Acceptability of adding a non-contrast abdominal CT scan to screen for kidney cancer and other abdominal pathology within a community-based CT screening programme for lung cancer: A qualitative study.

OBJECTIVES: The Yorkshire Kidney Screening Trial (YKST) is a feasibility study of adding non-contrast abdominal CT scanning to screen for kidney cancer and other abdominal malignancies to community-based CT screening for lung cancer within the Yorkshire Lung Screening Trial (YLST). This study explored the acceptability of the combined screening approach to participants and healthcare professionals (HCPs) involved in the trial. METHODS: We conducted semi-structured interviews with eight HCPs and 25 participants returning for the second round of scanning within YLST, 20 who had taken up the offer of the additional abdominal CT scan and five who had declined. Transcripts were analysed using thematic analysis, guided by the Theoretical Framework of Acceptability. RESULTS: Overall, combining the offer of a non-contrast abdominal CT scan alongside the low-dose thoracic CT was considered acceptable to participants, including those who had declined the abdominal scan. The offer of the additional scan made sense and fitted well within the process, and participants could see benefits in terms of efficiency, cost and convenience both for themselves as individuals and also more widely for the NHS. Almost all participants made an instant decision at the point of initial invitation based more on trust and emotions than the information provided. Despite this, there was a clear desire for more time to decide whether to accept the scan or not. HCPs also raised concerns about the burden on the study team and wider healthcare system arising from additional workload both within the screening process and downstream following findings on the abdominal CT scan. CONCLUSIONS: Adding a non-contrast abdominal CT scan to community-based CT screening for lung cancer is acceptable to both participants and healthcare professionals. Giving potential participants prior notice and having clear pathways for downstream management of findings will be important if it is to be offered more widely.

Unplanned Emergency Department or Inpatient Acute Care Within 1 Week After Administration of Peptide Receptor Radionuclide Therapy: Frequency of Occurrence and Standard Operating Procedures for Radioprotection in These Situations.

Peptide receptor radionuclide therapy (PRRT) is a rapidly developing treatment modality. These treatments are indicated for patients who are either heavily pretreated and/or may have neurohormonal active disease, increasing risk of acute adverse effects and the need for unplanned acute care. The goals of this report were to characterize the frequency of unplanned acute care utilization after PRRT infusion and to detail a comprehensive standard operating procedure (SOP) for radioprotection during unplanned post-PRRT acute care. The records of patients treated with PRRT were reviewed. The event of interest was emergency department (ED) utilization and/or inpatient admission within 7 days of PRRT infusion. A multidisciplinary group developed a radioprotection SOP for all phases of unplanned acute care including the clinical infusion space, emergency medical services (EMS) transport to the ED, within the ED, and on the inpatient floor. A total of 232 patients received 814 infusions of PRRT, with 134 (58%) receiving Lutathera and 98 (42%) receiving Pluvicto. Nineteen patients received unplanned acute care at an ED within 7 days of PRRT infusion (8% of patients, 2% of infusions), of which 10 received Lutathera (8% of patients, 2% of infusions). Two patients (2% of patients, 0.5% of infusions) experienced carcinoid crises within 24 hours of Lutathera infusion. The median and average interval between infusion and ED visit was 0.5 days and 1.3 days, respectively. Nine patients received Pluvicto (9% of patients, 3% of infusions). The median and average interval between infusion and ED visit was 4 days and 4.7 days, respectively. Emergency room utilization and/or inpatient admission after PRRT administration are relatively infrequent events, but not unexpected. Centers that administer PRRT should have a comprehensive SOP in place to effectively care for radioactive patient emergencies while maximizing medical staff protection.

Weekly Versus Bolus Cisplatin Concurrent With Definitive Radiation Therapy for Squamous Carcinoma of the Head and Neck: A Systematic Review and Network Meta-Analysis.

