A pragmatic approach to teaching physician assistant students basic pain management.

Chronic pain is increasing in prevalence, with new cases now outnumbering those of diabetes, depression, or hypertension. Advanced practice providers have reported that their training in pain management inadequately prepared them to care for patients suffering from painful conditions. In response, the authors of this work developed a basic pain management conceptual framework to provide physician assistant (PA) students with the foundational knowledge necessary to manage and treat patients suffering from a wide variety of painful conditions. The devised framework activity includes categories of pain management such as conservative therapies, medications, injections, minimally invasive procedures, and moderately to highly invasive procedures. This framework can be incorporated into the existing PA educational curriculum and presented alongside a realistic pain patient case study. Furthermore, other health science educational programs, such as nurse practitioner or pharmacy programs, could adopt this framework to increase student knowledge in pain management.

Artificial intelligence-based extraction of quantitative ultra-widefield fluorescein angiography parameters in retinal vein occlusion.

BACKGROUND: To examine the association between quantitative vascular parameters extracted from intravenous fluorescein angiography (IVFA) and baseline clinical characteristics of patients with retinal vein occlusion (RVO). METHODS: Our prospective single-centre study in Toronto, Canada, recruited patients with a diagnosis of macular edema secondary to RVO presenting with a central macular thickness (CMT) ≥310 µm from 2017 to 2023. IVFA images were captured using an ultra-widefield scanning laser ophthalmoscope and processed using the artificial intelligence-based RETICAD system to extract quantitative measurements of blood flow, perfusion, and blood-retinal barrier (BRB) permeability. Univariable and multivariable regression models were used to investigate associations between quantitative IVFA parameters and baseline best-corrected visual acuity (BCVA), CMT, and macular volume. RESULTS: The study included 41 eyes from 41 RVO patients. In the multivariable analysis, BRB permeability was significantly associated with both CMT (p < 0.001) and macular volume (p = 0.005). Subgroup analyses revealed that in central retinal vein occlusion patients, central BRB permeability remained significantly associated with CMT (p = 0.022) and macular volume (p = 0.010); however, there was no association with BCVA (p = 0.921). In branch retinal vein occlusion patients, central BRB permeability was significantly associated with BCVA (p = 0.006) and CMT (p = 0.009), but not with macular volume (p = 0.723). Additionally, both central and peripheral BRB permeability was significantly higher in patients with RVO compared to healthy controls (p < 0.001). CONCLUSIONS: Our investigation reveals novel associations between baseline clinical characteristics and quantitative IVFA parameters in RVO patients, which may serve as clinically relevant biomarkers. Future studies should explore these associations in diverse RVO patient populations with extended follow-up.

Engineering thioesterase as a driving force for novel itaconate production via its degradation scheme.

Incorporation of irreversible steps in pathway design enhances the overall thermodynamic favorability and often leads to better bioconversion yield given functional enzymes. Using this concept, here we constructed the first non-natural itaconate biosynthesis pathway driven by thioester hydrolysis. Itaconate is a commercially valuable platform chemical with wide applications in the synthetic polymer industry. Production of itaconate has long relied on the decarboxylation of TCA cycle intermediate cis-aconitate as the only biosynthetic route. Inspired by nature's design of itaconate detoxification, here we engineered a novel itaconate producing pathway orthogonal to native metabolism with no requirement of auxotrophic knock-out. The reversed degradation pathway initiates with pyruvate and acetyl-CoA condensation forming (S)-citramalyl-CoA, followed by its dehydration and isomerization into itaconyl-CoA then hydrolysis into itaconate. Phenylacetyl-CoA thioesterase (PaaI) from Escherichia coli was identified via screening to deliver the highest itaconate formation efficiency when coupled to the reversible activity of citramalate lyase and itaconyl-CoA hydratase. The preference of PaaI towards itaconyl-CoA hydrolysis over acetyl-CoA and (S)-citramalyl-CoA also minimized the inevitable precursor loss due to enzyme promiscuity. With acetate recycling, acetyl-CoA conservation, and condition optimization, we achieved a final itaconate titer of 1 g/L using the thioesterase driven pathway, which is a significant improvement compared to the original degradation pathway based on CoA transferase. This study illustrates the significance of thermodynamic favorability as a design principle in pathway engineering.

