Dynamic regulation of water potential in Juniperus osteosperma mediates ecosystem carbon fluxes.

Some plants exhibit dynamic hydraulic regulation, in which the strictness of hydraulic regulation (i.e. iso/anisohydry) changes in response to environmental conditions. However, the environmental controls over iso/anisohydry and the implications of flexible hydraulic regulation for plant productivity remain unknown. In Juniperus osteosperma, a drought-resistant dryland conifer, we collected a 5-month growing season time series of in situ, high temporal-resolution plant water potential ( Ψ $$ \Psi $$ ) and stand gross primary productivity (GPP). We quantified the stringency of hydraulic regulation associated with environmental covariates and evaluated how predawn water potential contributes to empirically predicting carbon uptake. Juniperus osteosperma showed less stringent hydraulic regulation (more anisohydric) after monsoon precipitation pulses, when soil moisture and atmospheric demand were high, and corresponded with GPP pulses. Predawn water potential matched the timing of GPP fluxes and improved estimates of GPP more strongly than soil and/or atmospheric moisture, notably resolving GPP underestimation before vegetation green-up. Flexible hydraulic regulation appears to allow J. osteosperma to prolong soil water extraction and, therefore, the period of high carbon uptake following monsoon precipitation pulses. Water potential and its dynamic regulation may account for why process-based and empirical models commonly underestimate the magnitude and temporal variability of dryland GPP.

Wilderness Medical Society Clinical Practice Guidelines for the Treatment of Acute Pain in Austere Environments: 2024 Update.

The Wilderness Medical Society (WMS) convened an expert panel to develop evidence-based guidelines for the management of pain in austere environments. Recommendations are graded based on the quality of supporting evidence as defined by criteria put forth by the American College of Chest Physicians. This is an update of the 2014 version of the "WMS Practice Guidelines for the Treatment of Acute Pain in Remote Environments" published in Wilderness & Environmental Medicine 2014; 25:41-49.

Endovascular Applications for the Management of High-Grade Gliomas in the Modern Era.

High-grade gliomas (HGGs) have a poor prognosis and are difficult to treat. This review examines the evolving landscape of endovascular therapies for HGGs. Recent advances in endovascular catheter technology and delivery methods allow for super-selective intra-arterial cerebral infusion (SSIACI) with increasing precision. This treatment modality may offer the ability to deliver anti-tumoral therapies directly to tumor regions while minimizing systemic toxicity. However, challenges persist, including blood-brain barrier (BBB) penetration, hemodynamic complexities, and drug-tumor residence time. Innovative adjunct techniques, such as focused ultrasound (FUS) and hyperosmotic disruption, may facilitate BBB disruption and enhance drug penetration. However, hemodynamic factors that limit drug residence time remain a limitation. Expanding therapeutic options beyond chemotherapy, including radiotherapy and immunobiologics, may motivate future investigations. While preclinical and clinical studies demonstrate moderate efficacy, larger randomized trials are needed to validate the clinical benefits. Additionally, future directions may involve endovascular sampling for peri-tumoral surveillance; changes in drug formulations to prolong residence time; and the exploration of non-pharmaceutical therapies, like radioembolization and photodynamic therapy. Endovascular strategies hold immense potential in reshaping HGG treatment paradigms, offering targeted and minimally invasive approaches. However, overcoming technical challenges and validating clinical efficacy remain paramount for translating these advancements into clinical care.

Radical surgical resection with molecular margins is associated with improved survival in IDH wildtype GBM.

