , Resultado do Tratamento , Combinação Trimetoprima e Sulfametoxazol/uso terapêuticoRESUMO
The R146G mutation of troponin I (TnI) is associated with hypertrophic cardiomyopathy in humans. Earlier data pointed to stabilization of the intermediate, C state, of actin-tropomyosin-troponin by this mutant. Because cardiac disorders appear to be linked to changes in regulated actin distributions, we determined the extent to which the R146G TnI mutant alters the distribution of states at low and high Ca(2+) concentrations. We show, from measurements of the kcat for actin-activated ATPase activity at saturating Ca(2+) concentrations, that R146G TnI reduced the population of the active, M, state to 25% of the wild-type level. Together with acrylodan-tropomyosin fluorescence measurements of the B state, it appeared that the C state was populated at â¼91% of the total for the R146G TnI-containing actin filaments. The C state was also more heavily populated at low Ca(2+) concentrations. Acrylodan-tropomyosin fluorescence changes showed a large diminution in the inactive state value relative to the wild-type value without a comparable increase in the active state. Furthermore, the rate of binding of rigor S1 to pyrene-labeled actin filaments containing R146G TnI was faster than the rate of binding to wild-type filaments at low free Ca(2+) concentrations. These results indicate that the inhibitory region of TnI affects the B-C and M-C equilibria of actin-tropomyosin-troponin. The observation that a mutation in the inhibitory region affects the M-C equilibrium may point to a novel regulatory interaction.
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Actinas/química , Actinas/metabolismo , Cálcio/farmacologia , Cardiomiopatias/genética , Mutação , Troponina I/genética , Animais , Cardiomiopatias/metabolismo , Bovinos , Relação Dose-Resposta a Droga , Cinética , Camundongos , Estabilidade Proteica , CoelhosRESUMO
BACKGROUND: Transanal pull-through with laparoscopic assistance is gaining popularity. How much rectal dissection to do laparoscopically and how much transanally is not clear. Laparoscopic rectal mobilization is akin to open pelvic dissection of Swenson's operation - the most physiological procedure. Through this comparative study, we aim to evolve a technique that maximizes the benefits of Swenson's technique and minimizes the problems of a transanal procedure. MATERIALS AND METHODS: Twenty patients (19 boys and one girl, newborn to 6 years) with Hirschsprung's disease (HD) were randomized for laparoscopic-assisted transanal pull-through (LATAPT) either by near complete (Group A) or partial (Group B) laparoscopic mobilization of rectum. Patients were followed up for at least 3 months. Demographic profile; operative details (time taken, blood loss, operative difficulty, and complications); postoperative course (duration of urinary catheter, oral feeding, and hospital stay); and follow-up stooling pattern, consistency, and continence were compared in the two groups. RESULTS: The time taken for laparoscopic mobilization was marginally higher in group A, but the time taken for transanal dissection in this group was significantly less than in group B. All other comparisons showed no significant difference in the two groups. Stool frequency and continence improved with time in both groups. CONCLUSION: Extent of laparoscopic mobilization of rectum does not appear to be a factor deciding the outcomes. No recommendations could be made in view of the small number of cases. However, it shows that laparoscopic assistance can be used to maximize the benefits of Swenson type of operation and a transanal pull-through.
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Background: The purpose of this study is to explore the effect of vitamin B complex supplementation following periodontal flap surgery on clinical and microbiological parameters. Materials and Methods: A randomized controlled trial on 10 patients with periodontitis in split-mouth design was undertaken to find the effect of vitamin B complex supplementation with open flap debridement on periodontal wound healing. Multiplex polymerase chain reaction (PCR) for Tannerella forsythus and Porphyromonas gingivalis was done using subgingival plaque samples at 0 and 90th day. Results: The results showed a significant reduction (P < 0.01) of clinical (plaque index, gingival index, gingival bleeding index, probing pocket depth, and relative attachment level) and microbial profile in both treatment groups, whereas on intergroup analysis, more reduction in all clinical parameters were observed in the test group, but statistically, the results were insignificant.
