P53 loss of heterozygosity (LOH) in formalin-fixed paraffin-embedded leiomyosarcoma (LMS): a novel report.

BACKGROUND: The occurrence of p53 loss of heterozygosity (LOH) is a common genetic event in malignancy. LOH occurs when a heterozygous locus loses one of its two parental alleles, becoming homozygous at that locus, by either copy number loss (CNL-LOH) or by becoming copy number neutral (CNN-LOH). A role for CNL-LOH (cnLOH) has been postulated in cancer aetiology. Loss of heterozygosity (LOH) results in irreversible genetic loss. AIMS: LOH was determined in DNA extracted from formalin-fixed paraffin-embedded (FFPE) leiomyosarcoma (LMS) specimens in a retrospective study from 30 patients, to assess the prognostic significance of LOH. The findings were analysed and their validity assessed. LOH was an adverse prognostic factor in LMS. Prospective uniform standardisation of formalin-fixation techniques is required. METHODS: DNA was extracted from 169 formalin-fixed paraffin blocks of 30 patients with LMS, following extensive tissue microdissection. Genomic DNA was amplified using the polymerase chain reaction (PCR) technique. Fluorescence-based microsatellite PCR was used to detect and quantitate heterozygosity loss. RESULTS: LOH was detected at gene locus 17p13 in 16 LMS (Four grade 2 and 12 grade 3 LMS). LOH was not detected in 14 LMS cases (one grade 1, five grade 2 and eight grade 3 LMS). LOH was associated with shorter patient survival. CONCLUSIONS: The results reported herein endorse the value of utilizing FFPE DNA in identifying LOH as a prognostic factor in LMS. The results have implications for tumour biobanking and precision medicine in patients with sarcomas.

Short-term outcomes following total correction of tetralogy of fallot in adult patients.

OBJECTIVES: Tetralogy of Fallot (TOF) is a common congenital heart disease which should be corrected. The recommended time for the Tetralogy of Fallot Total Correction (TFTC) surgery is during the infancy for the possible difficulties during the surgery and the related issues. However, sometimes TOF is diagnosed and managed during the adulthood. METHODS: This study is a descriptive and retrospective one which included all patients who underwent TFTC at the age of 15-year and older in 10 years (between the years 2010 and 2020) to identify short-term (in-hospital mortality, ICU stay, postoperative bleeding, respiratory complications after the surgery such as pulmonary edema, pneumonia, etc.) and one-year (left ventricle ejection fraction (LVEF), right ventricle (RV) ejection fraction, the severity of tricuspid and aortic regurgitation after surgery) outcomes. All data were taken from medical records at Rajaie Cardiovascular Medical and Research Center. Data were analyzed using SPSS 22. RESULTS: 94 patients with the mean ± SD age of 26.7 ± 9.6 years were enrolled. Most of them were male (59.6%) (P-value: 0.009). In-hospital mortality in our study were 5.3%. Tricuspid regurgitation (TR) was significantly resolved after the surgery (P-value: 0.006). Of 17 (18.1%) patients with small or hypoplastic pulmonary artery (PA) branches, 14 patients had acceptable PA branch size after surgery. CONCLUSION: TFTC at an older age is safe with acceptable results. Age is not a contraindication for TFTC and surgery should be recommended if the patients are diagnosed with TOF in adulthood. Also, the TOF diagnosis should be considered in adult patients with suspicious signs and symptoms.

Midterm prognosis following total correction of tetralogy of fallot in adult patients.

