An interactive resource to identify cancer genetic and lineage dependencies targeted by small molecules.

The high rate of clinical response to protein-kinase-targeting drugs matched to cancer patients with specific genomic alterations has prompted efforts to use cancer cell line (CCL) profiling to identify additional biomarkers of small-molecule sensitivities. We have quantitatively measured the sensitivity of 242 genomically characterized CCLs to an Informer Set of 354 small molecules that target many nodes in cell circuitry, uncovering protein dependencies that: (1) associate with specific cancer-genomic alterations and (2) can be targeted by small molecules. We have created the Cancer Therapeutics Response Portal (http://www.broadinstitute.org/ctrp) to enable users to correlate genetic features to sensitivity in individual lineages and control for confounding factors of CCL profiling. We report a candidate dependency, associating activating mutations in the oncogene ß-catenin with sensitivity to the Bcl-2 family antagonist, navitoclax. The resource can be used to develop novel therapeutic hypotheses and to accelerate discovery of drugs matched to patients by their cancer genotype and lineage.

Association between adherence to posttreatment National Comprehensive Cancer Network (NCCN) surveillance guidelines and detection of recurrent uterine cancer.

OBJECTIVE: To identify correlations between disease recurrence and adherence to NCCN posttreatment surveillance guidelines in patients who develop recurrent uterine cancer. METHODS: Retrospective analysis identified patients (n = 60) with recurrent uterine cancer and at least one surveillance visit with a gynecologic oncologist between 2011 and 2020. Adherence to NCCN guidelines and details of recurrence were recorded. RESULTS: Recurrent uterine cancer was identified in 60 patients with an average time to recurrence (TTR) of 25 months. Of those, 39 (65%) were adherent to NCCN surveillance guidelines and 36 (60%) were symptomatic at the time of recurrence diagnosis. Asymptomatic recurrence was diagnosed by imaging in 11 (46%), physical exam in 7 (29%), and blood work in 6 (25%) patients. Patients who were adherent to NCCN guidelines were diagnosed with recurrence on average 11 months earlier (p = 0.0336). Adherence was an independent predictor of TTR for all patients regardless of symptoms. There was no significant effect of age, race, primary language, or stage of disease on adherence. CONCLUSION: Adherence to NCCN posttreatment surveillance guidelines for uterine cancer is independently associated with an earlier diagnosis of recurrence.

Pembrolizumab alone and pembrolizumab plus chemotherapy in previously treated, extrapulmonary poorly differentiated neuroendocrine carcinomas.

BACKGROUND: To date, single-agent immune checkpoint inhibitor (CPI) therapy has proven to be ineffective against biomarker-unselected extrapulmonary poorly differentiated neuroendocrine carcinomas (EP-PDNECs). The efficacy of CPI in combination with chemotherapy remains under investigation. METHODS: Patients with advanced, progressive EP-PDNECs were enrolled in a two-part study of pembrolizumab-based therapy. In Part A, patients received pembrolizumab alone. In Part B, patients received pembrolizumab plus chemotherapy. PRIMARY ENDPOINT: objective response rate (ORR). Secondary endpoints: safety, progression-free survival (PFS) and overall survival (OS). Tumours were profiled for programmed death-ligand 1 expression, microsatellite-high/mismatch repair deficient status, mutational burden (TMB), genomic correlates. Tumour growth rate was evaluated. RESULTS: Part A (N = 14): ORR (pembrolizumab alone) 7% (95% CI, 0.2-33.9%), median PFS 1.8 months (95% CI, 1.7-21.4), median OS 7.8 months (95% CI, 3.1-not reached); 14% of patients (N = 2) had grade 3/4 treatment-related adverse events (TRAEs). Part B (N = 22): ORR (pembrolizumab plus chemotherapy) 5% (95% CI, 0-22.8%), median PFS 2.0 months (95% CI, 1.9-3.4), median OS 4.8 months (95% CI, 4.1-8.2); 45% of patients (N = 10) had grade 3/4 TRAEs. The two patients with objective response had high-TMB tumours. DISCUSSION: Treatment with pembrolizumab alone and pembrolizumab plus chemotherapy was ineffective in advanced, progressive EP-PDNECs. CLINICAL TRIAL REGISTRATION: ClinicalTrials.gov NCT03136055.

