Blockade of TGF-ß and PD-L1 by bintrafusp alfa promotes survival in preclinical ovarian cancer models by promoting T effector and NK cell responses.

BACKGROUND: Failure of immunotherapy in high-grade serous ovarian cancer (HGSC) may be due to high levels of transforming growth factor-ß (TGF-ß) in ascites or tumour immune microenvironment (TIME). Here, we test whether coordinated blockade of TGF-ß and PD-L1 with bintrafusp alfa (BA) can provoke anti-tumour immune responses in preclinical HGSC models. METHODS: BA is a first-in-class bifunctional inhibitor of TGF-ß and PD-L1, and was tested for effects on overall survival and altered TIME in syngeneic HGSC models. RESULTS: Using a mouse ID8-derived HGSC syngeneic model with IFNγ-inducible PD-L1 expression, BA treatments significantly reduced ascites development and tumour burden. BA treatments depleted TGF-ß and VEGF in ascites, and skewed the TIME towards cytotoxicity compared to control. In the BR5 HGSC syngeneic model, BA treatments increased tumour-infiltrating CD8 T cells with effector memory and cytotoxic markers, as well as cytolytic NK cells. Extended BA treatments in the BR5 model produced ∼50% BA-cured mice that were protected from re-challenge. These BA-cured mice had increased peritoneal T-effector memory and NK cells compared to controls. CONCLUSIONS: Our preclinical studies of BA in advanced ovarian cancer models support further testing of BA as an improved immunotherapy option for patients with advanced ovarian cancer.

Use of 3D chaos game representation to quantify DNA sequence similarity with applications for hierarchical clustering.

A 3D chaos game is shown to be a useful way for encoding DNA sequences. Since matching subsequences in DNA converge in space in 3D chaos game encoding, a DNA sequence's 3D chaos game representation can be used to compare DNA sequences without prior alignment and without truncating or padding any of the sequences. Two proposed methods inspired by shape-similarity comparison techniques show that this form of encoding can perform as well as alignment-based techniques for building phylogenetic trees. The first method uses the volume overlap of intersecting spheres and the second uses shape signatures by summarizing the coordinates, oriented angles, and oriented distances of the 3D chaos game trajectory. The methods are tested using: (1) the first exon of the beta-globin gene for 11 species, (2) mitochondrial DNA from four groups of primates, and (3) a set of synthetic DNA sequences. Simulations show that the proposed methods produce distances that reflect the number of mutation events; additionally, on average, distances resulting from deletion mutations are comparable to those produced by substitution mutations.

Mobile toolbox (MTB) remote measures of executive function and processing speed: development and validation.

OBJECTIVE: The ability to remotely monitor cognitive skills is increasing with the ubiquity of smartphones. The Mobile Toolbox (MTB) is a new measurement system that includes measures assessing Executive Functioning (EF) and Processing Speed (PS): Arrow Matching, Shape-Color Sorting, and Number-Symbol Match. The purpose of this study was to assess their psychometric properties. METHOD: MTB measures were developed for smartphone administration based on constructs measured in the NIH Toolbox® (NIHTB). Psychometric properties of the resulting measures were evaluated in three studies with participants ages 18 to 90. In Study 1 (N = 92), participants completed MTB measures in the lab and were administered both equivalent NIH TB measures and other external measures of similar cognitive constructs. In Study 2 (N = 1,021), participants completed the equivalent NIHTB measures in the lab and then took the MTB measures on their own, remotely. In Study 3 (N = 168), participants completed MTB measures twice remotely, two weeks apart. RESULTS: All three measures exhibited very high internal consistency and strong test-retest reliability, as well as moderately high correlations with comparable NIHTB tests and moderate correlations with external measures of similar constructs. Phone operating system (iOS vs. Android) had a significant impact on performance for Arrow Matching and Shape-Color Sorting, but no impact on either validity or reliability. CONCLUSIONS: Results support the reliability and convergent validity of MTB EF and PS measures for use across the adult lifespan in remote, self-administered designs.

