Phase 1 dose-escalation trial evaluating a group 2 influenza hemagglutinin stabilized stem nanoparticle vaccine.

The relative conservation of the influenza hemagglutinin (HA) stem compared to that of the immunodominant HA head makes the HA stem an attractive target for broadly protective influenza vaccines. Here we report the first-in-human, dose-escalation, open-label trial (NCT04579250) evaluating an unadjuvanted group 2 stabilized stem ferritin nanoparticle vaccine based on the H10 A/Jiangxi-Donghu/346/2013 influenza HA, H10ssF, in healthy adults. Participants received a single 20 mcg dose (n = 3) or two 60 mcg doses 16 weeks apart (n = 22). Vaccination with H10ssF was safe and well tolerated with only mild systemic and local reactogenicity reported. No serious adverse events occurred. Vaccination significantly increased homologous H10 HA stem binding and neutralizing antibodies at 2 weeks after both first and second vaccinations, and these responses remained above baseline at 40 weeks. Heterologous H3 and H7 binding antibodies also significantly increased after each vaccination and remained elevated throughout the study. These data indicate that the group 2 HA stem nanoparticle vaccine is safe and induces stem-directed binding and neutralizing antibodies.

Can AI Predict the Magnitude and Direction of Ortho-K Contact Lens Decentration to Limit Induced HOAs and Astigmatism?

Background: The aim is to investigate induced higher-order aberrations (HOA)s and astigmatism as a result of non-toric ortho-k lens decentration and utilise artificial intelligence (AI) to predict its magnitude and direction. Methods: Medmont E300 Video topographer was used to scan 249 corneas before and after ortho-k wear. Custom-built MATLAB codes extracted topography data and determined lens decentration from the boundary and midpoint of the central flattened treatment zone (TZ). An evaluation was carried out by conducting Zernike polynomial fittings via a computer-coded digital signal processing procedure. Finally, an AI-based machine learning neural network algorithm was developed to predict the direction and magnitude of TZ decentration. Results: Analysis of the first 21 Zernike polynomial coefficients indicate that the four low-order and four higher-order aberration terms were changed significantly by ortho-k wear. While baseline astigmatism was not correlated with lens decentration (R = 0.09), post-ortho-k astigmatism was moderately correlated with decentration (R = 0.38) and the difference in astigmatism (R = 0.3). Decentration was classified into three groups: ≤0.50 mm, reduced astigmatism by -0.9 ± 1 D; 0.5~1 mm, increased astigmatism by 0.8 ± 0.1 D; >1 mm, increased astigmatism by 2.7 ± 1.6 D and over 50% of lenses were decentred >0.5 mm. For lenses decentred >1 mm, 29.8% of right and 42.7% of left lenses decentred temporal-inferiorly and 13.7% of right and 9.4% of left lenses decentred temporal-superiorly. AI-based prediction successfully identified the decentration direction with accuracies of 70.2% for right and 71.8% for left lenses and predicted the magnitude of decentration with root-mean-square (RMS) of 0.31 mm and 0.25 mm for right and left eyes, respectively. Conclusions: Ortho-k lens decentration is common when fitting non-toric ortho-k lenses, resulting in induced HOAs and astigmatism, with the magnitude being related to the amount of decentration. AI-based algorithms can effectively predict decentration, potentially allowing for better control over ortho-k fitting and, thus, preferred clinical outcomes.

Social Determinants of Health Impact Complications Following Free-Flap Reconstruction for Head and Neck Cancer.

OBJECTIVE: Head and neck cancers (HNCs) have increased in prevalence and often require free-flap reconstruction (FFR) after tumor ablation. Postoperative complications following FFR can be high, occurring in as many as 48% and 71% of cases. HNC patients also have many disparities in Social Determinants of Health (SDOH), but the potential impact of SDOH disparities on postoperative complications following FFR has not been formally assessed. STUDY DESIGN: Retrospective cohort review. SETTING: Academic Tertiary Care Institution in Northeast United States. METHODS: Patients that underwent head and neck FFR between January 2018 and December 2021 were analyzed to determine associations between quartiles of the national Area Deprivation Index (ADI), a proxy for SDOH disparity, and various medical and surgical postoperative complications. Associations were assessed using χ2 analysis. RESULTS: Two hundred four patients were included in the study, and 61 patients had 97 complications. Significant associations between higher national ADI quartile and incidence of several postoperative complications were identified, including any surgical complication (P = .0419), wound dehiscence (P = .0494), myocardial infarction (MI) (P = .0215), and sepsis (P = .0464). CONCLUSION: There are significant associations between SDOH disparities and postoperative surgical complications, wound dehiscence, MI, and sepsis following head and neck FFR. Addressing SDOH disparities in HNC is pivotal to enhance postoperative outcomes and promote holistic patient care.

