RESUMEN

Designing faithful yet accurate AI models is challenging, particularly in the field of individual treatment effect estimation (ITE). ITE prediction models deployed in critical settings such as healthcare should ideally be (i) accurate, and (ii) provide faithful explanations. However, current solutions are inadequate: state-of-the-art black-box models do not supply explanations, post-hoc explainers for black-box models lack faithfulness guarantees, and self-interpretable models greatly compromise accuracy. To address these issues, we propose DISCRET, a self-interpretable ITE framework that synthesizes faithful, rule-based explanations for each sample. A key insight behind DISCRET is that explanations can serve dually as database queries to identify similar subgroups of samples. We provide a novel RL algorithm to efficiently synthesize these explanations from a large search space. We evaluate DISCRET on diverse tasks involving tabular, image, and text data. DISCRET outperforms the best self-interpretable models and has accuracy comparable to the best black-box models while providing faithful explanations. DISCRET is available at https://github.com/wuyinjun-1993/DISCRET-ICML2024.

RESUMEN

BACKGROUND: Medical professionals experienced high rates of burnout and moral distress during the COVID-19 pandemic. In Canada, burnout has been linked to a growing number of family physicians (FPs) leaving the workforce, increasing the number of patients without access to a regular doctor. This study explores the different factors that impacted FPs' experience with burnout and moral distress during the pandemic, with the goal of identifying system-based interventions aimed at supporting FP well-being and improving retention. METHODS: We conducted semi-structured qualitative interviews with FPs across four health regions in Canada. Participants were asked about the roles they assumed during different stages of the pandemic, and they were also encouraged to describe their well-being, including relevant supports and barriers. We used thematic analysis to examine themes relating to FP mental health and well-being. RESULTS: We interviewed 68 FPs across the four health regions. We identified two overarching themes related to moral distress and burnout: (1) inability to provide appropriate care, and (2) system-related stressors and buffers of burnout. FPs expressed concern about the quality of care their patients were able to receive during the pandemic, citing instances where pandemic restrictions limited their ability to access critical preventative and diagnostic services. Participants also described four factors that alleviated or exacerbated feelings of burnout, including: (1) workload, (2) payment model, (3) locum coverage, and (4) team and peer support. CONCLUSION: The COVID-19 pandemic limited FPs' ability to provide quality care to patients, and contributed to increased moral distress and burnout. These findings highlight the importance of implementing system-wide interventions to improve FP well-being during public health emergencies. These could include the expansion of interprofessional team-based models of care, alternate remuneration models for primary care (ie, non-fee-for-service), organized locum programs, and the availability of short-term insurance programs to cover fixed practice operating costs.

Asunto(s)

RESUMEN

PURPOSE: To develop a generalized signal model for dual-module velocity-selective arterial spin labeling (dm-VSASL) that can integrate arbitrary saturation and inversion profiles. THEORY AND METHODS: A recently developed mathematical framework for single-module VSASL is extended to address the increased complexity of dm-VSASL and to model the use of realistic velocity-selective profiles in the label-control and vascular crushing modules. Expressions for magnetization difference, arterial delivery functions, labeling efficiency, and cerebral blood flow (CBF) estimation error are presented. Sources of error are examined and timing requirements to minimize quantification errors are derived. RESULTS: For ideal velocity-selective profiles, the predicted signals match those of prior work. With realistic profiles, a CBF-dependent estimation error can occur when velocity-selective inversion (VSI) is used for the labeling modules and velocity-selective saturation (VSS) is used for the vascular crushing module. The error reflects a mismatch between the leading and trailing edges of the delivery function for the second bolus and can be minimized by choosing a nominal labeling cutoff velocity that is lower than the nominal saturation cutoff velocity. In the presence of B 0 $$ {\mathrm{B}}_0 $$ and B 1 $$ {\mathrm{B}}_1 $$ inhomogeneities, the labeling efficiency of dual-module VSI is more attenuated than that of dual-module VSS. CONCLUSION: The proposed signal model will enable researchers to more accurately assess and compare the performance of realistic dm-VSASL implementations and improve the quantification of dm-VSASL CBF measures.

