Apalutamide for High-Risk Localized Prostate Cancer Following Radical Prostatectomy (Apa-RP).

PURPOSE: Approximately 25% to 50% of patients with high-risk localized prostate cancer experience biochemical recurrence (BCR) within 2 years of radical prostatectomy. The Apa-RP study (NCT04523207) investigated whether adjuvant apalutamide plus androgen deprivation therapy (ADT) in high-risk patients who have undergone radical prostatectomy improved BCR-free survival. MATERIALS AND METHODS: Apa-RP was a multicenter, open-label, single-arm, phase 2 study conducted in community urology practices in the US. High-risk patients who had radical prostatectomy received 12 cycles of apalutamide (240 mg daily; 28-day cycles) plus ADT. The primary end point was BCR-free survival. Secondary end points included testosterone recovery (≥150 ng/dL) and safety. RESULTS: One hundred eight patients were enrolled; median age was 66.0 years (range 46.0-77.0 years). Median preoperative PSA and baseline testosterone were 7.6 ng/mL (range 2.2-62.7 ng/mL) and 340.0 ng/dL (range 43.0-939.0 ng/dL), respectively. The BCR-free rate at 24 months (12 months after completion of planned therapy) was 100% (90% CI 93-100). Serum testosterone recovery rate (≥50 and ≥150 ng/dL) 12 months after treatment completion was 96% (95% CI 88-98) and 77% (95% CI 66-85), respectively. Overall, 107 (99%) patients experienced treatment-emergent adverse events, with 24 (22%) experiencing grade 3 to 4 events. CONCLUSIONS: In Apa-RP, BCR-free survival was 100% with 77% of patients having testosterone recovery (≥150 ng/dL) within 12 months of actual treatment completion and a manageable safety profile. These results provide proof of concept that treatment intensification with 12 cycles of apalutamide plus ADT could become an option for patients with high-risk localized prostate cancer who have undergone radical prostatectomy. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT04523207.

Islatravir Dimer: Crystal Form Dependence of a Radiation-Induced Degradation Product.

A rare example of crystal form-dependent, gamma radiation-induced degradation is presented. Islatravir is known to exist in several polymorphic forms, but only one of these forms shows the generation of a specific dimer degradation product under gamma irradiation. Extended gamma irradiation studies demonstrated that only one of the known crystalline forms shows an appreciable rate of dimer formation. Additionally, this dimer is not observed to form under other forced stress conditions. We present the structural elucidation of this dimer impurity and rationalize its form-dependent generation based on the analysis of the underlying crystal structure.

Structure Based Machine Learning Prediction of Retention Times for LC Method Development of Pharmaceuticals.

PURPOSE: Significant resources are spent on developing robust liquid chromatography (LC) methods with optimum conditions for all project in the pipeline. Although, data-driven computer assisted modelling has been implemented to shorten the method development timelines, these modelling approaches require project-specific screening data to model retention time (RT) as function of method parameters. Sometimes method re-development is required, leading to additional investments and redundant laboratory work. Cheminformatics techniques have been successfully used to predict the RT of metabolites & other component mixtures for similar use cases. Here we will show that these techniques can be used to model structurally diverse molecules and predictions of these models trained on multiple LC conditions can be used for downstream data-driven modelling. METHODS: The Molecular Operating Environment (MOE) was used to calculate over 800 descriptors using the strucutres of the analytes. These descriptors were used to model the RT of the analytes under four chromatographic conditions. These models were then used to create data-driven models using LC-SIM. RESULTS: A structural-based Random Forest (RF) model outperformed other techniques in cross-validation studies and predicted the RTs of a randomized test set with a median percentage error less than 4% for all LC conditions. RTs predicted by this structure-based model were used to fit a data-driven model that identifies optimum LC conditions without any additional experimental work. CONCLUSIONS: These results show that small training sets yield pharmaceutically relevant models when used in a combination of structure-based and data-driven model.