Meaningful engagement through critical reflexivity: Engaging people with lived experience in continuing mental health professional development.

Engaging people with lived experience of mental health system encounters in the design and actualization of continuing professional development initiatives for mental health professionals can have transformative systemic impacts. Yet, despite evidence that involving people with lived experience benefits mental health professional education, far less focus has been placed on how to engage people with lived experience in continuing professional development initiatives. Tensions persist regarding the role of lived experience perspectives in continuing professional development, as well as how to establish people with lived experience as partners, educators and leaders in a thoughtful way. We propose that meaningful and equitable partnerships with people with lived experience can be realized by engaging in critical reflexivity and by systematically challenging assumptions. This paper explores three topics: (1) the current state of engagement with people with lived experience in continuing professional development initiatives; (2) barriers to meaningful engagement and (3) recommendations for using critical reflexivity to support the involvement and leadership of people with lived experience in continuing professional development for mental health professionals. PATIENT OR PUBLIC INVOLVEMENT: This viewpoint manuscript was co-designed and co-written by people with diverse lived and learned experiences. Each author's professional roles involve meaningfully and equitably partnering with and centring the perspectives of those with lived experience of mental health system encounters. In addition, approximately half of the authorship team identifies as having lived experience of accessing the psychiatric system and/or supporting family members who are navigating challenges related to mental health. These lived and learned experiences informed the conception and writing of this article.

Analysis of Sociodemographic Factors Affecting Ambulatory Surgical Center Discharge Patterns for Endometrial Cancer Hysterectomies.

STUDY OBJECTIVE: Investigate outcomes for patients undergoing minimally invasive hysterectomies (MIHs) performed for endometrial cancer at ambulatory surgery centers (ASCs). DESIGN: Our study aimed to explore the feasibility and discharge outcomes for MIHs for endometrial cancer in an ASC setting by using same-day discharge data. SETTING: The prevalence of MIH for endometrial cancer between 2016 and 2019 was estimated from the Nationwide Ambulatory Surgery Sample. PATIENTS: Patients who underwent MIHs for endometrial cancer at an ASC were included. INTERVENTIONS: N/A MEASUREMENTS MAIN RESULTS: Weighted estimates of prevalence and association between discharge status and sociodemographic factors were explored. Same-day discharge was defined as discharge on the day of surgery, and delayed discharge was defined as discharge after the day of surgery. An estimated 95 041 MIHs for endometrial cancer were performed at ASCs between 2016 and 2019. Notably, 91.9% (n = 87 372) resulted in same-day discharge, 1.2% (n = 1121) had delayed discharge, and 6.9% (n = 6548) had missing discharge information; 78.7% procedures (n = 68 812) were performed at public hospitals. The proportion of delayed discharges were lower in private, not-for profit ASCs (0.8%, p = .03) than public hospitals. Patients who had delayed discharges on average were older (69.7 vs 62.4 years, p <.001), more likely to have comorbid conditions including diabetes (adjusted odds ratio [aOR] 1.48, 95% confidence interval [CI] 1.25-1.75) and overweight or obese body mass indices (aOR 1.18, 95% CI 1.01-1.39), and more likely to have public insurance (aOR 1.78, 95% CI 1.40-2.25). CONCLUSION: MIHs for endometrial cancer are feasible in an ASC. Optimal candidates for receipt of MIHs for endometrial cancer at an ASC are patients who are younger and have less comorbidities, lower body mass index, and private insurance.

Popular repugnance contrasts with legal bans on controversial markets.

