Factors Related to Clinical Performance in Spine Surgery Fellowship: Can We Predict Success.

INTRODUCTION: The factors most important in the spine fellowship match may not ultimately correlate with quality of performance during fellowship. This study examined the spine fellow applicant metrics correlated with high application rank compared with the metrics associated with the strongest clinical performance during fellowship. METHODS: Spine fellow applications at three academic institutions were retrieved from the San Francisco Match database (first available to 2021) and deidentified for application review. Application metrics pertaining to research, academics, education, extracurriculars, leadership, examinations, career interests, and letter of recommendations were extracted. Attending spine surgeons involved in spine fellow selection at their institutions were sent a survey to rank (1) fellow applicants based on their perceived candidacy and (2) the strength of performance of their previous fellows. Pearson correlation assessed the associations of application metrics with theoretical fellow rank and actual performance. RESULTS: A total of 37 spine fellow applications were included (Institution A: 15, Institution B: 12, Institution C: 10), rated by 14 spine surgeons (Institution A: 6, Institution B: 4, Institution C: 4). Theoretical fellow rank demonstrated a moderate positive association with overall research, residency program rank, recommendation writer H-index, US Medical Licensing Examination (USMLE) scores, and journal reviewer positions. Actual fellow performance demonstrated a moderate positive association with residency program rank, recommendation writer H-index, USMLE scores, and journal reviewer positions. Linear regressions identified journal reviewer positions (ß = 1.73, P = 0.002), Step 1 (ß = 0.09, P = 0.010) and Step 3 (ß = 0.10, P = 0.002) scores, recommendation writer H-index (ß = 0.06, P = 0.029, and ß = 0.07, P = 0.006), and overall research (ß = 0.01, P = 0.005) as predictors of theoretical rank. Recommendation writer H-index (ß = 0.21, P = 0.030) and Alpha Omega Alpha achievement (ß = 6.88, P = 0.021) predicted actual performance. CONCLUSION: Residency program reputation, USMLE scores, and a recommendation from an established spine surgeon were important in application review and performance during fellowship. Research productivity, although important during application review, was not predictive of fellow performance. LEVEL OF EVIDENCE: III. STUDY DESIGN: Cohort Study.

Sequential emergence and contraction of epithelial subtypes in the prenatal human choroid plexus revealed by a stem cell model.

Despite the major roles of choroid plexus epithelial cells (CPECs) in brain homeostasis and repair, their developmental lineage and diversity remain undefined. In simplified differentiations from human pluripotent stem cells, derived CPECs (dCPECs) displayed canonical properties and dynamic multiciliated phenotypes that interacted with Aß uptake. Single dCPEC transcriptomes over time correlated well with human organoid and fetal CPECs, while pseudotemporal and cell cycle analyses highlighted the direct CPEC origin from neuroepithelial cells. In addition, time series analyses defined metabolic (type 1) and ciliogenic dCPECs (type 2) at early timepoints, followed by type 1 diversification into anabolic-secretory (type 1a) and catabolic-absorptive subtypes (type 1b) as type 2 cells contracted. These temporal patterns were then confirmed in independent derivations and mapped to prenatal stages using human tissues. In addition to defining the prenatal lineage of human CPECs, these findings suggest new dynamic models of ChP support for the developing human brain.

Microcystins with Modified Adda5-Residues from a Heterologous Microcystin Expression System.