Background: Tetralogy of Fallot is a common congenital heart disease characterized by cyanosis. The primary treatment approach involves corrective surgery typically performed within the first year of life to achieve complete resolution. However, certain patients may undergo surgery at an older age. This study seeks to assess the efficacy of surgery by examining the midterm outcomes of total correction of Tetralogy of Fallot when performed in older individuals. Methods: This interventional-longitudinal study focused on patients who underwent complete surgery to correct tetralogy of Fallot at an advanced age of over 15 years. All of the participants were referred to the Shahid Rajaei Heart and Vascular Center, which is a referral center for congenital heart diseases in Iran, between 2010 and 2020. The surgical procedures for these patients involved primary total correction of tetralogy of Fallot or surgery following by shunt implantation. Prior to the surgery, the necessary information was gathered from the patients' medical records. The patients were then monitored over a 5-year period, during which they received regular check-ups from cardiologist with fellowship in adult congenital heart disease. Results: A total of 94 participants were enrolled in the study, with an average age of 26.7 ± 9.6 years. Notably, the majority of the participants were male. The study reported a late mortality rate of 3.2%. Furthermore, 17 patients, constituting 18% of the cohort, underwent a secondary surgical procedure. This secondary surgery encompassed 14 cases of Pulmonary Valve Replacement (14.8%) and 3 cases of Ventricular Septal Defect repair (3.1%). Conclusion: While the optimal age for total correction of Tetralogy of Fallot is conventionally considered to be within the first year of life, this study demonstrated that surgical intervention performed at a later stage of life can yield favorable midterm prognoses. It is imperative to emphasize that individuals unable to undergo surgery at the ideal age due to a multitude of factors should not be deprived of the potential benefits associated with surgical intervention.

Designing infographics in health research with patients and the public: A scoping review protocol.

Information graphics or infographics combine visual representations of information or data with text. They have been used in health research to disseminate research findings, translate knowledge and address challenges in health communication to lay audiences. There is emerging evidence of the design of infographics with the involvement of patients and the public in health research. Approaches to involvement include public and patient involvement, patient engagement and participatory research approaches. To date, there has been no comprehensive review of the literature on the design of infographics with patients and the public in health research. This paper presents a protocol and methodological framework for a scoping review to identify and map the available evidence for the involvement of patients and the public in infographics design in health research. It has been informed by preliminary searches and discussions and will guide the conduct and reporting of this review.

Optimal Management of Asymptomatic Carotid Artery Stenosis: A Systematic Review and Network Meta-Analysis.

OBJECTIVE: Management of asymptomatic carotid artery stenosis (ACAS), including carotid endarterectomy (CEA), carotid artery stenting (CAS), and best medical treatment (BMT), remains inconsistent in current practice. Early studies reported a benefit of CEA vs. BMT; however, the current risk-benefit profile of invasive therapy lacks consensus. By evaluating the effects of modern BMT vs. invasive intervention on patient outcomes, this study aimed to influence the future management of ACAS. METHODS: A systematic review and series of network meta-analyses were performed assessing peri-operative (within 30 days) and long term (30 days - 5 years) stroke and mortality risk between ACAS interventions. Total stroke, major, minor, ipsilateral, and contralateral stroke subtypes were assessed independently. Traditional (pre-2000) and modern (post-2000) BMT were compared to assess clinical improvements in medical therapy over the previous two decades. Risks of myocardial infarction (MI) and cranial nerve injury (CNI) were also assessed. RESULTS: Seventeen reports of 14 310 patients with > 50% ACAS were included. CEA reduced the odds of a peri-operative stroke event occurring vs. CAS (odds ratio [OR] 1.6, 95% confidence interval [CI] 1.1 - 2.2 [0 - 20 fewer/1 000]). CEA and CAS reduced the long term odds of minor strokes (OR 0.35, 95% CI 0.21 - 0.59 [20 fewer/1 000]) and ipsilateral strokes (OR 0.27, 95% CI 0.19 - 0.39 [30 fewer/1 000]) vs. all BMT. CEA reduced the odds of major strokes and combined stroke and mortality vs. traditional BMT; however, no difference was found between CEA and modern BMT. CAS reduced the odds of peri-operative MI (OR 0.49, 95% CI 0. 26 - 0.91) and CNI (OR 0.07, 95% CI 0.01 - 0.42) vs. CEA. CONCLUSION: Modern BMT demonstrates similar reductions in major stroke, combined stroke, and mortality to CEA. The overall risk reductions are low and data were unavailable to assess subgroups which may benefit from intervention. However, BMT carries the potential to reduce the requirement for surgical intervention in patients with ACAS.