We study popular attitudes in Germany, Spain, the Philippines, and the United States toward three controversial markets-prostitution, surrogacy, and global kidney exchange (GKE). Of those markets, only prostitution is banned in the United States and the Philippines, and only prostitution is allowed in Germany and Spain. Unlike prostitution, majorities support legalization of surrogacy and GKE in all four countries. So, there is not a simple relation between public support for markets, or bans, and their legal and regulatory status. Because both markets and bans on markets require social support to work well, this sheds light on the prospects for effective regulation of controversial markets.

Outcomes of Shared Decision-Making for Low-Dose Screening for Lung Cancer in an Academic Medical Center.

Shared decision-making (SDM) helps patients weigh risks and benefits of screening approaches. Little is known about SDM visits between patients and healthcare providers in the context of lung cancer screening. This study explored the extent that patients were informed by their provider of the benefits and harms of lung cancer screening and expressed certainty about their screening choice. We conducted a survey with 75 patients from an academic medical center in the Southeastern U.S. Survey items included knowledge of benefits and harms of screening, patients' value elicitation during SDM visits, and decisional certainty. Patient and provider characteristics were collected through electronic medical records or self-report. Descriptive statistics, Kruskal-Wallis tests, and Pearson correlations between screening knowledge, value elicitation, and decisional conflict were calculated. The sample was predominately non-Hispanic White (73.3%) with no more than high school education (53.4%) and referred by their primary care provider for screening (78.7%). Patients reported that providers almost always discussed benefits of screening (81.3%), but infrequently discussed potential harms (44.0%). On average, patients had low knowledge about screening (score = 3.71 out of 8) and benefits/harms. Decisional conflict was low (score = - 3.12) and weakly related to knowledge (R= - 0.25) or value elicitation (R= - 0.27). Black patients experienced higher decisional conflict than White patients (score = - 2.21 vs - 3.44). Despite knowledge scores being generally low, study patients experienced low decisional conflict regarding their decision to undergo lung cancer screening. Additional work is needed to optimize the quality and consistency of information presented to patients considering screening.

Epidural electrical stimulation of the cervical spinal cord opposes opioid-induced respiratory depression.

Opioid overdose suppresses brainstem respiratory circuits, causes apnoea and may result in death. Epidural electrical stimulation (EES) at the cervical spinal cord facilitated motor activity in rodents and humans, and we hypothesized that EES of the cervical spinal cord could antagonize opioid-induced respiratory depression in humans. Eighteen patients requiring surgical access to the dorsal surface of the spinal cord between C2 and C7 received EES or sham stimulation for up to 90 s at 5 or 30 Hz during complete (OFF-State) or partial suppression (ON-State) of respiration induced by remifentanil. During the ON-State, 30 Hz EES at C4 and 5 Hz EES at C3/4 increased tidal volume and decreased the end-tidal carbon dioxide level compared to pre-stimulation control levels. EES of 5 Hz at C5 and C7 increased respiratory frequency compared to pre-stimulation control levels. In the OFF-State, 30 Hz cervical EES at C3/4 terminated apnoea and induced rhythmic breathing. In cadaveric tissue obtained from a brain bank, more neurons expressed both the neurokinin 1 receptor (NK1R) and somatostatin (SST) in the cervical spinal levels responsive to EES (C3/4, C6 and C7) compared to a region non-responsive to EES (C2). Thus, the capacity of cervical EES to oppose opioid depression of respiration may be mediated by NK1R+/SST+ neurons in the dorsal cervical spinal cord. This study provides proof of principle that cervical EES may provide a novel therapeutic approach to augment respiratory activity when the neural function of the central respiratory circuits is compromised by opioids or other pathological conditions. KEY POINTS: Epidural electrical stimulation (EES) using an implanted spinal cord stimulator (SCS) is an FDA-approved method to manage chronic pain. We tested the hypothesis that cervical EES facilitates respiration during administration of opioids in 18 human subjects who were treated with low-dose remifentanil that suppressed respiration (ON-State) or high-dose remifentanil that completely inhibited breathing (OFF-State) during the course of cervical surgery. Dorsal cervical EES of the spinal cord augmented the respiratory tidal volume or increased the respiratory frequency, and the response to EES varied as a function of the stimulation frequency (5 or 30 Hz) and the cervical level stimulated (C2-C7). Short, continuous cervical EES restored a cyclic breathing pattern (eupnoea) in the OFF-State, suggesting that cervical EES reversed the opioid-induced respiratory depression. These findings add to our understanding of respiratory pattern modulation and suggest a novel mechanism to oppose the respiratory depression caused by opioids.

