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Abstract Background Understanding the patient perspective of frailty is critical to offering holistic patient-centred care. Rehabilitation strategies for patients with advanced chronic kidney disease (CKD) and frailty are limited in their ability to overcome patient-perceived barriers to participation, resulting in high rates of drop-out and non-adherence. The aim of this study was to explore patient perspectives and preferences regarding experiences with rehabilitation to inform a CKD/Frailty rehabilitation model. Methods This qualitative study involved two focus groups, six individual semi-structured interviews and three caregiver semi-structured interviews with lived experience of advanced kidney disease and frailty. Interviews were recorded, transcribed, and coded for meaningful concepts and analysed using inductive thematic analysis using constant comparative method of data analysis employing Social Cognitive Theory. Results Six major themes emerged including accommodating frailty is an act of resilience, exercise is endorsed for rehabilitation but existing programs have failed to meet end-users’ needs. Rehabilitation goals were framed around return to normative behaviours and rehabilitation should have a social dimension, offering understanding for “people like us”. Participants reported on barriers and disruptors to frailty rehabilitation in the CKD context. Participants valued peer-to-peer education, the camaraderie of socialisation and the benefit of feedback for maintaining motivation. Patients undertaking dialysis described the commodity of time and the burden of unresolved symptoms as barriers to participation. Participants reported difficulty envisioning strategies for frailty rehabilitation, maintaining a focus on the immediate and avoidance of future uncertainty. Conclusions Frailty rehabilitation efforts in CKD should leverage shared experiences, address comorbidity and symptom burden and focus on goals with normative value.

Abstract Cavity-electromechanical systems are extensively used for sensing and controlling the vibrations of mechanical resonators down to their quantum limit. The nonlinear radiation-pressure interaction in these systems could result in an unstable response of the mechanical resonator showing features such as frequency-combs, period-doubling bifurcations and chaos. However, due to weak light-matter interaction, typically these effects appear at very high driving strengths. By using polariton modes formed by a strongly coupled flux-tunable transmon and a microwave cavity, here we demonstrate an electromechanical device and achieve a single-photon coupling rate $$\left({g}_{0}/2\pi \right)$$ g 0 / 2 π of 160 kHz, which is nearly 4% of the mechanical frequency ω m . Due to large g 0/ω m ratio, the device shows an unstable mechanical response resulting in frequency combs in sub-single photon limit. We systematically investigate the boundary of the unstable response and identify two important regimes governed by the optomechanical backaction and the nonlinearity of the electromagnetic mode. Such an improvement in the single-photon coupling rate and the observations of microwave frequency combs at single-photon levels may have applications in the quantum control of the motional states and critical parametric sensing. Our experiments strongly suggest the requirement of newer approaches to understand instabilities.

Abstract Accurate prediction of recurrence and progression in non-muscle invasive bladder cancer (NMIBC) is essential to inform management and eligibility for clinical trials. Despite substantial interest in developing artificial intelligence (AI) applications in NMIBC, their clinical readiness remains unclear. This systematic review aimed to critically appraise AI studies predicting NMIBC outcomes, and to identify common methodological and reporting pitfalls. MEDLINE, EMBASE, Web of Science, and Scopus were searched from inception to February 5th, 2024 for AI studies predicting NMIBC recurrence or progression. APPRAISE-AI was used to assess methodological and reporting quality of these studies. Performance between AI and non-AI approaches included within these studies were compared. A total of 15 studies (five on recurrence, four on progression, and six on both) were included. All studies were retrospective, with a median follow-up of 71 months (IQR 32−93) and median cohort size of 125 (IQR 93−309). Most studies were low quality, with only one classified as high quality. While AI models generally outperformed non-AI approaches with respect to accuracy, c-index, sensitivity, and specificity, this margin of benefit varied with study quality (median absolute performance difference was 10 for low, 22 for moderate, and 4 for high quality studies). Common pitfalls included dataset limitations, heterogeneous outcome definitions, methodological flaws, suboptimal model evaluation, and reproducibility issues. Recommendations to address these challenges are proposed. These findings emphasise the need for collaborative efforts between urological and AI communities paired with rigorous methodologies to develop higher quality models, enabling AI to reach its potential in enhancing NMIBC care.

Plasma medicine is an emerging field that applies the science and engineering of physical plasma to biomedical applications. Low-temperature plasma, also known as cold plasma, is generated via the ionization of atoms in a gas, generally via exposure to strong electric fields, and consists of ions, free radicals, and molecules at varying energy states. Plasmas generated at low temperatures (approximately room temperature) have been used for applications in dermatology, oncology, and anti-microbial strategies. Despite current and ongoing clinical use, the exact mechanisms of action and the full range of effects of cold plasma treatment on cells are only just beginning to be understood. Direct and indirect effects of plasma on immune cells have the potential to be utilized for various applications such as immunomodulation, anti-infective therapies, and regulating inflammation. In this review, we combine diverse expertise in the fields of plasma chemistry, device design, and immunobiology to cover the history and current state of plasma medicine, basic plasma chemistry and their implications, the effects of cold atmospheric plasma on host cells with their potential immunological consequences, future directions, and the outlook and recommendations for plasma medicine.

Amyotrophic Lateral Sclerosis (ALS) is a relentlessly progressive and fatal disease, caused by the degeneration of upper and lower motor neurons within the brain and spinal cord in the ageing human. The dying neurons contain cytoplasmic inclusions linked to the onset and progression of the disease. Here, we use a Drosophila model of ALS8 (VAPP58S) to understand the modulation of these inclusions in the ageing adult brain.The adult VAPP58S fly shows progressive deterioration in motor function till its demise 25 days post-eclosion. The density of VAPP58S-positive brain inclusions is stable for 5–15 days of age. In contrast, adding a single copy of VAPWT to the VAPP58S animal leads to a large decrease in inclusion density with concomitant rescue of motor function and lifespan. ER stress, a contributing factor in disease, shows reduction with ageing for the disease model. Autophagy, rather than the Ubiquitin Proteasome system, is the dominant mechanism for aggregate clearance.We explored the ability of Drosophila Valosin-containing protein (VCP/TER94), the ALS14 locus, which is involved in cellular protein clearance, to regulate age-dependent aggregation. Contrary to expectation, TER94 overexpression increased VAPP58S punctae density, while its knockdown led to enhanced clearance. Expression of a dominant positive allele, TER94R152H, further stabilised VAPP58S puncta, cementing roles for an ALS8-ALS14 axis. Our results are explained by a mechanism where autophagy is modulated by TER94 knockdown.Our study sheds light on the complex regulatory events involved in the neuronal maintenance of ALS8 aggregates, suggesting a context-dependent switch between proteasomal and autophagy-based mechanisms as the larvae develop into an adult. A deeper understanding of the nucleation and clearance of the inclusions, which affect cellular stress and function, is essential for understanding the initiation and progression of ALS.

