Large Cohort Of Patients Research Articles

TCT-83 Association of Regurgitant Fraction and of Liver Mapping Analysis Quantified by Cardiac Magnetic Resonance With Outcome in a Large Cohort of All-Comers Patients With Chronic Tricuspid Regurgitation

TCT-83 Association of Regurgitant Fraction and of Liver Mapping Analysis Quantified by Cardiac Magnetic Resonance With Outcome in a Large Cohort of All-Comers Patients With Chronic Tricuspid Regurgitation

Multicentre Validation of the RESECT-90 Prediction Model for 90-Day Mortality After Lung Resection

BackgroundThe RESECT-90 model was developed to predict 90-day mortality for patients undergoing lung resection but hasn't been externally validated. The aim of this study was to validate the RESECT-90 clinical prediction model using multicentre patient data from across the United Kingdom (UK). Materials and MethodsData from 12 UK thoracic surgery centers for patients undergoing lung resection between 2016 and 2020 with available 90-day mortality status were used to externally validate the RESECT-90 model. Measures of discrimination (area under the receiving operator characteristic curve [AUC]) and calibration (calibration slope, calibration intercept and flexible calibration plot) were assessed as measures of model performance. Model recalibration was also performed by updating the original model intercept and coefficients. ResultsA total of 12,241 patients were included. Overall 90-day mortality was 2.9% (n = 360). Acceptable model discrimination was demonstrated (AUC 0.74 [0.73, 0.75]). Calibration varied between centers with some evidence of overall model miscalibration (calibration slope 0.80 [0.66, 0.95] and calibration intercept 0.40 [0.29, 0.52]) despite acceptable appearances of the flexible calibration plot. The model was subsequently recalibrated, after which all measures of calibration indicated excellent performance. ConclusionsAfter external validation and recalibration using a large contemporary cohort of patients undergoing surgery in multiple geographical locations across the UK, the RESECT-90 model demonstrated satisfactory statistical performance for the prediction of 90-day mortality after lung resection. Whilst the recalibrated model will require ongoing validation, the results of this study suggest that routine use of the RESECT-90 model in UK thoracic surgery practice should be considered.

Concordance of ctDNA and tissue genomic profiling in advanced biliary tract cancer

Background & AimsRecent advances in molecular profiling enable the identification of potential therapeutic targets for biliary tract cancer (BTC). However, in patients with BTC, molecular profiling is hindered by challenges in obtaining adequate tissue samples. Circulating tumor DNA (ctDNA) may offer an alternative to tissue-based analysis. Here we aimed to assess the concordance between ctDNA and tissue genomic profiling in a large cohort of Asian patients with advanced BTC, and to evaluate the feasibility of liquid biopsy in BTC treatment. MethodsThis study included patients with systemic treatment-naive advanced BTC, treated at CHA Bundang Medical Center between January 2019 and December 2022. We enrolled patients with available baseline tissue-based next-generation sequencing (NGS), and sufficient plasma samples for ctDNA analysis (AlphaLiquid®100 from IMBdx). ResultsAmong 102 enrolled patients, 49.0% had intrahepatic cholangiocarcinoma, 26.5% extrahepatic cholangiocarcinoma, and 24.5% gallbladder cancer. The concordance between intra-patient ctDNA and tumor tissue mutations revealed a sensitivity of 84.8%, and positive predictive value of 79.4%. ctDNA revealed targetable alterations in 34.3% of patients—including FGFR2 fusion, IDH1 mutation, microsatellite instability (MSI)-high, ERBB2 amplification, PIK3CA mutations, BRCA1/2 mutations, and MET amplification. Notably, a novel FGFR2-TNS1 fusion was identified in ctDNA, which was not targeted in the tissue NGS panel. A high maximum somatic variant allele frequency in ctDNA was associated with poor prognosis after gemcitabine/cisplatin-based chemotherapy, in terms of both overall survival (p = 6.9 × 10−6) and progression-free survival (p = 3.8 × 10−7). ConclusionsAmong patients with advanced BTC, ctDNA-based genotyping showed acceptable concordance with tissue genomic profiling. Liquid biopsy using ctDNA could be a valuable complement to tissue-based genomic analysis in BTC. Impact and implicationsOur study is the first large-scale investigation of the clinical utility of liquid biopsy, focusing on ctDNA, as an alternative to conventional tumor tissue analysis, among Asian patients with advanced BTC. The results demonstrated acceptable concordance between analysis of ctDNA versus tissue for identifying therapeutic targets and potentially actionable genetic alterations. This indicates that ctDNA analysis can provide critical insights regarding advanced BTC treatment, particularly in cases where it is challenging to obtain or analyze tumor tissue.