An improved workflow for the development of MS-compatible liquid chromatography assay purity and purification methods by using automated LC Screening instrumentation and in silico modeling.

The development of liquid chromatography UV and mass spectrometry (LC-UV-MS) assays in pharmaceutical analysis is pivotal to improve quality control by providing critical information about drug purity, stability, and presence and identity of byproducts and impurities. Analytical method development of these assays is time-consuming, which often causes it to become a bottle neck in drug development and poses a challenge for process chemists to quickly improve the chemistry. In this study, a systematic and efficient workflow was designed to develop purity assay and purification methods for a wide range of compounds including peptides, proteins, and small molecules with MS-compatible mobile phases (MP) by using automated LC screening instrumentation and in silico modeling tools. Initial LC MPs and chromatography column screening experiments enabled quick identification of conditions which provided the best resolution in the vicinity of the target compounds, which is further optimized using computer-assisted modeling (LC Simulator from ACD/Labs). The experimental retention times were in good agreement with the predicted retention times from LC Simulator (ΔtR < 7%). This workflow presents a practical workflow to significantly expedite the time needed to develop optimized LC-UV-MS methods, allowing for a facile, automatic method optimization and reducing the amount of manual work involved in developing new methods during drug development.

Early and mid-term outcomes of double-chambered right ventricle repair: An 8-year experience.

BACKGROUND/AIM: Double-chambered right ventricle is a rare and progressive condition that is characterised by obstruction of the right ventricular tract. Double-chambered right ventricle is usually associated with ventricular septal defect. Early surgical intervention is recommended in patients with these defects. Based on this background, the present study aimed to review early and midterm outcomes of primary repair after double-chambered right ventricle. METHODS: Between January 2014 and June 2021, 64 patients with a mean age of 13.42 ± 12.31 years underwent surgical repair for double-chambered right ventricle. The clinical outcomes of these patients were reviewed and assessed retrospectively. RESULTS: An associated ventricular septal defect was present in all the recruited patients; 48 (75%) patients of sub-arterial type, 15 (23.4%) of perimembranous, and 1 (1.6%) patient of muscular type. The patients were followed up for a mean period of 46.73 ± 27.37 months. During their follow-up, a significant decrease in the mean pressure gradient from 62.33 ± 5.52 mmHg preoperatively to 15.73 ± 2.94 mmHg postoperatively was observed (p < 0.001). Notably, there were no hospital deaths. CONCLUSIONS: The development of double-chambered right ventricle in association with ventricular septal defect results in an increased pressure gradient within the right ventricle. The defect needs correction in a timely manner. In our experience, the surgical correction of double-chambered right ventricle is safe and shows excellent early and mid-term results.

Pediatric ERCP: Factors for Success and Complication-A 17-Year, Multisite Experience.

OBJECTIVES: Endoscopic retrograde cholangiopancreatography (ERCP) is an increasingly utilized procedure in pediatric populations. A lack of dedicated pediatric research has led endoscopists to extrapolate adult risk factors and preventative strategies to children. The aim of this multisite, retrospective study was to identify risks for adverse events, procedure failure, and prolonged courses in pediatric patients undergoing ERCP. METHODS: Pediatric patients who had an ERCP at one of our academic centers were identified by query of their electronic medical records. Pre-procedure and post-procedure data were collected with ERCP-related adverse events defined according to the consensus criteria developed by Cotton et al 2010. RESULTS: Between January 2004 and January 2021, 287 children had a total of 716 ERCPs. The procedure success rate was 95.5% with no mortality and an adverse event rate of 12.7%. Younger age was associated with increased case complexity, increased adverse events, and an increased rate of repeat ERCP. Case complexity score correlated with increased procedure time ( P < 0.001) and increased adverse events (tau 0.24, P < 0.01); stent removal and pancreatic stenting were more likely to precede an adverse event. Pancreatitis, pancreatic divisum, and pancreatic stricture/stenosis were associated with increased adverse events and rates of repeat ERCP. CONCLUSIONS: Pediatric ERCP adverse event rates are higher than adults. The complexity grading system proposed by the Cotton et al appears to have applicability to pediatric patients. Young age and interventions affecting the pancreatic duct are associated with adverse ERCP outcomes in pediatrics.

