Directional Deep Brain Stimulation Programming: Is the Segment Clearly Identifiable and Stable Over Time?

BACKGROUND: In our early experience programming directional deep brain stimulation (d-DBS) in PD, we found the optimal directional segment changed over time in some patients. To determine the frequency/reasons for this we examined whether (1) different programmers would identify the same segment as "optimal"; and (2) the same programmer would select the same "optimal" segment over time. We hypothesized there would be a moderately high level of agreement on optimal electrode selection between different assessors and repeated assessments by the same evaluator. METHODS: This was a prospective, double-blind investigation evaluating the reliability and stability of programming d-DBS. Each patient underwent a mono-polar survey four times (2 time points by 2 separate assessors). The primary aim was the inter-rater agreement of selecting the optimal electrode at 1 and 6 months. The secondary aim was to determine the intra-rater agreement of selecting the optimal electrode from 1 to 6 months. RESULTS: Twenty-one patients were enrolled. There was fair inter-rater agreement at 1 month and moderate at 6 months. There was minimal intra-rater agreement between 1 and 6 months. DISCUSSION: The data refuted our hypothesis. Potential reasons for low agreement include (1) the arduous/subjective nature of identifying the optimal electrode in d-DBS systems, especially in well-placed electrodes; and/or (2) acute changes to the location of stimulation delivery offering temporary improvement in symptoms. Key takeaways gathered were it may, (1) behoove the programmer to explore different electrode montages after a period of time; and (2) be more efficient to review the directional electrode montage only when dictated by clinical symptoms/disease progression.

A Realistic, Low-Cost Simulated Automated Chest Compression Device.

Audience: This simulated automated chest compression device was designed for use in simulation cardiac arrest cases involving emergency medicine residents, but it would be applicable to other learners such as nurses, pharmacists, and medical students. Background: Automated chest compression devices (ACCD) are commonly utilized in cardiac arrest in the emergency department and by emergency medical services (EMS) as patients arrive in the ED.1 Prolonged simulated cardiac arrest can be challenging to maintain proper chest compression depth and technique.2 Resident learning may be enhanced during cardiac arrest in the simulation environment by implementing the use of a simulated ACCD. Educational Objectives: By the end of this educational session using a resuscitation trainer or high-fidelity manikin, learners should be able to:Recognize appropriate application of simulated ACCD to an ongoing resuscitation caseDemonstrate proper positioning of simulated ACCD in manikin modelIntegrate simulated ACCD to provide compressions appropriately throughout cardiac arrest scenario. Educational Methods: We developed a cost-effective simulated ACCD for use in resuscitation simulation cases. An initial pilot session identified components of fidelity that were used to model the simulated ACCD after those utilized in clinical situations. Three simulated devices were created and then tested for efficacy during high-fidelity simulation with 25 emergency medicine residents. Research Methods: Visual analog scales were used to explore how the simulated ACCD affected perceived realism and stress level during the cardiac arrest simulation. Qualitative data were collected through open-ended learner feedback comments. The institutional review board at our institution reviewed this project and determined that it was exempt. Results: With inclusion of the simulated ACCD device, learners rated the simulation "more realistic" with an average rating of 74/100 and "less stressful" with an average rating of 69/100 on the visual analog scales. Learner comments noted that the use of the ACCD in simulation resulted in better resource availability and accurate environmental noise. Discussion: The simulated ACCD presented here was found to be effective, realistic, and practical for use by learners in a resuscitation curriculum. Our results suggest that implementating a cost-effective simulated ACCD ($98 for supplies) in high-fidelity simulation cardiac arrest cases enhances the perceived realism of the environment and offers physician learners a low-stress opportunity to practice the clinical application of ACCD in cardiac arrest resuscitation. Additionally, the use of the simulated ACCD, specifically in a prolonged resuscitation, eliminated the need for physically demanding manual chest compressions. Anecdotally, in simulated environments we have observed poor-quality manual chest compressions due to an understanding that the manikin is "not real," leading to decreased psychological fidelity from the shared acceptance of the poor-quality compressions. Thus, the presence of a simulated clinical device providing chest compressions could have increased the feel of realism through improved psychological fidelity. Additionally, we note that the physical and psychological fidelity of this simulated device was sufficient for physicians to perceive clinical implementation, but may be suboptimal for assistive staff, who are focused on the specific functionality and may benefit from training on the physical device in clinical use. Finally, our simulated ACCD resembles the clinical device our department uses; we advise modifications as appropriate to allow a simulated ACCD created for other learners to also resemble their clinically used ACCD. Topics: Automated chest compression device, ACLS, improvised equipment, high fidelity simulation.