Cytomegalovirus infection reduced CD70 expression, signaling and expansion of viral specific memory CD8+ T cells in healthy human adults.

BACKGROUND: Cytomegalovirus (CMV) infection leads to effector memory CD8+ T cell expansion and is associated with immune dysfunction in older adults. However, the molecular alterations of CMV-specific CD8+ T cells in CMV infected healthy young and middle-aged adults has not been fully characterized. RESULTS: We compared CD8+ T cells specific for a CMV epitope (pp65495-503, NLV) and an influenza A virus (IAV) epitope (M158-66, GIL) from the same young and middle-aged healthy adults with serum positive for anti-CMV IgG. Compared to the IAV-specific CD8+ T cells, CMV-specific CD8+ T cells contained more differentiated effector memory (TEM and TEMRA) cells. Isolated CMV-specific central memory (TCM) but not naïve (TN) cells had a significant reduced activation-induced expansion in vitro compared to their IAV-specific counterparts. Furthermore, we found that CD70 expression was reduced in CMV-specific CD28+CD8+ TCM and that CD70+ TCM had better expansion in vitro than did CD70- TCM. Mechanistically, we showed that CD70 directly enhanced MAPK phosphorylation and CMV-specific CD8+ TCM cells had a reduced MAPK signaling upon activation. Lastly, we showed that age did not exacerbate reduced CD70 expression in CMV- specific CD8+ TCM cells. CONCLUSION: Our findings showed that CMV infection causes mild expansion of CMV-NLV-specific CD8+ T cells, reduced CD70 expression and signaling, and proliferation of CMV-NLV-specific CD8+ TCM cells in young and middle-aged healthy adults and revealed an age-independent and CMV infection-specific impact on CD8+ memory T cells.

Incidence, Mortality, and Treatment Patterns of Synchronous Lower Genital Tract Squamous Cell Carcinoma.

OBJECTIVE: The aim of the study was to define the incidence, prognosis, and treatment patterns associated with synchronous lower genital tract squamous cell carcinoma (LGTSCC) among women diagnosed with any LGTSCC. MATERIALS AND METHODS: Surveillance, Epidemiology, and End Results (SEER) database patients diagnosed with synchronous cervical, vaginal, vulvar, and/or anal SCC from 2000 to 2016 were included. Incidence and mortality were evaluated using Kaplan-Meier curves. Multivariable Cox proportional hazards regression was used to identify treatment patterns, risk factors, and mortality associated with LGTSCC. RESULTS: Among 15,424 women with LGTSCC, 138 had synchronous LGTSCC (0.89%). Vulvar and vaginal SCC was the most common combination (49.3%), and cervical with anal SCC was the least common (1.4%). Only one patient had 3 or more primary LGTSCC. Synchronous LGTSCC was independently associated with higher mortality compared with single-site LGTSCC (adjusted hazards ratio [aHR] = 1.67; p < .001). Synchronous LGTSCC was significantly associated with older age (63 vs. 58 years, p < .001) and lower stage (adjusted odds ratio [aOR] = 0.38; p < .001) and grade of disease (aOR = 0.32; p < .001). Patients with synchronous LGTSCC were more likely to receive radiation (aOR = 1.74; p = .005) and were more likely to receive adjuvant radiation after primary surgical resection compared with single-site LGTSCC (aOR = 1.88; p = .007). Receipt of any treatment including radiation (aHR = 0.85; p < .001), chemotherapy (aHR = 0.50; p < .001), and surgery (aHR = 0.70; p < .001) was independently associated with decreased mortality hazard. CONCLUSIONS: Synchronous LGTSCC is rare but is associated with increased mortality and higher rates of adjuvant radiation compared with single-site LGTSCC despite lower stage and grade at diagnosis. More research is needed to define optimal therapy for these patients.

