Ribosomal protein s15 phosphorylation mediates LRRK2 neurodegeneration in Parkinson's disease.

Mutations in leucine-rich repeat kinase 2 (LRRK2) are a common cause of familial and sporadic Parkinson's disease (PD). Elevated LRRK2 kinase activity and neurodegeneration are linked, but the phosphosubstrate that connects LRRK2 kinase activity to neurodegeneration is not known. Here, we show that ribosomal protein s15 is a key pathogenic LRRK2 substrate in Drosophila and human neuron PD models. Phosphodeficient s15 carrying a threonine 136 to alanine substitution rescues dopamine neuron degeneration and age-related locomotor deficits in G2019S LRRK2 transgenic Drosophila and substantially reduces G2019S LRRK2-mediated neurite loss and cell death in human dopamine and cortical neurons. Remarkably, pathogenic LRRK2 stimulates both cap-dependent and cap-independent mRNA translation and induces a bulk increase in protein synthesis in Drosophila, which can be prevented by phosphodeficient T136A s15. These results reveal a novel mechanism of PD pathogenesis linked to elevated LRRK2 kinase activity and aberrant protein synthesis in vivo.

Target deconvolution of HDAC pharmacopoeia reveals MBLAC2 as common off-target.

Drugs that target histone deacetylase (HDAC) entered the pharmacopoeia in the 2000s. However, some enigmatic phenotypes suggest off-target engagement. Here, we developed a quantitative chemical proteomics assay using immobilized HDAC inhibitors and mass spectrometry that we deployed to establish the target landscape of 53 drugs. The assay covers 9 of the 11 human zinc-dependent HDACs, questions the reported selectivity of some widely-used molecules (notably for HDAC6) and delineates how the composition of HDAC complexes influences drug potency. Unexpectedly, metallo-ß-lactamase domain-containing protein 2 (MBLAC2) featured as a frequent off-target of hydroxamate drugs. This poorly characterized palmitoyl-CoA hydrolase is inhibited by 24 HDAC inhibitors at low nanomolar potency. MBLAC2 enzymatic inhibition and knockdown led to the accumulation of extracellular vesicles. Given the importance of extracellular vesicle biology in neurological diseases and cancer, this HDAC-independent drug effect may qualify MBLAC2 as a target for drug discovery.

Osteomyelitis by Microsporum canis and Staphylococcus spp. in cat (Felis catus) - case report.

BACKGROUND: Staphylococcus spp and Microsporum canis are zoonotic microorganisms which can cause infections and systemic diseases. The bone infection is usually caused by invasion of pathogen through the hematologic route. Mixed osteomyelitis caused by bacteria and fungi is rare, and to date, there have been no reports of mixed osteomyelitis with Staphylococcus spp. and Microsporum canis. CASE PRESENTATION: This essay reports an atypical presentation of mixed osteomyelitis (Staphylococcus spp. and Microsporum canis) in a domestic cat. A 15-month-old female Persian cat was presented to a veterinary service; the main complaint was the appearance of a nodule in the mandibular ventral rostral region. A radiographic exam performed on the animal showed proliferative and osteolytic bone lesions. The patient was submitted to a biopsy for histopathological evaluation, along with bacterial and fungal cultures. Results showed mixed osteomyelitis by Staphylococcus spp. and Microsporum canis. Microbial Sensitivity Test was performed to choose a more suitable treatment. Two surgical procedures were executed to resect and curette the lesion, and treatments with anti-inflammatory, antibiotic, and antifungal drugs were established, showing a positive clinical evolution. After 8 months of treatment, the patient's owner moved to a different city, and the animal was seen by other veterinarians, who followed along with the same treatment. However, due to complications and a diminishing quality of life over 4 years of diagnosis, the patient was euthanized. CONCLUSION: Given the above, mixed osteomyelitis is difficult to treat and can cause losses of life quality resulting death, especially in infections where M. canis is the agent causing the disease. Bacterial osteomyelitis is more frequently reported. But the lack of investigation of microorganisms other than bacteria, such as fungal cases, may imply in underdiagnosed cases. Treatment of osteomyelitis can be difficult considering the difficulties in isolating the pathological agent, resistance to the drug used, prolonged treatment time, and cost.

