To Evaluate the Effect of Vitamin B Complex on Wound Healing - A Clinical and Microbiological Study.

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.

The Prevalence and Association of Different Uropathogens Detected by M-PCR with Infection-Associated Urine Biomarkers in Urinary Tract Infections.

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.

Urine biomarkers individually and as a consensus model show high sensitivity and specificity for detecting UTIs.

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.

A Phase 2 Trial of Sibeprenlimab in Patients with IgA Nephropathy.

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.).

Emerging and Fastidious Uropathogens Were Detected by M-PCR with Similar Prevalence and Cell Density in Catheter and Midstream Voided Urine Indicating the Importance of These Microbes in Causing UTIs.

Introduction: This study compared microbial compositions of midstream and catheter urine specimens from patients with suspected complicated urinary tract infections to determine if emerging and fastidious uropathogens are infecting the bladder or are contaminants. Methods: Urine was collected by in-and-out catheter (n = 1000) or midstream voiding (n = 1000) from 2000 adult patients (≥60 years of age) at 17 DispatchHealth sites across 11 states. The two groups were matched by age (mean 81 years), sex (62.1% female, 37.9% male), and ICD-10-CM codes. Microbial detection was performed with multiplex polymerase chain reaction (M-PCR) with a threshold for "positive detection" ≥ 10,000 cells/mL for bacteria or any detection for yeast. Results were divided by sex. Results: In females, 28 of 30 microorganisms/groups were found by both collection methods, while in males 26 of 30 were found by both. There were significant overlaps in the detection and densities of classical uropathogens including Escherichia coli, Enterococcus faecalis, and Klebsiella pneumoniae, as well as emerging uropathogens including Actinotignum schaalii and Aerococcus urinae. In females, detection rates were slightly higher in midstream voided compared to catheter-collected (p = 0.0005) urine samples, while males showed the opposite trend (p < 0.0001). More polymicrobial infections were detected in midstream voided compared to catheter-collected samples (64.4% vs 45.7%, p < 0.0001) in females but the opposite in males (35.6% vs 47.0%, p = 0.002). Discussion: In-and-out catheter-collected and midstream voided urine specimens shared significant similarities in microbial detections by M-PCR, with some differences found for a small subset of organisms and between sexes. Conclusion: Non-invasive midstream voided collection of urine specimens for microbial detection and identification in cases of presumed UTI does not result in significantly more contamination compared to in-and-out catheter-collected specimens. Additionally, organisms long regarded as contaminants should be reconsidered as potential uropathogens.

Comparison Shows that Multiplex Polymerase Chain Reaction Identifies Infection-associated Urinary Biomarker-positive Urinary Tract Infections That Are Missed by Standard Urine Culture.

Background: Multiplex polymerase chain reaction (M-PCR) has increased sensitivity for microbial detection compared with standard urine culture (SUC) in cases diagnosed as urinary tract infections (UTIs), leading to questions whether detected microbes are likely causative of UTIs or are incidental findings. Objective: To compare infection-associated biomarker levels against M-PCR and SUC results in symptomatic cases with a presumptive diagnosis of a UTI by a urologist. Design setting and participants: Participants were ≥60 yr old and presented to urology clinics between January and April 2023 with symptoms of UTIs (n = 583). Urine microbial detection was by M-PCR and SUC. Three infection-associated biomarkers (neutrophil gelatinase-associated lipocalin, interleukin-8, and interleukin-1ß) were measured by enzyme-linked immunosorbent assay. Symptomatic cases with elevated biomarkers, detection of uropathogens, and a specialist clinical diagnosis of a UTI were considered definitive UTI cases. Outcome measurements and statistical analysis: Distributions were compared using two-sample Wilcoxon rank sum test, with two-tailed p values of <0.05 considered statistically significant. Results and limitations: In cases with M-PCR-positive/SUC-negative results (n = 80), all median biomarker levels were significantly higher (p < 0.0001) than in cases with M-PCR-negative/SUC-negative results (n = 107). Two or more biomarkers were positive in 76% of M-PCR-positive/SUC-negative specimens. Limitation was an inability to examine associations between each individual organism and inflammation. Conclusions: A significant number of M-PCR-positive/SUC-negative cases had elevated levels of infection-related urinary biomarkers, especially when infection was caused by organisms other than Escherichia coli. This is a strong indication that microbes detected by M-PCR, which would be missed by SUC, are associated with UTIs. Patient summary: We compared infection-associated biomarkers in patients diagnosed with urinary tract infections (UTIs) against the detection of microorganisms by standard urine culture (SUC) and multiplex polymerase chain reaction (M-PCR). We found that most patients with microorganisms detected by M-PCR, which were missed by SUC, had elevated markers of inflammation, indicating that these organisms were likely causative of UTIs.

A PRoliferation-Inducing Ligand (APRIL) in the Pathogenesis of Immunoglobulin A Nephropathy: A Review of the Evidence.

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.

Improving Patient Outcomes While Reducing Empirical Treatment with Multiplex-Polymerase-Chain-Reaction/Pooled-Antibiotic-Susceptibility-Testing Assay for Complicated and Recurrent Urinary Tract Infections.

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.

Safety, Pharmacokinetics, and Pharmacodynamics of Subcutaneous Sibeprenlimab in Healthy Participants.

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.

Elevated UTI Biomarkers in Symptomatic Patients with Urine Microbial Densities of 10,000 CFU/mL Indicate a Lower Threshold for Diagnosing UTIs.

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.

A test combining multiplex-PCR with pooled antibiotic susceptibility testing has high correlation with expanded urine culture for detection of live bacteria in urine samples of suspected UTI patients.

