Long term effectiveness on prescribing of two multifaceted educational interventions: Results of two large scale randomized cluster trials

Introduction: Information on benefits and risks of drugs is a key element affecting doctors' prescribing decisions. Outreach visits promoting independent information have proved moderately effective in changing prescribing behaviours. Objectives: Testing the short and long-term effectiveness on general practitioners' prescribing of small groups meetings led by pharmacists. Methods: Two cluster open randomised controlled trials (RCTs) were carried out in a large scale NHS setting. Ad hoc prepared evidence based material were used considering a therapeutic area approach - TEA, with information materials on osteoporosis or prostatic hyperplasia - and a single drug oriented approach - SIDRO, with information materials on me-too drugs of 2 different classes: barnidipine or prulifloxacin. In each study, all 115 Primary Care Groups in a Northern Italy area (2.2 million inhabitants, 1737 general practitioners) were randomised to educational small groups meetings, in which available evidence was provided together with drug utilization data and clinical scenarios. Main outcomes were changes in the six-months prescription of targeted drugs. Longer term results (24 and 48 months) were also evaluated. Results: In the TEA trial, one of the four primary outcomes showed a reduction (prescription of alfuzosin compared to tamsulosin and terazosin in benign prostatic hyperplasia: prescribing ratio -8.5%, p = 0.03). Another primary outcome (prescription of risedronate) showed a reduction at 24 and 48 months (-7.6%, p = 0.02; and -9,8%, p = 0.03), but not at six months (-5.1%, p = 0.36). In the SIDRO trial both primary outcomes showed a statistically significant reduction (prescription of barnidipine -9.8%, p = 0.02; prescription of prulifloxacin -11.1%, p = 0.04), which persisted or increased over time. Interpretation: These two cluster RCTs showed the large scale feasibility of a complex educational program in a NHS setting, and its potentially relevant long-term impact on prescribing habits, in particular when focusing on a single drug. National Health systems should invest in independent drug information programs. Trial Registration: Controlled-Trials.com ISRCTN05866587

WHO's essential medicines and AWaRe: recommendations on first- and second-choice antibiotics for empiric treatment of clinical infections.

The WHO Model List of Essential Medicines (EML) prioritizes medicines that have significant global public health value. The EML can also deliver important messages on appropriate medicine use. Since 2017, in response to the growing challenge of antimicrobial resistance, antibiotics on the EML were reviewed and categorized into three groups: Access, Watch and Reserve, leading to a new categorization called AWaRe. These categories were developed taking into account the impact of different antibiotics and classes on antimicrobial resistance, and the implications for their appropriate use. The 2023 AWaRe classification provides empiric guidance on 41 essential antibiotics for over 30 clinical infections targeting both the primary health care and hospital facility setting. A further 257 antibiotics not included on the EML have been allocated an AWaRe group for stewardship and monitoring purposes. This article describes the development of AWaRe focussing on the clinical evidence base that guided the selection of Access, Watch or Reserve antibiotics as first and second choices for each infection. The overarching objective was to offer a tool for optimising the quality of global antibiotic prescribing and reduce inappropriate use by encouraging the use of Access antibiotics (or no antibiotics) where appropriate. This clinical evidence evaluation and subsequent EML recommendations are the basis for the AWaRe antibiotic book and related smartphone applications. By providing guidance on antibiotic prioritization, AWaRe aims to facilitate the revision of national lists of essential medicines, update of national prescribing guidelines and surveillance of antibiotic use. Adherence to AWaRe would extend the effectiveness of current antibiotics while helping countries to expand access to these life-saving medicines for the benefit of current and future patients, health professionals, and the environment

INFLUENZA AVIARIA NELLE SPECIE SELVATICHE IN ITALIA: ECOLOGIA E FATTORI DI RISCHIO

L'ARTICOLO DESCRIVE L'ECOLOGIA DEI VIRUS INFLUENZALI DI TIPO A SOTTO IL PROFILO EVOLUZIONISTICO ED ECOLOGICO. VENGONO EVIDENZIATI I RUOLI DI SERBATOI E DI EPIFENOMENI NELLE POPOLAZIONI NATURALI SIA SELVATICHE SIA DOMESTICHE E NE VENGONO ANALIZZATI I FATTORI DI RISCHIO PER L'UOMO E PER LE PRODUZIONI ANIMALI

Il ruolo degli animali selvatici nel rapporto con le specie domestiche: l'esperienza dell'influenza aviaria

