Insight into the Relationship Between Motor and Cognitive Symptoms in Essential Tremor.

Essential tremor (ET) is a heterogeneous disorder characterized by bilateral upper limbs action tremor and, possibly, neurological signs of uncertain significance, including voluntary movement abnormalities and cognitive disturbances, i.e., the so-called 'soft' signs configuring the ET-plus definition. While motor and cognitive disturbances often coexist in ET, their interrelationship remains largely unexplored. Here we aim to further investigate the relationship between motor symptoms, objectively assessed through kinematic analysis, and cognitive dysfunctions in ET. Seventy ET patients underwent clinical examination, as well as kinematic recordings of tremor and finger tapping and a thorough cognitive assessment. We then tested clinic-demographic and kinematic differences between patients with and without cognitive abnormalities, i.e., with mild cognitive impairment (MCI). Correlation analysis served to explore potential associations between kinematic and cognitive data. Forty-three ET patients (61.42%) had MCI. ET-MCI patients exhibited reduced movement velocity during finger tapping compared to those with normal cognition (p < 0.001). Lower movement velocity during finger tapping was associated with poorer cognitive performance. Namely, we observed a correlation between movement velocity and performance on the Babcock Story Immediate and Delayed Recall Test (r = 0.52 and r = 0.45, both p < 0.001), as well as the interference memory task at 10 and 30 s (r = 0.3, p = 0.008 and r = 0.2, p = 0.03). In this study, we have provided data for a better pathophysiological interpretation of motor and cognitive signs in ET, including the role played by the cerebellum or extra-cerebellar areas, which possibly underpin both signs.

A randomized clinical trial assessing theranostic-guided corneal cross-linking for treating keratoconus: the ARGO protocol.

The Assessment of theranostic guided riboflavin/UV-A corneal cross-linking for treatment of keratoconus (ARGO; registration number NCT05457647) clinical trial tests the hypothesis that theranostic-guided riboflavin/UV-A corneal cross-linking (CXL) can provide predictable clinical efficacy for halting keratoconus progression, regardless of treatment protocol, i.e., either with or without epithelial removal. Theranostics is an emerging therapeutic paradigm of personalized and precision medicine that enables real-time monitoring of image-guided therapy. In this trial, the theranostic software module of a novel UV-A medical device will be validated in order to confirm its accuracy in estimating corneal cross-linking efficacy in real time. During CXL procedure, the theranostic UV-A medical device will provide the operator with an imaging biomarker, i.e., the theranostic score, which is calculated by non-invasive measurement of corneal riboflavin concentration and its UV-A light mediated photo-degradation. ARGO is a randomized multicenter clinical trial in patients aged between 18 and 40 years with progressive keratoconus aiming to validate the theranostic score by assessing the change of the maximum keratometry point value at 1-year postoperatively. A total of 50 participants will be stratified with allocation ratio 1:1 using a computer-generated stratification plan with blocks in two treatment protocols, such as epithelium-off or epithelium-on CXL. Following treatment, participants will be monitored for 12 months. Assessment of safety and performance of theranostic-guided corneal cross-linking treatment modality will be determined objectively by corneal tomography, corneal endothelial microscopy, visual acuity testing and slit-lamp eye examination.

Use of Extracorporeal Membrane Oxygenation in Acutely Poisoned Pediatric Patients in United States: A Retrospective Analysis of the Extracorporeal Life Support Registry From 2003 to 2019.

