Prehospital Care for Persons Experiencing Homelessness: A Cross-Sectional Survey of the Challenges, Experiences, and Perspectives of Operational EMS Agency Medical Directors.

OBJECTIVE: Persons experiencing homelessness (PEH) are among the most vulnerable populations and experience significant health disparities. Nationally, PEH utilize Emergency Medical Services (EMS) at disproportionately higher rates than their housed peers. Developing optimal strategies to care for PEH has become critically important. However, limited data exists on best practices, challenges, and experiences of providing care to PEH. The objective of this study was to describe the experiences, challenges and perspectives of operational EMS agency medical directors in Los Angeles (LA) County as they confront the homelessness crisis. METHODS: We performed a cross-sectional survey of 9-1-1 operational EMS agency medical directors in LA County, which has one of the largest populations of PEH nationally. Twenty-nine 9-1-1 operational EMS agencies operate in LA County. The link to an anonymous, web-based survey examining documentation, training, resources, operational impact, and care challenges was emailed to medical directors with three reminders during the study period (4/19/2023-9/15/2023). RESULTS: Three quarters (75.9%; 22/29) of operational EMS agencies responded to the survey, with all questions answered in 69% (20/29) of surveys. Of these, 68.2% (15/22) of agencies document housing status and 75% (15/20) agreed or strongly agreed that homelessness presents operational challenges. No operational EMS agency reported adequate EMS clinician training on homelessness. Operational EMS agencies most commonly utilized domestic violence resources (43%, 9/21), social services (38%, 8/21), and law enforcement (38%, 8/21) services to assist PEH. Referrals were limited by accessibility (86%, 18/21), time (52%, 11/21), lack of awareness (52% 11/21) and lack of mandates (52%, 11/21). All operational EMS agencies agreed or strongly agreed that mental health and substance use disorders are major issues for PEH. The most common daily challenges reported were mental health (55%, 11/20), substance use (55%, 11/20), and patient resistance (35%, 7/20). CONCLUSION: In LA County, EMS agencies experience important operational and clinical challenges in caring for PEH, with limited resources, minimal training, and high rates of substance use disorders and mental health comorbidities. Further prehospital research is essential to standardize documentation of housing status, to identify areas for intervention, increase linkage to services, and define best practices.

Rationalizing mineral gypsum use through microbially enriched municipal solid waste compost for amelioration and regaining productivity potential of degraded alkali soils.

Reclamation of alkali soils to harness their productivity potential is more complex due to the presence of excess sodium ions, poor hydraulic conductivity and infiltration rate, resulting in poor plant growth and crop productivity. Sodic soil reclamation using inorganic ameliorants like mineral gypsum or phosphogypsum is beyond the reach of small and marginal farmers having alkali soils because of their higher market prices and shortage of availability. Conjoint use of inorganic and organic amendments can be a pragmatic solution for improving soil physico-chemical and biological properties and sustaining crop productivity. Municipal solid waste compost (MSWC) available in abundant quantity if enriched with the efficient halophilic microbial consortium and used in conjunction with a reduced dose of gypsum can be a cost-effective approach for sustainable reclamation of alkali soils and harnessing their productivity potential. Hence, a field experiment was conducted on a high alkali soil (pH2 9.2 ± 0.10), electrical conductivity (EC) 1.14 ± 0.12 dS m-1, exchangeable sodium percentage 48 ± 2.50 and organic carbon (0.30%) was conducted during 2018-19 to 2020-21 to study the combined effect inorganic and organic (enriched municipal solid waste compost (EMSWC)) amendments on amelioration of alkali soils and sustaining productivity of rice-wheat cropping system. Application of gypsum @ 25% GR + enriched MSW compost @ 10 t ha-1 (T6) showed significant improvement in soil physico-chemical and biological properties over the sole application of organic (T3 and T4), inorganic (T2) and control (T1). A significant improvement in soil fertility status in terms of available nitrogen and micronutrients as well as CO3, HCO3, Cl, Ca and Mg content were recorded with the combined application of organic and inorganic soil amendments (T5 and T6) over the sole application of mineral gypsum. Soil microbial biomass carbon (MBC), nitrogen (MBN) and phosphorus (MBP) improved significantly due to the application of EMSWC with gypsum over the application of gypsum only. Grain yield of rice and wheat increased significantly (P < 0.05) owing to the application of a reduced dose of gypsum (25% GR) and EMSWC @ 10 t ha-1 (T6) with values of 5.55 and 3.83 t ha-1, respectively over rest of the treatments. Three years economic analysis of the study revealed that treatments T6 and T5 gave the highest positive net return whereas it was lowest in treatment T1 and negative in treatment T2. The highest benefit-to-cost ratio (B:C) was obtained in treatments T6 and T5 which were significantly higher compared to the rest of the treatments.

