Review article: MRI-targeted biopsies for prostate cancer diagnosis and management.

PURPOSE: Transrectal ultrasound (TRUS)-guided biopsy has been the traditional biopsy route in the detection of prostate cancer. However, due to concern regarding overdetection of low-risk cancer and missed clinically significant cancers as well as risk of sepsis, alternative approaches have been explored. Transperineal template biopsy-sampling the gland every 5 m to 10 mm-reduces error by sampling the whole prostate but increases risk of detecting clinically insignificant cancers as well as conferring risks of side effects such as urinary retention and bleeding. METHODS: There are various targeted biopsy techniques, each with different cancer detection rates, costs and learning curves. Current research focuses on refining biopsy methodology to maximize detection of significant cancers, whilst minimising invasiveness and complications. In this article, the up-to-date research data about MRI-targeted prostate biopsy were reviewed to show its utilization in prostate cancer management and diagnosis. RESULTS AND CONCLUSION: Prostate multiparametric MRI has become an effective tool in the detection of significant cancers and an essential component of the prostate cancer diagnostic pathway incorporating MRI-guided biopsy decisions.

A Multicenter Study of the Clinical Utility of Nontargeted Systematic Transperineal Prostate Biopsies in Patients Undergoing Pre-Biopsy Multiparametric Magnetic Resonance Imaging.

PURPOSE: The added value of nontargeted systematic prostate biopsies when performed alongside magnetic resonance imaging targeted biopsies in men referred with a suspicion of prostate cancer is unclear. We aimed to determine the clinical utility of transperineal nontargeted systematic prostate biopsies, when performed alongside targeted systematic prostate biopsies, using pre-biopsy multiparametric magnetic resonance imaging. MATERIALS AND METHODS: Consecutive patients referred with a suspicion of prostate cancer (April 2017 to October 2019) underwent pre-biopsy multiparametric magnetic resonance imaging. A transperineal biopsy was advised if multiparametric magnetic resonance imaging PI-RADS® (v.2.0) score was 4 or 5, and score 3 required a prostate specific antigen density 0.12 ng/ml or greater. Primary threshold for clinically significant prostate cancer was defined as any Gleason 3+4 or greater. Multivariable logistic regression analysis identified pre-biopsy predictors of clinically significant prostate cancer in nontargeted systematic prostate biopsies, regardless of targeted pathology (p <0.05, R, version 3.5.1). RESULTS: A total of 1,719 men underwent a pre-biopsy multiparametric magnetic resonance imaging, with 679 (39.5%) proceeding to combined targeted systematic prostate biopsies and nontargeted systematic prostate biopsies. In these men clinically significant prostate cancer was detected in 333 (49%) and 139 (20.5%) with targeted systematic prostate biopsies and nontargeted systematic prostate biopsies, respectively. In those men with clinically significant prostate cancer in targeted systematic prostate biopsies, clinically significant prostate cancer was also present in nontargeted systematic prostate biopsies in 117 (17.2%); Gleason 3+3 was present in 50 (7.4%). In 287 men without any cancer in the targeted systematic prostate biopsies, 13 (1.9%) had clinically significant prostate cancer in nontargeted systematic prostate biopsies. In addition 18/679 (2.7%) had Gleason 3+3 disease and no Gleason greater than 4+3 was detected. Predictors associated with clinically significant prostate cancer in nontargeted systematic prostate biopsies were prostate specific antigen 5 ng/ml or greater (OR 2.05, 95% CI 1.13-3.73, p=0.02), PI-RADS score 5 (OR 2.26, 95% CI 1.51-3.38, p <0.001) and prostate volume less than 50 cc (OR 2.47, 95% CI 1.57-3.87, p <0.001). CONCLUSIONS: Detection of clinically significant prostate cancer in exclusively nontargeted transperineal systematic biopsies in a pre-biopsy multiparametric magnetic resonance imaging pathway was low (1.9%).

All-polymer fiber-optic pH sensor.

A novel all-polymer fiber-optic pH sensor using a UV-cured pH-sensitive hydrogel, poly(ethylene glycol) diacrylate (PEGDA), coated on a polymer fiber Bragg grating was developed. The PEGDA increased in volume according to the pH value of the surrounding fluid, which subsequently induced a lateral stress in the polymer fiber Bragg grating. The proposed pH sensor exhibits a pH sensitivity of up to -0.41 nm/pH and a fast response time of 30 s.

