An Introduction to Biosimilars for the Treatment of Retinal Diseases: A Narrative Review.

Biological therapies have revolutionized the treatment of disease across a number of therapeutic areas including retinal diseases. However, on occasion, such treatments may be relatively more expensive compared to small molecule therapies. This can restrict patient access and treatment length leading to suboptimal clinical outcomes. Several biosimilar candidates of ranibizumab and aflibercept are currently in development and the first biosimilar of ranibizumab received EMA approval in August and FDA approval in September 2021. Biosimilars are biological medicines that are highly similar to an already-approved biological medicine (reference product). The physicochemical and clinical similarity of a biosimilar is determined by a rigorous analytical and clinical program, including extensive pharmacokinetic and pharmacodynamic analysis with phase III equivalence studies where appropriate. These phase III studies are carried out in a patient population that is representative of all of the potential approved therapeutic indications of the originator product and the most sensitive for detecting potential differences between the biosimilar and the reference product. Biosimilars have been used successfully across a wide range of therapeutic areas for the past 15 years where they have achieved substantial cost savings that can be reinvested into healthcare systems without affecting the quality of patient care. The current review provides an introduction to biosimilars with the aim of preparing retinal specialists for discussing these products with their patients.

Low back pain among Italian runners: A cross-sectional survey.

BACKGROUND: Low Back Pain (LBP) is commonly reported as a very frequent disorder in sports, but its prevalence in runners remains unclear. OBJECTIVES: To determine the prevalence of LBP in a wide sample of Italian runners. DESIGN: A cross-sectional online survey. SETTING: A national survey, according to the CHERRIES and STROBE guidelines, was performed in 2019. PARTICIPANTS: 2539 Italian runners. METHODS: A sample of Italian runners registered with national running associations was recruited. The survey was conducted using an online survey development platform. The questionnaire was self-reported and included 38 questions. MAIN OUTCOME MEASURES: Descriptive statistics and frequencies were used to analyze results. Relationships between demographics, daily habits and running characteristics and the responses given was calculated with Cramer's V. Only correlation values higher >0.60 were deemed of interest. RESULTS: 2539 questionnaires (63.5%) were valid for analysis. In total, 22.6% of runners reported having experienced LBP in the past year. Most participants (77.0%) reporting episodes of LBP believed it was not caused by running. No significant correlations (Cramer's V < 0.60) were found between LBP and demographics, training characteristics or lifestyle habits. CONCLUSION: The prevalence of LBP among Italian runners was 22,57%. LBP was not associated with training, equipment or lifestyle.

The Effects of Iron Rust on the Ageing of Woods and Their Derived Pulp Paper.

The accelerated ageing of wood in terms of heating or iron rusting has a potential effect on the physio-mechanical, chemical and biological properties of wood. The effects of accelerated ageing on the mechanical, physical and fungal activity properties of some wood materials (Schinus terebinthifolius, Erythrina humeana, Tectona grandis, Pinus rigida and Juglans nigra) were studied after several cycles of heating and iron rusting. The fungal activity was assayed against the growth of Aspergillus terreus, Aspergillus niger, Fusarium culmorum and Stemphylium solani. In addition, the mechanical and optical properties of paper sheets produced from those wood pulps by means of Kraft cooking were evaluated. The mechanical and chemical properties of the studied wood species were affected significantly (p < 0.05) by the accelerated ageing, compared to control woods. With Fourier transform infrared (FTIR) spectroscopy, we detected an increase in the intensity of the spectra of the functional groups of cellulose in the heated samples, which indicates an increase in cellulose content and decrease in lignin content, compared to other chemical compounds. For pulp properties, woods treated by heating showed a decrease in the pulp yield. The highest significant values of tensile strength were observed in pulp paper produced from untreated, heated and iron-rusted P. rigida wood and they were 69.66, 65.66 and 68.33 N·m/g, respectively; we calculated the tear resistance from pulp paper of untreated P. rigida (8.68 mN·m2/g) and T. grandis (7.83 mN·m2/g) and rusted P. rigida (7.56 mN·m2/g) wood; we obtained the values of the burst strength of the pulp paper of untreated woods of P. rigida (8.19 kPa·m2/g) and T. grandis (7.49 kPa·m2/g), as well as the fold number of the pulp paper of untreated, heated and rusted woods from P. rigida, with values of 195.66, 186.33 and 185.66, respectively. After 14 days from the incubation, no fungal inhibition zones were observed. Accelerated ageing (heated or iron-rusted) produced significant effects on the mechanical and chemical properties of the studied wood species and affected the properties of the produced pulp paper.