Abstract Introduction Hypoxia‐inducible factor‐2α (HIF‐2α) modulates the hypoxic response pathway in tumors; however, mutations in pathways (including SDHA, SDHB, SDHC, SDHD, FH, and VHL genes) that are suspected to activate HIF‐2α are poorly understood, with limited understanding of the prevalence and clinical prognosis. Methods This retrospective observational study used a de‐identified nationwide (US‐based) clinico‐genomic database (CGDB) across 15 available tumor types. Results Among the 9467 adult patients with advanced/metastatic solid tumors included in the analysis, any mutation at the above‐mentioned six genes was observed in 1.8% (95% CI: 1.5–2.1) of patients. The mutation prevalence ranged from 0.05% of SDHD to 0.93% of VHL. When further stratified by tumor type, the prevalence of gene mutation in each tumor type was well below 1%, except for VHL with 44% in renal cell carcinomas (RCC). Excluding RCC, the prevalence of any HIF‐2α gene mutations in the study population was 0.9% (95% CI: 0.8–1.2). The median overall survival (OS) from 1 and 2 L therapy among patients with any HIF‐2α gene mutation was 14.5 (95% CI: 11.5–24.2) and 9.3 (95% CI: 6.0–18.1) months, respectively, compared with 13.4 (95% CI: 12.9–13.9) and 9.8 (95% CI: 9.3–10.4) months among patients without HIF‐2α gene mutations. Discussion and Conclusions The prevalence of HIF‐2α related gene mutations was generally low (

Strong quantum correlated sources are essential but delicate resources for quantum information science and engineering protocols. Decoherence and loss are the two main disruptive processes that lead to the loss of nonclassical behavior in quantum correlations. In quantum systems, scattering can contribute to both decoherence and loss. In this work, we present an experimental scheme capable of significantly mitigating the adverse impact of scattering in quantum systems. Our quantum system is composed of a two-mode squeezed light generated with the four-wave-mixing process in hot rubidium vapor and a scatterer is introduced to one of the two modes. An integrating sphere is then placed after the scatterer to recollect the scattered photons. We use mutual information between the two modes as the measure of quantum correlations and demonstrate a 47.5% mutual information recovery from scattering, despite an enormous photon loss of greater than 85%. Our scheme is the very first step toward recovering quantum correlations from disruptive random processes and thus has the potential to bridge the gap between proof-of-principle demonstrations and practical real-world implementations of quantum protocols.

Abstract Introduction Survivors of SARS‐CoV‐2 pneumonia often develop persistent respiratory symptom and interstitial lung abnormalities (ILAs) after infection. Risk factors for ILA development and duration of ILA persistence after SARS‐CoV‐2 infection are not well described in immunocompromised hosts, such as cancer patients. Methods We conducted a prospective cohort study of 95 patients at a major cancer center and 45 patients at a tertiary referral center. We collected clinical and radiographic data during the index hospitalization for COVID‐19 pneumonia and measured pneumonia severity using a semi‐quantitative radiographic score, the Radiologic Severity Index (RSI). Patients were evaluated in post‐COVID‐19 clinics at 3 and 6 months after discharge and underwent comprehensive pulmonary evaluations (symptom assessment, chest computed tomography, pulmonary function tests, 6‐min walk test). The association of clinical and radiological factors with ILAs at 3 and 6 months post‐discharge was measured using univariable and multivariable logistic regression. Results Sixty‐six (70%) patients of cancer cohort had ILAs at 3 months, of whom 39 had persistent respiratory symptoms. Twenty‐four (26%) patients had persistent ILA at 6 months after hospital discharge. In adjusted models, higher peak RSI at admission was associated with ILAs at 3 (OR 1.5 per 5‐point increase, 95% CI 1.1–1.9) and 6 months (OR 1.3 per 5‐point increase, 95% CI 1.1–1.6) post‐discharge. Fibrotic ILAs (reticulation, traction bronchiectasis, and architectural distortion) were more common at 6 months post‐discharge. Conclusions Post‐COVID‐19 ILAs are common in cancer patients 3 months after hospital discharge, and peak RSI and older age are strong predictors of persistent ILAs.

Abstract Background Frailty is a clinical syndrome of accelerated aging associated with adverse outcomes. Frailty is prevalent among patients with chronic kidney disease but is infrequently assessed in clinical settings, due to lack of consensus regarding frailty definitions and diagnostic tools. This study aimed to review the practice of frailty assessment in nephrology populations and evaluate the context and timing of frailty assessment. Methods The search included published reports of frailty assessment in patients with chronic kidney disease, undergoing dialysis or in receipt of a kidney transplant, published between January 2000 and November 2021. Medline, CINAHL, Embase, PsychINFO, PubMed and Cochrane Library databases were examined. A total of 164 articles were included for review. Results We found that studies were most frequently set within developed nations. Overall, 161 studies were frailty assessments conducted as part of an observational study design, and 3 within an interventional study. Studies favoured assessment of participants with chronic kidney disease (CKD) and transplant candidates. A total of 40 different frailty metrics were used. The most frequently utilised tool was the Fried frailty phenotype. Frailty prevalence varied across populations and research settings from 2.8% among participants with CKD to 82% among patients undergoing haemodialysis. Studies of frailty in conservatively managed populations were infrequent (N = 4). We verified that frailty predicts higher rates of adverse patient outcomes. There is sufficient literature to justify future meta-analyses. Conclusions There is increasing recognition of frailty in nephrology populations and the value of assessment in informing prognostication and decision-making during transitions in care. The Fried frailty phenotype is the most frequently utilised assessment, reflecting the feasibility of incorporating objective measures of frailty and vulnerability into nephrology clinical assessment. Further research examining frailty in low and middle income countries as well as first nations people is required. Future work should focus on interventional strategies exploring frailty rehabilitation.

