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Sejal M Bhavsar,1 Nisha Polavarapu,2 Emery Haley,3 Natalie Luke,3 Mohit Mathur,4 Xiaofei Chen,5 Jim Havrilla,5 David Baunoch,6 Kenneth Lieberman7 1Department of Pediatric Infectious Disease, Hackensack University Medical Center, Hackensack, NJ, USA; 2Department of Pediatric Emergency Medicine, Hackensack University Medical Center, Hackensack, NJ, USA; 3Department of Clinical Research, Pathnostics, Irvine, CA, USA; 4Department of Medical Affairs, Pathnostics, Irvine, CA, USA; 5Department of Bioinformatics, Pathnostics, Irvine, CA, USA; 6Department of Research and Development, Pathnostics, Irvine, CA, USA; 7Department of Pediatric Nephrology, Hackensack University Medical Center, Hackensack, NJ, USACorrespondence: David Baunoch, Pathnostics, 15545 Sand Canyon Suite 100, Irvine, CA, 92618, USA, Tel +1-714-966-1221, Fax +1-714-966-1231, Email dbaunoch@pathnostics.comObjective: To establish the noninferiority of the rapid and sensitive multiplex polymerase chain reaction (M-PCR) method versus standard urine culture (SUC) in pediatric urinary tract infection (UTI) diagnostic testing.Methods: A United States of America (USA)-based single-center prospective observational study of 44 female and four male patients aged 3– 21 years old presenting to a Pediatric Emergency Department in New Jersey with clinically suspected UTI. Urine specimens were primarily collected via midstream voiding. Patients with antibiotic exposure within the week prior to presentation were excluded. Patient demographic data, clinical manifestations, and urinalysis results were recorded. Noninferiority testing comparing M-PCR and SUC was conducted using a method for paired binary data, with a noninferiority margin set at 5%. Noninferiority was concluded if the lower bound of the 95% confidence interval of the difference in detection rates between M-PCR and SUC lies entirely to the right of the value minus the noninferiority margin. All statistical calculations were performed using Python 3.10.12.Results: The two methods were concordant in two-thirds of cases. Of the 14 M-PCR-positive/SUC-negative discordant specimens, 13 (93%) contained a fastidious and/or emerging uropathogen (A. urinae, A. schaalii, G. vaginalis, C. riegelii, U. urealyticum, Viridans group Streptococci (VGS), and/or Coagulase-negative Staphylococci (CoNS)). Neither symptom presentation nor urinalysis results differed significantly between participants with concordant positive results for UTI diagnosis and those with concordant negative results (non-UTI group).Conclusion: In this pediatric population, similar to previous findings in an older adult population, M-PCR established not only noninferiority but also superiority over SUC in detecting microorganisms in the urine.Keywords: symptoms, urinalysis, UTI, SUC, M-PCR, Guidance UTI more...

Using a systematic approach for interpreting electrocardiograms (ECGs) is necessary. A specific framework helps the reader avoid diagnostic errors made by focusing on the ECG as a whole instead of the individual parts. A step-by-step analysis may aid the clinician in recognizing both the obvious and subtle abnormalities that help guide therapy. [ABSTRACT FROM AUTHOR] more...

Describes an instrument that combines the potential for near-field light microscope. Presents a technique that creates a point of sub-wavelength light without associated evanescent losses in its excitation while achieving the advantage of the exponential increase in intensity that occurs within the near-field. more...

