The cochlea is a complex organ comprising diverse cell types with highly specialized morphology and function. Until now, the molecular underpinnings of its specializations have mostly been studied from a transcriptional perspective, but accumulating evidence points to post-transcriptional regulation as a major source of molecular diversity. Alternative splicing is one of the most prevalent and well-characterized post-transcriptional regulatory mechanisms. Many molecules important for hearing, such as cadherin 23 or harmonin, undergo alternative splicing to produce functionally distinct isoforms. Some isoforms are expressed specifically in the cochlea, while some show differential expression across the various cochlear cell types and anatomical regions. Clinical phenotypes that arise from mutations affecting specific splice variants testify to the functional relevance of these isoforms. All these clues point to an essential role for alternative splicing in shaping the unique molecular landscape of the cochlea. Although the regulatory mechanisms controlling alternative splicing in the cochlea are poorly characterized, there are animal models with defective splicing regulators that demonstrate the importance of RNA-binding proteins in maintaining cochlear function and cell survival. Recent technological breakthroughs offer exciting prospects for overcoming some of the long-standing hurdles that have complicated the analysis of alternative splicing in the cochlea. Efforts toward this end will help clarify how the remarkable diversity of the cochlear transcriptome is both established and maintained. The cochlea is a highly specialized organ responsible for hearing. Its function depends on the intricate organization of its myriad cell types, including mechanosensory hair cells (HCs), more than five types of supporting cells (SCs), and many other non-sensory cells that contribute to the survival and function of the sensory cells. All these constituents of the mature cochlea are generated from the otocyst, a spherical and seemingly homogenous population of epithelial cells. How does the cochlea achieve its distinct anatomy, and how is its remarkable cellular diversity created and maintained? Until now, efforts to address these questions have focused largely on regulation at the transcription level. Conditional knockout studies and transcriptomic analyses have identified key transcription factors governing cochlear development . Single alternative splicing (AS), a post-transcriptional modification process that allows the production of multiple mRNA transcripts from a single gene.Proteomic studies have shown that roughly 37% of human protein-coding genes encode multiple isoforms, allowing the 20,000 genes in the genome to produce more than 290,000 peptides . AlternaAS is exceptional in both its extent and its contribution to transcriptomic diversity. AS is estimated to occur in roughly 95% of human multi-exon genes , about tAlthough no systematic attempt has yet been made to assess its splicing profiles, several reports hint at an active role for AS in the cochlea. Many of the molecules essential for hearing exist in multiple splice variants, some of which are expressed specifically in the cochlea. Biochemical properties differ among isoforms. Functional and morphological defects observed in isoform-specific knock-out (KO) animals and different clinical phenotypes arising from mutations that affect different isoforms testify to the distinct roles assumed by the splice variants. Furthermore, AS patterns vary according to cell type, spatial location, and developmental stage, suggesting the possibility that AS plays a role in creating morphological and functional heterogeneity within the cochlea. Finally, mice deficient for certain splicing regulators show hearing impairment, although the detailed pathogenic mechanisms underlying this defect remain unclear. These results highlight the importance of AS regulation in the normal development and function of the cochlea.This article aims to provide a comprehensive review of the literature focusing on the physiological relevance of AS in cochlear development and hearing function. We will first give a basic overview of AS and cochlear biology, and then explore the rich transcriptomic diversity of the cochlea conferred by AS and its regulator RNA-binding proteins (RBPs). Finally, we will discuss clinical cases of hearing loss caused by abnormal AS regulation and potential therapeutic approaches utilizing AS for correcting deafness-causing mutations.splice sites. A ribonucleoprotein complex known as the spliceosome excises parts of pre-mRNAs whose borders are defined by splice site sequences  of 5 types of binary processes: skipping of an alternative or “cassette” exon, alternative 5′ splice site usage, alternative 3′ splice site usage, utilization of mutually exclusive exons, and intron retention  and supporting cells (SCs). Movements of the basilar membrane displace the HCs relative to the overlying tectorial membrane, deflecting their hair bundles.The cochlea consists of three chambers . The scastereocilia located on the apical surface of every HC  machinery, an apparatus consisting of molecules such as TMC1, LHFPL5, and TMIE that triggers the influx of K+ and Ca2+ in response to mechanical tension  receive the majority of auditory afferent innervation and possess specialized structures called e fibers . Depolare fibers . This coUsher syndrome—a group of genetic conditions characterized by hearing loss and blindness—tend to exist in multiple isoforms with unique functions and distribution patterns  is an Usher protein that constitutes the upper part of the stereociliary tip link . The incAS event    , and witc domain . In vitreraction . One groeraction . Harmonieraction .CDH23, but it will have to be corroborated with biophysical measurements. To pinpoint the exact role of peptide 68 in cochlear function, it will be necessary to study exon-specific KO models.In contrast, a separate study reported that peptide 68 is a facilitator of protein-protein interactions. Another well-known inner ear-specific AS event concerns harmonin (USH1C), a scaffolding protein thought to act as a hub for Usher protein interactions . HarmoniV1.3 channels, which reduces the number of channels available at the basal cell surface  is the component of the stereociliary tip link that connects to both CDH23 and the MET machinery . Many PCing loss . This suing loss .The uniqueness of the cochlea in this case seems to lie in its specific requirement for AS, rather than in its AS profile. While each isoform is dispensable for the initial formation of hair bundles and for acquisition of MET , CD2 isoAlthough the cochlea is a small organ, it is astoundingly complex. It is conceivable that AS might help achieve the precise level of transcriptomic heterogeneity required for creating distinct anatomic regions and cell types within the cochlea. One study using single cell long-read RNA-sequencing found considerable AS variation between cell types, although the authors only provided a detailed analysis of isoform diversity and distribution for one example gene . FurtherCACNA1D encode truncated CaV1.3 channel α subunits with peculiar electrophysiological characteristics  signaling pathway, three FGF receptors (FGFRs) are alternatively spliced to produce two isoforms each. Selective expression of these isoforms enables specific communication across the epithelial-mesenchymal boundary . ESRP1 w hearing . Indeed,splicing .Esrp1 mutant mice exhibit many phenotypes other than inner ear malformation, including cleft lip and palate arising from a defective epithelial-to-mesenchymal transition  mouse, a spontaneous mutant characterized by recessively inherited hearing and balance abnormalities, harbors a large deletion in Srrm4 (nSR100). Srrm4 encodes a splicing factor predominantly expressed in neurons and HCs  is an RBP that regulates the splicing of several genes, including Sfswap itself , hair bundle link genes (Ptprq), and ion channel genes   .Cdh23 exon 68 does seem to be genuinely regulated by RBM24, there is ample residual expression of the exon 68-containing isoform in mutant cochleae to cast doubt on its implication in hearing pathogenesis . Interestingly, Gsdme knockout mice exhibit normal hearing . Three potentially pathogenic variants have been reported. One is a synonymous substitution that led in vitro to greatly reduced use of exon 5a relative to exon 5b. The other two variants are deletions in a conserved intronic region transcribed as the 3′-UTR of a short splice variant of HGF  were quantified separately, the use of exon 6a was reduced in the cochleae of mutant mice but not in other organs , these organs were normal in homozygous knock-in mice. Comparisons between these organs revealed that the intronic mutation reduced r organs .trans-regulatory elements to affect splicing decisions. Considering that all three pathogenic variants reduce the inclusion of exon 5a, functional differences among the various isoforms may also contribute to tissue specificity. We must also consider mutations in the MET gene, which encodes an HGF receptor, mutations of which can lead to non-syndromic hearing loss (DFNB97)  . As HGF-(DFNB97) , it is sESRP1, a splicing factor and regulator of cochlear non-sensory development, have been associated with hearing loss. Not only was the splicing of ESRP1-dependent cassette exons altered in patient-derived induced pluripotent stem cells carrying ESRP1 mutations, but the splicing defects were restored when the ESRP1 mutations were corrected. In fact, this very finding was the motivation for an investigation into the role of this splicing factor in cochlear development  may interact with several components of the spliceosome . Splice-switching ASOs are short oligonucleotides designed to bind specific RNA sequences and alter splicing, preventing the production of pathogenic transcripts. Splice-switching ASOs are actively being developed with the aim of treating hearing loss arising from cis-acting mutations .Analogous strategies have been pursued for other types of Usher syndrome , althoug exon 13 . Truncat exon 13 . Skippin exon 13 , and a pSLC26A4 gene can cause both non-syndromic  and syndromic  forms of deafness (SLC26A4 gene is one of the most frequent mutations causing deafness in East Asian populations (SLC26A4 mutations occur in 5′splice sites where they are predicted to hinder recognition by the U1 snRNA, a component of the core splicing machinery. Synthetic U1 snRNAs were created with sequences perfectly complementary to those of the mutated splice sites. In many cases, these modified U1 snRNAs prevented mis-splicing, but some mutations near exon 8 were resistant to this type of treatment. In the presence of these resistant mutations, a nearby cryptic splice site was being used instead. To reduce competition for U1 snRNA binding, ASOs designed to mask the cryptic splice site were delivered together with the modified U1 snRNAs, and this restored normal splicing of exon 8 (Mutations in the deafness . The c.9ulations . This muulations . One stuulations . The ASOulations . Anotherulations . Some SLf exon 8 . These rCDH23 exon 68 and the tonotopic splicing of KCNMA1 and KCNQ4. Clarifying the precise ways RBPs such as SRRM4, SFSWAP, and RBM24 affect cochlear function is yet another task where much work remains.In this review, we covered many clues that point to the importance of AS in the cochlea. Both unbiased studies and targeted approaches will be necessary to proceed further. Unbiased high-throughput studies will, first of all, help to quantify the extent to which AS contributes to the unique transcriptomic landscape of the cochlea, which still has not been adequately assessed. The task of identifying AS events that occur differentially either along the tonotopic axis or among the various cochlear cell types will also benefit from such unbiased studies. In addition, uncovering the network of splicing regulators that govern cochlear development will require further unbiased analysis of gene expression, transcript usage, and RBP motif distribution. Meanwhile, as more AS events are identified, targeted investigations will be required to identify their full physiological significance. Examples of AS events that demand interpretation include the usage of Transcriptome studies of the cochlea have typically been limited by its small size and considerable heterogeneity. In bulk RNA-sequencing, the diverse cell types within each sample are all lumped together, while the high levels of dropout in single cell sequencing data make it difficult to computationally quantify isoform abundance with any accuracy . Yet as trans-acting regulators, but also by chromatin structure and transcription kinetics (via alternative transcription/translation site usage, and they show different expression patterns (New venues of research are constantly opening up. For example, single cell-RNA sequencing has revealed unexpected cell type heterogeneity within the cochlear epithelium  or the akinetics . The intpatterns , subcellpatterns , and asspatterns . Isoform


