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Background: Experience-dependent functional adaptation of nucleus accumbens (NAc) circuitry underlies the development and expression of reward-motivated behaviors. Parvalbumin-expressing GABAergic (gamma-aminobutyric acidergic) interneurons (PVINs) within the NAc are required for this process. Perineuronal nets (PNNs) are extracellular matrix structures enriched around PVINs that arise during development and have been proposed to mediate brain circuit stability. However, their function in the adult NAc is largely unknown. Here, we studied the developmental emergence and adult regulation of PNNs in the NAc of male and female mice and examined the cellular and behavioral consequences of reducing the PNN component brevican in NAc PVINs., Methods: We characterized the expression of PNN components in mouse NAc using immunofluorescence and RNA in situ hybridization. We lowered brevican in NAc PVINs of adult mice using an intersectional viral and genetic method and quantified the effects on synaptic inputs to NAc PVINs and reward-motivated learning., Results: PNNs around NAc PVINs were developmentally regulated and appeared during adolescence. In the adult NAc, PVIN PNNs were also dynamically regulated by cocaine. Transcription of the gene that encodes brevican was regulated in a cell type- and isoform-specific manner in the NAc, with the membrane-tethered form of brevican being highly enriched in PVINs. Lowering brevican in NAc PVINs of adult mice decreased their excitatory inputs and enhanced both short-term novel object recognition and cocaine-induced conditioned place preference., Conclusions: Regulation of brevican in NAc PVINs of adult mice modulates their excitatory synaptic drive and sets experience thresholds for the development of motivated behaviors driven by rewarding stimuli., (Copyright © 2024 Society of Biological Psychiatry. Published by Elsevier Inc. All rights reserved.)

Background and Objective: Telesurgery is as a promising solution to support and deliver advanced health care services to underserved areas. The primary endpoint of our study was to prove the concept of low-latency long-distance connectivity and to describe the feasibility of remote surgery., Methods: A prospective study was conducted from February 29 to March 1, 2024, in live animal models (porcine) connecting surgeons from Orlando (USA) to the animal laboratory in Shanghai (China) using 5G and Wi-Fi connections, in combination with continental and transpacific fiber. We performed ten radical nephrectomies and two partial nephrectomies in five animals using the MicroPort MedBot robotic platform. Intraoperative and telesurgery connection variables were reported with a descriptive statistical analysis., Key Findings and Limitations: No complications or conversions were reported. The mean animal weight was 38.2 (35-40) kg, the mean operative time was 32.7 (21-45) min, and the mean blood loss was 23.3 (20-30) ml. The mean latency was 296 (±50) ms. Findings from animal studies may not always translate directly to human outcomes., Conclusions and Clinical Implications: We described the feasibility of transpacific low-latency telesurgery in live porcine models with no intraoperative complications. Achieving optimal low-latency connectivity via telecommunication networks was essential for effectively performing the surgical procedures. However, we still need further investigation to achieve even lower latencies for human trials. We found that long-distance telesurgery is safe and feasible in animal models. However, it is a complex practice, and we still need further studies before translating these results to human trials., Patient Summary: Our research has demonstrated the feasibility of low-latency long-distance telesurgery in live animal models. However, this type of telesurgery is a complex procedure, and further work is needed to translate these results to human trials., (© 2024 The Author(s).)

A case of a 44-year-old man presenting with a family history of LMNA mutation and cardiac symptoms (dizziness, weakness, palpitations, and shortness of breath) congruent with dilated cardiomyopathy. Genetic testing revealed a novel likely pathogenic mutation of the LMNA gene (c.513G>A, exon 2) not previously associated with dilated cardiomyopathy, and the patient underwent guideline direct treatment for dilated cardiomyopathy. In patients with LMNA mutations, VTA risk should be calculated to determine the need for prophylactic ICD placement., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (© 2024 Patel, Patel, Patel and Patel.)

Importance: There is a burgeoning interest in therapeutic development for cutaneous neurofibromas (cNFs), a major cause of morbidity in persons with neurofibromatosis type 1 (NF1). To determine meaningful clinical trial outcomes, deeper understanding is needed regarding how cNFs are associated with quality of life (QoL). However, this understanding has been hampered by challenges in recruiting participants with this rare genetic disease., Objective: To develop a large, crowdsourced validated registry of persons with NF1 and determine the association of specific cNF features with QoL, pain, and itch., Design, Setting, and Participants: From May 2021 to December 2023, a decentralized platform was developed and recruited persons 40 years or older with NF1 and at least 1 cNF from 49 states and 12 countries, who provided clinical survey data, detailed photographs, and genetic sequencing data. Photographs from 583 participants were scored on 12 features of cNFs, including general severity, number, size, facial severity, color, and subtypes., Exposure: cNF features derived from participant-supplied photographs., Main Outcomes and Measures: Total Skindex scores and subdomain scores (symptoms, emotion, function, pain, and itch)., Results: Of 583 participants, 384 (65.9%) were female, and the mean (range) age was 51.7 (40.0-83.0) years. Female sex, general severity, number, size, and facial severity of cNFs were negatively associated with QoL, as demonstrated by increased total Skindex scores. QoL had the largest association with the number of cNFs and presence of facial cNFs. Increasing number of cNFs was associated with worse QoL, and even individuals with a low cNF burden (<10 total cNFs) experienced a decrease in QoL., Conclusions and Relevance: The results of this study suggest that reducing cNF number, particularly on the face, may be associated with improved QoL in individuals with NF1. In addition, early intervention before the development of numerous tumors may lead to the highest benefit in QoL. These data potentially provide insight into which individuals and cNF tumors may benefit most from therapy and highlights the utility of a completely decentralized, photograph-validated and age-controlled study for rare genetic disease. This cohort will allow analysis of disease and tumor heterogeneity after full phenotypic expression is achieved in NF1 and potentially serves as an example in its design for other rare diseases that struggle from poor recruitment.

Background and Objective: Delivering radiotherapy to the bladder is challenging as it is a mobile, deformable structure. Dose-escalated adaptive image-guided radiotherapy could improve outcomes. RAIDER aimed to demonstrate the safety of such a schedule., Methods: RAIDER is an international phase 2 noncomparative randomised controlled trial (ISRCTN26779187). Patients with unifocal T2-T4a urothelial bladder cancer were randomised (1:1:2) to standard whole bladder radiotherapy (WBRT), standard-dose adaptive radiotherapy (SART), or dose-escalated adaptive radiotherapy (DART). Two fractionation (f) schedules recruited independently. WBRT and SART dose was 55 Gy/20f or 64 Gy/32f, and DART dose was 60 Gy/20f or 70 Gy/32f. For SART and DART, a radiotherapy plan (small, medium, or large) was chosen daily. The primary endpoint was the proportion of patients with radiotherapy-related late Common Terminology Criteria for Adverse Events grade ≥3 toxicity; the trial was designed to rule out >20% toxicity with DART., Key Findings and Limitations: A total of 345 patients were randomised between October 2015 and April 2020: 41/46 WBRT, 41/46 SART, and 81/90 DART patients in the 20f/32f cohorts, respectively. The median age was 72/73 yr; 78%/85% had T2 tumours, 46%/52% had neoadjuvant chemotherapy, and 70%/71% had radiosensitising therapy. The median follow-up was 42.1/38.2 mo. Sixty-six of 77 (86%) 20f and 74 of 82 (90%) 32f participants planned for DART met the mandatory medium plan dose constraints. Radiotherapy-related grade ≥3 toxicity was reported in one of 58 patients (90% confidence interval [CI] 0.1, 7.9) with 20f DART and zero of 56 patients with 32f DART. Two-year overall survival was 77% (95% CI 69, 82) for WBRT + SART and 80% (95% CI 73, 85) for DART (hazard ratio = 0.84, 95% CI 0.59, 1.21, p = 0.4). Thirteen of 345 (3.8%) participants had salvage cystectomy., Conclusions and Clinical Implications: Grade ≥3 late toxicity was low. DART was safe and feasible to deliver, meeting preset toxicity thresholds. Disease-related outcomes are promising for dose-escalated treatments, with a low salvage cystectomy rate and overall survival similar to that seen in cystectomy cohorts., (Copyright © 2024 The Authors. Published by Elsevier B.V. All rights reserved.)

