Opportunities of Topical Drug Products in a Changing Dermatological Landscape.

Despite the prevalence and the impact on quality of life of dermatological indications, drug products to treat such conditions have rarely been blockbusters. The prevailing perception of a limited commercial potential of dermatological drug products has restricted innovation and encouraged a more conservative development approach. For example, the focus was on repurposing/reformulation of existing active pharmaceutical ingredients (APIs) specifically for the topical delivery route. However, the situation is quite different today catalyzed in part by the blockbuster success of Dupixent (dupilimab), the first monoclonal antibody treatment for atopic dermatitis which has been approved by the US Food and Drug Administration (US FDA) in 2017. Dupixent's success not only encouraged the development of other biologics but also inspired the (re-)development of new dermal drug products that can reap the many benefits of topical administration. We have also witnessed a shift toward outsourcing development efforts (and associated risks) towards small- to mid-size pharmaceutical companies which often require support of contract research and development/manufacturing organizations (CRO and CDMO). Such trends also emphasize the need of greater expertise in topical formulation design, as well as associated commercial and regulatory considerations. Today, we believe that topical drug products remain not only an essential but also commercially viable class of dermatological therapeutics. In this opinion article, we will address the challenges as well as opportunities of coherent development strategies in the current market environment, formulation innovations of topical drug products and technological advances to facilitate rational topical drug formulation development.

A taxonomic revision of Parachela with descriptions of two new species (Cypriniformes: Xenocyprididae).

The taxonomy of the Parachela-Oxygaster-Macrochirichthys clade of Xenocyprididae has been confused since the original descriptions of Parachela oxygastroides and Parachela hypophthalmus in the mid-19th century. The confusion seems attributable to the substantial intraspecific variation in color and other morphological characteristics of species of Oxygaster and Parachela. Morphological data on 401 specimens from throughout the range of Parachela and molecular phylogenetic analyses indicate that six available species names for Parachela are valid: Parachela cyanea, P. hypophthalmus, Parachela ingerkongi, Parachela johorensis (removed from the synonymy of P. oxygastroides), P. oxygastroides, and Parachela williaminae. In addition, two new species of Parachela, Parachela melanosticta and Parachela microlepis, are described. Chela pointoni is a synonym of P. oxygastroides, not a valid species of Oxygaster as previously hypothesized, and Parachela maculicauda is a synonym of Parachela johorensis. Considerable morphological and genetic variation is present in all well-sampled species of Parachela.

A role for leucine-rich, glioma inactivated 1 in regulating pain sensitivity.

Neuronal hyperexcitability is a key driver of persistent pain states including neuropathic pain. Leucine-rich, glioma inactivated 1 (LGI1), is a secreted protein known to regulate excitability within the nervous system and is the target of autoantibodies from neuropathic pain patients. Therapies that block or reduce antibody levels are effective at relieving pain in these patients, suggesting that LGI1 has an important role in clinical pain. Here we have investigated the role of LGI1 in regulating neuronal excitability and pain-related sensitivity by studying the consequences of genetic ablation in specific neuron populations using transgenic mouse models. LGI1 has been well studied at the level of the brain, but its actions in the spinal cord and peripheral nervous system (PNS) are poorly understood. We show that LGI1 is highly expressed in DRG and spinal cord dorsal horn neurons in both mouse and human. Using transgenic muse models, we genetically ablated LGI1, either specifically in nociceptors (LGI1fl/Nav1.8+), or in both DRG and spinal neurons (LGI1fl/Hoxb8+). On acute pain assays, we find that loss of LGI1 resulted in mild thermal and mechanical pain-related hypersensitivity when compared to littermate controls. In from LGI1fl/Hoxb8+ mice, we find loss of Kv1 currents and hyperexcitability of DRG neurons. LGI1fl/Hoxb8+ mice displayed a significant increase in nocifensive behaviours in the second phase of the formalin test (not observed in LGI1fl/Nav1.8+ mice) and extracellular recordings in LGI1fl/Hoxb8+ mice revealed hyperexcitability in spinal dorsal horn neurons, including enhanced wind-up. Using the spared nerve injury model, we find that LGI1 expression is dysregulated in the spinal cord. LGI1fl/Nav1.8+ mice showed no differences in nerve injury induced mechanical hypersensitivity, brush-evoked allodynia or spontaneous pain behaviour compared to controls. However, LGI1fl/Hoxb8+ mice showed a significant exacerbation of mechanical hypersensitivity and allodynia. Our findings point to effects of LGI1 at both the level of the DRG and spinal cord, including an important impact of spinal LGI1 on pathological pain. Overall, we find a novel role for LGI1 with relevance to clinical pain.

