Exploring Current Molecular Targets in the Treatment of Neovascular Age-Related Macular Degeneration toward the Perspective of Long-Term Agents.

Long-lasting anti-vascular endothelial growth factor (anti-VEGF) agents have become an option to reduce treatment frequency, with ongoing research exploring optimal responses and safety profiles. This review delves into molecular targets, pharmacological aspects, and strategies for achieving effective and enduring disease control in neovascular age-related macular degeneration (AMD). The molecular pathways involved in macular neovascularization, including angiogenesis and arteriogenesis, are explored. VEGF, PlGF, Ang-1, and Ang-2 play crucial roles in regulating angiogenesis, influencing vessel growth, maturation, and stability. The complex interplay of these factors, along with growth factors like TGFß and bFGF, contributes to the pathogenesis of neovascular membranes. Current anti-VEGF therapies, including bevacizumab, ranibizumab, aflibercept, brolucizumab, and faricimab, are discussed with a focus on their pharmacokinetics and clinical applications. Strategies to achieve sustained disease control in AMD involve smaller molecules, increased drug dosages, and novel formulations. This narrative review provides a comprehensive overview of the molecular targets and pharmacological aspects of neovascular AMD treatment.

FcγRIIB Is an Immune Checkpoint Limiting the Activity of Treg-Targeting Antibodies in the Tumor Microenvironment.

Preclinical murine data indicate that fragment crystallizable (Fc)-dependent depletion of intratumoral regulatory T cells (Treg) is a major mechanism of action of anti-CTLA-4. However, the two main antibodies administered to patients (ipilimumab and tremelimumab) do not recapitulate these effects. Here, we investigate the underlying mechanisms responsible for the limited Treg depletion observed with these therapies. Using an immunocompetent murine model humanized for CTLA-4 and Fcγ receptors (FcγR), we show that ipilimumab and tremelimumab exhibit limited Treg depletion in tumors. Immune profiling of the tumor microenvironment (TME) in both humanized mice and humans revealed high expression of the inhibitory Fc receptor, FcγRIIB, which limits antibody-dependent cellular cytotoxicity/phagocytosis. Blocking FcγRIIB in humanized mice rescued the Treg-depleting capacity and antitumor activity of ipilimumab. Furthermore, Fc engineering of antibodies targeting Treg-associated targets (CTLA-4 or CCR8) to minimize FcγRIIB binding significantly enhanced Treg depletion, resulting in increased antitumor activity across various tumor models. Our results define the inhibitory FcγRIIB as an immune checkpoint limiting antibody-mediated Treg depletion in the TME, and demonstrate Fc engineering as an effective strategy to overcome this limitation and improve the efficacy of Treg-targeting antibodies.

Systematic evaluation of AML-associated antigens identifies anti-U5 SNRNP200 therapeutic antibodies for the treatment of acute myeloid leukemia.

Despite recent advances in the treatment of acute myeloid leukemia (AML), there has been limited success in targeting surface antigens in AML, in part due to shared expression across malignant and normal cells. Here, high-density immunophenotyping of AML coupled with proteogenomics identified unique expression of a variety of antigens, including the RNA helicase U5 snRNP200, on the surface of AML cells but not on normal hematopoietic precursors and skewed Fc receptor distribution in the AML immune microenvironment. Cell membrane localization of U5 snRNP200 was linked to surface expression of the Fcγ receptor IIIA (FcγIIIA, also known as CD32A) and correlated with expression of interferon-regulated immune response genes. Anti-U5 snRNP200 antibodies engaging activating Fcγ receptors were efficacious across immunocompetent AML models and were augmented by combination with azacitidine. These data provide a roadmap of AML-associated antigens with Fc receptor distribution in AML and highlight the potential for targeting the AML cell surface using Fc-optimized therapeutics.

Effects of Rapid Maxillary Expander and Delaire Mask Treatment on Airway Sagittal Dimensions in Pediatric Patients Affected by Class III Malocclusion and Obstructive Sleep Apnea Syndrome.

