Impact of AlphaFold on structure prediction of protein complexes: The CASP15-CAPRI experiment.

We present the results for CAPRI Round 54, the 5th joint CASP-CAPRI protein assembly prediction challenge. The Round offered 37 targets, including 14 homodimers, 3 homo-trimers, 13 heterodimers including 3 antibody-antigen complexes, and 7 large assemblies. On average ~70 CASP and CAPRI predictor groups, including more than 20 automatics servers, submitted models for each target. A total of 21 941 models submitted by these groups and by 15 CAPRI scorer groups were evaluated using the CAPRI model quality measures and the DockQ score consolidating these measures. The prediction performance was quantified by a weighted score based on the number of models of acceptable quality or higher submitted by each group among their five best models. Results show substantial progress achieved across a significant fraction of the 60+ participating groups. High-quality models were produced for about 40% of the targets compared to 8% two years earlier. This remarkable improvement is due to the wide use of the AlphaFold2 and AlphaFold2-Multimer software and the confidence metrics they provide. Notably, expanded sampling of candidate solutions by manipulating these deep learning inference engines, enriching multiple sequence alignments, or integration of advanced modeling tools, enabled top performing groups to exceed the performance of a standard AlphaFold2-Multimer version used as a yard stick. This notwithstanding, performance remained poor for complexes with antibodies and nanobodies, where evolutionary relationships between the binding partners are lacking, and for complexes featuring conformational flexibility, clearly indicating that the prediction of protein complexes remains a challenging problem.

Australian surgical revision rate for benign prostatic obstruction.

OBJECTIVE: To evaluate the rate of revision surgery following commonly performed procedures for benign prostatic hyperplasia (BPH) is hyperplasia of both glandular and stromal components of prostate especially in periurethral transitional gland, using real-world data from Medicare Australia. METHODS: Prospection is a Healthcare Data Analytics firm that has negotiated access with the Medicare Benefits Schedule (MBS) to provide longitudinal data on the use of specific procedural item codes. We identified patients over the age of 40 years who had undergone primary transurethral resection of the prostate (TURP), transurethral incision of the prostate (TUIP) or photoselective vaporization of the prostate (PVP) between 2005 and 2010 using MBS item numbers 37203, 37207 and 36854, respectively. Using longitudinal MBS data, primary outcomes included need for revision surgery at 5-years follow-up (2015). The release of these data was approved by Medicare Australia upon application. Data analysis was conducted using chi-squared tests and statistical significance was defined at P < 0.05. RESULTS: The distribution of primary surgical procedures performed between 2005 and 2010 was: TURP 5579 (90%), TUIP 345 (6%) and PVP 258 (4%). TURP was also the most prevalent procedure for treatment of lower urinary tract symptoms in men with BPH requiring revision surgery (75%). At 5-year follow-up the rate of revision surgery for TURP (573/5579), TUIP (47/345) and PVP (30/258) was 10.3%, 13.6% and 11.6%, respectively. The difference was not statistically significant (P = 0.12). There was no significant change (P = 0.59) observed over the years in number of men requiring revision surgery. CONCLUSION: This study indicates that TURP and PVP have a similar durability after 5 years of follow-up.

Expanding the role of PSMA PET in active surveillance.

INTRODUCTION: Accurate grading at the time of diagnosis is fundamental to risk stratification and treatment decision making, particularly for men being considered for Active Surveillance (AS). With the introduction of prostate-specific membrane antigen (PSMA) positron emission tomography (PET) there has been considerable improvement in sensitivity and specificity for the detection and staging of clinically significant prostate cancer. Our study aims to determine the role of PSMA PET/CT in men with newly diagnosed low or favourable intermediate risk prostate cancer to better select men for AS. METHOD: This is a retrospective single centre study performed from January 2019 and October 2022. This study includes men identified from electronic medical record system who had undergone a PSMA PET/CT following newly diagnosed low or favourable-intermediate risk prostate cancer. Primary outcome was to assess the change in management for men being considered for AS following PSMA PET/CT results on the basis of PSMA PET characteristics. RESULTS: In total, there were 11 of 30 men (36.67%) who were assigned management by AS and 19 of 30 men (63.33%) who had definitive treatment. 15 of the 19 men that needed treatment had concerning features on PSMA PET/CT results. Of the 15 men with concerning features on PSMA PET, 9 (60%) men were found to have adverse pathological features on final prostatectomy features. CONCLUSION: This retrospective study suggests that PSMA PET/CT has potential to influence the management of men with newly diagnosed prostate cancer that would otherwise be appropriate for active surveillance.