RESUMEN

Background: While directionally rotating tumor-treating fields (TTF) therapy has garnered considerable clinical interest in recent years, there has been comparatively less focus on directionally non-rotating electric field therapy (dnEFT). Methods: We explored dnEFT generated through customized electrodes as a glioblastoma therapy in in vitro and in vivo preclinical models. The effects of dnEFT on tumor apoptosis and microglia/macrophages in the tumor microenvironment were tested using flow-cytometric and qPCR assays. Results: In vitro, dnEFT generated using a clinical-grade spinal cord stimulator showed antineoplastic activity against independent glioblastoma cell lines. In support of the results obtained using the clinical-grade electrode, dnEFT delivered through a customized, 2-electrode array induced glioblastoma apoptosis. To characterize this effect in vivo, a custom-designed 4-electrode array was fabricated such that tumor cells can be implanted into murine cerebrum through a center channel equidistant from the electrodes. After implantation with this array and luciferase-expressing murine GL261 glioblastoma cells, mice were randomized to dnEFT or placebo. Relative to placebo-treated mice, dnEFT reduced tumor growth (measured by bioluminescence) and prolonged survival (median survival gain of 6.5 days). Analysis of brain sections following dnEFT showed a notable increase in the accumulation of peritumoral macrophage/microglia with increased expression of M1 genes (IFNγ, TNFα, and IL-6) and decreased expression of M2 genes (CD206, Arg, and IL-10) relative to placebo-treated tumors. Conclusions: Our results suggest therapeutic potential in glioblastoma for dnEFT delivered through implanted electrodes, supporting the development of a proof-of-principle clinical trial using commercially available deep brain stimulator electrodes.

RESUMEN

PURPOSE: To mitigate the B0/B1 + sensitivity of velocity-selective inversion (VSI) pulse trains for velocity-selective arterial spin labeling (VSASL) by implementing adiabatic refocusing. This approach aims to achieve artifact-free VSI-based perfusion imaging through single-pair label-control subtractions, reducing the need for the currently required four-pair dynamic phase-cycling (DPC) technique when using a velocity-insensitive control. METHODS: We introduce a Fourier-transform VSI (FT-VSI) train that incorporates sinc-modulated hard excitation pulses with MLEV-8-modulated adiabatic hyperbolic secant refocusing pairs. We compare performance between this train and the standard composite refocusing train, including with and without DPC, for dual-module VSI VSASL. We evaluate (1) simulated velocity-selective profiles and subtraction fidelity across a broad B0/B1 + range, (2) subtraction fidelity in phantoms, and (3) image quality, artifact presence, and gray-matter perfusion heterogeneity (as measured by the spatial coefficient of variation) in healthy human subjects. RESULTS: Adiabatic refocusing significantly improves FT-VSI robustness to B0/B1 + inhomogeneity for a single label-control subtraction. Subtraction fidelity is dramatically improved in both simulation and phantoms compared with composite refocusing without DPC, and is similar compared with DPC methods. In humans, marked artifacts seen with the non-DPC composite refocusing approach are eliminated, corroborated by significantly reduced gray-matter heterogeneity (via lower spatial coefficient of variation values). CONCLUSION: A novel VSASL labeling train using adiabatic refocusing pulses for VSI was found to reduce artifacts related to B0/B1 + inhomogeneity, thereby providing an alternative to DPC and its associated limitations, which include increased vulnerability to physiological noise and motion, reduced functional MRI applicability, and suboptimal data censoring.

Asunto(s)

RESUMEN

INTRODUCTION: Assessments with strong validity evidence are necessary to accurately assess health professions students' performance of clinical skills. The aim of this study was to develop and validate a checklist assessment of physical therapy students' performance of bed mobility skills. METHODS: A checklist was developed using a 4-step process: 1) evidence review and preliminary checklist development, 2) Delphi review to reach consensus on content, 3) pilot testing and checklist editing, 4) final round of Delphi review. Consensus during Delphi review was defined as 100% of participants rating an item "keep as is" and zero comments in Round 1, and >50% of participants rating each item agree/strongly agree in subsequent Delphi rounds. Interrater reliability (IRR) was measured by two raters scoring 32 recorded exam simulations. RESULTS: All 48 items of the checklist reached consensus after three rounds of Delphi review (12 participants in Round 1, 11 participants in Rounds 2-3). IRR was substantial with 88.5% agreement, Cohen's kappa coefficient=0.61, p<0.001, 95% CI [0.56, 0.66]. DISCUSSION: This checklist has potential to be used to assess student readiness to evaluate and train patients in bed mobility tasks for first-time clinical experiences and to serve as a methodological template for future checklist development.