Comparable Pain Levels and Functional Outcomes With and Without the Use of Dermal Allograft Augmentation in Endoscopic Gluteus Medius Repair.

PURPOSE: To retrospectively compare the clinical outcomes of patients undergoing endoscopic gluteal tendon repair with and without the use of dermal allograft augmentation. METHODS: A retrospective review of prospectively collected data, single-surgeon cohort study was performed on all patients undergoing endoscopic gluteus medius repair (GMR) and gluteus medius repair with augmentation (GMR-A) between April 2017 and April 2022. Dermal allograft augmentation was utilized in cases where intraoperative gluteus tissue quality was poor. An electronic survey of patient-reported outcome measures (PROMs) was completed at a minimum of 1 year postoperatively. PROMs included a Visual Analogue Scale (VAS) for pain; University of California, Los Angeles (UCLA) Activity Scale; modified Harris Hip Score (mHHS); Hip Outcome Score-Sport-Specific Subscale (HOS-SSS); and a Single Assessment Numeric Evaluation (SANE). The proportion of patients achieving the minimal clinically important difference (MCID), patient acceptable symptom state (PASS), and substantial clinical benefit (SCB) for each PROM were compared between groups. RESULTS: Sixty-four patients were reached for follow-up (26 GMR, 38 GMR-A). No differences were found between the groups in terms of demographics. There was a significantly longer time to follow-up in the GMR group (39.4±26.9 vs 24.2±11.7 months, p=0.003). There were no differences between the GMR and GMR-A groups in terms of postoperative PROMs including VAS (3.3±2.6 vs 3.3±2.8, p=0.99), UCLA (5.8±2.1 vs 5.1±2.0, p=0.17), mHHS (70.1±18.1 vs 68.9±17.8, p=0.80), HOS-SSS (67.7±28.9 vs 62.5±30.2, p=0.50), and SANE (71.7±27.9 vs 71.3±22.8, p=0.95). A significantly greater proportion of patients in the GMR group achieved a PASS for UCLA (64% vs. 34%, p=0.02). One patient each in the GMR (3.8%) and GMR-A (2.6%) groups underwent revision gluteus medius repair with dermal allograft augmentation at the final follow-up. CONCLUSIONS: Our study demonstrates comparable clinical outcomes with and without the use of dermal allograft augmentation in endoscopic gluteus medius repairs. LEVEL OF EVIDENCE: III, retrospective comparative series.

Mechanisms of crosstalk between the oropharyngeal microbiome and human papillomavirus in oropharyngeal carcinogenesis: a mini review.

Head and neck squamous cell carcinoma (HNSCC) is the sixth most common cancer globally. Notably, human papillomavirus (HPV)-positive oropharyngeal squamous cell carcinoma (OPSCC) is on the rise, accounting for 70% of all OPSCC cases. Persistent high-risk HPV infection is linked to various cancers, but HPV infection alone is not sufficient to cause cancer. Advances in next-generation sequencing have improved our understanding of changes in the human microbiome of cancerous environments. Yet, there remains a dearth of knowledge on the impact of HPV-microbiome crosstalk in HPV-positive OPSCC. In this review, we examine what is known about the oropharyngeal microbiome and the compositional shifts in this microbiome in HPV-positive OPSCC. We also review potential mechanisms of crosstalk between HPV and specific microorganisms. Additional research is needed to understand these interactions and their roles on cancer development and progression.

Management of Patellar and Trochlear Cartilage Lesions with Matrix-Induced Autologous Chondrocyte Implantation in Conjunction with Patellofemoral Realignment Procedures Improves Patient Reported Outcomes and Magnetic Resonance Image Appearance.

