Classification of weekly provincial overall age- and gender-specific mortality patterns during the COVID-19 epidemics in Italy.

OBJECTIVES: to provide a time-varying classification of the Italian provinces based on the weekly age- and gender-specific relative risks (RR) for overall mortality, obtained comparing the number of deaths from 13 weeks from the beginning of the COVID-19 epidemics, with the average number of deaths from the same period in 2015-19. DESIGN: population overall mortality data provided by the Italian National Statistical Office (Istat). SETTING AND PARTICIPANTS: Italian residents 60 years or older from 7,357/7,904 Italian municipalities. For the included municipalities, the number of deaths from any cause from 1 January to 30 May 2020 was available for each day of the 2015-2020 period. Data were stratified by gender, 4 age categories (60-69, 70-79, 80-89, 90+), week, and province. MAIN OUTCOME MEASURES: province- and gender-specific weekly RR curves (age category vs RR), obtained for 13 weeks between 26 February and 26 May; excess mortality; time-varying/weekly classification of provinces. RESULTS: these results provide a weekly classification of the Italian provinces based on their RR curves in 5 groups, 2 of which had high and very high excess mortality during the epidemics. Most of the provinces that appeared at least once in the highest-risk group are neighbouring provinces in the Northern Regions of Lombardy, Emilia-Romagna, Piedmont, and Marche (in central Italy), where most of the COVID-19 cases and deaths were identified. Temporally, most of these provinces remained in the highest-risk group for 4 or 5 weeks; those that entered the group later, improved faster. The overall RR curves for groups differed in magnitude, but also in the shape, which varied markedly also between men and women and, most importantly, in the highest-risk group. CONCLUSIONS: this study gives timely re-analysis of the Istat data at weekly level and provides a classification of the geographical and temporal characteristics of the excess mortality in the Italian provinces during the COVID-19 epidemics. As expected, the used clustering method groups the provinces that have similar RR values in the two gender-specific curves. The results facilitate the presentation of the spatio-temporal mortality patterns of the epidemics and provide evidence of high heterogeneity in the group of provinces that were defined as high-risk groups by others, based on their geographical position or on the time of the observed spread of the virus.

A note on bias of measures of explained variation for survival data.

Papers evaluating measures of explained variation, or similar indices, almost invariably use independence from censoring as the most important criterion. And they always end up suggesting that some measures meet this criterion, and some do not, most of the time leading to a conclusion that the first is better than the second. As a consequence, users are offered measures that cannot be used with time-dependent covariates and effects, not to mention extensions to repeated events or multi-state models. We explain in this paper that the aforementioned criterion is of no use in studying such measures, because it simply favors those that make an implicit assumption of a model being valid everywhere. Measures not making such an assumption are disqualified, even though they are better in every other respect. We show that if these, allegedly inferior, measures are allowed to make the same assumption, they are easily corrected to satisfy the 'independent-from-censoring' criterion. Even better, it is enough to make such an assumption only for the times greater than the last observed failure time τ, which, in contrast with the 'preferred' measures, makes it possible to use all the modeling flexibility up to τ and assume whatever one wants after τ. As a consequence, we claim that some of the measures being preferred as better in the existing reviews are in fact inferior.

A weighted clustering of population pyramids for the world's countries, 1996, 2001, 2006.

This paper presents clusters of the world's countries obtained by a novel weighted clustering method. The approach is based on data representations with symbolic descriptions of age-sex structures. To obtain clusters with similar descriptions, a weighted clustering method is used which is suitable for data described with discrete distributions. In contrast to the classical approach, this method allows the population of each sex to be included in the clustering process, thereby obtaining a representative age-sex structure corresponding to all the countries contained in the cluster. Observing the data over time reveals clusters of countries with similar changes in their population age-sex distributions. The resulting population pyramids are presented for 1996, 2001, and 2006.

Standard Heart Rate Variability Parameters-Their Within-Session Stability, Reliability, and Sample Size Required to Detect the Minimal Clinically Important Effect.