PURPOSE: The schedule of cisplatin concurrent with definitive radiation for squamous carcinoma of the head and neck remains controversial. Most institutions deliver either a high-dose "bolus" schedule once every 3 weeks or a low-dose weekly schedule. We compared these 2 schedules via a simplified network meta-analysis with a common comparator. METHODS AND MATERIALS: We performed a PRISMA-concordant systematic review to identify randomized controlled trials comparing cisplatin with cetuximab for nonmetastatic, locoregionally advanced squamous carcinoma of the head and neck treated with definitive radiation. Trials incorporating primary surgery or induction therapy were excluded. Patient survival times were extracted on a per-event basis from the published curves using a digitizer and validated against published point estimates and hazard ratios (HRs). Survival was compared using random effects Cox regression under a frequentist framework. Toxicity and secondary endpoints were analyzed qualitatively. The Cochrane method assessed the risk of bias. The analysis plan was preregistered with the Open Science Foundation. RESULTS: Five randomized trials were identified, including 1678 patients. There was no statistical difference in overall survival between weekly and bolus regimens (HR, 0.90; 95% CI, 0.53-1.52, P = .345). This Cox model suggested that for the average patient in the cohort, the absolute difference in 5-year overall survival between weekly and bolus regimens was +1.2% (95% CI, -6.1%-+5.9%, P = .345). Secondary endpoints and toxicity were not obviously different by regimen, qualitatively. CONCLUSIONS: The cetuximab trials provide indirect data suggesting that the differences between cisplatin schedules are subtle.

Development of low-cost, compact chiroptical imaging systems.

Circular dichroism spectroscopy is a key probe of the structural and optical properties of chiral materials, however, commercial circular dichroism spectrometers are large, prohibitively expensive and rarely offer environmental control of the sample under test. Using Fresnel rhombs as inexpensive broadband quarter-wave plates, we demonstrate two novel, low-cost (<£2000) and portable imaging systems controlled by our own bespoke open-source control software which are capable of spatially mapping the circular dichroism of chiral solid state films. By coupling these imaging systems with a temperature controlled stage, we show that we can rapidly identify the thermal processing conditions required to maximise circular dichroism in chiral solid state films by measuring circular dichroism in situ during thermal annealing of a sample under test. The accuracy and spatial resolution of these circular dichroism imagers are cross-compared against our previous studies using an existing circular dichroism imaging system at the Diamond Light Source and are shown to be in good agreement, with a sensitivity down to 250 mdeg and a spatial resolution of 100 µm.

Intensity-Modulated Reirradiation Therapy With Nivolumab in Recurrent or Second Primary Head and Neck Squamous Cell Carcinoma: A Nonrandomized Controlled Trial.

Importance: Intensity-modulated radiation therapy (IMRT) reirradiation of nonmetastatic recurrent or second primary head and neck squamous cell carcinoma (HNSCC) results in poor progression-free survival (PFS) and overall survival (OS). Objective: To investigate the tolerability, PFS, OS, and patient-reported outcomes with nivolumab (approved standard of care for patients with HNSCC) during and after IMRT reirradiation. Design, Setting, and Participants: In this multicenter nonrandomized phase 2 single-arm trial, the treatment outcomes of patients with recurrent or second primary HNSCC who satisfied recursive partitioning analysis class 1 and 2 definitions were evaluated. Between July 11, 2018, and August 12, 2021, 62 patients were consented and screened. Data were evaluated between June and December 2023. Intervention: Sixty- to 66-Gy IMRT in 30 to 33 daily fractions over 6 to 6.5 weeks with nivolumab, 240 mg, intravenously 2 weeks prior and every 2 weeks for 5 cycles during IMRT, then nivolumab, 480 mg, intravenously every 4 weeks for a total nivolumab duration of 52 weeks. Main Outcomes and Measures: The primary end point was PFS. Secondary end points included OS, incidence, and types of toxic effects, including long-term treatment-related toxic effects, patient-reported outcomes, and correlatives of tissue and blood biomarkers. Results: A total of 62 patients were screened, and 51 were evaluable (median [range] age was 62 [56-67] years; 42 [82%] were male; 6 [12%] had p16+ disease; 38 [75%] had salvage surgery; and 36 [71%.] had neck dissection). With a median follow-up of 24.5 months (95% CI, 19.0-25.0), the estimated 1-year PFS was 61.7% (95% CI, 49.2%-77.4%), rejecting the null hypothesis of 1-year PFS rate of less than 43.8% with 1-arm log-rank test P = .002 within a 1-year timeframe. The most common treatment-related grade 3 or higher adverse event (6 [12%]) was lymphopenia with 2 patients (4%) and 1 patient each (2%) exhibiting colitis, diarrhea, myositis, nausea, mucositis, and myasthenia gravis. Functional Assessment of Cancer Therapy-General and Functional Assessment of Cancer Therapy-Head and Neck Questionnaire quality of life scores remained stable and consistent across all time points. A hypothesis-generating trend favoring worsening PFS and OS in patients with an increase in blood PD1+, KI67+, and CD4+ T cells was observed. Conclusions and Relevance: This multicenter nonrandomized phase 2 trial of IMRT reirradiation therapy and nivolumab suggested a promising improvement in PFS over historical controls. The treatment was well tolerated and deserves further evaluation. Trial Registration: ClinicalTrials.gov Identifier: NCT03521570.