A randomized single-blind trial of standard diet versus fiber-free diet with polyethylene glycol electrolyte solution for colonoscopy preparation.

BACKGROUND AND STUDY AIMS: Colonoscopy preparation usually involves the intake of large volumes of polyethylene glycol electrolyte solution (PEG-ES) in combination with a clear-liquid diet (CLD). Liberalization of the diet might enhance the tolerance to PEG-ES without compromising the quality of the preparation. The primary aims of this study were to evaluate the efficacy and tolerability of PEG-ES given with a CLD compared with a fiber-free diet (FFD) for colonoscopy preparation. The incidence of adverse events among patients in the two diet groups was also assessed as a secondary outcome. METHODS: This was a single-center randomized, prospective, single-blind study. A total of 200 patients undergoing colonoscopy were randomized to either CLD or FFD in addition to PEG-ES. RESULTS: Patients in the FFD group were able to drink more PEG-ES (mean +/- SD, 3.9 +/- 0.3 L) compared with those in the CLD group (3.3 +/- 0.7 L) ( P < 0.01). The quality of the preparation was significantly better in the FFD group, with more patients having satisfactory preparations than those in the CLD group (81.4 % vs. 52.0 %; P < 0.001). Tolerance to the preparation was higher in the FFD group compared with the CLD group, with significantly more patients adhering to the FFD regimen ( P < 0.001). There were more adverse events experienced in the CLD group, with odds ratios of 1.9 for nausea (95 % confidence interval [CI] 1.0 - 3.6), 3.8 for vomiting (95 % CI 1.3 - 11.3), and 3.0 for headache (95 % CI 1.5 - 5.9). CONCLUSION: FFD given with PEG-ES on the day before colonoscopy is a more effective regimen than the standard CLD regimen, and is better tolerated by patients.

Correction to: Unlocking the Value of Anti-TNF Biosimilars: Reducing Disease Burden and Improving Outcomes in Chronic Immune-Mediated Inflammatory Diseases: A Narrative Review.

In the original article, under the "Access to treatment" heading.

Unlocking the Value of Anti-TNF Biosimilars: Reducing Disease Burden and Improving Outcomes in Chronic Immune-Mediated Inflammatory Diseases: A Narrative Review.

Immune-mediated inflammatory diseases (IMIDs) are chronic conditions that create a significant disease burden on millions of patients while adding a major financial burden to societies and healthcare systems. The introduction of biologic medicines has contributed majorly to improving the clinical outcomes of IMIDs and as such these modalities have gained first- or second-line positions in a wide range of treatment guidelines from different international clinical societies. However, the high cost of these biologics traditionally limited their accessibility and delayed their initiation, leaving millions of patients with unmet medical needs for a more affordable and sustainable solution. The introduction of cost-efficient biosimilar anti-TNFs within Europe since 2013 has allowed more patients with IMIDs to access biologic therapies earlier and for longer, potentially altering the course of the disease into a milder phenotype and reducing the long-term disease burden. This review provides the latest evidence for the impact of biosimilars on patient outcomes and demonstrates their clinical value beyond a reduction in price.

Real-World Evidence on Etanercept Biosimilar SB4 in Etanercept-Naïve or Switching Patients: A Systematic Review.