Microcystins are hepatotoxic cyclic heptapeptides produced by some cyanobacterial species and usually contain the unusual ß-amino acid 3S-amino-9S-methoxy-2S,6,8S-trimethyl-10-phenyl-4E,6E-decadienoic acid (Adda) at position-5. The full microcystin gene cluster from Microcystis aeruginosa PCC 7806 has been expressed in Escherichia coli. In an earlier study, the engineered strain was shown to produce MC-LR and [d-Asp3]MC-LR, the main microcystins reported in cultures of M. aeruginosa PCC 7806. However, analysis of the engineered strain of E. coli using semitargeted liquid chromatography with high-resolution tandem mass spectrometry (LC-HRMS/MS) and thiol derivatization revealed the presence of 15 additional microcystin analogues, including four linear peptide variants and, in total, 12 variants with modifications to the Adda moiety. Four of the Adda-variants lacked the phenyl group at the Adda-terminus, a modification that has not previously been reported in cyanobacteria. Their HRMS/MS spectra contained the product-ion from Adda at m/z 135.1168, but the commonly observed product-ion at m/z 135.0804 from Adda-containing microcystins was almost completely absent. In contrast, three of the variants were missing a methyl group between C-2 and C-8 of the Adda moiety, and their LC-HRMS/MS spectra displayed the product-ion from Adda at m/z 135.0804. However, instead of the product-ion at m/z 135.1168, these three variants gave product-ions at m/z 121.1011. These observations, together with spectra from microcystin standards using in-source fragmentation, showed that the product-ion at m/z 135.1168 found in the HRMS/MS spectra of most microcystins originated from the C-2 to C-8 region of the Adda moiety. Identification of the fragmentation pathways for the Adda side chain will facilitate the detection of microcystins containing modifications in their Adda moieties that could otherwise easily be overlooked with standard LC-MS screening methods. Microcystin variants containing Abu at position-1 were also prominent components of the microcystin profile of the engineered bacterium. Microcystin variants with Abu1 or without the phenyl group on the Adda side chain were not detected in the original host cyanobacterium. This suggests not only that the microcystin synthase complex may be affected by substrate availability within its host organism but also that it possesses an unexpected degree of biosynthetic flexibility.

Transforaminal lumbar interbody fusion subsidence: computed tomography analysis of incidence, associated risk factors, and impact on outcomes.

OBJECTIVE: The aims of this study were to 1) define the incidence of transforaminal lumbar interbody fusion (TLIF) interbody subsidence; 2) determine the relative importance of preoperative and intraoperative patient- and instrumentation-specific risk factors predictive of postoperative subsidence using CT-based assessment; and 3) determine the impact of TLIF subsidence on postoperative complications and fusion rates. METHODS: All adult patients who underwent one- or two-level TLIF for lumbar degenerative conditions at a multi-institutional academic center between 2017 and 2019 were retrospectively identified. Patients with traumatic injury, infection, malignancy, previous fusion at the index level, combined anterior-posterior procedures, surgery with greater than two TLIF levels, or incomplete follow-up were excluded. Interbody subsidence at the superior and inferior endplates of each TLIF level was directly measured on the endplate-facing surface of both coronal and sagittal CT scans obtained greater than 6 months postoperatively. Patients were grouped based on the maximum subsidence at each operative level classified as mild, moderate, or severe based on previously documented < 2-mm, 2- to 4-mm, and ≥ 4-mm thresholds, respectively. Univariate and regression analyses compared patient demographics, medical comorbidities, preoperative bone quality, surgical factors including interbody cage parameters, and fusion and complication rates across subsidence groups. RESULTS: A total of 67 patients with 85 unique fusion levels met the inclusion and exclusion criteria. Overall, 28% of levels exhibited moderate subsidence and 35% showed severe subsidence after TLIF with no significant difference in the superior and inferior endplate subsidence. Moderate (≥ 2-mm) and severe (≥ 4-mm) subsidence were significantly associated with decreases in cage surface area and Taillard index as well as interbody cages with polyetheretherketone (PEEK) material and sawtooth surface geometry. Severe subsidence was also significantly associated with taller preoperative disc spaces, decreased vertebral Hounsfield units (HU), the absence of bone morphogenetic protein (BMP) use, and smooth cage surfaces. Regression analysis revealed decreases in Taillard index, cage surface area, and HU, and the absence of BMP use predicted subsidence. Severe subsidence was found to be a predictor of pseudarthrosis but was not significantly associated with revision surgery. CONCLUSIONS: Patient-level risk factors for TLIF subsidence included decreased HU and increased preoperative disc height. Intraoperative risk factors for TLIF subsidence were decreased cage surface area, PEEK cage material, bullet cages, posterior cage positioning, smooth cage surfaces, and sawtooth surface designs. Severe subsidence predicted TLIF pseudarthrosis; however, the causality of this relationship remains unclear.