Antenatal diagnosis, neonatal brain volumes, and neurodevelopment in transposition of the great arteries.

AIM: To examine whether antenatal diagnosis modifies relationships between neonatal brain volumes and 18-month neurodevelopmental outcomes in children with transposition of the great arteries (TGA). METHOD: In a retrospective cohort of 139 children with TGA (77 antenatally diagnosed), we obtained total brain volumes (TBVs) on pre- (n = 102) and postoperative (n = 112) magnetic resonance imaging. Eighteen-month neurodevelopmental outcomes were assessed using the Bayley Scales of Infant and Toddler Development, Third Edition. Generalized estimating equations with interaction terms were used to determine whether antenatal diagnosis modified associations between TBVs and neurodevelopmental outcomes accounting for postmenstrual age at scan, brain injury, and ventricular septal defect. RESULTS: Infants with postnatal diagnosis had more preoperative hypotension (35% vs 14%, p = 0.004). The interactions between antenatal diagnosis and TBVs were significantly related to cognitive (p = 0.003) outcomes. Specifically, smaller TBVs were associated with lower cognitive scores in infants diagnosed postnatally; this association was attenuated in those diagnosed antenatally. INTERPRETATION: Antenatal diagnosis modifies associations between neonatal brain volume and 18-month cognitive outcome in infants with TGA. These findings suggest that antenatal diagnosis may be neuroprotective, possibly through improved preoperative clinical status. These data highlight the need to improve antenatal diagnosis rates. WHAT THIS PAPER ADDS: Antenatal diagnosis of transposition of the great arteries modified relationships between neonatal brain volume and neurodevelopment. Smaller brain volumes related to poorer cognitive scores with postnatal diagnosis only. There was more preoperative hypotension in the postnatal diagnosis group.

Using the Mobile Toolbox in child and adolescent samples: A feasibility study.

Cognitive research with developmental samples requires improved methods that support large-scale, diverse, and open science. This paper offers initial evidence to support the Mobile Toolbox (MTB), a self-administered remote smartphone-based cognitive battery, in youth populations, from a pilot sample of 99 children (Mage = 11.79 years; 36% female; 53% White, 33% Black or African American, 9% Asian, and 15% Hispanic). Completion rates (95%-99%), practice performance (96%-100%), internal consistency (0.60-0.98), and correlations with similar NIHTB measures (0.55-0.77) provide the first evidence to support the MTB in a youth sample, although there were some inconsistencies across measures. Preliminary findings provide promising evidence of the MTB in developmental populations, and further studies are encouraged.

Palliative care for patients with heart failure and family caregivers in rural Appalachia: a randomized controlled trial.

BACKGROUND: Heart failure (HF) is a debilitating disease with worsening symptoms and family caregiving burden. HF affects more than 8 million Americans. West Virginia has the highest HF death rate in the U.S. and limited healthcare services. This study tested whether the family HF palliative and end-of-life care intervention (FamPALcare) improved patient and caregiver outcomes at 3- and 6-month study endpoints. METHODS: This study used a randomized controlled trial design. Patients with HF and their caregivers were randomly assigned together to the intervention (n = 21) or control (n = 18) group. The intervention included five telephone coaching sessions on the HF home, palliative, and end-of-life care. The outcome data collected at baseline and at 3 and 6 months were from the patients' (a) HF-related health status and depression/anxiety scale scores; and from caregivers' (b) caregiving burden and depression/anxiety scale scores; and (c) anonymous ratings on the 11-item FamPALcare helpfulness scale, completed by the intervention participants. RESULTS: The mean age of the patients was 65.66 (SD = 13.72) years, and 67% were White males. The mean age of the caregivers was 62.05 (SD = 13.14) years, and 77% were White females. Compared to the controls, patients in the intervention group had significantly greater scores for HF-related health status (p < .05) and lower depression/anxiety scores at 6 months, the study endpoint. The family caregivers in the intervention group had significantly lower scores on caregiving burden (p < .05) and depression/anxiety (p < .01) at 3 months. The mean helpfulness rating was M = 4.46 out of 5 (SD = 0.49). CONCLUSIONS: The FamPALcare intervention was found to be effective at improving patient HF-related health status and reducing caregiver burden and improving both patient and caregiver depression and anxiety scores. The FamPALcare HF intervention was found feasible and consistently delivered (fidelity). The FamPALcare intervention's cost-effectiveness and helpfulness ratings information will be used to plan for subsequent clinical trials. TRIAL REGISTRATION: ClinicalTrials.gov NCT04153890, Registered on 4 November 2019, https://clinicaltrials.gov/ct2/show/NCT04153890 .