L\u2019allarme elevato indotto in Europa dall\u2019ipotesi che virus ad alta patogenicit\ue0 quale l\u2019H5N1 possa ricombinarsi con virus influenzali umani non \ue8 solo allarmismo. Gi\ue0 a fine 2004 il virus aviare era entrato in Europa al seguito di un contrabbandiere tailandese di Spizeti - Aquile da ciuffo tailandesi - ( Spizaetus nipalensis) e solo grazie al personale di sorveglianza dell\u2019aereoporto di Bruxelles aveva ultimato l\uec il suo viaggio. Oggi, i movimenti dell\u2019H5N1 verso Ovest che lo hanno portato in Kazakistan e sulle rive del mar Caspio portandolo a coinvolgere un numero progressivo di nazioni con un movimento verso ovest che gli sta consentendo di colonizzare gran parte dell\u2019Europa. Oggi ne \ue8 stata riscontrata la presenza in cigni reali, germani reali, polli sultani, poiane, cormorani, svassi, smerghi ed in molte altre specie. La diffusione verso occidente lo porta ad incontrare diversi elementi naturali che possono contribuire sia a rallentare sia a facilitarne la diffusione. Al primo posto troviamo la presenza di anticorpi contro virus del sottotipo H5 nella popolazione delle anatre selvatiche del mediterraneo evidenziata durante gli studi nella Oasi WWF di Orbetello. Gli anticorpi contro virus influenzali H5N2 e H5N3, H5N1 circolati negli ultimi anni tra le anatre selvatiche del nostro paese sono probabilmente in grado di limitare l\u2019infezione da virus H5N1 (Asiatico). L\u2019 evidenza sierologia della continua circolazione negli ultimi dieci anni tra le anatre di diversi virus influenzali AH5 non patogeni potrebbe funzionare un po\u2019 come una vaccinazione, creando una seppur parziale immunit\ue0 di popolazione che ostacolerebbe la diffusione dell\u2019infezione da H5N1. Di contro la stessa presenza di anticorpi potrebbe consentire una maggior diffusione del virus in virt\uf9 del fatto che i soggetti con anticorpi per il sottotipo H5 possono infettarsi e non ammalandosi contribuire al trasporto del virus tra popolazioni recettive in diverse aree. Fondamentale \ue8 quanto gi\ue0 viene attuato con i sistemi di sorveglianza veterinari degli allevamenti intensivi e con l\u2019applicazione di tutte le norme possibili di biosicurezza per gli allevamenti stessi. Qualsiasi intervento gestionale volto a eliminare l\u2019infezione dalle popolazioni selvatiche risulta inapplicabile e peraltro improponibile, cos\uec come sono da escludere azioni dirette a danno delle specie selvatiche. Le ipotesi di abbattimenti indiscriminati che ogni tanto vengono paventate risultano molto pericolose nel caso di circolazione del virus. L\u2019abbattimento delle anatre provocherebbe inoltre, spaventandole, una elevata dispersione delle stesse sul territorio con una conseguente maggior circolazione del virus (un analogo fattore di rischio \ue8 rappresentato dall\u2019effettuazione di censimenti aerei nelle aree di aggregazione)

Ricerca del virus dell\u2019epatite E (HEV) in una popolazione di cinghiali (Sus scrofa scrofa) in Italia.

