Lentigo maligna: a review.

Lentigo maligna (LM) is a melanoma in situ with distinct clinical features and histology. It commonly affects men after the sixth decade of life. Incidence rates of LM have increased based on early 21st century data from different countries; however, data are suboptimal. Data from England show a plateauing crude incidence between 2013 and 2019. By comparison, invasive melanoma and other types of melanoma in situ commonly appears in younger age groups (median age 58 and 67 years old, respectively) and incidence is rising. The most important risk factors for LM include fair skin and cumulative ultraviolet solar radiation exposure. Although LM is limited to the epidermis and connected skin adnexa, it may progress to invasive LM melanoma. The reported rate of malignant progression varies, reflecting a challenge for LM epidemiology research as often lesions are removed on diagnosis. LM poses a challenge in diagnosis and management. Although it can be diagnosed clinically or dermoscopically, histopathological assessment of biopsied skin tissue remains the gold standard. Reflectance confocal microscopy allows for better appreciation of the complexity of LM at a cellular level, often progressing beyond clinical margins. Management of LM may involve Mohs micrographic surgery or excision, although recurrence may occur even with 5 mm clinical margins. Imiquimod cream may be effective, but incomplete treatment and recurrence has been reported. Conservative management with observation or radiotherapy may be used in selected patients' cases. Five-year net survival rates are excellent. This paper reviews the natural history, epidemiology, aetiology, pathogenesis, diagnosis and management of LM.

In vivo human keyhole limpet hemocyanin challenge in early phase drug development: A systematic review.

Experimental exposure of healthy volunteers to the T-cell dependent neoantigen keyhole limpet hemocyanin (KLH) permits the evaluation of immunomodulatory investigational medicinal product (IMP) pharmacology prior to the recruitment of patient populations. Despite widespread use, no standardized approach to the design and conduct of such studies has been agreed. The objective of this systematic review was to survey the published literature where KLH was used as a challenge agent, describing methodology, therapeutic targets addressed, and pharmacodynamic outcome measures. We searched MEDLINE, EMBASE, clinicaltrials.gov, and Cochrane CENTRAL for studies using KLH challenge in humans between January 1, 1994, and April 1, 2022. We described key study features, including KLH formulation, dose, use of adjuvants, route of administration, co-administered IMPs, and end points. Of 2421 titles and abstracts screened, 46 met the inclusion criteria, including 14 (31%) early phase trials of IMP, of which 10 (71%) targeted T-cell co-stimulation. IMPs with diverse mechanisms demonstrated modulation of the humoral response to KLH, suggesting limited specificity of this end point. Two early phase IMP studies (14%) described the response to intradermal re-challenge (delayed type hypersensitivity). Challenge regimens for IMP assessment were often incompletely described, and exhibited marked heterogeneity, including primary KLH dose (25-fold variation: 100-2500 mcg), KLH formulation, and co-administration with adjuvants. Methodological heterogeneity and failure to exploit the access to tissue-level mechanism-relevant end points afforded by KLH challenge has impaired the translational utility of this paradigm to date. Future standardization, characterization, and methodological development is required to permit tailored, appropriately powered, mechanism-dependent study design to optimize drug development decisions.

Calcitonin: A useful old friend.

Calcitonin regulates blood calcium levels and possesses certain clinically useful anti-fracture properties. Specifically, it reduces vertebral fractures in postmenopausal osteoporotic women significantly compared to a placebo. Nevertheless, the use of calcitonin has declined over the years and salmon calcitonin is no longer the first-line treatment for many of its indications. Commercial calcitonin only exists in intranasal or injectable preparations, which are less preferable for patients. Efficacy of a potential oral formulation has been under investigation but achieving adequate bioavailability remains a conundrum and the latest phase III trials have not shown promising evidence justifying its use. Associations with cancer have also derailed this treatment option. Furthermore, the rise of bisphosphonates and, more recently, monoclonal antibodies (such as denosumab), has revolutionised the treatment of osteoporotic fractures. Therefore, we are posed with an interesting question: is calcitonin a treatment of the past? This review aims to explore the reasons behind this paradigm shift and outline the potential role of calcitonin in the management of fractures and other conditions in the years to come.

The Effect of Perioperative Vitamin D Levels on the Functional, Patient-Related Outcome Measures and the Risk of Infection Following Hip and Knee Arthroplasty: A Systematic Review.