An acto-myosin II constricting ring initiates the fission of activity-dependent bulk endosomes in neurosecretory cells.

Activity-dependent bulk endocytosis allows neurons to internalize large portions of the plasma membrane in response to stimulation. However, whether this critical type of compensatory endocytosis is unique to neurons or also occurs in other excitable cells is currently unknown. Here we used fluorescent 70 kDa dextran to demonstrate that secretagogue-induced bulk endocytosis also occurs in bovine chromaffin cells. The relatively large size of the bulk endosomes found in this model allowed us to investigate how the neck of the budding endosomes constricts to allow efficient recruitment of the fission machinery. Using time-lapse imaging of Lifeact-GFP-transfected chromaffin cells in combination with fluorescent 70 kDa dextran, we detected acto-myosin II rings surrounding dextran-positive budding endosomes. Importantly, these rings were transient and contracted before disappearing, suggesting that they might be involved in restricting the size of the budding endosome neck. Based on the complete recovery of dextran fluorescence after photobleaching, we demonstrated that the actin ring-associated budding endosomes were still connected with the extracellular fluid. In contrast, no such recovery was observed following the constriction and disappearance of the actin rings, suggesting that these structures were pinched-off endosomes. Finally, we showed that the rings were initiated by a circular array of phosphatidylinositol(4,5)bisphosphate microdomains, and that their constriction was sensitive to both myosin II and dynamin inhibition. The acto-myosin II rings therefore play a key role in constricting the neck of budding bulk endosomes before dynamin-dependent fission from the plasma membrane of neurosecretory cells.

Specific allergen immunotherapy for the treatment of atopic eczema: a Cochrane systematic review.

BACKGROUND: Specific allergen immunotherapy (SIT) is an effective allergy treatment, but it is unclear whether SIT is effective for atopic eczema (AE). We undertook a systematic review to assess SIT efficacy and safety for treating AE. METHODS: We searched databases, ongoing clinical trials registers, and conference proceedings up to July 2015. Randomized controlled trials (RCTs) of SIT using standardized allergen extracts, compared with placebo/control, for treating AE in patients with allergic sensitization were eligible. RESULTS: We identified 12 eligible trials with 733 participants. Interventions included subcutaneous (six trials), sublingual (four trials), oral or intradermal SIT in children/adults allergic to house dust mite (10 trials), grass pollen or other inhalants. Risk of bias was moderate, with high loss to follow-up and nonblinding as the main concerns. For our primary outcomes, three studies (208 participants) reported no significant difference - patient-reported global disease severity improvement RR 0.75 (95% CI 0.45, 1.26); and eczema symptoms mean difference -0.74 on a 20-point scale (95% CI -1.98, 0.50). Two studies (85 participants) reported a significant difference - SIT improved global disease severity RR 2.85 (95% CI 1.02, 7.96); and itch mean difference -4.20 on a 10-point scale (95% CI -3.69, -4.71). Meta-analysis was limited due to extreme statistical heterogeneity. For some secondary outcomes, meta-analyses showed benefits for SIT, for example investigator-rated improvement in eczema severity RR 1.48 (95% CI 1.16, 1.88; six trials, 262 participants). We found no evidence of adverse effects. The overall quality of evidence was low. CONCLUSION: We found no consistent evidence that SIT is effective for treating AE, but due to the low quality of evidence further research is needed to establish whether SIT has a role in AE treatment.

Coping measurement: Creating short form of Coping and Adaptation Processing Scale using item response theory and patients dealing with chronic and acute health conditions.

PURPOSE: The purpose of this study was to enhance the CAPS tool by clarifying the concept of coping, using item response theory (IRT) to shorten and assess the metric equivalence of the scale, and testing the preliminary validity of the resulting shortened scale. METHODS: A descriptive design of participants from different ethnic backgrounds was employed (USA n = 347 and Panama n = 327). To select items for the shortened CAPS, a well-established multi-step process grounded in IRT was used. Further, a coping ladder was created to approximate the a priori perceived location/difficulty of each item along the coping trait scale. Items for the shortened scale were selected based on considerations central to the middle range theory of coping and adaptation processing and the results of the item calibration and model testing. RESULTS: A total of 15 items were selected. The selected items were well distributed on the coping ladder and all basic subconcepts of the middle range theory were included. Further the sum of the DIF size for the selected short form items is − 0.01, so the overall bias of the total score is minimal. Finally, concurrent and divergent validity of the new scale was demonstrated in two separate correlational studies. CONCLUSION: The 15-item Coping and Adaptation Processing Scale (CAPS)--Short-Form can be a practical tool to effectively and efficiently measure coping and adaptation in both practice and research for people dealing with both chronic and acute health conditions.

