ING4 and ING5 are essential for histone H3 lysine 14 acetylation and epicardial cell lineage development.

Inhibitor of growth 4 and 5 (ING4, ING5) are structurally similar chromatin-binding proteins in the KAT6A, KAT6B and KAT7 histone acetyltransferase protein complexes. Heterozygous mutations in the KAT6A or KAT6B gene cause human disorders with cardiac defects, but the contribution of their chromatin-adaptor proteins to development is unknown. We found that Ing5-/- mice had isolated cardiac ventricular septal defects. Ing4-/-Ing5-/- embryos failed to undergo chorioallantoic fusion and arrested in development at embryonic day 8.5, displaying loss of histone H3 lysine 14 acetylation, reduction in H3 lysine 23 acetylation levels and reduced developmental gene expression. Embryonic day 12.5 Ing4+/-Ing5-/- hearts showed a paucity of epicardial cells and epicardium-derived cells, failure of myocardium compaction, and coronary vasculature defects, accompanied by reduced expression of epicardium genes. Cell adhesion gene expression and proepicardium outgrowth were defective in the ING4- and ING5-deficient state. Our findings suggest that ING4 and ING5 are essential for heart development and promote epicardium and epicardium-derived cell fates and imply mutation of the human ING5 gene as a possible cause of isolated ventricular septal defects.

Treatment of the infected sacral nerve stimulator: A scoping review.

BACKGROUND: Sacral nerve stimulators (SNSs) are a widely accepted, efficacious surgical option to treat patients who have failed conservative management for overactive bladder, nonobstructive urinary retention, fecal incontinence, or pelvic pain. As with all implanted devices, there are associated risks for surgical site and implant infections. There are currently no clear published data or guidelines regarding treating such infections. AIMS: We present a scoping review aiming to examine the existing literature on the treatment approaches of infected SNSs. METHODS: A scoping review was conducted using Preferred Reporting Items for Systematic Review and Meta-Analysis. The search strategy focused on "sacral modulation," and "infection," and "explantation," and conservative management methods such as "antibiotics." A search was conducted on medical databases, and a grey literature search was performed. RESULTS: Thirty articles were included for data extraction. Articles were published between 2006 and 2022. Outcomes were reported for 7446 patients. Two hundred and seventy-four infection events were reported, giving an overall 3.7% infection rate. Most infection events were treated with explantation, although there is some discussion on the role of conservative management using oral and intravenous antibiotics in the literature. Articles also discussed considerations for future reimplantation after explantation of SNS. CONCLUSIONS: There are currently no treatment protocols in the literature to help guide whether a patient is suited to conservative or surgical management. There is future scope for developing treatment algorithms to guide clinicians for optimal treatment of infected sacral neuromodulation devices.

Anatomical location and number of injection sites of intravesical OnabotulinumtoxinA for females with refractory idiopathic overactive bladder: A scoping review.

AIMS: The negative impact on quality of life and the economic-related burden to the patient and the health care system associated with idiopathic overactive bladder (iOAB) is well-documented. Intradetrusor OnabotulinumtoxinA (BTN/A) injections are a well-used treatment modality for the management of overactive detrusor refractory to medical management, with well-documented efficacy and safety profiles. There is currently no best practice guideline for the administration of BTN/A for this procedure and historically the trigone of the bladder has been excluded from the injection paradigm given the risk of vesicoureteral reflux (VUR). METHODS: A scoping review methodology was employed to assess available literature to evaluate current techniques used. There is emerging literature that the inclusion of the trigone may increase the efficacy of the procedure, while maintaining a similar adverse effect profile. Similar results could also be obtained by decreasing the number of injection sites. A scoping review was completed with systematic methodology using the Preferred Systematic Reviews and Meta Analyses extension for Scoping Review checklist. The search strategy looked to evaluate BTN/A and number of injection sites and the inclusion of the trigone in female patients with iOAB. Studies with male or neurogenic bladder only were excluded. Mixed studies were included. A specialist research librarian was engaged, with supervision from a functional urologist using a combination of MeSH and natural language terms. Two investigators independently reviewed the titles and abstracts. RESULTS: Twelve articles were included and were published between 2005 and 2021. There was no evidence of VUR in any of the results. All but one study reported similar if not improved efficacy of trigone-inclusion. Lower number of injection sites had similar efficacy profiles to higher numbers of intradetrusor injections. CONCLUSIONS: Further high-quality randomized control trials of trigone inclusion and reduction of injection sites are required. It is hoped that with further exploration of intraoperative methods for BTN/A injections, the development of universally accepted guidelines may optimize management and experiences for patients with iOAB.