The effect of COVID-19 on prostate cancer testing in Australia.

AIM: The effects of the COVID-19 pandemic on healthcare in Australia have yet to be fully determined. There are well documented decreases in the rates of screening and diagnostic testing for many cancers in 2020, with commensurate stage migration of cancers when they are eventually detected. We aimed to determine whether there was a decrease in the rate of prostate cancer (PC) screening and testing in Australia in 2020. METHOD: Data was extracted from the Department of Human Services (DHS) website for Medicare Benefits Schedule (MBS) item numbers for tests pertinent to detection of Prostate Cancer. This data is de-identified and publicly available. Data was analysed at both a national, and a state level. RESULTS: For 2020 nationwide the percentage change for prostate cancer testing was minor with 97% as many PSA tests, 99% as many prostate MRIs, and 105% as many prostate biopsies as the average for the preceding years. The differences were not significant (PSA tests p = 0.059 and prostate biopsies p = 0.109). The predicted values are fairly similar to both the average values for the preceding 5 years and the actual number of tests done in 2020. With exception of PSA tests in Victoria the actual number of tests performed was within the 95% Prediction Interval (performed: 167,426; predicted 171,194-196,699; p = 0.015). CONCLUSION: The current pandemic has had a widespread reach across Australia, with varying impact across each state and territory. Contrary to the trends across the world, our data suggest that during 2020 in Australia most areas remained unaffected in terms of prostate cancer testing excluding Victoria, which had statistically significant decrease in the number of PSA tests correlating with the extended lockdown that occurred in the state.

Female Genital Mutilation: Treatment Updates and the Need for Education.

INTRODUCTION: Female genital mutilation/cutting (FGM/C) refers to ritual surgical procedures performed that intentionally alter genitalia for nonmedical purposes. Female genital mutilation/ cutting is a lifelong problem for women that can have detrimental effects on menstruation, pregnancy, sexual health, and self-esteem. In 2016 the Centers for Disease Control and Prevention estimated 513,000 women and children in the United States were victims of or at risk for FGM/C. Currently, few studies discuss potential management options for FGM/C and their associated complications. Aims of this study are to review contemporary research on FGM/C, discuss current surgical therapies in the pediatric and adult populations, and draw attention to the urgent need for further education. METHODS: The authors conducted a literature review using PubMed, and identified 731 articles in the adult and pediatric populations. The articles were cross-referenced with 2 systematic reviews, and duplicates were discarded. Based on our criteria, 9 articles were included. RESULTS: Based on our findings, defibulation offers patients a better quality of life with a low rate of complication. Similarly, clitoral reconstruction has shown favorable results for treatment of FGM/C. Using the Female Sexual Function Index can better help standardize measurements of sexual health outcomes. Currently, established clinical guidelines are lacking and there is limited training on the recognition and treatment of FGM/C. CONCLUSIONS: This study supports clitoral reconstruction and defibulation as effective therapies for FGM/C. Reconstructive surgeons are at the forefront of developing and providing these surgical treatments. Further research including randomized controlled studies and long-term follow-up are needed to better elucidate the best therapeutic options.

Community perceptions of vaccination among influential stakeholders: qualitative research in rural India.