Sugarcane (Saccharum spp.)is an economically useful crop grown globally for sugar, ethanol and biofuel production. The crop is vulnerable to fungus Colletotrichum falcatum known to cause red rot disease. The pathogen hydrolyses stalk parenchyma cells where sucrose is accumulated resulting in upto 75% losses in sugar recovery. In this study, transgenic sugarcane having resistance against red rot was developed by introducing Trichoderma spp. endochitinase following Agrobacterium mediated transformation. The transgene introduction and expression in genetically modified plants were verified through qRT-PCR revealing upto 6-fold enhancement in endochitinase expression than non-transgenic plants. Hyperspectral Imaging of transgenic plants displayed altered leaf reflectance spectra and vegetative indices that were positively correlated with ransgene expression. The bioassay with virulent pathotypes of C. falcatumCF08 and CF13 known for epiphytotic occurrence resulted in identification of resistant plant Chit 3-13.The plants with higher reflectance also displayed improved disease resistance, implying their early classification into resistant/susceptible. The losses in sucrose content were minimized (up to 4-fold) in inoculated resistant plant Chit 3-13 as compared to susceptible non-transgenic plant, and a fewer pathogen hyphae were detected in vascular cells of the former through optical microscopy. The electron micrographs confirmed sucrose-filled stalk parenchyma cells in Chit 3-13; in contrast, cells of non-transgenic inoculated plant were depleted of sucrose. The active sites involved in cleaving 1-4 β-glycoside bonds of N-acetyl-d-glucosaminein the pathogen hyphal walls were detected through endochitinase protein structural modelling. The transgenic sugarcane is an important source for in trogressingred rot resistance in plant breeding programs., Competing Interests: The authors have declared that no competing interests exist., (Copyright: © 2024 Sharma et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

Objective: The purpose of this study was to examine the long-term effect of a quality improvement initiative at one-year post delivery., Study Design: This was a retrospective study of 1480 patients who delivered between October 2018 and June 2020 at the study institution and were enrolled in the Systematic Treatment and Management of PostPartum Hypertension Program (STAMPP). Patients received standardized cuffs, education, and follow-up. At the six-week postpartum follow-up, patients were again given instructions to establish follow-up., Main Outcome Measures: The primary outcome was a visit with a primary care physician (PCP) or cardiologist between 6 weeks and 1 year postpartum., Results: A total of 939 (63 %) patients had some follow-up within twelve months. Of these, 113 (12 %) and 175 (19 %) had follow-up with cardiology and primary care providers, respectively. Patients with no follow-up were more likely to have public aid (73.9 % vs 60.3 %; p < 0.001). 77 % identified as Black, with only 12 % of this cohort following up with cardiology and 13 % with a PCP., Conclusions: Despite specific counseling about long term follow-up, a minority of patients completed one year follow-up, notably amongst Black patients and those with public insurance. Further work is needed to optimize long-term follow-up after HDP to reduce the prevalence of cardiovascular disease, especially amongst high-risk patients., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 International Society for the Study of Hypertension in Pregnancy. Published by Elsevier B.V. All rights reserved.)

Purpose: The utilization of remote patient monitoring (RPM) with home blood pressure monitoring has shown improvement in blood pressure control and adherence with follow-up visits. Patient perceptions regarding its use in the obstetric population have not been widely studied. The aim of this study was to assess patients' knowledge about hypertensive disorders of pregnancy and perceptions and satisfaction of the RPM program., Methods: Descriptive analysis of survey responses of patients with PPHTN enrolled into the RPM program for 6 weeks after delivery between October 2021 and April 2022. Surveys were automatically administered at 1-, 3-, and 6-week postpartum. Responses were further compared between Black and non-Black patient-reported race., Results: 545 patients received the RPM program. Of these, 306 patients consented to data collection. At 1 week, 88% of patients that responded reported appropriately that a blood pressure greater than 160/110 is abnormal. At 3 weeks, 87.4% of patients responded reported they were "very" or "somewhat" likely to attend their postpartum follow-up visits because of RPM. At 6 weeks, 85.5% of the patients that responded were "very" or "somewhat" satisfied with the RPM program. Responses were not statistically different between races., Conclusions: Majority of postpartum patients enrolled in the RPM program had correct knowledge about hypertension. In addition, patients were highly satisfied with the RPM program and likely to attend postpartum follow-up based on responses. Further research is warranted to validate these findings and to address any barriers for patients who did not utilize the program., (© 2024. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Introduction: Robot-assisted radical prostatectomy (RARP) has become a popular surgical approach for localized prostate cancer due to its favorable oncological and functional outcomes, as well as lower morbidity. In cases of intermediate- and high-risk prostate cancer, bilateral pelvic lymphadenectomy (PLND) is recommended as an adjunct to RARP (1-3). Despite its benefits, PLND can lead to surgical complications, with postoperative lymphocele formation being the most common. Most postoperative lymphoceles are clinically insignificant with variable incidence, reaching up to 60% of cases 4. However, a small percentage of patients 2-8% may experience symptomatic lymphoceles (SL), which can cause significant morbidity (4, 5)., Surgical Technique: We perform our RARP technique with our standard approach in all patients (6). After vesicourethral anastomosis a modified PF created to prevent symptomatic lymphocele. We start by suturing the peritoneal fold on the right side, medially to the vas deferens, followed by a similar stitch on the left side to approximate the edges in the midline. A running suture bunches the bladder peritoneum from both sides, passing through the pubic bone periosteum to secure it in place (7). This approach keeps the lateral pelvic gutters open for lymphatic drainage, while allowing fluid drainage from the true pelvis into the abdomen. A pelvic ultrasound was done for all patients at 6 weeks post operative, and additional clinical follow-up was carried out at 3 months following surgery., Considerations: We have demonstrated a modified technique of peritoneal flap (PBFB) with an initial decrease in postoperative symptomatic lymphoceles, the technique is feasible, safe, does not add significant morbidity, and does not require a learning curve., Competing Interests: None declared., (Copyright® by the International Brazilian Journal of Urology.)

Introduction: Robotic surgery has transformed minimally invasive procedures, offering precision and efficiency. However, the ergonomic aspects of robotic consoles and their impact on surgeon health remain understudied. This review investigates the burden of ergonomics and muscle fatigue among robotic surgeons in China, comparing the findings to a multinational study., Methodology: A literature review identified themes related to physical discomfort in robotic surgery. A questionnaire was administered to Chinese robotic surgeons, yielding 40 responses. The study assessed demographic characteristics, surgeon experience, ergonomic practices, reported discomfort, and pain-relief mechanisms., Results: The study revealed that most surgeons experienced shoulder and neck pain, with mixed opinions on whether robotic surgery was the primary cause. Stretching exercises were commonly used for pain relief. Surgeons believed that case volume and surgery duration contributed to discomfort. Comparisons with a multinational study suggested potential demographic and experience-related differences., Conclusion: While the study has limitations, including a small sample size and potential translation issues, it underscores the importance of addressing ergonomic concerns and providing proper training to robotic surgeons to ensure their well-being and longevity in the field. Further research with larger cohorts and platform-specific analyses is warranted., Competing Interests: Declaration of Conflicting InterestsThe author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Objectives: To assess and evaluate the knowledge, awareness, and usage of inter-dental aids among the patients visiting a dental hospital., Materials and Methods: A cross-sectional descriptive study was conducted among patients using a questionnaire for evaluation of routine oral hygiene regimens., Results: 89% of patients brush their teeth only once a day. 77% of patients do not use any inter-dental aid, while 76% of patients are unaware about inter-dental aids., Conclusion: A very small part of the population is aware about the importance of using inter-dental aids in maintaining proper oral hygiene. Dentists play a key role in educating the society and encouraging them to use other aids apart from toothbrushes to prevent oral diseases., Competing Interests: There are no conflicts of interest., (Copyright: © 2024 Journal of Pharmacy and Bioallied Sciences.)

