Non-thyroidal illness syndrome and SARS-CoV-2-associated multisystem inflammatory syndrome in children.

PURPOSE: COVID-19 disease may result in a severe multisystem inflammatory syndrome in children (MIS-C), which in turn may alter thyroid function (TF). We assessed TF in MIS-C, evaluating its impact on disease severity. METHODS: We retrospectively considered children admitted with MIS-C to a single pediatric hospital in Milan (November 2019-January 2021). Non-thyroidal illness syndrome (NTIS) was defined as any abnormality in TF tests (FT3, FT4, TSH) in the presence of critical illness and absence of a pre-existing hormonal abnormality. We devised a disease severity score by combining severity scores for each organ involved. Glucose and lipid profiles were also considered. A principal component analysis (PCA) was performed, to characterize the mutual association patterns between TF and disease severity. RESULTS: Of 26 (19 M/7F) patients, median age 10.7 (IQR 5.8-13.3) years, 23 (88.4%) presented with NTIS. A low FT3 level was noted in 15/23 (65.3%), while the other subjects had varying combinations of hormone abnormalities (8/23, 34.7%). Mutually correlated variables related to organ damage and inflammation were represented in the first dimension (PC1) of the PCA. FT3, FT4 and total cholesterol were positively correlated and characterized the second axis (PC2). The third axis (PC3) was characterized by the association of triglycerides, TyG index and HDL cholesterol. TF appeared to be related to lipemic and peripheral insulin resistance profiles. A possible association between catabolic components and severity score was also noted. CONCLUSIONS: A low FT3 level is common among MIS-C. TF may be useful to define the impact of MIS-C on children's health and help delineate long term follow-up management and prognosis.

Monitoring the haemodynamic response to visual stimulation in glaucoma patients.

In this paper, we used time-domain functional near infrared spectroscopy (TD-fNIRS) to evaluate the haemodynamic response function (HRF) in the occipital cortex following visual stimulation in glaucomatous eyes as compared to healthy eyes. A total of 98 subjects were enrolled in the study and clinically classified as healthy subjects, glaucoma patients (primary open-angle glaucoma) and mixed subjects (i.e. with a different classification for the two eyes). After quality check data were used from HRF of 73 healthy and 62 glaucomatous eyes. The amplitudes of the oxygenated and deoxygenated haemoglobin concentrations, together with their latencies with respect to the stimulus onset, were estimated by fitting their time course with a canonical HRF. Statistical analysis showed that the amplitudes of both haemodynamic parameters show a significant association with the pathology and a significant discriminating ability, while no significant result was found for latencies. Overall, our findings together with the ease of use and noninvasiveness of TD-NIRS, make this technique a promising candidate as a supporting tool for a better evaluation of the glaucoma pathology.

Prospective evaluation of the aetiology of acute otitis media with spontaneous tympanic membrane perforation.

OBJECTIVES: To evaluate the aetiological role of the main bacterial pathogens associated with acute otitis media (AOM) in children with AOM and spontaneous tympanic membrane perforation (STMP). METHODS: Between 1 May 2015 and 30 April 2016, 177 children, aged 6 months to 7 years, with AOM complicated by STMP within 12 h were prospectively enrolled. Middle ear fluid (MEF) was tested by real-time PCR for Streptococcus pneumoniae, non-typeable Haemophilus influenzae, Streptococcus pyogenes, Moraxella catarrhalis and Staphylococcus aureus. RESULTS: Among the 177 children with AOM and STMP, 92/100 (92.0%) of those with recurrent AOM and 13/77 (16.9%) without recurrent AOM had recurrent STMP (p <0.001). A single pathogen was identified in 70 (39.5%) MEF samples, whereas two, three and four bacteria were detected in 54 (30.5%), 20 (11.3%), and 7 (4.0%) cases, respectively. Non-typeable H. influenzae was the most common and was identified in 90 children (50.8%), followed by M. catarrhalis (62 cases, 35.0%) and S. pneumoniae (48 cases, 27.1%). Non-typeable H. influenzae was the most frequent pathogen in children with co-infections. Children with co-infections, including non-typeable H. influenzae, had significantly more frequent recurrent AOM (adjusted OR 6.609, 95% CI 1.243-39.096, p 0.029). CONCLUSIONS: Recurrent AOM episodes appear to be associated with an increased risk of AOM with STMP. In AOM with STMP, non-typeable H. influenzae is detected at a high frequency, especially in children with recurrent STMP and often in association with other pathogens.