Quantifying the regime of thermodynamic control for solid-state reactions during ternary metal oxide synthesis.

The success of solid-state synthesis often hinges on the first intermediate phase that forms, which determines the remaining driving force to produce the desired target material. Recent work suggests that when reaction energies are large, thermodynamics primarily dictates the initial product formed, regardless of reactant stoichiometry. Here, we validate this principle and quantify its constraints by performing in situ characterization on 37 pairs of reactants. These experiments reveal a threshold for thermodynamic control in solid-state reactions, whereby initial product formation can be predicted when its driving force exceeds that of all other competing phases by ≥60 milli-electron volt per atom. In contrast, when multiple phases have a comparable driving force to form, the initial product is more often determined by kinetic factors. Analysis of the Materials Project data shows that 15% of possible reactions fall within the regime of thermodynamic control, highlighting the opportunity to predict synthesis pathways from first principles.

Alcohol Use Predicts Longer But More Fragmented Sleep: A Daily Diary Study of Alcohol, Sleep, and PTSD in Nurses.

BACKGROUND: Due to the demanding nature of their profession, nurses are at risk of experiencing irregular sleep patterns, substance use, and fatigue. Evidence supports a reciprocal relationship between alcohol use and sleep disturbances; however, no research has examined such a link in a sample of nurses. One factor that may further impact the dynamic between alcohol and sleep patterns is posttraumatic stress disorder (PTSD) symptoms. We investigated the daily bidirectional associations between alcohol use and several sleep domains (i.e., self-report and actigraphy-determined sleep), and moderation by baseline PTSD symptom severity. METHOD: Over a 14-day period, 392 nurses (92% female; 78% White) completed sleep diaries and actigraphy to assess alcohol use and sleep patterns. Within-person bidirectional associations between alcohol and sleep were examined using multilevel models, with symptoms of PTSD as a cross-level moderator. RESULTS: Daily alcohol use (i.e., ≥ 1 alcoholic beverage; 25.76%) was associated with shorter self-reported sleep onset latency (b = -4.21, p = .003) but longer self-reported wake after sleep onset (b = 2.36, p = .009). Additionally, days with any alcohol use were associated with longer self-reported sleep duration (b = 15.60, p = .006) and actigraphy-determined sleep duration (b = 10.06, p = .037). No sleep variables were associated with next-day alcohol use. Bidirectional associations between alcohol consumption and sleep were similar regardless of baseline PTSD symptoms. CONCLUSION: Our results suggested that on days when nurses drank alcohol, they experienced longer but also more fragmented sleep.

Follow up care for adults with diabetes treated for severe hypoglycemia by emergency medical Services, 2013-2019.

AIMS: To capture the types and content of healthcare encounters following severe hypoglycemia requiring emergency medical services (EMS) and to correlate their features with subsequent risk of severe hypoglycemia. METHODS: A retrospective cohort was obtained by linking data from a multi-state health system and an advanced life support ambulance service. This identified 1977 EMS calls by 1028 adults with diabetes experiencing hypoglycemia between 1/1/2013-12/31/2019. We evaluated the healthcare engagement over the following 7 days to identify rates of discussion of hypoglycemia, change of diabetes medications, glucagon prescribing, and referral for diabetes. RESULTS: Rates of hypoglycemia discussion increased with escalating levels of care, from 11.5 % after EMS calls without emergency department (ED) transport or outpatient clinical encounters to 98 % among hospitalized patients with outpatient follow-up. EMS transport and outpatient follow-up were associated with significantly higher odds of discussion of hypoglycemia (OR 60 and OR 22.1, respectively). Interventions were not impacted by previous severe hypoglycemia within 30 days. Prescription of glucagon was rare among all patients. CONCLUSIONS: Interventions to prevent recurrent hypoglycemia increase with escalating levels of care but remain inadequate and inconsistent with clinical guidelines. Greater attention is needed to ensure timely diabetes-related follow-up and treatment modification for patients experiencing severe hypoglycemia.

Evidence from comprehensive independent validation studies for smooth pursuit dysfunction as a sensorimotor biomarker for psychosis.