A large proportion of hospitalized patients receiving dialysis report not receiving preference-concordant care.Hospitalized patients on dialysis desiring a comfort-oriented medical plan were likely to report receiving preference-concordant care.Preference-concordant care is a cornerstone of high-quality medical decision-making, yet the prevalence and correlates of preference-concordant care have not been well-studied in patients receiving dialysis. We surveyed hospitalized people receiving maintenance dialysis to estimate the prevalence and correlates of preference-concordant care among this population.1) extending life or (2) relieving pain and discomfort. We assessed shared dialysis decision-making using the 9-item Shared Decision-Making Questionnaire. We examined the differences between those reporting lack of preference-concordant care and those reporting receipt of preference-concordant care using chi-squared analyses. We also studied whether patients' treatment plan preferences or shared dialysis decision-making scores were correlated with their likelihood of receiving preference-concordant care.We assessed preference concordance by asking participants , “How strongly do you agree or disagree that your current treatment plan meets your preference?” We assessed treatment plan preference by asking whether patients preferred a plan that focused on (P = <0.0001) to report receiving preference-concordant care; patients with higher shared decision-making scores were more likely  to report preference-concordant care.Of the 213 respondents who provided data on preference concordance, 90 (42.3%) reported that they were not receiving preference-concordant care. Patients who preferred pain and discomfort relief over life extension were less likely (odds ratio, 0.15  A substantial proportion of this sample of hospitalized people receiving maintenance dialysis reported not receiving preference-concordant care. Efforts to improve symptom management and enhance patient engagement in dialysis decision-making may improve the patients' perceptions of receiving preference-concordant care. In one study, one of 99 patients receiving dialysis recalled talking with a clinician about a palliative or conservative approach to kidney management.11 Similarly, other studies suggest that many patients receiving dialysis are not offered a comfort-oriented approach.13Previous studies have shown that the focus of patients' treatment plan preferences can determine their likelihood of receiving preference-concordant care.15 SDM is a process that involves patients and their families in making medical decisions according to patient treatment preferences.16 Previous studies in nondialysis populations have shown benefits of SDM, including improved satisfaction with health care decision-making and higher patient activation after the decision-making process.1719 Such positive long-term effects of SDM on patient self-efficacy suggest that SDM could potentially be associated with perceptions of receiving preference-concordant care after dialysis initiation even among hospitalized patients.One plausible approach to provide preference-concordant care is by incorporating shared decision-making (SDM) principles into dialysis decisions.8 the relative lack of support for patients preferring a comfort-oriented approach,20 and the possible association of SDM during dialysis decision-making with a subsequent perception of receiving preference-concordant care,2123 this study has three aims: (1) to estimate the proportion of hospitalized patients receiving maintenance dialysis who do not perceive their treatment as preference-concordant, (2) to test the hypothesis that patients who prefer a plan of care that prioritizes relieving pain and discomfort are less likely to perceive their treatment plan as preference-concordant than patients who prioritize extending life; and (3) to test the hypothesis that better SDM during the dialysis decision-making process is associated with improved preference concordance even after dialysis initiation. To the best of our knowledge, no previous study has examined these questions for hospitalized patients receiving maintenance dialysis.Based on the vital importance of preference-concordant care for persons receiving maintenance dialysis, especially those who are acutely ill and hospitalized,We surveyed hospitalized patients receiving maintenance dialysis from 06/2019 to 03/2020 at Strong Memorial Hospital in Rochester, New York. Using convenience sampling methodology, we identified eligible participants using an electronic medical record list of hospitalized patients receiving maintenance hemodialysis before hospitalization. We screened patients who were aged 18 years or older and were English-speaking. Subsequently, a survey team member (BK or SD) approached a patient's health care team member to determine whether the clinical team believed that the patient had capacity to consent. If so, a member of the study team approached eligible participants. We did not exclude patients based on their location , length of hospitalization, reason for hospitalization, or comorbidities. Study team members  explained the purpose of the study to the patient, asked the patient to explain back the purpose of the study and their role in the study, and then asked for and obtained verbal consent. All patients who consented to the study were given the option to either complete a paper survey or respond to orally administered survey questions. The 175 survey items covered participants' demographics, views on their dialysis decision-making process, and psychosocial aspects of their care. All participants had the option to skip any questions or stop the survey at any point for any reason. A physician was also available to speak with patients in case of psychological distress. Patients who completed the survey were offered a chance to enter a raffle to win one of four $50 gift cards. The Institutional Review Board at the University of Rochester Medical Center approved this study.The primary outcome variable for this study is preference-concordant care. To assess preference-concordant care, we asked patients: “How strongly do you agree or disagree that your current treatment plan meets your preference?” Response options included (1) strongly disagree, (2) disagree, (3) slightly disagree, (4) slightly agree, (5) agree, or (6) strongly agree. Any participant who responded slightly agree, agree, or strongly agree was deemed to be receiving preference-concordant care. Consistent with the previous literature, we assessed preference concordance after first assessing patients' treatment plan preferences .25 We specifically used this approach to prime patients to identify their treatment plan preferences before reflecting on whether their treatment plan meets these preferences. Consistent with the previous research evaluating patients' receipt of preference-concordant care, we intentionally did not state to the participants whether our questions were regarding their acute hospitalization or overall plan of care.25 This methodology provides us the benefit of capturing patients' assessment of the aspect of medical care most important to them.9The two independent variables were treatment plan preferences and SDM. To understand patients' treatment plan preferences, we asked patients the following question26: “If you had to make a choice at this time, would you prefer a plan of medical care that (1) focuses on extending life as much as possible, even if it means having more pain and discomfort, or (2) would you want a plan of medical care that focuses on relieving pain and discomfort as much as possible, even if that means not living as long?” While many patients may prefer both options, we offered only two mutually exclusive options to encourage respondents to pick their top priority.25 We used the 9-item Shared Decision-Making Questionnaire (SDM-Q-9) to assess SDM during the process of dialysis decision-making.27 This 9-item, internally consistent (α=0.93) questionnaire gives patients the option to completely disagree, strongly disagree, somewhat disagree, somewhat agree, strongly agree, or completely agree with statements such as “My doctor and I selected a treatment option together.” Patients were informed that each statement in the questionnaire specifically referred to the decision-making process that led them to receive dialysis. A score of zero through five for each question was recorded and summed to determine a raw score of 0–45. Consistent with the previous literature, we then multiplied this score by 20/9 to calculate an SDM-Q-9 score from 0 to 100, where the scores of 0 and 100 describe the lowest and highest levels of SDM, respectively.28The covariates included demographic data, financial strain, relationship status, time on dialysis, and advance care planning documentation (ACP). Demographic data included age, sex (woman versus man versus nonbinary), race (asked in the following order: White versus Black versus Asian versus Native Hawaiian or Pacific Islander versus American Indian versus Alaska Native versus Other), education, and income. Financial strain was measured using a set of four yes/no questions29 concerning respondents' beliefs that their income was enough for: (1) food and housing costs, (2) clothing, medicine, repairs to home, and transportation, (3) going out for a meal or entertainment, and (4) ability to take a vacation if their health permitted. Financial strain was considered present if participants responded yes to two or more questions.29 Relationship status was measured by asking patients whether they were married, divorced, widowed, separated, in a committed relationship, or single and never married. Patients were determined to be in a relationship if they reported they were married or were in a committed relationship. Time on dialysis