Efficacy and safety of tirbanibulin 1% ointment in actinic keratoses: Data from two phase-III trials and the real-life clinical practice presented at the European Academy of Dermatology and Venereology Congress 2022.

BACKGROUND: The 31st European Academy of Dermatology and Venereology (EADV) Congress took place between 7th and 10th of September 2022 in Milan, Italy. OBJECTIVES: We report presented clinical data on the efficacy/effectiveness, safety and tolerability of tirbanibulin 1% ointment that has recently been licensed for actinic keratosis (AK) of the face or scalp in adults. METHODS: Summary of presentations given at the EADV Congress. RESULTS: Prof. Pellacani presented two post hoc analyses from two phase-III trials with AK patients (NCT03285477 [N = 351] and NCT03285490 [N = 351]): A descriptive analysis of medical history, concomitant medications, and safety results confirming a favourable profile for tirbanibulin showing that number of baseline AK lesions was not correlated to severity of local skin reactions. The latter analysis showed that cases of tirbanibulin application site pain or pruritus were few, and most were found to be mild. Prof. Kunstfeld reported six real-life clinical cases in Austria showing good tirbanibulin effectiveness, safety and tolerability for the treatment of new or recurring AK lesions. Results demonstrated that after 2- to 4-month follow-up, tirbanibulin was well tolerated and effective in AK patients. Presentations by Dr. Patel confirmed good outcomes and tolerability of tirbanibulin in Olsen grade 1-2 AK (N = 12) and porokeratosis patients (N = 4) treated once daily for 5 consecutive days in the United Kingdom. Furthermore, real-world experience in solid organ transplant recipients (N = 2) demonstrated effectiveness of tirbanibulin in skin field cancerization treatment. A symposium sponsored by Almirall was conducted during the congress in which Dr. Hadshiew and Dr. Lear brought together their clinical experience in Germany and the United Kingdom respectively. Interesting clinical cases of 5 consecutive days of tirbanibulin treatment compared to other treatments were discussed with attendees, as well as current treatment needs of AK patients. CONCLUSIONS: This article provides an overview of presentations and symposium discussions, summarizing key phase-III results and real-life clinical experience with tirbanibulin shared by dermatologists across Europe.

High threshold efficacy responses in moderate-to-severe atopic dermatitis are associated with additional quality of life benefits: pooled analyses of abrocitinib monotherapy studies in adults and adolescents.

BACKGROUND: Once-daily abrocitinib treatment provided meaningful improvements in signs and symptoms of moderate-to-severe atopic dermatitis (AD) in randomized controlled studies. OBJECTIVE: To evaluate proportions of patients with responses meeting higher threshold efficacy responses than commonly used efficacy end points and to determine if these responses were associated with quality-of-life (QoL) benefits. METHODS: Data from a phase 2b (NCT02780167) and two phase 3 studies (NCT03349060/JADE MONO-1; NCT03575871/JADE MONO-2) in adult and adolescent patients (N = 942) with moderate-to-severe AD receiving once-daily abrocitinib 200 mg, abrocitinib 100 mg or placebo were pooled. Commonly used (Eczema Area and Severity Index [EASI]-75 and ≥4-point improvement in Pruritus Numerical Rating Scale [PP-NRS4]) and higher threshold efficacy end points (EASI-90 to

Timing of dental extractions in patients undergoing radiotherapy and the incidence of osteoradionecrosis: a systematic review and meta-analysis.