Smooth pursuit eye movements are considered a well-established and quantifiable biomarker of sensorimotor function in psychosis research. Identifying psychotic syndromes on an individual level based on neurobiological markers is limited by heterogeneity and requires comprehensive external validation to avoid overestimation of prediction models. Here, we studied quantifiable sensorimotor measures derived from smooth pursuit eye movements in a large sample of psychosis probands (N = 674) and healthy controls (N = 305) using multivariate pattern analysis. Balanced accuracies of 64% for the prediction of psychosis status are in line with recent results from other large heterogenous psychiatric samples. They are confirmed by external validation in independent large samples including probands with (1) psychosis (N = 727) versus healthy controls (N = 292), (2) psychotic (N = 49) and non-psychotic bipolar disorder (N = 36), and (3) non-psychotic affective disorders (N = 119) and psychosis (N = 51) yielding accuracies of 65%, 66% and 58%, respectively, albeit slightly different psychosis syndromes. Our findings make a significant contribution to the identification of biologically defined profiles of heterogeneous psychosis syndromes on an individual level underlining the impact of sensorimotor dysfunction in psychosis.

TRPV4 neuromuscular disease registry highlights bulbar, skeletal and proximal limb manifestations.

Dominant missense mutations of the calcium-permeable cation channel TRPV4 cause Charcot-Marie-Tooth disease (CMT) type 2C and two forms of distal spinal muscular atrophy. These conditions are collectively referred to as TRPV4-related neuromuscular disease and share features of motor greater than sensory dysfunction and frequent vocal fold weakness. Pathogenic variants lead to gain of ion channel function that can be rescued by TRPV4 antagonists in cellular and animal models. As small molecule TRPV4 antagonists have proven safe in trials for other disease indications, channel inhibition is a promising therapeutic strategy for TRPV4 patients. However, the current knowledge of the clinical features and natural history of TRPV4-related neuromuscular disease is insufficient to enable rational clinical trial design. To address these issues, we developed a TRPV4 patient database and administered a TRPV4-specific patient questionnaire. Here, we report demographic and clinical information, including CMT examination scores (CMTES), from 68 patients with known pathogenic TRPV4 variants, 40 of whom also completed the TRPV4 patient questionnaire. TRPV4 patients showed a bimodal age of onset, with the largest peak occurring in the first 2 years of life. Compared to CMT1A patients, TRPV4 patients showed distinct symptoms and signs, manifesting more ambulatory difficulties and more frequent involvement of proximal arm and leg muscles. Although patients reported fewer sensory symptoms, sensory dysfunction was often detected clinically. Many patients were affected by vocal fold weakness (55%) and shortness of breath (55%), and 11% required ventilatory support. Skeletal abnormalities were common, including scoliosis (64%), arthrogryposis (33%), and foot deformities. Strikingly, patients with infantile onset of disease showed less sensory involvement and less progression of symptoms. These results highlight distinctive clinical features in TRPV4 patients, including motor-predominant disease, proximal arm and leg weakness, severe ambulatory difficulties, vocal fold weakness, respiratory dysfunction, and skeletal involvement. In addition, patients with infantile onset of disease appeared to have a distinct phenotype with less apparent disease progression based on CMTES. These collective observations indicate that clinical trial design for TRPV4-related neuromuscular disease should include outcome measures that reliably capture non-length dependent motor dysfunction, vocal fold weakness, and respiratory disease.

Hybrid deep learning and optimal graph search method for optical coherence tomography layer segmentation in diseases affecting the optic nerve.