BACKGROUND: In India and other low- and middle-income countries, multiple family and community members are influential in caregivers' perceptions of vaccination. Existing literature indicates the primary caregiver, typically the mother, is instrumental in vaccine decision-making, but this may vary in contexts. We investigated the role of stakeholders in India who influence caregivers' vaccination perceptions, as this is essential to developing strategies to promote vaccine acceptance and improve uptake. METHODS: This research was conducted in 2019 in Mewat District in Haryana, an area in India with extremely low vaccination coverage. We conducted six focus group discussions with 60 participants in the following categories: fathers of children under-5 years old, expectant mothers, mothers-in-law, community health workers, and community influencers such as locally elected officials and religious leaders. RESULTS: Our results highlighted four themes that influence vaccine uptake. First, while caregivers associated vaccination with reductions in specific diseases, they also noted that vaccination services brought broad health gains, including improved nutrition, antenatal guidance, and social support. Second, community health workers critically influenced, positively or negatively, caregivers' vaccination perceptions. Third, community health workers faced gaps in their education such as limited training on vaccine side-effects, placing them at a disadvantage when dealing with families. Finally, we found that mothers-in-law, fathers, and religious leaders influence caregivers' perceptions of vaccination. CONCLUSIONS: Communication of broader benefits of vaccines and vaccination services by community health workers could be impactful in increasing vaccine acceptance. Vaccine uptake could potentially be improved by facilitating community health workers' ownership over vaccine acceptance and uptake by involving them in the design and implementation of interventions to target mothers and mothers-in-law. A 'bottom-up' approach, leveraging community health workers' knowledge to design interventions, and giving a voice to key members of the household and society beyond mothers alone, may sustain health improvement in low vaccine coverage areas.

Pott's disease post intravesical BCG.

This report describes a unique case of an 89-year-old-male who presented with a right psoas abscess and new erosive changes in the L3/L4 vertebral bodies. This is on a background of non muscle invasive bladder cancer (NMIBC) for which he received intravesical Bacillus Calmette-Guerin (BCG). Pott's disease is a rare complication of BCG therapy and there is paucity of data about the risk factors for systemic spread of intravesical BCG.

Less Is More: Oligomer Extraction and Hydrothermal Annealing Increase PDMS Adhesion Forces for Materials Studies and for Biology-Focused Microfluidic Applications.

Cues in the micro-environment are key determinants in the emergence of complex cellular morphologies and functions. Primary among these is the presence of neighboring cells that form networks. For high-resolution analysis, it is crucial to develop micro-environments that permit exquisite control of network formation. This is especially true in cell science, tissue engineering, and clinical biology. We introduce a new approach for assembling polydimethylsiloxane (PDMS)-based microfluidic environments that enhances cell network formation and analyses. We report that the combined processes of PDMS solvent-extraction and hydrothermal annealing create unique conditions that produce high-strength bonds between solvent-extracted PDMS (E-PDMS) and glass-properties not associated with conventional PDMS. Extraction followed by hydrothermal annealing removes unbound oligomers, promotes polymer cross-linking, facilitates covalent bond formation with glass, and retains the highest biocompatibility. Herein, our extraction protocol accelerates oligomer removal from 5 to 2 days. Resulting microfluidic platforms are uniquely suited for cell-network studies owing to high adhesion forces, effectively corralling cellular extensions and eliminating harmful oligomers. We demonstrate the simple, simultaneous actuation of multiple microfluidic domains for invoking ATP- and glutamate-induced Ca2+ signaling in glial-cell networks. These E-PDMS modifications and flow manipulations further enable microfluidic technologies for cell-signaling and network studies as well as novel applications.

Bioinformatic Approaches for Characterizing Molecular Structure and Function of Food Proteins.

Structural bioinformatics analyzes protein structural models with the goal of uncovering molecular drivers of food functionality. This field aims to develop tools that can rapidly extract relevant information from protein databases as well as organize this information for researchers interested in studying protein functionality. Food bioinformaticians take advantage of millions of protein amino acid sequences and structures contained within these databases, extracting features such as surface hydrophobicity that are then used to model functionality, including solubility, thermostability, and emulsification. This work is aided by a protein structure-function relationship framework, in which bioinformatic properties are linked to physicochemical experimentation. Strong bioinformatic correlations exist for protein secondary structure, electrostatic potential, and surface hydrophobicity. Modeling changes in protein structures through molecular mechanics is an increasingly accessible field that will continue to propel food science research.