Bioactive compounds from Morchella esculenta as potential inhibitors of RNA-binding protein La in ovarian cancer: a molecular modeling and quantum mechanics approach.

La protein is significantly expressed in various malignant tumors, including ovarian cancer (OC), which is related to the poor response to platinum-based chemotherapy. Thus, inhibiting La protein could control the expression of the potential downstream genes involved in promoting proliferation and chemotherapy resistance to OC, which could serve as a therapeutic intervention. Through a molecular docking approach, 12 compounds from Morchella esculenta were screened against the crystal structure of La protein and four hit compounds were identified, including beta-carotene, p-hydroxybenzoic acid, gamma-tocopherol, and alpha-tocopherol, with a binding affinity of - 10.7, - 8.1, - 7.9, and - 7.6 kcal/mol, respectively, higher than pyridine-2-carboxylate (control), with a binding affinity of - 5.2 kcal/mol. To explore the interaction of the hit compounds with the target receptor, they were selected for a molecular dynamic simulation and post-simulation analysis for 100 ns. The result showed promising reliability of the ligands due to a stable interaction with the La protein crystal structure. Furthermore, the drug-likeness and physicochemical chemical properties of the compounds were investigated using ADMET study and density functional theory analysis, respectively, and the result shows that the hit compounds could serve as a promising starting for the development of novel LA protein inhibitors for OC therapeutics. Finally, this study compared HOMO and LUMO values from global hybrids with long-range corrected DFAs, and the result from the two followed the same qualitative pattern while calculating HOMO values; however, MO62X/cc-pVTZ could better predict LUMO values when considering a global hybrid.

A flexible, thin-film microchannel electrode array device for selective subdiaphragmatic vagus nerve recording.

The vagus nerve (VN) plays an important role in regulating physiological conditions in the gastrointestinal (GI) tract by communicating via the parasympathetic pathway to the enteric nervous system (ENS). However, the lack of knowledge in the neurophysiology of the VN and GI tract limits the development of advanced treatments for autonomic dysfunctions related to the VN. To better understand the complicated underlying mechanisms of the VN-GI tract neurophysiology, it is necessary to use an advanced device enabled by microfabrication technologies. Among several candidates including intraneural probe array and extraneural cuff electrodes, microchannel electrode array devices can be used to interface with smaller numbers of nerve fibers by securing them in the separate channel structures. Previous microchannel electrode array devices to interface teased nerve structures are relatively bulky with thickness around 200 µm. The thick design can potentially harm the delicate tissue structures, including the nerve itself. In this paper, we present a flexible thin film based microchannel electrode array device (thickness: 11.5 µm) that can interface with one of the subdiaphragmatic nerve branches of the VN in a rat. We demonstrated recording evoked compound action potentials (ECAP) from a transected nerve ending that has multiple nerve fibers. Moreover, our analysis confirmed that the signals are from C-fibers that are critical in regulating autonomic neurophysiology in the GI tract.

Imaging and Biomarker Surveillance for Head and Neck Squamous Cell Carcinoma: A Systematic Review and American Radium Society Appropriate Use Criteria Statement.