The enigmatic Triassic ovulate reproductive structures of Dordrechtites are recurved cupules fundamentally comparable to the cupules of Doylea and similar plants.

Recent paleobotanical discoveries have renewed interest in the distinctively recurved, seed-bearing cupules of Mesozoic plants, which are important for understanding seed plant phylogeny and the origin of the second integument of the angiosperm ovule. Reanalysis of the enigmatic seed-bearing organ Dordrechtites elongatus from the Triassic of South Africa, the type species of the genus, combined with information from similar material from Antarctica, Argentina and Australia, indicates that Dordrechtites is a highly modified lateral branch of a seed cone. Short lateral projections from a primary cone axis each bear several Dordrechtites units. Each unit consists of a long stalk bearing a straight to sometimes recurved cupule with a long distal extension beyond the cupule apex. Each cupule is flattened in a plane perpendicular to the stalk and distal projection and contains up to two seeds. Structural similarities between Dordrechtites and the cupules of Doyleales indicate that they are homologous, providing new evidence for a close relationship. The persistent cupule stalk and apical extension of Dordrechtites, combined with the flattened cupule, suggests modification for wind and water dispersal.

Identifying transgene insertions in Caenorhabditis elegans genomes with Oxford Nanopore sequencing.

Genetically modified organisms are commonly used in disease research and agriculture but the precise genomic alterations underlying transgenic mutations are often unknown. The position and characteristics of transgenes, including the number of independent insertions, influences the expression of both transgenic and wild-type sequences. We used long-read, Oxford Nanopore Technologies (ONT) to sequence and assemble two transgenic strains of Caenorhabditis elegans commonly used in the research of neurodegenerative diseases: BY250 (pPdat-1::GFP) and UA44 (GFP and human α-synuclein), a model for Parkinson's research. After scaffolding to the reference, the final assembled sequences were ∼102 Mb with N50s of 17.9 Mb and 18.0 Mb, respectively, and L90s of six contiguous sequences, representing chromosome-level assemblies. Each of the assembled sequences contained more than 99.2% of the Nematoda BUSCO genes found in the C. elegans reference and 99.5% of the annotated C. elegans reference protein-coding genes. We identified the locations of the transgene insertions and confirmed that all transgene sequences were inserted in intergenic regions, leaving the organismal gene content intact. The transgenic C. elegans genomes presented here will be a valuable resource for Parkinson's research as well as other neurodegenerative diseases. Our work demonstrates that long-read sequencing is a fast, cost-effective way to assemble genome sequences and characterize mutant lines and strains.

Antiretroviral Therapy and Cardiovascular Risk in People With HIV in the United States-An Updated Analysis.

Background: Several antiretroviral therapy (ART) medications have been associated with increased cardiovascular risk, but less is known about the safety of modern ART. We sought to compare the risk of major adverse cardiac events (MACEs) among different ART regimens. Methods: Using insurance claims databases from 2008 to 2020, we identified adults aged <65 years who newly initiated ART. We compared non-nucleoside reverse transcriptase inhibitor (NNRTI)-based regimens to protease inhibitors (PI)- and integrase inhibitors (INSTI)-based regimens. We used propensity score-weighted Kaplan-Meier functions to estimate the 6, 12, 18, 24, 36, and 48 months' risk and risk differences (RD) of MACE. Results: Among 37 935 ART initiators (median age, 40 years; 23% female; 26% Medicaid-insured), 45% started INSTI-, 16% PI-, and 39% NNRTI-based regimens. MACE occurred in 418 individuals (1.1%) within 48 months after ART initiation. Compared to NNRTI initiators, the risk of MACE was higher at 12 months (RD, 0.50; 95% CI, 0.14-0.99), 18 months (RD, 0.53; 95% CI, 0.11-1.06), and 24 months (RD, 0.62; 95% CI, 0.04-1.29) for PI initiators, and at 12 (RD, 0.20; 95% CI, 0.03-0.37) and 18 months (RD, 0.31; 95% CI, 0.06-0.54) for INSTI initiators; the precision of estimates was limited for longer duration of follow-up. Conclusions: Among ART initiators, PI-based and INSTI-based regimens were associated with higher short-term risk of MACE compared to NNRTI-based regimens. The pattern of association between INSTIs and PIs with excess risk of MACE was similar.