A Novel Home-Based Telerehabilitation Program Targeting Fall Prevention in Parkinson Disease: A Preliminary Trial.

Background and Objectives: Falls in a person with Parkinson disease (PwP) are frequent, consequential, and only partially prevented by current therapeutic options. Notably, most falls in PwPs occur in the home or its immediate surroundings; however, our current strategies for fall prevention are clinic-centered. The primary objective of this nonrandomized pilot trial was to investigate the feasibility and preliminary efficacy of the novel implementation of home-based PD telerehabilitation (tele-physical/occupational therapy) focusing on fall risk reduction and home-safety modification. Methods: Persons with mild-to-moderate PD who were identified as being at risk of falls by their movement disorders neurologist were recruited from a tertiary movement disorders clinic. After an initial in-person evaluation by the study physical and occupational therapists, 15 patients with PD (Hoehn and Yahr Stage 2 (n = 8) and Stage 3 (n = 7)) participated in 4 biweekly PT/OT televisits with care partner supervision over the course of 10 weeks. The Goal Attainment Scale (GAS) was implemented to assess progress toward individualized PT/OT goals established at baseline. Outcomes were assessed at the end of the intervention at 10 weeks and at a six-month follow-up. Results: Participants completed all 120 protocol-defined televisits without dropouts and adverse events. At 10 weeks, mean composite PT and OT-GAS scores showed significant improvement from baseline (PT: p < 0.001, OT: p < 0.008), which continued at 6 months (PT: p < 0.0005, OT: p < 0.0005). Home-modification recommendations made through novel virtual home-safety tours were cumulatively met by participants at 87% at 10 weeks and 91% at 6 months. Discussion: Home-based telerehabilitation is a promising new strategy toward fall prevention in PD. The GAS has the potential to serve as an effective and patient-driven primary outcome variable for rehabilitation interventions for heterogeneous PwPs to assess progress toward personalized goals. Trial Registration Information: ClinicalTrial.gov identifier: NCT04600011.

Long-Term Clinical Experience with Directional Deep Brain Stimulation Programming: A Retrospective Review.

INTRODUCTION: Directional deep brain stimulation (d-DBS) axially displaces the volume of tissue activated (VTA) towards the intended target and away from neighboring structures potentially improving benefit and reducing side effects (SE) of stimulation. A clinical trial evaluating d-DBS demonstrated a wider therapeutic window (TW) with directional electrodes. While this seems advantageous, it remains unclear when and why directional stimulation is chosen clinically. To evaluate the implementation of d-DBS in our practice we examined the prevalence of and motivation for directional programming. METHODS: A retrospective review was completed in consecutive patients with Parkinson's disease (PD)/essential tremor (ET) implanted with the Abbott Infinity system from December 2016 to January 2020. At 3, 12, 24, and 36 months we extracted post-DBS stimulation parameters; use of directional electrodes and other advanced programming techniques; and reasons for directional programming. RESULTS: Fifty-six patients with PD and 18 patients with ET (104 and 33 leads, respectively) were identified. The numbers of patients programmed with a directional electrode in at least one DBS lead in PD and ET, respectively, were 22/56 (39%) and 13/18 (72%) at 3 months; 19/48 (40%) and 8/12 (67%) at 12 months; 12/31 (39%) and 5/8 (63%) at 24 months; and 6/9 (67%) and 1/2 (50%) at 36 months. In PD and ET, reasons for using directional stimulation were better symptom control, less SE, or combination of better symptom control/SE; additional reasons in ET were improved battery/TW%. CONCLUSION: Over a 36-month time period 39-68% of patients with PD and 50-72% of patients with ET had at least one lead programmed directionally in order to either improve symptom control or reduce side effects, an option not available with conventional omnidirectional stimulation. Initially directional electrodes were used in ET more frequently than PD, likely because of the less complex nature of programming for a monosymptomatic disorder. However, over time this shifted as we gained directional experience and sought solutions to reduce worsening symptoms.

