Role of Genetic Testing in Kidney Stone Disease: A Narrative Review

\ua9 The Author(s) 2024.Purpose of Review: Kidney stone disease (KSD) is a common and potentially life-threatening condition, and half of patients experience a repeat kidney stone episode within 5–10 years. Despite the ~50% estimate heritability of KSD, international guidelines have not kept up with the pace of discovery of genetic causes of KSD. The European Association of Urology guidelines lists 7 genetic causes of KSD as ‘high risk’. Recent Findings: There are currently 46 known monogenic (single gene) causes of kidney stone disease, with evidence of association in a further 23 genes. There is also evidence for polygenic risk of developing KSD. Evidence is lacking for recurrent disease, and only one genome wide association study has investigated this phenomenon, identifying two associated genes (SLC34A1 and TRPV5). However, in the absence of other evidence, patients with genetic predisposition to KSD should be treated as ‘high risk’. Further studies are needed to characterize both monogenic and polygenic associations with recurrent disease, to allow for appropriate risk stratification. Durability of test result must be balanced against cost. This would enable retrospective analysis if no genetic cause was found initially. Summary: We recommend genetic testing using a gene panel for all children, adults < 25 years, and older patients who have factors associated with high risk disease within the context of a wider metabolic evaluation. Those with a genetic predisposition should be managed via a multi-disciplinary team approach including urologists, radiologists, nephrologists, clinical geneticists and chemical pathologists. This will enable appropriate follow-up, counselling and potentially prophylaxis

Use of Temporally Validated Machine Learning Models To Predict Outcomes of Percutaneous Nephrolithotomy Using Data from the British Association of Urological Surgeons Percutaneous Nephrolithotomy Audit

\ua9 2024 European Association of Urology. Background and objective: Machine learning (ML) is a subset of artificial intelligence that uses data to build algorithms to predict specific outcomes. Few ML studies have examined percutaneous nephrolithotomy (PCNL) outcomes. Our objective was to build, streamline, temporally validate, and use ML models for prediction of PCNL outcomes (intensive care admission, postoperative infection, transfusion, adjuvant treatment, postoperative complications, visceral injury, and stone-free status at follow-up) using a comprehensive national database (British Association of Urological Surgeons PCNL). Methods: This was an ML study using data from a prospective national database. Extreme gradient boosting (XGB), deep neural network (DNN), and logistic regression (LR) models were built for each outcome of interest using complete cases only, imputed, and oversampled and imputed/oversampled data sets. All validation was performed with complete cases only. Temporal validation was performed with 2019 data only. A second round used a composite of the most important 11 variables in each model to build the final model for inclusion in the shiny application. We report statistics for prognostic accuracy. Key findings and limitations: The database contains 12 810 patients. The final variables included were age, Charlson comorbidity index, preoperative haemoglobin, Guy\u27s stone score, stone location, size of outer sheath, preoperative midstream urine result, primary puncture site, preoperative dimercapto-succinic acid scan, stone size, and image guidance (https://endourology.shinyapps.io/PCNL_Demographics/). The areas under the receiver operating characteristic curve was >0.6 in all cases. Conclusions and clinical implications: This is the largest ML study on PCNL outcomes to date. The models are temporally valid and therefore can be implemented in clinical practice for patient-specific risk profiling. Further work will be conducted to externally validate the models. Patient summary: We applied artificial intelligence to data for patients who underwent a keyhole surgery to remove kidney stones and developed a model to predict outcomes for this procedure. Doctors could use this tool to advise patients about their risk of complications and the outcomes they can expect after this surgery

Population Pharmacokinetic Modelling of FE 999049, a Recombinant Human Follicle-Stimulating Hormone, in Healthy Women After Single Ascending Doses

