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.

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.

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.

Venturing out safely: The biogeography of Homo erectus dispersal out of Africa.

The dispersal of Homo erectus out of Africa at some 1.9 million years ago is one of the most important, crucial, and yet controversial events in human evolution. Current opinions about this episode expose the contrast between those who see H. erectus as a highly social, cooperative species seeking out new ecological opportunities to exploit, and those preferring a passive, climate driven explanation for such an event. By using geostatistics techniques and probabilistic models, we characterised the ecological context of H. erectus dispersal, from its East African origin to the colonization of Eurasia, taking into account both the presence of other large mammals and the physical characteristics of the landscape as potential factors. Our model indicated that H. erectus followed almost passively the large herbivore fauna during its dispersal. In Africa, the dispersal was statistically associated with the presence of large freshwater bodies (Rift Valley Lakes). In Eurasia, the presence of H. erectus was associated with the occurrence of geological outcrops likely yielding unconsolidated flint. During the early phase of dispersal, our model indicated that H. erectus actively avoided areas densely populated by large carnivores. This pattern weakened as H. erectus dispersed over Europe, possibly because of the decreasing presence of carnivores there plus the later acquisition of Acheulean technology. During this later phase, H. erectus was associated with limestone and shaley marl, and seems to have been selecting for high-elevation sites. While our results do not directly contradict the idea that H. erectus may have been an active hunter, they clearly point to the fact that predator avoidance may have conditioned its long-distance diffusion as it moved outside Africa. The modelled dispersal route suggests that H. erectus remained preferentially associated with low/middle latitude (i.e., comparatively warm) sites throughout its colonization history.

Intralipid in acute caffeine intoxication: a case report.

Caffeine is arguably the most widely used stimulant drug in the world. Here we describe a suicide attempt involving caffeine overdose whereby the patient's severe intoxication was successfully treated with the prompt infusion of Intralipid. A 19-year-old man was found in an agitated state at home by the volunteer emergency team about 1 h after the intentional ingestion of 40 g of caffeine (tablets). His consciousness decreased rapidly, followed quickly by seizures, and electrocardiographic monitoring showed ventricular fibrillation. Advanced life support maneuvers were started immediately, with the patient defibrillated 10 times and administered 5 mg epinephrine in total and 300 + 150 mg of amiodarone (as well as lidocaine and magnesium sulfate). The cardiac rhythm eventually evolved to asystole, necessitating the intravenous injection of epinephrine to achieve the return of spontaneous circulation. However, critical hemodynamic instability persisted, with the patient's cardiac rhythm alternating between refractory irregular narrow complex tachycardia and wide complex tachycardia associated with hypotension. In an attempt to restore stability we administered three successive doses of Intralipid (120 + 250 + 100 mg), which successfully prevented a severe cardiovascular collapse due to a supra-lethal plasma caffeine level (>120 mg/L after lipid emulsion). The patient survived without any neurologic complications and was transferred to a psychiatric ward a few days later. The case emphasizes the efficacy of intravenous lipid emulsion in the resuscitation of patients from non-local anesthetic systemic toxicity. Intralipid appears to act initially as a vehicle that carries the stimulant drug away from heart and brain to less well-perfused organs (scavenging mechanism) and then, with a sufficient drop in the caffeine concentration, possibly as a tonic to the depressed heart.

Do the current performance-based schemes in Italy really work? "Success fee": a novel measure for cost-containment of drug expenditure.

BACKGROUND: Drug costs have risen rapidly in the last decade, driving third-party payers to adopt performance-based agreements that provide either a discount before payment or an ex post reimbursement on the basis of treatments' effectiveness and/or safety issues. OBJECTIVES: This article analyses the strategies currently approved in Italy and proposes a novel model called "success fee" to improve payment-by-result schemes and to guarantee patients rapid access to novel therapies. METHODS: A review of the existing risk-sharing schemes in Italy has been performed, and data provided by the Italian National report (2012) on drug use have been analyzed to assess the impact on drug expenditure deriving from the application of "traditional" performance-based strategies since their introduction in 2006. RESULTS: Such schemes have poorly contributed to the fulfillment of the purpose in Italy, producing a trifling refund, compared with relevant drugs costs for the National Health System : €121 million out of a total of €3696 million paid. The novel risk-sharing agreement called "success fee" has been adopted for a new high-cost therapy approved for idiopathic pulmonary fibrosis, pirfenidone, and consists of an ex post payment made by the National Health System to the manufacturer for those patients who received a real benefit from treatment. CONCLUSIONS: "Success fee" represents an effective strategy to promote value-based pricing, making available to patients a rapid access to innovative and expensive therapies, with an affordable impact on drug expenditure and, simultaneously, ensuring third-party payers to share with manufacturers the risk deriving from uncertain safety and effectiveness.

