Euthyroid sick syndrome as an early surrogate marker of poor outcome in mild SARS-CoV-2 disease.

BACKGROUND: The new coronavirus 19 disease (COVID-19) represents the current worldwide emergency. According to past evidence, a simple biomarker, such as low free triiodothyronine (fT3) levels, within the framework of euthyroid sick syndrome (ESS), might help to identify patients with unfavourable outcomes. OBJECTIVE: Evaluation of ESS significance in hospitalized mild COVID-19 patients. DESIGN: Prospective study, from 1 April 2020 to 31 May 2021. PARTICIPANTS: COVID-19 patients with mild disease at hospital admission. MAIN MEASURES: At hospital admission, eligible patients underwent a complete thyroid function evaluation. Subjects with previous thyroid disease or with thyroid-interfering medications were excluded. Levels of fT3 were correlated to biochemical markers and to patient outcome, the latter considered as favourable in the event of infection recovery and unfavourable in the event of death or transfer to an intensive care unit (ICU). KEY RESULTS: Of 600 screened patients, 506 were eligible for this study. Of those, 94 (19%) died during hospitalization and 80 (18%) required a transfer to ICU. The most frequent thyroid disorder was ESS (57%). Admission levels of fT3 were significantly lower within the unfavourable outcome subgroup (p < 0.001) and were negatively associated with several poor prognostic markers, including IL-6 (p < 0.001). In Kaplan-Meier and Cox regression analyses, fT3 was independently associated with poor outcome and death (p = 0.005 and p = 0.037, respectively). A critical fT3 threshold for levels < 2.7 pmol/l (sensitivity 69%, specificity 61%) was associated with a 3.5-fold increased risk of negative outcome (95%CI 2.34-5.34). CONCLUSION: Low fT3 levels, in the framework of ESS, resulted as being a valid predictor of unfavourable outcomes in a very early stage population of COVID-19.

A phase 2 study of three low-dose intensity subcutaneous bortezomib regimens in elderly frail patients with untreated multiple myeloma.

This phase 2 trial evaluated three low-dose intensity subcutaneous bortezomib-based treatments in patients ⩾75 years with newly diagnosed multiple myeloma (MM). Patients received subcutaneous bortezomib plus oral prednisone (VP, N=51) or VP plus cyclophosphamide (VCP, N=51) or VP plus melphalan (VMP, N=50), followed by bortezomib maintenance, and half of the patients were frail. Response rate was 64% with VP, 67% with VCP and 86% with VMP, and very good partial response rate or better was 26%, 28.5% and 49%, respectively. Median progression-free survival was 14.0, 15.2 and 17.1 months, and 2-year OS was 60%, 70% and 76% in VP, VCP, VMP, respectively. At least one drug-related grade ⩾3 non-hematologic adverse event (AE) occurred in 22% of VP, 37% of VCP and 33% of VMP patients; the discontinuation rate for AEs was 12%, 14% and 20%, and the 6-month rate of toxicity-related deaths was 4%, 4% and 8%, respectively. The most common grade ⩾3 AEs included infections (8-20%), and constitutional (10-14%) and cardiovascular events (4-12%); peripheral neuropathy was limited (4-6%). Bortezomib maintenance was effective and feasible. VP, VCP and VMP regimens demonstrated no substantial difference. Yet, toxicity was higher with VMP, suggesting that a two-drug combination followed by maintenance should be preferred in frail patients.

Pain management in internal medicine and effects of a standardised educational intervention: the FADOI-DOMINO study.

PURPOSE: Few real-world data are available on the frequency and management of pain in Internal Medicine (IM). Aims of our study were to assess the prevalence of pain in IM, and to evaluate the effects on pain management of a standardised educational programme. MATERIALS AND METHODS: The study was performed in 26 IM Units in Italy, with two cross-sectional surveys (PRE phase and POST phase) interspersed with an educational programme. In PRE phase each Centre reviewed the hospital charts of the last 100 consecutive patients hospitalised for any cause. An educational programme was conducted in each Centre by means of the 'outreach visit', a face-to-face meeting between health personnel and a trained external expert. Six months after, each Centre repeated the data collection (POST phase), specular to the PRE. RESULTS: A total of 5200 medical charts were analysed. Pain was documented in 37.5% of the patients. After the educational intervention, the intensity of pain was appropriately assessed in a higher percentage of patients (77.4% vs. 47.8%, p = 0.0001), and it was more frequently monitored during hospitalisation. Qualitative definition of pain (pathogenesis, duration, etc.) increased in POST phase (75.4% vs. 62.7%, p = 0.0001). A 73.3% increase in the use of strong opioids was detected following educational programme. CONCLUSIONS: Pain affects 4 out of 10 patients hospitalised in IM. According to our large real-world study, to implement a standardised one-shot educational programme may persistently improve the attitude of health personnel towards the characterisation and management of pain.

