To investigate the effects of the dramatic reduction in presentations to Italian Emergency Departments (EDs) on the main indicators of ED performance during the SARS-CoV-2 pandemic. From February to ...June 2020 we retrospectively measured the number of daily presentations normalized for the number of emergency physicians on duty (presentations/physician ratio), door-to-physician and door-to-final disposition (length-of-stay) times of seven EDs in the central area of Tuscany. Using the multivariate regression analysis we investigated the relationship between the aforesaid variables and patient-level (triage codes, age, admissions) or hospital-level factors (number of physician on duty, working surface area, academic vs. community hospital). We analyzed data from 105,271 patients. Over ten consecutive 14-day periods, the number of presentations dropped from 18,239 to 6132 (− 67%) and the proportion of patients visited in less than 60 min rose from 56 to 86%. The proportion of patients with a length-of-stay under 4 h decreased from 59 to 52%. The presentations/physician ratio was inversely related to the proportion of patients with a door-to-physician time under 60 min (slope − 2.91, 95% CI − 4.23 to − 1.59,
R
2
= 0.39). The proportion of patients with high-priority codes but not the presentations/physician ratio, was inversely related to the proportion of patients with a length-of-stay under 4 h (slope − 0.40, 95% CI − 0.24 to − 0.27,
R
2
= 0.36). The variability of door-to-physician time and global length-of-stay are predicted by different factors. For appropriate benchmarking among EDs, the use of performance indicators should consider specific, hospital-level and patient-level factors.
•Ultrasound and d-dimer were integrated for diagnosis of acute aortic syndromes.•The protocol allowed rapid triage for urgent computed tomography angiography.•Protocol based rule-out was safe since ...no major events were missed within 30 days.•The protocol averted 41 % of computed tomography angiography exams.•Age-adjusted interpretation of d-dimer maximized protocol efficiency.
In patients complaining common symptoms such as chest/abdominal/back pain or syncope, acute aortic syndromes (AAS) are rare underlying causes. AAS diagnosis requires urgent advanced aortic imaging (AAI), mostly computed tomography angiography. However, patient selection for AAI poses conflicting risks of misdiagnosis and overtesting.
We assessed the safety and efficiency of a diagnostic protocol integrating clinical data with point-of-care ultrasound (POCUS) and d-dimer (single/age-adjusted cutoff), to select patients for AAI.
This prospective study involved 12 Emergency Departments from 5 countries. POCUS findings were integrated with a guideline-compliant clinical score, to define the integrated pre-test probability (iPTP) of AAS. If iPTP was high, urgent AAI was requested. If iPTP was low and d-dimer was negative, AAS was ruled out. Patients were followed for 30 days, to adjudicate outcomes.
Within 1979 enrolled patients, 176 (9 %) had an AAS. POCUS led to net reclassification improvement of 20 % (24 %/-4 % for events/non-events, P < 0.001) over clinical score alone. Median time to AAS diagnosis was 60 min if POCUS was positive vs 118 if negative (P = 0.042). Within 941 patients satisfying rule-out criteria, the 30-day incidence of AAS was 0 % (95 % CI, 0–0.41 %); without POCUS, 2 AAS were potentially missed. Protocol rule-out efficiency was 48 % (95 % CI, 46–50 %) and AAI was averted in 41 % of patients. Using age-adjusted d-dimer, rule-out efficiency was 54 % (difference 6 %, 95 % CI, 4–9 %, vs standard cutoff).
The integrated algorithm allowed rapid triage of high-probability patients, while providing safe and efficient rule-out of AAS. Age-adjusted d-dimer maximized efficiency.
CLINICAL TRIAL REGISTRATION: Clinicaltrials.gov, NCT04430400
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Aim To determine the prevalence and characteristics of pulmonary embolism (PE) in patients presenting with hemoptysis. Additionally, we assessed the efficiency and failure rates of different clinical ...diagnostic algorithms for PE in this patient population. Methods We enrolled consecutive adult patients who presented to nine Italian Emergency Departments (ED) with hemoptysis as the primary complaint. PE diagnosis was ruled out in patients with a low pretest probability in combination with a negative age-adjusted D-dimer (referred to as the “age-adjusted” D-dimer strategy), a negative computed tomography pulmonary angiography, or when a clear alternative source of bleeding was identified, along with negative findings for venous thromboembolism during a 30-day follow-up. Results A total of 546 patients were included in the study. The prevalence of PE, including the 30-day follow-up, was 4.2% (95% confidence interval, CI, 2.7–6.3%). The majority of these cases (78%) exhibited distal (segmental or subsegmental) emboli, and there were no PE-related fatalities. The “age-adjusted” D-dimer strategy initially excluded PE in 24% of patients (95% CI, 21–28%), with a failure rate of 0.8% (95% CI, 0.0–4.1%). Retrospectively applied, the “clinical probability-adjusted” D-dimer strategies, specifically the YEARS and PEGeD algorithms, excluded PE in a significantly higher proportion (30% and 32%, respectively) compared to the “age-adjusted” D-dimer strategy (p<0.05 for both), with similar failure rates. Conclusions Pulmonary embolism is infrequent among patients presenting with hemoptysis, showing segmental or subsegmental emboli distribution. The “clinical probability-adjusted” D-dimer strategies seem to have significantly higher efficiency compared to the “age-adjusted” strategy.