OBJECTIVES: The aim of this study is to evaluate the relationship between the achievement of clinically significant improvement in patient-reported outcome measures (PROMs) and the postoperative magnetic resonance image (MRI) appearance of matrix-associated chondrocyte implantation (MACI), in conjunction with patellofemoral realignment procedures, for the treatment of grade IV chondral defects about the patellofemoral joint. METHODS: A retrospective review of patients undergoing MACI for grade IV chondral defects of the patella or trochlea by a single sports medicine fellowship-trained surgeon from 2017-2020 was performed. Concomitant realignment procedures, including tibial tubercle osteotomy and medial patellofemoral ligament reconstruction, were also performed as needed. Patients with preoperative and minimum 1-year postoperative PROMs and postoperative knee MRI were included. MRI were obtained at 6.3 [Interquartile range (IQR): 5.8, 7.5] months postoperatively. A fellowship-trained musculoskeletal radiologist assigned a Magnetic Resonance Observation of Cartilage Repair Tissue (MOCART) score (range: 0-100, with 100 equating to complete graft healing) to each MRI. Achievement of the minimal clinically important difference (MCID) for International Knee Documentation Committee (IKDC), Knee Injury and Osteoarthritis Score-Quality of Life (KOOS-QoL), and Kujala scores were determined for each patient. Paired t-tests or Wilcoxon Rank-Sum tests were used to evaluate for an association between achievement of the MCID for each PROM and MOCART scores. The average follow-up time and time from surgery to PROMs were 2.7±1.5 years and 1.7±0.66 years, respectively. RESULTS: Thirty patients were included. There was a significant improvement in all PROMs from pre- to postoperative (p<0.001). More than two thirds of patients achieved the MCID for each PROM. Patients who achieved the MCID for IKDC had significantly higher MOCART scores (66.5±16.2) compared to those who did not meet the MCID for IKDC (50.6±23.6, p=0.043). CONCLUSION: MACI for the treatment of patellofemoral chondral injuries is associated with clinically significant improvement in PROMs at short-term follow up. Clinically significant improvements in IKDC scores are associated with a more mature MRI appearance of the ACI graft on postoperative MRI, as indicated by higher MOCART scores. LEVEL OF EVIDENCE: IV - Case Series.

Interpretation of Clinical Retinal Images Using an Artificial Intelligence Chatbot.

Purpose: To assess the performance of Chat Generative Pre-Trained Transformer-4 in providing accurate diagnoses to retina teaching cases from OCTCases. Design: Cross-sectional study. Subjects: Retina teaching cases from OCTCases. Methods: We prompted a custom chatbot with 69 retina cases containing multimodal ophthalmic images, asking it to provide the most likely diagnosis. In a sensitivity analysis, we inputted increasing amounts of clinical information pertaining to each case until the chatbot achieved a correct diagnosis. We performed multivariable logistic regressions on Stata v17.0 (StataCorp LLC) to investigate associations between the amount of text-based information inputted per prompt and the odds of the chatbot achieving a correct diagnosis, adjusting for the laterality of cases, number of ophthalmic images inputted, and imaging modalities. Main Outcome Measures: Our primary outcome was the proportion of cases for which the chatbot was able to provide a correct diagnosis. Our secondary outcome was the chatbot's performance in relation to the amount of text-based information accompanying ophthalmic images. Results: Across 69 retina cases collectively containing 139 ophthalmic images, the chatbot was able to provide a definitive, correct diagnosis for 35 (50.7%) cases. The chatbot needed variable amounts of clinical information to achieve a correct diagnosis, where the entire patient description as presented by OCTCases was required for a majority of correctly diagnosed cases (23 of 35 cases, 65.7%). Relative to when the chatbot was only prompted with a patient's age and sex, the chatbot achieved a higher odds of a correct diagnosis when prompted with an entire patient description (odds ratio = 10.1, 95% confidence interval = 3.3-30.3, P < 0.01). Despite providing an incorrect diagnosis for 34 (49.3%) cases, the chatbot listed the correct diagnosis within its differential diagnosis for 7 (20.6%) of these incorrectly answered cases. Conclusions: This custom chatbot was able to accurately diagnose approximately half of the retina cases requiring multimodal input, albeit relying heavily on text-based contextual information that accompanied ophthalmic images. The diagnostic ability of the chatbot in interpretation of multimodal imaging without text-based information is currently limited. The appropriate use of the chatbot in this setting is of utmost importance, given bioethical concerns. Financial Disclosures: Proprietary or commercial disclosure may be found in the Footnotes and Disclosures at the end of this article.

Neuromodulation guide for the non-neuromodulator clinician: What it is and how it can benefit patients?