Accurate segmentation of retinal layers in optical coherence tomography (OCT) images is critical for assessing diseases that affect the optic nerve, but existing automated algorithms often fail when pathology causes irregular layer topology, such as extreme thinning of the ganglion cell-inner plexiform layer (GCIPL). Deep LOGISMOS, a hybrid approach that combines the strengths of deep learning and 3D graph search to overcome their limitations, was developed to improve the accuracy, robustness and generalizability of retinal layer segmentation. The method was trained on 124 OCT volumes from both eyes of 31 non-arteritic anterior ischemic optic neuropathy (NAION) patients and tested on three cross-sectional datasets with available reference tracings: Test-NAION (40 volumes from both eyes of 20 NAION subjects), Test-G (29 volumes from 29 glaucoma subjects/eyes), and Test-JHU (35 volumes from 21 multiple sclerosis and 14 control subjects/eyes) and one longitudinal dataset without reference tracings: Test-G-L (155 volumes from 15 glaucoma patients/eyes). In the three test datasets with reference tracings (Test-NAION, Test-G, and Test-JHU), Deep LOGISMOS achieved very high Dice similarity coefficients (%) on GCIPL: 89.97±3.59, 90.63±2.56, and 94.06±1.76, respectively. In the same context, Deep LOGISMOS outperformed the Iowa reference algorithms by improving the Dice score by 17.5, 5.4, and 7.5, and also surpassed the deep learning framework nnU-Net with improvements of 4.4, 3.7, and 1.0. For the 15 severe glaucoma eyes with marked GCIPL thinning (Test-G-L), it demonstrated reliable regional GCIPL thickness measurement over five years. The proposed Deep LOGISMOS approach has potential to enhance precise quantification of retinal structures, aiding diagnosis and treatment management of optic nerve diseases.

An Analysis of Clinical Outcomes of Exploratory Pediatric Metformin Ingestions Reported to the Texas Poison Center Network From 2011 to 2021.

Background: Poison centers develop triage threshold guidelines for pediatric metformin ingestions. Our network uses 1700 mg, or 85 mg/kg. Objective: To describe the dose, clinical course, and outcomes for inadvertent metformin ingestions in children 5 years old and younger reported to our statewide poison center network. Methods: We searched the poison center database 2011 to 2021 for metformin ingestions in patients 5 years and younger. Variables included age, sex, weight, dose, symptoms, outcome, and more. We used descriptive statistics with medians and interquartile ranges (IQR) for continuous variables. Results: Of 669 cases, exposures by age were 208 (31.1%) 1 to 2 years, and 275 (41.1%) 2 years. Weight was recorded in 342 (51.1%) (median 13.5 kg; IQR: 3.7 kg), and dose in 149 (22.3%) (median 500 mg; IQR: 500 mg). Milligram/kilogram values were available for 103 (15.4%) with median 42.4 mg/kg, IQR: 39 mg/kg. Most (647, 98.5%) exposures were unintentional. Most (445/669, 66.5%) were managed at a non-healthcare facility, while 204 (30.7%) were already at or referred to a healthcare facility. Of these 204 patients, 169 (82.8%) were evaluated and treated at the emergency department and discharged. Four (2%) were admitted to critical care, and 7 (3.4%) to the ward. Medical outcomes by effect were 5 (0.7%) minor, 2 (0.3%) moderate, 253 (37.8%) none, 292 (43.6%) not followed (minimal effects possible), and no major effects or deaths. Of 20 clinical occurrences reported, vomiting was most common (8, 1.2%). Conclusion: Despite little recorded dosage information, pediatric metformin ingestions under 85 mg/kg had predominantly uneventful medical outcomes.

Study protocol of a systematic review and metaanalysis of stress and burnout among general surgery residents.

Introduction: Chronic workplace stress and burnout are impediments to physicians' professional fulfillment, healthcare organizations' efficiency, and patient care quality/safety. General surgery residents are especially at risk due to the complexity of their training. We report the protocol of a metaanalysis of chronic stress and burnout among Accreditation Council for Graduate Medical Education (ACGME)-affiliated general surgery residents in the era after duty-hour reforms, plus downstream effects on their health and clinical performance. Methods: The proposed systematic review and metaanalysis (PROSPERO registration CRD42021277626) will synthesize/pool data from studies of chronic stress and burnout among general surgery residents at ACGME-affiliated programs. The timeframe under review is subdivided into three intervals: (a) after the 2003 duty-hour restrictions but before 2011 reforms, (b) after the 2011 reforms but before the coronavirus pandemic, and (c) the first 3 years after the pandemic's outbreak. Only studies reporting outcomes based on validated instruments will be included. Qualitative studies, commentaries/editorials, narrative reviews, and studies not published in English will be excluded. Multivariable analyses will adjust for sample characteristics and the methodological quality of included studies. Conclusions: The metaanalysis will yield evidence reflecting experiences of North American-based general surgery residents in the years after ACGME-mandated duty-hour restructuring.

