Clusters of adipose tissue dysfunction in adults with type 2 diabetes identify those with worse lipidomic profile despite similar glycaemic control.

AIMS: To investigate clusters of adipose tissue dysfunction, that is, with adipose tissue insulin resistance (ADIPO-IR) and large waist circumference (WC), identify a worse lipidomic profile characterised by a high proportion of lipids rich in saturated fatty acids (SFA). MATERIALS AND METHODS: Hierarchical clustering based on WC and ADIPO-IR (calculated as fasting plasma non-esterified fatty acids times fasting plasma insulin, FFA×INS), was performed in 192 adults with overweight/obesity and type 2 diabetes (T2D) treated with metformin (HbA1c = 7.8%). Free fatty acid composition and lipidomic profile were measured by mass spectrometry (GC-MS and LC-MSQTOF). Indexes of fatty acid desaturation (stearoyl-coA desaturase-1 activity, SCD116 = palmitoleic acid/palmitic acid and SCD118 = oleic acid/stearic acid) and of insulin resistance (HOMA-IR) were also calculated. RESULTS: Three clusters were identified: CL1 (ADIPO-IR = 4.9 ± 2.4 and WC = 96±7 cm, mean ± SD), CL2 (ADIPO-IR = 6.5 ± 2.5 and WC = 114 ± 7 cm), and CL3 (ADIPO-IR = 15.0 ± 4.7 and WC = 107 ± 8 cm). Insulin concentrations, ADIPO-IR, and HOMA-IR significantly increased from CL1 to CL3 (all p < 0.001), while fasting glucose concentrations, HbA1c, dietary lipids and caloric intake were similar. Moreover, CL3 showed significantly higher concentrations of monounsaturated free fatty acids, oleic and palmitoleic acids, triglycerides (TAG) rich in saturated FA and associated with de novo lipogenesis (i.e., TAG 46-50), higher SCD116, SCD118, ceramide (d18:0/18:0), and phosphatidylcholine aa(36:5) compared with CL1/CL2 (all p < 0.005). CONCLUSIONS: High ADIPO-IR and large WC identify a worse lipid profile in T2D characterised by complex lipids rich in SFA, likely due to de novo synthesis given higher plasma monounsaturated FFA and increased desaturase activity indexes. REGISTRATION NUMBER TRIAL: ID NCT00700856 https://clinicaltrials.gov.

Altered microbial bile acid metabolism exacerbates T cell-driven inflammation during graft-versus-host disease.

Microbial transformation of bile acids affects intestinal immune homoeostasis but its impact on inflammatory pathologies remains largely unknown. Using a mouse model of graft-versus-host disease (GVHD), we found that T cell-driven inflammation decreased the abundance of microbiome-encoded bile salt hydrolase (BSH) genes and reduced the levels of unconjugated and microbe-derived bile acids. Several microbe-derived bile acids attenuated farnesoid X receptor (FXR) activation, suggesting that loss of these metabolites during inflammation may increase FXR activity and exacerbate the course of disease. Indeed, mortality increased with pharmacological activation of FXR and decreased with its genetic ablation in donor T cells during mouse GVHD. Furthermore, patients with GVHD after allogeneic hematopoietic cell transplantation showed similar loss of BSH and the associated reduction in unconjugated and microbe-derived bile acids. In addition, the FXR antagonist ursodeoxycholic acid reduced the proliferation of human T cells and was associated with a lower risk of GVHD-related mortality in patients. We propose that dysbiosis and loss of microbe-derived bile acids during inflammation may be an important mechanism to amplify T cell-mediated diseases.

Digital postprocessing analysis of prostatic perfusion in neutered dogs.

