An update on clinical presentation and responses to therapy of patients with hereditary hypophosphatemic rickets with hypercalciuria (HHRH).

Pathogenic variants in solute carrier family 34, member 3 (SLC34A3), the gene encoding the sodium-dependent phosphate cotransporter 2c (NPT2c), cause hereditary hypophosphatemic rickets with hypercalciuria (HHRH). Here, we report a pooled analysis of clinical and laboratory records of 304 individuals from 145 kindreds, including 20 previously unreported HHRH kindreds, in which two novel SLC34A3 pathogenic variants were identified. Compound heterozygous/homozygous carriers show above 90% penetrance for kidney and bone phenotypes. The biochemical phenotype for heterozygous carriers is intermediate with decreased serum phosphate, tubular reabsorption of phosphate (TRP (%)), fibroblast growth factor 23, and intact parathyroid hormone, but increased serum 1,25-dihydroxy vitamin D, and urine calcium excretion causing idiopathic hypercalciuria in 38%, with bone phenotypes still observed in 23% of patients. Oral phosphate supplementation is the current standard of care, which typically normalizes serum phosphate. However, although in more than half of individuals this therapy achieves correction of hypophosphatemia it fails to resolve the other outcomes. The American College of Medical Genetics and Genomics score correlated with functional analysis of frequent SLC34A3 pathogenic variants in vitro and baseline disease severity. The number of mutant alleles and baseline TRP (%) were identified as predictors for kidney and bone phenotypes, baseline TRP (%) furthermore predicted response to therapy. Certain SLC34A3/NPT2c pathogenic variants can be identified with partial responses to therapy, whereas with some overlap, others present only with kidney phenotypes and a third group present only with bone phenotypes. Thus, our report highlights important novel clinical aspects of HHRH and heterozygous carriers, raises awareness to this rare group of disorders and can be a foundation for future studies urgently needed to guide therapy of HHRH.

Unveiling the potential of breast MRI: a game changer for BI-RADS 4A microcalcifications.

PURPOSE: To assess the diagnostic performance of breast MRI for BI-RADS 4A microcalcifications on mammography and propose a potential clinical pathway to avoid unnecessary biopsies. METHODS: Bibliometrics analysis of breast MRI and BI-RADS 4 was provided. A retrospective analysis was conducted on 139 women and 142 cases of BI-RADS 4A microcalcifications on mammography from Fudan University Shanghai Cancer Center. The mammographic BI-RADS level and the MRI reports were compared with the final pathological diagnosis. RESULTS: Much attention has been given to breast MRI and BI-RADS 4 in the literature. However, studies on BI-RADS 4A are limited. Pathological results showed 117 cases (82.4%) were benign lesions, malignant cases of 25 (17.6%) in our study. The positive predictive values (PPV), specificity, sensitivity and negative predictive values (NPV) of MRI were 44.2% (23/52), 75.2% (88/117), 92.0% (23/25), and 97.8% (88/90), respectively. Therefore, 75.2% (88/117) of biopsies for benign lesions could potentially be avoided. There were 2.2% (2/90) malignant lesions missed. Logistic regression indicated that patients who are postmenopausal (HR = 2.655, p = 0.012), have a history of breast cancer (family history) (HR = 2.833, p = 0.029), and exhibit clustered microcalcifications (HR = 2.179, p = 0.046) are more likely to have a higher MRI BI-RADS level. CONCLUSIONS: Breast MRI has the potential to improve the diagnosis of BI-RADS 4A microcalcifications on mammography. We propose a potential clinical pathway that patients with BI-RADS 4A on mammography who are premenopausal, have no personal history of breast cancer (family history) or have non-clustered distribution of calcifications can undergo MRI to avoid unnecessary biopsies.

High ankle-brachial index participants experienced similar long-term mortality as peripheral artery disease in a national sample of community-dwelling adults.

