Intraperitoneal immunotherapy with denileukin diftitox (ONTAK) in recurrent refractory ovarian cancer.

BACKGROUND: Denileukin diftitox (ONTAK) is a diphtheria/IL-2R fusion protein able to deplete regulatory T cells in peripheral blood. Regulatory T cells in the local immune microenvironment have been shown to be associated with poor prognosis in ovarian cancer. This study examined whether denileukin diftitox (ONTAK) could be safely administered intraperitoneal in patients with advanced refractory ovarian cancer and assessed its effects on regulatory T cells and tumor associated cytokines in ascites and peripheral blood. PATIENTS AND METHODS: A phase I dose escalation study of intraperitoneal denileukin diftitox (ONTAK) enrolled 10 patients with advanced, refractory ovarian carcinoma at 3 doses (5 µg/kg, 15 µg/kg, and 25 µg/kg). Serial CA-125 measurements assessed clinical response. Regulatory T cells were quantified using RT-PCR and cytokine levels measured by Luminex. RESULTS: The maximum tolerated dose was 15 µg/kg with a dose limiting toxicity observed in 1 out of 6 patients in the expansion group. The majority of adverse events were transient grades 1-2. One patient treated at the 25 µg/kg dose experienced cytokine storm with prolonged hospitalization. 3 patients had decreases in CA-125 after treatment but none met criteria for partial response. Treatment with denileukin diftitox (ONTAK) decreased regulatory T cells in peripheral blood and ascites. Treated patients did not show any significant changes in IL-8, TGF-ß, sIL2Ra in ascites or peripheral blood. CONCLUSIONS: Denileukin diftitox (ONTAK) can be safely administered intraperitoneally to recurrent refractory ovarian cancer patients. Regulatory T cells were reduced in ascites and peripheral blood, but there were no significant changes in cytokine levels. CLINICAL TRIAL REGISTRATION: ClinicalTrials.gov # NCT00357448.

Impaired Visual Function in Posterior Vitreous Detachment Assessed With the Active-Learning Quantitative Contrast Sensitivity Function Test.

Introduction: To investigate whether there is visual function impairment in patients with posterior vitreous detachment (PVD) using the active-learning quantitative contrast sensitivity function test. Methods: In this cross-sectional study, contrast sensitivity was measured in eyes with PVD and eyes without PVD using the quantitative contrast sensitivity function algorithm on the Adaptive Sensory Technology platform. Outcomes included the area under the log contrast sensitivity function curve, contrast acuity, and contrast sensitivity thresholds at 1 to 18 cycles per degree (cpd). Snellen visual acuity (VA) was also measured. Mixed-effects multiple linear regression analyses were performed to evaluate the association between the presence of PVD and visual function, controlling for age and lens status. Results: The cohort comprised 232 healthy eyes of 205 participants; of these, 80 eyes of 69 patients had PVD. There was no significant association between VA and PVD presence. However, PVD was significantly associated with decreased contrast sensitivity thresholds at 1.5 cpd (ß, -0.058; P = .003) and 3 cpd (ß, -0.067; P = .004). Contrast sensitivity thresholds at lower (1 cpd) or higher (6, 12, 18 cpd) spatial frequencies did not significantly correlate with PVD presence. Even in the subgroup of symptomatic PVD eyes, VA was not significantly decreased, while quantitative contrast sensitivity function outcomes showed visual function deficits at low spatial frequencies (1.5 cpd and 3 cpd). Conclusions: Contrast sensitivity measured with the quantitative contrast sensitivity function test showed visual function deficits in eyes with PVD that would have been missed with VA testing alone. Incorporating this test in the retina clinic might offer a more comprehensive functional assessment of eyes with PVD, serving as an adjunct outcome metric in clinical decision-making.

New enantiornithine diversity in the Hell Creek Formation and the functional morphology of the avisaurid tarsometatarsus.