Obstructive sleep apnea syndrome (OSAS) is a sleep-related breathing disorder that is very common in pediatric patients. In the literature, there are very few studies concerning the association between OSAS and class III malocclusion in children. The use of a rapid maxillary expander (RME) in association with the Delaire mask is a common treatment protocol for class III malocclusion. The aim of this work was to evaluate the cephalometric variations of upper airway dimensions and OSA-related clinical conditions after orthodontic treatment with an RME and the Delaire mask, as recorded in pediatric patients with a class III malocclusion who were affected by OSAS. In this preliminary study, 14 pediatric patients with mixed dentition, aged between 6 and 10 years, were selected. All patients were treated with an RME and the Delaire mask. Pre- and post-treatment cephalometric radiographs were traced, analyzed, and compared. The results demonstrated a significant increase in the upper airway linear measurements and the nasopharyngeal and oropharyngeal dimensions (p ≤ 0.05). This increase creates an improvement in airway patency and in OSAS-related clinical conditions. The use of the RME in association with the Delaire mask can be effective in the treatment of pediatric patients with a class III malocclusion who are affected by OSAS.

Direct drug provocation test for the diagnosis of self-reported, mild and immediate drug hypersensitivity reaction in children and adolescents: our real-life experience.

BACKGROUND: Approximately 10% of the parents report suspected drug hypersensitivity reactions to at least one drug in their children, but most of these reactions are not confirmed after an adequate diagnostic work-up. The diagnosis of drugs hypersensitivity is frequently laborious and based on anamnesis, skin tests, serum specific IgE research and drug provocation test. Nevertheless, drug provocation test is necessary to confirm or definitively exclude the diagnosis of allergy. Aims of our study were to evaluate the real incidence of drug hypersensitivity in a large pediatric population and the validity of a short diagnostic algorithm. METHODS: One hundred nine patients with a history of self-reported, immediate and mild drug hypersensitivity reactions to ß-lactam antibiotics, macrolides and non-steroidal anti-inflammatory drugs underwent drug provocation test without prior skin or blood tests. After one-year, a telephone questionnaire was conducted in order to evaluate patient's use of the tested drug and any reactions. RESULTS: Only 7 of the 109 patients (6.4%) resulted positive to drug provocation test. No severe reactions were reported. After the challenge, 64 patients took the culprit drug again within one year and only two reported a drug reaction. CONCLUSIONS: Drug hypersensitivity is highly overestimated. Our results prompt the opportunity to directly perform the challenge for those children with self-reported, mild and immediate drug hypersensitivity reaction.

Obstructive sleep apnea severity and dental arches dimensions in children with late primary dentition: An observational study.

Objective: The aim of this study was to compare the dimensions of the upper and lower arches in children affected by OSAS with different levels of severity of obstruction.Methods: Twenty-seven Caucasian children (14 males, 13 females; mean age 6, range 5.2-6.1 years) with a diagnosis of OSAS determined by polysomnography were enrolled in this study. The dimensions of both dental arches were measured, and the data were compared among children affected by severe, moderate, and mild OSAS.Results: Statistically significant differences among the three groups revealed that children with severe OSAS had the highest values of upper intercanine and intermolar distances in the sample.Discussion: A severe OSAS grade (AHI > 10) is associated with statistically significantly higher upper intercanine and intermolar distances compared with mild and moderate grades. An early approach to OSAS in children with late primary dentition is auspicated in order to prevent an influence on dental arches growth.

High Prevalence of Skin Reactions Among Pediatric Patients with Type 1 Diabetes Using New Technologies: The Alarming Role of Colophonium.

In the past few years, the increasing use of devices for diabetes treatment, such as continuous subcutaneous insulin infusion pumps, flash glucose monitoring, continuous glucose monitoring systems, sensor-augmented pumps, and automated insulin delivery devices, has resulted in important improvements in disease management. Meanwhile, the longer a patient uses a device, the greater the likelihood of developing a skin reaction. Allergic contact dermatitis is the most frequently described skin side effect caused by adhesive tapes contained in the insulin infusion sets or glucose sensor sets and used to connect these devices to the body. We describe 18 patients, followed up at our Pediatric Diabetes Centre, who experienced dermatological complications due to diabetes device use from January 2018 to December 2018. All the patients were patch tested with allergens from a "standard" series and from a "plastics and glues" series. Patch tests resulted positive in 66.7% of patients. Colophonium was the most frequently isolated sensitizing allergen (41.1% of cases). It is a complex mixture of >100 compounds derived from pine trees. Colophonium is commonly used, in both unmodified and modified forms, as a fast-acting adhesive for industrial, medical, or other commercial uses. Its presence in the adhesive of the insulin sets and glucose sensors was confirmed by the manufacturer of some devices brand. On the basis of our results, we stress the importance of contacting manufacturers for product information. We also highlight that there should be stricter legal restrictions to label medical adhesives, even if only small amounts of colophonium are used.