Asunto(s)

Asunto(s)

RESUMEN

Introduction: Throughout the COVID-19 pandemic, primary care nurses were often redeployed to areas outside of primary care to mitigate staffing shortages. Despite this, there is a scarcity of literature describing their perceptions of and experiences with redeployment during the pandemic. Objectives: This paper aims to: 1) describe the perspectives of primary care nurses with respect to redeployment, 2) discuss the opportunities/challenges associated with redeployment of primary care nurses, and 3) examine the nature (e.g., settings, activities) of redeployment by primary care nurses during the COVID-19 pandemic. Methods: In this qualitative study, semi-structured interviews were conducted with primary care nurses (i.e., Nurse Practitioners, Registered Nurses, and Licensed/Registered Practical Nurses), from four regions in Canada. These include the Interior, Island, and Vancouver Coastal Health regions in British Columbia; Ontario Health West region in Ontario; the province of Nova Scotia; and the province of Newfoundland and Labrador. Data related to redeployment were analyzed thematically. Results: Three overarching themes related to redeployment during the COVID-19 pandemic were identified: (1) Call to redeployment, (2) Redeployment as an opportunity/challenge, and (3) Scope of practice during redeployment. Primary care nurses across all regulatory designations reported variation in the process of redeployment within their jurisdiction (e.g., communication, policies/legislation), different opportunities and challenges that resulted from redeployment (e.g., scheduling flexibility, workload implications), and scope of practice implications (e.g., perceived threat to nursing license). The majority of nurses discussed experiences with redeployment being voluntary in nature, rather than mandated. Conclusions: Redeployment is a useful workforce strategy during public health emergencies; however, it requires a structured process and a decision-making approach that explicitly involves healthcare providers affected by redeployment. Primary care nurses ought only to be redeployed after other options are considered and arrangements made for the care of patients in their original practice area.

RESUMEN

A new class of amphiphilic tetradentate platinum(ii) Schiff base complexes has been designed and synthesized. The self-assembly properties by exploiting the potential Pt⋯Pt interactions of amphiphilic platinum(ii) Schiff base complexes in the solution state have been systematically investigated. The presence of Pt⋯Pt interactions has further been supported by computational studies and non-covalent interaction (NCI) analysis of the dimer of the complex. The extent of the non-covalent Pt⋯Pt and π-π interactions could be regulated by a variation of the solvent compositions and the hydrophobicity of the complexes, which is accompanied by attractive spectroscopic and luminescence changes and leads to diverse morphological transformations. The present work represents a rare example of demonstration of directed cooperative assembly of amphiphilic platinum(ii) Schiff base complexes by intermolecular Pt⋯Pt interactions in solution with an in-depth mechanistic investigation, providing guiding principles for the construction of supramolecular structures with desirable properties using platinum(ii) Schiff base building blocks.

RESUMEN

BACKGROUND: Over the past two decades, Canadian provinces and territories have introduced a series of primary care reforms in an attempt to improve access to and quality of primary care services, resulting in diverse organizational structures and practice models. We examine the impact of these reforms on family physicians' (FPs) ability to adapt their roles during the COVID-19 pandemic, including the provision of routine primary care. METHODS: As part of a larger case study, we conducted semi-structured qualitative interviews with FPs in four Canadian regions: British Columbia, Newfoundland and Labrador, Nova Scotia, and Ontario. During the interviews, participants were asked about their personal and practice characteristics, the pandemic-related roles they performed over different stages of the pandemic, the facilitators and barriers they experienced in performing these roles, and potential roles FPs could have filled. Interviews were transcribed and a thematic analysis approach was applied to identify recurring themes in the data. RESULTS: Sixty-eight FPs completed an interview across the four regions. Participants described five areas of primary care reform that impacted their ability to operate and provide care during the pandemic: funding models, electronic medical records (EMRs), integration with regional entities, interdisciplinary teams, and practice size. FPs in alternate funding models experienced fewer financial constraints than those in fee-for-service practices. EMR access enhanced FPs' ability to deliver virtual care, integration with regional entities improved access to personal protective equipment and technological support, and team-based models facilitated the implementation of infection prevention and control protocols. Lastly, larger group practices had capacity to ensure adequate staffing and cover additional costs, allowing FPs more time to devote to patient care. CONCLUSIONS: Recent primary care system reforms implemented in Canada enhanced FPs' ability to adapt to the uncertain and evolving environment of providing primary care during the pandemic. Our study highlights the importance of ongoing primary care reforms to enhance pandemic preparedness and advocates for further expansion of these reforms.

