Close-range photogrammetry reveals morphometric changes on replicative ground stones.

The pursuit of a quantitative approach to functional analysis of stone tools is an ongoing endeavour for traceologists. Technological advancements in 3D imaging techniques, such as photogrammetry/3D scanners, CT scanning, 3D digital microscopy, confocal microscopy, AFM and FEG-SEM and micro-topographical scanning, have greatly facilitated the detailed capturing of the geometry and surface texture at multiple levels of observation, from the object-scale to the nano-scale. However, while such technological innovations have predominantly focused on flaked assemblages, ground stone tools have only recently begun to receive due attention, and a standardised protocol for their study is yet to be established. In order to comprehend the function(s) of these tools, analytical techniques that enable a 3D visualisation of the entire item and the wear affecting the used surfaces have proven to be of great support. To this end, an analytical procedure was developed and tested on slabs and pebbles in order to replicate the use-wear traces observed on Upper Palaeolithic tools. The purpose was to assemble a site-specific reference collection tailored on the artefacts from the cultural level III of the Brînzeni I cave in north-west Moldova. Experimental replicas were used to treat different plant organs during controlled sequential experiments. The present article reports on the analysis based on photogrammetric data acquired during two stages of replicative usage. We tested multiple acquisition setups and elaborations to assess the geometry modification and the surface depletion. By exploring various acquisition strategies, a critical evaluation of potential sources of bias in data collection and subsequent elaboration were performed, and the methodology was accordingly adjusted thereby enhancing the reliability and reproducibility of the results. This study highlights the importance of carefully considering the acquisition strategy in archaeological related research to ensure accurate analyses and to validate robust interpretation.

Severe Gastrointestinal Toxicity Following the Use of Gilteritinib: A Case Series and Analysis of Postmarketing Surveillance Data.

Gilteritinib has been approved as monotherapy in adults with acute myeloid leukemia (AML) FLT3 mutated with relapsed or refractory disease, in light of its advantages in terms of survival and the favorable safety profile. Hepatobiliary disorders and musculoskeletal and connective tissue disorders represent the most frequent adverse reactions associated with gilteritinib, whereas the most frequent serious adverse reaction is acute kidney injury. In the summary of product characteristics, gastrointestinal (GI) events are indicated as very common, in particular diarrhea, nausea and stypsis. Furthermore, serious GI disorders have been observed with gilteritinib in clinical trials, including GI hemorrhage, GI perforation and GI obstruction. However, the association with the FLT3 inhibitor has not been confirmed. Nevertheless, serious GI AEs have been recognized as an important potential risk to be monitored in postmarketing surveillance. We present three cases of serious self-limiting GI events observed in patients on gilteritinib treatment for AML, and an analysis of relevant available postmarketing surveillance data.

The therapeutic value of treatment for multiple sclerosis: analysis of health technology assessments of three European countries.

In accordance with European regulation, medicines containing a new active substance to treat neurodegenerative diseases as well as autoimmune and other immune dysfunctions must be approved by the European Medicines Agency (EMA) through the centralized procedure before they can be marketed. However, after EMA approval, each country is responsible for national market access, following the assessment performed by health technology assessment (HTA) bodies with regard to the therapeutic value. This study aims to provide a comparative analysis of HTA recommendations issued by three EU countries (France, Germany, and Italy) for new drugs for multiple sclerosis (MS) following EMA approval. In the reference period, we identified 11 medicines authorized in Europe for MS, including relapsing forms of MS (RMS; n = 4), relapsing-remitting MS (RRMS; n = 6), secondary progressive MS (SPMS; n = 1), and the primary progressive form (PPMS; n = 1). We found no agreement on the therapeutic value (in particular, the "added value" compared to the standard of care) of the selected drugs. Most evaluations resulted in the lowest score ("additional benefit not proven/no clinical improvement"), underlining the need for new molecules with better efficacy and safety profiles for MS, especially for some forms and clinical settings.

Off-Label Use of Venetoclax in Patients With Acute Myeloid Leukemia: Single Center Experience and Data From Pharmacovigilance Database.