BACKGROUND: Survival is variable in patients with glioblastoma IDH wild-type (GBM), even after comparable surgical resection of radiographically-detectable disease, highlighting the limitations of radiographic assessment of infiltrative tumor anatomy. The majority of post-surgical progressive events are failures within 2cm of the resection margin, motivating supramaximal resection strategies to improve local control. However, which patients benefit from such radical resections remains unknown. METHODS: We developed a predictive model to identify which IDH wild-type GBM are amenable to radiographic gross total resection (GTR). We then investigated whether GBM survival heterogeneity following GTR is correlated with microscopic tumor burden a by analyzing tumor cell content at the surgical margin with a rapid qPCR-based method for detection of TERT promoter mutation. RESULTS: Our predictive model for achievable GTR, developed on retrospective radiographic and molecular data of GBM patients undergoing resection, had an AUC of 0.83, sensitivity of 62%, and specificity of 90%. Prospective analysis of this model in 44 patients found 89% of patients were correctly predicted to achieve a RV<4.9cc. Of the 44 prospective patients undergoing rapid qPCR TERT promoter mutation analysis at the surgical margin, 7 had undetectable TERT mutation, of which 5 also had a gross total resection (RV<1cc). In these 5 patients at 30 months follow up, 75% showed no progression, compared to 0% in the group with TERT mutations detected at the surgical margin (p=0.02). CONCLUSIONS: These findings identify a subset of patients with GBM that may derive local control benefit from radical resection to undetectable molecular margins.

Tobacco smoking and nicotine vaping in persons with first episode psychosis.

Tobacco smoking is highly prevalent in persons with psychosis and is the leading cause of preventable mortality in this population. Less is known about tobacco smoking in persons with first episode psychosis (FEP) and there have been no estimates about the prevalence of nicotine vaping in FEP. This study reports rates of tobacco smoking and nicotine vaping in young people with FEP enrolled in Coordinated Specialty Care programs in Pennsylvania and Maryland. Using data collected from 2021 to 2023, we examined lifetime and recent smoking and vaping and compared smokers and vapers to nonusers on symptoms, functioning, and substance use. The sample included 445 participants aged 13-35 with recent psychosis onset. Assessments were collected by program staff. Overall, 28 % of participants engaged in either smoking or vaping within 30 days of the admission assessment. Smokers and vapers were disproportionately male, cannabis users, and had lower negative symptom severity than non-smokers. Vapers had higher role and social functioning. Both smoking and vaping were related to a longer time from psychosis onset to program enrollment. We compare these findings to previous studies and suggest steps for addressing smoking and vaping in this vulnerable population.

Improving the performance of machine learning penicillin adverse drug reaction classification with synthetic data and transfer learning.

BACKGROUND: Machine learning may assist with the identification of potentially inappropriate penicillin allergy labels. Strategies to improve the performance of existing models for this task include the use of additional training data, synthetic data and transfer learning. AIMS: The aims of this study were to investigate the use of additional training data and novel machine learning strategies, namely synthetic data and transfer learning, to improve the performance of penicillin adverse drug reaction (ADR) machine learning classification. METHODS: Machine learning natural language processing was applied to free-text penicillin ADR data extracted from a public health system electronic health record (EHR). The models were developed by training on various labelled data sets. ADR entries were split into training and testing data sets and used to develop and test a variety of machine learning models. The effect of training on additional data and synthetic data versus the use of transfer learning was analysed. RESULTS: Following the application of these techniques, the area under the receiver operator curve of best-performing models for the classification of penicillin allergy (vs intolerance) and high-risk allergy (vs low-risk allergy) improved to 0.984 (using the artificial neural network model) and 0.995 (with the transfer learning approach) respectively. CONCLUSIONS: Machine learning models demonstrate high levels of accuracy in the classification and risk stratification of penicillin ADR labels using the reaction documented in the EHR. The model can be further optimised by incorporating additional training data and using transfer learning. Practical applications include automating case detection for penicillin allergy delabelling programmes.

Clinical indications, safety, and effectiveness of percutaneous image-guided adrenal mass biopsy: an 8-year retrospective analysis in 160 patients.

