Immunotherapy for Alzheimer's disease: from anti-β-amyloid to tau-based immunization strategies

The exact mechanisms leading to Alzheimer's disease (AD) are largely unknown, limiting the identification of effective disease-modifying therapies. The two principal neuropathological hallmarks of AD are extracellular β-amyloid (Aβ), peptide deposition (senile plaques) and intracellular neurofibrillary tangles containing hyperphosphorylated tau protein. During the last decade, most of the efforts of the pharmaceutical industry were directed against the production and accumulation of Aβ. The most innovative of the pharmacological approaches was the stimulation of Aβ clearance from the brain of AD patients via the administration of Aβ antigens (active vaccination) or anti-Aβ antibodies (passive vaccination). Several active and passive anti-Aβ vaccines are under clinical investigation. Unfortunately, the first active vaccine (AN1792, consisting of preaggregate Aβ and an immune adjuvant, QS-21) was abandoned because it caused meningoencephalitis in approximately 6% of treated patients. Anti-Aβ monoclonal antibodies (bapineuzumab and solanezumab) are now being developed. The clinical results of the initial studies with bapineuzumab were equivocal in terms of cognitive benefit. The occurrence of vasogenic edema after bapineuzumab, and more rarely brain microhemorrhages (especially in Apo E ε4 carriers), has raised concerns on the safety of these antibodies directed against the N-terminus of the Aβ peptide. Solanezumab, a humanized anti-Aβ monoclonal antibody directed against the midregion of the Aβ peptide, was shown to neutralize soluble Aβ species. Phase II studies showed a good safety profile of solanezumab, while studies on cerebrospinal and plasma biomarkers documented good signals of pharmacodynamic activity. Although some studies suggested that active immunization may be effective against tau in animal models of AD, very few studies regarding passive immunization against tau protein are currently available. The results of the large, ongoing Phase III trials with bapineuzumab and solanezumab will tell us if monoclonal anti-Aβ antibodies may slow down the rate of deterioration of AD. Based on the new diagnostic criteria of AD and on recent major failures of anti-Aβ drugs in mild-to-moderate AD patients, one could argue that clinical trials on potential disease-modifying drugs, including immunological approaches, should be performed in the early stages of AD.     

Improving Adult Immunization Practices Using a Team Approach in the Primary Care Setting