Deep Contrast Clustering Analysis to Distinguish Diabetic Complications in Elderly Chinese Patients.

To establish an innovative clustering method for predicting variable categories of diabetic complications in Chinese ≥65 with diabetes. We selected and extracted data from elderly patients with diabetes (n=4980) from a medical examination group of 51,400 people followed up annually from 2014 to date in Kunshan, China. A deep contrast clustering approach was used to cluster and predict diabetic complications. The clustering approach was further validated using data from elderly patients with diabetes (n=397) from one medical examination cohort of 20,000 people followed up yearly from 2014 to date in Beijing Jiuhua Hospital. The patients were clustered into 6 categories by analysing 20 indicators. Cluster 1-Heavy smoking and a high cardiovascular disease (CVD) risk; Cluster 2-High alcohol consumption, high aminotransferase levels, the highest risk of stroke complications, and a high fatty liver disease (FLD) risk; Cluster 3-High blood lipid levels and a risk of FLD and stroke complications; Cluster 4-Good health indicators and a low risk of FLD, stroke, and CVD complications; Cluster 5-Older age, higher uric acid concentration and creatinine level, and the highest risk of CVD complications; Cluster 6-Large waist circumference, high BMI, high blood pressure, and the highest risk of FLD complications. The gene for nonalcoholic fatty liver disease in cluster 2 had the highest risk coefficient. This was consistent with cluster 2, which had a higher FLD prevalence. A new clustering method was developed from two large Chinese cohorts of older patients with diabetes, which may effectively predict complications by clustering into different categories.

Systemic inflammation markers independently associated with increased mortality in individuals with hyperuricemia: Results from the NHANES prospective cohort study.

Hyperuricemia is associated with increased systemic inflammation. The systemic immune-inflammation index (SII) and systemic inflammation response index (SIRI) are novel systemic inflammation markers and prognostic markers. However, no studies have evaluated the association between the SII/SIRI and mortality risk in individuals with hyperuricemia. This study aimed to investigate the predictive value of the SII and SIRI for all-cause and cardiovascular mortality in a large cohort of hyperuricemia patients. We conducted a prospective cohort study using data from the National Health and Nutrition Examination Survey (NHANES) 2001-2020. Hyperuricemia was defined as serum uric acid (SUA) levels of ≥7 mg/dL in men and ≥6 mg/dL in women. The SII and SIRI were calculated based on complete blood count parameters. Associations with all-cause and cardiovascular mortality were analyzed using Cox proportional hazards models. Nonlinearity and effect modification were assessed using restricted cubic splines (RCS) and interaction analysis. Among the 6181 participants with hyperuricemia aged 20 years and older, over a total 181 months of follow-up, there were 936 all-cause deaths, of which 195 were cardiovascular mortality. In the fully adjusted models, the hazard ratios (HRs) were 1.73 (95% CI 1.42-2.13) for the SII and 2.18 (95% CI 1.82-2.62) for the SIRI with all-cause mortality. The adjusted HRs were 2.08 (95% CI 1.37-3.14) for the SII and 2.32 (95% CI 1.56-3.45) for the SIRI with cardiovascular mortality. Spline models identified nonlinear U-shaped (SII) and J-shaped (SIRI) relationships of inflammation markers with mortality. Elevated SII and SIRI are independent predictors of mortality in hyperuricemia patients. These inflammatory biomarkers may improve risk stratification in this high-risk population. Further research should evaluate utility in guiding preventive interventions.

A Comparison of GOLD and STAR Severity Stages in Individuals with Chronic Obstructive Pulmonary Disease Undergoing Pulmonary Rehabilitation.