Many intervention studies assume the stability of heart rate variability (HRV) parameters, and their sample sizes are often small, which can significantly affect their conclusions. The aim of this study is to assess the stability and reliability of standard HRV parameters within a single resting session, and to estimate the sample size required to detect the minimal clinically important effect of an intervention. Heart rate was recorded in 50 adult healthy subjects for 50 min in a seated position. Eight standard HRV parameters were calculated from five evenly spaced 5 min intervals. Stability was assessed by comparing the mean values of HRV parameters between the consecutive five test-retest measurements. Absolute reliability was determined by standard error of measurement, and relative reliability by intraclass correlation coefficient. The sample size required to detect a mean difference of ≥30% of between-subject standard deviation was estimated. As expected, almost all HRV parameters had poor absolute reliability but most HRV parameters had substantial to excellent relative reliability. We found statistically significant differences in almost all HRV parameters between the first 20 min and the last 30 min of the session. The estimated sample size ranged from 19 to 300 subjects for the first 20 min and from 36 to 194 subjects for the last 30 min of the session, depending on the selected HRV parameter. We concluded that optimal HRV measurement protocols in a resting seated position should be performed within the first 20 min or between 20 and 50 min after assuming a resting seated position. Future interventional HRV studies should include a sufficient number of subjects and consider the Bonferroni correction according to the number of selected HRV parameters to achieve an appropriate level of study power and precision.

SARS-CoV-2 Vaccination and Clinical Presentation of COVID-19 in Patients Hospitalized during the Delta- and Omicron-Predominant Periods.

Evidence suggests that monovalent vaccine formulations are less effective against the Omicron SARS-CoV-2 than against previous variants. In this retrospective cohort study of hospitalized adults with PCR-confirmed COVID-19 during the Delta (October-November 2021) and Omicron (January-April 2022) variant predominant periods in Slovenia, we assessed the association between primary vaccination against SARS-CoV-2 and progression to critically severe disease (mechanical ventilation or death). Compared with the 529 patients hospitalized for acute COVID-19 during the Delta period (median age 65 years; 58.4% men), the 407 patients hospitalized during the Omicron period (median age 75 years; 50.6% men) were older, more often resided in long-term care facilities, and had higher Charlson comorbidity index scores. After adjusting for age, sex, the Charlson comorbidity index, the presence of immunocompromising conditions, and vaccination status, the patients admitted during the Omicron period had comparable odds of progressing to critically severe disease to those admitted during the Delta period. The 334/936 (35.7%) patients completing at least primary vaccination had lower odds of progression to critically severe disease and shorter hospital stay than unvaccinated patients; however, the protective effect of vaccination was less pronounced during the Omicron than during the Delta period. Although the Omicron variant appeared to better evade immunity induced by monovalent vaccines than the Delta variant, vaccination against SARS-CoV-2 remained an effective intervention to decrease morbidity and mortality in COVID-19 patients infected with the Omicron variant.

Associations among different functional and structural arterial wall properties and their relations to traditional cardiovascular risk factors in healthy subjects: a cross-sectional study.

BACKGROUND: The arterial wall possesses several functional and structural properties that define arterial health. Once they become impaired, cardiovascular risk increases. We aimed to ascertain the pattern of correlations among different arterial wall properties and to explore their relations to traditional risk factors and cardiovascular risk stratification. To allow such an investigation a middle-aged healthy population was recruited. METHODS: This cross-sectional study included 100 healthy males (aged 41.9 ± 6.4 years). Pulse wave velocity (PWV), ß-stiffness and intima-media thickness (IMT) of the carotid artery, and brachial artery flow-mediated dilation (FMD) were measured by a standardized ultrasound approach. RESULTS: No correlation between FMD and IMT was found; only relatively poor correlations between PWV (or ß-stiffness) and FMD existed, as well as between PWV (or ß-stiffness) and IMT. PWV and ß-stiffness highly correlated. Unexpectedly, only weak associations between PWV, ß-stiffness, FMD, IMT and traditional risk factors were revealed. Hence, traditional risk factors (mainly age) explained only 10-50% of variability for PWV, ß-stiffness, FMD and IMT. Although the subjects had low cardiovascular risk according to their Framingham score, their arterial wall properties were already impaired, particularly FMD. CONCLUSIONS: In healthy middle-age males we found: i) absent or poor correlations among arterial stiffness, IMT and endothelial function; ii) a low impact of traditional risk factors on the studied variables, and iii) the presence of impaired arterial wall properties despite low calculated cardiovascular risk. These results provide a deepened understanding of arterial wall properties and could help to improve cardiovascular risk stratification.

