Effect of Circadian Rhythm Modulated Blood Flow on Nanoparticle based Targeted Drug Delivery in Virtual In Vivo Arterial Geometries.

Delivery of drug using nanocarriers tethered with vasculature-targeting epitopes aims to maximize the therapeutic efficacy of the drug while minimizing the drug side effects. Circadian rhythm which is governed by the central nervous system has implications for targeted drug delivery due to sleep-wake cycle changes in blood flow dynamics. This paper presents an advanced fluid dynamics modeling method that is based on viscous incompressible shear-rate fluid (blood) coupled with an advection-diffusion equation to simulate the formation of drug concentration gradients in the blood stream and buildup of concentration at the targeted site. The method is equipped with an experimentally calibrated nanoparticle-endothelial cell adhesion model that employs Robin boundary conditions to describe nanoparticle retention based on probability of adhesion, a friction model accounting for surface roughness of endothelial cell layer, and a dispersion model based on Taylor-Aris expression for effective diffusion in the boundary layer. The computational model is first experimentally validated and then tested on engineered bifurcating arterial systems where impedance boundary conditions are applied at the outflow to account for the downstream resistance at each outlet. It is then applied to a virtual geometric model of an in vivo arterial tree developed through MRI-based image processing techniques. These simulations highlight the potential of the computational model for drug transport, adhesion, and retention at multiple sites in virtual in vivo models. The model provides a virtual platform for exploring circadian rhythm modulated blood flow for targeted drug delivery while minimizing the in vivo experimentation.

Modeling of spatiotemporal dynamics of ligand-coated particle flow in targeted drug delivery processes.

Nanoparticles tethered with vasculature-binding epitopes have been used to deliver the drug into injured or diseased tissues via the bloodstream. However, the extent that blood flow dynamics affects nanoparticle retention at the target site after adhesion needs to be better understood. This knowledge gap potentially underlies significantly different therapeutic efficacies between animal models and humans. An experimentally validated mathematical model that accurately simulates the effects of blood flow on nanoparticle adhesion and retention, thus circumventing the limitations of conventional trial-and-error-based drug design in animal models, is lacking. This paper addresses this technical bottleneck and presents an integrated mathematical method that derives heavily from a unique combination of a mechanics-based dispersion model for nanoparticle transport and diffusion in the boundary layers, an asperity model to account for surface roughness of endothelium, and an experimentally calibrated stochastic nanoparticle-cell adhesion model to describe nanoparticle adhesion and subsequent retention at the target site under external flow. PLGA-b-HA nanoparticles tethered with VHSPNKK peptides that specifically bind to vascular cell adhesion molecules on the inflamed vascular wall were investigated. The computational model revealed that larger particles perform better in adhesion and retention at the endothelium for the particle sizes suitable for drug delivery applications and within physiologically relevant shear rates. The computational model corresponded closely to the in vitro experiments which demonstrates the impact that model-based simulations can have on optimizing nanocarriers in vascular microenvironments, thereby substantially reducing in vivo experimentation as well as the development costs.

Navigating Post-Traumatic Osteoporosis: A Comprehensive Review of Epidemiology, Pathophysiology, Diagnosis, Treatment, and Future Directions.

Post-traumatic osteoporosis (PTO) presents a significant challenge in clinical practice, characterized by demineralization and decreased skeletal integrity following severe traumatic injuries. This literature review manuscript addresses the knowledge gaps surrounding PTO, encompassing its epidemiology, pathophysiology, risk factors, diagnosis, treatment, prognosis, and future directions. This review emphasizes the complexity of the etiology of PTO, highlighting the dysregulation of biomineralization processes, inflammatory cytokine involvement, hormonal imbalances, glucocorticoid effects, vitamin D deficiency, and disuse osteoporosis. Moreover, it underscores the importance of multidisciplinary approaches for risk mitigation and advocates for improved diagnostic strategies to differentiate PTO from other musculoskeletal pathologies. This manuscript discusses various treatment modalities, including pharmacotherapy, dietary management, and physical rehabilitation, while also acknowledging the limited evidence on their long-term effectiveness and outcomes in PTO patients. Future directions in research are outlined, emphasizing the need for a deeper understanding of the molecular mechanisms underlying PTO and the evaluation of treatment strategies' efficacy. Overall, this review provides a comprehensive overview of PTO and highlights avenues for future investigation to enhance clinical management and patient outcomes.