Neurodevelopmental outcomes at 18 months of children diagnosed with CHD compared to children born very preterm.

OBJECTIVE: To compare neurodevelopmental outcomes and parent behaviour ratings of children born term with CHD to children born very preterm. METHODS: A clinical research sample of 181 children (CHD [n = 81]; very preterm [≤32 weeks; n = 100]) was assessed at 18 months. RESULTS: Children with CHD and born very preterm did not differ on Bayley-III cognitive, language, or motor composite scores, or on expressive or receptive language, or on fine motor scaled scores. Children with CHD had lower ross motor scaled scores compared to children born very preterm (p = 0.047). More children with CHD had impaired scores (<70 SS) on language composite (17%), expressive language (16%), and gross motor (14%) indices compared to children born very preterm (6%; 7%; 3%; ps < 0.05). No group differences were found on behaviours rated by parents on the Child Behaviour Checklist (1.5-5 years) or the proportion of children with scores above the clinical cutoff. English as a first language was associated with higher cognitive (p = 0.004) and language composite scores (p < 0.001). Lower median household income and English as a second language were associated with higher total behaviour problems (ps < 0.05). CONCLUSIONS: Children with CHD were more likely to display language and motor impairment compared to children born very preterm at 18 months. Outcomes were associated with language spoken in the home and household income.

The influence of spirituality on caregiver burden and quality of life in older adult informal caregivers.

BACKGROUND: Caregiver burden (CB) reduces quality of life (QOL) and causes poor health outcomes. Spirituality impacts this relationship. AIMS: To determine prevalence of CB and investigate relationships among CB, spirituality, and QOL in older U.S. adult informal caregivers (n = 754). METHODS: This was a cross-sectional, descriptive secondary analysis of data from the 2020 Health and Retirement Study using GLM and SEM. RESULTS: Caregiver mean age was 65.93 (SD=8.37). Caregivers were primarily female (n = 456, 54.0%), White (n = 500, 79.5%), and married (n = 469, 65.3%). Most caregivers had moderate CB (n = 369, 49.8%). Black caregivers who were spiritual (p=.031) and caregivers with a high school diploma/GED who were spiritual (p=.021) had lower CB. Lower CB was correlated with higher QOL (p=< 0.001). SEM depicting an influencing effect of spirituality revealed good model fit (NFI=0.988; IFI=0.993; TLI=0.983; PCFI=0.397, RMSEA=0.043; χ2=9.577, p=.048, DF=4) CONCLUSIONS: Fostering spirituality in older adult caregivers could reduce CB and improve QOL.

Early-life exposure to analgesia and 18-month neurodevelopmental outcomes in very preterm infants.

