Immobilisation protocols for wild giraffe (Giraffa spp.) - a review.

BACKGROUND: Immobilisation of wild giraffe (Giraffa spp.) is challenging due to their unique anatomy and physiology. Field immobilisations are required for numerous conservation, tourism, and veterinary purposes. Wild giraffe immobilisation techniques have evolved considerably from physical to chemical with ultrapotent drugs. OBJECTIVE: To provide a detailed overview of historic and present protocols used for immobilising giraffe in the wild as a valuable resource tool for future research into best practices. METHODS: A systematic review was undertaken of the published literature on wild giraffe capture and immobilisation techniques with no restrictions on publication date. RESULTS: The review detailed the evolution of capture techniques used for wild giraffe. The trend has moved from purely physical capture in the 1950s to the use of high dose ultrapotent opioids or a combination of opioids and alpha-2 agonists and/or tranquilisers. With a better understanding of giraffe physiology and wild giraffe capture, mortality rates have decreased significantly from ~ 35% to < 1%. CONCLUSION: The advent of ultrapotent opioids has caused a paradigm shift in wildlife immobilisation, especially for wild giraffe. While the use of these drugs, as sole immobilisation agents or in combination with alpha-2 agonists or tranquilisers, has greatly reduced mortality rates associated with wild giraffe immobilisations, there is a startling lack of physiological data evaluating the impact of these drugs on giraffe during and after immobilisation. Future research should focus on measuring physiological variables to determine the impact and best practice of these protocols on wild giraffe immobilisation.

Socioeconomic burden of cystic fibrosis in Canada.

BACKGROUND: Cost of illness studies are important tools to summarise the burden of disease for individuals, the healthcare system and society. The lack of standardised methods for reporting costs for cystic fibrosis (CF) makes it difficult to quantify the total socioeconomic burden. In this study, we aimed to comprehensively report the socioeconomic burden of CF in Canada. METHODS: The total cost of CF in Canada was calculated by triangulating information from three sources (Canadian CF Registry, customised Burden of Disease survey and publicly available information). A prevalence-based, bottom-up, human capital approach was applied, and costs were categorised into four perspectives (ie, healthcare system, individual/caregiver, variable (ie, medicines) and society) and three domains (ie, direct, indirect and intangible). All costs were converted into 2021 Canadian dollars (CAD) and adjusted for inflation. The cost of cystic fibrosis transmembrane conductance regulator (CFTR) modulator therapies was excluded. RESULTS: The total socioeconomic burden of CF in Canada in 2021 across the four perspectives was $C414 million. Direct costs accounted for two-thirds of the total costs, with medications comprising half of all direct costs. Out-of-pocket costs to individuals and caregivers represented 18.7% of all direct costs. Indirect costs representing absenteeism accounted for one-third of the total cost. CONCLUSION: This comprehensive cost of illness study for CF represents a community-oriented approach describing the socioeconomic burden of living with CF and serves as a benchmark for future studies.

Improving Access to Patient-Focused, Decentralized Clinical Trials Requires Streamlined Regulatory Requirements: An ASCO Research Statement.

Strategies to bring clinical trials closer to patients gained momentum during the COVID-19 pandemic, enabling more participants to receive treatment and/or testing in their local communities. Incorporation of decentralized trial elements presents both opportunities and challenges, spanning regulatory, technical, and operational aspects. This ASCO research statement includes timely consensus-driven recommendations and a call for engagement of all research stakeholders. ASCO held multistakeholder meetings with leaders in oncology research and concluded that research-related regulatory and administrative requirements and burdens present critical barriers to decentralizing trials. One example is sponsor and contract research organization (CRO) use of US Food and Drug Administration (FDA)'s Statement of Investigator (Form 1572), which was found to exceed FDA's stated intent and used in conservative ways disproportionate to potential risks to participants and scientific integrity. As a result, research sites experience an avalanche of downstream administrative and regulatory activities that consume considerable resources. This statement recommends four key solutions to address such barriers and recalibrate regulatory and administrative expectations for decentralizing trials: (1) FDA should engage the research community in a public-private partnership to modernize standards and enable local access to trials; (2) sponsors and CROs should develop standards and protocols that accommodate flexible approaches, enable local participation, provide clarity around roles and requirements, and promote consistency; (3) research centers, networks, and sites should update policies and procedures to implement decentralized trial elements; and (4) research community should develop a streamlined, uniform mechanism to simplify regulatory data collection and documentation and use it consistently across trials. We can and must prioritize a concerted commitment to simplify and streamline regulatory requirements and practices to broaden access to and participation in cancer clinical trials.