Background: Hospital nurse practitioner (NP) turnover is costly and complex., Purpose: Provide a pre-COVID-19 pandemic baseline of hospital NP turnover., Methods: A secondary analysis of NSSRN18 data on 6,558 (67,863 weighted) NPs employed in hospitals on 12/31/2017. We describe rates of turnover, intention to leave, and reasons for leaving or staying. Using multivariate logistic regression, we examine the association between individual and organizational characteristics and turnover. Survey weights and jackknife standard errors were applied to analyses., Discussion: Approximately 10% of NPs left their job the following year, and 53% of NPs that remained considered leaving at some point. The top reasons cited for leaving or staying were largely organizational factors. Regression analysis revealed not practicing to one's fullest scope, lower income, lack team-based care, and non-white race were associated with an increased likelihood to leave., Conclusion: We find several modifiable factors associated with hospital NP turnover that can be used to tailor recruitment and retention strategies., Competing Interests: Declaration of Competing Interest The authors declare no conflicts of interest., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Environmental mismatches are defined as changes in the environment that induce public health crises. Well known mismatches leading to chronic disease include the availability of technologies that facilitate unhealthy diets and sedentary lifestyles, both factors that adversely affect cardiovascular health. This commentary puts these mismatches in context with biota alteration, an environmental mismatch involving hygiene-related technologies necessary for avoidance of infectious disease. Implementation of hygiene-related technologies causes a loss of symbiotic helminths and protists, profoundly affecting immune function and facilitating a variety of chronic conditions, including allergic disorders, autoimmune diseases, and several inflammation-associated neuropsychiatric conditions. Unfortunately, despite an established understanding of the biology underpinning this and other environmental mismatches, public health agencies have failed to stem the resulting tide of increased chronic disease burden. Both biomedical research and clinical practice continue to focus on an ineffective and reactive pharmaceutical-based paradigm. It is argued that the healthcare of the future could take into account the biology of today, effectively and proactively dealing with environmental mismatch and the resulting chronic disease burden., (Copyright ©2024, Yale Journal of Biology and Medicine.)

Objective: This study examined whether use of bedside medication delivery (Meds to Beds, M2B) or on-campus pharmacy at discharge was associated with improved postpartum blood pressure (BP) control compared to outside pharmacy use in patients with hypertensive disorders of pregnancy (HDP)., Study Design: This was a secondary analysis of 357 patients with HDP enrolled in STAMPP-HTN (Systematic Treatment and Management of Postpartum Hypertension Program) who were discharged from delivery admission with antihypertensives between October 2018 and June 2020. Patients were grouped by discharge medication location: M2B/on-campus pharmacy (on-site) versus outside pharmacy (off-site)., Main Outcome Measures: The primary outcome was BP values at the immediate postpartum visit. Secondary outcomes included six-week visit BP values, attendance at both visits, and readmission within six weeks., Results: Median BP values were no different based on pharmacy location at immediate postpartum visit for both systolic ((135 [IQR 127, 139] on-site vs 137 [127, 145] off-site, p = 0.22) and diastolic (81 [74, 91] vs 83 [76, 92], p = 0.45) values. Similar findings were noted at six weeks. Patients who used an off-site pharmacy had higher attendance rates at the immediate postpartum visit but this difference was attenuated after adjusting for group differences (OR 0.67 [95 % CI 0.37-1.20], p = 0.18). Readmission rates were also not different between groups (12.2 % on-site vs 15.8 % off-site pharmacy, p = 0.43)., Conclusion: In the context of a preexisting multicomponent HDP quality improvement program, on-campus pharmacy and bedside medication delivery use was not associated with additional improvement in postpartum BP control, follow-up rates, or readmission rates., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024. Published by Elsevier B.V.)

Background: In high-resource settings, biomarkers of angiogenic balance, such as the soluble fms-like tyrosine kinase-1 (sFlt1)/placental growth factor (PlGF) ratio, have been studied extensively to aid in evaluation of patients with suspected preeclampsia (PE), and have been incorporated into the 2021 International Society for the Study of Hypertension in Pregnancy definition of PE. The utility in under-resourced settings has not been as well characterized., Objective: This analysis sought to identify the role of the sFlt1/PlGF ratio in the evaluation of patients with or without hypertension who are suspected of having PE without other diagnostic information., Study Design: This is a secondary analysis of a prior prospective study of patients who were presented with suspected PE at ≥20+0 weeks' gestation at a single academic tertiary care center. Patients were recruited in the parent study from July 2009 to June 2012. In the original study, clinicians were masked to biomarker results, and patients were followed by chart review. In this analysis, the performance of the sFlt1/PlGF ratio (≤38, >38, or >85) was assessed alone in identifying both hypertensive and non-hypertensive patients at risk of evolving into PE with severe features (PE-SF; American College of Obstetricians and Gynecologists' definition) within two weeks of the triage visit (PE-SF 2 ). Hypertension was defined as a blood pressure (BP)≥140/90 mmHg., Results: There were 1043 patients included in the analysis; of whom, 579 (55.5%) and 464 (44.5%) presented with or without hypertension, respectively. In triage, 332 (75.4%) of hypertensive patients presented due to BP concerns, and the remainder were evaluated due to other features (new-onset headache, proteinuria, or edema). On triage evaluation, 66.8% of all patients had a normal sFlt1/PlGF ratio ≤38, and 17.0% had an elevated ratio >85. Among hypertensive patients, a sFlt1/PlGF ratio ≤38 was a good rule-out test for PE-SF 2 (negative likelihood ratio [LR-] of 0.15), and a ratio >85 was a good rule-in test (positive likelihood ratio [LR+] of 5.75). Among normotensive patients, sFlt1/PlGF was useful as a rule-in test for ratio >38 (LR+ 5.13) and >85 (LR+ 12.80). Stratified by gestational age, sFlt1/PlGF continued to be a good rule in and good rule out test at <35 weeks among those with hypertension but did not have good test performance ≥35 weeks. sFlt1/PlGF had a good test performance as a rule in test for >85 regardless of gestational age. In triage, 4.3% (30/693) of patients with sFlt1/PlGF ratio <38 had concurrent laboratory evidence of PE, compared with 15.9% (28/176) patients with ratio >85., Conclusion: These findings support the potential for the use of sFlt1/PlGF and BP measurement alone in resource-limited settings where other laboratory tests or clinical expertise are unavailable for risk stratification. Performance of the biomarker varied by the presence of hypertension and gestational age., Competing Interests: S. Rana reports serving as a consultant for Roche Diagnostics, Thermo Fisher, Beckman Coulter, Siemens and has received research funding from Roche Diagnostics and Siemens for work related to angiogenic biomarkers unrelated to the submitted work. A. Mueller reports serving as a statistical consultant to Roche Diagnostics for a study related to the use of angiogenic factors in preeclampsia. S.V. received speaker fees and participated in advisory boards from Roche Diagnostics, ThermoFisher, Siemens and Beckman Coulter outside the submitted work. All other authors report no conflict of interest. No commercial organization was involved in the conception or delivery of this work., (© 2024 The Authors.)

Efforts to genetically reverse C9orf72 pathology have been hampered by our incomplete understanding of the regulation of this complex locus. We generated five different genomic excisions at the C9orf72 locus in a patient-derived induced pluripotent stem cell (iPSC) line and a non-diseased wild-type (WT) line (11 total isogenic lines), and examined gene expression and pathological hallmarks of C9 frontotemporal dementia/amyotrophic lateral sclerosis in motor neurons differentiated from these lines. Comparing the excisions in these isogenic series removed the confounding effects of different genomic backgrounds and allowed us to probe the effects of specific genomic changes. A coding single nucleotide polymorphism in the patient cell line allowed us to distinguish transcripts from the normal vs. mutant allele. Using digital droplet PCR (ddPCR), we determined that transcription from the mutant allele is upregulated at least 10-fold, and that sense transcription is independently regulated from each allele. Surprisingly, excision of the WT allele increased pathologic dipeptide repeat poly-GP expression from the mutant allele. Importantly, a single allele was sufficient to supply a normal amount of protein, suggesting that the C9orf72 gene is haplo-sufficient in induced motor neurons. Excision of the mutant repeat expansion reverted all pathology (RNA abnormalities, dipeptide repeat production, and TDP-43 pathology) and improved electrophysiological function, whereas silencing sense expression did not eliminate all dipeptide repeat proteins, presumably because of the antisense expression. These data increase our understanding of C9orf72 gene regulation and inform gene therapy approaches, including antisense oligonucleotides (ASOs) and CRISPR gene editing., Competing Interests: Competing interests statement:B.R.C. is a founder of Tenaya Therapeutics, a company focused on finding treatments for heart failure, including genetic cardiomyopathies. B.R.C. holds equity in Tenaya. C.D.C. is a founder, with equity, in Ciznor Co., a CNS therapeutics company. B.R.C. and C.D.C. are inventors on a patent application for this work. Y.-C.T. is a full-time employee at PacBio, a company developing single-molecule sequencing technologies. The other authors declare no competing interests.