Relative Risk of Bladder and Kidney Cancer in Lynch Syndrome: Systematic Review and Meta-Analysis.

Background: The association between Lynch syndrome (LS) and a higher risk of upper tract urothelial carcinoma is well established, but its effect on the risk of bladder and kidney cancers remains controversial. This review aimed to compare the relative risk (RR) of bladder and kidney cancer in confirmed LS germline mutation carriers compared to the general population. Methods: Medline, Embase, Cochrane Central, and Google Scholar were searched on 14 July 2022 for studies published in English that reported on the rates of urological cancer in adults with confirmed LS germline mutation. The quality of included studies was assessed using Cochrane's tool to evaluate risk of bias in cohort studies. Random effects meta-analysis estimated the pooled relative risk of bladder and kidney cancer in LS carriers compared to the general population. The quality of the overall evidence was evaluated using GRADE. Results: Of the 1839 records identified, 5 studies involving 7120 participants from 3 continents were included. Overall, LS carriers had a statistically significantly higher RR of developing bladder cancer (RR: 7.48, 95% CI: 3.70, 15.13) and kidney cancer (RR: 3.97, 95% CI: 1.23, 12.81) compared to unaffected participants (p < 0.01). The quality of the evidence was assessed as "low" due to the inclusion of cohort studies, the substantial heterogeneity, and moderate-to-high risk of bias. Conclusion: Lynch syndrome is associated with a significant increase in the relative risk of kidney and bladder cancer. Clinicians should adopt a lower threshold for germline mutation genetic testing in individuals who present with bladder cancer. Further studies evaluating the role and cost-effectiveness of novel urine-based laboratory tests are needed. High-quality studies in histologically proven renal cell carcinoma and their underlying germline mutations are necessary to strengthen the association with LS.

Whole-exome sequencing of Indian prostate cancer reveals a novel therapeutic target: POLQ.

PURPOSE: Prostate cancer is the second most common cancer diagnosed worldwide and the third most common cancer among men in India. This study's objective was to characterise the mutational landscape of Indian prostate cancer using whole-exome sequencing to identify population-specific polymorphisms. METHODS: Whole-exome sequencing was performed of 58 treatment-naive primary prostate tumors of Indian origin. Multiple computational and statistical analyses were used to profile the known common mutations, other deleterious mutations, driver genes, prognostic biomarkers, and gene signatures unique to each clinical parameter. Cox analysis was performed to validate survival-associated genes. McNemar test identified genes significant to recurrence and receiver-operating characteristic (ROC) analysis was conducted to determine its accuracy. OncodriveCLUSTL algorithm was used to deduce driver genes. The druggable target identified was modeled with its known inhibitor using Autodock. RESULTS: TP53 was the most commonly mutated gene in our cohort. Three novel deleterious variants unique to the Indian prostate cancer subtype were identified: POLQ, FTHL17, and OR8G1. COX regression analysis identified ACSM5, a mitochondrial gene responsible for survival. CYLC1 gene, which encodes for sperm head cytoskeletal protein, was identified as an unfavorable prognostic biomarker indicative of recurrence. The novel POLQ mutant, also identified as a driver gene, was evaluated as the druggable target in this study. POLQ, a DNA repair enzyme implicated in various cancer types, is overexpressed and is associated with a poor prognosis. The mutant POLQ was subjected to structural analysis and modeled with its known inhibitor novobiocin resulting in decreased binding efficiency necessitating the development of a better drug. CONCLUSION: In this pilot study, the molecular profiling using multiple computational and statistical analyses revealed distinct polymorphisms in the Indian prostate cancer cohort. The mutational signatures identified provide a valuable resource for prognostic stratification and targeted treatment strategies for Indian prostate cancer patients. The DNA repair enzyme, POLQ, was identified as the druggable target in this study.

Multiparametric Magnetic Resonance Imaging of the Prostate and Prostate-specific Membrane Positron Emission Tomography Prior to Prostate Biopsy (MP4 Study).

