Vitamin K insufficiency and the prophylaxis strategy in term healthy infants: A multicentre study.

BACKGROUND/AIM: Late vitamin K deficiency bleeding (VKDB) during early infancy is a serious problem worldwide. Vitamin K (VK) deficiency commonly occurs in newborns who are exclusively breastfed. Protein Induced by VK Absence (PIVKA-II) has been identified as an early indicator of subclinical VK deficiency in neonates, surpassing prothrombin time. To assess PIVKA-II levels at 48 h, 1 and 3 months of age in full-term newborns who were exclusively breastfed and received varying VKDB prophylaxis regimens. METHODS: A prospective observational study was conducted in four hospitals, enrolling 105 newborns. PIVKA-II levels were measured using a sandwich-type enzyme-linked immunosorbent assay. RESULTS: At 48 h of age, there was no significant difference in PIVKA-II concentrations between newborns who received intramuscular administration of 1 mg of phylloquinone (VK1) and those who received oral administration of 2 mg of VK1 at birth. At 1 and 3 months of life, infants who received any supplementation regimen between 2 and 14 weeks exhibited significantly lower PIVKA-II concentrations compared to infants who received only 1 mg of intramuscular VK1 at birth. The prophylaxis involving a dose of 1 mg of intramuscular VK1 at birth followed by oral administration of 150 µg/day of VK1 from the 2nd to the 14th week of life showed the lowest PIVKA-II blood concentrations. CONCLUSIONS: Oral supplementation of VK1 after discharge significantly reduced PIVKA-II concentrations in exclusively breastfed term infants. These findings suggest the importance of oral VK1 supplementation in exclusively breastfed infants during their first 3 months of life to avoid the risk of VK insufficiency.

Circulating Cytokine and Chemokine Profiles of Trypanosoma cruzi-Infected Women During Pregnancy and Its Association With Congenital Transmission.

BACKGROUND: Trypanosoma cruzi, the causative agent of Chagas disease, can be transmitted to the offspring of infected women, which constitutes an epidemiologically significant parasite transmission route in nonendemic areas. It is relevant to evaluate differentially expressed factors in T. cruzi-infected pregnant women as potential markers of Chagas congenital transmission. METHODS: Circulating levels of 12 cytokines and chemokines were measured by enzyme-linked immunosorbent assay or cytometric bead array in T. cruzi-infected and uninfected pregnant women in their second trimester of pregnancy and control groups of T. cruzi-infected and uninfected nonpregnant women. RESULTS: Trypanosoma cruzi-infected women showed a proinflammatory Th1-biased profile, with increased levels of tumor necrosis factor (TNF)-α, interleukin (IL)-12p70, IL-15, and monokine induced by interferon-gamma (MIG). Uninfected pregnant women presented a biased response towards Th2/Th17/Treg profiles, with increased plasma levels of IL-5, IL-6, IL-1ß, IL-17A, and IL-10. Finally, we identified that high parasitemia together with low levels of TNF-α, IL-15, and IL-17, low TNF-α/IL-10 ratio, and high IL-12p70 levels are factors associated with an increased probability of Chagas congenital transmission. CONCLUSIONS: Trypanosoma cruzi-infected pregnant women who did not transmit the infection to their babies exhibited a distinct proinflammatory cytokine profile that might serve as a potential predictive marker of congenital transmission.

Reduced Trypanosoma cruzi-specific humoral response and enhanced T cell immunity after treatment interruption with benznidazole in chronic Chagas disease.

BACKGROUND: Interruption of benznidazole therapy due to the appearance of adverse effects, which is presumed to lead to treatment failure, is a major drawback in the treatment of chronic Chagas disease. METHODS: Trypanosoma cruzi-specific humoral and T cell responses, T cell phenotype and parasite load were measured to compare the outcome in 33 subjects with chronic Chagas disease treated with an incomplete benznidazole regimen and 58 subjects treated with the complete regimen, during a median follow-up period of 48 months. RESULTS: Both treatment regimens induced a reduction in the T. cruzi-specific antibody levels and similar rates of treatment failure when evaluated using quantitative PCR. Regardless of the regimen, polyfunctional CD4+ T cells increased in the subjects, with successful treatment outcome defined as a decrease of T. cruzi-specific antibodies. Regardless of the serological outcome, naive and central memory T cells increased after both regimens. A decrease in CD4+ HLA-DR+ T cells was associated with successful treatment in both regimens. The cytokine profiles of subjects with successful treatment showed fewer inflammatory mediators than those of the untreated T. cruzi-infected subjects. High levels of T cells expressing IL-7 receptor and low levels of CD8+ T cells expressing the programmed cell death protein 1 at baseline were associated with successful treatment following benznidazole interruption. CONCLUSIONS: These findings challenge the notion that treatment failure is the sole potential outcome of an incomplete benznidazole regimen and support the need for further assessment of the treatment protocols for chronic Chagas disease.