Implementation and Evaluation of an Automated Text Message-Based Diabetes Prevention Program for Adults With Pre-diabetes.

BACKGROUND: Despite the efficacy of diabetes prevention programs, only an estimated 5% of people with pre-diabetes actually participate. Mobile health (mHealth) holds promise to engage patients with pre-diabetes into lifestyle modification programs by decreasing the referral burden, centralizing remote enrollment, removing the physical requirement of a brick-and-mortar location, lowering operating costs through automation, and reducing time and transportation barriers. METHODS: Non-randomized implementation study enrolling patients with pre-diabetes from a large health care organization. Patients were exposed to a text message-based program combining live human coaching guidance and support with automated scheduled, interactive, data-driven, and on-demand messages. The primary analysis examined predicted weight outcomes at 6 and 12 months. Secondary outcomes included predicted changes in HbA1c and minutes of exercise at 6 and 12 months. RESULTS: Of the 163 participants included in the primary analysis, participants had a mean predicted weight loss of 5.5% at six months (P < .001) and of 4.3% at 12 months (P < .001). We observed a decrease in predicted HbA1c from 6.1 at baseline to 5.8 at 6 and 12 months (P < .001). Activity minutes were statistically similar from a baseline of 155.5 minutes to 146.0 minutes (P = .567) and 142.1 minutes (P = .522) at 6 and 12 months, respectively, for the overall cohort. CONCLUSIONS: In this real-world implementation of the myAgileLife Diabetes Prevention Program among patients with pre-diabetes, we observed significant decreases in weight and HbA1c at 6 and 12 months. mHealth may represent an effective and easily scalable potential solution to deliver impactful diabetes prevention curricula to large numbers of patients.

Indigenous Practices of Soil and Water Conservation for Sustainable Hill Agriculture and Improving Livelihood Security.

In the foothills of the North-West Himalayan region of India, agriculture is the main occupation of the residents. The soil and water resources are becoming the major constraints in agricultural production in the erosion-prone fragile ecosystem of the region. However, due to intensive rains and sloping lands of the region, erosion of the topsoil becoming the major problem for practicing sustainable agriculture in the region, which further dissects the lands, reduces the fertility potentials and land productivities of the region. The root cause of this huge erosion in the region is the intensive rains within a short interval of time on the bare sloping hillsides and handling this problem in both ways could reduce their erosion damage. Socio-economically the farmers are illiterate, poor, and hesitate to adopt innovative techniques of both land and water conservation. All this makes the challenge of reducing erosion losses quite difficult. Farmers in the region do have the skills to manage the problem of soil erosion which they learned from their forefathers and have faith in them. These technologies put together are termed as "Indigenous Technical Knowledge" (ITKs) and these ITKs have helped them a lot for sustainable agriculture in the region. Among different ITKs bunding of field, plowing before monsoon, filter strips, earthing-up in maize, mulching, compression of soil in sugarcane are the important ones for restoring the fertility of soils, reducing erosion losses, improving land productivity, and ultimately livelihoods in the region.

Characteristics and Outcomes of 360 Consecutive COVID-19 Patients Discharged From the Emergency Department With Supplemental Oxygen.