Surveillance for survivors of head and neck cancer (HNC) is focused on early detection of recurrent or second primary malignancies. After initial restaging confirms disease-free status, the use of surveillance imaging for asymptomatic patients with HNC is controversial. Our objective was to comprehensively review literature pertaining to imaging and biomarker surveillance of asymptomatic patients treated for head and neck squamous cell carcinoma and to convene a multidisciplinary expert panel to provide appropriate use criteria for surveillance in representative clinical scenarios. The evidence base for the appropriate use criteria was gathered through a librarian-mediated search of literature published from 1990 to 2022 focused on surveillance imaging and circulating tumor-specific DNA for nonmetastatic head and neck squamous cell carcinoma using MEDLINE (Ovid), Embase, Web of Science Core Collection, and the Cochrane Central Register of Controlled Trials. The systematic review was reported according to PRISMA guidelines. Using the modified Delphi process, the expert panel voted on appropriate use criteria, providing recommendations for appropriate use of surveillance imaging and human papillomavirus (HPV) circulating tumor DNA. Of 5178 studies identified, 80 met inclusion criteria (5 meta-analyses/systematic reviews, 1 randomized control trial, 1 post hoc analysis, 25 prospective, and 48 retrospective cohort studies [with ≥50 patients]), reporting on 27,525 patients. No large, randomized, prospective trials examined whether asymptomatic patients who receive surveillance imaging or HPV circulating tumor DNA monitoring benefit from earlier detection of recurrence or second primary tumors in terms of disease-specific or quality-of-life outcomes. In the absence of prospective data, surveillance imaging for HNC survivors should rely on individualized recurrence-risk assessment accounting for initial disease staging, HPV disease status, and tobacco use history. There is an emerging surveillance role for circulating tumor biomarkers.

Dysphagia and Diets in Skilled Nursing Facilities When Patient's Health Status Changes: The Role of Imaging.

OBJECTIVES: Research suggests that clinical decision making for assessing and treating patients with swallowing dysfunction varies significantly, and decisions may harm patients. The study aimed to investigate clinical practice of speech-language pathologists (SLPs) assessing and treating swallowing in skilled nursing facilities (SNFs). DESIGN: Retrospective review of 120 medical records of patients recommended for a flexible endoscopic evaluation of swallowing (FEES). SETTING AND PARTICIPANTS: 120 SNF patients. METHODS: Records from 25 SNFs were reviewed to determine which patients were receiving swallowing therapy, their diet level pre- and post-FEES, and if they received prior imaging studies. Recordings of FEES were assigned severity ratings based on the Dynamic Imaging Grade of Swallowing Toxicity-FEES scores to determine the relationship between diet and liquid recommendations before and after FEES, how often patients consume a modified diet in the absence of dysphagia, percentage of patients without dysphagia receiving swallowing treatment, percentage of patients receiving alternative means of nutrition without dysphagia, and the percentage of patients with a feeding tube without an imaging assessment. RESULTS: Chi-square tests revealed no agreement between pre- and postimaging diet levels. Ordinal regressions indicated preimaging diets did not fit the DIGEST severity rating model; however, investigators found a good fit with postimaging diet recommendations. Descriptive statistics indicated that 67% of the patients receiving a modified solid and/or liquid did not have dysphagia. Treatment was provided to 100% of the patients without dysphagia. Sixty-one percent of patients with feeding tubes had no dysphagia. Forty-five percent of NPO (nothing by mouth) patients had imaging during their acute stay. CONCLUSIONS AND IMPLICATIONS: The results strongly suggest that the practice of continuing acute care diet recommendations in a SNF increases cost and may negatively impact patient quality of life. The practice may also lead to negative health consequences. A new imaging assessment is required to inform treatment when medical status changes.

Short-term psychosocial outcomes of adding a non-contrast abdominal computed tomography (CT) scan to the thoracic CT within lung cancer screening.