was measured by asking patients, “How long have you been undergoing dialysis?” ACP was assessed by asking patients if they had a health care proxy, had a living will, or completed a Medical Orders for Life-Sustaining Treatment form. Advance care planning was considered present if the respondent had completed at least one of the three ACP documents.P-value of <0.1 in the bivariate analyses. Ten respondents did not answer the question regarding preference-concordant care and were excluded from all statistical analyses. Of the remaining surveys, we found eight missing responses for age and sex, six for race and income, and ten missing responses for education. Forty-three respondents had missing responses for relationship status, seven for financial strain, and 15 for time of dialysis dependency. We did not find any missing responses for items on advance care planning, treatment plan preferences, and SDM. For the multiple logistic regression, the missing data for each of these variables were imputed over 15 iterations using the fully efficient fractional imputation method to reduce variability and effects on subsequent statistical analysis.30 We report odds ratios (OR), 95% confidence intervals (CIs), and the P-values in the bivariate analysis and the multiple logistic regression analysis as . Findings in the multiple logistic regression were deemed to be statistically significant if P-value was ≤0.05.All statistical analyses were conducted using SAS 9.4. Race was categorized as White versus Black versus Other, education as at least some college or technical school versus high school or below, and income as ≤$20,000 versus >$20,000. No participant identified as nonbinary leading to a categorization of sex as women versus men. We applied chi-squared testing to examine the differences between those reporting lack of preference-concordant care  versus those reporting receipt of preference-concordant care . We then built a multiple logistic regression model for hypothesis testing by including variables with a 1) building two separate logistic regression models for each independent variable, (2) building a stepwise regression model by including all the variables, and (3) building an ordinal logistic regression model by grouping the six response options of the question related to preference-concordant care into three ordinal variables . We conducted these sensitivity analyses using the same imputation method described for main model.30We conducted additional sensitivity analyses by . Of these 223 respondents, 213 responded to the questions on preference concordance and were included in our analyses. We did not purposely exclude people receiving peritoneal dialysis, but our sample comprised only of people receiving hemodialysis, likely because of a relatively lower number of patients receiving peritoneal dialysis in the Greater Rochester Area. Table One hundred and twenty-three patients (57.7%) reported that their current treatment plan was preference-concordant, while 90 (42.3%) reported their treatment plan was not preference-concordant. One hundred twenty-three patients (57.7%) reported that if they had to choose at this time, they would prefer a plan of medical care that focused on relieving pain and discomfort as much as possible, even if that meant possibly living for less time than they might on dialysis. Ninety patients (42.3%) preferred a treatment plan that focused on extending life as much as possible, even if it meant having more pain and discomfort.P = <0.0001), and patients who scored higher on the SDM-Q-9 scale were more likely to report preference-concordant care . Other variables with a P-value of <0.1 included educational attainment beyond high school , married or in a committed relationship , and the presence of an advance directive .Table P = <0.0001). Notably, patients with higher SDM scores were more likely to report preference-concordant care . Educational attainment, relationship status, and the presence of and advance directive were not statistically significant in this model.Table Supplemental materials) were also broadly consistent with the findings reported in Table We ran bivariate and logistic regression analyses without imputing the missing variables. The results (data not shown) were broadly consistent with those reported in Table In this cohort of hospitalized people receiving maintenance dialysis, we found that over 40% reported that their current treatment plan did not align with their preferences. Notably, preference for a plan of medical care focused on relieving pain and discomfort was associated with lower odds, while higher shared dialysis decision-making scores were associated with greater odds of receiving preference-concordant care. To the best of our knowledge, this is the first study to examine the prevalence and correlates of preference-concordant care in hospitalized patients receiving maintenance dialysis.10 Compared with some other studies of chronically ill patients, the proportion of patients reporting a lack of preference concordance is somewhat higher in our study.10 For example, in one recent study of hospitalized patients with a serious illness (not just ESKD), only 22% reported a lack of preference-concordant care.10 One possible explanation for this apparent discrepancy could be that patients with ESKD in our study reported lower rates of preference-concordant care because of their disease complexity and high number of comorbidities.31 Another plausible explanation is that previous studies provided their participants with a neutral or uncertain option,10 which we intentionally did not provide, mainly to identify patients' top priority.25 Future mixed-method studies comparing and exploring preference concordance among hospitalized patients by comorbidity may be helpful.This study has three main findings. First, a significant proportion of patients did not feel that they were receiving preference-concordant care. Such lapses in preference-concordant medical care are striking but not surprising. Importantly, the proportion of patients reporting a lack of preference concordance can vary depending on the method of measuring preference-concordant care.9 including those hospitalized.10 One explanation for this finding is that some health care providers may assume that patients receiving maintenance dialysis prefer more aggressive treatments, given that dialysis itself is a life-sustaining treatment.32 However, an exclusive focus on life extension may potentially deprive patients of good symptom control with the help of primary or specialist palliative care.33 Another explanation is that some health care providers may be less equipped to treat the complex symptoms associated with ESKD and dialysis, leaving these patients largely undertreated.12 It is also plausible that some patients wish to explore dialysis withdrawal but are not offered opportunities to engage in such conversations.35 Future studies may provide clarity on some of these questions.Second, patients who preferred a plan of medical care focused on relieving pain and discomfort were less likely to report preference concordance than patients who desired a plan focused on extending life. This finding is consistent with previous literature showing a negative correlation between the preference for a comfort-oriented approach and preference concordance in patients with chronic illnesses,36 Although a positive association of SDM with preference-concordant care has been demonstrated in patients with cancer,22 our study adds to the literature by suggesting a similar association in hospitalized patients receiving maintenance dialysis. Future studies are needed to establish a causal relationship between SDM and preference-concordant care.Third, our data suggest that patients who had engaged in SDM with their nephrologists during the dialysis decision-making process in the past were more likely to report preference-concordant care. Our findings broadly support the extensive literature on the benefits of SDM in nondialysis populations ranging from improved patient satisfaction, higher self-efficacy, and better quality of life to reduced decisional conflict, less decisional regret, lower health care costs, and fewer emergency department visits.25 our choice did not reference specific medical care  and may have potentially led to different interpretations of the question by different participants. While this methodology certainly has limitations, it still provides us the benefit of capturing patients' assessment of the focus of the aspect of medical care most important to them. Finally, we assessed patients' treatment plan preferences at one period in time, and treatment plan preferences may change with time.37 Future research assessing patients' treatment plan preferences at multiple time points would gather a more robust understanding of these preferences.Our study has several limitations. We did not capture patients' comorbid conditions, reasons for hospitalization, length of hospitalization, severity of illness, understanding of illness, symptom burden, kidney transplantation status, or affective state. All these may have potentially influenced patient responses. We also recognize that our study's participants' interpretation of the SDM process for their dialysis decision is subject to recall bias, especially during an acute hospitalization, when symptom burden may be high. Another notable limitation is that although our question assessing preference concordance was consistent with previous literature,39 Second, our findings, like others,40 encourage improved treatment of symptoms for patients receiving dialysis. Patients who receive dialysis report a high symptom burden,41 and many desire health care that focuses on relief of symptoms and suffering.42 However, many patients' symptoms remain undertreated, and many report being unaware of palliative care services.42 Finally, our findings call to improve dialysis decision-making by incorporating principles and practice of SDM.14 Encouraging routine use of decision aids and decision coaching may be a helpful adjunct in clinical SDM.44 Training clinicians in primary palliative care skills around communication and decision-making holds some promise in improving SDM and delivering preference-concordant care to patients receiving dialysis.46 Development and implementation of educational interventions for clinicians to develop primary palliative care skills are much needed.48Our results have several implications. First, our findings encourage health care providers to explore patients' treatment preferences during hospitalization by engaging in timely goals-of-care conversations. These conversations offer vital opportunities to learn and incorporate patient preferences into their treatment plan and are associated with improved patient satisfaction, fewer hospitalizations, and lower health care costs.In summary, many hospitalized people receiving dialysis report that their treatment plan does not align with their preferences. There is a critical need for more robust efforts to not only align patients' preferences with their treatment plans by engaging in goals-of-care conversations but also to adequately treat the symptom burden of hospitalized patients receiving maintenance dialysis, perhaps with support from palliative care services. Our findings also suggest further incorporating the principles and practices of SDM into the treatment plan of people with chronic kidney disease facing dialysis decisions.