BackgroundAlongside the recognized Global Initiative for Obstructive Lung Disease (GOLD) classification, the STaging of Airflow obstruction by Ratio (STAR) severity scheme has been proposed for categorizing chronic obstructive pulmonary disease (COPD). Study QuestionWhat is the agreement and utility of the GOLD and STAR classifications in severe COPD patients entering the rehabilitation setting? Study Design and MethodsMedical records were reviewed in this multicenter retrospective study, examining key functional variables and their changes in a large cohort of COPD patients undergoing pulmonary rehabilitation (PR). ResultsA total of 1,516 participants (33.7% females, median age 72.0 years) were included in the analysis. Compared to GOLD, the use of the STAR classification resulted in a different disease severity category for 53.4% of patients. An unweighted Cohen’s κ of 0.25 and a Bangdiwala B value of 0.24 revealed a fair agreement between the two classifications. Higher weighted agreement measures (0.47 and 0.78, respectively) suggested that discrepancies between the classifications mainly occurred for contiguous stages. GOLD demonstrated superior discrimination between stages for chronic respiratory failure, while STAR exhibited better performance in detecting hyperinflation. In terms of their application within PR settings, GOLD exhibited superior performance compared to STAR in identifying the minimal clinically important difference (MCID) in 6-minute walking distance and modified Medical Research Council (mMRC) score. Accordingly, GOLD but not STAR acted as an independent predictor for achieving a MCID in mMRC (OR: 1.48; 95% CI: 1.12-1.94; P=0.005) and also independently predicted changes in Braden score (β=0.154; P=0.004). Interpretation.STAR shows a more uniform gradation of disease severity and enhanced performance in detecting hyperinflation but our preliminary findings do not endorse its utilization in the rehabilitation setting.

555P Assessment of IBM-FRS total score and specific domains in a large cohort of inclusion body myositis patients

555P Assessment of IBM-FRS total score and specific domains in a large cohort of inclusion body myositis patients

Developmental uterovaginal anomalies and histologic findings in transgender patients receiving gender-affirming hysterectomies: A large case series.

To describe the incidence of uterovaginal anomalies and histologic findings in transgender and nonbinary (TGNB) patients seeking hysterectomies. All patients receiving gender-affirming hysterectomies between 2013 and 2023 were retrospectively reviewed. Primary outcomes included uterovaginal anomalies and histological findings. Multivariable logistic regressions were performed to evaluate relationships between variables of interest and whether they predict findings of uterovaginal anomalies, inactive endometrium, adenomyosis, leiomyoma, endometriosis, and cervical atrophy. 278 patients received hysterectomies at an average age of 29.2 ± 8.3 years. Seven patients (2.5%) were found to have a developmental anomaly, including two bicornuate uterus (0.7%), two unicornuate uterus (0.7%), one septate uterus (0.4%), and two vaginal septum (0.7%). 60 patients (21.6%) were found to have inactive endometrium and 26 patients (9.4%) had cervical atrophy. Although 262 patients (94.2%) were on testosterone therapy, hormone duration was not a significant predictor of any uterine findings. This study describes uterovaginal anomalies in a large cohort of patients receiving gender-affirming hysterectomies. Although long-term testosterone use is commonly believed to be associated with endometrial and cervical atrophy, this study shows no such association.

Predicting recurrence of instability after a primary traumatic anterior shoulder dislocation.

The risk factors for recurrent instability (RI) following a primary traumatic anterior shoulder dislocation (PTASD) remain unclear. In this study, we aimed to determine the rate of RI in a large cohort of patients managed nonoperatively after PTASD and to develop a clinical prediction model. A total of 1,293 patients with PTASD managed nonoperatively were identified from a trauma database (mean age 23.3 years (15 to 35); 14.3% female). We assessed the prevalence of RI, and used multivariate regression modelling to evaluate which demographic- and injury-related factors were independently predictive for its occurrence. The overall rate of RI at a mean follow-up of 34.4 months (SD 47.0) was 62.8% (n = 812), with 81.0% (n = 658) experiencing their first recurrence within two years of PTASD. The median time for recurrence was 9.8 months (IQR 3.9 to 19.4). Independent predictors increasing risk of RI included male sex (p < 0.001), younger age at PTASD (p < 0.001), participation in contact sport (p < 0.001), and the presence of a bony Bankart (BB) lesion (p = 0.028). Greater tuberosity fracture (GTF) was protective (p < 0.001). However, the discriminative ability of the resulting predictive model for two-year risk of RI was poor (area under the curve (AUC) 0.672). A subset analysis excluding identifiable radiological predictors of BB and GTF worsened the predictive ability (AUC 0.646). This study clarifies the prevalence and risk factors for RI following PTASD in a large, unselected patient cohort. Although these data permitted the development of a predictive tool for RI, its discriminative ability was poor. Predicting RI remains challenging, and as-yet-undetermined risk factors may be important in determining the risk.

