Assessing Endoscopic Response in Locally Advanced Rectal Cancer Treated with Total Neoadjuvant Therapy: Development and Validation of a Highly Accurate Convolutional Neural Network.

BACKGROUND: Rectal tumors display varying degrees of response to total neoadjuvant therapy (TNT). We evaluated the performance of a convolutional neural network (CNN) in interpreting endoscopic images of either a non-complete response to TNT or local regrowth during watch-and-wait surveillance. METHODS: Endoscopic images from stage II/III rectal cancers treated with TNT from 2012 to 2020 at a single institution were retrospectively reviewed. Images were labelled as Tumor or No Tumor based on endoscopy timing (before, during, or after treatment) and the tumor's endoluminal response. A CNN was trained using ResNet-50 architecture. The area under the curve (AUC) was analyzed during training and for two test sets. The main test set included images of tumors treated with TNT. The other contained images of local regrowth. The model's performance was compared to sixteen surgeons and surgical trainees who evaluated 119 images for evidence of tumor. Fleiss' kappa was calculated by respondent experience level. RESULTS: A total of 2717 images from 288 patients were included; 1407 (51.8%) contained tumor. The AUC was 0.99, 0.98, and 0.92 for training, main test, and local regrowth test sets. The model performed on par with surgeons of all experience levels for the main test set. Interobserver agreement was good ( k = 0.71-0.81). All groups outperformed the model in identifying tumor from images of local regrowth. Interobserver agreement was fair to moderate ( k = 0.24-0.52). CONCLUSIONS: A highly accurate CNN matched the performance of colorectal surgeons in identifying a noncomplete response to TNT. However, the model demonstrated suboptimal accuracy when analyzing images of local regrowth.

Association of Lateral Pelvic Lymph Nodes with Disease Recurrence and Organ Preservation in Patients with Distal Rectal Adenocarcinoma Treated with Total Neoadjuvant Therapy.

OBJECTIVE: Assess the significance of enlarged lateral lymph nodes (LLN) for disease recurrence, metastasis, and organ preservation in patients with rectal cancer. BACKGROUND: Optimal treatment of rectal adenocarcinoma involving LLN is subject to debate. METHODS: A post hoc analysis of the OPRA trial, a multicenter study of patients with rectal cancer treated with total neoadjuvant therapy (TNT) followed by total mesorectal excision or watch-and-wait management. We analyzed the association of visible LLN (LLN+), LLN≥7 mm (short axis) on baseline MRI, and LLN≥4 mm on restaging MRI with recurrence, metastasis, and rectum preservation. RESULTS: At baseline, 57 out of 324 (18%) patients had LLN+. In 30 (53%) of 57 patients with LLN+ on baseline MRI, the LLN disappeared after TNT. Disease recurrence in LLN was rare (3.5% of patients with LLN+ and 0.4% of patients with LLN-). All patients with recurrence in LLN also had distant metastasis. The rate of organ preservation was significantly lower in patients with LLN≥4 mm on restaging MRI (P=0.013). We found no significant differences in rates of local recurrence or metastasis between patients with LLN+ vs. LLN- and in patients with LLN≥7 vs.<7 mm on baseline MRI. LLN dissection was performed in 3 patients; 2 of them died of distant metastasis. CONCLUSIONS: LLN involvement is not associated with disease recurrence or metastasis, but persistence of LLN≥4 mm after TNT is negatively associated with rectum preservation in patients with locally advanced rectal cancer treated with TNT. Dissection of lateral nodes likely benefits few patients.

Overcoming Barriers to Discovery and Implementation of Equitable Pharmacogenomic Testing in Oncology.