B-mode ultrasound is routinely performed to evaluate the prostate gland in neutered dogs, although, the detection of malignancies may be challenging. Contrast-enhanced ultrasound (CEUS) has shown to be useful for the assessment of prostatic perfusion in normal and diseased dogs, although the interpretation of contrast ultrasonographic features may still be subjective. A quantitative tool for evaluating prostatic perfusion might improve the reliability of the results in terms of early detection of prostate neoplasia in neutered dogs. The present study aimed to evaluate the applicability of a postprocessing analysis tool to CEUS of the prostate in healthy neutered dogs, to provide quantitative measurements, and to study the influence of individual characteristics on prostatic regression. Twenty-three neutered dogs underwent a B-mode and CEUS examination of the prostate to acquire data about prostatic morphology and microcirculation. The prostate was imaged using a 5-7.5 MHz linear transducer and contrast was administered intravenously. Videoclips were analyzed by using Qontrast software and a postprocessing digital analysis tool (ImageJ) to measure perfusion peak intensity, time to peak, and vascularization ratio at the moment of the peak, which were then related to body weight, age, and time elapsed since orchiectomy. Correlation tests revealed higher vascularization in younger compared with older dogs (P < .05) and in smaller compared with larger dogs (P < .05). Time elapsed since orchiectomy (P > .05) did not affect prostatic perfusion. Contrast-enhanced ultrasound and the postprocessing analysis tool ImageJ allowed analysis of vascular perfusion in all dogs and have the potential to improve the diagnostic possibilities for andrological examination.

Extended septal myectomy for obstructive hypertrophic cardiomyopathy and its impact on mitral valve function.

AIMS: Septal myectomy is the treatment of choice for hypertrophic obstructive cardiomyopathy (HOCM). Around 30-60% of patients with HOCM have a secondary mitral valve regurgitation due to systolic anterior motion (SAM). We report our experience with extended septal myectomy and its impact on the incidence of concomitant mitral valve procedures. METHODS: This is a retrospective study on 84 patients who underwent SM from January 2008 to February 2022. Surgical procedure was performed according to the concept of 'extended myectomy' described by Messmer in 1994. Follow-up outcomes in terms of survival, hospital admissions for heart failure or MV disease, cardiac reoperations, and pacemaker (PMK) implantation were recorded. RESULTS: Mean age was 61 ±â€Š15 years. Mitral valve surgery was performed in seven cases (8%); particularly only one patient without degenerative mitral valve disease underwent mitral valve surgery, with a plicature of the posterior leaflet. In-hospital mortality was 5%. Mitral valve regurgitation greater than mild was present in four patients (5%) at discharge. Twelve-year survival was 78 ±â€Š22%. Cumulative incidence of rehospitalization for heart failure and rehospitalization for mitral valve disease was 10 ±â€Š4 and 2.5 ±â€Š2.5%, respectively. PMK implantation was 5% at discharge, with a cumulative incidence of 15 ±â€Š7%. Freedom from cardiac reoperations was 100%. CONCLUSION: Septal myectomy for HOCM is associated with good outcomes. Although concomitant surgery on the mitral valve to address SAM and associated regurgitation has been advocated, these procedures were needed in our practice only in patients with intrinsic mitral valve disease. Adequate myectomy addresses the underlying pathophysiology in most patients.

G Protein-Coupled Estrogen Receptor (GPER) and ERs Are Modulated in the Testis-Epididymal Complex in the Normal and Cryptorchid Dog.

There is growing evidence by the literature that the unbalance between androgens and estrogens is a relevant condition associated with a common canine reproductive disorder known as cryptorchidism. The role of estrogens in regulating testicular cell function and reproductive events is supposedly due to the wide expression of two nuclear estrogen receptors (ERs), ER-alpha and ER-beta and a trans-membrane G protein-coupled estrogen receptor (GPER) in the testis. In this study, immunohistochemistry, Western blotting and qRT-PCR were used to assess the distribution and expression of GPER in the testis-epididymal complex in the normal and cryptorchid dog. ER-alpha and ER-beta were also evaluated to better characterize the relative abundances of all three receptors. In addition, in these tissues, the expression level of two proteins as SOD1 and Nrf2 normally associated with oxidative stress was investigated to evaluate a possible relationship with ERs. Our data revealed changes in the distribution and expression of the GPER between the normal and cryptorchid dog. In particular, dogs affected by cryptorchidism showed an upregulation of GPER at level of the examined reproductive tract. Also considering the obtained result of a modulation of SOD1 and Nrf2 expression, we could hypothesize the involvement of GPER in the cryptorchid condition. Further studies are, however, necessary to characterize the role of GPER and its specific signaling mechanisms.