OBJECTIVES: To describe the use of extracorporeal membrane oxygenation (ECMO) in the management of pediatric poisoning in the United States and to identify predictors of mortality. DESIGN: Retrospective cohort study. SETTING: Data reported to the Extracorporeal Life Support Organization by 76 U.S. ECMO centers from 2003 to 2019. PATIENTS: Pediatric patients (0-18 yr) receiving ECMO for poisoning. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: During our study period, 86 cases of acute poisoning were identified and included in the analysis. The median age was 12.0 year and 52.9% were female. The most commonly reported substance exposures were hydrocarbon (n = 17; 19.8%), followed by chemical asphyxiants (n = 14; 16.3%), neuroactive agents (n = 14; 16.3%), opioid/analgesics (n = 13; 15.1%), and cardiovascular agents (n = 12; 14.0%). Single substance exposures were reported in 83.7% of the cases. The intention of the exposure was unknown in 65.1%, self-harm in 20.9% and 10.5% was unintentional exposure. Fifty-six patients (65.1%) survived. Venoarterial ECMO was used more frequently than venovenous ECMO, and its use increased significantly during the study period (p < 0.01). A bimodal distribution of ECMO support was observed among two age groups: less than or equal to 3 years (n = 34) and 13-17 years (n = 41). Hemodynamic and metabolic parameters improved for all patients with ECMO. Persistent systolic hypotension, acidemia/metabolic acidosis, and elevated Pao2) after 24 hours of ECMO support were associated with mortality. Time from PICU admission to ECMO cannulation was not significantly different between survivors (24.0 hr; interquartile range [IQR], 11.0-58.0 hr) and nonsurvivors (30.5 hr; IQR, 10.0-60.2 hr; p = 0.58). ECMO duration and PICU length of stay were significantly longer in survivors than in nonsurvivors (139.5 vs 70.5 hr; p = 0.007 and 25.0 vs 4.0 d; p = 0.002, respectively). CONCLUSIONS: ECMO may improve the hemodynamic and metabolic status of poisoned pediatric patients. Persistent hypotension, acidemia/acidosis, and elevated Pao2 after 24 hours of ECMO were associated with mortality.

Estimated glomerular filtration rate is a marker of mortality in the European Scleroderma Trials and Research Group (EUSTAR) database.

OBJECTIVES: The study aim was to evaluate the estimated glomerular filtration rate (eGFR), its association with clinical disease and its predictive ability with respect to mortality in SSc patients from the European Scleroderma Trials and Research Group (EUSTAR) database. METHODS: SSc patients from the EUSTAR database who had items required for the calculation of eGFR at a baseline visit and a second follow-up visit available were included. A cut-off eGFR value of 60 ml/min was chosen for all SSc patients, and 30 ml/min for those with scleroderma renal crisis (SRC). Cox regression and competing risk analysis were performed to evaluate the use of eGFR as a predictive factor of mortality. RESULTS: A total of 3650 SSc patients were included in this study. The median serum level of creatinine and the mean of eGFR were 0.8 mg/dl (interquartile range = 0.6-0.9) and 86.6 ± 23.7 ml/min, respectively. The eGFR was significantly lower in patients with pulmonary hypertension. Overall survival (OS) was significantly reduced in SSc patients with eGFR < 60 ml/min compared with patients with eGFR ≥ 60 ml/min [OS at 5 years 0.763 (95% CI: 0.700, 0.814) vs 0.903 (95% CI: 0.883, 0.919; P < 0.001)]. In multivariable analysis, OS was associated with male gender (P < 0.01), systolic pulmonary arterial pressure (sPAP) (P < 0.001) and eGFR (P < 0.001). The cumulative incidence of deaths due to SSc was associated with increased sPAP (P < 0.001) and reduced eGFR (P < 0.05). The OS at 5 years of 53 SRC patients was not significantly different between SSc patients with eGFR > 30 ml/min and those with eGFR <30 ml/min. CONCLUSION: eGFR represents a predictive risk factor for overall survival in SSc. The eGFR, however, does not represent a risk factor for death in SRC.

Diagnostic Value of Persistently Low Positive TGA-IgA Titers in Symptomatic Children With Suspected Celiac Disease.

OBJECTIVES: While the algorithm to diagnose celiac disease (CD) in children with elevated anti-transglutaminase IgA (TGA-IgA) titers (>10 times upper limit of normal, ULN) is well defined, the management of children with low TGA-IgA values represents a clinical challenge. We aimed to identify the diagnostic value of persistently low positive TGA-IgA titers in predicting CD in children. METHODS: We retrospectively analyzed children with symptoms or signs of CD, not eligible for a no-biopsy approach. We included children with at least 2 TGA-IgA measurements, endomysial antibody (EMA) assessment and esophagogastroduodenoscopy with biopsies. TGA-IgA values were provided as multiples of ULN. Patients were classified in groups according to median TGA-IgA values: A (TGA-IgA>1 ≤ 5 × ULN; defined as "low-positive"), B (TGA-IgA > 5 < 10 × ULN; "moderate-positive"), and C (controls). RESULTS: Data of 281 children were analyzed. Of 162 children in group A, CD was diagnosed in 142 (87.7%), whereas normal duodenal mucosa was found in 20. In group B, all 62 children (100%) received a CD diagnosis. Group C included 57 controls. EMA were undetectable in 31 (15%) of mucosal atrophy cases. On the receiver-operating characteristic curve (area under the curve = 0.910), a mean value of 1.7 ULN showed a sensitivity of 81.4% and specificity of 81.8% to predict mucosal damage. CONCLUSIONS: Repeated low or moderate TGA-IgA values (<5 ULN or <10 ULN) are good predictors of a CD diagnosis. Symptomatic children with persistently low positive TGA-IgA titers should undergo esophagogastroduodenoscopy regardless of their EMA status.