Background: Prostate-specific membrane antigen (PSMA) positron emission tomography/computerised tomography (PET/CT) is increasingly being utilised in the diagnostic pathway for prostate cancer (PCa). Recent publications have suggested that this might help identify those who can avoid biopsy. Objective: The primary objective of this study was to determine whether PET magnetic resonance imaging (MRI) fusion could negate the need to biopsy prior to prostatectomy in a selected population of men. Design setting and participant: Multiparametric MRI (mpMRI) for PCa is our standard of care prior to prostate biopsy. Biopsy-naïve men with one or more Prostate Imaging Reporting and Data System (PI-RADS) 4 or 5 lesions ≥10 mm on mpMRI were invited to undergo PSMA PET/CT prior to biopsy. Following ethics approval, 60 men were recruited between September 2020 and March 2021. The key exclusion criteria included a previous history of PCa and previous prostate surgery or biopsy. Outcome measurements and statistical analysis: A positive PET MRI fusion scan was defined as "consistent with" as per the Memorial Sloan Kettering Cancer Center lexicon of certainty, and concordance with biopsy results was analysed. Clinically significant PCa (csPCa) was defined as grade group (GG) ≥2 on pathology. A chi-square analysis was performed with statistical significance defined at p < 0.05. Results and limitations: A total of 71 mpMRI lesions were positive on 61 (86%) PET MRI fusion scans. Fifty-nine of 61 lesions biopsied confirmed csPCa in 54 (92%). Of five of 59 lesions for which either biopsy was negative or low-grade cancer was found, three had rebiopsy of which two were confirmed to have csPCa corroborating with PET MRI fusion and one was reconfirmed to have GG1 only. For the remaining two, both had another lesion elsewhere in the gland confirming csPCa, and hence rebiopsy was not performed. Ultimately, 56 of 59 (95%) lesions with a positive PET MRI fusion scan were confirmed to have csPCa. All GG ≥3 cancers had a positive PET MRI fusion scan. Conclusions: This prospective study of PET MRI fusion assessment of men with PI-RADS 4 or 5 lesion ≥10 mm on mpMRI confirms that the majority of men (95%) with a positive PET MRI fusion scan will have csPCa. This supports recently published retrospective data suggesting that selected men might avoid prostate biopsy prior to radical prostatectomy. Patient summary: In this research, we have confirmed that prostate-specific membrane antigen positron emission tomography/computerised tomography in combination with magnetic resonance imaging could have an important role in enabling a diagnosis of prostate cancer. Using the combination of these scans, we could confidently predict the presence of aggressive prostate cancer in some men for which treatment is warranted. This means that there are some men who could possibility proceed directly to having prostate cancer surgery without the need for a confirmatory prostate biopsy.

Facilitating hand hygiene in displacement camps during the COVID-19 pandemic: a qualitative assessment of a novel handwashing stand and hygiene promotion package.

BACKGROUND: Handwashing with soap is critical for the prevention of diarrhoeal diseases and outbreak related diseases, including interrupting the transmission of COVID-19. People living in large displacement settings are particularly vulnerable to such outbreaks, however, practicing handwashing is typically challenging in these contexts. METHODS: We conducted a qualitative assessment of the implementation of a combined intervention to facilitate handwashing behaviour in displacement camps and in surrounding communities in Bangladesh, Ethiopia and the Democratic Republic of Congo during the COVID-19 pandemic. The intervention comprised a 'hardware' infrastructural component (provision of the Oxfam Handwashing Station) and a 'software' hygiene promotion package (Mum's Magic Hands). We used programmatic logbooks, interviews with implementation staff and focus group discussions with crisis-affected populations to assess the use, feasibility and acceptability of the intervention. RESULTS: Both components of the intervention were viewed as novel and appealing by implementing staff and crisis-affected populations across the study sites. The acceptability of the handwashing station could be improved by redesigning the tap and legs, exploring local supply chain options, and by providing a greater number of facilities. The implementation of the hygiene promotion package varied substantially by country making it challenging to evaluate and compare. A greater focus on community engagement could address misconceptions, barriers related to the intuitiveness of the handwashing station design, and willingness to participate in the hygiene promotion component. CONCLUSIONS: The combination of a 'hardware' and 'software' intervention in these settings appeared to facilitate both access and use of handwashing facilities. The acceptability of the combined intervention was partially because a great deal of effort had been put into their design. However, even when delivering well-designed interventions, there are many contextual aspects that need to be considered, as well as unintended consequences which can affect the acceptability of an intervention.