Pulsatile versus non-pulsatile perfusion in coronary artery bypass operation: The comparison of laboratory and clinical outcomes.

INTRODUCTION: The superiority of pulsatile or non-pulsatile perfusion in cardiopulmonary bypass (CPB) regarding morbidity and mortality is still debated. Therefore, we aimed to investigate the effect of different pulse rates in pulsatile perfusion in patients undergoing coronary artery bypass graft (CABG) and compared it with non-pulsatile perfusion. MATERIALS AND METHODS: In this randomized clinical trial, 90 patients who were all candidates for CABG under CPB were enrolled. Patients in groups A and B received pulsatile perfusion with 30 and 70 pulses per minute, and group C received non-pulsatile perfusion. The biochemical and clinical parameters in the ICU were evaluated in the study groups. RESULTS: There was no statistically significant difference between patients' clinical outcomes and kidney and liver function markers (all Ps> 0.05). Mean serum lactate level increased but did not show a statistically significant difference between the study groups (p = 0.8). The mean urine volume at 12 and 24 h after surgery was higher in group A, but there was no statistically significant difference between the three groups during the study period (p = 0.3). No significant difference was found in the length of the ICU stay between the study groups (p = 0.2). CONCLUSION: Our studied parameters demonstrated no significant difference between pulsatile and non-pulsatile and between 30 and 70 pulse rate pulsatile perfusion methods. Our findings support that pulsatile perfusion with different pulse rates has no advantages over non-pulsatile perfusion in selected CABG cases.

Peripheral Blood Cell Ratios as Prognostic Indicators in a Neoadjuvant Chemotherapy-Treated Breast Cancer Cohort.

Breast cancer represents a heterogeneous condition in which the interaction between host immune response and primary oncogenic events can impact disease progression. Ratios of systemic blood-based immunocytes have emerged as clinically-relevant prognostic biomarkers in cancer patients. The NLR (neutrophil-to-lymphocyte ratio) has been shown to be prognostic in a variety of cancers, including breast cancer. However, evaluation of the prognostic value for overall survival (OS) and disease-free survival (DFS) of other key immunocyte ratios-neutrophil-to-lymphocyte ratio (NLR), lymphocyte-to-monocyte ratio (LMR), neutrophil-to-white cell count ratio (NWR), lymphocyte-to-white cell count ratio (LWR), monocyte-to-white cell count ratio (MWR), platelet-to-lymphocyte (PLR)-by breast cancer subtypes in a neoadjuvant chemotherapy (NAC) cohort remains to be fully explored. An NAC-treated breast cancer cohort, comprised of Luminal A, Luminal B, HER2-positive, and triple negative/basal breast cancers, treated at a tertiary referral center (minimum 3-year follow-up), was used to calculate immunocyte ratios and immunocyte cut-off values, calculated with >80% specificity (using decision tree modeling). The association with subtype-specific OS, DFS, and tumor grade was analyzed using cut offs calculated using both receiver operating characteristic curves and decision tree modelling. Decision tree calculated ratios showed that LMR (5.29) and MWR (0.06) were significantly associated with Luminal A OS (p = 0.004 and p = 0.022) and DFS (p = 0.004 and p = 0.022), and Luminal B OS (p = 0.027 and p = 0.008) and DFS (p = 0.005 and p = 0.007). NLR (1.79) and LWR (0.30) were significantly associated with HER2-positive OS (p = 0.013 and p = 0.043). NLR (1.79) and NWR (0.62) were significantly associated with DFS (p = 0.035 and p = 0.021). No significant association we observed between any immunocyte ratio in the triple negative cohort. Our results demonstrate the subtype-specific prognostic value of immunocyte ratios in NAC-treated breast cancer patients. Further validation of immunocyte ratios will provide clinicians with a new prognostic aid for disease management and monitoring.