Unilateral Condylar Hyperplasia: A Comparison With Two Open-Source Softwares.

Unilateral condylar hyperplasia (UCH) is a condyle disorder that arises due to osteoblastic hyperactivity, resulting in facial asymmetry, malocclusion and dysfunction. Authors, in this retrospective study, compared "gold standard" manual-segmentation with a "semi-manual one" using 2 kinds of open-source software (Horos and ITK-SNAP; Penn Image Computing and Science Laboratory) to calculate volume of 80 UCH condyles (40 patients). Moreover, volumetric differences between affected condyle and unaffected 1, between males and females, ages, and classification type were also analyzed. Fifteen patients (37.5%) were male and 25 (62.5%) were female. The gender ratio was 5:2, not far from the ratio 2:1 shown in literature. The mean age was 24 (SD 8.6) years; 22.9 (SD 6.6) for males and 24.6 (SD 9.6) for females according with the mean age derived from the Raijmakers et al meta-analysis and the Nitzan et al study. Right side (60%, 24 patients) was more often affected than the left side (40%, 16 patients). The 67.5% (27 patients) were classified as trasversal type, 25% (10 patients) as vertical types and 7.5% (3 patients) as combined. Despite Horos and ITK-SNAP values presenting some differences, the data follows the same tendency. The relationship is stronger for healthy condyles than affected condyles.

Tremor Distribution and the Variable Clinical Presentation of Essential Tremor.

In addition to having postural and kinetic tremor of the upper limbs, some patients with essential tremor (ET) may have head tremor as well as cognitive and psychiatric disorders. We aimed to investigate whether the variable clinical presentation in ET patients, including motor and non-motor symptoms, differs in patients with and without head tremor. We consecutively enrolled 70 patients with a diagnosis of ET. Tremor severity was assessed by means of clinical rating scales. Patients also underwent kinematic recordings of postural and kinetic tremor of the upper limbs based on an optoelectronic system. Several neuropsychological tests were also administered. Finally, we adopted the structured interviews for DSM-IV, SCID-I, and SCID-II to investigate psychiatric and personality disorders. ET patients with upper limb tremor plus head tremor exhibited more severe kinetic tremor of the upper limbs and a higher occurrence of axis I psychiatric disorders than ET patients with upper limb tremor only. Cognitive and other motor and psychiatric features did not differ significantly with respect to tremor distribution. The study findings support the hypothesis that body tremor distribution, i.e., the presence of head tremor, influences the variable clinical presentation of ET. The study results support the notion that cases with head tremor may represent a distinct ET subtype, characterized by a prominent cerebellar involvement, and that psychiatric disorders should be considered as a specific manifestation of ET.

Identification of predictive factors for overall survival at baseline and during azacitidine treatment in high-risk myelodysplastic syndrome patients treated in the clinical practice.

