Policy measures and instruments used in European countries to increase biosimilar uptake: a systematic review.

Introduction: While biosimilar medicines can contribute to the sustainability of healthcare systems, their utilization rate varies across European countries. This study aims to identify and systematize policy measures and instruments used in European countries to increase biosimilar market share. Methods: A systematic review was conducted according to PRISMA 2020 recommendations. Medline-PubMed, Web of Science and ScienceDirect databases were searched using inclusion criteria that required full articles published in English between January 2006 and November 2023. Reviews, letters, reports, editorials and comments or opinion articles were excluded from this study. Results: Of the 1,137 articles, only 13 met the eligibility criteria for analysis, which covered a total of 28 European countries. Pricing regulation measures were found in 27 of these countries with tendering, price-linkage and internal reference price being the most used. Tendering was used by 27 countries to procure biosimilars in inpatient setting. Prescribing guidelines and recommendations were the widely used instrument. Some European countries adopted physician incentives, quotas, and prescription by international non-proprietary name. Conclusion: Automatic substitution was not commonly recommended or applied. Interchangeability and switching will become increasingly relevant issues. It is important that the positive results from some countries serve as an example for the future of these medicines in the European market. Systematic review registration: https://inplasy.com/, Identifier INPLASY2023120032.

Documentation and classification of hospital pharmacist interventions: A scoping review.

The practice of documenting pharmacist interventions (PIs) has been endorsed by many hospital pharmacists' societies and organizations worldwide. Current systems for recording PIs have been developed to generate data on better patient and healthcare outcomes, but harmonization and transferability are apparently minimal. The present work aims to provide a descriptive and comprehensive overview of the currently utilized PI documentation and classification tools contributing to increased evidence systematization. A systematic literature search was conducted in PubMed, Scopus, Web of Science and the Cumulative Index to Nursing and Allied Health Literature. Studies from 2008, after the release of the Basel Statements, were included if interventions were made by hospital or clinical pharmacists in a global hospital setting. Publications quality assessment was accomplished using the Mixed Methods Appraisal Tool. A total of 26 studies were included. Three studies did not refer to the documentation/classification method, 10 used an in-house developed documentation/classification method, seven used externally developed documentation/classification tools and six described method validation or translation. Evidence confirmed that most documentation/classification systems are designed in-house, but external development and validation of PI systems to be used in hospital practice is gradually increasing. Reports on validated PI documentation/classification tools that are being used in hospital clinical practice are limited, including in countries with advanced hospital pharmacy practice. Needs and gaps in practice were identified. Further research should be conducted to understand why using validated documentation/classification methods is not a disseminated practice, knowing patients' and organizational advantages.

Vasorelaxant effect of (E,E)-farnesol in human umbilical vein ex vivo assays.

(E,E)-farnesol is a sesquiterpene acyclic alcohol produced by bacteria, protozoa, fungi, plants, and animals. The literature describes its applications in food, pharmaceutical, and cosmetic industries, and also in the pharmacological context with a vasorelaxant effect. However, its effects on human umbilical vessels remain poorly investigated. Thus, this study aims to investigate, in a new way, the vasorelaxant effect of (E,E)-farnesol in human umbilical veins (HUV) from healthy donors. Rings obtained from isolated HUV were suspended in an organ bath to record their isometric tension in different experimental sections. (E,E)-farnesol (1 µmol/L to 1 mmol/L) promoted vasorelaxant effect in venous preparations contracted by depolarization (KCl 60 mmol/L) or pharmacological agonism (5-HT 10 µmol/L), with EC50 values of 239.9 µmol/L and 424 µmol/L, respectively. In calcium-free solution, this effect was also observable. (E,E)-farnesol was able to suppress contractions evoked by CaCl2 and BaCl2 suggesting a blockade of voltage-dependent (especially L-type) calcium channels. The vasorelaxant efficacy and potency of (E,E)-farnesol were affected in the presence of tetraethylammonium (1 and 10 mmol/L), glibenclamide (10 µmol/L) and BaCl2 (1 mmol/L) indicating a possible involvement of potassium channels (BKCa, KATP and KIR) in this effect. Our data suggest that (E,E)-farnesol has a promising potential to be applicable as a vasodilator in hypertensive conditions in pregnancy that alter HUV reactivity.