Origin and modern microbial ecology of secondary mineral deposits in Lehman Caves, Great Basin National Park, NV, USA.

Lehman Caves is an extensively decorated high desert cave that represents one of the main tourist attractions in Great Basin National Park, Nevada. Although traditionally considered a water table cave, recent studies identified abundant speleogenetic features consistent with a hypogenic and, potentially, sulfuric acid origin. Here, we characterized white mineral deposits in the Gypsum Annex (GA) passage to determine whether these secondary deposits represent biogenic minerals formed during sulfuric acid corrosion and explored microbial communities associated with these and other mineral deposits throughout the cave. Powder X-ray diffraction (pXRD), scanning electron microscopy with electron dispersive spectroscopy (SEM-EDS), and electron microprobe analyses (EPMA) showed that, while most white mineral deposits from the GA contain gypsum, they also contain abundant calcite, silica, and other phases. Gypsum and carbonate-associated sulfate isotopic values of these deposits are variable, with δ34SV-CDT between +9.7‰ and +26.1‰, and do not reflect depleted values typically associated with replacement gypsum formed during sulfuric acid speleogenesis. Petrographic observations show that the sulfates likely co-precipitated with carbonate and SiO2 phases. Taken together, these data suggest that the deposits resulted from later-stage meteoric events and not during an initial episode of sulfuric acid speleogenesis. Most sedimentary and mineral deposits in Lehman Caves have very low microbial biomass, with the exception of select areas along the main tour route that have been impacted by tourist traffic. High-throughput 16S rRNA gene amplicon sequencing showed that microbial communities in GA sediments are distinct from those in other parts of the cave. The microbial communities that inhabit these oligotrophic secondary mineral deposits include OTUs related to known ammonia-oxidizing Nitrosococcales and Thaumarchaeota, as well as common soil taxa such as Acidobacteriota and Proteobacteria. This study reveals microbial and mineralogical diversity in a previously understudied cave and expands our understanding of the geomicrobiology of desert hypogene cave systems.

The airway microbiome of persons with cystic fibrosis correlates with acquisition and microbiological outcomes of incident Stenotrophomonas maltophilia infection.

Rationale: Chronic infection with Stenotrophomonas maltophilia in persons with cystic fibrosis (pwCF) has been linked to an increased risk of pulmonary exacerbations and lung function decline. We sought to establish whether baseline sputum microbiome associates with risk of S. maltophilia incident infection and persistence in pwCF. Methods: pwCF experiencing incident S. maltophilia infections attending the Calgary Adult CF Clinic from 2010-2018 were compared with S. maltophilia-negative sex, age (+/-2 years), and birth-cohort-matched controls. Infection outcomes were classified as persistent (when the pathogen was recovered in ≥50% of cultures in the subsequent year) or transient. We assessed microbial communities from prospectively biobanked sputum using V3-V4 16S ribosomal RNA (rRNA) gene sequencing, in the year preceding (Pre) (n = 57), at (At) (n = 22), and after (Post) (n = 31) incident infection. We verified relative abundance data using S. maltophilia-specific qPCR and 16S rRNA-targeted qPCR to assess bioburden. Strains were typed using pulse-field gel electrophoresis. Results: Twenty-five pwCF with incident S. maltophilia (56% female, median 29 years, median FEV1 61%) with 33 total episodes were compared with 56 uninfected pwCF controls. Demographics and clinical characteristics were similar between cohorts. Among those with incident S. maltophilia infection, sputum communities did not cluster based on infection timeline (Pre, At, Post). Communities differed between the infection cohort and controls (n = 56) based on Shannon Diversity Index (SDI, p = 0.04) and clustered based on Aitchison distance (PERMANOVA, p = 0.01) prior to infection. At the time of incident S. maltophilia isolation, communities did not differ in SDI but clustered based on Aitchison distance (PERMANOVA, p = 0.03) in those that ultimately developed persistent infection versus those that were transient. S. maltophilia abundance within sputum was increased in samples from patients (Pre) relative to controls, measuring both relative (p = 0.004) and absolute (p = 0.001). Furthermore, S. maltophilia abundance was increased in sputum at incident infection in those who ultimately developed persistent infection relative to those with transient infection, measured relatively (p = 0.04) or absolute (p = 0.04), respectively. Conclusion: Microbial community composition of CF sputum associates with S. maltophilia infection acquisition as well as infection outcome. Our study suggests sputum microbiome may serve as a surrogate for identifying infection risk and persistence risk.