N-Methyl-D-Aspartate (NMDA) receptors. The discovery of its rapid antidepressant effects in patients with depression and treatment-resistant depression fostered novel effective treatments for mood disorders. This discovery not only provided new insight into the neurobiology of mood disorders but also uncovered fundamental synaptic plasticity mechanisms that underlie its treatment. In this review, we discuss key clinical aspects of ketamine’s effect as a rapidly acting antidepressant, synaptic and circuit mechanisms underlying its action, as well as how these novel perspectives in clinical practice and synapse biology form a road map for future studies aimed at more effective treatments for neuropsychiatric disorders.Ketamine is an open channel blocker of ionotropic glutamatergic  Psychiatric disorders and neurotherapeutics are exhibiting a renaissance of new treatments for mood disorders that engage novel synaptic signaling mechanisms. The fertility of this moment is illustrated by the U.S. Food and Drug Administration (FDA) approvals of Esketamine (Spravato) and Brexanolone (Zulresso) in 2019. Further, the FDA approval of Esketamine has seemed to open the door to impending FDA approvals of other consciousness-altering medications including psilocybin and methylenedioxymethamphatemine (MDMA). This impressive concentration of emerging novel treatments has been unmatched since 1957, the year that the last mechanistically novel antidepressants were discovered, the monoamine transporter antagonists and the monoamine oxidase inhibitors . The neeIn the 1970s through the 1990s, Yale University was a hotbed of preclinical and translational research attempting to characterize disturbances in monoamine signaling contributing to the neurobiology of depression and the mechanisms through which monoamine signaling-targeting antidepressants produced their therapeutic effects. Studies led by Dennis Charney, Pedro Delgado, George Heninger, and others clearly implicated ongoing monoaminergic availability in monoaminergic antidepressant efficacy. In depressed patients who had responded to antidepressant treatment, depletion of either serotonin or norepinephrine prevented or transiently reversed the antidepressant effects of serotonin transporter antagonists or norepinephrine transporter antagonists, respectively –16. HoweIn parallel, one of us (J.K.) developed R,S-ketamine infusion as a psychopharmacology research platform to probe NMDAR function relevant to cognitive function, psychosis, and dissociation in healthy humans . This woThe convergence of the broadening perspective of the biology of depression with the development of an approach to probe glutamate synaptic function resulted in the discovery of the rapid antidepressant effects of ketamine. The initial pilot study used the previously ketamine infusion strategy to conduct the first randomized, placebo-controlled test of ketamine response in depression . This stSubsequent research validated the safety and efficacy of R,S-ketamine and Esketamine for the treatment of a growing array of psychiatric disorders. When used to treat depression, ketamine is dosed with the minimal frequency possible. Although clinical practices may vary , it is gNMDAR antagonists studied to date appear to have a narrow dose window for optimized clinical response. Three randomized placebo-controlled studies in treatment-resistant depression and PTSD , 47–49 sThere may be specific roles for psychotherapies combined with ketamine or Esketamine treatment. Ketamine, due to its primary action as a NMDAR blocker, is known to interfere with NMDAR-dependent forms of Hebbian neuroplasticity , 54. Thi1H-MRS) provided the first non-invasive measurements of brain glutamate and glutamine levels, generally reporting reductions in frontal cortex measurements [13C-MRS in combination with an isotopically labeled metabolic substrates , which enable dynamic tracking of the levels of isotopically-labeled metabolites of these substrates and the characterization of the rates cellular processes, such as anaerobic metabolism, aerobic metabolism , and the rate of conversion of glutamate to glutamine, which is stoichiometrically related to the rate of glutamate release (VCycle) [TCA but not VCycle was reduced in medication-free depressed patients compared to healthy subjects [Glutamate synaptic function appears to be downregulated in cortical circuits in major depression. Glutamate synaptic dysfunction has long been thought to be a contributor to the neurobiology of depression . Proton urements , althougurements . These murements , 66. The(VCycle) –69. Usinsubjects . A seconsubjects ). Functisubjects , 73. Simsubjects .A second form of glutamate synaptic dysfunction in MDD and PTSD is synaptic loss. In animals, chronic stress exposure produces clear evidence of synaptic pruning –77. StruSince the landmark papers on the mechanisms of action of ketamine , 87, theResearch in the Duman laboratory proposed that ketamine action involves the blockade of NMDARs on inhibitory interneurons , 89. ThiThe Monteggia and Kavalali labs were also investigating the mechanism of ketamine action and identified a key role for synaptic plasticity, specifically a novel form of rapid homeostatic plasticity, in the behavioral effects. Ketamine produces rapid antidepressant effects that in some patients persist for days to more than a week in some patients. Following administration, ketamine has a short half-life suggesting that its antidepressant effects are due to a form of plasticity that outlast the systemic presence of ketamine. Although ketamine is a well characterized NMDA receptor antagonist, rather unexpectedly it was shown to induce synaptic potentiation in the hippocampus. This potentiation involves block of NMDA receptors and the engagement of intracellular signaling to increase neurotransmission carried out by α-amino-3-hydroxy-5-methylisoxazole-4-propionic acid (AMPA) type glutamate receptors that persists for several hours , 95.While NMDA receptor activation by activity dependent release of glutamate has been traditionally associated with Hebbian forms of plasticity such as Long-Term Potentiation and Long-Term Depression, blockade of NMDA receptors has been shown to elicit a form of homeostatic synaptic plasticity . Unlike BDNF [Earlier studies on the mechanisms of action of classical antidepressant in preclinical models established a strong causal link of BDNF and subsequent signaling via TrkB receptors as a key mediator of antidepressant action , 100. KeBDNF . The forBDNF , 95, 98.The identification of a key requirement for BDNF-TrkB signaling in ketamine action provided a starting point to investigate the intracellular signaling that produces rapid antidepressant action. This effort lead to elucidation of the essential role of eukaryotic elongation factor 2 and its phosphorylation by its dedicated kinase, eukaryotic elongation factor 2 kinase (eEF2K), in this process.eEF2 kinase is a calcium-calmodulin-dependent protein kinase , which activity is maintained by a high affinity interaction with calcium-calmodulin complexes. Due to the high affinity nature of this interaction, even resting levels of calcium signaling triggered by spontaneous glutamate release mediated NMDA receptor activation is sufficient to maintain its activity . DetaileRecent studies have begun to uncover how intracellular signaling mechanisms that produce the acute antidepressant action of ketamine transition to a sustained effect that may last over a week . This woMeCP2 is a transcriptional regulator that controls gene expression both at the level of individual genes and via modulation of larger chromatin structure , 106. MeAs stated above, recent findings demonstrated a causal link between initial homeostatic neuroplasticity events elicited by ketamine and subsequent transcriptional mechanism that sustains ketamine’s behavioral effects. According to these results, the ketamine elicited AMPA receptor dependent synaptic potentiation induces a subsequent shift in excitation-inhibition balance towards excitation that ultimately leads to increases in MeCP2 Ser421 phosphorylation. Previous work has shown an increase in MeCP2 Ser421 phosphorylation broadly alters the MeCP2-dependent transcriptional landscape and thus acts as a global regulator of transcription, and likely impacts expression of target genes . In agreAcute subanesthetic ketamine increases MeCP2 Ser421 phosphorylation in the hippocampus a week after treatment but not in the initial hours after injection when the rapid antidepressant response occurs. These effects were specific to MeCP2 and were not paralleled by changes in other transcriptional factors . The reqAs stated above, this initial and rapid antidepressant protein translation component involves the rapid increase in BDNF protein synthesis which drives the downstream intracellular signaling of MeCP2. Endogenous BDNF is also a potent activator of mTOR, which had previously been proposed to trigger rapid antidepressant action. Previous work demonstrated that ketamine’s effects on mTOR are not initial engagement at the synapse but rather downstream of BDNF and are not required for the rapid antidepressant effects . This daThe involvement of MeCP2 is also particularly intriguing as it plays a critical role in spine maturation , 111–11318F-deoxyglucose-PET [13C-MRS involving the infusion of 13C-glucose as a metabolic tracer, in a mixed group of healthy subjects (n = 14) and MDD patients (n = 7), described a 13% increase in 13C-glutamine enrichment, i.e., an increase in VCycle, that correlated with the emergence of dissociation symptoms [11C-ABP688, 18F-FPEB) binding to mGluR5 in two ways, through direct competition of glutamate and the PET ligand and by stimulating mGluR5 internalization [13C-MRS study, ketamine produced a 14% reduction in 11C-ABP688 binding in depressed patients and an 19% reduction in ligand binding in healthy subjects. In the depressed patients (n = 13), reductions in hippocampal ligand binding correlated  with improvement in depression [Clinical studies showed ketamine transiently increases cortical glutamate release in a manner that is related to the magnitude of its antidepressant effects. Ketamine increases nearly every index of cortical activity in healthy humans including glucose metabolism measured with cose-PET , 116 andcose-PET . Early!Hcose-PET , 119. Susymptoms . This stsymptoms . The parlization . Consistpression .The involvement of BDNF dependent homeostatic synaptic plasticity may account for the observation that extracellular glutamate levels surge after ketamine administration  and the In animals, pretreatment with AMPAR antagonists prevents the emergence of the antidepressant effects of ketamine  and is tAs noted earlier, the antidepressant effects of ketamine in animals is associated with activation of mTORC1 (increases in pmTOR/mTOR). When directly injected into the brain, the mTOR antagonist, rapamycin, attenuates the antidepressant effects of ketamine . In contRecent clinical studies have also suggested that the antidepressant effects of ketamine may be associated with restoration of synaptic efficacy. The clearest preliminary signal with respect to the restoration of synaptic efficacy comes from a MEG study that showed that a single dose of ketamine failed to modulate the magnitude of sensory evoked potentials in healthy subjects or non-responding patients. However, depressed patients who responded to ketamine showed an increase in the amplitude of their sensory evoked response , 129. Ken = 7), depressed patients without synaptic deficits (n = 6), and depressed patients with synaptic deficits (n = 6). Both groups of depressed patients improved with ketamine. However, only the deficit group showed increases in ligand binding to the SV2A tracer suggestive of increases in synaptic density and SV2A binding increases that correlated with improvement in depression.To date there has been a single pilot study directly addressing whether the antidepressant response to ketamine is associated with restoration of synapse density . This stThe discovery of ketamine’s rapid antidepressant effects in patients with depression and treatment resistant depression fostered a renaissance in clinical as well as preclinical neuropsychiatry. Ketamine’s rapid clinical efficacy indicated that symptoms of depression can be alleviated in patients with long history of resistance to conventional treatments within hours. The rapidity of ketamine action focused preclinical studies on fast synaptic signaling mechanisms and away from structural alterations associated with longer treatments such as synaptic rewiring and neurogenesis. These findings may suggest that ketamine’s rapid antidepressant action is due to its ability to induce homeostatic plasticity and not necessarily to ‘fix’ depression. In other words, the production of homeostatic plasticity may be a ‘masking’ effect to alleviate symptoms of depression rather than fixing the underlying causes of the disorder.The requirement for homeostatic plasticity to produce the behavioral effects of ketamine also provides a potential novel therapeutic opportunity. Would the identication of compounds that directly target homeostatic plasticity represent a new avenue for treatment? In preclinical studies, this hypothesis was tested by proof of principle experiments. Retinoic acid receptor activaction produces rapid upscaling of homeostatic plasticity similar to ketamine but does not involve the NMDA receptor or its intracellular signaling pathway . The retAnother critical aspect of research is sustaining the antidepressant effects of ketamine. One approach may be the administration of ketamine to elicit the rapid antidepressant effects and then specific targeting of the downstream signaling pathway to extend the antidepressant effects without the need for repeated ketamine. This type of approach may prove advantangeous in avoiding repeated ketamine dosing that may be required for the treatment of depression in the long-term.As this article illustrates, studies aimed at addressing ketamine’s mechanism of action built a direct bridge between basic synaptic signaling mechanisms and clinical practice. For decades, neuropsychiatric studies have centered around “slow” neurotransmission predominantly carried out by monoaminergic neurotransmitters . Today,