Establishing electroporation thresholds for targeted cell specific cardiac ablation in a 2D culture model.

BACKGROUND: Irreversible electroporation has emerged as a new modality to overcome issues associated with other energy sources for cardiac ablation. Strong evidence on the optimal, effective, and selective voltage threshold is lacking for both in vitro and preclinical in vivo studies. The aim of this study is to examine the optimal threshold for selective cell ablation on cardiac associated cell types. METHODS: Conventional monophasic and biphasic pulses of different field strength were delivered in a monolayer culture system of cardiomyocytes, neurons, and adipocytes. The dynamics of cell death mechanisms were examined at different time points. RESULTS: Neurons exhibit higher susceptibility to electroporation and cell death at higher field strength of 1250 V/cm in comparison to cardiomyocytes. Cardiac adipocytes showed lower susceptibility to electroporation in comparison to other cell types. A significant proportion of cardiomyocytes recovered after 24 h postelectroporation, while neuronal cell death remained consistent but with a significant delayed cell death at a higher voltage threshold. Caspase 3/7 activity was observed in both cardiomyocytes and neurons, with a higher level of activity in cardiomyocytes in response to electroporation. Biphasic and monophasic pulses showed no significant difference in both cell types, and significantly lower cell death in neurons when inter pulse interval was reduced. CONCLUSIONS: This study presents important findings on the differences in the susceptibility of neurons and cardiomyocytes to irreversible electroporation. Cell type alone yielded selective and different dynamics in terms of the evolution and signaling mechanism of cell death in response to electroporation.

A Novel Surrogate Nomogram Capable of Predicting OncotypeDX Recurrence Score©.

Background: OncotypeDX Recurrence Score© (RS) is a commercially available 21-gene expression assay which estimates prognosis and guides chemoendocrine prescription in early-stage estrogen-receptor positive, human epidermal growth factor receptor-2-negative (ER+/HER2−) breast cancer. Limitations of RS testing include the cost and turnaround time of several weeks. Aim: Our aim is to develop a user-friendly surrogate nomogram capable of predicting RS. Methods: Multivariable linear regression analyses were performed to determine predictors of RS and RS > 25. Receiver operating characteristic analysis produced an area under the curve (AUC) for each model, with training and test sets were composed of 70.3% (n = 315) and 29.7% (n = 133). A dynamic, user-friendly nomogram was built to predict RS using R (version 4.0.3). Results: 448 consecutive patients who underwent RS testing were included (median age: 58 years). Using multivariable regression analyses, postmenopausal status (ß-Coefficient: 0.25, 95% confidence intervals (CIs): 0.03−0.48, p = 0.028), grade 3 disease (ß-Coefficient: 0.28, 95% CIs: 0.03−0.52, p = 0.026), and estrogen receptor (ER) score (ß-Coefficient: −0.14, 95% CIs: −0.22−−0.06, p = 0.001) all independently predicted RS, with AUC of 0.719. Using multivariable regression analyses, grade 3 disease (odds ratio (OR): 5.67, 95% CIs: 1.32−40.00, p = 0.037), decreased ER score (OR: 1.33, 95% CIs: 1.02−1.66, p = 0.050) and decreased progesterone receptor score (OR: 1.16, 95% CIs: 1.06−1.25, p = 0.002) all independently predicted RS > 25, with AUC of 0.740 for the static and dynamic online nomogram model. Conclusions: This study designed and validated an online user-friendly nomogram from routinely available clinicopathological parameters capable of predicting outcomes of the 21-gene RS expression assay.

Outcomes of Saphenous Vein Intervention in the Management of Superficial Venous Incompetence: A Systematic Review and Network Meta-analysis.