Soluble urokinase-type plasminogen activator receptor (suPAR) is elevated in caregivers of patients with parkinsonism.

Caregivers are integral to the care of those with neurological disorders such as Parkinson's Disease (PD), but are often burdened by stress, anxiety, and depression. Previous research has suggested that the foundation of such stress is low-grade systemic inflammation, as evidenced by increased interleukin 6 (IL-6) and C-reactive protein (CRP) levels. Soluble urokinase-type plasminogen activator receptor (suPAR) is a kidney disease risk factor and marker of chronic inflammation that integrates psycho-social stress and organ dysfunction. Caregivers of PD experience an extraordinary amount of stress and suPAR's role as prognostic marker has not yet been assessed in caregivers of PD. The aim of this study was to determine the relationship between suPAR levels and PD caregiver burden. Healthy volunteers who accompanied patients with parkinsonism (n = 35) donated blood samples, and complete blood counts (CBC), CRP, and suPAR levels were measured. Participants were then interviewed by telephone and stratified into primary and non-primary caregiver groups. Their caregiver burden was quantified through the Zarit Caregiver Burden Short Form (ZBI-12). The resultant data demonstrated higher plasma levels of suPAR and ZBI-12 scores for the primary caregiver group relative to the non-primary caregiver group (suPAR level: 3.73 vs. 2.72 ng/mL, p = 0.01; ZBI-12: 18.57 vs. 5.4, p < 0.0001; Table). The data also revealed a moderate positive correlation between suPAR and ZBI-12 scores. These findings not only demonstrate a correlation between elevated suPAR and caregiving burden in PD, but also further support and raise awareness for the overall psychosocial burden and stress experienced by those caregivers.

Thermostability of Measles and Rubella Vaccines in a Microneedle Patch.

Measles and rubella vaccinations are highly effective at reducing disease prevalence; however, logistic issues related to subcutaneous administration and vaccine wastage limit the extent of vaccination coverage. Microneedle (MN) patches can increase coverage by easing logistics through simplified administration and improved stability. This study demonstrates the thermostability of a bivalent measles and rubella vaccine MN patch. Rubella vaccine stability required pH buffering during drying; potassium phosphate buffer at neutral pH was optimal for both vaccines. Screening 43 excipients for their ability to retain potency during drying and storage yielded sucrose-threonine-potassium phosphate buffer formulation at pH 7.5 as an optimal formulation. MN patches made with this formulation had no significant loss of vaccine titer after one month and remained within a one log10 titer loss cutoff after 3 - 4 months at 5°C, 25°C and 40°C. Finally, these patches were shown to be immunogenic in juvenile rhesus macaques. This work demonstrates the potential for MN patches for measles and rubella vaccination to be removed from the cold chain, which is expected to decrease vaccine cost and wastage, and increase vaccination coverage.

Fabrication of microneedle patches with lyophilized influenza vaccine suspended in organic solvent.

Skin vaccination by microneedle (MN) patch simplifies the immunization process to increase access to vaccines for global health. Lyophilization has been widely used to stabilize vaccines and other biologics during storage, but is generally not compatible with the MN patch manufacturing processes. In this study, our goal was to develop a method to incorporate lyophilized inactivated H1N1 influenza vaccine into MN patches during manufacturing by suspending freeze-dried vaccine in anhydrous organic solvent during the casting process. Using a casting formulation containing chloroform and polyvinylpyrrolidone, lyophilized influenza vaccine maintained activity during manufacturing and subsequent storage for 3 months at 40 °C. Influenza vaccination using these MN patches generated strong immune responses in a murine model. This manufacturing process may enable vaccines and other biologics to be stabilized by lyophilization and administered via a MN patch.

The Effects of Dual Task Cognitive Interference and Fast-Paced Walking on Gait, Turns, and Falls in Men and Women with FXTAS.

