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HP 029 (1,2,3,4-tetrahydro-9-aminoacridin-1-ol-maleate) is a cholinesterase inhibitor and one of a series of compounds synthesized at Hoechst-Roussel Pharmaceuticals Inc. (HRPI) as a potential therapeutic agent for senile dementia of the Alzheimer type (SDAT). An ongoing clinical development program for HP 029 (velnacrine maleate) reflects a rational, traditional progression from therapeutic concept through clinical evaluation. Prior to the initiation of outpatient studies, sufficient data had been obtained from normal volunteers and hospitalized patients to support the following conclusions: the pharmacokinetic profile of HP 029 in young and elderly normal men is predictable; tolerance and safety data for HP 029 using normal volunteers poorly correlates with experience in patients with SDAT; patients with SDAT exhibit marked intersubject variability in tolerance within a suspected therapeutic dose range; mandatory endpoints for drug discontinuation for outpatients can be reliably established in an inpatient environment. Subsequently, Protocol 201 was initiated as a multicenter, multistage investigation of HP 029 in patients with probable SDAT (NINCDS-ADRDA criteria). A dose-ranging component determined patient eligibility for a subsequent dose-replication phase based upon explicit safety and efficacy criteria defined within protocol. One a priori specified interim analysis was conducted by the sponsor (HRPI) for administrative purposes after completing approximately 50% of the planned sample (September 1989). Results suggested that (1) beneficial effects of HP 029 existed on key and secondary measures for the approximately 30% of enrolled patients; (2) interim results would provide an accurate reflection of the results at the conclusion of the study (1991); (3) HP 029-induced hepatocellular injury appeared to be a reversible, predominantly dose-related event; and (4) cholinergically mediated adverse events are infrequent and clinically inconsequential at dosages less than or equal to 225 mg/day. Post hoc hypotheses based on the interim dataset suggest that: (1) carry-over effects of HP 029 exist within a dose-ranging/dose-replication paradigm that militate against the utility of an "enriched population" design; (2) beneficial effects are more robust on initial exposure to HP 029 with effects discerned on both memory and arousal; (3) patient characteristics associated with toxicity or response are not identified; (4) dosage reduction in subsequent efficacy trials may reduce hepatocellular injury and yield clinically unimportant differences in overall efficacy results.

Introduction High levels of aerobic exercise in individuals who have a gene mutation associated with arrhythmogenic right ventricular cardiomyopathy (ARVC) are associated with clinical disease progression. Guidelines consequently restrict patients from competitive athletics. However, there is minimal literature to guide the safe dosing of physical activity outside of the setting of competitive athletics. Patients may be physically active pursuant to a variety of careers, including military service. This study aimed to define a therapeutic window for exercise for ARVC gene-positive individuals that are compatible with continuing military service and general health while maintaining a level of exercise below that which risks disease progression. Materials and Methods Using standard metabolic equations, we calculated the minimum VO2 max (amount of oxygen utilized at peak exercise capacity) required to pass the physical fitness tests for each branch. We then developed a sample exercise prescription to maintain this level of fitness. We compared the prescribed exercise load with the physical activity levels associated with non-inferior clinical outcomes in ARVC gene-positive individuals. Additionally, we determined the physical activity exposure sustained by service members based on self-report data and compared these values with the upper limit of safe exercise exposure. Results Based on a review of the currently available literature, aerobic exercise exposure less than 700 to 1,100 MET-hours/year (metabolic equivalent-hours per year) is not associated with inferior clinical outcomes for gene-positive individuals. A military service member needs 600 to 700 MET-hours/year to minimally pass the physical fitness test. However, many military members are exercising in excess of this minimum, with typical exposures between 900 and 2,400 MET-hours/year. Conclusions A therapeutic window of aerobic exercise may exist for ARVC gene-positive individuals which would allow continuation of military service while maintaining levels of exercise restriction associated with non-inferior clinical outcomes.

Introduction While deployed, military medical personnel manage routine medical issues that fall under the category of Disease Non-Battle Injury (DNBI). The 86th Combat Support Hospital (CSH) partnered with Combined Joint Task Force-Operation Inherent Resolve (CJTF-OIR) Surgeon Cell, and Special Operations Joint Task Force-Operation Inherent Resolve (SOJTF-OIR) Surgeon Cell, to introduce the Health Experts onLine Portal (HELP) telemedicine system to medical personnel in Iraq and Syria. HELP is an asynchronous (store and forward) online system that provides secure provider-to-provider teleconsultation services for routine patient care and medical evacuation (MEDEVAC) coordination. The goal was to reduce the need for MEDEVAC by providing expert consultation to medical providers in farther-forward deployed units. Material and Methods In June 2017, the 86th CSH launched HELP telemedicine services for Kuwait. Following the successful implementation of the telemedicine system in Kuwait, the 86th CSH leadership partnered with CJTF-OIR and SOJTF-OIR medical leadership in launching the system within Iraq and Syria as well as making the system available to all deployed locations in Central Command (CENTCOM). This was a prospective cohort study designed to determine if having convenient and secure access to remote subspecialty consultation would be associated with a reduction in routine MEDEVACs from far forward in the battle space. In August 2017, new-user training was completed and the program launched in Iraq and Syria. This study analyzes the baseline MEDEVAC rate in 3 months before the implementation of HELP telemedicine compared to 3 months following the implementation. Results Iraq and Syria cases in the HELP telemedicine system accounted for 17.2% (76) of total CENTCOM telemedicine case volume over the 7-month study period. Comparing the 3-month period before and after implementation of HELP, use of asynchronous telemedicine in Iraq and Syria was associated with a reduction in total MEDEVACs from 157 to 68 (56.7% reduction, p < 0.001). DNBI represented the majority of the change, (65.0% reduction, p < 0.001). MEDEVAC for battle-related injuries decreased slightly from 13 to 6 per 3-month period (p = 0.03). Conclusions This is the first prospective study to demonstrate an association between the initiation of asynchronous telemedicine capabilities in a combat zone and decreased MEDEVACs. Annualized numbers would predict a reduction of 328 MEDEVACs/year for each 10,000 personnel by utilizing asynchronous telemedicine. This represents a significant potential cost savings of $1.2 million/year through avoidance of routine medical movement of personnel and supports unit readiness by retaining service members in areas of combat operations.

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