Nebulised delivery of RNA formulations to the lungs: From aerosol to cytosol.

In the past decade RNA-based therapies such as small interfering RNA (siRNA) and messenger RNA (mRNA) have emerged as new and ground-breaking therapeutic agents for the treatment and prevention of many conditions from viral infection to cancer. Most clinically approved RNA therapies are parenterally administered which impacts patient compliance and adds to healthcare costs. Pulmonary administration via inhalation is a non-invasive means to deliver RNA and offers an attractive alternative to injection. Nebulisation is a particularly appealing method due to the capacity to deliver large RNA doses during tidal breathing. In this review, we discuss the unique physiological barriers presented by the lung to efficient nebulised RNA delivery and approaches adopted to circumvent this problem. Additionally, the different types of nebulisers are evaluated from the perspective of their suitability for RNA delivery. Furthermore, we discuss recent preclinical studies involving nebulisation of RNA and analysis in in vitro and in vivo settings. Several studies have also demonstrated the importance of an effective delivery vector in RNA nebulisation therefore we assess the variety of lipid, polymeric and hybrid-based delivery systems utilised to date. We also consider the outlook for nebulised RNA medicinal products and the hurdles which must be overcome for successful clinical translation. In summary, nebulised RNA delivery has demonstrated promising potential for the treatment of several lung-related conditions such as asthma, COPD and cystic fibrosis, to which the mode of delivery is of crucial importance for clinical success.

Traumatic Wounds of the Foot and Ankle: The Landstuhl Regional Medical Center Experience and Historical Perspectives.

As this is more of a reference article, I chose not to have an abstract similar to the paper I wrote in 2016 regarding flat feet in the military.

Shared Care to Destination Therapy Left Ventricular Assist Device Site: a Novel Strategy to Start a Successful Mechanical Circulatory Support Program.

PURPOSE OF REVIEW: Heart failure is an important healthcare issue because of its high prevalence, mortality, and morbidity. Advanced heart failure therapies have improved significantly over the years with improved outcomes. Heart transplantation remains an elusive treatment option for most patients; hence, the need for alternative therapy has given rise to the use of mechanical circulatory support (MCS) devices, initially as bridge to transplantation, but with more recent use as destination therapy. This review focuses on the intricacies of establishing a successful left ventricular assist device (LVAD) program for destination therapy in the setting of a growing anticipated need for wider availability of such treatment options. RECENT FINDINGS: Guidelines have established the role of MCS in patients with advanced HF refractory to optimal guideline-directed medical therapy (GDMT) and cardiac device interventions. Multiple studies have shown generational improvement in the overall safety profile of MCS devices with the use of newer devices for destination therapy showing improved outcomes. Heart failure is a growing cardiovascular problem with an anticipated growing need for advanced HF therapies including MCS devices. A model of shared care LVAD to destination therapy implanting site should be considered as a strategy to start a successful LVAD program.

Cavopulmonary assist: Long-term reversal of the Fontan paradox.

OBJECTIVE: Fontan circulatory inefficiency can be addressed by replacing the missing subpulmonary power source to reverse the Fontan paradox. An implantable cavopulmonary assist device is described that will simultaneously reduce systemic venous pressure and increase pulmonary arterial pressure, improving preload and cardiac output, in a univentricular Fontan circulation on a long-term basis. METHODS: A rotary blood pump that was based on the von Karman viscous pump was designed for implantation into the total cavopulmonary connection (TCPC). It will impart modest pressure energy to augment Fontan flow without risk of obstruction. In the event of rotational failure, it is designed to default to a passive flow diverter. Pressure-flow performance was characterized in vitro in a Fontan mock circulatory loop with blood analog. RESULTS: The pump performed through the fully specified operating range, augmenting flow in all 4 directions of the TCPC. Pressure rise of 6 to 8 mm Hg was readily achieved, ranging to 14 mm Hg at highest speed (5600 rpm). Performance was consistent across a wide range of cardiac outputs. In stalled condition (0 rpm), there was no discernible pressure loss across the TCPC. CONCLUSIONS: A blood pump technology is described that can reverse the Fontan paradox and may permit a surgical strategy of long-term biventricular maintenance of a univentricular Fontan circulation. The technology is intended for Fontan failure in which right-sided circulatory inefficiencies predominate and ventricular systolic function is preserved. It may also apply before clinical Fontan failure as health maintenance to preempt the progression of Fontan disease.