Safeguarding China's long-term sustainability against systemic disruptors.

China's long-term sustainability faces socioeconomic and environmental uncertainties. We identify five key systemic risk drivers, called disruptors, which could push China into a polycrisis: pandemic disease, ageing and shrinking population, deglobalization, climate change, and biodiversity loss. Using an integrated simulation model, we quantify the effects of these disruptors on the country's long-term sustainability framed by 17 Sustainable Development Goals (SDGs). Here we show that ageing and shrinking population, and climate change would be the two most influential disruptors on China's long-term sustainability. The compound effects of all disruptors could result in up to 2.1 and 7.0 points decline in the China's SDG score by 2030 and 2050, compared to the baseline with no disruptors and no additional sustainability policies. However, an integrated policy portfolio involving investment in education, healthcare, energy transition, water-use efficiency, ecological conservation and restoration could promote resilience against the compound effects and significantly improve China's long-term sustainability.

Disparate reactivity of a chiral iron(II) tetracarbene complex with organic azides.

A chiral tetra-NHC iron(II) complex and its disparate reactivity with multiple organic azides is reported. Both aryl and alkyl azides react with the iron(II) complex yielding three distinct products: an iron(IV) imide, an iron(IV) tetrazene, and a surprising and unprecedented double imide insertion complex.

Controlling Charge Percolation in Solutions of Metal Redox Active Polymers: Implications of Microscopic Polyelectrolyte Dynamics on Macroscopic Energy Storage.

Soluble redox-active polymers (RAPs) enable size-exclusion nonaqueous redox flow batteries (NaRFBs) which promise high energy density. Pendants along the RAPs not only store charge but also engage in electron transfer to varying extents based on their designs. Here, we explore these phenomena in Metal-containing Redox Active Polymers (M-RAPs, M = Ru, Fe, Co). We assess by using cyclic voltammetry and chronoamperometry with ultramicroelectrodes the current response to electrolyte concentration spanning 3 orders of magnitude. Currents scaled as Ru-RAP > Fe-RAP ≫ Co-RAP, consistent with electron self-exchange trends in the small molecule analogues of the MII/III redox pair. Varying the ionic strength of the electrolyte also revealed nonmonotonic behavior, evidencing the impact of polyelectrolytic dynamics on M-RAP redox response. We developed a model to account for the behavior by combining kinetic Monte Carlo and Brownian dynamics near a boundary representing an electrode. While 1D pendant-to-pendant charge transfer along the chain is not a strong function of electrolyte concentration, the microstructure of the RAP at different electrolyte concentrations is decisively impacted, yielding qualitative trends to those observed experimentally. M-RAP size-exclusion NaRFBs using a poly viologen as negolyte varied in average potential with ∼1.54 V for Ru-RAP, ∼1.37 V for Fe-RAP, and ∼0.52 V for Co-RAP. Comparison of batteries at their optimal and suboptimal solution conditions as gauged from analytical experiments showed clear correlations in performance. This work provides a blueprint for understanding the factors underpinning charge transfer in solutions of RAPs for batteries and beyond.

Optimizing accrual to a large-scale, clinically integrated randomized trial in anesthesiology: A 2-year analysis of recruitment.