Vascular access surgery training in the United Kingdom is currently perceived (by trainees) to be inadequate.

INTRODUCTION: Vascular access surgery (VAS) involves the creation and maintenance of arteriovenous access to facilitate haemodialysis. The prevalence of haemodialysis is rising despite increases in kidney transplants on a yearly basis. There is currently only one access surgery fellowship accredited by the Royal College of Surgeons of England. We aimed to establish the experience and perceived competence in access surgery of senior vascular surgery trainees. METHODS: A short questionnaire (SurveyMonkey) was used to survey all senior (ST6-ST8) vascular surgery trainees in Health Education England (HEE) vascular surgery training programmes. The short survey asked trainees to report their: (1) training grade; (2) training deanery; (3) experience of access surgery; and (4) whether senior trainees thought they would be able to independently undertake primary access surgery post-completion of training (post Certificate of Completion of Training). The survey was circulated via HEE deaneries and the vascular surgery trainees' society: the Rouleaux Club. RESULTS: Twenty-eight senior (ST6-ST8) vascular surgery trainees responded to the survey: 29.6% were ST6 level, 33.3% were ST7 and 37.1% were ST8. Deanery respondence was evenly spread, although London was overrepresented (37.1%). In total, 28.6% had been involved in fewer than 10 cases, 35.7% in 10-25 cases, and 35.7% in more than 25 cases. Almost 54% of senior vascular surgery trainees believed they would not be able to undertake independent access surgery once they had completed training. CONCLUSIONS: Competence in access surgery is an increasing requirement of a consultant vascular surgeon. More formalised training is required to adequately train the next generation of vascular surgeons.

Bisbiguanide analogs induce mitochondrial stress to inhibit lung cancer cell invasion.

Targeting cancer metabolism to limit cellular energy and metabolite production is an attractive therapeutic approach. Here, we developed analogs of the bisbiguanide, alexidine, to target lung cancer cell metabolism and assess a structure-activity relationship (SAR). The SAR led to the identification of two analogs, AX-4 and AX-7, that limit cell growth via G1/G0 cell-cycle arrest and are tolerated in vivo with favorable pharmacokinetics. Mechanistic evaluation revealed that AX-4 and AX-7 induce potent mitochondrial defects; mitochondrial cristae were deformed and the mitochondrial membrane potential was depolarized. Additionally, cell metabolism was rewired, as indicated by reduced oxygen consumption and mitochondrial ATP production, with an increase in extracellular lactate. Importantly, AX-4 and AX-7 impacted overall cell behavior, as these compounds reduced collective cell invasion. Taken together, our study establishes a class of bisbiguanides as effective mitochondria and cell invasion disrupters, and proposes bisbiguanides as promising approaches to limiting cancer metastasis.

Vascular access surgery training in the United Kingdom is currently perceived (by trainees) to be inadequate.