Diagnostic Accuracy of the World Health Organization Pediatric Emergency Triage, Assessment and Treatment Tool Plus Among Patients Seeking Care in Nairobi, Kenya: A Cross-sectional Study.

INTRODUCTION: The World Health Organization developed Emergency Triage Assessment and Treatment Plus (ETAT+) guidelines to facilitate pediatric care in resource-limited settings. ETAT+ triages patients as nonurgent, priority, or emergency cases, but there is limited research on the performance of ETAT+ regarding patient-oriented outcomes. This study assessed the diagnostic accuracy of ETAT+ in predicting the need for hospital admission in a pediatric emergency unit at Kenyatta National Hospital in Nairobi, Kenya. METHODS: This was a secondary analysis of a cross-sectional study of pediatric emergency unit patients enrolled over a 4-week period using fixed random sampling. Diagnostic accuracy of ETAT+ was evaluated using receiver operating curves (ROCs) and respective 95% confidence intervals (CIs) with associated sensitivity and specificity (reference category: nonurgent). The ROC analysis was performed for the overall population and stratified by age group. RESULTS: A total of 323 patients were studied. The most common reasons for presentation were upper respiratory tract disease (32.8%), gastrointestinal disease (15.5%), and lower respiratory tract disease (12.4%). Two hundred twelve participants were triaged as nonurgent (65.6%), 60 as priority (18.6%), and 51 as emergency (15.8%). In the overall study population, the area under the ROC curve was 0.97 (95% CI, 0.95-0.99). The ETAT+ sensitivity was 93.8% (95% CI, 87.0%-99.0%), and the specificity was 82.0% (95% CI, 77.0%-87.0%) for admission of priority group patients. The sensitivity and specificity for the emergency patients were 66.0% (95% CI, 55.0%-77.0%) and 98.0% (95% CI, 97.0%-100.0%), respectively. CONCLUSIONS: ETAT+ demonstrated diagnostic accuracy for predicting patient need for hospital admission. This finding supports the utility of ETAT+ to inform emergency care practice. Further research on ETAT+ performance in larger populations and additional patient-oriented outcomes would enhance its generalizability and application in resource-limited settings.

Metallo-ß-lactamase domain-containing protein 2 is S-palmitoylated and exhibits acyl-CoA hydrolase activity.

Members of the metallo-ß-lactamase (MBL) superfamily of enzymes harbor a highly conserved αßßα MBL-fold domain and were first described as inactivators of common ß-lactam antibiotics. In humans, these enzymes have been shown to exhibit diverse functions, including hydrolase activity toward amides, esters, and thioesters. An uncharacterized member of the human MBL family, MBLAC2, was detected in multiple palmitoylproteomes, identified as a zDHHC20 S-acyltransferase interactor, and annotated as a potential thioesterase. In this study, we confirmed that MBLAC2 is palmitoylated and identified the likely S-palmitoylation site as Cys254. S-palmitoylation of MBLAC2 is increased in cells when expressed with zDHHC20, and MBLAC2 is a substrate for purified zDHHC20 in vitro. To determine its biochemical function, we tested the ability of MBLAC2 to hydrolyze a variety of small molecules and acylprotein substrates. MBLAC2 has acyl-CoA thioesterase activity with kinetic parameters and acyl-CoA selectivity comparable with acyl-CoA thioesterase 1 (ACOT1). Two predicted zinc-binding residues, Asp87 and His88, are required for MBLAC2 hydrolase activity. Consistent with a role in fatty acid metabolism in cells, MBLAC2 was cross-linked to a photoactivatable fatty acid in a manner that was independent of its S-fatty acylation at Cys254. Our study adds to previous investigations demonstrating the versatility of the MBL-fold domain in supporting a variety of enzymatic reactions.

Neutrophil Extracellular Traps as an Exacerbating Factor in Bacterial Pneumonia.

