BPSDiary study protocol: a multi-center randomized controlled trial to compare the efficacy of a BPSD diary vs. standard care in reducing caregiver's burden

Behavioral and Psychological Symptoms of Dementia (BPSD) are a heterogeneous set of psychological and behavioral abnormalities seen in persons with dementia (PwD), significantly impacting their quality of life and that of their caregivers. Current assessment tools, such as the Neuropsychiatric Inventory (NPI), are limited by recall bias and lack of direct observation. This study aims to overcome this limitation by making caregiver reports more objective through the use of a novel instrument, referred to as the BPSDiary. This randomized controlled trial will involve 300 caregiver-PwD dyads. The objective is to evaluate whether the use of the BPSDiary could significantly reduce caregiver burden, assessed using the Zarit Burden Interview (ZBI), compared to usual care. The study will include adult PwD, caregivers living with or close to the patient, and BPSD related to the HIDA (hyperactivity, impulsivity, irritability, disinhibition, aggression, agitation) domain. Caregivers randomized to the intervention arm will use the BPSDiary to record specific BPSD, including insomnia, agitation/anxiety, aggression, purposeless motor behavior, and delusions/hallucinations, registering time of onset, severity, and potential triggers. The primary outcome will be the change in ZBI scores at 3 months, with secondary outcomes including changes in NPI scores, olanzapine equivalents, NPI-distress scores related to specific BPSD domains, and caregiver and physician satisfaction. The study will be conducted in 9 Italian centers, representing diverse geographic and sociocultural contexts. While potential limitations include the relatively short observation period and the focus on specific BPSD disturbances, the BPSDiary could provide physicians with objective data to tailor appropriate non-pharmacological and pharmacological interventions. Additionally, it may empower caregivers by encouraging reflection on BPSD triggers, with the potential to improve the quality of life for both PwD and their caregivers.Trial registryNCT05977855

First occurrence of strobilurin-resistant isolates of Stemphylium vesicarium in an Italian pear orchard

Stemphylium vesicarium (Wallr) Simm. is the causal agent of brown spot, the main fungal disease of pear in Italy (Po valley) since the late 1970s, but it is also present in other European countries such as Spain, France, The Netherlands, Portugal and Belgium. Many fungicides (mainly dithiocarbamates and dicarboximides) have been applied in field to control it. From the late 1990s new products have been introduced and among them the strobilurins kresoxim-methyl (1998), trifloxystrobin (2002) and more recently pyraclostrobin+boscalid (2006). Till 2005 S. vesicarium sensitivity to strobilurin fungicides have not shown any shift (MIC<0.5 mg/l) from baseline values both for kresoxim-methyl and trifloxystrobin according to a good efficacy in field. During the season 2006, the first strobilurin-resistant isolates of Stemphylium vesicarium were detected in a commercial pear orchard in north-eastern Italy (Emilia-Romagna region) where a heavy control failure was observed. In vitro sensitivity tests on conidial germination were carried out on this population with the 3 strobilurins. The concentrations used were 0.5 and 2 mg a.i./l and the evaluations were made after 3, 5 and 24 hours after inoculation. Already after 3 hours of incubation the population showed germination greater than 74% referred to untreated control at both the concentrations tested and towards all strobilurins. Another sensitivity test on conidial germination was carried out using the formulated compounds Stroby (kresoxim-methyl, BASF) and Flint (trifloxystrobin, Bayer) at 2, 10 and 100 mg a.i./l. Also in this case after 3 hours of incubation the germination of the population was greater than 90% of the untreated control. Finally the mitochondrial DNA of the isolates was analysed. After DNA extraction PCR was performed to amplify a gene fragment codifying for the region containing the G143A mutation. The presence of this mutation was then confirmed. In conclusion both in vitro test and genetic analysis showed that these isolates of S. vesicarium were resistant to all strobilurin fungicides tested. This is the first time where a failure in pear brown spot control in field is demonstrated to be caused by the occurrence of resistant isolates

Baseline sensitivity of Stemphylium vesicarium, the causal agent of pear brown spot, to boscalid