Widefield Retinal Imaging in Gyrate Atrophy: Correlation of Structural, Biochemical, and Functional Characteristics

ObjectivesTo profile a cohort of gyrate atrophy patients classified by widefield retinal imaging and correlate the structural, biochemical, and functional characteristics. DesignRetrospective observational cohort study. ParticipantsSixty-five patients (129 eyes) with gyrate atrophy. MethodsData of participants with a diagnosis of gyrate atrophy were retrieved from their electronic medical records (January 2015 to December 2023). Retinal involvement was classified into three zones using widefield retinal images. Zone 3 had atrophic patches in the area anterior to the equator; Zone 2 had involvement limited to the arcades but posterior to the equator; Zone 1 had involvement within the vascular arcades and/or peripapillary region, with or without any other zone involvement. Macular assessment was performed using swept-source OCT (n=104). Flash ERG was performed in 40 eyes. serum ornithine levels (n=35) were measured, and genetic analysis was conducted (n=18). Main Outcome MeasuresDemography, patient profile, zone of retina involved, macular features, and serum ornithine levels. ResultsThe average age at presentation was 26.4 (range: 5-67) years, majority were male. Nyctalopia (n=35, 53.8%) and blurred vision (n=29, 44.6%) were the most common symptoms. Positive family history was reported in 32.3% of patients. Most eyes were myopic (69.8%<-3 D). Posterior subcapsular cataracts were documented in 36.4% of eyes. The highest frequency of retinal area affected was Zone 1 (57.14%), followed by Zone 2 (33.33%) and Zone 3 (9.52%), correlating with age at presentation. Foveoschisis was observed in 57.7% of eyes, with a higher prevalence in eyes with Zone 1 disease. Elevated serum ornithine levels (>163 μmol/L) were found in 77.14% of patients. ERG showed non-recordable (n=32) or severely reduced (n=8) responses in scotopic and photopic phases. Genetic analysis of 18 patients identified mutations in the OAT gene, including a novel missense variant (c.290T>C). ConclusionsThis large cohort of patients with gyrate atrophy revealed symmetrical involvement, predominantly in Zone 1. Most patients presented between the first and third decades, experienced nyctalopia, vision reduction, early posterior subcapsular cataracts, and varying degrees of myopia. Zone 1 involvement was strongly associated with foveoschisis and visual compromise.

Fear of reinjury after acute Achilles tendon rupture is related to poorer recovery and lower physical activity postinjury.

The aim of this study was to investigate how fear of reinjury to the Achilles tendon affects return to previous levels of physical activity and self-reported Achilles tendon Total Rupture Score (ATRS) outcomes. Data were collected from a large cohort of patients treated for an acute Achilles tendon rupture at Sahlgrenska University Hospital Mölndal between 2015 and 2020. The ATRS and additional questions concerning fear of reinjury, treatment modality, satisfaction of treatment and recovery were analyzed 1-6 years postinjury. Analysis was performed to determine the impact of fear of reinjury on patient-reported recovery and physical activity. Of a total of 856 eligible patients, 550 (64%) answered the self-reported questionnaire and participated in the follow-up. Of the participants, 425 (77%) were men and 125 (23%) were women. ATRS, recovery in percentage, satisfaction of treatment, recovery on a 5-point scale and physical activity level post- versus preinjury were significantly related to fear of reinjury (p < 0.001). Of the nonsurgically treated patients, 59% reported fear of reinjury compared to 48% of the surgically treated patients (p = 0.024) Patients that reported fear of reinjury had a 15-point lower median ATRS score than those who did not (p < 0.001). More than half of patients who have suffered an Achilles tendon rupture are afraid of reinjuring their tendon. Patients who reported fear of reinjury exhibited a significantly lower ATRS score. This indicates the importance of addressing psychological aspects in the treatment after this injury. Level II.

National outcomes of cardiac surgery in patients receiving kidney replacement therapy.

Studies estimating risks following cardiac surgery for patients receiving kidney replacement therapy have been limited by the size and generalizability of those cohorts. This study used data linked between registries to estimate short-term postoperative outcomes for large patient cohorts receiving kidney replacement therapy at the time of surgery. This population-based observational cohort study included adult patients who had undergone cardiac surgery in Australia between 2010 and 2019. Patient data were linked with a kidney replacement therapy registry to accurately identify cohorts and extract relevant data. Multivariable logistic regression estimated risk of operative (30-day) mortality and other postoperative outcomes for long-term dialysis and functioning kidney transplant cohorts compared with each other and the general cardiac surgical population. Of 114,496 surgeries, 1,241 were for patients receiving long-term dialysis and 298 for those with a kidney transplant. The mortality rate was highest for valve-with-coronary artery bypass grafting for dialysis (18.78 per 100 surgeries (95% CI 13.37,25.25) and transplant patients (14.00 [5.82,26.74]). Dialysis patients had higher adjusted odds of mortality (odds ratio [OR] 4.17 [95% CI 3.31,5.25]) and all other measured outcomes than the general population. Kidney transplant recipients had similarly elevated odds of mortality (OR 3.52 [95% CI 2.16,5.72]). Despite the younger age of dialysis and transplant cohorts at surgery, operative mortality rates were higher, and for valve-with-coronary artery bypass grafting were 3.7- to 5-fold those of the general population. Dialysis patients were a high risk for cardiac surgery, and the prognosis for kidney transplant recipients was similarly poor.

