Synthesis and In vitro Efficacy of Tetracyclic Benzothiazepines Against Blood-Stage Plasmodium falciparum and Liver-Stage P. berghei.

OBJECTIVE: A series of novel, substituted tetracyclic benzothiazepines were designed and prepared in an effort to optimize the potency of this chemical class against drug-resistant strains of the malaria parasite. METHODS: Tetracyclic benzothiazepines bearing structural modification at seven distinct positions within the structure were synthesized in Knoevenagel condensation reactions followed by sequential intermolecular thio-Michael and then intramolecular imine formation reactions. Following purification and chemical characterization, the novel compounds were tested for in vitro efficacy against blood-stage P. falciparum and liver-stage P. berghei and also for in vivo efficacy against P. berghei. RESULTS: Benzothiazepines bearing structural modification at the sulfur atom and at the three carbocycles within the molecule were successfully synthesized. The majority of analogs inhibited bloodstage P. falciparum with submicromolar IC50 values. The potency of an 8-methoxy-substituted analog 12 exceeded that of chloroquine in all three P. falciparum strains tested. The parent benzothiazepine 1 possessed liver-stage activity, inhibiting P. berghei sporozoites infecting HepG2 cells with an IC50 of 106.4 nM and an IC90 of 408.9 nM, but failed to enhance the longevity of P. berghei infected mice compared to the controls. Compounds displayed modest toxicity toward HepG2 cells and were tolerated by mice at the highest dose tested, 640 mg/kg/dose once daily for three days. CONCLUSION: The tetracyclic benzothiazepine described, which inhibits P. berghei infected hepatic cells with an IC50 of 106.4 nM, would appear to warrant further investigation. Optimization of ADME properties may be required since the most active analogs are probably excessively lipophilic.

An Analysis of Essential Pediatric Surgical Cases Encountered During a Decade of Large-Scale Military Humanitarian Aid Missions.

INTRODUCTION: Disease Control Priorities, 3rd Edition (DCP3) is an evidence-based, published resource that outlines essential procedures recommended for developing health care systems. These systems must consider various populations and the incidence of certain surgical conditions that require treatment. In relation to pediatric patients, the prevalence of certain surgical conditions encountered remains unclear in several low- and middle-income countries. Over the past 15 years, the USNS Mercy, one of the U.S. Navy's large hospital ships, has led the Pacific Partnership missions, which provide large-scale humanitarian aid throughout Southeast Asia. The data collected during these missions provide an opportunity to analyze the scope of pediatric operations performed in resource-limited countries. This analysis may assist in future planning for specific needs during military humanitarian missions. MATERIALS AND METHODS: Surgical case data were prospectively collected during the six Pacific Partnership missions from 2006 to 2018. Demographic data were analyzed for all patients ≤8 years of age who underwent an operation. These data were retrospectively reviewed and all case logs were categorized by mission year, procedure-type, and host nation. Operations were classified based on 44 essential operations delineated in DCP3. Primary outcome was incidence of DCP3 essential operations. Secondary outcomes were perioperative complications. Standard statistical methods were performed for descriptive analysis. RESULTS: A total of 3,209 major and minor operations were performed during 24 port visits in nine countries. Pediatric cases represented 1,117 (38%) of these procedures. Pediatric surgeons performed 291 (26%) of these cases. Based on DCP3 criteria, 789 pediatric operations (71%) were considered essential procedures. The most common DCP3-aligned procedures were cleft lip repair (432, 57%), hernia repair (207, 27%), and hydrocelectomy (60, 8%). Operative volume for pediatric surgery was highest during the 2008 mission (522 cases), when two pediatric surgeons were deployed, and lowest during the 2018 mission (five cases), when the mission focus was on education rather than surgical procedures and lack of pediatric cases referred by the host nation. Overall complication rate for pediatric cases was 1%. CONCLUSIONS: This study represents the largest known analysis of military humanitarian assistance. Pediatric operations represented over one-third of the surgical volume during Pacific Partnership missions from 2006 to 2018. The majority of cases were DCP3-aligned and associated with a low complication rate. Future humanitarian aid missions and host nations should allocate appropriate medical and educational resources to treat DCP3 pediatric surgical diseases in low- and middle-income countries to support long-term capacity building while maintaining optimal surgical outcomes.

The History of Surgical Staplers: A Combination of Hungarian, Russian, and American Innovation.

Since their development in 1908, surgical staplers have been used as a method of "mechanical suturing" in efforts to divide hollow viscera and create anastomoses in an efficient and sterile manner. The concept for the surgical stapler was first developed by Humér Hultl, a Hungarian professor and surgeon, and designed by Victor Fischer, a Hungarian businessman and designer of surgical instruments. The design was highly acclaimed; however, it was bulky, cumbersome, and expensive to manufacture. In 1920, Aladár Petz, a student of Hultl, incorporated two innovations to the Fischer-Hultl stapler to create a more lightweight model, which was named the Petz clamp. In 1934, Friedrich of Ulm designed what would be the predecessor to the modern-day linear stapler. In the 1950s, Russian and American staplers began to emerge. Throughout the 1960s, a variety of stapling instruments were developed in the United States, manufactured by the United States Surgical Corporation. In the 1970s, Johnson & Johnson Ethicon brand joined the market. The United States Surgical Corporation was later bought by Tyco Healthcare and became Covidien in 2007. Through the collaboration of Felicien Steichen, Mark Ravitch, and Leon Hirsch, surgical staplers were further modified to incorporate interchangeable cartridges with various designs. With the advent of minimally invasive surgery began production of laparoscopic surgical staplers. Since its inception, the surgical stapler has provided a means to efficiently create safe and effective visceral and vascular anastomoses. The surgical stapler design continues to evolve while still maintaining the basic principles that were implemented in the original design.

Pilot Study: The Role of Predeployment Ethics Training, Professional Ethics, and Religious Values on Naval Physicians' Ethical Decision Making.

Military physicians serving overseas in cross-cultural settings face the challenge of meeting patients' needs and adhering to their personal and professional ethics while abiding by military obligations and duties. Predeployment ethics training for Naval physicians continues to be received in many forms, if received at all, and has largely not addressed their specific roles as medical providers in the military. This study explores the perceived effectiveness of predeployment ethics training received by Naval physicians. Additionally, it considers the contribution of different types of ethics training, religious values, and the professional ethics on Naval physicians' perceived ability to effectively manage ethically challenging scenarios while on deployment. A total of 49 Naval physicians participated in an online survey. 16.3% reported not receiving any form of ethics training before deployment. Of those that reported receiving ethics training before deployment, 92.7% found the ethics training received was helpful in some way while on deployment. While a medical school course was most contributory overall to their ability to handle ethically difficult situations while on deployment (70.7%), what most Naval physicians felt would help them better handle these types of situations would be a mandatory military training/military course (63.2%) or personal mentorship (57.9%).