BACKGROUND: Only a few small studies have shown the association between high ankle-brachial pressure index (ABI >1.4) and adverse cardiovascular (CV) events and mortality. Although there is abundant literature depicting the association between ABI and overall systemic atherosclerosis, it typically focuses on low ABI. Furthermore, historically, many studies focusing on peripheral artery disease have excluded high ABI participants. We aimed to study the mortality outcomes of persons with high ABI in the National Health and Nutrition Examination Survey (NHANES). METHODS: We obtained ABI from participants aged ≥40 years for survey years 1999 to 2004. We defined low a ABI as ≤0.9, normal ABI as 0.9 to 1.4, and high ABI as >1.4 or if the ankle pressures were >245 mm Hg. Demographics, various comorbidities, and laboratory test results were obtained at the time of the survey interview. Multivariable adjusted hazard ratios (HRs) along with 95% confidence intervals (CIs) were calculated for CV and all-cause mortality via Cox proportional hazards regression. Mortality was linked to all NHANES participants for follow-up through December 31, 2019, by the Centers for Disease Control and Prevention. RESULTS: We identified 7639 NHANES participants with available ABI. Of these, 6787 (89%) had a normal ABI, 646 (8%) had a low ABI, and 206 (3%) had elevated ABI. Of participants with high ABI, 50% were men, 15% were African Americans, 10% were current smokers, 56% had hypertension, 33% had diabetes, 15% had chronic kidney disease (CKD), and 18% had concomitant coronary artery disease (CAD). Diabetes (odds ratio [OR], 2.4; 95% CI, 1.7-3.2), CAD (OR, 1.6; 95% CI, 1.0-2.4), and CKD (OR, 1.5; 95% CI, 1.0-2.3) at baseline were associated with having a high ABI, respectively. A high ABI was associated independently with elevated CV (HR, 2.6; 95% CI, 2.1-3.1; P < .0001) and all-cause mortality (HR, 2.5; 95% CI, 2.2-2.8; P < .0001) after adjusting for covariates, including diabetes, CKD, CAD, current smoking, cancer, and hypertension. CONCLUSIONS: A high ABI is associated with an elevated CV and all-cause mortality, similar to patients with PAD. High ABI participants should receive the same attention and aggressive medical therapies as patients with PAD.

Biochemical Clusters as Substitutes of Bone Biopsies in Kidney Transplant Patients.

Bone and mineral metabolism abnormalities are frequent in kidney transplant recipients and have been associated with cardiovascular morbidity. The primary aim of this study was to analyse the association between routine clinically available biochemical evaluation, non-routine histomorphometric bone evaluation, and vascular disease in kidney transplanted patients. A cross-sectional analysis was performed on 69 patients, 1-year after kidney transplantation. Laboratory analysis, radiography of hands and pelvis, bone biopsy, bone densitometry, and coronary CT were performed. One-year post-transplantation, nearly one-third of the patients presented with hypercalcemia, 16% had hypophosphatemia, 39.3% had iPTH levels > 150 pg/mL, 20.3% had BALP levels > 40 U/L, and 26.1% had hypovitaminosis D. Evaluation of extraosseous calcifications revealed low Adragão and Agatston scores. We divided patients into three clusters, according to laboratory results routinely used in clinical practice: hypercalcemia and hyperparathyroidism (Cluster1); hypercalcemia and high BALP levels (Cluster2); hypophosphatemia and vitamin D deficiency (Cluster 3). Patients in clusters 1 and 2 had higher cortical porosity (p = 0.001) and osteoid measurements, although there was no difference in the presence of abnormal mineralization, or low volume. Patients in cluster 2 had a higher BFR/BS (half of the patients in cluster 2 had high bone turnover), and most patients in cluster 1 had low or normal bone turnover. Cluster 3 has no differences in volume, or turnover, but 60% of the patients presented with pre-osteomalacia. All three clusters were associated with high vascular calcifications scores. Vascular calcifications scores were not related to higher bone mineral density. Instead, an association was found between a higher Adragão score and the presence of osteoporosis at the femoral neck (p = 0.008). In conclusion, inferring bone TMV by daily clinical biochemical analysis can be misleading, and bone biopsy is important for assessing both bone turnover and mineralization after kidney transplantation, although hypophosphatemia combined with vitamin D deficiency is associated with abnormal mineralization. The presence of hypercalcemia with high levels of PTH or high levels of BALP, or hypophosphatemia and vitamin D deficiency should remind us to screen vascular calcification status of patients.Clinical Research: ClinicalTrials.gov ID NCT02751099.

Intracranial calcifications simulating Aicardi-Goutières syndrome in PARS2-related mitochondrial disease.

PARS2 encodes an aminoacyl-tRNA synthetase that catalyzes the ligation of proline to mitochondrial prolyl-tRNA molecules. Diseases associated with PARS2 primarily affect the central nervous system, causing early infantile developmental epileptic encephalopathies (EIDEE; DEE75; MIM #618437) with infantile-onset neurodegeneration. Dilated cardiomyopathy has also been reported in the affected individuals. About 10 individuals to date have been described with pathogenic biallelic variants in PARS2. While many of the reported individuals succumbed to the disease in the first two decades of life, autopsy findings have not yet been reported. Here, we describe neuropathological findings in a deceased male with evidence of intracranial calcifications in the basal ganglia, thalamus, cerebellum, and white matter, similar to Aicardi-Goutières syndrome. This report describes detailed autopsy findings in a child with PARS2-related mitochondrial disease and provides plausible evidence that intracranial calcifications may be a previously unrecognized feature of this disorder.