STUDY OBJECTIVE: To describe characteristics and outcomes of coronavirus disease (COVID-19) patients with new supplemental oxygen requirements discharged from a large public urban emergency department (ED) with supplemental oxygen. METHODS: This observational case series describes the characteristics and outcomes of 360 consecutive COVID-19 patients with new supplemental oxygen requirements discharged from a large urban public ED between April 2020 and March 2021 with supplemental oxygen. Primary outcomes included 30-day survival and 30-day survival without unscheduled inpatient admission. Demographic and clinical data were collected through a structured chart review. RESULTS: Among 360 patients with COVID-19 discharged from the ED with supplemental oxygen, 30-day survival was 97.5% (95% confidence interval (CI) 95.3 to 98.9%; n=351), and 30-day survival without unscheduled admission was 81.1% (95% CI 76.7 to 85.0%; n=292). A sensitivity analysis incorporating worst-case-scenario for 12 patients without complete follow-up 30 days after index visit yields 30-day survival of 95.5% (95% CI 92.5 to 97.2%; n=343), and 30-day survival without unscheduled admission of 78.9% (95% CI 74.3 to 83.0%; n=284). Among study patients, 32.2% (n=116) had a nadir ED oxygen saturation of <90%, among these 30-day survival was 97.4% (95% CI 92.6 to 99.4%; n=113), and 30-day survival without unscheduled admission was 76.7% (95% CI 68.8 to 84.1%; n=89). CONCLUSION: COVID-19 patients with new supplemental oxygen requirements discharged from the ED had survival comparable to COVID-19 ED patients with mild exertional hypoxia treated with supplemental oxygen in other settings, and this held true when the analysis was restricted to patients with nadir ED index visit oxygen saturations <90%. Discharge of select COVID-19 patients with supplemental oxygen from the ED may provide a viable alternative to hospitalization, particularly when inpatient capacity is limited.

Technological Proficiencies, Engagement, and Practical Considerations for mHealth Programs at an Urban Safety-Net Hospital Emergency Departments: Data Analysis.

BACKGROUND: Safety-net emergency departments often serve as the primary entry point for medical care for low income predominantly minority patient populations. Herein, we sought to provide insight into the feasibility, technological proficiencies, engagement characteristics, and practical considerations for a mHealth intervention at a safety-net emergency department. OBJECTIVE: We aimed to analyze patient technological proficiency to understand the feasibility of and draw practical considerations for mobile phone technology (mHealth) solutions for patients with chronic disease served by safety-net emergency departments. METHODS: We analyzed data from a previous diabetes randomized clinical mHealth trial for a diabetes social support intervention. Patients from a safety-net emergency department with preexisting diabetes who used SMS text messages, owned a mobile phone, and with hemoglobin A1c levels >8.5% were enrolled. A text message-based mHealth program to improve disease self-management was provided to all patients. Supporters of patients were randomized to receive a mailed copy or mHealth-based curriculum designed to improve diabetes support. Among enrolled patients, we surveyed mobile technological capacity and frequency of use. We performed latent class analysis to identify classes of patients by level of technological proficiency and compared demographic characteristics between the latent classes to identify demographic subgroups that may require more training or tailoring of the mHealth approach. Study engagement between classes was assessed by comparing the mean number of text messages exchanged, loss to follow-up, and early termination. RESULTS: Of 1876 patients who were approached, 44.2% (n=829) of patients had a stable mobile phone and were able to use text messages. Among them 166 met the trial inclusion and enrolled, 90% (149/166) of the cohort were ethnically diverse. Significant variance was found in technology capacity and frequency of use. Our latent class analysis classified 75% (124/166) of patients as highly technologically proficient and 25% (42/166) patients as minimally technologically proficient. Age (P<.001) and level of education (P<.001) were associated with class membership. Highly technologically proficient patients were younger and had higher levels of education (45.74 years old; high school or more: 90%) than minimally technologically proficient patients (53.64 years old; high school or more: 18%). Highly technologically proficient participants exchanged a mean of 40 text messages with the system coordinators compared to a mean of 10 text messages by minimally technologically proficient patients (P<.001). CONCLUSIONS: This study found that nearly half of the patients screened at the safety-net emergency department were equipped for an SMS text message-based mHealth intervention. In the small sample of patients who were enrolled, the majority were classified as highly technologically proficient. These highly proficient patients had greater study engagement. mHealth use in emergency departments may be an opportunity to improve health of ethnically diverse populations by pairing sophisticated chronic disease self-management program with SMS text message-based and traditional in-person interventions to reach patients through the method that is most familiar and comfortable. INTERNATIONAL REGISTERED REPORT IDENTIFIER (IRRID): RR2-10.1016/j.cct.2019.03.003.

Cognitive load during training for out-of-department emergency responses.