Treatment trends and clinical outcomes of endovascular embolization for unruptured intracranial aneurysms in the pediatric population.

BACKGROUND: Owing to the relative rarity of unruptured intracranial aneurysms (UIAs) in the pediatric population, evidence regarding treatment modalities and clinical outcomes remains limited. OBJECTIVE: To characterize the use and clinical outcomes of endovascular therapy (EVT) and microsurgical clipping (MSC) for pediatric UIAs over a two-decade interval using a large national registry. METHODS: Pediatric (<18 years of age) UIA hospitalizations were identified in the National Inpatient Sample from 2002 to 2019. Temporal use and clinical outcomes were compared for treatment with EVT and MSC. RESULTS: Among 734 UIAs identified, 64.9% (n=476) were treated with EVT. Use of EVT significantly increased during the study period from 54.3% (2002-2004) to 78.6% (2017-2019) (P=0.002 by Cochrane-Armitage test). In comparison with those treated with MSC, pediatric patients treated with EVT demonstrated higher rates of favorable outcomes (discharge to home without services) (96.0% vs 91.1%, P=0.006), shorter durations of hospital stay (4.6 vs 10.0 days, P<0.001), and lower rates of ischemic or hemorrhagic procedural-related complications (1% vs 4%, P=0.010). Conservative management also increased significantly over the study period (P<0.001 by Cochrane-Armitage test). CONCLUSION: A retrospective evaluation of nearly 20 years of population-level data from the United States demonstrates increasing use of EVT for the treatment of pediatric UIAs, with high rates of favorable outcomes and shorter hospital stays in comparison with those treated with microsurgery.

Endovascular thrombectomy for treatment of isolated posterior cerebral artery occlusion: a real-world analysis of hospitalizations in the United States.

BACKGROUND: Despite renewed interest and recently demonstrated efficacy for endovascular thrombectomy (EVT) for treatment of acute ischemic stroke (AIS) of the posterior circulation, to date, no randomized clinical trials have been conducted to evaluate EVT for isolated occlusions of the posterior cerebral artery (IPCA). METHODS: Hospitalizations for adult patients with primary admission diagnoses of IPCA occlusion were identified in the National Inpatient Sample registry during the period of 2016-2020. The study exposure was treatment with EVT, and primary clinical endpoints included favorable functional outcome (defined as discharge disposition to home without services, previously shown to have high concordance with modified Rankin scale scores 0-2), in-hospital mortality, and any intracranial hemorrhage (ICH). Inverse probability of treatment weighting (IPTW) was performed to balance baseline clinical characteristics between those receiving EVT or medical management (MM). RESULTS: This analysis identified 34,880 IPCA occlusion hospitalizations, 730 (2.1%) of which documented treatment with EVT. Following IPTW adjustment, EVT was associated with favorable outcome in IPCA patients presenting with mild deficits (M-D) (NIHSS < 6) [adjusted odds ratio (aOR) 2.36, 95% confidence interval (CI) 2.27, 2.45; p < 0.001] and in those presenting with moderate-to-severe deficits (M-S-D) (NIHSS 6-42) (aOR 2.00, 95% CI 1.86, 2.15; p < 0.001). Mortality rates did not differ among those with M-S-D [EVT 4.8% vs. MM 4.7%, p = 0.742], while ICH rates were lower. CONCLUSION: Retrospective analysis of a large administrative registry in the Unites States demonstrates an association of EVT with favorable outcomes following IPCA occlusion, without concomitant risk of hemorrhagic transformation or mortality.

The Impact of Inoculation of Two Strains of Rhizobacteria on Radionuclide Transfer in Sesbania Grandiflora.

Transfer factors of some naturally-occurring and artificial radionuclides from an agricultural soil to rhizobacteria-treated Sesbania grandiflora, a small leguminous tree, were studied. Two plant growth promoting rhizobacteria (PGPR) strains (SCR17 and PCE2) were used to carry out an agricultural experiment in pots in semi-arid region (Syria). The results showed the bacterial strain (SCR17) increased the transfer and accumulation of 238U and 40K in Sesbania grandiflora, while both bacterial strains showed no effect on the accumulation of 234Th, 226Ra, 210Po and 210Pb in the treated plants. The transfer factor of 137Cs from soil to rhizobacteria-treated Sesbania grandiflora was negligible. The values of the transfer factors of 234Th, 226Ra, 210Po and 40K were found to be within the global values, while the values of the transfer factors of 238U and 210Pb were found to be relatively higher. This study highlights the importance of using Phytoremediation by PGPR strains for radionuclides-contaminated soils. Therefore, this method is a promising technique for the restoration and rehabilitation of contaminated sites with radionuclides, as it is low cost, easy to apply, and environmentally friendly.