Re-defining 18 F-DCFPyl prostate-specific membrane antigen positron emission tomography detected local recurrence from radical prostatectomy histopathology.

OBJECTIVE: To assess topographic concordance between the histopathological features of patients' radical prostatectomy (RP) specimens and the location of the prostate-specific membrane antigen positron emission tomography (PSMA PET) local recurrences, qualitatively and quantitatively. PATIENTS AND METHODS: Our cohort was selected from the 100 men who received a 18 F-DCFPyL PET scan in the IMPPORT trial (Australian New Zealand Clinical Trials Registry Number: ACTRN12618001530213), a prospective non-randomised study completed by GenesisCare Victoria. Eligibility included patients with a rising prostate-specific antigen (PSA) level (>0.2 ng/mL) after RP and PSMA PET detected local recurrence. Histopathological parameters collated included the location of tumour, extraprostatic extension (EPE), and positive margins. Criteria for the location and 'concordance' between histopathological features and local recurrences were pre-defined. RESULTS: A total of 24 patients were eligible; the median age was 71 years, the median PSA level was 0.37 ng/mL, and the time between RP and PSMA PET was 2.6 years. In all, 15 patients had recurrences within the vesicourethral anastomotic region and nine within the lateral surgical margins. There was 100% concordance in the left-right plane between tumour location and local recurrence, with 79% of these lesions concordant three-dimensionally; across craniocaudal, left-right, and anterior-posterior planes. In all, 10 of the 16 (63%) patients with EPE and five of the nine patients with positive margins had three-dimensional concordance between their pathology and their local recurrence. In quantitative assessment, 17 of the 24 patients, had local recurrences that correlated with the location of their original tumour in the craniocaudal plane. CONCLUSION: Local recurrence is highly concordant with the position of the tumour within the prostate. Predicting the location of local recurrence using the location of the EPE and positive margins is less helpful. Further investigation into this field, could impact surgical technique and salvage radiotherapy clinical target volume.

Patient preference for urologist gender.

OBJECTIVES: To determine the factors associated with patients preferring the gender of their treating urologist in various clinical settings. METHODS: A total of 400 urology outpatients participated in a structured interview on the nature of their presenting complaint, perception of their complaint and the preference for the gender of their urologist in four specific scenarios of consultation, physical examination, office-based procedure and surgery. Patients who expressed a gender preference received follow-up telephone calls. RESULTS: A gender preference was expressed by 63 (15.8%), 108 (27.0%), 89 (22.3%) and 29 (7.3%) patients for the scenarios of consultation, physical examination, office-based procedure and surgery, respectively. Patients were more likely to have a preference if they were female or had a condition they considered embarrassing, with most preferences being for a gender-concordant urologist. Reasons included a previous negative experience and perceived gender-specific treatment styles. Patients who subsequently saw a doctor of the opposite gender to their preference were more likely to change their mind if their clinical interaction was positive. CONCLUSIONS: Female patients, those with a perceived embarrassing condition and patients undergoing examination or office-based procedures are more likely to have a gender preference for their urologist, with a subsequent positive experience leading to patients discarding pre-existing preferences. With improved understanding of how patient characteristics, perception of their condition and previous experiences can affect their choices in various clinical situations, urologists can better meet patient expectations and address barriers to healthcare in urology.

Molecular recognition of a branched peptide with HIV-1 Rev Response Element (RRE) RNA.

