LINDO (private) WING of St.Mary's (teaching) Hosp LONDON (now part of IMPERIAL COLLEGE)

1937 F.C.LINDO , Hospital Board Member donated GBP 100,000 ($10-million today) St.Mary's Hosp on Praed St.close to PADDINGTON STATION(connection with Ascot, Eton, Oxford & Windsor). Menu & wine service. Cost of parturition between GBP 6-10,000.

FUTURE MEDICINE: Prof.S.SCHEY on MULTIPLE MYELOMA

International Journal of Hematologic Oncology April 2013, Vol. 2, No. 2, Pages 109-112 , DOI 10.2217/ijh.13.7 (doi:10.2217/ijh.13.7) Interview: A lifetime of working to improve outcomes in multiple myeloma Steve Schey* Steve Schey speaks to Roshaine Gunawardana, Managing Commissioning Editor: Professor Stephen Schey is Consultant Haematologist and Honorary Senior Lecturer at King’s College Hospital and King’s College School of Medicine, King’s College London (London, UK). Schey qualified at St George’s Hospital (London, UK) in 1974, and later travelled to Australia where he worked at the Institute of Clinical Pathology and Medical Research in Sydney as Clinical Lecturer in Haematology. Subsequently, he returned to London to work at the Royal Free Hospital as Transplant Co-ordinator before working at the Royal Marsden (London, UK) and later the Middlesex Hospital (London, UK). Schey took up a Senior Lecturer post in 1985 and subsequently served as Director of Clinical Haematology for the Guy’s and St Thomas’ National Health Service (NHS) Foundation Trust from 1993 to 2004. Schey has contributed his services to a number of national and international professional bodies. He was chair of the UK Myeloma Forum from 2003 to 2009, following two terms as the Secretary from 1997. This was a productive period during which Schey managed the development of guidelines, clinical trials and advocacy for the UK Myeloma Forum patients and healthcare professionals. He has been Clinical Research Lead for the South East London Cancer Network since 2005. He also served on the National Cancer Research Institute (NCRI) Haemoncology Cancer Steering Group between 2002 and 2010, the NCRI Industry Adoption Panel and was Chairman of the NCRI Myeloma Clinical Trials Committee until 2010. Schey was a member of the American Society for Hematology (ASH) Scientific Committee for Immunosecretory Disorders. He is currently the Professor of Plasma Cell Dyscrasias at King’s College London. Q What led to your initial interest in hematology and how did this evolve into a more specific interest in hemoncology? Previous sectionNext section I fell into hematology fortuitously when I took time out in the late 1970s and early 1980s to travel around the world. I initially had a job as a lecturer in medicine at Princess Alexandra Hospital (Brisbane, Australia) and was offered a post in the Institute of Pathology and Medical Research (Sydney, Australia) as a clinical lecturer in hematology at the Institute of Clinical Pathology and Medical Research in Westmead Hospital (Sydney, Australia) by the Director at that time, Dr Wilbur Hughes. He was a superb teacher and I was fortunate enough to become involved in establishing the Bone Marrow Transplant Unit at Westmead and to then be offered a job back in the UK at the Royal Free Hospital in London (London, UK) as Transplant Coordinator by Professor Grant Prentice. My training and exposure to such leaders in the field of this exciting, newly emerging therapeutic area of hemopoeitic stem cell transplantation, here and subsequently at the Middlesex Hospital (London, UK), resulted in me developing an interest in malignant hematology. When I obtained my first consultant job at Guy’s Hospital (London, UK) in 1985, I realized that myeloma was a field where progress had not been made in the previous 25 years, unlike many other hematological tumors, and I resolved to focus my efforts on investigating this malignancy to improve outcomes. Q Some of your research interests include multiple myeloma and the bone marrow microenvironment. Can you briefly describe your latest research in these areas? The crosstalk between multiple myeloma (MM) cells and the cells in the bone marrow (BM) microenvironment, such as osteoblasts, osteoclasts, stromal cells and endothelial cells, are mediated by both soluble factors, as well as by cell–cell contact-dependent mechanisms, such as cellular adhesion molecules and interactions with extracellular matrix proteins. Such interactions result in antiapoptotic signaling and drug resistance, and myeloma cell survival, proliferation and apoptosis can therefore be modulated by both interacting directly with the myeloma cell itself and indirectly through influencing the cellular milieu of the BM. The myeloma group at King’s College London (London, UK) has been studying: ▪ The coordination between integrin-mediated adhesions and actin dynamics leading to cell polarity, directional migration and tissue invasion; ▪ The reciprocal communication between the cytoplasm and the nucleus through the organization of adhesion/cytoskeletal complexes leading to changes in protein levels that regulate the migratory/adhesive properties and tumor-initiating potential of cancer cells. We are currently studying the dynamics of adhesion and cytoskeletal remodeling in myeloma- and tumor-associated myeloid cells (macrophages, dendritic cells and osteoclasts) within the BM microenvironment. We believe these interactions are crucial for the proliferative potential of myeloma cells, their adhesion-dependent drug resistance and tissue invasion. They are also critical for specific features of myeloma, such as hyperactivation of osteoclasts leading to bone lytic lesions and fractures in patients. Currently under investigation is the myeloma cell podia. We are the first group to have identified and characterize podia as the structures that myeloma cells form to interact with BM stromal cells leading to cell adhesion-mediated drug resistance [1]. We combine our basic science with translational research to identify new anticancer therapies by performing functional studies to determine whether specific signaling pathways that are associated with cell adhesion in the tumor microenvironment can be used as therapeutic targets. In order to validate the identified targets we have developed a fluorescence-based experimental model based on fluorimetry, flow cytometry and image analysis that employs mCherry-labeled stromal cells (e.g., BM fibroblastic stromal cells) cocultured in direct contact with enhanced GFP-labeled tumor cell lines for accurate assessment of proliferation and viability in both cell compartments and adhesion of tumor cells. In addition, we use fluorescent-based image analysis to determine morphological changes that predict cell function (e.g., morphology of the actin cytoskeleton and nuclearity of osteoclasts to predict their bone resorption activity). Using this platform we have revealed that dexamethasone induces HS5 fibroblast proliferation and contact with MM cells via a process involving Src/c-Abl kinases. Osteoclasts also inhibited dexamethasone-induced apoptosis in myeloma cells while retaining their normal morphology and functionality in bone resorption. Myeloma resistance to dexamethasone supported by HS5 cells and osteoclasts was reversed by treatment with the Src/c-Abl inhibitor dasatinib but not with bortezomib. This model is scalable to high-throughput application and can be used for more accurate screening of drug efficacy in MM [2]. Effective candidates identified in vitro are then tested in vivo using a myeloma mouse model that we use for basic in vivo studies on adhesion and migration, and use this information to identify combinations that will lead to clinical trials. This new experimental platform provides a more focused model for screening of new therapeutics for improved efficacy of tumor cell killing within the BM microenvironment. Q Your expertise also extends to hemopoeitic stem cell transplantation. How have you seen this technique and its application develop in recent years? Previous sectionNext section The year before I qualified in 1968 the first successful hemopoeitic cell transplant was performed on three patients with severe combined immunodeficiency disease in The Netherlands and the USA. Over the last 40 years there has been an explosion in our knowledge of hemopoiesis and immune biology that has seen better tissue typing and an expanding source of hemopoietic stem cells that has made this approach safer and available to a much increased number of patients. While autologous and allogeneic stem cell transplantation are set to play a role in patient management in the future, current research is looking at identifying which patients are most likely to benefit and, equally as important, who is not likely to benefit from transplantation and at what point in the pathway it should be applied. Biological and genetic engineering of the graft in the future may also be utilized to capitalize on the graft-versus-tumor effect to eradicate tumor stem cells. Q In your experience, what are the main challenges associated with the treatment of MM patients? Previous sectionNext section The massive increase in our understanding of the biology as well as the molecular and cytogenetic anomalies that underlie myeloma has resulted in an appreciation of the fact that myeloma is a heterogeneous disease. This knowledge has, in turn, led to the development of a large number of different