Prevalence and clinical implications of coronary artery calcium scoring on non-gated thoracic computed tomography: a systematic review and meta-analysis.

OBJECTIVES: Coronary artery calcifications (CACs) indicate the presence of coronary artery disease. CAC can be found on thoracic computed tomography (CT) conducted for non-cardiac reasons. This systematic review and meta-analysis of non-gated thoracic CT aims to assess the clinical impact and prevalence of CAC. METHODS: Online databases were searched for articles assessing prevalence, demographic characteristics, accuracy and prognosis of incidental CAC on non-gated thoracic CT. Meta-analysis was performed using a random effects model. RESULTS: A total of 108 studies (113,406 patients) were included (38% female). Prevalence of CAC ranged from 2.7 to 100% (pooled prevalence 52%, 95% confidence interval [CI] 46-58%). Patients with CAC were older (pooled standardised mean difference 0.88, 95% CI 0.65-1.11, p < 0.001), and more likely to be male (pooled odds ratio [OR] 1.95, 95% CI 1.55-2.45, p < 0.001), with diabetes (pooled OR 2.63, 95% CI 1.95-3.54, p < 0.001), hypercholesterolaemia (pooled OR 2.28, 95% CI 1.33-3.93, p < 0.01) and hypertension (pooled OR 3.89, 95% CI 2.26-6.70, p < 0.001), but not higher body mass index or smoking. Non-gated CT assessment of CAC had excellent agreement with electrocardiogram-gated CT (pooled correlation coefficient 0.96, 95% CI 0.92-0.98, p < 0.001). In 51,582 patients, followed-up for 51.6 ± 27.4 months, patients with CAC had increased all cause mortality (pooled relative risk [RR] 2.13, 95% CI 1.57-2.90, p = 0.004) and major adverse cardiovascular events (pooled RR 2.91, 95% CI 2.26-3.93, p < 0.001). When CAC was present on CT, it was reported in between 18.6% and 93% of reports. CONCLUSION: CAC is a common, but underreported, finding on non-gated CT with important prognostic implications. CLINICAL RELEVANCE STATEMENT: Coronary artery calcium is an important prognostic indicator of cardiovascular disease. It can be assessed on non-gated thoracic CT and is a commonly underreported finding. This represents a significant population where there is a potential missed opportunity for lifestyle modification recommendations and preventative therapies. This study aims to highlight the importance of reporting incidental coronary artery calcium on non-gated thoracic CT. KEY POINTS: • Coronary artery calcification is a common finding on non-gated thoracic CT and can be reliably identified compared to gated-CT. • Coronary artery calcification on thoracic CT is associated with an increased risk of all cause mortality and major adverse cardiovascsular events. • Coronary artery calcification is frequently not reported on non-gated thoracic CT.

Variants in CLDN5 cause a syndrome characterized by seizures, microcephaly and brain calcifications.

The blood-brain barrier ensures CNS homeostasis and protection from injury. Claudin-5 (CLDN5), an important component of tight junctions, is critical for the integrity of the blood-brain barrier. We have identified de novo heterozygous missense variants in CLDN5 in 15 unrelated patients who presented with a shared constellation of features including developmental delay, seizures (primarily infantile onset focal epilepsy), microcephaly and a recognizable pattern of pontine atrophy and brain calcifications. All variants clustered in one subregion/domain of the CLDN5 gene and the recurrent variants demonstrate genotype-phenotype correlations. We modelled both patient variants and loss of function alleles in the zebrafish to show that the variants analogous to those in patients probably result in a novel aberrant function in CLDN5. In total, human patient and zebrafish data provide parallel evidence that pathogenic sequence variants in CLDN5 cause a novel neurodevelopmental disorder involving disruption of the blood-brain barrier and impaired neuronal function.

Metastatic pulmonary calcifications after pediatric liver transplantation.