Infection following mini-open rotator cuff repair: a single surgeon experience

Surgical technique has been shown to influence risk of surgical site infection following rotator cuff repair (RCR). Few studies have reported the rate of infection associated with mini-open RCR. The goal of this study was to report the postoperative infection rate and risk factors for infection among patients undergoing RCR performed by a single surgeon using a modified mini-open technique. Our hypothesis was that the rate of infection after mini-open RCR would be lower than previously reported for this surgical approach. We retrospectively reviewed an institutional shoulder surgery database to identify patients who underwent mini-open RCR performed by one surgeon at an academic tertiary care institution between 2003 and 2020. Patient records were reviewed to determine which individuals returned within 3 months postoperatively with a superficial or deep surgical site infection requiring operative management. Patient demographics, preoperative clinical characteristics, intraoperative variables, microbiological findings, infection management, and clinical course after infection were recorded. Backward elimination multivariate regression was used to assess for significant risk factors for infection. Of the 925 patients identified, 823 (89%) had at least 3 months of follow-up and were included for further analysis. A majority of the patients undergoing RCR were men (57%). The mean age was 58.4 ± 9.9 years, and the mean body mass index was 29.3 ± 5.9 kg/m2. Fourteen cases (1.7%) of postoperative surgical site infection were identified in 13 patients. Ten infections (1.2%) were superficial and 4 (0.49%) were deep. The most commonly identified organisms were Staphylococcus aureus and Cutibacterium acnes. Male sex (odds ratio [OR] 4.3, 95% CI 1.2-15.3) and diabetes mellitus (OR 3.9, 95% CI 1.2-12.6) were found to be associated with greater risk of infection. The RCR construct was found to be intact in all 10 patients with superficial infections and 2 of the 4 patients with deep infections. All infections were successfully treated with 1 round of surgical débridement and wound irrigation, and with 6 or fewer weeks of intravenous antibiotic therapy. All patients with postoperative infections recovered with no sequelae at a median final follow-up of 63.5 months (range, 3-215 months). This single-surgeon series of a large patient cohort undergoing mini-open RCR over an 18-year period demonstrated a low overall infection rate of 1.7%. Only 4 infections were deep, which suggests that deep infection after mini-open RCR is uncommon and approximates infection rates seen with arthroscopic techniques.

Vitiligo: From mechanisms of disease to treatable pathways

AbstractVitiligo is a chronic autoimmune‐mediated disease characterised by the loss of pigmentary melanocytes in the epidermis. Vitiligo is associated with loss of functional epithelium and significant reductions in quality of life with limited long‐term treatment options, highlighting a continued unmet clinical need. A comprehensive understanding of the pathophysiology and newly investigated treatment pathways may guide multimodal treatment strategies and identify future drug targets. The pathology of vitiligo is multifactorial; however, environmental insults in genetically susceptible populations may lead to disease development. Autoreactive CD8+ T‐cells that target melanocytes and release inflammatory mediators, including interferon‐γ and interleukins 2, 6, 15, 17 and 33 among others, have been identified in vitiligo pathogenesis. Treatment modalities for vitiligo revolve around six broad disease concepts, including procedural modalities (tissue and cellular grafting), phototherapy, stem cells, anti‐inflammatories, genetic polymorphisms and antioxidants/vitamins/herbals. Genetic polymorphisms, such as catalase gene variations and toll‐like receptor polymorphisms, along with stem cell targets such as melanocytes derived from stem cells, have been implicated in vitiligo onset and possible treatment. Novel JAK‐STAT inhibitors have been recently investigated for vitiligo, whereas topical corticosteroids and calcineurin inhibitors continue to be used. Vitamin D, vitamin E, zinc, copper, piperine, pseudo catalase and other vitamins/herbals may improve vitiligo outcomes primarily through antioxidant supplementation pathways. Future studies should investigate alternative drug pathways and targets implicated in vitiligo in large patient cohorts, as well as treatments that target suspected causative immune cells, including memory T‐cells, which may provide long‐lasting disease‐free remission.

