Adjuvant Everolimus in Patients with Completely Resected, Very High-risk Renal Cell Carcinoma of Clear Cell Histology: Results from the Phase 3 Placebo-controlled SWOG S0931 (EVEREST) Trial.

BACKGROUND AND OBJECTIVE: EVEREST is a phase 3 trial in patients with renal cell cancer (RCC) at intermediate-high or very high risk of recurrence after nephrectomy who were randomized to receive adjuvant everolimus or placebo. Longer recurrence-free survival (RFS) was observed with everolimus (hazard ratio [HR] 0.85, 95% confidence interval [CI] 0.72-1.00; p = 0.051), but the nominal significance level (p = 0.044) was not reached. To contextualize these results with positive phase 3 trials of adjuvant sunitinib and pembrolizumab, we conducted a secondary analysis in a similar population of EVEREST patients with very high-risk disease and clear cell histology. METHODS: Postnephrectomy patients with any clear cell component and very high-risk disease, defined as pT3a (grade 3-4), pT3b-c (any grade), T4 (any grade), or node-positive status (N+), were identified. A Cox regression model stratified by performance status was used to compare RFS and overall survival (OS) between the treatment arms. KEY FINDINGS AND LIMITATIONS: Of 1499 patients, 717 had clear cell histology and very high-risk disease; 699 met the eligibility criteria, of whom 348 were randomized to everolimus arm, and 351 to the placebo arm. Patient characteristics were similar between the arms. Only 163/348 (47%) patients in the everolimus arm completed all treatment as planned, versus 225/351 (64%) in the placebo arm. Adjuvant everolimus resulted in a statistically significant improvement in RFS (HR 0.80; 95%CI 0.65-0.99, p = 0.041). Evidence of a survival benefit was not seen (HR 0.85; 95%CI 0.64-1.14, p = 0.3) CONCLUSIONS AND CLINICAL IMPLICATIONS: In patients with clear cell RCC at very high-risk for recurrence, adjuvant everolimus resulted in significantly improved RFS compared to placebo but resulted in a high discontinuation rate due to adverse events. Although the treatment HR for OS was consistent with RFS findings, it did not reach statistical significance. With a focus on risk stratification tools and/or biomarkers to minimize toxicity risk in those not likely to benefit, this information can help inform the design of future adjuvant trials in high-risk RCC PATIENT SUMMARY: We assessed treatment with everolimus in comparison to placebo after complete surgical removal of clear-cell kidney cancer at very high risk of recurrence. We found that survival outcomes were better for patients treated with everolimus, although these patients had a higher rate of side effects.

Prevalence, severity and impacts of breathlessness in Indian adults: An exploratory, nationally representative, cross-sectional online survey.

There are no known estimates of the prevalence, severity and impacts from breathlessness in low- and middle-income countries. This study aimed to explore the prevalence, severity, self-attributed underlying conditions and impacts of breathlessness limiting exertion in community-dwelling adults in India. This exploratory, population-based online survey recruited a pre-planned sample of 3,000 adult respondents stratified by age, sex and rurality (quotas as per the 2011 Indian National Census). Measures included: demographics; breathlessness limiting exertion (modified Medical Research [mMRC] scale); health-related quality of life (EQ-5D-5L); and disability (World Health Organisation's Disability Assessment Schedule 2.0 12-item questionnaire [WHODAS-12]). Respondents (n = 3,046) had a mean age of 38 years (SD 15); 57% were male, 59% lived in rural areas and 33% had completed 12th grade. Breathlessness limiting exertion (mMRC ≥1) was reported by 44%, mostly attributed to poor nutrition (28%), lung conditions excluding tuberculosis (17%) or anaemia (13%). Compared to those without breathlessness, a higher proportion of people with breathlessness (mMRC ≥1) reported problems across all EQ-5D-5L dimensions. Most people reporting breathlessness (81%) indicated the symptom had adversely affected their normal activities. Disability scores (WHODAS-12 total and individual domains) increased as breathlessness worsened. To conclude, in India, conservative estimates indicate 626 million people live with breathlessness of whom 52 million people live with severe breathlessness. The symptom is associated with poorer health-related quality of life and marked disability, including reduced ability to perform daily activities.

Assessing wild turkey productivity before and after a 14-day delay in the start date of the spring hunting season in Tennessee.