A phase 3b, open-label, single-arm, multicenter, expanded-access study of the safety and clinical outcomes of StrataGraft® treatment in adults with deep partial-thickness thermal burns.

BACKGROUND: A phase 3b, open-label, multicenter, expanded-access study (NCT04123548) evaluated safety and clinical outcomes of StrataGraft treatment in adults with deep partial-thickness thermal burns with intact dermal elements. METHODS: Adult patients with 3 % to < 50 % total body surface area burns were treated with a single application of ≤ 1:1 meshed StrataGraft and followed for 24 weeks. Primary endpoint was count and percentage of patients with treatment-emergent adverse events (TEAEs). Secondary endpoints included confirmed wound closure (WC) at Week 12, durable WC at Week 24, time to WC, scar evaluation, and wound infection-related events. RESULTS: Fifty-two patients with 96 treatment sites were enrolled. Pruritus was the most common TEAE (22 patients [42.3 %]). Twenty serious TEAEs occurred in 10 patients (19.2 %); none were related to StrataGraft. There were 4 (7.7 %) deaths (aspiration, myocardial infarction, self-injury, Gram-negative rod sepsis); none were related to StrataGraft. Confirmed WC was achieved by Week 12 in 33 patients (63.5 %; 95 % CI: 50.4-76.5 %) and 69 treatment sites (71.9 %; 95 % CI: 62.9-80.9 %). Durable WC was achieved by Week 24 in 29 patients (55.8 %; 95 % CI: 42.3-69.3 %) and 58 treatment sites (60.4 %; 95 % CI: 50.6-70.2 %). CONCLUSIONS: StrataGraft demonstrated clinical benefit. Safety data were consistent with previously reported findings.

Laparoscopic training workshop to assess medical students' skill acquisition and interest in surgical careers.

BACKGROUND: With its minimally invasive approach, laparoscopic surgery has transformed the medical landscape. As the demand for these procedures escalates, there is a pressing need for adept surgeons trained in laparoscopic techniques. However, current training often falls short of catering to medical school education. This study evaluates the impact of a custom-designed laparoscopic training workshop on medical students' surgical skills and career aspirations. METHODS: This prospective experimental study was conducted at the E-Da hospital in Kaohsiung City, Taiwan. Medical students from Taiwanese medical schools undergoing Clerk 5, Clerk 6, and Postgraduate Year 1 and 2 were invited to participate. Medical students (n = 44) underwent an endoscopic skill training workshop consisting of lectures, box training, and live tissue training. The trainees performed multiple tasks before and after training using our objective evaluation system. The primary outcome was assessed before and after training through a questionnaire assessing the influence of training on students' interest in surgery as a career. The secondary outcome measured improvement in skill acquisition, comparing the task completion time pre- and post-workshop. For the primary outcome, descriptive statistics were used to summarize the questionnaire responses, and paired t-tests were performed to determine significant changes in interest levels post-workshop. For the secondary outcome, paired t-tests were used to compare the time recorded pre- and post-training. RESULTS: Post-training, participants exhibited significant proficiency gains, with task completion times reducing notably: 97 s (p = 0.0015) for Precision Beads Placement, 88.5 s (p < 0.0001) for Beads Transfer Exercise, 95 s (p < 0.0001) for Precision Balloon Cutting, and 137.8 s (p < 0.0001) for Intracorporeal Suture. The primary outcome showcased an increased mean score from 8.15 pre-workshop to 9.3 post-workshop, indicating a bolstered interest in surgery as a career. Additionally, post-training sentiment analysis underscored a predominant inclination toward surgery among 88% of participants. CONCLUSION: The custom-designed laparoscopic workshop significantly improved technical skills and positively influenced students' career aspirations toward surgery. Such hands-on training workshops can play a crucial role in medical education, bridging the gap between theoretical knowledge and practical skills and potentially shaping the future of budding medical professionals.