PURPOSE: To assess indications, safety, and effectiveness of percutaneous adrenal mass biopsy in contemporary practice. METHODS: This institutional review board-approved, retrospective study included all patients undergoing percutaneous image-guided adrenal mass biopsies at an academic health system from January 6, 2015, to January 6, 2023. Patient demographics, biopsy indications, mass size, laboratory data, pathology results, and complications were recorded. Final diagnoses were based on pathology or ≥ 1 year of imaging follow-up when biopsy specimens did not yield malignant tissue. Test performance calculations excluded repeat biopsies. Continuous variables were compared with Student's t test, dichotomous variables with chi-squared test. RESULTS: A total of 160 patients underwent 186 biopsies. Biopsies were indicated to diagnose metastatic disease (139/186; 74.7%), for oncologic research only (27/186; 14.5%), diagnose metastatic disease and oncologic research (15/186; 8%), and diagnose an incidental adrenal mass (5/186; 2.7%). Biopsy specimens were diagnostic in 154 patients (96.3%) and non-diagnostic in 6 (3.8%). Diagnostic biopsies yielded malignant tissue (n = 136), benign adrenal tissue (n = 12), and benign adrenal neoplasms (n = 6) with sensitivity = 98.6% (136/138), specificity = 100% (16/16), positive predictive value = 100% (136/136), and negative predictive value = 88.9% (16/18). Adverse events followed 11/186 procedures (5.9%) and most minor (7/11, 63.6%). The adverse event rate was similar whether tissue was obtained for clinical or research purposes (10/144; 6.9% vs. 1/42; 2.4%, p = 0.27), despite more specimens obtained for research (5.8 vs. 3.7, p < 0.001). CONCLUSION: Percutaneous adrenal mass biopsy is safe, accurate, and utilized almost exclusively to diagnose metastatic disease or for oncologic research. The negative predictive value is high when diagnostic tissue samples are obtained. Obtaining specimens for research does not increase adverse event risk.

Novel multimodal cation-exchange membrane for the purification of a single-chain variable fragment from Pichia pastoris supernatant.

A novel salt-tolerant cation-exchange membrane, prepared with a multimodal ligand, 2-mercaptopyridine-3-carboxylic acid (MMC-MPCA), was examined for its purification properties in a bind-and-elute mode from the high conductivity supernatant of a Pichia pastoris fermentation producing and secreting a single-chain variable fragment (scFv). If successful, this approach would eliminate the need for a buffer exchange prior to product capture by ion-exchange. Two fed-batch fermentations of Pichia pastoris resulted in fermentation supernatants reaching an scFv titer of 395.0 mg/L and 555.7 mg/L, both with a purity of approximately 83 %. The MMC-MPCA membrane performance was characterized in terms of pH, residence time (RT), scFv load, and scFv concentration to identify the resulting dynamic binding capacity (DBC), yield, and purity achieved under optimal conditions. The MMC-MPCA membrane exhibited the highest DBC of 39.06 mg/mL at pH 5.5, with a residence time of 1 min, while reducing the pH below 5.0 resulted in a significant decrease of the DBC to around 2.5 mg/mL. With almost no diffusional limitations, reducing the RT from 2 to 0.2 min did not negatively impact the DBC of the MMC-MPCA membrane, resulting in a significant improvement in productivity of up to 180 mg/mL/min at 0.2 min RT. Membrane fouling was observed when reusing the membranes at 0.2 and 0.5 min RT, likely due to the enhanced adsorption of impurities on the membrane. Changing the amount of scFv loaded onto the membrane column did not show any changes in yield, instead a 10-20 % loss of scFv was observed, which suggested that some of the produced scFv were fragmented or had aggregated. When performing the purification under the optimized conditions, the resulting purity of the product improved from 83 % to approximately 92-95 %.

Chronic total occlusion in non-ST elevation myocardial infarction - A multi-centre observational study.