Ten state wildlife management agencies in the United States, including six within the Southeast, have delayed their spring wild turkey (Meleagris gallopavo) hunting seasons since 2017 by five or more days to address concerns related to the potential effects of hunting on wild turkey seasonal productivity. One hypothesis posits that if the spring hunting season is too early, there may be insufficient time for males to breed hens before being harvested, thus leading to reduced seasonal productivity. We conducted an experiment to determine whether delaying the wild turkey hunting season by 2 weeks in south-middle Tennessee would affect various reproductive rates. In 2021 and 2022, the Tennessee Fish and Wildlife Commission experimentally delayed the spring hunting season to open 14 days later than the traditional date (the Saturday closest to 1 April) in Giles, Lawrence, and Wayne counties. We monitored reproductive rates from 2017 to 2022 in these three counties as well as two adjacent counties, Bedford and Maury, that were not delayed. We used a Before-After-Control-Impact design to analyze the proportion of hens nesting, clutch size, hatchability, nest success, poult survival and hen survival with linear mixed-effect models and AIC model selection to detect relationships between the 14-day delay and reproductive parameters. We detected no relationship (p > .05) between the 14-day delay and any individual reproductive parameter. In addition, recruitment (hen poults per hen that survived until the next breeding season) was very low (<0.5) and did not increase because of the 14-day delay. The traditional Tennessee start date had been in place since 1986 while the turkey harvest increased markedly until about 2006 and more recently stabilized. Our data indicate that moving the start of the hunting season from a period just prior to peak nest initiation to 2 weeks later, to coincide with a period just prior to peak nest incubation initiation, resulted in no change to productivity or populations in wild turkey flocks in south-middle Tennessee.

Sense of neighborhood belonging and health: geographic, racial, and socioeconomic variation in Wisconsin.

Background: Individuals' sense of belonging (SoB) to their neighborhood is an understudied psychosocial factor that may influence the association between neighborhood characteristics, health, and disparities across socio-demographic groups. Methods: Using 2014-2016 data from the Survey of the Health of Wisconsin (SHOW, N = 1,706), we conduct a detailed analysis of SoB and health in an American context. We construct OLS and logistic regressions estimating belonging's association with general, physical, and mental health. We explore geographic, racial, and socioeconomic variation to understand both the differential distribution of SoB and its heterogeneous relationship with health. Results: A higher SoB is positively associated with better physical, mental, and general health. White participants report higher SoB than Black participants, yet the association between SoB and mental health is strongest among participants of color and urban residents. Conclusion: Sense of belonging to neighborhood significantly predicts many facets of health, with place and individual characteristics appearing to moderate this relationship. Racial, geographic, and socioeconomic disparities in belonging-health associations raise important questions about who benefits from the social, economic, and physical aspects of local communities.

Total Nasal Reconstruction: Advances in Free Tissue Transfer for Internal Lining and Structural Support.

Total nasal reconstruction is a complex challenge due to the need to establish new internal lining, internal structural support, and external skin covering that is both functional and esthetic. The medial femoral condyle corticoperiosteal free flap represents an innovative option for restoration internal structure and internal nasal lining. When used in conjunction with a paramedian forehead flap, acceptable results in both function and esthetics can be achieved.

Substrate Prediction for RiPP Biosynthetic Enzymes via Masked Language Modeling and Transfer Learning.

Ribosomally synthesized and post-translationally modified peptide (RiPP) biosynthetic enzymes often exhibit promiscuous substrate preferences that cannot be reduced to simple rules. Large language models are promising tools for predicting such peptide fitness landscapes. However, state-of-the-art protein language models are trained on relatively few peptide sequences. A previous study comprehensively profiled the peptide substrate preferences of LazBF (a two-component serine dehydratase) and LazDEF (a three-component azole synthetase) from the lactazole biosynthetic pathway. We demonstrated that masked language modeling of LazBF substrate preferences produced language model embeddings that improved downstream classification models of both LazBF and LazDEF substrates. Similarly, masked language modelling of LazDEF substrate preferences produced embeddings that improved the performance of classification models of both LazBF and LazDEF substrates. Our results suggest that the models learned functional forms that are transferable between distinct enzymatic transformations that act within the same biosynthetic pathway. Our transfer learning method improved performance and data efficiency in data-scarce scenarios. We then fine-tuned models on each data set and showed that the fine-tuned models provided interpretable insight that we anticipate will facilitate the design of substrate libraries that are compatible with desired RiPP biosynthetic pathways.