The aim of this study was to compare choroidal adjusted flow index (AFI) in healthy, hypertensive & preeclamptic pregnancies using optical coherence tomography angiography (OCTA).In this prospective study, healthy, hypertensive & preeclamptic third trimester pregnant women underwent OCTA imaging. 3x3 & 6x6 mm choriocapillaris slabs were exported and the parafoveal area was marked by two concentric ETDRS circles at 1 & 3 mm, centered on the foveal avascular zone. Parafoveal AFI was calculated as a parameter of choroidal blood flow.Fifteen eyes of fifteen women per group were recruited (45 eyes). AFI was significantly lower in the preeclamptic compared to the healthy & hypertensive groups , and in the hypertensive compared to the healthy group (0.005 & 0.03 in 3x3 & 6x6 mm scans respectively).Pregnancies complicated with preeclampsia revealed the lowest choroidal blood flow on OCTA followed by pregnancies with systemic hypertension compared to healthy pregnancies. We provide in-vivo documentation of choroidal ischemia, highlighting its culpability in hypertensive and preeclamptic retinochoroidal pathology, and the possibility of utilizing choroidal blood flow on OCTA as a precursor for disease progression. Preeclampsia, commonly a disorder affecting first pregnancies, is characterized by hypertension (more than 140 mmHg systolic or 90 mmHg diastolic) occurring after 20 weeks’ gestation and may be accompanied by proteinuria [Retinal and choroidal affection is considered one of the most serious ocular complications of preeclampsia, speculated to be brought on arteriolar constriction, in up to 60% of preeclamptic patients in one study , leadingPrevious attempts at describing the underlying pathology of this retinal and choroidal aggravation in preeclamptic patients have mostly been limited to post-mortem histological studies, as well as in-vivo cross-sectional examination using optical coherence tomography (OCT) –7. DespiIn recent years, optical coherence tomography angiography (OCTA) has emerged as a non-invasive tool, capable of providing a highly-detailed, cross-sectioned angiographic representation of the retinal capillary plexuses and choroidal vasculature, along with the ability to assess their perfusion state, both qualitatively and quantitatively –12. ThesThe purpose of our study was to investigate the impact of hypertension and preeclampsia on choroidal blood flow in pregnant women in their third trimester, using OCTA, and to compare these changes with healthy pregnant women.This was a prospective, observational, cross sectional, comparative analysis of pregnant women undergoing their routine prenatal care at the obstetrics clinic at Cairo University Hospitals in Cairo, Egypt. The study was approved by the institutional review board of Kasr Al-Ainy School of Medicine, and the ethical committees of both the departments of Ophthalmology & Obstetrics and Gynecology. The study followed the tenets of the Declaration of Helsinki and was performed in accordance with Health Insurance Portability and Accountability Act regulations. Written informed consent was obtained from all participants.All pregnant women presenting to the obstetrics clinic were screened for hypertensive disorders in every antenatal care visit. Blood pressure measurement was done by a trained specialized nurse and hypertension was diagnosed clinically when systolic blood pressure was ≥ 140 mmHg or diastolic blood pressure was ≥ 90 mmHg (defined by Korotkoff phase V) occurring in two occasions at least 4 hours apart. Severe hypertension was diagnosed when systolic blood pressure ≥ 160 mmHg or diastolic pressure ≥ 110 mmHg [Inclusion criteria were treatment-naïve eyes of healthy third trimesteric pregnant women, third trimesteric hypertensive patients & third trimesteric preeclamptic patients, based on the above-mentioned criteria. Only eyes with no clinically abnormal retinal or choroidal features were considered in order to avoid imaging artifacts, and to allow the assessment of subclinical choroidal changes in these eyes. Patients underwent OCTA imaging, as described later, and the eye with the higher quality index (Q) was used for analysis. When both eyes showed a similar Q index, the right eye was uniformly chosen. For all patients, only eyes that had OCTA images without significant movement or shadow artifacts, a Q index of 6 or more and a signal strength index (SSI) score above 50 were considered eligible.Exclusion criteria included patients with any other systemic disorders which may affect the retinochoroidal vasculature, including diabetes mellitus, renal, cardiovascular, or immunological disease. They also included eyes with other retinal or choroidal diseases that may confound our results, eyes with vitreomacular traction causing macular edema, and eyes that have received intravitreal anti-VEGF agents, intravitreal triamcinolone acetonide, dexamethasone intravitreal implant, focal laser or pars plana vitrectomy. We excluded eyes with astigmatism (more than 3 diopters), high refractive error (more than 6 diopters), or cataract graded above nuclear opalescence grade three or nuclear color grade three, to avoid optical artifacts that may potentially compromise OCTA image quality. Electronic medical records were reviewed to extract demographic and clinical information.En face OCT angiograms were segmented automatically using the built-in software to define the choriocapillaris. The inner boundary of the en face image segment was set at 10 μm above, and the lower boundary at 30 μm below the Bruch’s membrane. The angiograms were then exported for adjusted flow index analysis.Patients underwent imaging using RTVue-XR Avanti device , with split-spectrum amplitude-decorrelation angiography (SSADA) software . This inen face angiogram of the parafoveal area [We exported the full retinal thickness & choriocapillaris angiograms into ImageJ  Nationa. We decieal area , 18.To eliminate the risk of bias, the images were randomized, and the grader was masked to the randomization process. The figures were calculated twice and an intra-class correlation coefficient (ICC) for the repeatability of the assessed parameter was recorded.We used IBM SPSS statistics version 25 . Intra-class correlation coefficient (ICC) for the repeatability of the measurement of adjusted flow index by the single grader (intra-grader repeatability) was 0.936. Shapiro-Wilk tests were used to determine if data was distributed normally. One-way analysis of variance (ANOVA)was used to examine the global difference between the three groups in terms of age, as well as adjusted flow index. Post-hoc Tukey Honest Significant Difference (HSD) analyses were run between group pairs. A p value of <0.05 was considered statistically significant.Sample size was calculated using Power Analysis and Sample Size (PASS) Software  Based on a worldwide prevalence of preeclampsia at an estimated 2% , a samplThe study included 15 eyes of 15 patients in each of the three study groups: healthy third trimester, hypertensive third trimester & preeclamptic third trimester patients, for a total of 45 eyes of 45 patients. Consecutive sampling of pregnant women attending the OBGYN clinic who met the inclusion and exclusion criteria was followed. The overall demographics and disease-related characteristics are reported in In both 3x3 & 6x6 mm scans, a statistically significant difference in the parafoveal choroidal AFI between the three study groups: healthy third trimester, hypertensive third trimester & preeclamptic third trimester, has been recorded. .  AFI was In this study, we used both 3x3 & 6x6 mm OCTA macular scans to evaluate the variations in adjusted blood flow in the subfoveal choriocapillaris slab in healthy, hypertensive & preeclamptic third trimester pregnancies. We demonstrated a statistically significant difference in the parafoveal choroidal blood flow between the three groups, where healthy individuals showed significantly higher blood flow compared to both hypertensive & preeclamptic patients, and the same trend was found comparing hypertensive patients to those presenting with preeclampsia.Pregnancy is associated with significant vascular changes affecting most organs & systems, attributed mostly to the hormonal variations occurring with pregnancy. Although the mainstay of these changes is vasodilation & early hypotension brought on by various prostaglandins & endothelium-dependent factors, some pregnancies are complicated by elevated levels of blood pressure, ie. gestational hypertension, which may materialize into preeclampsia, characterized by urinary loss of protein, or more life-threatening conditions, such as eclampsia & HELLP syndrome .The impact of hypertension, both in the setting of pregnant and non-pregnant individuals, on the ocular circulation has been extensively stated in literature. Nevertheless, the study of the retinal & choroidal changes brought on by hypertension during pregnancy have largely been limited by the lack of adequate angiographic representation of these changes based on the inability to utilize dye-based imaging modalities, such as fluorescein & indocyanine green angiography, which are speculated to be hazardous to the growing fetus . These cen face depictions of the vascular anatomy of the retina and choroid, along with the capacity to modulate these images based on retinal layer segmentation [Considered one of the most promising imaging modalities in overcoming these mentioned setbacks, OCTA is capable of presenting high quality angiographic representations of the retinal and choroidal vascular network, which are superimposed on the structural cross section of the OCT , 26. It entation . When apSeveral studies were able to demonstrate significantly decreased levels of macular capillary vessel density & retinal blood flow in eyes of poorly controlled hypertensive patients compared to healthy individuals & hypertensive patients with better control of their arterial blood pressure –29. ThesPertaining to preeclampsia, similar findings to those detected in hypertension have been observed. Both the superficial and deep foveal & parafoveal densities were recorded to be significantly lower in preeclamptic women compared to healthy pregnant & non-pregnant individuals , 33. HatOur study was limited by the relatively small number of eyes, which was imposed by our use of strict criteria to ensure the quality of the included images, as well as the delicate & vulnerable nature of our study groups. We also did not include analysis of the retinal blood flow & capillary density indices, in order to focus on the novelty of the choroidal perfusion indices that are widely believed to be the culprit behind the ischemic changes seen in gestational hypertensive & preeclamptic patients. Moreover, we did not perform a longitudinal analysis of these changes after the termination of pregnancy, which can be the prospect of a future study to explore the reversibility of these choroidal flow changes. Lastly, we did not use swept-source OCTA to explore whether these results would be extrapolated when using a longer wavelength, which may theoretically exhibit less artifactual images of the choroid. The strengths of our study include the inclusion of both hypertensive & preeclamptic study groups, rather than only preeclamptic patients, in order to underscore the existing differences in choroidal blood flow between the two disease entities & the possibility of utilizing them as a precursor for disease progression.In summary, our study used 3x3 & 6x6 mm macular OCTA scans to demonstrate significantly lower parafoveal choroidal blood flow in third trimester pregnant women with preeclampsia & systemic hypertension compared to healthy third trimesteric pregnant women. We also highlighted lower choroidal blood flow in preeclampsia compared to pregnancy-related hypertension. These findings provide insight into the impact of increasingly elevated levels of arterial blood pressure on the choroidal circulation & their potential burden on the function of the overlying retinal pigmentary pump mechanism. Larger longitudinal studies are needed to examine the possibility of utilizing choroidal blood flow on OCTA as a potential marker for follow up of pregnant women with warning signs of developing gestational hypertension & preeclampsia. These findings would carry significant implications on the potential role of choroidal blood flow assessment as a routine non-invasive prenatal care modality capable of providing diagnostic data for preeclampsia from other less threatening hypertensive disorders.


