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Osteomyelitis (OM) is a progressive, inflammatory infection of bone caused predominately by Staphylococcus aureus. Herein, we engineered an antibiotic-eluting collagen-hydroxyapatite scaffold capable of eliminating infection and facilitating bone healing. An iterative freeze-drying and chemical crosslinking approach was leveraged to modify antibiotic release kinetics, resulting in a layered dual-release system whereby an initial rapid release of antibiotic to clear infection was followed by a sustained controlled release to prevent reoccurrence of infection. We observed that the presence of microbial collagenase accelerated antibiotic release from the crosslinked layer of the scaffold, indicating that the material is responsive to microbial activity. As exemplar drugs, vancomycin and gentamicin-eluting scaffolds were demonstrated to be bactericidal, and supported osteogenesis in vitro. In a pilot murine model of OM, vancomycin-eluting scaffolds were observed to reduce S. aureus infection within the tibia. Finally, in a rabbit model of chronic OM, gentamicin-eluting scaffolds both facilitated radial bone defect healing and eliminated S. aureus infection. These results show that antibiotic-eluting collagen-hydroxyapatite scaffolds are a one-stage therapy for OM, which when implanted into infected bone defects simultaneously eradicate infection and facilitate bone tissue healing.

Asunto(s)

Antibacterianos , Gentamicinas , Osteomielitis , Infecciones Estafilocócicas , Staphylococcus aureus , Andamios del Tejido , Animales , Andamios del Tejido/química , Antibacterianos/farmacología , Antibacterianos/química , Infecciones Estafilocócicas/tratamiento farmacológico , Osteomielitis/tratamiento farmacológico , Conejos , Staphylococcus aureus/efectos de los fármacos , Gentamicinas/farmacología , Gentamicinas/administración & dosificación , Gentamicinas/química , Gentamicinas/uso terapéutico , Ratones , Vancomicina/farmacología , Vancomicina/química , Vancomicina/administración & dosificación , Durapatita/química , Cinética , Cicatrización de Heridas/efectos de los fármacos , Osteogénesis/efectos de los fármacos , Colágeno/química , Femenino

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PURPOSE: The magnitude of cardiorespiratory fitness (CRF) impairment during anticancer treatment and CRF response to aerobic exercise training (AT) are highly variable. The aim of this ancillary analysis was to leverage machine learning approaches to identify patients at high risk of impaired CRF and poor CRF response to AT. METHODS: We evaluated heterogeneity in CRF among 64 women with metastatic breast cancer randomly assigned to 12 weeks of highly structured AT (n = 33) or control (n = 31). Unsupervised hierarchical cluster analyses were used to identify representative variables from multidimensional prerandomization (baseline) data, and to categorize patients into mutually exclusive subgroups (ie, phenogroups). Logistic and linear regression evaluated the association between phenogroups and impaired CRF (ie, ≤16 mL O2·kg-1·min-1) and CRF response. RESULTS: Baseline CRF ranged from 10.2 to 38.8 mL O2·kg-1·min-1; CRF response ranged from -15.7 to 4.1 mL O2·kg-1·min-1. Of the n = 120 candidate baseline variables, n = 32 representative variables were identified. Patients were categorized into two phenogroups. Compared with phenogroup 1 (n = 27), phenogroup 2 (n = 37) contained a higher number of patients with none or >three lines of previous anticancer therapy for metastatic disease and had lower resting left ventricular systolic and diastolic function, cardiac output reserve, hematocrit, lymphocyte count, patient-reported outcomes, and CRF (P < .05) at baseline. Among patients allocated to AT (phenogroup 1, n = 12; 44%; phenogroup 2, n = 21; 57%), CRF response (-1.94 ± 3.80 mL O2·kg-1·min-1 v 0.70 ± 2.22 mL O2·kg-1·min-1) was blunted in phenogroup 2 compared with phenogroup 1. CONCLUSION: Phenotypic clustering identified two subgroups with unique baseline characteristics and CRF outcomes. The identification of CRF phenogroups could help improve cardiovascular risk stratification and guide investigation of targeted exercise interventions among patients with cancer.