Incidence of Surgical Reintervention for Benign Prostatic Hyperplasia Following Prostatic Urethral Lift, Transurethral Resection of the Prostate, and Photoselective Vaporization of the Prostate: A TriNetX Analysis.

Background: Prostatic urethral lift, or UroLift, has gained popularity as a treatment for lower urinary tract symptoms associated with benign prostatic hyperplasia (BPH). Surgical reintervention rates are a reliable indicator for treatment durability. Objective: The objective of this study was to utilize TriNetX, a third-party database, to investigate the incidence of surgical reintervention following UroLift, transurethral resection of the prostate (TURP), and photoselective vaporization of the prostate (PVP) procedures for BPH from 2015 to 2018. Design setting and participants: Male patients aged 18-100 yr diagnosed with BPH were identified in the TriNetX Diamond Network database between January 2015 and December 2018. Cohorts of individuals undergoing their first UroLift procedure were built using Current Procedural Terminology and International Classification of Diseases 10th Revision codes. TURP and PVP cohorts were built as comparison groups. The cohorts were then queried for subsequent BPH-related procedures. Outcome measurements and statistical analysis: Reprocedure rates were assessed and descriptive statistics were used. Results and limitations: The mean age at first-time UroLift was 70.1 ± 9.4 yr (n = 14 343). Cumulative reprocedure rates collected after first-time UroLift included 1 yr after UroLift (5.1%, n = 14 343) and 4 yr after UroLift (16.1%, n = 710), with an average annual increase of +3.6% per year following 1 yr after the procedure. Comparatively, TURP (n = 22 071) and PVP (n = 14 110) had 4-yr reprocedure rates of 7.5% and 7.8%, respectively, during the same timeframe. Limitations include a lack of clinical data and loss of follow-up data outside the Diamond Network. Conclusions: The reprocedure rate of UroLift at 4 yr is double the rate of TURP and PVP. In appropriately selected patients, UroLift might be a suitable option for those who desire symptomatic relief from BPH with minimal erectile and ejaculatory side effects. However, the risk of secondary surgical intervention should be considered when considering BPH treatments. Patient summary: We compared the reintervention rates of prostatic urethral lift (PUL), transurethral resection of the prostate (TURP), and photoselective vaporization of the prostate (PVP) using the TriNetX database, and have found that the highest reintervention rates were for PUL of 16% at 4 yr of follow-up, compared with about 8% for those who had TURP and PVP. Interestingly, the most common reintervention was the same operation at 1 yr. This has important implications when counseling patients about the durability of these various outlet procedures for BPH.

National Trends in Surgical Management for Benign Prostatic Hyperplasia From 2013 to 2019 in the United States.

INTRODUCTION: Benign prostatic hyperplasia (BPH) is a common urologic pathology for older men. The prevalence and effect on quality of life have prompted the development of new surgical procedures to manage BPH while attempting to minimize treatment side effects. The objective of this study is to utilize TriNetX, a third-party database, to investigate temporal trends in BPH procedures from 2013 to 2019 in the United States. METHODS: Male patients aged 18 to 100 who were diagnosed with BPH from 2013 to 2019 were filtered from the TriNetX Diamond Network. Yearly cohorts undergoing a BPH-related procedure were searched using Current Procedural Terminology and International Classification of Diseases 10th Revision codes. Temporal and descriptive analytics were utilized to describe trends in treatment utilization. RESULTS: There were 302,646 BPH procedures recorded on the TriNetX Diamond Network. Transurethral resection of the prostate was the most commonly performed procedure, accounting for 47.2% of procedures in 2013 and 44.9% in 2019. Photoselective vaporization of the prostate remained a popular treatment but showed the greatest decrease in utilization over time (31.8% in 2013, 21.5% in 2019). Prostatic urethral lift (UroLift) was rapidly embraced as a treatment modality, as usage increased by 18.3% over a 6-year period (0.0% in 2014, up to 18.3% in 2019). Other procedures such as Rezum (5.8%) and holmium laser enucleation of the prostate (5.1%) made up greater proportions of BPH procedures by 2019. CONCLUSIONS: Transurethral resection of the prostate was the most common procedure from 2013 to 2019. However, minimally invasive surgeries represent an increased percentage of BPH surgeries every year.