Timing of coronary artery bypass grafting after myocardial infarction influences late survival.

Objectives: The role of timing of coronary artery bypass grafting after acute myocardial infarction on early and late outcomes remains uncertain. Methods: We reviewed 1631 consecutive adult patients who underwent isolated coronary artery bypass grafting with information on timing of acute myocardial infarction. Early and late mortality were compared between patients receiving coronary artery bypass grafting within 24 hours after acute myocardial infarction, between 1 and 7 days after acute myocardial infarction, and more than 7 days after acute myocardial infarction. Sensitivity analyses were performed in subgroups of patients with ST-segment elevation myocardial infarction or non-ST-segment elevation myocardial infarction, and other high-risk groups. Results: A total of 124 patients (5.7%) underwent coronary artery bypass grafting within 24 hours, 972 patients (51.2%) received coronary artery bypass grafting between 1 and 7 days after acute myocardial infarction, and 535 patients (43.2%) underwent coronary artery bypass grafting more than 7 days after acute myocardial infarction. Overall operative mortality was 2.7% with comparable adjusted early mortality among 3 groups. Over a median follow-up of 13.5 years (interquartile range, 8.9-17.1), compared with patients receiving coronary artery bypass grafting between 1 and 7 days after acute myocardial infarction, those receiving coronary artery bypass grafting at 7 days had greater adjusted risk for late overall mortality (hazard ratio, 1.39, 95% CI, 1.16-1.67; P < .001), whereas those receiving coronary artery bypass grafting within 24 hours had comparable risk of late overall mortality (hazard ratio, 1.12, 95% CI, 0.86-1.47; P = .39). Timing of coronary artery bypass grafting was associated with late mortality in patients with non-ST-segment elevation myocardial infarction (patients receiving coronary artery bypass grafting at >7 days had a higher risk of late mortality [hazard ratio, 1.38, 95% CI, 1.14-1.67, P < .001] compared with those receiving coronary artery bypass grafting between 1 and 7 days), but not in patients with ST-segment elevation myocardial infarction. Conclusions: Early revascularization through coronary artery bypass grafting within 7 days during the same hospitalization appears beneficial, especially for patients presenting with non-ST-segment elevation myocardial infarction.

Same-Day Discharge for Elective Pediatric Laparoscopic Gastrostomy Tube Insertion is Safe and Increasing in Frequency; a NSQIP Pediatric Retrospective Review 2017 to 2021.

BACKGROUND: There is limited literature reviewing same-day discharge for elective pediatric gastrostomy tube placement. Our aim was to assess the outcomes and national trends of same-day discharge following elective pediatric laparoscopic gastrostomy. METHODS: ACS NSQIP-P registry data from 2017 to 2021 was used to evaluate elective pediatric laparoscopic gastrostomy patients who presented from home and discharged home with a diagnosis of failure to thrive, feeding difficulty or dysphagia. Patients discharged same-day postoperatively (SDD) were compared to those discharged 1-2 days postoperatively (non-SDD) for the primary outcome of unplanned 30-day readmission. Secondary outcomes included bleeding events, wound infection, and 30-day reoperation. RESULTS: There were 5,947 patients identified; 4.7% were discharged same-day. The annual rate of SDD over 5 years went from 2.7% to 4.6%-4.8% to 4.5%-6.3%. There were no significant differences between SDD and non-SDD patients for early readmission or reoperation (0.7% vs 0.3%, p = 0.279), 30-day unplanned readmission (8.5% vs 8.0%, p = 0.407), reoperation (0.1% vs 1.4%, p = 1.000), or any other complications (p > 0.05). Binary logistic regression found pre-operative steroid use within 30 days increased risk of serious complication (OR 2.02, 95% CI 1.29-3.15, p = 0.002) and 30-day readmission or reoperation (OR 2.10, 95% CI 1.34-3.27, p = 0.001). All 6 patients (0.1%) who required reoperation within 3 days were identified prior to discharge, and none of the 16 patients readmitted within 3 days of surgery required reoperation. CONCLUSION: Though rates of same-day discharge following pediatric gastrostomy tube placement are low, they continue to increase annually. There were no significant differences in outcomes between same-day and non-same-day day discharge for elective cases presenting from and discharging home. In non-steroid using patients, same-day discharge following laparoscopic gastrostomy can be a safe option. LEVEL OF EVIDENCE (I-V): Level III.