Exploring Patient Safety Culture: A Study of Community Pharmacies in Karachi, Pakistan.

Background Community pharmacies are integral to the healthcare system, actively contributing to patient safety through accurate dispensing, education, collaboration, monitoring, and the implementation of safety protocols. Their accessibility and role as medication experts make them key partners in promoting positive health outcomes for individuals and communities. Objective The current study will evaluate the patient safety culture (PSC) among community pharmacies in Karachi, Pakistan. Additionally, this study will measure the association between patient safety culture in community pharmacies and the demographic characteristics of the pharmacy staff. Methods A cross-sectional survey of pharmacy staff was conducted using a survey instrument developed by the US Agency for Healthcare Research and Quality (AHRQ). Demographic variables and assessments of safety culture in pharmacies were studied. The data were analyzed using descriptive statistics. Results Among the 102 participants, positive responses ranged from 30% to 87.5%. The highest positive response was for the dimension "mistakes in communication" (86.3%), followed by "communication across shifts" (82.2%) and "communication openness" (81.7%). The dimensions "overall perceptions of patient safety" and "response to mistakes" had the lowest positive responses (56.0% and 60.9%, respectively). Furthermore, many staff did not regularly record the errors, even if they impacted the practices. Conclusion There was an overall unfavorable perception of patient safety culture among the surveyed pharmacies of Karachi, Pakistan. However, the communication dimensions showed the highest positive response. There is a strong need to improve the overall perception of patient safety among the staff and develop an optimistic response to mistakes.

Mapping geographic disparities in treatment and clinical outcomes of high-grade aneurysmal subarachnoid hemorrhage in the United States.

BACKGROUND AND OBJECTIVE: Although high-grade (Hunt and Hess 4 and 5) aneurysmal subarachnoid hemorrhage (aSAH) typically portends a poor prognosis, early and aggressive treatment has previously been demonstrated to confer a significant survival advantage. This study aims to evaluate geographic, demographic, and socioeconomic determinants of high-grade aSAH treatment in the United States. METHODS: The National Inpatient Sample (NIS) was queried to identify adult high-grade aSAH hospitalizations during the period of 2015 to 2019 using the International Classification of Diseases, 10th Revision, Clinical Modification (ICD) codes. The primary clinical endpoint of this analysis was aneurysm treatment by surgical or endovascular intervention (SEI), while the exposure of interest was geographic region by census division. Favorable functional outcome (assessed by the dichotomous NIS-SAH Outcome Measure, or NIS-SOM) and in-hospital mortality were evaluated as secondary endpoints in treated and conservatively managed groups. RESULTS: Among 99 460 aSAH patients identified, 36 795 (37.0%) were high-grade, and 9210 (25.0%) of these were treated by SEI. Following multivariable logistic regression analysis, determinants of treatment by SEI included female sex (adjusted OR (aOR) 1.42, 95% CI 1.35 to 1.51), transfer admission (aOR 1.18, 95% CI 1.12 to 1.25), private insurance (ref: government-sponsored insurance) (aOR 1.21, 95% CI 1.14 to 1.28), and government hospital ownership (ref: private ownership) (aOR 1.17, 95% CI 1.09 to 1.25), while increasing age (by decade) (aOR 0.93, 95% CI 0.91 to 0.95), increasing mortality risk (aOR 0.60, 95% CI 0.57 to 0.63), urban non-teaching hospital status (aOR 0.66, 95% CI 0.59 to 0.73), rural hospital location (aOR 0.13, 95% CI 0.7 to 0.25), small hospital bedsize (aOR 0.68, 95% CI 0.60 to 0.76), and geographic region (South Atlantic (aOR 0.72, 95% CI 0.63 to 0.83), East South Central (aOR 0.75, 95% CI 0.64 to 0.88), and Mountain (aOR 0.72, 95% CI 0.61 to 0.85)) were associated with a lower likelihood of treatment. High-grade aSAH patients treated by SEI experienced significantly greater rates of favorable functional outcomes (20.1% vs 17.3%; OR 1.20, 95% CI 1.13 to 1.28, P<0.001) and lower rates of mortality (25.8% vs 49.1%; OR 0.36, 95% CI 0.34 to 0.38, P<0.001) in comparison to those conservatively managed. CONCLUSION: A complex interplay of demographic, socioeconomic, and geographic factors influence treatment patterns of high-grade aSAH in the United States.