BACKGROUND: We assessed variability of analgesic use across three tertiary neonatal intensive care units (NICUs) accounting for early-life pain, quantified as number of invasive procedures. We also determined whether analgesia exposure modifies associations between early-life pain and neurodevelopment. METHODS: Multicenter prospective study of 276 very preterm infants (born <24-32 weeks' gestational age [GA]). Detailed data of number of invasive procedures and duration of analgesia exposure were collected in initial weeks after birth. Eighteen-month neurodevelopmental assessments were completed in 215 children with Bayley Scales for Infant Development-Third edition. RESULTS: Multivariable linear regressions revealed significant differences in morphine use across sites, for a given exposure to early-life pain (interaction p < 0.001). Associations between early-life pain and motor scores differed by duration of morphine exposure (interaction p = 0.01); greater early-life pain was associated with poorer motor scores in infants with no or long (>7 days) exposure, but not short exposure (≤7 days). CONCLUSIONS: Striking cross-site differences in morphine exposure in very preterm infants are observed even when accounting for early-life pain. Negative associations between greater early-life pain and adverse motor outcomes were attenuated in infants with short morphine exposure. These findings emphasize the need for further studies of optimal analgesic approaches in preterm infants. IMPACT: In very preterm neonates, both early-life exposure to pain and analgesia are associated with adverse neurodevelopment and altered brain maturation, with no clear guidelines for neonatal pain management in this population. We found significant cross-site variability in morphine use across three tertiary neonatal intensive care units in Canada. Morphine use modified associations between early-life pain and motor outcomes. In infants with no or long durations of morphine exposure, greater early-life pain was associated with lower motor scores, this relationship was attenuated in those with short morphine exposure. Further trials of optimal treatment approaches with morphine in preterm infants are warranted.

Self-reported adherence to direct oral anticoagulants versus warfarin therapy in a specialized thrombosis service-a cross-sectional study of patients in a Canadian Health Region.

PURPOSE: Direct oral anticoagulants (DOACs) have a better safety and efficacy profile than warfarin and are currently recommended for stroke prevention in non-valvular atrial fibrillation (AF) and treatment of venous thromboembolism (VTE). Given that DOACs do not require regular laboratory monitoring compared to warfarin, patients' interactions with the health care system is reduced. Adequate adherence to DOACs is important and reported adherence to anticoagulation is unclear in clinical practice. This study aims to assess self-reported adherence to oral anticoagulants in a specialized Adult Outpatient Thrombosis Service (TS).  METHODS: This cross-sectional study included patients aged ≥ 18 years who were prescribed an oral anticoagulant and had attended at least one appointment with an Adult Outpatient Thrombosis Service (TS) between October 10, 2017, and May 31, 2019. Adherence to oral anticoagulant therapy was assessed using the 12-item validated Adherence to Refills and Medications Scale (ARMS) score. Logistic regression analyses were used to evaluate association between patient characteristics and medication adherence. Adherence rates in DOACs and warfarin were compared. RESULTS: Three hundred and ninety-nine patients completed and returned the survey. Of the 399 who completed the survey, 74% were prescribed DOACs and 26% received warfarin. Most of the patients (89.3%) were ≥ 50 years of age and half (57.3%) were male. About two-thirds (67%) had at least post-secondary education. The duration of anticoagulation use differed between patients on DOAC and warfarin; a greater proportion of those who had used anticoagulants for less than 1 year was on DOACs compared to warfarin (20.9% vs 4.9%, p = 0.001). For patients who had been on anticoagulation for > 5 years, the proportion of warfarin patients was greater than DOAC (57.8% vs 20.5%, p = 0.001). Self-reported adherence to oral anticoagulant therapy using the 12-item ARMS scale for warfarin and DOACs were 87.3% and 90.9%, respectively. Among the warfarin users, patient satisfaction with TS was associated with medication adherence (OR = 0.22; 95% CI: 0.05-0.89). CONCLUSIONS: Self-reported medication adherence was similar between warfarin and DOACs. Since suboptimal adherence is associated with poor clinical outcomes and increased costs, various stakeholders should emphasize the importance of medication adherence to oral anticoagulants at each patient encounter.

Evaluation of a continuing professional development strategy on COVID-19 for 10 000 health workers in Ghana: a two-pronged approach.