BACKGROUND: Pulmonary calcification (PC) is a rare clinical entity observed following liver transplantation (LT). Most often identified in adults or in patients with concomitant renal failure, PC is rarely reported in children. While the clinical course of PC is largely benign, cases of progressive respiratory failure and death have been reported. Additionally, PC may mimic several other disease processes making diagnosis and management challenging. Currently, little is reported regarding the diagnosis, management, and long-term outcomes of children with PC following LT. METHODS: We performed a retrospective chart review of patients undergoing LT at our institution between 2006 and 2023. We identified two patients who developed PC following LT. Their diagnosis, clinical course, and long-term outcomes are reported. A literature review of the presentation, diagnosis, management, and outcomes of adult and pediatric patients with PC post-LT was also performed. CONCLUSIONS: Pulmonary calcifications are a rare but notable complication after pediatric liver transplantation. Our case series adds to the limited literature on this clinical entity in children but also highlights the fact that effective diagnosis and treatment may be safely accomplished without the use of lung biopsy.

Diagnostic performance of coronary calcifications on CT to rule out acute coronary syndrome in the emergency department.

BACKGROUND: At present, the diagnosis of acute coronary syndrome (ACS) can be made by emergency physicians using the usual complementary tests, since the current troponin and electrocardiogram (ECG) protocols have been extensively tested for their safety. However, the detection of coronary calcifications on CT associated with coronary obstruction may be of interest for the diagnostic strategy in the emergency department (ED). The aim of this study was to evaluate a strategy combining a non-ischemic ECG with an initial normal troponin assay and the diagnostic accuracy of chest CT in detecting coronary calcifications to rule out the presence of an acute coronary event in patients presenting with chest pain in the ED. METHODS: This was a retrospective, single-center study carried out in an ED in France and included all patients over 18 years of age presenting with chest pain between 1 June 2021 and 31 December 2021 with a non-ischemic ECG and a negative first troponin assay. The primary endpoint was the diagnostic performance of the combing strategy in ruling out ACS. The secondary endpoints were the sensitivity and specificity of calcifications in acute coronary syndrome, comparison with the diagnostic performance of a second troponin assay and the rate of reconsultation, rehospitalisation and investigations within 2 months of the ED. RESULTS: Of the 280 patients included, 141 didn't have calcifications. A total of 14 events were found with a negative predictive value for the combining strategy of 99.8% [95%CI: 98.2 - 100]. Sensitivity and specificity were 98.4% [95%CI: 83.8 - 100] and 53% [95%CI: 47 - 58.9], respectively. Among patients with no calcification, 8.2% were admitted to hospital and none suffered an acute coronary event. A total of 36 patients (12.8%) consulted a doctor within 2 months, with 23 investigations, all of which were negative in the non-calcification group. CONCLUSIONS: A strategy combining the detection of coronary calcifications on chest CT in patients with a non-ischemic ECG and a single troponin assay is effective to rule out ACS in the ED, and may perform better then ECG and troponin alone.

Characterization of stromal calcifications in odontogenic keratocyst: a multicentric study.

Odontogenic keratocysts (OKCs) are locally aggressive cysts that exhibit typical histopathological features and have a propensity for recurrence. Though histological variations are observed in OKCs, hard tissue formation and metaplastic changes are rare, and the underlying pathogenesis is not well understood. This study aimed to characterize stromal calcifications and analyze their association with odontogenic components in non-syndromic and syndrome-associated cases of OKCs. We analyzed 153 cases of OKCs from healthcare institutes in India and Japan. The epithelial and stromal features were evaluated, and the relationship of calcifications with odontogenic rests was determined. Immunohistochemistry for cytokeratin-19 and special stains including Masson Trichrome and Van Gieson, were used for identification of odontogenic rests and calcifications respectively. Stromal calcifications were observed in 29.41% OKCs. The calcification patterns included irregular dystrophic, dentinoid with linear or calcospherite-type mineralization, and psammoma calcifications. Psammoma and dentinoid calcifications were found in the proximity of cytokeratin-19-positive odontogenic rests or satellite cysts, whereas majority cases with dystrophic calcifications did not exhibit co-localization with stromal odontogenic components. Distinct patterns of calcifications were observed in OKCs. Calcifications found in proximity of the odontogenic rests were possibly indicative of an inductive or host-mediated response.

NOTCH1-Related Leukoencephalopathy: A Novel Variant and Literature Review.