Diagnostic Utility of Endocervical Curettage During Colposcopy Among Patients of Varying Risk Factors.

OBJECTIVE: Endocervical curettage (ECC) during colposcopy is recommended in certain circumstances; however, diagnostic use remains unclear. We evaluate the utility of ECC among patients with non-fully visualized squamocolumnar junction (SCJ) and certain patient socioeconomic factors. METHODS: Retrospective chart analysis was completed for patients aged older than 21 years who underwent a colposcopy at 2 study sites between 2012 and 2021. Demographics and histopathologic results were analyzed. RESULTS: A total of 1,516 colposcopies were reviewed; 73.8% (n = 1,119) had an ECC with colposcopy. Of those, 92.1% (n = 1,031) had benign ECC whereas 13.9% (n = 156) had a positive ECC at time of colposcopy. Most patients with benign ECC had benign/low-grade squamous intraepithelial lesion pathology on colposcopy biopsy (82.3%; n = 914; p < .001), and most patients with high-grade squamous intraepithelial lesion (HSIL) on ECC had HSIL on colposcopy biopsy (63.4%; n = 52; p < .001) However, when looking at patients with high-grade pathology on colposcopy biopsy, it was seen that most had benign or low-grade squamous intraepithelial lesion on ECC (79.5%; n = 205; p < .001). Most patients with adequately visualized SCJ on colposcopy were noted to have HSIL on biopsy and negative ECC (73%; n = 81; p < .001). This result was similar in patients with non-fully visualized SCJ, although not statistically significant. When stratified by socioeconomic status, most patients with high-grade lesions had a benign ECC. CONCLUSIONS: Endocervical curettage has been described to increase the identification of high-grade lesions at time of colposcopy. This descriptive study shows that many high-grade lesions at time of excisional procedure had a benign ECC on colposcopy, with no demonstrated clear additional utility in high-risk groups.

Association between common telomere length genetic variants and telomere length in an African population and impacts of HIV and TB.

Prior studies in predominantly European (Caucasian) populations have discovered common genetic variants (single nucleotide polymorphisms, SNPs) associated with leukocyte telomere length (LTL), but whether these same variants affect LTL in non-Caucasian populations are largely unknown. We investigated whether six genetic variants previously associated with LTL (TERC (rs10936599), TERT (rs2736100), NAF1 (7675998), OBFC1 (rs9420907), ZNF208 (rs8105767), and RTEL1 (rs755017)) are correlated with telomere length (TL) in peripheral blood mononuclear cells (PBMCs) in a cohort of Africans living with and without HIV and undergoing evaluation for tuberculosis (TB). We found OBFC1 and the genetic sum score of the effect alleles across all six loci to be associated with shorter TL (adjusted for age, gender, HIV status, and smoking pack-years (p < 0.02 for both OBFC1 and the genetic sum score). In an analysis stratified by HIV status, the genetic sum score is associated with LTL in both groups with and without HIV. On the contrary, a stratified analysis according to TB status revealed that in the TB-positive subgroup, the genetic sum score is not associated with LTL, whereas the relationship remains in the TB-negative subgroup. The different impacts of HIV and TB on the association between the genetic sum score and LTL indicate different modes of modification and suggest that the results found in this cohort with HIV and TB participants may not be applied to the African general population. Future studies need to carefully consider these confounding factors.

Optogenetic neuronal stimulation promotes functional recovery after stroke.