Evaluation of a Novel Automated Suturing Technology for Mitral Chordal Implantation: 1-Year Results.

PURPOSE: A new automated expanded polytetrafluoroethylene (ePTFE) suture placement device and a new customized titanium fastener deployment device were clinically evaluated in open and less-invasive mitral valve repair (MVr). DESCRIPTION: Twelve patients were monitored for 1 year after undergoing MVr using the study devices. The study end points included surgical outcomes, operative times, valve repair durability, adverse events, and mortality. EVALUATION: Three patients received 1 ePTFE chord using the study technology, and 9 patients received 2 chords. Mitral regurgitation at 30 days was absent in 8 patients, trace in 2, and mild in 2. At the 1-year follow-up, mitral regurgitation was absent in 7 patients, trace in 2, mild in 2, and moderate in 1. There were no replacement chord failures, reoperations, or death. CONCLUSIONS: The initial outcomes of new automated ePTFE suture placement and titanium fastener deployment devices encourage further clinical evaluations.

Features and outcomes of bailout repeat transcatheter aortic valve implantation (TAVI): the Bailout Acute TAVI-in-TAVI to Lessen Events (BATTLE) international registry.

AIM: Transcatheter aortic valve implantation (TAVI) is a mainstay in the management of severe aortic stenosis in patients with intermediate to prohibitive surgical risk. When a single TAVI device fails and cannot be retrieved, TAVI-in-TAVI must be performed acutely, but outcomes of bailout TAVI-in-TAVI have been incompletely appraised. We aimed at analyzing patient, procedural and outcome features of patients undergoing bailout TAVI-in-TAVI in a multicenter registry. METHODS: Details of patients undergoing bailout TAVI-in-TAVI, performed acutely or within 24 h of index TAVI, in 6 international high-volume institutions, were collected. For every case provided, 2 same-week consecutive controls (prior TAVI, and subsequent TAVI) were provided. Outcomes of interest were procedural and long-term events, including death, myocardial infarction, stroke, access site complication, major bleeding, and reintervention, and their composite (i.e. major adverse events [MAE]). RESULTS: A total of 106 patients undergoing bailout TAVI-in-TAVI were included, as well as 212 controls, for a total of 318 individuals. Bailout TAVI-in-TAVI was less common in younger patients, those with higher body mass index, or treated with Portico/Navitor or Sapien devices (all p < 0.05). Bailout TAVI-in-TAVI was associated with higher in-hospital rates of death, emergency surgery, MAE, and permanent pacemaker implantation (all p < 0.05). Long-term follow-up showed that bailout TAVI-in-TAVI was associated with higher rates of death and MAE (both < 0.05). Similar findings were obtained at adjusted analyses (all p < 0.05). However, censoring early events, outlook was not significantly different when comparing the two groups (p = 0.897 for death, and p = 0.645 for MAE). CONCLUSIONS: Bail-out TAVI-in-TAVI is associated with significant early and long-term mortality and morbidity. Thus, meticulous preprocedural planning and sophisticated intraprocedural techniques are of paramount importance to avoid these emergency procedures.

Tricuspid valve disease and cardiac implantable electronic devices.

The role of cardiac implantable electronic device (CIED)-related tricuspid regurgitation (TR) is increasingly recognized as an independent clinical entity. Hence, interventional TR treatment options continuously evolve, surgical risk assessment and peri-operative care improve the management of CIED-related TR, and the role of lead extraction is of high interest. Furthermore, novel surgical and interventional tricuspid valve treatment options are increasingly applied to patients suffering from TR associated with or related to CIEDs. This multidisciplinary review article developed with electrophysiologists, interventional cardiologists, imaging specialists, and cardiac surgeons aims to give an overview of the mechanisms of disease, diagnostics, and proposes treatment algorithms of patients suffering from TR associated with CIED lead(s) or leadless pacemakers.

Aortic Valve Replacement: Understanding Predictors for the Optimal Ministernotomy Approach.