Risk factors and epidemiology of Acinetobacter baumannii infections in a university hospital in Northern Italy: A case-control study.

BACKGROUND: Acinetobacter baumannii has emerged as a major cause of outbreaks of hospital-associated infections with increased morbidity and mortality among those affected. METHODS: We performed a 1:1 matched case-control study involving 68 cases in a teaching hospital in Northern Italy. Risk factors included general health conditions, comorbidities, diagnostic and therapeutic procedures, and antibiotic therapies. A multiple correspondence analysis (MCA) was performed to highlight possible association patterns among risk factors. After this, a conditional logistic regression model was applied. RESULTS: The combined results of the MCA and univariate regression models suggest that invasive procedures performed before intensive care unit admission, in particular bronchoscopy (odds ratio, 48.06) and oxygen therapy (odds ratio, 2.11), are associated with development of an infection. Malnutrition or obesity, lack of self-sufficiency, and severe liver diseases also proved to be significantly associated with infection. When analyzing antibiotic therapies, both the number of molecules administered and duration of therapy were significantly associated. CONCLUSIONS: Early recognition of patients at high risk, environmental hygiene control measures, appropriate antibiotic prescriptions, especially regarding carbapenems, and high-quality training of health care workers in all hospital departments are all key aspects for prevention and control of Acinetobacter infection. Further studies are needed to investigate the role of antibiotics on microbial competition dynamics in relation to multidrug-resistant outbreaks.

Prevalence and Risk Factors Associated with Use of QT-Prolonging Drugs in Hospitalized Older People.

AIMS: The objective of this study was to evaluate the prevalence of the prescription of QT-prolonging drugs at hospital admission and discharge and the risk factors associated with their use in older people (aged 65 years and older). METHODS: Data were obtained from the REPOSI (REgistro POliterapie SIMI [Società Italiana di Medicina Interna]) registry, which enrolled 4035 patients in 2008 (n = 1332), 2010 (n = 1380), and 2012 (n = 1323). Multivariable logistic regression was performed to determine the risk factors independently associated with QT-prolonging drug use. QT-prolonging drugs were classified by the risk of Torsades de Pointes (TdP) (definite, possible, or conditional) according to the Arizona Center for Education and Research on Therapeutics (AzCERT) classification. Specific drug combinations were also assessed. RESULTS: Among 3906 patients prescribed at least one drug at admission, 2156 (55.2%) were taking at least one QT-prolonging drug. Risk factors independently associated with the use of any QT-prolonging drugs were increasing age (odds ratio [OR] 1.02, 95% CI 1.01-1.03), multimorbidity (OR 2.69, 95% CI 2.33-3.10), hypokalemia (OR 2.79, 95% CI 1.32-5.89), atrial fibrillation (OR 1.66, 95% CI 1.40-1.98), and heart failure (OR 3.17, 95% CI 2.49-4.05). Furosemide, alone or in combination, was the most prescribed drug. Amiodarone was the most prescribed drug with a definite risk of TdP. Both the absolute number of QT-prolonging drugs (2890 vs. 3549) and the number of patients treated with them (2456 vs. 2156) increased at discharge. Among 1808 patients not prescribed QT-prolonging drugs at admission, 35.8% were prescribed them at discharge. CONCLUSIONS: Despite their risk, QT-prolonging drugs are widely prescribed to hospitalized older persons. The curriculum for both practicing physicians and medical students should be strengthened to provide more education on the appropriate use of drugs in order to improve the management of hospitalized older people.

Survey on professional training in three Italian. Post-Graduate Schools of Public Health.