Moderate alcohol use and health: a consensus document.

AIMS: The aim of this consensus paper is to review the available evidence on the association between moderate alcohol use, health and disease and to provide a working document to the scientific and health professional communities. DATA SYNTHESIS: In healthy adults and in the elderly, spontaneous consumption of alcoholic beverages within 30 g ethanol/d for men and 15 g/d for women is to be considered acceptable and do not deserve intervention by the primary care physician or the health professional in charge. Patients with increased risk for specific diseases, for example, women with familiar history of breast cancer, or subjects with familiar history of early cardiovascular disease, or cardiovascular patients should discuss with their physician their drinking habits. No abstainer should be advised to drink for health reasons. Alcohol use must be discouraged in specific physiological or personal situations or in selected age classes (children and adolescents, pregnant and lactating women and recovering alcoholics). Moreover, the possible interactions between alcohol and acute or chronic drug use must be discussed with the primary care physician. CONCLUSIONS: The choice to consume alcohol should be based on individual considerations, taking into account the influence on health and diet, the risk of alcoholism and abuse, the effect on behaviour and other factors that may vary with age and lifestyle. Moderation in drinking and development of an associated lifestyle culture should be fostered.

Relationship between clinical and BK virological response in patients with late hemorrhagic cystitis treated with cidofovir: a retrospective study from the European Group for Blood and Marrow Transplantation.

To investigate the relationship between clinical response and modification of BK viremia, we assessed retrospectively 32 cases of hemorrhagic cystitis (HC) after allogeneic hematopoietic SCT that were treated with i.v. cidofovir (CDV). They were 22 men (69%) and 10 women (31%) with a median age of 24 years, range 3-62. The median number of CDV doses was 3, range 1-8, and the treatment lasted for a median of 3 weeks, range 1-10. Clinical improvement of HC was observed in 27 patients (84%). In 12 of 32 episodes (37.5%), BK viremia was determined before every CDV administration and a complete clinical response was observed in 10 of 12 patients (83%), the reduction of BK viremia load being 1 log by 2 weeks after starting CDV. Nephrotoxicity related to CDV was observed in nine patients. Among 26 patients with 100-day follow-up, 4 of 4 patients who had a complete clinical response by 30 days were alive vs 16 of 22 (73%) who did not have the resolution of HC in this time frame. We conclude that in patients with HC, the response to CDV treatment is usually associated with a significant reduction of BK viremia load.

Atypical acute leukemia early after liver transplantation.

Acute myeloid leukemia (AML) has been rarely reported after transplantation, namely seven cases described so far. The putative mechanism of action is long-standing immunosuppression, even though no clear correlation with the type of drug has ever been demonstrated. We report the case of a 28-year-old male patient who presented with a early onset of AML after liver transplantation for hepatitis B virus-related acute liver failure. The AML was characterized by aggressive clinical features with extrahematologic sites of involvement and an atypical immunophenotype; the laboratory findings were consistent with the diagnosis of monocytic acute leukemia.

Stiff person syndrome and motor mononeuropathy with conduction block: a singular association.

The "Stiff person syndrome"(SPS) is a rare dysimmune chronic neurological disorder, sometimes paraneoplastic, characterized by progressive stiffness, painful persistent or spasmodic muscle contractions, mostly involving spine and lower extremities. In 60 to 90 percent of cases, non-paraneoplastic forms are associated to the presence of anti-glutamic acid decarboxylase (anti-GAD) antibodies in the cerebrospinal fluid and in the serum, while anti-amphiphysin antibodies are frequently associated to paraneoplastic types. The relevant treatment consists of three basic approaches: increase in the inhibitory processes in charge of muscle activity control, re-modulation of the immune response, removal of any associated neoplasia. Indications regarding the efficacy of high-dose intravenous immunoglobulin (IVIG) also in this dysimmune pathology are on the increase. We described an unusual case of autoimmune SPS associated with an exclusively motor left peroneal nerve neuropathy, with conduction block, treated with high-dose intravenous immunoglobulin (IVIG), oral cyclosporine, sodium valproate, baclofen and diazepam.

Markers of hypercoagulability and inflammation predict mortality in patients with heart failure.