Objectives. The objective of this study was to improve the immunization rates of primary care practices using a team approach.Methods. Practices performed 35 random chart abstractions at 2 time points and completed a survey about immunizations at baseline and 12 months after intervention. Data were collected for the following immunizations: influenza, pneumococcal, tetanus diphtheria (Td)/tetanus diphtheria pertussis (Tdap), hepatitis A, hepatitis B, meningococcal, varicella, herpes zoster, and human papilloma virus. Between baseline and after intervention, practice teams were given feedback reports and access to an online educational tool, and attended quality improvement coaching conference calls.Results. Statistically significant improvements were seen for Td/Tdap (45.6% pre-intervention, 55.0% post-intervention; P ≤ .01), herpes zoster (12.3% pre-intervention, 19.3% post-intervention; P ≤ .01), and pneumococcal (52.2% pre-intervention, 74.5% post-intervention; P ≤ .01) immunizations. Data also revealed an increase in the number of physicians who discussed herpes zoster and pneumococcal vaccinations with their patients (23.2% pre-intervention, 43.3% post-intervention; P ≤ .01 and 19.9% pre-intervention, 43.0% post-intervention; P ≤ .01, respectively) as well as an increase in physicians using the Centers for Disease Control and Prevention immunization schedule (52.9% pre-intervention, 88.2% post-intervention; P ≤ .02).Conclusions. The immunization rates of the primary care practices involved in this study improved.The need for improving quality is pervasive in the primary care setting, involving physicians, their practice teams, and administrative staff. The issue of low quality is well documented1–3 and is not partial to any 1 disease condition.4–15 Poor quality is a result of our medical system’s orientation to the urgent, its focus on acute and not chronic care, lack of adherence to evidence-based guidelines, and an increasing number of patients with complex medical conditions.2 Quality is characterized as a systems issue rather than an individual one,16 which has led efforts to focus on the practice team. Practice teams have been shown to improve quality in primary care.17,18 The issues with poor quality in primary care extend to the practice of adult immunizations.19 It is estimated that between 50 000 and 70 000 US adults die each year because of diseases that could be prevented by vaccination.20 For example, influenza is the sixth leading cause of death for adults and contributes to at least 200 000 hospitalizations and 36 000 deaths annually.21,22 Economic costs associated with influenza are projected to be $87.1 billion.23Adult vaccination guidelines, such as those published by the Centers for Disease Control and Prevention (CDC) and Advisory Committee on Immunization Practices,24 are increasingly evidence-based and are a good reference for practices to measure themselves against when doing immunization practice redesign work. Although childhood vaccinations have become a public health success, adult vaccination rates are low, prompting the movement toward “lifespan immunizations.”20,25 However, quality gaps and missed opportunities for vaccination exist between the number of patients who are recommended to receive vaccinations and those who actually receive them.26–30 A variety of barriers at the practice, patient, economic, and social level help explain these missed opportunities. For instance, only 60% of physicians reported using CDC and Advisory Committee on Immunization Practice guidelines as their reference for adult immunizations, and most often reported recommending vaccinations at well visits compared with sick visits.31 Physicians also reported multiple barriers to vaccinating patients, including lack of health insurance, fear of needles, and misconception of the safety and efficacy of vaccinations.31 In turn, patients consistently reported that their physicians do not recommend vaccinations.31,32A comprehensive quality approach was considered to be more effective than mere guideline dissemination because the latter has not been shown to be successful alone in changing practice patterns.33,34 The American College of Physicians (ACP) developed this quality improvement program to help physicians and practice teams learn about the current recommendations and best practices for adult immunization. The goal of this prospective study was to improve the immunization practices of primary care practices by using a team approach.     

Determinants of patient and health care services delays for tuberculosis diagnosis in Italy: a cross-sectional observational study

Background

Prompt diagnosis of active tuberculosis (TB) has paramount importance to reduce TB morbidity and mortality and to prevent the spread of Mycobacterium tuberculosis. Few studies so far have assessed the diagnostic delay of TB and its risk factors in low-incidence countries.

Methods

We present a cross-sectional multicentre observational study enrolling all consecutive patients diagnosed with TB in seven referral centres in Italy. Information on demographic and clinical characteristics, health-seeking trajectories and patients’ knowledge and awareness of TB were collected. Diagnostic delay was assessed as patient-related (time between symptoms onset and presentation to care) and healthcare-related (time between presentation to care and TB diagnosis). Factors associated with patient-related and healthcare-related delays in the highest tertile were explored using uni- and multivariate logistic regression analyses.

Results

We enrolled 137 patients, between June 2011 and May 2012. The median diagnostic delay was 66?days (Interquartile Range [IQR] 31–146). Patient-related and healthcare-related delay were 14.5?days (IQR 0–54) and 31?days (IQR: 7.25–85), respectively. Using multivariable analysis, patients living in Italy for <?5?years were more likely to have longer patient-related delay (>?3?weeks) than those living in Italy for >?5?years (Odds Ratio [OR] 3.47; 95% Confidence Interval [CI] 1.09–11.01). The most common self-reported reasons to delay presentation to care were the mild nature of symptoms (82%) and a good self-perceived health (76%). About a quarter (26%) of patients had wrong beliefs and little knowledge of TB, although this was not associated with longer diagnostic delay. Regarding healthcare-related delay, multivariate analysis showed that extra-pulmonary TB (OR 4.3; 95% CI 1.4–13.8) and first contact with general practitioner (OR 5.1; 95% CI 1.8–14.5) were both independently associated with higher risk of healthcare-related delay >?10?weeks.

