Developing nanosize carrier systems for Amphotericin-B: A review on the biomedical application of nanoparticles for the treatment of leishmaniasis and fungal infections.

New formulations of Amphotericin-B (Am-B), the most popular therapeutic drug for many human infections such as parasitic and fungal pathogens, are safe, economical, and effective in the world. Several newly designed carrier systems for Am-B can also be considered orally with sufficient gastrointestinal permeability and good solubility. However, the clinical application of several new formulations of Am-B with organ cytotoxicity, low bioavailability, high costs, and technical problems have caused some issues. Therefore, more attention and scientific design are required to progress safe and effective drug delivery systems. Currently, the application of nano-based technology and nanomaterials in the advancement of drug delivery systems exhibits promising outcomes to cure many human systemic infections. Designing novel drug delivery systems including solid lipid nanostructured materials, lipo-polymersomes, drug conjugates and microneedles, liposomes, polymer and protein-based nanostructured materials, dendrimers, emulsions, mixed micelles, polymeric micelles, cyclodextrins, nanocapsules, and nanocochleate for Am-B has many advantages to reducing several related issues. The unique properties of nanostructured particles such as proper morphology, small size, surface coatings, and, electrical charge, permit scientists to design new nanocomposite materials against microorganisms for application in various human diseases. These features have made these nanoparticles an ideal candidate for drug delivery systems in clinical approaches to cure a number of human disorders and currently, several therapeutic nanostructured material formulations are under different stages of clinical tests. Hence, this scientific paper mainly discussed the advances in new formulations of Am-B for the treatment of human systemic infections and related clinical tests.

The effects of the LaSota strain of oncolytic Newcastle disease virus vaccine on cervical intraepithelial neoplasia Patients-Clinical cohort study.

BACKGROUND: Cervical cancer is one of the most common malignancies in women, and its treatment has many side effects. Therefore, in this research, the effects of the LaSota strain of oncolytic Newcastle disease virus vaccine on cervical intraepithelial neoplasia (CIN) patients were investigated. METHODS: 15 patients who met the inclusion criteria and diagnosed as CIN II and CIN III were included in the study. The vaccine was injected inside the cervix (neoplasia site) at increasing doses during 21 days, and they were evaluated for adverse events. NDV antibody titer was measured in 90 days and the levels of ki-67 and p16 proteins were studied by immunohistochemistry. Also, the levels of some important inflammatory cytokines in the serum of CIN patients were measured and finally the patients were evaluated according to the final outcomes and the reduction of tumor lesions. RESULTS: Only in the first dose of vaccine some patients showed flu-like symptoms. The accumulation of NDV antibodies started on the 7th day of the study and increased until the 90th day. Administration of LaSota vaccine had no significant effect on the expressions of Ki-67 and p16 proteins. Nevertheless, a decrease in the serum levels of Il-1ß was observed in patients after the administration of the vaccine, but the serum levels of both Il-2 and INF-γ upregulated significantly. Also, vaccine administration had no significant effect in reducing CIN grades and lesions. CONCLUSIONS: In general, we concluded that LaSota strain of NDV vaccine has no therapeutic effectiveness in CIN patients.

Relationship Between Amoxicillin Use in Pregnancy and Congenital Anomalies: A Systematic Review.

OBJECTIVE: Amoxicillin is among the most used antibiotics in the treatment of a wide spectrum of bacterial infections. Although amoxicillin is categorized as group B in pregnancy, the findings of studies regarding its effects on the fetus are controversial. The aim of this systematic review was to review the reported effects of amoxicillin administration in pregnancy on congenital anomalies. METHODS: Published articles in PubMed, Scopus, SID, and Magiran databases, as well as Google Scholar were searched till May 2021 based on a search strategy. Case-control and cohort studies in Persian or English language were included. Four studies, including two case-control and two cohort studies, with an overall sample size of 260491 pregnant mothers, were included in the review. RESULTS: A review of case-control studies revealed an increased risk for cleft palate in one study. Cohort studies did not reveal a significant relationship between amoxicillin use and major congenital anomalies. CONCLUSION: The findings of this systematic review showed that although no major congenital anomaly was reported for the administration of amoxicillin consumption with or without clavulanic acid, there is a possibility that amoxicillin administration in pregnancy might be related to some anomalies, including cleft palate. Amoxicillin should be administered with caution during pregnancy till more evidence is provided regarding its safety.