BACKGROUND: COVID-19 has created unprecedented challenges for health systems worldwide. Since the confirmation of the first COVID-19 case in Ghana in March 2020 Ghanian health workers have reported fear, stress, and low perceived preparedness to respond to COVID-19, with those who had not received adequate training at highest risk. Accordingly, the Paediatric Nursing Education Partnership COVID-19 Response project designed, implemented, and evaluated four open-access continuing professional development courses related to the pandemic, delivered through a two-pronged approach: e-learning and in-person. METHODS: This manuscript presents an evaluation of the project's implementation and outcomes using data for a subset of Ghanaian health workers (n = 9966) who have taken the courses. Two questions were answered: first, the extent to which the design and implementation of this two-pronged strategy was successful and, second, outcomes associated with strengthening the capacity of health workers to respond to COVID-19. The methodology involved quantitative and qualitative survey data analysis and ongoing stakeholder consultation to interpret the results. RESULTS: Judged against the success criteria (reach, relevance, and efficiency) the implementation of the strategy was successful. The e-learning component reached 9250 health workers in 6 months. The in-person component took considerably more resources than e-learning but provided hands-on learning to 716 health workers who were more likely to experience barriers to accessing e-learning due to challenges around internet connectivity, or institutional capacity to offer training. After taking the courses, health workers' capacities (addressing misinformation, supporting individuals experiencing effects of the virus, recommending the vaccine, course-specific knowledge, and comfort with e-learning) improved. The effect size, however, varied depending on the course and the variable measured. Overall, participants were satisfied with the courses and found them relevant to their well-being and profession. An area for improvement was refining the content-to-delivery time ratio of the in-person course. Unstable internet connectivity and the high upfront cost of data to access and complete the course online were identified as barriers to e-learning. CONCLUSIONS: A two-pronged delivery approach leveraged distinct strengths of respective e-learning and in-person strategies to contribute to a successful continuing professional development initiative in the context of COVID-19.

Survey of ptosis practice patterns among surgeons in Asia Pacific Society of Ophthalmic Plastic and Reconstructive Surgery (APSOPRS).

OBJECTIVE: To characterize the preferred ptosis practice patterns and variations among oculoplastic surgeons in the Asia-Pacific region. METHODS: A web-based questionnaire was sent to both members and non-members registered under the Asia Pacific Society of Ophthalmic Plastic and Reconstructive Surgery (APSOPRS)'s email database. The survey included preoperative testing practices, surgical preferences for adult aponeurotic and congenital ptosis, various surgical techniques (anterior and posterior approach ptosis procedures, and frontalis sling procedures) and postoperative practices. RESULTS: A total of 386 survey invitations were sent. There was a response rate of 68.7% from respondents from 20 countries in the Asia-Pacific region. There was variation in the preoperative evaluation and management of ptosis. Anterior approach ptosis surgery (96.6%) and frontalis sling procedures (86.8%) were performed by more surgeons than posterior approach ptosis surgery (47.2%). There was a deviation from the traditional frontalis sling procedures for patients with poor levator function. CONCLUSIONS: Our survey results provide insight into the variation in the assessment and management of ptosis amongst oculoplastic surgeons in the Asia-Pacific region. It also demonstrates some differences between practice patterns in Asia-Pacific and America.

Hyaluronic acid gel injection for dysthyroid upper eyelid retraction in Asian patients.