BACKGROUND: In 2005 the European Union (EU) recognized the equivalence within its member states of qualifications conferred by post-graduate schools (PGS) in public health. In Italy, ministerial decree no. 176 of 1st August 2005 defined the training goals and the related training programmes (Training Activities) leading to conferral of the qualification of specialist in Public Health and Preventive Medicine (PHPM). This study aimed to develop and validate an assessment tool for professional training programmes. The purpose has been to identify and evaluate their typical features and, at the same time, to enable comparison between Italian PGSs in PHPMs. METHODS: In the first phase, a multiple-choice questionnaire was created, using a Likert scale with scores from 1 to 6. This was prepared by post-graduates attending the Milan PGS. This tool was validated by applying it to a pilot sample of post-graduates attending the Milan PGS in PHPM. Following this, a second round of discussion and validation of the model took place, involving 61 post-graduates attending PGSs in PHPM at the Universities of Palermo, Pisa and Turin. A web platform was used that enabled the survey to be created and managed by defining and managing pre-set interview templates. RESULTS: The questionnaire consisted of three sections: Section A - Twenty-eight percent of post-graduates attended their training programme in a university or research centre, 29.8% in a hospital and 35.1% in a Local Health Unit. This training program lasted more than 12 months in 37% of the cases. Section B - The answers were all above pass-level (3 to 4 = satisfactory) except as regards the level of empowerment and the workload, which was judged to be unsatisfactory overall.The skills of the staff present in the facility attended were judged favourably (3.5). Section C - Section C investigates the duration and autonomy of the activities performed during the training programmes aimed at meeting the training requirements set out in ministerial decree no. 176/2005. Among respondents, 87% had taken part in ongoing statistical public health analyses, 81% had given presentations and contributed posters in public health congresses and 79% had planned or implemented an epidemiological survey. CONCLUSIONS: A pre-set form for the assessment of training programmes by the post-graduates themselves is a useful tool with which to obtain their feedback. Public health providers must be able to view their training programme as a means of developing the numerous skills the profession requires. Eventually, they must be capable of acting autonomously, and to this end they need to interact with the numerous tutors with whom they come into contact. These latter were judged very favourably by the survey.

The influence of age on the recovery of the ERG photostress test.

INTRODUCTION: Focal ERG associated with photostress test could be a useful diagnostic method for evaluating macular visual function. The main aim of this study was to evaluate the effect of age on the recovery time constant of the ERG photostress test. The second aim was to assess the sources of variability which affect the measurements. METHODS: Fifty-four healthy subjects (108 eyes), aged between 21 and 77, with corrected VA of 20/20 or more and absence of any ocular or systemic disease, were recruited. For each eye ERG response to focal (20° in diameter) 42-Hz stimulation was recorded: three series of 200 summations in base conditions and a six series of 42-Hz ERGs (100 summations each) at 10, 40, 80, 180, 300 and 420 s after bleaching by a white spot of light (20° in diameter) from a direct ophthalmoscope (800 cd/m²) pointed at macular region for 30 s. Fourier analysis was performed and amplitude of the first harmonica calculated. The relationship of basal amplitudes with subject age and gender, and the kinetics of macular function recovery were assessed through mixed-effects models. RESULTS: Mean basal amplitude decreases by 0.046 µV for year of life. The recovery after bleaching is proportional to age with an increase of 4.31 s for decade. Restoration of amplitude is slower in older subjects. DISCUSSION: There is a significant decrease in macular ERG amplitude with age. The macular recovery after photostress shows exponential kinetics that are less efficient in older subjects: this could be related to lower effectiveness of photopigment restoration in advanced age.

An immunohistochemically positive E-cadherin status is not always predictive for a good prognosis in human breast cancer.

BACKGROUND: in primary breast cancers dichotomic classification of E-cadherin expression, according to an arbitrary cutoff, may be inadequate and lead to loss of prognostic significance or contrasting prognostic indications. We aimed to assess the prognostic value of high and low E-cadherin levels in a consecutive case series (204 cases) of unilateral node-negative non-lobular breast cancer patients with a 8-year median follow-up and that did not receive any adjuvant therapy after surgery. METHODS: expression of E-cadherin was investigated by immunohistochemistry and assessed according to conventional score (0, 1+, 2+, 3+). Multiple correspondence analysis was used to visualise associations of both categorical and continuous variables. The impact of E-cadherin expression on patients outcome was evaluated in terms of event-free survival curves by the Kaplan-Meier method and proportional hazard Cox model. RESULTS: respect to intermediate E-cadherin expression values (2+), high (3+) or low (0 to 1+) E-cadherin expression levels had a negative prognostic impact. In fact, both patients with a low-to-nil (score 0 to 1+) expression level of E-cadherin and patients with a high E-cadherin expression level (score 3+) demonstrated an increased risk of failure (respectively, hazard ratio (HR)=1.71, confidence interval (CI)=0.72-4.06 and HR=4.22, CI=1.406-12.66) and an interesting association with young age. CONCLUSIONS: the findings support the evidence that high expression values of E-cadherin are not predictive for a good prognosis and may help to explain conflicting evidence on the prognostic impact of E-cadherin in breast cancer when assessed on dichotomic basis.