Portable capillary LC for in-line UV monitoring and MS detection: Comparable sensitivity and much lower solvent consumption.

Pharmaceutical development currently relies on quality separation methods from early discovery through to line-of-site manufacturing. There have been significant advancements made regarding the column particle packing, internal diameter, length connectivity, the understanding of the impact key parameters like void volume, flow rate, and temperature all that affects the resultant separation quality, that is, resolution, peak shape, peak width, run time, and signal-to-noise ratio. There is however a strong need to establish better alternatives to large bulky high-performance liquid chromatography racks either for process analytical reaction monitoring or mass spectrometry analysis in establishing product quality. Compact, portable high-pressure liquid chromatography can be a more efficient alternative to traditional ultra-high pressure liquid chromatography and traditional liquid chromatography. The compact versatile instrument evaluated here allows good separation control with either the on-board column with fixed ultra-violet wavelength cartridge or for use with a high-resolution mass spectrometry. Significant space reduction results in greener lab spaces with improved energy efficiency for smaller labs with lower energy demands. In addition, this compact liquid chromatography was used as a portable reaction monitoring solution to compare forced degradation kinetics and assess portable liquid chromatography-mass spectrometry capability for the analyses required for pharmaceutical drug product testing.

Surgical outcomes of double-orifice mitral valve repair in patients with atrioventricular canal defects: a systematic review and meta-analysis.

INTRODUCTION: Double-orifice mitral valve or left atrioventricular valve is a rare congenital cardiac anomaly that may be associated with an atrioventricular septal defect. The surgical management of double-orifice mitral valve/double-orifice left atrioventricular valve with atrioventricular septal defect is highly challenging with acceptable clinical outcomes. This meta-analysis is aimed to evaluate the surgical outcomes of double-orifice mitral valve/double-orifice left atrioventricular valve repair in patients with atrioventricular septal defect. METHODS AND RESULTS: A total of eight studies were retrieved from the literature by searching through PubMed, Google Scholar, Embase, and Cochrane databases. Using Bayesian hierarchical models, we estimated the pooled proportion of incidence of double-orifice mitral valve/double-orifice left atrioventricular valve with atrioventricular septal defect as 4.88% in patients who underwent surgical repair (7 studies; 3295 patients; 95% credible interval [CI] 4.2-5.7%). As compared to pre-operative regurgitation, the pooled proportions of post-operative regurgitation were significantly low in patients with moderate status: 5.1 versus 26.39% and severe status: 5.7 versus 29.38% [8 studies; 171 patients]. Moreover, the heterogeneity test revealed consistency in the data (p < 0.05). Lastly, the pooled estimated proportions of early and late mortality following surgical interventions were low, that is, 5 and 7.4%, respectively. CONCLUSION: The surgical management of moderate to severe regurgitation showed corrective benefits post-operatively and was associated with low incidence of early mortality and re-operation.

Implications of left atrial enlargement and patent foramen ovale creation on early surgical outcomes in patients with total anomalous pulmonary venous connection.