We evaluated whether multiplex polymerase chain reaction (M-PCR) detects viable micro-organisms by comparing micro-organism identification with standard urine culture (SUC) and expanded quantitative urine culture (EQUC). Of the 395 organisms detected by M-PCR, EQUC detected 89.1% (p = 0.10), whereas SUC detected 27.3% (p < 0.0001 vs. M-PCR and p < 0.0001 vs EQUC). M-PCR identified 260 nonfastidious bacteria, EQUC detected 96.5% (p = 0.68), whereas SUC detected 41.5% (p < 0.0001). Common nonfastidious bacteria missed by SUC included Escherichia coli (72.5% detected), Klebsiella pneumoniae (66.7% detected), Enterococcus faecalis (34.6% detected) and Enterococcus faecium (0% detected). M-PCR identified 135 fastidious bacteria and EQUC 101 (74.8%, p = 0.01), whereas SUC failed to detect any (0%, p < 0.0001). Clinical samples evaluated using EQUC and M-PCR yielded very similar findings, indicating that most microbes identified by M-PCR represented viable organisms, and validating M-PCR as a diagnostic tool for UTIs.

Quantitative multiplex polymerase chain reaction in copies ml-1 linearly correlates with standard urine culture in colonies ml-1 for urinary tract infection (UTI) pathogens.

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.

A Diagnostic Test Combining Molecular Testing with Phenotypic Pooled Antibiotic Susceptibility Improved the Clinical Outcomes of Patients with Non-E. coli or Polymicrobial Complicated Urinary Tract Infections.

Purpose: Complicated UTIs (cUTIs) cause significant morbidity and healthcare resource utilization and cost. Standard urine culture has limitations in detecting polymicrobial and non-E. coli infections, resulting in the under-diagnosis and under-treatment of cUTIs. In this study, patient-reported outcomes were compared between treated and untreated patients when an advanced diagnostic test combining multiplex-polymerase chain reaction (M-PCR) with a pooled antibiotic susceptibility method (P-AST) was incorporated into the patients' clinical management. Methods: Patients who had symptoms typical of cUTI and positive M-PCR/P-AST test results were recruited from urology clinics. Symptom reduction and clinical cure rates were measured from day 0 through day 14 using the American English Acute Cystitis Symptom Score (ACSS) Questionnaire. Clinical cure was defined based on the sum of the scores of four US Food and Drug Administration (FDA) symptoms and the absence of visible blood in the urine. Results: Of 264 patients with suspected cUTI, 146 (55.4%) had exclusively non-E. coli infections (115 treated and 31 untreated) and 190 (72%) had polymicrobial infections (162 treated and 28 untreated). Treated patients exhibited greater symptom reduction compared to untreated ones on day 14 for those with exclusively non-E. coli organisms (3.18 vs 1.64, p = 0.006) and polymicrobial infections (3.52 vs 1.41, p = 0.002), respectively. A higher percentage of treated patients than of untreated patients achieved clinical cure for polymicrobial infections on day 14 (58.7% vs 36.4%, p = 0.049). Conclusion: Patients with cUTIs treated based on the M-PCR/P-AST diagnostic test had significantly improved symptom reduction and clinical cure rates compared to untreated patients among those with non-E. coli or polymicrobial infections.

The incidence and prevalence of IgA nephropathy in Europe.

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.

Multiplex Polymerase Chain Reaction/Pooled Antibiotic Susceptibility Testing Was Not Associated with Increased Antibiotic Resistance in Management of Complicated Urinary Tract Infections.

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.

Multi-omic single cell sequencing: Overview and opportunities for kidney disease therapeutic development.

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.

Short-Term Effect of Spiritual Music on Heart Rate Variability in Medical Students: A Single-Group Experimental Study.

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.

Safety, Tolerability, Pharmacokinetics, and Pharmacodynamics of VIS649 (Sibeprenlimab), an APRIL-Neutralizing IgG2 Monoclonal Antibody, in Healthy Volunteers.

Introduction: VIS649 (sibeprenlimab), a humanized IgG2 monoclonal antibody that inhibits APRIL, is being developed as a potential treatment for IgA nephropathy (IgAN). This phase 1, first-in-human, randomized, double-blind, single ascending dose study aimed to evaluate the safety, pharmacokinetics (PK), and pharmacodynamics (PD) of VIS649 in healthy adults. Methods: Participants were randomized to VIS649 (sequential i.v. dosing cohorts: 0.5, 2.0, 6.0, 12.0 mg/kg) or placebo; a further cohort received VIS649 6.0 mg/kg or placebo followed by a tetanus/diphtheria vaccine challenge. Results: A total of 51 participants were randomized, dosed, and analyzed for safety (7 for each VIS649 dose; 8 for placebo; 10 for VIS649 + vaccine; 5 for placebo + vaccine). There were no serious adverse events (AEs) or AEs leading to study discontinuation. VIS649 had nonlinear PK: half-life increased with dose and drug exposure increased in a greater than dose-proportional manner. Serum APRIL, IgA, galactose-deficient (Gd) IgA1, IgG, and IgM were reversibly suppressed in a dose-dependent manner, with a dose-response in time to recovery. Tetanus and diphtheria serum IgG titers increased after recall vaccination. Conclusion: VIS649 was safe, well tolerated, and reversibly suppressed APRIL and various immunoglobulins, without loss of antigen-specific vaccination response. Further clinical development of VIS649 for IgAN is warranted. Trial registration: ClinicalTrials.gov: NCT03719443.