Effects of Schistosoma haematobium infection and treatment on the systemic and mucosal immune phenotype, gene expression and microbiome: A systematic review.

BACKGROUND: Urogenital schistosomiasis caused by Schistosoma haematobium affects approximately 110 million people globally, with the majority of cases in low- and middle-income countries. Schistosome infections have been shown to impact the host immune system, gene expression, and microbiome composition. Studies have demonstrated variations in pathology between schistosome subspecies. In the case of S. haematobium, infection has been associated with HIV acquisition and bladder cancer. However, the underlying pathophysiology has been understudied compared to other schistosome species. This systematic review comprehensively investigates and assimilates the effects of S. haematobium infection on systemic and local host mucosal immunity, cellular gene expression and microbiome. METHODS: We conducted a systematic review assessing the reported effects of S. haematobium infections and anthelmintic treatment on the immune system, gene expression and microbiome in humans and animal models. This review followed PRISMA guidelines and was registered prospectively in PROSPERO (CRD42022372607). Randomized clinical trials, cohort, cross-sectional, case-control, experimental ex vivo, and animal studies were included. Two reviewers performed screening independently. RESULTS: We screened 3,177 studies and included 94. S. haematobium was reported to lead to: (i) a mixed immune response with a predominant type 2 immune phenotype, increased T and B regulatory cells, and select pro-inflammatory cytokines; (ii) distinct molecular alterations that would compromise epithelial integrity, such as increased metalloproteinase expression, and promote immunological changes and cellular transformation, specifically upregulation of genes p53 and Bcl-2; and (iii) microbiome dysbiosis in the urinary, intestinal, and genital tracts. CONCLUSION: S. haematobium induces distinct alterations in the host's immune system, molecular profile, and microbiome. This leads to a diverse range of inflammatory and anti-inflammatory responses and impaired integrity of the local mucosal epithelial barrier, elevating the risks of secondary infections. Further, S. haematobium promotes cellular transformation with oncogenic potential and disrupts the microbiome, further influencing the immune system and genetic makeup. Understanding the pathophysiology of these interactions can improve outcomes for the sequelae of this devastating parasitic infection.

Alternating magnetic fields (AMF) and linezolid reduce Staphylococcus aureus biofilm in a large animal implant model.

OBJECTIVES: We aimed to evaluate the effectiveness of alternating magnetic fields (AMF) combined with antibiotics in reducing Staphylococcus aureus biofilm on metal implants in a large animal model, compared to antibiotics alone. METHODS: Metal plates were inoculated with a clinical MRSA strain and then implanted into thirty-three ewes divided into three groups: positive control, linezolid only, and a combination of linezolid and AMF. Animals had either titanium or cobalt-chrome plates and were sacrificed at 5 or 21 days post-implantation. Blood and tissue samples were collected at various time points post-AMF treatment. RESULTS: In vivo efficacy studies demonstrated significant biofilm reduction on titanium and cobalt-chrome implants with AMF-linezolid combination treatment compared to controls. Significant bacterial reductions were also observed in surrounding tissues and bones. Cytokine analysis showed improved inflammatory responses with combination therapy, and histopathology confirmed reduced inflammation, necrosis, and bacterial presence, especially at 5 days post-implantation. CONCLUSIONS: This study demonstrates that combining AMF with antibiotics significantly reduces biofilm-associated infections on metal implants in a large animal model. Numerical simulations confirmed targeted heating, and in vivo results showed substantial bacterial load reduction and reduced inflammatory response. These findings support the potential of AMF as a non-invasive treatment for prosthetic joint infections.

Predictive utility of self-efficacy in early stroke rehabilitation.