Background: Emergency medicine (EM) physicians sometimes respond to critical events outside the emergency department. To prepare for these complex cases-typically called "rapid responses" (RRs)-EM residents receive simulation-based training involving four practice tasks and three exam tasks during a 1-day session. Cognitive load (CL) theory describes how humans function with limited working memories to perform complex tasks. RRs are expected to generate high levels of CL, but the profile of CL across providers and RR cases is not well understood. In this study, we analyzed resident's CL during RR training. We hypothesized variations in CL across individual and case and that exam cases would cause higher CLs than practice cases. Methods: Residents anonymously self-reported CL levels after each case using the Paas scale, a single-item, 9-point scale from "very, very low CL" to "very, very high CL." To examine case-based differences in CL, data were rescaled by individual residents. "High CL" was defined as a score of 9/9. Results: Among 18 residents participating, CLs ranged from 4 to 9, with median of 7 and interquartile range of 7-8. While many cases showed bell curve-like distributions of CLs, one case-a bleeding tracheostomy-showed a rightward skew reflecting higher levels of CL. No significant difference was found in CL between practice and exam cases. There were 20 reports (16.5%) of "high" CL with variation across residents (0/7 [0%] to 5/6 [83.3%] cases) and across cases (1/18 [5.6%) to 8/18 [44.4%]). Conclusions: The CL that EM residents experienced did show considerable interpersonal and intercase variation, but there was no significant difference between practice and exam cases. These results highlight several questions about how to optimally design future training, including how best to balance low and high CL training cases and which cases may require further training.

Functionalized nanoparticles for brain targeted BDNF gene therapy to rescue Alzheimer's disease pathology in transgenic mouse model.

Brain-derived neurotrophic factor (BDNF) is actively produced and utilized in cortical circuits throughout life to sustain neuronal function and synaptic plasticity. In animal models of Alzheimer's Disease (AD), highly invasive BDNF gene therapy using viral vectors has successfully shown enhanced synaptic protein expression, proliferation of neurons and attenuation of amyloidogenic processes. However, to eliminate virus-related safety issues and invasive procedures, our present study has explored brain-targeted lipid-based nanoparticles that can deliver plasmid encoding BDNF to brain in a safe and efficient manner. Efficacy of these nanoparticles was tested in early (6-months) and advanced stage (9-months) transgenic APP/PS1 AD mice. Liposomes were surface-functionalized with brain targeting ligand, mannose, and cell-penetrating peptides (rabies virus-derived peptide or penetratin). These bifunctionalized nanoparticles enhanced BDNF expression by ~2 times and resulted in >40% (p < 0.05) reduction in toxic amyloid-beta peptides in 6- and 9-months old APP/PS1 mice brains compared to their age-matched untreated controls. Plaque load was reduced ~7 and ~3 times (p < 0.05), respectively, whereas synaptic proteins, synaptophysin and PSD-95, were found to be increased >90% (p < 0.05) in both age groups of transgenic mice treated with bifunctionalized nanoparticles. No untoward adverse effects were observed throughout treatment, suggesting a safe and effective strategy to rescue AD pathology.

Synthesis and Characterization of Fatty Acid Grafted Chitosan Polymeric Micelles for Improved Gene Delivery of VGF to the Brain through Intranasal Route.

Multifunctional fatty acid grafted polymeric micelles are an effective and promising approach for drug and gene delivery to the brain. An alternative approach to bypass the blood-brain barrier is administration through intranasal route. Multifunctional fatty acid grafted polymeric micelles were prepared and characterized for pVGF delivery to the brain. In vitro pVGF expression was analyzed in bEnd.3 cells, primary astrocytes, and neurons. Comparative in-vivo pVGF expression was analyzed to evaluate the effective route of administration between intranasal and intravenous. Biocompatible, multifunctional polymeric micelles were prepared, having an average size of 200 nm, and cationic zeta potential. Modified polymers were found to be hemo- and cyto-compatible. When transfected with the different modified chitosan formulations, significantly (p < 0.05) higher VGF expression was observed in primary astrocytes and neurons using the mannose, Tat peptide, and oleic acid grafted chitosan polymer. Compared to intravenous administration, intranasal administration of pVGF in polyplex formulation led to significantly (p < 0.05) higher pVGF expression. Developed multifunctional polymeric micelles were an effective pVGF delivery platform to the brain. Mannose and Tat ligand tagging improved the pVGF delivery to the brain.