Clinical Outcomes after Endovascular Revascularisation of the Femoropopliteal Arterial Segment in Patients with Anticoagulant versus Antiplatelet Therapy: A Single-Centre Retrospective Cohort Study.

To prevent atherothrombotic events, patients with peripheral arterial disease are typically prescribed antiplatelet therapy (APT). However, some of them receive anticoagulant therapy (ACT) due to comorbidities. Our aim was to determine possible differences in the effectiveness and safety of both treatments in patients after endovascular femoropopliteal revascularisation. We retrospectively analysed 1247 patients after successful femoropopliteal revascularisation performed in a single tertiary medical centre and classified them into the ACT or APT group, based on their prescribed treatment. The groups were characterised by descriptive statistics, and their characteristics were adjusted for confounders by propensity score matching. Effectiveness and safety outcomes were assessed within one year after revascularisation. The odds ratio for the composite outcome of all-cause death, PAD exacerbation, and major amputation due to vascular causes with ACT versus APT was 1.21 (95% CI 0.53-2.21; p = 0.484). The odds ratio for major bleeding as defined by the International Society on Thrombosis and Haemostasis with ACT versus APT was 0.77 (95% CI 0.13-3.84; p = 0.251). We found no statistically significant difference in the effectiveness and safety of ACT, when compared to APT in patients with similar cardiovascular risk factors and other baseline characteristics. Further prospective research is warranted.

The Impact of SARS-CoV-2 Primary Vaccination in a Cohort of Patients Hospitalized for Acute COVID-19 during Delta Variant Predominance.

Vaccine breakthrough SARS-CoV-2 infections necessitating hospitalization have emerged as a relevant problem with longer time interval since vaccination and the predominance of the Delta variant. The aim of this study was to evaluate the association between primary vaccination with four SARS-CoV-2 vaccines authorized for use in the European Union-BNT162b2, ChAdOx-1S, mRNA-1273 or Ad.26.COV2.S-and progression to critically severe disease (mechanical ventilation or death) and duration of hospitalization among adult patients with PCR-confirmed acute COVID-19 hospitalized during the Delta variant predominance (October-November 2021) in Slovenia. Among the 529 enrolled patients hospitalized with COVID-19 (median age, 65 years; 58.2% men), 175 (33.1%) were fully vaccinated at the time of symptom onset. Compared with 345 unvaccinated patients, fully vaccinated patients with breakthrough infections were older, more often immunocompromised, and had higher Charlson comorbidity index scores. After adjusting for sex, age, and comorbidities, fully vaccinated patients had lower odds for progressing to critically severe disease and were discharged from the hospital earlier than unvaccinated patients. Vaccination against SARS-CoV-2 remains an extremely effective intervention to alleviate morbidity and mortality in COVID-19 patients.

COVID-19 in Slovenia, from a Success Story to Disaster: What Lessons Can Be Learned?