Asunto(s)

RESUMEN

Tumor-treating fields (TTFields) are currently a Category 1A treatment recommendation by the US National Comprehensive Cancer Center for patients with newly diagnosed glioblastoma. Although the mechanism of action of TTFields has been partly elucidated, tangible and standardized metrics are lacking to assess antitumor dose and effects of the treatment. This paper outlines and evaluates the current standards and methodologies in the estimation of the TTFields distribution and dose measurement in the brain and highlights the most important principles governing TTFields dosimetry. The focus is on clinical utility to facilitate a practical understanding of these principles and how they can be used to guide treatment. The current evidence for a correlation between TTFields dose, tumor growth, and clinical outcome will be presented and discussed. Furthermore, we will provide perspectives and updated insights into the planning and optimization of TTFields therapy for glioblastoma by reviewing how the dose and thermal effects of TTFields are affected by factors such as tumor location and morphology, peritumoral edema, electrode array position, treatment duration (compliance), array "edge effect," electrical duty cycle, and skull-remodeling surgery. Finally, perspectives are provided on how to optimize the efficacy of future TTFields therapy.

RESUMEN

A complex networked system typically has a time-varying nature in interactions among its components, which is intrinsically complicated and therefore technically challenging for analysis and control. This paper investigates an epidemic process on a time-varying network with a time delay. First, an averaging theorem is established to approximate the delayed time-varying system using autonomous differential equations for the analysis of system evolution. On this basis, the critical time delay is determined, across which the endemic equilibrium becomes unstable and a phase transition to oscillation in time via Hopf bifurcation will appear. Then, numerical examples are examined, including a periodically time-varying network, a blinking network, and a quasi-periodically time-varying network, which are simulated to verify the theoretical results. Further, it is demonstrated that the existence of time delay can extend the network frequency range to generate Turing patterns, showing a facilitating effect on phase transitions.

Asunto(s)

RESUMEN

BACKGROUND: Admission avoidance hospital at home provides active treatment by healthcare professionals in the patient's home for a condition that would otherwise require acute hospital inpatient care, and always for a limited time period. This is the fourth update of this review. OBJECTIVES: To determine the effectiveness and cost of managing patients with admission avoidance hospital at home compared with inpatient hospital care. SEARCH METHODS: We searched the Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE, Embase, and CINAHL on 24 February 2022, and checked the reference lists of eligible articles. We sought ongoing and unpublished studies by searching ClinicalTrials.gov and WHO ICTRP, and by contacting providers and researchers involved in the field. SELECTION CRITERIA: Randomised controlled trials recruiting participants aged 18 years and over. Studies comparing admission avoidance hospital at home with acute hospital inpatient care. DATA COLLECTION AND ANALYSIS: We followed the standard methodological procedures expected by Cochrane and the Effective Practice and Organisation of Care (EPOC) Group. We performed meta-analysis for trials that compared similar interventions, reported comparable outcomes with sufficient data, and used individual patient data when available. We used the GRADE approach to assess the certainty of the body of evidence for the most important outcomes. MAIN RESULTS: We included 20 randomised controlled trials with a total of 3100 participants; four trials recruited participants with chronic obstructive pulmonary disease; two trials recruited participants recovering from a stroke; seven trials recruited participants with an acute medical condition who were mainly older; and the remaining trials recruited participants with a mix of conditions. We assessed the majority of the included studies as at low risk of selection, detection, and attrition bias, and unclear for selective reporting and performance bias. For an older population, admission avoidance hospital at home probably makes little or no difference on mortality at six months' follow-up (risk ratio (RR) 0.88, 95% confidence interval (CI) 0.68 to 1.13; P = 0.30; I2 = 0%; 5 trials, 1502 participants; moderate-certainty evidence); little or no difference on the likelihood of being readmitted to hospital after discharge from hospital at home or inpatient care within 3 to 12 months' follow-up (RR 1.14, 95% CI 0.97 to 1.34; P = 0.11; I2 = 41%; 8 trials, 1757 participants; moderate-certainty evidence); and probably reduces the likelihood of living in residential care at six months' follow-up (RR 0.53, 95% CI 0.41 to 0.69; P < 0.001; I2 = 67%; 4 trials, 1271 participants; moderate-certainty evidence). Hospital at home probably results in little to no difference in patient's self-reported health status (2006 patients; moderate-certainty evidence). Satisfaction with health care received may be improved with admission avoidance hospital at home (1812 participants; low-certainty evidence); few studies reported the effect on caregivers. Hospital at home reduced the initial average hospital length of stay (2036 participants; low-certainty evidence), which ranged from 4.1 to 18.5 days in the hospital group and 1.2 to 5.1 days in the hospital at home group. Hospital at home length of stay ranged from an average of 3 to 20.7 days (hospital at home group only). Admission avoidance hospital at home probably reduces costs to the health service compared with hospital admission (2148 participants; moderate-certainty evidence), though by a range of different amounts and using different methods to cost resource use, and there is some evidence that it decreases overall societal costs to six months' follow-up. AUTHORS' CONCLUSIONS: Admission avoidance hospital at home, with the option of transfer to hospital, may provide an effective alternative to inpatient care for a select group of older people who have been referred for hospital admission. The intervention probably makes little or no difference to patient health outcomes; may improve satisfaction; probably reduces the likelihood of relocating to residential care; and probably decreases costs.

