The impact of psoriasis biologic therapy on HIV viral load and CD4+ cell counts in HIV-positive individuals: A real-world cohort study.

BACKGROUND: Psoriasis is a chronic immune-mediated inflammatory disorder that also occurs in the setting of human immunodeficiency virus (HIV). Biological therapy has transformed the treatment landscape for psoriasis; however, individuals with HIV are excluded from clinical trials. The impact of biological therapy on blood parameters in HIV is unclear and is only observed in small case series. OBJECTIVE: The aim of this study was to assess the effect of biological therapy in psoriasis vulgaris in individuals with well-controlled HIV on CD4+ cell counts, CD4+ proportion and HIV viral load over 12 months. METHODS: This retrospective cohort study was conducted at a tertiary referral centre in Sydney, Australia and included 36 HIV-positive individuals with psoriasis treated with biological therapy, compared with 144 age-, gender- and HAART-matched individuals without psoriasis seen between 2010 and 2022. Outcomes of interest included HIV viral load, CD4+ cell count and incidence of infections. RESULTS: No statistically significant difference was seen in baseline HIV viral load and CD4+ count between individuals with and without psoriasis. No significant change in CD4+ count or HIV viral load was seen over the 12-month period of analysis in the HIV cohort without psoriasis. The HIV cohort treated with biological therapy for psoriasis also did not demonstrate any significant change in HIV viral load and CD4+ counts over the 12-month period examined. Stratification by type of biological therapy used did not identify any significant changes in these parameters. Rates of infections and adverse events were also not significantly different between cohorts. It is possible that minor blips seen in the biologics cohort may be a risk factor for future virological failure, and future prospective longitudinal studies are required. CONCLUSIONS: In individuals with well-controlled HIV, the use of biological therapy for psoriasis does not significantly impact HIV viral load, CD4+ cell count, CD4+ proportion and rates of infection over the first 12 months of therapy.

Meds to Beds at Hospital Discharge Improves Medication Adherence and Readmission Rates in Select Populations.

OBJECTIVES: Medication nonadherence caused by difficulty obtaining and paying for medicines can increase hospital readmissions. This project implemented Medications to Beds ("Meds to Beds," M2B), a multidisciplinary predischarge medication delivery program, at a large urban academic hospital that provided subsidized medications for uninsured and underinsured patients to reduce readmissions. METHODS: This 1-year retrospective analysis of patients discharged from the hospitalist service after implementing M2B contained two groups: one with subsidized medications (M2B-S) and one with unsubsidized medications (M2B-U). Primary analysis was 30-day readmission rates for patients, stratified by Charlson Comorbidity indexes (CCIs) of 0, 1-3, ≥4 to represent low, medium, and high comorbidity burden. Secondary analysis included readmission rates by Medicare Hospital Readmission Reduction Program diagnoses. RESULTS: Compared with controls, the M2B-S and M2B-U programs had significantly reduced readmission rates among patients with CCIs of 0 (10.5% [controls] vs 9.4% [M2B-U] and 5.1% [M2B-S], P < 0.05). A nonsignificant reduction occurred in readmissions for patients with CCIs ≥4 (20.4% [controls] vs 19.4% [M2B-U] vs 14.7% [M2B-S], P < 0.07). Patients with CCIs of 1 to 3 showed a significant increase in readmission rates in the M2B-U, but a decrease in readmission rates among the M2B-S (15.4% [controls] vs 20% [M2B-U] vs 13.1% [M2B-S], P < 0.05). Secondary analyses found no significant differences in readmission rates when patients were stratified by Medicare Hospital Readmission Reduction Program diagnosis. Cost analyses demonstrated that subsidizing medicines cost less per patient for every 1% readmission reduction than delivery alone. CONCLUSIONS: Providing medicine to patients predischarge tends to lower readmission rates for populations with no comorbidities or with a high burden of disease. This effect is amplified when prescription costs are subsidized.

The Effects of Minimalist Shoes on Plantar Intrinsic Foot Muscle Size and Strength: A Systematic Review.