INTRODUCTION: Vascular access surgery (VAS) involves the creation and maintenance of arteriovenous access to facilitate haemodialysis. The prevalence of haemodialysis is rising despite increases in kidney transplants on a yearly basis. There is currently only one access surgery fellowship accredited by the Royal College of Surgeons of England. We aimed to establish the experience and perceived competence in access surgery of senior vascular surgery trainees. METHODS: A short questionnaire (SurveyMonkey) was used to survey all senior (ST6-ST8) vascular surgery trainees in Health Education England (HEE) vascular surgery training programmes. The short survey asked trainees to report their: (1) training grade; (2) training deanery; (3) experience of access surgery; and (4) whether senior trainees thought they would be able to independently undertake primary access surgery post-completion of training (post Certificate of Completion of Training). The survey was circulated via HEE deaneries and the vascular surgery trainees' society: the Rouleaux Club. RESULTS: Twenty-eight senior (ST6-ST8) vascular surgery trainees responded to the survey: 29.6% were ST6 level, 33.3% were ST7 and 37.1% were ST8. Deanery respondence was evenly spread, although London was overrepresented (37.1%). In total, 28.6% had been involved in fewer than 10 cases, 35.7% in 10-25 cases, and 35.7% in more than 25 cases. Almost 54% of senior vascular surgery trainees believed they would not be able to undertake independent access surgery once they had completed training. CONCLUSIONS: Competence in access surgery is an increasing requirement of a consultant vascular surgeon. More formalised training is required to adequately train the next generation of vascular surgeons.

Inhibition of p70 Ribosomal S6 Kinase (S6K1) Reduces Cortical Blood Flow in a Rat Model of Autism-Tuberous Sclerosis.

The manifestations of tuberous sclerosis complex (TSC) in humans include epilepsy, autism spectrum disorders (ASD) and intellectual disability. Previous studies suggested the linkage of TSC to altered cerebral blood flow and metabolic dysfunction. We previously reported a significant elevation in cerebral blood flow in an animal model of TSC and autism of young Eker rats. Inhibition of the mammalian target of rapamycin (mTOR) by rapamycin could restore normal oxygen consumption and cerebral blood flow. In this study, we investigated whether inhibiting a component of the mTOR signaling pathway, p70 ribosomal S6 kinase (S6K1), would yield comparable effects. Control Long Evans and Eker rats were divided into vehicle and PF-4708671 (S6K1 inhibitor, 75 mg/kg for 1 h) treated groups. Cerebral regional blood flow (14C-iodoantipyrine) was determined in isoflurane anesthetized rats. We found significantly increased basal cortical (+ 32%) and hippocampal (+ 15%) blood flow in the Eker rats. PF-4708671 significantly lowered regional blood flow in the cortex and hippocampus of the Eker rats. PF-4708671 did not significantly lower blood flow in these regions in the control Long Evans rats. Phosphorylation of S6-Ser240/244 and Akt-Ser473 was moderately decreased in Eker rats but only the latter reached statistical significance upon PF-4708671 treatment. Our findings suggest that moderate inhibition of S6K1 with PF-4708671 helps to restore normal cortical blood flow in Eker rats and that this information might have therapeutic potential in tuberous sclerosis complex and autism.

A phase Ib study evaluating the recommended phase II dose, safety, tolerability, and efficacy of mivavotinib in combination with nivolumab in advanced solid tumors.

Mivavotinib (TAK-659/CB-659), a dual SYK/FLT3 inhibitor, reduced immunosuppressive immune cell populations and suppressed tumor growth in combination with anti-PD-1 therapy in cancer models. This dose-escalation/expansion study investigated the safety, pharmacokinetics, pharmacodynamics, and preliminary efficacy of mivavotinib plus nivolumab in patients with advanced solid tumors. Patients received oral mivavotinib 60-100 mg once-daily plus intravenous nivolumab 3 mg/kg on days 1 and 15 in 28-day cycles until disease progression or unacceptable toxicity. The dose-escalation phase evaluated the recommended phase II dose (RP2D; primary endpoint). The expansion phase evaluated overall response rate (primary end point) at the RP2D in patients with triple-negative breast cancer (TNBC). During dose-escalation (n = 24), two dose-limiting toxicities (grade 4 lipase increased and grade 3 pyrexia) occurred in patients who received mivavotinib 80 mg and 100 mg, respectively. The determined RP2D was once-daily mivavotinib 80 mg plus nivolumab 3 mg/kg. The expansion phase was terminated at ~50% enrollment (n = 17) after failing to meet an ad hoc efficacy futility threshold. Among all 41 patients, common treatment-emergent adverse events (TEAEs) included dyspnea (48.8%), aspartate aminotransferase increased, and pyrexia (46.3% each). Common grade ≥3 TEAEs were hypophosphatemia and anemia (26.8% each). Mivavotinib plasma exposure was generally dose-proportional (60-100 mg). One patient had a partial response. Mivavotinib 80 mg plus nivolumab 3 mg/kg was well tolerated with no new safety signals beyond those of single-agent mivavotinib or nivolumab. Low response rates highlight the challenges of treating unresponsive tumor types, such as TNBC, with this combination and immunotherapies in general. TRIAL REGISTRATION ID: NCT02834247.