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Background: Many emerging uropathogens are currently identified by multiplex polymerase chain reaction (M-PCR) in suspected UTI cases. Standard urine culture (SUC) has significantly lower detection rates, raising questions about whether these organisms are associated with UTIs and truly cause inflammation. Objective: To determine if microbes detected by M-PCR were likely causative of UTI by measuring inflammatory biomarkers in the urine of symptomatic patients. Design Setting and Participants: Midstream voided urine was collected from subjects ≥60 years presenting to urology clinics with symptoms of UTI (n = 1132) between 01/2023 and 05/2023. Microbe detection was by M-PCR and inflammation-associated biomarker (neutrophil gelatinase-associated lipocalin, interleukin 8, and interleukin 1ß) was by enzyme-linked immunosorbent assay. Biomarker positivity was measured against individual and groups of organisms, E. coli and non-E. coli cases, emerging uropathogens, monomicrobial and polymicrobial cases. Outcome Measurements and Statistical Analysis: Distributions were compared using 2-sample Wilcoxon Rank Sum test with 2-tailed p-values < 0.05 considered statistically significant. Results and Limitations: M-PCR was positive in 823 (72.7%) specimens with 28 of 30 (93%) microorganisms/groups detected. Twenty-six of twenty-eight detected microorganisms/groups (93%) had ≥2 biomarkers positive in >66% of cases. Both non-E. coli cases and E. coli cases had significant biomarker positivity (p < 0.05). Limitations were that a few organisms had low prevalence making inferences about their individual significance difficult. Conclusion: The majority of microorganisms identified by M-PCR were associated with active inflammation measured by biomarker positivity, indicating they are likely causative of UTIs in symptomatic patients. This includes emerging uropathogens frequently not detected by standard urine culture.
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Randomized clinical trials are underway to evaluate the efficacy of novel agents targeting the alternative complement pathway in patients with C3 glomerulopathy (C3G), a rare glomerular disease. The Kidney Health Initiative convened a panel of experts in C3G to ( 1 ) assess the data supporting the use of the prespecified trial end points as measures of clinical benefit and ( 2 ) opine on efficacy findings they would consider compelling as treatment(s) of C3G in native kidneys. Two subpanels of the C3G Trial Endpoints Work Group reviewed the available evidence and uncertainties for the association between the three prespecified end points-( 1 ) proteinuria, ( 2 ) eGFR, and ( 3 ) histopathology-and anticipated outcomes. The full work group provided feedback on the summaries provided by the subpanels and on what potential treatment effects on the proposed end points they would consider compelling to support evidence of an investigational product's effectiveness for treating C3G. Members of the full work group agreed with the characterization of the data, evidence, and uncertainties, supporting the end points. Given the limitations of the available data, the work group was unable to define a minimum threshold for change in any of the end points that might be considered clinically meaningful. The work group concluded that a favorable treatment effect on all three end points would provide convincing evidence of efficacy in the setting of a therapy that targeted the complement pathway. A therapy might be considered effective in the absence of complete alignment in all three end points if there was meaningful lowering of proteinuria and stabilization or improvement in eGFR. The panel unanimously supported efforts to foster data sharing between academic and industry partners to address the gaps in the current knowledge identified by the review of the end points in the aforementioned trials.
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Single cell sequencing technologies have rapidly advanced in the last decade and are increasingly applied to gain unprecedented insights by deconstructing complex biology to its fundamental unit, the individual cell. First developed for measurement of gene expression, single cell sequencing approaches have evolved to allow simultaneous profiling of multiple additional features, including chromatin accessibility within the nucleus and protein expression at the cell surface. These multi-omic approaches can now further be applied to cells in situ, capturing the spatial context within which their biology occurs. To extract insights from these complex datasets, new computational tools have facilitated the integration of information across different data types and the use of machine learning approaches. Here, we summarize current experimental and computational methods for generation and integration of single cell multi-omic datasets. We focus on opportunities for multi-omic single cell sequencing to augment therapeutic development for kidney disease, including applications for biomarkers, disease stratification and target identification.