In this digital era, customers in the insurance sector always look for better insurance products and services at an affordable price. When customers are unsure about service, they switch over to a better service provider. This behavior is more relevant to non-life insurance. However, the switching behavior of customers is hampered by certain switchover barriers such as “brand consciousness”, “brand pride”, “brand loyalty”, etc. This study focuses on exploring switching intentions and switching behaviors of adults in India keeping “brand love” as a mediator. A structured questionnaire was employed to collect the primary data from adults having non-life insurance products to analyze switching intentions and switching behaviors. The collected data were analyzed employing SPSS software and Hayes Process Model and appropriate statistical tools. The study results show that the switching intentions of adults vary based on their age, annual income, and education. Mean scores reveal that the lesser the age, the higher the intention to switch over. Further, based on annual income, adults who earn up to Rs 2 lakhs annually have more switching-over intentions (Mean score: 3.9719) followed by adults who earn Rs more than 2 lakhs to 5 lakhs annually (Mean score: 3.7590). Mean scores of education levels regarding switching intentions are higher among more educated adults and less among those who are qualified up to the school level.

Background: The 1064 nm Q-switched neodymium-doped yttrium aluminum garnet (QS Nd:YAG) laser was developed to treat unwanted pigmentation in the skin such as lentigines caused by photoaging, and tattoos from dye/ink insertion. This laser has also been used for non-ablative epidermal rejuvenation (skin toning). Objective: To evaluate changes in skin tone, skin texture and overall improvement after a series of treatments with the QS Nd:YAG laser. Methods: Participants received seven full-face treatments with M22 or Stellar M22, a 1064 nm QS Nd:YAG laser, at 2-week intervals. The investigators and participants evaluated the improvement in skin tone and texture at 1, 3 and 6 months after the last treatment. Patient satisfaction, patient discomfort, downtime and adverse events were recorded. Histological changes in the treated area were also evaluated. Results: Thirteen women with a median age of 45 years (range, 34–61 years) were included in the study. The majority of the participants (53.9%) had skin type VI. One month after the last treatment session, 38% of participants reported good to very good improvement. This value increased to 100% participant improvement at both the 3-month and 6-month follow-up visits. The reduction in melanin index and the histological analysis demonstrated that the laser procedure contributed to a reduction in epidermal melanin content. Treatments were not associated with high levels of pain or discomfort. The most common immediate post-treatment response was erythema and edema. Most participants were satisfied with the resulting treatment outcome. Conclusion: Skin treatment with the 1064 nm QS Nd:YAG laser module on the M22 and Stellar M22 devices, using a large spot size, low fluence, moderately high repetition rate, improves skin tone and texture in patients with skin types II–VI.

Quantum estimation of parameters defining open-system dynamics may be enhanced by using ancillas that are entangled with the probe but are not submitted to the dynamics. Here we consider the important problem of estimation of transmission of light by a sample, with losses due to absorption and scattering. We show, through the determination of the quantum Fisher information, that the ancilla strategy leads to the best possible precision in single-mode estimation—the one obtained for a Fock-state input—through joint photon counting of probe and ancilla, which are modes of a bimodal squeezed state produced by an optical parametric amplifier. This proposal overcomes the challenge of producing and detecting high-photon-number Fock states, and it is quite robust in the presence of additional noise: We show that it is immune to phase noise and the precision does not change if the incoming state gets disentangled. Furthermore, the quantum gain is still present under moderate photon losses of the input beams. We also discuss an alternative to joint photon counting, which is readily implementable with present technology and approaches the quantum Fisher information result for weak absorption, even with moderate photon losses of the input beams before the sample is probed: a time-reversal procedure, placing the sample between two optical parametric amplifiers, with the second undoing the squeezing produced by the first one. The precision of estimation of the loss parameter is obtained from the average outgoing total photon number and its variance. In both procedures, the state of the probe and the detection procedure are independent of the value of the parameter.

Summary: Background: Accurate prediction of side-specific extraprostatic extension (ssEPE) is essential for performing nerve-sparing surgery to mitigate treatment-related side-effects such as impotence and incontinence in patients with localised prostate cancer. Artificial intelligence (AI) might provide robust and personalised ssEPE predictions to better inform nerve-sparing strategy during radical prostatectomy. We aimed to develop, externally validate, and perform an algorithmic audit of an AI-based Side-specific Extra-Prostatic Extension Risk Assessment tool (SEPERA). Methods: Each prostatic lobe was treated as an individual case such that each patient contributed two cases to the overall cohort. SEPERA was trained on 1022 cases from a community hospital network (Trillium Health Partners; Mississauga, ON, Canada) between 2010 and 2020. Subsequently, SEPERA was externally validated on 3914 cases across three academic centres: Princess Margaret Cancer Centre (Toronto, ON, Canada) from 2008 to 2020; L'Institut Mutualiste Montsouris (Paris, France) from 2010 to 2020; and Jules Bordet Institute (Brussels, Belgium) from 2015 to 2020. Model performance was characterised by area under the receiver operating characteristic curve (AUROC), area under the precision recall curve (AUPRC), calibration, and net benefit. SEPERA was compared against contemporary nomograms (ie, Sayyid nomogram, Soeterik nomogram [non-MRI and MRI]), as well as a separate logistic regression model using the same variables included in SEPERA. An algorithmic audit was performed to assess model bias and identify common patient characteristics among predictive errors. Findings: Overall, 2468 patients comprising 4936 cases (ie, prostatic lobes) were included in this study. SEPERA was well calibrated and had the best performance across all validation cohorts (pooled AUROC of 0·77 [95% CI 0·75–0·78] and pooled AUPRC of 0·61 [0·58–0·63]). In patients with pathological ssEPE despite benign ipsilateral biopsies, SEPERA correctly predicted ssEPE in 72 (68%) of 106 cases compared with the other models (47 [44%] in the logistic regression model, none in the Sayyid model, 13 [12%] in the Soeterik non-MRI model, and five [5%] in the Soeterik MRI model). SEPERA had higher net benefit than the other models to predict ssEPE, enabling more patients to safely undergo nerve-sparing. In the algorithmic audit, no evidence of model bias was observed, with no significant difference in AUROC when stratified by race, biopsy year, age, biopsy type (systematic only vs systematic and MRI-targeted biopsy), biopsy location (academic vs community), and D'Amico risk group. According to the audit, the most common errors were false positives, particularly for older patients with high-risk disease. No aggressive tumours (ie, grade >2 or high-risk disease) were found among false negatives. Interpretation: We demonstrated the accuracy, safety, and generalisability of using SEPERA to personalise nerve-sparing approaches during radical prostatectomy. Funding: None.