Asunto(s)

Neoplasias de la Mama , Capacidad Cardiovascular , Aprendizaje Automático , Humanos , Femenino , Neoplasias de la Mama/patología , Neoplasias de la Mama/terapia , Neoplasias de la Mama/genética , Persona de Mediana Edad , Metástasis de la Neoplasia , Terapia por Ejercicio/métodos , Ejercicio Físico , Anciano , Adulto

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Background: Arthroscopic revision rotator cuff repairs (RCRs) exhibit lower healing rates and inferior outcomes compared to primary repairs. There is limited evidence regarding the use of bioaugmentation in the setting of revision RCRs. Autologous conditioned plasma (ACP) is a promising adjunct that has been shown to improve healing rates and patient-reported outcomes (PROs) in the primary setting. In addition, bioinductive patches such as collagen bovine patches have become a popular adjunct for stimulating healing in the primary setting. The aim of this study is to assess the outcomes after use of ACP and collagen bovine patch augmentation for revision arthroscopic RCR. We hypothesized improved PROs and higher healing rates would be observed with bioaugmentation for revision repair compared to without. Methods: This was an institutional review board-approved, retrospective case-control study from 2 fellowship-trained surgeons that included all consecutive patients undergoing arthroscopic revision RCR from 2010 to 2021. Reconstruction such as superior capsular reconstruction, partial revision repair, and less than 1-year follow-up were excluded. The bioaugmentation cohort received ACP and/or collagen bovine patch at the time of revision repair. PROs were collected from all patients including American Shoulder and Elbow Surgeons Standardized Assessment Form (ASES), visual analog scale for pain (VAS), Brophy score, and Patient-Reported Outcomes Measurement Information System (PROMIS) mental and physical scores. Failure of revision RCR was defined as an ASES postoperative total score less than 60 or a symptomatic retear confirmed on magnetic resonance imaging. Student's t-test was used for all comparisons of continuous variables. Chi-squared test used for comparison of all categorical variables. Statistical significance was set at <0.05. Results: Thirty-eight patients met inclusion criteria with average follow-up of 3.5 ± 1.7 years. There was no significant difference in follow-up between patients with and without bioaugmentation. Of the 38 patients, 14 patients met failure criteria. There was no significant difference in the rate of failure between the bioaugmentation cohort (6/19, 31.6%) vs. patients who did not receive bioaugmentation (8/19, 42.1%) (P = .74). In addition, no significant differences were identified for ASES (64.6 ± 20.1 vs. 57.5 ± 17.2, P = .32), Brophy (6.4 ± 5.2 vs. 6.0 ± 4.1, P = .84), PROMIS Mental (13.4 ± 3.9 vs. 11.7 ± 3.2), or PROMIS Physical (12.8 ± 3.1 vs. 11.9 ± 3.2) scores between the bioaugmentation vs. no bioaugmentation groups. Conclusion: Bioaugmentation with a bioinductive collagen patch or ACP demonstrated similar failure and PROs compared to without bioaugmentation in the setting of revision RCR.

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Existing clinical biomarkers do not reliably predict treatment response or disease progression in patients with advanced intrahepatic cholangiocarcinoma (ICC). Circulating neoplastic-immune hybrid cells (CHCs) have great promise as a blood-based biomarker for patients with advanced ICC. Peripheral blood specimens were longitudinally collected from patients with advanced ICC enrolled in the HELIX-1 phase II clinical trial (NCT04251715). CHCs were identified by co-expression of pan-cytokeratin (CK) and CD45, and levels were correlated to patient clinical disease course. Unsupervised machine learning was then performed to extract their morphological features to compare them across disease courses. Five patients were included in this study, with a median of nine specimens collected per patient. A median of 13.5 CHCs per 50,000 peripheral blood mononuclear cells were identified at baseline, and levels decreased to zero following the initiation of treatment in all patients. Counts remained undetectable in three patients who demonstrated end-of-trial clinical treatment response and conversely increased in two patients with evidence of therapeutic resistance. In the post-trial surveillance period, interval counts increased prior to or at the time of clinical progression in three patients and remain undetectable in one patient with continued long-term disease stability. Using our machine learning platform, treatment-resistant CHCs exhibited upregulation of CK and downregulation of CD45 relative to treatment-responsive CHCs. CHCs represent a promising blood-based biomarker to supplement traditional radiographic and biochemical measures.