A case of false identity: Primary cutaneous diffuse large B-cell lymphoma masquerading as Madura Foot.

Primary cutaneous - diffuse large B-cell lymphoma - leg type (PC-DLBCL-LT) is a less frequent but more aggressive, and potentially curable, type of cutaneous B-cell lymphoma, with intermediate prognosis, that affects elderly individuals. Our patient with indurated, pigmented foot previously treated for Filariasis, now presented with ulcers, multiple discharging sinuses, clinically suspected to have Madura Foot. Histopathological examination confirmed a diagnosis of PC-DLBCL-LT after which he underwent below-knee amputation.

A diagnostic and management conundrum in a rare case of a small renal mass UTUC with IVC and bilateral renal vein tumour thrombus.

Upper Tract Urothelial Carcinomas (UTUC) are generally uncommon, accounting for approximately 5% of all urinary tract tumours. This report describes a unique Case of a 52-year-old-male with no known risk factors or symptoms of UTUC, who presented with bilateral sub-massive pulmonary embolus (PE). Subsequent computed tomography (CT) demonstrated a small (<2cm) right cortical based mass a discordant venous tumour thrombus (VTT) extending in the IVC, up to the level of the hepatic vein and bilateral renal veins. The patient had surgical excision in the form of right radical nephroureterectomy, IVC resection with bovine pericardial graft reconstruction and left renal autotransplant.

Influence of Age and Geography on Chemical Composition of 98043 Urinary Stones from the USA.

BACKGROUND: Urolithiasis is a growing issue globally, but it is heterogeneous, with a different epidemiology and pathophysiology for each different stone composition. OBJECTIVE: The purpose of this study is to describe the incidence of urinary stones in the USA from 2016 to 2019 by chemical composition and to investigate the influence of age and geography on these stone types. DESIGN SETTING AND PARTICIPANTS: We obtained compositional analyses for all urinary stones submitted to a national laboratory over an approximately 3-yr period. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: Data collected included the chemical constituents of a stone, patient age, and geographical origin. We describe the incidence of each stone type by frequency. Statistical testing was performed to determine the influence of age and geographical region on overall incidence of each stone composition. RESULTS AND LIMITATIONS: In total, 99 908 specimens were analyzed. When pure stones were ordered by frequency, we found that the most common stone type was calcium oxalate (CaOx) (79.2%), followed by uric acid (UA; 14.3%), calcium phosphate (CaPO4; 3.7%), cystine (0.51%), drug induced (0.12%), and magnesium ammonium phosphate (0.04%). CaOx, UA, and CaPO4 were often mixed with one another. Among CaOx stones, the plurality (28.0%) was made of pure calcium oxalate monohydrate (COM), and only 0.002% was pure calcium oxalate dihydrate. There was an overall association between stone composition and both geographical distribution and age (p < 0.001). CONCLUSIONS: CaOx stones comprise the majority of urinary stones in the USA, of which almost 28% were pure COM. Additionally, age and geographical region are significantly associated with variations in stone composition. PATIENT SUMMARY: We evaluated the incidence of urinary stones in the USA based on their chemical composition. The most common stone type was calcium oxalate, the majority of which was pure calcium oxalate monohydrate. We also found age and geographical region to be significantly associated with variations in stone composition.

The Lived Experiences of Community Health Workers Serving in a Large-Scale Water, Sanitation, and Hygiene Intervention Trial in Rural Bangladesh.