OBJECTIVES: To evaluate the characteristics and outcomes of patients with a chronic total occlusion (CTO) in a Non-ST Elevation Myocardial Infarction (NSTEMI) cohort. BACKGROUND: There is limited data on the clinical characteristics, revascularisation strategies and outcomes of patients presenting with a NSTEMI and a CTO. METHODS: Retrospective analysis of a six-centre percutaneous coronary intervention (PCI) registry in the UK between January 2015 and December 2020 was performed. Patients with a NSTEMI with and without a CTO were compared for baseline characteristics and outcomes. RESULTS: There were 17,355 NSTEMI patients in total of whom 1813 patients had a CTO (10.4 %). Patients with a CTO were more likely to be older (CTO: 67.8 (±11.5) years vs. no CTO: 67.2 (±12) years, p = 0.04), male (CTO: 81.1 % vs.71.9 %, p < 0.0001) with a greater prevalence of cardiovascular risk factors. All-cause mortality at 30 days: HR 2.63, 95 % CI 1.42-4.84, p = 0.002 and at 1 year: HR: 1.87, 95 % CI 1.25-2.81, p = 0.003 was higher in the CTO cohort. CTO patients who underwent revascularisation were younger (Revascularisation 66.4 [±11.7] years vs. no revascularisation 68.4 [±11.4] years, p = 0.001). Patients with failed CTO revascularisation had lower survival (HR 0.21, 95 % CI 0.10-0.42, p < 0.0001). The mean time to revascularisation was 13.4 days. There was variation in attempt at CTO revascularisation between the 6 centres for (16 % to 100 %) with success rates ranging from 65 to 100 %. CONCLUSIONS: In conclusion, the presence of a CTO in NSTEMI patients undergoing PCI was associated with worse in-hospital and long-term outcomes.

Antibiotic prophylaxis in immunosuppressed patients - Missed opportunities from trimethoprim-sulfamethoxazole allergy label.

Trimethoprim-sulfamethoxazole (TMP-SMX) is a broad spectrum antibiotic in use for more than 50 years. It has an important indication as first line agent in the prophylaxis of opportunistic infections, particularly Pneumocystis jirovecii pneumonia (PJP), in immunosuppressed patients. For those who have a history of allergy or severe intolerance to TMP-SMX, pentamidine, dapsone or atovaquone may be substituted; however there is evidence that TMP-SMX offers superior coverage for PJP, toxoplasmosis, and nocardiosis. Compared to pentamidine, it has the added benefit of cost-effectiveness and self-administration as opposed to required hospital attendance for administration. Many patients who report a history of allergy or adverse reaction to TMP-SMX (or "sulfur allergy") will be found not to be allergic; and even those who are allergic may be able to be desensitized. The evaluation and, where appropriate, removal of TMP-SMX allergy label enables the use of TMP-SMX for prophylaxis against opportunistic infections. This is a cost-effective intervention to optimize antimicrobial prescribing and reduce the risk of opportunistic infections in immunosuppressed patients.

Evaluating real-world emissions from in-use buses and taxis using on-road remote sensing.

Assessing real-world emissions from buses and taxis is vital to comprehend their impact on urban air quality. Such vehicles differ significantly from the majority of the fleet owing to their higher mileage rates. However, few studies have focused on specifically assessing the emissions from this segment of the vehicle fleet. In this context, this study evaluated the real-world emissions of nitrogen oxides (NOx) from in-use buses and taxis in Dublin, Ireland, using crossroad remote sensing technology. The remote sensing system was deployed at strategic locations throughout the city to capture on-road emissions from passing vehicles. The collected data included vehicle related information such as emission standard, make, and mileage, and pollutants including NOx. Based on this data, analysis was aimed to understand the impact of Euro emission standard, ambient temperature, mileage, and make of the vehicle on NOx emissions. The results reveal that the average emissions from taxis reduce by 37% from Euro 5 to Euro 6b, and average emissions from Euro 6 buses are 87% lower compared to Euro 5. The trends in emission factors (EFs) of buses and taxis were similar during summer and winter sampling. Moreover, on comparing the emissions from the top five taxi manufacturers, different trends in the emission factors were observed. Finally, the study found that the effect of vehicle mileage on emissions was unclear for both buses and taxis. In any case, these findings provide valuable insights into the real-world emission performance of the existing fleet of buses and taxis in Dublin and highlight the need for targeted measures to reduce emissions from these vehicles. The results can assist policymakers and urban planners in formulating evidence-based strategies to improve air quality in Dublin and other cities facing similar challenges.