The outcome of high-risk myelodysplastic syndrome (MDS) patients treated with 5-azacitidine (5-AZA) in the real-life setting remains largely unknown. We evaluated 110 MDS patients (IPSS intermediate 2/high) treated outside of clinical trials at a single institution between September 2003 and January 2017. Median duration of therapy was 9.5 cycles. The overall survival (OS) of the whole cohort was 66.1% at 1 year and 38.3% at 2 years. No differences in terms of OS were observed with regard to gender (p = 0.622) and age at baseline (< 65 years, 65-75, and > 75 years, p = 0.075). According to the IPSS-R, the very high-risk group had an inferior 2-year OS (17%) compared with intermediate-group patients (64%, p < 0.001). Transfusion independency at baseline was identified as a favorable prognostic factor on 1-year (66.8%) and 2-year OS (43.4%) (p < 0.001). After four cycles, the persistence of bone marrow blasts > 10% identified patients with a worse outcome, with a 2-year OS of 9.4% (p = 0.002). The occurrence of an infection during the first four cycles impacted on the 2-year OS (31.6% vs 58.3% in patients without infections, p = 0.032). Patients receiving at least 24 cycles of the drug have a 5-year OS of 38.2%. This analysis allowed to identify features at baseline or during treatment with 5-AZA associated with a different 2-year OS.

Ten-year outcome of chronic-phase chronic myeloid leukemia patients treated with imatinib in real life.

Imatinib, the first BCR/ABL kinase inhibitor approved for the treatment of chronic myeloid leukemia (CML), has changed the long-term outcome of patients affected by this disease. The aim of our analysis was to report, after a median follow-up of 10.2 years (range 5.8-14.8), the long-term outcome, efficacy, and safety of imatinib treatment (frontline and after interferon failure) in a single institution cohort of 459 patients with CML in chronic phase treated outside of clinical trials. The 10-year overall survival of the whole cohort was 77.1%, while the 10-year probability of dying due to CML and other causes was 7.8% and 16%, respectively. The prognostic value of the BCR-ABL1 ratio at 3 months (⩽ 10%) and of complete cytogenetic response and major molecular response at 1 year was confirmed also in the real-life practice. The EUTOS long-term survival score better stratified the baseline risk of dying of CML compared with other risk scores. Two hundred thirty-six (51.4%) patients achieved a deep molecular response during imatinib treatment after a median time of 4.57 years, and 95 (20.6%) had a stable deep molecular response maintained for at least 2 consecutive years. Imatinib was associated with a low rate of serious cardiovascular events and second neoplasia. This 10-year real-life follow-up study shows that imatinib maintains efficacy over time and that long-term administration of imatinib is not associated with notable cumulative or late toxic effects.

Neurophysiological correlates of bradykinesia in Parkinson's disease.

Many neurophysiological abnormalities have been described in the primary motor cortex of patients with Parkinson's disease. However, it is unclear whether there is any relationship between them and bradykinesia, one of the cardinal motor features of the condition. In the present study we aimed to investigate whether objective measures of bradykinesia in Parkinson's disease have any relationship with neurophysiological measures in primary motor cortex as assessed by means of transcranial magnetic stimulation techniques. Twenty-two patients with Parkinson's disease and 18 healthy subjects were enrolled. Objective measurements of repetitive finger tapping (amplitude, speed and decrement) were obtained using a motion analysis system. The excitability of primary motor cortex was assessed by recording the input/output curve of the motor-evoked potentials and using a conditioning-test paradigm for the assessment of short-interval intracortical inhibition and facilitation. Plasticity-like mechanisms in primary motor cortex were indexed according to the amplitude changes in motor-evoked potentials after the paired associative stimulation protocol. Patients were assessed in two sessions, i.e. OFF and ON medication. A canonical correlation analysis was used to test for relationships between the kinematic and neurophysiological variables. Patients with Parkinson's disease tapped more slowly and with smaller amplitude than normal, and displayed decrement as tapping progressed. They also had steeper input/output curves, reduced short-interval intracortical inhibition and a reduced response to the paired associative stimulation protocol. Within the patient group, bradykinesia features correlated with the slope of the input/output curve and the after-effects of the paired associative stimulation protocol. Although dopaminergic therapy improved movement kinematics as well as neurophysiological measures, there was no relationship between them. In conclusion, neurophysiological changes in primary motor cortex relate to bradykinesia in patients with Parkinson's disease, although other mechanisms sensitive to dopamine levels must also play a role.

Ultrasound as a new tool in the assessment of airway difficulties: An observational study.