NOTCH1-related leukoencephalopathy is a new diagnostic entity linked to heterozygous gain-of-function variants in NOTCH1 that neuroradiologically show some overlap with the inflammatory microangiopathy Aicardi-Goutières syndrome (AGS). To report a 16-year-old boy harbouring a novel NOTCH1 mutation who presented neuroradiological features suggestive of enhanced type I interferon signalling. We describe five years of follow-up and review the current literature on NOTCH1-related leukoencephalopathy. Clinical evaluation, standardised scales (SPRS, SARA, CBCL, CDI-2:P, WISCH-IV and VABS-2) and neuroradiological studies were performed, as well as blood DNA analysis. For the literature review, a search was performed on Pubmed, Scopus and Web of Science up to December 2023 using the following text word search strategy: (NOTCH1) AND (leukoencephalopathy). Our patient presents clinical features consistent with other reported cases with NOTCH1 mutations but is among the minority of patients with an onset after infancy. During the five-year follow-up, we observed an increase in the severity of spasticity and ataxia. However, at the age of 16 years, our proband is still ambulatory. As for other reported patients, he manifests psychiatric features ranging from hyperactivity during childhood to anxiety and depression during adolescence. The neuroradiological picture remained essentially stable over five years. In addition to the typical findings of leukoencephalopathy with cysts and calcifications already described, we report the presence of T2-hyperintensity and T1-hypotensity of the transverse pontine fibres, enhancement in the periventricular white matter after gadolinium administration and decreased NAA and Cho peaks in the periventricular white matter on MRS. We identified a novel heterozygous variant in NOTCH1 (c.4788_4799dup), a frame insertion located in extracellular negative regulatory region (NRR)-domain as in previously published cases. Blood interferon signalling was not elevated compared to controls. This case provides further data on a new diagnostic entity, i.e., NOTCH1-related leukoencephalopathy. By describing a standardised five-year follow-up in one case and reviewing the other patients described to date, we outline recommendations relating to monitoring in this illness, emphasising the importance of psychiatric and gastroenterological surveillance alongside neurological and neuropsychological management. Studies are needed to better understand the factors influencing disease onset and severity, which are heterogeneous.

Identification and classification of pulp calcifications in posterior teeth according to dental condition using digital panoramic radiography and cone beam CT.

OBJECTIVE: To compare digital panoramic radiography (DPR) and cone beam CT (CBCT) in the detection and classification of pulp calcifications in posterior teeth in relation to tooth condition and its location. METHODS: Two hundred and fifty patients with simultaneous DPR and CBCT scans were selected from a dental image bank. For each posterior tooth, its condition was registered (healthy, restored, or decayed). The presence of calcifications was assessed and classified according to location (coronal or radicular) and type (total obliteration, partial obliteration, narrowing, and no calcification). Chi-square and McNemar tests were used to compare DPR and CBCT results, with a significance level of 5%. DPR diagnostic values were calculated using CBCT as reference. RESULTS: Decayed and restored teeth showed a significantly (P < .001) higher prevalence of pulp calcifications than healthy teeth in both imaging exams. There was a significant discrepancy between the imaging modalities in the identification of calcifications (P < .001), especially for radicular calcifications of maxillary teeth (DPR = 55.2%; CBCT = 30.9%). In the case of coronal calcifications, there was a greater discrepancy between CBCT and DPR in the mandibular teeth (10.7%) than in the maxillary teeth (7.7%). Overall, DPR presents higher sensitivity (0.855) than specificity (0.483) for pulp calcifications detection. CONCLUSION: DPR considerably overestimates pulp calcifications in posterior teeth, as compared to CBCT. A higher prevalence of pulp calcifications is related to decayed and restored teeth.

Peri-lesion regions in differentiating suspicious breast calcification-only lesions specifically on contrast enhanced mammography.

PURPOSE: The explore the added value of peri-calcification regions on contrast-enhanced mammography (CEM) in the differential diagnosis of breast lesions presenting as only calcification on routine mammogram. METHODS: Patients who underwent CEM because of suspicious calcification-only lesions were included. The test set included patients between March 2017 and March 2019, while the validation set was collected between April 2019 and October 2019. The calcifications were automatically detected and grouped by a machine learning-based computer-aided system. In addition to extracting radiomic features on both low-energy (LE) and recombined (RC) images from the calcification areas, the peri-calcification regions, which is generated by extending the annotation margin radially with gradients from 1 mm to 9 mm, were attempted. Machine learning (ML) models were built to classify calcifications into malignant and benign groups. The diagnostic matrices were also evaluated by combing ML models with subjective reading. RESULTS: Models for LE (significant features: wavelet-LLL_glcm_Imc2_MLO; wavelet-HLL_firstorder_Entropy_MLO; wavelet-LHH_glcm_DifferenceVariance_CC; wavelet-HLL_glcm_SumEntropy_MLO;wavelet-HLH_glrlm_ShortRunLowGray LevelEmphasis_MLO; original_firstorder_Entropy_MLO; original_shape_Elongation_MLO) and RC (significant features: wavelet-HLH_glszm_GrayLevelNonUniformityNormalized_MLO; wavelet-LLH_firstorder_10Percentile_CC; original_firstorder_Maximum_MLO; wavelet-HHH_glcm_Autocorrelation_MLO; original_shape_Elongation_MLO; wavelet-LHL_glszm_GrayLevelNonUniformityNormalized_MLO; wavelet-LLH_firstorder_RootMeanSquared_MLO) images were set up with 7 features. Areas under the curve (AUCs) of RC models are significantly better than those of LE models with compact and expanded boundary (RC v.s. LE, compact: 0.81 v.s. 0.73, p < 0.05; expanded: 0.89 v.s. 0.81, p < 0.05) and RC models with 3 mm boundary extension yielded the best performance compared to those with other sizes (AUC = 0.89). Combining with radiologists' reading, the 3mm-boundary RC model achieved a sensitivity of 0.871 and negative predictive value of 0.937 with similar accuracy of 0.843 in predicting malignancy. CONCLUSIONS: The machine learning model integrating intra- and peri-calcification regions on CEM has the potential to aid radiologists' performance in predicting malignancy of suspicious breast calcifications.