INTRODUCTION: A biopsychosocial approach entailing person-centered factors provides valuable insight to post-stroke rehabilitation potential. The consideration of an individual's belief in their capabilities, known as self-efficacy, may prove especially informative in the inpatient rehabilitation setting where motor learning often occurs. OBJECTIVE: To assess the predictive utility of self-efficacy in functional independence status change during inpatient rehabilitation. METHODS: Individuals with stroke admitted to an inpatient rehabilitation facility (IRF) completed an assessment battery near IRF admission and discharge involving motor assessments, participant-reported self-efficacy (Stroke Self-Efficacy Questionnaire), and functional independence status evaluation (sum of self-care and mobility Quality Indicators (QI) from the IRF-Patient Assessment Instrument). Linear regression was performed to determine the predictive performance of self-efficacy on QI change during IRF stay while accounting for age, time post-stroke, and IRF length of stay. Regression procedures were repeated for separate subgroups based on initial motor impairment level. RESULTS: Thirty individuals with stroke (14 females, age = 67.0 ± 9.80 years, 10.4 ± 3.46 days post-stroke) were enrolled. Self-efficacy at IRF admission explained a significant percentage of variance in QI Change for the cohort (R2 = 30.7%, p = .001) and for the moderate to severe motor impairment subgroup (n = 12; R2 = 49.9%, p = .010). After accounting for confounders, self-efficacy remained a significant predictor for the cohort (n = 30) model. DISCUSSION: Findings generated from this work support the predictive utility of self-efficacy in early post-stroke motor recovery. The inclusion of self-efficacy in a multi-faceted evaluation framework may therefore optimize rehabilitation outcomes by providing therapists with additional knowledge to better tailor an individual's care.

Radiographic Accuracy of Identifying Anterolateral Tibial Plafond Involvement in Pronation Abduction Ankle Fractures.

OBJECTIVES: To evaluate the incidence of anterolateral tibial plafond involvement in pronation-abduction (PAB) ankle fractures and analyze the accuracy of radiographs in detecting anterolateral tibial plafond involvement, impaction, and predicting the need for direct visualization and an articular reduction. METHODS: Design: A multi-institutional retrospective chart review. SETTING: Five level 1 trauma centers in the United States. PATIENT SELECTION CRITERIA: Adult patients with PAB ankle fractures (OTA/AO 44B2.3, 44C2.2, 44C2.3) from 2020-2022 were reviewed by 7 fellowship-trained orthopedic trauma surgeons. They were queried about the presence of anterolateral tibial plafond involvement and impaction, and whether they would need direct visualization and an articular reduction using both radiographs and CT. OUTCOME MEASUREMENTS AND COMPARISONS: The presence of anterolateral tibial plafond impaction was tabulated separately using radiographs and CT scans. The accuracy of radiographs and changes in surgical plan after CT review were calculated using CT as the gold standard. RESULTS: 61 fractures in 61 patients were evaluated with CT and/or plain radiographs. Using plain radiographs, anterolateral tibial plafond involvement and impaction were identified in 61% and 36% of cases, respectively. In the 38 fractures with both plain radiographs and CT scans, anterolateral tibial plafond involvement was identified in 66% of radiographs and 74% of CT scans (p = 0.4). Plafond impaction was identified in 42% of plain radiographs and 37% of CT scans (p = 0.62). There was no difference in the rate of involvement between radiographs and CT scan. The diagnosis of anterolateral tibial plafond impaction using plain radiographs was correct in 74% of fractures when compared to CT imaging, resulting in a sensitivity of 71%, a specificity of 75%, a positive predictive value (PPV) of 62%, and a negative predictive value (NPV) of 82%. Plain radiographs correctly predicted the need for direct visualization and an articular reduction in 74% of cases and had a PPV of 59% and a NPV of 86%. CONCLUSIONS: Anterolateral tibial plafond involvement and impaction was present on CT in 74% and 37% of pronation-abduction (PAB) ankle fractures, respectively. Plain radiographs had higher NPV for identifying impaction and the need for articular reduction than they did sensitivity, specificity or PPV. CT is an important tool for preoperative planning that should be considered when planning for operative fixation of PAB ankle fractures. LEVEL OF EVIDENCE: Prognostic level III. See Instructions for Authors for a complete description of levels of evidence.