BACKGROUND An unmet need exists for focal segmental glomerulosclerosis (FSGS) treatment. In an 8-week, phase 2 trial, sparsentan, a dual endothelin-angiotensin receptor antagonist, reduced proteinuria in patients with FSGS. The efficacy and safety of longer- term treatment with sparsentan for FSGS are unknown. METHODS In this phase 3 trial, we enrolled patients with FSGS (without known secondary causes) who were 8 to 75 years of age; patients were randomly assigned to receive sparsentan or irbesartan (active control) for 108 weeks. The surrogate efficacy end point assessed at the prespecified interim analysis at 36 weeks was the FSGS partial remission of proteinuria end point (defined as a urinary protein-to-creatinine ratio of El.5 [with protein and creatinine both measured in grams] and a >40% reduction in the ratio from baseline). The primary efficacy end point was the estimated glomerular filtration rate (eGFR) slope at the time of the final analysis. The change in eGFR from baseline to 4 weeks after the end of treatment (week 112) was a secondary end point. Safety was also evaluated. RESULTS A total of 371 patients underwent randomization: 184 were assigned to receive sparsentan and 187 to receive irbesartan. At 36 weeks, the percentage of patients with partial remission of proteinuria was 42.0% in the sparsentan group and 26.0% in the irbesartan group (P= 0.009), a response that was sustained through 108 weeks. At the time of the final analysis at week 108, there were no significant between-group differences in the eGFR slope; the between-group difference in total slope (day 1 to week 108) was 0.3 ml per minute per 1.73 mz of body-surface area per year (95% confidence interval ICI], -1.7 to 2.4), and the between-group difference in the slope from week 6 to week 108 (i.e., chronic slope) was 0.9 ml per minute per 1.73 mz per year (95% CI, -1.3 to 3.0). The mean change in eGFR from baseline to week 112 was -10.4 ml per minute per 1.73 mz with sparsentan and -12.1 ml per minute per 1.73 mz with irbesartan (difference, 1.8 ml per minute per 1.73 mz; 95% CI, -1.4 to 4.9). Sparsentan and irbesartan had similar safety profiles, and the frequency of adverse events was similar in the two groups. CONCLUSIONS Among patients with FSGS, there were no significant between-group differences in eGFR slope at 108 weeks, despite a greater reduction in proteinuria with sparsentan than with irbesartan. (Funded by Travere Therapeutics; DUPLEX ClinicalTrials.gov number, NCT03493685.) [ABSTRACT FROM AUTHOR] more...

Healthcare chaplains in the United States increasingly report being tasked by their organizations to participate in the formal work of clinical ethics, by serving on ethics committees, performing clinical ethics consultations, or leading clinical ethics programs. This mapping study documents that professionally-trained chaplains possess a number of skills and attributes that enhance their capability for this work; however, they often lack certain knowledge specific to the discipline of clinical ethics that is needed for roles they are being asked to perform. The professional associations of both chaplaincy and clinical ethics are encouraged to address this educational gap for the benefit of both disciplines., Competing Interests: Declarations Conflict of interest The authors have no relevant financial or non-financial interests to disclose. Consent to Participate Informed consent was obtained from all individual participants included in the study.Ethical ApprovalThis study was reviewed by Northwestern University IRB (STU00218441) and determined to be exempt., (© 2024. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.) more...

In yeast and animals, cyclin B binds and activates the cyclin-dependent kinase ('CDK') CDK1 to drive entry into mitosis. We show that CYCB1, the sole cyclin B in Chlamydomonas, activates the plant-specific CDKB1 rather than the CDK1 ortholog CDKA1, confirming and extending previous results. Time-lapse microscopy shows that CYCB1 is synthesized before each division in the multiple fission cycle, then is rapidly degraded 3-5 minutes before division occurs. CYCB1 degradation is dependent on the anaphase-promoting complex (APC). Like CYCB1, CDKB1 is not synthesized until late G1; however, CDKB1 is not degraded with each division within the multiple fission cycle, but is degraded after all divisions have ceased. The microtubule plus-end-binding protein EB1 labeled with mNeonGreen allowed detection of mitotic events in live cells. The earliest detectable step in mitosis, splitting of polar EB1 signal into two foci, likely associated with future spindle poles, was dependent on CYCB1. CYCB1-GFP localized close to these foci immediately before spindle formation. Spindle breakdown, cleavage furrow formation and accumulation of EB1 in the furrow were dependent on the APC. In interphase, rapidly growing microtubules are marked by 'comets' of EB1; comets are absent in the absence of APC function. Thus CYCB1/CDKB1 and the APC modulate microtubule function and assembly while regulating mitotic progression. Genetic results suggest an independent additional role for the APC in regulating sister chromatid cohesion; this role is likely conserved across eukaryotes., Competing Interests: The authors have declared that no competing interests exist. more...