Application of Global Lung Function Initiative Global Spirometry Reference Equations across a Large, Multicenter Pulmonary Function Lab Population.

Rationale: Global Lung Function Initiative (GLI) Global spirometry reference equations were recently derived to offer a "race-neutral" interpretation option. The impact of transitioning from the race-specific GLI-2012 to the GLI Global reference equations is unknown. Objectives: Describe the direction and magnitude of changes in predicted lung function measurements in a population of diverse race and ethnicity using GLI Global in place of GLI-2012 reference equations. Methods: In this multicenter cross-sectional study using a large pulmonary function laboratory database, 109,447 spirometry tests were reanalyzed using GLI Global reference equations and compared with the existing GLI-2012 standard, stratified by self-reported race and ethnicity. Measurements and Main Results: Mean FEV1 and FVC percent predicted increased in the White and Northeast Asian groups and decreased in the Black, Southeast Asian, and mixed/other race groups. The prevalence of obstruction increased by 9.7% in the White group, and prevalences of possible restriction increased by 51.1% and 37.1% in the Black and Southeast Asian groups, respectively. Using GLI Global in a population with equal representation of all five race and ethnicity groups altered the interpretation category for 10.2% of spirometry tests. Subjects who self-identified as Black were the only group with a relative increase in the frequency of abnormal spirometry test results (32.9%). Conclusions: The use of GLI Global reference equations will significantly impact spirometry interpretation. Although GLI Global offers an innovative approach to transition from race-specific reference equations, it is important to recognize the continued need to place these data within an appropriate clinical context.

Rational design and experimental evaluation of peptide ligands for the purification of adeno-associated viruses via affinity chromatography.

Adeno-associated viruses (AAVs) have acquired a central role in modern medicine as delivery agents for gene therapies targeting rare diseases. While new AAVs with improved tissue targeting, potency, and safety are being introduced, their biomanufacturing technology is lagging. In particular, the AAV purification pipeline hinges on protein ligands for the affinity-based capture step. While featuring excellent AAV binding capacity and selectivity, these ligands require strong acid (pH <3) elution conditions, which can compromise the product's activity and stability. Additionally, their high cost and limited lifetime has a significant impact on the price tag of AAV-based therapies. Seeking to introduce a more robust and affordable affinity technology, this study introduces a cohort of peptide ligands that (i) mimic the biorecognition activity of the AAV receptor (AAVR) and anti-AAV antibody A20, (ii) enable product elution under near-physiological conditions (pH 6.0), and (iii) grant extended reusability by withstanding multiple regenerations. A20-mimetic CYIHFSGYTNYNPSLKSC and AAVR-mimetic CVIDGSQSTDDDKIC demonstrated excellent capture of serotypes belonging to distinct clones/clades - namely, AAV1, AAV2, AAV5, AAV6, AAV8, and AAV9. This corroborates the in silico models documenting their ability to target regions of the viral capsid that are conserved across all serotypes. CVIDGSQSTDDDKIC-Toyopearl resin features binding capacity (≈1014 vp mL-1 ) and product yields (≈60%-80%) on par with commercial adsorbents, and purifies AAV2 from HEK293 and Sf9 cell lysates with high recovery (up to 78%), reduction of host cell proteins (up to 700-fold), and high transduction activity (up to 65%).

Endocervical crypt involvement by high-grade cervical intraepithelial neoplasia and its association with high-grade histopathological recurrence after cervical excision in women with negative excision margins: a systematic review and meta-analysis.