Abstract Quantum entanglement has emerged as a great resource for spectroscopy and its importance in two-photon spectrum and microscopy has been demonstrated. Current studies focus on the two-photon absorption, whereas the Raman spectroscopy with quantum entanglement still remains elusive, with outstanding issues of temporal and spectral resolutions. Here we study the new capabilities provided by entangled photons in coherent Raman spectroscopy. An ultrafast frequency-resolved Raman spectroscopy with entangled photons is developed for condensed-phase molecules, to probe the electronic and vibrational coherences. Using quantum correlation between the photons, the signal shows the capability of both temporal and spectral resolutions not accessible by either classical pulses or the fields without entanglement. We develop a microscopic theory for this Raman spectroscopy, revealing the electronic coherence dynamics even at timescale of 50fs. This suggests new paradigms of optical signals and spectroscopy, with potential to push detection below standard quantum limit.

Background: A phase 1b study of photosensitizer TLD-1433–mediated photodynamic therapy (PDT) was performed in bacillus Calmette-Guérin (BCG)-unresponsive non–muscle-invasive bladder cancer (NMIBC) patients. Objective: The primary objectives were safety and tolerability of PDT, with secondary objectives of (1) pharmacokinetic (PK) properties of TLD-1433 and (2) efficacy, as evaluated by recurrence-free survival and complete response (CR) at 90 and 180 d for patients treated at the maximum recommended starting dose (0.35 mg/cm2 bladder surface area) and the therapeutic dose (0.70 mg/cm2). Design, setting, and participants: Six BCG-unresponsive patients were enrolled in an open-label, single-arm, dose-escalating study of PDT. TLD-1433 was instilled intravesically for 60 min preoperatively. PDT was performed under general anesthesia using intravesically delivered irradiation of the bladder wall with green light (520 nm) to a dose of 90 J/cm2. Outcome measurements and statistical analysis: Patients were followed by standard cystoscopy and cytology for up to 18 mo to assess time to recurrence. Results and limitations: PDT was well tolerated by all patients. All patients experienced at least one grade ≤2 adverse event (AE). There were no patient deaths or light sensitivity reactions. The most common AE was moderate bladder irritability, which resolved within the first weeks after treatment. AEs were independent of the TLD-1433 dose. TLD-1433 was cleared in the urine and from the plasma within 24 and 72 h, respectively. Of three patients treated at the therapeutic dose, two achieved a CR at 180 d, which was durable at 18 mo. The other patient was diagnosed with metastatic disease at 138 d. Conclusions: PDT with TLD-1433 appears safe for the treatment of BCG-unresponsive NMIBC. Early efficacy signals from full-dose photosensitizer are encouraging and warrant phase 2 trial investigation. The safety and PK results obtained support the potential for administration of consecutive PDT treatments as required. Patient summary: Photodynamic therapy with TLD-1433 appears to be safe and effective for the treatment of bacillus Calmette-Guérin (BCG)-unresponsive bladder cancer.

Lung cancer is the leading cause of cancer deaths in men and women in the United States. Accurate staging is needed to determine prognosis and devise effective treatment plans. The International Association for the Study of Lung Cancer (IASLC) has made multiple revisions to the tumor, node, metastasis (TNM) staging system used by the Union for International Cancer Control and the American Joint Committee on Cancer to stage lung cancer. The eighth edition of this staging system includes modifications to the T classification with cut points of 1 cm increments in tumor size, grouping of lung cancers associated with partial or complete lung atelectasis or pneumonitis, grouping of tumors with involvement of a main bronchus regardless of distance from the carina, and upstaging of diaphragmatic invasion to T4. The N classification describes the spread to regional lymph nodes and no changes were proposed for TNM-8. In the M classification, metastatic disease is divided into intra- versus extrathoracic metastasis, and single versus multiple metastases. In order to optimize patient outcomes, it is important to understand the nuances of the TNM staging system, the strengths and weaknesses of various imaging modalities used in lung cancer staging, and potential pitfalls in image interpretation.

Bound states in continuum (BICs) are states of a system possessing significantly large lifetimes with applications across various branches of science. In this work, we propose an expedient protocol to engineer BICs using the Kerr nonlinearities of a system which otherwise has no BICs. The generation of BICs is a direct artifact of the nonlinearity and the associated expansion in the dimensionality of the system. In particular, we consider single- and two-mode anharmonic systems and provide a number of solutions apposite for the creation of BICs. The nonlinearity-induced BICs can be controlled by external drive. In close vicinity to the BIC, the steady state response of the system is immensely sensitive to perturbations in natural frequencies of the system, and we illustrate its propitious sensing potential in the context of experimentally realizable setups for both optical and magnetic nonlinearities.

Radiation therapy using conventional or newer high-precision dose techniques, including three-dimensional conformal radiotherapy, intensity-modulated radiation therapy, stereotactic body radiation therapy, four-dimensional conformational radiotherapy, and proton therapy, is an important component of treating patients with lung cancer. Knowledge of the radiation technique used and the expected temporal evolution of radiation-induced lung injury, as well as patient-specific parameters such as previous radiotherapy, concurrent chemoradiotherapy, or immunotherapy, is important in image interpretation. This review discusses factors that affect the development and severity of radiation-induced lung injury and its radiological manifestations, as well as the differences between conventional and high-precision dose radiotherapy techniques.

Thin-section computed tomography (CT) has improved the detection of pericardial recesses and sinuses. Physiologic fluid in the pericardial recesses and sinuses can mimic mediastinal adenopathy. The misinterpretation of pericardial recesses and other benign pericardial entities in the oncologic setting can lead to inappropriate staging and management. Knowledge of the anatomy of the pericardium with emphasis on the imaging of different pericardial recesses on CT is important to avoid misdiagnosis, unnecessary further investigations, and/or biopsy.