Antimitochondrial Antibodies and Primary Biliary Cholangitis in Patients with Polymyalgia Rheumatica/Giant Cell Arteritis.

Background and Objectives: Laboratory liver abnormalities can be observed in patients affected with polymyalgia rheumatica (PMR) and/or giant cell arteritis (GCA), especially with a cholestatic pattern. The first objective of our review article is to discuss the potential link between antimitochondrial antibodies (AMA) and/or primary biliary cholangitis (PBC) and PMR/GCA, according to the evidences of literature. The second objective is to discuss the association of PMR/GCA with the other rheumatic diseases having PBC as a common manifestation. Materials and Methods: A literature search was performed on PubMed and Medline (OVID interface) using these terms: polymyalgia rheumatica, giant cell arteritis, antimitochondrial antibodies, primary biliary cholangitis, primary Sjogren's syndrome, systemic sclerosis, and systemic lupus erythematosus. The search was restricted to all studies and case reports published in any language. Reviews, conference abstracts, comments, and non-original articles were excluded; however, each review's reference list was scanned for additional publications meeting this study's aim. When papers reported data partially presented in previous articles, we referred to the most recent published data. Results and Conclusions: Our literature search highlighted that cases reporting an association between AMA, PBC and PMR/GCA were very uncommon; AMA antigenic specificity had never been detected and biopsy-proven PBC was reported only in one patient with PMR/GCA. Finally, the association of PMR/GCA with autoimmune rheumatic diseases in which PBC is relatively common was anecdotal.

New Scheme of Intermittent Benznidazole Administration in Patients Chronically Infected with Trypanosoma cruzi: Clinical, Parasitological, and Serological Assessment after Three Years of Follow-Up.

In a pilot study, we showed that the intermittent administration of benznidazole in chronic Chagas disease patients resulted in a low rate of treatment suspension and therapeutic failure, as assessed by quantitative PCR (qPCR) at the end of treatment. Here, a 3-year posttreatment follow-up study of the same cohort of patients is presented. The treatment scheme consisted of 12 doses of benznidazole at 5 mg/kg of body weight/day in two daily doses every 5 days. Parasite load, Trypanosoma cruzi-specific antibodies, and serum chemokine levels were measured prior to treatment and after a median follow-up of 36 months posttreatment by DNA minicircle kinetoplastid and nuclear DNA satellite sequence qPCR methods, conventional serological techniques, a Luminex-based assay with recombinant T. cruzi proteins, and a cytometric bead array. At the end of follow-up, 14 of 17 (82%) patients had negative qPCR findings, whereas three of 17 (18%) had detectable nonquantifiable findings by at least one of the qPCR techniques. A decline in parasite-specific antibodies at 12 months posttreatment was confirmed by conventional serological tests and the Luminex assays. Monocyte chemoattractant protein 1 levels increased after treatment, whereas monokine induced by gamma interferon levels decreased. New posttreatment electrocardiographic abnormalities were observed in only one patient who had cardiomyopathy prior to treatment. Together, these data strengthen our previous findings by showing that the intermittent administration of benznidazole results in a low rate of treatment suspension, with treatment efficacy comparable to that of a daily dose of 5 mg/kg for 60 days.

Radioguided sentinel node biopsy to avoid unnecessary neck dissection in T1-T2N0 oral cavity squamous cell carcinoma: personal experience with same day protocol.