A Relative Bioavailability, Bioequivalence, and Food Effect Study of Niraparib Tablets in Patients with Advanced Solid Tumors.

PURPOSE: The poly (ADP-ribose) polymerase inhibitor niraparib is indicated as maintenance treatment in patients with certain subtypes of advanced ovarian cancer, and is being investigated in patients with other solid tumors. Niraparib is available in 100-mg capsules with a starting dosage of 200 or 300 mg/d. This study assessed the relative bioavailability (BA) and bioequivalence (BE) between a 1 × 300-mg tablet relative to 3 × 100-mg niraparib capsules. In addition, the food effect (FE) of a high-fat meal on the pharmacokinetic (PK) properties of tablet-formulated niraparib was investigated. METHODS: This was a US-based, 3-stage, open-label, multicenter, single-crossover, randomized-sequence study. Enrolled patients were 18 years and older, with histologically or cytologically confirmed advanced solid tumors (metastatic or local) and disease progression despite standard therapy. Patients were randomly assigned 1:1 to receive niraparib 1 × 300-mg tablet or 3 × 100-mg capsules in the BA and BE stages or 1 × 300-mg tablet in a fasted or fed (high-fat meal) state in the FE stage. Across all study stages, PK parameters were assessed for 7 days after each dose (tablet or capsule) or prandial state (fasted or fed). In the BA stage, patients crossed over to the other treatment after a 7-day washout period, which was extended to 14 days in the BE and FE stages. Tolerability was assessed for patients who received any amount of niraparib. FINDINGS: The BA-, BE-, and FE-evaluable populations comprised 23, 108, and 19 patients, respectively, who completed both treatment periods in each study stage, had sufficient concentration data to accurately estimate PK parameters without niraparib carryover, and did not experience disqualifying events. PK parameters were similar after dosing with tablet or capsule formulations; the 90% CIs of the geometric least square means for Cmax, AUC0-t, and AUC0-∞ were within the 0.80 to 1.25 BE limits. In the FE stage, Cmax, AUC0-t, and AUC0-∞ were 11%, 32%, and 28% higher, respectively, in the fed versus fasted state. The safety population included 29, 168, and 28 patients in the BA, BE, and FE stages, respectively, who received niraparib. No new safety signals were identified. IMPLICATIONS: Niraparib tablets were found to be bioequivalent to capsules. A modest (≤32%) FE was observed with a high-fat meal, but was not considered to be clinically meaningful, given niraparib's PK variability. CLINICALTRIALS: gov identifier: NCT03329001. (Clin Ther. 2024;46:XXX-XXX) © 2024 Elsevier HS Journals, Inc.

Enhanced Risk Stratification for Children and Young Adults with B-Cell Acute Lymphoblastic Leukemia: A Children's Oncology Group Report.

Current strategies to treat pediatric acute lymphoblastic leukemia rely on risk stratification algorithms using categorical data. We investigated whether using continuous variables assigned different weights would improve risk stratification. We developed and validated a multivariable Cox model for relapse-free survival (RFS) using information from 21199 patients. We constructed risk groups by identifying cutoffs of the COG Prognostic Index (PICOG) that maximized discrimination of the predictive model. Patients with higher PICOG have higher predicted relapse risk. The PICOG reliably discriminates patients with low vs. high relapse risk. For those with moderate relapse risk using current COG risk classification, the PICOG identifies subgroups with varying 5-year RFS. Among current COG standard-risk average patients, PICOG identifies low and intermediate risk groups with 96% and 90% RFS, respectively. Similarly, amongst current COG high-risk patients, PICOG identifies four groups ranging from 96% to 66% RFS, providing additional discrimination for future treatment stratification. When coupled with traditional algorithms, the novel PICOG can more accurately risk stratify patients, identifying groups with better outcomes who may benefit from less intensive therapy, and those who have high relapse risk needing innovative approaches for cure.