Conclusions

In this study, TB was diagnosed with a remarkable delay, mainly attributable to the healthcare services. Delay was higher in patients with extra-pulmonary disease and in those first assessed by general practitioners. We suggest the need to improve knowledge and raise awareness about TB not only in the general population but also among medical providers. Furthermore, specific programs to improve access to care should be designed for recent immigrants, at significantly high risk of patient-related delay.

Trial registration

The study protocol was registered under the US National Institute of Health ClinicalTrials.gov register, reference number: NCT01390987. Study start date: June 2011.

     

Fibrosis Evaluation by Transient Elastography in Patients With Long-Term Sustained HCV Clearance

Background

Reversibility of advanced fibrosis after HCV-clearance is an important goal of therapy.

Objectives

Measuring liver stiffness (LS) by transient elastography (TE) might be helpful in this setting.

Patients and Methods

We evaluated 104 patients with biopsy-proven chronic hepatitis C (CHC) and sustained virological response (SVR) after Peg-Interferon (IFN) plus ribavirin since at least 18 months. HCV-eradication was confirmed searching for serum HCV-RNA (TMA® sensitivity > 5-10 IU/ml). Data from literature reported the best LS cut-off values for different stages of liver fibrosis were 7.1 kPa for Metavir stage 2 (F2), 9.5 kPa for F3 and 12.5 for cirrhosis (F4).

Results

TE was not reliable in four SVR obese patients. Metavir-stage of biopsy was F0-1 in 28, F2 in 47, F3 in 17 and F4 in eight patients. The median interval elapsed since achieving SVR was 36 months (range: 18-77, SD¬¬:18). Stratifying patients according to the histological stage assessed before treatment, a clear-cut gradient of LS values was observed from F0-1: median: 3.8 kPa (range: 3.5-4.9) to F2: 4.6 kPa (3.8-6.0), F3: 6.2 kPa (4.8-8.6) and F4: 8.4 kPa (6.2-9.2) (P = 0.001). Overall, 86 patients had lower values of LS than the expected LS values according to Metavir-stage. At multivariate logistic analysis γ-GT and histological steatosis were independently associated with persistence of higher values of LS.

Conclusion

Long term responders to IFN-based therapies have lower LS values than those who are untreated and still viraemic. High levels of γ-GT and liver steatosis, all markers of insulin resistance, may hamper reduction of liver stiffness after HCV-clearance.     

Extracellular vesicles mediate the communication between multiple myeloma and bone marrow microenvironment in a NOTCH dependent way

Multiple myeloma (MM) is an incurable hematologic neoplasm, whose poor prognosis is deeply affected by the propensity of tumor cells to localize in the bone marrow (BM) and induce the protumorigenic activity of normal BM cells, leading to events associated with tumor progression, including tumor angiogenesis, osteoclastogenesis, and the spread of osteolytic bone lesions. The interplay between MM cells and the BM niche does not only rely on direct cell-cell interaction, but a crucial role is also played by MM-derived extracellular vesicles (MM-EV). Here, we demonstrated that the oncogenic NOTCH receptors are part of MM-EV cargo and play a key role in EV protumorigenic ability. We used in vitro and in vivo models to investigate the role of EV-derived NOTCH2 in stimulating the protumorigenic behavior of endothelial cells and osteoclast progenitors. Importantly, MM-EV can transfer NOTCH2 between distant cells and increase NOTCH signaling in target cells. MM-EV stimulation increases endothelial cell angiogenic ability and osteoclast differentiation in a NOTCH2-dependent way. Indeed, interfering with NOTCH2 expression in MM cells may decrease the amount of NOTCH2 also in MM-EV and affect their angiogenic and osteoclastogenic potential. Finally, we demonstrated that the pharmacologic blockade of NOTCH activation by γ-secretase inhibitors may hamper the biological effect of EV derived by MM cell lines and by the BM of MM patients. These results provide the first evidence that targeting the NOTCH pathway may be a valid therapeutic strategy to hamper the protumorigenic role of EV in MM as well as other tumors.