A prediction model for breast cancer recurrence after adjuvant hormone therapy.

Hormone therapy with tamoxifen has long been the established adjuvant treatment for node-positive, estrogen-receptor-positive breast cancer in postmenopausal women. Since 30-40% of these patients fail to respond, reliableoutcome prediction is necessary for successful treatment allocation. Using pathobiological variables (available in mostclinical records: tumor size, nodal involvement, estrogen and progesterone receptor content) from 596 patients recruitedat a comprehensive cancer center, we developed a prediction model which we validated in an independent cohort of 175patients recruited at a general hospital. Calculated at 3 and 4 years of follow-up, the discrimination indices were 0.716[confidence limits (CL) 0.641, 0.752] and 0.714 (CL 0.650, 0.750) for the training data, and 0.726 (CL 0.591, 0.769) and0.677 (CL 0.580, 0.745) for the testing data. Waiting for more effective approaches from genomic and proteomic studies, amodel based on consolidated pathobiological variables routinely assessed at relatively low costs may be considered as thereference for assessing the gain of new markers over traditional ones, thus substantially improving the conventional use ofprognostic criteria.

Double-blind evaluation and benchmarking of survival models in a multi-centre study.

Accurate modelling of time-to-event data is of particular importance for both exploratory and predictive analysis in cancer, and can have a direct impact on clinical care. This study presents a detailed double-blind evaluation of the accuracy in out-of-sample prediction of mortality from two generic non-linear models, using artificial neural networks benchmarked against a partial logistic spline, log-normal and COX regression models. A data set containing 2880 samples was shared over the Internet using a purpose-built secure environment called GEOCONDA (www.geoconda.com). The evaluation was carried out in three parts. The first was a comparison between the predicted survival estimates for each of the four survival groups defined by the TNM staging system, against the empirical estimates derived by the Kaplan-Meier method. The second approach focused on the accurate prediction of survival over time, quantified with the time dependent C index (C(td)). Finally, calibration plots were obtained over the range of follow-up and tested using a generalization of the Hosmer-Lemeshow test. All models showed satisfactory performance, with values of C(td) of about 0.7. None of the models showed a systematic tendency towards over/under estimation of the observed survival at tau=3 and 5 years. At tau=10 years, all models underestimated the observed survival, except for COX regression which returned an overestimate. The study presents a robust and unbiased benchmarking methodology using a bespoke web facility. It was concluded that powerful, recent flexible modelling algorithms show a comparative predictive performance to that of more established methods from the medical and biological literature, for the reference data set.

Prognosis in node-negative primary breast cancer: a neural network analysis of risk profiles using routinely assessed factors.

BACKGROUND: The present study investigated complex time-dependent effects of routinely assessed factors on the risk of breast cancer recurrence over follow-up time, with a partial logistic artificial neural network (PLANN) model. PATIENTS AND METHODS: PLANN was applied to data from 1793 patients with node-negative breast cancer, not submitted to any adjuvant treatment and with a minimal potential follow-up of 10 years. RESULTS: The shape of the hazard function changed according to histology, which showed a time-dependent effect, partly modulated by estrogen receptors (ERs). Age and progesterone receptors (PgR) showed protective effects; the latter was more evident for short follow-up and high ER values. Tumour size and ER content showed time-dependent unfavourable effects at early and long follow-up times, respectively. Predicted values of disease recurrence probability at 2 years of follow-up showed that low steroid-receptor content, young age and large tumour size were associated with the highest risk of relapse. Although the oldest patients with high ER content seem to be those most protected overall, high risk predictions tend to spread also to higher steroid-receptor contents, intermediate ages and small tumour size, with an increase in follow-up time. CONCLUSION: PLANN with suitable visualisation techniques provided thorough insights into the dynamics of breast cancer recurrence for improving individual risk staging of node-negative breast cancer patients.

Vascular endothelial growth factor in node-positive breast cancer patients treated with adjuvant tamoxifen.

In 212 postmenopausal women with node-positive oestrogen receptor-positive (ER(LBA)) breast cancer subjected to radical surgery and adjuvant tamoxifen, the risk of 6-year relapse increased with increasing values of intratumoral vascular endothelial growth factor (VEGF) in patients whose tumours had a low/intermediate ER(LBA) content compared to patients with high-ER(LBA) tumours. These findings indicate that tumour progression, activated or sustained by high VEGF levels, may be counteracted in high-ER(LBA) cancers by tamoxifen, which in contrast fails to contrast the metastatic potential in low-ER(LBA) tumours.