Pharmacogenomics (PGx), the study of inherited genomic variation and drug response or safety, is a vital tool in precision medicine. In oncology, testing to identify PGx variants offers patients the opportunity for customized treatments that can minimize adverse effects and maximize the therapeutic benefits of drugs used for cancer treatment and supportive care. Because individuals of shared ancestry share specific genetic variants, PGx factors may contribute to outcome disparities across racial and ethnic categories when genetic ancestry is not taken into account or mischaracterized in PGx research, discovery, and application. Here, we examine how the current scientific understanding of the role of PGx in differential oncology safety and outcomes may be biased toward a greater understanding and more complete clinical implementation of PGx for individuals of European descent compared with other genetic ancestry groups. We discuss the implications of this bias for PGx discovery, access to care, drug labeling, and patient and provider understanding and use of PGx approaches. Testing for somatic genetic variants is now the standard of care in treatment of many solid tumors, but the integration of PGx into oncology care is still lacking despite demonstrated actionable findings from PGx testing, reduction in avoidable toxicity and death, and return on investment from testing. As the field of oncology is poised to expand and integrate germline genetic variant testing, it is vital that PGx discovery and application are equitable for all populations. Recommendations are introduced to address barriers to facilitate effective and equitable PGx application in cancer care.

Is White Evangelical Antistructural Theology Related to Poor Health Outcomes?

Policy Points White evangelical theology has an "antistructural" component. Counties with a high percentage of White evangelicals have higher mortality rates and more persons with fair/poor health. The potential influence of antistructural components in evangelical theology on decision making and resource allocation and, ultimately, the length and quality of life of community members presents a point of intervention for religious leaders and policymakers to improve population health. CONTEXT: Structural factors are important determinants of health. Because antistructuralism has been identified as a tenet of White evangelical theology, we explored if there is an association of the percentage of White evangelicals in a US county with two county health outcomes: premature mortality and percentage of fair/poor health. METHODS: Regression analysis was performed with data from 2022 County Health Rankings and the American Value Atlas from the Public Religion Research Institute. FINDINGS: Every percent of evangelicals in a county is associated with 4.01 more premature deaths per 100,000 population and 0.13% fair/poor health. After controlling for income, education, political ideology, and county school funding adequacy (a proxy for antistructuralism), the associations remain positive and significant. CONCLUSIONS: We hope these findings could inform dialogue and critical analysis among individuals of evangelical faith, particularly fundamental and Pentecostal subsets, regarding a belief system that is inclusive of individual dimensions and health-promoting structural policies like school funding, Medicaid expansion, and antipoverty programs. These findings also demonstrate the importance of considering cultural factors like religion and political ideology in population health outcomes research.

Historical Perspectives: Malignancy in Crohn's Disease and Ulcerative Colitis.

While both Crohn' disease (CD) and ulcerative colitis (UC) are known to predispose patients to certain intestinal malignancies, the exact mechanism of carcinogenesis remains unknown and optimal screening guidelines have not been established. This article will explore the history of our understanding of intestinal malignancy in inflammatory bowel disease (IBD). To contextualize the medical community's difficulty in linking each condition to cancer, the first section will review the discovery of CD and UC. Next, we discuss early attempts to define IBD's relationship with small bowel adenocarcinoma and colorectal cancer. The article concludes with a review of each disease's surgical history and the ways in which certain procedures produced poor oncologic outcomes.

Long-Term Results of Organ Preservation in Patients With Rectal Adenocarcinoma Treated With Total Neoadjuvant Therapy: The Randomized Phase II OPRA Trial.