Symptomatic Calcifications after Mastectomy: A Rare Case Report with a Review of the Literature.

Introduction: Symptomatic calcifications of the breast or skin after breast cancer surgery and adjuvant radiotherapy are a rare entity, with only a few case reports published worldwide, reducing the patient's quality of life, whilst asymptomatic calcifications are a common finding on imaging methods. Case presentation: Herein, we present a rare case report of calcifications after mastectomy and post-mastectomy radiation therapy causing chronic inflammation with ulceration and fistula formation, with a two-step surgical approach consisting of excision with linear suture and excision with the reconstruction using a thoraco-epigastric flap. Conclusions: To our knowledge, this is the first publication proving the feasibility of this therapy in patients with symptomatic dystrophic calcifications of the skin or the breast. Moreover, the article provides an up-to-date review of published studies about symptomatic calcifications after breast cancer surgery and radiotherapy with a focus on the time of the clinical manifestation from the radiotherapy and the used radiotherapy scheme.

Cardiovascular calcification in hemodialysis patients: A Qatar-based prevalence and risk factors study.

BACKGROUND: Patients with end-stage kidney disease on hemodialysis (HD) have an increased risk of death due to the high prevalence of cardiovascular disease. Vascular calcification (VC) is predictive of cardiovascular disease and mortality. We conducted a study to evaluate the prevalence and risk factors for VC in dialysis patients in Qatar. METHODS: This is a retrospective nationwide study including all chronic ambulatory dialysis patients in Qatar from 2020 to 2022. We used our national electronic medical record to track demographics, clinical characteristics, comorbidities, laboratory values, and diagnostic data for each patient. Calcifications were assessed by echocardiography (routinely done for all our dialysis population per national protocol), computed tomography, X-ray, and ultrasound. The study protocol was approved by the local medical research ethics committee (MRC-01-20-377). RESULTS: 842 HD patients were included in this study. Vascular calcifications (VC) were prevalent in 52.6% of patients. The main site of VC was Mitral valve calcifications in 55.5% of patients. Patients with VC were significantly older and had more prevalence of diabetes mellitus (p = 0.001 and p = 0.006, respectively). There was no statistically significant difference between patients with calcifications and patients without calcifications regarding serum calcium, phosphorus, and PTH level. In multivariate analysis, age and diabetes significantly increased the risk factor for calcification (95% CI 1.033-1.065, p < 0.0001, and 95% CI 1.128-2.272, p < 0001, respectively). Moreover, higher vitamin D levels and higher doses of IV Alfacalcidol were significant risk factors for calcifications (95% CI 1.005-1.030, p < 0.007, and 95% CI 1.092-1.270, p < 0.0001, respectively). CONCLUSION: Our study found that vascular calcification was widespread among our dialysis population in Qatar. Implementing the practice of echocardiography in dialysis patients was extremely helpful and the most productive in detecting vascular calcification. Diabetes mellitus almost doubles the risk for vascular calcifications in dialysis patients. These results are beneficial in identifying risk factors for vascular calcification, which can help stratify dialysis patients' risk of cardiovascular disease and optimize prevention efforts.

Intracranial Artery Calcifications Profile as a Predictor of Recanalization Failure in Endovascular Stroke Treatment.