Readability of Patient Education Materials in Head and Neck Cancer: A Systematic Review.

Importance: Patient education materials (PEMs) can promote patient engagement, satisfaction, and treatment adherence. The American Medical Association recommends that PEMs be developed for a sixth-grade or lower reading level. Health literacy (HL) refers to an individual's ability to seek, understand, and use health information to make appropriate decisions regarding their health. Patients with suboptimal HL may not be able to understand or act on health information and are at risk for adverse health outcomes. Objective: To assess the readability of PEMs on head and neck cancer (HNC) and to evaluate HL among patients with HNC. Evidence Review: A systematic review of the literature was performed by searching Cochrane, PubMed, and Scopus for peer-reviewed studies published from 1995 to 2024 using the keywords head and neck cancer, readability, health literacy, and related synonyms. Full-text studies in English that evaluated readability and/or HL measures were included. Readability assessments included the Flesch-Kincaid Grade Level (FKGL grade, 0-20, with higher grades indicating greater reading difficulty) and Flesch Reading Ease (FRE score, 1-100, with higher scores indicating easier readability), among others. Reviews, conference materials, opinion letters, and guidelines were excluded. Study quality was assessed using the Appraisal Tool for Cross-Sectional Studies. Findings: Of the 3235 studies identified, 17 studies assessing the readability of 1124 HNC PEMs produced by professional societies, hospitals, and others were included. The mean FKGL grade ranged from 8.8 to 14.8; none of the studies reported a mean FKGL of grade 6 or lower. Eight studies assessed HL and found inadequate HL prevalence ranging from 11.9% to 47.0%. Conclusions and Relevance: These findings indicate that more than one-third of patients with HNC demonstrate inadequate HL, yet none of the PEMs assessed were developed for a sixth grade or lower reading level, as recommended by the American Medical Association. This incongruence highlights the need to address the readability of HNC PEMs to improve patient understanding of the disease and to mitigate potential barriers to shared decision-making for patients with HNC. It is crucial to acknowledge the responsibility of health care professionals to produce and promote more effective PEMs to dismantle the potentially preventable literacy barriers.

Hedgehog pathway inhibitors for locally advanced and metastatic basal cell carcinoma: A real-world single-center retrospective review.

Basal cell carcinoma (BCC) is highly curable by surgical excision or radiation. In rare cases, BCC can be locally destructive or difficult to surgically remove. Hedgehog inhibition (HHI) with vismodegib or sonidegib induces a 50-60% response rate. Long-term toxicity includes muscle spasms and weight loss leading to dose decreases. This retrospective chart review also investigates the impact of CoQ10 and calcium supplementation in patients treated with HHI drugs at a single academic medical center from 2012 to 2022. We reviewed the charts of adult patients diagnosed with locally advanced or metastatic BCC treated with vismodegib or sonidegib primarily for progression-free survival (PFS). Secondary objectives included overall survival, BCC-specific survival, time to and reasons for discontinuation, overall response rate, safety and tolerability, use of CoQ10 and calcium supplements, and insurance coverage. Of 55 patients assessable for outcome, 34 (61.8%) had an overall clinical benefit, with 25 (45.4%) having a complete response and 9 (16.3%) a partial response. Stable disease was seen in 14 (25.4%) and 7 (12.7%) progressed. Of the 34 patients who responded to treatment, 9 recurred. Patients who were rechallenged with HHI could respond again. The median overall BCC-specific survival rate at 5 years is 89%. Dose reductions or discontinuations for vismodegib and sonidegib occurred in 59% versus 24% of cases, or 30% versus 9% of cases, respectively. With CoQ10 and calcium supplementation, only 17% required a dose reduction versus 42% without. HHI is highly effective for treating advanced BCC but may require dosing decreases. Sonidegib was better tolerated than vismodegib. CoQ10 and calcium supplementation can effectively prevent muscle spasms.

Current Perceptions, Practice Patterns, and Barriers to Adoption of Transperineal Prostate Biopsy Under Local Anesthesia.