BACKGROUND AND AIMS: Plasma levels of inflammatory markers are increased in chronic heart failure (HF) and are also subclinical indicators of future HF. Inflammation is strictly correlated with clotting activation, but the association between inflammation, hypercoagulability and prognosis in HF has not been previously reported. METHODS AND RESULTS: Markers of inflammation (interleukin-6; IL-6, and C-reactive protein; CRP) and hypercoagulability (D-dimer; DD, and thrombin-antithrombin III complex; TAT) were prospectively assessed in 214 subjects with New York Heart Association (NYHA) functional class II-IV HF. During a median follow-up of 8.5 months, 32 patients had an event: 13 died and 19 were hospitalized because of worsening of HF. IL-6, DD and TAT levels were all significantly associated with increased risk of death after adjustment for other known HF prognostic factors (age, gender, traditional cardiovascular risk factors, NYHA class, systolic left ventricular function, renal failure, hemoglobin, serum sodium) in a Cox multivariate proportional hazard model (P = 0.003, P = 0.01 and P = 0.02, respectively). When these markers were added simultaneously to the known prognostic factors in a new Cox multivariate model, only DD levels were significant predictors of mortality (hazard ratio [95% confidence interval; CI]: 11 [2.7-45.1], P = 0.001). The Kaplan-Meier curve revealed a significantly better outcome in patients with DD below 450 ng mL(-1). NT-pro-BNP was the only significant predictor of rehospitalization (HR [95% CI]: 5.3 [2.0-13.8], P < 0.001). CONCLUSION: Hypercoagulability and inflammation, as assessed by DD, TAT and IL-6 levels, are associated with an increased mortality risk in HF.

Epstein-Barr virus-associated post-transplant lymphoproliferative disease with central nervous system involvement after unrelated allogeneic hematopoietic stem cell transplantation.

Post-transplant lymphoproliferative disorders (PTLD) represent an heterogeneous group of abnormal lymphoid proliferation related to Epstein-Barr virus (EBV) reactivation that arise early after allogeneic hematopoietic stem cell transplant (HSCT). PLTD with central nervous system (CNS) involvement has been reported in few cases. We describe the case of a 31-year-old-man who developed an EBV-related PTLD with CNS involvement 2 months after an allogeneic unrelated HSCT for acute myeloid leukemia in first complete remission who was successfully treated with rituximab, cidofovir and intrathecal infusion of methotrexate and methylprednisolone.

Cerebellar subacute syndrome due to corticosteroid-responsive encephalopathy associated with autoimmune thyroiditis (also called "Hashimoto's encephalopathy").

The corticosteroid-responsive encephalopathy associated with autoimmune thyroiditis (the so-called "Hashimoto's Encephalopathy") is a rare disorder with multiple symptomatology, breaking out with an acute or subacute onset and having a relapsing course, not correlated to thyroid hormone levels, with autoimmune pathogenesis, and usually associated with Hashimoto's thyroiditis. In this paper, we report on a case study regarding a 46 year-old woman showing a subacute course cerebellar syndrome, associated with Hashimoto's thyroiditis, diagnosed as "Hashimoto's encephalopathy". The possible pathogenesis and the major aspects of the differential diagnostic sector are discussed with particular reference to an ataxic syndrome caused by a progressive non-familial adult onset cerebellar degeneration (PNACD), associated with the thyroid disease itself.

Iron lung versus conventional mechanical ventilation in acute exacerbation of COPD.

The aim of this randomised study was to compare the effects of iron lung ventilation (ILV) with invasive mechanical ventilation (IMV) in patients with acute respiratory failure (ARF) due to exacerbation of chronic obstructive pulmonary disease. Forty-four patients with ARF were assigned either to ILV (22 patients) or IMV (22 patients). Primary end-points were the improvement in gas exchange and complications related to mechanical ventilation. On admission ILV and IMV groups did not differ in age, simplified acute physiology score II, arterial oxygen tension (Pa,O2)/inspiratory oxygen fraction (FI,O2), arterial carbon dioxide tension (Pa,CO2) and pH. Compared with baseline, ILV and IMV induced a similar and significant improvement in Pa,O2/FI,O2, Pa,CO2 and pH after 1 h of treatment and at discontinuation of mechanical ventilation. Major complications tended to be more frequent in patients treated with IMV than in those treated with ILV (27.3% versus 4.5%), whereas mortality rate was similar (27.3% versus 18.2%). The ventilator-free days and the length of hospital stay were significantly lower in the ILV than in the IMV group. This study suggests that iron lung ventilation is as effective as invasive mechanical ventilation in improving gas exchange in chronic obstructive pulmonary disease patients with acute respiratory failure, and is associated with a tendency towards a lower rate of major complications.

Internal tandem duplications of Flt3 gene (Flt3/ITD) predicts a poor post-remission outcome in adult patients with acute non-promyelocytic leukemia.