Wearable sensors provide a tool for at-home monitoring of motor impairment progression in neurological conditions such as Parkinson’s disease (PD). This study examined the ability of deep learning approaches to grade the motor impairment severity in a modified version of the Movement Disorders Society-sponsored revision of the Unified Parkinson’s Disease Rating Scale (MDS-UPDRS) using low-cost wearable sensors. We hypothesized that expanding training datasets with motion data from healthy older adults (HOAs) and initializing classifiers with weights learned from unsupervised pre-training would lead to an improvement in performance when classifying lower vs. higher motor impairment relative to a baseline deep learning model (XceptionTime). This study evaluated the change in classification performance after using expanded training datasets with HOAs and transferring weights from unsupervised pre-training compared to a baseline deep learning model (XceptionTime) using both upper extremity  and lower extremity (toe tapping and leg agility) tasks consistent with the MDS-UPDRS. Overall, we found a 12.2% improvement in accuracy after expanding the training dataset and pre-training using max-vote inference on hand movement tasks. Moreover, we found that the classification performance improves for every task except toe tapping after the addition of HOA training data. These findings suggest that learning from HOA motion data can implicitly improve the representations of PD motion data for the purposes of motor impairment classification. Further, our results suggest that unsupervised pre-training can improve the performance of motor impairment classifiers without any additional annotated PD data, which may provide a viable solution for a widely deployable telemedicine solution. Parkinson’s disease (PD) is a prevalent neurodegenerative disorder that is characterized by motor symptoms including bradykinesia, rigidity, resting tremor, and postural instability ,2, whileTraditional clinical evaluations of PD patients can often be time-consuming and inefficient for both patients and clinicians. While multiple rating scales have been proposed, the gold standard evaluation of motor impairment in people with PD is the Movement Disorder Society-sponsored revision of the Unified Parkinson’s Disease Rating Scale (MDS-UPDRS) . The MDSTelemedicine solutions may be well suited to evaluate people with PD, particularly in rural and underserved communities that usually lack access to healthcare ,9. TelecThe use of machine learning with behavioral data has shown great promise in differentiating the pathological and physiological motor responses arising from PD ,12,13 anHowever, one of the major challenges with machine learning in telemedicine is the extensive amounts of labeled data required to train supervised learning models . There eIn this study, we explored how transferring unsupervised pre-trained weights onto supervised models can improve the performance of motor impairment classification for PD patients. We experimented with models trained on datasets containing motion sequences from only PD patients as well as both PD patients and healthy older adults (HOAs). Firstly, we hypothesized that the inclusion of HOA motion sequences in training datasets would lead to performance improvements, since such sequences could act as a healthy control for anomaly detection. Secondly, we predicted that using unsupervised pre-trained weights to initialize our supervised classification models would improve the performance relative to random weight initialization (RandInit). We suspected that the unsupervised models from which we transferred weights would implicitly learn meaningful representations of motion sequences for the motor impairment classification objective.Overall, we sought to determine if unsupervised learning, transfer learning, and the inclusion of HOA motion sequences in training datasets can improve motor impairment classification for PD patients without using any additional data from PD patients.We collected continuous motion data from the extremities of both PD and HOA participants using a custom-built, low-cost quantitative measurement system. It consisted of a 3-axis accelerometer (ADXL335) and an evaluation board (EVAL-ADXL335Z) with USB connectors . We receThe dorsal surface of the second (middle) phalanx of each index finger;The dorsum of each arm, midway between the radius and the ulna and two inches proximal to each wrist joint.For upper extremity movements (finger tapping (FT), hand movements (HMs), and pronation–supination movement of the hands (PS)), repetitive movements were recorded at 80 Hz using two accelerometers placed at:The anterior surface of each tibia, two inches proximal to the medial malleolus;The dorsal surface of the proximal phalanx of each big toe.For lower extremity movements  and leg agility (LA)), repetitive movements were recorded at 80 Hz using two accelerometers placed at:Participants returned after a week or more for repeat testing. We used an open-source dataset  that recAll of our experiments were performed on an Apple M2 Max machine Ventura 13.4 using a 12-core CPU. We trained our models using tsai v0.3.6 , an openi at timestep j was calculated as:N of the recording was arbitrary, and two accelerometers were used. The derivative of the resultant of each accelerometer, or jerk, was calculated. Further, the root mean square was taken over the time series sequences using a 1 s window. Since the length N of each time series sequence was arbitrary, overlapping snippets of five seconds in duration  from the recordings were segmented out. Each segmented sequence was standardized at an individual sample level . Additionally, each of these segmented sequences shared a motor impairment severity label associated with the movement of the participant for the given task. These labels, originally scaled in the range of 0 to 4, were aggregated to either low (0/1) or high (3/4) levels of motor impairment. We ignored all sequences labelled as severity level 2.For each participant’s session in which a task  was performed, the resultant acceleration of the sensor The first step was to divide our sequences and labels into training, validation, and test sets, as K-fold, which divided the set of groups into K equally sized folds while maintaining the associated label distribution in each fold. We used K and set the test set K-fold guarantees that every segmented PD sequence is used at least once to evaluate the model’s performance via the test set. As such, it mitigates some of the bias surrounding model performance estimations that is caused by the arbitrary selection of training, validation, and test datasets.The set of PD groups went through a stratified XceptionTime  is a conr of the input with zeros. The masking was applied such that:The length of each masked segment was drawn from a geometric distribution with a mean of Each succeeding unmasked segment had a mean length Recent work  has demoith masked input, ith masked input, and N is the total number of masked inputs. Our procedure used the hyper-parameters K and retrieved Using the specifications detailed in K and trained 10 different supervised XceptionTime models. Of the ten models, five used For each task, we iterated from In each group of five supervised XceptionTime models, one model used random initialization for its weights. It underwent training for 50 epochs with a maximum learning rate of N is the number of training sequences, All of the supervised XceptionTime models were optimized using the binary cross entropy loss function:We considered the supervised XceptionTime model trained with Recall that the original sequences were segmented into 400 time steps. We evaluated two forms of inference from our supervised XceptionTime models on test datasets containing PD sequences. The first was segmented inference, where a motor impairment prediction was made from a single segmented sequence. The other was max-vote inference, where the motor impairment prediction for an original sequence was based on the mode of the predictions from its segmented sequences. For each form of inference, we saved and averaged metrics including the accuracy and F1 score.In addition to classifying motor impairment in individual motor tasks , we also trained aggregate unsupervised and supervised XceptionTime models. To do this, we followed the same steps as described in the previous In real-world applications, factors including administrator inexperience, positioning, and calibration issues can make accelerometer sensor measurements unexpected and noisy. To analyze how our models’ robustness to perturbations is correlated with their training set   to measu modules  within tUnder max-vote inference, every model that showed at least 10% improvement over the baseline used K trials. The models for FT improved the most, by 5.83% on average. The improvements that training with We suspect that the addition of HOA training data improves the performance by making models more generalizable and robust. Recent work  has demore equal , which hAs displayed by Overall, we have demonstrated that the use of pre-trained weights, learned from masked unsupervised learning , increasPre-trained weights have also been shown to improve the robustness of machine learning models ,33,34 foDespite the small dataset size used to generate our pre-trained weights, the max-vote accuracy improvements that we presented in all tasks in the non-perturbed case support the notion that large-scale datasets are not necessary for pre-training; even unsupervised pre-training on small-scale datasets can provide a boost in performance ,37.re space ,38. We dAnother important finding is that the feature similarities between models initialized with dings in , highligConsistent with prior work , we founFurthermore, while most tasks demonstrated a considerable improvement over baseline models, toe tapping tasks did not demonstrate an improvement in performance. These findings may be partly due to the dissimilarity of kinematics in healthy controls relative to PD participants while toe tapping, but necessitate further investigation. The current findings are consistent with the prior findings of a good reliability of bradykinesia evaluations using individual upper extremity movements  and bradIn this study, we find that expanding training datasets with HOA motion data using unsupervised learning and transferring pre-trained weights for initialization can improve the motor impairment classification performance of a continuous motion data monitor for PD patients in telemedicine applications. Our method shows particular promise in low-data domains as it does not use additional PD or annotated data compared to the baseline classification model. Thus, the incorporation of data from healthy individuals could be instrumental in refining deep learning classification models tailored for neurological disorders, serving as both a baseline and a point of reference. Such an approach could pave the way for the development of extensive datasets, since acquiring data from healthy individuals is more straightforward and may provide an easier way to enhance models in future work.In particular, we find that the addition of HOA training data improves both the classification accuracy and the robustness for most tasks in a clinical motor impairment evaluation. Furthermore, we show that unsupervised pre-training, even on small scale datasets, can provide a boost in motor impairment classification performance. Our observation that CKA feature similarities are generally higher between pre-trained classifiers than between a pre-trained and randomly initialized classifier suggests that pre-trained models exhibit feature re-use.While these result are promising, future work should focus on evaluating the current approach in a larger cohort by either collecting more PD and HOA training data, collecting healthy young adult data to establish baseline age-related changes, or by generating synthetic data with generative machine learning models. Additionally, a natural expansion of this work is to consider methods to expand the feature selection of the input data, for instance, by using data from additional IMU sensors placed on different parts of the upper or lower extremities, using spectral components of IMU motion data (with fast Fourier transforms or spectrograms), or using multiple orders of differentiation of IMU motion data. A multi-modal approach should also be considered, which uses data from different domains such as muscle activations (retrieved from electromyogram sensors).