Background: Pelvic lymph node dissection (PLND) is recommended while performing robot-assisted radical prostatectomy (RARP) for patients with localized intermediate or high-risk prostate cancer. However, symptomatic lymphoceles can occur after surgery, adding significant morbidity to patients. Our objective is to describe a novel Peritoneal Bladder Flap Bunching technique (PBFB) to reduce the risk of clinically significant lymphoceles in patients undergoing RARP and PLND., Methods: We evaluated 2267 patients who underwent RARP with PLND, dividing them into two groups: Group 1, comprising 567 patients who had the peritoneal flap (PBFB), and Group 2, comprising 1700 patients without the flap; propensity score matching carried out at a 1:3 ratio. Variables analyzed included estimated blood loss (EBL), operative time, postoperative complications, lymphocele formation, and the development of symptomatic lymphocele., Results: The two groups exhibited similar preoperative characteristics after matching. There was no statistically significant difference in the occurrence of lymphoceles between the flap group and the non-flap group, with rates of 24% and 20.9%, respectively ( p = 0.14). However, none of the patients in the flap group (0%) developed symptomatic lymphoceles, whereas 2.2% of patients in the non-flap group experienced symptomatic lymphoceles ( p = 0.01)., Conclusion: We have demonstrated a modified technique for a peritoneal flap (PBFB) with the initial elimination of postoperative symptomatic lymphoceles and promising short-term outcomes.

Background: Treatment-resistant depression (TRD) occurs more commonly in women. Deep brain stimulation (DBS) is an emerging treatment for TRD, and its efficacy continues to be explored. However, differences in treatment outcomes between males and females have yet to be explored in formal analysis., Methods: A PRISMA-compliant systematic review of DBS for TRD studies was conducted. Patient-level data were independently extracted by two authors. Treatment response was defined as a 50 % or greater reduction in depression score. Percent change in depression scores by gender were evaluated using random-effects analyses., Results: Of 737 records, 19 studies (129 patients) met inclusion criteria. The mean reduction in depression score for females was 57.7 % (95 % CI, 64.33 %-51.13 %), whereas for males it was 35.2 % (95 % CI, 45.12 %-25.23 %) (p < 0.0001). Females were more likely to respond to DBS for TRD when compared to males (OR = 2.44, 95 % CI 1.06, 1.95). These differences varied in significance when stratified by DBS anatomical target, age, and timeframe for responder classification., Limitations: Studies included were open-label trials with small sample sizes., Conclusions: Our findings suggest that females with TRD respond at higher rates to DBS treatment than males. Further research is needed to elucidate the implications of these results, which may include connectomic sexual dimorphism, depression phenotype variations, or unrecognized symptom reporting differences. Methodological standardization of outcome scales, granular demographic data, and individual subject outcomes would allow for more robust comparisons between trials., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal., (Copyright © 2024 Elsevier B.V. All rights reserved.)

IL12 is a proinflammatory cytokine, that has shown promising antitumor activity in humans by promoting the recruitment and activation of immune cells in tumors. However, the systemic administration of IL12 has been accompanied by considerable toxicity, prompting interest in researching alternatives to drive preferential IL12 bioactivity in the tumor. Here, we have generated XTX301, a tumor-activated IL12 linked to the human Fc protein via a protease cleavable linker that is pharmacologically inactivated by an IL12 receptor subunit beta 2 masking domain. In vitro characterization demonstrates multiple matrix metalloproteases, as well as human primary tumors cultured as cell suspensions, can effectively activate XTX301. Intravenous administration of a mouse surrogate mXTX301 demonstrated significant tumor growth inhibition (TGI) in inflamed and non-inflamed mouse models without causing systemic toxicities. The superiority of mXTX301 in mediating TGI compared with non-activatable control molecules and the greater percentage of active mXTX301 in tumors versus other organs further confirms activation by the tumor microenvironment-associated proteases in vivo. Pharmacodynamic characterization shows tumor selective increases in inflammation and upregulation of immune-related genes involved in IFNγ cell signaling, antigen processing, presentation, and adaptive immune response. XTX301 was tolerated following four repeat doses up to 2.0 mg/kg in a nonhuman primate study; XTX301 exposures were substantially higher than those at the minimally efficacious dose in mice. Thus, XTX301 has the potential to achieve potent antitumor activity while widening the therapeutic index of IL12 treatment and is currently being evaluated in a phase I clinical trial., (©2023 The Authors; Published by the American Association for Cancer Research.)

Background and Objective: Robot-assisted radical prostatectomy (RARP) is the main surgical approach for treatment of prostate cancer in the USA. Prostate size is always depicted as a factor affecting the outcomes of RARP as shown by many studies, but these studies are limited to a small number of patients. Our aim was to evaluate functional and oncologic outcomes of RARP across varying prostate size measured as prostate specimen weight., Methods: A cohort of 14 481 patients who underwent RARP in a single center was divided into four groups according to prostate specimen weight: group 1, <50 g; group 2, 50-100 g; group 3, 100-150 g; and group 4, >150 g. Perioperative and postoperative variables and pathological and functional outcomes were compared among the four groups. Cumulative incidence functions were plotted to visualize the distribution of event-time variables among the groups, and differences were evaluated using the log-rank test., Key Findings and Limitations: Patients with larger prostates (groups 3 and 4) were more likely to have higher prostate-specific antigen (PSA), lower biopsy grade group, and worse baseline urinary and sexual characteristics. Group 4 had lower rates of full nerve-sparing surgery (13.7% vs 38.3%) and lymph node dissection (51.3% vs 71.4%), more pT2 disease (69.8% vs 60.3%), less pT3 disease (30.2% vs 39.7%), and lower rates of positive surgical margins (12.8% vs 19.3%) and biochemical recurrence (5.9% vs 7.5%) than group 1. Finally, we observed differences in functional outcomes among the groups for greater prostate size, and patients in group 4 had worse rates of urinary continence (77.8% vs 89.5%) and recovery of sexual function (70.0% vs 84.1%) than group 1. Our study is limited by its retrospective design., Conclusions and Clinical Implications: The results demonstrate that in this large cohort of patients, greater prostate size affects multiple outcomes, including the rate of nerve-sparing surgery, potency and continence recovery, and oncological and pathological outcomes. These data will be valuable when counseling patients regarding possible RARP outcomes and the timeline for recovery., Patient Summary: Our study shows that prostate size can affect the outcomes of robot-assisted removal of the prostate for patients with prostate cancer. Larger prostate size can be associated with worse functional outcomes after surgery., (Published by Elsevier B.V.)

The dramatic rise in opioid use over the last two decades has led to a surge in their harmful health effects. Lesser known among clinicians is the impact of opioids on the endocrine system, especially with regard to cortisol. Opioids can suppress the hypothalamus-pituitary-adrenal (HPA) axis and may result in clinically significant adrenal insufficiency, especially in those treated at higher doses and for a longer time. A high clinical suspicion is necessary in this population for early diagnosis of opioid-induced adrenal insufficiency (OAI). Diagnosis of OAI is challenging, as the symptoms are often vague and overlap with those due to opioid use or the underlying pain disorder. Traditional assays to diagnose adrenal insufficiency have not been widely studied in this population, and more investigation is needed to determine how opioids might affect assay results. Once a diagnosis of adrenal insufficiency has been made, glucocorticoid replacement in the form of hydrocortisone is likely the mainstay of treatment, and effort should be made to taper down opioids where possible. Cortisol levels should be retested periodically, with the goal of stopping glucocorticoid replacement once the HPA axis has recovered. In this review, we provide context for diagnostic challenges in OAI, suggest diagnostic tools for this population based on available data, and offer recommendations for the management of this disorder. There is a paucity of literature in this field; given the widespread use of opioids in the general population, more investigation into the effects of opioids on the HPA axis is sorely needed., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2024 Patel and Ben-Shlomo.)

Robotic surgery has expanded globally across various medical specialties since its inception more than 20 years ago. Accompanying this expansion were significant technological improvements, providing tremendous benefits to patients and allowing the surgeon to perform with more precision and accuracy. This review lists some of the different types of platforms available for use in various clinical applications. We performed a literature review of PubMed and Web of Science databases in May 2023, searching for all available articles describing surgical robotic platforms from January 2000 (the year of the first approved surgical robot, da Vinci® System, by Intuitive Surgical) until May 1st, 2023. All retrieved robotic platforms were then divided according to their clinical application into four distinct groups: soft tissue robotic platforms, orthopedic robotic platforms, neurosurgery and spine platforms, and endoluminal robotic platforms. Robotic surgical technology has undergone a rapid expansion over the last few years. Currently, multiple robotic platforms with specialty-specific applications are entering the market. Many of the fields of surgery are now embracing robotic surgical technology. We review some of the most important systems in clinical practice at this time., (© 2024. The Author(s), under exclusive licence to Springer-Verlag London Ltd., part of Springer Nature.)