Rapid Enantiomeric Excess Measurements of Enantioisotopomers by Molecular Rotational Resonance Spectroscopy.

Recent work in drug discovery has shown that selectively deuterated small molecules can improve the safety and efficacy for active pharmaceutical ingredients. The advantages derive from changes in metabolism resulting from the kinetic isotope effect when deuterium is substituted for a hydrogen atom at a structural position where rate limiting C-H bond breaking occurs. This application has pushed the development of precision deuteration strategies in synthetic chemistry that can install deuterium atoms with high regioselectivity and with stereocontrol. Copper-catalyzed alkene transfer hydrodeuteration chemistry has recently been shown to have high stereoselectivity for deuteration at the metabolically important benzyl C-H position. In this case, stereocontrol results in the creation of enantioisotopomers-molecules that are chiral solely by virtue of the deuterium substitution-and chiral analysis techniques are needed to assess the reaction selectivity. It was recently shown that chiral tag molecular rotational resonance (MRR) spectroscopy provides a routine way to measure the enantiomeric excess and establish the absolute configuration of enantioisotopomers. High-throughput implementations of chiral tag MRR spectroscopy are needed to support optimization of the chemical synthesis. A measurement methodology for high-throughput chiral analysis is demonstrated in this work. The high-throughput ee measurements are performed using cavity-enhanced MRR spectroscopy, which reduces measurement times and sample consumption by more than an order-of-magnitude compared to the previous enantioisotopomer analysis using a broadband MRR spectrometer. It is also shown that transitions for monitoring the enantiomers can be selected from a broadband rotational spectrum without the need for spectroscopic analysis. The general applicability of chiral tag MRR spectroscopy is illustrated by performing chiral analysis on six enantioisotopomer reaction products using a single molecule as the tag for chiral discrimination.

A Novel Hierarchical Security Solution for Controller-Area-Network-Based 3D Printing in a Post-Quantum World.

As the popularity of 3D printing or additive manufacturing (AM) continues to increase for use in commercial and defense supply chains, the requirement for reliable, robust protection from adversaries has become more important than ever. Three-dimensional printing security focuses on protecting both the individual Industrial Internet of Things (I-IoT) AM devices and the networks that connect hundreds of these machines together. Additionally, rapid improvements in quantum computing demonstrate a vital need for robust security in a post-quantum future for critical AM manufacturing, especially for applications in, for example, the medical and defense industries. In this paper, we discuss the attack surface of adversarial data manipulation on the physical inter-device communication bus, Controller Area Network (CAN). We propose a novel, hierarchical tree solution for a secure, post-quantum-supported security framework for CAN-based AM devices. Through using subnet hopping between isolated CAN buses, our framework maintains the ability to use legacy or third-party devices in a plug-and-play fashion while securing and minimizing the attack surface of hardware Trojans or other adversaries. The results of the physical implementation of our framework demonstrate 25% and 90% improvement in message costs for authentication compared to existing lightweight and post-quantum CAN security solutions, respectively. Additionally, we performed timing benchmarks on the normal communication (hopping) and authentication schemes of our framework.

BREATHLEssness in INDIA (BREATHE-INDIA)-Study protocol for the co-design of a community breathlessness intervention in India using realist methods and intervention mapping.