People recently released from prison engage with emergency healthcare at greater rates than the general population. While retention in opioid agonist treatment (OAT) is associated with substantial reductions in the risk of opioid-related mortality postrelease, it is unknown how OAT affects contact with emergency healthcare. In a cohort of men who injected drugs regularly prior to imprisonment, we described rates of contact with ambulance services and EDs, and their associations with use of OAT, in the 3 months after release from prison.Self-report data from a prospective observational cohort of men who regularly injected drugs before a period of sentenced imprisonment, recruited between September 2014 and May 2016, were linked to state-wide ambulance and ED records over a 3-month postrelease period in Victoria, Australia. We used generalised linear models to estimate associations between OAT use (none/interrupted/retained) and contact with ambulance and EDs postrelease, adjusted for other covariates.Among 265 participants, we observed 77 ambulance contacts and 123 ED contacts over a median of 98 days of observation (IQR 87–125 days). Participants who were retained in OAT between prison release and scheduled 3-month postrelease follow-up interviews had lower rates of contact with ambulance (adjusted incidence rate ratio (AIRR) 0.33, 95% CI 0.14 to 0.76) and ED , compared with participants with no OAT use postrelease. Participants with interrupted OAT use did not differ from those with no OAT use in rates of contact with ambulance or ED.We found lower rates of contact with emergency healthcare after release among people retained in OAT, but not among people reporting interrupted OAT use, underscoring the benefits of postrelease OAT retention. Strategies to improve accessibility and support OAT retention after leaving prison are important for men who inject drugs. People recently released from prison have frequent contact with emergency healthcare.Opioid agonist treatment (OAT) reduces the risk of drug-related mortality postrelease, but it is unknown how OAT use affects emergency healthcare contact among people recently released from prison.This study compares rates of postrelease emergency healthcare contact among men with histories of injecting drug use according to whether they used OAT postrelease.Men retained in OAT had lower rates of emergency healthcare contact than men who did not use OAT.There was no difference between men who reported interrupted OAT use and no OAT use after release.This study highlights that access to and support for retention in OAT is associated with reduced postrelease emergency healthcare use.The physical and mental health of people in prison is typically worse than that of the general population.Previous research has sought to understand people at increased risk of postrelease emergency healthcare contact to inform postrelease support. Poor postrelease health-related quality of life,Our previous work found people who regularly injected drugs before imprisonment presented to EDs at nearly double the rate of a cohort of Australians released from prison.Investigation of whether OAT use and retention after release reduces rates of emergency healthcare contact is warranted. Among a cohort of men who regularly injected drugs preceding imprisonment in Victoria, Australia, we describe ambulance and ED contact, and examine differences in rates of emergency healthcare contact in the first 3 months after release from prison by OAT use.We used data from the Prison and Transition Health (PATH) Cohort Study,For this study, we used self-report data linked with state-wide administrative ambulance, ED, specialist public mental health service and correctional records; and national primary healthcare (Medicare) and death records. Probabilistic linkage between survey and administrative data was completed by Ambulance Victoria (ambulance), the Centre for Victorian Data Linkage , Australian Department of Human Services (Medicare) and the Australian Institute of Health and Welfare (death). Victorian Department of Justice and Community Safety (DJCS) completed deterministic data linkage between survey and reimprisonment data.At the time of manuscript preparation, reincarceration data were unavailable beyond 3-month interviews. Therefore, we only included participants who completed a 3-month follow-up interview in this analysis.Participants or the public were not involved in the design, conduct or reporting of this study; however, consultations occurred between researchers and stakeholders including government, support services and peak consumer bodies. Study findings are disseminated to interested participants as requested.Our primary outcomes for this study were total counts of contacts with Victorian (1) ambulances and (2) EDs that occurred on or between the dates of index release (determined by DJCS) and 3-month follow-up interview. If participants had multiple ambulance or ED attendances in 1 day, all attendances were counted. However, if multiple ambulance crews attended the same event, only one contact was counted. We also excluded any emergency healthcare contact that occurred from prison, for those reincarcerated during the observation period, determined by usual place of residence recorded in ambulance and ED datasets.To describe categories of emergency healthcare contacts, we used the International Statistical Classification of Disease and Related Health Problems 10th revision (ICD-10) chapter headings. ED data were supplied with ICD-10 diagnostic codes; if a participant left the ED prior to treatment, no diagnostic code was available. Given frequent misclassification of drug-related ED contacts, we also created ‘drug-related contact’  and ‘opioid-related contact’  categories.“Since we last saw you, have you been prescribed [OAT (methadone/buprenorphine)]?”, “Are you currently [prescribed OAT (methadone/buprenorphine)]?” and if currently prescribed OAT at interview, “How long have you been [prescribed OAT (methadone/buprenorphine)] for?”. Using the responses to these questions, we classified participants into one of three postrelease OAT categories . We calculated days in the community as days between the date of index release and the date of 3-month follow-up interview, minus the total number of days reimprisoned during this interval. We used likelihood ratio tests to confirm that modelling the number of times participants moved accommodation (0/1–2/3+) as a continuous, rather than categorical variable, did not worsen model fit. We used a complete-case approach to missing data, and reported model estimates as crude (IRR) and adjusted (AIRR) incidence rate ratios with 95% CIs.We conducted additional analyses to determine whether the inclusion of people who did not use opioids during observation, and were therefore ineligible for OAT, affected associations between OAT use and postrelease emergency healthcare contact. We refit each model described above, restricting the sample to include only participants who reported opioid use  between baseline and 3-month follow-up interview: (1) at least once; (2) on 15 or more days in the 30 days before follow-up interview and (3) on 25 or more days in the 30 days before follow-up interview. We used these thresholds because PATH did not enable determination of opioid use disorder. We used Stata V.14.2Of 400 PATH participants, 5 died before completing a 3-month follow-up interview. Of the remaining 395, 277 (70%) completed a 3-month follow-up interview. We excluded 12 participants from analysis, 9 because linkage to DJCS data occurred before their follow-up interview, preventing calculation of days in the community, and 3 with missing covariate data (psychiatric well-being).Participants (n=265) contributed 81 person-years at-risk during the study period . Participants were, on average, 36 years old at baseline; 16% were Aboriginal and/or Torres Strait Islander, 57% moved accommodation at least once since index release and 32% had a historical psychiatric inpatient admission. Among 263 participants for whom data were available, the most common self-reported lifetime mental health diagnoses included depression, anxiety and drug-induced psychosis, reported by 175 (67%), 128 (49%) and 90 (34%) participants, respectively. Between index release and 3-month follow-up, 59% reported no OAT use, 13% reported interrupted OAT use and 28% reported being retained on OAT . We founSeventy-six participants (29%) had at least one contact with emergency healthcare during observation; 46 participants contributed 77 ambulance contacts and 64 participants contributed 123 ED contacts between index release and 3-month follow-up interview. Thirty-four participants had at least one contact with both ambulance and ED. Drug-related contacts (42%) and symptoms, signs and abnormal clinical and laboratory findings, not elsewhere classified (26%) were the most common reasons for ambulance contact. Injury, poisoning and certain other consequences of external causes (31%), and mental and behavioural disorders (24%), were the most common reasons for ED contact .In adjusted model, we found men retained in OAT between index release and 3-month follow-up had lower rates of ambulance  and ED  contact than men who reported no use of OAT postrelease . We founMost  participants reported at least one instance of opioid use since baseline interview, and were included in secondary analysis. Associations between use of OAT and rates of ambulance and ED contact were consistent with the primary analyses .In a cohort of men who injected drugs regularly in the 6 months prior to imprisonment, approximately one in four had contact with emergency healthcare in the 3 months after release from prison. The rate of contact with emergency healthcare among men retained in OAT postrelease was less than half that of men who did not receive OAT during this time.Our results suggest that, among people released from prison, rates of emergency healthcare contact are elevated among those who regularly injected drugs before imprisonment. For example, the proportion of participants in our study who had contact with an ED during a median of 96 days of observation was approximately three times higher than that reported in a retrospective case-control study of people released from prisons in Canada.Our finding that retention in OAT was associated with lower rates of emergency healthcare contact than no OAT use is consistent with previous findings from community-recruited OAT cohortsWe found no difference between rates of postrelease emergency healthcare contact for people who did not use OAT and people who reported interrupted OAT use, although our study was likely underpowered to detect this. A previous community-based study of people enrolling in buprenorphine-OAT for the first time found that the proportion of people with at least one opioid-related ED presentation reduced in an approximate dose-response relationship as the proportion of observed days spent on OAT increased.However, improved access to OAT does not address the broader social and structural determinants of poor health and drivers of high rates of acute health episodes among people recently released from prison. Indeed, improving prerelease discharge planning and transitional healthcare,The combination of linked self-report and administrative data is a strength of our study. Linked administrative ambulance and ED data provided objective measures of emergency healthcare contact; self-report data enabled adjustment for covariates not captured in administrative data. However, our findings have limitations. A key limitation is the inability to determine current opioid use disorder from PATH data. The inclusion of people who did not use opioids or who were not opioid dependent, and therefore were not suitable for OAT, could have impacted results. However, results of secondary analyses restricting the sample to various levels of postrelease opioid use were broadly consistent with the primary analysis. Future research should re-examine this research question among people diagnosed with opioid use disorder. Participants were sentenced men; our results do not generalise to women, minors or people on pretrial detention. Our research took place in Victoria, Australia; differing prison-based and community-based health systems may limit generalisability elsewhere. Future work should seek to include groups excluded from our analysis, and occur across multiple jurisdictions. Reliance on self-report data for OAT exposure classification potentially introduced recall and misclassification bias, and precluded determination of timing of emergency healthcare contacts relative to OAT status among the interrupted OAT group, crucial to improving understanding of the relationship between interrupted OAT use and postrelease emergency healthcare contact. Although we found no differences between participants included and excluded from analysis on select covariates, we cannot exclude attrition bias. Sample size precluded examination of whether associations differed according to OAT medicine. Finally, while receiving OAT is associated with improved outcomes among people with opioid dependence,People recently released from prison have frequent contact with emergency healthcare. In men who regularly injected drugs before imprisonment in Victoria, Australia, we found that retention in OAT was associated with reduced rates of contact with ambulance and EDs in the 3 months after release. Our findings highlight the importance of programmes that provide access to OAT and support retention after release from prison. Such programmes are likely to reduce morbidity and mortality outcomes among people experiencing opioid dependence recently released from prison, while also reducing the burden on emergency healthcare.