The potent oral inhibitor of BCL2, venetoclax (VEN), used to treat adults with chronic lymphocytic leukaemia, has been approved in US for the treatment of naïve patients with acute myeloid leukemia (AML) unfit for intensive chemotherapy and recently in Europe, too. However, the drug has been used for years in combination with hypomethylating agents (HMAs) in patients not eligible to other treatment option, according to the so-called off-label use. We collected real-world data about patients treated with VEN + HMAs in the context of a pharmacovigilance project focused on the evaluation of the safety and effectiveness of drugs used for unapproved indication in Italian hospitals. From March to December 2020, 24 patients started treatment with VEN combined with HMAs. 21 patients have been assessed for response. Eleven (52%) patients reached complete remission (CR), and three patients (14%) CR with partial hematological recovery (CRh), with a median duration of response of 4.5 months (range 0.5-12.5). 19 patients experienced at least 1 adverse drug reaction (ADR), mostly serious, including 3 deaths (9% of ADRs; 12.5% of patients) in febrile neutropenia. Hematological toxicities and infections (cytopenia, neutropenia, febrile neutropenia, sepsis), were the most reported ADRs (84.4%). In general, neutropenic fever occurred more frequently in patients treated with decitabine (7 out of 9, 78%) compared to azacitidine (5 out of 15, 33%; p = 0.03), whereas response assessment did not differ based on used HMA (p = 0.1). These results confirm the benefit-risk profile of VEN in a real-world setting of patients with no adequate therapeutic options.

Health Technology Assessment of Advanced Therapy Medicinal Products: Comparison Among 3 European Countries.

Even for centrally approved products, each European country is responsible for the effective national market access. This step can result in inequalities in terms of access, due to different opinions about the therapeutic value assessed by health technology assessment (HTA) bodies. Advanced therapy medicinal products (ATMPs) represent a major issue with regard to the HTA in order to make them available at a national level. These products are based on genes, tissues, or cells, commonly developed as one-shot treatment for rare or ultrarare diseases and mandatorily authorized by the EMA with a central procedure. This study aims to provide a comparative analysis of HTA recommendations issued by European countries (France, Germany, and Italy) following EMA approval of ATMPs. We found a low rate of agreement on the therapeutic value (in particular the "added value" compared to the standard of care) of ATMPs. Despite the differences in terms of clinical assessment, the access has been usually guaranteed, even with different timing and limitations. In view of the importance of ATMPs as innovative therapies for unmet needs, it is crucial to understand and act on the causes of disagreement among the HTA. In addition, the adoption of the new EU regulation on HTA would be useful to reduce disparities of medicine's assessment among European countries.

Rituximab in Multiple Sclerosis: Are We Ready for Regulatory Approval?

Despite the availability of a lot of effective disease-modifying drugs, multiple sclerosis (MS) (in particular the progressive forms) still represents an important unmet medical need, because of issues in terms of effectiveness, duration of response, safety, and patient compliance. An increasing body of evidence from randomized clinical trials and real-world data suggest that rituximab is a highly effective alternative in both relapsing and progressive MS, with a low discontinuation rate, related to a good benefit/risk profile, and a good compliance. To date, the use of rituximab in patients with multiple sclerosis is not in accordance with the authorized product information (off-label use). However, the use of this medicine is widespread in several countries, and in some cases, it is the most commonly used disease-modifying drug for MS subtypes. This use could be officially recognized by national regulatory authorities, according to specific procedures, to ensure equal access for patients to a safe and effective option.

Fertility Preservation in Female Pediatric Patients With Cancer: A Clinical and Regulatory Issue.

Fertility preservation represents one important goal of cancer patients' management due to the high impact on health and quality of life of survivors. The available preventive measures cannot be performed in all patients and are not feasible in all health-care facilities. Therefore, the pharmacological treatment with GnRHa has become a valuable non-invasive and well-tolerated alternative, especially in those who cannot access to cryopreservation options due to clinical and/or logistic issues. Supporting data demonstrate a significant advantage for the survivors who received GnRHa in the long-term maintenance of ovarian function and preservation of fertility. The prevention of the risk of ovarian failure with GnRHa is a typical off-label use, defined as the administration of a medicinal product not in accordance with the authorized product information. Italy has officially recognized the off-label use of GnRHa in adult women at risk of premature and permanent menopause following chemotherapy. However, fertility preservation still represents an unmet medical need in adolescents who cannot access to other treatment options.