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Neoplasias de los Conductos Biliares , Biomarcadores de Tumor , Colangiocarcinoma , Células Neoplásicas Circulantes , Humanos , Colangiocarcinoma/sangre , Colangiocarcinoma/patología , Biomarcadores de Tumor/sangre , Masculino , Neoplasias de los Conductos Biliares/patología , Neoplasias de los Conductos Biliares/sangre , Neoplasias de los Conductos Biliares/diagnóstico , Neoplasias de los Conductos Biliares/metabolismo , Femenino , Persona de Mediana Edad , Pronóstico , Células Neoplásicas Circulantes/metabolismo , Células Neoplásicas Circulantes/patología , Anciano , Antígenos Comunes de Leucocito/metabolismo , Queratinas/metabolismo

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BACKGROUND: Two-stage models of heterogenous treatment effects (HTE) may advance personalized medicine in multiple sclerosis (MS). Brain atrophy is a relatively objective outcome measure that has strong relationships to MS prognosis and treatment effects and is enabled by standardized MRI. OBJECTIVES: To predict brain atrophy outcomes for patients initiating disease-modifying therapies (DMT) with different efficacies, considering the patients' baseline brain atrophy risk measured via brain parenchymal fraction (BPF). METHODS: Analyses included patients enrolled in the Multiple Sclerosis Partners Advancing Technology and Health Solutions (MS PATHS) network who started DMT and had complete baseline data and ≥ 6-month brain MRI follow-up. All brain MRIs were acquired using standardized acquisition sequences on Siemens 3T scanners. BPF change risk was derived by linear mixed effects models using baseline covariates. Model performance was assessed by predicted versus actual BPF change R2. Propensity score (PS) weighting was used to balance covariates between groups defined by DMT efficacy (high: natalizumab, alemtuzumab, ocrelizumab, and rituximab; moderate: dimethyl fumarate, fingolimod, and cladribine; low: teriflunomide, interferons, and glatiramer acetate). HTE models predicting 1 year change in BPF were built using a weighted linear mixed effects model with low-efficacy DMT as the reference. RESULTS: Analyses included 581 high-, 183 moderate-, and 106 low-efficacy DMT-treated patients. The mean and median number of brain MRI observations per treatment period were 2.9 and 3.0, respectively. Risk model performance R2=0.55. After PS weighting, covariate standardized mean differences were <10 %, indicating excellent balance across measured variables. Changes in BPF between baseline and follow-up were found to be statistically significant (p < 0.001), suggesting a pathological change. Patients with low brain atrophy risk had a similar outcome regardless of DMT selection. In patients with high brain atrophy risk, high- and moderate-efficacy DMTs performed similarly, while a 2-fold worse BPF change was predicted for patients selecting low-efficacy DMTs (p < 0.001). Similar results were observed in a sensitivity analysis adjusting for pseudoatrophy effects in a sub-population of patients treated with natalizumab. CONCLUSIONS: The relative benefit of selecting higher efficacy treatments may vary depending on patients' baseline brain atrophy risk. Poor outcomes are predicted in individuals with high baseline risk who are treated with low-efficacy DMTs.

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OBJECTIVES: The intergenerational stake hypothesis and theories of the life course posit that older generations are invested in the well-being of younger generations. Consistent with this, previous research has shown that adult children's problems are associated with worse parental well-being. Because multigenerational ties have become increasingly important in the 21st century, we propose that adult grandchildren's problems may also impact grandparents' well-being. In this paper, we test this hypothesis and investigate the moderating effects of grandparents' race and maternal/paternal status. METHODS: The analytic sample includes 206 grandparents aged 65-95 who participated in the second wave of the Family Exchanges Study. Adult grandchildren's problems were operationalized as the proportions of adult grandchildren who experienced (1) physical-emotional problems and (2) lifestyle-behavioral problems. RESULTS: Main effects multilevel analyses suggested that adult grandchildren's problems did not predict grandparents' well-being. However, moderation analyses revealed that the association between grandparents' depressive symptoms and adult grandchildren's physical-emotional problems was larger among Black than White grandparents, and maternal than paternal grandparents. Adult grandchildren's lifestyle-behavioral problems did not predict grandparents' depression, and these effects were not conditioned by race or maternal/paternal status. DISCUSSION: These findings expand research on the importance of grandparent-adult grandchild relationships and contribute to research on multigenerational relationships and health by considering how problems experienced by members of younger generations impact the psychological well-being of older adults.