The association between perinatal depressive symptoms and child neurodevelopment.

BACKGROUND: Perinatal depression has been suggested to adversely impact child neurodevelopment. However, the complexity of the early childhood environment challenges conclusive findings. OBJECTIVE: To evaluate whether there is an association between perinatal depressive symptoms and child intelligence quotient (IQ) at 5 years of age. STUDY DESIGN: Secondary analysis of an ancillary study to a multicenter randomized trial of thyroxine therapy for pregnant individuals with subclinical hypothyroidism. Dyads of infants and birthing parent, with completed Center for Epidemiological Studies-Depression (CES-D) screens during pregnancy and postpartum and child neurodevelopment testing completed at five years of age (n=209) were included. CES-D screening was performed at 11-20 weeks, 34-38 weeks, and one-year postpartum. Depressive symptoms were categorized as antenatal (i.e., a positive screen at any point during pregnancy) or postpartum. The primary outcome was child IQ score < 85 at 5 years of age using the Wechsler Preschool and Primary Scale of Intelligence III (WPPSI-III) Full Scale test. Secondary outcomes included other assessments of childhood neurodevelopment. Bivariable analyses and multivariable logistic regressions were utilized. RESULTS: Of the 209 birthing people included, 72 (34%) screened positive for depression during pregnancy and 32 (15%) screened positive one year postpartum. Children born to individuals with a positive antenatal depression screen had a higher odds of IQ <85 at 5 years of age compared with children born to individuals with a CES-D <16 (35% vs. 18 %, OR 2.4, 95% CI 1.2-4.7). Similar findings were seen for children born to individuals with a positive postpartum depression screen (47% vs. 21%, OR 3.3, 95% CI 1.5-7.3). These associations did not persist in multivariable analyses that controlled for social determinants of health and clinical characteristics (adjusted odd ratio (aOR) 1.4, 95% CI 0.7-3.1; aOR 2.1, 95% CI 0.9-5.1, for antenatal and postpartum depressive symptoms, respectively). Similar findings were observed for other adverse neurodevelopmental outcomes. CONCLUSIONS: Having a positive perinatal depression screen was not associated with child cognitive outcomes after controlling for covariates including social determinants of health.

Simultaneous observation of 2H and 13C enrichment of methyl phosphonic acid via Orbitrap-IRMS with applications to nerve agent forensics.

Quantification of the stable isotopes within a compound aids forensic investigations as it provides a fingerprint which can determine that compound's source substrates, synthetic route, and possible mechanisms of degradation. Previous stable isotope studies have explored 13C and 2H measurements of the sarin precursors methylphosphonic dichloride (DC) and methylphosphonic difluoride (DF) as forensic signatures. However, these measurements required different sample preparations and measurement techniques. Orbitrap isotope ratio mass spectrometry (Orbitrap-IRMS) is a developing technique which can characterize multiple stable isotopes simultaneously. Here, we apply Orbitrap-IRMS to simultaneously observe the 13C and 2H content of methylphosphonic acid (MPA), the hydrolysis product of DC and DF, which can be used as a proxy for the isotopic content of DC and DF. Our method requires 20 min analyses and consumes ≈60 nmol of sample, with precisions of ≈0.9 ‰ (13C) and ≈3.6 ‰ (2H). We apply our method to both commercially acquired MPA and MPA obtained from the hydrolysis of commercially acquired DC. We validate our methods via comparison to elemental-analyzer isotope ratio mass spectrometry (EA-IRMS). The combined 13C and 2H measurement creates a more robust forensic tool than either isotope individually. Our results demonstrate the viability of Orbitrap-IRMS for chemical forensic measurements.

Generative AI in Pediatric Gastroenterology.