INTRODUCTION: The most common minimally invasive approach for aortic valve replacement (AVR) is the partial upper mini-sternotomy. The aim of this study is to understand which preoperative computed tomography (CT) features are predictive of longer operations in terms of cardio-pulmonary bypass timesand cross-clamp times. METHODS: From 2011 to 2022, we retrospectively selected 246 patients which underwent isolated AVR and had a preoperative ECG-gated CT scan. On these patients, we analysed the baseline anthropometric characteristics and the following CT scan parameters: aortic annular dimensions, valve calcium score, ascending aorta length, ascending aorta inclination and aorta-sternum distance. RESULTS: We identified augmented body surface area (>1.9 m2), augmented annular diameter (>23 mm), high calcium score (>2500 Agatson score) and increased aorta-sternum distance (>30 mm) as independent predictors of elongated operation times (more than two-fold). CONCLUSIONS: Identifying the preoperative predictive factors of longer operations can help surgeons select cases suitable for minimally invasive approaches, especially in a teaching context.

Lymph Node Ratio as a Predictive Factor of Persistent/Recurrent Disease in Patients With Medullary Thyroid Cancer: A Single-Center Retrospective Study.

OBJECTIVE: Thyroidectomy with neck lymph node dissection is curative for most patients with medullary thyroid cancer (MTC). Lymph node ratio (LNR, ie, the ratio between the metastatic and the removed lymph nodes) is a reliable parameter with which to estimate both disease extent and quality of neck dissection. The aim of this study was to investigate the prognostic role of LNR to predict persistent/recurrent disease in patients with MTC. METHODS: A single-center, retrospective study of a consecutive cohort of 95 patients with MTC treated with total thyroidectomy and neck dissection. Receiver operating characteristics curve analysis was performed to identify the LNR cut-off. RESULTS: LNR was positively associated with tumor size, preoperative and postoperative calcitonin values, postsurgery carcinoembryonic antigen values, persistent/recurrent disease, and the occurrence of distant metastases during follow-up. At multivariate analysis, persistent/recurrent disease was independently associated with the LNR value and was accurately predicted by a cut-off value of 0.12 (area under the curve = 0.85). Indeed, patients with LNR ≥0.12 had a higher probability of developing persistent/recurrent disease (79.3% vs 10.6%, odds ratio = 32.3, 95% CI = 9.8-106.4; P < .001) and distant metastasis (34.5% vs 3.0%, odds ratio = 16.8, 95% CI = 3.4-83.6; P < .001) than patients with LNR <0.12. The median time to progression was 15 months in patients with LNR ≥0.12 whereas it was not reached in patients with LNR <0.12 (hazard ratio: 7.18, 95% CI = 3.01-17.11, P < .001). CONCLUSIONS: LNR is a reliable prognostic factor to predict the risk of recurrence, persistence, and distant metastases in patients with MTC.

Panoramic on Epigenetics in Coronary Artery Disease and the Approach of Personalized Medicine.

Epigenetic modifications play a fundamental role in the progression of coronary artery disease (CAD). This panoramic review aims to provide an overview of the current understanding of the epigenetic mechanisms involved in CAD pathogenesis and highlights the potential implications for personalized medicine approaches. Epigenetics is the study of heritable changes that do not influence alterations in the DNA sequence of the genome. It has been shown that epigenetic processes, including DNA/histone methylation, acetylation, and phosphorylation, play an important role. Additionally, miRNAs, lncRNAs, and circRNAs are also involved in epigenetics, regulating gene expression patterns in response to various environmental factors and lifestyle choices. In the context of CAD, epigenetic alterations contribute to the dysregulation of genes involved in inflammation, oxidative stress, lipid metabolism, and vascular function. These epigenetic changes can occur during early developmental stages and persist throughout life, predisposing individuals to an increased risk of CAD. Furthermore, in recent years, the concept of personalized medicine has gained significant attention. Personalized medicine aims to tailor medical interventions based on an individual's unique genetic, epigenetic, environmental, and lifestyle factors. In the context of CAD, understanding the interplay between genetic variants and epigenetic modifications holds promise for the development of more precise diagnostic tools, risk stratification models, and targeted therapies. This review summarizes the current knowledge of epigenetic mechanisms in CAD and discusses the fundamental principles of personalized medicine.