Quality of life and length of survival in advanced cancer patients on home parenteral nutrition.

BACKGROUND: The use of home parenteral nutrition (HPN) in patients with advanced cancer is controversial because survival is usually short and there are no data regarding the quality of life (QoL). METHODS: Sixty-nine advanced cancer patients enrolled in a program of HPN in six different Italian centers were prospectively studied as regards nutritional status (body weight, serum albumin, serum transferrin and total lymphocyte count), length of survival and QoL through the Rotterdam Symptom Checklist questionnaire. These variables were collected at the start of HPN and then at monthly intervals. All these patients were severely malnourished, almost aphagic and beyond any possibility of cure. RESULTS: Nutritional indices maintained stable until death. Median survival was 4 months (range 1-14) and about one-third of patients survived more than 7 months. QoL parameters remained stable till 2-3 months before death. CONCLUSIONS: HPN may benefit a limited percentage of patients who may survive longer than the time allowed by a condition of starvation and depletion. Provided that these patients survive longer than 3 months, there is some evidence that QoL remains stable for some months and acceptable for the patients.

Prognostic role of serum CA15.3 in 362 node-negative breast cancers. An old player for a new game.

The aims of the present investigation were to evaluate the association between serum CA15.3 levels and other biological and clinical variables and its prognostic role in patients with node-negative breast cancer. We evaluated 362 patients operated upon primary breast cancer from 1982 to 1992 (median follow-up 69 months). Serum CA15.3 was measured by an immunoradiometric assay. The association between variables was investigated by a Principal Component Analysis (PCA) and the prognostic role of CA15.3 on relapse-free survival (RFS) was investigated by Cox regression models adjusting for age, oestrogen receptor (ER), tumour stage, and ER x age interaction, with both the likelihood ratio test and Harrell's c statistic. The prognostic contribution of CA 15.3 was highly significant. Log relative hazard of relapse was constant until approximately 10 (U/ml) of CA15.3 and increased thereafter with increasing marker levels. CA15.3 showed a significant contribution using as a cut-off point a value of 31 U/ml. However, the contribution to the model of the marker as a continuous variable is much greater. From these findings, we can conclude that: (i) CA15.3 is a prognostic marker in node-negative breast cancer; (ii) its relationship with prognosis is continuous, with the risk of relapse increasing progressively from approximately 10 U/ml.

Contribution of vascular endothelial growth factor to the Nottingham prognostic index in node-negative breast cancer.

The prognostic contribution of intratumour VEGF, the most important factor in tumour-induced angiogenesis, to NPI was evaluated by using flexible modelling in a series of 226 N-primary breast cancer patients in which steroid receptors and cell proliferation were also accounted for. VEGF provided an additional prognostic contribution to NPI mainly within ER-poor tumours.

Angiogenesis sustains tumor dormancy in patients with breast cancer treated with adjuvant chemotherapy.

Experimental studies performed in Folkman laboratories suggest that angiogenesis is involved in the biology of tumor dormancy. We determined the vascular index in a series of 190 women operated of node-positive invasive breast cancer treated with adjuvant chemotherapy (CMF schedule) and we studied the relationship between vascularity of primary tumors with the behaviour in time of metastasis. The study of the hazard function of recurrence (in any site) was performed resorting to a generalized linear modelling approach with a binominal error according to Efron. A total of 80 cases developed recurrences during the period of observation. We found that the hazard function of metastasis in time presented two peaks of incidence at 20 and 60 months, respectively. We also plotted the curves of the hazard function by considering three values of microvessel counts corresponding to the quartiles of their distribution. The risk of first recurrence was associated with vascular index, and the patients of the third quartile of distribution of microvessels had the highest risk. In the final full model for the risk of recurrence at 5 years vascular index provided the highest prognostic contribution followed by the number of involved axillary lymph nodes. The observation that the patients with highly angiogenic tumors are at high risk of recurrence coupled with the identification of the second peak of incidence after 5 years which was also mainly sustained by angiogenic tumors suggest that a fraction of breast cancers promote metastasis after a period of tumor dormancy. The clinical and therapeutic implications of our results are discussed.