Pipkin fractures: fracture type-specific management.

Femoral head fractures are rare, which limits the experience of individual surgeons with these injuries. This overview examines historical data, injury mechanisms, and classification systems, as well as epidemiological data from larger patient cohorts. Significant controversies persist regarding the optimal surgical approach and fracture-type-specific treatment for Pipkin fractures. The literature is often inconsistent, as many studies fail to differentiate between specific fracture types and instead report aggregated results, leading to ambiguous conclusions about the most effective treatment strategies. Thus, this article reviews fracture-type-specific outcomes of both non-operative and operative treatments over the past 25 years and summarizes their clinical implications, with the aim of assisting surgeons in their decision-making processes.

Fourth ventricular roof angle does not predict surgical outcome in paediatric patients with Chiari I malformation.

Pre-operative fourth ventricle roof angle (FVRA) has recently been highlighted as a novel radiographic predictor of clinical severity in Chiari type-I malformation (CM-I) as reported by Seaman et al. (J Neurosurg Pediatr 25:1-8, 2021). This has led to suggestions that FVRA could be included in algorithms to determine indications for surgery. We aimed to test the accuracy of FVRA as a predictor of clinical severity and its effect on post-operative outcome in a large retrospective cohort of paediatric patients who underwent decompression for CM-I. Patients undergoing craniocervical decompression for CM-I at the Queensland Children's Hospital and Mater Hospital, Brisbane, between 2006 and 2018 were included. Data was collected from 66 patients aged 0-18years. Post-operative outcome was assessed by calculating Chicago Chiari Outcomes Score (CCOS) at follow-up. The FVRA was taken from a mid-sagittal T1-weighted MRI as previously described (Seaman et al. in J Neurosurg Pediatr 25:1-8, 2021). The angle is subtended between superior and inferior medullary velum. Whilst results from Seaman et al. demonstrated a strong correlation between a FVRA > 65° and symptomatic CM-I, this did not translate to our dataset (p = 0.61). Additionally, pre-operative FVRA is not useful as a predictive tool for post-surgical outcome as assessed by CCOS (p = 0.50), and post-operative reduction in FVRA did not correlate with improved outcomes (p = 0.81). We did note significantly worse outcomes in patients presenting with pre-operative brainstem dysfunction (p = 0.03). Paediatric CM-I is a challenging cohort to manage, often due to young age and a lack of language skills. There is a heavy reliance on radiological findings. Whilst FVRA has previously been reported to be of value as a determinant of clinical severity in adult and paediatric patients, we find that this measurement is of dubious value in our retrospective cohort.

Can we rely on magnetic resonance imaging for prostate cancer detection and surgical planning? Comprehensive analysis of a large cohort of patients undergoing transperineal mapped biopsies.

To evaluate MRI and histological concordance in prostate cancer (PCa) identification via mapped transperineal biopsies. Retrospective per-lesion analysis of patients undergoing MRI and transperineal biopsy at the Valencian Institute of Oncology (2016-2024) using CAPROSIVO PCa data. Patients underwent MRI, with or without regions of interest (ROI), followed by transperineal biopsies (3-5 cores/ROI, 20-30 systematic). Sensitivity (Se), specificity (Sp), negative predictive value (NPV), positive predictive value (PPV), and area under the curve (AUC) were calculated, considering PI-RADS 3 lesions as positive or negative. Gleason Grade Group (GG) > 1 defined clinically significant PCa (csPCa). 1817 lesions were analyzed from 1325 patients (median age 67, median PSA 6.3 ng/ml). 53% MRI were negative, GG > 1 prevalence was 38.4%. MRI-negative cases showed varying PCa rates: 57.4% negative, 30.2% GG 1, and 12.4% GG > 1. PI-RADS 3 lesions had mixed outcomes: 45.6% benign, 13.1% GG 1, and 41.3% GG > 1. 9.2% PI-RADS 4-5 lesions were negative, 9% GG 1, and 81.7% GG > 1. For PI-RADS 3 lesions considered positive, Se, Sp, NPV, PPV, and AUC were 82.9%, 75%, 87.6%, 67.4%, and 0.79 respectively. Considering PI-RADS 3 as negative yielded 64.8% Se, 91% Sp, 80.6% NPV, 81.7% PPV, and 0.78 AUC. MRI and mapped prostate biopsies exhibited moderate concordance. MRI could miss up to one in five csPCa foci and misinterpret one in three ROIs. Careful MRI interpretation is crucial for optimizing patient care.