Eosinophilic myocarditis: from etiology to diagnostics and therapy.

Eosinophilic myocarditis (EM) is a rare, potentially life-threatening, form of inflammatory heart disease characterized by eosinophilic infiltration of the myocardium. Different diseases are involved in its etiopathogeneses, such as eosinophilic granulomatosis with polyangiitis (or Churg-Strauss Syndrome), hypereosinophilic syndromes, parasitic infections, drug reactions, paraneoplastic syndromes and primary immunodeficiencies (e.g. Omenn Syndrome). There is a wide spectrum of clinical pictures at presentation ranging from chronic restrictive cardiomyopathy (Loeffler cardiomyopathy) to acute necrotizing myocarditis with cardiogenic shock. The genetic contribution and the environmental interplay, such as SARS-CoV-2 infection and related vaccines, are fields not well studied yet. Many non-invasive tools, mainly echocardiography and cardiac magnetic resonance imaging, along with invasive procedures, such as endomyocardial biopsy, are the crucial steps in the diagnostic workup. The correct diagnosis is a challenge but mandatory for timely and appropriate immunosuppressive therapy.

Interesterification of Glyceryl Trioctanoate Catalyzed by Sulfonic Silica-Based Materials: Insight into the Role of Catalysts on the Reaction Mechanism.

In the present work, the acid-catalyzed interesterification of glyceryl trioctanoate (GTO) with ethyl acetate was investigated as a model reaction for the one-step production of biofuel and its additives. The activity of heterogeneous acid catalysts, such as silica-based propyl-sulfonic ones, was evaluated. Propyl-sulfonic groups were grafted on both amorphous and mesoporous silica oxide (SBA-15, KIT-6) using different functionalization processes and characterized by N2 adsorpion-desorption isotherm (BET), thermogravimetric analysis (TGA), scanning electron microscopy (SEM), attenuated total reflectance-Fourier transform infrared (ATR-FTIR) spectroscopy, and potentiometric titration. During the optimization of the reaction conditions with the most active catalyst (Am-Pr-SO3H), it was shown that the addition of ethanol allowed a total conversion of GTO together with 89% and 56% yield of ethyl octanoate and triacetin, respectively. The catalytic performance is strictly correlated to the catalyst features, in terms of both the acid capacity and the porous structure. Moreover, the catalytic performance is also affected by a synergistic mechanism between silanols and Pr-SO3H groups towards the 'silanolysis' of ethyl acetate. The overall results show that the presence of ethanol, the reaction time, and the amount of catalyst shifts the reaction towards the formation of the biofuel mixture composed by ethyl octanoate and triacetin.

Hyperacute Sapien Aortic Valve thrombosis in a patient with Antiphospholipid Syndrome (APS).

In this case we briefly describe the case of an old woman presenting with acute exertional dyspnea due to hyperacute Sapien Valve thrombosis.

Canine prostatic serum esterase and strain and 2D-shear wave sonoelastography for evaluation of normal prostate in dogs: Preliminary results.

Canine prostatic serum esterase (CPSE) is considered a useful tool to identify prostate disorders in dogs, with increasing interest in ultrasound (US)-based sonoelastography to non-invasively detect prostate disorders. Since no report is available about a possible correlation between these diagnostic tools, we aimed to investigate a possible correlation between strain elastography (SE) and 2D-shear wave elastography (SWE) and CPSE. Twenty-one dogs were included and, on each animal, CPSE was evaluated followed by a complete US examination and SE and 2D-SWE application. Healthy dogs were identified based on the CPSE results. All the dogs included were characterized by normal CPSE values (<52.3 ng/mL) and normal US prostate appearance. The prostate was characterized by intermediate stiffness with SE (pattern III - 84.7% for the left lobe and 79.27% for the right lobe) and softer than the abdominal wall (SR 0.6 for the left lobe and 0.56 for the right lobe), with low values for both m/s and kilopascals (kPa) for 2D-SWE, pointing that the healthy tissue is not hard. 2D-SWE results were, respectively, 13.51 ± 5.55 kPa and 2.31 ± 0.42 m/s for the left lobe and 18.05 ± 6.47 kPa and 2.39 ± 0.43 m/s for the right lobe. The significant difference between the right and left measurements expressed with kPa, not evidenced with m/s, can be considered indicative of m/s as the most reliable measurement to be considered regarding the prostate parenchyma. Even though no linear correlation was detected between CPSE and elastography values, these preliminary results evidence that the healthy prostates were characterized by a similar elastographic pattern, thus pointing that these techniques can be potentially useful to be applied in case of prostatic disorders to improve the accuracy of the final diagnosis in a non-invasive way.