BACKGROUND: Breathlessness that persists despite treatment of causal disease(s) is disabling, associated with high therapy-related costs and poor socioeconomic outcomes. Low resource countries bear a disproportionate burden of respiratory problems, often characterised by disabling breathlessness. Low-cost self-management breathlessness-targeted interventions are effective and deliverable in community settings but have been developed in high-income countries. We aim to understand how breathlessness self-management works in 'real life' populations and cultural contexts, to develop programme theory and co-design a prototype intervention to improve persistent breathlessness management in India. METHODS AND ANALYSIS: Using a Realist approach, Intervention Mapping and the Medical Research Council Complex Intervention Framework we will undertake two phases of work supported by our Expert Group (of respiratory, primary, palliative care physicians) and key stakeholder groups (opinion leader clinicians, community health workers and people with lived experiences of breathlessness). 1) Realist review and evaluation to identify and refine evidence and theory for breathlessness self-management, producing intervention and implementation programme theory. We will identify literature through our Expert Group, scoping searches and systematic searches (Medline, Ebscohost, CINAHL, Scopus, Psychinfo). We will map intervention components to 'what works, for whom, and where.' 2) Intervention development using Intervention Mapping to map intervention and implementation programme theory to intervention components, develop materials to support intervention delivery, and co-design a prototype educational intervention ready for early acceptability and delivery-feasibility testing and evaluation planning in India. Use of stakeholder groups is to allow people with experience of breathlessness and/or its management to contribute their views on content developed by our team based upon review of secondary data sources. Experts and Stakeholders are therefore not research subjects but are included as extended members of the study team and will not follow informed consent procedures. Experts and stakeholders will be acknowledge in outputs arising from our project if they wish to be. Our review conduct will be consistent with RAMESES quality standards. DISCUSSION: At the conclusion of our study, we will have co-designed a breathlessness intervention for use in the community setting in India ready for further evaluation of: effectiveness, socioeconomic outcomes, acceptability and transferability to other low resource settings.

Updates in Butterfly Graft Technique.

Nasal obstruction is a significant challenge greatly affecting individual quality of life. It is one of the most common presentations in the otolaryngology clinic, often persisting despite medical and, at times, surgical intervention. The butterfly graft has proven to be a veritable option addressing nasal valve collapse. Herein, we describe our most recent operative technique, highlight its application in ethnic rhinoplasty and revision cases, and discuss incorporation of dorsal preservation techniques in functional rhinoplasty.

Views and experiences of opioid access amongst palliative care providers and public representatives in a low-resource setting: A qualitative interview study.

Opioids (e.g. morphine) are affordable, effective interventions for cancer-related pain. However, equity of access to this key medication remains a global challenge, particularly in low- and middle-income countries. We aimed to explore views of palliative care providers and public-representatives about opioid analgesia access in two States in India. We conducted a qualitative study using semi-structured interviews. Transcribed audio-recordings were subjected to thematic analysis using a Framework Approach. Palliative care providers and public-representatives were purposively sampled from services reporting consistent opioid availability and prescribing (≥4kg per annum) from Karnataka and Kerala. Twenty participants (doctors (10), nurses (4), pharmacists (2), service managers (2) and public-representatives (2) were interviewed. Three themes were identified: 1) Attitudes and awareness: opioid treatments are perceived as end-of-life (last days/weeks) interventions; fears of addiction and misunderstanding of pain management goals limit access. 2) Expected and unexpected inequities: patients/carers from lower socioeconomic strata accept doctor recommendations if opioids are affordable, more educated patients/families have reservations about opioids, delay access and perceive expensive medicines as better. Non-palliative care specialist doctors have negative entrenched views and require specialist training. 3) Experiential learning-positive experiences can positively alter attitudes (e.g., participants in Kerala report improved attitudes, awareness and understanding influenced by exposure and community awareness, but experience can also reinforce perceptions as end-of-life care. Entrenched negative views are reinforced by poor experiences while positive experiences improve attitudes. To promote access, opioid prescribing must be needs-based rather than prognosis-based. Addressing the lack of training for non-palliative care workforce would help overcome a major barrier.

Experiences of a Novel Integrated Service for Older Adults at Risk of Frailty: A Qualitative Study.

The UK has a significant and growing population of older adults with frailty and complex healthcare needs, necessitating innovative care solutions. This study aimed to explore patients' and carers' experiences of a novel integrated service that was set up to address the increasing healthcare needs of older people living with frailty. A qualitative study that combined free-text survey questions with in-depth interviews. This study is part of a larger non-randomized trial of the service, with evaluation of wellbeing and quality of life at baseline, 2 to 4 weeks, and 10 to 14 weeks. Patients (aged 65 and above) with an electronic Frailty Index in the severe range and their informal family carers participated in this study. Data were collected between April 2019 and March 2020. Free text survey responses and interview data were subjected to reflexive thematic analyses. Four themes were generated: the overall experience of the service; interactions within the service; treatment and interventions; and outcomes due to the service. Most participants wanted further follow-up and more extensive integration with other services. Most participants described their overall experience positively, especially the available time to address their full range of concerns, but opportunities to integrate the service more fully and to extend follow-up remain.