INTRODUCTION The control of Stemphylium vesicarium (Wallr.) Simm., the causal agent of pear brown spot, is a true concern for pear growers in Italy because many fungicide treatments are required from petal fall to fruit ripening (Ponti et al.,1996; Brunelli et al., 2004). The occurrence of resistance to dicarboximides in the early 1990’s (Brunelli et al., 1997) and to strobilurins in 2006 (Collina et al., 2007) complicated the control of this pathogen even more. The introduction in the field of new fungi-cides with different mechanisms of action is thus fundamental in order to enlarge the range of effective fungicides against pear brown spot and to reduce the risk of further resistances. At the end of the 2006 season boscalid was registered in Italy for pear. It belongs to the carboxamide-fungicide group and inhibits the respiratory chain acting on the enzyme succinate dehydrogenase in complex II (Stammler et al., 2007). This mode of action is different from that of both dicarboximide and strobilurin fungicides and it could be used in cases of field resistance to these compounds. Nevertheless, boscalid is considered by the FRAC to have a medium risk of resistance for its spe-cific target (www.frac.info). In order to evaluate the sensitivity of S. vesicarium to this fungicide, an in vitro assay was developed comparing different methods (on mycelial growth with differ-ent media and on conidial germination). Baseline sensitivity was then determined for isolates which have never been exposed to boscalid

EVOLUZIONE DELLA SENSIBILITÀ DI STEMPHYLIUM VESICARIUM, AGENTE DELLA MACULATURA BRUNA DEL PERO AI FUNGICIDI IN ITALIA

Riassunto E’ stata osservata una diffusa resistenza di Stemphylium vesicarium ai dicarbossimidici e la sua regressione, in seguito all’interruzione dei trattamenti, in tempi variabili a seconda della frequenza di individui resistenti selezionati nel frutteto. Si è riscontrata una resistenza incrociata del patogeno tra dicarbossimidici e fludioxonil, presente però solo in un fenotipo raro e che pertanto non costituisce un reale problema in campo. La sensibilità di S. vesicarium agli analoghi delle strobilurine, dopo circa dieci anni dalla loro introduzione in campo, non ha subito modifiche sostanziali, anche se sono stati recentemente riscontrati sporadici isolati resistenti. I noti ditiocarbammati e il recente boscalid non hanno evidenziato variazioni di sensibilità. Evolution in Italy of the sensitivity to fungicides in Stemphylium vesicarium, the causal agent of pear brown spot Abstract The control of Stemphylium vesicarium, the causal agent of pear brown spot, needs many treatments from petal fall to fruit ripening, therefore a knowledge of the effectiveness of fungicides is important. After the occurrence of the first problems in pear brown spot control in the early 1990s with procymidone, in vitro studies have demonstrated the occurrence of pathogen resistance in Italy. Further studies identified four phenotypes of S. vesicarium with different degrees of sensitivity to dicarboximides: the sensitive (S), the S+ slightly resistant to procymidone and iprodione, the R1 highly resistant to procymidone and moderately resistant to the other dicarboximides and the R2 highly resistant to all dicarboximides. These phenotypes are spread in all pear growing areas of Po valley. Fortunately the sensitive phenotype is still the most frequent followed by the R1 phenotype. The other resistant phenotypes are very rarely found in the field. Another important aspect considered was the possibility of the resistance to regress. The frequency of the phenotypes inside the populations of each orchard influences the time of resistance regression. If the resistant frequency is high more years of interruption of treatments are needed. The cross resistance between dicarboximides and phenylpyrroles was observed only in R2 phenotype, therefore it does not represent a real problem in the field because of their rarity. A wide monitoring was carried out also to evaluate the sensitivity of S. vesicarium to strobilurins. Ten years after their introduction in the field, they are still active and with EC50 values comparable to baseline ones, albeit the first few resistant isolates have been found since 2006. Only one of these cases was linked to a failure of strobilurins in pear brown spot control and it has appeared after several years of intense use of these compounds. Nevertheless this is an interesting information, because it demonstrates that S. vesicarium is able to develop strobilurin resistance and therefore it underlines again the importance of following strictly anti-resistance strategies. No changes in sensitivity were noted in S. vesicarium to dithiocarbamates, multi-site fungicides with a low resistance risk but widely used against pear brown spot since its appearance in the late 1970s. The study of S. vesicarium sensitivity to boscalid had the same result, in fact two years after its registration on pear in Italy, the level of sensitivity is comparable to that of populations collected before its introduction in the field