Fragile X-associated tremor/ataxia syndrome (FXTAS) is a genetic neurodegenerative disorder characterized by cerebellar ataxia, tremor, and cognitive dysfunction. We examined the impact of dual-task (DT) cognitive-motor interference and fast-paced (FP) gait on gait and turning in FXTAS. Thirty participants with FXTAS and 35 age-matched controls underwent gait analysis using an inertial sensor-based 2-min walk test under three conditions: (1) self-selected pace (ST), (2) FP, and (3) DT with a concurrent verbal fluency task. Linear regression analyses were performed to assess the association between FXTAS diagnosis and gait and turn outcomes. Correlations between gait variables and fall frequency were also calculated. FXTAS participants had reduced stride length and velocity, swing time, and peak turn velocity and greater double limb support time and number of steps to turn compared to controls under all three conditions. There was greater dual task cost of the verbal fluency task on peak turn velocity in men with FXTAS compared to controls. Additionally, stride length variability was increased and cadence was reduced in FXTAS participants in the FP condition. Stride velocity variability under FP gait was significantly associated with the number of self-reported falls in the last year. Greater motor control requirements for turning likely made men with FXTAS more susceptible to the negative effects of DT cognitive interference. FP gait exacerbated gait deficits in the domains of rhythm and variability, and increased gait variability with FP was associated with increased falls. These data may inform the design of rehabilitation strategies in FXTAS.

Normative database of spatiotemporal gait parameters using inertial sensors in typically developing children and young adults.

BACKGROUND: Inertial sensors are increasingly useful to clinicians and researchers to detect gait deficits. Reference values are necessary for comparison to children with gait abnormalities. OBJECTIVE: To present a normative database of spatiotemporal gait and turning parameters in 164 typically developing children and young adults ages 5-30 utilizing the APDM Mobility Lab® system. METHODS: Participants completed the i-WALK test at both self-selected (SS) and fast as possible (FAP) walking speeds. Spatiotemporal gait and turning parameters included stride length, stride length variability, gait speed, cadence, stance, swing, and double support times, and foot strike, toe-off, and toe-out angles, turn duration, peak turn velocity and number of steps to turn. RESULTS: Absolute stride length and gait speed increased with age. Normalized gait speed, absolute and normalized cadence, and stride length variability decreased with age. Normalized stride length and all parameters of gait cycle phase and foot position remained unaffected by age except for greater FSA in children 7-8. Foot position parameters in children 5-6 were excluded due to aberrant values and high standard deviations. Turns were faster in children ages 5-13 and 7-13 in the SS and FAP conditions, respectively. There were no differences in number of steps to turn. Similar trends were observed in the FAP condition except: normalized gait speed did not demonstrate a relationship with age and children ages 5-8 demonstrated increased stance and double support times and decreased swing time compared to children 11-13 and young adults (ages 5-6 only). Females ages 5-6 demonstrated increased stride length variability in the SS condition; males ages 7-8 and 14-30 ha d increased absolute stride length in the FAP condition. Similarities and differences were found between our values and previous literature. SIGNIFICANCE: This normative database can be used by clinicians and researchers to compare abnormal gait patterns and responses to interventions.

Gait asymmetry in glucocerebrosidase mutation carriers with Parkinson's disease.

BACKGROUND: GBA mutation carriers with PD (PD-GBA) are at higher risk of cognitive decline, but there is limited data regarding whether there are differences in gait dysfunction between GBA mutation and non-mutation carriers with PD. OBJECTIVES/METHODS: The primary aim of this study was to use quantitative inertial sensor-based gait analysis to compare gait asymmetry in 17 PD-GBA subjects, 17 non-mutation carriers with PD, and 15 healthy control subjects using parameters that had gait laterality and were markers of bradykinesia, in particular arm swing velocity and arm swing range of motion and stride length. RESULTS: Arm swing velocity was more symmetric in PD-GBA subjects vs. non-mutation carriers in the OFF state (12.5 +/- 8.3 vs. 22.9 +/- 11.8%, respectively, p = 0.018). In the ON-medication state, non-mutation carriers with PD, but not PD-GBA subjects, exhibited arm swing velocity (16.8 +/- 8.6 vs. 22.9 +/- 11.8%, p = 0.006) and arm range of motion (26.7 +/- 16.3 vs. 33.4 +/- 18.6%, p = 0.02) that was more asymmetric compared with the OFF-medication state. CONCLUSIONS: In the OFF medication state, arm swing velocity asymmetry may be a useful parameter in helping to distinguish GBA mutation carriers with PD from non-mutation carriers.

Tremorography in fragile X-associated tremor/ataxia syndrome, Parkinson's disease and essential tremor.