Minimalist shoes are proposed to prevent injury and enhance performance by strengthening intrinsic foot muscles, yet there is little consensus on the effectiveness of minimalist shoes in increasing muscle strength or size. This systematic review assesses using minimalist shoes as an intervention on changes in plantar intrinsic foot muscle size and strength. PubMed, CINHAL, Scopus, and SPORT Discus were systematically searched for articles from January 2000 to March 2022. Studies were included if they had an intervention of at least 2 weeks with a control group and examined the effect of minimalist shoes on plantar intrinsic foot strength or size (either volume, cross-sectional area, or thickness). Nine studies were included. There were significant increases and percent changes in foot muscle strength, volume, cross-sectional area, and thickness. Strength increased between 9-57%, and size increased between 7.05-10.6%. Minimalist shoes may effectively increase intrinsic foot muscle size and strength in healthy individuals, and they may also be more convenient than implementing time-intensive physical therapy programs. Future research is needed to explore using minimalist shoes as an intervention in clinical populations who would benefit from increased IFM strength and function. It will also be vital to improve upon IFM assessment methods.

QUBIC2: a novel and robust biclustering algorithm for analyses and interpretation of large-scale RNA-Seq data.

MOTIVATION: The biclustering of large-scale gene expression data holds promising potential for detecting condition-specific functional gene modules (i.e. biclusters). However, existing methods do not adequately address a comprehensive detection of all significant bicluster structures and have limited power when applied to expression data generated by RNA-Sequencing (RNA-Seq), especially single-cell RNA-Seq (scRNA-Seq) data, where massive zero and low expression values are observed. RESULTS: We present a new biclustering algorithm, QUalitative BIClustering algorithm Version 2 (QUBIC2), which is empowered by: (i) a novel left-truncated mixture of Gaussian model for an accurate assessment of multimodality in zero-enriched expression data, (ii) a fast and efficient dropouts-saving expansion strategy for functional gene modules optimization using information divergency and (iii) a rigorous statistical test for the significance of all the identified biclusters in any organism, including those without substantial functional annotations. QUBIC2 demonstrated considerably improved performance in detecting biclusters compared to other five widely used algorithms on various benchmark datasets from E.coli, Human and simulated data. QUBIC2 also showcased robust and superior performance on gene expression data generated by microarray, bulk RNA-Seq and scRNA-Seq. AVAILABILITY AND IMPLEMENTATION: The source code of QUBIC2 is freely available at https://github.com/OSU-BMBL/QUBIC2. SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics online.

"First Do No Harm": Significance of Delays from Diagnosis to Surgery in Patients with Non-metastatic Breast Cancer.

BACKGROUND: The majority of patients with non-metastatic breast cancer will undergo surgery. This involves complex decisions that inevitably increase time from diagnosis to surgery beyond the currently recommended 30 days. This study aims to analyse factors that increase time to surgery and establish whether it is justifiable in the context of improved individualised breast cancer management. METHODS: A retrospective analysis of all patients at Austin Health surgically managed for non-metastatic invasive breast carcinoma between 2013 and 2019 was conducted. Time to surgery (TTS) was defined as time between informed diagnosis and cancer surgery. The patients were grouped into TTS groups of ≤30 days and >30 days. Kaplan-Meier survival analysis and Cox proportional hazards regression model were used to evaluate the impact of time interval between diagnosis and surgery. RESULTS: Seven hundred and thirty-one patients were included in our TTS analysis, only half of this cohort received surgery within the recommended 30 days. Many of the factors identified to be associated with increased TTS are the key to optimal management. Median follow-up for the cohort was 30 months. Between wait groups of ≤30 and >30 days, there were no significant association found between TTS and survival outcomes for DFS (HR 1.20 95% CI 0.56-2.60) and OS (HR 1.58 95% CI 0.82-3.03). CONCLUSION: Breast cancer management involves complex factors that significantly increase TTS. Surgery within 30 days of diagnosis is not associated with improved DFS and OS. Outcomes from this study support a revision of current recommendations for TTS in non-metastatic breast cancer care.