Neutrophils are capable of extruding neutrophil extracellular traps (NETs), a network of granule proteins and chromatin material, upon activation. NETs provide defense against extracellular microbes, but histones in NETs can also induce cytotoxicity and activate inflammatory responses. The relevance of NETs to bacterial pneumonias is beginning to be defined. In the present study, we found that the extracellular concentration of citrullinated histone H3, a component of NETs, was elevated in bronchoalveolar lavage fluid recovered from mice with diverse bacterial pneumonias and correlated with neutrophil infiltration and cell death in the lungs as well as levels of H4. Because the histone H4 component of NETs is sufficient to stimulate inflammation, we tested its effects in the air spaces of the lungs. Recombinant histone H4 in the noninflamed lung produced only modest effects, but in the setting of neutrophilic inflammation, H4 substantially increased pulmonary neutrophils, NETs, necrosis, and edema. However, blockade of histone H4 with a monoclonal antibody during pneumonia did not significantly alter measures of lung damage. Taken together, these results implicate NETs and extracellular histone H4 in exacerbating the lung injury resulting from bacterial pneumonia.

CPHEN-011: Comprehensive phenotyping of murine lung resident lymphocytes after recovery from pneumococcal pneumonia.

Recovery from pneumococcal (Spn) pneumonia induces development of tissue resident memory CD4+ TRM cells, BRM cells, and antibody secreting plasma cells in experienced lungs. These tissue resident lymphocytes confer protection against subsequent lethal challenge by serotype mismatched Spn (termed as heterotypic immunity). While traditional flow cytometry and gating strategies support premeditated identification of cells using a limited set of markers, discovery of novel tissue resident lymphocytes necessitates stable platforms that can handle larger sets of phenotypic markers and lends itself to unbiased clustering approaches. In this report, we leverage the power of full spectrum flow cytometry (FSFC) to develop a comprehensive panel of phenotypic markers that allows identification of multiple subsets of tissue resident lymphocytes in Spn-experienced murine lungs. Using Phenograph algorithm on this multidimensional data, we identify unforeseen heterogeneity in lung resident adaptive immune landscape which includes unexpected subsets of TRM and BRM cells. Further, using conventional gating strategy informed by our unsupervised clustering data, we confirm their presence exquisitely in Spn-experienced lungs as potentially relevant to heterotypic immunity and define CD73 as a highly expressed marker on TRM cells. Thus, our study emphasizes the utility of FSFC for confirmatory and discovery studies relating to tissue resident adaptive immunity.

Short-term impact of COVID-19 on quality of life, perceived stress, and serious psychological distress in an adult population in the midwest United States.

PURPOSE: This study aimed to investigate changes over time in quality of life, perceived stress, and serious psychological distress for individuals diagnosed with COVID-19 in an urban academic health system. METHODS: Phone-based surveys were completed with adult patients tested for COVID-19 during emergency department visits, hospitalizations, or outpatient visits at the Froedtert and Medical College of Wisconsin Health Network. Data were then matched to medical record data. Unadjusted and adjusted mixed effects linear models using random intercept were run for each outcome (physical health-related quality of life, mental health-related quality of life, perceived stress, and serious psychological distress) with time (baseline vs 3-month follow-up) as the primary independent variable. Individuals were treated as a random effect, with all covariates (age, sex, race/ethnicity, payor, comorbidity count, hospitalization, and intensive care unit (ICU) stay) treated as fixed effects. RESULTS: 264 adults tested positive for COVID-19 and completed baseline and 3-month follow-up assessments. Of that number, 31.8% were hospitalized due to COVID-19, and 10.2% were admitted for any reason to the ICU. After adjustment, patients reported higher physical health-related quality of life at 3 months compared to baseline (0.63, 95% CI 0.15, 1.11) and decreased stress at 3 months compared to baseline (- 0.85, 95% CI - 1.33, - 0.37). There were no associations between survey time and mental health-related quality of life or serious psychological distress. CONCLUSIONS: Results suggest the influence of COVID-19 on physical health-related quality of life and stress may resolve over time, however, the influence of mental health on daily activities, work, and social activities may not.

Pediatric Medical Emergencies and Injury Prevention Practices in the Pediatric Emergency Unit of Kenyatta National Hospital, Nairobi, Kenya.