Asunto(s)

RESUMEN

BACKGROUND: Family physicians (FPs) fill an essential role in public health emergencies yet have frequently been neglected in pandemic response plans. This exclusion harms FPs in their clinical roles and has unintended consequences in the management of concurrent personal responsibilities, many of which were amplified by the pandemic. The objective of our study was to explore the experiences of FPs during the first year of the COVID-19 pandemic to better understand how they managed their competing professional and personal priorities. METHODS: We conducted semi-structured interviews with FPs from four Canadian regions between October 2020 and June 2021. Employing a maximum variation sampling approach, we recruited participants until we achieved saturation. Interviews explored FPs' personal and professional roles and responsibilities during the pandemic, the facilitators and barriers that they encountered, and any gender-related experiences. Transcribed interviews were thematically analysed. RESULTS: We interviewed 68 FPs during the pandemic and identified four overarching themes in participants' discussion of their personal experiences: personal caregiving responsibilities, COVID-19 risk navigation to protect family members, personal health concerns, and available and desired personal supports for FPs to manage their competing responsibilities. While FPs expressed a variety of ways in which their personal experiences made their professional responsibilities more complicated, rarely did that affect the extent to which they participated in the pandemic response. CONCLUSIONS: For FPs to contribute fully to a pandemic response, they must be factored into pandemic plans. Failure to appreciate their unique role and circumstances often leaves FPs feeling unsupported in both their professional and personal lives. Comprehensive planning in anticipation of future pandemics must consider FPs' varied responsibilities, health concerns, and necessary precautions. Having adequate personal and practice supports in place will facilitate the essential role of FPs in responding to a pandemic crisis while continuing to support their patients' primary care needs.

Asunto(s)

RESUMEN

INTRODUCTION: Early in the COVID-19 pandemic, Canadian primary care practices rapidly adapted to provide care virtually. Most family physicians lacked prior training or expertise with virtual care. In the absence of formal guidance, they made individual decisions about in-person versus remote care based on clinical judgement, their longitudinal relationships with patients, and personal risk assessments. Our objective was to explore Canadian family physicians' perspectives on the strengths and limitations of virtual care implementation for their patient populations during the COVID-19 pandemic and implications for the integration of virtual care into broader primary care practice. METHODS: We conducted semi-structured qualitative interviews with family physicians working in four Canadian jurisdictions (Vancouver Coastal health region, British Columbia; Southwestern Ontario; the province of Nova Scotia; and Eastern Health region, Newfoundland and Labrador). We analyzed interview data using a structured applied thematic approach. RESULTS: We interviewed 68 family physicians and identified four distinct themes during our analysis related to experiences with and perspectives on virtual care: (1) changes in access to primary care; (2) quality and efficacy of care provided virtually; (3) patient and provider comfort with virtual modalities; and (4) necessary supports for virtual care moving forward. CONCLUSIONS: The move to virtual care enhanced access to care for select patients and was helpful for family physicians to better manage their panels. However, virtual care also created access challenges for some patients (e.g., people who are underhoused or living in areas without good phone or internet access) and for some types of care (e.g., care that required access to medical devices). Family physicians are optimistic about the ongoing integration of virtual care into broader primary care delivery, but guidance, regulations, and infrastructure investments are needed to ensure equitable access and to maximize quality of care.