Determinants of mental and financial health during COVID-19: Evidence from data of a developing country.

Mental and emotional issues are the top-level concerns of public health worldwide. These issues surged during Coronavirus (COVID-19) pandemic due to varied medical, social, and personal reasons. The social determinants highlighted in the literature mainly focus on household solutions rather than on increasing the financial wellbeing of individuals, especially for the most vulnerable groups where the psychological distress coming from the social inequalities cannot be entirely treated. Hence, this study attempts to familiarize the financial capability (the financial literacy, attitude, skills and behavior required for effective financial management) construct into public health domain in the times of COVID-19 as a determinant of psychological distress, and also explores the role of gender in it. The study uses Ordinary Least Square (OLS) regression analysis and employs mental distress questions and Organization for Economic Cooperation and Development (OECD) 2018 financial capability toolkit to collect data from a large sample of households from all over Pakistan. It is inferred that the higher the financial capability, the lower the financial and mental distress during COVID-19. Additionally, females are less financially knowledgeable, depict poor financial behaviors, and face more psychological issues than their counterparts. Age and education are also linked to mental stress during COVID-19. Finally, gender plays a moderating role in financial behavior, and financial and mental stress of households. As evident, COVID-19 is not going away soon hence the findings are relevant for policymakers to proactively plan for the pandemic's upcoming waves and help people be better financially equipped to fight against this or any upcoming crisis, and achieve better mental and physical health.

A Tertiary Care Center's Experience with Clinicopathological Characteristics of Gallbladder Carcinoma in Our Population.

Introduction: Gallbladder cancer (GBC) is the most common malignant biliary tract tumor with the shortest survival from the time of diagnosis. This poor prognosis is due to the destructive biologic behavior of GBC, lack of sensitive screening tests for early detection, and vague nature of first presentation. Here in this study, we will evaluate the baseline characteristics of the patients presenting with gallbladder carcinoma in our population. Materials and methods: This retrospective study was conducted in the Department of Gastroenterology at Sindh Institute of Urology and Transplantation (SIUT), Karachi. Patient data were compiled and composed from the in-patient health records, radiology, and operational records. Those patients with suspicion of GBC, but negative at histology, or patients having inconclusive radiologic findings, were excluded. Baseline characteristics were recorded. Results were presented as means ± SD for quantitative data or as numbers with percentages for qualitative data. Continuous variables were analyzed using the Student's t-test, while categorical variables were analyzed using the Chi-square test. A p-value of <0.05 was considered statistically significant. Results: A total of 162 patients were included in our study. Among them, 101 (62.3%) were females. Hypertension was the most common comorbid illness noted in 29 (17.9%) patients while 91 (56.2%) patients had no concurrent comorbidities. Most common risk factor for carcinoma of gallbladder was gallstones seen in 106 (65.1%) patients. The most common presenting complaint was combination of obstructive jaundice, weight loss with right hypochondrial pain seen in 66 (40.7%) patients. On CT abdomen, direct liver infiltration without lymphovascular invasion was noted in 77 (47.5%) patients followed by liver infiltration along with lymphovascular invasion in 26 (16%) patients and distant metastasis in 24 (14.8%) patients. On gallbladder (GB) mass biopsy, 58 (35.8%) patients had well-differentiated, 46 (28.4%) had moderately differentiated, while 33 (20.4%) had poorly differentiated adenocarcinoma. Of 162 patients, 103 (63.6%) patients underwent endoscopic retrograde cholangiopancreatography (ERCP). The most common finding on ERCP was proximal common bile duct (CBD) stricture with intrahepatic biliary system dilatation which was noted in 95 (58.6%) patients. Percutaneous transhepatic cholangiography (PTC) was performed only in 9 (5.6%) patients. Seventeen (10.5%) patients were managed by simple cholecystectomy, 39 (24.1%) patients underwent extended cholecystectomy, 14 (8.6%) patients underwent chemotherapy, while 102 (56.8%) patients were given palliative management. When followed for 1 year, 101 (62.3%) patients died within 6 months. Conclusion: The baseline characteristics, biopsy findings, modes of treatment, and rates of 1 year mortality were studied in patients with gallbladder carcinoma in our population. Advanced age, high white blood cell counts, and serum bilirubin at presentation with low lymphocyte count and presence of comorbid illnesses were the factors independently associated with increased mortality in patients with gallbladder carcinoma. However, further studies with large sample size and stratification with respect to age, gender, and different variables can be done in terms of mortality in patients with gallbladder carcinoma. How to cite this article: Akbar N, Yaseen T, Muhammad A, et al. A Tertiary Care Center's Experience with Clinicopathological Characteristics of Gallbladder Carcinoma in Our Population. Euroasian J Hepato-Gastroenterol 2022;12(1):35-39.