First evidence of a serine arginine protein kinase (SRPK) in leishmania braziliensis and its potential as therapeutic target.

Leishmaniasis is a parasitic disease found in tropical and subtropical regions around the world, caused by parasites of the genus Leishmania. The disease is a public health concern and presents clinical manifestations that can cause death, disability, and mutilation. The parasite has promastigote (vector) and amastigote (vertebrate host) forms and kinase enzymes are involved in this differentiation process. In the present investigation, we show, for the first time, evidence of a serine/arginine protein kinase in Leshmania braziliensis (LbSRPK). Our results show that amastigotes express more LbSRPK than promastigotes.  Analogues of SRPIN340 (a known inhibitor of SRPK) were evaluated for their leishmanicidal activity and two of them, namely SRVIC22 and SRVIC32 showed important leishmanicidal activity in vitro. SRVIC22 and SRVIC32 were able to reduce the infection rate in macrophages and the number of intracellular amastigotes by 55 and 60%, respectively. Bioinformatics analysis revealed the existence of two different amino acid residues in the active site of LbSRPK compared to their human homologue (Tyr/Leu-and Ser/Tyr), which could explain the absence of leishmanicidal activity of SRPIN340 on infected macrophages. In order to enhance leishmanicidal activity of the analogues, optimizations were proposed in the structures of the ligands, suggesting strong interactions with the catalytic site of LbSRPK. Although the evidence on the action of inhibitors upon LbSRPK is only indirect, our studies not only reveal, for the first time, evidence of a SRPK in Leishmania, but also shed light on a new therapeutic target for drug development.

Hypoglycemic, Hypolipidemic, and Anti-Inflammatory Effects of Beta-Pinene in Diabetic Rats.

Background: Diabetes is a metabolic disease linked to multiple comorbidities, such as low-grade inflammation. ß-pinene, a monoterpene commonly found in aromatic plants, is endowed with anti-inflammatory effect and this fact lead us to investigate the possible hypoglycemic, hypolipidemic and anti-inflammatory effects of the monoterpene in the alloxan-induced diabetes experimental model. Methods: Male Wistar rats (200-250 g) were treated orally with ß-pinene (25, 50, 100, and 200 mg/kg) or glibenclamide (5 mg/kg), for seven consecutive days. Diabetes was induced by alloxan (40 mg/kg) through the penile vein. On the seventh day of treatment, blood samples were collected for biochemical analysis. The anti-inflammatory effect of ß-pinene was evaluated using the carrageenan-induced paw edema model, followed by the carrageenan-induced peritonitis. Results: The treatment with ß-pinene decreased plasma glucose, triglyceride, VLDL, LDL, and HDL levels, when compared to those of the control group. In addition, the association ß-pinene 10 mg/kg + glibenclamide 2 mg/kg significantly decreased blood glucose, total cholesterol, and triglyceride level. Finally, oral treatment with ß-pinene reduced carrageenan-induced paw edema and leukocyte migration in the peritoneum. Taken together, our results indicate that ß-pinene shows hypoglycemic and hypolipemic effects, which may involve some common mechanisms of glibenclamide. Besides, the monoterpene presented an anti-inflammatory action in diabetic rats that needs further investigation in order to clarify such effect and its correlation with the alterations observed in plasma parameters of ß-pinene-treated diabetic rats.

Headaches and the use of personal protective equipment in the general population during the COVID-19 pandemic.