Specific inactivation of two immunomodulatory SIGLEC genes during human evolution.

Sialic acid-recognizing Ig-like lectins (Siglecs) are signaling receptors that modulate immune responses, and are targeted for interactions by certain pathogens. We describe two primate Siglecs that were rendered nonfunctional by single genetic events during hominin evolution after our common ancestor with the chimpanzee. SIGLEC13 was deleted by an Alu-mediated recombination event, and a single base pair deletion disrupted the ORF of SIGLEC17. Siglec-13 is expressed on chimpanzee monocytes, innate immune cells that react to bacteria. The human SIGLEC17P pseudogene mRNA is still expressed at high levels in human natural killer cells, which bridge innate and adaptive immune responses. As both resulting pseudogenes are homozygous in all human populations, we resurrected the originally encoded proteins and examined their functions. Chimpanzee Siglec-13 and the resurrected human Siglec-17 recruit a signaling adapter and bind sialic acids. Expression of either Siglec in innate immune cells alters inflammatory cytokine secretion in response to Toll-like receptor-4 stimulation. Both Siglecs can also be engaged by two potentially lethal sialylated bacterial pathogens of newborns and infants, agents with a potential impact on reproductive fitness. Neanderthal and Denisovan genomes show human-like sequences at both loci, corroborating estimates that the initial pseudogenization events occurred in the common ancestral population of these hominins. Both loci also show limited polymorphic diversity, suggesting selection forces predating the origin of modern humans. Taken together, these data suggest that genetic elimination of Siglec-13 and/or Siglec-17 represents signatures of infectious and/or other inflammatory selective processes contributing to population restrictions during hominin origins.

Thirty thousand-year-old evidence of plant food processing.

European Paleolithic subsistence is assumed to have been largely based on animal protein and fat, whereas evidence for plant consumption is rare. We present evidence of starch grains from various wild plants on the surfaces of grinding tools at the sites of Bilancino II (Italy), Kostenki 16-Uglyanka (Russia), and Pavlov VI (Czech Republic). The samples originate from a variety of geographical and environmental contexts, ranging from northeastern Europe to the central Mediterranean, and dated to the Mid-Upper Paleolithic (Gravettian and Gorodtsovian). The three sites suggest that vegetal food processing, and possibly the production of flour, was a common practice, widespread across Europe from at least ~30,000 y ago. It is likely that high energy content plant foods were available and were used as components of the food economy of these mobile hunter-gatherers.

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.

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.

Safety profile assessment of buflomedil: an overview of adverse reactions between 1975 and 2011.

PURPOSE: Review all the individualized cases of adverse drug reaction (ADR) potentially related to buflomedil, a vasodilator with the indication for peripheral arterial disease (PAD), marketed in Europe since the 1970s but recently suspended by the European Medicines Agency. METHODS: A review of all available individualised case safety data relating to oral buflomedil from the buflomedil global safety database (provided by the manufacturer of buflomedil), the worldwide published medical literature, toxicology/poison centres and regulatory authorities. RESULTS: The main ADRs reported were in the cardiovascular (CVS) and nervous systems (NS), grouped under four (MedDRA) System Organ Classes (SOCs): (i) Cardiac disorders; (ii) Vascular disorders; (iii) Investigations; (iv) NS disorders. From an initial cumulative number of 1054 case reports, there were 401 cases of intentional overdose (IOD) of which 63 were fatal, and 137 cases of accidental overdose, with two fatalities, and 516 case reports of ADRs under normal conditions of use of the product at normal therapeutic dosage with 11 fatalities. Overdosage (intentional or accidental) represented 50.9% of cases, with 47.6% of patients <40 years of age. The indications for which these young patients were prescribed buflomedil were not reported in most cases. CONCLUSIONS: The main indication of buflomedil is PAD; however, because most cases of IOD occurred in people <40 years of age, where PAD is unlikely, it is possible that buflomedil was prescribed for other indications and/or that it was not directly prescribed to the end user, who rather gained access to the medication prescribed to family members or friends.

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.

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.

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.

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.

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.