PURPOSE: To evaluate the role of hyaluronic acid (HA) filler injection in the management of upper eyelid retraction (UER) in thyroid eye disease (TED). METHODS: Retrospective interventional series of all patients with TED who had undergone HA injection, from February 2011 to April 2013 by a single surgeon (Y-DK) in a tertiary medical institution. Outcome measures: Mean margin reflex distance 1 (MRD1) pre- and post-filler. RESULTS: There was a total of 13 patients and 17 eyes included in the study. The injection dosage for 15 eyes was 0.5 ml, one patient had 0.35cc on the right eye and 0.65cc on the left eye. Mean MRD1 at presentation was 6.21 mm. There was a mean decrease in MRD1 of 2.01 mm (p < .001) at 1 month post filler, 2.06 mm (p < .001) at 6 months post filler and 2.61 mm (p < .001) at 1 year post filler. There was no correlation between pre-filler MRD1 and change in MRD1 at various time points post-filler, nor any correlation between pre-filler upper scleral show (USS) and change in USS post-filler. There was also no correlation found between clinical activity score (CAS) and change in MRD1, as well as duration of thyroid eye disease (TED) and change in MRD1. Complications included mild upper lid lumpiness on downgaze (n = 4, 23.5%) which improved but persisted with time. There were no untoward intravascular or vision-threatening complications. CONCLUSION: Transconjunctival HA injection is an effective treatment option for TED-related UER in both active and inactive TED patients in an East Asian population, with a potentially long-lasting effect.

The role of cytoreductive surgery and intraperitoneal chemotherapy in gastric cancer.

Gastric cancer (GC) with peritoneal carcinomatosis (PC) progresses rapidly and has historically dismal survival rates. Given the aggressive tumor biology and poor survival outcomes of patients with GC/PC, additional treatments beyond systemic chemotherapy are needed. Cytoreductive surgery and intraperitoneal chemotherapy have been effective management options for peritoneal surface malignancies, with increasing data to support their use in GC/PC. This review highlights the evolution of the surgical treatment of GC/PC, and discusses critical studies supporting the role of cytoreductive surgery, appropriate patient selection, and various methods in the delivery of intraperitoneal chemotherapy for patients with GC/PC.

Patient satisfaction with quality of care of a multidisciplinary thrombosis service - a cross sectional survey.

BACKGROUND: In October 2017 we opened a multidisciplinary Adult Outpatient Thrombosis Service (Thrombosis Service) in a regional health authority servicing over 300 000 people. The Thrombosis Service is a comprehensive thrombosis and anticoagulation management program with unique, interrelated clinics providing a broad spectrum of care for this patient group. Evaluation of patient satisfaction with this new model of patient care is an important quality measurement. METHODS: We conducted a cross-sectional survey of patients who attended the Thrombosis Service between October 2017 and May 2019. We measured patient satisfaction with the seven-item Short Assessment of Patient Satisfaction (SAPS) which uses a 5 point scale (0-4) for responses. The continuous score range for SAPS is 0 to 28. Categorical responses for SAPS are defined as 0-10 very dissatisfied, 11-18 dissatisfied, 19-26 satisfied, and 27-28 very satisfied. We used linear regression analysis to examine the associations between patients' characteristics and their satisfaction with the Thrombosis Service. RESULTS: Of the 1058 surveys distributed, 563 were returned. The mean score for the SAPS was 22.1 (SD 4.1, range 8 to 28). For the categorical response, 85% were satisfied or very satisfied with the Thrombosis Service. The multivariate analysis showed patients with post-secondary education were more satisfied with the Thrombosis Service (ß-coefficient 1.6153, p = 0.024), and patients taking warfarin were less likely to be satisfied with the Thrombosis Service (ß-coefficient -1.5832, p = 0.0390). CONCLUSIONS: The majority of survey participants (85%) who attended an appointment in one of the Thrombosis Service clinics were satisfied or very satisfied with the care they received. This information may benefit other centres who are interested in developing a program to manage thrombosis and anticoagulation.

Intraocular Pressure and Glaucoma in Thyroid Eye Disease.