OBJECTIVES: To evaluate psychological, social, and financial outcomes amongst individuals undergoing a non-contrast abdominal computed tomography (CT) scan to screen for kidney cancer and other abdominal malignancies alongside the thoracic CT within lung cancer screening. SUBJECTS AND METHODS: The Yorkshire Kidney Screening Trial (YKST) is a feasibility study of adding a non-contrast abdominal CT scan to the thoracic CT within lung cancer screening. A total of 500 participants within the YKST, comprising all who had an abnormal CT scan and a random sample of one-third of those with a normal scan between 14/03/2022 and 24/08/2022 were sent a questionnaire at 3 and 6 months. Outcomes included the Psychological Consequences Questionnaire (PCQ), the short-form of the Spielberger State-Trait Anxiety Inventory, and the EuroQoL five Dimensions five Levels scale (EQ-5D-5L). Data were analysed using regression adjusting for participant age, sex, socioeconomic status, education, baseline quality of life (EQ-5D-5L), and ethnicity. RESULTS: A total of 380 (76%) participants returned questionnaires at 3 months and 328 (66%) at 6 months. There was no difference in any outcomes between participants with a normal scan and those with abnormal scans requiring no further action. Individuals requiring initial further investigations or referral had higher scores on the negative PCQ than those with normal scans at 3 months (standardised mean difference 0.28 sd, 95% confidence interval 0.01-0.54; P = 0.044). The difference was greater in those with anxiety or depression at baseline. No differences were seen at 6 months. CONCLUSION: Screening for kidney cancer and other abdominal malignancies using abdominal CT alongside the thoracic CT within lung cancer screening is unlikely to cause significant lasting psychosocial or financial harm to participants with incidental findings.

A Spatially Resolved and Environmentally Informed Forecast Model of West Nile Virus in Coachella Valley, California.

West Nile virus (WNV) is the most significant arbovirus in the United States in terms of both morbidity and mortality. West Nile exists in a complex transmission cycle between avian hosts and the arthropod vector, Culex spp. mosquitoes. Human spillover events occur when humans are bitten by an infected mosquito and predicting these rates of infection and therefore the risk to humans may be associated with fluctuations in environmental conditions. In this study, we evaluate the hydrological and meteorological drivers associated with mosquito biology and viral development to determine if these associations can be used to forecast seasonal mosquito infection rates with WNV in the Coachella Valley of California. We developed and tested a spatially resolved ensemble forecast model of the WNV mosquito infection rate in the Coachella Valley using 17 years of mosquito surveillance data and North American Land Data Assimilation System-2 environmental data. Our multi-model inference system indicated that the combination of a cooler and dryer winter, followed by a wetter and warmer spring, and a cooler than normal summer was most predictive of the prevalence of West Nile positive mosquitoes in the Coachella Valley. The ability to make accurate early season predictions of West Nile risk has the potential to allow local abatement districts and public health entities to implement early season interventions such as targeted adulticiding and public health messaging before human transmission occurs. Such early and targeted interventions could better mitigate the risk of WNV to humans.

Educating the healthcare workforce of the future: lessons learned from the development and implementation of a 'Wearables in Healthcare' course.

Digital health technologies will play an ever-increasing role in the future of healthcare. It is crucial that the people who will help make that transformation possible have the evidence-based and hands-on training necessary to address the many challenges ahead. To better prepare the future health workforce with the knowledge necessary to support the re-engineering of healthcare in an equitable, person-centric manner, we developed an experiential learning course-Wearables in Healthcare-for advanced undergraduate and graduate university students. Here we describe the components of that course and the lessons learned to help guide others interested in developing similar courses.

Radiation therapy for cT1-2 carcinoma of the palatine tonsil diagnosed via a simple tonsillectomy: Dosimetry and patterns of care in the IMRT era.

OBJECTIVE: Small carcinomas of the palatine tonsil are often diagnosed via simple tonsillectomy, a maneuver with non-therapeutic intent. Herein, practice patterns for this unique situation are evaluated. PATIENTS AND METHODS: A retrospective review was performed across 10 facilities to identify patients with cT1-2 squamous carcinomas of the tonsil diagnosed by simple tonsillectomy between 2010 and 2018. Patients who received curative-intent intensity modulated radiotherapy (IMRT) without additional surgery were included. Target volumes were reviewed, and cumulative incidences of local failure and severe late dysphagia were calculated. RESULTS: From 638 oropharyngeal patients, 91 were diagnosed via simple tonsillectomy. Definitive IMRT with no additional surgery to the primary site was utilized in 57, and three with gross residual disease were excluded, leaving 54 for analysis. Margins were negative in 13%, close (<5 mm) in 13%, microscopically positive in 61%, and not reported in 13%. Doses typically delivered to gross disease (68-70.2 Gy in 33-35 fx or 66 Gy/30 fx) were prescribed to the tonsil bed in 37 (69%). Sixteen patients (29%) received doses from 60 to 66 Gy (≤2 Gy/fx) and one received 50 Gy (2 Gy/fx). No local failures were observed. One late oropharyngeal soft tissue ulcer occurred, treated conservatively (grade 2). At five years, the cumulative incidence of severe late dysphagia was 17.4% (95% CI 6.1-28.8%). CONCLUSION: Small tonsil carcinomas diagnosed by simple tonsillectomy represent a niche subset with favorable oncologic outcomes. Regardless, radiation oncologists tend to deliver full-dose to the tonsil bed. The necessity of this routine could be questioned in the modern era.