OBJECTIVE: To assess perceptions, practice patterns, and barriers to adoption of transperineal prostate biopsy (TPBx) under local anesthesia. METHODS: Providers from Michigan urological surgery improvement collaborative (MUSIC) and Pennsylvania urologic regional collaborative (PURC) were administered an online survey to assess beliefs and educational needs regarding TPBx. Providers were divided into those who performed or did not perform TPBx. The MUSIC and PURC registries were queried to assess TPBx utilization. Descriptive analytics and bivariate analysis determined associations between provider/practice demographics and attitudes. RESULTS: Since 2019, TPBx adoption has increased more than 2-fold to 7.0% and 16% across MUSIC and PURC practices, respectively. Of 350 urologists invited to participate in a survey, a total of 91 complete responses were obtained with 21 respondents (23%) reported performing TPBx. Participants estimated the learning curve was <10 procedure for TPBx performers and non-performers. No significant association was observed between learning curve and provider age/practice setting. The major perceived benefits of TPBx were decreased risk of sepsis, improved cancer detection rate and antibiotic stewardship. The most commonly cited challenges to implementation included access to equipment and patient experience. Urologists performing TPBx reported learning curve as an additional barrier, while those not performing TPBx reported duration of procedure. CONCLUSION: Access to equipment and patient experience concerns remain substantial barriers to adoption of TPBx. Dissemination of techniques utilizing existing equipment and optimization of local anesthetic protocols for TPBx may help facilitate the continued adoption of TPBx.

FEA-Based Stress-Strain Barometers as Forecasters for Corneal Refractive Power Change in Orthokeratology.

PURPOSE: To improve the effectivity of patient-specific finite element analysis (FEA) to predict refractive power change (RPC) in rigid Ortho-K contact lens fitting. Novel eyelid boundary detection is introduced to the FEA model to better model the effects of the lid on lens performance, and stress and strain outcomes are investigated to identify the most effective FEA components to use in modelling. METHODS: The current study utilises fully anonymised records of 249 eyes, 132 right eyes, and 117 left eyes from subjects aged 14.1 ± 4.0 years on average (range 9 to 38 years), which were selected for secondary analysis processing. A set of custom-built MATLAB codes was built to automate the process from reading Medmont E300 height and distance files to processing and displaying FEA stress and strain outcomes. Measurements from before and after contact lens wear were handled to obtain the corneal surface change in shape and power. Tangential refractive power maps were constructed from which changes in refractive power pre- and post-Ortho-K wear were determined as the refractive power change (RPC). A total of 249 patient-specific FEA with innovative eyelid boundary detection and 3D construction analyses were automatically built and run for every anterior eye and lens combination while the lens was located in its clinically detected position. Maps of four stress components: contact pressure, Mises stress, pressure, and maximum principal stress were created in addition to maximum principal logarithmic strain maps. Stress and strain components were compared to the clinical RPC maps using the two-dimensional (2D) normalised cross-correlation and structural similarity (SSIM) index measure. RESULTS: On the one hand, the maximum principal logarithmic strain recorded the highest moderate 2D cross-correlation area of 8.6 ± 10.3%, and contact pressure recorded the lowest area of 6.6 ± 9%. Mises stress recorded the second highest moderate 2D cross-correlation area with 8.3 ± 10.4%. On the other hand, when the SSIM index was used to compare the areas that were most similar to the clinical RPC, maximum principal stress was the most similar, with an average strong similarity percentage area of 26.5 ± 3.3%, and contact pressure was the least strong similarity area of 10.3 ± 7.3%. Regarding the moderate similarity areas, all components were recorded at around 34.4% similarity area except the contact pressure, which was down to 32.7 ± 5.8%. CONCLUSIONS: FEA is an increasingly effective tool in being able to predict the refractive outcome of Ortho-K treatment. Its accuracy depends on identifying which clinical and modelling metrics contribute to the most accurate prediction of RPC with minimal ocular complications. In terms of clinical metrics, age, Intra-ocular pressure (IOP), central corneal thickness (CCT), surface topography, lens decentration and the 3D eyelid effect are all important for effective modelling. In terms of FEA components, maximum principal stress was found to be the best FEA barometer that can be used to predict the performance of Ortho-K lenses. In contrast, contact pressure provided the worst stress performance. In terms of strain, the maximum principal logarithmic strain was an effective strain barometer.