Community health workers (CHWs) are key to implementing community-based health interventions and quality can be enhanced by better understanding their lived experiences. The WASH Benefits, Bangladesh trial engaged 540 female CHWs to promote varying health intervention packages. We report on factors influencing their lived experiences during the trial, to aid future recruitment, training and retention of CHWs. Nine focus groups and 18 in-depth interviews were conducted with CHWs. Focus groups and interviews were transcribed and thematic content analysis performed to summarize the results. All CHWs described experiencing positive working conditions and many benefits both socially and financially; these contributed to their retention and job satisfaction. Their honorarium was commonly applied towards their children's education and invested for income generation. CHWs gained self-confidence as women, to move unaccompanied in the community and speak in public. They earned respect from the community and their family members who helped them manage their family obligations during work and were viewed as a resource for advice on health and social issues. Many participated in family decision-making from which they were previously excluded. Health programs should foster a positive experience among their CHWs to aid the recruitment, retention and development of this important human resource.

Multidimensional Mutational Profiling of the Indian HNSCC Sub-Population Provides IRAK1, a Novel Driver Gene and Potential Druggable Target.

Head and neck squamous cell carcinomas (HNSCC) include heterogeneous group of tumors, classified according to their anatomical site. It is the sixth most prevalent cancer globally. Among South Asian countries, India accounts for 40% of HNC malignancies with significant morbidity and mortality. In the present study, we have performed exome sequencing and analysis of 51 Head and Neck squamous cell carcinoma samples. Besides known mutations in the oncogenes and tumour suppressors, we have identified novel gene signatures differentiating buccal, alveolar, and tongue cancers. Around 50% of the patients showed mutation in tumour suppressor genes TP53 and TP63. Apart from the known mutations, we report novel mutations in the genes AKT1, SPECC1, and LRP1B, which are linked with tumour progression and patient survival. A highly curated process was developed to identify survival signatures. 36 survival-related genes were identified based on the correlation of functional impact of variants identified using exome-seq with gene expression from transcriptome data (GEPIA database) and survival. An independent LASSO regression analysis was also performed. Survival signatures common to both the methods led to identification of 4 dead and 3 alive gene signatures, the accuracy of which was confirmed by performing a ROC analysis (AUC=0.79 and 0.91, respectively). Also, machine learning-based driver gene prediction tool resulted in the identification of IRAK1 as the driver (p-value = 9.7 e-08) and also as an actionable mutation. Modelling of the IRAK1 mutation showed a decrease in its binding to known IRAK1 inhibitors.

Impact of perioperative factors on nadir serum prostate-specific antigen levels after holmium laser enucleation of prostate.

Objective: To investigate the relationship of preoperative prostate size, urinary retention, positive urine culture, and histopathological evidence of prostatitis or incidental prostate cancer on baseline and 3-month nadir prostate-specific antigen (PSA) value after Holmium laser enucleation of prostate (HoLEP). Patients and methods: Data from 90 patients who underwent a HoLEP by En-bloc technique were analyzed. PSA values at baseline and at 3-month follow-up, preoperative urinary retention and urine culture status, weight of resected tissue, and histopathological evidence of prostatitis or prostate cancer were recorded. We performed univariable and multivariable gamma-regression analyses to determine the impact of the aforementioned perioperative variables on preoperative PSA, 3-month postoperative PSA, and change in PSA. Results: Serum PSA reduced significantly at 3 months from 6.3 ± 5.9 ng/mL to 0.6 ± 0.6 ng/mL. On both univariable and multivariable analysis, 3-month nadir level was independent of all preoperative factors examined, except preoperative urinary retention status. Although patients with smaller prostate (resected tissue weight <40 g) had less percentile reduction in PSA when compared with those with larger prostate (resected tissue weight >80 g) (77.67% vs 89.06%; P < .001), patients from both these groups noted a similar PSA nadir level after 3 months (0.54 vs 0.56 ng/dL). The drop in PSA level after HoLEP remained stable up to 1-year follow-up. Conclusions: PSA nadir 3 months after HoLEP remains relatively consistent across patients, regardless of preoperative prostate size, PSA value, urine culture status, and histopathological evidence of prostatitis or incidental prostate cancer.