OBJECTIVE: To determine the most effective modality of intervention to treat saphenous vein insufficiency. SUMMARY OF BACKGROUND DATA: Endovenous therapies have instigated a paradigm shift in the management of superficial venous incompetence. When compared with open surgery, endovenous interventions (foam sclerotherapy, radiofrequency ablation, endovenous laser ablation (EVLA), mechanochemical ablation, and CAE closure) potentially offer reduced morbidity with similar procedural efficacy. METHODS: A systematic review and series of network meta-analyses of randomized controlled trials were performed assessing risks of procedural failure (within 6-weeks) and recurrence (6-weeks to 5-years), defined by ultrasound, between the different modalities of intervention for superficial venous incompetence. Treatment comparisons addressing risks of common adverse events, venous clinical severity score, and pain were also performed. RESULTS: A systematic search identified 51 articles, describing 36 randomized controlled trials, incorporating 7576 limbs. Outcome data on 10 modalities of intervention were analyzed up to 5-year follow-up. CAE resulted in the lowest risk of procedural failure within 6-weeks. Foam sclerotherapy had the highest risk of recurrence while high ligation with stripping (HLS) and Conservatrice Hemodynamique de l'Insuffisance Veineuse en Ambulatoire were ranked best to reduce long-term recurrence. No intervention increased risks of venous thromboembolism and there was minimal difference in morbidity between treatments. All interventions improved venous clinical severity score (range -1.02 to -4.95), however, radiofrequency ablation demonstrated the greatest improvement, followed by EVLA and HLS between 2 to 5-years. EVLA was associated with the highest risk of pain, while mechanochemical ablation offered the least. CONCLUSIONS: Although CAE offered the lowest risk of initial procedural failure, HLS resulted in lower rates of long-term recurrence without considerably increasing morbidity when compared with other endovenous options.

NRXN1α+/- is associated with increased excitability in ASD iPSC-derived neurons.

BACKGROUND: NRXN1 deletions are identified as one of major rare risk factors for autism spectrum disorder (ASD) and other neurodevelopmental disorders. ASD has 30% co-morbidity with epilepsy, and the latter is associated with excessive neuronal firing. NRXN1 encodes hundreds of presynaptic neuro-adhesion proteins categorized as NRXN1α/ß/γ. Previous studies on cultured cells show that the short NRXN1ß primarily exerts excitation effect, whereas the long NRXN1α which is more commonly deleted in patients involves in both excitation and inhibition. However, patient-derived models are essential for understanding functional consequences of NRXN1α deletions in human neurons. We recently derived induced pluripotent stem cells (iPSCs) from five controls and three ASD patients carrying NRXN1α+/- and showed increased calcium transients in patient neurons. METHODS: In this study we investigated the electrophysiological properties of iPSC-derived cortical neurons in control and ASD patients carrying NRXN1α+/- using patch clamping. Whole genome RNA sequencing was carried out to further understand the potential underlying molecular mechanism. RESULTS: NRXN1α+/- cortical neurons were shown to display larger sodium currents, higher AP amplitude and accelerated depolarization time. RNASeq analyses revealed transcriptomic changes with significant upregulation glutamatergic synapse and ion channels/transporter activity including voltage-gated potassium channels (GRIN1, GRIN3B, SLC17A6, CACNG3, CACNA1A, SHANK1), which are likely to couple with the increased excitability in NRXN1α+/- cortical neurons. CONCLUSIONS: Together with recent evidence of increased calcium transients, our results showed that human NRXN1α+/- isoform deletions altered neuronal excitability and non-synaptic function, and NRXN1α+/- patient iPSCs may be used as an ASD model for therapeutic development with calcium transients and excitability as readouts.

Integrating Serum Biomarkers into Prediction Models for Biochemical Recurrence Following Radical Prostatectomy.