Human milk oligosaccharides promote intestinal epithelium regeneration independent of the microbiota during necrotizing enterocolitis.

PURPOSE: Necrotizing enterocolitis (NEC) is a severe intestinal disease primarily affecting premature infants, marked by impaired epithelial regeneration. Breastfed infants are less susceptible to NEC than formula-fed ones, and human milk oligosaccharides (HMO) found in breast milk have prebiotic properties that can protect against NEC. However, it is unclear how HMOs influence intestinal epithelium regeneration in relation to the gut microbiota. METHODS: Broad-spectrum antibiotics were administered to pregnant dams to reduce the microbiota in offspring. NEC was induced through administration of hyperosmolar formula, lipopolysaccharide, and hypoxia from postnatal days (p) 5-9. Intestinal epithelial organoids were derived from p9 mice. HMOs were isolated from human donor breast milk and then solubilized in the formula for each feed or culture media for organoids. RESULTS: HMOs did not alter the microbiota profile in the presence of a normal or reduced microbiota. In the reduced microbiota, HMO treatment decreased NEC intestinal injury, and increased proliferation and stem cell activity. Additionally, in the complete absence of the microbiota, HMOs stimulated intestinal organoid growth. CONCLUSION: This study demonstrates that HMOs promoted intestinal epithelial regeneration independent of the gut microbiota. These findings provide further insight into the various benefits HMOs may have in the protection against NEC.

Uncovering the Potential of CD40 Agonism to Enhance Immune Checkpoint Blockade.

In this CCR Translations, we discuss the therapeutic potential of CD40 agonism, which stimulates antigen-presenting cells (APC) to activate effector T and NK cells. CD40 agonism may lead to development of an interferon-activated, T cell-inflamed tumor microenvironment and has the potential to facilitate long-term response with immune checkpoint blockade. See related article by Weiss et al., p. 74.

Single-Cell RNA-Seq Analysis of Patient Myeloid-Derived Suppressor Cells and the Response to Inhibition of Bruton's Tyrosine Kinase.

Myeloid-derived suppressor cell (MDSC) levels are elevated in patients with cancer and contribute to reduced efficacy of immune checkpoint therapy. MDSC express Bruton's tyrosine kinase (BTK) and BTK inhibition with ibrutinib, an FDA-approved irreversible inhibitor of BTK, leads to reduced MDSC expansion/function in mice and significantly improves the antitumor activity of anti-PD-1 antibody treatments. Single-cell RNA sequencing (scRNA-seq) was used to characterize the effect of ibrutinib on gene expression of fluorescence-activated cell sorting-enriched MDSC from patients with different cancer types [breast, melanoma, head and neck squamous cell cancer (HNSCC)]. Melanoma patient MDSC were treated in vitro for 4 hours with 5 µmol/L ibrutinib or DMSO, processed for scRNA-seq using the Chromium 10× Genomics platform, and analyzed via the Seurat v4 standard integrative workflow. Baseline gene expression of MDSC from patients with breast, melanoma, and HNSCC cancer revealed similarities among the top expressed genes. In vitro ibrutinib treatment of MDSC from patients with melanoma resulted in significant changes in gene expression. GBP1, IL-1ß, and CXCL8 were among the top downregulated genes whereas RGS2 and ABHD5 were among the top upregulated genes (P < 0.001). Double positive CD14+CD15+ MDSC and PMN-MDSC responded similarly to BTK inhibition and exhibited more pronounced gene changes compared with early MDSC and M-MDSC. Pathway analysis revealed significantly downregulated pathways including TREM1, nitric oxide signaling, and IL-6 signaling (P < 0.004). IMPLICATIONS: scRNA-seq revealed characteristic gene expression patterns for MDSC from different patients with cancer and BTK inhibition led to the downregulation of multiple genes and pathways important to MDSC function and migration.

Acral lentiginous melanoma with multiple bone metastasis: case report.