INTRODUCTION: Headaches associated with personal protective equipment were reported in health-care workers in previous epidemiological studies. METHODS: National web-based survey advertised by the Portuguese Headache Society and National Headache and Migraine patient´s organization between September-December 2020 screening for personal protective equipment usage pattern, pre-existing and de novo headaches after the onset of the COVID-19 pandemic, and its relation to personal protective equipment use. RESULTS: Of 5064 participants, 90.6% (4562/5034) were women, mean age was 37.2 ± 11 years. Most questions had a completion rate above 87% (non-completion rate ranging from 0-12.7%). Twenty percent were health-care professionals (993/5046). Surgical and cloth masks were the most common personal protective equipment type, whereas protective eyewear and FFP2/FFP3 masks were mostly used by health-care professionals. About 97% (1814/1870) of migraine and headache participants reported aggravation of pre-existing headaches with personal protective equipment use, and 56% (2476/4420) had de novo headaches. Participants with de novo headaches had a higher frequency of pre-existing migraine (1118/1226, 91.2% vs 1408/1600, 88%, P = .042), and wore personal protective equipment for longer periods of time (7 ± 2 h 42 vs 6 ± 2 h 54 min per day, P < .001). In multivariate analysis longer mean duration of personal protective equipment use (OR of 1.1, 95% CI 1-1.2) and previous migraine (OR of 1.2, 95% CI 1-1.4) were predictors of developing de novo headaches. CONCLUSIONS: Almost all participants with pre-existing headache reported worsening of their headaches, and more than half of the study population developed de novo headaches following personal protective equipment use. Duration of personal protective equipment usage and pre-existing migraine were the strongest predictors of de novo headaches.

Midlife Wealth Mobility and Long-term Cardiovascular Health.

Importance: The association of socioeconomic status and cardiovascular outcomes has been well described, but little is known about whether longitudinal changes in wealth are associated with cardiovascular health status. Objective: To evaluate the association between midlife wealth mobility and risk of cardiovascular events. Design, Setting, and Participants: This longitudinal, retrospective cohort study included US adults 50 years or older who participated in the Health and Retirement Study. Participants in the primary analysis had no history of cardiovascular disease and had observations in at least two of three 5-year age intervals (50-54, 55-59, and 60-64 years) and follow-up after 65 years of age. Data were collected from January 1, 1992, to December 31, 2016, and analyzed from November 10, 2020, to April 26, 2021. Exposures: Quintiles of wealth (reflecting total nonhousing assets) were defined within each of 4 birth cohorts (1931-1935, 1936-1940, 1941-1945, and 1946-1950). Wealth mobility was defined as an increase or a decrease of 1 or more wealth quintiles and was compared with wealth stability (same quintile over time) using covariate-adjusted Cox proportional hazards regression models. Main Outcomes and Measures: Composite outcome of nonfatal cardiovascular event (myocardial infarction, heart failure, cardiac arrhythmia, or stroke) or cardiovascular death. Results: A total of 5579 participants were included in the primary analysis (mean [SD] age, 54.2 [2.6] years; 3078 women [55.2%]). During a mean (SD) follow-up of 16.9 (5.8) years, 1336 participants (24.0%) experienced a primary end point of nonfatal cardiovascular event or cardiovascular death (14.4 [95% CI, 13.6-15.2] per 1000 patient-years). Higher initial wealth (per quintile) was associated with lower cardiovascular risk (adjusted hazard ratio [aHR] per quintile, 0.89 [95% CI, 0.84-0.95]; P = .001). When compared with stable wealth, participants who experienced upward wealth mobility (by at least 1 quintile) had independently lower hazards of a subsequent nonfatal cardiovascular event or cardiovascular death (aHR, 0.84 [95% CI, 0.73-0.97]; P = .02), and participants who experienced downward wealth mobility had higher risks (aHR, 1.15 [95% CI, 1.00-1.32]; P = .046). Conclusions and Relevance: These findings suggest that upward wealth mobility relative to peers in late middle age is associated with lower risks of cardiovascular events or death after 65 years of age.

Neglected Achilles tendon rupture associated with rheumatoid arthritis: a case report and a brief review of the literature.

We report a case about a 69-year-old man, suffering from rheumatoid arthritis, diagnosed with a neglected Achilles tendon rupture. Considering the large Achilles tendon gap and the bad quality of the autologous tendons caused by rheumatoid disease, a reconstruction using an Achilles tendon with calcaneus bone block allograft was performed, with excellent clinical and functional outcomes.

Medicaid Expansion and Utilization of Antihyperglycemic Therapies.