IntroductionThe aim of our study was to assess the initial impact of COVID-19 on total publicly-funded direct healthcare costs and health services use in two Canadian provinces, Ontario and British Columbia (BC).MethodsThis retrospective repeated cross-sectional study used population-based administrative datasets, linked within each province, from January 1, 2018 to December 27, 2020. Interrupted time series analysis was used to estimate changes in the level and trends of weekly resource use and costs, with March 16-22, 2020 as the first pandemic week. Also, in each week of 2020, we identified cases with their first positive SARS-CoV-2 test and estimated their healthcare costs until death or December 27, 2020.ResultsThe resources with the largest level declines (95% confidence interval) in use in the first pandemic week compared to the previous week were physician services [Ontario: -43% (-49%,-37%); BC: -24% (-30%,-19%) (both pConclusionsReduced utilization of healthcare services in the overall population outweighed utilization by COVID-19 patients in 2020. Meeting the needs of all patients across all services is essential to maintain resilient healthcare systems.

Introduction: High pacing frequency or irregular activity due to arrhythmia produces complex optical mapping signals and challenges for processing. The objective is to establish an automated activation time-based analytical framework applicable to optical mapping images of complex electrical behavior.Methods: Optical mapping signals with varying complexity from sheep (N = 7) ventricular preparations were examined. Windows of activation centered on each action potential upstroke were derived using Hilbert transform phase. Upstroke morphology was evaluated for potential multiple activation components and peaks of upstroke signal derivatives defined activation time. Spatially and temporally clustered activation time points were grouped in to wave fronts for individual processing. Each activation time point was evaluated for corresponding repolarization times. Each wave front was subsequently classified based on repetitive or non-repetitive events. Wave fronts were evaluated for activation time minima defining sites of wave front origin. A visualization tool was further developed to probe dynamically the ensemble activation sequence.Results: Our framework facilitated activation time mapping during complex dynamic events including transitions to rotor-like reentry and ventricular fibrillation. We showed that using fixed AT windows to extract AT maps can impair interpretation of the activation sequence. However, the phase windowing of action potential upstrokes enabled accurate recapitulation of repetitive behavior, providing spatially coherent activation patterns. We further demonstrate that grouping the spatio-temporal distribution of AT points in to coherent wave fronts, facilitated interpretation of isolated conduction events, such as conduction slowing, and to derive dynamic changes in repolarization properties. Focal origins precisely detected sites of stimulation origin and breakthrough for individual wave fronts. Furthermore, a visualization tool to dynamically probe activation time windows during reentry revealed a critical single static line of conduction slowing associated with the rotation core.Conclusion: This comprehensive analytical framework enables detailed quantitative assessment and visualization of complex electrical behavior.

Concrete is a heterogeneous, complex composite construction material. Fresh property of concrete is a critical property with significant effect on quality , cost of construction, strength, and durability. Even to this day the workability of fresh concrete is measured by empirical test, notably by slump test in spite of its drawbacks and sometimes with misleading results with less practical significance. There is an urgent need to characterize the flow of fresh concrete b y its rheological properties based on material science approach to overcome the inadequacies of the empirical test methods.Fluid rheology approach is the most fundamental one and describes the concrete flow by at least two parameters namely yield stress and plastic viscosity by considering fresh concrete as a Bingham fluid. Understanding and controlling the two fundamental fresh properties of concrete allow for more economical and better performing concrete mixes with the use of wide range of ingredients.This paper brings out the importance of rheology and advocates the use of fundamental science approach with two parameter tests along with advantages and limitations of using rheometers. Also highlights the use of concrete shear box static tests for wide range of workability requirements with the use of new and marginal materials in concrete industry.

Background: Osteoarthritis of knee is one of the common conditions seen in older individuals and known to affect quality of life considerably. It makes it difficult for individuals with knee osteoarthritis to climb stairs, walk long distances, and stand for long time and squatting. In intractable cases not responding to conservative management surgical management such as proximal fibular Osteotomy (PFO) or high tibial Osteotomy (HTO) is routinely done. We conducted this comparative study to analyse the functional outcome of patients who had undergone HTO and PFO for medial compartment osteoarthritis of knee joint. Aims and Objectives: 1) To analyse the functional outcome of patients who had undergone HTO and PFO for medial compartment osteoarthritis of knee joint. 2) To compare complication rates in both the groups. Materials and Methods: A total of 60 patients with medial compartment knee osteoarthritis were included in this study on the basis of a predefined inclusion and exclusion criteria. Patients were randomized to 2 groups. Thirty patients undergoing proximal fibular osteotomy (Group A) and 30 patients undergoing high tibial osteotomy (Group B). The patients were followed up for improvements in functional outcome for 12 months. The statistical analysis was done using SSPS 21.0 software and p value less than 0.05 were taken as statistically significant. Results: Mean time for surgery was less for PFO surgery as compared to HTO and the difference was statistically significant. Moreover mean bleeding amount, drainage volume and time required for full weight bearing was low in PFO group as compared to HTO group and the difference was found to be statistically significant (P

Background:. ATX-101 is an injectable, synthetically derived formulation of deoxycholic acid used for submental fat reduction. Methods:. A narrative review of references relevant to the mechanism of action of ATX-101 and its relationship to efficacy and inflammatory adverse events was conducted. Results:. When injected into subcutaneous fat, deoxycholic acid physically disrupts adipocyte cell membranes, leading to local adipocytolysis, cell death, and a mild, local inflammatory reaction consisting of macrophage infiltration and fibroblast recruitment. At Day 28 postinjection, inflammation largely resolves, and key histologic features include fibrotic septal thickening, neovascularization, and atrophy of fat lobules. Based on the mechanism of action of ATX-101 and the demonstrated inflammatory response, localized inflammation and swelling are expected following treatment. Indeed, postinjection swelling and other local injection-site events, including pain, erythema, and bruising, are common during and after treatment. Because of inflammatory sequelae following injection, reduction in submental fat is gradual and may require months before the full response is apparent. Patients may also require multiple treatment sessions to achieve their treatment goals. Repeated treatments may result in less pain and swelling over time owing to a combination of factors, including less target tissue allowing for lower doses/injection volumes, persistent numbness, and greater tissue integrity from thickened fibrous septa. Conclusions:. Physicians can manage expectations by counseling patients that, based on the mechanism of action of ATX-101 and data from pivotal clinical trials, ATX-101 treatment results in localized inflammation/swelling and gradual submental fat reduction. Patient education about common local adverse events is critical.