PURPOSE: Current literature lacks a summary of knowledge on intraocular pressure (IOP) elevation and glaucoma in thyroid eye disease (TED). This review aims to augment existing literature by providing such a summary. It qualitatively evaluates current knowledge on the pathogenesis, prevalence, and management of concomitant ocular hypertension or glaucoma in TED patients. METHODS: In this narrative review, relevant publications were identified through a computerized database search. Search results were screened for relevance. Correspondence, Editorials, and Letters to the Editors were excluded. References cited within the identified articles were used to further augment the search. Information extracted for qualitative analysis included epidemiologic data, methods of IOP assessment, management protocols, and response to treatment. RESULTS: Studies in current literature are relatively heterogenous, differing in country of origin, TED cohort sizes, and IOP measurement techniques. Further studies are required to elucidate the true epidemiologic relationship between TED and ocular hypertension or glaucoma. Proposed models of IOP elevation include elevation of episcleral venous pressure, mucopolysaccharide deposition within the trabecular meshwork, restrictive myopathy, steroid-induced glaucoma, and secondary glaucoma. IOP-reducing effects of TED treatment options are discussed. CONCLUSIONS: While raised IOP in TED is a common phenomenon, the diagnosis of glaucoma in TED requires a high index of suspicion before any intervention.

Prebending of Prefabricated Orbital Implants: Towards Improved Orbital Angle Symmetry Post Craniofacial Trauma Surgery.

PURPOSE: Reconstructive surgery after craniofacial trauma aim to restore orbital anatomy for function and aesthetic reasons. The purpose of this study is to improve postoperative orbital symmetry with the use of prebent prefabricated titanium implants. METHODS: In this retrospective study, patients with combined unilateral medial wall and floor fractures who underwent orbital reconstruction surgery were selected. The angle of inferomedial orbital strut (AIOS) was measured at 3 standard locations on preoperative facial computed tomography guided scans of the nonfractured orbit in the coronal view and used as a guide to bend the prefabricated titanium implants intraoperatively. The corresponding values were measured on the postoperative computed tomography and compared for symmetry. RESULTS: Out of 83 patients recruited for the study, 54 were in the prebent group while 29 were in the control group. All other demographics were similar among the 2 groups. Anterior AIOS has a difference of 4.9° between 2 orbits in the prebent group whereas a difference of 15.5° was noted in the nonprebent group. For middle AIOS, a difference of 4.7° was noted in the prebent group whereas nonprebent group had a difference of 14.1°. For posterior AIOS, the prebent group had a difference of 3.8° versus 14.1° in the nonprebent group. The difference in AIOS at all 3 points between the prebent and nonprebent group were significant. CONCLUSIONS: Anatomical prefabricated titanium plates are versatile implants that facilitate orbital reconstruction. Prebending of these implants according to the fellow orbit can achieve better surgical outcomes in a cost-effective manner.

Surgical approach to pediatric mediastinal masses based on imaging characteristics.

BACKGROUND: Pediatric mediastinal masses may be resected using an open or video-assisted thoracoscopic surgery (VATS) approach. We sought to define the preoperative imaging findings predicting amenability to VATS. METHODS: This multicenter retrospective study of pediatric patients undergoing either VATS or open surgical mediastinal mass resection between 2008 and 2018 evaluated the preoperative imaging descriptors associated with VATS. Postoperative endpoints included length of stay (LOS), 30-day readmission, 90-day mortality and complication rates. RESULTS: Mediastinal mass resection was performed in 33 patients. Median tumor size was 6 cm, and 51.5% had anterior mediastinal tumors. The 23 (69.7%) patients who underwent VATS were significantly older (144 months vs 32, P = 0.01) and larger (33.6 kg vs 13.8 P = 0.03). Preoperative imaging characteristics in VATS included "well circumscribed", "smooth margins" and "cystic", while the open surgery group were "heterogeneous" and "coarse calcification". The open group had more germ cell tumors (60.0% vs 13.0%, P = 0.16) but no difference in malignancy. VATS patients had shorter LOS (2 days vs 6.5, P = 0.24). Readmission, complication and mortality rates were similar. CONCLUSIONS: Pediatric patients with apparent malignancy frequently underwent open resection compared with the thoracoscopic group, although final malignant pathology was similar. Equivalent outcomes and shorter LOS should favor a minimally invasive approach. LEVEL OF EVIDENCE: Level III.