Clinical trials frequently include multiple end points that mature at different times. The initial report, typically based on the primary end point, may be published when key planned co-primary or secondary analyses are not yet available. Clinical Trial Updates provide an opportunity to disseminate additional results from studies, published in JCO or elsewhere, for which the primary end point has already been reported.To assess long-term risk of local tumor regrowth, we report updated organ preservation rate and oncologic outcomes of the OPRA trial (ClinicalTrials.gov identifier: NCT02008656). Patients with stage II/III rectal cancer were randomly assigned to receive induction chemotherapy followed by chemoradiation (INCT-CRT) or chemoradiation followed by consolidation chemotherapy (CRT-CNCT). Patients who achieved a complete or near-complete response after finishing treatment were offered watch-and-wait (WW). Total mesorectal excision (TME) was recommended for those who achieved an incomplete response. The primary end point was disease-free survival (DFS). The secondary end point was TME-free survival. In total, 324 patients were randomly assigned (INCT-CRT, n = 158; CRT-CNCT, n = 166). Median follow-up was 5.1 years. The 5-year DFS rates were 71% (95% CI, 64 to 79) and 69% (95% CI, 62 to 77) for INCT-CRT and CRT-CNCT, respectively (P = .68). TME-free survival was 39% (95% CI, 32 to 48) in the INCT-CRT group and 54% (95% CI, 46 to 62) in the CRT-CNCT group (P = .012). Of 81 patients with regrowth, 94% occurred within 2 years and 99% occurred within 3 years. DFS was similar for patients who underwent TME after restaging (64% [95% CI, 53 to 78]) and patients in WW who underwent TME after regrowth (64% [95% CI, 53 to 78]; P = .94). Updated analysis continues to show long-term organ preservation in half of the patients with rectal cancer treated with total neoadjuvant therapy. In patients who enter WW, most cases of tumor regrowth occur in the first 2 years.

Endoscopic Predictors of Residual Tumor After Total Neoadjuvant Therapy: A Post Hoc Analysis From the Organ Preservation in Rectal Adenocarcinoma Trial.