Interaction of HIV-1 rev response element (RRE) RNA with its cognate protein, Rev, is critical for HIV-1 replication. Understanding the mode of interaction between RRE RNA and ligands at the binding site can facilitate RNA molecular recognition as well as provide a strategy for developing anti-HIV therapeutics. Our approach utilizes branched peptides as a scaffold for multivalent binding to RRE IIB (high affinity rev binding site) with incorporation of unnatural amino acids to increase affinity via non-canonical interactions with the RNA. Previous high throughput screening of a 46,656-member library revealed several hits that bound RRE IIB RNA in the sub-micromolar range. In particular, the lead compound, 4B3, displayed a Kd value of 410 nM and demonstrated selectivity towards RRE. A ribonuclease protection assay revealed that 4B3 binds to the stem-loop structure of RRE IIB RNA, which was confirmed by SHAPE analysis with 234 nt long NL4-3 RRE RNA. Our studies further indicated interaction of 4B3 with both primary and secondary Rev binding sites.

Characterization and in vitro activity of a branched peptide boronic acid that interacts with HIV-1 RRE RNA.

A branched peptide containing multiple boronic acids was found to bind RRE IIB selectively and inhibit HIV-1 p24 capsid production in a dose-dependent manner. Structure-activity relationship studies revealed that branching in the peptide is crucial for the low micromolar binding towards RRE IIB, and the peptide demonstrates selectivity towards RRE IIB in the presence of tRNA. Footprinting studies suggest a binding site on the upper stem and internal loop regions of the RNA, which induces enzymatic cleavage of the internal loops of RRE IIB upon binding.

HIV-1 drug discovery: targeting folded RNA structures with branched peptides.

Human immunodeficiency virus type 1 (HIV-1) is an RNA virus that is prone to high rates of mutation. While the disease is managed with current antiretroviral therapies, drugs with a new mode of action are needed. A strategy towards this goal is aimed at targeting the native three-dimensional fold of conserved RNA structures. This perspective highlights medium-sized peptides and peptidomimetics used to target two conserved RNA structures of HIV-1. In particular, branched peptides have the capacity to bind in a multivalent fashion, utilizing a large surface area to achieve the necessary affinity and selectivity toward the target RNA.

What to do about recurrent urinary tract infections: A review of evidence behind emerging therapies.

BACKGROUND: Recurrent urinary tract infections (rUTIs) can be debilitating for patients and pose an increasing challenge in the primary care setting. An efficient approach enables timely access and effective care for patients. Recent research and pharmaceutical developments have provided new avenues for treating this common condition. OBJECTIVE: A narrative review was conducted to provide a targeted overview of contemporary management strategies in rUTIs to assist primary care physicians in managing patients with rUTIs efficiently and effectively. DISCUSSION: Recurrent urinary tract infections require investigation and risk factor identification. Appropriate patient education in the primary care setting, behavioural modifications and commencement of non-antibiotic treatment might reduce rUTI. Certain patients might require referral to a urologist for consideration of other treatment strategies and further investigation.

Targeting folded RNA: a branched peptide boronic acid that binds to a large surface area of HIV-1 RRE RNA.

On-bead high-throughput screening of a medium-sized (1000-2000 Da) branched peptide boronic acid (BPBA) library consisting of 46,656 unique sequences against HIV-1 RRE RNA generated peptides with binding affinities in the low micromolar range. In particular, BPBA1 had a K(d) of 1.4 µM with RRE IIB, preference for RNA over DNA (27 fold), and selectivity of up to >75 fold against a panel of RRE IIB variants. Structure-activity studies suggest that the boronic acid moiety and "branching" in peptides are key structural features for efficient binding and selectivity for the folded RNA target. BPBA1 was efficiently taken up by HeLa and A2780 cells. RNA-footprinting studies revealed that the BPBA1 binding site encompasses a large surface area that spans both the upper stem as well as the internal loop regions of RRE IIB.

A series of the first 13 combined Magseed and Magtrace cases in a single centre in regional Victoria.