Blue light phones as potential locations for deploying public access naloxone kits on a college campus.

Objective Opioid use and the risk of opioid overdose are growing public health concerns for college-aged adults. Naloxone can temporarily reverse opioid overdoses, but only if easily accessible. On most college campuses, "blue light" phones (BLPs)-call boxes topped with a blue light-offer visible access to emergency services. We hypothesized that BLPs would provide potential naloxone access points. Participants: A major university campus in Los Angeles, CA. Methods: BLP locations were obtained using Google Maps, and the area of campus within a set distance to each BLP calculated. To model effects of loss or diversion, we simulated the random loss of various BLPs. Results: Placing naloxone kits at the 59 BLP locations could provide access within 100 m to 91.5% of the campus. With loss of half of the BLPs, campus access remained above 70%. Conclusions: Naloxone at BLP locations could be accessed from almost all campus areas.

A Review of Brain-Targeted Nonviral Gene-Based Therapies for the Treatment of Alzheimer's Disease.

Diseases of the central nervous system (CNS) are difficult to treat owing to the complexity of the brain and the presence of a natural blood-brain-barrier (BBB). Alzheimer's disease (AD) is one of the major progressive and currently incurable neurodegenerative disorders of the CNS, which accounts for 60-80% of cases of dementia. The pathophysiology of AD involves the accumulation of amyloid beta (Aß) plaques and neurofibrillary tangles (NFTs) in the brain. Additionally, synaptic loss and imbalance of neuronal signaling molecules are characterized as important markers of AD. Existing treatments of AD help in the management of its symptoms and aim toward the maintenance of cognitive functions, behavior, and attenuation of gradual memory loss. Over the past decade, nonviral gene therapy has attracted increasing interest due to its various advantages over its viral counterparts. Moreover, advancements in nonviral gene technology have led to their increasing contributions in clinical trials. However, brain-targeted nonviral gene delivery vectors come across various extracellular and intracellular barriers, limiting their ability to transfer the therapeutic gene into the target cells. Chief barriers to nonviral gene therapy have been discussed briefly in this review. We have also highlighted the rapid advancement of several nonviral gene therapies for AD, which are broadly categorized into physical and chemical methods. These methods aim to modulate Aß, beta-site amyloid precursor protein (APP) cleaving enzyme 1 (BACE1), apolipoprotein E, or neurotrophic factors' expression in the CNS. Overall, this review discusses challenges and recent advancements of nonviral gene therapy for AD.

In vitro and in vivo optimization of liposomal nanoparticles based brain targeted vgf gene therapy.

Vgf (non-acronymic), a neurotrophin stimulated protein which plays a crucial role in learning, synaptic activity, and neurogenesis, is markedly downregulated in the brain of Alzheimer's disease (AD) patients. However, since vgf is a large polar protein, a safe and efficient gene delivery vector is critical for its delivery across the blood brain barrier (BBB). This research work demonstrates brain-targeted liposomal nanoparticles optimized for delivering plasmid encoding vgf across BBB and transfecting brain cells. Brain targeting was achieved by surface functionalization using glucose transporter-1 targeting ligand (mannose) and brain targeted cell-penetrating peptides (chimeric rabies virus glycoprotein fragment, rabies virus derived peptide, penetratin peptide, or CGNHPHLAKYNGT peptide). The ligands were conjugated to lipid via nucleophilic substitution reaction resulting in >75% binding efficiency. The liposomes were formed by film hydration technique demonstrating size <200 nm, positive zeta potential (15-20 mV), and polydispersity index <0.3. The bifunctionalized liposomes demonstrated âˆ¼3 pg/µg protein vgf transfection across in vitro BBB, and âˆ¼80 pg/mg protein in mice brain which was 1.5-2 fold (p < 0.05) higher compared to untreated control. The nanoparticles were also biocompatible in vitro and in vivo, suggesting a safe and efficient gene delivery system to treat AD.

A review of the tortuous path of nonviral gene delivery and recent progress.