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Background: A major challenge in learning rhinoplasty is correlating patients' external and internal nasal structures. We aim to explore the application of three dimensional (3D)-printed models of nasal bony-cartilaginous structures in identifying accurate nasal anatomy. Methods: Otolaryngology-head and neck surgery and plastic and reconstructive surgery residents matched patient photograph models, described relative nasal bony-cartilaginous anatomy, completed pre- and postactivity self-evaluations (based on otolaryngology "nasal deformity" milestones including "anatomy," "function," "aesthetic," and "etiology"), and rated the 3D-printed models' usefulness. Descriptive statistics were measured. Results: Thirty-seven residents correctly matched four of six model-photograph pairs and correctly described 15 of 30 anatomic relationships, on average. There was a moderate, statistically significant correlation between postgraduate year and number of correctly matched model-photograph pairs (Spearman rho = 0.58, 95% CI 0.24-0.79) and total items correct (Spearman rho = 0.61, 95% CI 0.28-0.81). Self-ratings on milestones decreased postexercise in all subcategories except "function." From 0 (low) to 100 (high), learners found the exercise useful (median 85 of 100) with a high recommendation for future use (median 87 of 100). Conclusions: Three-dimensional printed models are a valuable tool for understanding nasal anatomy. Continued standardization of designs and assessments of their educational utility will enhance their broader dissemination and implementation.

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OBJECTIVE: Progressive outer retinal necrosis (PORN) is an alphaherpesvirus-caused panuveitis with devastating consequences for the eye. Our study aims to describe new findings in the clinical spectrum and propose a mechanism for the pathogenesis of PORN. METHODS: Observational, consecutive case series. Seven eyes from five patients diagnosed with PORN were enrolled. Detailed case histories, ocular examination findings and multimodal images of retina were collected. Optic nerve and brain imaging were obtained by MRI. RESULTS: All eyes were confirmed human alphaherpesviruses positive in ocular fluid by qPCR. Optic nerve oedema was observed on MRI in all eyes. A relative afferent pupillary defect was recorded in the affected eye for the unilateral cases. Two patients with unilateral involvement had a history of viral encephalitis and focal encephalomalacia found in the temporal lobe on brain MRI. The affected eyes were characterised by sensory retinal necrosis sparing retinal pigment epithelium, starting at the end of the retinal nerve fibre (horizontal raphe or peripheral area of the retina) and progressing rapidly along the nerve fibre. The wall of the retinal artery and vein was destroyed, resulting in blood flow interruption on fluorescein angiography and retinal haemorrhages along the large vessels. CONCLUSIONS: Combination the neurotropic characteristics of alphaherpesviruses and the signs of PORN, we hypothesised that the reactivated PORN virus originated from the lateral geniculate nucleus, then propagated along the optic nerve and was released at the terminals, causing necrosis of the entire sensory retina rather than just affecting the outer segment.

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Oral broad-spectrum antivirals are urgently needed for the treatment of many emerging and contemporary RNA viruses. We previously synthesized 1-O-octadecyl-2-O-benzyl-sn-glyceryl-P-RVn (ODBG-P-RVn, V2043), a phospholipid prodrug of GS-441524 (remdesivir nucleoside, RVn), and demonstrated its in vivo efficacy in a SARS-CoV-2 mouse model. Structure-activity relationship studies focusing on the prodrug scaffold identified two modifications, 3-fluoro-4-methoxy-benzyl (V2053) and 4-cyano-benzyl (V2067), that significantly enhanced the in vitro broad-spectrum antiviral activity against multiple RNA viruses when compared to V2043. Here, we demonstrate that V2043, V2053, and V2067 are all orally bioavailable, well-tolerated, and achieve high sustained plasma levels after single oral daily dosing. All three phospholipid prodrugs are significantly more active than RVn in vitro and significantly reduce SARS-CoV-2 lung titers in prophylaxis and treatment mouse models of SARS-CoV-2 B.1.351 infection. On a molar basis, V2043 and V2067 are substantially more active than obeldesivir/GS-5245 and molnupiravir in vivo. Together, these data support the continued development of phospholipid RVn prodrugs for the treatment of SARS-CoV-2 and other RNA viruses of clinical concern.