Access to Innovative Neurological Drugs in Europe: Alignment of Health Technology Assessments Among Three European Countries.

Even for products centrally approved, each European country is responsible for national market access after European Medicines Agency (EMA) approval. This step can result in inequalities in terms of access, due to different opinions about the therapeutic value assessed by Health Technology Assessment (HTA) bodies. This study aims to provide a comparative analysis of HTA recommendations issued by EU countries (France, Germany, and Italy) for new neurological drugs following EMA approval. In the reference period, we identified 11 innovative medicines authorized in Europe for five neurological diseases (cerebral adrenoleukodystrophy, spinal muscular atrophy, metachromatic leukodystrophy, migraine, and polyneuropathy in patients with hereditary transthyretin amyloidosis), including eight drugs for genetic rare diseases. We found no agreement on the therapeutic value (in particular the "added value" compared to the standard of care) of the selected drugs. Despite the differences in terms of assessment, the access has been usually guaranteed even if with various types of limitations. The heterogeneity of the HTA assessment of clinical data among countries is probably related to the uncertainties about clinical value at the time of EMA approval and the lack of long-term data and of direct comparison with available alternatives. Given the importance of new medicines especially for rare diseases, it is crucial to understand and act on the causes of inconsistency among the HTA assessments, in order to ensure rapid and uniform access to innovation for patients who can benefit.

Venetoclax in Relapsed/Refractory Acute Myeloid Leukemia: Are Supporting Evidences Enough?

Despite the progress in the development of new therapeutic strategies, relapsed/refractory (R/R) acute myeloid leukemia (AML) still represents a high unmet medical need. Treatment options in this setting include enrollment into clinical trials, allogeneic stem cell transplantation and/or targeted therapy. Nevertheless, it is associated with poor outcomes. Thus, the development of new treatments, which could ameliorate the prognosis of these patients with a good safety profile are highly demanded. Recently, venetoclax (VEN) has been approved for naïve AML patients unfit for intensive chemotherapy. In this regard, regimens including VEN could represent a valuable treatment option even in those with R/R disease and several studies have been conducted to demonstrate its role in this clinical setting. This review aims to summarize the current evidence on the use of VEN regimens in the treatment of R/R AML.

The Potential Role of Heparin in Patients With COVID-19: Beyond the Anticoagulant Effect. A Review.

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection is responsible of variable clinical manifestations, ranging from no symptoms to severe pneumonia with acute respiratory distress syndrome, septic shock, and multi-organ failure resulting in death. To date no specific antiviral drug have been approved for COVID-19, so the treatment of the disease is mainly focused on symptomatic treatment and supportive care. Moreover, there are no treatments of proven efficacy to reduce the progression of the disease from mild/moderate to severe/critical. An activation of the coagulation cascade leading to severe hypercoagulability has been detected in these patients, therefore early anticoagulation may reduce coagulopathy, microthrombus formation, and the risk of organ damages. The role of heparin in COVID-19 is supported by a lot of studies describing its pleiotropic activity but it must be proven in clinical trials. Several protocols have been designed to assess the risk-benefit profile of heparin (low-molecular-weight or unfractionated heparin) in hospitalized subjects. Although prophylactic doses may be adequate in most patients, it is important to wait the results of clinical trials in order to define the appropriate effective dose able to improve disease outcome.

Ethnic, gender, and seasonal difference in heavy drinking and protective behavioral strategies among student-athletes.

Relations among gender, ethnicity, athlete seasonal status, alcohol consumption, and protective behavioral strategies were examined among student-athletes. The national sample (N = 670, Mage = 18.90) included Black (n = 199), Hispanic (n = 236), and White (n = 235) college student-athletes who use alcohol. There were significant gender and ethnic differences in alcohol consumption as well as gender differences in use of protective behavioral strategies. Within-group gender differences in alcohol use and PBS were present for White and Hispanic but not Black student-athletes. Implications for tailored prevention/intervention efforts and future directions are discussed.