The Value of Pretherapeutic Basal Calcitonin Cut-Offs for the Therapeutic Strategy and Prediction of Long-Term Outcome of Patients with Medullary Thyroid Cancer—A 30-Year Single-Center Experience

Background: The clinical relevance of clearly defined pretherapeutic basal calcitonin (bCt) cut-offs for predicting lymph node metastases (LNMs) and long-term outcomes (LOs) has so far not been tested in a large cohort of patients with medullary thyroid cancer included in a Ct screening program during the initial diagnostic workup of thyroid nodules. Material and Methods: Female (f) patients with a bCt level of ≤23 pg/mL and male (m) patients with a level of ≤43 pg/mL were assigned to Group 1 (minimal oncologic risk), patients with a bCt between 24 and 84 pg/mL (f) and 44–99 pg/mL (m) to Group 2 (low oncologic risk), and those with a bCt of ≥85 pg/mL (f) and ≥100 pg/mL (m) to Group 3 (high oncologic risk). All patients underwent surgery applying a uniform surgical protocol. The median follow-up was 100 months. Results: The study included 306 patients. In 3/115 (2.6%) patients in Group 1 and in 3/50 (6.0%) in Group 2, LNM in the central but not lateral neck and no distant metastases (DMet) were documented. In both groups, the biochemical long-term cure rate was 95.7% and the disease-specific-survival (DSS) rate was 100% at 10, 15 and 20 years. Lateral LNM and DMet were diagnosed only in Group 3. The bCt levels of N0 and N1 patients showed broadly overlapping ranges, thus impeding the differentiation between those patients through bCt. Both the cure rate and DSS were significantly worse in Group 3. The overall biochemical long-term cure rate was 78.2%. Conclusions: Within a Ct screening program, grouping patients upon pretherapeutic bCt provides a simple risk classification system for indicating surgery, predicting LN involvement, and LOs.

High rate of detected variants in male PLCZ1 and ACTL7A genes causing failed fertilization after ICSI.