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Background: The human immunodeficiency virus (HIV) epidemic in South Africa is among the worst in the world; in 2017, 38% of new infections were among young people aged 15-24 years. Estimates for HIV infection in 2020 worldwide indicate that there will be 1.5 million new cases, 10.2 million untreated cases (out of 37.7 million), and 680 000 deaths from acquired immunodeficiency syndrome (AIDS). Despite a 46% decline in new HIV infections among adolescents and youth over the previous 10 years, two of the seven new HIV infections in 2019 occurred in people between the ages of 15 and 24. HIV prevalence among young people has remained unchanged since 2008. This consistent pattern among people under 30 years of age indicates a failure in HIV prevention. Aim: The study aimed to explore HIV and sexual risk behaviours by 18-25-year-old youth at Nyandeni Municipality in the Eastern Cape province. Setting: The investigation was conducted Nyandeni Municipality in the Eastern Cape province. Methods: Qualitative approach was used to explore, describe and investigate the knowledge and attitudes about HIV among the 18-25 years old youth. Results: The findings are based on three themes namely, knowledge and attitudes about HIV and AIDS in youth, sexual risk behaviour among youth, and HIV prevention strategies. Conclusion: This exploratory investigation confirms that the participants' knowledge is limited by showing that most of them knew very little about HIV and AIDS infection and prevention. Ongoing educational initiatives are required. Contribution: Youth experience high HIV incidence because of their knowledge gaps.

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INTRODUCTION: Ceramic-on-highly crosslinked polyethylene (HXLPE) has become the most common bearing surface utilized in primary total hip arthroplasty (THA). The purpose of this study was to determine the implant survivorship and clinical outcomes of THAs with ceramic-on-HXLPE in a large, single institutional, series. METHODS: We identified 5,536 primary THAs performed from 2007 to 2017 using a ceramic-on-HXLPE bearing through our total joint registry. The mean age was 60 years, 51% were women, and the mean body mass index (BMI) was 30. A cementless femoral component was used in 98% of cases, and a head size of ≥ 36 was used in 75%. Kaplan-Meier survivorship analyses were completed to assess survivorship free of any revision or reoperation. Clinical outcomes were assessed via Harris Hip Scores (HHS). The mean follow-up was 4 years. RESULTS: The 5-year survivorship free of any revision was 97%. The most common indications for revision were dislocation (41 hips), periprosthetic joint infection (PJI) (39 hips), and periprosthetic femur fracture (18 hips). The 5-year survivorship free of any reoperation was 96%. There were an additional 70 reoperations, with the most common indications being wound dehiscence (32 hips), iliopsoas impingement (11 hips), and periprosthetic femur fracture (11 hips). There were only two bearing surface failures: one HXLPE liner fractured and one dissociated. There were no ceramic head fractures or failures. The mean HHS increased from 57 to 92 (P < 0.0001). CONCLUSION: In over 5,500 THAs completed with modern ceramic-on-HXLPE bearings, failures of the bearing surface were nearly eliminated at midterm follow-up, and overall 5-year survivorship free of revision was excellent. Dislocation, PJI, and periprosthetic femur fracture were the most common causes of failure. As bearing surfaces have evolved, traditional failure mechanisms such as polyethylene wear, corrosion and metal reactions, and ceramic fractures have become nearly extinct.

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BACKGROUND: A wealth of clinically relevant information is only obtainable within unstructured clinical narratives, leading to great interest in clinical natural language processing (NLP). While a multitude of approaches to NLP exist, current algorithm development approaches have limitations that can slow the development process. These limitations are exacerbated when the task is emergent, as is the case currently for NLP extraction of signs and symptoms of COVID-19 and postacute sequelae of SARS-CoV-2 infection (PASC). OBJECTIVE: This study aims to highlight the current limitations of existing NLP algorithm development approaches that are exacerbated by NLP tasks surrounding emergent clinical concepts and to illustrate our approach to addressing these issues through the use case of developing an NLP system for the signs and symptoms of COVID-19 and PASC. METHODS: We used 2 preexisting studies on PASC as a baseline to determine a set of concepts that should be extracted by NLP. This concept list was then used in conjunction with the Unified Medical Language System to autonomously generate an expanded lexicon to weakly annotate a training set, which was then reviewed by a human expert to generate a fine-tuned NLP algorithm. The annotations from a fully human-annotated test set were then compared with NLP results from the fine-tuned algorithm. The NLP algorithm was then deployed to 10 additional sites that were also running our NLP infrastructure. Of these 10 sites, 5 were used to conduct a federated evaluation of the NLP algorithm. RESULTS: An NLP algorithm consisting of 12,234 unique normalized text strings corresponding to 2366 unique concepts was developed to extract COVID-19 or PASC signs and symptoms. An unweighted mean dictionary coverage of 77.8% was found for the 5 sites. CONCLUSIONS: The evolutionary and time-critical nature of the PASC NLP task significantly complicates existing approaches to NLP algorithm development. In this work, we present a hybrid approach using the Open Health Natural Language Processing Toolkit aimed at addressing these needs with a dictionary-based weak labeling step that minimizes the need for additional expert annotation while still preserving the fine-tuning capabilities of expert involvement.