Absent or diminished pedal pulses and estimated GFR decline in patients with diabetic kidney disease.

Background: Peripheral artery disease (PAD) is a complication of type 2 diabetes that leads to critical limb ischemia and amputation. We tested whether absent or diminished pedal pulses (ADPPs) predicts subsequent renal functional decline in patients with diabetic chronic kidney disease (CKD). We also examined the association between urinary biomarkers and ADPP as well as worsening CKD. Methods: Using a prospective longitudinal design, we studied 91 patients with type 2 diabetes and estimated glomerular filtration rate (eGFR) from 7 to 146 mL/min/1.73 m2. Baseline pedal pulses were assessed by standardized history and physical examination. The primary endpoint was decline in eGFR >30%. Potential confounders of the relationship between pedal pulses and eGFR were assessed by multivariable logistic regression. Results: Of 91 participants (median age 58 (range 30-83); median eGFR 72.4 ± 33.4 mL/min/1.73 m2), 43% had at least one ADPP. Baseline ADPP associated with increased risk of greater than 30% decline in eGFR (OR= 3.67, p = .004). This association remained significant (OR = 3.09, p = .029) after adjustment for traditional risk factors of renal function decline in diabetic kidney disease (DKD). In addition, urinary endothelin-1 (ET-1) was higher among patients with ADPP (p =.0006) and associated with eGFR decline greater than 30% (adjusted OR = 1.81, p = .035). Conclusions: ADPP is a strong predictor of decline in renal function in type 2 diabetes. Patients with type 2 diabetes and abnormal pedal pulses should be screened for DKD and monitored closely for progression of CKD.

Identification of obscure yet conserved actin-associated proteins in Giardia lamblia.

Consistent with its proposed status as an early branching eukaryote, Giardia has the most divergent actin of any eukaryote and lacks core actin regulators. Although conserved actin-binding proteins are missing from Giardia, its actin is utilized similarly to that of other eukaryotes and functions in core cellular processes such as cellular organization, endocytosis, and cytokinesis. We set out to identify actin-binding proteins in Giardia using affinity purification coupled with mass spectroscopy (multidimensional protein identification technology [MudPIT]) and have identified >80 putative actin-binding proteins. Several of these have homology to conserved proteins known to complex with actin for functions in the nucleus and flagella. We validated localization and interaction for seven of these proteins, including 14-3-3, a known cytoskeletal regulator with a controversial relationship to actin. Our results indicate that although Giardia lacks canonical actin-binding proteins, there is a conserved set of actin-interacting proteins that are evolutionarily indispensable and perhaps represent some of the earliest functions of the actin cytoskeleton.

MicroRNA-17-92 cluster mediates the proliferation and survival of neural progenitor cells after stroke.

The role of microRNAs (miRNAs) in mediating adult neurogenesis after stroke has not been extensively studied. The present study investigated the function of the miR17-92 cluster in adult neural progenitor cells after experimental stroke. We found that stroke substantially up-regulated miR17-92 cluster expression in neural progenitor cells of the adult mouse. Overexpression of the miR17-92 cluster either in cultured ischemic neural progenitor cells or in the subventricular zone (SVZ) of ischemic animals significantly increased cell proliferation, whereas inhibition of individual members of the miR17-92 cluster, miR-18a and miR-19a, suppressed cell proliferation and increased cell death. The miR17-92 cluster mediated PTEN (phosphatase and tensin homolog) expression, which is a predicted target of the miR17-92 cluster. Addition of Sonic hedgehog (Shh) protein up-regulated miR17-92 expression and elevated c-Myc protein in ischemic neural progenitor cells, whereas blockade of the Shh signaling pathway down-regulated miR17-92 cluster expression and reduced c-Myc levels. Overexpression of c-Myc up-regulated miR17-92 cluster expression. Intraventricular infusion of Shh and a Shh receptor inhibitor, cyclopamine, to ischemic animals further elevated and suppressed, respectively, miR17-92 cluster expression in the SVZ. These data indicate that the miR17-92 cluster plays an important role in mediating neural progenitor cell function and that the Shh signaling pathway is involved in up-regulating miR17-92 cluster expression.