Predicting factors for breast cancer screening in Middle Eastern women based on health belief model: a systematic review.

BACKGROUND: Breast cancer screening can reduce mortality and improve the quality of life in affected women. The present study aimed to determine the predictive factors of breast cancer screening in Iranian women based on the health belief model (HBM). METHODS: This review was conducted by searching electronic databases of Google Scholar; electronic databases, including Scopus, PubMed/MEDLINE, Cochrane Library, Web of Science, ProQuest, Embase, and Google scholar Magiran; and SID with the English keywords of "breast cancer," "mammography," "health belief model," and "breast self-exam" and the equivalent Persian keywords. The results were evaluated based on the health belief model (HBM) constructs. Articles were evaluated for quality and the findings were extracted and reviewed. RESULTS: A total of 8 relevant articles were selected for review. Women's awareness of breast cancer screening methods was moderate in two studies and poor in two other studies. Among the constructs of HBM, knowledge, perceived susceptibility, perceived severity, perceived benefits, and action plan were poor in the majority of the studies, while perceived barriers, cues to action, and self-efficacy were mainly good. CONCLUSION: Considering the observed weakness of many HBM constructs, it is recommended that special attention be given to all HBM constructs in implementing HBM-based education programs.

A randomized clinical trial on the effect of foot reflexology performed in the fourth stage of labor on uterine afterpain.

BACKGROUND: Uterine afterpains are among the most prevalent complaints after natural vaginal delivery. Non-pharmacological treatment modalities to relieve afterpains are an important care priority. This study was conducted to investigate the effect of foot reflexology in the fourth stage of labor on afterpains in multiparous women. METHODS: This single-blind, randomized, clinical trial recruited 80 eligible pregnant women presenting to Allameh Bohlool Hospital in Gonabad and 17-Shahrivar Hospital in Mashhad, Iran, in 2019. In the first and second hours postpartum, the reflexology group received 10 min of general massage and specific reflexology massage on each foot on the uterine, pituitary, and solar plexus points. The control group received 10 min of general massage, and then rotational massage on a neutral point on the lateral side of the heel. The pain was measured every hour up to 4 h postpartum using a visual analogue  scale. The collected data were analyzed in SPSS-16 software at a significance level of P < 0.05. RESULTS: The median of the afterpain score in the first hour (P = 0.05) and second hour (P = 0.274) postpartum did not differ significantly between the two groups, but this score was lower in the reflexology group at the third hour (P < 0.001) and fourth hour (P < 0.001) postpartum. The mean total afterpain score in the 4 h postpartum was significantly lower in the reflexology group (P < 0.001). CONCLUSION: The results revealed that foot reflexology in the fourth stage of labor has positive effects on relief from uterine afterpain. Reflexology is therefore recommended as a measure to reduce postpartum uterine afterpains.

Tension-Relaxation In Vivo Computing Principle for Tumor Sensitization and Targeting.