classes of novel therapeutic agents and the concept of targeted therapy. Unfortunately, cytogenetic mutations are rarely single abnormalities, may vary in different parts of the tumor, and evolve and change over time, maybe even being driven by treatment. Hence, if one molecular pathway is therapeutically blocked the tumor can overcome this by utilizing a previously redundant pathway for progression or survival. For this reason no single drug is likely to be effective in all patients at all stages of the disease and this is the rationale that has led to combination treatment. Given the large and increasing number of new drugs that are in development, the challenge is to select and optimize appropriate drug combinations and to design and conduct clinical trials to identify the most effective combinations going forward. Although responses utilizing triple agents are approaching 100%, virtually all patients will relapse and die of their disease. We know that the microenvironmental tumor niche is able to protect the myeloma progenitor/stem cell from the effects of antitumor drugs, therefore, we need to devise ways of attacking the tumor precursors in their BM niche if we are to prevent relapse and cure the disease. The challenge is to develop strategies utilizing agents that will either attack the tumor cell in the BM niches or render them susceptible to currently available treatments. Q You have been the chief investigator and coinvestigator for several clinical trials. Why does drug-development research appeal to you? Previous sectionNext section The exciting thing about hematology is that when you see a patient you have the opportunity to follow them through all stages of the diagnostic and therapeutic pathway, first by assessing them clinically and then by performing and analyzing the laboratory investigations in order to come to a diagnosis. Patient-orientated clinical research offers the opportunity to then treat patients in novel ways to improve outcomes while investigating mechanisms of action. Q Could you outline the aims of the recent Phase III trial (MM-003) investigating pomalidomide in combination with low-dose dexamethasone? Previous sectionNext section The recent Phase III (MM-003) pomalidomide trial was a multicenter, randomized, open-label study comparing the efficacy and safety of pomalidomide in combination with low-dose dexamethasone versus high-dose dexamethasone in subjects with refractory, or relapsed and refractory MM [3]. Patients were eligible if they progressed on treatment or relapsed within 60 days of discontinuing their last antimyeloma treatment, which had to have included bortezomib and lenalidomide, either alone or in combination. Treatment was continued until disease progression or unacceptable toxicity occured. The primary end point was progression-free survival. Secondary end points were overall survival, overall response rate, time to progression and safety. Recent retrospective data published by a multicenter international myeloma working group [4] showed that in 286 myeloma patients who relapsed and/or were refractory to bortezomib, and relapsed or refractory to or ineligible to receive an immunomodulatory drug, the median overall survival and event-free survival were 9 and 5 months, respectively. This demonstrates an unmet need for patients who are no longer eligible or are unresponsive to current treatment options. Q How does pomalidomide differ from other available drugs, such as lenalidomide, and what were the main outcomes of the trial? Previous sectionNext section Pomalidomide is a new third-generation immunomodulatory agent originally known as CC-4047 that demonstrates in vitro anti-MM activity, and when compared with thalidomide and lenalidomide (Actimid™), has enhanced immunomodulatory activity through multiple mechanisms, including a direct apoptotic activity via caspase-8, inhibition of NF-κB activation and angiogenesis, and reduction of secretion of stromal cell stimulatory cytokines. Our first-in-man Phase I study of pomalidomide as a single agent in patients with relapsed/refractory MM established the maximum tolerated dose as 2 mg daily on days 1–28 of a 28-day cycle, and a subsequent study of 5 mg on alternate days was shown to be equally efficacious. The drug was well tolerated, the main side effect being myelosuppression, particularly neutropenia, but with a low rate of febrile neutropenia. Subsequently, it has been shown that when given in combination with dexamethasone in the relapsed/refractory setting it can induce partial responses in up to 67% of patients and very good partial responses or better in 33% of patients with median progression-free survivals of up to 12 months. Pomalidomide