This study undertook to predict biochemical recurrence (BCR) in prostate cancer patients after radical prostatectomy using serum biomarkers and clinical features. Three radical prostatectomy cohorts were used to build and validate a model of clinical variables and serum biomarkers to predict BCR. The Cox proportional hazard model with stepwise selection technique was used to develop the model. Model evaluation was quantified by the AUC, calibration, and decision curve analysis. Cross-validation techniques were used to prevent overfitting in the Irish training cohort, and the Austrian and Norwegian independent cohorts were used as validation cohorts. The integration of serum biomarkers with the clinical variables (AUC = 0.695) improved significantly the predictive ability of BCR compared to the clinical variables (AUC = 0.604) or biomarkers alone (AUC = 0.573). This model was well calibrated and demonstrated a significant improvement in the predictive ability in the Austrian and Norwegian validation cohorts (AUC of 0.724 and 0.606), compared to the clinical model (AUC of 0.665 and 0.511). This study shows that the pre-operative biomarker PEDF can improve the accuracy of the clinical factors to predict BCR. This model can be employed prior to treatment and could improve clinical decision making, impacting on patients' outcomes and quality of life.

Nomogram to Predict the Overall Survival of Colorectal Cancer Patients: A Multicenter National Study.

BACKGROUND: Colorectal cancer (CRC) is the third foremost cause of cancer-related death and the fourth most commonly diagnosed cancer globally. The study aimed to evaluate the survival predictors using the Cox Proportional Hazards (CPH) and established a novel nomogram to predict the Overall Survival (OS) of the CRC patients. MATERIALS AND METHODS: A historical cohort study, included 1868 patients with CRC, was performed using medical records gathered from Iran's three tertiary colorectal referral centers from 2006 to 2019. Two datasets were considered as train set and one set as the test set. First, the most significant prognostic risk factors on survival were selected using univariable CPH. Then, independent prognostic factors were identified to construct a nomogram using the multivariable CPH regression model. The nomogram performance was assessed by the concordance index (C-index) and the time-dependent area under the ROC curve. RESULTS: The age of patients, body mass index (BMI), family history, tumor grading, tumor stage, primary site, diabetes history, T stage, N stage, and type of treatment were considered as significant predictors of CRC patients in univariable CPH model (p < 0.2). The multivariable CPH model revealed that BMI, family history, grade and tumor stage were significant (p < 0.05). The C-index in the train data was 0.692 (95% CI, 0.650-0.734), as well as 0.627 (0.670, 0.686) in the test data. CONCLUSION: We improved a novel nomogram diagram according to factors for predicting OS in CRC patients, which could assist clinical decision-making and prognosis predictions in patients with CRC.

Integrating inflammatory serum biomarkers into a risk calculator for prostate cancer detection.

Improved prostate cancer detection methods would avoid over-diagnosis of clinically indolent disease informing appropriate treatment decisions. The aims of this study were to investigate the role of a panel of Inflammation biomarkers to inform the need for a biopsy to diagnose prostate cancer. Peripheral blood serum obtained from 436 men undergoing transrectal ultrasound guided biopsy were assessed for a panel of 18 inflammatory serum biomarkers in addition to Total and Free Prostate Specific Antigen (PSA). This panel was integrated into a previously developed Irish clinical risk calculator (IPRC) for the detection of prostate cancer and high-grade prostate cancer (Gleason Score ≥ 7). Using logistic regression and multinomial regression methods, two models (Logst-RC and Multi-RC) were developed considering linear and nonlinear effects of the panel in conjunction with clinical and demographic parameters for determination of the two endpoints. Both models significantly improved the predictive ability of the clinical model for detection of prostate cancer (from 0.656 to 0.731 for Logst-RC and 0.713 for Multi-RC) and high-grade prostate cancer (from 0.716 to 0.785 for Logst-RC and 0.767 for Multi-RC) and demonstrated higher clinical net benefit. This improved discriminatory power and clinical utility may allow for individualised risk stratification improving clinical decision making.

A risk calculator to inform the need for a prostate biopsy: a rapid access clinic cohort.