By modeling the tumor sensitization and targeting (TST) as a natural computational process, we have proposed the framework of nanorobots-assisted in vivo computation. The externally manipulable nanorobots are steered to detect the tumor in the high-risk tissue, which is analogous to the process of searching for the optimal solution by the computing agents in the search space. To overcome the constraint of a nanorobotic platform that can only generate a uniform magnetic field to actuate the nanorobots, we have proposed the weak priority evolution strategy (WP-ES) in our previous works. However, these works do not consider the proportions of the nanorobot control and tracking operations, which are part and parcel of in vivo computation as the control operation aims at searching for the tumor effectively while the tracking mode is used for gathering information about the biological gradient function (BGF). Careful planning about the durations spent in these operations is needed for optimal performance of the TST strategy. To account for this issue, in the current article, we propose a novel computational principle, called the tension-relaxation (T-R) principle, to balance the displacements of nanorobots during each control and tracking cycle. Furthermore, we build three tumor vascular models with different sizes to represent three different targeting regions as the morphology of tumor vasculature determined by the tumor growth process is an important factor affecting TST. We carry out the computational experiments for tumors with three different sizes for several representative landscapes by introducing the T-R principle into the WP-ES-based swarm intelligence algorithms and considering the realistic internal constraints. The experimental outcomes demonstrate the effectiveness of the proposed TST strategy.

The effects of yoga on quality of life among postmenopausal women: A systematic review study.

INTRODUCTION: The quality of life in menopausal women is considered to be an important health issue in different societies and one of the main objectives of health care in this period. This study aimed to investigate the effects of yoga on improving the quality of life in menopausal women. METHOD: English databases of Google Scholar, Science Direct, PubMed, Scopus, and Cochrane Library were searched to access related articles using keywords of menopause, quality of life, and yoga. Furthermore, Persian equivalents of the same keywords were searched in databases of Google Scholar, SID, and Magiran, in addition to a combination of the keywords. The search interval was from the inspection to January 2020. The quality of the included studied was assessed based on CONSORT 2017 checklist. RESULTS: Out of 120 articles found in the databases, six articles entered the study based on the inclusion criteria and were investigated for intervention methods and consequences. The results indicated the positive impact of yoga on the quality of life in menopausal women. CONCLUSION: Considering the effects of yoga on the symptoms and quality of life in menopausal women, it is suggested that this low-cost method be used to improve their quality of life and health.

Effect of Complementary Medicine on Pain Relief and Wound Healing after Cesarean Section: A Systematic Review.

OBJECTIVES: Cesarean sections are one of the common surgical procedures around the world. Management of cesarean section side effects, including pain, hematoma, delayed wound healing, is of particular importance in maintaining maternal health and ability to care for the baby. The tendency to use complementary medicine strategies is on the rise because of the easy treatment with low side effects. The purpose of this study was to systematically review the efficacy and safety of clinical trials performed in Iran and worldwide on the effect of complementary medicine on pain relief and wound healing after cesarean section. METHODS: PRISMA checklist was followed to prepare the report of this systematic review. The search process was carried out on databases on databases of Magiran, SID, Iran Medex, Scopus, Pub Med, Science direct, Medline and Cochrane library using keywords of cesarean, pain, wound healing, Herbal medicine, acupressure, massage, complementary medicine and their Persian equivalent and all possible combinations, from inception until February 2020. We used the Jadad scale to assess the quality of the searched articles. According to the Jadad scale, the articles with a score of at least 3 were included in the study. RESULTS: Finally, 28 clinical trials (with a sample size of 3,245) scored at least 3 on the Jadad scale were included into the analysis. This article reviewed 13 articles on medicinal herbs, 4 articles on massage, 1 article on reflexology, 2 articles on acupressure. CONCLUSION: According to the present review, the use of medicinal herbs was the most common method of complementary medicine in pain relief and wound healing after cesarean section.

Isolation, molecular identification, and phylogenetic evaluation of Cryptococcus neoformans isolated from pigeon lofts, Psittaciformes, and Passeriformes in Ahvaz, Iran.