Gene therapy encompasses the transfer of exogenous genetic materials into the patient's target cells to treat or prevent diseases. Nevertheless, the transfer of genetic material into desired cells is challenging and often requires specialized tools or delivery systems. For the past 40 years, scientists are mainly pursuing various viruses as gene delivery vectors, and the overall progress has been slow and far from the expectation. As an alternative, nonviral vectors have gained substantial attention due to their several advantages, including superior safety profile, enhanced payload capacity, and stealth abilities. Since nonviral vectors encounter multiple extra- and intra-cellular barriers limiting the transfer of genetic payload into the target cell nucleus, we have discussed these barriers in detail for this review. A direct approach, utilizing physical methods like electroporation, sonoporation, gene gun, eliminate the requirement for a specific carrier for gene delivery. In contrast, chemical methods of gene transfer exploit natural or synthetic compounds as carriers to increase cellular targeting and gene therapy effectiveness. We have also emphasized the recent advancements aimed at enhancing the current nonviral approaches. Therefore, in this review, we have focused on discussing the current evolving state of nonviral gene delivery systems and their future perspectives.

Who Stayed Home Under Safer-at-Home? Impacts of COVID-19 on Volume and Patient-Mix at an Emergency Department.

INTRODUCTION: To describe the impact of COVID-19 on a large, urban emergency department (ED) in Los Angeles, California, we sought to estimate the effect of the novel coronavirus 2019 (COVID-19) and "safer-at-home" declaration on ED visits, patient demographics, and diagnosis-mix compared to prior years. METHODS: We used descriptive statistics to compare ED volume and rates of admission for patients presenting to the ED between January and early May of 2018, 2019, and 2020. RESULTS: Immediately after California's "safer-at-home" declaration, ED utilization dropped by 11,000 visits (37%) compared to the same nine weeks in prior years. The drop affected patients regardless of acuity, demographics, or diagnosis. Reductions were observed in the number of patients reporting symptoms often associated with COVID-19 and all other complaints. After the declaration, higher acuity, older, male, Black, uninsured or non-Medicaid, publicly insured, accounted for a disproportionate share of utilization. CONCLUSION: We show an abrupt, discontinuous impact of COVID-19 on ED utilization with a slow return as safer-at-home orders have lifted. It is imperative to determine how this reduction will impact patient outcomes, disease control, and the health of the community in the medium and long terms.

Improved insulin sensitivity in obese-diabetic mice via chitosan Nanomicelles mediated silencing of pro-inflammatory Adipocytokines.

Obesity induced chronic low-level inflammation is strongly associated with the development of insulin resistance and progression of type-2 diabetes. Systemic treatment with anti-inflammatory therapeutics requires high doses and is associated with serious adverse effects owing to generalized suppression of the immune system. Here we study localized knockdown of pro-inflammatory adipocytokines in adipose tissue macrophages (ATMs) and adipocytes using RNA interference for the treatment of insulin resistance. Chitosan nanomicelles conjugated to ATM and adipocyte targeting ligands were used to transfect short hairpin RNA (shRNA) against tumor necrosis factor-α (TNFα) and monocyte chemoattractant protein-1 (MCP-1). Subcutaneous administration of nanomicellar/pDNA polyplexes in obese-diabetic mice resulted in decreased concentration of pro-inflammatory cytokines TNFα, MCP-1, IL-6, and IL-1ß along with increased concentration of insulin-sensitizing adipokine adiponectin. Downregulation of inflammatory cytokines resulted in improved insulin sensitivity and glucose tolerance for up to six-weeks following single dose, compared to untreated obese-diabetic mice.

Plummeting anthropogenic environmental degradation by amending nutrient-N input method in saffron growing soils of north-west Himalayas.

Nitrous-oxide emission and nitrate addition from agriculture to earth's environment are two main agriculture related anthropogenic causes of environmental degradation that needs greater attention. For addressing the aforesaid issue, new techniques/practices need to be developed and implemented. The present investigation, which was focused on this issue, resulted in developing a new mode of nitrogen (N) placement, i.e. 'mid rib placement upper to corms in two splits (MRPU-2S)', that could reduce nitrous oxide N emission by around 70.11% and, nitrate N leaching and runoff by around 68.26 and 67.09%, respectively, over conventional method, in saffron growing soils of northwest Himalayas. Besides plummeting environmental degradation, MRPU-2S further resulted in enhancing saffron yield by 33.33% over conventional method. The findings of the present investigation were used to develop new empirical models for predicting saffron yield, nitrate N leaching and nitrous-oxide N emission. The threshold limits of nitrate N leaching and nitrous oxide N emission have also been reported exclusively in the present study.

