Impact of HLA class I functional divergence on HIV control.

Heterozygosity of Human leukocyte antigen (HLA) class I genes is linked to beneficial outcomes after HIV infection, presumably through greater breadth of HIV epitope presentation and cytotoxic T cell response. Distinct allotype pairs, however, differ in the extent to which they bind shared sets of peptides. We developed a functional divergence metric that measures pairwise complementarity of allotype-associated peptide binding profiles. Greater functional divergence for pairs of HLA-A and/or HLA-B allotypes was associated with slower AIDS progression and independently with enhanced viral load control. The metric predicts immune breadth at the peptide level rather than gene level and redefines HLA heterozygosity as a continuum differentially affecting disease outcome. Functional divergence may affect response to additional infections, vaccination, immunotherapy, and other diseases where HLA heterozygote advantage occurs.

The Wrong Fight-Prior Authorization.

This essay describes the author's experience with denial of prior authorization for imaging to complete cancer staging.

Risk of secondary malignancy following radiation therapy for prostate cancer.

We investigated whether prostate cancer patients treated with external beam radiation therapy (EBRT) have a higher cumulative incidence of secondary cancer compared with patients treated with radical prostatectomy (RP). We used state-wide linked data from South Australia to follow men with prostate cancer diagnosed from 2002 to 2019. The cumulative incidence of overall and site-specific secondary cancers between 5 and 15 years after treatment was estimated. Fine-Gray competing risk analyses were performed with additional sensitivity analyses to test different scenarios. A total of 7625 patients were included (54% underwent RP and 46% EBRT). Characteristics of the two groups differed significantly, with the EBRT group being older (71 vs. 64 years), having higher comorbidity burden and being more likely to die during follow-up than the RP group. Fifteen-year cumulative incidence for all secondary cancers was 27.4% and 22.3% in EBRT and RP groups, respectively. In the adjusted models, patients in the EBRT group had a significantly higher risk of genitourinary (adjusted subhazard ratio (aSHR), 2.29; 95%CI 1.16-4.51) and lung (aSHR, 1.93; 95%CI 1.05-3.56) cancers compared with patients in the RP group. However, there was no statistically significant difference between the two groups for risk of any secondary cancer, gastro-intestinal, skin or haematologic cancers. No statistically significant differences in overall risk of secondary cancer were observed in any of the sensitivity analyses and patterns for risk at specific cancer sites were relatively consistent across different age restriction and latency/time-lag scenarios. In conclusion, the increased risk of genitourinary and lung cancers among men undergoing EBRT may relate partly to treatment effects and partly to unmeasured residual confounding.

HLA class I signal peptide polymorphism determines the level of CD94/NKG2-HLA-E-mediated regulation of effector cell responses.

Human leukocyte antigen (HLA)-E binds epitopes derived from HLA-A, HLA-B, HLA-C and HLA-G signal peptides (SPs) and serves as a ligand for CD94/NKG2A and CD94/NKG2C receptors expressed on natural killer and T cell subsets. We show that among 16 common classical HLA class I SP variants, only 6 can be efficiently processed to generate epitopes that enable CD94/NKG2 engagement, which we term 'functional SPs'. The single functional HLA-B SP, known as HLA-B/-21M, induced high HLA-E expression, but conferred the lowest receptor recognition. Consequently, HLA-B/-21M SP competes with other SPs for providing epitope to HLA-E and reduces overall recognition of target cells by CD94/NKG2A, calling for reassessment of previous disease models involving HLA-B/-21M. Genetic population data indicate a positive correlation between frequencies of functional SPs in humans and corresponding cytomegalovirus mimics, suggesting a means for viral escape from host responses. The systematic, quantitative approach described herein will facilitate development of prediction algorithms for accurately measuring the impact of CD94/NKG2-HLA-E interactions in disease resistance/susceptibility.

Long term genitourinary toxicity following curative intent intensity-modulated radiotherapy for prostate cancer: a systematic review and meta-analysis.