Acral lentiginous melanoma (ALM) is a type of melanoma that is traditionally seen on the soles of the feet, palms of the hand, and under the fingernails or toenails. It is the least frequently diagnosed melanoma among the four histologic subtypes of cutaneous melanoma, accounting for less than 5% of all cases. ALM is frequently diagnosed at late stages and has higher incidences in non-white populations in relation to the other forms of cutaneous malignant melanoma. The most common sites of metastases in melanoma are the skin and subcutaneous tissue followed by lung, liver, brain, and bone. Bone metastases from malignant melanoma usually occur in patients who already have widespread metastases. We present this paper as a unique case study of ALM lesion in an 84-year-old African American male presenting originally in the base of right fifth toe plantar aspect then found multiple bone metastases without any other organ involved.

Association between Prostate Carcinoma and Multiple Myeloma.

Synchronous or sequential development of multiple myeloma and prostate carcinoma is rare. It is not sure whether these two occur independently or if one influences the development of the other. We reviewed the cases published in the English literature; eight cases of myeloma developing after diagnosis and treatment for prostate carcinoma, five cases of simultaneous occurrence of myeloma and prostate carcinoma, and five cases where the patient with multiple myeloma later developed prostate carcinoma were found. This short review attempts to analyze the occurrence of these two diseases in the same patient and dissect whether there is a close association or it is just a mere coincidence.

A cost-effective transperineal prostate biopsy method utilizes the original transrectal setting.

PURPOSE: Transperineal prostate biopsy (TPB) offers an alternative to transrectal prostate biopsy (TRB) for prostate cancer diagnosis. However, TPB may result in additional disposable and capital equipment costs, which can limit implementation within urology practice. Herein, we report the initial experience of a novel TPB technique within a tertiary referral center in Taiwan. MATERIALS AND METHODS: A retrospective review of all men undergoing prostate biopsy January to October in 2021 was performed. Both biopsy techniques were performed with the same setting using the convex-convex array ultrasound probe under local anesthesia alone or with the addition of sedation using double free-hand technique. Complications within 30 days and cancer detection rate (CDR) were compared between the groups. RESULTS: A total of 118 biopsies were included for final analysis. Eleven patients received systematic biopsy with additional MRI-targeted biopsy (TB) cores with all performed via a transperineal approach. The TPB group (n = 47) and TRB group (n = 58) had similar CDR after excluding TB cores (46.8% vs. 44.8%, p = 0.675). General complication rates for TPB were significantly lower than in the TRB group (27.7% vs. 46.6%, p = 0.047). No patients undergoing TPB had infectious complications, where five episodes were recorded in the TRB group (p = 0.114). CONCLUSIONS: TPB performed with convex-convex ultrasound probe and double free-hand technique is safe, feasible, cost-effective, and demonstrates equivalent CDR to TRB. Its use may eliminate infectious hospitalizations while minimizing the need for additional capital in the adoption of TPB.

Review of Merkel cell carcinoma with solitary pancreatic metastases mimicking primary neuroendocrine tumor of the pancreas.

OBJECTIVE/BACKGROUND: Merkel cell carcinoma (MCC) but metastases to the pancreas are very rare. There are only a few cases of isolated metastases of MCC to the pancreas. Because of this rarity, it can be wrongly diagnosed as a neuroendocrine tumor of the pancreas(pNET), especially the poorly differentiated neuroendocrine carcinoma (PNEC) subtype, in which the treatment is vastly different than that of MCC with isolated metastases of the pancreas. METHODS: An electronic search of the PubMed and google scholar databases was performed to obtain the literature on MCC with pancreatic metastases, using the following search terms: Merkel cell carcinoma, pancreas, and metastases. Results are limited to the following available article types: case reports and case series. We identified 45 cases of MCC with pancreatic metastases from the PubMed and Google Scholar database search and examined their potential relevance. Only 22 cases with isolated pancreatic metastases were taken for review including one case that we encountered. RESULTS: The results from our review of cases of isolated pancreatic metastases of MCC were compared to the characteristics of the poorly differentiated pancreatic neuroendocrine tumor (PNEC). We found the following: (a) MCC with isolated pancreatic metastases occurred at an older age than PNEC and with male gender predominance (b) Most of the metastases occurred within 2 years of initial diagnosis of MCC (c) Resection of pancreatic mass was the first line treatment in case of resectable PNECs whereas resection of metastases was infrequently performed in MCC with pancreatic metastases.