OBJECTIVE: The purpose of this analysis was to develop a population pharmacokinetic model for a novel recombinant human follicle-stimulating hormone (FSH) (FE 999049) expressed from a human cell line of foetal retinal origin (PER.C6(®)) developed for controlled ovarian stimulation prior to assisted reproductive technologies.METHODS: Serum FSH levels were measured following a single subcutaneous FE 999049 injection of 37.5, 75, 150, 225 or 450 IU in 27 pituitary-suppressed healthy female subjects participating in this first-in-human single ascending dose trial. Data was analysed by nonlinear mixed effects population pharmacokinetic modelling in NONMEM 7.2.0.RESULTS: A one-compartment model with first-order absorption and elimination rates was found to best describe the data. A transit model was introduced to describe a delay in the absorption process. The apparent clearance (CL/F) and apparent volume of distribution (V/F) estimates were found to increase with body weight. Body weight was included as an allometrically scaled covariate with a power exponent of 0.75 for CL/F and 1 for V/F.CONCLUSIONS: The single-dose pharmacokinetics of FE 999049 were adequately described by a population pharmacokinetic model. The average drug concentration at steady state is expected to be reduced with increasing body weight

Characteristics associated with significantly worse quality of life in mycosis fungoides/Sezary syndrome from the Prospective Cutaneous Lymphoma International Prognostic Index (PROCLIPI) study

Background Mycosis fungoides (MF) and Sezary Syndrome (SS) are the most common cutaneous T-cell lymphomas. MF/SS is accompanied by considerable morbidity from pain, itching and disfigurement. Aim To identify factors associated with poorer health-related quality of life (HRQoL) in patients newly diagnosed with MF/SS. Methods Patients enrolled into Prospective Cutaneous Lymphoma International Prognostic Index (PROCLIPI; an international observational study in MF/SS) had their HRQoL assessed using the Skindex-29 questionnaire. Skindex-29 scores were analysed in relation to patient- and disease-specific characteristics. Results The study population consisted of 237 patients [60 center dot 3% male; median age 60 years, (interquartile range 49-70)], of whom 179 had early MF and 58 had advanced MF/SS. In univariate analysis, HRQoL, as measured by Skindex-29, was worse in women, SS, late-stage MF, those with elevated lactate dehydrogenase, alopecia, high modified Severity Weighted Assessment Tool and confluent erythema. Linear regression models only identified female gender (beta = 8 center dot 61; P = 0 center dot 003) and alopecia (beta = 9 center dot 71, P = 0 center dot 02) as independent predictors of worse global HRQoL. Item-level analysis showed that the severe impairment in symptoms [odds ratio (OR) 2 center dot 14, 95% confidence interval (CI) 1 center dot 19-3 center dot 89] and emotions (OR 1 center dot 88, 95% CI 1 center dot 09-3 center dot 27) subscale scores seen in women was caused by more burning/stinging, pruritus, irritation and greater feelings of depression, shame, embarrassment and annoyance with their diagnosis of MF/SS. Conclusions HRQoL is significantly more impaired in newly diagnosed women with MF/SS and in those with alopecia. As Skindex-29 does not include existential questions on cancer, which may cause additional worry and distress, a comprehensive validated cutaneous T-cell lymphoma-specific questionnaire is urgently needed to more accurately assess disease-specific HRQoL in these patients.Peer reviewe

The techno-ecological practice as the politics of ontological coalitions

The paper focuses on the art projects aimed at visualizing (grasping) the physical or biological phenomena through interfaces and / or installations designed specifically for such purpose. Such works often mirror the post-­digital condition of our time where the digital technologies constitute the common background for everyday activities, no longer having the allure of "new" and "exciting" (Berry, Dieter et al., 2015). In this process, both the networked technologies of wireless communication and the act of crossing the boundaries between the digital and the physical play the crucial role as the post-­digital networked imagery increasingly becomes directly connected to the physical environment. I would like to ponder on the questions of processuality and relationality involved in such instances where the complexity of the hybrid works of art clearly transgresses the paradigm of representationalism (Thrift, 2008;; Anderson and Harrison, 2010;; Kember and Zylinska, 2012). The particular attention is given to the fact that such artworks bond different ontological realms (discursive, physical, digital) and different agents (human and non-­human, carbon-­based and software-­based) forging “ontological coalitions” (Malafouris, 2013). Throughout the article the mutlirealist and relational perspective is offered, inspired by the propositions of Gilbert Simondon and Etienne Souriau. Based on the research project supported by National Science Centre Poland ("The aesthetics of post-­digital imagery: between new materialism and object-­oriented philosophy", 2016/21/B/HS2/00746)