Despite progress in AML therapy, most patients eventually relapse, even the ones with normal or favorable karyotype. Since survival is poor once relapse occurs, new genetic tools above karyotype at diagnosis are needed to predict leukemia free survival. Recently, Flt3/ITD has been reported as an independent marker for clinical outcome in most studies concerning adult AML patients. To assess the prognostic relevance of activating mutations of Flt3, pretreatment samples of 100 not-M3 AML patients, all of them subjected to an intensive chemotherapy regimen, were analyzed for Flt3/ITD; 25/100 patients had one or more Flt3-ITD. Flt3/ITD patients had higher WBC count (P = 0.005), a lower incidence of a preceding MDS (P = 0.004) and most of them had a normal karyotype. Flt3/ITD had no impact on CR achievement while karyotype remained the most powerful prognostic factor (HR 2.8 95% CI 1.2 6.3). However, post-remission outcome was significantly worsened by the presence of Flt3/ITD. Median RFS of the Flt3/ITD patients was 5 vs. 27 months compared to the patients with wild-type Flt3 (P = 0.0002); moreover, Flt3/ITD patients had a significantly poorer post-remission survival (11 vs. 38 months, P = 0.01). On multivariate analysis, the presence of Flt3-ITD significantly affected relapse free survival and post-remission survival (HR 3.1 and 2.1, respectively). Thus, post-remission outcome highly depends on Flt3 status. Flt3 mutations identify patients at high risk of relapse, who should prospectively receive, according to age, either more aggressive or alternative therapeutic approaches.

[Therapeutic infusion of heparin. Application of a nomogram correlated with weight]. / L'infusione terapeutica di eparina. Applicazione di un nomogramma correlato al peso.

We performed a retrospective study to determine whether the use of a nomogram in General Medicine Wards is superior to the empiric method for the adjustment of heparin dosage. In the period october 1998-september 1999 we treated 138 patients with continuous infusion of heparin using a weight-based nomogram. Then we compared these data (nomogram group) with data from period october 1997-september 1998, when we had treated 155 patients with heparin, using empiric method for dose adjustments (empiric group). The proportion of patients reaching the therapeutic aPTT 24 hours after the start of therapy was 90.5% in nomogram group compared with 56.1% in the empiric group (P < 0.001). The proportion of nontherapeutic and subtherapeutic aPTT was significantly reduced in the nomogram group (6.0% vs. 11.1%, P < 0.001; 13.7% vs. 19.3%, P < 0.001). Furthermore, in the nomogram group the proportion of consecutive nontherapeutic or overtherapeutic values were significantly reduced (0.1% vs. 2.2%, P < 0.001; 1.8% vs. 2.3%, P < 0.001). We conclude that a weight-based heparin nomogram adapted for own aPTT range is successfully used in General Medical Wards of a community hospital.

Aetiologic diagnosis of ischaemic stroke in the emergency department: relevance for triage and clinical management.

Effective strategies for the aetiologic diagnosis in patients with ischaemic stroke can be implemented based on simple clinical criteria and instrumental tests which can be performed in a modern emergency room (ER) within 24 hours from admission. This may bear prognostic and therapeutic relevance for patients with acute stroke. Therefore, in this study we set out to establish the feasibility and accuracy of the aetiologic diagnosis of ischaemic stroke in an ER. A total of 136 consecutive patients (mean age 72+/-10 years, 60 females) with first ever ischaemic stroke admitted during 1996-1997 were evaluated with assessment of clinical features, CT scan, ECG, ultrasonography of the extracranial arteries, transthoracic echocardiography, and, in selected patients, transoesophageal echocardiography. Patients were classified into two major categories defined as stroke of determined origin and stroke of undetermined origin (a stroke with two or more possible causes or with a negative evaluation), according to the TOAST criteria. Ninety-six patients were considered affected by stroke of determined origin (70.5%), (22.7% with large artery atherosclerosis, 19.1% with cardioembolic stroke, 26.4% with lacunar stroke and 1.4% with other aetiology). The remaining 40 patients (29.4%) had stroke of undetermined origin: of these, 13 patients (9.5%) had a totally negative evaluation, 15 patients (12.5%) showed cardioembolism among the two or more possible causes of stroke and seven patients (5.1%) had atherothrombotic or lacunar aetiology. Additional work-up with transoesophageal echocardiography succeeded in demonstrating aortic embolism in five patients (3.6%; i.e. four patients with aortic plaques more than 4 mm in thickness and one patient with ulcerated plaques). In conclusion, the subtype classification system for ischaemic stroke allowed the aetiological diagnosis in 70.5% of patients while in the ER. Stroke of undetermined origin represented one-third of patients in a consecutive population with acute onset neurologic deficit of ischaemic origin. In approximately half of the patients with negative standard evaluation, cardiogenic or aortic arch embolic sources could be identified by transoesophageal echocardiography. Thus, the latter is indicated in patients with stroke of undetermined origin with negative first-line evaluation in order to identify embolic sources in the aortic arch.