POTENTIAL OF BIOFUNGICIDES FOR THE CONTROL OF STEMPHYLIUM VESICARIUM ON PEAR

The control of brown spot of pear caused by Stemphylium vesicarium (Pleospora allii), is mainly based on numerous chemical treatments. However, new perspectives are offered by the integration with biological products based on Trichoderma, which has been showed to reduce the pathogen inoculum on the orchard floor. The aim of this study was to test the competitive interaction and the mechanisms of action of several biocontrol agents against S. vesicarium. We considered the biofungicides Rootshield (Trichoderma harzianum T22), Remedier (T. asperellum ICC012 and T. gamsii ICC080), Trichover (T. harzianum ITEM 908), Mycostop (Streptomyces griseoviridis K61) and Serenade (Bacillus subtilis QST713). Each microorganism was tested for substrate colonization and inhibitory effect against the pathogen. T. harzianum T22 and S. griseoviridis K61 were the most active in inhibiting the pathogen mycelial growth, while T. harzianum ITEM908 showed the highest substrate colonization. Trichoderma strains exhibited parasitic action of pathogen hyphae, visible as coiling, lysis and collapse. All microorganisms produced chitinolytic enzymes. B. subtilis QST713 produced the highest level of glucosaminidase, S. griseoviridis K61 the highest level of chitobiosidase and T. asperellum ICC012 the highest level of endochitinase. Non volatile metabolites produced by T. harzianum T22, S. griseoviridis K61 and B. subtilis QST713 on PDA were the most active in reducing the pathogen mycelial growth. Metabolites caused also morphological alteration of hyphae. Metabolites from liquid culture of the microorganisms, did not reduce conidia germination, but reduced the number of germ tubes/conidia (B. subtilis QST713) and their elongation (T. asperellum ICC012 and T. gamsii ICC080)

Sewer Flow Prediction at a Large Urban Scale: Influence of Radar Rainfall Spatial Resolution

There is a growing interest in using radar rainfall data to evaluate the performance of urban drainage systems in near real time. This paper describes a study based on a large (55 km2) urban catchment in northern Italy. Different spatial resolutions of radar data have been compared and used as input to a numerical hydrological-hydraulic model of the drainage system, constructed by means of Infoworks CS software. The results show that the spatial resolution of weather radar data plays a significant role when modelling the hydrological behaviour of the drainage system and using different resolutions may result in significant differences in peak flows and runoff volumes

Clinical Perception and Treatment Options for Behavioral and Psychological Symptoms of Dementia (BPSD) in Italy

Background: Behavioral and psychological symptoms of dementia (BPSD) have a high prevalence, and their presence is associated with a severe impact in terms of social costs. However, dedicated clinical tools or biomarkers to detect these symptoms are lacking. Thus, BPSD management in clinical settings is challenging. The aim of this study was to investigate the perception and the treatment strategies for BPSD in Italian centers working in the dementia field. Methods: A multicenter, national survey was developed by BPSD Study Group of the Italian Neurological Society for Dementia (SINDEM). The survey consisted of a semi-structured questionnaire that was e-mailed to SINDEM members, dementia centers part of the national network of memory clinics (Centers for Cognitive Deterioration and Dementia [CDCD]), and clinicians working in dementia care settings. The questions were focused on (1) perceived global frequency and relevance of BPSD; (2) tools used to assess BPSD; (3) pharmacological treatment for psychosis, apathy, agitation, aggression, depression, anxiety, sleep, and nutrition disturbances; (4) non-pharmacological treatments; (5) drugs side effects. Results: One-hundred and thirty-six clinicians participated in this study. Seventy-nine participants worked in a CDCD and 57 in other settings. The perceived frequency of BPSD was 74%. BPSD are detected by means of a clinical assessment for 96.3% or a caregiver interview for 97%. For psychosis treatment the first choice was atypical antipsychotics (83.3%), followed by typical antipsychotic (8.9%) and antidepressants (4.8%). For agitation, atypical antipsychotics were the first-choice treatment in 64% of cases and antidepressants in 16.1%. For aggression, the most used drugs were atypical antipsychotics (82.9%). For anxiety, 55.2% use antidepressants, 17.9% use atypical antipsychotics, and 16.9% use benzodiazepines. Interestingly, most of the centers apply non-pharmacological treatments for BPSD. Some differences emerged comparing the responses from CDCD and other care settings. Conclusion: The survey results revealed many differences in BPSD perception, treatment options, and observed side effect according to the clinical setting. This variability can be explained by the absence of clear guidelines, by differences in patients' characteristics, and by clinical practice based on subjective experience. These results suggest that producing guidelines for the pharmacological treatment of BPSD is a major need