Therapeutics Systems Research Laboratories (United States)

The war in Gaza has triggered an unprecedented humanitarian crisis and severely impacted the healthcare system. It has overwhelmed orthopedic care at Al-Aqsa Martyrs' Hospital, the only public hospital serving the middle region of the Gaza Strip. With over a million displaced individuals and a sharp rise in war-related injuries, the department has been operating under extreme constraints, including shortages of medical supplies, staff, and infrastructure. The orthopedic department, initially small and under-equipped, has rapidly expanded and adapted to handle mass casualties. This has involved restructuring staff shifts, implementing a three-team 24-h rotation system, and repurposing existing facilities to accommodate the influx of patients. Emergency care evolved around a fluidic triage system, and surgical capacity was extremely strained. The repurposed obstetrics and gynecology theaters and delivery rooms became primary operating rooms, with two-thirds of all surgeries being orthopedic-related. Innovative solutions, such as field hospitals and tents for dressing, have helped alleviate some of the pressure. The introduction of the Dressing Under General Anesthesia (DUGA) system has improved wound care for severe injuries. International collaboration, particularly with Médecins Sans Frontières (MSF) and other NGOs, has played a critical role in supplementing medical services and expertise, providing medical and surgical supplies, and facilitating certain procedures. Despite these adaptations, the department remains overwhelmed. Resource limitations have caused delays in essential procedures, leading to complications such as non-union fractures and infections. Additionally, coordination between local and international teams has been challenging, underscoring the need for a more structured response to improve efficiency. The study highlights the adaptation and resilience of the orthopedic department at Al-Aqsa Martyrs' Hospital. It underscores the urgent need for policy reforms to enhance emergency preparedness, expand surgical capacity, and develop a sustainable, resilient healthcare system. Key recommendations include standardizing clinical protocols, strengthening supply chains, and supporting overburdened and burnout medical staff. Addressing these challenges is crucial to sustaining orthopedic care in Gaza's war-torn healthcare system.

Human adenoviruses can cause serious, disseminated infections in immunocompromised patients. For pediatric allogeneic stem cell transplant patients, the case fatality rate can reach 80%. Still, there is no available antiviral drug that is specifically approved by the Food and Drug Administration for the treatment of adenovirus infections. To fill this pressing medical need, we have developed NPP-669, a prodrug of cidofovir with broad activity against double-stranded DNA viruses, including adenoviruses. Here, we report on the in vivo anti-adenoviral efficacy of NPP-669. Using the immunosuppressed Syrian hamster as the model, we show that NPP-669 is highly efficacious when dosed orally at 1 mg/kg and 3 mg/kg. In a delayed administration experiment, NPP-669 was more effective than brincidofovir, a similar compound that reached Phase III clinical trials. Furthermore, parenteral administration of NPP-669 increased its efficacy approximately 10-fold compared to oral dosing without apparent toxicity, suggesting that this route may be preferable in a hospital setting. Based on these findings, we believe that NPP-669 is a promising new compound that needs to be further investigated.

A non‐human primate model of spontaneous hypertension has potential for understanding mechanisms of cardiovascular disease but requires a novel method for telemetric blood pressure measurement. Stellar Telemetry solid‐state pressure sensors were surgically implanted into the abdominal aorta of feral, male monkeys (Chlorocebus aethiops sabaeus). Systolic (SBP), diastolic (DBP) and mean (MBP) arterial pressures, core body temperature and heart rate were determined using different data acquisition parameters to assess system precision and reliability in this physically active non‐human primate. Animals were pre‐phenotyped for normotension (NT) or hypertension (HT) using forearm plethysmography. Various recording parameters yielded consistent blood pressure in NT (MBP=104±4.35 mmHg) and HT (MBP=126±7.57 mmHg) animals. Ultrasonography documented effective placement of sensors within the aorta lumen. Consistent aortic blood pressure recordings were obtained for 6 months post catheter implantation. Necropsy revealed no sensor induced blood or organ pathologies. The Stellar Telemetry system effectively monitors conscious blood pressure, heart rate and body temperature in active primates allowing for physiological assessments during natural social interactions and species specific behaviors. This model of hypertension in an old world, non‐human primate is translational to human essential hypertension and allows for new directions in a genetically similar species.Supported by Biomedical Sciences Research Group, LLC; TSE Systems, Inc.; Behavioural Sciences Foundation