also shows activity in patients who are refractory to lenalidomide. More recently, the Mayo Group have shown refractoriness to both lenaolidomide and bortezomib using two different doses of pomalidomide in patients, with rates of minimal response in the 4- and 2-mg cohorts of 49 and 43%, respectively, including very good partial remission and partial response rates of 28.5 and 26%, respectively [5]. Furthermore, the responses occur rapidly within 2 months of initiating therapy and the median duration of response was not reached in the 2-mg dose study. Follow-up was only for 6 months but overall survival rates were 67 and 78% in the 4- and 2-mg cohorts. The average previous number of therapies in this current trial was five and 72% of patient entered were refractory to prior use of both lenalidomide and bortezomib. After a median follow-up of 18 months a significant increase in progression-free survival of 15.7 weeks in the combination of pomalidomide with low-dose steroid versus 8 weeks in the high-dose steroid arm (hazard ratio: 0.45; p < 0.001) was reported. Median overall survival was not reached in the combination arm, compared with a median of 35 weeks in the comparator arm (hazard ratio: 0.53; p < 0.001). An independent review by the study’s Data Safety Monitoring Board recommended that all patients in the high-dose steroid arm be switched over to treatment with pomalidomide and low-dose steroid, leading to a discontinuation of the comparator arm. The combination was well tolerated, although neutropenia (reported in 42% of patients on the combination and 15% in the comparator arm), thrombocytopenia (21 vs 24%, respectively) and fever (7 vs 0%, respectively) were reported in both arms. The primary reason for discontinuation was progressive disease (in 35 vs 49 patients, respectively). A total of 25% of patients died in both arms during the study, primarily from progressive disease and infections. Q Celgene (NJ, USA) anticipates a decision by the European regulatory authorities in the second half of 2013. Given the results of the trial, are you confident of a positive decision? Previous sectionNext section As we have become more successful with improved progression-free and overall survival in patients with myeloma, there is an increasing unmet need for agents and strategies to treat patients who have become resistant or refractory to currently available agents. Pomalidomide and the newer third-generation proteasome inhibitors are active in a significant proportion of these patients and have an excellent toxicity profile. I think that the improved survival and quality of life reported in those patients responding to treatment will result in a positive outcome from the regulatory authorities. Q If approved, how do you see pomalidomide impacting the MM patient population? Previous sectionNext section Given the plethora of active agents that are now available, we expect the vast majority of patients to respond to first-line therapy. However, the disease remains incurable with currently available treatments but patients are living 5–8 years longer than previously with a median overall survival of 7–10 years from diagnosis, with an excellent quality of life. I see pomalidomide being used in the intermediate future for patients who relapse or are refractory to our standard first-line agents, such as bortezomib and lenalidomide, and owing to its excellent tolerability and potent immunomodulatory activity I suspect this agent will have a role in long-term maintenance going forward. Q How would you like to see research in this field developing over the next 5–10 years? Previous sectionNext section I believe that the immune system will prove to be important in controlling myeloma progression and pomalidomide will be a valuable tool to explore this avenue of research. In clinical practice I believe pomalidomide will be used to maintain responses post-stem cell transplantation and possibly in preventing progression in high-risk monoclonal gammopathy. The excellent toxicity profile of pomalidomide makes it an ideal drug for long-term use as maintenance or to enhance immune strategies utilizing cellular and antibody therapy. Disclaimer The opinions expressed in this interview are those of the interviewee and do not necessarily reflect the views of Future Medicine Ltd. Financial & competing interests disclosure S Schey has no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties. No writing assistance was utilized in the production of this manuscript.

MYELOMA BEACON: ENT Dr.A.GOODMAN blog on personal therapy.

http://www.myelomabeacon.com/author/arnold-goodman FREE SUBSCRIPTION

USA NIH: GONORRHOEA - TREATMENT OF RESISTANT CASES.