BACKGROUND: Recent studies have shown that radiation-induced pelvic toxicity often requires urological consultation. However, the 10-year incidence of genitourinary toxicity following intensity-modulated radiotherapy (IMRT) amongst patients with localised prostate cancer remains unclear. Hence, we conducted a systematic review and meta-analysis to determine the incidence of late genitourinary toxicity relying on Radiation Therapy Oncology Group (RTOG) and Common Terminology Criteria for Adverse Events (CTCAE) grade as well as the incidence of specific genitourinary toxicity. Secondary objectives involved quantifing the number of studies reporting 120-month follow-up endpoints, time to event analysis, predictive factors or economic evaluation. METHODS: Articles published from January 2008 to December 2021 describing prospective studies were systematically searched in MEDLINE, EMBASE and Cochrane (PROSPERO protocol CRD42019133320). Quality assessment was performed by use of the Cochrane Risk of Bias 2 Tool for RCTs and the Newcastle Ottowa Scale for non-RCTs. Meta-analysis was performed on the 60-month incidence of RTOG and CTCAE Grade ≥2 genitourinary toxicity, haematuria, urinary retention and urinary incontinence. RESULTS: We screened 4721 studies and six studies met our inclusion criteria. All included studies involved normofractionation, three included a hypofractionation comparator arm and none involved nodal irradiation. The pooled 60-month cumulative incidence of RTOG and CTCAE Grade ≥2 genitourinary toxicity were 17% (95% CI: 5-20%, n = 678) and 33% (95% CI: 27-38%, n = 153), respectively. The pooled 60-month cumulative incidence of Haematuria was 5% (95% CI: -4-14%, n = 48), Urinary incontinence 12% (95% CI: 6-18%, n = 194), Urinary retention 24% (95% CI: 9-40%, n = 10). One study reported time to event analyses, one reported predictive factors, no studies reported economic analysis or 120-month toxicity. There was considerable heterogeneity amongst the studies. CONCLUSION: There are few high-quality studies reporting 60-month toxicity rates after IMRT. Conservative estimates of 60-month toxicity rates are high and there is need for longer follow-up and consistent toxicity reporting standards.

Distinct frequency patterns of LILRB3 and LILRA6 allelic variants in Europeans.

The leukocyte immunoglobulin-like receptor (LILR)B3 and LILRA6 genes encode homologous myeloid inhibitory and activating orphan receptors, respectively. Both genes exhibit a strikingly high level of polymorphism at the amino acid level and LILRA6 (but not LILRB3) displays copy number variation (CNV). Although multiple alleles have been reported for both genes, limited data is available on frequencies of these alleles among humans. We have sequenced LILRB3/A6 exons encoding signal peptides and ectodomains in 91 healthy blood donors of European descent who carry one or two copies of LILRA6 per diploid genome. Analysis of haplotypes among individuals with two LILRA6 copies, representing the majority in this cohort (N = 86), shows that common LILRB3 and LILRA6 alleles encode some distinct amino acid sequences in homologous regions of the receptors, which could potentially impact their respective functions differentially. Comparison of sequences in individuals with one vs. two copies of LILRA6 supports non-allelic homologous recombination between LILRB3 and LILRA6 as a mechanism for generating LILRA6 CNV and LILRB3 diversity. These data characterize LILRB3/LILRA6 genetic variation in more detail than previously described and underscore the need to determine their ligands.

Prevalence, comorbidities and mediators of childhood anxiety disorders in urban Turkey: a national representative epidemiological study.

PURPOSE: The aim of this study is to evaluate the prevalence of anxiety disorders, its correlation with sociodemographic characteristics, its comorbidities with other psychiatric disorders and its predictors in school-aged children. METHODS: This study is part of a representative, multi-centered national study that is planned by the Turkish Association of Child and Adolescent Mental Health to evaluate the prevalence of psychopathology among elementary school students in Turkey between the years 2014-2015. Children are screened via Kiddie Schedule for Affective Disorders and Schizophrenia for School Age Children Present and Lifetime Version. Impairment is assessed by a 3-point Likert type scale independently by the parent and the teacher. The final sample included 5842 children with the mean age of 8.7 years. RESULTS: The prevalence of any anxiety disorder without considering impairment is 16.7% and considering impairment is 5.2% in children according to our study. We found significant differences for comorbid Attention Deficit Hyperactivity Disorder, Disruptive Behavior Disorder, Mood Disorders, Tic Disorders, Obsessive Compulsive Disorder, Enuresis Nocturna, Encopresis, and Intellectual Disability. Having a history of paternal physical disorder, living in the regions of Marmara, Mediterranean and Black Sea were found to be the main predictors of having childhood anxiety disorders according to the logistic regression analysis. CONCLUSION: Better understanding of childhood anxiety disorders, comorbid conditions and predictors will result in earlier diagnosis and more appropriate treatment.