INTRODUCTION: In patients with total anomalous pulmonary venous connection (TAPVC), left atrium (LA) is small and suprasystemic pulmonary artery (PA) pressures may be present in some patients. In our study, we studied the relationship between surgical LA enlargement and patent foramen ovale (PFO) creation separately on the outcomes of patients with TAPVC. MATERIALS AND METHODS: Out of the 130 patients operated in our institute between January 2014 and December 2020, LA was enlarged in 60 patients. LA enlargement was done using a larger patch for atrial septal defect (ASD) closure. Thus, the LA volume was increased by shifting the patch towards the right atrium (RA). Suprasystemic or high PA pressures were present in 60 patients. In 33 patients, PFO was created. Early surgical outcomes were determined on the basis of vasoactive inotropic score (VIS), hours of ventilation, hours of inotropic support, intensive care unit (ICU) stay, and hospital stay. RESULT: Between the LA enlarged and nonenlarged group there was statistically significant less VIS score (18 [13-27.5] vs. 24 [18-30], p value .019), hours of ventilation (23 [16-46.5] vs. 26 [18-60], p value .039), hours of inotropic support (45.5 [30-72] vs. 55 [38-84], p value .038), and ICU stay (7 [5-9] vs. 8 [7-10] p value .0352) and statistically nonsignificant less hospital stay (11.5 [9-13] vs. 12 [9-14], p value .424). In patients with preoperative suprasystemic or high PA pressures, there was a statistically significant less VIS score (16 [11-23.5] vs. 18 [13-25], p value .044), hours of ventilation (20 [14-37] vs. 22 [18-39], p value .038), hours of inotropic support (34 [29.5-71] vs. 38 [30-78], p value .042), and hospital stay (9 [5-12] vs. 11 [9-14], p value .038) and statistically nonsignificant less ICU stay (7 [5.5-9] vs. 7 [6-9], p value .886) in the group with a PFO with respect to the other group in which no PFO was created. CONCLUSION: In patients with TAPVC, LA can be enlarged by using a large ASD patch and thus shifting the septum towards RA. Early surgical outcomes were improved with LA enlargement. In patients with suprasystemic or high PA pressures, leaving a PFO improved the postoperative outcomes.

Reflux Hypersensitivity: How to Approach Diagnosis and Management.

PURPOSE OF REVIEW: This paper aims to review the definition and diagnostic criteria for reflux hypersensitivity and comment on the present and future management of this condition. RECENT FINDINGS: In 2016, the Rome IV criteria redefined reflux hypersensitivity as characterized by typical reflux symptoms, absence of endoscopic mucosal disease, absence of pathologic gastroesophageal reflux, and positive symptom correlation between reflux and heartburn episodes. Though uncertain, TPRV1 receptors have been implicated in the pathophysiology of reflux hypersensitivity. Recent studies have shown neuromodulators like SSRIs, SNRIs, and TCAs may be the future of managing this condition. With the release of the Rome IV criteria and availability of continuous pH monitoring, the diagnosis of reflux hypersensitivity has become more streamlined. Though there is no definitive therapy for reflux hypersensitivity, several anti-secretory agents and neuromodulators have shown some efficacy in therapeutic trials. The lack of large-scale, randomized controlled trials, however, reinforces the need for further research into the pharmacotherapy of reflux hypersensitivity.

Antiviral Treatment for Colonic Cytomegalovirus Infection in Ulcerative Colitis Patients Significantly Improved Their Surgery Free Survival.

BACKGROUND: The frequency of cytomegalovirus (CMV) colitis in steroid-refractory inflammatory bowel disease has been reported to range from 15.8% to 34.0%. Infected patients are more likely to become hospitalized, have longer lengths of stay, and higher mortality rates. Current data are limited to small scale studies and showed conflicting result regarding the role of antiviral therapy. AIMS: (1) To investigate the role of antiviral treatment in ulcerative colitis (UC) patients with CMV infection. (2) To investigate the role of viremia in the outcomes of these patients. MATERIALS AND METHODS: The Cleveland Clinic pathology database identified 1478 patients who had colon biopsy and were tested for CMV during 1990 to 2013. After inclusion and exclusion, 41 UC patients were selected. Among them, 24 (58.5%) received treatment, 17 (41.5%) did not. A total of 14 demographic data and 4 clinical outcomes (surgery free survival, hospitalization, rehospitalization, and mortality) were compared between treated and nontreated patients. The same outcomes were also compared in patients who received treatment based on their viremia status. RESULTS: All demographic variables are similar between those treated and nontreated groups. Antiviral therapy significantly improved the surgery free survival within 30 days, and lasted 70 months (P<0.01). In contrast, hospitalization, rehospitalization, and mortality were comparable (P>0.05). No significant difference was observed in any of the clinical outcomes based on viremia status. CONCLUSIONS: Our small scale study demonstrates that antiviral treatment for colonic CMV infection significantly improves the surgery free survival short-term and long-term in patients with UC.