Cryptococcus neoformans, the main pathogen in immunocompromised patients, is a ubiquitous free-living fungus that can be isolated from avian excreta, soils, and plant material. This study was carried out to determine the infection rate of pigeon lofts, Passeriformes, and Psittaciformes in Ahvaz, the capital of Khuzestan province in Iran and to determine varieties of Cryptococcus neoformans (C. neoformans). The 80 samples were collected from pigeon lofts. Also, 163 feces of captive birds (Passeriformes and Psittaciformes) which kept in Ahvaz pet shops, and the 70 cloacal swabs of pet birds (Passeriformes and psittaciformes) referring to the department of avian medicine (the faculty of veterinary medicine of Shahid Chamran University of Ahvaz) were analyzed. The samples were directly inoculated on niger seed agar (NSA) and also enriched in brain heart infusion broth and then inoculated on NSA. Dark brown colonies suspected to C. neoformans subcultured on saborouds dextrose agar and pure cultures subjected to molecular (polymerase chain reaction (PCR)) diagnosis. For detection of C. neoformans, primer sets that targeting the CNLAC1 gene were selected and nested PCR was conducted. For identification of C. neoformans varieties, a primer set targeting the STR1 gene was selected. For more accurate confirmation, the purified PCR products of some isolates were also sequenced, and based on the gene sequences, all of the isolates belonged to C. neoformans variety grubii (var. grubii)(serotype A). Totally 16 out of 80 pigeon samples (20%) were contaminated with C. neoformans. The results in pigeons disclosed a 98.64% identity when compared with other strains of C. neoformans (CN1525, T4, and T1) which were previously deposited in GenBank from Italy and Thailand. Also, 21 out of 233 samples from Psittaciformes (9.01%) were contaminated with C. neoformans. The results in Psittaciformes disclosed a 99.7% identity when compared with other strains of C. neoformans (TIMM1313, IFM5882, CN1525, etc.) which were previously deposited in GenBank from Japan and Italy, etc. In the present study, the samples belonging to the passerine order were free of C. neoformans infection. According to the results, C. neoformans is prevalent in pigeon flocks and pet birds including Psittaciformes in the Ahvaz area, and should be considered by pigeon and captive bird breeders, veterinarians, and public health organizations in Ahvaz. The cryptococcus species isolated from captive birds and pigeons could be potential pathogens in humans.

A Feasibility Study of In Vivo Control and Tracking of Microrobot Using Taxicab Geometry for Direct Drug Targeting.

In vivo direct drug targeting aims at delivering drug molecules loaded on microrobots to the diseased site using the shortest possible physiological routes, which potentially improves targeting efficiency and reduces systemic toxicity. It is thus essential to consider realistic in-body limitations for direct drug targeting applications. Here, we present a novel controller for microrobot maneuver by considering four key in vivo constraints: non-Euclidean structure of capillaries, irreversibility of blood flow, invisibility of microvasculature, and inaccuracy of microrobot tracking. We use the taxicab geometry of capillaries as the a priori knowledge for steering and tracking a microrobot in lattice-like vessels. Furthermore, we introduce a minimax repulsive boundary function to prevent the microrobot from getting too close to the boundaries imposed by the direction of blood flow. We also propose a novel Kalman filtering algorithm to reduce tracking error, while avoiding possible obstacles such as vessel walls without knowing their actual locations. The proposed control method consists of four modules, namely a model predictive control module for tumor targeting, a Kalman filtering module for microrobot tracking, a blind obstacle detection module, and a vessel structure estimation module. The interplay of these four modules offers successful maneuver and tracking of the microrobot while avoiding obstacles in a blind manner by utilizing the taxicab geometry of blood vessels. We present a comprehensive in silico simulation study to verify our designed controller.

Self-Regulated and Co-ordinated Smart Tumor Homing for Complex Vascular Networks.