Telesurgery, a cutting-edge field at the intersection of medicine and technology, holds immense promise for enhancing surgical capabilities, extending medical care, and improving patient outcomes. In this scenario, this article explores the landscape of technical and ethical considerations that highlight the advancement and adoption of telesurgery. Network considerations are crucial for ensuring seamless and low-latency communication between remote surgeons and robotic systems, while technical challenges encompass system reliability, latency reduction, and the integration of emerging technologies like artificial intelligence and 5G networks. Therefore, this article also explores the critical role of network infrastructure, highlighting the necessity for low-latency, high-bandwidth, secure and private connections to ensure patient safety and surgical precision. Moreover, ethical considerations in telesurgery include patient consent, data security, and the potential for remote surgical interventions to distance surgeons from their patients. Legal and regulatory frameworks require refinement to accommodate the unique aspects of telesurgery, including liability, licensure, and reimbursement. Our article presents a comprehensive analysis of the current state of telesurgery technology and its potential while critically examining the challenges that must be navigated for its widespread adoption., (© 2024. The Author(s), under exclusive licence to Springer-Verlag London Ltd., part of Springer Nature.)

Objective: Placement of human placenta derived grafts during robotic-assisted radical prostatectomy (RARP) hastens the return of continence and potency. The long-term impact on the oncologic outcomes remains to be investigated. Our objective was to determine the oncologic outcomes of patients with dehydrated human amnion chorion membrane (dHACM) at RARP compared to a matched cohort., Methods: In a referral centre, from August 2013 to October 2019, 599 patients used dHACM in bilateral nerve-sparing RARP. We excluded patients with less than 12 months follow-up, simple prostatectomy, and unilateral nerve-sparing. Patients with dHACM (amnio group) were 529, and were propensity score matched 1:1 to 2465 patients without dHACM (non-amnio group) and a minimum follow-up of 36 months. At the time of RARP, dHACM was placed around the neurovascular bundle in the amnio group. Continuous and categorical variables in matched groups was tested by two-sample Kolmogorov-Smirnov test and Fisher's exact test respectively. Outcomes measured were biochemical recurrence (BCR), adjuvant and salvage therapy rates., Results: Propensity score matching resulted in two groups of 444 patients. Cumulative incidence functions for BCR did not show a difference between the groups ( p =0.3). Patients in the non-amnio group required salvage therapy more frequently than the amnio group, particularly after partial nerve-sparing RARP (6.3% vs. 2.3%, p =0.001). Limitations are the absence of prospective randomization., Conclusion: The data suggest that using dHACM does not have a negative impact on BCR in patients. Outcomes of cancer specific and overall survival will require follow-up study to increase our understanding of these grafts' impact on prostate cancer biology., Competing Interests: Vipul Patel was previously a medical consultant for MiMedx. All remaining authors declare no conflict of interest. The study was partially funded by MiMedx, Georgia, USA to provide the grafts., (© 2024 Editorial Office of Asian Journal of Urology. Production and hosting by Elsevier B.V.)

Objective: In the following years after the United States Preventive Service Task Force (USPSTF) recommendation against prostate cancer screening with PSA in 2012, several authors worldwide described an increase in higher grades and aggressive prostate tumors. In this scenario, we aim to evaluate the potential impacts of USPSTF recommendations on the functional and oncological outcomes in patients undergoing robotic-assisted radical prostatectomy (RARP) in a referral center., Material and Methods: We included 11396 patients who underwent RARP between 2008 and 2021. Each patient had at least a 12-month follow-up. The cohort was divided into two groups based on an inflection point in the outcomes at the end of 2012 and the beginning of 2013. The inflection point period was detected by Bayesian regression with multiple change points and regression with unknown breakpoints. We reported continuous variables as median and interquartile range (IQR) and categorical variables as absolute and relative percent frequencies., Results: Group 1 had 4760 patients, and Group 2 had 6636 patients, with a median follow-up of 109 and 38 months, respectively. In the final pathology, Group 2 had 9.5% increase in tumor volume, 24% increase on Gleason ≥ 4+3 (ISUP 3) , and 18% increase on ≥ pT3. This translated to a 6% increase in positive surgical margins and 24% reduction in full nerve sparing in response to the worsening pathology. There was a significant decline in post-operative outcomes in Group 2, including a 12-month continence reduction of 9%, reduction in potency by 27%, and reduction of trifecta by 22%., Conclusions: The increasing number of high-risk patients has led to worse functional and oncologic outcomes. The initial rapid rise in PSM was leveled by the move towards more partial nerve sparing. Among some historical changes in prostate cancer diagnosis and management in the period of our study, the USPSTF recommendation coincided with worse outcomes of prostate cancer treatment in a population who could benefit from PSA screening at the appropriate time., Competing Interests: None declared., (Copyright® by the International Brazilian Journal of Urology.)

Objective : This retrospective, single-center case series was designed to characterize the effects of perinatal COVID-19 diagnosis on obstetric and neonatal outcomes in a predominantly high-risk, urban Black population. Study Design : Data were collected via retrospective chart review on all COVID-19-positive obstetric patients and their neonates who presented to the University of Chicago Medical Center between March 2020 and November 2020, before the availability of the COVID-19 vaccine. Patient demographics, delivery outcomes, COVID-19 symptoms, treatment, and outcomes were analyzed. Results : A total of 56 COVID-19-positive obstetric patients were included in the study, of which four were lost to follow-up before delivery. The median age of patients was 27 years (IQR 23, 32), with 73.2% publicly insured and 66.1% Black. Patients had a median body mass index (BMI) of 31.6 kg/m 2 (IQR 25.9, 35.5). 3.6% of patients had chronic hypertension, 12.5% had diabetes, and 16.1% had asthma. Perinatal complications were common. Twenty-six patients (50.0%) had a diagnosis of a hypertensive disorder of pregnancy (HDP). 28.8% had gestational hypertension, and 21.2% had preeclampsia (with and without severe features). The rate of maternal ICU admission was 3.6%. Furthermore, 23.5% of patients delivered preterm (<37 weeks gestation), and 50.9% of infants were admitted to the Neonatal Intensive Care Unit (NICU). Conclusion : In our study of a predominantly Black, publicly-insured, unvaccinated group of COVID-19-positive pregnant patients, we found high rates of hypertensive disorders of pregnancy, preterm delivery, and NICU admission compared to rates reported in existing literature before widespread vaccine availability. Our findings suggest that SARS-CoV-2 infection during pregnancy, irrespective of maternal disease severity, may exacerbate existing obstetric health disparities by disproportionately impacting Black, publicly insured patients. Larger comparative studies are needed to better characterize possible racial and socioeconomic disparities in obstetric outcomes in the setting of SARS-CoV-2 infection during pregnancy. These studies should examine the pathophysiology of SARS-CoV-2 infection during pregnancy, as well as potential associations between adverse perinatal outcomes and disparities in access to care, COVID-19 vaccination, and other social determinants of health amongst more vulnerable populations infected with SARS-CoV-2 during pregnancy.

Background: Pregnant patients of racial/ethnic minorities have higher preeclampsia rates. Home blood pressure monitoring (HBPM) has been investigated for disparity reduction. Smaller studies showed patients find HBPM to be a helpful intervention postpartum. Further investigation is needed to define the role of HPBM in an at-risk and diverse population antepartum., Objective: To assess patient perception of HBPM among diverse patients at high risk of disease development., Study Design: Prospective study conducted from April 2020-September 2021. HBPM kits were advertised and interested parties across the United States responded. Cuff Kits were then distributed to participating providers. Providers distributed the kits to patients meeting high-risk criteria for disease development, prioritizing those of racial/ethnic minorities. Surveys were distributed quarterly to providers and patients to assess HBPM perception., Results: 2910 Cuff Kits were distributed to patients at 179 sites in 14 states. Of those, 1160 were distributed to Black patients, 1045 to White patients, and 500 to Hispanic patients. 117 patients completed surveys, with most patients finding Cuff Kits "very valuable" or "valuable" (68.4% and 19.7%, respectively). Most providers (73.4%) felt the Cuff Kits influenced patient care., Conclusions: Most patients receiving Cuff Kits reported a beneficial impact on disease understanding and most belonged to racial/ethnic groups at higher risk of adverse outcomes. Providers found HBPM had a beneficial impact on care. Though more research is needed to illustrate the impact of HBPM on outcomes, this study suggests that among racial/ethnic minorities and those at the high risk, HBPM is a well-received intervention., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 International Society for the Study of Hypertension in Pregnancy. Published by Elsevier B.V. All rights reserved.)