INTRODUCTION: The epidemiology and presence of pediatric medical emergencies and injury prevention practices in Kenya and resource-limited settings are not well understood. This is a barrier to planning and providing quality emergency care within the local health systems. We performed a prospective, cross-sectional study to describe the epidemiology of case encounters to the pediatric emergency unit (PEU) at Kenyatta National Hospital in Nairobi, Kenya; and to explore injury prevention measures used in the population. METHODS: Patients were enrolled prospectively using systematic sampling over four weeks in the Kenyatta National Hospital PEU. Demographic data, PEU visit data and lifestyle practices associated with pediatric injury prevention were collected directly from patients or guardians and through chart review. Data were analyzed with descriptive statistics with stratification based on pediatric age groups. RESULTS: Of the 332 patients included, the majority were female (56%) and 76% were under 5 years of age. The most common presenting complaints were cough (40%) fever (34%), and nausea/vomiting (19%). The most common PEU diagnoses were upper respiratory tract infections (27%), gastroenteritis (11%), and pneumonia (8%). The majority of patients (77%) were discharged from the PEU, while 22% were admitted. Regarding injury prevention practices, the majority (68%) of guardians reported their child never used seatbelts or car seats. Of 68 patients that rode bicycles/motorbikes, one reported helmet use. More than half of caregivers cook at potentially dangerous heights; 59% use ground/low level stoves. CONCLUSIONS: Chief complaints and diagnoses in the PEU population were congruent with communicable disease burdens seen globally. Measures for primary injury prevention were reported as rarely used in the sample studied. The epidemiology described by this study provides a framework for improving public health education and provider training in resource-limited settings.

In pursuit of inter-specialty consensus on excited delirium syndrome: a scoping literature review.

Excited delirium syndrome (ExDS) is a controversial and disputed diagnosis involving altered mentation, agitation, and, frequently, substance abuse. Recently, it has become a common pre-hospital diagnosis, serving as justification for use of force, restraint, and/or medication administration. To conduct a scoping review across three databases to describe the most frequently reported diagnostic criteria for ExDS, as well as to explore its use as a diagnosis for deaths of individuals in the custody of law enforcement. In 2021, three literature databases were searched: Ovid Medline, PsycInfo, and Scopus. Studies were included if they were peer-reviewed, English articles describing (1) ExDS symptoms, (2) substance intoxication with at least 2 ExDS symptoms present, or (3) centering on deaths occurring in the custody of law enforcement and attributed to ExDS. Key study data were extracted and the current literature was described qualitatively. Analysis took place between March and December 2021. A total of 97 studies were identified through initial abstract and secondary full-text review, with noted discrepancies in the definition of ExDS itself. After review, differences in ExDS diagnosis among organizations were explored, along with subsequent clinical impact, particularly in the pre-hospital setting. Resulting impact on patients, particularly those of minoritized ethnic and racial groups, was also noted. Prone aggressive restraint, in particular, is noted as an established risk factor for fatalities in ExDS cases. At this time, ExDS should not be utilized as a diagnosis; major medical organizations have an urgent responsibility to convene to formalize consensus-based diagnostic criteria or to propose alternate management guidelines for agitated and altered persons.

Dietary Amino Acids Impact LRRK2-Induced Neurodegeneration in Parkinson's Disease Models.