BACKGROUND: There is a growing body of evidence suggesting that endocervical crypt involvement by high-grade cervical intraepithelial neoplasia (CIN) may represent a risk factor for disease recurrence after cervical treatment. OBJECTIVES: To provide a systematic review and meta-analysis on whether endocervical crypt involvement by high-grade CIN on the excised cervical specimen is associated with high-grade histopathological recurrence during the follow-up of women after cervical excisional treatment. SEARCH STRATEGY: We searched the Medline, Scopus, Central, and Clinical Trials.gov databases from inception till May 2023. SELECTION CRITERIA: Studies that reported on women with a single cervical treatment with any method of excision for CIN2 or CIN3 lesion, negative excision margins, and whose recurrence was defined histopathologically were included. DATA COLLECTION AND ANALYSIS: Two reviewers independently evaluated study eligibility. We used the fixed effects model for meta-analysis. MAIN RESULTS: There were 4 eligible studies included in the present systematic review that evaluated 1088 women treated with either large loop excision of the transformation zone (LLETZ) or with cold knife conization (CKC). We found no significant association of endocervical crypt involvement by CIN2-3 with high-grade histopathological recurrence at follow-up after cervical excision (OR 1.93; 95% CI 0.51-3.35). The subgroup analysis of women with LLETZ cervical excision showed again no significant association with high-grade histopathological recurrence at follow-up (OR 2.00; 95% CI 0.26-3.74). CONCLUSION: Endocervical crypt involvement by high-grade CIN does not seem to be a risk factor for high-grade histopathological recurrence after cervical excision with negative excision margins.

Wilderness Medical Society Clinical Practice Guidelines for Prevention and Management of Avalanche and Nonavalanche Snow Burial Accidents: 2024 Update.

To provide guidance to the general public, clinicians, and avalanche professionals about best practices, the Wilderness Medical Society convened an expert panel to revise the evidence-based guidelines for the prevention, rescue, and resuscitation of avalanche and nonavalanche snow burial victims. The original panel authored the Wilderness Medical Society Practice Guidelines for Prevention and Management of Avalanche and Nonavalanche Snow Burial Accidents in 2017. A second panel was convened to update these guidelines and make recommendations based on quality of supporting evidence.

Phase 1 trial supports safety and mechanism of action of peptide immunotherapy for peanut allergy.

BACKGROUND: Food allergy is a leading cause of anaphylaxis worldwide. Allergen-specific immunotherapy is the only treatment shown to modify the natural history of allergic disease, but application to food allergy has been hindered by risk of severe allergic reactions and short-lived efficacy. Allergen-derived peptides could provide a solution. PVX108 comprises seven short peptides representing immunodominant T-cell epitopes of major peanut allergens for treatment of peanut allergy. METHODS: Pre-clinical safety of PVX108 was assessed using ex vivo basophil activation tests (n = 185). Clinical safety and tolerability of single and repeat PVX108 doses were evaluated in a first-in-human, randomized, double-blind, placebo-controlled trial in peanut-allergic adults (46 active, 21 placebo). The repeat-dose cohort received six doses over 16 weeks with safety monitored to 21 weeks. Exploratory immunological analyses were performed at pre-dose, Week 21 and Month 18 after treatment. RESULTS: PVX108 induced negligible activation of peanut-sensitised basophils. PVX108 was safe and well tolerated in peanut-allergic adults. There were no treatment-related hypersensitivity events or AEs of clinical concern. The only events occurring more frequently in active than placebo were mild injection site reactions. Exploratory immunological analyses revealed a decrease in the ratio of ST2+ Th2A:CCR6+ Th17-like cells within the peanut-reactive Th pool which strengthened following treatment. CONCLUSION: This study supports the concept that PVX108 could provide a safe alternative to whole peanut immunotherapies and provides evidence of durable peanut-specific T-cell modulation. Translation of these findings to clinical efficacy in ongoing Phase 2 trials would provide important proof-of-concept for using peptides to treat food allergy.