Controlled crosslinking of trimethylolpropane trimethacrylate for preparation of organic monolithic columns for capillary liquid chromatography.

Organic monolithic columns based on single crosslinking of trimethylolpropane trimethacrylate (TRIM) monomer were prepared in a single step by living/controlled free-radical polymerization. Full optimization of the preparation, such as using different percentages of TRIM and different amounts of radical promoter as well as various porogen solvents were explored. The resulting monolithic columns were characterized by scanning electronic microscopy and nitrogen sorption for structure morphology studies and surface area measurements, respectively. Using capillary liquid chromatography, 150 µm i.d. columns were applied to separate a mixture of small hydrophobic molecules. The results indicated that column performance is highly sensitive to the type and the amount of porogen solvents used in the polymerization mixture composition. Good resolution factors and methylene selectivity were obtained, indicating the promising potential of this material for capillary liquid chromatography separations.

Helping fellow beings: anthropomorphized social causes and the role of anticipatory guilt.

People are often reluctant to comply with social causes because doing so may involve personal sacrifices of time, money, and effort for benefits that are shared by other members of society. In an effort to increase compliance, government agencies and public institutions sometimes employ financial tools to promote social causes. However, employing financial tools to induce prosocial behavior is expensive and often ineffective. We propose that anthropomorphizing a social cause is a practical and inexpensive tool for increasing compliance with it. Across three prosocial contexts, we found that individuals exposed to a message from an anthropomorphized social cause, compared with individuals exposed to a message relating to a nonanthropomorphized social cause, were more willing to comply with the message. This effect was mediated by feelings of anticipatory guilt experienced when they considered the likely consequences of not complying with the cause. The theoretical and practical implications of these findings are discussed.

Post-ductal coarctation of aorta aneurysm repair in adult via left antero-axillary thoracotomy with antegrade cerebral perfusion-a case series.

Coarctation of the aorta is a common congenital abnormality that may be associated with serious and rare anomalies like aneurysms. Severe coarctation or interrupted aortic arch in adults is usually managed by percutaneous interventions or extra-anatomic bypass. However, the presence of an aneurysm beyond the coarcted segment implies the opening of a collateral-rich segment of the aorta with redressal of the arch if hypoplastic. We describe our experience in managing three such patients through antero-lateral thoracotomy with antegrade cerebral perfusion. We have found this technique helpful in treating aneurysms of the distal aortic arch or proximal descending thoracic aorta.

Correction to: Post­ductal coarctation of aorta aneurysm repair in adult via left antero­axillary thoracotomy with antegrade cerebral perfusion-a case series.

[This corrects the article DOI: 10.1007/s12055-024-01734-5.].

Diagnostic accuracy of lever sign test in acute and chronic ACL injuries.

Introduction: The anterior cruciate ligament (ACL) is a commonly affected knee ligament prone to frequent injuries. Henceforth, we aimed to determine the diagnostic accuracy of lever sign test in Acute and chronic ACL injuries. Method: At the institution's initial outpatient visit, 150 consecutive patients (92 males and 58 females) were evaluated. Total 108 patients had injury in their right leg, whereas 42 had injury in their left leg. Based on time since injury, the patients were divided into Acute and chronic groups. Clinical examinations (lachman's test and lelli's test) of all patients were confirmed with arthroscopic findings and compared between the two groups. Results: In the acute ACL injury, the lever test had a kappa value 0.704. The accuracy and sensitivity of the Lachman, anterior drawer, pivot shift, and lever tests were calculated. We found that the lever test had the highest accuracy and sensitivity (85.48 %, 91.18 %) than the rest. In the chronic ACL injury, the kappa value for the results of the Lachman test evaluation was 0.723. The chronic ACL injuries accuracy and sensitivity values for the Lachman (86.36 %, 91.67 %), anterior drawer (76.14 %, 81.25 %), pivot shift (55.68 %, 58.49 %), and lever tests were determined. Conclusion: The lever sign test is more accurate and reliable in the acute ACL injuries, while the Lachman test is more accurate and reliable in the chronic ACL injuries.