OBJECTIVE: Certain antihyperglycemic therapies modify cardiovascular and kidney outcomes among patients with type 2 diabetes, but early uptake in practice appears restricted to particular demographics. We examine the association of Medicaid expansion with use of and expenditures related to antihyperglycemic therapies among Medicaid beneficiaries. RESEARCH DESIGN AND METHODS: We employed a difference-in-difference design to analyze the association of Medicaid expansion on prescription of noninsulin antihyperglycemic therapies. We used 2012-2017 national and state Medicaid data to compare prescription claims and costs between states that did (n = 25) and did not expand (n = 26) Medicaid by January 2014. RESULTS: Following Medicaid expansion in 2014, average noninsulin antihyperglycemic therapies per state/1,000 enrollees increased by 4.2%/quarter in expansion states and 1.6%/quarter in nonexpansion states. For sodium-glucose cotransporter 2 inhibitors (SGLT2i) and glucagon-like peptide 1 receptor agonists (GLP-1RA), quarterly growth rates per 1,000 enrollees were 125.3% and 20.7% for expansion states and 87.6% and 16.0% for nonexpansion states, respectively. Expansion states had faster utilization of SGLT2i and GLP-1RA than nonexpansion states. Difference-in-difference estimates for change in volume of prescriptions after Medicaid expansion between expansion versus nonexpansion states was 1.68 (95% CI 1.09-2.26; P < 0.001) for all noninsulin therapies, 0.125 (-0.003 to 0.25; P = 0.056) for SGLT2i, and 0.12 (0.055-0.18; P < 0.001) for GLP-1RA. CONCLUSIONS: Use of noninsulin antihyperglycemic therapies, including SGLT2i and GLP-1RA, increased among low-income adults in both Medicaid expansion and nonexpansion states, with a significantly greater increase in overall use and in GLP-1RA use in expansion states. Future evaluation of the population-level health impact of expanded access to these therapies is needed.

Multivariate time-series analysis of biomarkers from a dengue cohort offers new approaches for diagnosis and prognosis.

Dengue is a major public health problem worldwide with distinct clinical manifestations: an acute presentation (dengue fever, DF) similar to other febrile illnesses (OFI) and a more severe, life-threatening form (severe dengue, SD). Due to nonspecific clinical presentation during the early phase of dengue infection, differentiating DF from OFI has remained a challenge, and current methods to determine severity of dengue remain poor early predictors. We present a prospective clinical cohort study conducted in Caracas, Venezuela from 2001-2005, designed to determine whether clinical and hematological parameters could distinguish DF from OFI, and identify early prognostic biomarkers of SD. From 204 enrolled suspected dengue patients, there were 111 confirmed dengue cases. Piecewise mixed effects regression and nonparametric statistics were used to analyze longitudinal records. Decreased serum albumin and fibrinogen along with increased D-dimer, thrombin-antithrombin complex, activated partial thromboplastin time and thrombin time were prognostic of SD on the day of defervescence. In the febrile phase, the day-to-day rates of change in serum albumin and fibrinogen concentration, along with platelet counts, were significantly decreased in dengue patients compared to OFI, while the day-to-day rates of change of lymphocytes (%) and thrombin time were increased. In dengue patients, the absolute lymphocytes to neutrophils ratio showed specific temporal increase, enabling classification of dengue patients entering the critical phase with an area under the ROC curve of 0.79. Secondary dengue patients had elongation of Thrombin time compared to primary cases while the D-dimer formation (fibrinolysis marker) remained always lower for secondary compared to primary cases. Based on partial analysis of 31 viral complete genomes, a high frequency of C-to-T transitions located at the third codon position was observed, suggesting deamination events with five major hot spots of amino acid polymorphic sites outside in non-structural proteins. No association of severe outcome was statistically significant for any of the five major polymorphic sites found. This study offers an improved understanding of dengue hemostasis and a novel way of approaching dengue diagnosis and disease prognosis using piecewise mixed effect regression modeling. It also suggests that a better discrimination of the day of disease can improve the diagnostic and prognostic classification power of clinical variables using ROC curve analysis. The piecewise mixed effect regression model corroborated key early clinical determinants of disease, and offers a time-series approach for future vaccine and pathogenesis clinical studies.