Association Between Running Shoe Characteristics and Lower Extremity Injuries in United States Military Academy Cadets.

BACKGROUND: Running-related overuse injuries are very common among recreational runners, with the reported annual injury rates ranging from 39% to 85%. Relatively few large prospective cohort studies have been conducted to investigate injury risk associated with different running shoe characteristics, and the results of the existing studies are often contradictory. PURPOSE/HYPOTHESIS: The purpose was to investigate the relationship between running shoe characteristics and lower extremity musculoskeletal injury. It was hypothesized that the risk of injury would be increased in individuals wearing shoes with minimal torsional stiffness and heel height compared with those wearing shoes with greater levels of torsional stiffness and heel height. STUDY DESIGN: Cohort study; Level of evidence, 2. METHODS: The study included 1025 incoming cadets. Shoe torsional stiffness and heel height were calculated and recorded. Demographic data were recorded and analyzed as potential covariates. Lower extremity injuries sustained over 9 weeks during cadet basic training were documented by use of the Armed Forces Health Longitudinal Technology Application and the Cadet Illness and Injury Tracking System. Kaplan-Meier survival curves were estimated, with time to incident lower extremity injury as the primary outcome by level of the independent predictor variables. Risk factors or potential covariates were carried forward into multivariable Cox proportional hazards regression models. Absolute and relative risk reduction and numbers needed to treat were calculated. RESULTS: Approximately 18.1% of participants incurred a lower extremity injury. Cadets wearing shoes with moderate lateral torsional stiffness were 49% less likely to incur any type of lower extremity injury and 52% less likely to incur an overuse lower extremity injury than cadets wearing shoes with minimal lateral torsional stiffness, both of which were statistically significant observations. Injury risk was similar among cadets wearing shoes with minimal and extreme lateral torsional stiffness. CONCLUSION: Shoes with mild to moderate lateral torsional stiffness may be appropriate in reducing risk of lower extremity injury in cadets. Shoes with minimal lateral torsional stiffness should be discouraged in this population.

The relationship between foot arch flexibility and medial-lateral ground reaction force distribution.

BACKGROUND: Overuse running injury susceptibility has previously been associated with the magnitude and slope of ground reaction force profiles, most often in the vertical axis. However, despite the implications of excessive pronation and supination on injury susceptibility, very little research has examined the factors that might affect distribution of force in the medial-lateral directions. RESEARCH QUESTION: The purpose of this study was to consider how foot structure, specifically arch flexibility, affects the distribution of ground reaction force between the medial-lateral and vertical planes of motion. METHODS: Twenty-five participants were classified as having stiff or flexible arches, and three dimensional kinetic data were gathered while the volunteers ran at 7 mph on an instrumented treadmill. A mixed-effects ANOVA was used to analyze the effect of arch flexibility type on distribution of ground reaction force impulse in the medial and lateral directions. RESULTS: The results suggest that individuals with relatively stiff arches experience a greater proportion of ground reaction force in the medial-lateral plane of motion, as compared with those with more flexible arches (p = 0.03). Further, the results suggest that most individuals, regardless of foot structure, experience greater impulse of force in the lateral than in the medial direction (p < 0.01). SIGNIFICANCE: Considering previously explored relationships between ground reaction force, foot pronation/supination, and chronic running injuries, the results of this study suggest that arch flexibility could be used as a criterion for assessing injury susceptibility. Further, conclusions drawn from this study add to the discussion on the pros and cons of training or using devices to increase or restrict arch flexibility while running.

Comprehensive biomechanical characterization of feet in USMA cadets: Comparison across race, gender, arch flexibility, and foot types.