Incorporation of Testicular Ultrasonography and Hair Steroid Concentrations in Bull Breeding Soundness Evaluation.

Testicular ultrasonography and steroid concentrations (cortisol, dehydroepiandrosterone sulfate (DHEA-S), cortisol/DHEA-S ratio, testosterone) in hair were examined for their utility in the bull breeding soundness evaluation (BBSE). Beef and dairy bulls (n = 16; 2.7 ± 0.4 years old; body condition score 3.2 ± 0.1) of five breeds were maintained under the same conditions at an accredited semen collection center. Bulls underwent routine semen collection twice weekly for 12 weeks and semen was processed and cryopreserved. Ultrasonography and hair sampling were undertaken at the last semen collection. Bulls with homogeneous testicular parenchyma (n = 8) had a higher (p < 0.05) percentage of motile sperm post-thawing compared with bulls with heterogeneous parenchyma (n = 8). There were no differences (p > 0.05) in the hair concentrations of cortisol, DHEA-S, and testosterone between bulls with homogeneous and heterogeneous parenchyma. In bulls with homogeneous parenchyma, hair DHEA-S concentration was positively correlated with percentage motile sperm (R2 = 0.76), progressively motile sperm (R2 = 0.70), and motility yield (R2 = 0.71). The findings indicate that the integration of testicular ultrasonography and hair DHEA-S status in the BBSE could provide a more comprehensive assessment of indicative fertility in bulls. Additionally, ultrasonography can be used in the BBSE when the evaluation of semen parameters is not available.

Hypersensitivity reactions to anti-SARS-CoV-2 vaccines: Basophil reactivity to excipients.

Basophil activation test (BAT) can tackle multiple mechanisms underlying acute and delayed hypersensitivity to drugs and vaccines and might complement conventional allergy diagnostics but its role in anti-severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) vaccine-related hypersensitivity is ill-defined. Therefore, 89 patients with possible hypersensitivity (56 % with delayed mucocutaneous manifestations) to anti-SARS-CoV-2 vaccines were tested with BAT for Macrogol 3350, DMG-PEG 2000, PEG 20000, polysorbate-80 and trometamol and compared to 156 subjects undergoing pre-vaccine BAT. A positive BAT was associated with delayed reaction onset (p = 0.010) and resolution (p = 0.011). BAT was more frequently positive to DMG-PEG 2000 than to other excipients in both groups (p < 0.001). DMG-PEG 2000 reactivity was less frequent in vaccine-naïve (6 %) than vaccinated subjects (35 %, p < 0.001) and associated with mRNA-1273 vaccination. DMG-PEG 2000 BAT might therefore have a diagnostic role in subjects with delayed hypersensitivity reactions. Natural immunity might be a key player in basophil activation.

Treatment of a subcutaneous tibialis anterior tendon rupture with a semitendinosus autograft.

The subcutaneous rupture of the tibialis anterior tendon is a rare and silent lesion which can lead to foot and ankle dysfunction with gait difficulty. The treatment can be either conservative or surgical. Conservative management is reserved for inactive patients and those with a general or local contraindication to surgery, whereas surgical repair includes direct and rotational suture, as well as tendon transfer and auto- or allograft. The choice of surgical treatment is based on multiple factors, including the symptoms, the timespan from injury to treatment, the anatomopathological pattern of the lesion, and the patient's age and level of activity. Large defects present a particular reconstructive challenge, and there is no consensus on the optimal method of treatment. That being said, one of the options is an autograft using the semitendinosus hamstring tendon. We present a case of a 69-year-old woman who sustained a hyperflexion trauma to her left ankle. Three months later, ultrasound examination and a magnetic resonance imaging showed a complete tibialis anterior rupture with a gap of more than 10 cm. The patient was successfully treated with surgical repair. An autograft of the semitendinosus tendon was used to bridge the gap. The tibialis anterior rupture is a rare lesion that must be promptly diagnosed and treated, especially in physically active patients. Large defects pose particular challenges. Surgical management was found to be the treatment of choice. In the case of a lesion with a major gap, semitendinosus grafting can be successfully employed.