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Background: Physician patients requiring surgery present with occupational risks and personality traits that may affect outcomes. This study compared implant survivorship, complications, and clinical outcomes of physicians undergoing primary total hip arthroplasty (THA) or total knee arthroplasty (TKA). Methods: A retrospective review of our institutional total joint registry identified 185 physicians undergoing primary THA (n = 94) or TKA (n = 91). Physicians were matched 1:2 with nonphysician controls according to age, sex, body mass index, joint (hip or knee), and surgical year. Physician type (medical, n = 132 vs surgical, n = 53) subanalysis was performed. Implant survivorship was assessed via Kaplan-Meier methods. Clinical outcomes were evaluated by Harris hip scores and Knee Society Scores. Mean follow-up was 5 years. Results: There was no significant difference in 5-year implant survivorship free of any reoperation (P > .5) or any revision (P > .2) between physician and nonphysician patients after THA and TKA. Similarly, the 90-day complication risk was not significantly different after THA or TKA (P = 1.0 for both). Physicians and nonphysicians demonstrated similar improvement in Harris hip scores (P = .6) and Knee Society Scores (P = .4). When comparing physician types, there was no difference in implant survivorship (P > .4), complications (P > .6), or patient reported outcomes (P > .1). Conclusions: Physician patients have similar implant survivorship, complications, and clinical outcomes when compared to nonphysicians after primary THA and TKA. Physicians should feel reassured that their profession does not appear to increase risks when undergoing lower extremity total joint arthroplasty.

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OBJECTIVES: To compare the efficacy of the 445-nm blue laser to the 585-nm pulsed dye laser (PDL) and 532-nm potassium-titanyl-phosphate (KTP) laser in the treatment of benign laryngeal lesions. DATA SOURCES: Cochrane Library, PubMed, Scopus, and CINAHL. REVIEW METHODS: Following PRISMA guidelines, databases were searched from inception through January 29, 2024, for studies reporting the use of photoangiolytic lasers for treatment of benign laryngeal lesions, including the 585-nm PDL, 532-nm KTP laser, and 445-nm blue laser. Outcome measures included lesion resolution (%), mean differences (Δ) in Voice Handicap Index (VHI-10), and summed dysphonia grade, roughness, and breathiness (GRB) scale. RESULTS: A total of 45 studies were included for meta-analysis, consisting of 348 patients treated with PDL, 550 patients with KTP laser, and 338 patients with blue laser. Treatment with blue laser resulted in the greatest lesion resolution (94.0%; 95% confidence interval [CI]: 90.2%-96.7%), followed by KTP laser (90.4%; 95% CI: 84.1%-95.2%), and PDL (86.9%; 95% CI: 62.9%-99.2%). VHI-10 improved significantly in patients following treatment with blue laser (Δ13.3; 95% CI: 10.7-16.0; p < 0.0001), KTP laser (Δ10.3; 95% CI: 7.4-13.3; p < 0.0001), and PDL (Δ7.4; 95% CI: 4.8-10.1; p < 0.0001). GRB improved significantly in patients following treatment with blue laser (Δ4.1; 95% CI: 2.9-5.2; p < 0.0001), KTP laser (Δ3.0; 95% CI: 2.0-4.0; p < 0.0001), and PDL (Δ2.5; 95% CI: 0.8-4.2; p = 0.005). CONCLUSIONS: Photoangiolytic lasers are effective in treating benign laryngeal lesions. Blue lasers are promising for laryngeal laser surgery. Laryngoscope, 2024.