INTRODUCTION: In 2016, SB4 (Benepali®) became the first etanercept (ETN) biosimilar to obtain marketing authorisation in Europe. Despite robust analytical and clinical comparisons, outstanding questions remain on SB4 use in routine practice. METHODS: A systematic search for publications on real-world evidence of SB4 effectiveness, safety and drug survival was undertaken using search terms (SB4 OR Benepali OR biosimilar etanercept OR innovator etanercept) in the BIOSIS® Toxicology, BIOSIS Previews®, Embase® and MEDLINE® databases up to 17 January 2019. RESULTS: Of 959 articles identified, eight journal articles, two journal letters and 23 congress abstracts were selected on criteria of original real-world evidence with a clinical focus. As expected with real-world evidence, quality scoring showed that the evidence had high external validity but lower internal validity. A total of 13,552 patients were described across nine European countries and all approved SB4 indications: 2499 were ETN-naïve and 11,053 switched from reference ETN to SB4 (switchers). Switch acceptance rates (a combination of clinicians offering and patients accepting initiation on SB4) ranged between 51.6% and 99.0%; patient support programmes positively contributed to acceptance. Disease activity was generally similar pre- and post-switch (typically 3-month timeframe). Retention rates across studies were at least 75% (up to 12 months follow-up). No new safety signals were identified. Differences in discontinuation rates versus historic controls reported in some studies may have been influenced by differences in treatment practices, lack of clinician confidence and nocebo effects. CONCLUSION: Nearly 2500 ETN-naïve patients have been initiated on SB4 and outcomes are similar to those patients receiving reference ETN. Overall this systematic review of real-world evidence provides additional reassurance that SB4 is as effective and safe as reference ETN in both switched and naïve patients. FUNDING: Biogen International GmbH.

Correction to: To See or NOsee: The Debate on the Nocebo Effect and Optimizing the Use of Biosimilars.

The article "To See or NOsee: The Debate on the Nocebo Effect and Optimizing the Use of Biosimilars", written by Mourad F. Rezk and Burkhard Pieper was originally published electronically on the publisher's internet portal (currently SpringerLink) on June 5, 2018 without open access.

To See or NOsee: The Debate on the Nocebo Effect and Optimizing the Use of Biosimilars.

In addition to the general clinical benefit offered, biosimilars may not only generate savings for healthcare budgets but also improve patient access to biologic products. Since the first biosimilar was approved in Europe in 2006, a further 36 different biosimilar drugs have been approved for several indications. Despite the wealth of experience gained and the reported data supporting the use of biosimilars, both in naïve and biologic-experienced patients, some healthcare professionals continue to express doubt regarding the rigorous approval process for biosimilars and uncertainty with how to incorporate them into daily clinical practice. These opinions can be transferred to patients through poor or lack of communication, meaning that patients may lack confidence in treatment quality and, as a result, be susceptible to the nocebo effect. At the 2017 American College of Rheumatology/Association of Rheumatology Health Professionals annual meeting, during a debate the question was asked as to whether the nocebo effect was in fact being used to describe "any result you don't agree with". Here, we detail that the nocebo effect has been demonstrated in a number of clinical trials, and that this effect may negatively affect acceptance in patients switching from an originator product to a biosimilar. Awareness of the potential for the nocebo effect and adoption of enhanced communication techniques may be useful in mitigating the nocebo effect. Effective healthcare professional-patient dialogue is key in transferring confidence to the patient, and has been shown to reduce nocebo effects in patients when switching from an originator to a biosimilar. FUNDING: Biogen International GmbH.

Treatment Outcomes with Biosimilars: Be Aware of the Nocebo Effect.

Over the years, biologic agents have proven their importance in the management of chronic autoimmune diseases, such as rheumatoid arthritis, psoriasis, and inflammatory bowel disease. Biosimilars, which are biologic medicines, are highly similar to approved biologic medicines, and are comprehensively developed and rigorously tested to ensure efficacy and safety are similar to the reference product. A broader armamentarium of biosimilars is expected to improve patients' access to safe and effective biologic medicines, thus offering benefits to healthcare systems around the globe. Here we consider the factors that may compromise the benefits of biosimilars being realized, including patient and physician perception of biosimilars, and an often overlooked factor, the nocebo effect, which is re-emerging with the widespread adoption of biosimilar medicines. We have also described a variety of strategies and recommendations that could help limit the nocebo effect. FUNDING: Biogen.

Experimental colitis decreases rat jejunal amino acid absorption: role of capsaicin sensitive primary afferents.