Asunto(s)

RESUMEN

The early posthatch period is crucial to intestinal development, shaping long-term growth, metabolism, and health of the chick. The objective of this study was to determine the effect of genetic selection on morphological characteristics and gene expression during early intestinal development. Populations of White Plymouth Rocks have been selected for high weight (HWS) and low weight (LWS) for over 63 generations, and some LWS display symptoms of anorexia. Intestinal structure and function of these populations were compared to a commercial broiler Cobb 500 (Cobb) during the perihatch period. Egg weights, yolk-free embryo BW, yolk weights, and jejunal samples from HWS, LWS, and Cobb were collected on embryonic day (e) 17, e19, day of hatch, day (d) 3, d5, and d7 posthatch for histology and gene expression analysis. The RNAscope in-situ hybridization method was used to localize expression of the stem cell marker, olfactomedin 4 (Olfm4). Villus height (VH), crypt depth (CD), and VH/CD were measured from Olfm4 stained images using ImageJ. mRNA abundance for Olfm4, stem cell marker Lgr5, peptide transporter PepT1, goblet cell marker Muc2, marker of proliferation Ki67, and antimicrobial peptide LEAP2 were examined. Two-factor ANOVA was performed for measurements and Turkey's HSD was used for mean separation when appropriate. Cobb were heaviest and LWS the lightest (P < 0.01). at each timepoint. VH increased in Cobb and CD increased in HWS compared to LWS (P < 0.01). PepT1 mRNA was upregulated in LWS (P < 0.01), and Muc2 mRNA was decreased in both HWS and LWS compared to Cobb (P < 0.01). Selection for high or low 8-wk body weight has caused differences in intestinal gene expression and morphology when compared to a commercial broiler.

Asunto(s)

RESUMEN

Tumor treating fields (TTFields) are nonionizing alternating electric fields that have anticancer properties. After the initial approval for use in patients with recurrent glioblastoma in 2011 and newly diagnosed glioblastomas in 2015, they are now being tested in those with advanced lung cancer, ovarian carcinoma, and pancreatic cancer. Unlike ionizing radiation therapy, TTFields have nonlinear propagation characteristics; therefore, it is difficult for clinicians to recognize intuitively the location where these fields have the most impact. However, finite element analysis offers a means of delineating TTFields in the human body. Our analyses in the brain, pelvis, and thorax revealed that cerebrospinal fluid, edema, urine, ascites, pleural fluid, and necrotic core within a tumor greatly influence their distribution within these body cavities. Our observations thus provided a unified framework on the role of these compartmentalized fluids in influencing the propagation of TTFields.

RESUMEN

PURPOSE: To present a theoretical framework that rigorously defines and analyzes key concepts and quantities for velocity selective arterial spin labeling (VSASL). THEORY AND METHODS: An expression for the VSASL arterial delivery function is derived based on (1) labeling and saturation profiles as a function of velocity and (2) physiologically plausible approximations of changes in acceleration and velocity across the vascular system. The dependence of labeling efficiency on the amplitude and effective bolus width of the arterial delivery function is defined. Factors that affect the effective bolus width are examined, and timing requirements to minimize quantitation errors are derived. RESULTS: The model predicts that a flow-dependent negative bias in the effective bolus width can occur when velocity selective inversion (VSI) is used for the labeling module and velocity selective saturation (VSS) is used for the vascular crushing module. The bias can be minimized by choosing a nominal labeling cutoff velocity that is lower than the nominal cutoff velocity of the vascular crushing module. CONCLUSION: The elements of the model are specified in a general fashion such that future advances can be readily integrated. The model can facilitate further efforts to understand and characterize the performance of VSASL and provide critical theoretical insights that can be used to design future experiments and develop novel VSASL approaches.

Asunto(s)