http://www.niaid.nih.gov/news/newsreleases/2013/Pages/GonorrheaTrial.aspx

New PC Federal Health Minister Brazilian-Canadian Ronalee AMBROSE BA(Victoria) MA(Pol.Sci. Edmonton) 44y. Born Valleyview, Alb.(pop.1,761) Marital status not listed. Replaced 46y Inuk-Canadian Leona AGLUKKAQ

H3N2v VIRUS

Distributed via the CDC Health Alert Network July 05, 2013, 09:00 ET (9:00 AM ET) CDCHAN-00351 Variant Influenza Virus (H3N2v) Infections Summary: This Health Alert Network Health Advisory provides an update on H3N2 variant virus (or “H3N2v”) activity and summarizes CDC’s updated H3N2v case definitions and recommendations for H3N2v surveillance for the summer and fall of 2013. It supersedes the last H3N2v-related HAN Health Advisory, HAN 325, which was issued August 3, 2012. Background The first cases of influenza A (H3N2) variant1 (H3N2v) virus infection this year were reported in June 2013. These cases were associated with exposure to swine at an agricultural fair prior to illness onset. H3N2v viruses with the matrix (M) gene from the 2009 H1N1 pandemic virus were first detected in people in 2011 and were responsible for a multi-state outbreak in the summer of 2012 that resulted in 306 cases, including 16 hospitalizations and 1 fatality. Genetic sequencing by CDC has confirmed that H3N2v viruses isolated in June 2013 are nearly identical to those detected during summer 2012. Most cases of H3N2v identified during 2012 were associated with exposure to pigs at agricultural fairs. Agricultural fairs take place across the United States every year, primarily during the summer months and into early fall. Many fairs have swine barns, where pigs from different places come in close contact with each other and with people. These venues may allow spread of influenza viruses both among pigs and between pigs and people. Data indicate that infected pigs may spread influenza viruses even if they are not symptomatic (e.g., coughing and/or sneezing). Although instances of limited person-to-person spread of this virus have been identified in the past, sustained or community-wide transmission of H3N2v has not occurred. Clinical characteristics of the 2012 and 2013 H3N2v cases have been generally consistent with those of seasonal influenza, and have included fever, cough, pharyngitis, myalgia, and headache. Of the 16 H3N2v hospitalized patients, most were at increased risk for complications of influenza because of age or the presence of an underlying medical condition. None of the persons ill with 2013 H3N2v infection have been hospitalized, and no deaths have occurred among them. Rapid detection and characterization of novel influenza viruses remain important components of national efforts to prevent further cases and evaluate clinical illness associated with these viruses. As a result, clinicians are reminded to consider influenza as a possible diagnosis when evaluating patients with acute respiratory illnesses, and clinicians should consider the possibility of H3N2v in persons presenting with respiratory illness and recent swine contact or attendance at an agricultural fair. The H3N2v case definitions for 2013 (http://www.cdc.gov/flu/swineflu/case-definitions.htm) include laboratory-confirmed cases and cases under investigation for H3N2v virus infection; the probable case definition used in 2012 has been deleted. CDC anticipates that state health departments will identify more H3N2v cases in 2013 as agricultural fair season continues. The number of cases may exceed those identified last year, and CDC recommends a surveillance strategy for 2013 designed primarily to identify increases in person-to-person transmission or clinical severity. Testing for H3N2v should focus primarily on persons with exposures known to be associated with H3N2v virus infection (e.g., fair attendance) and in settings where person-to-person transmission has been identified previously (e.g., influenza-like illness outbreaks in child-care centers). For more information on 2013 testing recommendations, please see http://www.cdc.gov/flu/swineflu/h3n2v-surveillance.htm. Novel influenza A virus infections, which include those caused by H3N2v, remain notifiable conditions in the United States, and all confirmed cases should be reported to CDC within 24 hours. CDC continues to share information and guidance for local and state public health officials regarding the surveillance and investigation of human infections with H3N2v. This information is available at http://www.cdc.gov/flu/swineflu/h3n2v-publichealth.htm.