The purpose of this study was to improve the membrane permeability and oral absorption of the poorly permeable anti-influenza agent, zanamivir. The poor oral bioavailability is attributed to the high polarity (cLogP ∼ -5) resulting from the polar and zwitterionic nature of zanamivir. In order to improve the permeability of zanamivir, prodrugs with amino acids were developed to target the intestinal membrane transporter, hPepT1. Several acyloxy ester prodrugs of zanamivir conjugated with amino acids were synthesized and characterized. The prodrugs were evaluated for their chemical stability in buffers at various pHs and for their transport and tissue activation by enzymes. The acyloxy ester prodrugs of zanamivir were shown to competitively inhibit [(3)H]Gly-Sar uptake in Caco-2 cells (IC(50): 1.19 ± 0.33 mM for L-valyl prodrug of zanamivir). The L-valyl prodrug of zanamivir exhibited ∼3-fold higher uptake in transfected HeLa/hPepT1 cells compared to wild type HeLa cells, suggesting, at least in part, carrier mediated transport by the hPepT1 transporter. Further, enhanced transcellular permeability of prodrugs across Caco-2 monolayer compared to the parent drug (P(app) = 2.24 × 10(-6) ± 1.33 × 10(-7) cm/s for L-valyl prodrug of zanamivir), with only parent zanamivir appearing in the receiver compartment, indicates that the prodrugs exhibited both enhanced transport and activation in intestinal mucosal cells. Most significantly, several of these prodrugs exhibited high intestinal jejunal membrane permeability, similar to metoprolol, in the in situ rat intestinal perfusion system, a system highly correlated with human jejunal permeability. In summary, this mechanistic targeted prodrug strategy, to enhance oral absorption via intestinal membrane carriers such as hPepT1, followed by activation to parent drug (active pharmaceutical ingredient or API) in the mucosal cell, significantly improves the intestinal epithelial cell permeability of zanamivir and has the potential to provide the high oral bioavailability necessary for oral zanamivir therapy.

While monitoring multiple conversations, a listener often needs to know not only what was said but who said what to whom. An exploratory investigation into these questions involved eight talkers saying similar, simultaneous messages. Four male and four female talkers speaking call sign phrases and logical phrases were digitally recorded. All phrases were adjusted in overall gain to have the same average power and onset time. Between one and seven competing messages were played back over loudspeakers in an anechoic chamber. Thereby, angular separation between the speech signal and speech babble was also a controlled factor. Physical attributes of the eight talkers’ speech were analyzed using the Multi-Dimensional Voice Program from Kay Elemetrics. Nineteen acoustic attributes of the talkers’ voice samples were quantified. Voice samples were analyzed during sustained phonation and continuous speech conditions. A correlational analysis was used to investigate which aspects of the talkers’ speech facilitate detection and intelligibility against a cacophony of competing voices. The salient features of the eight talkers’ voice samples will be discussed.

Abstract This paper describes a joint industry project to develop an electrically powered bottom hole assembly for use in coiled tubing drilling (CTD) applications. Phase I of the project, recently completed in Aberdeen, produced a highly successful prototype assembly that recorded over 190 hours of drilling time without failure. Whilst the prototype was made almost entirely from existing technology, the success of the test has generated confidence to develop a more fit for purpose' motor. A system overview explains the concept behind, and the advantages of, electric coiled tubing drilling (ECTD). The bottom hole assembly is described in detail, along with various surface components and the electrical power transmission system. The testing program and operational procedures are outlined, together with some of the key results. The development plan for the technology is reviewed to highlight the ultimate goal of producing a smart' drilling system. It is envisaged that, based upon feedback from near-bit sensors, such a system would be able to automatically adjust certain parameters to optimize drilling performance. The paper concludes that electric coiled tubing is a feasible and practical alternative to conventional CTD, although there are certain technological barriers that must be overcome. P. 61