Clinical and research efforts have focused on promoting functional recovery after stroke. Brain stimulation strategies are particularly promising because they allow direct manipulation of the target area's excitability. However, elucidating the cell type and mechanisms mediating recovery has been difficult because existing stimulation techniques nonspecifically target all cell types near the stimulated site. To circumvent these barriers, we used optogenetics to selectively activate neurons that express channelrhodopsin 2 and demonstrated that selective neuronal stimulations in the ipsilesional primary motor cortex (iM1) can promote functional recovery. Stroke mice that received repeated neuronal stimulations exhibited significant improvement in cerebral blood flow and the neurovascular coupling response, as well as increased expression of activity-dependent neurotrophins in the contralesional cortex, including brain-derived neurotrophic factor, nerve growth factor, and neurotrophin 3. Western analysis also indicated that stimulated mice exhibited a significant increase in the expression of a plasticity marker growth-associated protein 43. Moreover, iM1 neuronal stimulations promoted functional recovery, as stimulated stroke mice showed faster weight gain and performed significantly better in sensory-motor behavior tests. Interestingly, stimulations in normal nonstroke mice did not alter motor behavior or neurotrophin expression, suggesting that the prorecovery effect of selective neuronal stimulations is dependent on the poststroke environment. These results demonstrate that stimulation of neurons in the stroke hemisphere is sufficient to promote recovery.

An efficient synthesis of an exo-enone analogue of LL-Z1640-2 and evaluation of its protein kinase inhibitory activities.

An efficient synthesis of an exo-enone analogue (5) of resorcylic acid lactone (RAL), natural product LL-Z1640-2 (1), has been achieved using a Ni-catalysed regioselective reductive coupling macrocyclisation of an alkyne-aldehyde as a key step. The synthetic route is significantly shorter than those for the natural product and avoids the isomerisation problem of the cis-double bond in the molecule. The preliminary biological evaluation showed that the exo-enone analogue is a potent inhibitor of several important kinases relevant to cancer drug development.

Poverty and Economic Decision-Making: Evidence from Changes in Financial Resources at Payday.

We study the effect of financial resources on decision-making. Low-income U.S. households are randomly assigned to receive an online survey before or after payday. The survey collects measures of cognitive function and administers risk and intertemporal choice tasks. The study design generates variation in cash, checking and savings balances, and expenditures. Before-payday participants behave as if they are more present-biased when making intertemporal choices about monetary rewards but not when making intertemporal choices about non-monetary real-effort tasks. Nor do we find before-after differences in risk-taking, the quality of decision-making, the performance in cognitive function tasks, or in heuristic judgments.

Misfolded proteins impose a dosage-dependent fitness cost and trigger a cytosolic unfolded protein response in yeast.

Evolving lineages face a constant intracellular threat: most new coding sequence mutations destabilize the folding of the encoded protein. Misfolded proteins form insoluble aggregates and are hypothesized to be intrinsically cytotoxic. Here, we experimentally isolate a fitness cost caused by toxicity of misfolded proteins. We exclude other costs of protein misfolding, such as loss of functional protein or attenuation of growth-limiting protein synthesis resources, by comparing growth rates of budding yeast expressing folded or misfolded variants of a gratuitous protein, YFP, at equal levels. We quantify a fitness cost that increases with misfolded protein abundance, up to as much as a 3.2% growth rate reduction when misfolded YFP represents less than 0.1% of total cellular protein. Comparable experiments on variants of the yeast gene orotidine-5'-phosphate decarboxylase (URA3) produce similar results. Quantitative proteomic measurements reveal that, within the cell, misfolded YFP induces coordinated synthesis of interacting cytosolic chaperone proteins in the absence of a wider stress response, providing evidence for an evolved modular response to misfolded proteins in the cytosol. These results underscore the distinct and evolutionarily relevant molecular threat of protein misfolding, independent of protein function. Assuming that most misfolded proteins impose similar costs, yeast cells express almost all proteins at steady-state levels sufficient to expose their encoding genes to selection against misfolding, lending credibility to the recent suggestion that such selection imposes a global constraint on molecular evolution.