A practical approach to interpretation of 18F-fluorodeoxyglucose positron emission tomography/computed tomography for postoperative spine infection.

OBJECTIVE: 18F-fluorodeoxyglucose-PET/CT is the imaging modality of choice for the diagnosis of postoperative spine infection. Published interpretation criteria are variable and often incompletely described. The objective was to develop a practical and standardized approach. MATERIALS AND METHODS: Two-hundred-twenty-seven FDG-PET/CTs performed on 140 postoperative patients over a 7-year period were reviewed retrospectively. The presence or absence of infection was determined from clinical history, microbiology, other investigations, and clinical outcome during a minimum 6-month follow-up. RESULTS: No activity attributable to normal healing was seen in the post-discectomy space or at the bone-hardware interface in the absence of a complication at any stage. Within the incision, activity from normal healing persisted for months. Wound infections were diagnosed clinically, and most had already been treated before FDG-PET/CT was done to assess deep structures. With proven infection, 95% of cases had activity in bone or soft tissue outside the surgical field. The remaining 5% had activity confined to the post-discectomy space. Sterile hardware loosening may cause elevated activity which remains confined to the bone/hardware interface. Pathogens are introduced directly at the time of surgery and may be avirulent resulting in indolent infection with low-grade activity. At the same time, activity from non-infectious causes can be intense. A semi-quantitative method using SUVmax performed poorly compared with assessment of the distribution of activity. CONCLUSION: These observations have been incorporated into a checklist which is now being used at the time of interpretation. The potential sensitivity and specificity in the diagnosis of infection are close to 100%.

Widening the Prostacyclin Paradigm: Tissue Fibroblasts Are a Critical Site of Production and Antithrombotic Protection.

BACKGROUND: Prostacyclin is a fundamental signaling pathway traditionally associated with the cardiovascular system and protection against thrombosis but which also has regulatory functions in fibrosis, proliferation, and immunity. Prevailing dogma states that prostacyclin is principally derived from vascular endothelium, although it is known that other cells can also synthesize it. However, the role of nonendothelial sources in prostacyclin production has not been systematically evaluated resulting in an underappreciation of their importance relative to better characterized endothelial sources. METHODS: To address this, we have used novel endothelial cell-specific and fibroblast-specific COX (cyclo-oxygenase) and prostacyclin synthase knockout mice and cells freshly isolated from mouse and human lung tissue. We have assessed prostacyclin release by immunoassay and thrombosis in vivo using an FeCl3-induced carotid artery injury model. RESULTS: We found that in arteries, endothelial cells are the main source of prostacyclin but that in the lung, and other tissues, prostacyclin production occurs largely independently of endothelial and vascular smooth muscle cells. Instead, in mouse and human lung, prostacyclin production was strongly associated with fibroblasts. By comparison, microvascular endothelial cells from the lung showed weak prostacyclin synthetic capacity compared with those isolated from large arteries. Prostacyclin derived from fibroblasts and other nonendothelial sources was seen to contribute to antithrombotic protection. CONCLUSIONS: These observations define a new paradigm in prostacyclin biology in which fibroblast/nonendothelial-derived prostacyclin works in parallel with endothelium-derived prostanoids to control thrombotic risk and potentially a broad range of other biology. Although generation of prostacyclin by fibroblasts has been shown previously, the scale and systemic activity was unappreciated. As such, this represents a basic change in our understanding and may provide new insight into how diseases of the lung result in cardiovascular risk.

Phase I Study of Elraglusib (9-ING-41), a Glycogen Synthase Kinase-3ß Inhibitor, as Monotherapy or Combined with Chemotherapy in Patients with Advanced Malignancies.