BACKGROUND: Prediction of difficult mask ventilation (DMV) is as challenging as difficult laryngoscopy. Ultrasound could be a helpful tool in the prediction of these difficulties. OBJECTIVES: The purpose of this study was to evaluate the ability of pre-operative ultrasound assessment of neck anatomy in predicting DMV and difficult laryngoscopy in patients undergoing during elective surgery requiring tracheal intubation. DESIGN: Prospective, single blind, observational study. SETTING: Operating theatre of a teaching hospital in Italy from April 2018 to July 2018. PATIENTS: A total of 194 patients aged more than 18 years, without neck masses, previous thyroid surgery or tracheotomy undergoing general anaesthesia and tracheal intubation for elective ear, nose and throat-surgery were included in the study. OUTCOME MEASURES: Ultrasound distances were recorded with a linear 6 to 13 MHz ultrasound transducer: measurements included the minimum distance from the thyroid isthmus to skin surface, the minimum distance from the hyoid bone to skin surface (DSHB), the minimum distance from skin to anterior commissure of the vocal cords, the minimum distance from skin to trachea at the level of the jugular notch and the distance from skin to epiglottis midway. The degree of DMV and difficult laryngoscopy was quantified. RESULTS: The mean (SD) of DSHB was 0.88 (0.3) cm in the easy mask ventilation group, 1.4 (0.19) cm in DMV group. The mean of DSHB and of the other ultrasound distances increased according to the DMV and difficult laryngoscopy level. The DSHB was correlated with an increase in the risk for DMV (0.61 [IQR 0.5 to 0.69]). DMV groups were associated with a greater ultrasound-measured DSHB. CONCLUSION: The prospective observational study confirms the relationship between ultrasound assessment of the anterior soft tissues of the neck and difficult laryngoscopy and DMV. DSHB and the other distances extend the available evidence, not only for difficult laryngoscopy but also for DMV. TRIAL REGISTRATION: Clinicaltrials.gov. identified NCT03592758.

The Prevalence of Multiple Sclerosis in the Metropolitan Area of Rome: A Capture-Recapture Analysis.

BACKGROUND: Limited data are available on the prevalence of multiple sclerosis (MS) in central Italy. The objective of this study is to estimate MS prevalence in the metropolitan area of Rome. METHODS: We used the capture-recapture method to calculate prevalence estimates in the study area. The selected prevalence day was December 31, 2015. A total of 1,007 patients, with a definite diagnosis of MS according to the revised McDonald's criteria, were considered for crude, age- and sex-specific prevalence estimation. RESULTS: The overall crude prevalence rate was 146.2 cases per 100,000 (95% CI 119.9-172.5). A higher prevalence rate was recorded in females (194.1, 95% CI 149.6-238.6) than in males (93.0, 95% CI 67.2-118.8) with a female to male ratio of 1.8. Age-specific prevalence peaked in the 25-34 , 35-44 and 45-54 years class; moreover, it was found to increase up to the 45-54 years age group in females and the 35-44 years age group in males, decreasing thereafter. CONCLUSION: The results confirm that the metropolitan area of Rome is a high-risk area for MS.

Flexible behavioral capture-recapture modeling.

We develop alternative strategies for building and fitting parametric capture-recapture models for closed populations which can be used to address a better understanding of behavioral patterns. In the perspective of transition models, we first rely on a conditional probability parameterization. A large subset of standard capture-recapture models can be regarded as a suitable partitioning in equivalence classes of the full set of conditional probability parameters. We exploit a regression approach combined with the use of new suitable summaries of the conditioning binary partial capture histories as a device for enlarging the scope of behavioral models and also exploring the range of all possible partitions. We show how one can easily find unconditional MLE of such models within a generalized linear model framework. We illustrate the potential of our approach with the analysis of some known datasets and a simulation study.

On the design of closed recapture experiments.

We propose a method to plan the number of occasions of recapture experiments for population size estimation. We do so by fixing the smallest number of capture occasions so that the expected length of the profile confidence interval is less than or equal to a fixed threshold. In some cases, we solve the optimization problem in closed form. For more complex models we use numerical optimization. We detail models assuming homogeneous, time-varying, subject-specific capture probabilities, behavioral response to capture, and combining behavioral response with subject-specific effects. The principle we propose can be extended to plan any other model specification. We formally show the validity of the approach by proving distributional convergence. We illustrate with simulations and challenging examples in epidemiology and ecology. We report that in many cases adding as few as two sampling occasions may substantially reduce the length of confidence intervals.

Estimated prevalence of keratoconus in the largest metropolitan area of Italy.