Predicting post-radiation genitourinary hospital admissions in patients with localised prostate cancer.

PURPOSE: The risk of treatment-related toxicity is important for patients with localised prostate cancer to consider when deciding between treatment options. We developed a model to predict hospitalisation for radiation-induced genitourinary toxicity based on patient characteristics. METHODS: The prospective South Australian Prostate Cancer Clinical Outcomes registry was used to identify men with localised prostate cancer who underwent curative intent external beam radiotherapy (EBRT) between 1998 and 2019. Multivariable Cox proportional regression was performed. Model discrimination, calibration, internal validation and utility were assessed using C-statistics and area under ROC, calibration plots, bootstrapping, and decision curve analysis, respectively. RESULTS: There were 3,243 patients treated with EBRT included, of which 644 (20%) patients had a treated-related admission. In multivariable analysis, diabetes (HR 1.35, 95% CI 1.13-1.60, p < 0.001), smoking (HR 1.78, 95% CI 1.40-2.12, p < 0.001), and bladder outlet obstruction (BOO) without transurethral resection of prostate (TURP) (HR 7.49, 95% CI 6.18-9.08 p < 0.001) followed by BOO with TURP (HR 4.96, 95% CI 4.10-5.99 p < 0.001) were strong independent predictors of hospitalisation (censor-adjusted c-statistic = 0.80). The model was well-calibrated (AUC = 0.76). The global proportional hazards were met. In internal validation through bootstrapping, the model was reasonably discriminate at five (AUC 0.75) years after radiotherapy. CONCLUSIONS: This is the first study to develop a predictive model for genitourinary toxicity requiring hospitalisation amongst men with prostate cancer treated with EBRT. Patients with localised prostate cancer and concurrent BOO may benefit from TURP before EBRT.

Pelvic Radiation Disease.

Pelvic radiation is increasingly being used for the neoadjuvant and definitive treatment of pelvic organ malignancy. While this treatment can be highly effective, and may assist in organ sparing, it is also associated with significant toxicity and devastating adverse events that need to be considered. In broad terms, pelvic radiation disease affects both the primary target organ as well as adjacent organs and soft tissue structures, with complications that can be classified and graded according to consensus criteria. The complication grade is often modality, dose, and area dependent. The most common manifestations are proctitis, cystitis, recto-urethral fistula, ureteric stricture, and bone involvement. Toxicity can be misdiagnosed for many years, resulting in significant management delays. Complications can be difficult to prevent and challenging to treat, requiring specialized multi-disciplinary input to achieve the best possible strategy to minimize impact and improve patient quality of life.

Effects of metastatic CRC predictors on treatment outcomes.

BACKGROUND: Colorectal cancer (CRC) is the third most commonly diagnosed malignant tumor. The problem of mCRC is urgent due to both an increase in the number of metastatic tumors and the implementation of high-tech treatment methods that have significantly improved the results of a 5-year survival. METHODS: The research used the method of experiment and observation. Current study included data of 332 patients with CRC who received comprehensive treatment from 2014 to 2018 in oncology centers of the Republic of Kazakhstan. The patients were treated according to the clinical protocols for the treatment of oncological diseases approved in the Republic of Kazakhstan, including surgical treatment, as well as chemotherapy and radiation therapy, depending on the stage and localization of the process. A comprehensive treatment also included surgical treatment, chemotherapy, targeted chemotherapy and, in some cases, radiation therapy for rectal cancer. The diagnosis was confirmed morphologically in all patients; process dissemination was recorded using standard examination methods. Among the patients, women prevailed - 182 (54.8%) women and 150 men (45.2%) were included; the Caucasian race prevailed - 170 (51.2%) patients and 162 (48.8%) patients were of the Asian race. The mean age of the patients at the time of treatment was 56.4 ± 0.6 years (from 25 to 79 years). Histologically, adenocarcinoma prevailed represented by glandular - in 95.6%, mucous - in 2.9% and trabecular - in 1.5% of cases. A comprehensive treatment was used in 209 (63.0%) patients and other types of treatment were used in 123 (37.0%) patients (PCT, stoma + PCT). Radiation therapy was administered to 13 (3.9%) patients diagnosed with rectal cancer. RESULTS: A comparative analysis of the results of pharmacotherapy in the patients with mCRC showed that of 332 patients, 263 (79.2%) received targeted chemotherapy and 69 (20.8%) received standard polychemotherapy. At the time of the study, 85 (32.3%) patients in the targeted chemotherapy group were still alive, with a median survival of 42.0 ± 1.7 months, 95% CI (38.6-45.4). In the polychemotherapy group, 7 (10.1%) patients were alive, while the median survival rate was 20.0 ± 1.7 months, 95% CI (16.6-23.4). CONCLUSION: Based on the results, it was concluded that targeted chemotherapy schemes increased progression-free survival, compared to standard polychemotherapy schemes.