Design and Validation of Liposomal ApoE2 Gene Delivery System to Evade Blood-Brain Barrier for Effective Treatment of Alzheimer's Disease.

Targeting gene-based therapeutics to the brain is a strategy actively sought to treat Alzheimer's disease (AD). Recent findings discovered the role of apolipoprotein E (ApoE) isoforms in the clearance of toxic amyloid beta proteins from the brain. ApoE2 isoform is beneficial for preventing AD development, whereas ApoE4 is a major contributing factor to the disease. In this paper, we demonstrated efficient brain-targeted delivery of ApoE2 encoding plasmid DNA (pApoE2) using glucose transporter-1 (glut-1) targeted liposomes. Liposomes were surface-functionalized with a glut-1 targeting ligand mannose (MAN) and a cell-penetrating peptide (CPP) to enhance brain-targeting and cellular internalization, respectively. Among various CPPs, rabies virus glycoprotein peptide (RVG) or penetratin (Pen) was selected as a cell-penetration enhancer. Dual (RVGMAN and PenMAN)-functionalized liposomes were cytocompatible at 100 nM phospholipid concentration and demonstrated significantly higher expression of ApoE2 in bEnd.3 cells, primary neurons, and astrocytes compared to monofunctionalized and unmodified (plain) liposomes. Dual-modified liposomes also showed ∼2 times higher protein expression than other formulation controls in neurons cultured below the in vitro BBB model. These results translated well to in vivo efficacy study with significantly higher transfection of pApoE2 in the C57BL/6 mice brain following single tail vein administration of RVGMAN and PenMAN functionalized liposomes without any noticeable signs of toxicity. These results illustrate the potential of surface-modified liposomes for safe and brain-targeted delivery of the pApoE2 gene for effective AD therapy.

Smart Thermosensitive Copolymer Incorporating Chitosan-Zinc-Insulin Electrostatic Complexes for Controlled Delivery of Insulin: Effect of Chitosan Chain Length.

This work was designed to optimize thermosensitive copolymeric depot-based system for delivering insulin at a controlled rate for a prolonged period following a single subcutaneous injection. Intrinsic ability of insulin to form hexamers in the presence of zinc and electrostatic complexes with chitosan (CS) were explored for improving stability and release characteristics of insulin through the copolymeric depot. CS-zinc-insulin complexes were prepared using CS of different chain lengths (5, 30, 50, 200 kDa). Effect of different chain lengths of CS on the thermal stability, binding constant, and release profile of insulin was determined. Increasing chain length of CS demonstrated increasing thermal stability of insulin. However, higher chain length of CS adversely affected the release profile of insulin. Hydrolytic degradation analysis showed rapid degradation of copolymer in formulation containing higher chain length of CS (200 kDa)-zinc-insulin complexes, implying formation of bigger pores and channels in copolymeric matrix during initial release in this system. However, formulation containing smaller chain length of CS (5 kDa)-zinc-insulin complexes demonstrated slow copolymer degradation and sustained insulin release profile. Additionally, CS-zinc-insulin complexes were effective in preserving stability of insulin during the entire duration of release and storage.

Feasibility and Acceptability of a Text Message-Based Intervention to Reduce Overuse of Alcohol in Emergency Department Patients: Controlled Proof-of-Concept Trial.