Enantiornithines were the most diverse group of birds during the Cretaceous, comprising over half of all known species from this period. The fossil record and subsequently our knowledge of this clade is heavily skewed by the wealth of material from Lower Cretaceous deposits in China. In contrast, specimens from Upper Cretaceous deposits are rare and typically fragmentary, yet critical for understanding the extinction of this clade across the K-Pg boundary. The most complete North American Late Cretaceous enantiornithine is Mirarce eatoni, a member of the diverse clade Avisauridae. Except for Mirarce, avisaurids are known only from isolated hindlimb elements from North and South America. Here we describe three new enantiornithines from the Maastrichtian Hell Creek Formation, two of which represent new avisaurid taxa. These materials represent a substantial increase in the known diversity of Enantiornithes in the latest Cretaceous. Re-examination of material referred to Avisauridae through phylogenetic analysis provides strong support for a more exclusive Avisauridae consisting of six taxa. Exploration of the functional morphology of the avisaurid tarsometatarsus indicates potential strong constriction and raptorial attributes. The lower aspect ratio of the tarsometatarsus facilitates a more biomechanically efficient lever system which in extant birds of prey equates to lifting proportionally heavier prey items. In addition, the proportional size and distal position of the m. tibialis cranialis tubercle of the tarsometatarsus is similar to the morphology seen in extant birds of prey. Together with the deeply-grooved metatarsal trochlea facilitating robust and likely powerful pedal digits, morphologies of the hindlimb suggest avisaurids as Late Cretaceous birds of prey.

Allostasis as a consequence of high heat load in grain-fed feedlot cattle.

Heat wave intensity, frequency, and duration are increasing in many regions of the world, including locations where highly productive livestock are raised. There are animal health and welfare, as well as economic impacts from these events. In this study, the physiological responses of grain-fed steers during a high heat load challenge through to recovery in climate-controlled rooms (CCR) were intensively evaluated. Two cohorts of 12 Black Angus steers (BW, 615.4 ±â€…40.1 kg) sequentially underwent a simulated heatwave event that consisted of 3 phases in the CCR: PreChallenge (5 d duration and temperature humidity index (THI) range of 65 to 71), Challenge (7-d duration and THI 66 to 95 with diurnal cycling), and Recovery (5 d duration and THI 65 to 70). The Challenge period was modeled on a severe heat wave, characterized by 3 very hot days. Individual rumen temperature (RumT, °C) was collected every 10 min, and respiration rate (RR, breaths per minute), panting score (PS), and water usage (L·steer-1·day-1) were obtained at multiple time points daily, by trained observers. Individual animal daily DMI was also determined. Morning (0700 hours) rectal temperature (RecT, °C) was measured on days 3, 5, 7 to 13, 15, and 17. Not unexpectedly, RumT, RecT, RR, and PS rose during Challenge and fell rapidly as conditions eased. Conversely, DMI was reduced during Challenge. During the transition between PreChallenge and Challenge, there were abrupt increases in RumT, and RR. It was also very apparent that during Recovery the steers did not return to the baseline PreChallenge state. Compared to PreChallenge, Recovery was characterized by persistent lowered daily mean RumT (P = 0.0010), RecT (P = 0.0922), RR (P = 0.0257), PS (P ≤ 0.0001), and DMI (P ≤ 0.0001). These results provide evidence that these steers have undergone an allostatic response in response to high heat load, and the new adjusted physiological state post-heat event may not be transient.

Human cytomegalovirus UL18 prevents priming of MHC-E- and MHC-II-restricted CD8+ T cells.

Rhesus cytomegalovirus (RhCMV) vectors elicit major histocompatibility complex (MHC)-E-restricted CD8+ T cells that stringently control simian immunodeficiency virus (SIV) in rhesus macaques. These responses require deletion of eight RhCMV chemokine-like open reading frames (ORFs) that are conserved in human cytomegalovirus (HCMV). To determine whether HCMV encodes additional, nonconserved inhibitors of unconventional T cell priming, we inserted 41 HCMV-specific ORFs into a chemokine-deficient strain (68-1 RhCMV). Monitoring of epitope recognition revealed that HCMV UL18 prevented unconventional T cell priming, resulting in MHC-Ia-targeted responses. UL18 is homologous to MHC-I but does not engage T cell receptors and, instead, binds with high affinity to inhibitory leukocyte immunoglobulin-like receptor-1 (LIR-1). UL18 lacking LIR-1 binding no longer interfered with MHC-E-restricted T cell stimulation by RhCMV-infected cells or the induction of unconventionally restricted T cells. Thus, LIR-1 binding needs to be deleted from UL18 of HCMV/HIV vaccines to allow for the induction of protective MHC-E-restricted T cells.