BACKGROUND: Acute ischemic stroke with large or medium-vessel occlusion associated with intracranial artery calcification (IAC) is an infrequent phenomenon presumably associated with intracranial atherosclerotic disease. We aimed to characterize IAC and its impact on endovascular treatment outcomes. METHODS: We performed a retrospective cross-sectional study of consecutive patients with stroke treated with thrombectomy from January 2020 to July 2021 in our institution. We described IAC findings (length, density, and location pattern) on baseline noncontrast computed tomography. Patients were divided into 3 groups: IAC related to the occlusion location (symptomatic-IAC group), unrelated to the occlusion (asymptomatic-IAC group), and absence of any IAC (non-IAC group). We analyzed the association between the IAC profile and outcomes using logistic regression models. Intracranial angioplasty and stenting were considered rescue treatments. RESULTS: Of the 393 patients included, 26 (6.6%) patients presented a symptomatic-IAC, 77 (19.6%) patients an asymptomatic-IAC, and in 290 (73.8%) patients no IAC was observed. The rate of failed recanalization (expanded Thrombolysis in Cerebral Infarction 0-2a) before rescue treatment was higher in symptomatic-IAC (65.4%) than in asymptomatic-IAC (15.6%; P<0.001) or non-IAC (13.4%; P<0.001). Rescue procedures were more frequently performed in symptomatic-IAC (26.9%) than in asymptomatic-IAC (1.3%; P<0.001) and non-IAC (4.1%; P<0.001). After adjusting for identifiable clinical and radiological confounders, symptomatic-IAC emerged as an independent predictor of failed recanalization (odds ratio, 11.89 [95% CI, 3.94-35.91]; P<0.001), adoption of rescue procedures (odds ratio, 12.38 [95% CI, 2.22-69.09]; P=0.004), and poor functional outcome (90-day modified Rankin Scale score ≥3; odds ratio, 3.51 [95% CI, 1.02-12.00]; P=0.046). CONCLUSIONS: The presence of IAC related to the occlusion location is associated with worse angiographic and functional outcomes. Therefore, identification of symptomatic-IAC on baseline imaging may guide optimal endovascular treatment strategy, predicting the need for intracranial stenting and angioplasty.

Analysis of U8 snoRNA Variants in Zebrafish Reveals How Bi-allelic Variants Cause Leukoencephalopathy with Calcifications and Cysts.

How mutations in the non-coding U8 snoRNA cause the neurological disorder leukoencephalopathy with calcifications and cysts (LCC) is poorly understood. Here, we report the generation of a mutant U8 animal model for interrogating LCC-associated pathology. Mutant U8 zebrafish exhibit defective central nervous system development, a disturbance of ribosomal RNA (rRNA) biogenesis and tp53 activation, which monitors ribosome biogenesis. Further, we demonstrate that fibroblasts from individuals with LCC are defective in rRNA processing. Human precursor-U8 (pre-U8) containing a 3' extension rescued mutant U8 zebrafish, and this result indicates conserved biological function. Analysis of LCC-associated U8 mutations in zebrafish revealed that one null and one functional allele contribute to LCC. We show that mutations in three nucleotides at the 5' end of pre-U8 alter the processing of the 3' extension, and we identify a previously unknown base-pairing interaction between the 5' end and the 3' extension of human pre-U8. Indeed, LCC-associated mutations in any one of seven nucleotides in the 5' end and 3' extension alter the processing of pre-U8, and these mutations are present on a single allele in almost all individuals with LCC identified to date. Given genetic data indicating that bi-allelic null U8 alleles are likely incompatible with human development, and that LCC is not caused by haploinsufficiency, the identification of hypomorphic misprocessing mutations that mediate viable embryogenesis furthers our understanding of LCC molecular pathology and cerebral vascular homeostasis.

Spondyloenchondrodysplasia in five new patients: identification of three novel ACP5 variants with variable neurological presentations.

Spondyloenchondrodysplasia (SPENCD) is an immune-osseous disorder caused by biallelic variants in ACP5 gene and is less commonly associated with neurological abnormalities such as global developmental delay, spasticity and seizures. Herein, we describe five new patients from four unrelated Egyptian families with complex clinical presentations including predominant neurological presentations masking the skeletal and immunological manifestations. All our patients had spasticity with variable associations of motor and mental delay or epilepsy. All except for one patient had bilateral calcification in the basal ganglia. One patient had an associated growth hormone deficiency with fair response to growth hormone therapy (GH) where the height improved from -3.0 SD before GH therapy to -2.35 SD at presentation. Patients had different forms of immune dysregulation. All patients except for one had either cellular immunodeficiency (3 patients) or combined immunodeficiency (1 patient). Whole exome sequencing was performed and revealed four ACP5 variants: c.629C > T (p.Ser210Phe), c.526C > T (p.Arg176Ter), c.742dupC (p.Gln248ProfsTer3) and c.775G > A (p.Gly259Arg). Of them, three variants were not described before. Our study reinforces the striking phenotypic variability associated with SPENCD and expands the mutational spectrum of this rare disorder. Further, it documents the positive response to growth hormone therapy in the studied patient.