During the first wave of the COVID-19 pandemic in spring 2020, Slovenia was among the least affected countries, but the situation became drastically worse during the second wave in autumn 2020 with high numbers of deaths per number of inhabitants, ranking Slovenia among the most affected countries. This was true even though strict non-pharmaceutical interventions (NPIs) to control the progression of the epidemic were being enforced. Using a semi-parametric Bayesian model developed for the purpose of this study, we explore if and how the changes in mobility, their timing and the activation of contact tracing can explain the differences in the epidemic progression of the two waves. To fit the model, we use data on daily numbers of deaths, patients in hospitals, intensive care units, etc., and allow transmission intensity to be affected by contact tracing and mobility (data obtained from Google Mobility Reports). Our results imply that though there is some heterogeneity not explained by mobility levels and contact tracing, implementing interventions at a similar stage as in the first wave would keep the death toll and the health system burden low in the second wave as well. On the other hand, sticking to the same timeline of interventions as observed in the second wave and focusing on enforcing a higher decrease in mobility would not be as beneficial. According to our model, the 'dance' strategy, i.e., first allowing the numbers to rise and then implementing strict interventions to make them drop again, has been played at too-late stages of the epidemic. In contrast, a 15-20% reduction of mobility compared to pre-COVID level, if started at the beginning and maintained for the entire duration of the second wave and coupled with contact tracing, could suffice to control the epidemic. A very important factor in this result is the presence of contact tracing; without it, the reduction in mobility needs to be substantially larger. The flexibility of our proposed model allows similar analyses to be conducted for other regions even with slightly different data sources for the progression of the epidemic; the extension to more than two waves is straightforward. The model could help policymakers worldwide to make better decisions in terms of the timing and severity of the adopted NPIs.

Prognostic value of CT perfusion and permeability imaging in traumatic brain injury.

BACKGROUND: Currently established prognostic models in traumatic brain injury (TBI) include noncontrast computed tomography (CT) which is insensitive to early perfusion alterations associated with secondary brain injury. Perfusion CT (PCT) on the other hand offers insight into early perfusion abnormalities. We hypothesized that adding CT perfusion and permeability data to the established outcome predictors improves the performance of the prognostic model. METHODS: A prospective cohort study of consecutive 50 adult patients with head injury and Glasgow Coma Scale score of 12 or less was performed at a single Level 1 Trauma Centre. Perfusion CT was added to routine control CT 12 hours to 24 hours after admission. Region of interest analysis was performed in six major vascular territories on perfusion and permeability parametric maps. Glasgow Outcome Scale (GOS) was used 6 months later to categorize patients' functional outcomes to favorable (GOS score > 3) or unfavorable (GOS score ≤ 3). We defined core prognostic model, consisting of age, motor Glasgow Coma Scale score, pupillary reactivity, and CT Rotterdam Score. Next, we added perfusion and permeability data as predictors and compared updated models to the core model using cross-validated areas under the receiver operator curves (cv-AUC). RESULTS: Significant advantage over core model was shown by the model, containing both mean cerebral extravascular-extracellular volume per unit of tissue volume and cerebral blood volume of the least perfused arterial territory in addition to core predictors (cv-AUC, 0.75; 95% confidence interval, 0.51-0.84 vs. 0.6; 95% confidence interval, 0.37-0.74). CONCLUSION: The development of cerebral ischemia and traumatic cerebral edema constitutes the secondary brain injury and represents the target for therapeutic interventions. Our results suggest that adding CT perfusion and permeability data to the established outcome predictors improves the performance of the prognostic model in the setting of moderate and severe TBI. LEVEL OF EVIDENCE: Prognostic study, level III.

Contrast-enhanced ultrasound for evaluation of tumor perfusion and outcome following treatment in a murine melanoma model.

Due to a lack of data on predictors of electroporation-based treatment outcomes, we investigated the potential predictive role of contrast-enhanced harmonic ultrasound (CEUS) in mice B16F10 melanoma treated by gene electrotransfer (GET) to silence melanoma cell adhesion molecule (MCAM) and radiotherapy, which has not been evaluated yet. CEUS evaluation was verified by tumor histological analysis. Mice bearing subcutaneous tumors were treated with GET to silence MCAM, irradiation or the combination of GET to silence MCAM and irradiation (combined treatment). CEUS of the tumors used to evaluate tumor perfusion was performed before and up to 10 days after the beginning of the experiment, and the CEUS results were compared with tumor growth and the number of blood vessels analyzed in the histological tumor sections. CEUS revealed a decrease in tumor perfusion in the combined therapy groups compared with the control groups and correlated with tumor histological analyses, which showed a decreased vascular density. In this study a trend of inverse correlation was observed between tumor perfusion and treatment efficacy. The greater the perfusion of the tumor, the shorter the expected doubling time. Furthermore, decreased perfusion showed a trend to correlate with higher antitumor efficacy. Thus, CEUS could be used to predict tumoral vascular density and treatment effectiveness.