Building a better dynasore: the dyngo compounds potently inhibit dynamin and endocytosis.

Dynamin GTPase activity increases when it oligomerizes either into helices in the presence of lipid templates or into rings in the presence of SH3 domain proteins. Dynasore is a dynamin inhibitor of moderate potency (IC50 ~ 15 µM in vitro). We show that dynasore binds stoichiometrically to detergents used for in vitro drug screening, drastically reducing its potency (IC50 = 479 µM) and research tool utility. We synthesized a focused set of dihydroxyl and trihydroxyl dynasore analogs called the Dyngo™ compounds, five of which had improved potency, reduced detergent binding and reduced cytotoxicity, conferred by changes in the position and/or number of hydroxyl substituents. The Dyngo compound 4a was the most potent compound, exhibiting a 37-fold improvement in potency over dynasore for liposome-stimulated helical dynamin activity. In contrast, while dynasore about equally inhibited dynamin assembled in its helical or ring states, 4a and 6a exhibited >36-fold reduced activity against rings, suggesting that they can discriminate between helical or ring oligomerization states. 4a and 6a inhibited dynamin-dependent endocytosis of transferrin in multiple cell types (IC50 of 5.7 and 5.8 µM, respectively), at least sixfold more potently than dynasore, but had no effect on dynamin-independent endocytosis of cholera toxin. 4a also reduced synaptic vesicle endocytosis and activity-dependent bulk endocytosis in cultured neurons and synaptosomes. Overall, 4a and 6a are improved and versatile helical dynamin and endocytosis inhibitors in terms of potency, non-specific binding and cytotoxicity. The data further suggest that the ring oligomerization state of dynamin is not required for clathrin-mediated endocytosis.

Modern Measurement Approaches to Health Literacy Scale Development and Refinement: Overview, Current Uses, and Next Steps.

There are currently more than 100 health literacy instruments. The procedures used to develop and test the measures are primarily guided by classical test theory. However, a small and growing number (n = 13) of health literacy measures are guided by modern measurement theories such as item response theory. This article briefly describes (a) the benefits of using modern measurement approaches for the development of health literacy measures, (b) how these approaches have been used with existing health literacy measures, and (c) some considerations for how modern measurement theory can help strengthen future work in health literacy measurement. Ultimately, this article provides evidence to support an assertive shift toward the use of modern measurement approaches in health literacy instrument development.

SPECT-CT in total hip arthroplasty.

Single photon emission computed tomography combined with computed tomography (SPECT-CT), which combines functional and anatomical imaging, provides superior spatial localization to plain radiography and is more tolerant to metallic artefacts than conventional imaging such as magnetic resonance imaging (MRI). It is increasingly used in musculoskeletal imaging to enable accurate anatomical localization of increased tracer uptake, and is particularly useful in assessing metal prosthesis and the surrounding bone following total hip arthroplasty (THA). In addition to detecting complications of THA, SPECT-CT enables multiplanar reconstruction and manipulation of imaging data, which may aid surgical planning. SPECT-CT is an important adjunct to conventional imaging in the management of post-THA complications. It is vital that radiologists are able to identify the specific features of different complications and use this novel imaging technique to guide management. In this article, the use of SPECT-CT to follow post-THA complications, including aseptic loosening, periprosthetic infection, histiocytic reactions, periprosthetic fractures, polyethylene wear, and pseudotumour formation, will be reviewed.

Community-based cardiovascular health interventions in vulnerable populations: a systematic review.