Inspired by the collaborative movements of the living cells in different natural biological processes, this paper highlights a self-regulated and co-ordinated targeting strategy to detect tumor in complex human vasculature. We show by computational experiments that simple and non-centralized nanoparticles with limited locomotive capability, when they collaborate and move in the form of groups, can be very robust in the tumor homing process. Once reaching tumor location, such nanoparticles (potential contrast agents) can deposit themselves on tumor through the enhanced permeability and retention (EPR) effect thereby making the malignant cancerous area more prominent. Hence, existing medical imaging techniques with limited resolution can be used to detect small malignant tumors. We believe that our work will help in early cancer detection through an independent, non-centralized and self-controlled system.Clinical Relevance:- With the help of target amplification through contrast agents such as self-regulated nanoparticles contrast enhanced medical imaging can detect the tumor at its initial stages when 90% of the cancers are curable.

Blind Obstacle Avoidance Using Taxicab Geometry for NanorobotAssisted Direct Drug Targeting.

In this paper, we present a novel controller for steering nanorobots in lattice-like vessel systems while avoiding potential obstacles such as the vessel walls without any prior knowledge of the obstacles' positions. The proposed control method consists of two sub-modules, namely a blind obstacle avoidance (BOA) and a model predictive control (MPC). In the case that a nanorobot might encounter an obstacle on its path, the BOA module is activated, which gives rise to a desirable heading angle to change the direction of the nanorobot's movement to bypass the obstacle. On the other hand, the MPC module offers a series of actuating field's directions that control the nanorobots' movement in the blood vessel with a grid structure representing potential paths of vascular growth, and introduces a repulsive boundary function to stop nanorobots from getting too close to the boundaries. This new formulation offers successful control and steering of nanorobots while avoiding obstacles in a blind manner by taking into account realistic in vivo physical constraints. Simulation results demonstrate the effectiveness of the proposed feedback control design.

The Effect of Information Therapy on Treatment Adherence among Patients Referred to Addiction Treatment Centers.

BACKGROUND: The low level of drug adherence in addicts who are quitting is one of the biggest challenges in the treatment and management of this disease. Therefore, this study aimed to evaluate the effect of information therapy on adherence to treatment among the patients in addiction treatment centers. METHODS: The present quasi-experimental study was performed on 60 patients referred to addiction treatment centers in Jiroft City, Iran. The control and experimental groups were selected using simple random sampling method. The 8-item Morisky Medication Adherence Scale was used for data collection. The level of adherence to treatment was assessed before and after the intervention, which consisted of 6 one-hour training sessions per week. FINDINGS: The adherence to medication was low in both experimental and control groups before the notification. However, the chi-square value obtained by comparing the frequencies of the experimental and control groups in three variables of adherence level (high, moderate, and low) was 9.84 which was statistically significant (P = 0.007). Therefore, there was a significant difference between the experimental and control groups after information therapy. In fact, the information in the experimental group had a significant and positive effect. CONCLUSION: Because of the low level of adherence to treatment, it is recommended to use information therapy to give information on timely and correct use of drugs as well as its importance in the treatment of addiction; so that the level of adherence would improve.

Cytogenetic assessment of Iranian infertile men with undescended testis: A retrospective study.

OBJECTIVE: Undescended testis (UDT) is a urogenital disease that affects fertility. This study looked into the cytogenetic abnormalities of Iranian infertile patients with UDT. METHODS: Our study included 522 infertile patients with UDT (case group) and two control groups, one with 300 infertile men without UDT and another with 268 fertile men. RESULTS: Chromosomal abnormalities were found in 45 patients with UDT (8.62%). Seven of the alterations were considered as normal features. Klinefelter syndrome and mosaicism were the most common anomalies. Chromosomal abnormalities were found in 31 infertile men in the control group (10.33%), 13 of which deemed normal and 18 (6%) anomalous. Nine chromosomal abnormalities were found in the second control group with fertile men (3.35%), six deemed normal and three (1.11%) anomalous. CONCLUSION: Despite the high rate of abnormalities in infertile controls (6%) and the higher rate seen in infertile individuals with UDT indicate a significant prevalence of chromosomal abnormalities in the Iranian population, particularly when the literature suggests that the normal rate of abnormal karyotypes should be within the 0.7-1% range in the general population. The incidence of abnormal karyotypes increased when infertile patients had additional conditions such as UDT.