BACKGROUND: Restaging endoscopy plays a critical role in selecting patients with locally advanced rectal cancer who respond to neoadjuvant therapy for nonoperative management. OBJECTIVE: This study evaluated the restaging endoscopic features that best predict the presence of residual tumor in the bowel wall. DESIGN: This was a post hoc analysis of a prospective randomized trial. SETTINGS: The Organ Preservation in Rectal Adenocarcinoma Trial randomly assigned patients across 18 institutions with stage II/III rectal adenocarcinoma to receive either induction or consolidation total neoadjuvant therapy. Surgeons completed a restaging tumor assessment form, which stratified patients across 3 tiers of clinical response. PATIENTS: Patients enrolled in the Organ Preservation in Rectal Adenocarcinoma Trial with a completed tumor assessment form were included. MAIN OUTCOME MEASURES: The main outcome was residual tumor, which was defined as either an incomplete clinical response or local tumor regrowth within 2 years of restaging. Independent predictors of residual tumor were identified using backward-selected multivariable logistic regression analysis. Subgroup analyses for complete and near complete clinical responders were performed. RESULTS: Surgeons completed restaging forms for 263 patients at a median of 7.7 weeks after neoadjuvant therapy; 128 patients (48.7%) had a residual tumor. On multivariable regression analysis, several characteristics of a near complete response, including ulcer (OR 6.66; 95% CI, 2.54-19.9), irregular mucosa (OR 3.66; 95% CI, 1.61-8.68), and nodularity (OR 2.96; 95% CI, 1.36-6.58), remained independent predictors of residual tumor. A flat scar was associated with lower odds of harboring residual disease (OR 0.32; 95% CI, 0.11-0.93) for patients categorized as clinical complete responders. LIMITATIONS: Limitations include analysis of endoscopic features at a single time point and ambiguities in tumor assessment form response criteria. CONCLUSIONS: Patients with ulcer, nodularity, or irregular mucosa, on restaging endoscopy have higher odds of residual tumor. Recognizing negative prognostic implications of these features will help surgeons better select candidates for nonoperative management and suggests that patients with high-risk characteristics would benefit from close interval surveillance. See Video Abstract . PREDICTORES ENDOSCPICOS DE TUMOR RESIDUAL DESPUS DE TERAPIA NEOADYUVANTE TOTAL UN ANLISIS POST HOC DEL ENSAYO DE PRESERVACIN DE RGANOS EN ADENOCARCINOMA RECTAL: ANTECEDENTES:La reestadificación por endoscopia juega un papel crítico en la selección de pacientes con cáncer de recto localmente avanzado que responden a la terapia neoadyuvante para el manejo no quirúrgico.OBJETIVO:Este estudio evaluó las características endoscópicas de reestadificación que mejor predicen la presencia de tumor residual en la pared intestinal.DISEÑO:Este fue un análisis post hoc de un ensayo prospectivo aleatorizado.ESCENARIO:El ensayo Organ Preservation in Rectal Adenocarcinoma aleatorizó a pacientes de 18 instituciones con adenocarcinoma de recto en estadio II/III para recibir terapia neoadyuvante total de inducción o consolidación. Los cirujanos completaron un formulario de reestadificación de evaluación del tumor, que estratificó a los pacientes en tres niveles de respuesta clínica.PACIENTES:Se incluyeron pacientes inscritos en el ensayo de preservación de órganos en adenocarcinoma rectal con un formulario de evaluación del tumor completado.PRINCIPALES MEDIDAS DE RESULTADO:El resultado principal fue presencia de tumor residual, que se definió como una respuesta clínica incompleta o un nuevo crecimiento local del tumor dentro de los dos años posteriores a la reestadificación. Los predictores independientes de tumor residual se identificaron mediante un análisis de regresión logística multivariable seleccionado hacia atrás. Se realizaron análisis de subgrupos para pacientes con respuesta clínica completa y casi completa.RESULTADOS:Los cirujanos completaron formularios de reestadificación para 263 pacientes en una mediana de 7.7 semanas después de la terapia neoadyuvante; 128 (48.7%) tenían tumor residual. En el análisis de regresión multivariable, varias características de una respuesta casi completa, incluyendo úlcera (OR 6.66; IC 95% 2.54-19.9), mucosa irregular (OR 3.66; IC 95% 1.61-8.68) y nodularidad (OR 2.96; IC 95% 1.36 -6.58) siguieron siendo predictores independientes de tumor residual. Una cicatriz plana se asoció con menores probabilidades de albergar enfermedad residual (OR 0.32; IC del 95 %: 0.11-0.93) para los pacientes clasificados como respondedores clínicos completos.LIMITACIONES:Las limitaciones de este estudio incluyen el análisis de las características endoscópicas en un solo momento y las ambigüedades en los criterios de respuesta.en la forma de evaluación del tumorCONCLUSIONES:Los pacientes con úlcera, nodularidad o mucosa irregular en la endoscopia de reestadificación tienen mayores probabilidades de tumor residual. El reconocer las implicaciones pronósticas negativas de estas características ayudará a los cirujanos a seleccionar mejor a los candidatos para el tratamiento no quirúrgico y sugiere que los pacientes con características de alto riesgo se beneficiarían de una vigilancia a intervalos estrechos. (Traducción-Dr. Jorge Silva Velazco ).

Sensory collectives in natural systems.

Groups of animals inhabit vastly different sensory worlds, or umwelten, which shape fundamental aspects of their behaviour. Yet the sensory ecology of species is rarely incorporated into the emerging field of collective behaviour, which studies the movements, population-level behaviours, and emergent properties of animal groups. Here, we review the contributions of sensory ecology and collective behaviour to understanding how animals move and interact within the context of their social and physical environments. Our goal is to advance and bridge these two areas of inquiry and highlight the potential for their creative integration. To achieve this goal, we organise our review around the following themes: (1) identifying the promise of integrating collective behaviour and sensory ecology; (2) defining and exploring the concept of a 'sensory collective'; (3) considering the potential for sensory collectives to shape the evolution of sensory systems; (4) exploring examples from diverse taxa to illustrate neural circuits involved in sensing and collective behaviour; and (5) suggesting the need for creative conceptual and methodological advances to quantify 'sensescapes'. In the final section, (6) applications to biological conservation, we argue that these topics are timely, given the ongoing anthropogenic changes to sensory stimuli (e.g. via light, sound, and chemical pollution) which are anticipated to impact animal collectives and group-level behaviour and, in turn, ecosystem composition and function. Our synthesis seeks to provide a forward-looking perspective on how sensory ecologists and collective behaviourists can both learn from and inspire one another to advance our understanding of animal behaviour, ecology, adaptation, and evolution.