Diabetes drugs and the incidence of solid cancers: a survey of the current evidence.

INTRODUCTION: The evaluation of the relationship between the use of antidiabetic drug and the occurrence of cancer is extremely challenging, both from the clinical and pharmacoepidemiological standpoint. This narrative review described the current evidence supporting a relationship between the use of antidiabetic drugs and the incidence of solid cancers. Areas covered: Data from pharmacoepidemiological studies on cancer incidence were presented for the main antidiabetic drugs and drug classes, including human insulin and insulin analogues, metformin, sulfonylureas, glinides, alpha-glucosidase inhibitors, thiazolidinediones, incretin mimetics, and sodium glucose co-transporter 2 inhibitors. The relationship between the use of antidiabetics and the incidence of solid cancer was described in strata by any cancer and by organ-specific cancer and by drug and by drug classes. Information supporting biological evidence and putative mechanisms were also provided. Expert opinion: The history of exploration of the relationship between antidiabetic drugs and the risk of solid cancers has showed several issues. Unrecognized biases and misinterpretations of study results have had important consequences that delayed the identification of actual risk and benefits of the use of antidiabetic drugs associated with cancer occurrence or progression. The lesson learned from the past should address the future research in this area, since in the majority of cases findings are controversial and confirmatory studies are warranted.

Muscular Adverse Drug Reactions Associated with Proton Pump Inhibitors: A Disproportionality Analysis Using the Italian National Network of Pharmacovigilance Database.

INTRODUCTION: Proton pump inhibitors (PPIs) have been implicated in the occurrence of moderate to severe myopathies in several case reports. AIM: This study was performed to assess the reporting risk of muscular adverse drug reactions (ADRs) associated with PPIs in the Italian National Network of Pharmacovigilance database. METHODS: A disproportionality analysis (case/non-case) was performed using spontaneous reports collected in the database between July 1983 and May 2016. Reporting odds ratio (ROR) and 95% confidence intervals (CIs) were calculated as a measure of disproportionality. In a secondary and tertiary analysis, we explored the association of PPIs with muscular ADRs after taking into account the masking effect of statins. Moreover, the possibility of an interaction between PPIs and statins, leading to the occurrence of muscular ADRs, was also tested. RESULTS: The study was carried out on 274,108 reports. The ROR of muscular ADRs for PPIs, adjusted for age and gender, was 1.484 (95% CI 1.204-1.829; p < 0.001), whereas the ROR for rhabdomyolysis was 0.621 (95% CI 0.258-1.499). Similar results were obtained in the secondary analysis. The tertiary analysis, where PPIs were considered regardless of whether their role was suspected or concomitant, showed a potential disproportionate reporting for the combination PPIs-rhabdomyolysis (ROR 1.667, 95% CI 1.173-2.369; p < 0.01). The PPIs-statins combination was not associated with an enhanced ROR of muscular ADRs/rhabdomyolysis compared with statins alone. CONCLUSIONS: This explorative study suggests that the class of PPIs could be involved in reports of muscular ADRs, rather than any other ADR, more frequently than any non-statin drug. Our results must be corroborated by further studies.

Clinical differences among the elderly admitted to the emergency department for accidental or unexplained falls and syncope.