Incidence of genitourinary complications following radiation therapy for localised prostate cancer.

PURPOSE: Studies of genitourinary toxicity following radiotherapy for prostate cancer are mainly from high volume single institutions and the incidence and burden of treatment remain uncertain. Hence we determine the cumulative incidence of treatment-related genitourinary toxicity in patients with localised prostate cancer treated with primary external beam radiotherapy (EBRT) at a state population level. METHODS: We analysed data from a prospective population-based cohort, including hospital admission and cancer registry data, for men with localised prostate cancer who underwent primary EBRT without nodal irradiation between 1998 and 2019 in South Australia. The 10-year cumulative incidence of genitourinary toxicity requiring hospitalisation or procedures was determined. Clinical predictors of toxicity and the volume of admissions, non-operative, minor operative and major operative procedures were determined. RESULTS: All the included patients (n = 3350) had EBRT, with a median (IQR) of 74 Gy (70-78) in 37 fractions (35-39). The 10-year cumulative incidence of was 28.4% (95% CI 26.3-30.6) with a total of 2545 hospital admissions, including 1040 (41%) emergency and 1893 (74%) readmissions. The 10-year cumulative incidence of patients in this cohort requiring a urological operative procedure was 18% (95% CI 16.1-19.9), with a total of 106 (4.2%) non-operative, 1044 (41%) minor operative and 57 (2.2%) major operative urological procedures. CONCLUSIONS: Genitourinary toxicity after radiotherapy for prostate cancer is common. Although there continue to be advancements in radiotherapy techniques, patients and physicians should be aware of the risk of late toxicity when considering EBRT.

Valsalva leak point pressure (VLPP) greater than 70 cm H2O is an indicator for sling success: a success prediction model for the male transobturator sling.

INTRODUCTION AND OBJECTIVES: Urodynamic studies are often performed in the evaluation of post-prostatectomy urinary incontinence (PPUI). The male transobturator sling (TOS) is a minimally invasive treatment for PPUI. Others have reported their results with a specific Valsalva leak point pressure (VLPP) that predicts a good outcome with the male TOS. Our objective was to determine the relationship of the pre-operative VLPP on the success rate of the male TOS in a high-volume, single center. We hypothesized that a higher pre-operative VLPP better predicts successful outcomes. METHODS: We reviewed patients undergoing a male TOS placement from 2006 to 2012 at our institution. Patients who underwent TOS placement were identified using our patient data portal (DEDUCE). Demographic, urodynamic, and follow-up data were extracted by chart review. Post-operative success was defined by the use of 0 or 1 security pad, a negative stress test on exam, or pad weight of less than 8 g per 24 h. Cox and linear regression models were performed. RESULTS: 290 patients were included. All patients underwent a radical prostatectomy for prostate cancer and presented with PPUI. Mean age at surgery was 66.3 (± 7.4) years and 84% were Caucasian. Median time to follow-up was 5 months (IQR 1-15). A linear regression model shows an inverse prediction curve for sling failure versus VLPP (p = 0.02). The hazard ratio for failure with a VLPP of ≤ 70 cm H2O compared with a VLPP of > 70 cm H2O, adjusted for pelvic radiation and 24-h pad weight was 0.5 (95% CI 0.2-0.98). CONCLUSION: Patient selection is imperative in the success of the male TOS for patients with PPUI. In our cohort of patients with PPUI, those with a pre-procedural VLPP of > 70 cm H2O were 50% less likely to fail after TOS placement versus those with a VLPP ≤ 70 cm H2O. In our practice, we use these data to support the use of VLPP cut off of 70 cm H2O as an indicator for success to help in the evaluation and counseling of patients.

The bidirectional association between depression and lower urinary tract symptoms (LUTS) in men: A systematic review and meta-analysis of observational studies.