Few data exists on predictive factors of hemorrhagic transformation (HT) in real-world acute ischemic stroke patients. The aims of this study were: (i) to identify predictive variables of HT (ii) to ...develop a score for predicting HT.
We retrospectively analyzed the clinical, radiographic, and laboratory data of patients with acute ischemic stroke consecutively admitted to our Stroke Unit along two years. Patients with HT were compared with those without HT. A multivariate logistic regression analysis was performed to identify independent predictors of HT on CT scan at 24 hours to develop a practical score.
The study population consisted of 564 patients with mean age 77.5±11.8 years. Fifty-two patients (9.2%) showed HT on brain CT at 24 hours (4.9% symptomatic). NIHSS score ≥8 at Stroke Unit admission (3 points), cardioembolic etiology (2 points), acute revascularization by systemic thrombolysis and/or mechanical thrombectomy (1 point), history of previous TIA/stroke (1 point), and major vessel occlusion (1 point) were found independent risk factors of HT and were included in the score (Hemorrhagic Transformation Empoli score (HTE)). The predictive power of HTE score was good with an AUC of 0.785 (95% CI: 0.749-0.818). Compared with 5 HT predictive scores proposed in the literature (THRIVE, SPAN-100, MSS, GRASPS, SITS-SIC), the HTE score significantly better predicted HT.
NIHSS score ≥8 at Stroke Unit admission, cardioembolism, urgent revascularization, previous TIA/stroke, and major vessel occlusion were independent predictors of HT. The HTE score has a good predictive power for HT. Prospective studies are warranted.
We report a family with three members affected by a typically X-linked McLeod syndrome. In the proband a very weak positivity for antigens of the Kell group was detected. His sister showed a normal ...antigenic pattern. We emphasize the prominent neurological picture characterized by a choreic syndrome with atrophy of the caudate nucleus on MRI, psychiatric disturbances, peripheral nerve and muscle biopsy findings indicating slight neuromuscular involvement, and cardiac abnormalities. The differential diagnosis is discussed.
The cases of two sisters with late infantile Hallervorden-Spatz disease are reported, one of whom has died. Autopsy of the deceased patient showed typical pallidal lesions, such as axonal spheroids ...and iron deposits, without involvement of the substantia nigra. Ultrastructural examination revealed that pallidal axonal enlargements consisted of collection of mitochondria, dense bodies, vesicles and amorphous material. In the living patient, brain MRI showed the classical "tiger's eye" appearance of the globus pallidus. Retinitis pigmentosa, acanthocytosis and slight neuromuscular involvement with an increase in serum creatine kinase were observed in both subjects. The appearance of the globus pallidus on MRI was in line with the pathological abnormalities. Ultrastructural differences between the principal disorders characterized by neuroaxonal dystrophy are compared and the clinical spectrum and similarities of the different forms of neuroacanthocytosis analysed.
International collaborations over the years have produced a series of prognostic models for primary myelofibrosis (PMF), including the recently unveiled mutation-enhanced international prognostic ...scoring systems for transplant-age patients (MIPSS70 and MIPSS70-plus). In the current study, we considered the feasibility of a genetically inspired prognostic scoring system (GIPSS) that is exclusively based on genetic markers. Among 641 cytogenetically annotated patients with PMF and informative for previously recognized adverse mutations, multivariable analysis identified "VHR" karyotype, "unfavorable" karyotype, absence of type 1/like CALR mutation and presence of ASXL1, SRSF2, or U2AF1Q157 mutation, as inter-independent predictors of inferior survival; the respective HRs (95% CI) were 3.1 (2.1-4.3), 2.1 (1.6-2.7), 2.1 (1.6-2.9), 1.8 (1.5-2.3), 2.4 (1.9-3.2), and 2.4 (1.7-3.3). Based on HR-weighted risk points, a four-tiered GIPSS model was devised: low (zero points; n = 58), intermediate-1 (1 point; n = 260), intermediate-2 (2 points; n = 192), and high (≥3 points; n = 131); the respective median (5-year) survivals were 26.4 (94%), 8.0 (73%), 4.2 (40%), and 2 (14%) years; the model was internally validated by bootstrapping and its predictive accuracy was shown to be comparable to that of MIPSS70-plus. GIPPS offers a low-complexity prognostic tool for PMF that is solely dependent on genetic risk factors and, thus, forward-looking in its essence.