Modeling COVID-19 pandemic using Bayesian analysis with application to Slovene data.

In the paper, we propose a semiparametric framework for modeling the COVID-19 pandemic. The stochastic part of the framework is based on Bayesian inference. The model is informed by the actual COVID-19 data and the current epidemiological findings about the disease. The framework combines many available data sources (number of positive cases, number of patients in hospitals and in intensive care, etc.) to make outputs as accurate as possible and incorporates the times of non-pharmaceutical governmental interventions which were adopted worldwide to slow-down the pandemic. The model estimates the reproduction number of SARS-CoV-2, the number of infected individuals and the number of patients in different disease progression states in time. It can be used for estimating current infection fatality rate, proportion of individuals not detected and short term forecasting of important indicators for monitoring the state of the healthcare system. With the prediction of the number of patients in hospitals and intensive care units, policy makers could make data driven decisions to potentially avoid overloading the capacities of the healthcare system. The model is applied to Slovene COVID-19 data showing the effectiveness of the adopted interventions for controlling the epidemic by reducing the reproduction number of SARS-CoV-2. It is estimated that the proportion of infected people in Slovenia was among the lowest in Europe (0.350%, 90% CI [0.245-0.573]%), that infection fatality rate in Slovenia until the end of first wave was 1.56% (90% CI [0.94-2.21]%) and the proportion of unidentified cases was 88% (90% CI [83-93]%). The proposed framework can be extended to more countries/regions, thus allowing for comparison between them. One such modification is exhibited on data for Slovene hospitals.

Progression of coronary calcium burden and carotid stiffness in patients with essential thrombocythemia associated with JAK2 V617F mutation.

BACKGROUND AND AIMS: Patients with myeloproliferative neoplasms often succumb to cardiovascular events, but little is known on the early stages of their vascular disease. We studied how patients with JAK2 V617F positive essential thrombocythemia (ET) without overt atherosclerotic disease differed from control subjects in the progression of carotid artery stiffness and preclinical atherosclerosis. METHODS: Thirty-six patients with JAK2 V617F positive ET and 38 age-, gender- and Framingham coronary heart disease (CHD) -matched control subjects were examined twice within 4 years. Clinical and laboratory testing, echo-tracking ultrasound of carotid arteries, coronary calcium measurement and digital plethysmography were performed (ClinTrials.gov NCT03828422). RESULTS: Coronary calcium correlated with the Framingham CHD risk score at the first examination in the control group (rs = 0.410), but not among the ET patients (rs = 0.116). Both groups progressed in coronary calcium, but the outliers were more prominent among ET patients. Carotid artery stiffness increased with time in the ET patients much more than in the control group: the increase in ß-index 1.95 (SD 2.18) vs. 0.22 (SD 1.99), p < 0.001, and the increase in carotid pulse wave velocity 0.72 (SD 0.92) vs. 0.08 (SD 0.72) m/s, p = 0.001. There was no correlation between carotid stiffness and Framingham CHD risk in either group. Digital endothelial function did not change. CONCLUSION: Carotid artery stiffness progressed faster in patients with JAK2 V617F positive ET than in control subjects. Coronary calcium correlated with the Framingham CHD risk only in control subjects. This indicates that JAK2 V617F positive ET acted as a non-classical risk factor for vascular disease.

Window of opportunity for surgical decompression in patients with acute traumatic cervical spinal cord injury.