Perspective: Computational Nanobiosensing.

With the development of nanotechnology, externally manipulable or self-regulatable smart nanosystems can be utilized as effective tools for computational nanobiosensing, where natural computing strategies are exploited for knowledge-aided nanobiosensing.

Overcoming Channel Uncertainties in Touchable Molecular Communication for Direct-Drug-Targeting-Assisted Immuno-Chemotherapy.

OBJECTIVE: The performance of targeted immuno-chemotherapy of tumor is highly exposed to drug absorption in systemic circulation, which reduces its efficiency and increases side-effects. Direct drug targeting (DDT) combined with immuno-chemotherapy has the potential to mitigate the undesired systemic exposure, by using drug-loaded nanorobots to target cancer cells with the shortest possible physiological routes. This process can be modeled by the "touchable" (i.e., externally controllable and trackable) molecular communication system. However, such a complex process still suffers from various pharmacokinetic uncertainties caused by diffusion, degeneration, and branching of nanorobots (DDT pharmacokinetic uncertainties), as well as tumor/immune system modeling errors. The current work aims at identifying optimal drug administration plans by overcoming such challenges. METHODS: A revisited tumor-immune interaction model is proposed to incorporate randomness of the drug concentration in the tumor site. Then, a robust multiple model predictive control (MMPC) scheme for the proposed tumor-immune interaction model is designed that uses multiple system models and an adaptive switch to identify the optimal plans for mixed drug administration via drug-loaded nanorobots. Furthermore, a wide range of prediction horizons under different loss scenarios of drug-loaded nanorobots and system model mismatches have been investigated in order to identify safe operating regions. From the molecular communications paradigm, this can be considered as a more robust information transmission system with feedback of channel state information to the transmitter implemented in the control unit. RESULTS: The efficacy of the proposed MMPC is illustrated through identification of globally optimized drug administration schedules subject to various controller operation imperfections, which lead to successful cancer treatment as demonstrated through computational experiments. CONCLUSION: By combining DDT with conventional mixed immunotherapy and chemotherapy, the proposed robust MMPC offers promising performance in controlling tumor growth while keeping the immune cell density higher than a specific level in the presence of both DDT pharmacokinetic uncertainties and system model mismatches. SIGNIFICANCE: We believe that the proposed design framework represents an important first step towards clinically relevant DDT in the combined immunotherapy and chemotherapy of tumor given its robust performance.

Nanoswimmer-oriented Direct Targeting Strategy Inspired by Momentum-based Gradient Optimization.

This paper considers the advantage of knowledgeaided direct targeting strategy (DTS) over systemic targeting for tumor homing in complex human vasculature. Tumor location in the body can be estimated by closely observing the tumortriggered bio-physical gradients in its vicinity, helping drugloaded magnetic nanoswimmers to accumulate at the disease location. These nanoswimmers are assembled by magnetic nanoparticles (MNPs), which act as contrast agents increasing the diagnostic capability of different medical imaging techniques. We propose a novel DTS inspired by the iterative gradient descent (GD) with momentum optimization for tumor targeting amplification. We show by computational experiments that the MNPs accumulate at the disease location at a faster rate and the probability of tumor detection is higher for the proposed knowledge-aided DTS as compared to the knowledgeless systemic targeting. We believe that our work for tumor targeting amplification based on such nanosystem will open new horizons in the field of diagnosing tumor at its early stage.

Overcoming Channel Uncertainties in Molecular-Communication-Inspired Direct Drug Targeting.