The G2019S mutation in leucine-rich repeat kinase 2 (LRRK2) is a common cause of Parkinson's disease (PD) and results in age-related dopamine neuron loss and locomotor dysfunction in Drosophila melanogaster through an aberrant increase in bulk neuronal protein synthesis. Under nonpathologic conditions, protein synthesis is tightly controlled by metabolic regulation. Whether nutritional and metabolic influences on protein synthesis can modulate the pathogenic effect of LRRK2 on protein synthesis and thereby impact neuronal loss is a key unresolved question. Here, we show that LRRK2 G2019S-induced neurodegeneration is critically dependent on dietary amino acid content in Drosophila studies with both sexes. Low dietary amino acid concentration prevents aberrant protein synthesis and blocks LRRK2 G2019S-mediated neurodegeneration in Drosophila and rat primary neurons. Unexpectedly, a moderately high-amino acid diet also blocks dopamine neuron loss and motor deficits in Drosophila through a separate mechanism involving stress-responsive activation of 5'-AMP-activated protein kinase (AMPK) and neuroprotective induction of autophagy, implicating the importance of protein homeostasis to neuronal viability. At the highest amino acid diet of the range tested, PD-related neurodegeneration occurs in an age-related manner, but is also observed in control strains, suggesting that it is independent of mutant LRRK2 expression. We propose that dietary influences on protein synthesis and autophagy are critical determinants of LRRK2 neurodegeneration, opening up possibilities for future therapeutic intervention.SIGNIFICANCE STATEMENT Parkinson's disease (PD) prevalence is projected to rise as populations continue to age, yet there are no current therapeutic approaches that delay or stop disease progression. A broad role for leucine-rich repeat kinase 2 (LRRK2) mutations in familial and idiopathic PD has emerged. Here, we show that dietary amino acids are important determinants of neurodegeneration in a Drosophila model of LRRK2 PD. Restricting all amino acids effectively suppresses dopaminergic neuron loss and locomotor deficits and is associated with reduced protein synthesis, while moderately high amino acids similarly attenuate these PD-related phenotypes through a stress-responsive induction of 5'-AMP-activated protein kinase and autophagy. These studies suggest that diet plays an important role in the development of PD-related phenotypes linked to LRRK2.

Dopamine neuron-specific LRRK2 G2019S effects on gene expression revealed by translatome profiling.

Leucine-rich repeat kinase 2 (LRRK2) mutations are the most common genetic cause of late-onset Parkinson's disease. The pathogenic G2019S mutation enhances LRRK2 kinase activity and induces neurodegeneration in C. elegans, Drosophila and rodent models through unclear mechanisms. Gene expression profiling has the potential to provide detailed insight into the biological pathways modulated by LRRK2 kinase activity. Prior in vivo studies have surveyed the effects of LRRK2 G2019S on genome-wide mRNA expression in complex brain tissues with high cellular heterogeneity, limiting their power to detect more restricted gene expression changes occurring in a cell type-specific manner. Here, we used translating ribosome affinity purification (TRAP) coupled to RNA-seq to profile dopamine neuron-specific gene expression changes caused by LRRK2 G2019S in the Drosophila CNS. A number of genes were differentially expressed in the presence of mutant LRRK2 that represent a broad range of molecular functions including DNA repair (RfC3), mRNA metabolism and translation (Ddx1 and lin-28), calcium homeostasis (MCU), and other categories (Ugt37c1, disp, l(1)G0196, CG6602, CG1126 and CG11068). Further analysis on a subset of these genes revealed that LRRK2 G2019S did not alter their expression across the whole brain, consistent with dopamine neuron-specific effects uncovered by the TRAP approach that may yield insight into the neurodegenerative process. To our knowledge, this is the first study to profile the effects of LRRK2 G2019S specifically on DA neuron gene expression in vivo. Beyond providing a set of differentially expressed gene candidates relevant to LRRK2, we demonstrate the effective use of TRAP to perform high-resolution assessment of dopamine neuron gene expression for the study of PD.

Potential obesogenic effect of a complex contaminant mixture on Cree First Nations adults of Northern Québec, Canada.