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BACKGROUND: There are ancient texts and modern studies alluding to the therapeutic benefits obtained from listening to music. Studies have shown that chanting "OM" has a relaxing effect by causing parasympathetic dominance, limbic deactivation, and decreasing the brain's dopamine levels. This research aims to study the effect of listening to OM chanting on the cardiovascular system and heart rate variability and its possible use as a stress buster among medical students. MATERIALS AND METHODS: Fifty medical undergraduates were selected for the study. After a 20-minute relaxation, a lead 2 electrocardiogram (EKG) was recorded for 10 minutes. Their blood pressure (BP) and heart rate were measured. The subjects were then made to listen to OM chanting for 20 minutes, immediately after which their BP and heart rate were measured. This was followed by another 10-minute lead 2 EKG. The EKGs recorded were then used to calculate the standard deviation in N-N interval (SDNN), total power, high-frequency power, and low-frequency power. RESULTS: The study reported a significant decrease in blood pressure and heart rate and a significant increase in SDNN and total power. There was also an insignificant increase in low frequency and an insignificant decrease in high frequency. CONCLUSION: This study provides insight into the importance of spiritual music therapy in the maintenance of mental as well as cardiovascular health among medical students.
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This study compared rates of empirical-therapy use and negative patient outcomes between complicated and recurrent urinary tract infection (r/cUTI) cases diagnosed with a multiplex polymerase chain reaction or pooled antibiotic susceptibility testing (M-PCR/P-AST) vs. standard urine culture (SUC). Subjects were 577 symptomatic adults (n = 207 males and n = 370 females) presenting to urology/urogynecology clinics between 03/30/2022 and 05/24/2023. Treatment and outcomes were recorded by the clinician and patient surveys. The M-PCR/P-AST (n = 252) and SUC (n = 146) arms were compared after patient matching for confounding factors. The chi-square and Fisher's exact tests were used to analyze demographics and clinical outcomes between study arms. Reduced empirical-treatment use (28.7% vs. 66.7%), lower composite negative events (34.5% vs. 46.6%, p = 0.018), and fewer individual negative outcomes of UTI-related medical provider visits and UTI-related visits for hospitalization/an urgent care center/an emergency room (p < 0.05) were observed in the M-PCR/P-AST arm compared with the SUC arm. A reduction in UTI symptom recurrence in patients ≥ 60 years old was observed in the M-PCR/P-AST arm (p < 0.05). Study results indicate that use of the M-PCR/P-AST test reduces empirical antibiotic treatment and negative patient outcomes in r/cUTI cases.
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A PRoliferation-Inducing Ligand (APRIL), the thirteenth member of the tumor necrosis factor superfamily, plays a key role in the regulation of activated B cells, the survival of long-lived plasma cells, and immunoglobulin (Ig) isotype class switching. Several lines of evidence have implicated APRIL in the pathogenesis of IgA nephropathy (IgAN). Globally, IgAN is the most common primary glomerulonephritis, and it can progress to end-stage kidney disease; yet, disease-modifying treatments for this condition have historically been lacking. The preliminary data in ongoing clinical trials indicate that APRIL inhibition can reduce proteinuria and slow the rate of kidney disease progression by acting at an upstream level in IgAN pathogenesis. In this review, we examine what is known about the physiologic roles of APRIL and evaluate the experimental and epidemiological evidence describing how these normal biologic processes are thought to be subverted in IgAN. The weight of the preclinical, clinical, and genetic data supporting a key role for APRIL in IgAN has galvanized pharmacologic research, and several anti-APRIL drug candidates have now entered clinical development for IgAN. Herein, we present an overview of the clinical results to date. Finally, we explore where more research and evidence are needed to transform potential therapies into clinical benefits for patients with IgAN.