This systematic review aimed to examine whether the incidence of osteonecrosis differed between patients who have dental extractions before or after radiotherapy (RT). The reported incidence of osteoradionecrosis (ORN) of the jaws following RT to the head and neck varies widely in the literature. Currently, for patients with head and neck cancer there are no universally accepted guidelines on the optimal timing of dental surgery relative to RT to minimise incident ORN. A literature review was conducted using the Preferred Reporting Items for Systematic Review and Meta-Analysis (PRISMA) criteria. A search of PubMed, EMBASE, Evidence-Based Medicine, and Web of Science databases targeted literature published up to and including 10 April 2020. Two independent reviewers assessed studies for eligibility against inclusion criteria. An assessment of bias was conducted for each of the included studies and relevant data extracted. A meta-analysis was undertaken using the statistical methods described. Twenty-four of 708 studies were included. They were heterogeneous and included a wide variation of RT methods, head and neck malignancies, and comorbidities. While some concluded that the incidence of ORN was dependent on the timing of dental extractions in relation to RT, with regard to the risk of its development, others reported additional factors such as age, comorbidities, extent of surgical resection, and dose and field of radiation, as more important predictors than timing. In many there was consistent lack of detail around the timing of dental procedures in relation to the delivery of RT. From 21 studies including 36,294 patients, of whom 14,389 had extractions before RT, the pooled incidence of ORN was 5.5% (95% CI: 2.1% to 10.1%). Significant heterogeneity was found in Cochran's Q-test (p<0.001) and Higgins I2=98.0%. From 21 studies including 37,805 patients, of whom 6030 had extractions after RT, the pooled incidence of ORN was 5.3% (95% CI: 2.9% to 8.2%). Significant heterogeneity was found in Cochran's Q-test (p<0.001) and Higgins I2=80.0%. There was no statistically significant difference between these two groups (random-effects model Q=0.12, p=0.73). Large, longitudinal studies with a priori-specified methods are needed to identify, recruit, and prospectively follow patients with head and neck cancer for the onset of ORN after dental surgery. This will allow clinical guidelines to be established to assist clinicians to plan treatment when extractions are indicated in patients undergoing RT to the head and neck.

Molecular dissection of TNFR-TNFα bidirectional signaling reveals both cooperative and antagonistic interactions with p75 neurotrophic factor receptor in axon patterning.

During neural development, complex organisms rely on progressive and regressive events whereby axons, synapses, and neurons are overproduced followed by selective elimination of a portion of these components. Tumor necrosis factor α (TNFα) together with its cognate receptor (Tumor necrosis factor receptor 1; TNFR1) have been shown to play both regressive (i.e. forward signaling from the receptor) and progressive (i.e. reverse signaling from the ligand) roles in sympathetic neuron development. In contrast, a paralog of TNFR1, p75 neurotrophic factor receptor (p75NTR) promotes mainly regressive developmental events in sympathetic neurons. Here we examine the interplay between these paralogous receptors in the regulation of axon branch elimination and arborization. We confirm previous reports that these TNFR1 family members are individually capable of promoting ligand-dependent suppression of axon growth and branching. Remarkably, p75NTR and TNFR1 physically interact and p75NTR requires TNFR1 for ligand-dependent axon suppression of axon branching but not vice versa. We also find that p75NTR forward signaling and TNFα reverse signaling are functionally antagonistic. Finally, we find that TNFα reverse signaling is necessary for nerve growth factor (NGF) dependent axon growth. Taken together these findings demonstrate several levels of synergistic and antagonistic interactions using very few signaling pathways and that the balance of these synergizing and opposing signals act to ensure proper axon growth and patterning.

The oral Janus kinase/spleen tyrosine kinase inhibitor ASN002 demonstrates efficacy and improves associated systemic inflammation in patients with moderate-to-severe atopic dermatitis: results from a randomized double-blind placebo-controlled study.

BACKGROUND: ASN002 is an oral dual inhibitor of Janus kinase and spleen tyrosine kinase, which are involved in the pathogenesis of atopic dermatitis (AD) through their regulatory role on T helper (Th)1, Th2 and Th17/Th22 pathways. OBJECTIVES: The objectives of this study were to evaluate the efficacy, safety, pharmacokinetics and effects on systemic biomarkers of ASN002 in patients with moderate-to-severe AD. Methods A total of 36 patients with moderate-to-severe AD were randomized (3 : 1) to ASN002 or placebo in the phase Ib study. Three dosage cohorts were studied over a 28-day period (20 mg, 40 mg and 80 mg once daily). RESULTS: ASN002 was superior to placebo for the proportion of patients achieving Eczema Area and Severity Index (EASI) 50 (20 mg 20%, P = 0·93; 40 mg 100%, P = 0·003; 80 mg 83%, P = 0·03; placebo 22%), EASI 75 (20 mg 0%, P = 0·27; 40 mg 71%, P = 0·06; 80 mg 33%, P = 0·65; placebo 22%) and in change from baseline in pruritus (20 mg -1·3 ± 2·1, P = 0·81; 40 mg -3·1 ± 2·7, P = 0·27; 80 mg -4·7 ± 2·1, P = 0·01; placebo -1·6 ± 1·8). Adverse events were generally mild and similar across all groups. ASN002 showed dose-dependent plasma exposure with low interpatient variability, significantly downregulated several serum biomarkers involved in Th1, Th2 and Th17/Th22 immunity, and decreased the atherosclerosis-associated biomarker E selectin/SELE. CONCLUSIONS: In patients with moderate-to-severe AD, ASN002 showed strong efficacy with rapid onset of action and associated improvements in systemic inflammation.