BACKGROUND: Obesity incidence and prevalence is of increasing concern in First Nations communities around Canada. In addition to diet and physical activity, environmental pollutants have been suggested as a potential contributory factor to obesity associated morbidity. Owing to the exposure of Cree First Nations people to various persistent organic pollutants (POPs) and toxic metals, it is important to examine the association between obesity in these communities, and contaminant body burdens. OBJECTIVE: To determine whether selected morphometry measures (body mass index [BMI], waist circumference [WC] and body fat percentage) are associated with body burdens of 10 POPs and toxic metals. METHODS: Using data from the Nituuchischaayihtitaau Aschii Multi-community Environment-and-Health study in the eastern James Bay (Eeyou Istchee) Cree communities, this cross-sectional study examined morphometric and contaminant measures of 695 eligible participants. Sex stratified principal component analysis was conducted on blood plasma concentrations of 10 POPs and toxic metals. BMI, WC, body fat percent, and resultant contaminant components were used to create generalized linear models, and adjusted for covariates (age, total lipids, smoking, and n-3 fatty acids). RESULTS: Two principal components (PCs; PC-1 and PC-2) were extracted for both males and females. For females, PC-1 explained 73.3% and PC-2 explained 10.5%, and for males, PC-1 explained 71.6% and PC-2 explained 11.2% of the variance in contaminant burden. For both sexes, PC-1 loaded highly for polychlorinated biphenyl (PCB) congeners, organochlorine pesticides and, to a lesser extent, mercury and lead. PC-2 loaded highly for cadmium for females, and cadmium and lead for males. After adjusting for covariates, the generalized linear model showed that PC-2 was significantly and negatively associated with BMI, body fat percent, and WC in males and females. CONCLUSIONS: Our cross-sectional analysis indicates a negative association between cadmium with various obesity measures in both males and females. Null associations were found between PCBs and organochlorine pesticides and morphometry.

Using the electronic medical record to increase testing for HIV and hepatitis C virus in an Appalachian emergency department.

BACKGROUND: The ongoing Appalachian opioid epidemic has led to increasing hepatitis C virus (HCV) infections among people who inject drugs (PWID), and Human Immunodeficiency Virus (HIV) outbreaks have been observed. The primary aim of this study was to assess the potential increase in screening for HIV and HCV in an academic central Appalachian emergency department (ED) through the use of Best Practice Alerts (BPAs) in the electronic medical record (EMR). A secondary aim was to assess for an increase in linkage to care using patient navigators. METHODS: EMR algorithms based on current Centers for Disease Control and Prevention HIV and HCV testing recommendations were created that triggered Best Practice Alerts (BPAs), giving providers a one-click acceptance option to order HIV and/or HCV testing. Placards were placed in care areas, informing patients of the availability of routine screening. Patient navigators facilitated linkage to care for seropositive patients. RESULTS: The BPA appeared 58,936 times on 21,098 patients eligible for HIV screening and 24,319 times on 11,989 patients eligible for HCV screening over a one-year period. Of those, 7106 (33.7%) patients were screened for HIV and 3496 (29.2%) patients were screened for HCV, for an overall testing increase of 2269% and 1065% for HIV and HCV, respectively. Linkage to care increased by 15% for HIV to 100, and 14% for HCV to 64%. CONCLUSION: HIV and HCV screening and linkage to care were increased in an academic ED setting in central Appalachia using EMR alerts. This approach could be utilized in multiple ambulatory settings. Increased testing and earlier linkage to care may help combat the current injection drug use-related HCV epidemic and avoid additional HIV outbreaks.

The Role of Chest Imaging in Patient Management during the COVID-19 Pandemic: A Multinational Consensus Statement from the Fleischner Society.

With more than 900 000 confirmed cases worldwide and nearly 50 000 deaths during the first 3 months of 2020, the coronavirus disease 2019 (COVID-19) pandemic has emerged as an unprecedented health care crisis. The spread of COVID-19 has been heterogeneous, resulting in some regions having sporadic transmission and relatively few hospitalized patients with COVID-19 and others having community transmission that has led to overwhelming numbers of severe cases. For these regions, health care delivery has been disrupted and compromised by critical resource constraints in diagnostic testing, hospital beds, ventilators, and health care workers who have fallen ill to the virus exacerbated by shortages of personal protective equipment. Although mild cases mimic common upper respiratory viral infections, respiratory dysfunction becomes the principal source of morbidity and mortality as the disease advances. Thoracic imaging with chest radiography and CT are key tools for pulmonary disease diagnosis and management, but their role in the management of COVID-19 has not been considered within the multivariable context of the severity of respiratory disease, pretest probability, risk factors for disease progression, and critical resource constraints. To address this deficit, a multidisciplinary panel comprised principally of radiologists and pulmonologists from 10 countries with experience managing patients with COVID-19 across a spectrum of health care environments evaluated the utility of imaging within three scenarios representing varying risk factors, community conditions, and resource constraints. Fourteen key questions, corresponding to 11 decision points within the three scenarios and three additional clinical situations, were rated by the panel based on the anticipated value of the information that thoracic imaging would be expected to provide. The results were aggregated, resulting in five main and three additional recommendations intended to guide medical practitioners in the use of chest radiography and CT in the management of COVID-19.