Neuromodulation is being utilized across a variety of medical subspecialties to treat both painful and non-painful medical conditions. However, publications on neuromodulation topics infrequently occur in journals targeting generalists and medical specialties outside of pain medicine and neurosurgery. This study reviewed implantable neuromodulation devices, their respective Food and Drug Administration-approved indications for use, as well as off-label usage, and the associated potential risks and benefits for each device. PubMed and Medline databases were queried for systematic reviews with or without meta-analyses and randomized controlled trials of implantable neuromodulation devices. The literature review resulted in 106 studies eligible for inclusion, and 67 were included in the final review. In conclusion, as the clinical volume of neuromodulation continues to grow, supporting and educating medical professionals who care for patients that receive implanted neuromodulation devices is paramount. It is likely the use of neuromodulation will continue to expand across all medical subspecialties, and as such, every clinician should have a baseline understanding of this treatment.

Alveolar ridge preservation in posterior maxillary teeth for reduction in the potential need for sinus floor elevation procedures: A pilot study.

OBJECTIVES: To investigate the effects of alveolar ridge preservation (ARP) on ridge height, sinus pneumatization and the potential need for lateral sinus augmentation following extraction in the posterior maxilla. MATERIALS AND METHODS: This randomized controlled pilot study included 28 patients requiring extraction in the posterior maxilla with bone height between 6 and 8 mm. The sites were randomly allocated to either unassisted socket healing (Control), ARP with deproteinized bovine bone mineral (DBBM) (Test 1), or collagen-stabilized DBBM (Test 2) groups. Pre- and post-operative CTs at 4 months were taken to determine changes in ridge heights, sinus volume, and the need for sinus floor elevation (SFE) procedures for cases where the residual mid-ridge height was < 5 mm. Site-level analyses for changes in vertical ridge dimensions and sinus volume pre- and post-extraction/ARP were conducted using paired t-tests. Differences in mean changes in vertical ridge dimensions and sinus volume between the groups were determined using one-way ANOVA. RESULTS: Significantly greater mean mid-ridge height reduction occurred in the control group (-2.7 ± 0.9 mm) compared to Test 1 (0.9 ± 3.7 mm) and Test 2 (1.0 ± 2.8 mm) groups (p < .05). No significant changes in mean mid-ridge height were found in either test groups. Volumetric analysis showed a significantly greater increase in sinus volume in the control group (0.7 ± 0.7 cm3) compared to Test 1 (n = 3, -0.7 ± 0.8 cm3) group (p = .03). 89% of patients in the control group would require lateral window SFE  compared to Test 1 (42.8%) and Test 2 (40%) groups. CONCLUSION: ARP was effective in attenuating height changes in the middle of the ridge and may reduce sinus pneumatization following extraction in the posterior maxilla. This could potentially decrease the need for more invasive sinus augmentation procedures.

Revision after prior failed pectus excavatum repair: higher risks and greater complications than primary surgery.

Background: Revision of a prior failed pectus excavatum (PE) repair is occasionally required. These procedures may be technically more complex and have a greater risk of complications. This study was performed to evaluate the outcomes of adult patients undergoing revision procedures. Methods: A retrospective review of adult patients who underwent revision of a prior PE repair from 2010 to 2023 at Mayo Clinic Arizona was performed. Patients were classified by prior procedure [minimally invasive repair of pectus excavatum (MIRPE), Open/Ravitch, and both] and the type of revision procedure performed [MIRPE, hybrid MIRPE, complex hybrid reconstruction, or complex reconstruction of acquired thoracic dystrophy (ATD)]. Outcomes and complications of these groups were analyzed and compared. Results: In total, 190 revision cases were included (mean age was 33±10 years; 72.6% males, mean Haller Index: 4.4±1.8). For the initial repair procedure, 90 (47.4%) patients had a previous MIRPE, 87 (45.8%) patients a prior open repair, and thirteen (6.8%) patients had both. Furthermore, 30 (15.8%) patients had two or more prior interventions. Patients having had a prior MIRPE were able to be repaired with a revision MIRPE in 82.2% of the cases. Conversely, patients with a prior open repair (including those who had both prior MIRPE and open repairs) were much more likely to require complex reconstructions (85%) as none of the ATD patients in this group had an attempted MIRPE. Operative times were shortest in the MIRPE redo approach and longest in the complex reconstruction of the ATD patients (MIRPE 3.5±1.3 hours, ATD 6.9±1.8 hours; P<0.001). The median length of hospital stay was 5 days [interquartile range (IQR), 3.0 days] with the shortest being the MIRPE approach and the longest occurring in the complex reconstruction of the ATD patients [MIRPE 4 days (IQR, 3.0 days); ATD 7 days (IQR, 4.0 days); P<0.001]. Major and minor complications were more frequent in the ATD complex reconstruction group. Preoperative chronic pain was present in over half of the patients (52.6%). Although resolution was seen in a significant number of patients, significant pain issues persisted in 8.8% of the patients postoperatively. Overall, persistent, long term chronic pain was greatest in the post open/Ravitch patient group (open 13.6% vs. MIRPE 3.6%, P=0.02). Conclusions: Revision of a prior failed PE repair can be technically complex with a high risk of complications, prolonged duration of surgery, and lengthy hospitalization. Chronic pain is prevalent and its failure to completely resolve after surgery is not uncommon. The initial failed repair will influence the type of procedure that can be performed and potentially subsequent complications. Even when some recurrences after previous PE surgeries can be repaired with acceptable results, this study demonstrates the importance of proper primary repair due to these increased risks.