Post-translational modifications (PTMs) are critical drivers and attenuators for proteins that regulate immune signalling cascades in host defence. In this review, we explore functional roles for one such PTM, the small ubiquitin-like modifier (SUMO). Very few of the SUMO conjugation targets identified by proteomic studies have been validated in terms of their roles in host defence. Here, we compare and contrast potential SUMO substrate proteins in immune signalling for flies and mammals, with an emphasis on NFκB pathways. We discuss, using the few mechanistic studies that exist for validated targets, the effect of SUMO conjugation on signalling and also explore current molecular models that explain regulation by SUMO. We also discuss in detail roles of evolutionary conservation of mechanisms, SUMO interaction motifs, crosstalk of SUMO with other PTMs, emerging concepts such as group SUMOylation and finally, the potentially transforming roles for genome-editing technologies in studying the effect of PTMs.

Post-translational modification by the small ubiquitin-like modifier, SUMO can modulate the activity of its conjugated proteins in a plethora of cellular contexts. The effect of SUMO conjugation of proteins during an immune response is poorly understood in Drosophila. We have previously identified that the transcription factor Jra, the Drosophila Jun ortholog and a member of the AP-1 complex is one such SUMO target. Here, we find that Jra is a regulator of the Pseudomonas entomophila induced gut immune gene regulatory network, modulating the expression of a few thousand genes, as measured by quantitative RNA sequencing. Decrease in Jra in gut enterocytes is protective, suggesting that reduction of Jra signaling favors the host over the pathogen. In Jra, lysines 29 and 190 are SUMO conjugation targets, with the JraK29R+K190R double mutant being SUMO conjugation resistant (SCR). Interestingly, a JraSCR fly line, generated by CRISPR/Cas9 based genome editing, is more sensitive to infection, with adults showing a weakened host response and increased proliferation of Pseudomonas. Transcriptome analysis of the guts of JraSCR and JraWT flies suggests that lack of SUMOylation of Jra significantly changes core elements of the immune gene regulatory network, which include antimicrobial agents, secreted ligands, feedback regulators, and transcription factors. Mechanistically, SUMOylation attenuates Jra activity, with the TFs, forkhead, anterior open, activating transcription factor 3 and the master immune regulator Relish being important transcriptional targets. Our study implicates Jra as a major immune regulator, with dynamic SUMO conjugation/deconjugation of Jra modulating the kinetics of the gut immune response.

Imaging is integral in the management of patients with thymoma and thymic carcinoma. At initial diagnosis and staging, imaging provides the clinical extent of local invasion as well as distant metastases to stratify patients for therapy and to determine prognosis. Following various modalities of therapy, imaging serves to assess treatment response and detect recurrent disease. While imaging findings overlap, a variety of CT, MRI, and PET/CT characteristics can help differentiate thymoma and thymic carcinoma, with new CT and MRI techniques currently under evaluation showing potential.

Abstract Background Single‐arm trials are currently an accepted study design to investigate the efficacy of novel therapies (NT) in non‐muscle invasive bladder cancer (NMIBC) unresponsive to intravesical Bacillus Calmette‐Guérin (BCG) immunotherapy as randomized controlled trials are either unfeasible (comparator: early radical cystectomy; ERC), or unethical (comparator: placebo). To guide the design of such single‐arm trials, expert groups published recommendations for clinically meaningful outcomes. The aim of this study was to quantitatively verify the appropriateness of these recommendations. Methods We used a discrete event simulation framework in combination with a supercomputer to find the required efficacy at which a NT can compete with ERC when it comes to quality‐adjusted life expectancy (QALE). In total, 24 different efficacy thresholds (including the recommendations) were investigated. Results After ascertaining face validity with content experts, repeated verification, external validation, and calibration we considered our model valid. Both recommendations rarely showed an incremental benefit of the NT over ERC. In the most optimistic scenario, an increase in the IBCG recommendation by 10% and an increase in the FDA/AUA recommendation by 5% would yield results at which a NT could compete with ERC from a QALE perspective. Conclusions This simulation study demonstrated that the current recommendations regarding clinically meaningful outcomes for single‐arm trials evaluating the efficacy of NT in BCG‐unresponsive NMIBC may be too low. Based on our quantitative approach, we propose increasing these thresholds to at least 45%‐55% at 6 months and 35% at 18‐24 months (complete response rates/recurrence‐free survival) to promote the development of clinically truly meaningful NT.

The COVID-19 pandemic has taken tragic proportions and has disrupted lives globally. In the wake of governmental lockdowns, ophthalmologists need practical and actionable guidelines based on advisories from national health departments on how to conduct their duties during nationwide lockdowns and after these are lifted. In this paper, we present a preferred practice pattern (PPP) based on consensus discussions between leading ophthalmologists and health care professionals in India including representatives from major governmental and private institutions as well as the All India Ophthalmological Society leadership. In this document, the expert panel clearly defines the range of activities for Indian ophthalmologists during the ongoing lockdown phase and precautions to be taken once the lockdown is lifted. Guidelines for triage, governmental guidelines for use of personal protective equipment from ophthalmologists' point of view, precautions to be taken in the OPD and operating room as well as care of various ophthalmic equipment have been described in detail. These guidelines will be applicable to all practice settings including tertiary institutions, corporate and group practices and individual eye clinics and should help Indian ophthalmologists in performing their professional responsibilities without being foci of disease transmission.

Advanced cancers of oral tongue and recurrent/residual tumors arising from base of tongue may require total glossectomy for curative intent treatment. This procedure is considered morbid due to possibility of life threatening aspiration. This review discusses the technical nuances to reduce functional morbidity. The pull through resection technique allows a compartmental resection of these tumors with adequate margin control without a need for mandibulotomy. Selection of appropriate flap to replace bulk and laryngeal suspension are essential components of reconstruction. With application of these technical advances and adequate post-operative swallow therapy, patients undergoing total glossectomy have acceptable functional outcome.

Introduction: Surgical site infection (SSI) is one of the most common hospitals acquired infection. The present study describes resistogram of bacterial pathogens in SSIs in the hospitals in and around Sangli, Maharashtra, India. Materials and Methods: The resistogram pattern was studied by modified Kirby-Bauer disc diffusion method. Results: A total of 1491 pus samples from patients clinically diagnosed of SSIs were processed and 911 isolates were obtained. The most common Gram-positive isolates were Staphylococcus aureus(53.92%), coagulase-negative Staphylococci (31.17%), Enterococcus (10.58%), and Streptococcus pyogens (4.31%); while Gram-negative isolates were Escherichia coli (33.16%), Klebsiella spp. (28.92%), Citrobacter species (4.98%), Pseudomonas aeruginosa (12.96%), Acinetobacter species (1.99%), Proteus mirabilis (10.97%), and Proteus vulgaris (6.98%). The frequency of methicillin-resistant S. aureus (MRSA) was 28% whereas the frequency of methicillin sensitive S. aureus was 72%. The MRSA showed multidrug resistance pattern. Conclusion: Twenty-eight percent are MRSA which showed multidrug resistance pattern. While most of the Gram-positive isolates were resistance toward the amoxicillin/clavulanate, gentamicin, and ceftriaxone. Most of the Gram-negative isolates were resistant to ampicillin, ciprofloxacin and ceftriaxone.

