Degradation of Obidoxime Chloride Solution for Injection upon Long-Term Storage under Field Conditions of Mediterranean Climate vs the Controlled Environment.

Obidoxime chloride is an antidote for nerve gas intoxication. As an emergency medicine, it is being stored by the Israel Defense Forces (IDF) scattered throughout Israel in depots without a controlled environment (field conditions), thus being exposed to high and fluctuating temperatures. These conditions do not meet the manufacturer's requirements. In addition, due to possible supply shortages, the utilization of expired batches was suggested. The current work investigated these matters. Long-term (15 years) storage under different conditions was initiated. Chemical stability and toxicity in rats were assessed. No difference was found between field conditions vs the controlled environment. The obidoxime assay remained >95% for 5 years and >90% for 7 years. The pH remained above the lower specification limit for 7-8 years. The major degradation product, 4-pyridinealdoxime, surpassed the allowed limit at 5 years. The content of total unknown impurities reached its maximum allowed by the IDF limit at 4-5 years. Threefold higher than clinically utilized doses of valid-to-date Toxogonin batches administered to rats did not cause any abnormality. However, expired batches produced significant toxic effects. Although no difference was found between storage of obidoxime ampoules when adhering to manufacturer's recommendations vs field conditions, accumulation of degradants over the limit allowed by the IDF at 4-5 years of storage and the toxicity of the expired batches observed in rats led the IDF to a decision to shorten the shelf-life of this product from 5 to 4 years when stored in an uncontrolled environment of the Mediterranean climate.

Efficacy and safety of antiviral treatments for symptomatic COVID-19 outpatients: Systematic review and network meta-analysis.

BACKGROUND: Remdesivir, molnupiravir, and nirmatrelvir/ritonavir are three antiviral agents approved by FDA emergency authorization for treating mild to moderate symptomatic COVID-19 adult outpatients at high risk for hospitalization and death. OBJECTIVES: To compare the efficacy and safety of these antivirals based on updated published RCT and real-world data. STUDY DESIGN: This systematic review followed the preferred reporting items for systematic reviews and meta-analysis framework guidelines. We searched all publications up to January 2023. RRs and 95% CIs for death, hospitalization, and adverse events were calculated. RESULTS: Six RCTs and seven cohort studies were included, with 1,456,523 participants, of whom 50,979 were treated with antivirals. Remdesivir was associated with the lowest probability of hospitalization and death compared to nirmatrelvir/ritonavir and molnupiravir (P-scores 0.99 and 0.90, respectively, for remdesivir, 0.64 and 0.55, respectively for nirmatrelvir/ritonavir, and 0.26 and 0.49, respectively for molnupiravir). Based on indirect comparisons, remdesivir was associated with a statistically significant decreased risk for hospitalization compared to molnupiravir (RR 0.09; 95% CI 0.02-0.40) and to nirmatrelvir/ritonavir (RR 0.11; 95% CI 0.03-0.73). No statistically significant difference was found between antivirals in the mortality risk reduction and the risk for side effects. CONCLUSIONS: This is the most comprehensive network meta-analysis integrating RCTs and real-world data. In our indirect comparison, remdesivir was associated with the highest efficacy in preventing hospitalization among high risk symptomatic COVID-19 outpatients, compared to nirmatrelvir/ritonavir and molnupiravir. This finding supports current guidelines, and may have importance when deciding which antiviral to use, together with other important factors.

Are intelligent people more likely to get vaccinated? The association between COVID-19 vaccine adherence and cognitive profiles.