Celiac disease and nonceliac enteropathies.

PURPOSE OF REVIEW: This review highlights recent research in the field of celiac disease. RECENT FINDINGS: Epidemiological studies continue to identify celiac disease-associated diseases such as inflammatory arthritis, irritable bowel syndrome, and cardiovascular disease. Recently published consensus guidelines provide recommendations for the long-term management and monitoring of patients with celiac disease. There are multiple pharmaceutical therapies for celiac disease under investigation, and recent phase I and phase II trials are reviewed here. Finally, a recent trial of patients with nonceliac gluten sensitivity demonstrates a significant nocebo effect in this condition. SUMMARY: Recent advances in celiac disease include the development of new clinical guidelines as well as promising new therapeutics. Continued high-quality research is needed to improve the outcomes of patients with celiac disease and nonceliac enteropathies.

The evolving pathophysiology of TBI and the advantages of temporally-guided combination therapies.

Several clinical and experimental studies have demonstrated that traumatic brain injury (TBI) activates cascades of biochemical, molecular, structural, and pathological changes in the brain. These changes combine to contribute to the various outcomes observed after TBI. Given the breadth and complexity of changes, combination treatments may be an effective approach for targeting multiple detrimental pathways to yield meaningful improvements. In order to identify targets for therapy development, the temporally evolving pathophysiology of TBI needs to be elucidated in detail at both the cellular and molecular levels, as it has been shown that the mechanisms contributing to cognitive dysfunction change over time. Thus, a combination of individual mechanism-based therapies is likely to be effective when maintained based on the time courses of the cellular and molecular changes being targeted. In this review, we will discuss the temporal changes of some of the key clinical pathologies of human TBI, the underlying cellular and molecular mechanisms, and the results from preclinical and clinical studies aimed at mitigating their consequences. As most of the pathological events that occur after TBI are likely to have subsided in the chronic stage of the disease, combination treatments aimed at attenuating chronic conditions such as cognitive dysfunction may not require the initiation of individual treatments at a specific time. We propose that a combination of acute, subacute, and chronic interventions may be necessary to maximally improve health-related quality of life (HRQoL) for persons who have sustained a TBI.

Targeting IRE1α reprograms the tumor microenvironment and enhances anti-tumor immunity in prostate cancer.

Unfolded protein response (UPR) is a central stress response pathway that is hijacked by tumor cells for their survival. Here, we find that IRE1α signaling, one of the canonical UPR arms, is increased in prostate cancer (PCa) patient tumors. Genetic or small molecule inhibition of IRE1α in syngeneic mouse PCa models and an orthotopic model decreases tumor growth. IRE1α ablation in cancer cells potentiates interferon responses and activates immune system related pathways in the tumor microenvironment (TME). Single-cell RNA-sequencing analysis reveals that targeting IRE1α in cancer cells reduces tumor-associated macrophage abundance. Consistently, the small molecule IRE1α inhibitor MKC8866, currently in clinical trials, reprograms the TME and enhances anti-PD-1 therapy. Our findings show that IRE1α signaling not only promotes cancer cell growth and survival but also interferes with anti-tumor immunity in the TME. Thus, targeting IRE1α can be a promising approach for improving anti-PD-1 immunotherapy in PCa.

High-Resolution Spectroscopy and Structure of Heavy Carbon Subchalcogenides: Tricarbon Selenide, C3Se.

Linear tricarbon selenide, C3Se, has been studied spectroscopically for the first time using a combination of high-resolution infrared and microwave techniques. Probing laser ablation products from carbon-selenium targets in a free jet expansion with He, initial spectroscopic detection was accomplished in the infrared at a wavelength of 5 µm in search of the ν1 vibrational fundamental. Along with the band of the most abundant isotopic species C380Se found centered at about 2039 cm-1, the corresponding bands of the C382Se, C378Se, C376Se, and C377Se isotopologues were also detected. Pure rotational spectra of the five C3Se isotopologues in the 8-18 GHz frequency range were observed in a supersonic jet expansion using chirped-pulse microwave spectroscopy of the discharge products of selenophene, c-C4H4Se. Spectroscopic analyses were guided by results from high-level quantum-chemical calculations carried out at the coupled-cluster level of theory using large correlation-consistent basis sets. Using the experimentally derived ground-state rotational constants of five isotopologues and calculated zero-point vibrational corrections, an accurate semiexperimental equilibrium carbon-selenium bond length is derived.