HEPATITIS A VIRUS : ITALIAN FROZEN BERRIES (redcurrent, black-,blue- raspberries)

HEPATITIS A - EU (05): (ITALY) FROZEN BERRIES ********************************************* A ProMED-mail post ProMED-mail is a program of the International Society for Infectious Diseases Date: Thu 4 Jul 2013 Source: Eurosurveillance Edition 2013, 18(27) [summ., edited] Ongoing outbreak of hepatitis A in Italy ---------------------------------------- [Byline: Rizzo C, Alfonsi V, Bruni R, Busani L, Ciccaglione AR, De Medici D, Di Pasquale S, Equestre M, Escher M, Montaño-Remacha MC, Scavia G, Taffon S, Carraro V, Franchini S, Natter B, Augschiller M, Tosti ME, the Central Task Force on Hepatitis] Since January 2013, an unusual increase in hepatitis A cases has been detected in northern Italy. A total number of 352 cases were reported to the integrated surveillance system between January 2013 and the end of May 2013, and this represents a 70 percent increase compared to the same period of the previous year [2012]. The outbreak is ongoing and the public health authorities are continuing their investigations to establish the transmission vehicle and to control the outbreak. From 1 Jan 2013 to 31 May 2013 a total of 352 cases of hepatitis A were reported to the Italian national surveillance system, corresponding to a 70 percent, 54 percent, and 34 percent increase in HAV [hepatitis A virus] notifications compared to the same period in 2012, 2011 and 2010, respectively. Here we describe the epidemiological features of the cases and the investigation of the outbreak. Surveillance of hepatitis A in Italy ------------------------------------ Hepatitis A is a notifiable disease in Italy. According to the national legislation, laboratory-confirmed cases of hepatitis A virus (HAV) infection are reported by clinicians to the local health units (LHUs) which are responsible for the epidemiological investigation. From the LHUs, notifications are sent to the regional health authorities (RHAs) and from here to the Ministry of Health. However, the routine notification system does not collect information on risk groups and risk factors associated with hepatitis A and there is an important delay in the transmission of the data [1]. For this reason, in 1984, a specific sentinel surveillance system for acute viral hepatitis (SEIEVA -- Sistema Epidemiologico Integrato Epatiti Virali Acute) was set up in parallel with the official notification system in Italy [2]. Data included in the SEIEVA system provide insight into the risk factors associated with the disease. Data collected by SEIEVA are provided by LHUs, which participate on a voluntary basis. A case is defined as a person with an acute illness including symptoms clinically compatible with hepatitis A, such as fever, fatigue, nausea, vomiting, abdominal pain, dark urine and jaundice, and positive for IgM anti-HAV. Cases are interviewed using a standardised online questionnaire collecting socio-demographic, clinical and laboratory information, and information on possible risk factors (shellfish consumption, contact with a jaundice case, travel to an endemic area, child attending daycare in the household, intravenous drug use in the last 6 months). After the alert issued by the northern European countries about a possible association between the hepatitis A cases and frozen berries [3], the consumption of mixed frozen berries was included as another possible risk factor in the SEIEVA questionnaire at the end of April 2013. As of 31 May 2013, 76 percent of the Italian LHUs (139/181) participate in the SEIEVA. The participating LHUs are distributed all over the country and cover 70 percent of the population. Data were adjusted considering the total population of the LHUs' catchment areas. Epidemiological situation of hepatitis A in Italy ------------------------------------------------- In recent decades, the epidemiological pattern of hepatitis A has changed. Italy is considered to be at low/intermediate endemicity for HAV [2,4]. The improved health and sanitary conditions have favored a progressive decrease of the infection rate in children, and a major shift of the population at risk, with the highest incidence reported in young adults. Outbreaks were described in 1996-1997 and 2004 mainly in southern Italian regions (Apulia and Campania) and were related to the consumption of contaminated raw shellfish [5,6]. From 1997, when the incidence was 19 per 100 000 population [2] to date, a decreasing trend in the incidence of HAV has been observed, to 1.1 cases, 0.7 and 0.8 per 100 000 population in 2010, 2011, and 2012, respectively [7]. The 2013 hepatitis A outbreak in Italy -------------------------------------- From 1 Jan 2013 to 31 May 2013 a total number of 352 cases of hepatitis A were reported to SEIEVA surveillance system, corresponding to a 70 percent, 54 percent and 34 percent increase in HAV notifications compared to the same period in 2012, 2011 and 2010, respectively. The highest increase in the number of cases was observed in 7 northern Italian regions (Trento and Bolzano, Emilia-Romagna, Lombardy, Friuli Venezia Giulia, Piedmont, and