BACKGROUND: Although cardiovascular health has been improving for many Americans, this is not true of those in "vulnerable populations." To address this growing disparity, communities and researchers have worked for decades, and as a result of their work, a growing body of literature supports the use of community engagement as a component of successful interventions. However, little literature synthesizes community-based interventions that address this disparity among a wide range of vulnerable populations. OBJECTIVE: This article provides a critical review of community-based cardiovascular disease interventions to improve cardiovascular health behaviors and factors among vulnerable populations based on the American Heart Association's 7 metrics of ideal cardiovascular health. METHODS: In February 2011, 4 databases (PubMed, PsychInfo, CINAHL, and Scopus) were searched using the following keywords: vulnerable populations OR healthcare disparities AND cardiovascular disease AND clinical trials OR public health practice AND English. RESULTS: This search strategy resulted in the retrieval of 7120 abstracts. Each abstract was reviewed by at least 2 authors, and eligibility for the systematic review was confirmed after reading the full article. Thirty-two studies met eligibility criteria. Education was the most common intervention (41%), followed by counseling or support (38%) and exercise classes (28%). Half of the interventions were multicomponent. Healthcare providers were the most frequent interventionists. Interventions aimed at decreasing blood pressure were the most promising, whereas behavior change interventions were the most challenging. Almost all of the interventions were at the individual level and were proof-of-concept or efficacy trials. CONCLUSIONS: This analysis provides a step toward understanding the current literature on cardiovascular interventions for vulnerable population. The next step should be integrating the identified successful interventions into larger health systems and/or social policies.

Effects of virtual reality on anxiety and pain in adult patients undergoing wound-closure procedures: A pilot randomized controlled trial.

Background: In emergency departments, suturing is a typical procedure for closing lacerated wounds but is invasive and often causes anxiety and pain. Virtual reality (VR) intervention has been reported as a relaxing measure. Objective: The study aims to examine the effects of VR intervention on anxiety, pain, physiological parameters, local anesthesia requirements and satisfaction in Chinese adult patients undergoing wound closure in emergency departments in Hong Kong. Methods: Adult patients who had lacerated wounds and were undergoing wound closure by suturing can communicate in Chinese and were hemodynamically stable were invited for this trial. Eighty patients were randomly assigned to the VR group, which received VR intervention and standard care, or to the control group, which received standard care only. The primary outcome was anxiety, and the secondary outcomes included pain, blood pressure, pulse rate, satisfactory with pain management, service satisfactory, and extra local analgesia requirement. Outcomes were conducted at baseline, during the procedure and 5 min after the procedure. Results: The VR group had a significantly greater reduction in anxiety (p < 0.001), pain (p < 0.001), systolic blood pressure (p < 0.001), diastolic blood pressure (p < 0.001), pulse rate (p = 0.003) and requested less amount of additional local anesthesia (p = 0.025). The satisfactory level with pain management (p = 0.019) and service (p = 0.002) were significantly higher in participants who received VR intervention. In addition, most participants preferred to have VR in the future, and no major adverse events associated with the use of VR were reported. Conclusion: This pilot study provides insight into the use of VR and the direction of future studies. It may effectively improve psychological and physiological outcomes in adult patients during wound-closure procedures in emergency departments.

Synthetic self-assembling clostridial chimera for modulation of sensory functions.

Clostridial neurotoxins reversibly block neuronal communication for weeks and months. While these proteolytic neurotoxins hold great promise for clinical applications and the investigation of brain function, their paralytic activity at neuromuscular junctions is a stumbling block. To redirect the clostridial activity to neuronal populations other than motor neurons, we used a new self-assembling method to combine the botulinum type A protease with the tetanus binding domain, which natively targets central neurons. The two parts were produced separately and then assembled in a site-specific way using a newly introduced 'protein stapling' technology. Atomic force microscopy imaging revealed dumbbell shaped particles which measure ∼23 nm. The stapled chimera inhibited mechanical hypersensitivity in a rat model of inflammatory pain without causing either flaccid or spastic paralysis. Moreover, the synthetic clostridial molecule was able to block neuronal activity in a defined area of visual cortex. Overall, we provide the first evidence that the protein stapling technology allows assembly of distinct proteins yielding new biomedical properties.

Topological optimization for designing patient-specific large craniofacial segmental bone replacements.

Restoring normal function and appearance after massive facial injuries with bone loss is an important unsolved problem in surgery. An important limitation of the current methods is heuristic ad hoc design of bone replacements by the operating surgeon at the time of surgery. This problem might be addressed by incorporating a computational method known as topological optimization into routine surgical planning. We tested the feasibility of using a multiresolution three-dimensional topological optimization to design replacements for massive midface injuries with bone loss. The final solution to meet functional requirements may be shaped differently than the natural human bone but be optimized for functional needs sufficient to support full restoration using a combination of soft tissue repair and synthetic prosthetics. Topological optimization for designing facial bone tissue replacements might improve current clinical methods and provide essential enabling technology to translate generic bone tissue engineering methods into specific solutions for individual patients.