Metabolomic changes in preterminal serum samples of rhesus macaques exposed to two different lethal doses of total-body gamma-radiation.

Exposure to ionizing radiation induces cellular and molecular damage leading to a cascade of events resulting in tissue and organ injury. Our study strives to characterize and validate metabolomic changes in preterminal stage (immediately prior to death) samples collected from rhesus macaques lethally irradiated with one of two different doses of radiation. Peripheral blood samples were collected pre-exposure, post-exposure, and at the preterminal stage of nonhuman primates (NHPs that did not survive exposure with 7.2 Gy or 7.6 Gy total-body radiation (LD60-80/60)). We analyzed global metabolomic alterations using ultra-performance liquid chromatography (UPLC) quadrupole time-of-flight mass spectrometry (QTOF-MS) in serum samples collected at various timepoints in relation to radiation exposure. The goal of this study was to validate the metabolic shifts present in samples collected just prior to death, which were reported earlier in a preliminary study with a limited number of samples and a single dose of radiation. Here, we demonstrate that radiation exposure induced significant time-dependent metabolic alterations compared with pre-exposure samples. We observed significant metabolite dysregulation in animals exposed to 7.6 Gy compared to 7.2 Gy. Greater metabolic disruption was observed in the preterminal groups than all of the other post-irradiation timepoints in both cohorts. Metabolomic shifts in these preterminal groups also revealed consistent disturbances in sphingolipid metabolism, steroid hormone biosynthesis, and glycerophospholipid metabolism pathways. Overall, the sphingolipid metabolism pathway appears to be representative of the preterminal phenotype, confirming the results of our preliminary study. These results offer important and novel insights for identification and validation of biomarkers for lethality, and such observations would be valuable for triage during a radiological/nuclear mass casualty scenario.

Carbon, climate, and natural disturbance: a review of mechanisms, challenges, and tools for understanding forest carbon stability in an uncertain future.

In this review, we discuss current research on forest carbon risk from natural disturbance under climate change for the United States, with emphasis on advancements in analytical mapping and modeling tools that have potential to drive research for managing future long-term stability of forest carbon. As a natural mechanism for carbon storage, forests are a critical component of meeting climate mitigation strategies designed to combat anthropogenic emissions. Forests consist of long-lived organisms (trees) that can store carbon for centuries or more. However, trees have finite lifespans, and disturbances such as wildfire, insect and disease outbreaks, and drought can hasten tree mortality or reduce tree growth, thereby slowing carbon sequestration, driving carbon emissions, and reducing forest carbon storage in stable pools, particularly the live and standing dead portions that are counted in many carbon offset programs. Many forests have natural disturbance regimes, but climate change and human activities disrupt the frequency and severity of disturbances in ways that are likely to have consequences for the long-term stability of forest carbon. To minimize negative effects and maximize resilience of forest carbon, disturbance risks must be accounted for in carbon offset protocols, carbon management practices, and carbon mapping and modeling techniques. This requires detailed mapping and modeling of the quantities and distribution of forest carbon across the United States and hopefully one day globally; the frequency, severity, and timing of disturbances; the mechanisms by which disturbances affect carbon storage; and how climate change may alter each of these elements. Several tools (e.g. fire spread models, imputed forest inventory models, and forest growth simulators) exist to address one or more of the aforementioned items and can help inform management strategies that reduce forest carbon risk, maintain long-term stability of forest carbon, and further explore challenges, uncertainties, and opportunities for evaluating the continued potential of, and threats to, forests as viable mechanisms for forest carbon storage, including carbon offsets. A growing collective body of research and technological improvements have advanced the science, but we highlight and discuss key limitations, uncertainties, and gaps that remain.

Lisavanbulin (BAL101553), a novel microtubule inhibitor, plus radiation in patients with newly diagnosed, MGMT promoter unmethylated glioblastoma.