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The literature lacks consensus on the minimum microbial density required for diagnosing urinary tract infections (UTIs). This study categorized the microbial densities of urine specimens from symptomatic UTI patients aged ≥ 60 years and correlated them with detected levels of the immune response biomarkers neutrophil gelatinase-associated lipocalin (NGAL), interleukin-8 (IL-8), and interleukin-1-beta (IL-1ß). The objective was to identify the microbial densities associated with significant elevation of these biomarkers in order to determine an optimal threshold for diagnosing symptomatic UTIs. Biobanked midstream voided urine samples were analyzed for microbial identification and quantification using standard urine culture (SUC) and multiplex-polymerase chain reaction (M-PCR) testing, while NGAL, IL-8, and IL-1ß levels were measured via enzyme-linked immunosorbent assay (ELISA). NGAL, IL-8, and IL-1ß levels were all significantly elevated at microbial densities ≥ 10,000 cells/mL when measured via M-PCR (p < 0.0069) or equivalent colony-forming units (CFUs)/mL via SUC (p < 0.0104) compared to samples with no detectable microbes. With both PCR and SUC, a consensus of two or more elevated biomarkers correlated well with microbial densities > 10,000 cells/mL or CFU/mL, respectively. The association between ≥10,000 cells and CFU per mL with elevated biomarkers in symptomatic patients suggests that this lower threshold may be more suitable than 100,000 CFU/mL for diagnosing UTIs.
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Sibeprenlimab blocks the cytokine "A Proliferation-Inducing Ligand" (APRIL), which may play a key role in immunoglobulin A nephropathy pathogenesis. A phase 1 study of subcutaneous (SC) sibeprenlimab evaluated preliminary safety, tolerability, pharmacokinetics, and pharmacodynamics in healthy participants. This was an open-label, single-ascending-dose study. Twelve participants in each of 4 sequential dosing cohorts received 1 SC dose of sibeprenlimab (200 mg [1×1 mL injection], 400 mg [2×1 mL injections], 400 mg [1×2 mL injection], or 600 mg [1 mL+2 mL injections]) and underwent 16-week follow-up for adverse events, pharmacokinetics, and pharmacodynamics (serum APRIL, immunoglobulin [Ig] levels). Sibeprenlimab in single SC doses of 200-600 mg was slowly absorbed into the systemic circulation, with a median time to maximum serum concentration of approximately 6-10.5 days, and a mean elimination half-life of approximately 8-10 days. Serum APRIL, IgA, IgM, and, to a lesser extent, IgG decreased in a dose-dependent and reversible manner. Maximal reduction in serum IgA was approximately 60% at the 400- and 600-mg doses and 40% at 200 mg. Serum APRIL rapidly decreased to near the lower limit of quantification, and duration of suppression was dose-dependent, with near complete suppression until weeks 4-6 at the 400-mg dose and week 8 at the 600-mg dose. Adverse events occurred in 30/48 (62.5%) participants; none were serious or led to study discontinuation. Sibeprenlimab rapidly and sustainably reduced target APRIL and Ig biomarkers in a dose-dependent and reversible manner, with acceptable preliminary safety and pharmacokinetics.
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Imunoglobulina A , Humanos , Voluntários Saudáveis , Área Sob a Curva , Relação Dose-Resposta a Droga , Injeções SubcutâneasRESUMO
Objective: To compare antibiotic resistance results at different time points in patients with urinary tract infections (UTIs), who were either treated based upon a combined multiplex polymerase chain reaction (M-PCR) and pooled antibiotic susceptibility test (P-AST) or were not treated. Methods: The M-PCR/P-AST test utilized here detects 30 UTI pathogens or group of pathogens, 32 antibiotic resistance (ABR) genes, and phenotypic susceptibility to 19 antibiotics. We compared the presence or absence of ABR genes and the number of resistant antibiotics, at baseline (Day 0) and 5-28 days (Day 5-28) after clinical management in the antibiotic-treated (n = 52) and untreated groups (n = 12). Results: Our results demonstrated that higher percentage of patients had a reduction in ABR gene detection in the treated compared to the untreated group (38.5% reduction vs 0%, p = 0.01). Similarly, significantly more patients had reduced numbers of resistant antibiotics, as measured by the phenotypic P-AST component of the test, in the treated than in the untreated group (42.3% reduction vs 8.3%, p = 0.04). Conclusion: Our results with both resistance gene and phenotypic antibiotic susceptibility results demonstrated that treatment based upon rapid and sensitive M-PCR/P-AST resulted in reduction rather than induction of antibiotic resistance in symptomatic patients with suspected complicated UTI (cUTI) in an urology setting, indicating this type of test is valuable in the management of these types of patients. Further studies of the causes of gene reduction, including elimination of ABR gene-carrying bacteria and loss of ABR gene(s), are warranted.