PURPOSE: To estimate the prevalence of keratoconus in a population of subjects undergoing first eye examination in an eye clinic in Italy. METHODS: A single-center, cross-sectional, study was conducted involving patients who underwent first eye examination at an eye clinic in Rome between September 2021 and June 2022. The prevalence of keratoconus was determined by Placido-disk corneal topography using the maximum keratometry (Kmax) value and the Cone Magnitude and Location Index (CLMI) for keratoconus screening. Subjective analysis was performed by two experienced corneal specialists, who classified the outcome into two groups: normal and keratoconus. Risk factors, including family history of keratoconus, allergy or atopy, thyroid disease, eye rubbing habit and gender were also examined. RESULTS: A total of 512 subjects between 7 and 81 years old were evaluated. The inter-observer agreement to classify subjects in normal or keratoconus group was excellent (k = 1.0); the estimated prevalence in the specific population was 2.1%. Presence of positive family history (9% of keratoconus vs 5% normal), concomitant allergy or atopy (27% vs 9%) and eye rubbing habit (18% vs 4%) were associated with a higher risk of disease. CONCLUSION: This study reported a high estimated prevalence of keratoconus in a metropolitan area of Italy, as found in recent studies in the Mediterranean and Middle East countries. Screening for keratoconus is highly recommendable and easily feasible with corneal topography under expert supervision and may be indicated primarily in young population to improve early detection and prompt therapeutic management for halting disease progression.

Accuracy of an Air-Puff Dynamic Tonometry Biomarker to Discriminate the Corneal Biomechanical Response in Patients With Keratoconus.

PURPOSE: The aim of this study was to assess accuracy of the mean corneal stiffness ( kc , N/m) parameter to discriminate between patients with keratoconus and age-matched healthy subjects. METHODS: Dynamic Scheimpflug imaging tonometry was performed with Corvis ST (Oculus Optikgeräte GmbH, Germany) in patients with keratoconus (n = 24; study group) and age-matched healthy subjects (n = 32; control). An image processing algorithm was developed to analyze the video sequence of the Corvis ST air-puff event and to determine the geometric and temporal parameters that correlated with the corneal tissue biomechanical properties. A modified 3-element viscoelastic model was used to derive the kc parameter, which represented the corneal tissue resistance to deformation under load. Receiver operating characteristic curves were used to assess the overall diagnostic performance for determining the area under the curve, sensitivity, and specificity of the kc in assessing the corneal tissue deformation to the Corvis ST air-puff event in keratoconus and control eyes. The Corvis Biomechanical Index ( CBI ) was analyzed for external validation. RESULTS: The kc parameter was significantly different between keratoconus and controls ( P < 0.001), ranging from 24.9 ±3.0 to 34.2 ±3.5 N/m, respectively. It was highly correlated with CBI (r = -0.69; P < 0.001); however, the kc parameter had greater specificity (94%) than CBI (75%), whereas the 2 biomarkers had similar area under the curve (0.98 vs. 0.94) and sensitivity (96% vs. 92%) in predicting the occurrence of keratoconus. CONCLUSIONS: The kc parameter extracted by video processing analysis of dynamic Scheimpflug tonometry data was highly accurate in discriminating patients with clinically manifest keratoconus compared with controls.

Extracorporeal Membrane Oxygenation After Liver Transplant in Children: A Review of the ELSO Registry.

There are minimal data describing use of extracorporeal membrane oxygenation (ECMO) in pediatric patient after a liver transplantation (LT). This study aimed at describing ECMO run in this specific situation using the data from Extracorporeal Life Support Organization (ELSO) Registry between January 1, 2010, to December 31, 2022. We described patients' characteristics at ECMO initiation, outcome and mortality risk factors. We identified 27 patients with a median age of 2.7 years (interquartile range (IQR) = 1.5-9.9). Main indication for ECMO support was respiratory (14/27 [52%]) followed by extracorporeal cardiopulmonary resuscitation (ECPR) (7/27 [26%]) and cardiac (6/27 [22%]). Overall in-hospital mortality was 63% (17/27). Mortality rate according to ECMO indications was 50% for both respiratory and cardiac failure and reached 100% for ECPR patients. Overall, nonsurvivors experienced significantly more complications under ECMO support (p = 0.007). Main on-ECMO complications were hemorrhagic (11/27 [41%]) and thrombotic (7/27 [26%]). No clinical or biologic factors was predictive of patients' outcome. Our results suggest that ECMO support is a viable option for cardiac and respiratory indications after pediatric LT. Occurrence of complications while on ECMO are associated with unfavorable outcomes. The extremely high mortality rate in ECPR patients merits further research.