Veneto) that accounted for 193/352 (55 percent) of the total cases recorded in 2013. In these 7 regions, the cumulative incidence was 2.66 per 100 000 population in the 5-month reference period. Another region that showed an increase in the number of cases in 2013 is Apulia, in southern Italy, which recorded a 22 percent increase in the number of cases in 2013; 77 of the 352 cases were reported from this region. The mean age of cases was 35 years (range: 2-63 years) and the median was 39 years; 23 cases (12 percent) were recorded in children under 14 years. The cases were equally distributed among men and women: 55 percent of the cases were men and 45 percent were women. A total of 159 persons were hospitalised, with the majority of hospitalised cases in the age group of 35-54 years. As of 31 May 2013, no acute liver failures and deaths occurred; 4 cases had been vaccinated against hepatitis A, with one dose within the 3 weeks before the onset of symptoms, so these were not considered vaccine failures. With regard to the risk factors, among those who answered the questionnaire (193 cases), 3 percent (7/193) reported to have travelled to Egypt, 17 percent (33/193) reported to have eaten raw seafood and 20 percent (37/193) mixed berries in the 6 weeks before the symptom onset. When considering risk factors distribution after the end of April [2013] (date of introduction of the question on the consumption of frozen mixed berries), the majority of cases (37 of 46) reported having consumed frozen mixed berries. Description of the 2013 hepatitis A outbreak in the provinces of Trento and Bolzano --------------------------------------------------------------------------- In May 2013, Germany, the Netherlands and Poland reported through the Epidemic Intelligence Information System for food- and waterborne diseases (EPIS-FWD) and the Early Warning and Response System (EWRS) 15 cases of HAV infection associated with a ski holiday in the autonomous provinces of Trento and Bolzano (northern Italy). The sequencing of the VP1-region of these 5 Italian isolates, from Trento province, showed 100 percent nucleotides homology with those isolated from 2 German and one Dutch case [8]. After the EPIS and EWRS notifications, a retrospective epidemiological investigation started in the provinces of Trento and Bolzano, contacting cases notified through the regional notification system. For the epidemiological investigation, a confirmed case was defined as a person resident in the provinces of Trento and Bolzano with an acute illness including symptoms clinically compatible with hepatitis A, such as fever, fatigue, nausea, vomiting, abdominal pain, dark urine and jaundice, and identified as positive for IgM anti-HAV after 1 Jan 2013. Between 1 Jan and 31 May 2013, 31 cases of HAV infection were notified in the province of Trento (a 13-fold, 19-fold and 6-fold increase approximately, compared to the same period in 2012, 2011, and, 2010 respectively). The 1st case reported the onset of symptoms on 2 Feb 2013 and the most recent case was identified on 31 May 2013. Most of the cases had the onset of symptoms in May 2013 (15 cases). In the province of Bolzano, 7 cases were reported in the same period. The epidemic curve of the 38 confirmed HAV infection cases in these 2 provinces shows the evolution of the outbreak over time and suggests a common vehicle of transmission. In these 2 provinces, the mean age of the cases was 36.3 years (range: 3-63 years) and the median was 38.5 years. Men were more represented than women (24 versus 14). A total of 31 persons were hospitalised and the majority of them were 35 to 54 years old. There was only one case vaccinated and this case was reported from the province of Trento; however, this case had been vaccinated with one dose within the 3 weeks before the onset of symptoms, so this was not considered a vaccine failure. Preliminary epidemiological investigation for the identification of risk factors and common exposures focused on consumption of contaminated food as no epidemiological link between the cases could be confirmed. The only common food consumed by all cases was mixed berries or food containing mixed berries (cakes). Serum samples were collected during the acute phase of the disease from 5 of the 38 cases, all from the Trento province. The sequence of the VP1/2A region of the HAV 1A virus obtained from all of them (with GenBank accession number KF182323) showed a 100 percent nucleotides homology with sequences of the isolates from the German and Dutch cases. Investigation of food items implicated -------------------------------------- The preliminary epidemiological investigation in the provinces of Trento and Bolzano showed that the only common food consumed by different cases was mixed berries or food containing mixed berries (cakes). Moreover, the hypothesis was strongly supported by the results of an epidemiological investigation conducted in a family cluster in Veneto region. Part of the mixed berries (redcurrant, blackberries, raspberries, blueberries) that the cases indicated to have eaten within the period of time compatible with