Stiff person spectrum disorders: An illustrative case series of their phenotypic and antibody diversity.

Stiff person spectrum disorders (SPSD) are a broad group of immune-mediated disorders. Clinical presentations include classical stiff person syndrome (SPS), focal SPS, and progressive encephalomyelitis with rigidity and myoclonus (PERM). The most frequently associated antibodies are anti-GAD65, anti-GlyR, anti-amphiphysin, and anti-DPPX. Immunotherapy is the primary treatment modality. We present an illustrative case series of three patients: anti-GlyR antibody-mediated PERM presenting as rapidly progressive dementia; anti-amphiphysin antibody-mediated SPS; and SPS presentation with anti-Zic4 antibodies, spasmodic laryngeal stridor and fluctuating eyelid ptosis. Clinical characteristics, CSF findings, neurophysiological features, adequate immunological assays and a high suspicion index are essential for prompt diagnosis and management.

In-Hospital and Long-Term Prognosis after Spontaneous Intracerebral Hemorrhage among Young Adults Aged 18-65 Years.

BACKGROUND: Spontaneous intracerebral hemorrhage (ICH) accounts for 10%-15% of all strokes and has an estimated annual incidence of 5/100,000 in young adults. Limited data on prognosis after ICH in young adults are available. We aimed to identify prognostic predictors after ICH among adults aged 18-65 years. METHODS: We retrospectively selected all patients with ICH from a prospective single-center registry of adults with first stroke before 65 years between 1997 and 2002. We recorded in-hospital mortality as well as mortality and recurrent stroke after discharge until December 1, 2018. For in-hospital analysis, we compared patients that died in-hospital versus patients discharged alive. For long-term analysis, we compared patients that died in follow-up versus patients still alive. Independent prognostic predictors were identified using multivariate analyses. RESULTS: Among 161 patients included, 24 (14.9%) died in-hospital. Among in-hospital survivors, 5-year survival was 92.0%, 10-year survival 78.1%, and 15-year survival 62.0%. After median follow-up of 17 years, 47.4% of patients died, 18 patients had ischemic stroke, and 6 recurrent ICH. Regarding in-hospital prognosis, coma at admission (OR .02 [.00-.11]) was independent predictor for mortality whereas alcoholic habits (OR 12.32 [1.82-83.30]) was independent predictor for survival. An increasing age (OR 1.08 [1.03-1.12]), higher blood glucose levels (OR 1.01 [1.00-1.01]), and hypertension (OR 2.21 [1.22-4.00]) were independent predictors of long-term mortality after ICH. CONCLUSIONS: Alcoholic habits may influence in-hospital survival after ICH in young adults. Long-term mortality in young adults seems to be lower than in elderly and was predicted by higher blood glucose levels and hypertension.

Relationship between HbA1c and capillary blood glucose self-monitoring in type 2 diabetics.

INTRODUCTION: Diabetes Control and Complications Trial has established the importance of glycemic control in reducing the progression of retinopathy, nephropathy, and neuropathy in type 1 diabetics. There is little literature linking the frequency of glycemic monitoring with glycated hemoglobin A (HbA1c) in type 2 diabetics. The objectives were to assess the influence of glycemic self-monitoring on HbA1c in three groups of patients with type 2 diabetes (with insulin, with oral antidiabetics and with combination therapy). METHODS: The glucometer capillary surveys of 117 patients were counted in the 30 days prior to the visit to the Integrated Diabetes Unit at Centro Hospitalar Tondela-Viseu. In the three groups considered, sociodemographic characteristics (age, gender, area of residence, household and schooling) were evaluated and compared. RESULTS: There was no statistically significant association between HbA1c and the frequency of capillary glucose in any of the groups. In the evaluation of sociodemographic data, contrary to what was expected, the area of residence and schooling did not influence the value of HbA1c. CONCLUSION: These results question the role of glycemic monitoring in the metabolic control of type 2 diabetics, highlighting the need to implement therapeutic education programs so that these patients can adequately intervene in the therapeutic adjustment as a function of the information obtained by capillary glycemia.