Targeted next-generation sequencing analysis in Italian patients with keratoconus.

OBJECTIVE: To report variants in 26 candidate genes and describe the clinical features of Italian patients with keratoconus (KC). SUBJECTS/METHODS: Sixty-four patients with a confirmed diagnosis of KC were enrolled in this genetic association study. Patients were classified into two study groups according to whether they had a confirmed diagnosis of progressive or stable KC. A purpose-developed Next Generation Sequencing (NGS) panel was used to identify and analyse the coding exons and flanking exon/intron boundaries of 26 genes known to be associated with KC and corneal dystrophies. Interpretation of the pathogenic significance of variants was performed using in silico predictive algorithms. RESULT: The targeted NGS research identified a total of 167 allelic variants of 22 genes in the study population; twenty-four patients had stable keratoconus (n. 54 variants) and forty patients had progressive disease (n. 113 variants). We identified genetic variants of certain pathogenic significance in five patients with progressive KC; in addition, eight novel genetic variants were found in eight patients with progressive KC. Mutations of FLG, LOXHD1, ZNF469, and DOCK9 genes were twice more frequently identified in patients with progressive than stable disease. Filaggrin gene variants were found in 49 patients (76% of total), of whom 32 patients (80% of progressive KC group) had progressive disease. CONCLUSIONS: Targeted NGS research provided new insights into the causative effect of candidate genes in the clinical phenotype of keratoconus. Filaggrin mutations were found to represent a genetic risk factor for development of progressive disease in Italy.

Heart failure 'the cancer of the heart': the prognostic role of the HLM score.

AIMS: The multi-systemic effects of heart failure (HF) resemble the spread observed during cancer. We propose a new score, named HLM, analogous to the TNM classification used in oncology, to assess the prognosis of HF. HLM refers to H: heart damage, L: lung involvement, and M: systemic multiorgan involvement. The aim was to compare the HLM score to the conventional New York Heart Association (NYHA) classification, American College of Cardiology/American Heart Association (ACC/AHA) stages, and left ventricular ejection fraction (LVEF), to assess the most accurate prognostic tool for HF patients. METHODS AND RESULTS: We performed a multicentre, observational, prospective study of consecutive patients admitted for HF. Heart, lung, and other organ function parameters were collected. Each patient was classified according to the HLM score, NYHA classification, ACC/AHA stages, and LVEF assessed by transthoracic echocardiography. The follow-up period was 12 months. The primary endpoint was a composite of all-cause death and rehospitalization due to HF. A total of 1720 patients who completed the 12 month follow-up period have been enrolled in the study. 520 (30.2%) patients experienced the composite endpoint of all-cause death and rehospitalization due to HF. 540 (31.4%) patients were female. The mean age of the study population was 70.5 ± 12.9. The mean LVEF at admission was 42.5 ± 13%. Regarding the population distribution across the spectrum of HLM score stages, 373 (21.7%) patients were included in the HLM-1, 507 (29.5%) in the HLM-2, 587 (34.1%) in the HLM-3, and 253 (14.7%) in the HLM-4. HLM was the most accurate score to predict the primary endpoint at 12 months. The area under the receiver operating characteristic curve (AUC) was greater for the HLM score compared with the NYHA classification, ACC/AHA stages, or LVEF, regarding the composite endpoint (HLM = 0.645; NYHA = 0.580; ACC/AHA = 0.589; LVEF = 0.572). The AUC of the HLM score was significantly better compared with the LVEF (P = 0.002), ACC/AHA (P = 0.029), and NYHA (P = 0.009) AUC. CONCLUSIONS: The HLM score has a greater prognostic power compared with the NYHA classification, ACC/AHA stages, and LVEF assessed by transthoracic echocardiography in terms of the composite endpoint of all-cause death and rehospitalization due to HF at 12 months of follow-up.