the onset of clinical symptoms were still available and were sampled. The analysis for HAV detection in the sample of mixed berries provided positive results. As a consequence, on 17 May 2013, the Italian Ministry of Health (which is the food safety authority at national level) communicated these findings through the European Rapid Alert System for Food and Feed (RASFF). Following these preliminary positive results, the surveillance of these food items was intensified. More samples of berries were collected throughout the country once they were identified as potential risk factors, and 2 sampled berries in Trento were found positive for HAV. On 30 May 2013, 2 additional RASFF notifications were issued to inform about new HAV findings in frozen mixed berries from Italy. Environmental investigations have been done on the mixed frozen berries suppliers of raw material in 6 different countries. Results on samples collected are pending at the time of the present rapid communication. Control measures ---------------- On 23 May 2013 the Ministry of Health (the General Direction for Prevention together with the food safety authority) published a note for RHAs in order to enhance surveillance and awareness of HAV recommending to report within 24 hours any new HAV cases, to collect additional epidemiological information on risk factors associated, and perform virus genotyping and sequencing from all new cases. In addition to the recommendation mentioned above, a case-control study in the regions that experienced the highest increase of cases was planned, in order to support the hypothesis of berries as a source of infection, to find other potential risk factors and to identify appropriate control measures. The National Institute of Health (Istituto Superiore di Sanita, ISS) is responsible for the coordination of the virological and epidemiological investigations, and of the case-control study. Moreover, after the positive results on the sampled frozen mixed berries from different regions, the Ministry of Health started the tracing back of this food item. The investigation identified a dealer that received consignments of berries from different countries (mix made in Italy, with raw material from Bulgaria, Canada, Poland, and Serbia). Following the RASFF notification from the Ministry of Health, regions recalled the lots that were identified positive for HAV and advised the population through the website of the Ministry of Health regarding the use of the leftover frozen mixed berries. Trace back investigations on food are ongoing for each new case notified. The European Centre for Disease Prevention and Control (ECDC) performed a rapid risk assessment that was published on 16 Apr 2013 [8]. Discussion ---------- Preliminary analysis of the case interviews on possible risk factors associated with the ongoing outbreak identified consumption of frozen mixed berries (redcurrant, blackberries, raspberries, blueberries) as a potential vehicle of infection. The hypothesis that they could be implicated is strongly supported by the detection of HAV virus in a sample of frozen mixed berries. The surveillance on these frozen mixed berries together with other food items potentially carrying the HAV (vegetables, seafood, and other food reported as potential risk factors by cases in the epidemiological investigation), has been intensified, to provide a clear picture of the distribution of the contaminated items and the risk of exposure through these. A total of 7 sequences of HAV genotype 1A isolated from cases in different countries (the Netherlands, Germany and Italy) and in different laboratories showed a 100 percent similarity. The genotype and the sequence of the virus isolated in the Italian outbreak is different from the currently ongoing outbreak with frozen berries as a suspected vehicle described in northern European countries and in the United States]. -- Communicated by: ProMED-mail [Remarkably, a 3rd outbreak of hepatitis A virus infection is described above to supplement the outbreaks in 4 Nordic countries of the European Union and several states in North America. Again, mixed frozen berries are implicated as the source of the outbreak. Hepatitis genotype 1a is implicated in the Italian outbreak in contrast to the Nordic countries and US outbreaks where the agent is hepatitis A virus genotype 1b. In contrast to the other 2 outbreaks, in the Italian outbreak hepatitis A virus was recovered directly from the frozen berries product. Frozen mixed berries are now being revealed as a previously unrecognised vehicle of hepatitis A virus infection. By their nature these soft fruits are frozen to enable them to be marketed far from their sites and time of production. The eastern Mediterranean region appears to be the source of at least some of these products. Harvesting berried soft fruits is a labour-intensive occupation which increases the risk of transmission of infectious agents. The habit of the mixing of different berried fruits increases the risk, since some fruits require a greater amount of handing than others. - Mod.CP A HealthMap/ProMED-mail map can be accessed at: .]