Il virus dell'epatite E (HEV) \ue8 l'agente causale dell'epatite E dell'uomo ed \ue8 un RNA virus a singolo filamento positivo privo di envelope classificato nella famiglia Hepeviridae genere Hepevirus. Nel suino domestico HEV \ue8 responsabile di infezioni sub-cliniche tuttavia, ceppi di origine suina sono spesso risultati geneticamente simili a ceppi responsabili di episodi sporadici di malattia nell'uomo, suggerendo la possibilit\ue0 di una trasmissione zoonotica. A conferma di ci\uf2 sono strati recentemente descritti in Giappone casi umani di epatite E conseguenti all'ingestione di carne e organi crudi o poco cotti di suino, cervo e cinghiale. La malattia \ue8 oggi considerata una zoonosi emergente. Nonostante HEV sia stato frequentemente rilevato in allevamenti suini di tutto il mondo, nessuna informazione sulla prevalenza e la circolazione del virus in popolazioni di cinghiali in Europa \ue8 al momento disponibile. In questo studio \ue8 stata valutata la prevalenza di HEV in una popolazione selvatica di Cinghiale (Sus scrofa) presente nel Parco regionale dei Gessi Bolognesi, Bologna. Sono stati inoltre esaminati possibili fattori di rischio associati all'infezione e le correlazioni genetiche esistenti tra i ceppi identificati e altri ceppi umani e suini. La ricerca del genoma virale \ue8 stata effettuata su campioni di bile provenienti da 88 animali abbattuti nel periodo marzo-settembre 2006 nell'ambito del piano di controllo demografico della popolazione insistente del parco, utilizzando una nested-reverse transcriptase PCR. Informazioni riguardanti il sesso, l'et\ue0, il peso e le misure biometriche degli animali sono stati raccolti e valutati in relazione all'infezione da HEV. RNA virale \ue8 stato identificato in 22/88 animali esaminati (25%). Non \ue8 stata riscontrata una differenza statisticamente significativa della prevalenza nei due sessi e nelle diverse classi di et\ue0 degli animali. Le misure biometriche ed il peso dei soggetti infetti non differivano in modo significativo da quello degli animali non infetti. Campioni PCR positivi sono stati purificati e sequenziati e l'analisi filogenetica delle sequenze ottenute ha permesso di evidenziare un'omologia nucleotidica del 100% nella regione genomica analizzata. Questa osservazione permette di ipotizzare la presenza di un unico ceppo virale circolante nella popolazione esaminata. Tale ceppo \ue8 risultato geneticamente pi\uf9 simile a ceppi umani e suini circolanti in Europa che a ceppi di cinghiale identificati in Giappone. Questi risultati suggeriscono la possibile presenza di un clustering geografico di ceppi di HEV. Considerando che, analogamente a quanto accade nei suini domestici anche nei cinghiali l'infezione sembra essere subclinca e che il virus \ue8 presente anche in animali di interesse venatorio, questi risultati destano una certa preoccupazione relativamente alla possibile trasmissione zoonotica di HEV

Rotavirus and Hepatitis E virus infections in rabbits

Zoonotic viruses are thought to be the highest risk of epidemic diseases for next years. Among others, these also include group A rotaviruses (RVA) and hepatitis E virus (HEV). RVA infection is preferentially speciesspecific, and heterologous infections may also occur (animal-to-human virus transmission). Recently, a human RVA of rabbit origin was described in a child, and a bovine-like RVA was isolated from a rabbit. Hepatitis E is an emerging disease recognized as a zoonosis. Recently HEV was detected in both farmed and wild rabbits in several countries. Risk of HEV zoonotic transmission from rabbits to humans is supported by experimental infection of non-human primates and swine with rabbit HEV and by the detection of a rabbit related HEV strain in a man. During 2013, a total of 121 rabbits attending veterinary examination were enrolled in this study. Sera and feces were collected from the same animal (except 7 fecal samples). Twenty-one samples were collected from studmare rabbits. Sera were analyzed in Western blotting and Immunocytochemistry using as antigens: i. a baculovirus expressed HEV capsid protein, ii. purified SA11 RV or iii. a crude extract of mock-infected Sf9. RNA was extracted using Qiagen RNAEasy. RT-PCRs were performed using the OneStep RT-PCR (Qiagen). None of the 135 fecal samples, showed presence of HEV genome. IgG against HEV were detected in 4/121 pet rabbits tested. Rabbits showed no clinical signs of RVA infection. Twelve out of 52 sera recognized specific RVA proteins. Twelve samples were positive in RT-PCR, one of which was confirmed through sequence analyses. One animal was positive for both RVA and HEV IgG. The seroprevalence to HEV in rabbits was low (3.3%); pets living in households have no contact with other animals, implying that apossible HEV transmission through the fecal-oral route is reduced. Studying naturally occurring heterologous rotaviruses may help understand how rotavirus cross the host-species barrier and enlighten the molecular determinants that control host-species specificity and pathogenicity. Contact between pet rabbits and their owners might favor bi-directional animal-to-human transmission. Possible foodborne transmission of rabbit HEV should also be evaluated