OBJECTIVE: The objective of this prospective study was to determine the optimal timing for surgical decompression (SD) in patients with acute traumatic cervical spinal cord injury (tSCI) within the first 24 hours of injury. METHODS: In successive patients with fracture and/or dislocation of the subaxial cervical spine and American Spinal Injury Association Impairment Scale (AIS) grades A-C, receiver operating characteristic curve analysis was used to determine the optimal timing for SD within the first 24 hours of cervical tSCI to obtain a neurological recovery of at least two AIS grades. Multivariate logistic regression was used to model significant neurological recovery with time to SD, degree of spinal canal compromise (SCC), and severity of injury. RESULTS: In this cohort of 64 patients, the optimal timing for SD to obtain a significant neurological improvement was within 4 hours of injury (95% confidence interval 4-9 hours). Increasing the delay from injury to SD or the degree of SCC significantly reduced the likelihood of significant neurological improvement. Due to the strong correlation with SCC, the severity of injury was a marginally significant predictor of neurological recovery. CONCLUSIONS: These findings indicate that in patients with acute cervical tSCI and AIS grades A-C, the optimal timing for SD is within the first 4-9 hours of injury, depending on the degree of SCC and the severity of injury. Further studies are required to better understand the interrelationships among the timing of SD, injury severity, and degree of SCC in these patients.

Sequential assessment of clinical and laboratory parameters in patients with hemorrhagic fever with renal syndrome.

BACKGROUND: Information on the sequential appearance, duration, and magnitude of clinical and laboratory parameters in hemorrhagic fever with renal syndrome (HFRS) is limited. METHODS: Analysis of clinical and laboratory parameters obtained serially in 81 patients with HFRS, of whom 15 were infected with Dobrava virus and 66 with Puumala virus. RESULTS: The initial signs/symptoms, appearing on median day 1 of illness, were fever, headache, and myalgia. These were present in 86%, 65%, and 40% of patients and had a median duration of 4, 4, and 5.5 days, respectively. The signs/symptoms were followed by myopia (appearance on day 5), insomnia (day 6), oliguria/anuria (day 6), polyuria (day 9), and sinus bradycardia (day 9.5). These were present in 35%, 30%, 28%, 91%, and 35% of patients; their median duration was 2, 2, 2, 7, and 1 day, respectively. Laboratory abnormalities, including thrombocytopenia, elevated alanine aminotransferase, CRP, procalcitonin, creatinine, diminished glomerular filtration rate, and leukocytosis, were ascertained on admission to hospital or on the following day (day 5 or 6 of illness) and were established in 95%, 87%, 99%, 91%, 94%, 87%, and 55% of patients, and had a median duration of 4, 3, 7, 3, 9, 8, and 2 days, respectively. Comparison of patients infected with Dobrava and Puumala viruses found several differences in the frequency, magnitude, and duration of abnormalities, indicating that Dobrava virus causes the more severe HFRS. CONCLUSIONS: In the majority of patients, the classic clinical distinction into febrile, hypotonic, oliguric, polyuric, and convalescent phases of illness is unclear.

Relationship between circulating vascular endothelial growth factor and its soluble receptor in patients with hemorrhagic fever with renal syndrome.

Hemorrhagic fever with renal syndrome (HFRS) is characterized by endothelial dysfunction with capillary leakage without obvious cytopathology in the capillary endothelium. The aim of the study was to analyze the kinetics of vascular endothelial growth factor (VEGF) and its soluble receptor (sVEGFR-2) in HFRS patients infected with Dobrava (DOBV) or Puumala virus (PUUV). VEGF and sVEGFR-2 levels were measured in daily plasma and urine samples of 73 patients with HFRS (58 with PUUV, 15 with DOBV) and evaluated in relation to clinical and laboratory variables. In comparison with the healthy controls, initial samples (obtained in the first week of illness) from patients with HFRS had higher plasma and urine VEGF levels, whereas sVEGFR-2 levels were lower in plasma but higher in urine. VEGF levels did not differ in relation to hantavirus species, viral load, or the severity of HFRS. The comparison of VEGF dynamics in plasma and urine showed the pronounced secretion of VEGF in urine. Significant correlations were found between daily VEGF/sVEGFR-2 levels and platelet counts, as well as with diuresis: the correlations were positive for plasma VEGF/sVEGFR-2 levels and negative for urine levels. In addition, patients with hemorrhagic manifestations had very high plasma and urine VEGF, together with high urine sVEGFR-2. Measuring the local secretion of sVEGFR-2 in urine might be a useful biomarker for identifying HFRS patients who will progress to severe disease.