Random quantum states serve as a powerful tool in various scientific fields, including quantum supremacy and black hole physics. It has been theoretically predicted that entanglement transitions may happen for different partitions of multipartite random quantum states; however, the experimental observation of these transitions is still absent. Here, we experimentally demonstrate the entanglement transitions witnessed by negativity on a fully connected superconducting processor. We apply parallel entangling operations, that significantly decrease the depth of the pseudo-random circuits, to generate pseudo-random pure states of up to 15 qubits. By quantum state tomography of the reduced density matrix of six qubits, we measure the negativity spectra. Then, by changing the sizes of the environment and subsystems, we observe the entanglement transitions that are directly identified by logarithmic entanglement negativities based on the negativity spectra. In addition, we characterize the randomness of our circuits by measuring the distance between the distribution of output bit-string probabilities and the Porter-Thomas distribution. Our results show that superconducting processors with all-to-all connectivity constitute a promising platform for generating random states and understanding the entanglement structure of multipartite quantum systems. It has been predicted that entanglement phase diagrams of Haar-measure random states can show interesting phenomenology, including entanglement phase transitions. Here, the authors confirm these predictions using up to 15 qubits in a fully-connected superconducting quantum processor. In addition, reduced density matrices of random states have also attracted extensive interest owing to the strong connection between quantum chaos and black hole physics10. Entanglement is a crucial property of quantum states17, and it is expected that random quantum states may hold universal entanglement characteristics, which can be classified into different phases22.Random quantum states, sampled from Haar measure, have broad applications in quantum supremacy27. Negativity also plays a significant role in diagnosing finite-temperature topological order of toric code28, entanglement properties of diffusive fermion model29, replica symmetry breaking in holography30 and finite-temperature phase transitions31. By modifying the sizes of subsystems and environment, a transition from positive partial transpose (PPT) states with a vanishing negativity to negative partial transpose (NPT) states with a non-zero negativity was numerically predicted in the large Hilbert space limit20. Recently, another phase transition between two types of NPT states was uncovered theoretically22. However, the experimental observation is still absent since the complexity of the generation of random quantum states grows exponentially with the system size32, and the measurement of entanglement is experimentally challenging42.The classification of phases is based on the entanglement between two subsystems of a tripartite random state, with the remaining party regarded as an environment. The entanglement between subsystems is quantified by the negativity, which is an effectively computable measure of entanglement for quantum states, particularly for mixed states50. The all-to-all architecture of our processor, which has been suggested to realize polynomial or exponential improvements in some quantum algorithms52, helps to decrease the circuit depth and exposure to noise. Then, we utilize the quantum state tomography (QST) to directly obtain reduced density matrices of subsystems with six qubits58 and calculate the negativity spectra. Other proposals to explore negativity require either multiple copies of target states27 or global random unitary operators59, which are both demanding for the present noisy intermediate-scale quantum devices. Our results represent the first experimental investigation of the entanglement negativity transition for random quantum states. It should be noted that many efforts have been made in studying negativity experimentally61. Our results are established on the reconstruction of reduced density matrices, which contain complete entanglement information in the mixed states.In this work, we report our experiments in probing entanglement negativity transition for pseudo-random quantum states using a fully connected superconducting quantum processor. A fully connected quantum processor may enhance the entangling power of shallow circuits compared with short-range connected processors and facilitate the realization of random quantum states. We apply the parallel entangling gates to realize the pseudo-random quantum circuits for generating pseudo-random states of 7–15 qubits, which can mimic specific statistical properties of random statesN random single-qubit gates sampled from Haar measure on the SU(2) group and a global entangling gate U. By controlling the amplitudes and phases of Gaussian-enveloped microwave pulses transmitted by the XY lines, as shown in Fig. xy plane62. The global entangling gate U acting on the N qubits is defined asN qubits by equally detuning them from resonator 64. 65.Our processor contains 20 frequency-tunable transmon qubits and one central resonator. We use 15 qubits in the experiments and tune the frequencies of remaining qubits lower than 4 GHz. All qubits are capacitively coupled to the central resonator, as shown in Fig. }Qj Fig. , and \doBy dividing all qubits into three parts, 22. NPT states can be furthermore classified into maximally entangled (ME) states and entanglement saturation (ES) states via negativity22. The phase diagram of the reduced density matrix 22. To characterize the transition from PPT to NPT, which occurs at 22, we fix the sizes of two subsystems as 22, i.e.,22. When The volume or size 22. Next, we set 22.The second phase transition from ES to ME occurs at 22Figure N68. Figure 69. 69. Although the output of three-layer circuits for nine qubits is closest to the PT distribution in experiments, we observe that three-layer circuits are not deep enough for the negativity spectra to converge  operator into two rotations of which rotation axes both lie in the The rotation angle of the second rotation is always 72Since any SU(2) operator sampled from Haar measure can be written as72. Then we can obtain the experiment parameters For each random single-qubit gate in experiments, we firstly draw into Eq. . BesidesSupplementary InformationPeer Review File


Colonic self-expandable metallic stent (SEMS) placement enables preoperative total colonoscopy (TCS) in patients with obstructive colorectal cancer. Following SEMS placement, it is possible to assess the presence or absence of synchronous proximal colon cancers and perform preoperative endoscopic resection (ER) for neoplastic lesions proximal to the primary lesion. The objective of this study was to determine the usefulness and safety of preoperative TCS and ER after SEMS placement in patients with obstructive colorectal cancer.From April 2016 to March 2022, we enrolled 100 patients with obstructive colorectal cancer who underwent SEMS placement, including 86 patients who underwent preoperative TCS after SEMS placement. Complications associated with preoperative TCS and ER after SEMS placement and the characteristics of the neoplastic lesions were assessed.The success rate of SEMS placement as bridge-to-surgery was 98.0%; six patients had associated complications. Preoperative TCS was performed 8 (range: 1–30) days after SEMS placement. Four patients had synchronous advanced cancers. Nine non-advanced synchronous cancers, 116 adenomas, and 18 sessile-serrated lesions were treated by preoperative TCS and ER after SEMS placement. No procedure-related complications, namely stent migration, bleeding, and perforation were observed. Forty-five patients underwent follow-up TCS 1 year after surgery. Only one patient with submucosal invasive cancer required a second surgery.Preoperative TCS and ER after SEMS placement was performed with no complications. This approach allows preoperative evaluation of the entire colon and the treatment of precancerous lesions. (240 words) Placement of colonic self-expandable metallic stents (SEMS) is widely performed in patients with obstructive colorectal cancer as a bridge-to-surgery (BTS). This procedure avoids emergency surgery by resolving obstruction to the passage of stool and obstructive enterocolitis. Colonic SEMS placement for BTS not only minimizes postoperative complications and the risk of colostomy compared with emergency surgery –3, but aFrom April 2016 to March 2022, 100 patients with obstructive colorectal cancer admitted to our hospital underwent colonic SEMS placement for BTS. The Niti-S colonic stent  or HANAROSTENT Naturfit colonic stent  were used. In all cases, plain abdominal X-rays were obtained 2 days after colonic SEMS placement to confirm sufficient expansion. Eighty-six patients underwent preoperative TCS after preparation with an osmotic laxative . Forty-seven patients underwent ER, which comprised CSP, EMR, or ESD, after stent placement (Table Of the 100 patients with obstructive colorectal cancer, colonic SEMS placement for BTS was performed successfully in 98 patients Fig. . PreoperIn obstructive colorectal cancer, the reported frequency of synchronous colon cancers is 9% . RecentlIt is important to note that colorectal cancer can be detected even in patients who undergo TCS between 6 months and several years before the diagnosis, namely post-colonoscopy colorectal cancer. Patients with a history of colorectal cancer surgery have a risk of developing post-colonoscopy colorectal cancer . The JapBeing able to perform colonoscopy with a thin-diameter colonoscope through the SEMS provides very important advantages for the treatment of the patient, but colonic SEMS placement for the sole purpose of proximal colon observation or ER, but not for BTS, should be avoided. There were no complications associated with preoperative TCS and ER after SEMS placement in the present study. However, colonic SEMS placement is not recommended for patients with obstructive colorectal cancer without obstructive symptoms in accordance with the Japanese Society for Cancer of the Colon and Rectum Guideline 2022 for the treatment of colorectal cancer. This is because the procedure-related perforation rate is reported to be 1.6%, and the rate of the risk of deviation is reported to be 1.3% .The limitations of this study are small sample size, for there is no data for long-term course but only short follow-up after surgery. More statistical analysis of those patients by longer follow-up is necessary.In conclusion, preoperative TCS and ER after SEMS placement was performed without complications, in this study. This approach permits preoperative evaluation of the entire colon and the treatment of precancerous lesions, which can avoid unnecessary multiple surgeries in patients with obstructive colorectal cancer.