Per-Cutaneous Trans-splenic Vein Thrombolysis of Acute Major Portal Vein Thrombosis in Post-Liver Transplant Recipient: A Unique Experience.

Portal venous thrombosis (PVT) is an uncommon complication in post-liver transplant recipients. The reported incidence is 1-4%. It may occur within a month, called early or after one month of transplantation, known as late PVT. Early PVT has a poor prognosis, leading to graft failure in most cases. Treatment of such cases is quite challenging because of difficult alternative portal inflow establishment. We performed successful thrombolysis of acute major PVT with a unique technique using ultrasound-guided percutaneous trans-splenic vein access in a post-liver transplant recipient. The per-cutaneous trans- splenic vein approach-based thrombolysis described here in this report might be very helpful in similar cases. This technique minimizes the potential risk of graft loss, avoids re-exploration, has a low risk of bleeding, and is cost-effective.

Chemical activation of SAT1 corrects diet-induced metabolic syndrome.

The pharmacological targeting of polyamine metabolism is currently under the spotlight for its potential in the prevention and treatment of several age-associated disorders. Here, we report the finding that triethylenetetramine dihydrochloride (TETA), a copper-chelator agent that can be safely administered to patients for the long-term treatment of Wilson disease, exerts therapeutic benefits in animals challenged with hypercaloric dietary regimens. TETA reduced obesity induced by high-fat diet, excessive sucrose intake, or leptin deficiency, as it reduced glucose intolerance and hepatosteatosis, but induced autophagy. Mechanistically, these effects did not involve the depletion of copper from plasma or internal organs. Rather, the TETA effects relied on the activation of an energy-consuming polyamine catabolism, secondary to the stabilization of spermidine/spermine N1-acetyltransferase-1 (SAT1) by TETA, resulting in enhanced enzymatic activity of SAT. All the positive effects of TETA on high-fat diet-induced metabolic syndrome were lost in SAT1-deficient mice. Altogether, these results suggest novel health-promoting effects of TETA that might be taken advantage of for the prevention or treatment of obesity.

A Model to Study NMDA Receptors in Early Nervous System Development.

N-methyl-D-aspartate receptors (NMDARs) are glutamate-gated ion channels that play critical roles in neuronal development and nervous system function. Here, we developed a model to study NMDARs in early development in zebrafish, by generating CRISPR-mediated lesions in the NMDAR genes, grin1a and grin1b, which encode the obligatory GluN1 subunits. While receptors containing grin1a or grin1b show high Ca2+ permeability, like their mammalian counterpart, grin1a is expressed earlier and more broadly in development than grin1b Both grin1a-/- and grin1b-/- zebrafish are viable. Unlike in rodents, where the grin1 knockout is embryonic lethal, grin1 double-mutant fish (grin1a-/-; grin1b-/-), which lack all NMDAR-mediated synaptic transmission, survive until ∼10 d dpf (days post fertilization), providing a unique opportunity to explore NMDAR function during development and in generating behaviors. Many behavioral defects in the grin1 double-mutant larvae, including abnormal evoked responses to light and acoustic stimuli, prey-capture deficits, and a failure to habituate to acoustic stimuli, are replicated by short-term treatment with the NMDAR antagonist MK-801, suggesting that they arise from acute effects of compromised NMDAR-mediated transmission. Other defects, however, such as periods of hyperactivity and alterations in place preference, are not phenocopied by MK-801, suggesting a developmental origin. Together, we have developed a unique model to study NMDARs in the developing vertebrate nervous system.SIGNIFICANCE STATEMENT Rapid communication between cells in the nervous system depends on ion channels that are directly activated by chemical neurotransmitters. One such ligand-gated ion channel, the NMDAR, impacts nearly all forms of nervous system function. It has been challenging, however, to study the prolonged absence of NMDARs in vertebrates, and hence their role in nervous system development, due to experimental limitations. Here, we demonstrate that zebrafish lacking all NMDAR transmission are viable through early development and are capable of a wide range of stereotypic behaviors. As such, this zebrafish model provides a unique opportunity to study the role of NMDAR in the development of the early vertebrate nervous system.