Amino acid solution mitigates hypothermia response and intestinal damage following exertional heat stroke in male mice.

Increased gut permeability is implicated in the initiation and extent of the cytokine inflammatory response associated with exertional heat stroke (EHS). The primary objective of this study was to determine if a five amino acid oral rehydration solution (5AAS), specifically designed for the protection of the gastrointestinal lining, would prolong time to EHS, maintain gut function and dampen the systemic inflammatory response (SIR) measured during EHS recovery. Male C57/BL6J mice instrumented with radiotelemetry were gavaged with 150 µL of 5AAS or H2 O, and ≈12 h later were either exposed to an EHS protocol where mice exercised in a 37.5°C environmental chamber to a self-limiting maximum core temperature (Tc,max) or performed the exercise control (EXC) protocol (25°C). 5AAS pretreatment attenuated hypothermia depth and length (p < 0.005), which are indicators of EHS severity during recovery, without any effect on physical performance or thermoregulatory responses in the heat as determined by percent body weight lost (≈9%), max speed (≈6 m/min), distance (≈700 m), time to Tc,max (≈160 min), thermal area (≈550°C∙min), and Tc,max (42.2°C). EHS groups treated with 5AAS showed a significant decrease in gut transepithelial conductance, decreased paracellular permeability, increased villus height, increased electrolyte absorption and changes in tight junction protein expression pattern suggestive of improved barrier integrity (p < 0.05). No differences were witnessed between EHS groups in acute phase response markers of liver, circulating SIR markers, or indicators of organ damage during recovery. These results suggest that a 5AAS improves Tc regulation during EHS recovery through maintaining mucosal function and integrity.

Uridine-derived ribose fuels glucose-restricted pancreatic cancer.

Pancreatic ductal adenocarcinoma (PDA) is a lethal disease notoriously resistant to therapy1,2. This is mediated in part by a complex tumour microenvironment3, low vascularity4, and metabolic aberrations5,6. Although altered metabolism drives tumour progression, the spectrum of metabolites used as nutrients by PDA remains largely unknown. Here we identified uridine as a fuel for PDA in glucose-deprived conditions by assessing how more than 175 metabolites impacted metabolic activity in 21 pancreatic cell lines under nutrient restriction. Uridine utilization strongly correlated with the expression of uridine phosphorylase 1 (UPP1), which we demonstrate liberates uridine-derived ribose to fuel central carbon metabolism and thereby support redox balance, survival and proliferation in glucose-restricted PDA cells. In PDA, UPP1 is regulated by KRAS-MAPK signalling and is augmented by nutrient restriction. Consistently, tumours expressed high UPP1 compared with non-tumoural tissues, and UPP1 expression correlated with poor survival in cohorts of patients with PDA. Uridine is available in the tumour microenvironment, and we demonstrated that uridine-derived ribose is actively catabolized in tumours. Finally, UPP1 deletion restricted the ability of PDA cells to use uridine and blunted tumour growth in immunocompetent mouse models. Our data identify uridine utilization as an important compensatory metabolic process in nutrient-deprived PDA cells, suggesting a novel metabolic axis for PDA therapy.

Computational evaluation of bioactive compounds from Viscum album (mistletoe) as inhibitors of p63 for pancreatic cancer treatment.