BACKGROUND: Fragile X-associated tremor/ataxia syndrome (FXTAS), a neurodegenerative disease affecting carriers of a 55-200 CGG repeat in the fragile X mental retardation 1 gene, may receive an initial diagnosis of Parkinson's disease (PD) or essential tremor (ET) due to overlapping motor symptoms. Therefore, tremor and bradykinesia were compared in these disorders using quantitative tremorography. METHODS: The inertial sensor based Kinesia ™ system was used to quantify upper extremity tremor and bradykinesia in participants with FXTAS (n = 25), PD (n = 23), ET (n = 18) and controls (n = 20) and regression analysis was performed to determine whether tremorography measures distinguished between the groups. The FXTAS Rating scale (FXTAS-RS) was administered to determine whether sub-score items on the clinician rated scale correlated with tremorography variables. RESULTS: FXTAS participants had reduced finger tap speed compared to those with ET, and ET had increased kinetic tremor compared to PD. Higher kinetic tremor distinguished FXTAS from PD (p = .02), and lower finger tap speed distinguished FXTAS from ET (p = .004). FXTAS-RS tremor and bradykinesia items correlated with tremorography measures (p = .005 to <0.0001). CONCLUSIONS: This is the first quantitative study to compare tremor and bradykinesia in FXTAS, PD and ET. Kinetic tremor and bradykinesia measures using a quantitative inertial sensor system distinguished FXTAS from PD and ET, respectively. Such technologies may be useful for detecting precise tremor and bradykinesia abnormalities and distinguishing the tremor and bradykinesia profiles in each of these disorders.

Extended delivery of vaccines to the skin improves immune responses.

Vaccines prevent 2-3 million childhood deaths annually; however, low vaccine efficacy and the resulting need for booster doses create gaps in immunization coverage. In this translational study, we explore the benefits of extended release of licensed vaccine antigens into skin to increase immune responses after a single dose in order to design improved vaccine delivery systems. By administering daily intradermal injections of inactivated polio vaccine according to six different delivery profiles, zeroth-order release over 28 days resulted in neutralizing antibody titers equivalent to two bolus vaccinations administered one month apart. Vaccinations following this profile also improved immune responses to tetanus toxoid and subunit influenza vaccine but not a live-attenuated viral vaccine, measles vaccine. Finally, using subunit influenza vaccine, we demonstrated that daily vaccination by microneedle patch induced a potent, balanced humoral immunity with an increased memory response compared to bolus vaccination. We conclude that extended presentation of antigen in skin via intradermal injection or microneedle patch can enhance immune responses and reduce the number of vaccine doses, thereby enabling increased vaccination efficacy.

Self-determination theory and food-related parenting: The Parent Socioemotional Context of Feeding Questionnaire.

There has been wide application of Self-Determination Theory (SDT) to understanding motivation and regulation of eating and weight. Yet, there are no measures of the socioemotional-contextual family conditions in the eating domain, which are identified in SDT and should influence development of eating behavior in young children. Two studies were conducted to develop and validate a measure to assess the SDT socioemotional-contextual dimensions of food-related parenting. These dimensions were derived from extensions of SDT, which argue that autonomy support, warmth, and appropriate structure (as well as low coercion, hostility, and chaos) are the conditions that will fulfill children's psychological needs for autonomy, relatedness and competence, resulting in more intrinsic motivation and better self-regulation of behavior. In the first study, 230 parents completed the food-related parenting items in reference to their 4- to 8-year-old children, and the factor structure and construct and convergent validity of the items were examined. Generally consistent with SDT, factors suggested 4 food-related socioemotional parenting contexts of supportiveness (autonomy support/warmth), coerciveness (coercion/hostility), structure, and chaos. In a second study of 221 parents, a 24-item Parent Socioemotional Context of Feeding Questionnaire (PSCFQ) was confirmed to have a 4-factor structure. In each study, good reliability was found for each subscale. Construct, convergent, and divergent validity were supported by small to moderate correlations with aspects of child feeding (e.g., restriction) and general parenting styles. PSCFQ subscales were not associated with child BMI, family income or parent education. (PsycINFO Database Record (c) 2019 APA, all rights reserved).

Hepatitis B vaccination using a dissolvable microneedle patch is immunogenic in mice and rhesus macaques.