Abstract: The Advanced Practice Registered Nurse (APRN) Consensus Model was developed in 2008 by the APRN Consensus Work Group and the National Council of State Boards of Nursing APRN Advisory Committee. This model aims to improve access to APRN care through standardization of licensure, accreditation, certification, and education and has been adopted by many organizations throughout the United States. However, the Consensus Model is not a legislative document, and there is variation in adoption and implementation throughout states and organizations. Since the Consensus Model was developed, little is known about how this change has affected hiring practices for nurse practitioners (NPs) and physician assistants (PAs). There are concerns that the model may place burdensome hiring constraints on NP hires, which could inadvertently lead to preferential hiring of PAs over NPs. We evaluated whether there was a significant association between the proportion of NPs versus PAs hired after the implementation of the APRN Consensus Model in 2017 in a large not-for-profit health system in North Carolina. Our study revealed no association between implementation of hiring practices to align with the APRN Consensus Model and preferential hiring of PAs over NPs., Competing Interests: Competing interests: The authors report no conflicts of interest., (Copyright © 2023 American Association of Nurse Practitioners.)

Neoadjuvant chemotherapy (NAC) has long been considered technically difficult in locally advanced colon cancer (LACC). However, the introduction of oxaliplatin-based regimens led to a growing interest in NAC for patients with LACC. Several cohort studies showed that NAC was safe and reduced the rate of incomplete resection in patients with LACC. This was followed by the pivotal phase III FOxTROT trials, which showed significant benefits of NAC in this population. However, in patients with deficient mismatch repair (dMMR), the response to a neoadjuvant fluoropyrimidine regimen may be poor, limiting the benefit of NAC in this subset of patients. Neoadjuvant immunotherapy is a potential alternative for NAC in LACC patients with dMMR. In this concise review, we present the published clinical evidence evaluating the efficacy and safety of NAC and/or neoadjuvant immunotherapy in patients with LACC. Overall, the evidence suggests that NAC can be associated with significant downstaging and tumor regression, which facilitate surgical resection. However, the impact of NAC on long-term survival is still under investigation. Despite the promising results of NAC in LACC, several concerns still exist that necessitate further evidence. On the other hand, LACC patients with dMMR can benefit from neoadjuvant immunotherapy; however, further trials are still needed to confirm its effectiveness, as well as biomarkers that can predict response.

Background: Clinicians often report that their own anxiety and low self-efficacy inhibit their use of evidence-based suicide prevention practices, including gold-standard screening and brief interventions. Exposure therapy to reduce clinician maladaptive anxiety and bolster self-efficacy use is a compelling but untested approach to improving the implementation of suicide prevention evidence-based practices (EBPs). This project brings together an interdisciplinary team to leverage decades of research on behavior change from exposure theory to design and pilot test an exposure-based implementation strategy (EBIS) to target clinician anxiety to improve suicide prevention EBP implementation., Methods: We will develop, iteratively refine, and pilot test an EBIS paired with implementation as usual (IAU; didactic training and consultation) in preparation for a larger study of the effect of this strategy on reducing clinician anxiety, improving self-efficacy, and increasing use of the Columbia Suicide Severity Rating Scale and the Safety Planning Intervention in outpatient mental health settings. Aim 1 of this study is to use participatory design methods to develop and refine the EBIS in collaboration with a stakeholder advisory board. Aim 2 is to iteratively refine the EBIS with up to 15 clinicians in a pilot field test using rapid cycle prototyping. Aim 3 is to test the refined EBIS in a pilot implementation trial. Forty community mental health clinicians will be randomized 1:1 to receive either IAU or IAU + EBIS for 12 weeks. Our primary outcomes are EBIS acceptability and feasibility, measured through questionnaires, interviews, and recruitment and retention statistics. Secondary outcomes are the engagement of target implementation mechanisms (clinician anxiety and self-efficacy related to implementation) and preliminary effectiveness of EBIS on implementation outcomes (adoption and fidelity) assessed via mixed methods (questionnaires, chart-stimulated recall, observer-coded role plays, and interviews)., Discussion: Outcomes from this study will yield insight into the feasibility and utility of directly targeting clinician anxiety and self-efficacy as mechanistic processes informing the implementation of suicide prevention EBPs. Results will inform a fully powered hybrid effectiveness-implementation trial to test EBIS' effect on implementation and patient outcomes., Trial Registration: Clinical Trials Registration Number: NCT05172609 . Registered on 12/29/2021., (© 2023. The Author(s).)

Importance: Failure to recognize and address data missingness in cohort studies may lead to biased results. Although Strengthening the Reporting of Observational Studies in Epidemiology reporting guidelines advocate data missingness reporting, the degree to which missingness is reported and addressed in the critical care literature remains unclear., Objectives: To review published ICU cohort studies to characterize data missingness reporting and the use of methods to address it., Design Setting and Participants: We searched the 2022 table of contents of 29 critical care/critical care subspecialty journals having a 2021 impact factor greater than or equal to 3 to identify published prospective clinical or retrospective database cohort studies enrolling greater than or equal to 100 patients., Main Outcomes and Measures: In duplicate, two trained researchers conducted a manuscript/supplemental material PDF word search for "missing*" and extracted study type, patient age, ICU type, sample size, missingness reporting, and the use of methods to address it., Results: A total of 656 studies were reviewed. Of the 334 of 656 (50.9%) studies mentioning missingness, missingness was reported for greater than or equal to 1 variable in 234 (70.1%) and it exceeded 5% for at least one variable in 160 (47.9%). Among the 334 studies mentioning missingness, 88 (26.3%) used exclusion criteria, 36 (10.8%) used complete-case analysis, and 164 (49.1%) used a formal method to avoid missingness. In these 164 studies, imputation only was used in 100 (61.0%), an analytic strategy only in 24 (14.6%), and both in 40 (24.4%). Only missingness greater than 5% (in ≥ 1 variable) was independently associated with greater use of a missingness method (adjusted odds ratio 2.91; 95% CI, 1.85-4.60). Among 140 studies using imputation, multiple imputation was used in 87 studies (62.1%) and simple imputation in 49 studies (35.0%). For the 64 studies using an analytic method, 12 studies (18.8%) assigned missingness as an unknown category, whereas sensitivity analysis was used in 47 studies (73.4%)., Conclusions and Relevance: Among published critical care cohort studies, only half mentioned result missingness, one-third reported actual missingness and only one-quarter used a method to manage missingness. Educational strategies to promote missingness reporting and resolution methods are required., Competing Interests: Dr. Devlin disclosed he has received unrelated grant support from the National Institute of Aging, Agency for Healthcare Research and Quality, Sedana Medical, and BioXcel Therapeutics and has served as a consultant to Ceribell Inc. and La Jolla Pharmaceuticals. The remaining authors have disclosed that they do not have any potential conflicts of interest., (Copyright © 2023 The Authors. Published by Wolters Kluwer Health, Inc. on behalf of the Society of Critical Care Medicine.)

Cutaneous neurofibromas (cNF) contribute to the impairment of QOL in individuals with neurofibromatosis 1. The cNF-Skindex, validated in a French population, specifically assesses the cNF-related QOL. In this study, we first defined severity strata using an anchoring approach on the basis of patient's burden. In total, 209 patients answered the anchor question and the cNF-Skindex. We tested the agreement among the three strata, generated by all potential couples of cut-off values of the cNF-Skindex and the three strata defined in the anchor question. The cut-off values 12 and 49 provided the highest Kappa value (κ = 0.685, 95% confidence interval = 0.604-0.765). Second, we validated the score and the strata in a United States population using the answers provided by 220 French and 148 United States adults. In the multivariable linear regression analysis, the country of origin was not a factor associated with the score (P = 0.297). The number of cNF along the different severity strata was similar between the French and the United States populations. In conclusion, stratification constitutes a powerful tool to better interpret the cNF-Skindex in daily practice and in clinical trials. This study validates its use in two populations that together constitute a large cohort of patients willing to participate in clinical research., (Copyright © 2023 The Authors. Published by Elsevier Inc. All rights reserved.)