INTRODUCTION: The aim of this study was to evaluate the effect of perioperative vitamin D levels in terms of functional results, patient-related outcome measures (PROMs) and infection risk after hip or knee replacement. MATERIALS AND METHODS: A systematic search in PubMed, Cochrane library, ScienceDirect and ClinicalTrials.gov was conducted according to the PRISMA guidelines from inception to January 2020. RESULTS: Eighteen studies with more than 8000 knee and 1500 hip joint arthroplasties were included. The mean follow-up ranged from 6 weeks to 1 year and mean patients' age from 59.4 to 76 years. Hypovitaminosis was diagnosed in 26.7% of cases. Most studies did not find significant differences in pre- and postoperative functional results, PROMs and length of hospital stay between hypovitaminosis and euvitaminosis groups. Deficient patients may be at higher risk of postoperative joint stiffness. Patients suffering from hip and knee periprosthetic joint infection seem to have lower vitamin D levels compared to those with aseptic loosening of implants. CONCLUSION: The necessity of pre-operative correction of vitamin D levels to achieve better functional results and minimize the risk of infection following hip and knee arthroplasty remains inconclusive. Extend of exposure to low vitamin D levels and comparison between outliers needs further evaluation.

Evaluation of a pneumatic surgical robot with dynamic force feedback.

Robot-assisted surgery is limited by the lack of haptic feedback and increased operating times. Force scaling adjusts feedback transmitted to the operator through the use of scaling factors. Herein, we investigate how force scaling affects forces exerted in robotic surgery during simple and complex tasks, using a pneumatic surgical robot, IBIS VI. Secondary objectives were to test the effects of force scaling on operating time, depth of needle insertion and user satisfaction. Two novice males performed simple (modified block transfer) and complex (needle insertion) tasks under four scaling factors: 0.0, 0.5, 1.0 and 2.0. Single-blind experiments were repeated five times, with alternating scaling factors in random order. Increasing the scaling factor from 0.0 to 2.0 reduces forces in block transfer (p = 0.04). All feedback conditions reduce forces in needle insertion compared to baseline (0.5: p < 0.001, 1.0: p = 0.001, 2.0: p = 0.001). Time to complete block transfer is shorter for scaling factor 0.5 (p = 0.02), but not for 1.0 (p = 0.05) or 2.0 (p = 0.48), compared to baseline. Depth of needle insertion decreases consistently with incremental scaling factors (p < 0.001). Further reductions are observed upon augmenting feedback (0.5-2.0: p = 0.02). User satisfaction in block transfer is highest for intermediate scaling factors (0.0-1.0: p = 0.01), but no change is observed in needle insertion (p = 0.99). Increments in scaling factor reduce forces exerted, particularly in tasks requiring precision. Depth of needle insertion follows a similar pattern, but operating time and user satisfaction are improved by intermediate scaling factors. In summary, dynamic adjustment of force feedback can improve operative outcomes and advance surgical automation.

High-Performance Enzyme-Free Glucose Sensor with Co-Cu Nanorod Arrays on Si Substrates.

BACKGROUND: Glucose sensors have been extensively researched in patent studies and manufactured a tool for clinical diabetes diagnosis. Although some kinds of electrochemical enzymatic glucose sensors have been commercially successful, there is still room for improvement, in selectivity and reliability of these sensors. Because of the intrinsic disadvantages of enzymes, such as high fabrication cost and poor stability, non-enzymatic glucose sensors have recently been promoted as next generation diagnostic tool due to their relatively low cost, high stability, prompt response, and accuracy. OBJECTIVE: In this research, a novel free standing and binder free non-enzymatic electrochemical sensor was manufactured using in situ grown copper (Cu) and cobalt (Co) on a silicon (Si) substrate. METHODS: Scanning High-Energy Electron Diffraction (SHEED) and Edward deposition methods were used to synthesise the sensors. RESULTS: Morphological observations showed that Cu and Co homogeneously formed nanorod-like shapes over the Si substrate. The elemental composition and structure of the prepared sensors were identified by Reflection High-Energy Electron Diffraction (RHEED). In terms of electrochemical properties, for the enzyme-free glucose sensor, voltammograms showed that the peak currents increased when the glucose solution was injected into the electrolytic cell. The electrical relation of voltage versus current was linear, as shown in the experimental data. Another effective parameter changed the magnetic field; and the linear behaviour of the electrical resistance of Co remained unaltered. CONCLUSION: In the optimum annealing temperature, where the magnetic field increased, the properties of the samples remained constant. In other words, in the selected annealing temperature, resistance and stability of the layers increased in a significant manner.

Nanoparticles in wound healing; from hope to promise, from promise to routine.

Chronic non-healing wounds represent a growing problem due to their high morbidity and cost. Despite recent advances in wound healing, several systemic and local factors can disrupt the weighed physiologic healing process. This paper critically reviews and discusses the role of nanotechnology in promoting the wound healing process. Nanotechnology-based materials have physicochemical, optical and biological properties unique from their bulk equivalent. These nanoparticles can be incorporated into scaffolds to create nanocomposite smart materials, which promote wound healing through their antimicrobial, as well as selective anti- and pro-inflammatory, and pro-angiogenic properties. Owed to their high surface area, nanoparticles have also been used for drug delivery as well as gene delivery vectors. In addition, nanoparticles affect wound healing by influencing collagen deposition and realignment and provide approaches for skin regeneration and wound healing.

Efficacy and Safety of Deep Brain Stimulation in the Treatment of Parkinson's Disease: A Systematic Review and Meta-analysis of Randomized Controlled Trials.