Chronic Hepatitis B virus infection remains a major global public health problem, accounting for about 887,000 deaths in 2015. Perinatal and early childhood infections are strongly associated with developing chronic hepatitis B. Adding a birth dose of the hepatitis B vaccine (HepB BD) to routine childhood vaccination can prevent over 85% of these infections. However, HepB BD coverage remains low in many global regions, with shortages of birth attendants trained to vaccinate and limited HepB BD supply at birth. To address the challenges, we developed coated metal microneedle patches (cMNPs) and dissolvable microneedle patches (dMNPs) that deliver adjuvant-free hepatitis B vaccine to the skin in a simple-to-administer manner. The dMNP contains micron-scale, solid needles encapsulating vaccine antigen and dissolve in the skin, generating no sharps waste. We delivered HepB BD via cMNP to BALB/c mice and via dMNP to both mice and rhesus macaques. Both cMNP and dMNP were immunogenic, generating hepatitis B surface antibody levels similar to human seroprotection. Biomechanical analysis showed that at high forces the microneedles failed mechanically by yielding but microneedles partially blunted by axial compression were still able to penetrate skin. Overall, this study indicates that with further development, dMNPs could offer a method of vaccination to increase HepB BD access and reduce needle waste in developing countries.

Plantation performance of chestnut hybrids and progenitors on reclaimed Appalachian surface mines.

Reclamation of surface mined sites to forests is a preferred post-mining land use option, but performance of planted trees on such sites is variable. American chestnut (Castanea dentata (Marsh.) Borkh.) is a threatened forest tree in the eastern USA that may become an important species option for mine reclamation. Chestnut restoration using backcross hybrids that incorporate blight resistance may be targeted to the Appalachian coal mining region, which corresponds closely with the species' native range. Thus, it is important to understand how chestnut hybrids perform relative to progenitors on reclamation sites to develop restoration prescriptions. Seeds of parents and three backcross generations of chestnut (100% American, 100% Chinese, and BC1F3, BC2F3, and BC3F2 hybrids) were planted into mine soils in West Virginia, USA with shelter treatments. Survival for all stock types was 44% after 8 years (American 39%, Chinese 77%, BC1F3 40%, BC2F3 28%, and BC3F2 35%). Height for all stock types was 33 cm after 8 years (American 28 cm, Chinese 67 cm, BC1F3 30 cm, BC2F3 21 cm, and BC3F2 20 cm). At another site a year later, seedlings of the chestnut stock types were planted into brown (pH 4.6) or gray sandstone (pH 6.3) mine soils and seedling survival across all stock types was 58% after 7 years. Chinese had the highest survival at 82%, while the others ranged from 38 to 66%. Height was 63 cm for all stock types after 7 years. More advanced backcross hybrids (BC2F3 and BC3F2) had the lowest vigor ratings at both sites after 7-8 years. Our results indicate that surface mines in Appalachia may provide a land base for planting blight-resistant chestnuts, although Chinese chestnut outperformed American chestnut and later generation backcross hybrids. As blight-resistant chestnuts establish and spread after planting, chestnut trees may become a component of the forest canopy again and possibly occupy its former niche, but their spread may alter future forest stand dynamics.

A Microneedle Patch for Measles and Rubella Vaccination Is Immunogenic and Protective in Infant Rhesus Macaques.

Background: New methods to increase measles and rubella (MR) vaccination coverage are needed to achieve global and regional MR elimination goals. Methods: Here, we developed microneedle (MN) patches designed to administer MR vaccine by minimally trained personnel, leave no biohazardous sharps waste, remove the need for vaccine reconstitution, and provide thermostability outside the cold chain. This study evaluated the immunogenicity of MN patches delivering MR vaccine to infant rhesus macaques. Results: Protective titers of measles neutralizing antibodies (>120 mIU/mL) were detected in 100% of macaques in the MN group and 75% of macaques in the subcutaneous (SC) injection group. Rubella neutralizing antibody titers were >10 IU/mL for all groups. All macaques in the MN group were protected from challenge with wild-type measles virus, whereas 75% were protected in the SC group. However, vaccination by the MN or SC route was unable to generate protective immune responses to measles in infant macaques pretreated with measles immunoglobulin to simulate maternal antibody. Conclusions: These results show, for the first time, that MR vaccine delivered by MN patch generated protective titers of neutralizing antibodies to both measles and rubella in infant rhesus macaques and afforded complete protection from measles virus challenge.