Developmental and epileptic encephalopathy in a young Italian woman with a de novo missense variant in the CLCN4 gene: A case report.

INTRODUCTION: Raynaud-Claes syndrome is a very rare X-linked condition, characterized by intellectual disability, impaired language development, brain abnormalities, facial dysmorphisms and drug-resistant epilepsy. It is caused by loss-of-function variants in the CLCN4 gene, which encodes the 2Cl-/H + exchanger ClC-4, prominently expressed in the hippocampus and cerebellum. Different genotypic variants have been described, each exhibiting specific phenotypic characteristics. The loss-of-function variant p.Gly544Arg in the CLCN4 gene has been described in only two male probands, but there are no reports on phenotypic characterization in females. CASE PRESENTATION: We present a 30-year-old Italian woman with early-onset drug-resistant epilepsy, developmental and epileptic encephalopathy, developmental delay, absence of verbal language development, behavioral impairment with autistic features, and clusters of seizures during catamenial periods. The interictal EEG showed slight inconstant slowing of the background rhythm, with abnormal frontal predominant mu like rhythm and generalized spike and polyspike wave discharges, which increased in frequency during drowsiness. A brain MRI showed slight cranio-encephalic asymmetry and a smaller size of the left hippocampus. The whole exome sequencing (WES) revealed a de novo heterozygous c.1630G > A variant in the CLCN4 gene, resulting in the amino acid substitution p.Gly544Arg (rs587777161), consistent with Raynaud-Claes syndrome. DISCUSSION AND CONCLUSION: Our patient is the first case of a de novo p.Gly544Arg variant of the CLCN4 gene in a female proband, confirming that female patients with Raynaud-Claes syndrome can be as severely affected as the male counterparts. Our case expands the phenotypic characterization of different genotypic CLCN4 variants, which can become crucial in the future for early diagnosis if targeted therapy becomes available.

Can artificial intelligence simplify the screening of muscle mass loss?

Background: Sarcopenia is a risk factor for morbidity and preventable mortality in old age, with consequent high costs for the national health system. Its diagnosis requires costly radiological examinations, such as the DEXA, which complicate screening in medical centers with a high prevalence of sarcopenia. Objectives: Developing a nearly zero-cost screening tool to emulate the performance of DEXA in identifying patients with muscle mass loss. This can crucially help the early diagnosis of sarcopenia at large-scale, contributing to reduce its prevalence and related complications with timely treatments. Methods: We exploit cross-sectional data for about 14,500 patients and 38 non-laboratory variables from successive NHANES over 7 years (1999-2006). Data are analyzed through a state-of-the-art artificial intelligence approach based on decision trees. Results: A reduced number of anthropometric parameters allows to predict the outcome of DEXA with AUC between 0.92 and 0.94. The most complex model derived in this paper exploits 6 variables, related to the circumference of key corporal segments and to the evaluation of body fat. It achieves an optimal trade-off sensitivity of 0.89 and a specificity of 0.82. Restricting exclusively to variables related to lower limb, we obtain an even simpler tool with only slightly lower accuracy (AUC 0.88-0.90). Conclusions: Anthropometric data seem to contain the entire informative content of a more complex set of non-laboratory variables, including anamnestic and/or morbidity factors. Compared to previously published screening tools for muscle mass loss, the newly developed models are less complex and achieve a better accuracy. The new results might suggest a possible inversion of the standard diagnostic algorithm of sarcopenia. We conjecture a new diagnostic scheme, which requires a dedicated clinical validation that goes beyond the scope of the present study.