INTRODUCTION: Since vaccination adherence is crucial in reducing morbidity and mortality during a pandemic, we characterized the association between demographic, intelligence, and personal attributes and COVID-19 vaccination adherence among young adults. METHODS: Cohort study including vaccination data of 185,061 personnel, collected during 13 months of COVID-19 vaccination campaign, while a wide array of vaccination incentives were offered. The effect of demographic data (age, gender and socioeconomic status), military medical fitness - fit for combat service, administrative service, or unfit (volunteering), general intelligence score (GIS) and military social score (MSS) assessing social abilities, on vaccine adherence (allocating by IMOH guidelines) was examined. RESULTS: Adherent (vs. nonadherent) personnel presented higher GIS (mean 5.68 ± 1.84 vs. 4.72 ± 1.91) and MSS (median 26 (IQR 23-29) vs. 24 (IQR 19-26)), p < 0.001 for both. Higher intelligence was the strongest predictor for vaccine adherence (OR = 5.38, 95 %CI 5.11-5.67, p < 0.001). The probability for vaccine adherence increased in association with escalating GIS scores, with highest GIS females more likely to adhere to vaccination than same-level males (OR = 5.66, 95 %CI 5.09-6.28 vs. OR = 3.69, 95 %CI 3.45-3.94, respectively, p < 0.001 for both). Medically fit service-members were approximately three times as likely to be adherent than volunteering personnel (OR = 2.90 (95 %CI 2.65-3.17) for administrative and OR = 2.94 (95 %CI 2.70-3.21) for combative fitness, p < 0.001 for both). CONCLUSIONS: During a COVID-19 vaccination campaign, addressing vaccine hesitancy contributing factors and providing wide vaccine availability, GIS and physical fitness had the strongest association with vaccination adherence among young adults. When planning future vaccination campaigns, implementing these insights should be considered to improve adherence.

Sub-cutaneous Pfizer/BioNTech COVID-19 vaccine administration results in seroconversion among young adults.

Route of vaccine administration plays a role in extent and quality of immunogenicity. 790 military personnel accidentally received the first of two doses of Pfizer/BioNTech mRNA anti Covid-19 vaccine using a needle intended for subcutaneous administration. A serological blood test (on day 21, prior to the second intramuscular dose) was performed, analyzing whether immunological response was elicited. 98.2% demonstrated seroconversion. IgG titers were negatively correlated with age and did not correlate with BMI. Our results could help reassure providers confronted with a similar mistake and may even imply a possibly new and effective administration route.

Post-expiry stability of freeze-dried plasma under field conditions - Can shelf life be extended?

BACKGROUND: This prospective study evaluated the effect of routine, uncontrolled, Israeli field storage conditions on the safety and efficacy of Lyo-Plas N Freeze-Dried Plasma (FDP) at the end of the manufacturer's shelf life, and up to 24 months post expiry. Clotting factors V, VIII and XI, proteins S, C, fibrinogen, PTT, ATIII, VWF, and INR as well as TEG, DDM, residual moisture, pH, and sterility of FDP returned from field units after uncontrolled storage were evaluated. STUDY DESIGN AND METHODS: Parameters measured at the end of manufacturer shelf life, as well as 6, 12, 18, and 24 months after expiry, were compared to those of freshly supplied FDP doses. RESULTS: Changes were found when comparing freshly supplied FDP to all field-stored groups in INR, PT, PTT, pH, fibrinogen, and factor VIII. A significant change was also seen in Factor XI in the 12, 18, and 24 months post-expiry samples, Factor V and R in the 24 months post-expiry samples, MA in the 12, 24 months post-expiry group, and Protein C in the 18 months post-expiry group. An increase in the residual moisture from 0.90% in freshly supplied FDP to 1.35% in 24 months post-expiry FDP.; all p < .05. No growth was found in sterility analysis. CONCLUSION: Despite uncontrolled field storage conditions, the findings demonstrate that the safety and efficacy of FDP units, stored in uncontrolled conditions are only slightly affected, even beyond their expiration date. This information allows consideration of possibly extending the shelf life.

Stability of Diazepam Solution for Injection Following Long-Term Storage in an Ambient Temperature of the Mediterranean Climate.

PURPOSE: Diazepam is utilized as a convulsion antidote following nerve gas attacks. As an emergency medicine, it requires storage at ambient temperatures which often doesn't meet manufacturers' requirements, leading to an early invalidation of the product. Current work investigated this issue. METHODS: Long-term stability of diazepam ampoules for injection stored in an ambient temperature of the Mediterranean climate for ~10 years vs storage at room temperature was studied. RESULTS: Diazepam assay and pH remained within pharmacopeial specifications irrespective of storage conditions. A major degradation product 2-methylamino-5-chlorobenzophenone (MACB) showed a clear trend of accumulation as a function of storage time, exceeding the permitted limit at ~2 years, irrespective of storage conditions. A strong correlation between the discoloration of the solutions and the concentration of MACB was obtained. Intravenous administration of MACB to rats at doses ~2200-fold higher than permissible specification levels caused neither mortality nor any toxicological nor post-mortem findings. CONCLUSIONS: Regarding the parameters tested: diazepam assay, MACB assay, and pH, storing ampoules of diazepam solution for injection in field conditions of high temperatures of the Mediterranean climate did not cause accelerated degradation as compared to room temperature. These findings open an option for the usage of expired ampoules in special scenarios.