Self-reported throat symptoms in Ehlers-Danlos syndromes and hypermobility spectrum disorders: A cross-sectional survey study.

Objectives: This study identified the frequency and severity of dysphagia, dysphonia, and laryngopharyngeal reflux symptoms in people with Ehlers-Danlos syndromes (EDS) or hypermobility spectrum disorders (HSD) and explored differences between diagnostic groups. Methods: Participants were recruited via non-probability convenience sampling. Information was gathered via online survey, including the Reflux Symptom Index (RSI; Belafsky et al., J Voice. 2002;16:274-277), the Eating and Drinking Assessment Tool (EAT-10; Belafsky et al., Ann Otol Rhinol Laryngol. 2008;117:919-924), and the Voice Handicap Index (VHI; Jacobson et al., Am J Speech Lang Pathol. 1997;6(3):66-70). These were analyzed using ANOVAs. Results: There were 1620 participants (96.6% female, 2.8% male) that met the inclusion criteria. The mean age was 38.09 (SD 12.22). 75.51% had hypermobile EDS (hEDS), 17.83% had HSD and 3.33% had classic EDS (cED). The cohort's mean scores were RSI = 22.95 (SD 9.01), EAT-10 = 11.91 (SD 9.66), and VHI score = 31.99 (SD 24.36). The hEDS group had significantly higher mean scores than the HSD group on RSI score and on some RSI items, on EAT-10 score and on all EAT-10 items, and on one VHI item. Conclusion: People with EDS/HSD experience symptoms of acid reflux, dysphagia, and dysphonia to varying degrees with significant differences between hEDS than HSD. Awareness of the impact of EDS/HSD on throat symptoms will enable health care professionals to anticipate throat symptoms more readily in this population, providing individualized and effective management plans. Level of Evidence: IV.

Pediatric Hospitalizations and ICU Admissions Due to COVID-19 and Pediatric Inflammatory Multisystem Syndrome Temporally Associated With SARS-CoV-2 in England.

Importance: Investigating how the risk of serious illness after SARS-CoV-2 infection in children and adolescents has changed as new variants have emerged is essential to inform public health interventions and clinical guidance. Objective: To examine risk factors associated with hospitalization for COVID-19 or pediatric inflammatory multisystem syndrome temporally associated with SARS-CoV-2 (PIMS-TS) among children and adolescents during the first 2 years of the COVID-19 pandemic and change in risk factors over time. Design, Setting, and Participants: This population-level analysis of hospitalizations after SARS-CoV-2 infection in England among children and adolescents aged 0 to 17 years was conducted from February 1, 2020, to January 31, 2022. National data on hospital activity were linked with data on SARS-CoV-2 testing, SARS-CoV-2 vaccination, pediatric intensive care unit (PICU) admissions, and mortality. Children and adolescents hospitalized with COVID-19 or PIMS-TS during this time were included. Maternal, elective, and injury-related hospitalizations were excluded. Exposures: Previous medical comorbidities, sociodemographic factors, and timing of hospitalization when different SARS-CoV-2 variants (ie, wild type, Alpha, Delta, and Omicron) were dominant in England. Main Outcomes: PICU admission and death within 28 days of hospitalization with COVID-19 or PIMS-TS. Results: A total of 10 540 hospitalizations due to COVID-19 and 997 due to PIMS-TS were identified within 1 125 010 emergency hospitalizations for other causes. The number of hospitalizations due to COVID-19 and PIMS-TS per new SARS-CoV-2 infections in England declined during the second year of the COVID-19 pandemic. Among 10 540 hospitalized children and adolescents, 448 (4.3%) required PICU admission due to COVID-19, declining from 162 of 1635 (9.9%) with wild type, 98 of 1616 (6.1%) with Alpha, and 129 of 3789 (3.4%) with Delta to 59 of 3500 (1.7%) with Omicron. Forty-eight children and adolescents died within 28 days of hospitalization due to COVID-19, and no children died of PIMS-TS (PIMS-S data were limited to November 2020 onward). Risk of severe COVID-19 in children and adolescents was associated with medical comorbidities and neurodisability regardless of SARS-CoV-2 variant. Results were similar when children and adolescents with prior SARS-CoV-2 exposure or vaccination were excluded. Conclusions: In this study of data across the first 2 years of the COVID-19 pandemic, risk of severe disease from SARS-CoV-2 infection in children and adolescents in England remained low. Children and adolescents with multiple medical problems, particularly neurodisability, were at increased risk and should be central to public health measures as further variants emerge.