Background: Lisavanbulin (BAL101553) is a small, lipophilic, oral microtubule destabilizer with promising antitumoral activity observed in preclinical glioblastoma (GBM) models. Methods: This multicenter phase 1 study sought to determine the MTD of oral Lisavanbulin in combination with standard RT (60 Gy/30 fractions) but without temozolomide in patients with newly diagnosed MGMT promoter unmethylated GBM (uGBM). Dose escalation followed a modified 3 + 3 design. Secondary objectives included estimation of OS and PFS and pharmacokinetic analysis. Results: Twenty-six patients with uGBM (median age, 63 years, 42.3% male, 61.5% with gross total resection, median Karnofsky performance status 80) were enrolled; 2 tumors had an IDH1 mutation. Predefined dose levels of Lisavanbulin, administered daily concomitantly with RT, were: 4 mg (5 pts), 6 mg (5 pts), 8 mg (7 pts), 12 mg (5 pts), and 15 mg (4 pts). The initial starting dose was 8 mg. Due to grade 4 aseptic meningoencephalitis in the first patient, the dose was decreased to 4 mg. Dose escalation resumed and continued to 15 mg with dose-limiting toxicities of grade 2 confusion and memory impairment observed at 12 mg. Avanbulin exposures increased in a relatively dose-proportional manner with increasing oral dose of Lisavanbulin from 4 to 15 mg. Conclusions: Lisavanbulin in combination with RT was considered safe up to the highest predefined oral dose level of 15 mg daily.

Efficacy of rituximab in the treatment of epidermolysis bullosa acquisita.

BACKGROUND: Epidermolysis bullosa acquisita (EBA) is a chronic mucocutaneous disease that is mediated by antibodies that bind collagen VII. The treatment of EBA can be challenging and often multiple immunomodulatory drugs are required. Rituximab has been reported to be an effective treatment for recalcitrant EBA, although its evidence base is limited to case reports and case series. This study therefore aimed to evaluate the efficacy of rituximab in patients with EBA. METHODS: EBA patients treated with rituximab were identified by searching electronic medical records. Diagnostic criteria for EBA were as follows; mechanobullous skin lesions and / or mucosal ulceration, indirect immunofluorescence localising to the base of salt split skin and positive collagen VII antibodies. Clinical disease activity, collagen VII antibody levels and serum immunoglobulins were recorded at each follow up visit over 600 day period. Treatment responses were classified as follows; complete remission (CR) as the absence of new or established lesions on minimal therapy for 2 months, partial remission (PR) as transient lesions that heal within 1 week on minimal therapy and active disease (AD) as the development of new lesions. RESULTS: 14 patients with EBA were treated with rituximab. CR or PR was observed in 11 patients, and the duration of response varied between 4 and 24 months. A reduction in collagen VII antibody levels was observed in all patients. No significant adverse events were reported. CONCLUSIONS: Rituximab is a safe and effective treatment for patients with recalcitrant EBA although there was significant heterogeneity in the disease response.

Comparing Open, Laparoscopic and Robotic Liver Resection for Metastatic Colorectal Cancer-A Systematic Review and Network Meta-Analysis.

Colorectal liver metastases (CRLM) can be surgically managed through open resections (OLR), laparoscopic resections (LLR), or robotic liver resections (RLR). However, there is ongoing uncertainty regarding the safety and effectiveness of minimally invasive approaches like LLR and RLR. This study aims to clarify these issues by conducting a network meta-analysis (NMA) to compare outcomes across OLR, LLR and RLR for patients with CRLM. Following the PRISMA-NMA guidelines, the meta-analysis included 13 studies with a combined total of 6582 patients. Of these, 50.6% underwent LLR, 45.3% underwent OLR, and 4.1% underwent RLR. The analysis found no significant differences in R0 resection rates between LLR (odds ratio [OR] 1.03, 95% confidence interval [CI]: 0.84-1.26) and RLR (OR 1.57, 95% CI: 0.98-2.51) when compared to OLR. Additionally, there were no significant differences in disease-free survival (DFS) and overall survival (OS) at 1, 3, and 5 years. Despite these findings, both LLR and RLR were associated with reduced postoperative complication rates (RLR: OR 0.52, 95% CI: 0.32-0.86; LLR: OR 0.50, 95% CI: 0.37-0.68). However, patients undergoing LLR were more likely to require conversion to open surgery compared to those undergoing RLR (OR: 12.46, 95% CI: 2.64-58.67). Furthermore, RLR was associated with a reduced need for blood transfusions (OR: 0.13, 95% CI: 0.05-0.32), and LLR resulted in shorter hospital stays (mean difference: -6.66 days, 95% CI: -11.6 to -1.88 days). This study demonstrates the oncological safety of LLR and RLR approaches for CRLM relative to OLR, with enhanced perioperative outcomes anticipated following minimally invasive resections of CRLM.