CD3+T-lymphocyte infiltration is an independent prognostic factor for advanced nasopharyngeal carcinoma.

BACKGROUND: Locally advanced nasopharyngeal carcinoma (LA-NPC) is a relatively rare disease in the west but more common in East Asia and areas of the Middle East like Saudi Arabia. Despite the advances in radiation therapy techniques, some patients relapse after treatment. In the coming era of cancer immunotherapy, prognostic factors for LA-NPC need to be further defined using immune-relevant markers. Several markers are available; however, the most robust and accessible/affordable marker is not well-defined. METHODS: Retrospectively, tumor-infiltrating lymphocytes (TIL), their subsets as well as tumoral PD-L1 expression were analyzed in tumor tissues from 63 LA-NPC patients treated with platinum-based concurrent chemo-radiotherapy (CCRT) in addition to 20 cases with metastatic (MET) disease. Immunostaining was done using a validated and fully automated system. Scoring was done by two independent pathologists and results were compared. RESULTS: There was no statistical difference between LA-NPC and MET disease in terms of CD3+, CD8+ TIL infiltration, or tumoral PD-L1 expression. In LA-NPC, low CD3+ TIL infiltration highly correlated with shorter disease-free survival (DFS, HR = 8.5, p = < 0.001) and overall survival (OS, HR = 13, p = 0.015) with substantial agreement between scoring pathologists. A similar correlation was found between low CD8+ TIL and survival. Correlation of total TIL was significant with DFS (HR = 4.0, p = 0.008), borderline with OS and the correlation was dependent on the scoring pathologist. Having histological WHO type I&II correlated significantly with shorter DFS (HR 4.03, p = 0.008) and low CD3+ TIL (p = 0.009). Subgroup analysis of LA-NPC that included undifferentiated type (WHO type III) cases only (n = 58), showed a strong correlation between low CD3+ TIL and shorter DFS (HR = 7.2, p = < 0.001) and OS (HR = 17.3, p = 0.008). PD-L1 was expressed in 72% of type III LA-NPC cases while lacking PD-L1 expression correlated with shorter OS (HR = 6.1, p = 0.031). Patients with a combination of low CD3+ TIL and lack of PD-L1 expression had the worst OS (p < 0.001). CONCLUSIONS: CD3+ TIL is promising as a robust and independent prognostic marker for DFS and OS of LA-NPC patients treated with platinum-based CCRT. We would suggest the use of CD3 + TIL as a stratifying factor for LA-NPC, which warrants further validation in prospective trials.

Yield of prostate cancer screening at a community based clinic in Saudi Arabia.

OBJECTIVES: To estimate the incidence and prevalence of prostate cancer in Saudi Arabia. METHODS: This is a retrospective cohort study including male patients aged 40 years and over. The prostate-specific antigen screening tests were carried out in a community-based clinic affiliated with King Faisal Specialist Hospital and Research Centre, Riyadh, Kingdom of Saudi Arabia between September 2002 and December 2016. RESULTS: A total of 2,160 male patients were included in the study. Of these, 1,521 (70%) were Saudi nationals and 639 (30%) were non-Saudi nationals. A total of 108 (5%) patients underwent a prostate biopsy. The biopsy results confirmed that 31 (2%) Saudi patients and 6 (0.93%) non-Saudi patients had prostate adenocarcinoma. The age-standardized incidence rate of prostate cancer in the Saudi male population is 70 per 100,000 males. Nearly two-thirds (71%) of the Saudi patients' prostate cancer was found to be in the early stages. Conclusion: The prevalence of prostate cancer in the Saudi male population is higher than that reported by the Saudi Cancer Registry; however, it is low compared with prevalences in developed countries. The mortality rate is also very low. Prostate-specific antigen screening in Saudi Arabia should not be carried out routinely; instead, it should only be carried out on an individual basis.

Aspirin Recapitulates Features of Caloric Restriction.