PURPOSE: Data from literature show a mean incidence of occult metastases of 33% in early OCSCC. The gold standard for most authors is a selective neck dissection and a routine pathological examination. 60-70% of unnecessary neck dissections with associated morbidity, can be avoided by using SNB. The aim of this study is to present the results of one of the major Italian centres for the SNB procedure, reserving neck dissection only for proven positive lymphatic metastases. METHODS: From July 2004 to March 2015, 48 patients with transorally resectable cT1-T2N0 oral SCC were submitted to a lymphoscintigraphic examination one-three hours before surgery and a radio-guided SNB (same day protocol). Patients with a negative SNB were checked every 3 months by ultrasound examination. The minimum follow-up was 5 years. RESULTS: Sentinel nodes were found in all cases, with 71% localized in the ipsilateral neck only in levels I-II. Metastases were found in 15 out of 48 cases (31.2%), on levels I, II and III. Further metastatic nodes were found in 6 cases in the neck dissection specimen. In the cohort of 33 patients with SNB negative at 5 years, no-one had a recurrence on the ipsilateral neck. CONCLUSION: This study confirms the accuracy of SNB in predicting the presence of occult metastases, sparing the need for unnecessary neck dissection in 70% of cases. The same day protocol is designed to detect sentinel nodes, which are almost always on neck level I-II, thereby limiting the number of nodes examined and the extension of the surgical approach.

Polymyalgia rheumatica with normal inflammatory indices at the time of diagnosis: can we just move a step forward?

The existence of polymyalgia rheumatica (PMR) with normal inflammatory indices at the time of diagnosis still represents a diagnostic conundrum. According to the literature, some patients with PMR following immune checkpoint inhibitory therapy had normal values of both erythrocyte sedimentation rate and C-reactive protein concentrations at the time of diagnosis. In this short communication we investigated the possibility that in some patients with PMR the main pathogenic mechanism is constituted by inhibition of some checkpoints, such as programmed death receptor-1, programmed death ligand 1, and "cytotoxic" lymphocyte antigen 4. In these patients, the pathogenetic mechanisms underlying PMR can act much more upstream than commonly suggested. Also, we addressed the question of whether these patients should be considered as affected by PMR-like syndromes or by PMR subset.

Depression and depressive symptoms in patients with polymyalgia rheumatica: discussion points, grey areas and unmet needs emerging from a systematic review of published literature.

OBJECTIVES: In 1979, Bird et al. proposed depression as a diagnostic criterion for polymyalgia rheumatica (PMR). More recently, the significance of depression in PMR patients has been re-proposed, , and some researchers have suggested that PMR may increase the risk of depression. The aim of our article is to evaluate the relationship between PMR and depression. MATERIAL AND METHODS: Systematic literature searches were performed on 19th and 20th May 2020 based on Preferred Reporting Items for Systematic reviews and Meta-Analyses (PRISMA) guidelines. The search was restricted to all studies and case reports with English abstract, published in any language, since 1979 (when depression was first proposed as a diagnostic criterion for PMR) describing the association of PMR with depression. Exclusion criteria were as follows: reviews, conference abstracts, comments, non-original articles; and articles discussing giant cell arteritis (GCA) and PMR when data and observations for the two conditions were not clearly subdivided. RESULTS: The initial search yielded 812 papers, of which 115 duplicates were removed. A total of 697 articles had a first screening and 506 were excluded based on title and abstract reviews; 117 articles underwent full-length scrutiny, and 99 full-text articles were excluded because they did not meet the inclusion and exclusion criteria (reviews and comments = 58; articles with outcome of interest not reported = 34; low-quality articles = 7). At least, 18 articles were included in this review. CONCLUSIONS: The review did not find any studies that clarified the prevalence rates of depression in patients with PMR. Furthermore, the studies reviewed did not offer any clarity as to whether patients suffered from just depressive symptoms or clinical depression, and that accepted diagnostic criteria for depression had not been employed, indicating that a robust method for diagnosing depression had not been employed. Collaboration of different professionals should be improved through shared guidelines.

Diagnosis of polymyalgia rheumatica in primary health care: favoring and confounding factors - a cohort study.