BACKGROUND: Emergency department (ED) patients have high rates of risky alcohol use, and an ED visit offers an opportunity to intervene. ED-based screening, brief intervention, and referral to treatment (SBIRT) reduces alcohol use and health care costs. Mobile health (mHealth) interventions may expand the impact of SBIRTs but are understudied in low-resource ED populations. OBJECTIVE: The objective of this study was to assess the feasibility of and patient satisfaction with a text-based mHealth extension of an ED screening program to reduce risky alcohol use in low-income, urban patients. METHODS: Research assistants screened a convenience sample of ED patients in person for risky alcohol use via the Alcohol Use Disorders Identification Test (AUDIT). Patients who reported AUDIT scores ≥8 and <20 were informed of their AUDIT score and risk. RAs invited patients with SMS text message-capable phones to receive mROAD (mobilizing to Reduce Overuse of Alcohol in the ED), an SMS text message-based extension of the ED screening program. mROAD is a 7-day program of twice-daily SMS text messages based on the National Institutes of Health's Rethinking Drinking campaign. Participants were allocated to a control group (daily sham text messages without specific guidance on behaviors, such as "Thanks for taking part!") or to the mROAD intervention group. Patients were interviewed at 30 days to assess acceptability, satisfaction, and changes in drinking behavior. Satisfaction was examined descriptively. Pre and post measurements of drinking behaviors and motivation were compared, as were differences in change scores between the intervention arms. RESULTS: Of 1028 patients screened, 95 (9.2%) exhibited risky alcohol use based on AUDIT, and 23/95 (24%) of those patients did not own an SMS text messaging-capable phone; this left 72/95 (76%) eligible patients. Among eligible participants, 48/72 (67%) agreed to enroll; 31/48 (65%) achieved follow-up (18/24 (75%) in the intervention group and 13/24 (55%) in the control group). Participants who completed follow-up reported high satisfaction. Changes in behavior were similar between the arms. Overall, the number of drinking days reported in the prior 30 days decreased by 5.0 (95% CI 1.7-8.3; P=.004), and the number of heavy drinking days decreased by 4.1 (95% CI 1.0 to 7.15, P=.01). Patients reported an 11-point increase (95% CI 2.6-20, P=.01, 10% overall increase) in motivation to change alcohol use via the Change Questionnaire. The were no statistical differences in drinking days, heavy drinking days, or motivation to change between the arms. CONCLUSIONS: The mROAD trial was feasible. Over three-quarters of ED patients with risky alcohol use owned a text message-capable phone, and two-thirds of these patients were willing to participate; only 1 patient opted out of the intervention. Although 35% of patients were lost to follow-up at 30 days, those patients who did follow up had favorable impressions of the program; more than 90% reported that SMS text messages were a "good way to teach," and 89% of intervention arm participants enjoyed the program and found that the messages were motivating. Both the mROAD and sham message groups showed promising changes in alcohol use and motivation to change. mROAD is a feasible intervention that may reduce rates of risky alcohol use in ED patients. TRIAL REGISTRATION: ClinicalTrials.gov NCT02158949; https://clinicaltrials.gov/ct2/show/NCT02158949.

GLUT-1: An Effective Target To Deliver Brain-Derived Neurotrophic Factor Gene Across the Blood Brain Barrier.

Alzheimer's disease (AD), the most common cause of dementia, inflicts enormous suffering to patients and their family members. It is the third deadliest disease, affecting 46.8 million people worldwide. Brain-derived neurotrophic factor (BDNF) is involved in the development, maintenance, and plasticity of the central nervous system. This crucial protein is significantly reduced in AD patients leading to reduced plasticity and neuronal death. In this study, we demonstrate the targeted delivery of the BDNF gene to the brain using liposome nanoparticles. These liposomes were surface modified with glucose transporter-1 targeting ligand (mannose) and cell penetrating peptides (penetratin or rabies virus glycoprotein) to promote selective and enhanced delivery to the brain. Surface modified liposomes showed significantly higher transfection of BDNF in primary astrocytes and neurons, compared to unmodified (plain) liposomes. BDNF transfection via dual modified liposomes resulted in an increase in presynaptic marker synaptophysin protein in primary neuronal cells, which is usually found to be reduced in AD patients. Liposomes surface modified with mannose and cell penetrating peptides demonstrated ∼50% higher transport across the in vitro blood brain barrier (BBB) model and showed significantly higher transfection efficiency in primary neuronal cells compared to plain liposomes. These results were correlated with significantly higher transport of surface modified liposomes (∼7% of injected dose/gram of tissue) and BDNF transfection (∼1.7 times higher than baseline level) across BBB following single intravenous administration in C57BL/6 mice without any signs of inflammation or toxicity. Overall, this study suggests a safe and targeted strategy to increase BDNF protein in the brain, which has the potential to reverse AD pathophysiology.