Fluoroquinolone resistance in urinary tract infections: Epidemiology, mechanisms of action and management strategies.

Background: Fluoroquinolone resistance is an issue of concern amongst physicians worldwide. In urology, fluoroquinolones are often used in the treatment of acute pyelonephritis and prostatitis, as well as infections caused by multidrug-resistant pathogens. Aims: We aim to highlight the importance of antimicrobial stewardship and the need for ongoing biomedical research to discover novel agents in our losing battle against resistant pathogens. Materials and methods: In this review, we survey the literature and summarise fluoroquinolone resistance as it pertains to pyelonephritis and prostatitis, as well as alternative treatment strategies and prevention of multidrug resistance. Results: The rise of fluoroquinolone resistance in bacteria has reduced the available treatment options, often necessitating hospital admission for intravenous antibiotics, which places an additional burden on both patients and the healthcare system. Many countries such as Australia have attempted to limit fluoroquinolone resistance by imposing strict prescribing criteria, though these efforts have not been entirely successful. Solutions to overcome resistance include prevention, combination therapy and the development of novel antimicrobial agents. Conclusions: Prevention of the proliferation of resistant organisms by antimicrobial stewardship is paramount, and urologists are obliged to be aware of responsible prescribing practices such as referring to local guidelines when prescribing. By reserving fluoroquinolones for infections in which they are truly indicated and by prescribing based on both patient and local environmental factors, we can preserve this effective resource for future use.

Atrial Tachycardia Facilitating Transcatheter Edge-to-Edge Repair for Severe Functional Mitral Regurgitation.

An 89-year-old woman with paroxysmal atrial tachycardia (AT) was diagnosed with severe atrial functional mitral regurgitation. On transesophageal echocardiography, the mitral regurgitation jet appeared larger during sinus rhythm and smaller during AT. During transcatheter repair of the valve, chronotropic agents were given to induce AT, assisting with leaflet capture.

The Tactical Athlete: Definitions, Cardiovascular Assessment, and Management, and "Fit for Duty" Standards.

Tactical athletes are individuals in the military, law enforcement, and other professions whose occupations have significant physical fitness requirements coupled with the potential for exposure to life-threatening situations. Such exposures can have varied hemodynamic effects on the cardiovascular system. It is crucial that their clinical evaluation is inclusive of specific occupational requirements. Safety protocols regarding medical clearance are relatively more stringent for this population than for competitive athletes due to the increased impact to the tactical athlete, their team, and the population they aim to serve and protect should they experience a cardiovascular event on the job.

Effects of gene dosage and development on subcortical nuclei volumes in individuals with 22q11.2 copy number variations.

The 22q11.2 locus contains genes critical for brain development. Reciprocal Copy Number Variations (CNVs) at this locus impact risk for neurodevelopmental and psychiatric disorders. Both 22q11.2 deletions (22qDel) and duplications (22qDup) are associated with autism, but 22qDel uniquely elevates schizophrenia risk. Understanding brain phenotypes associated with these highly penetrant CNVs can provide insights into genetic pathways underlying neuropsychiatric disorders. Human neuroimaging and animal models indicate subcortical brain alterations in 22qDel, yet little is known about developmental differences across specific nuclei between reciprocal 22q11.2 CNV carriers and typically developing (TD) controls. We conducted a longitudinal MRI study in a total of 385 scans from 22qDel (n = 96, scans = 191, 53.1% female), 22qDup (n = 37, scans = 64, 45.9% female), and TD controls (n = 80, scans = 130, 51.2% female), across a wide age range (5.5-49.5 years). Volumes of the thalamus, hippocampus, amygdala, and anatomical subregions were estimated using FreeSurfer, and the linear effects of 22q11.2 gene dosage and non-linear effects of age were characterized with generalized additive mixed models (GAMMs). Positive gene dosage effects (volume increasing with copy number) were observed for total intracranial and whole hippocampus volumes, but not whole thalamus or amygdala volumes. Several amygdala subregions exhibited similar positive effects, with bi-directional effects found across thalamic nuclei. Distinct age-related trajectories were observed across the three groups. Notably, both 22qDel and 22qDup carriers exhibited flattened development of hippocampal CA2/3 subfields relative to TD controls. This study provides novel insights into the impact of 22q11.2 CNVs on subcortical brain structures and their developmental trajectories.