A growth-differentiation factor 15 receptor agonist in randomized placebo-controlled trials in healthy or obese persons.

BACKGROUND: Growth Differentiation Factor 15 (GDF15), a divergent member of the TGF-ß superfamily, signals via the hindbrain glial-derived neurotrophic factor receptor alpha-like and rearranged during transfection receptor co-receptor (GFRAL-RET) complex. In nonclinical species, GDF15 is a potent anorexigen leading to substantial weight loss. MBL949 is a half-life extended recombinant human GDF15 dimer. METHODS: MBL949 was evaluated in multiple nonclinical species and then in humans in two randomized and placebo-controlled clinical trials. In the Phase 1 first-in-human, single ascending dose trial MBL949 or placebo was injected subcutaneously to overweight and obese healthy volunteers (n=65) at doses ranging from 0.03 to 20 mg. In Phase 2, MBL949 or placebo was administered subcutaneously every other week for a total of 8 doses to obese participants (n=126) in five different dose regimens predicted to be efficacious based on data from the Phase 1 trial. RESULTS: In nonclinical species, MBL949 was generally safe and effective with reduced food intake and body weight in mice, rats, dogs, and monkeys. Weight loss was primarily from reduced fat, and metabolic endpoints improved. A single ascending dose study in overweight or obese healthy adults demonstrated mean terminal half-life of 18-22 days, and evidence of weight loss at the higher doses. In the Phase 2, weight loss was minimal following biweekly dosing of MBL949 for 14 weeks. MBL949 was safe and generally tolerated in humans over the dose range tested, adverse events of the gastrointestinal system were the most frequent observed. CONCLUSION: The prolonged half-life of MBL949 supports biweekly dosing in patients. MBL949 had an acceptable safety profile. The robust weight loss observed in nonclinical species did not translate to weight loss efficacy in humans. TRIAL REGISTRATION: ClinicalTrials.gov NCT05199090.

Testing Outlier Detection Algorithms for Identifying Early Stage Solute Clusters in Atom Probe Tomography.

Atom probe tomography (APT) is commonly used to study solute clustering and precipitation in materials. However, standard techniques used to identify and characterize clusters within atom probe data, such as the density-based spatial clustering applications with noise (DBSCAN), often underperform with respect to small clusters. This is a limitation of density-based cluster identification algorithms, due to their dependence on the parameter Nmin, an arbitrary lower limit placed on detectable cluster sizes. Therefore, this article attempts to consider the characterization of clustering in atom probe data as an outlier detection problem of which k-nearest neighbors local outlier factor and learnable unified neighborhood-based anomaly ranking algorithms were tested against a simulated dataset and compared to the standard method. The decision score output of the algorithms was then auto thresholded by the Karcher mean to remove human bias. Each of the major models tested outperforms DBSCAN for cluster sizes of <25 atoms but underperforms for sizes >30 atoms using simulated data. However, the new combined k-nearest neighbors (k-NN) and DBSCAN method presented was able to perform well at all cluster sizes. The combined k-NN and seven methods are presented as a new approach to identifying clusters in APT.