Ulcerative colitis and experimental colitis are known to be associated with functional and structural abnormalities of the small intestine. The aim of this study was to determine whether experimental colitis in the rat has any effect on jejunal amino acid absorption and to investigate the neural mechanisms involved. In Sprague Dawley rats, colitis was induced by intracolonic administration of 0.1 ml of 6% iodoacetamide. Alanine absorption in the jejunum was measured using the single pass intraluminal perfusion technique in vivo and the three-compartment model in vitro. Experiments were done in normal and sham treated rats, as well as in rats that underwent neonatal capsaicin treatment, adult capsaicin treatment, or subdiaphragmatic vagotomy. Colitis was more severe in rats subjected to neonatal or adult capsaicin treatment, but was not affected by subdiaphragmatic vagotomy. In rats with colitis, jejunal alanine absorption was reduced by 2% (P>0.05), 28%, 40%, and 18% (P<0.001) at 1, 1.5, 2, and 3 days post rectal iodoacetamide administration. A rebound increase of 12% above baseline was noted at 4 days (P<0.05). Similar results were noted in vitro. In rats that received two consecutive injections of iodoacetamide, the decrease in jejunal alanine absorption occurred earlier, was more severe, and persisted for more than 30 days. Neonatal as well as adult capsaicin treatment aggravated both the colitis and the decrease in jejunal alanine absorption. On the other hand, subdiaphragmatic vagotomy attenuated the decrease in jejunal alanine absorption, but had no significant effect on colitis severity. It is concluded that iodoacetamide induced colitis impairs jejunal amino acid absorption and that this effect involves vagal efferents as well as capsaicin sensitive primary afferents.

Inferior vena cava obstruction in Budd-Chiari syndrome: successful treatment by radiological stenting followed by a portosystemic shunt.

Surgical decompression by a portosystemic shunt in Budd-Chiari syndrome depends on the caval state. Obstruction of the inferior vena cava (IVC) precludes such an operation due to the risk of reduced blood flow across the shunt and subsequent thrombosis. Similar risks are encountered in more complicated operations such as mesoatrial shunt. We report a patient with Budd-Chiari syndrome in whom obstruction of the intrahepatic IVC by a hypertrophied caudate lobe of the liver precluded the construction of a standard portocaval shunt. A two-step procedure with preoperative radiological stenting of the narrowed IVC followed by a portocaval shunt was successfully performed. This is the fifth case reported in the literature of such an approach.

Protective effect of the nitric oxide donor molsidomine on indomethacin and aspirin-induced gastric injury in rats.

OBJECTIVE: To study the effect of the nitric oxide donor, molsidomine, on gastric and duodenal injury induced by indomethacin and aspirin. METHODS: Sprague-Dawley rats weighing 180-200 g were used after 24 h fasting. Indomethacin (5 mg/kg) was given subcutaneously as a single dose and followed by multiple injections of histamine. Molsidomine (0.05 mg/kg) or distilled water was given by gavage 30 min before indomethacin and repeated at 3 h intervals for two doses. Rats were killed 2 h after the last dose of molsidomine. Aspirin (500 mg/kg) was given by gavage and repeated 2.5 h later. Molsidomine or distilled water was given 30 min before the initial aspirin dose and repeated after 2 h. Animals were killed 2.5 h after the second dose of aspirin. The severity of the gastric mucosal damage was graded from 0 to 3, and the duodenal bulb ulcer surface area calculated by two independent observers using a dissecting microscope. RESULTS: Indomethacin and aspirin resulted in significant gastric mucosal damage with median scores of 2 (interquartile ranges 1.4-3, n = 16 and 2-3, n = 10, respectively). Molsidomine significantly ameliorated indomethacin- and aspirin-induced damage with median scores of 1 (interquartile ranges 0.5-1.5, n = 19 and 0.6-1.9, n = 10, respectively; P<0.008 and P<0.02, respectively (Mann-Whitney Utest)). Molsidomine had no effect on duodenal bulb ulcerations caused by indomethacin. CONCLUSION: Oral molsidomine has a protective effect on gastric mucosa against damage induced by ulcerogenic agents. This could have an important clinical benefit, especially in cardiac patients taking aspirin in addition to a nitric oxide donor such as molsidomine.

General practitioner access to gastroscopy: is 'censorship' valuable?

An audit was carried out on the activities of a one stop clinic where patients referred by GPs for endoscopy are first interviewed by a gastroenterologist, directly before the procedure. Such a barrier to open access endoscopy did not seem to reduce the workload or the rate of normal examinations.

Constipation: common-sense care of the older patient.