BACKGROUND: Performing large randomized trials in anesthesiology is often challenging and costly. The clinically integrated randomized trial is characterized by simplified logistics embedded into routine clinical practice, enabling ease and efficiency of recruitment, offering an opportunity for clinicians to conduct large, high-quality randomized trials under low cost. Our aims were to (1) demonstrate the feasibility of the clinically integrated trial design in a high-volume anesthesiology practice and (2) assess whether trial quality improvement interventions led to more balanced accrual among study arms and improved trial compliance over time. METHODS: This is an interim analysis of recruitment to a cluster-randomized trial investigating three nerve block approaches for mastectomy with immediate implant-based reconstruction: paravertebral block (arm 1), paravertebral plus interpectoral plane blocks (arm 2), and serratus anterior plane plus interpectoral plane blocks (arm 3). We monitored accrual and consent rates, clinician compliance with the randomized treatment, and availability of outcome data. Assessment after the initial year of implementation showed a slight imbalance in study arms suggesting areas for improvement in trial compliance. Specific improvement interventions included increasing the frequency of communication with the consenting staff and providing direct feedback to clinician investigators about their individual recruitment patterns. We assessed overall accrual rates and tested for differences in accrual, consent, and compliance rates pre- and post-improvement interventions. RESULTS: Overall recruitment was extremely high, accruing close to 90% of the eligible population. In the pre-intervention period, there was evidence of bias in the proportion of patients being accrued and receiving the monthly block, with higher rates in arm 3 (90%) compared to arms 1 (81%) and 2 (79%, p = 0.021). In contrast, in the post-intervention period, there was no statistically significant difference between groups (p = 0.8). Eligible for randomization rate increased from 89% in the pre-intervention period to 95% in the post-intervention period (difference 5.7%; 95% confidence interval = 2.2%-9.4%, p = 0.002). Consent rate increased from 95% to 98% (difference of 3.7%; 95% confidence interval = 1.1%-6.3%; p = 0.004). Compliance with the randomized nerve block approach was maintained at close to 100% and availability of primary outcome data was 100%. CONCLUSION: The clinically integrated randomized trial design enables rapid trial accrual with a high participant compliance rate in a high-volume anesthesiology practice. Continuous monitoring of accrual, consent, and compliance rates is necessary to maintain and improve trial conduct and reduce potential biases. This trial methodology serves as a template for the implementation of other large, low-cost randomized trials in anesthesiology.

Vaccine effectiveness of 3rd generation mpox vaccines against mpox and disease severity: A systematic review and meta-analysis.

INTRODUCTION: Before the global mpox outbreak which began in 2022, the real-world vaccine effectiveness (VE) of mpox vaccines was unknown. We quantified the VE in the global population of 3rd generation or later mpox vaccines (MVA-BN, LC16m8, OrthopoxVac) compared with unvaccinated or other vaccinated states for infection, hospitalization and death. VE was stratified by 1-dose and 2-doses and post-exposure prophylaxis (PEP). METHODS: Studies were included if they measured vaccine efficacy or effectiveness in humans. Animal studies and immunogenicity studies were excluded. MEDLINE, Web of Science, Google Scholar, Embase, MedRxiv and grey literature were searched from January 1st, 1970, with the last search run on November 3, 2023 (Prospero, CRD42022345240). Risk of publication bias was assessed via funnel plots and Egger's test, and study quality via Newcastle-Ottawa scales. RESULTS: A total of 11,892 records were identified via primary search, 3,223 via citation chasing. Thirty-three studies were identified of 3rd generation vaccines, 32 of which were MVA-BN. Two additional studies were re-analysis of existing data. Most of these studies were focused on gay, bisexual, or other men who have sex with men between the ages of 18-49 in May to October of 2022. VE of 1 dose of MVA-BN was 76% (95%CI 64-88%) from twelve studies. VE of 2 doses was 82% (95%CI 72-92%) from six studies. VE of MVA-BN PEP against mpox was 20% (95%CI -24-65%) from seven studies. All VE are calculated from random effects estimates. 18/33(55%) studies were rated as poor, 3/33(9%) as fair and 12/33(36%) as good. Studies included in the meta-analysis had higher quality: 11/16 (69%) were rated as good quality. CONCLUSION: Both 1 and 2 doses of MVA-BN are highly effective at preventing mpox. Effectiveness estimates, specifically of PEP are limited by immortal time bias, predominant mode of mpox transmission, and real-world vaccine timing of administration.

Machine learning-based surrogate modelling of a robust, sustainable development goal (SDG)-compliant land-use future for Australia at high spatial resolution.