Low-lipoxygenase soybean cultivars are highly desirable because lower lipoxygenase content in soybean seeds leads to better quality soybean-based products and oils that are free from off-flavor or beany flavor. The expression of the Lox-2 gene is mainly responsible for this flavor. Over the years, natural antioxidants have been tested biochemically to inhibit Lox-2 activity, but in-silico studies are still lacking. To investigate the structural basis of inhibition, site-specific docking, as well as molecular dynamics (MD) simulations, were performed. Molecular docking analysis revealed that daidzein and genistein could be effective Lox2 receptor inhibitors. Furthermore, docked complexes were subjected to 100 ns MD simulation studies to analyze the structural conformations and stability of the complex. The analysis demonstrated that daidzein formed a more stable complex with the Lox-2 receptor and showed a higher H-bond propensity with the Asp775 residue. We discovered that the initial conformation of Lox2-daidzein complex changed to a more stable conformation at the beginning of the MD simulation and remained stable until the end with minor fluctuations. Furthermore, our analysis suggested that daidzein acts as a potential Lox-2 inhibitor and is a better candidate compared to genistein, which could be used to solve the beany flavor problem in soybean.Communicated by Ramaswamy H. Sarma.

Robotic surgery has revolutionized surgical procedures and has provided many advantages over traditional laparoscopic and open surgeries. Despite the benefits, there are concerns about the physical discomfort and injuries that may be experienced by surgeons during robotic surgeries. This study aimed to identify the most common muscle groups implicated in robotic surgeons' physical pain and discomfort. A questionnaire was created and sent to 1000 robotic surgeons worldwide, with a response rate of 30.9%. The questionnaire consisted of thirty-seven multiple-choice questions, three short answer questions, and one multiple-option question pertaining to the surgeon's workload as well as their level of discomfort while and after performing surgery. The primary endpoint was to identify the most common muscle groups implicated in robotic surgeons' physical pain and discomfort. Secondary endpoints were to highlight any correlation between age group, BMI, hours of operation, workout regimen, and significant pain levels. The results showed that the most common muscle groups implicated in physical pain and discomfort were the neck, shoulders, and back, with many of the surgeons attributing their muscular fatigue and discomfort to the ergonomic design of the surgeon console. Despite the level of surgeon comfort the robotic console provides when compared to other conventional forms of surgery, the findings suggest the need for better ergonomic practices during robotic surgeries to minimize physical discomfort and injuries for surgeons., (© 2023. The Author(s), under exclusive licence to Springer-Verlag London Ltd., part of Springer Nature.)

Objective: To provide insight into the intraoperative management, admission course, pain management, and graft success of microscope- and endoscope-assisted tympanoplasty., Study Design: Retrospective Chart Review., Methods: This study included children 18 years and younger who underwent ambulatory tympanoplasty at a tertiary pediatric hospital between January 2018 and December 2020. Medical records were reviewed and information about intraoperative factors, surgical approach, laterality, complications, and post-operative perforation closure success rates was collected. Multivariate analysis was performed to compare and contrast the two surgical approaches., Results: The review included 321 pediatric patients who underwent a tympanoplasty. Endoscopic tympanoplasty accounted for 17.4%, while microscopic tympanoplasty accounted for 82.6%. In both approaches, the rate of intraoperative complications, postoperative complications, audiological improvements, and perforation closure success rates were statistically similar. However, patients who underwent endoscopic tympanoplasty were 3.96 times less likely to require opioids in the post-anesthesia care unit (PACU) and had a shorter post-operative admission length. This pattern emerged regardless of the type of graft used. Obtaining an autograft was not associated with a higher opioid requirement in the PACU., Conclusion: While both approaches are viable, our findings demonstrate the reduced need for opioids with similar success rates following an endoscopic tympanoplasty. Ultimately, the trade-off for the minimally invasive endoscopic approach appears to be a less painful experience for the child while promoting clinically appropriate opioid stewardship in the perioperative setting., Competing Interests: Declaration of competing interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Dr. Kristan Alfonso has a clinical consulting agreement with Cochlear Corp. All other authors have no conflicts of interest to disclose., (Copyright © 2023 Elsevier B.V. All rights reserved.)

Background: Suicide attempts and suicide death disproportionately affect sexual and gender minority emerging adults (age 18-24 years). However, suicide prevention strategies tailored for emerging adult sexual and gender minority (EA-SGM) groups are not widely available. The Safety Planning Intervention (SPI) has strong evidence for reducing the risk for suicide in the general population, but it is unclear how best to support EA-SGM groups in their use of a safety plan. Our intervention (Supporting Transitions to Adulthood and Reducing Suicide [STARS]) builds on content from an existing life skills mobile app for adolescent men who have sex with men (iREACH) and seeks to target core risk factors for suicide among EA-SGM groups, namely, positive affect, discrimination, and social disconnection. The mobile app is delivered to participants randomized to STARS alongside 6 peer mentoring sessions to support the use of the safety plan and other life skills from the app to ultimately reduce suicide risk., Objective: We will pilot-test the combination of peer mentoring alongside an app-based intervention (STARS) designed to reduce suicidal ideation and behaviors. STARS will include suicide prevention content and will target positive affect, discrimination, and social support. After an in-person SPI with a clinician, STARS users can access content and activities to increase their intention to use SPI and overcome obstacles to its use. EA-SGM groups will be randomized to receive either SPI alone or STARS and will be assessed for 6 months., Methods: Guided by the RE-AIM (reach, efficacy, adoption, implementation, and maintenance) framework, we will recruit and enroll a racially and ethnically diverse sample of 60 EA-SGM individuals reporting past-month suicidal ideation. Using a type-1 effectiveness-implementation hybrid design, participants will be randomized to receive SPI (control arm) or to receive SPI alongside STARS (intervention arm). We will follow the participants for 6 months, with evaluations at 2, 4, and 6 months. Preliminary effectiveness outcomes (suicidal ideation and behavior) and hypothesized mechanisms of change (positive affect, coping with discrimination, and social support) will serve as our primary outcomes. Secondary outcomes include key implementation indicators, including participants' willingness and adoption of SPI and STARS and staff's experiences with delivering the program., Results: Study activities began in September 2021 and are ongoing. The study was approved by the institutional review board of the University of Pennsylvania (protocol number 849500). Study recruitment began on October 14, 2022., Conclusions: This project will be among the first tailored, mobile-based interventions for EA-SGM groups at risk for suicide. This project is responsive to the documented gaps for this population: approaches that address chosen family, focus on a life-course perspective, web approaches, and focus on health equity and provision of additional services relevant to sexual and gender minority youth., Trial Registration: ClinicalTrials.gov NCT05018143; https://classic.clinicaltrials.gov/ct2/show/NCT05018143., International Registered Report Identifier (irrid): DERR1-10.2196/48177., (©Lily A Brown, Jessica L Webster, Jennifer T Tran, James R Wolfe, Jesse Golinkoff, Esha Patel, Amanda C Arcomano, Jennifer Ben Nathan, Alexander Azat O'Connor, Yiqin Zhu, Maria Oquendo, Gregory K Brown, David Mandell, Danielle Mowery, José A Bauermeister. Originally published in JMIR Research Protocols (https://www.researchprotocols.org), 29.09.2023.)

Lipoxygenases (LOXs) catalyze the oxidation of polyunsaturated fatty acids and synthesize oxylipin products that drive important cellular signaling processes in plants and animals. While there has been indirect evidence presented for the interaction of mammalian LOXs with membranes, a quantitative study of the molecular details of LOX-membrane interactions is lacking. Here, we mimicked biological membranes using surface plasmon resonance (SPR) sensor chips derivatized with 2-D planar lipophilic anchors (2D LP) to capture liposomes of varying phospholipid compositions that self-assemble into lipid bilayers on the SPR chip. The sensor chip surfaces were then used to investigate the membrane-binding properties of model LOX enzymes. SPR binding assays displayed reproducible and stable liposome capture to the sensor chip surface that allowed for the detailed characterization of LOX-membrane interactions. Our studies demonstrate a calcium-dependence for the membrane binding activities of coral 8R-LOX and human 15-LOX-2. Furthermore, our data confirm the importance of key membrane insertion loop residues in each of these LOX enzymes for membrane binding activity. Experiments utilizing model plant and human LOXs reveal differences in membrane-binding specificities. Our study establishes and validates a robust SPR-based platform using 2D LP sensor chips that allows for the detailed study of LOX-membrane interactions under different experimental conditions, including altered membrane compositions. Collectively, this investigation improves our overall understanding of LOX-membrane interaction properties, and our SPR-based approach holds potential for future use in the development of LOX-based therapeutics., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 Elsevier Inc. All rights reserved.)

Tracheal perforation is an extremely rare and potentially dangerous complication of a partial thyroidectomy. The current case represents a unique presentation of delayed tracheal perforation following an uncomplicated thyroid isthmusectomy for tissue diagnosis of an aggressive appearing thyroid mass in the setting of high-dose steroid administration and recent intubation and self-extubation. While conservative management of tracheal perforation can sometimes be appropriate, our patient was successfully managed via primary closure and infrahyoid muscle transposition flap to cover a 5 mm right lateral tracheal wall defect. We recommend caution be exercised following thyroid surgery in the setting of intubation and high-dose steroids.