PURPOSE OF REVIEW: The integration of digital technology into medical practice is often thrust upon clinicians, with standards and routines developed long after initiation. Clinicians should endeavor towards a basic understanding even of emerging technologies so that they can direct its use. The intent of this review is to describe the current state of rapidly evolving generative artificial intelligence (GAI), and to explore both how pediatric gastroenterology practice may benefit as well as challenges that will be faced. RECENT FINDINGS: Although little research demonstrating the acceptance, practice, and outcomes associated with GAI in pediatric gastroenterology is published, there are relevant data adjacent to the specialty and overwhelming potential as professed in the media. Best practice guidelines are widely developed in academic publishing and resources to initiate and improve practical user skills are prevalent. Initial published evidence supports broad acceptance of the technology as part of medical practice by clinicians and patients, describes methods with which higher quality GAI can be developed, and identifies the potential for bias and disparities resulting from its use. GAI is broadly available as a digital tool for incorporation into medical practice and holds promise for improved quality and efficiency of care, but investigation into how GAI can best be used remains at an early stage despite rapid evolution of the technology.

A Longitudinal Analysis of Memory Immune Responses in Convalescent Crimean-Congo Hemorrhagic Fever Survivors in Uganda.

Evaluating the adaptive immune responses to natural infection with Crimean-Congo hemorrhagic fever (CCHF) virus (CCHFV) in human survivors is critical to the development of medical countermeasures. However, the correlates of protection are unknown. As the most prevalent tick-borne human hemorrhagic fever virus with case fatality rates of 5%-30% and worldwide distribution, there is an urgent need to fill these knowledge gaps. Here, we describe adaptive immune responses in a cohort of Ugandan CCHF survivors via serial sampling over 6 years. We demonstrate persistent antibodies after infection and cross-neutralization against various clades of authentic CCHFV, as well as potent effector function. Moreover, we show for the first time persistent, polyfunctional antigen-specific memory T-cell responses to multiple CCHFV proteins up to 9 years after infection. Together, this data provides immunological benchmarks for evaluating CCHFV medical countermeasures and information that can be leveraged toward vaccine immunogen design and viral target identification for monoclonal antibody therapies.

Arthroscopic Technique for Headless Compression Screw Fixation of Large Bony Bankart Fractures in Anterior Shoulder Instability.

A bony Bankart fracture is a common injury pattern in anterior shoulder instability. The fracture fragment size varies and the larger the fragment the more likely recurrent instability will occur. When a large bony Bankart fracture is present, surgical fixation is preferred. Both open and arthroscopic approaches exist with multiple fixation techniques including anterior-to-posterior screw fixation, suture anchor bridge fixation, and suture button fixation. Arthroscopic screw fixation is difficult, as the angle necessary to be parallel to the glenoid surface requires a far medial start point and places the nerve at risk. The use of a variable-pitch, headless compression screw placed from posterior to anterior avoids these risks. We describe an arthroscopic technique for glenoid fixation using a posterior-to-anterior, cannulated, variable-pitch headless compression screw for the treatment of an anterior BBF.

Short-term HIIT impacts HDL function differently in lean, obese, and diabetic subjects.

Introduction: High density lipoproteins (HDL) exert cardiovascular protection in part through their antioxidant capacity and cholesterol efflux function. Effects of exercise training on HDL function are yet to be well established, while impact on triacylglycerol (TG)-lowering has been often reported. We previously showed that a short-term high-intensity interval training (HIIT) program improves insulin sensitivity but does not inhibit inflammatory pathways in immune cells in insulin-resistant subjects. The purpose of this study is to evaluate HDL function along with changes of lipoproteins after the short-term HIIT program in lean, obese nondiabetic, and obese type 2 diabetic (T2DM) subjects. Methods: All individuals underwent a supervised 15-day program of alternative HIIT for 40 minutes per day. VO2peak was determined before and after this training program. A pre-training fasting blood sample was collected, and the post-training fasting blood sample collection was performed 36 hours after the last exercise session. Results: Blood lipid profile and HDL function were analyzed before and after the HIIT program. Along with improved blood lipid profiles in obese and T2DM subjects, the HIIT program affected circulating apolipoprotein amounts differently. The HIIT program increased HDL-cholesterol levels and improved the cholesterol efflux capacity only in lean subjects. Furthermore, the HIIT program improved the antioxidant capacity of HDL in all subjects. Data from multiple logistic regression analysis showed that changes in HDL antioxidant capacity were inversely associated with changes in atherogenic lipids and changes in HDL-TG content. Discussion: We show that a short-term HIIT program improves aspects of HDL function depending on metabolic contexts, which correlates with improvements in blood lipid profile. Our results demonstrate that TG content in HDL particles may play a negative role in the anti-atherogenic function of HDL.