We developed a high-resolution machine learning based surrogate model to identify a robust land-use future for Australia which meets multiple UN Sustainable Development Goals. We compared machine learning models with different architectures to pick the best performing model considering the data type, accuracy metrics, ability to handle uncertainty and computational overhead requirement. The surrogate model, called ML-LUTO Spatial, was trained on the Land-Use Trade-Offs (version 1.0) model of Australian agricultural land system sustainability. Using the surrogate model, we generated projections of land-use futures at 1.1 km resolution with 95% classification accuracy, and which far surpassed the computational benchmarks of the original model. This efficiency enabled the generation of numerous SDG-compliant (SDGs 2, 6, 7, 13, 15) future land-use maps on a standard laptop, a task previously dependent upon high-performance computing clusters. Combining these projections, we derived a single, robust land-use future and quantified the uncertainty. Our findings indicate that while agricultural land-use remains dominant in all Australian regions, extensive carbon plantings were identified in Queensland and environmental plantings played a role across the study area, reflecting a growing urgency for offsetting greenhouse gas emissions and the restoration of ecosystems to support biodiversity across Australia to meet the 2050 Sustainable Development Goals.

Prediction of the Liver Safety Profile of a First-in-Class Myeloperoxidase Inhibitor Using Quantitative Systems Toxicology Modeling.

The novel myeloperoxidase inhibitor verdiperstat was developed as a treatment for neuroinflammatory and neurodegenerative diseases. During development, a computational prediction of verdiperstat liver safety was performed using DILIsym v8A, a quantitative systems toxicology (QST) model of liver safety.A physiologically-based pharmacokinetic (PBPK) model of verdiperstat was constructed in GastroPlus 9.8, and outputs for liver and plasma time courses of verdiperstat were input into DILIsym. In vitro experiments measured the likelihood that verdiperstat would inhibit mitochondrial function, inhibit bile acid transporters, and generate reactive oxygen species (ROS); these results were used as inputs into DILIsym, with two alternate sets of parameters used in order to fully explore the sensitivity of model predictions. Verdiperstat dosing protocols up to 600 mg BID were simulated for up to 48 weeks using a simulated population (SimPops) in DILIsym.Verdiperstat was predicted to be safe, with only very rare, mild liver enzyme increases as a potential possibility in highly sensitive individuals. Subsequent Phase 3 clinical trials found that ALT elevations in the verdiperstat treatment group were generally similar to those in the placebo group. This validates the DILIsym simulation results and demonstrates the power of QST modeling to predict the liver safety profile of novel therapeutics.

Pulsed reduced-dose rate re-irradiation for patients with recurrent grade 2 gliomas.

Background: Patients with grade 2 glioma exhibit highly variable survival. Re-irradiation for recurrent disease has limited mature clinical data. We report treatment results of pulsed reduced-dose rate (PRDR) radiation for patients with recurrent grade 2 glioma. Methods: A retrospective analysis of 58 patients treated with PRDR from 2000 to 2021 was performed. Radiation was delivered in 0.2 Gy pulses every 3 minutes encompassing tumor plus margin. Survival outcomes and prognostic factors on outcome were Kaplan-Meier and Cox regression analyses. Results: The median survival from the date of initial surgery was 8.6 years (95% CI: 5.5-11.8 years). 69% of patients showed malignant transformation to grade 3 (38%) or grade 4 (31%) glioma. Overall survival following PRDR was 12.6 months (95% CI: 8.3-17.0 months) and progression-free survival was 6.2 months (95% CI: 3.8-8.6 months). Overall response rate based on post-PRDR MRI was 36%. In patients who maintained grade 2 histology at recurrence, overall survival from PRDR was 22.0 months with 5 patients remaining disease-free, the longest at 8.2 and 11.4 years. PRDR was generally well tolerated. Conclusions: To the best of our knowledge, this is the largest reported series of patients with recurrent grade 2 gliomas treated with PRDR radiation for disease recurrence. We demonstrate promising survival and acceptable toxicity profiles following re-irradiation. In the cohort of patients who maintain grade 2 disease, prolonged survival (>5 years) is observed in selected patients. For the entire cohort, 1p19q codeletion, KPS, and longer time from initial diagnosis to PRDR were associated with improved survival.