Detection of hepatitis E virus in an Italian wild boar population

Hepatitis E virus (HEV) is the causative agent of Hepatitis E, and is a plus-stranded RNA virus. The genome of HEV is approximately 7.2 kb and contains three open reading frames, ORF1, ORF2 and ORF3. ORF2 encodes the capsid protein, and is the target for molecular diagnosis. HEV is an emerging public health concern, and has caused large water-borne epidemics in developing countries. In Europe, sporadic hepatitis E outbreaks have been reported. In Japan, hepatitis E has linked to eating raw or undercooked meat from deer, wild boar or pigs, suggesting zoonotic transmission. Swine HEV has been detected in pig herds in Europe, but no information exist on HEV circulation in European wild boars. In this study, the presence of HEV in a wild boar population in of a Northern Italy Regional Park was investigated. Detection of HEV was accomplished by a nested reverse-transcription PCR on bile samples from 88 shot animals, aged 4-37 months. HEV RNA was identified in 22 animals (25%). Animal sex, age, weight, and biometrics measures were evaluated in association with infection. No significant differences (P > 0.05) in the prevalence of infection relating to any animal characteristics were found. Positive PCR samples were sequenced to investigate correlation bwith human and swine European strains of HEV. Phylogenetic analysis on the nucleotide sequences from 10 PCR product confirmed that only one HEV strain was circulating in the wild boar population considered, and that this strain was closer to human and swine HEV strains circulating in Europe than to wild boar Japanese strains

Rotavirus and Hepatitis E virus infections in rabbits

Zoonotic viruses are thought to be the highest risk of epidemic diseases for next years. Among others, these also include rotavirus, agent of gastroenteritis in man and animals and hepatitis E virus (HEV), which causes acute hepatitis in humans and infect domestic and wild animals. Group A rotaviruses (RVA) infection is preferentially species-specific, heterologous rotavirus infections may also occur, including animal-tohuman virus transmission. Recently, a human RVA of rabbit origin was described in a child with gastroenteritis, and a bovine-like RVA was isolated from a laboratory rabbit . Hepatitis E is an emerging disease now recognized to be a zoonosis. Swine, wild boar, deer and rabbit are considered reservoirs of the zoonotic HEV genotypes 3 and 4. Recently HEV was detected in both farmed and wild rabbits in several areas of China, USA and France. The prevalence of serum antibodies against HEV ranges between 7% and 57% in young animals. Several evidences support a risk of zoonotic transmission of HEV from rabbits to humans, including experimental infection of non-human primates and swine with rabbit HEV and detection of HEV closely related to rabbit HEV in a man. HEV and RVA infections were studied in 21 farmed and 121 pet rabbits in Italy. Virus infection was investigated by serological analysis in sera and by detection of RNA in fecal samples. During 2013, a total of 121 rabbits attending veterinary examination were enrolled in this study. Sera and feces were collected from the same animals (except 7 fecal samples). Seventy-seven pets were asymptomatic, most others were affected by different pathologies. Between October 2013 and February 2014, 21 samples were collected from stud-mare rabbits affected by reproductive failure. Western blotting (WB). The capsid protein of an Italian gt3 swine HEV strain expressed in Sf9 cells from a recombinant baculovirus (Bac\u394111ORF2HEV), the purified SA11 RV and crude extract of mock Sf9 (negative control) were subjected to WB. Sera were diluted 1:100. Immunocytochemistry. Sf9 cells infected with Bac\u394111ORF2HEV and mock cells were fixed and incubated with rabbit sera (1:500). Replication foci were visualized by reaction with amino-ethylcarbazole. Reverse-transcription\u2013polymerase chain reaction (RT\u2013PCR) and DNA sequencing. RNA was extracted using Qiagen RNA-Easy-Mini kit. For both viruses, RT-PCRs were performed using the OneStep RT-PCR kit (Qiagen). For Rotavirus the NSP5 segment was amplified. For HEV an RT-PCR and a nested-PCR were conducted, amplifying a 300 bp ORF2 fragment. None of the 135 fecal samples, (114 pets and 21 farmed rabbits), showed presence of HEV genome. IgG against HEV were detected in 4 of 121 pet rabbits tested. Two seropositive animals were asymptomatic, one was affected by rhinitis. Rabbits showed no clinical signs of RVA infection. Twelve out of 52 sera recognized specific RVA proteins. Twelve samples resulted positive in RT-PCR, one was confirmed through sequence analyses. One animal was positive for both RVA and HEV IgG. None of the feces (farmed or pet rabbits) were positive for HEV genome. The seroprevalence in pet rabbits was 3.3% in this study, markedly lower than observed in farmed animals (36% in China and 55% in USA). The lower seroprevalence in our study might be explained with the different animal population; pets living in households have no contact with other animals, which reduces the possible HEV transmission through the fecal-oral route. The study of naturally occurring heterologous rotaviruses may help understand how rotavirus cross the host-species barrier and investigate the molecular determinants that control rotavirus host-species specificity and pathogenicity. Contact between pet rabbits and their owners, e.g. changing the litter, might favor animal-to-human transmission; similar risks occur in persons with occupational exposure to farmed rabbits. Possible foodborne transmission of rabbit HEV should also be evaluated