Roles for the Synechococcus elongatus RNA-Binding Protein Rbp2 in Regulating the Circadian Clock.

The cyanobacterial circadian oscillator, consisting of KaiA, KaiB, and KaiC proteins, drives global rhythms of gene expression and compaction of the chromosome and regulates the timing of cell division and natural transformation. While the KaiABC posttranslational oscillator can be reconstituted in vitro, the Kai-based oscillator is subject to several layers of regulation in vivo. Specifically, the oscillator proteins undergo changes in their subcellular localization patterns, where KaiA and KaiC are diffuse throughout the cell during the day and localized as a focus at or near the pole of the cell at night. Here, we report that the CI domain of KaiC, when in a hexameric state, is sufficient to target KaiC to the pole. Moreover, increased ATPase activity of KaiC correlates with enhanced polar localization. We identified proteins associated with KaiC in either a localized or diffuse state. We found that loss of Rbp2, found to be associated with localized KaiC, results in decreased incidence of KaiC localization and long-period circadian phenotypes. Rbp2 is an RNA-binding protein, and it appears that RNA-binding activity of Rbp2 is required to execute clock functions. These findings uncover previously unrecognized roles for Rbp2 in regulating the circadian clock and suggest that the proper localization of KaiC is required for a fully functional clock in vivo.

In vivo inhibition of nuclear ACE2 translocation protects against SARS-CoV-2 replication and lung damage through epigenetic imprinting.

In vitro, ACE2 translocates to the nucleus to induce SARS-CoV-2 replication. Here, using digital spatial profiling of lung tissues from SARS-CoV-2-infected golden Syrian hamsters, we show that a specific and selective peptide inhibitor of nuclear ACE2 (NACE2i) inhibits viral replication two days after SARS-CoV-2 infection. Moreover, the peptide also prevents inflammation and macrophage infiltration, and increases NK cell infiltration in bronchioles. NACE2i treatment increases the levels of the active histone mark, H3K27ac, restores host translation in infected hamster bronchiolar cells, and leads to an enrichment in methylated ACE2 in hamster bronchioles and lung macrophages, a signature associated with virus protection. In addition, ACE2 methylation is increased in myeloid cells from vaccinated patients and associated with reduced SARS-CoV-2 spike protein expression in monocytes from individuals who have recovered from infection. This protective epigenetic scarring of ACE2 is associated with a reduced latent viral reservoir in monocytes/macrophages and enhanced immune protection against SARS-CoV-2. Nuclear ACE2 may represent a therapeutic target independent of the variant and strain of viruses that use the ACE2 receptor for host cell entry.

Dynamin inhibition blocks botulinum neurotoxin type A endocytosis in neurons and delays botulism.

The botulinum neurotoxins (BoNTs) are di-chain bacterial proteins responsible for the paralytic disease botulism. Following binding to the plasma membrane of cholinergic motor nerve terminals, BoNTs are internalized into an endocytic compartment. Although several endocytic pathways have been characterized in neurons, the molecular mechanism underpinning the uptake of BoNTs at the presynaptic nerve terminal is still unclear. Here, a recombinant BoNT/A heavy chain binding domain (Hc) was used to unravel the internalization pathway by fluorescence and electron microscopy. BoNT/A-Hc initially enters cultured hippocampal neurons in an activity-dependent manner into synaptic vesicles and clathrin-coated vesicles before also entering endosomal structures and multivesicular bodies. We found that inhibiting dynamin with the novel potent Dynasore analog, Dyngo-4a(TM), was sufficient to abolish BoNT/A-Hc internalization and BoNT/A-induced SNAP25 cleavage in hippocampal neurons. Dyngo-4a also interfered with BoNT/A-Hc internalization into motor nerve terminals. Furthermore, Dyngo-4a afforded protection against BoNT/A-induced paralysis at the rat hemidiaphragm. A significant delay of >30% in the onset of botulism was observed in mice injected with Dyngo-4a. Dynamin inhibition therefore provides a therapeutic avenue for the treatment of botulism and other diseases caused by pathogens sharing dynamin-dependent uptake mechanisms.