Evaluation of educational videos to increase skin cancer risk awareness and sun-safe behaviors among adult Hispanics.

Although skin cancer is less common in Hispanics, they are at higher risk for presenting with more advanced stage skin cancer. We performed semi-structured interviews with Hispanic women that found high concern for photoaging from sun exposure. Based on these results, we developed two short Spanish-language films. The first emphasized photoaging benefits of sun protection, while the second focused on its benefits for skin cancer prevention. Our hypothesis was that the reduction of photoaging would be a more persuasive argument than skin cancer prevention for the adoption of sunscreen use by Hispanic women. Study participants were recruited from beauty salons located in predominantly Hispanic neighborhoods. Each of the two Spanish-language films was approximately 3 min long. A pre-intervention questionnaire assessed subjects' general knowledge and sunscreen habits, and a second questionnaire administered after viewing both films assessed for improvements in risk perception and inquired about which film was more persuasive. Eighty Hispanics participated ranging in age from 19 to 75. The pre-education survey found that 54 out of 80 believed that fair-skin Hispanics (FS) were at risk for skin cancer, and 44 out of 80 believed that dark-skin Hispanics (DS) were at risk. These numbers increased to 72 (FS) and 69 (DS) after the intervention (p value: <0.0002 FS, <0.0001 DS). Hispanics overwhelmingly selected the video emphasizing the benefits of sun protection for skin cancer prevention as the more persuasive film (74 out of 80). A Spanish-language video has the potential to make an impact in healthy sun-protective behaviors, and information on how to properly apply sunscreen should be included in educational messages.

Short-Term Outcomes After Hysterectomy for Endometrial Cancer/EIN With Concomitant Pelvic Floor Disorder Surgery.

IMPORTANCE: Endometrial cancer and precancer are common gynecologic problems for many women. A majority of these patients require surgery as the mainstay of treatment. Many of these patients often have concurrent pelvic floor disorders. Despite the prevalence and shared risk, fewer than 3% of women undergo concomitant surgery for PFDs at the time of surgery for endometrial cancer or endometrial intraepithelial neoplasia/hyperplasia. OBJECTIVE: This study aimed to evaluate postoperative morbidity of concomitant pelvic organ prolapse (POP) and/or urinary incontinence (UI) procedures at the time of hysterectomy for endometrial cancer (EC) or endometrial intraepithelial neoplasia/endometrial hyperplasia (EIN/EH). METHODS: This retrospective analysis of women undergoing hysterectomy for EC or EIN/EH between 2017 and 2022 used the American College of Surgeons National Surgical Quality Improvement Program database. The primary outcome was any major complication within 30 days of surgery. Comparisons were made between 2 cohorts: hysterectomy with concomitant pelvic organ prolapse/urinary incontinence procedures (POPUI) versus hysterectomy without concomitant POP or UI procedures (HYSTAlone). A subgroup analysis was performed in patients with EC. A propensity score matching cohort was also created. RESULTS: A total of 23,144 patients underwent hysterectomy for EC or EIN/EH: 1.9% (n = 432) had POP and/or UI procedures. Patients with POPUI were older, were predominantly White, had higher parity, and had lower body mass index with lower American Society of Anesthesiologists class. Patients with POPUI were less likely to have EC (65.7% vs 78.3%, P < 0.0001) and more likely to have their hysterectomy performed by a general obstetrician- gynecologists or urogynecologists. Major complications were low and not significantly different between POPUI and HYSTAlone (3.7% vs 3.6%, P = 0.094). A subgroup analysis of EC alone found that the HYSTAlone subset did not have more advanced cancers, yet the surgeon was more likely a gynecologic oncologist (87.1% vs 68.0%, P < 0.0001). There were no statistically significant differences between the 2 cohorts for the primary and secondary outcomes using propensity score matching analysis. CONCLUSIONS: Concomitant prolapse and/or incontinence procedures were uncommon and did not increase the rate of 30-day major complications for women undergoing hysterectomy for EC/EH.