Constipation is a common complaint in older patients. Contributing factors are impaired general health, use of medications, and decreased mobility and physical activity. Diet has an indeterminate effect. Many patients become gradually more constipated with age and self-treat with over-the-counter laxatives. Investigation is warranted if defecation is associated with pain or bloating and/or represents a recent change in bowel habit. Although constipation is usually just an annoyance, it can have more serious consequences, such as impaction and ulceration. A combination of bowel training, dietary management, and regular exercise is the first phase of treatment. Bulk laxatives are second-line treatment, followed by other laxatives if needed.

Acquired protein C deficiency following cisplatinum-navelbine administration for locally advanced breast cancer. Case report.

Thromboembolic events have recently been reported following diverse regimens of chemotherapy for breast cancer. This is a report of a 39-year-old woman, a diagnosed case of locally advanced breast cancer, who received many regimens of chemotherapy. She presented with deep venous thrombosis 2 months after starting the cisplatinum-navelbine regimen. Protein C deficiency was the only abnormal coagulation test that normalized after cessation of chemotherapy.

Gluconimycin an inhibitor of pyrimidine synthesis in Bacillus subtilis.

Pyrimidine synthesis in Bacillus subtilis PCI-219 cells was the primary site of action of the antibiotic gluconimycin as indicated by its arresting the activity of aspartate carbamoyltransferase as well as accumulation of aspartic acid in cultures fortified with gluconimycin. Microbial growth and viable counts were suppressed by the antibiotic whereas glycolysis and aerobic respiration were insignificantly affected. Gluconimycin failed to induce a lytic effect on cell protoplasts while considerable amounts of substances absorbing at 260 nm were released from microbial cells treated with gluconimycin.

Thermomonospora sp. T-SA-125 and its production of a growth promoting antibiotic.

Thermomonospora sp. T-SA-125 is a true thermophilic actinomycete isolated from a soil sample collected from the Saudi Arabian desert. It is characterized by the formation of single spores at the tips of dichotomously branched aerial mycelium and differs from Thermomonospora curvata and T. viridis in certain aspects. It produces a basic water-soluble antibiotic which is active against Gram-positive bacteria, moderately active against Gram-negative bacteria and inactive against fungi. At high concentrations, this antibiotic, stimulated the growth of both Hordeum coleoptile and lettuce hypocotyl.

Troubleshooting in animal models of colitis: The use of a novel electrocautery model.

INTRODUCTION: Experimental colitis induced by chemical agents leads to upregulation of inflammatory cytokines in distant unaffected small intestine and to a decrease in nutrient absorption. To preclude any possible proximal diffusion of these chemicals, we designed a novel method for ulcer induction in the colon by electrocautery. METHODS: Under light anesthesia, a colonic ulcer was induced in rats by a special electrocautery probe introduced in the descending colon through the rectum allowing the injection of a controlled electrolytic current. A direct current (3-7 mA) was delivered through the electrodes for 30s and then for another 30s after reversing the polarity of the electrodes. Then, the probe was moved for a distance of +/-0.5 cm and the current injection was repeated. Rats were sacrificed at various time intervals after ulcer induction (3-96 h). Samples from colon and jejunum were taken for histological assessment and determination, by ELISA, of the levels of interleukin-1beta (IL-1beta) and tumor necrosis factor alpha (TNF-alpha). In other groups of animals, jejunal amino acid absorption was determined in vivo at 24 and 48 h post electrocautery. RESULTS: A colonic ulcer persisted for 72 h after cauterization. A significant upregulation of the levels of different cytokines was observed in the colon and jejunum post cauterization and persisted for at least 48 h. In the jejunum, IL-1beta increased from 81+/-9 to 652+/-110 (p<0.01) and 243+/-47 (p<0.05) pg/mg protein at 24 and 48 h, respectively. Similarly, jejunal TNF-alpha levels increased by approximately 2 folds at 24 and 48 h post ulcer induction (p<0.05). A similar but higher increase in cytokines was observed in the colon. Jejunal alanine absorption (0.2+/-0.02 micromol/20 min/cm) decreased significantly at 24 and 48 h after colitis induction (0.12+/-0.01 and 0.14+/-0.02, respectively; p<0.01). DISCUSSION: This model may be used as an alternative or a complement to chemical models of colitis.