BACKGROUND: Recent evidence from observational studies suggests a bidirectional association between lower urinary tract symptoms (LUTS) and depression in men. We sought to systematically quantify the effect of the presence of LUTS on depression symptoms, compared to those without LUTS, in adult males, and vice versa. METHODS: Electronic databases (MEDLINE, PsycINFO, SCOPUS, Embase) were examined for articles in English before March 2021. Observational studies of men aged over 18 years; reporting an association between LUTS and depression; including a validated scale for LUTS and depression symptoms were eligible for study inclusion. RESULTS: Seventeen studies out of 1787 records identified 163 466 men with reported depression symptoms by LUTS status, while 10 studies reported 72 363 men with LUTS by depression symptoms. Pooled estimates showed a strong effect of LUTS presence on depression risk (OR: 2.89, 95% CI: 2.50-3.33), with a high degree of heterogeneity among the examined studies (I2 = 83%; τ2 = 0,06; p < 0.001). Subgroup analyses demonstrated differences by study region (Q value:13.7, df:4, p = 0.003), setting (7.8(2), p = 0.020), design (7.2(1), p = 0.003), quality (6.2(1), p = 0.013), and LUTS measure (40.9(3), p < 0.001). Pooled estimates also showed a strong effect of depression presence on LUTS risk in men (OR: 3.13, 95% CI: 2.72-3.60), with only moderate heterogeneity between studies (I2 = 58%; τ2 = 0,02; p = 0.001). CONCLUSIONS: The strong relationship observed between LUTS and depression implies shared risk factors that cannot be solely attributed to the prostate. This has immediate implications for future studies and the assessment and management of patients with either condition.

The impact of the coronavirus disease 2019 pandemic on elective urological procedures in Australia.

OBJECTIVE: To investigate the changes in elective private urological procedures in Australia during the coronavirus disease 2019 pandemic. METHODS: Data were extracted from publicly available datasets from Medicare Benefits Schedule using item numbers assigned to each commonly performed urological intervention. These procedures were divided into three groups: Oncological therapeutic, diagnostic, and non-oncological therapeutic procedures. A smoothing model, based on the historic procedure numbers from 2017 to 2019, was used to forecast monthly number of procedures performed in each category between January 2020 and June 2020. These forecasted models were compared with reported figures. RESULTS: A total of 108 169 procedures were performed between January 2020 and June 2020 based on the Medicare Benefits Schedule item numbers listed. There was a significant reduction (percentage change) in total procedures performed in April 2020 (-22.6%, 95% confidence interval [CI]: -28.7% to -15.4%) and May 2020 (-33.2%, 95% CI: -37.5% to -28.3%). There was a significant reduction in oncological therapeutic, non-oncological therapeutic, and diagnostic procedures performed in April 2020 and May 2020 (p<0.05). These numbers did not include procedures performed in public sector. CONCLUSION: There was a significant reduction in total urological procedures (including diagnostic, oncological, and non-oncological) performed in months of April 2020 and May 2020 during time of federal restrictions. Both public and private healthcare sectors need to be supported in the upcoming months to prevent further delays in treatment and poorer clinical outcomes.

Vitamin D Receptor Polymorphisms Among the Turkish Population are Associated with Multiple Sclerosis.

Multiple sclerosis (MS) is an inflammatory disease characterized by demyelination and axonal degeneration affecting the central nervous system. Among the genetic factors suggested to be associated with this disease are polymorphisms to the vitamin D receptor (VDR) gene. We tested the hypothesis that polymorphisms in the vitamin D receptor (VDR) gene are associated with MS. The aim of the study was to investigate the relationship of MS with the VDR gene Fok-I, Bsm-I and Taq-I polymorphisms among the Turkish population. This study contains 271 MS patients and 203 healthy controls. Genomic DNA was isolated from the samples and the VDR gene Fok-I, Bsm-I and Taq-I polymorphism regions were amplified by polymerase chain reaction (PCR). The PCR products were digested, and the genotypes were determined based on size of digested PCR products. Our results demonstrate associations between MS and the distribution of the VDR gene Fok-I T/T polymorphism genotype in a dominant model, VDR gene Fok-I T allele frequency, distribution of VDR gene Taq-I C/C polymorphism genotype in a dominant model and VDR gene Taq-I C allele frequency (Pearson test, p<0.05). However, there was no association between MS and the VDR gene Bsm-I polymorphisms for the genotype distribution (Pearson test, p>0.05) or allele frequency (Pearson test, p>0.05). Fok-I and Taq-I VDR gene polymorphisms are significantly associated with MS in dominant, homozygote and heterozygote inheritance models among the Turkish population.