It is difficult to distinguish unexplained falls (UFs) from accidental falls (AFs) or syncope in older people. This study was designed to compare patients referred to the emergency department (ED) for AFs, UFs or syncope. Data from a longitudinal study on adverse drug events diagnosed at the ED (ANCESTRAL-ED) in older people were analyzed in order to select cases of AF, syncope, or UF. A total of 724 patients (median age: 81.0 [65-105] years, 66.3% female) were consecutively admitted to the ED (403 AF, 210 syncope, and 111 UF). The number of psychotropic drugs was the only significant difference in patients with AF versus those with UF (odds ratio [OR] 1.44; 95% confidence interval 1.17-1.77). When comparing AF with syncope, female gender, musculoskeletal diseases, dementia, and systolic blood pressure >110 mmHg emerged as significantly associated with AF (OR 0.40 [0.27-0.58], 0.40 [0.24-0.68], 0.35 [0.14-0.82], and 0.31 [0.20-0.49], respectively), while valvulopathy and the number of antihypertensive drugs were significantly related to syncope (OR 2.51 [1.07-5.90] and 1.24 [1.07-1.44], respectively). Upon comparison of UF and syncope, the number of central nervous system drugs, female gender, musculoskeletal diseases, and SBP >110 mmHg were associated with UF (OR 0.65 [0.50-0.84], 0.52 [0.30-0.89], 0.40 [0.20-0.77], and 0.26 [0.13-0.55]), respectively. These results indicate specific differences, in terms of demographics, medical/pharmacological history, and vital signs, among older patients admitted to the ED for AF and syncope. UF was associated with higher use of psychotropic drugs than AF. Our findings could be helpful in supporting a proper diagnostic process when evaluating older patients after a fall.

Neonatal Adaptation Issues After Maternal Exposure to Prescription Drugs: Withdrawal Syndromes and Residual Pharmacological Effects.

Exposure to drugs during pregnancy has the potential to harm offspring. Teratogenic effects are the most feared adverse outcomes in newborns; however, a wide spectrum of less known, usually reversible and often acute, neonatal adverse events can also occur due to drug intake by mothers during pregnancy, particularly in close proximity to delivery. This narrative review is aimed at the description of drugs and drug classes for which licit maternal use in the predelivery period has been associated with neonatal non-teratogenic disorders. For each drug class, epidemiology, clinical features, biological mechanism and management of these adverse reactions have been discussed in detail. Although these adverse reactions have been described mainly for substances used illicitly for recreational purposes, several prescription drugs have also been involved; these include mainly psychotropic medications such as opioids, antidepressants, antiepileptics and antipsychotics. These effects can be partly explained by withdrawal syndromes (defined also as 'neonatal abstinence syndrome') caused by the delivery-related discontinuation of the drug disposition from the mother to the fetus, with symptoms that may include feeding disorders, tremors, irritability, hypotonia/hypertonia, vomiting and persistent crying, occurring a few hours to 1 month after delivery. Otherwise, neonatal neurological and behavioral effects can also be caused by a residual pharmacological effect due to an accumulation of the drug in the blood and tissues of the newborn, with various symptoms related to the toxic effects of the specific drug class, usually developing a few hours after birth. With few exceptions, validated protocols for the assessment and management of withdrawal or residual pharmacological effects of these drugs in neonates are often lacking or incomplete. Spontaneous reporting of these adverse reactions seems limited, although it might represent a useful tool for improving our knowledge about drug-induced neonatal syndromes.

Safety Profile of Certolizumab Pegol in Patients with Immune-Mediated Inflammatory Diseases: A Systematic Review and Meta-Analysis.

INTRODUCTION: Certolizumab pegol (CZP), an anti-tumor necrosis factor PEGylated Fab' fragment of a humanized monoclonal antibody, is currently approved for treatment of some immune-mediated inflammatory diseases (IMIDs). To our knowledge, no systematic review and meta-analysis evaluating the overall safety profile of CZP has been performed. OBJECTIVE: The objective of this systematic review was to assess the adverse event (AE) patterns of CZP versus a control in patients with IMIDs. METHODS: A systematic literature search was performed using PubMed/MEDLINE, EMBASE, the Cochrane Library, and the FDA database for clinical trials up to March 2014. Eligible studies were those that compared the safety profile of CZP to a control group in patients with IMIDs. The following data were extracted: number of patients experiencing AEs, serious AEs (SAEs), adverse drug reactions (ADRs), withdrawals due to AEs, fatal AEs, infectious AEs and SAEs, upper respiratory tract infections, injection-site reactions, neoplasms, and tuberculosis. RESULTS: A total of 2023 references were identified and 18 randomized controlled trials were included. The main pooled risk ratios of CZP-treated versus control patients were as follows: AEs 1.09 (95% confidence interval, CI 1.04-1.14), SAEs 1.50 (95% CI 1.21-1.86), ADRs 1.20 (95% CI 1.03-1.39), infectious AEs 1.28 (95% CI 1.13-1.45), infectious SAEs 2.17 (95% CI 1.36-3.47), and upper respiratory tract infections 1.34 (95% CI 1.15-1.57). CONCLUSION: Safety data on CZP suggest an overall favorable tolerability profile, with infections being the most common AE. However, CZP-treated patients had a twofold higher risk of infectious SAEs than control patients. Large observational studies and data from national registries are needed to detect rare AEs, which might occur after long-term exposures to CZP.