Deep brain stimulation (DBS) is a neurosurgical procedure indicated for patients with advanced Parkinson's disease (PD). Whether similar benefits may be realized by patients with early PD, however, is currently unclear, especially given the potential risks of the procedure. This systematic review and meta-analysis aimed to investigate the relative efficacy and safety of DBS in comparison to best medical therapy (BMT) in the treatment of PD. It also aimed to compare the efficacy of DBS between patients with early and advanced PD. A systematic search was performed in Medline, Embase, and Cochrane Central Register of Controlled Trials (CENTRAL). Randomized controlled trials (RCTs) comparing DBS to BMT in PD patients were included. Outcome measures were impairment/disability using the Unified Parkinson's Disease Rating Scale (UPDRS), quality of life (QoL) using the Parkinson's Disease Questionnaire (PDQ-39), levodopa equivalent dose (LED) reduction, and rates of serious adverse events (SAE). Eight eligible RCTs (n = 1,189) were included in the meta-analysis, two of which recruited early PD patients. Regarding efficacy outcomes, there were significant improvements in UPDRS, PDQ-39, and LED scores in favour of DBS (P < 0.00001). There was a significantly greater reduction of LED in patients with early PD (P < 0.00001), but no other differences between early and advanced PD patients were found. The risk of a patient experiencing an SAE was significantly higher in the DBS group (P = 0.005), as was the total number of SAEs (P < 0.00188). Overall, DBS was superior to BMT at improving impairment/disability, QoL, and reducing medication doses, but these benefits need to be weighed against the higher risk of SAEs. There was insufficient evidence to determine the impact of the PD stage on the efficacy of DBS.

Disproportionately Large Communicating Fourth Ventricle: Pearls for Diagnosis and Management.

Introduction Disproportionately large communicating fourth ventricle (DLCFV) is an unusual presentation of communicating hydrocephalus, in which patients with hydrocephalus have a disproportionately enlarged fourth ventricle in the absence of obstructive pathology. We present six cases of DLCFV which, to date, is the largest series of this relatively rare condition. We highlight the significance of diagnosis and its differentiation from trapped fourth ventricle (TFV) and discuss the nuances for optimal management of DLCFV. Methods Retrospective case series of consecutive patients with DLCFV, managed by the senior author (LT) over a 10-year period. Results Six cases were identified, five of whom had previous posterior fossa surgery and one with previous encephalitis. All patients presented with cerebellar signs, the initial group had unsuccessful initial management with typical cerebrospinal fluid (CSF) diversion. Consistent symptom resolution was achieved by the application of negative CSF pressures via external ventricular drainage (EVD), maintained with subsequent ventriculopleural shunt (VPL), valveless lumbopleural shunt (LPS) or valveless ventriculoperitoneal shunt (VPS), or proceeding directly to a low-pressure system. Conclusions DLCFV is a diagnosis characterised by cerebellar dysfunction, with or without cranial nerve palsies, often in the setting of previous posterior fossa pathology. Optimal management relies on knowledge of this unique diagnostic entity, and use of an EVD at negative pressures to confirm symptomatic and radiological improvement prior to definitive treatment.

The role of thyrostimulin and its potential clinical significance.

Thyrostimulin is a glycoprotein heterodimer of GPA2 and GPB5, first described in 2002. It is involved in the physiological function of several tissues. Moreover, evidence points towards the ability of thyrostimulin's individual monomers to induce a biological effect, which could denote the circulatory/systemic effects of the molecule when found in higher concentrations. From the evolutionary point of view, thyrostimulin shares a binding epitope with the thyroid-stimulating hormone for the thyroid stimulating hormone receptor, whilst possessing affinity for another unique binding site on the same receptor. Although thyrostimulin can be involved in the hypothalamicpituitary- thyroid axis, its presence in various tissues in an eclectic array of different species renders it multifunctional. From weight loss via increasing metabolic rate to progression of cancer in human ovaries, it is certainly not a signaling molecule to overlook. Furthermore, thyrostimulin has been implicated in bone metabolism, acute illness, and reproductive function. In summary, to our knowledge, this is the first review dealing with the physiological role of thyrostimulin and its potential applications in the clinical practice.

An arsenal of magnetic nanoparticles; perspectives in the treatment of cancer.

Nanomedicine is an emerging field, which constitutes a new direction in the treatment of cancer. Magnetic nanoparticles (MNPs) can circumvent vascular tissue to concentrate at the site of the tumor. Under the influence of an external, alternating magnetic field, MNPs generate high temperatures within the tumor and ablate malignant cells while inflicting minimal damage to healthy host tissue. Due to their theranostic properties, they constitute a promising candidate for the treatment of cancer. A critical review of the type, size and therapeutic effect of different MNPs is presented, following an appraisal of the literature in the last 5 years. This is a multibillion dollar industry, with a few studies moving to clinical trials within the next 5 years.