The age-associated deterioration in cellular and organismal functions associates with dysregulation of nutrient-sensing pathways and disabled autophagy. The reactivation of autophagic flux may prevent or ameliorate age-related metabolic dysfunctions. Non-toxic compounds endowed with the capacity to reduce the overall levels of protein acetylation and to induce autophagy have been categorized as caloric restriction mimetics (CRMs). Here, we show that aspirin or its active metabolite salicylate induce autophagy by virtue of their capacity to inhibit the acetyltransferase activity of EP300. While salicylate readily stimulates autophagic flux in control cells, it fails to further increase autophagy levels in EP300-deficient cells, as well as in cells in which endogenous EP300 has been replaced by salicylate-resistant EP300 mutants. Accordingly, the pro-autophagic activity of aspirin and salicylate on the nematode Caenorhabditis elegans is lost when the expression of the EP300 ortholog cpb-1 is reduced. Altogether, these findings identify aspirin as an evolutionary conserved CRM.

Smoking cessation advice in limb reconstruction: An opportunity not to be missed.

The adverse health effects of smoking are well known, including its effects on the musculoskeletal system. Limb reconstruction using external fixators is a high intensity process with high levels of patient contact time, complications and cost. The aim of this study was to examine smoking patterns in this group and in particular to assess trends in smoking cession. Data was collected from 41 patients all undergoing treatment using circular frame external fixation, for a variety of pathologies, most commonly acute tibial trauma. A patient reported questionnaire was used. Data was collected over a six-month period. In our population 56.1% of patients were smokers. During the study 47.8% patients stopped smoking and a further 39.1% decreased their smoking behaviour. 78.3% of patients could recall being given smoking cessation advice. In our group, 87% of patients were unaware of the effects of smoking on bone healing. Once made aware during discussion of proposed treatment, 73.9% stated that it was, in part, this knowledge that prompted them to positively change their smoking habits. The results of this study show that advice regarding smoking cessation during limb reconstruction treatment can potentially have a positive impact on patients smoking habits. The effect of smoking should be linked to the patient pathology and discussed during the consent process. Taking the time with the patient for this simple free intervention can have a positive impact on patient health, and potentially on the outcome of their current treatment, and is an opportunity not to be missed.

Self-Sensing Composites: In-Situ Detection of Fibre Fracture.

The primary load-bearing component in a composite material is the reinforcing fibres. This paper reports on a technique to study the fracture of individual reinforcing fibres or filaments in real-time. Custom-made small-diameter optical fibres with a diameter of 12 (±2) micrometres were used to detect the fracture of individual filaments during tensile loading of unreinforced bundles and composites. The unimpregnated bundles were end-tabbed and tensile tested to failure. A simple technique based on resin-infusion was developed to manufacture composites with a negligible void content. In both cases, optical fibre connectors were attached to the ends of the small-diameter optical fibre bundles to enable light to be coupled into the bundle via one end whilst the opposite end was photographed using a high-speed camera. The feasibility of detecting the fracture of each of the filaments in the bundle and composite was demonstrated. The in-situ damage detection technique was also applied to E-glass bundles and composites; this will be reported in a subsequent publication.

New anti-resorptives and antibody mediated anti-resorptive therapy.

UNLABELLED: The ageing population and an increase in both the incidence and prevalence of cancer pose a healthcare challenge, some of which is borne by the orthopaedic community in the form of osteoporotic fractures and metastatic bone disease. In recent years there has been an increasing understanding of the pathways involved in bone metabolism relevant to osteoporosis and metastases in bone. Newer therapies may aid the management of these problems. One group of drugs, the antibody mediated anti-resorptive therapies (AMARTs) use antibodies to block bone resorption pathways. This review seeks to present a synopsis of the guidelines, pharmacology and potential pathophysiology of AMARTs and other new anti-resorptive drugs. We evaluate the literature relating to AMARTs and new anti-resorptives with special attention on those approved for use in clinical practice. Denosumab, a monoclonal antibody against Receptor Activator for Nuclear Factor Kappa-B Ligand. It is the first AMART approved by the National Institute for Health and Clinical Excellence and the US Food and Drug Administration. Other novel anti-resorptives awaiting approval for clinical use include Odanacatib. Denosumab is indicated for the treatment of osteoporosis and prevention of the complications of bone metastases. Recent evidence suggests, however, that denosumab may have an adverse event profile similar to bisphosphonates, including atypical femoral fractures. It is, therefore, essential that orthopaedic surgeons are conversant with these medications and their safe usage. TAKE HOME MESSAGE: Denosumab has important orthopaedic indications and has been shown to significantly reduce patient morbidity in osteoporosis and metastatic bone disease.