Mouse models of hyper- and hypothyroidism were used to examine the effects of thyroid hormone (TH) dyshomeostasis on the aging mammalian brain. 13-14 month-old mice were treated for 4months with either levothyroxine (hyperthyroid) or a propylthiouracil and methimazole combination (PTU/Met; hypothyroid). Hyperthyroid mice performed better on Morris Water Maze than control mice, while hypothyroid mice performed worse. Brain weight was increased in thyroxine-treated, and decreased in PTU/Met-treated animals. The brain weight change was strongly correlated with circulating and tissue T4. Quantitative measurements of microvessels were compared using digital neuropathologic methods. There was an increase in microvessel area in hyperthyroid mice. Hypothyroid mice showed a trend for elevated glial fibrillary acidic protein-immunoreactive astrocytes, indicating an increase in neuroinflammation. Gene expression alterations were associated with TH perturbation and astrocyte-expressed transcripts were particularly affected. For example, expression of Gli2 and Gli3, mediators in the Sonic Hedgehog signaling pathway, were strongly impacted by both treatments. We conclude that TH perturbations produce robust neurobehavioral, pathological, and brain gene expression changes in aging mouse models., Competing Interests: Disclosure statement The authors have no actual or potential conflicts of interest., (Copyright © 2023 Elsevier Inc. All rights reserved.)

The new SP robot incorporates a single trocar that houses a flexible camera and three bi-articulated arms, which minimize the number of incisions needed to assess the surgical site, allowing for a less invasive procedure. To compare the postoperative pain scale and outcomes in patients with similar demographic characteristics undergoing robotic-assisted radical prostatectomy (RARP) with SP and Xi robots, One-hundred consecutive patients undergoing RARP with the SP robot were matched, using a propensity score (PS), with 100 patients from a cohort of 1757 who were operated on with the da Vinci Xi from June 2019 to January 2021. We described and compared the perioperative pain scores and outcomes of both groups. The SP group had less blood loss (50 cc vs. 62.5 cc, P < 0.001) and longer operative time (114 min. vs. 94 min, P < 0.001). The only period we could show a difference in postoperative pain scores was 6 h after surgery, with a small advantage for the SP (2 vs. 2.5, P < 0.001). Both groups had satisfactory postoperative continence recovery, 91% vs. 90% for the SP and Xi, respectively. The groups had a mean follow-up of 24.5 and 22 months for SP and Xi, respectively. The tumor stage and percentage of positive surgical margins were similar between groups (15% vs. 15%, P = 1). Patients undergoing RARP with the SP had longer operative times with less blood loss than the Xi. However, despite the lower number of abdominal incisions on the SP, the groups had similar intraoperative performance, and we were unable to demonstrate clinically significant differences in postoperative pain scores between the groups 6, 12, and 18 h after surgery., (© 2023. The Author(s), under exclusive licence to Springer-Verlag London Ltd., part of Springer Nature.)

Objectives: Review the incidence and factors associated with respiratory compromise requiring intensive care unit level interventions in children with planned admission to the pediatric intensive care unit (PICU) following tonsillectomy or adenotonsillectomy (T/AT)., Study Design: Retrospective cohort study., Methods: Review of all patients with PICU admissions following T/AT from 2015 to 2020 at a tertiary care pediatric hospital. Patient demographics, underlying comorbidities, operative data, and respiratory complications during PICU admission were extracted., Results: Seven hundred and seventy-two patients were admitted to the PICU following T/AT, age 6.1 ± 4.6 years. All children were diagnosed with obstructive sleep apnea or sleep-disordered breathing (mean pre-operative apnea-hypopnea index 29 ± 26.5 and O2 nadir 77.1% ± 11.1). Neuromuscular disease, enteral feed dependence, and obesity were common findings (N = 240 (31%), N = 106 (14%), and N = 209 (27%) respectively). Overall, 29 patients (3.7%) developed respiratory compromise requiring PICU-level support, defined as new-onset continuous or bilevel positive airway pressure support (n = 25) or reintubation (n = 9). Three patients were diagnosed with pulmonary edema. Multivariable regression analysis demonstrated pre-operative oxygen nadir and enteral feed dependence were associated with respiratory compromise (OR = 0.97, 95% CI 0.94-0.99, P  = .04; OR = 6.3, 95% CI 2.36-52.6, P  = .001 respectively)., Conclusions: Our study found respiratory compromise in 3.7% of patients with planned PICU admissions following T/AT. Oxygen nadir and enteral feeds were associated with higher respiratory compromise rates. Attention should be given to these factors in planning for post-operative disposition.

APOE is the largest genetic risk factor for late-onset Alzheimer disease (AD) with E4 conferring an increased risk for AD compared to E3. The ApoE protein can impact diverse pathways in the brain including neuroinflammation but the precise impact of ApoE isoforms on inflammation remains unknown. As microglia are a primary source of neuroinflammation, this study determined whether ApoE isoforms have an impact on microglial morphology and activation using immunohistochemistry and digital analyses. Analysis of ionized calcium-binding adaptor molecule 1 (Iba1) immunoreactivity indicated greater microglial activation in both the hippocampus and superior and middle temporal gyrus (SMTG) in dementia participants versus non-demented controls. Further, only an increase in activation was seen in E3-Dementia participants in the entire SMTG, whereas in the grey matter of the SMTG, only a diagnosis of dementia impacted activation. Specific microglial morphologies showed a reduction in ramified microglia in the dementia group. For rod microglia, a reduction was seen in E4-Control patients in the hippocampus whereas in the SMTG an increase was seen in E4-Dementia patients. These findings suggest an association between ApoE isoforms and microglial morphologies and highlight the importance of considering ApoE isoforms in studies of AD pathology., (© The Author(s) 2023. Published by Oxford University Press on behalf of American Association of Neuropathologists, Inc. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

Consolidation immunotherapy after concurrent chemoradiation has improved five-year survival rates in unresectable, locally advanced lung cancer, but disease progression and treatment personalization remain challenges. New treatment approaches with concurrent immunotherapy and consolidative novel agents are being investigated and show promising efficacy data, but at the risk of additive toxicity. Patients with PD-L1 negative tumors, oncogenic driver mutations, intolerable toxicity, or limited performance status continue to require innovative therapies. This review summarizes historical data that galvanized new research efforts, as well as ongoing clinical trials that address the challenges of current therapeutic approaches for unresectable, locally advanced lung cancer., (Copyright © 2023 Elsevier Inc. All rights reserved.)

Purpose: SABR is a treatment option for patients with lung tumors that employs fiducials to track tumors during the breathing cycle. Currently, there is a paucity of data on how relative fiducial location and patient clinical characteristics affect fiducial tracking and clinical outcomes. This study aimed to identify factors that reduce the number of fiducials tracked with respiratory motion management during SABR., Methods and Materials: An institutional review board-approved retrospective review was performed of patients receiving robotic SABR for lung tumors at our institution from 2016 to 2019. Clinical data including demographics, medical history, treatment data, and follow-up were collected. Fiducial geometries were obtained with Velocity contouring software and MATLAB. Mann-Whitney U , χ 2 , and t tests were completed using MedCalc., Results: A total of 73 patients with 77 treatments were identified. The χ 2 analysis revealed that chronic obstructive pulmonary disease was associated with having 3 or more fiducials tracked ( P  = .034). Tumors in lower lobes were associated with higher rates of uncertainty errors ( P  = .015). The number of fiducials tracked had no effect on local tumor control or overall survival, with a median of 36 months of follow-up. A total of 28 treatments had fiducial centroid data available for geometric analysis. The most common tracking errors were rigid body error (RBE; 57%) and spacing errors (36.4%). Spacing errors had a shorter average minimum interfiducial distance than nonspacing errors (1.0 cm vs 1.7 cm, respectively; P  = .017). RBE treatments had a longer average maximum distance than non-RBE treatments (4.0 cm vs 3.0 cm; P  = .022)., Conclusions: Greater motion in lower lobes can contribute to certain tracking errors that prevent more fiducials from being tracked. Maintaining interfiducial distance between experimentally determined guidelines may limit spacing errors and RBEs, the 2 most common tracking errors. An increased number of patients in a data set may result in stronger correlations between patient and tumor factors and outcomes., Competing Interests: Mark Bowling reports a relationship with Medtronic that includes consulting or advisory., (© 2023 The Authors.)