Comprehensive engineering of the tarantula venom peptide huwentoxin-IV to inhibit the human voltage-gated sodium channel hNav1.7.

Pain is a significant public health burden in the United States, and current treatment approaches rely heavily on opioids, which often have limited efficacy and can lead to addiction. In humans, functional loss of the voltage-gated sodium channel Nav1.7 leads to pain insensitivity without deficits in the central nervous system. Accordingly, discovery of a selective Nav1.7 antagonist should provide an analgesic without abuse liability and an improved side-effect profile. Huwentoxin-IV, a component of tarantula venom, potently blocks sodium channels and is an attractive scaffold for engineering a Nav1.7-selective molecule. To define the functional impact of alterations in huwentoxin-IV sequence, we produced a library of 373 point mutants and tested them for Nav1.7 and Nav1.2 activity. We then combined favorable individual changes to produce combinatorial mutants that showed further improvements in Nav1.7 potency (E1N, E4D, Y33W, Q34S-Nav1.7 pIC50 = 8.1 ± 0.08) and increased selectivity over other Nav isoforms (E1N, R26K, Q34S, G36I, Nav1.7 pIC50 = 7.2 ± 0.1, Nav1.2 pIC50 = 6.1 ± 0.18, Nav1.3 pIC50 = 6.4 ± 1.0), Nav1.4 is inactive at 3 µm, and Nav1.5 is inactive at 10 µm We also substituted noncoded amino acids at select positions in huwentoxin-IV. Based on these results, we identify key determinants of huwentoxin's Nav1.7 inhibition and propose a model for huwentoxin-IV's interaction with Nav1.7. These findings uncover fundamental features of huwentoxin involved in Nav1.7 blockade, provide a foundation for additional optimization of this molecule, and offer a basis for the development of a safe and effective analgesic.

FIVE-YEAR INCIDENCE AND VISUAL ACUITY OUTCOMES FOR INTRAVITREAL THERAPY IN BILATERAL NEOVASCULAR AGE-RELATED MACULAR DEGENERATION: Fight Retinal Blindness! Project.

PURPOSE: To compare treatment intensity and mean visual acuity gains for first- and second-affected eyes with age-related macular degeneration nAMD over 5 years of treatment. The cumulative incidence of second-eye involvement was assessed. METHOD: We analyzed data from the Fight Retinal Blindness! project database, a prospectively designed registry of "real-world" outcomes from Australia, New Zealand, Switzerland, and Singapore. Patients with bilateral age-related macular degeneration with ≥5 years of follow-up on treatment were included. RESULTS: Six thousand five hundred and forty-two eyes being treated for age-related macular degeneration were tracked from 2005 to 2017. Thousand two hundred and sixty-one patients had bilateral age-related macular degeneration; of whom, 302 had 5 years of follow-up. Of these, 170 patients started treatment for each eye at least 2 months apart. The mean baseline visual acuity of second-affected eyes was significantly higher than that of first-eyes (20/50 + 2 vs. 20/80; P < 0.01). Second-affected eyes lost a mean of 5.8 (-9.1 to -2.6) logarithm of the minimum angle of resolution letters after 5 years of treatment, whereas the vision of the first-affected eyes remained stable (P = 0.01). Second-affected eyes received fewer injections than the first-affected eyes after the first year of treatment (6.2/year vs. 7.8/year; P < 0.01) and reactivated earlier (376 vs. 507 days; P = 0.04). The cumulative incidence of second eye involvement was 54% over 5 years. CONCLUSION: Second-affected eyes received fewer treatments and reactivated earlier. Care should be taken to avoid undertreating second-affected eyes.