PURPOSE: The safety, pharmacokinetics, and efficacy of elraglusib, a glycogen synthase kinase-3ß (GSK-3ß) small-molecule inhibitor, as monotherapy or combined with chemotherapy, in patients with relapsed or refractory solid tumors or hematologic malignancies was studied. PATIENTS AND METHODS: Elraglusib (intravenously twice weekly in 3-week cycles) monotherapy dose escalation was followed by dose escalation with eight chemotherapy regimens (gemcitabine, doxorubicin, lomustine, carboplatin, irinotecan, gemcitabine/nab-paclitaxel, paclitaxel/carboplatin, and pemetrexed/carboplatin) in patients previously exposed to the same chemotherapy. RESULTS: Patients received monotherapy (n = 67) or combination therapy (n = 171) elraglusib doses 1 to 15 mg/kg twice weekly. The initial recommended phase II dose (RP2D) of elraglusib was 15 mg/kg twice weekly and was defined, without dose-limiting toxicity observation, due to fluid volumes necessary for drug administration. The RP2D was subsequently reduced to 9.3 mg/kg once weekly to reduce elraglusib-associated central/peripheral vascular access catheter blockages. Other common elraglusib-related adverse events (AE) included transient visual changes and fatigue. Grade ≥3 treatment-emergent AEs occurred in 55.2% and 71.3% of patients on monotherapy and combination therapy, respectively. Part 1 monotherapy (n = 62) and part 2 combination (n = 138) patients were evaluable for response. In part 1, a patient with melanoma had a complete response, and a patient with acute T-cell leukemia/lymphoma had a partial response (PR). In part 2, seven PRs were observed, and the median progression-free survival and overall survival were 2.1 [95% confidence interval (CI), 2-2.6] and 6.9 (95% CI, 5.7-8.4) months, respectively. CONCLUSIONS: Elraglusib had a favorable toxicity profile as monotherapy and combined with chemotherapy and was associated with clinical benefit supporting further clinical evaluation in combination with chemotherapy.

Measuring the burden of cystic fibrosis: A scoping review.

BACKGROUND: Cystic fibrosis (CF) contributes a significant economic burden on individuals, healthcare systems, and society. Understanding the economic impact of CF is crucial for planning resource allocation. METHODS: We conducted a scoping review of literature published between 1990 and 2022 that reported the cost of illness, and/or economic burden of CF. Costs were adjusted for inflation and reported as United States dollars. RESULTS: A total of 39 studies were included. Direct healthcare costs (e.g., medications, inpatient and outpatient care) were the most frequently reported. Most studies estimated the cost of CF using a prevalence-based (n = 18, 46.2 %), bottom-up approach (n = 23, 59 %). Direct non-healthcare costs and indirect costs were seldom included. The most frequently reported direct cost components were medications (n = 34, 87.2 %), inpatient care (n = 33, 84.6 %), and outpatient care (n = 31, 79.5 %). Twenty-eight percent (n = 11) of studies reported the burden of CF from all three perspectives (healthcare system (payer), individual, and society). Indirect costs of CF were reported in approximately 20 % of studies (n = 8). The reported total cost of CF varied widely, ranging from $451 to $160,000 per person per year (2022 US$). The total cost depended on the number of domains and perspectives included in each study. CONCLUSIONS: Most studies only reported costs to the healthcare system (i.e., hospitalizations and healthcare encounters) which likely underestimates the total costs of CF. The wide range of costs reported highlights the importance of standardizing perspectives, domains and costs when estimating the economic burden of CF.

Leucine Reduced Blood-Brain Barrier Disruption and Infarct Size in Early Cerebral Ischemia-Reperfusion.