BACKGROUND: Prostate cancer (PCa) represents a significant healthcare problem. The critical clinical question is the need for a biopsy. Accurate risk stratification of patients before a biopsy can allow for individualised risk stratification thus improving clinical decision making. This study aims to build a risk calculator to inform the need for a prostate biopsy. METHODS: Using the clinical information of 4801 patients an Irish Prostate Cancer Risk Calculator (IPRC) for diagnosis of PCa and high grade (Gleason ≥7) was created using a binary regression model including age, digital rectal examination, family history of PCa, negative prior biopsy and Prostate-specific antigen (PSA) level as risk factors. The discrimination ability of the risk calculator is internally validated using cross validation to reduce overfitting, and its performance compared with PSA and the American risk calculator (PCPT), Prostate Biopsy Collaborative Group (PBCG) and European risk calculator (ERSPC) using various performance outcome summaries. In a subgroup of 2970 patients, prostate volume was included. Separate risk calculators including the prostate volume (IPRCv) for the diagnosis of PCa (and high-grade PCa) was created. RESULTS: IPRC area under the curve (AUC) for the prediction of PCa and high-grade PCa was 0.6741 (95% CI, 0.6591 to 0.6890) and 0.7214 (95% CI, 0.7018 to 0.7409) respectively. This significantly outperforms the predictive ability of cancer detection for PSA (0.5948), PCPT (0.6304), PBCG (0.6528) and ERSPC (0.6502) risk calculators; and also, for detecting high-grade cancer for PSA (0.6623) and PCPT (0.6804) but there was no significant improvement for PBCG (0.7185) and ERSPC (0.7140). The inclusion of prostate volume into the risk calculator significantly improved the AUC for cancer detection (AUC = 0.7298; 95% CI, 0.7119 to 0.7478), but not for high-grade cancer (AUC = 0.7256; 95% CI, 0.7017 to 0.7495). The risk calculator also demonstrated an increased net benefit on decision curve analysis. CONCLUSION: The risk calculator developed has advantages over prior risk stratification of prostate cancer patients before the biopsy. It will reduce the number of men requiring a biopsy and their exposure to its side effects. The interactive tools developed are beneficial to translate the risk calculator into practice and allows for clarity in the clinical recommendations.

Visualising statistical models using dynamic nomograms.

Translational Statistics proposes to promote the use of Statistics within research and improve the communication of statistical findings in an accurate and accessible manner to diverse audiences. When statistical models become more complex, it becomes harder to evaluate the role of explanatory variables on the response. For example, the interpretation and communication of the effect of predictors in regression models where interactions or smoothing splines are included can be challenging. Informative graphical representations of statistical models play a critical translational role; static nomograms are one such useful tool to visualise statistical models. In this paper, we propose the use of dynamic nomogram as a translational tool which can accommodate models of increased complexity. In theory, all models appearing in the literature could be accompanied by the corresponding dynamic nomogram to translate models in an informative manner. The R package presented will facilitate this communication for a variety of linear and non-linear models.

Increased Ca2+ signaling in NRXN1α+/- neurons derived from ASD induced pluripotent stem cells.

Background: Autism spectrum disorder (ASD) is a neurodevelopmental disorder with a high co-morbidity of epilepsy and associated with hundreds of rare risk factors. NRXN1 deletion is among the commonest rare genetic factors shared by ASD, schizophrenia, intellectual disability, epilepsy, and developmental delay. However, how NRXN1 deletions lead to different clinical symptoms is unknown. Patient-derived cells are essential to investigate the functional consequences of NRXN1 lesions to human neurons in different diseases. Methods: Skin biopsies were donated by five healthy donors and three ASD patients carrying NRXN1α+/- deletions. Seven control and six NRXN1α+/- iPSC lines were derived and differentiated into day 100 cortical excitatory neurons using dual SMAD inhibition. Calcium (Ca2+) imaging was performed using Fluo4-AM, and the properties of Ca2+ transients were compared between two groups of neurons. Transcriptome analysis was carried out to undercover molecular pathways associated with NRXN1α+/- neurons. Results: NRXN1α+/- neurons were found to display altered calcium dynamics, with significantly increased frequency, duration, and amplitude of Ca2+ transients. Whole genome RNA sequencing also revealed altered ion transport and transporter activity, with upregulated voltage-gated calcium channels as one of the most significant pathways in NRXN1α+/- neurons identified by STRING and GSEA analyses. Conclusions: This is the first report to show that human NRXN1α+/- neurons derived from ASD patients' iPSCs present novel phenotypes of upregulated VGCCs and increased Ca2+ transients, which may facilitate the development of drug screening assays for the treatment of ASD.