Thyroid cancer epidemiology in Ireland from 1994 to 2019 - Rising diagnoses without mortality benefit.

BACKGROUND: The epidemiology and management of thyroid cancer has changed radically in the recent past, with rising international incidence of early-stage papillary thyroid cancer (PTC) in particular. In this paper, we review the epidemiology of thyroid cancer in Ireland. METHODS: A retrospective cohort study of National Cancer Registry of Ireland data, 1994-2019. RESULTS: Records from 4158 patients were analysed. 73 % (n = 3040) were female. The average age was 50.4 years. Patient sex did not change over time (p = 0.662), while age decreased significantly (p < 0.0001). The most common diagnoses were PTC (n = 2,905, 70 %) and follicular thyroid carcinoma (n = 549, 13 %). Incidence rose over threefold (1.8-6.2 cases/100000 person-years). The incidence of T1 PTC rose over twelvefold (0.169-2.1 cases/100000 person-years), while the incidence of stage III and IV disease did not change significantly. Five-year disease-specific survival (DSS) was 85 % and varied significantly by diagnosis - 97 % for PTC versus 5 % for anaplastic thyroid carcinoma. Survival did not change significantly over time. Male sex was a risk factor for more advanced disease (p < 0.0001) but did not independently predict overall survival except in PTC (HR 1.6, p = 0.03). The use of radioactive iodine declined markedly from 49 % to 12.5 %. RAI improved DSS for PTC patients aged over 55 years (p = 0.02) without a notable effect on survival for those under 55 years (p = 0.99). CONCLUSION: The epidemiology and management of thyroid cancer in Ireland has changed dramatically in a manner reflective of international trends.

The Relationship between the Infrared Eye Temperature of Beef Cattle and Associated Biological Responses at High Environmental Temperatures.

Cattle in regions with high ambient temperatures are at risk of heat stress. Early detection is important to allow action to be taken to minimise the risks to cattle exposed to thermal stress. This study aimed to investigate the impact of heat stress on IRT-Eye temperature and its association with the behavioural and physiological responses of heat-stressed Angus steers (n = 24) on finisher and or substituted diets. Overall, 2 cohorts of 12 Angus steers were individually housed in a climate-controlled facility to examine responses to heat stress when fed on a standard finisher diet, based on a high percentage of cereal grains, and on a substituted diet in which 8% of the grains were replaced by an isoenergetic amount of lucerne hay. Exposing feedlot cattle to hot environmental conditions increased IRT-Eye temperature, which had a strong association with behaviour and physiology. There was no evidence of differences between the different dietary cohorts. The cattle with increased IRT-Eye temperature showed stress-related responses, including a downward-facing head, ears directed backwards, and other indicators of heat stress such as increased panting, standing, and increased rumen temperature. The strong association of IRT-Eye temperature with stress-related behaviours, as well as with rumen temperature and panting behaviour, highlights the potential for IRT-Eye to be utilised as a non-invasive tool to assess cattle responses in hot conditions.

The human ciliopathy protein RSG1 links the CPLANE complex to transition zone architecture.

Cilia are essential organelles and variants in genes governing ciliary function result in ciliopathic diseases. The Ciliogenesis and PLANar polarity Effectors (CPLANE) protein complex is essential for ciliogenesis in animals models but remains poorly defined. Notably, all but one subunit of the CPLANE complex have been implicated in human ciliopathy. Here, we identify three families in which variants in the remaining CPLANE subunit CPLANE2/RSG1 also cause ciliopathy. These patients display cleft palate, tongue lobulations and polydactyly, phenotypes characteristic of Oral-Facial-Digital Syndrome. We further show that these alleles disrupt two vital steps of ciliogenesis, basal body docking and recruitment of intraflagellar transport proteins. Moreover, APMS reveals that Rsg1 binds the CPLANE and also the transition zone protein Fam92 in a GTP-dependent manner. Finally, we show that CPLANE is generally required for normal transition zone architecture. Our work demonstrates that CPLANE2/RSG1 is a causative gene for human ciliopathy and also sheds new light on the mechanisms of ciliary transition zone assembly.