The essential micronutrient Selenium (Se) is co-translationally incorporated as selenocysteine into proteins. Selenoproteins contain one or more selenocysteines and are vital for optimum immunity. Interestingly, many pathogenic bacteria utilize Se for various biological processes suggesting that Se may play a role in bacterial pathogenesis. A previous study had speculated that Francisella tularensis, a facultative intracellular bacterium and the causative agent of tularemia, sequesters Se by upregulating Se-metabolism genes in type II alveolar epithelial cells. Therefore, we investigated the contribution of host vs. pathogen-associated selenoproteins in bacterial disease using F. tularensis as a model organism. We found that F. tularensis was devoid of any Se utilization traits, neither incorporated elemental Se, nor exhibited Se-dependent growth. However, 100% of Se-deficient mice (0.01 ppm Se), which express low levels of selenoproteins, succumbed to F. tularensis-live vaccine strain pulmonary challenge, whereas 50% of mice on Se-supplemented (0.4 ppm Se) and 25% of mice on Se-adequate (0.1 ppm Se) diet succumbed to infection. Median survival time for Se-deficient mice was 8 days post-infection while Se-supplemented and -adequate mice was 11.5 and >14 days post-infection, respectively. Se-deficient macrophages permitted significantly higher intracellular bacterial replication than Se-supplemented macrophages ex vivo, corroborating in vivo observations. Since Francisella replicates in alveolar macrophages during the acute phase of pneumonic infection, we hypothesized that macrophage-specific host selenoproteins may restrict replication and systemic spread of bacteria. F. tularensis infection led to an increased expression of several macrophage selenoproteins, suggesting their key role in limiting bacterial replication. Upon challenge with F. tularensis, mice lacking selenoproteins in macrophages (TrspM) displayed lower survival and increased bacterial burden in the lung and systemic tissues in comparison to WT littermate controls. Furthermore, macrophages from TrspM mice were unable to restrict bacterial replication ex vivo in comparison to macrophages from littermate controls. We herein describe a novel function of host macrophage-specific selenoproteins in restriction of intracellular bacterial replication. These data suggest that host selenoproteins may be considered as novel targets for modulating immune response to control a bacterial infection.

SUMO conjugation of a substrate protein can modify its activity, localization, interaction or function. A large number of SUMO targets in cells have been identified by Proteomics, but biological roles for SUMO conjugation for most targets remains elusive. The multi-aminoacyl tRNA synthetase complex (MARS) is a sensor and regulator of immune signaling. The proteins of this 1.2 MDa complex are targets of SUMO conjugation, in response to infection. Arginyl tRNA Synthetase (RRS), a member of the sub-complex II of MARS, is one such SUMO conjugation target. The sites for SUMO conjugation are Lys 147 and 383. Replacement of these residues by Arg (RRSK147R,K383R), creates a SUMO conjugation resistant variant (RRSSCR). Transgenic Drosophila lines for RRSWT and RRSSCR were generated by expressing these variants in a RRS loss of function (lof) animal, using the UAS-Gal4 system. The RRS-lof line was itself generated using CRISPR/Cas9 genome editing. Expression of both RRSWT and RRSSCR rescue the RRS-lof lethality. Adult animals expressing RRSWT and RRSSCR are compared and contrasted for their response to bacterial infection by gram positive M. luteus and gram negative Ecc15. We find that RRSSCR, when compared to RRSWT, shows modulation of the transcriptional response, as measured by quantitative 3′ mRNA sequencing. Our study uncovers a possible non-canonical role for SUMOylation of RRS, a member of the MARS complex, in host-defense.

Vitamin D supplementation is linked to improved outcomes from respiratory virus infection, and the COVID-19 pandemic renewed interest in understanding the potential role of vitamin D in protecting the lung from viral infections. Therefore, we evaluated the role of vitamin D using animal models of pandemic H1N1 influenza and severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) infection. In mice, dietary-induced vitamin D deficiency resulted in lung inflammation that was present prior to infection. Vitamin D sufficient (D+) and deficient (D−) wildtype (WT) and D+ and D− Cyp27B1 (Cyp) knockout (KO, cannot produce 1,25(OH)2D) mice were infected with pandemic H1N1. D− WT, D+ Cyp KO, and D− Cyp KO mice all exhibited significantly reduced survival compared to D+ WT mice. Importantly, survival was not the result of reduced viral replication, as influenza M gene expression in the lungs was similar for all animals. Based on these findings, additional experiments were performed using the mouse and hamster models of SARS-CoV-2 infection. In these studies, high dose vitamin D supplementation reduced lung inflammation in mice but not hamsters. A trend to faster weight recovery was observed in 1,25(OH)2D treated mice that survived SARS-CoV-2 infection. There was no effect of vitamin D on SARS-CoV-2 N gene expression in the lung of either mice or hamsters. Therefore, vitamin D deficiency enhanced disease severity, while vitamin D sufficiency/supplementation reduced inflammation following infections with H1N1 influenza and SARS-CoV-2.