Isokinetic Dynamometer Leg Extensor Peak Torque Measurement: A Time-Delayed Reliability and Score Selection Analysis Study.

The reliability of isokinetic peak torque (PT) has been reported mostly using a short-term (<~10 day) inter-trial testing time frame. However, many studies and programs utilize a long-term (several weeks to months) inter-trial testing period. Additionally, the methods by which the PT value is selected and reported from a multiple rep testing scheme have not been well investigated for both reliability and PT absolute performance comparisons. The purpose of this study was to investigate the long-term reliability of isokinetic and isometric PT of the leg extensors with an emphasis on the differences among several PT score selection methods. Thirteen men and women (age = 19.5 years) underwent two testing trials separated by 28.8 (±1.8) days. Testing included maximal voluntary contractions of three sets of three reps for two isokinetic contraction conditions of 60 (Isok60) and 240 (Isok240) deg/s velocities, and three sets of one rep of isometric contractions for the leg extensors. The PT score was derived from seven different methods (see text for descriptions). Reliability as assessed from intraclass correlation coefficients (ICCs) varied widely across contraction conditions and PT score selection parameters. The Isok60 velocity overall had lower reliability (ICCs = 0.48-0.81) than Isok240 (0.77-0.87) across the conditions whereas the isometric PT variables showed moderate reliability (0.71-0.73). Overall the set 1 PT score selection parameters were generally lower (p ≤ 0.05) than those that involved sets two and three. Systematic error (p ≤ 0.05) was shown for 6 out of the 17 PT selection variables. On a subjective interpretation basis, when taking everything into account the best overall combination of time/trial efficiency, reliability, best/highest PT score parameter, and reduced risk of systematic bias appears to be the PT variable that uses the average of the highest two reps of the first two sets of three reps-i.e., averaging the highest two values of the six total reps from the first two sets.

A Novel Intrinsic Foot Muscle Strength Dynamometer Demonstrates Moderate-To-Excellent Reliability and Validity.

Background: Intrinsic foot muscle (IFM) weakness can result in reduced foot function, making it crucial for clinicians to track IFM strength changes accurately. However, assessing IFM strength can be challenging for clinicians, as there is no clinically applicable direct measure of IFM strength that has been shown to be reliable and valid with the foot on the ground. Purpose: The purpose was to investigate the intra-rater and inter-rater reliability of a novel, budget-friendly IFM dynamometer and determine its agreement with a handheld dynamometer (HHD). The researchers also examined correlations of foot morphology and activity level to IFM strength. Study design: Descriptive Laboratory Study. Methods: Two assessors measured IFM strength of 34 healthy volunteers (4 male, 30 female; age=21.14±2.57, height=164.66 ±7.62 cm, mass=64.45±11.93 kg) on two occasions 6.62±0.78 days apart with the novel dynamometer to assess intra- and inter-rater reliability. The HHD was used to measure IFM in the first session in order to assess validity. Results: For the novel dynamometer, intra- and inter-rater reliability was moderate-to-excellent (ICC = 0.73 - 0.95), and the majority of the strength tests were within the 95% limits of agreement with the HHD. Wider foot morphology and a higher number of days walking over the prior seven days had small but significant correlations with IFM strength (dominant foot r = 0.34, non-dominant foot r = 0.39; r = -0.33, -0.39 respectively). Conclusion: This novel IFM dynamometer is a budget-friendly ($75) tool that was shown to be reliable and valid in a healthy population. Levels of evidence: Level 3©The Author(s).