Adaptor protein-2 sigma subunit mutations causing familial hypocalciuric hypercalcaemia type 3 (FHH3) demonstrate genotype-phenotype correlations, codon bias and dominant-negative effects

The adaptor protein-2 sigma subunit (AP2σ2) is pivotal for clathrin-mediated endocytosis of plasma membrane constituents such as the calcium-sensing receptor (CaSR). Mutations of the AP2σ2 Arg15 residue result in familial hypocalciuric hypercalcaemia type 3 (FHH3), a disorder of extracellular calcium (Ca(2+) o) homeostasis. To elucidate the role of AP2σ2 in Ca(2+) o regulation, we investigated 65 FHH probands, without other FHH-associated mutations, for AP2σ2 mutations, characterized their functional consequences and investigated the genetic mechanisms leading to FHH3. AP2σ2 mutations were identified in 17 probands, comprising 5 Arg15Cys, 4 Arg15His and 8 Arg15Leu mutations. A genotype-phenotype correlation was observed with the Arg15Leu mutation leading to marked hypercalcaemia. FHH3 probands harboured additional phenotypes such as cognitive dysfunction. All three FHH3-causing AP2σ2 mutations impaired CaSR signal transduction in a dominant-negative manner. Mutational bias was observed at the AP2σ2 Arg15 residue as other predicted missense substitutions (Arg15Gly, Arg15Pro and Arg15Ser), which also caused CaSR loss-of-function, were not detected in FHH probands, and these mutations were found to reduce the numbers of CaSR-expressing cells. FHH3 probands had significantly greater serum calcium (sCa) and magnesium (sMg) concentrations with reduced urinary calcium to creatinine clearance ratios (CCCR) in comparison with FHH1 probands with CaSR mutations, and a calculated index of sCa × sMg/100 × CCCR, which was ≥ 5.0, had a diagnostic sensitivity and specificity of 83 and 86%, respectively, for FHH3. Thus, our studies demonstrate AP2σ2 mutations to result in a more severe FHH phenotype with genotype-phenotype correlations, and a dominant-negative mechanism of action with mutational bias at the Arg15 residue

A phase I randomized therapeutic MVA-B vaccination improves the magnitude and quality of the T cell immune responses in HIV-1-infected subjects on HAART

Trial Design Previous studies suggested that poxvirus-based vaccines might be instrumental in the therapeutic HIV field. A phase I clinical trial was conducted in HIV-1-infected patients on highly active antiretroviral therapy (HAART), with CD4 T cell counts above 450 cells/mm3 and undetectable viremia. Thirty participants were randomized (2:1) to receive either 3 intramuscular injections of MVA-B vaccine (coding for clade B HIV-1 Env, Gag, Pol and Nef antigens) or placebo, followed by interruption of HAART. Methods The magnitude, breadth, quality and phenotype of the HIV-1-specific T cell response were assayed by intracellular cytokine staining (ICS) in 22 volunteers pre- and post-vaccination. Results MVA-B vaccine induced newly detected HIV-1-specific CD4 T cell responses and expanded pre-existing responses (mostly against Gag, Pol and Nef antigens) that were high in magnitude, broadly directed and showed an enhanced polyfunctionality with a T effector memory (TEM) phenotype, while maintaining the magnitude and quality of the pre-existing HIV-1- specific CD8 T cell responses. In addition, vaccination also triggered preferential CD8+ T cell polyfunctional responses to the MVA vector antigens that increase in magnitude after two and three booster doses