Pancreatic ductal adenocarcinoma is an aggressive malignancy usually detectable at the advanced stage, with a 5-year survival rate of less than 8%. It has been reported that a gene called tumor-protein 63 (TP63) is expressed in an aggressive form of pancreatic cancer with a squamous signature. Thus, inhibiting the activity of p63 can be a means of treating and managing PDA. Different studies have shown that plant constituents are rich and can be a promising source for discovering drug candidates. The extract from mistletoe (Viscum album) is known to contain anticancer compounds; however, the specific molecular mechanism of the bioactive compounds is unknown. This study examines the pancreatic cancer therapeutic potential of the bioactive compounds in the flavonoid and phenolic acid constituents of mistletoe by adopting structural bioinformatics and advanced theoretical chemistry techniques via molecular docking, molecular dynamics simulation, molecular mechanics/generalized Born surface area (MM/GBSA) calculations, pharmacokinetic analysis, and density functional theory analysis. The six best compounds from the flavonoid constituent with the highest binding affinity ranging from -6.8 kcal/mol to -6.7 kcal/mol were selected with the control gemcitabine (-5.5 kcal/mol) for further computational analysis after molecular docking. Furthermore, MM/GBSA calculation showed the highest binding energy for the selected docked compounds, which validates their inhibitory potential. Hence, the molecular dynamics simulation, post-simulation analysis, pharmacokinetics model, and DFT results showed that mistletoe compounds are reliable due to their stable interaction with the target protein and drug-likeness properties.Communicated by Ramaswamy H. Sarma.

Fractal Microelectrodes for More Energy-Efficient Cervical Vagus Nerve Stimulation.

Vagus nerve stimulation (VNS) has the potential to treat various peripheral dysfunctions, but the traditional cuff electrodes for VNS are susceptible to off-target effects. Microelectrodes may enable highly selective VNS that can mitigate off-target effects, but they suffer from the increased impedance. Recent studies on microelectrodes with non-Euclidean geometries have reported higher energy efficiency in neural stimulation applications. These previous studies use electrodes with mm/cm-scale dimensions, mostly targeted for myelinated fibers. This study evaluates fractal microelectrodes for VNS in a rodent model (N = 3). A thin-film device with fractal and circle microelectrodes is fabricated to compare their neural stimulation performance on the same radial coordinate of the nerve. The results show that fractal microelectrodes can activate C-fibers with up to 52% less energy (p = 0.012) compared to circle microelectrodes. To the best of the knowledge, this work is the first to demonstrate a geometric advantage of fractal microelectrodes for VNS in vivo.

Acute central corneal haze and thinning with atypical keratitis presentation.

A 24-year-old woman presented with a 7-day history of blurry vision, redness, and extreme pain in her right eye. She had no pertinent medical or ocular history and did not use spectacles or contacts. Uncorrected distance visual acuity (UDVA) was 20/40 in the right eye and could not be improved with refraction. Slitlamp examination revealed a 1.5 × 1.5 mm central epithelial defect with surrounding white blood cell recruitment. Confocal microscopy (Figure 1JOURNAL/jcrs/04.03/02158034-202304000-00020/figure1/v/2023-03-24T200747Z/r/image-tiff) was performed, and she was treated with chlorhexidine 0.02% drops every hour in the right eye. 2 weeks later, the cornea had completely re-epithelialized; however, persistent corneal haze, decreased visual acuity, and corneal thinning and flattening was noted. Pachymetry was 484 µm in the right eye and UDVA was 20/40 (Supplemental Figure 1, available at http://links.lww.com/JRS/A836). In the following 2 weeks, UDVA improved to 20/25. 6 months after the initial presentation, UDVA was unchanged and faint central corneal haze was noted on examination (Figure 2JOURNAL/jcrs/04.03/02158034-202304000-00020/figure2/v/2023-03-24T200747Z/r/image-tiff). Of interest, her family history is significant for her younger 16-year-old brother with 3 prior episodes of a similar type of keratitis/keratopathy over the course of 2 years in both eyes with similar central paracentral corneal haze, thinning, and flattening and similar confocal findings (Figure 3JOURNAL/jcrs/04.03/02158034-202304000-00020/figure3/v/2023-03-24T200747Z/r/image-tiff). He also was unresponsive to topical antibiotics and antivirals except topical chlorhexidine. Her brother has been our patient for the last several years prior to her first visit to our clinic. What is your diagnosis? What medical diagnostic tests, if any, would you recommend? Is this an infectious or simply an inflammatory response? Is there any genetic or familial predisposition?