Effects of Early Lactation Milking Frequency in an Automated Milking System on Cow Performance.

Automated milking systems (AMS) are increasingly adopted for dairy cow production, promoting individualized cow management dependent on factors like lactation stage, age, and productivity. The study objective was to investigate the effects of early lactation milking frequency on cows milked via AMS. Multiparous Holstein cows blocked by parity and due date were randomly assigned to treatments (n = 8 per treatment): three (3X) or six (6X) milkings per day (MPD). The experimental phase (EXP) was defined as 4 to 29 days in milk (DIM). The AMS settings were programed so 3X cows were limited to three MPD while 6X cows were allowed six MPD. Afterwards was the carry over phase (CO) ranging from 30 to 90 DIM; all cows were allowed up to six MPD. Measurements by the AMS included bodyweight, milk yield (MY), and pellet intake. Weekly composite milk samples were analyzed for macronutrient composition and fatty acid (FA) profile. Coccygeal blood was sampled at 3, 8 ± 1, and 13 ± 1 DIM; concentrations of blood plasma analytes were quantified. Greater MPD was achieved for 6X cows versus 3X cows during EXP, but similar during the CO. Daily MY was non-separable during the EXP while 6X cows in their third or greater lactation group (3 + LG) had greater MY than 3X cows of the same LG during the CO. Milk fat content and 4% fat-corrected MY were both greater for 6X, 3 + LG cows during the EXP compared to 3X, 3 + LG cows. Milk FA methyl esters (FAME) proportions were different between MPD groups, with 6X, 3 + LG cows having the lowest short, even-chain FA from de novo or post-absorptive origin. Differences in analytes indicated that 6X, 3 + LG cows experienced metabolic stress and incorporated greater FA from adipose tissue. Greater early lactation MPD in AMS may shift cow nutrient partitioning to support greater production in 3+ parity cows.

Relationship between morphologic remission with or without hematologic recovery and outcome after allogeneic hematopoietic cell transplantation in adult acute myeloid leukemia.

Outcomes of adults with AML after allografting vary widely. While numerous covariates have been associated with relapse, non-relapse mortality (NRM), and/or shorter survival, the impact of incomplete blood count recovery before transplantation has remained unclear. To address this uncertainty, we examined all adults with AML or MDS/AML who received an allograft in first or second remission between 2006 and 2023 at a single institution. Of 1264 patients, 891 (70%) met criteria for CR, whereas 291 (23%), 24 (2%), and 58 (5%) were classified as CRh, CRi, and morphologic leukemia-free state (MLFS), respectively. CR, CRh, CRi, and MLFS patients differed significantly regarding demographics, disease biology, pre-transplant measurable residual disease, and types of transplants. After multivariable adjustment, outcomes for CRh and CRi patients were not significantly different from each other or from those of CR patients. In contrast, outcomes of MLFS patients were substantially worse than those of CR and CRh patients, with significantly higher risk of NRM and relapse, and significantly shorter relapse-free and overall survival. Similar results were obtained in several distinct subsets. Together, our analysis provides empiric evidence for the importance of distinguishing MLFS from CR and CRh patients for optimized risk assessment and, possibly, individualized treatment decision making.

A conserved regulation of cell expansion underlies notochord mechanics, spine morphogenesis, and endochondral bone lengthening.