Circulating progenitor cells in patients with familial hypercholesterolemia.

OBJECTIVE: Familial hypercholesterolemia (FH) is a genetic disease with very high levels of circulating low density lipoprotein cholesterol (LDL-C) levels that leads to accelerated atherosclerosis. Lipoprotein apheresis is an effective treatment option for patients with FH and results in reduced cardiovascular morbidity and mortality. Circulating progenitor cells (CPCs) are markers of overall vascular health and diminished levels have been associated with decreased reparative potential and worse outcomes. We assessed the short-term change in CPC levels following a single lipoprotein apheresis session in FH patients who are already on stable lipoprotein apheresis therapy. We hypothesized that in addition to a reduction in atherogenic lipids, the cardiovascular benefit from lipoprotein apheresis therapy is mediated by enhanced vascular reparative capacity through mobilization of CPCs. METHODS: Eight FH patients (1 homozygous and 7 heterozygous) on stable lipoprotein apheresis therapy for at least three months had CPCs measured at baseline (prior to apheresis) and two hours after apheresis. Results were compared with data from age-matched hyperlipidemic (HLP) patients on statin therapy and healthy volunteers. RESULTS: FH patients had higher baseline circulating levels of CD34+/CD133+ and CD34+/CD133+/CXCR4+ cells compared to HLP and healthy subjects. There was no significant change in CPCs after apheresis in FH patients. CONCLUSIONS: FH patients had higher CPC counts at baseline compared to age-matched HLP and healthy controls, suggesting activation of reparative mechanism in this high risk population. Larger studies are needed to better characterize differences in CPC counts between FH subjects and HLP patients over time.

End-tidal sevoflurane concentration for ProSeal(TM) versus Classic(TM) laryngeal mask airway insertion in unpremedicated anaesthetised adult females.

The optimal end-tidal sevoflurane concentration for successful ProSealTM (Teleflex, Morrisville, NC, USA) laryngeal mask airway (PLMA) versus ClassicTM (Teleflex, Morrisville, NC, USA) laryngeal mask airway (CLMA) insertion in unpremedicated anaesthetised adults is unknown. We determined end-tidal sevoflurane concentrations for successful insertion in fifty percent of anaesthetised adults. This randomised, prospective, double-blind study was conducted in the operating theatre of a government tertiary care hospital. Forty-four unpremedicated American Society of Anesthesiologists physical status I and II women with cervical carcinoma (aged 30 to 60 years), scheduled for intracavity caesium implantation under general anaesthesia with a laryngeal mask airway (LMA) were included in the study. The participants were randomised to one of the two groups, to receive either a PLMA or CLMA. After anaesthetic induction with sevoflurane, a predetermined end-tidal sevoflurane concentration (starting at 2.5%) was sustained for 10 minutes before LMA insertion was attempted. End-tidal sevoflurane concentration was increased/decreased (step-size 0.25%) using Dixon and Massey's up-and-down method for the next patient based on the previous patient's response. Placement without clenching, movement, coughing or biting within one minute was considered successful insertion. The end-tidal sevoflurane concentration required for successful LMA insertion in fifty percent of anaesthetised adults was calculated as the mean of the crossover pairs' midpoints in each group and further confirmed by probit regression analysis. The end-tidal sevoflurane concentration (95% confidence interval) required for successful PLMA insertion in 50% of anaesthetised adults (3.15% [3.12% to 3.18%]) was significantly higher than that for CLMA insertion (2.71% [2.66% to 2.76%], P<0.001). These findings suggest that deeper anaesthesia is required for placement of a PLMA in comparison to a CLMA.

Patterns of differentially expressed genes in oral mucosal lesions visualised under autofluorescence (VELscope(™) ).