Rapid maxillary expansion outcomes in treatment of obstructive sleep apnea in children.

OBJECTIVES: The objectives of this study were to confirm the efficacy of rapid maxillary expansion in children with moderate adenotonsillar hypertrophy in a larger sample and to evaluate retrospectively its long-term benefits in a group of children who underwent orthodontic treatment 10 years ago. METHODS: After general clinical examination and overnight polysomnography, all eligible children underwent cephalometric evaluation and started 12 months of therapy with rapid maxillary expansion. A new polysomnography was performed at the end of treatment (T1). Fourteen children underwent clinical evaluation and Brouilette questionnaire, 10 years after the end of treatment (T2). RESULTS: Forty patients were eligible for recruitment. At T1, 34/40 (85%) patients showed a decrease of apnea-hypopnea index (AHI) greater than 20% (ΔAHI 67.45% ± 25.73%) and were defined responders. Only 6/40 (15%) showed a decrease <20% of AHI at T1 and were defined as non-responders (ΔAHI -53.47% ± 61.57%). Moreover, 57.5% of patients presented residual OSA (AHI > 1 ev/h) after treatment. Disease duration was significantly lower (2.5 ± 1.4 years vs 4.8 ± 1.9 years, p <0.005) and age at disease onset was higher in responder patients compared to non-responders (3.8 ± 1.5 years vs 2.3 ± 1.9 years, p <0.05). Cephalometric variables showed an increase of cranial base angle in non-responder patients (p <0.05). Fourteen children (mean age 17.0 ± 1.9 years) who ended orthodontic treatment 10 years previously showed improvement of Brouilette score. CONCLUSION: Starting an orthodontic treatment as early as symptoms appear is important in order to increase the efficacy of treatment. An integrated therapy is needed.

A nonsurgical approach to treatment of high-angle Class II malocclusion.

Malocclusions with a hyperdivergent vertical facial pattern are often difficult to treat without a combined surgical/orthodontic approach. The aim of this article is to describe a nonsurgical approach to the treatment of a high-angle Class II malocclusion in a growing patient. Some fundamental aspects, such as correct diagnosis, treatment timing, favorable mandibular growth pattern, and patient compliance, proved to be critical to correct the severe dentoskeletal disharmony.

Evaluation of the atmospheric pressure photoionization source for the determination of benzidines and chloroanilines in water and industrial effluents by high performance liquid chromatography-tandem mass spectrometry.

A solid phase extraction-high performance liquid chromatography-tandem mass spectrometry based analytical method suitable for simultaneous analysis of benzidine, 3,3'-dichlorobenzidine, mono-, di-, and tri-chloroanilines has been developed. Normal phase separation by liquid chromatography was performed using a cyano propyl methyl silica column, and atmospheric pressure photoionization was employed as interface with mass spectrometer. The developed method was evaluated in terms of limit of detection, accuracy, and precision. The quantification limit for all the compounds ranged between 7 and 112ngL(-1), while recovery for all the compounds was higher than 94%. The method was tested by analyzing different industrial wastes, showing residual contamination by most of the analytes.

Analytical approach for monitoring endocrine-disrupting compounds in urban waste water treatment plants.