A disruption of the blood-brain barrier (BBB) is a crucial pathophysiological change that can impact the outcome of a stroke. Ribosomal protein S6 (S6) and protein kinase B (Akt) play significant roles in early cerebral ischemia-reperfusion injury. Studies have suggested that branched-chain amino acids (BCAAs) may have neuroprotective properties for spinal cord or brain injuries. Therefore, we conducted research to investigate if leucine, one of the BCAAs, could offer neuroprotection and alter BBB disruption, along with its effects on the phosphorylation of S6 and Akt during the early phase of cerebral ischemia-reperfusion, specifically within the thrombolytic therapy time window. In rats, ten min after left middle cerebral artery occlusion (MCAO), 5 µL of 20 mM L-leucine or normal saline was injected into the left lateral ventricle. After two hours of reperfusion following one hour of MCAO, we determined the transfer coefficient (Ki) of 14C-α-aminoisobutyric acid to assess the BBB disruption, infarct size, and phosphorylation of S6 and Akt. Ischemia-reperfusion increased the Ki (+143%, p < 0.001) and the intra-cerebroventricular injection of leucine lowered the Ki in the ischemic-reperfused cortex (-34%, p < 0.001). Leucine reduced the percentage of cortical infarct (-42%, p < 0.0001) out of the total cortical area. Ischemia-reperfusion alone significantly increased the phosphorylation of both S6 and Akt (p < 0.05). However, the administration of leucine had no further effect on the phosphorylation of S6 or Akt in the ischemic-reperfused cortex. This study suggests that an acute increase in leucine levels in the brain during early ischemia-reperfusion within a few hours of stroke may offer neuroprotection, possibly due to reduced BBB disruption being one of the major contributing factors. Leucine did not further increase the already elevated phosphorylation of S6 or Akt by ischemia-reperfusion under the current experimental conditions. Our data warrant further studies on the effects of leucine on neuronal survival and its mechanisms in the later stages of cerebral ischemia-reperfusion.

Survival of Campylobacter jejuni during in vitro culture with mixed bovine ruminal microorganisms in the presence of methanogen inhibitors.

Foodborne pathogen Campylobacter jejuni has been associated with ruminants. The objectives of this experiment were to determine C. jejuni survivability in mixed in vitro rumen microbial populations and the impact on methane production with or without methane inhibitors 2-bromosulfonate (BES) and/or sodium nitrate. When inoculated into rumen microbial populations without or with 0.5 mM BES, 5.0 mM nitrate or their combination, C. jejuni viability decreased from 4.7 ± 0.1 log10 colony forming units (CFU)/mL after 24 h. Loss of C. jejuni viability was greater (P < 0.05) when incubated under 100% CO2 compared to 50% H2:50% CO2, decreasing 1.46 versus 1.15 log units, respectively. C. jejuni viability was also decreased (P < 0.05) by more than 0.43 log units by the anti-methanogen treatments. Rumen microbial populations produced less methane (P = 0.05) when incubated with than without C. jejuni regardless of whether under 100% CO2 or 50% H2:50% CO2. For either gas phase, nitrate was decreased (13.2 versus 37.9%) by the anti-methanogen treatments versus controls although not always significant. C. jejuni-inoculated populations metabolized 16.4% more (P < 0.05) nitrate under H2:CO2 versus 100% CO2. Apparently, C. jejuni can compete for H2 with methanogens but has limited survivability under rumen conditions.

Consensus criteria for chronic rhinosinusitis disease control: an international Delphi Study.

BACKGROUND: Chronic rhinosinusitis (CRS) disease control is a global metric of disease status for CRS. While there is broad acceptance that it is an important treatment goal, there has been inconsistency in the criteria used to define CRS control. The objective of this study was to identify and develop consensus around essential criteria for assessment of CRS disease control. METHODS: Modified Delphi methodology consisting of three rounds to review a list of 24 possible CRS control criteria developed by a 12-person steering committee. The core authorship of the multidisciplinary EPOS 2020 guidelines was invited to participate. RESULTS: Thirty-two individuals accepted the invitation to participate and there was no dropout of participants throughout the entire study (3 rounds). Consensus essential criteria for assessment of CRS control were: overall symptom severity, need for CRS-related systemic corticosteroids in the prior 6 months, severity of nasal obstruction, and patient-reported CRS control. Near-consensus items were: nasal endoscopy findings, severity of smell loss, overall quality of life, impairment of normal activities and severity of nasal discharge. Participants’ comments provided insights into caveats of, and disagreements related to, near-consensus items. CONCLUSIONS: Overall symptom severity, use of CRS-related systemic corticosteroids, severity of nasal obstruction, and patient-reported CRS control are widely agreed upon essential criteria for assessment of CRS disease control. Consideration of near-consensus items to assess CRS control should be implemented with their intrinsic caveats in mind. These identified consensus CRS control criteria, together with evidence-based support, will provide a foundation upon which CRS control criteria with wide-spread acceptance can be developed.