Abstract Background A male gender driven obesity paradox (improved survival for overweight/obese patients compared to normal weight) was recently shown in melanoma in the context of checkpoint inhibition (anti-PD-1/anti-CTLA4 monotherapy) in a pooled meta-analysis. We characterized the relationship of Body Mass Index (BMI) with survival and explored gender-based interactions with surrogates of body composition/malnutrition in the context of PD-1 blockade as monotherapy or in combination with ipilimumab in a real-world setting. Methods Advanced melanoma patients who received at least one dose of pembrolizumab, nivolumab, or nivolumab plus ipilimumab (combination) from June 2014 to September 2016 were included in this retrospective cohort study (N = 139). Overall Survival (OS) and Progression Free Survival (PFS) were the main outcomes. Analysis was performed using Random Survival Forests (RSF)/ multivariable Cox Proportional-Hazards models. Results Overweight/Class-I (25-

BackgroundNon-schistosomiasis related-squamous cell carcinoma of urinary bladder (NSR-SCCUB) is a rare tumor subtype distinct from urothelial carcinoma (UC). Studies assessing molecular biomarkers in bladder cancer have generally focused on UC, and genomic data of NSR-SCCUB is limited. We aim to provide additional insight into the molecular underpinnings of this rare entity.MethodsNSR-SCCUB patients were identified retrospectively at Princess Margaret Cancer Centre between 2002 and 2017. Demographics, disease characteristics, therapeutic approaches, and outcomes were collected. Tissue samples were interrogated using the Oncomine Comprehensive Assay v3 (ThermoFisher). Kaplan-Meier method was used to estimate the disease-free survival and overall survival (OS).ResultsOverall, 11 patients with NSR-SCCUB were identified between 2002 and 2017 with adequate tissue samples. Median age was 71 years (45-86), predominantly male (63.6%). At time of diagnosis, 9 patients (81.8%) had muscle-invasive disease, 1 (9.1%) had non-muscle invasive, and 1 (9.1%) had advanced disease. Nine (81.8%) patients had radical cystectomy and pelvic lymph nodes dissection. Eight (72.7%) patients had pT3 or pT4 with N0, and 5 (45.5%) were grade 3. Median OS was 12.5 months (95% CI 7.7-17.2 months). Single nucleotide variants or insertion/deletions were identified in TP53, TERT, PIK3CA, PTEN, CREBBP, FBXW7, and FGFR3. Amplifications were found in CCND1, and EGFR.ConclusionsNSR-SCCUB has potentially actionable genomic alterations with anticancer agents and many of these aberrations are also seen in UC. The recruitment of NSR-SCCUB patients harboring such mutations should be considered in biomarker driven urinary bladder cancer studies.

BackgroundThe Government of Ontario, Canada, announced hospital funding reforms in 2011, including Quality-based Procedures (QBPs) involving pre-set funds for managing patients with specific diagnoses/procedures. A key goal was to improve quality of care across the jurisdiction.MethodsInterrupted time series evaluated the policy change, focusing on four QBPs (congestive heart failure, hip fracture surgery, pneumonia, prostate cancer surgery), on patients hospitalized 2010-2017. Outcomes included return to hospital or death within 30 days, acute length of stay (LOS), volume of admissions, and patient characteristics.ResultsAt 2 years post-QBPs, the percentage of hip fracture patients who returned to hospital or died was 3.13% higher in absolute terms (95% CI: 0.37% to 5.89%) than if QBPs had not been introduced. There were no other statistically significant changes for return to hospital or death. For LOS, the only statistically significant change was an increase for prostate cancer surgery of 0.33 days (95% CI: 0.07 to 0.59). Volume increased for congestive heart failure admissions by 80 patients (95% CI: 2 to 159) and decreased for hip fracture surgery by 138 patients (95% CI: -183 to -93) but did not change for pneumonia or prostate cancer surgery. The percentage of patients who lived in the lowest neighborhood income quintile increased slightly for those diagnosed with congestive heart failure (1.89%; 95% CI: 0.51% to 3.27%) and decreased for those who underwent prostate cancer surgery (-2.08%; 95% CI: -3.74% to -0.43%).InterpretationThis policy initiative involving a change to hospital funding for certain conditions was not associated with substantial, jurisdictional-level changes in access or quality.

Proper specification of germline stem cells (GSCs) in Drosophila ovaries depends on niche derived non-autonomous signaling and cell autonomous components of transcriptional machinery. Stonewall (Stwl), a MADF-BESS family protein, is one of the cell intrinsic transcriptional regulators involved in the establishment and/or maintenance of GSC fate in Drosophila ovaries. Here we report identification and functional characterization of another member of the same protein family, CG3838/ Brickwall (Brwl) with analogous functions. Loss of function alleles of brwl exhibit age dependent progressive degeneration of the developing ovarioles and loss of GSCs. Supporting the conclusion that the structural deterioration of mutant egg chambers is a result of apoptotic cell death, activated caspase levels are considerably elevated in brwl- ovaries. Moreover, as in the case of stwl mutants, on several instances, loss of brwl activity results in fusion of egg chambers and misspecification of the oocyte. Importantly, brwl phenotypes can be partially rescued by germline specific over-expression of stwl arguing for overlapping yet distinct functional capabilities of the two proteins. Taken together with our phylogenetic analysis, these data suggest that brwl and stwl likely share a common MADF-BESS ancestor and they are expressed in overlapping spatiotemporal domains to ensure robust development of the female germline.

Purpose: Precision radiation therapy such as stereotactic body radiation therapy and limited resection are being used more frequently to treat intrathoracic malignancies. Effective local control requires precise radiation target delineation or complete resection. Lung biopsy tracts (LBT) on computed tomography (CT) scans after the use of tract sealants can mimic malignant tract seeding (MTS) and it is unclear whether these LBTs should be included in the calculated tumor volume or resected. This study evaluates the incidence, appearance, evolution, and malignant seeding of LBTs. Methods and materials: A total of 406 lung biopsies were performed in oncology patients using a tract sealant over 19 months. Of these patients, 326 had follow-up CT scans and were included in the study group. Four thoracic radiologists retrospectively analyzed the imaging, and a pathologist examined 10 resected LBTs. Results: A total of 234 of 326 biopsies (72%, including primary lung cancer [n = 98]; metastases [n = 81]; benign [n = 50]; and nondiagnostic [n = 5]) showed an LBT on CT. LBTs were identified on imaging 0 to 3 months after biopsy. LBTs were typically straight or serpiginous with a thickness of 2 to 5 mm. Most LBTs were unchanged (92%) or decreased (6.3%) over time. An increase in LBT thickness/nodularity that was suspicious for MTS occurred in 4 of 234 biopsies (1.7%). MTS only occurred after biopsy of metastases from extrathoracic malignancies, and none occurred in patients with lung cancer. Conclusions: LBTs are common on CT after lung biopsy using a tract sealant. MTS is uncommon and only occurred in patients with extrathoracic malignancies. No MTS was found in patients with primary lung cancer. Accordingly, potential alteration in planned therapy should be considered only in patients with LBTs and extrathoracic malignancies being considered for stereotactic body radiation therapy or wedge resection.