Somatic mutations of calreticulin (CALR) have been described in approximately 60-80% of JAK2 and MPL unmutated Essential Thrombocythemia and Primary Myelofibrosis patients. CALR is an endoplasmic ...reticulum (ER) chaperone responsible for proper protein folding and calcium retention. Recent data demonstrated that the TPO receptor (MPL) is essential for the development of CALR mutant-driven Myeloproliferative Neoplasms (MPNs). However, the precise mechanism of action of CALR mutants haven't been fully unraveled. In this study, we showed that CALR mutants impair the ability to respond to the ER stress and reduce the activation of the pro-apoptotic pathway of the unfolded protein response (UPR). Moreover, our data demonstrated that CALR mutations induce increased sensitivity to oxidative stress, leading to increase oxidative DNA damage. We finally demonstrated that the downmodulation of OXR1 in CALR-mutated cells could be one of the molecular mechanisms responsible for the increased sensitivity to oxidative stress mediated by mutant CALR. Altogether, our data identify novel mechanisms collaborating with MPL activation in CALR-mediated cellular transformation. CALR mutants negatively impact on the capability of cells to respond to oxidative stress leading to genomic instability and on the ability to react to ER stress, causing resistance to UPR-induced apoptosis.
At the time of the COVID-19 pandemic, the impact of lockdown measures highlights changes in terms of sounds and noises present in the everyday life. The present paper deals with this peculiar and ...unexpected scenario as studied by means of an online survey consisting of 18 questions and distributed to residents in the Italian territory. For studying the unprecedented effect of the pandemic, participants were asked to fill the questionnaire, providing personal data, describing context and characteristics of the house in which they live and making a comparison of the lockdown soundscape with the pre-lockdown one. About four hundred questionnaires have been collected and analysed in order to define correlations between personal and perception variables. Using logistic regression models, changes have been studied during the two abovementioned periods. It has been observed that the perception of traffic noise has increased for people over 35 years old and the noise produced by the neighbourhood has been more statistically significant for employed respondents. Future outlook might provide the spread of the questionnaire in other countries for a global evaluation of the data, to be also acquired with reference to the after-lockdown period.
Dysregulated signaling of the JAK/STAT pathway is a common feature of chronic myeloproliferative neoplasms (MPN), usually associated with JAK2V617F mutation. Recent clinical trials with JAK2 ...inhibitors showed significant improvements in splenomegaly and constitutional symptoms in patients with myelofibrosis but meaningful molecular responses were not documented. Accordingly, there remains a need for exploring new treatment strategies of MPN. A potential additional target for treatment is represented by the PI3K/AKT/mammalian target of rapamycin (mTOR) pathway that has been found constitutively activated in MPN cells; proof-of-evidence of efficacy of the mTOR inhibitor RAD001 has been obtained recently in a Phase I/II trial in patients with myelofibrosis. The aim of the study was to characterize the effects in vitro of mTOR inhibitors, used alone and in combination with JAK2 inhibitors, against MPN cells.
Mouse and human JAK2V617F mutated cell lines and primary hematopoietic progenitors from MPN patients were challenged with an allosteric (RAD001) and an ATP-competitive (PP242) mTOR inhibitor and two JAK2 inhibitors (AZD1480 and ruxolitinib). mTOR inhibitors effectively reduced proliferation and colony formation of cell lines through a slowed cell division mediated by changes in cell cycle transition to the S-phase. mTOR inhibitors also impaired the proliferation and prevented colony formation from MPN hematopoietic progenitors at doses significantly lower than healthy controls. JAK2 inhibitors produced similar antiproliferative effects in MPN cell lines and primary cells but were more potent inducers of apoptosis, as also supported by differential effects on cyclinD1, PIM1 and BcLxL expression levels. Co-treatment of mTOR inhibitor with JAK2 inhibitor resulted in synergistic activity against the proliferation of JAK2V617F mutated cell lines and significantly reduced erythropoietin-independent colony growth in patients with polycythemia vera.
These findings support mTOR inhibitors as novel potential drugs for the treatment of MPN and advocate for clinical trials exploiting the combination of mTOR and JAK2 inhibitor.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
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