OBJECTIVES: We aimed to elucidate the molecular pathways associated with fluorescence properties of oral potentially malignant disorders (OPMD) visualised under direct tissue autofluorescence (VELscope(™)). MATERIALS AND METHODS: Forty-two oral mucosal biopsies correlated with clinical fluorescence characteristics were categorised based on histopathological diagnosis. Four oral squamous cell carcinoma (OSCC), 15 oral epithelial dysplasia (OED), nine oral lichen planus (OLP) and 14 oral epithelial hyperplasia (OEH) presenting with three fluorescence patterns including retained fluorescence (RF), loss of fluorescence (LAF) with blanching (LB) and LAF with no blanching (LNB) were assessed. Relative gene expression was measured through RNA sequencing. RESULTS: Although each lesion type had a specific set of histology-related differentially expressed genes (DEGs), all tested samples shared a number of DEGs, and we could not identify a discriminatory component between histological groups. Gene ontology enrichment revealed LAF in OEH was mostly due to changes in inflammation, cell cycle regulation and apoptosis, while in OED was due to inflammation, angiogenesis and extracellular matrix remodelling. Inflammatory reactions were associated with diascopic fluorescence (DF) for both OEH and OED. CONCLUSION: Uncovering the molecular mechanisms underlying LAF and DF may lead to reduction in the number of false-positive and false-negative findings and improve the efficacy and utility of VELscope(™).

A comparison of single dose dexmedetomidine with propofol for the prevention of emergence delirium after desflurane anaesthesia in children.

Emergence delirium is a common problem in children recovering from general anaesthesia. We performed a study comparing emergence characteristics in 100 patients who were randomly allocated to receive either 0.3 µg.kg(-1) dexmedetomidine, 1 mg.kg(-1) propofol or saline 0.9% and undergoing infra-umbilical surgery. The Pediatric Anesthesia Emergence Delirium scale was used to grade emergence delirium. Emergence delirium occurred in 9.4% of children in the dexmedetomidine group compared with 13.9% in the propofol group and 40.6% in the control group (p = 0.004). In the dexmedetomidine group, sedation occurred in 62.5% of children at 10 min after transfer to the recovery area, compared with 44.4% in the propofol group and 12.5% in the control group (p = 0.010). We conclude that dexmedetomidine significantly reduced the incidence of emergence delirium but this was at the expense of a greater incidence of sedation in the recovery period.

Therapeutic goals in patients with pheochromocytoma: a guide to perioperative management.

INTRODUCTION: Pheochromocytomas are rare neuroendocrine tumors of the adrenal medulla that may present with protean manifestations. Surgical resection is the mainstay of therapy and patients are at risk of significant hemodynamic and circulatory complications mainly attributable to catecholamine excess. The mainstay of medical therapy in order to optimize patients for surgery includes: alpha-blockers, beta-blockers, calcium channel blocker and other agents to achieve normal blood pressure, heart rate, as well as normal volume status. Understanding the pathophysiology of pheochromocytoma, the pharmacology of medications used, and recognizing postoperative complications will impact patient outcomes. CONCLUSION: A multidisciplinary team approach is best throughout the perioperative period to prevent potential complications that arise. The hospital physician, intensivist, anesthetist and cardiovascular specialist play a pivotal role in the management of patients with pheochromocytoma. In addition to the pharmacologic and volume recommendations, a multidisciplinary discussion allows for seamless implementation of an organized plan of care.

Impact of weekly iron folic acid supplementation with and without vitamin B12 on anaemic adolescent girls: a randomised clinical trial.