The CHARMS pilot study: a multi-method assessment of the feasibility of a sexual counselling implementation intervention in cardiac rehabilitation in Ireland.

BACKGROUND: Many people living with cardiovascular disease (CVD) are affected by sexual problems associated with the condition. International guidelines recommend all patients with CVD should receive sexual counselling, yet this is rarely provided by health professionals. The current study piloted the Cardiac Health and Relationship Management and Sexuality (CHARMS) intervention, a complex multi-level intervention designed to increase the implementation of sexual counselling guidelines in hospital-based cardiac rehabilitation (CR) in Ireland. METHODS: The CHARMS intervention, consisting of awareness training and skills development for staff, and education and support for patients, was implemented in two CR centres. Following a repeated measures design, quantitative and qualitative feasibility, fidelity, cost, and outcome data were collected from staff and patients at baseline (T1, pre-intervention), at 3 months post-baseline (T2, post-intervention), and at 6 months post-baseline (T3, post-intervention). Data were organised according to a 14-point reporting framework of methodological issues that should be examined in pilot and feasibility studies. To inform a future definitive trial, potential solutions to identified feasibility issues were generated using the ADePT process for decision-making after pilot and feasibility trials. RESULTS: Most elements of the study protocol were executed smoothly, and intervention implementation was successful. Patients' (N = 42) responses to the intervention were positive. The reporting framework and the ADePT process facilitated the identification of two overarching feasibility problems, as well as solutions to be implemented in a definitive trial: (1) a high level of patient attrition in the pilot study, to be addressed through the use of financial incentives, reducing the length of the patient questionnaire, and providing a telephone survey option; and (2) negative staff perceptions, to be addressed through an augmented staff intervention, reframing 'sexual counselling' as 'sexual education and support' to fit with professional role perceptions, and reviewing all intervention terminology with a CR staff member to ensure acceptability. CONCLUSIONS: This article reports the successful piloting of a novel sexual counselling implementation intervention in cardiac rehabilitation. The utilisation of an extended reporting framework and the ADePT process facilitated the identification of adaptations necessary to ensure the feasibility of a definitive trial, thereby maximising methodological transparency.

Comparison of Two brands of Methylphenidate (Stimdate(®) vs. Ritalin(®)) in Children and Adolescents with Attention Deficit Hyperactivity Disorder: A Double-Blind, Randomized Clinical Trial.

OBJECTIVE: To compare the effectiveness and safety of the methylphenidate produced in Iran (Stimdate®) with its original brand (Ritalin®) in children with Attention deficit hyperactivity disorder (ADHD). METHODS: In this double-blinded randomized clinical trial, 30 patients with ADHD who were 6 to 16 years old, were divided into two groups: 15 in Stimdate® and 15 in Ritalin® group. The two groups were compared for side effects profile, Conner's Parent's Rating Scale-Persion version (CPRS-R), Child Symptom Inventory-4 (CSI-4), Clinical Global Impressions (CGI), and Children's Global Assessment Scale (CGAS), at baseline and at the 4(th) and 6(th) weeks. RESULTS: The subjects showed significant decreases in the CPRS-Rand CSI-4 scores and significant increase of CGAS scores during the follow-up, but there were no significant difference between Stimdate® and Ritalin® group, regarding the pattern of changes observed. The mean therapeutic dose and the number of side effects were not significantly different between the two studied groups. CONCLUSIONS: Both Stimdate® and Ritalin® had comparable clinical efficacy and safety in children with ADHD.