Assessing the Costs of Intravenous Push Waste in Intraoperative Areas Through Observation: A Multi-site Study.

INTRODUCTION: The costs associated with proper disposal, management, and regulatory compliance of controlled substances in healthcare systems are substantial. In the context of the current opioid crisis, and given the high abuse potential of controlled substances, it is imperative that waste is minimized and waste procedures are followed to ensure safe disposal of controlled substances. This study aims to quantify the costs associated with fentanyl, hydromorphone, morphine, midazolam, and ketamine waste in intraoperative areas through a multi-site observational analysis. METHODS: The study used an observational design across various hospital procedural and post-procedural units in the Southwest Florida region of the United States. Automated and non-automated workflows for wasting controlled substances were compared. As with a previous study conducted by Hertig et al., waste was evaluated as (1) the quantity (mg/µg) of medication disposed defined as 'pharmaceutical waste' or 'product waste' (PW); and (2) workforce time associated with the waste disposal process defined as 'workforce time waste' (WTW). Secondary measures include workforce costs associated with the waste disposal process. The product waste analysis was conducted between October and December 2023. The workforce time waste analysis was examined over a 10-day period in January and February 2024. A yearly extrapolation model was applied to cost data. RESULTS: The findings revealed substantial costs linked to both PW and WTW, emphasizing the financial burden of controlled substance waste. Study data validated previous literature describing the extent of fentanyl, hydromorphone, and morphine waste while documenting significant amounts of midazolam and ketamine waste. The combined annual waste cost for the two study hospitals was estimated at US$56,557, with workforce time accounting for 36%-50% of this total cost. CONCLUSION: This study provides vital insights into the financial and operational impact of medication waste in procedural and post-procedural areas, supporting ongoing efforts to minimize waste, ensuring the safe and effective use of controlled substances. Future research should explore the impact of medication waste across diverse healthcare settings and the cost implications associated with pharmacy professionals in the waste compliance process.

Patient-derived organoid model of olfactory ensheathing cell tumor.

KEY POINTS: We developed a culture model of a human olfactory ensheathing cell tumor. Cultured organoids resemble normal ensheathing cells. Assays suggest that this model provides a tool for studying the roles of these glial cells in the maintenance of the peripheral olfactory system.

Utilizing Relative Citation Ratio to Compare Academic Productivity by Gender in Plastic Surgery.

INTRODUCTION: The relative citation ratio (RCR) is a bibliometric index utilized to assess research productivity. Mean relative citation ratio (m-RCR) and weighted relative citation ratio (w-RCR) can be utilized to assess individual research quality as well as career-long productivity, respectively. We sought to determine differences in academic productivity between genders and identify demographic variables associated with increased academic productivity. METHODS: A list of Plastic and Reconstructive Surgery residency programs was compiled utilizing the American Council of Academic Plastic Surgeons website. Each program department's website was utilized to generate a list of practicing surgeons and respective demographic information. Both mean and weighted RCR were obtained using the iCite, a National Institutes of Health bibliometric tool. Surgeons were excluded if any demographic or RCR data was not accessible. Chi-squared test, Mann-Whitney U test, Kruskal-Wallis test, and multivariable linear regressions were performed. RESULTS: A total of 785 academic plastic surgeons met the criteria and were included in the analysis, 186 of whom were women and 599 men. Both academic rank and model of residency training were significantly associated with gender in chi-squared analysis (P < 0.05). Mean relative citation ratio was higher among men in departments. Mean w-RCR was higher among men of assistant professor status, chief/chairperson status, integrated model of residency training, faculty size ≥six and in departments and divisions. Academic rank and faculty size were associated with higher w-RCR upon multivariable linear regression. CONCLUSIONS: Although differences exist in mean w-RCR between men and women in plastic surgery, gender is not a predictor of increased academic productivity. RCR is an accurate means of assessing gender differences in academic productivity as it comprehensively considers both quality and quantity of research and may be superior to other, older bibliometric indices.