Impact of a rash management guide in patients receiving apalutamide for high-risk localized prostate cancer in the Apa-RP study.

BACKGROUND/OBJECTIVES: Based on the SPARTAN and TITAN studies, apalutamide is approved for patients with nonmetastatic castration-resistant and metastatic castration-sensitive prostate cancer. Skin rash was a common adverse reaction across indications. We hypothesized that earlier identification and intervention could improve rash outcomes. SUBJECTS/METHODS: A prespecified rash management guide outlining recommended skin care practices was provided to all patients enrolled in Apa-RP (NCT04523207). Rash-related safety data from Apa-RP were compared descriptively with data from SPARTAN and TITAN. RESULTS: Patients in Apa-RP experienced improved rash-related outcomes vs those in SPARTAN and TITAN. CONCLUSIONS: Increased vigilance and proactive management may reduce the incidence, severity, and duration of rash during apalutamide treatment.

Machine learning models and performance dependency on 2D chemical descriptor space for retention time prediction of pharmaceuticals.

The predictive modeling of liquid chromatography methods can be an invaluable asset, potentially saving countless hours of labor while also reducing solvent consumption and waste. Tasks such as physicochemical screening and preliminary method screening systems where large amounts of chromatography data are collected from fast and routine operations are particularly well suited for both leveraging large datasets and benefiting from predictive models. Therefore, the generation of predictive models for retention time is an active area of development. However, for these predictive models to gain acceptance, researchers first must have confidence in model performance and the computational cost of building them should be minimal. In this study, a simple and cost-effective workflow for the development of machine learning models to predict retention time using only Molecular Operating Environment 2D descriptors as input for support vector regression is developed. Furthermore, we investigated the relative performance of models based on molecular descriptor space by utilizing uniform manifold approximation and projection and clustering with Gaussian mixture models to identify chemically distinct clusters. Results outlined herein demonstrate that local models trained on clusters in chemical space perform equivalently when compared to models trained on all data. Through 10-fold cross-validation on a comprehensive set containing 67,950 of our company's proprietary analytes, these models achieved coefficients of determination of 0.84 and 3 % error in terms of retention time. This promising statistical significance is found to translate from cross-validation to prospective prediction on an external test set of pharmaceutically relevant analytes. The observed equivalency of global and local modeling of large datasets is retained with METLIN's SMRT dataset, thereby confirming the wider applicability of the developed machine learning workflows for global models.

Predictions of Chromatography Methods by Chemical Structure Similarity to Accelerate High-Throughput Medicinal Chemistry.

We introduce a new workflow that relies heavily on chemical quantitative structure-retention relationship (QSRR) models to accelerate method development for micro/mini-scale high-throughput purification (HTP). This provides faster access to new active pharmaceutical ingredients (APIs) through high-throughput experimentation (HTE). By comparing fingerprint structural similarity (e.g., Tanimoto index) with small training data sets containing a few hundred diverse small molecule antagonists of a lipid metabolizing enzyme, we can predict retention time (RT) of new compounds. Machine learning (ML) helps to identify optimal separation conditions for purification without performing the traditional crude QC step involving ultrahigh performance liquid chromatography (UHPLC) analyses of each compound. This green-chemistry approach with the use of predictive tools reduces cost and significantly shortens the design-make-test (DMT) cycle of new drugs by way of HTE.