BACKGROUND: The standard journey for a patient with impalpable breast cancer wishing to undergo breast-conserving surgery involves placement of a guidewire and lymphoscintigraphy pre-operatively. Access to these procedures is limited in the regional centres, this scheduling can require overnight stays away from home and can delay theatre which can increase patient distress. The Sentimag technology uses magnetism for localisation of preoperatively inserted Magseeds (for impalpable breast lesions) and Magtrace (for sentinel node biopsy), avoiding guidewire placement and nuclear medicine. This study evaluates the first 13 cases using this combined technique by a single specialist breast surgeon in a regional centre. METHODS: Thirteen consecutive patients were enrolled with ethics approval. Magseeds were placed under ultrasound guidance preoperatively, and Magtrace was injected at the time of pre-operative consultation. RESULTS: The median age of patients was 60 (range 27-78). The average distance from hospital was 81.63 km (2.8-238 km). The average operating time was 1h54m (range 1 h 17 m-2 h 39 m) and the mean total journey time was 8h54m (range 6-23 h). The earliest time-out was 8:40 am. Re-excision rate was 23% (n = 3), however, in each re-excision case the lesions were in the axilla, were small (<15 mm) and were in patients with dense breasts on mammography. There were no significant adverse outcomes. CONCLUSION: In this preliminary study Sentimag localisation appears to be safe and reliable when used in combination. Re-excision rates were only slightly higher than reported in the literature and predicted to downtrend with ongoing learning curve.

Gastrointestinal histoplasmosis presenting as a small bowel obstruction in an immunocompetent patient.

The clinical presentation of gastrointestinal histoplasmosis (GIH) is often non-specific, mimicking several other gastrointestinal diseases, making diagnosis difficult. We present a case of GIH, causing bowel obstruction in an immunocompetent patient. A woman in her 80s presented with anorexia and a distended abdomen. A CT scan of the abdomen and pelvis (CTAP) showed ileal thickening. Endoscopy was performed and ileal biopsies were taken. A diagnosis of histoplasmosis was made by histopathology, and she began treatment with liposomal amphotericin and itraconazole. Despite presenting well at her routine follow-up appointments, she presented 4 months after diagnosis with worsening symptoms of anorexia and abdominal distention. CTAP showed the ileal stricture causing bowel obstruction. She underwent itraconazole and steroid treatment while having nasogastric tube decompression. Subsequent gastrografin follow through showing partial obstruction and surgical resection was planned. Unfortunately, her condition deteriorated, her kidney function worsened and she suffered from aspiration pneumonia with eventual demise.

Discovery of a Branched Peptide That Recognizes the Rev Response Element (RRE) RNA and Blocks HIV-1 Replication.

We synthesized and screened a unique 46 656-member library composed of unnatural amino acids that revealed several hits against RRE IIB RNA. Among the hit peptides identified, peptide 4A5 was found to be selective against competitor RNAs and inhibited HIV-1 Rev-RRE RNA interaction in cell culture in a p24 ELISA assay. Biophysical characterization in a ribonuclease protection assay suggested that 4A5 bound to the stem-loop region in RRE IIB while SHAPE MaP probing with 234 nt RRE RNA indicated additional interaction with secondary Rev binding sites. Taken together, our investigation suggests that HIV replication is inhibited by 4A5 blocking binding of Rev and subsequent multimerization.

Branched Peptides: Acridine and Boronic Acid Derivatives as Antimicrobial Agents.

The emergence of microbial resistance presents a challenge in the development of next generation therapeutics. Herein, we report the discovery of branched peptides decorated with acridine and boronic acid moieties with potent antimicrobial activity. The results revealed minimal inhibitory concentrations (MICs) as low as 1 µg/mL against Staphylococcus aureus, Candida albicans, and Escherichia coli. These peptides were nonhemolytic, and significantly inhibited growth of C. albicans in suspension and biofilm formation. Structure-activity relationship studies suggest the acridine functional group as a driving force for the potent inhibition observed against bacteria.

Effect of intercalator and Lewis acid-base branched peptide complex formation: boosting affinity towards HIV-1 RRE RNA.

High throughput screening of a 4096 compound library of boronic acid and acridine containing branched peptides revealed compounds that have dissociation constants in the low nanomolar regime for HIV-1 RRE IIB RNA. We demonstrate that branched peptide boronic acids A5, A6, and A7 inhibit the production of p24, an HIV-1 capsid protein, in a dose-dependent manner.

Branched peptide boronic acids (BPBAs): a novel mode of binding towards RNA.

We report branched peptide boronic acids (BPBAs) that bind to RRE IIB from an on-bead high-throughput screening of a 3.3.4-library (46 656 compounds). We demonstrate that boronic acids are tunable moieties that afford a novel binding mode towards RNA.