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INTRODUCTION: Patients with pectus excavatum (PE) often undergo cross-sectional imaging (CSI) to quantify severity for insurance authorization before surgical repair. The modified percent depth (MPD), an external caliper-based metric, was previously validated to be similar to the pectus index and correction index. This study explored family perceptions of CSI and MPD with respect to value and costs. METHODS: This is a cross-sectional survey study including families of patients enrolled in an ongoing prospective multicenter study evaluating the use of MPD as an alternative to CSI for quantifying PE severity. Families of PE patients who underwent both MPD and CSI completed a survey to determine their perceptions of MPD and costs of CSI. Responses were described and associations were evaluated using chi squared, Wilcoxon rank-sum test and logistic regression as appropriate. Statistical significance was set to 0.05. RESULTS: There were 136 surveys completed for a response rate of 88%. Respondents were confident in MPD (86%) and confident in its similarity to CSI (76%). Families of females were less confident in the measurements than males (55% versus 80%, P = 0.02; odds ratio 0.30 (0.11, 0.83). Obtaining CSI required time off work/school in 90% and a copay in 60%. Nearly half (49%) of respondents reported CSI was a time/financial hardship. Increasing copay led to decreased reassurance in CSI (55%: copay > $100 versus 77%: lower copay/75%: no copay; P = 0.04). CONCLUSIONS: From the family perspective, MPD is valuable in assessing the severity of PE. Obtaining CSI was financially burdensome, particularly for those with higher copays. MPD measurements provide high value at low cost in assessing the severity of PE.

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Voice fatigue (VF) has many symptoms and can occur after extended or brief voice use, depending on the presence or absence of voice pathology, and other factors. However, fatigue is difficult to detect and quantify through current approaches. This study explores the use of artificial intelligence (AI) in the automatic detection and analysis of VF, presenting a novel approach to detect and monitor the condition. OBJECTIVE: This study aims to create an AI-based system for detecting VF. The AI model's performance is evaluated against traditional methods of assessment conducted by speech-language pathologists (SLPs). METHODS: Voice samples were collected from individuals experiencing varying levels of VF. To validate these samples, we calculated fo, increases that have been shown to be correlated with VF, at the beginning and end of the recordings. The samples were processed using a machine learning model trained to recognize patterns associated with VF. To build the model, we extracted embeddings from an ECAPA-TDNN model that has been shown to capture changes in the voice characteristics of a speaker over time and used a Convolutional Neural Network for classification. To validate the model, the model's accuracy in detecting VF was compared with assessments from SLPs. RESULTS: We achieved an accuracy score of 93% on our dataset of English academic lectures and podcasts. As further validation, we asked three experienced SLPs to classify audio segments from our dataset and compared their responses to the classifications from our model, and achieved an accuracy of 86% as compared to their ratings. CONCLUSION: The application of AI in the detection of VF shows a generalizable approach for the analysis of VF. Future research will incorporate patient data to validate further the models that we created.

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Iron is critical for neuronal activity and metabolism, and iron dysregulation alters these functions in age-related neurodegenerative disorders, such as Alzheimer's disease (AD). AD is a chronic neurodegenerative disease characterized by progressive neuronal dysfunction, memory loss and decreased cognitive function. AD patients exhibit elevated iron levels in the brain compared to age-matched non-AD individuals. However, the degree to which iron overload contributes to AD pathogenesis is unclear. Here, we evaluated the involvement of ferroptosis, an iron-dependent cell death process, in mediating AD-like pathologies in C. elegans. Results showed that iron accumulation occurred prior to the loss of neuronal function as worms age. In addition, energetic imbalance was an early event in iron-induced loss of neuronal function. Furthermore, the loss of neuronal function was, in part, due to increased mitochondrial reactive oxygen species mediated oxidative damage, ultimately resulting in ferroptotic cell death. The mitochondrial redox environment and ferroptosis were modulated by pharmacologic processes that exacerbate or abolish iron accumulation both in wild-type worms and worms with increased levels of neuronal amyloid beta (Aß). However, neuronal Aß worms were more sensitive to ferroptosis-mediated neuronal loss, and this increased toxicity was ameliorated by limiting the uptake of ferrous iron through knockout of divalent metal transporter 1 (DMT1). In addition, DMT1 knockout completely suppressed phenotypic measures of Aß toxicity with age. Overall, our findings suggest that iron-induced ferroptosis alters the mitochondrial redox environment to drive oxidative damage when neuronal Aß is overexpressed. DMT1 knockout abolishes neuronal Aß-associated pathologies by reducing neuronal iron uptake.