Associations among Negative Urgency, Sensation Seeking, Alcohol Use, Self-Esteem, and Casual Sexual Behavior for College Students.

Background: The present study proposed a moderated mediation model of relations among negative urgency, sensation seeking, alcohol use, self-esteem, and casual sexual behavior among college students. We hypothesized students' alcohol use would mediate a positive relation between two facets of impulsivity, negative urgency and sensation seeking, with casual sexual behavior. We also examined the influence of self-esteem on alcohol use and casual sexual behavior to determine if self-esteem may serve as a point of intervention. We hypothesized that self-esteem might moderate the relation between casual sexual behavior and alcohol use, such that students who report high alcohol use in addition to low self-esteem would engage in more casual sexual behavior than individuals who report relatively higher levels of self-esteem. Methods: Data were collected in 2015 from 413 undergraduate students at a large Northeastern public university. Structural equation modeling tested the moderated mediation model. Results: Contrary to hypotheses, the theorized model demonstrated an inadequate fit to the data when self-esteem was included. A second structural model was calculated to test alcohol use as a mediator of associations between negative urgency and sensation seeking, and casual sexual behavior. As hypothesized, students' alcohol use was found to be a mediator of the positive associations between negative urgency and casual sexual behavior and sensation seeking and casual sexual behavior. Conclusions: Findings suggest that alcohol use, negative urgency, and sensation seeking may serve as points of intervention to address casual sexual behavior, as appropriate, among college student populations.

Evaluation of Unowned Domestic Cat Management in the Urban Environment of Rome After 30 Years of Implementation of the No-Kill Policy (National and Regional Laws).

Law no. 281, enacted by the Italian Parliament in 1991, was the first that aimed at managing urban free-roaming cats living in colonies, without killing and/or moving them from their site. It had been anticipated by the Lazio Regional Law no. 63/1988 and subsequently refined by the Lazio Regional Law no. 34/1997. These laws introduced: (i) the cats' right to live free and safe; (ii) the compulsory neutering of cats by the Veterinary Services of the Local Health Unit; (iii) the institutionalization of cat caretakers. Within this context, this paper intends to evaluate the effects of the application of the Italian laws on management of urban free-roaming cats for the years 1988 to 2018. To this end, some indicators have been built and applied to our activity data: number of censused colonies and number of cats; number of stable colonies due to neutering; number of hygiene and sanitary notifications; number of notifications to check cat welfare; number of bites by unowned free-roaming cats; number of notifications of cat poisoning. The number of citizens' requests for institutional interventions by public veterinary services in cat colonies management and, accordingly, the detection of cat colonies yet unknown, seem to confirm the interest of people to control the cat colonies in Rome in a humanitarian way, as evidenced in our data. This fact/phenomenon should be analyzed in its multiple dimensions, also including the many changes and social unrests which have affected the human-cat relationship in the last 30 years.

Long-term efficacy and safety profile of multiple injections of intravitreal dexamethasone implant to manage diabetic macular edema: A systematic review of real-world studies.

INTRODUCTION: Systematic review of real-world studies about repeated dexamethasone intravitreal implant (DEXi) 0.7 mg in diabetic macular edema management, in order to identify the effective window of time occurring between injections, the critical evaluation of efficacy of the treatment, and the relative long-term safety in the real life setting. METHODS: Literature databases such as PubMed, SCOPUS, and EMBASE were used to identify reports including DEX implant injections. RESULTS: Twenty-one peer-reviewed publications were identified. DEX implants retreatment was considered on a pro re nata (PRN) basis at any time or starting from month three or four. About 1/3 of the eyes were retreated before six months from first injection (range 0-86.7%). Mean retreatment average time was 5.3 ± 0.9 months, with an estimated average of 1.3 injections each six months. There was no statistical correlation between average retreatment time and incidence of adverse events or other variables investigated. Limited safety issues related to implants number have been found, suggesting an overall good tolerance of long-term DEXi. CONCLUSIONS: Comprehensive evaluation of real-world data suggests an average DEXi duration close to five months, following a PRN treatment strategy, including about 1/3 of patients. Repeated DEXi administration revealed an acceptable long-term efficacy/safety ratio.