Recent progress in the development of new methods for cancer treatment has shown advantages of multiple therapies over mono-therapy. In particular, direct drug targeting (DDT) combined with mixed immunotherapy and chemotherapy has the potential to mitigate the undesired side-effects allied with conventional therapies, where nanorobots in DDT carry therapeutic agents through the blood vessel channel in order to localize and target diseased tissue with a safe drug interaction. This process can be modeled by a "touchable" (i.e., externally controllable and trackable) molecular communication (MC) system. However, in such a complex process overcoming unavoidable vascular channel uncertainties remains a great challenge. In this paper a multiple model predictive controller (MMPC) is proposed, which is robust against random channel uncertainties. The efficacy of the proposed method is illustrated through identification of globally optimized drug administration schedules. Furthermore, we introduce upper and lower bounds on the inputs and outputs which lead to clinically realistic constraints on the system. Simulation results demonstrate the promising performance of proposed MMPC to control tumor growth in presence of vascular channel uncertainties in MC-inspired DDT for cancer treatment.

A study on prevalence and identification of Ovine Theileria and Babesia infection in Zabol using PCR method.

Infection with Babesia and Theileria Causes high mortality and economical losses in livestock and has a relatively high prevalence in Iran. In Zabol, animals are susceptible to this disease because of presence of vector ticks, weather conditions and smuggle animal across the border and they cause great damages to the economy and production. However, few studies have been done for differentiation of Theileria and Babesia in sheep in this area. The purpose of the present study was to determine the prevalence of Babesiosis and Theileriosis in sheep in Zabol. A number of 80 animals were randomly selected and their blood samples were examined. The presence of Theileria and Babesia parasites in each sample was determined with PCR and microscopic examination. Of 80 blood samples obtained from sheep, 8 cases (10 %) were positive by microscopic examination where 6 samples were infected with Theileria and 2 samples with Babesia. The result of PCR method determined the prevalence of 66.25 % (53 samples) and 3.75 % (3 samples) for Theileria and Babesia, respectively. The correlation between these two methods (PCR and microscopic examination) was determined with Kappa statistical test. Based on the obtained results, it is concluded that Babesiosis has a low prevalence among the sheep of Zabol. This is the first report in which ovine Babesiosis has been studied in this region using molecular identification techniques.

Improving multivariable prostate cancer risk assessment using the Prostate Health Index.

OBJECTIVES: To analyse the clinical utility of a prediction model incorporating both clinical information and a novel biomarker, p2PSA, in order to inform the decision for prostate biopsy in an Irish cohort of men referred for prostate cancer assessment. PATIENTS AND METHODS: Serum isolated from 250 men from three tertiary referral centres with pre-biopsy blood draws was analysed for total prostate-specific antigen (PSA), free PSA (fPSA) and p2PSA. From this, the Prostate Health Index (PHI) score was calculated (PHI = (p2PSA/fPSA)*√tPSA). The men's clinical information was used to derive their risk according to the Prostate Cancer Prevention Trial (PCPT) risk model. Two clinical prediction models were created via multivariable regression consisting of age, family history, abnormality on digital rectal examination, previous negative biopsy and either PSA or PHI score, respectively. Calibration plots, receiver-operating characteristic (ROC) curves and decision curves were generated to assess the performance of the three models. RESULTS: The PSA model and PHI model were both well calibrated in this cohort, with the PHI model showing the best correlation between predicted probabilities and actual outcome. The areas under the ROC curve for the PHI model, PSA model and PCPT model were 0.77, 0.71 and 0.69, respectively, for the prediction of prostate cancer (PCa) and 0.79, 0.72 and 0.72, respectively, for the prediction of high grade PCa. Decision-curve analysis showed a superior net benefit of the PHI model over both the PSA model and the PCPT risk model in the diagnosis of PCa and high grade PCa over the entire range of risk probabilities. CONCLUSION: A logical and standardized approach to the use of clinical risk factors can allow more accurate risk stratification of men under investigation for PCa. The measurement of p2PSA and the integration of this biomarker into a clinical prediction model can further increase the accuracy of risk stratification, helping to better inform the decision for prostate biopsy in a referral population.