Lower extremity musculoskeletal injuries are common, complex, and costly problems. Literature supports associations between static foot structure and dynamic foot function, as well as between overuse injury and demographic characteristics. Previous studies failed to provide a comprehensive biomechanical foot characteristics of at-risk military personnel. In this study, foot structure, function, and arch height flexibility (AHF) were objectively measured in 1090 incoming cadets (16.3% female, mean age of 18.5years and BMI of 24.5kg/m2) of the United States Military Academy at the start of their training. A Generalized Linear Model with an identity link function was used to examine the effects of race, gender, foot types, and AHF while accounting for potential dependence in bilateral data. Planus and flexible feet independently demonstrated over-pronation, as measured by reduced Center of Pressure Excursion Index (CPEI). When comparing across race, Black participants showed a significantly lower arch height index (AHI), a larger malleolar valgus index (MVI), and a higher prevalence of pes planus (91.7% versus 73.3% overall). However, Asian participants with flexible arches, rather than Black with low arch, displayed over-pronation in gait. Females showed no significant difference in standing AHI and MVI but demonstrated a significantly greater AHF and a reduced CPEI than male participants. This was the first large scale investigation that comprehensively characterized biomechanical foot in a cohort of young at-risk individuals with lower limb musculoskeletal injuries. Long-term goal is to examine the relationship between these biomechanical features and injuries, ultimately to develop effective preventive measures.

The Relationship Between Arch Height and Arch FlexibilityA Proposed Arch Flexibility Classification System for the Description of Multidimensional Foot Structure.

BACKGROUND: The correlation between arch structure and injury may be related to the fact that foot structure influences foot function. Foot structure is often defined by arch height, although arch flexibility may be just as important to form a more complete description. We propose an arch flexibility classification system, analogous to arch height classification, and then use the classification system to examine the relationship between arch flexibility and arch height. METHODS: Arch height index was calculated in 1,124 incoming military cadets, of whom 1,056 had usable data. By measuring arch height during both sitting and standing, a measurement of arch flexibility could also be calculated. These values were used to create five arch flexibility categories: very stiff, stiff, neutral, flexible, and very flexible. The distribution of arch flexibility types among arch height categories was statistically compared. RESULTS: The goodness of fit test showed a disproportionate number of each arch flexibility type in each of the arch height categories (P < .01). The largest proportion of cavus feet was very stiff and the smallest proportion was very flexible. Conversely, the largest proportion of planus feet was very flexible and the smallest proportion was very stiff. CONCLUSIONS: The results of this research support the common belief that cavus feet tend to be very stiff and planus feet tend to be very flexible.

Operation Iraqi Freedom: the Landstuhl Regional Medical Center experience.

Landstuhl Regional Medical Center, Germany, the only American medical center in Europe, received approximately 80% of American military patients evacuated out of theater during the first 4 months of Operation Iraqi Freedom. 1236 patients arrived at Landstuhl Regional Medical Center from the beginning of Operation Iraqi Freedom until May 15, 2003, consisting of 256 battle casualties (20.7%), 510 injury patients (41.3%), and 470 disease patients (38.0%). Retrospective record reviews were done on all battle casualties, as well as all disease and injury patients with a musculoskeletal diagnosis. Of the battle casualty patients, 68.4% suffered an extremity injury--a percentage that is consistent with that from prior wars. 52.8% had a lower extremity injury and 21.5% had a foot or ankle injury. Additionally, of all disease and non-battle injury patients with a musculoskeletal diagnosis, 74.7% had an extremity complaint, 44.1% had a lower extremity diagnosis, and 23.2% had foot or ankle pathology. Of all 1236 patients evacuated during this period, 39.5% had extremity pathology, 25.8% had lower extremity pathology, and 12.4% had foot and ankle pathology in isolation or combined with other complaints. Extremity injuries, and specifically lower extremity injuries, continue to be the predominant wounding pattern found in surviving troops in modern warfare. Proper staffing and positioning of medical specialties involved in musculoskeletal trauma care is vital in ensuring proper casualty care in future conflicts.