BACKGROUND/OBJECTIVES: In India, approx. 70% of the adolescent girls are anaemic (haemolgobin <120 g/l). The present study was a supervised randomised double-blind clinical trial conducted among adolescent girls (11-18 years) to assess and compare the impact of weekly iron folic acid (IFA) supplementation with or without vitamin B12 on reduction in the prevalence of anaemia and on blood/serum levels of haemoglobin, serum ferritin, folic acid and vitamin B12. SUBJECTS/METHODS: Community-based randomized controlled trial was carried out in Kirti Nagar slums of West Delhi. A total of 446 mild (100-119 g/l) and moderate (70-99 g/l) anaemic volunteer adolescent girls were identified and randomised into two groups. Weekly supervised supplementation was given for 26 weeks: Group A (n=222): iron (100 mg), folic acid (500 mcg) and placebo; Group B (n=224): iron (100 mg), folic acid (500 mcg) and cyanocobalamin (500 mcg for 6 weeks and 15 mcg for 20 weeks). Haemoglobin, serum ferritin, folic acid and vitamin B12 levels were assessed at baseline and after intervention. A total of 373 subjects completed 26 weeks of supplementation successfully. RESULTS: The mean haemoglobin increased from 106.7±11.2 g/l and 108.9±8.91 g/l in Group A and Group B at baseline to 116.4±10.8 g/l (P<0.001) and 116.5±10.26 g/l (P<0.001) at post-intervention, respectively, with the reduction in the prevalence of anaemia by 35.9% in Group A and 39.7% in Group B (P>0.05). A total of 63.3% participants had deficient vitamin B12 levels (<203 pg/ml) at baseline, which reduced to 40.4% after intervention with cyanocobalamin, whereas no change was observed in vitamin B12 status in the other group. Significant reduction (P=0.01) in the prevalence of serum ferritin deficiency (<15 ng/ml) was observed in the group supplemented with vitamin B12 (from 36.5 to 6.4%) as compared with the other group supplemented with only IFA (from 39.1 to 15.2%). CONCLUSIONS: IFA supplementation with or without vitamin B12 is an effective measure to cure anaemia. Although addition of vitamin B12 had similar impact on improving haemoglobin status as IFA alone, it resulted in better ferritin status. Hence, more multi-centre studies with a longer duration of supplementation or higher dose of vitamin B12 may be undertaken to assess the possible impact of vitamin B12 on improving haemoglobin levels in the population.

Noninvasive cellular internalization of silver molecules by chitosan nanoneedles: a novel nanocarrier.

We explore with molecular modeling, dynamics simulations, and a statistical model the ability of chitosan nanoneedles (CNNs) to be internalized into a model lipid bilayer as a function of their length, keeping in view of their applications in the field of biomedicine for advanced targeted drug delivery. In this study, we have computationally modeled and studied the structural geometry and the stability of CNNs formed by 4, 6, and 8 subunits. We reported the molecular surface analysis of the modeled CNNs along with molecular dynamic (MD) simulations studies toward revealing the noninvasive cellular internalization potential of these CNNs and a case study has been carried to study the ability of CNNs to translocate silver nanoparticles across membrane. The present results are strongly in support of further exploration of 8 subunits based CNNs for their application as target drug delivery vehicles. The hydrophilicity of the CNNs has been attributed as one of the key factors responsible for the internalization process. Moreover, our MD simulation studies marched the ability of CNNs to translocate silver nanoparticles through biological membrane in a similar manner that resembles cell-penetrating peptides.

Federal public health strategies to minimize the importation of communicable diseases into Canada.

BACKGROUND: The global spread of communicable diseases is a growing concern largely as a result of increased international travel. In Canada, although most public health management of communicable diseases occurs at the front line, the federal government also takes actions to prevent and mitigate their importation. OBJECTIVE: To describe the role of the Public Health Agency of Canada (PHAC) in minimizing the importation of communicable diseases through preventive measures taken before travellers leave Canada and through early detection and prompt containment measures taken when travellers arrive in the country with a potential communicable disease. INTERVENTIONS: PHAC works to minimize the importation of communicable diseases into Canada by developing evidence-based travel health advice and targeted outreach activities geared to the public and to health care professionals. On the basis of the Quarantine Act and the International Health Regulations (2005), PHAC also conducts inspections of conveyances such as aircraft and boats and works with partners to conduct border screening to assess ill travellers entering the country. CONCLUSION: PHAC plays an important role in preventing and minimizing the importation of communicable diseases into Canada in conjunction with clinicians, public health authorities at all levels of government and other federal government departments.

Acute renal failure as an initial manifestation of acute lymphoblastic leukemia.

Acute lymphoblastic leukemia (ALL) is the most common malignancy in children. Acute renal failure is a well-recognized complication of ALL after initiation of chemotherapy. Renal failure as the primary manifestation of ALL is rare. Here, we report three children who presented with acute renal failure and hyperuricemia and were subsequently diagnosed to have ALL.

Minimum intervention dentistry in oral medicine.