Brief Report: Statin Effects on Myocardial Fibrosis Markers in People Living With HIV.

BACKGROUND: In observational studies, patients with HIV have higher levels of soluble ST2 (sST2), galectin-3, and growth differentiation factor-15 (GDF-15) than non-HIV controls. As statins exert pleiotropic immunomodulatory effects that may affect markers of myocardial fibrosis, the objective of the current study is to determine whether biomarkers of myocardial fibrosis reflecting subclinical pathology may be modified by statin therapy in patients with HIV. SETTING AND METHODS: Forty HIV+ men and women participated in a single center 12-month randomized, double-blind placebo-controlled trial of atorvastatin 40 mg every day vs. placebo. At baseline and 12-months, sST2, GDF-15, galectin-3 were measured. RESULTS: The changes in sST2 were -0.310 (-4.195, 2.075) vs. 1.163 (0.624, 4.715) ng/mL, median (interquartile range) atorvastatin vs. placebo (P = 0.04). The change in sST2 was significantly related to changes in monocyte activation marker sCD14 (r = 0.63, P < 0.0001) and MCP (r = 0.52, P = 0.0009), markers of generalized inflammation hs-IL-6 (r = 0.58, P = 0.0002), oxLDL (r = 0.49, P = 0.002), and GDF-15 (r = 0.54, P = 0.0008). CONCLUSIONS: sST2, a member of the IL-1 receptor family and a marker of fibrosis and inflammation increases over time among patients with HIV and this increase is attenuated by statin therapy in HIV. This effect may relate to immunomodulatory mechanisms of statins.

Inactivated rotavirus vaccine by parenteral administration induces mucosal immunity in mice.

To improve the safety and efficacy of oral rotavirus vaccines, we developed an inactivated rotavirus vaccine (IRV) for parenteral administration. Since it remains unknown whether parenteral vaccination can induce mucosal immunity, we performed a comprehensive assessment of immune responses to IRV in mice with an adjuvant-free dissolving polymer MN patch or by alum-adjuvanted IM injection. We demonstrated that IRV induced the expression of the gut homing receptor LPAM-1 on T and B cells in spleen and mLN of vaccinated mice. MN patch IRV vaccination induced a slight Th1 phenotype while IM vaccination induced a balanced Th1/Th2 phenotype. In addition, a dose-sparing effect was seen for rotavirus-specific serum IgG and neutralizing activity for both vaccination routes. Our study is the first to show that parenterally administered IRV can induce mucosal immunity in the gut, in addition to strong serum antibody response, and is a promising candidate vaccine in achieving global immunization against rotavirus.

Dihydroergotamine mesylate-loaded dissolving microneedle patch made of polyvinylpyrrolidone for management of acute migraine therapy.

Migraine is a widespread neurological disease with negative effects on quality of life and productivity. Moderate to severe acute migraine attacks can be treated with dihydroergotamine mesylate (DHE), an ergot derivative that is especially effective in non-responders to triptan derivatives. To overcome limitations of current DHE formulations in subcutaneous injection and nasal spray such as pain, adverse side effects and poor bioavailability, a new approach is needed for DHE delivery enabling painless self-administration, quick onset of action, and high bioavailability. In this study, we developed a dissolving microneedle patch (MNP) made of polyvinylpyrrolidone, due to its high aqueous solubility and solubility enhancement properties, using a MNP design previously shown to be painless and simple to administer. DHE-loaded MNPs were shown to have a content uniformity of 108±9% with sufficient mechanical strength for insertion to pig skin ex vivo and dissolution within 2min. In vivo pharmacokinetic studies were carried out on hairless rats, and DHE plasma levels were determined by liquid chromatography-tandem mass spectrometry (LC-MS/MS). The area under curve (AUC) value after DHE delivery by MNP (1259±917ng/mL min) was not significantly different (p>0.05) as compared to subcutaneous injection, with a relative bioavailability of 97%. Also, appreciable plasma levels of DHE were seen within 5min for both delivery methods and tmax value of MNPs (38±23min) showed no significant difference (p>0.05) compared to subcutaneous injection (24±13min). These results suggest that DHE-loaded MNPs have promise as an alternative DHE delivery method that can be painlessly self-administered with rapid onset and high bioavailability.