What is the frequency of PLCZ1, ACTL7A, and ACTL9 variants in male patients showing fertilization failure after ICSI, and how effective is assisted oocyte activation (AOA) for them? Male patients with fertilization failure after ICSI manifest variants in PLCZ1 (29.09%), ACTL7A (14.81%), and ACTL9 (3.70%), which can be efficiently overcome by AOA treatment with ionomycin. Genetic variants in PLCZ1, and more recently, in ACTL7A, and ACTL9 male genes, have been associated with total fertilization failure or low fertilization after ICSI. A larger patient cohort is required to understand the frequency at which these variants occur, and to assess their effect on the calcium ion (Ca2+) release during oocyte activation. AOA, using ionomycin, can restore fertilization and pregnancy rates in patients with PLCZ1 variants, but it remains unknown how efficient this is for patients with ACTL7A and ACTL9 variants. This prospective study involved two patient cohorts. In the first setting, group 1 (N = 28, 2006-2020) underwent only PLCZ1 genetic screening, while group 2 (N = 27, 2020-2023) underwent PLCZ1, ACTL7A, and ACTL9 genetic screening. Patients were only recruited when they had a mean fertilization rate of ≤33.33% in at least one ICSI cycle with at least four MII oocytes. Patients underwent a mouse oocyte activation test (MOAT) and at least one ICSI-AOA cycle using calcium chloride (CaCl2) injection and double ionomycin exposure at our centre. All patients donated a saliva sample for genetic screening and a sperm sample for further diagnostic tests, including Ca2+ imaging. Genetic screening was performed via targeted next-generation sequencing. Identified variants were classified by applying the revised ACMG guidelines into a Bayesian framework and were confirmed by bidirectional Sanger sequencing. If variants of uncertain significance or likely pathogenic or pathogenic variants were found, patients underwent additional determination of the sperm Ca2+-releasing pattern in mouse (MOCA) and in IVM human (HOCA) oocytes. Additionally, ACTL7A immunofluorescence and acrosome ultrastructure analyses by transmission electron microscopy (TEM) were performed for patients with ACTL7A and/or ACTL9 variants. Overall, the frequency rate of PLCZ1 variants was 29.09%. Moreover, 14.81% of patients carried ACTL7A variants and 3.70% carried ACTL9 variants. Seven different PLCZ1 variants were identified (p.Ile74Thr, p.Gln94*, p.Arg141His, p.His233Leu, p.Lys322*, p.Ile379Thr, and p.Ser500Leu), five of which are novel. Interestingly, PLCZ1 variants p.Ser500Leu and p.His233Leu occurred in 14.55% and 9.09% of cases. Five different variants were found in ACTL7A (p.Tyr183His, p.Gly214Ser, p.Val340Met, p.Ser364Glnfs*9, p.Arg373Cys), four of them being identified for the first time. A novel variant in ACTL9 (p.Arg271Pro) was also described. Notably, both heterozygous and homozygous variants were identified.The MOCA and HOCA tests revealed abnormal or absent Ca2+ release during fertilization in all except one patient, including patients with PLCZ1 heterozygous variants. TEM analysis revealed abnormal acrosome ultrastructure in three patients with ACTL7A variants, but only patients with homozygous ACTL7A variants showed reduced fluorescence intensity in comparison to the control.AOA treatment significantly increased the fertilization rate in the 19 patients with detected variants (from 11.24% after conventional ICSI to 61.80% after ICSI-AOA), as well as positive hCG rate (from 10.64% to 60.00%) and live birth rate (from 6.38% to 37.14%), resulting in 13 healthy newborns. In particular, four live births and two ongoing pregnancies were produced using sperm from patients with ACTL7A variants. Genetic screening included exonic and outflanking intronic regions, which implies that deep intronic variants were missed. In addition, other male genes or possible female-related factors affecting the fertilization process remain to be investigated. Genetic screening of PLCZ1, ACTL7A, and ACTL9 offers a fast, cost-efficient, and easily implementable diagnostic test for total fertilization failure or low fertilization after ICSI, eliminating the need for complex diagnostic tests like MOAT or Ca2+ analysis. Nonetheless, HOCA remains the most sensitive functional test to reveal causality of uncertain significance variants. Interestingly, heterozygous PLCZ1 variants are sufficient to cause inadequate Ca2+ release during ICSI. Most importantly, AOA treatment using CaCl2 injection followed by double ionomycin exposure is highly effective for this patient group, including those with ACTL7A variants, who also display a Ca2+-release deficiency. This study was supported by the Flemish Fund for Scientific Research (FWO) (TBM-project grant T002223N awarded to B.H.) and by the Special Research Fund (BOF) (starting grant BOF.STG.2021.0042.01 awarded to B.H.). A.C.B., R.R.G., C.C., E.V.D.V., A.R., D.S., L.L., P.C., S.S., A.B., and F.V.M. have nothing to disclose. B.H. reports a research grant from FWO and BOF, and reports being a board member of the Belgian Ethical Committee on embryo research. N/A.

Usage of the Anemia Control Model Is Associated with Reduced Hospitalization Risk in Hemodialysis.

The management of anemia in chronic kidney disease (CKD-An) presents significant challenges for nephrologists due to variable responsiveness to erythropoietin-stimulating agents (ESAs), hemoglobin (Hb) cycling, and multiple clinical factors affecting erythropoiesis. The Anemia Control Model (ACM) is a decision support system designed to personalize anemia treatment, which has shown improvements in achieving Hb targets, reducing ESA doses, and maintaining Hb stability. This study aimed to evaluate the association between ACM-guided anemia management with hospitalizations and survival in a large cohort of hemodialysis patients. This multi-center, retrospective cohort study evaluated adult hemodialysis patients within the European Fresenius Medical Care NephroCare network from 2014 to 2019. Patients treated according to ACM recommendations were compared to those from centers without ACM. Data on demographics, comorbidities, and dialysis treatment were used to compute a propensity score estimating the likelihood of receiving ACM-guided care. The primary endpoint was hospitalizations during follow-up; the secondary endpoint was survival. A 1:1 propensity score-matched design was used to minimize confounding bias. A total of 20,209 eligible patients were considered (reference group: 17,101; ACM adherent group: 3108). Before matching, the mean age was 65.3 ± 14.5 years, with 59.2% men. Propensity score matching resulted in two groups of 1950 patients each. Matched ACM adherent and non-ACM patients showed negligible differences in baseline characteristics. Hospitalization rates were lower in the ACM group both before matching (71.3 vs. 82.6 per 100 person-years, p < 0.001) and after matching (74.3 vs. 86.7 per 100 person-years, p < 0.001). During follow-up, 385 patients died, showing no significant survival benefit for ACM-guided care (hazard ratio = 0.93; p = 0.51). ACM-guided anemia management was associated with a significant reduction in hospitalization risk among hemodialysis patients. These results further support the utility of ACM as a decision-support tool enhancing anemia management in clinical practice.