Cutting balloon to optimize predilation for stent implantation: The COPS randomized trial.

OBJECTIVES: The objective of this study is to investigate the use of cutting balloon (CB) inflated at high pressure compared with noncompliant balloon (NCB) for the treatment of calcified coronary lesions. BACKGROUND: No data are available regarding the safety and efficacy of CB inflated at high pressure in coronary artery calcifications. METHODS: Patients with calcified lesions (more than 100° of calcium demonstrated at baseline intravascular ultrasound) were randomized. Primary endpoint of the study was the final minimal stent area (MSA) and stent symmetry in the calcific segment. Secondary endpoints included rate of device failure and the 1-year rate of target lesion revascularization, target vessel revascularization, and major adverse cardiovascular events. RESULTS: From September 2019 to June 2021, a total of 100 patients were included and randomized; 13 patients were excluded for major protocol deviations. Lesions were complex (type B2/C n = 61 [71.2%]) with a mean arch of calcium of 266 ± 84°, a calcium length of 12 ± 6.6 mm. CB was inflated at comparable atmospheres when compared with NCB (18.3 ± 5 vs. 19 ± 4.5, p = 0.46). In the per-protocol population, the final MSA at the level of the calcium site was significantly higher in the CB group (8.1 ± 2 vs. 7.3 ± 2.1, p = 0.035) with a higher eccentricity index achieved in the CB group (0.84 ± 0.07 vs. 0.8 ± 0.08, p = 0.013). Three device failure occurred in the CB group. One-year follow-up outcomes were comparable. CONCLUSIONS: Treatment of calcified lesions with high-pressure CB has a good safety profile and is associated with a larger MSA and higher eccentricity of the stent at the level of the calcium site compared with NCB.

Stent expansion in calcified coronary chronic total occlusions: The impact of different stent platforms.

OBJECTIVES: To evaluate the stent expansion of the durable-polymer Zotarolimus-eluting stent (dp-ZES), the durable-polymer Everolimus-eluting stent (dp-EES), and the bioabsorbable-polymer Sirolimus-eluting stent (bp-SES) in calcified coronary chronic total occlusions (CTO). BACKGROUND: The newer generation stents with ultrathin struts might raise concerns regarding reduced radial strength and higher stent recoil (SR) when implanted in calcified CTOs. METHODS: Between January 2017 and June 2021 consecutive patients with CTO undergoing percutaneous coronary intervention with dp-ZES, dp-EES, or bp-SES were evaluated. The analysis was performed in calcific and in noncalcific CTOs. Quantitative coronary angiography analysis was used to assess diameter stenosis (DS), absolute and relative SR, absolute and relative focal SR, absolute and relative balloon deficit (BD), and absolute and relative focal BD. The primary endpoint was DS. RESULTS: A total of 213 CTOs were evaluated, 115 calcific CTOs (dp-ZES:25, dp-EES:29, bp-SES:61) and 98 non-calcific CTOs (dp-ZES:41, dp-EES:11, bp-SES:46). In calcific CTOs, residual DS was lower in dp-ZES than in dp-EES and bp-SES (-1.00% [-6.50-6.50] vs. 13.00% [7.0-19.00] vs. 15.00% [5.00-20.00]; p < 0.001). Dp-ZES was also an independent predictor of residual DS ≤ 10% (OR 11.34, 95% CI 2.6-49.43, p = 0.001). Absolute and relative focal SR and absolute and relative SR were similar between dp-ZES, dp-EES, and bp-SES (p = 0.913, p = 0.890, p = 0.518, p = 0.426, respectively). In noncalcified CTOs, the residual DS was similar in the three groups (p = 0.340). High relative focal SR was less frequent in dp-ZES than in dp-EES and in bp-SES (19.5% vs. 54.5% vs. 37.0%; p < 0.048). CONCLUSIONS: The three stent platforms demonstrated an overall low residual DS when implanted in CTOs. However, dp-ZES was associated with the lowest residual DS and identified as independent predictor of residual DS ≤ 10% in patients with calcific CTOs. Dp-ZES was associated with a lower incidence of high relative focal stent recoil, in noncalcific CTOs. Balloon deficit might be considerate as a surrogate for stent expansion in calcified CTOs.