Predicting reoperation and readmission for head and neck free flap patients using machine learning.

BACKGROUND: To develop machine learning (ML) models predicting unplanned readmission and reoperation among patients undergoing free flap reconstruction for head and neck (HN) surgery. METHODS: Data were extracted from the 2012-2019 NSQIP database. eXtreme Gradient Boosting (XGBoost) was used to develop ML models predicting 30-day readmission and reoperation based on demographic and perioperative factors. Models were validated using 2019 data and evaluated. RESULTS: Four-hundred and sixty-six (10.7%) of 4333 included patients were readmitted within 30 days of initial surgery. The ML model demonstrated 82% accuracy, 63% sensitivity, 85% specificity, and AUC of 0.78. Nine-hundred and four (18.3%) of 4931 patients underwent reoperation within 30 days of index surgery. The ML model demonstrated 62% accuracy, 51% sensitivity, 64% specificity, and AUC of 0.58. CONCLUSION: XGBoost was used to predict 30-day readmission and reoperation for HN free flap patients. Findings may be used to assist clinicians and patients in shared decision-making and improve data collection in future database iterations.

A Real-World Precision Medicine Program Including the KidneyIntelX Test Effectively Changes Management Decisions and Outcomes for Patients With Early-Stage Diabetic Kidney Disease.

INTRODUCTION/OBJECTIVE: The KidneyIntelX is a multiplex, bioprognostic, immunoassay consisting of 3 plasma biomarkers and clinical variables that uses machine learning to predict a patient's risk for a progressive decline in kidney function over 5 years. We report the 1-year pre- and post-test clinical impact on care management, eGFR slope, and A1C along with engagement of population health clinical pharmacists and patient coordinators to promote a program of sustainable kidney, metabolic, and cardiac health. METHODS: The KidneyIntelX in vitro prognostic test was previously validated for patients with type 2 diabetes and diabetic kidney disease (DKD) to predict kidney function decline within 5 years was introduced into the RWE study (NCT04802395) across the Health System as part of a population health chronic disease management program from [November 2020 to April 2023]. Pre- and post-test patients with a minimum of 12 months of follow-up post KidneyIntelX were assessed across all aspects of the program. RESULTS: A total of 5348 patients with DKD had a KidneyIntelX assay. The median age was 68 years old, 52% were female, 27% self-identified as Black, and 89% had hypertension. The median baseline eGFR was 62 ml/min/1.73 m2, urine albumin-creatinine ratio was 54 mg/g, and A1C was 7.3%. The KidneyIntelX risk level was low in 49%, intermediate in 40%, and high in 11% of cases. New prescriptions for SGLT2i, GLP-1 RA, or referral to a specialist were noted in 19%, 33%, and 43% among low-, intermediate-, and high-risk patients, respectively. The median A1C decreased from 8.2% pre-test to 7.5% post-test in the high-risk group (P < .001). UACR levels in the intermediate-risk patients with albuminuria were reduced by 20%, and in a subgroup treated with new scripts for SGLT2i, UACR levels were lowered by approximately 50%. The median eGFR slope improved from -7.08 ml/min/1.73 m2/year to -4.27 ml/min/1.73 m2/year in high-risk patients (P = .0003), -2.65 to -1.04 in intermediate risk, and -3.26 ml/min/1.73 m2/year to +0.45 ml/min/1.73 m2/year in patients with low-risk (P < .001). CONCLUSIONS: Deployment and risk stratification by KidneyIntelX was associated with an escalation in action taken to optimize cardio-kidney-metabolic health including medications and specialist referrals. Glycemic control and kidney function trajectories improved post-KidneyIntelX testing, with the greatest improvements observed in those scored as high-risk.