Cell size is a key contributor to tissue morphogenesis 1 . As a notable example, growth plate hypertrophic chondrocytes use cellular biogenesis and disproportionate fluid uptake to expand 10-20 times in size to drive lengthening of endochondral bone 2,3 . Similarly, notochordal cells expand to one of the largest cell types in the developing embryo to drive axial extension 4-6 . In zebrafish, the notochord vacuolated cells undergo vacuole fusion to form a single large, fluid-filled vacuole that fills the cytoplasmic space and contributes to vacuolated cell expansion 7 . When this process goes awry, the notochord lacks sufficient hydrostatic pressure to support vertebral bone deposition resulting in adult spines with misshapen vertebral bones and scoliosis 8 . However, it remains unclear whether endochondral bone and the notochord share common genetic and cellular mechanisms for regulating cell and tissue expansion. Here, we demonstrate that the 5'-inositol phosphatase gene, inppl1a , regulates notochord expansion, spine morphogenesis, and endochondral bone lengthening in zebrafish. Furthermore, we show that inppl1a regulates notochord expansion independent of vacuole fusion, thereby genetically decoupling these processes. We demonstrate that inppl1a -dependent notochord expansion is essential to establish normal mechanical properties of the notochord to facilitate the development of a straight spine. Finally, we find that inppl1a is also important for endochondral bone lengthening in fish, as has been shown in the human INPPL1 -related endochondral bone disorder, Opsismodysplasia 9 . Overall, this work reveals a conserved mechanism of cell size regulation that influences disparate tissues critical for skeletal development and short-stature disorders.

Large Language Models Improve the Identification of Emergency Department Visits for Symptomatic Kidney Stones.

Background: Recent advancements of large language models (LLMs) like Generative Pre-trained Transformer 4 (GPT-4) have generated significant interest among the scientific community. Yet, the potential of these models to be utilized in clinical settings remains largely unexplored. This study investigated the abilities of multiple LLMs and traditional machine learning models to analyze emergency department (ED) reports and determine if the corresponding visits were caused by symptomatic kidney stones. Methods: Leveraging a dataset of manually annotated ED reports, we developed strategies to enhance the performance of GPT-4, GPT-3.5, and Llama-2 including prompt optimization, zero- and few-shot prompting, fine-tuning, and prompt augmentation. Further, we implemented fairness assessment and bias mitigation methods to investigate the potential disparities by these LLMs with respect to race and gender. A clinical expert manually assessed the explanations generated by GPT-4 for its predictions to determine if they were sound, factually correct, unrelated to the input prompt, or potentially harmful. The evaluation includes a comparison between LLMs, traditional machine learning models (logistic regression, extreme gradient boosting, and light gradient boosting machine), and a baseline system utilizing International Classification of Diseases (ICD) codes for kidney stones. Results: The best results were achieved by GPT-4 (macro-F1=0.833, 95% confidence interval [CI]=0.826-0.841) and GPT-3.5 (macro-F1=0.796, 95% CI=0.796-0.796), both being statistically significantly better than the ICD-based baseline result (macro-F1=0.71). Ablation studies revealed that the initial pre-trained GPT-3.5 model benefits from fine-tuning when using the same parameter configuration. Adding demographic information and prior disease history to the prompts allows LLMs to make more accurate decisions. The evaluation of bias found that GPT-4 exhibited no racial or gender disparities, in contrast to GPT-3.5, which failed to effectively model racial diversity. The analysis of explanations provided by GPT-4 demonstrates advanced capabilities of this model in understanding clinical text and reasoning with medical knowledge.

Retrospective Seroprevalence of Orthopoxvirus Antibodies among Key Populations, Kenya.

We identified a cluster of mpox exposures among key populations in Kenya through retrospective serologic screening. We identified strong seropositivity among sex workers and gay, bisexual, and other men who have sex with men. These findings demonstrate the need for increased mpox surveillance among mpox-endemic and mpox-endemic-adjacent regions in Africa.

Entropy-Based Strategies for Multi-Bracket Pools.

Much work in the parimutuel betting literature has discussed estimating event outcome probabilities or developing optimal wagering strategies, particularly for horse race betting. Some betting pools, however, involve betting not just on a single event, but on a tuple of events. For example, pick six betting in horse racing, March Madness bracket challenges, and predicting a randomly drawn bitstring each involve making a series of individual forecasts. Although traditional optimal wagering strategies work well when the size of the tuple is very small (e.g., betting on the winner of a horse race), they are intractable for more general betting pools in higher dimensions (e.g., March Madness bracket challenges). Hence we pose the multi-brackets problem: supposing we wish to predict a tuple of events and that we know the true probabilities of each potential outcome of each event, what is the best way to tractably generate a set of n predicted tuples? The most general version of this problem is extremely difficult, so we begin with a simpler setting. In particular, we generate n independent predicted tuples according to a distribution having optimal entropy. This entropy-based approach is tractable, scalable, and performs well.