OBJECTIVES: To evaluate in a primary care setting the favoring and confounding factors for the diagnosis of polymyalgia rheumatica (PMR). MATERIAL AND METHODS: Among 303 patients consecutively referred by their general practitioners (GPs) to our rheumatologic outpatient clinic, we identified three groups: group A - patients with confirmed diagnosis of PMR, group B - patients with unconfirmed diagnosis, group C - patients with unrecognized PMR. All the diagnostic confounding and favoring factors were discussed with GPs using an e-mail questionnaire. Participation in rheumatology training courses represented the final question. The collected data were statistically assessed in a blind way. In Fisher's exact test and ANOVA test, a p-value was significant if < 0.05. The study was carried out in compliance with the Helsinki Declaration and approved by the Ethics Committee of Mariano Lauro Hospital. Every patient signed an informed consent form at the time of the first visit. RESULTS: All patients were Caucasian; 24.1% were male; mean age was 72.3 ±8.6 years (min. - 51, max. - 94). There were 41 patients in group A, 93 in group B and 169 in group C. The percentage of misdiagnoses was very high (87.1%): among 134 patients diagnosed with PMR by their GPs (group A + group B) confirmation was made in 41, and in 169 unrecognized PMR was found. Participation in training courses was very significant compared to the diagnostic accuracy (p < 0.0001 in χ2 test) and to the diagnosis timing (24.3 days ±12.5 vs. 42.9 ±15.5 with p-value < 0.05 in the ANOVA test). When the percentages were assessed according to participation, an inadequate evaluation of some clinical manifestations favored over-diagnosis among the trained GPs. CONCLUSIONS: The level of diagnostic accuracy for PMR must be improved in primary care. Participation in rheumatology training courses can be an important step.

ANMCO Position Paper: long-term follow-up of patients with pulmonary thromboembolism.

Venous thromboembolism (VTE), including pulmonary embolism and deep venous thrombosis, is the third most common cause of cardiovascular death. The management of the acute phase of VTE has already been described in several guidelines. However, the management of the follow-up (FU) of these patients has been poorly defined. This consensus document, created by the Italian cardiologists, wants to clarify this issue using the currently available evidence in VTE. Clinical and instrumental data acquired during the acute phase of the disease are the cornerstone for planning the FU. Acquired or congenital thrombophilic disorders could be identified in apparently unprovoked VTE during the FU. In other cases, an occult cancer could be discovered after a VTE. The main targets of the post-acute management are to prevent recurrence of VTE and to identify the patients who can develop a chronic thromboembolic pulmonary hypertension. Knowledge of pathophysiology and therapeutic approaches is fundamental to decide the most appropriate long-term treatment. Moreover, prognostic stratification during the FU should be constantly updated on the basis of the new evidence acquired. Currently, the cornerstone of VTE treatment is represented by both the oral and the parenteral anticoagulation. Novel oral anticoagulants should be an interesting alternative in the long-term treatment.

Relapse of polymyalgia rheumatica after a fall.

Approximately half of PMR patients have a relapse with a necessity to increase GC dosages. The role of external factors in inducing PMR relapse have been poorly investigated. We present a case-series of five PMR patients in remission with low doses of glucocorticosteroids (GC), who presented with relapse immediately after a fall. The assessment of PMR relapse was made using PMR-AS by Leeb and Bird, and a score > 9.35 was consistent with diagnosis of relapse. Gender, age, and cumulative dose of GC at the time of the fall were compared between the group of these five patients and a group of 41 PMR patients who had no PMR relapse after a fall: using the Fischer's exact test a significant difference was pointed out when the p-value was < 0.05. In our five PMR patients, the sharp worsening of clinical manifestations was always accompanied by a significant rise of the inflammatory indices and the increase of GC dosage (almost always 10 mg/day of prednisone) prompted a fast return (seven days as average) to the previous clinical and laboratory features. All other potentially responsible factors were excluded. Several months (6-10 months on average) after the fall, none of these five patients had a new relapse. No significant differences were found when we compared age, sex, and the cumulative dose of GC at the time of the fall between the group of patients with PMR relapse and the group of patients without. The possibility of PMR relapse being realised immediately after a fall should be kept in mind in daily practice, especially when typical manifestations reappear immediately after a fall and other diagnostic hypotheses have been carefully excluded. The lack of important data (genetic factors, hormonal dosages, serum levels of IL-6 and/or serum soluble IL-6 receptor) in our case-series represented important limits for clarifying the nature of our observations and should be included in any subsequent study design on this argument. If our monocentric data are confirmed by multicentric data, the assessment of the risk of falls through specific scales should be an integral part of the visit of all PMR patients.