Off-Label Use of Drugs and Adverse Drug Reactions in Pediatric Units: A Prospective, Multicenter Study.

BACKGROUND: Given the growing use of off-label in pediatric practice, there is a growing interest on pharmacovigilance programs monitoring the occurrence of adverse drug reactions related to off-label drug prescription in childhood. PATIENTS AND METHODS: The results of a one-year program of pharmacovigilance issued in the Sicilian Region, Italy, are herein presented. The study involved 6 pediatric and neonatal centres and prospectively reviewed the prescriptions of 5,060 patients, who were stratified for age (newborn, infant, children, adolescents). RESULTS: A total of 14,916 prescriptions were issued for 5,060 patients. Among them, 454 patients [8.97%] received at least one off-label drug. Among the off-label treated patients, 255 [56.2%] were newborns. Anti-infective drugs were the most frequent off-label used drugs, followed by drugs for alimentary tract and metabolism and drugs for blood or blood forming organs. Ninety adverse drug reactions were recorded [1.78% of the total patients]. They occurred after an off-label prescription in 33 out of 90 [36.7%], while those occurring after an on-label prescription were 57 [63.3%]. Patients treated with an off-label drug had a significantly higher risk of adverse drug reactions [7.3% vs. 1.2%; p <0.01]. CONCLUSION: The present study indicates that children admitted to neonatal intensive care units are likely to receive an off-label medication; children who receive an off-label medication are usually more likely to be treated with more medication than the others; adverse drug reactions occur in patients admitted in neonatal intensive care and pediatrics are units are more frequently with off-label than with on-label drugs.

Safety of Antiplatelet Agents: Analysis of 'Real-World' Data from the Italian National Pharmacovigilance Network.

INTRODUCTION: According to the Italian National Report on drug use, thienopyridines (ticlopidine, clopidogrel and prasugrel) and ticagrelor represent the most prescribed antiplatelet agents, beside aspirin. The aim of this study was to analyse the safety profile of these drugs using data from spontaneous reporting of suspected adverse reactions (ADRs). METHODS: Suspected ADRs for ticlopidine, clopidogrel, prasugrel and ticagrelor, reported on the Italian National Pharmacovigilance Network between January 2009 and December 2016, were included in the analysis. All suspected ADRs were classified by frequency, seriousness, outcome, age and system organ class. RESULTS: Clopidogrel showed the highest absolute number of suspected ADRs, followed by ticlopidine. However, these data need to be contextualized in view of the differences in marketing authorization dates, prescription rates and a characterization of the relative seriousness of ADRs per each drug. After the correction for prescription rate, ticagrelor showed the highest reporting trend and ticlopidine the lowest. Most ADRs occurred in the elderly, in particular for ticlopidine. Bleeding represents one of the most reported events (ticlopidine 40%, clopidogrel 26%, prasugrel 42%, ticagrelor 30%) and aspirin was the most frequently associated suspected drug. The majority of ADRs had complete recovery and were non-serious, except for ticlopidine (serious ADRs 53%). Prasugrel showed the highest percentage of 'life-threatening' events and 'death'. CONCLUSIONS: Based on the analysis conducted on spontaneous ADRs reporting system in Italy, the safety profile of antiplatelet drugs seems favourable. However, the overall risk-benefit ratio of these drugs needs to be reassessed taking into account the appropriateness of use in particular populations at risk, such as the elderly. Based on this information, we believe that more attention from clinicians and/or an implementation of regulatory measures could be useful for clinical practice.

Social media and college student risk behaviors: A mini-review.

Use of social media use is widespread and frequent among college students. Posting photos and text related to risk behaviors (e.g., problematic alcohol use, illicit drug use) on social media websites is common and has been linked to personal substance use and negative outcomes. This mini-review summarizes current findings related to associations between college students' social media use and engagement in risk behaviors. Conducting research on social media poses unique challenges for researchers; these challenges are reviewed and their impact on the state of the current literature discussed. Finally, implications for prevention and intervention efforts are discussed as well as recommendations regarding future research in the area of social media and college student risk behaviors.