Nationwide randomised trial evaluating elective neck dissection for early stage oral cancer (SEND study) with meta-analysis and concurrent real-world cohort.

BACKGROUND: Guidelines remain unclear over whether patients with early stage oral cancer without overt neck disease benefit from upfront elective neck dissection (END), particularly those with the smallest tumours. METHODS: We conducted a randomised trial of patients with stage T1/T2 N0 disease, who had their mouth tumour resected either with or without END. Data were also collected from a concurrent cohort of patients who had their preferred surgery. Endpoints included overall survival (OS) and disease-free survival (DFS). We conducted a meta-analysis of all six randomised trials. RESULTS: Two hundred fifty randomised and 346 observational cohort patients were studied (27 hospitals). Occult neck disease was found in 19.1% (T1) and 34.7% (T2) patients respectively. Five-year intention-to-treat hazard ratios (HR) were: OS HR = 0.71 (p = 0.18), and DFS HR = 0.66 (p = 0.04). Corresponding per-protocol results were: OS HR = 0.59 (p = 0.054), and DFS HR = 0.56 (p = 0.007). END was effective for small tumours. END patients experienced more facial/neck nerve damage; QoL was largely unaffected. The observational cohort supported the randomised findings. The meta-analysis produced HR OS 0.64 and DFS 0.54 (p < 0.001). CONCLUSION: SEND and the cumulative evidence show that within a generalisable setting oral cancer patients who have an upfront END have a lower risk of death/recurrence, even with small tumours. CLINICAL TRIAL REGISTRATION: NIHR UK Clinical Research Network database ID number: UKCRN 2069 (registered on 17/02/2006), ISCRTN number: 65018995, ClinicalTrials.gov Identifier: NCT00571883.

Noninvasive Transdermal Delivery System of Lidocaine Using an Acoustic Droplet-Vaporization Based Wearable Patch.

Current technologies for managing acute and chronic pain have focused on reducing the time required for achieving high therapeutic efficiency. Herein a wearable transdermal patch is introduced, employing an acoustic droplet vaporization (ADV) methodology, as an effective noninvasive transdermal platform, for a fast local delivery of the anesthetic agent lidocaine. The skin-worn patch consists of a flexible drug reservoir containing hundreds of micropores loaded with lidocaine, and mixed with the perfluorocarbon (PFC) emulsion. The ultrasound-triggered vaporization of the PFC emulsion provides the necessary force to breach dermal barriers. The drug release kinetics of our model was investigated by measuring the amount of lidocaine that passed through phantom tissue and pigskin barriers. The ADV platform increases the payload skin penetration resulting in shorter treatment times compared to passive diffusion or ultrasound alone, holding considerable promise for addressing the delayed therapeutic action and slow pain relief of existing delivery protocols. It is envisioned that the integration of ADV-based transdermal devices could be expanded to the depth-dependent delivery of other pain management, vaccines, and gene therapy modalities.

Source identification of human exposure to lead in nine Cree Nations from Quebec, Canada (Eeyou Istchee territory).

While policies to decrease lead in the environment have been implemented to reduce human exposure to various lead sources, the use of lead ammunition to harvest wild game may continue to contribute significantly to human blood lead levels (BLLs). As part of a multi-community environment-and-health study, BLLs representing all age groups were evaluated in the nine Cree Nations located in the James and Hudson Bay regions of Quebec, Canada. Personal, market food, traditional food and 24-h recall questionnaires were administered. Predictor variables were assessed for various exposure sources, including diet and hunting practices. Elevated BLLs were observed in association with increased hunting status, use of firearms and leaded ammunition, and consumption of traditional foods. Significant differences were observed between all communities, age groups and sexes. Recommendations include educational campaigns that promote switching to non-lead ammunition and, if lead ammunition continues to be used, careful removal from tissues of pellets, bullet fragments and ammunition paths.