Acute pulmonary embolism: mortality prediction by the 2014 European Society of Cardiology risk stratification model.

The European Society of Cardiology (ESC) has proposed an updated risk stratification model for death in patients with acute pulmonary embolism based on clinical scores (Pulmonary Embolism Severity Index (PESI) or simplified PESI (sPESI)), right ventricle dysfunction (RVD) and elevated serum troponin (2014 ESC model).We assessed the ability of the 2014 ESC model to predict 30-day death after acute pulmonary embolism. Consecutive patients with symptomatic, confirmed pulmonary embolism included in prospective cohorts were merged in a collaborative database. Patients' risk was classified as high (shock or hypotension), intermediate-high (RVD and elevated troponin), intermediate-low (RVD or increased troponin or none) and low (sPESI 0). Study outcomes were death and pulmonary embolism-related death at 30 days.Among 906 patients (mean±sd age 68±16, 489 females), death and pulmonary embolism-related death occurred in 7.2% and 4.1%, respectively. Death rate was 22% in "high-risk" (95% CI 14.0-29.8), 7.7% in "intermediate-high-risk" (95% CI 4.5-10.9) and 6.0% in "intermediate-low-risk" patients (95% CI 3.4-8.6). One of the 196 "low-risk" patients died (0.5%, 95% CI 0-1.0; negative predictive value 99.5%).By using the 2014 ESC model, RVD or troponin tests would be avoided in about 20% of patients (sPESI 0), preserving a high negative predictive value. Risk stratification in patients at intermediate risk requires further improvement.

Biomarkers and Biochemical Indicators to Evaluate Bone Metabolism in Preterm Neonates.

The purpose of the present study was to evaluate the concentrations of some bone turnover markers in preterm neonates with uncomplicated clinical course in the first month of life. Samples from 13 preterm neonates were collected at three different times: at birth (T0) from umbilical cord blood (UCB); and at 15 (T1) and 30 (T2) days of life from peripheral blood (PB). The concentrations of calcium (Ca), phosphate (P), total alkaline phosphatase (ALP), Collagen Type 1 Amino-terminal Propeptide (PINP), osteocalcin (OC), Collagen Type 1 Carboxyl-Terminal Telopeptide (CTX) and Leptin were assessed. A statistically significant difference for ALP concentration at birth versus T1 and T2 was found. An evident increase in the median concentrations of CTX, OC and PINP from T0 to T2 were observed. A significant difference was also found for Leptin concentration at T0 compared to T1. In preterm infants, in the absence of acute or chronic medical conditions and without risk factors for metabolic bone disease (MBD) of prematurity, there is a significant increase in bone turnover markers during the first month of life. The knowledge of the variations in these markers in the first weeks of life, integrated by the variations in the biochemical indicators of bone metabolism, could help in recognizing any conditions at risk of developing bone diseases.

Increased Natural Killer (NK)-cell cytotoxicity and Trypanosoma cruzi-specific memory B cells in subjects with discordant serology for Chagas disease.

The presence of memory T cell specific for Trypanosoma cruzi in subjects with discordant serology for Chagas disease supports a cleared infection in these subjects. Using high-dimensional flow cytometry, ELISPOT assays and quantitative PCR, antibody-secreting cells and memory B cells specific for T. cruzi, total B-cell phenotypes, innate immune responses and parasite DNA were evaluated in serodiscordant, seropositive and seronegative subjects for T. cruzi infection. T. cruzi-specific memory B cells but no antibody-secreting cells specific for T. cruzi, increased proportion of nonclassical monocytes and increased levels of polyfunctional NK cells were found in serodiscordant compared with seropositive subjects. None of the serodiscordant subjects evaluated showed detectable parasite DNA, most of them did not show cardiac abnormalities and a group of them had had confirmed positive serology for Chagas disease. The unique immune profiles in serodiscordant subjects support that T. cruzi infection was cleared or profoundly controlled in these subjects.