Freeze-dried plasma stability under prehospital field conditions.

BACKGROUND: This study evaluated the effect of routine, uncontrolled, Israeli field storage conditions on the stability and efficacy of Lyo-Plas N freeze-dried plasma (FDP). We evaluated clotting factors V, VIII, and XI; proteins S and C; fibrinogen; partial thromboplastin time (PTT); antithrombin III (ATIII); von Willebrand factor (VWF); and international normalized ratio (INR) in FDP stored at 4°C, 25°C, and 40°C for 6 and 12 months, as well as FDP returned from field units after uncontrolled storage for 15 months (manufacturer's shelf life). METHODS AND MATERIALS: After reconstitution, clotting factor levels were compared to those of freshly supplied FDP doses. RESULTS: At 4°C for 12 months, factor V decreased slightly. At 25°C, average fibrinogen and factor V content were significantly lower at both periods, and INR was higher after 12 months. At 40°C, all samples were out of normal range in at least one clotting factor after 6 or 12 months. After field storage for 15 months, fibrinogen, factors V and XI, PTT, and protein S were significantly decreased, and INR increased. However, these levels were still within laboratory norms. Statistically significant difference in clotting factors compared to laboratory normal range was found in INR (higher) and factor V (lower). CONCLUSIONS: Our data show minimal decreases in clotting factors in FDP after storage under field conditions, when compared to laboratory normal ranges. Along with the many advantages of FDP, this supports its use at the point of injury under battlefield conditions, despite uncontrolled storage environments. Under controlled storage conditions at 4°C, shelf life could possibly be extended, although further study is required.

The Impact of Adherence to Treatment for ADHD on the Quality of Military Service - The Israeli Military Experience.

INTRODUCTION: Attention deficit hyperactive disorder (ADHD) is prevalent in 5.9-7.1% of children and adolescents, and 5% of adults. It results in poor academic, occupational, and social functioning. Pharmacotherapy improves core symptoms; however, average adherence levels are low and decrease at 16-17 years of age, just before the recruitment age to Israel Defense Forces (IDF). This study evaluated the effect of adherence to ADHD pharmacotherapy on occupational performance among soldiers. MATERIALS AND METHODS: Retrospective data were collected for the study cohort, which included all soldiers serving in the IDF from 2008 through 2012 (n > 500,000). Each soldier in the cohort was categorized based on adherence to treatment, as measured by prescriptions filled monthly: (1) no treatment, (2) low adherence (<2/year), (3) medium adherence (2-6/year), and (4) high adherence (>6/year). Occupational performance was evaluated by 3 indicative parameters: (1) number of sick days, (2) number of exemptions from daily activities, and (3) military profession disqualification, including sub-analysis to military profession groups. RESULTS: ADHD pharmacotherapy adherence correlated inversely with occupational performance, as exhibited by more sick days and exemptions from daily activities. All soldiers pharmacologically treated for ADHD had higher professional disqualification rates compared with soldiers who did not require ADHD treatment. In contrast to the general trend, in the military drivers group, higher rates of ADHD adherence correlated with lower professional disqualification rates. CONCLUSIONS: Our hypothesis that greater adherence would correlate positively with better occupational performance was refuted. We speculate that increased adherence levels are indicative of more severe ADHD and thus, accompanied by lower occupational performance. The correlation between increased adherence and improved driving ability could be attributed to the nature of driving professions, which require a high level of concentration. Due to the importance of driving in both military and civilian settings, interventions designed to enhance adherence to treatment for ADHD among drivers could have a broad effect on driving consequences, and should be considered by policymakers.