Objective : The effectiveness of a cognitive behavioural intervention to prevent perinatal depression in low-income Latina immigrant pregnant women and mothers receiving WIC services was evaluated in a mixed methods study using a community based observational design. Background : The Mothers and Babies Course is a preventive intervention for perinatal depression that is based on cognitive behavioural theory (CBT). CBT is an evidence-based treatment and preventive intervention for perinatal depression. Method : Phase 1 includes 86 Latinas, predominantly Central American immigrant women at high risk for depression, who self-selected into the Mothers and Babies Course, a six-week Spanish CBT group intervention aimed at teaching women mood regulation skills to prevent the onset of depression. Participants, who were recruited from the Women, Infants, and Children services, completed measures of depression and psychopathology at pre-, 6 weeks, and 3 months post-intervention. Phase 2 includes qualitative interviews with a randomly selected subsample (n = 26) from Phase 1 to understand the mechanisms and impact of participants' experiences with the intervention and study. Results : Results indicated no significant differences in depressive symptoms among participants with varied attendance levels (0 class; 1-3 classes = non-completers; 4-6 classes = completers). None of the participants met diagnostic criteria for major depressive disorder at the final data collection period. Despite the varied attendance, both quantitative and qualitative results indicated that completers and non-completers reported similar experiences in the intervention and benefiting from study participation. Conclusion : Conducting mixed methods research highlights the complexity of understanding who can benefit from preventive interventions. more...

Background: We evaluated and compared the effects of sparsentan, a dual endothelin type A (ET A ) and angiotensin II type 1 receptor antagonist, with those of the angiotensin II type 1 receptor antagonist irbesartan in patients with primary FSGS., Methods: In this phase 2, randomized, double-blind, active-control Efficacy and Safety of Sparsentan (RE-021), a Dual Endothelin Receptor and Angiotensin Receptor Blocker, in Patients with Focal Segmental Glomerulosclerosis (FSGS): A Randomized, Double-blind, Active-Control, Dose-Escalation Study (DUET), patients aged 8-75 years with biopsy-proven FSGS, eGFR>30 ml/min per 1.73 m 2 , and urinary protein-to-creatinine ratio (UP/C) ≥1.0 g/g received sparsentan (200, 400, or 800 mg/d) or irbesartan (300 mg/d) for 8 weeks, followed by open-label sparsentan only. End points at week 8 were reduction from baseline in UP/C (primary) and proportion of patients achieving FSGS partial remission end point (FPRE) (UP/C: ≤1.5 g/g and >40% reduction [secondary])., Results: Of 109 patients randomized, 96 received study drugs and had baseline and week 8 UP/C measurements. Sparsentan-treated patients had greater reductions in UP/C than irbesartan-treated patients did when all doses (45% versus 19%; P =0.006) or the 400 and 800 mg doses (47% versus 19%; P =0.01) were pooled for analysis. The FSGS partial remission end point was achieved in 28% of sparsentan-treated and 9% of irbesartan-treated patients ( P =0.04). After 8 weeks of treatment, BP was reduced with sparsentan but not irbesartan, and eGFR was stable with both treatments. Overall, the incidence of adverse events was similar between groups. Hypotension and edema were more common among sparsentan-treated patients but did not result in study withdrawals., Conclusions: Patients with FSGS achieved significantly greater reductions in proteinuria after 8 weeks of sparsentan versus irbesartan. Sparsentan was safe and well tolerated., (Copyright © 2018 by the American Society of Nephrology.) more...

We generated a large collection of temperature-sensitive lethal mutants in the unicellular green alga Chlamydomonas reinhardtii , focusing on mutations specifically affecting cell cycle regulation. We used UV mutagenesis and robotically assisted phenotypic screening to isolate candidates. To overcome the bottleneck at the critical step of molecular identification of the causative mutation ("driver"), we developed MAPS-SEQ (meiosis-assisted purifying selection sequencing), a multiplexed genetic/bioinformatics strategy. MAPS-SEQ allowed us to perform multiplexed simultaneous determination of the driver mutations from hundreds of neutral "passenger" mutations in each member of a large pool of mutants. This method should work broadly, including in multicellular diploid genetic systems, for any scorable trait. Using MAPS-SEQ, we identified essential genes spanning a wide range of molecular functions. Phenotypic clustering based on DNA content analysis and cell morphology indicated that the mutated genes function in the cell cycle at multiple points and by diverse mechanisms. The collection is sufficiently complete to allow specific conditional inactivation of almost all cell-cycle-regulatory pathways. Approximately seventy-five percent of the essential genes identified in this project had clear orthologs in land plant genomes, a huge enrichment compared with the value of ∼20% for the Chlamydomonas genome overall. Findings about these mutants will likely have direct relevance to essential cell biology in land plants., (© 2018 American Society of Plant Biologists. All rights reserved.) more...