The presence of endocrine-disrupting compounds in influent and effluent water samples from four waste water treatment plants located in Italy was studied. The estrogen-like activity of the water samples was measured using a chemiluminescent recombinant yeast assay which is based on genetically engineered yeast cells that express the human estrogen receptor. This receptor, once activated, elicits the expression of the reporter gene lac-Z and, consequently, the production of beta-galactosidase, which is then measured by chemiluminescence. To control and minimize sample matrix effects, an external control based on a modified yeast strain stably expressing beta-galactosidase was developed and also used in the assay. Rapid and sensitive chemiluminescent enzyme immunoassays were also developed and validated for the quantification of 17beta-estradiol, estrone, and estriol in waste water samples. Results from both methods were compared with a reference high-performance liquid chromatography and electrospray ionization tandem mass spectrometry (HPLC ESI-MS-MS) method developed for the quantification of natural estrogens. The recombinant yeast assay revealed a significant estrogenic activity in the influent samples, ranging from 80 to 400 pmol/L 17beta-estradiol equivalents (EEQ), which was reduced by 70-95% in the effluent samples. The yeast assay also showed a systematic 20-30% overestimation of estrogenic activity relative to the HPLC ESI-MS-MS method, suggesting the presence of other compounds in the samples with estrogenic activity. The chemiluminescent enzyme immunoassays showed the presence of estrogens in the influent samples (mean concentrations: 350-450 pmol/L for estrone, 5-100 pmol/L for 17beta-estradiol, 25-300 pmol/L for estriol), with significantly lower concentrations detected in the respective effluent samples. The waste water treatment was able to reduce natural estrogen concentrations by 40-95%, although a high variability was observed. The enzyme immunoassay data correlated well with data obtained by the HPLC ESI-MS-MS method. Although the recombinant yeast assay represents a useful tool for a first-level screening of estrogenic activity due to its simplicity and high analytical throughput, sample matrix effects observed in waste water of industrial origin were found to strongly affect the yeast cells response, even when properly corrected for using the external control, thereby limiting its use to urban waste water. Its integration with chemiluminescent enzyme immunoassays would improve its performance by reducing false negative results, thereby enabling its use in extensive studies monitoring for the presence of endocrine-disrupting compounds in urban treatment plant effluents.

Orthodontic treatment of an impacted dilacerated maxillary incisor: a case report.

Dilaceration is one of the causes of permanent maxillary incisor eruption failure. It is a developmental distortion of the form of a tooth that commonly occurs in permanent incisors as result of trauma to the primary predecessors whose apices lie close to the permanent tooth germ. We present a case of post-traumatic impaction of a dilacerated central maxillary left incisor in a young patient with a class II malocclusion.

Interceptive management of eruption disturbances: case report.

The aim of the present report is to describe a case of a patient with eruption disturbances of an ankylosed lower primary second molar, delayed development of a maxillary permanent canine associated with an odontoma and a class III dental malocclusion. In such a case the objectives of treatment are: to prevent impaction of the lower second premolar and tipping of the lower first molar; to establish correct anterior overbite and overjet and to control the development of the permanent upper canine.

An orthopaedic approach to the treatment of Class III malocclusions in the early mixed dentition.

The aim of this investigation was to study cephalometrically the skeletal, dental and soft tissue modifications induced by a Delaire facemask and Bionator III appliance in a sample of 30 patients (17 boys and 13 girls), aged 4.1-9 years [mean 5.85 years, confidence interval (CI) 5.41-6.29], in the early mixed dentition with a skeletal Class III malocclusion caused by maxillary retrognathism (group 1) and compared with a control sample of 24 subjects (14 boys and 10 girls), aged 4-9 years (mean 5.97 years, CI 5.35-6.58) with untreated Class III malocclusions (group 2). For each patient a lateral cephalogram was taken before treatment (T0), after facemask removal (T1), and at the end of the retention period with a Bionator III (T2). Cephalometric analysis was carried out. The post-treatment cephalometric values in the treated group showed a forward displacement of the maxilla resulting in a statistically significant increase (P < 0.001) in the SNA angle, A-NPg (mm) and PNS-A (mm) linear values. There was a clockwise rotation of the mandible, with a decrease in the SNB angle and a satisfactory correction of the Class III relationship. The beneficial effects on the facial profile were confirmed by an increase in UL-EL distance and in NB--HL and NsPgs--HL angles, and by a decrease in the facial convexity angle. These findings indicate that the Delaire facemask and Bionator III treatment is effective for correcting skeletal Class III malocclusions caused by maxillary retrognathism in the early mixed dentition.

Orthodontic treatment of a patient with an unusual impaction of a central incisor: case report.

This report documented an unusual case with impaction of a right permanent central incisor. The purpose of this work was to illustrate how the original lingual lever arm moved the impacted central incisor in the dental arch. The authors used a modified lingual arch made of .036 inch stainless steel wire soldered to bands on the second primary molars. The lingual arch caused some minor inconveniences, but the discomfort was slight. Patient compliance was not a problem because a fixed appliance was used in the primary dentition.