Oral medicine sits at the interface of medicine and dentistry. Minimum intervention dentistry (MID) borrows a medical model of disease control by oral health professionals. As an oral physician, the oral medicine specialist practices MID on a daily basis. With the advent of sophisticated early detection and diagnostic technology, and the growing understanding of oral diseases at the microscopic and molecular levels, all oral health practitioners can contribute to the practice of oral medicine from a MID perspective. MID in oral medicine allows the practice of comprehensive oral care where the patient is fully engaged in their own healthcare, with the use of advanced diagnostic technology, the application of medicines and therapeutics depending on disease processes, important risk assessment of both the oral disease and the affected patient with identification of those at high risk, monitoring of compliance, and patient recall. In this article we highlight minimum intervention in oral medicine by exploring oral cancer as the most significant disease we encounter and are involved with. Advances in patient care, particularly in relation to minimum intervention, are underpinned by high calibre cutting edge translational research. It is this research that allows us to positively transform our patients' lives.

Sensorineural deafness in patients of type 2 diabetes mellitus in uttar pradesh: a pilot study.

B/L symmetrical sensorineural hearing loss has long been associated with diabetes Mellitus. Microangiopathy associated with thickening of the basement membrane of small vessels has been implicated as a major source. This study was done to observe the predominant site of lesion whether cochlear or retrocochlear in patients of diabetic sensorineural hearing loss. This was a random study. Forty two patients with diabetic B/L symmetrical sensorineural hearing loss were selected in a tertiary referral centre. All the patients selected were of diabetic B/L symmetrical sensorineural hearing loss. The study was designed to show the predominant site of lesion whether cochlear or retrocochlear in patients of diabetes with or without noise exposure. The parameter for inferring blood sugar control was level of glycosylated haemoglobin (Hb1AC). The incidence of the classical symptoms of diabetes mellitus namely polyurea, polydypsia and polyphagia were seen in (40.8%) of patients. The present study was designed to show that even early diabetic patients without symptoms of hearing loss had mild bilaterally symmetrical purely sensorineural hearing loss (32.65%) signifying the diabetic hypoacusis is present significantly even in early aural symptomless diabetics. On follow up it was revealed that the hearing loss of these patients was irreversible. The predominant site of lesion was found to be cochlear by performing Chi Square test P < .05 and so this is applicable to the general population of Uttar Pradesh.

Exploring the influence of steric, electronic and lipophilic descriptors of 1,3-diarly propenones on their anti-inflammatory activity.

BACKGROUND AND THE PURPOSE OF THE STUDY: Various compounds from natural and synthetic origins containing the 1,3-diarylpropenone structure have been reported to produce a variety of biological activities like anti-microbial, anti-inflammatory, vascular muscle relaxant, etc. A systematic analysis of the structural features responsible for anti-inflammatory activity and a possible mode of their actions were proposed to be evaluated by synthesizing a set of compounds, screening them for anti-inflammatory activity and developing a QSAR model. METHODS: Two types of 1,3-diarylpropenone derivatives were synthesized employing the Claisen-Schmidt condensation. These compounds were then screened for their in vivo anti- inflammatory activity by the carrageenin induced rat paw edema method and also for in vitro cyclooxygenase-2 (COX-2) inhibition activity using a colorimetric kit for COX (ovine) inhibitor screening assay. These derivatives and their anti-inflammatory activity data were employed for QSAR analysis on Vlife MDS 3.5 software. The molecules were divided into training and test sets based on observed activity and QSAR models were generated for the training set and validated. The activity of the molecules of the test set was predicted according to the QSAR equation fit. Possible correlation between observed anti-inflammatory activity and in vitro cyclooxygenase-2 inhibition was also studied. RESULTS AND CONCLUSION: Insignificant difference between the observed and predicted biological activity revealed that the selected electronic, steric and lipophilic parameters have a significant correlation (r(2)=0.85) with anti-inflammatory activity of the selected class of compounds. On the basis of results it may be suggested that the 1,3-diaryl-2-propen-1-ones framework is an attractive template for structural optimization to achieve better potency of anti-inflammatory activity. Similarly, the relatively low correlation between anti-inflammatory activity and cyclooxygenase-2 inhibition indicates that other modes of actions may also be responsible for the anti-inflammatory activity of the tested compounds.