The behaviour and activity budgets of two sympatric sloths; Bradypus variegatus and Choloepus hoffmanni.

It is usually beneficial for species to restrict activity to a particular phase of the 24-hour cycle as this enables the development of morphological and behavioural adaptations to enhance survival under specific biotic and abiotic conditions. Sloth activity patterns are thought to be strongly related to the environmental conditions due to the metabolic consequences of having a low and highly variable core body temperature. Understanding the drivers of sloth activity and their ability to withstand environmental fluctuations is of growing importance for the development of effective conservation measures, particularly when we consider the vulnerability of tropical ecosystems to climate change and the escalating impacts of anthropogenic activities in South and Central America. Unfortunately, the cryptic nature of sloths makes long term observational research difficult and so there is very little existing literature examining the behavioural ecology of wild sloths. Here, we used micro data loggers to continuously record, for the first time, the behaviour of both Bradypus and Choloepus sloths over periods of days to weeks. We investigate how fluctuations in the environmental conditions affect the activity of sloths inhabiting a lowland rainforest on the Caribbean coast of Costa Rica and examined how this might relate to their low power lifestyle. Both Bradypus and Choloepus sloths were found to be cathemeral in their activity, with high levels of between-individual and within-individual variation in the amounts of time spent active, and in the temporal distribution of activity over the 24-hour cycle. Daily temperature did not affect activity, although Bradypus sloths were found to show increased nocturnal activity on colder nights, and on nights following colder days. Our results demonstrate a distinct lack of synchronicity within the same population, and we suggest that this pattern provides sloths with the flexibility to exploit favourable environmental conditions whilst reducing the threat of predation.

Comparison of short-term outcomes and survival between minimally invasive colectomy and open colectomy in patients 80 years of age and older.

We investigated the short- and long-term outcomes of patients 80 years of age and older with colon cancer who underwent robotic colectomy versus laparoscopic colectomy. Data for patients treated at a comprehensive cancer center between January 2006 and November 2018 were collected retrospectively. Outcomes from minimally invasive laparoscopic or robotic colectomy were compared. Survival was analyzed by the Kaplan-Meier method with significance evaluated by the log-rank test. The laparoscopic (n = 104) and the robotic (n = 75) colectomy groups did not differ across baseline characteristics. Patients who underwent a robotic colectomy had a shorter median length of hospital stay (5 versus 6 days; p < 0.001) and underwent fewer conversions to open surgery (3% versus 17%; p = 0.002) compared to the laparoscopic cohort. The groups did not differ in postoperative complication rates, overall survival or disease-free survival. Elderly patients undergoing robotic colectomy for colon cancer have a shorter hospital stay and lower rates of conversion without compromise to oncologic outcomes.

Discounting Health Grades for Disparity: The 2021 Wisconsin Population Health and Equity Report Card.

We describe updates to the University of Wisconsin Population Health Institute's methodology for a state health report card, first described in Preventing Chronic Disease in 2010, and the considerations that were weighed in making those updates. These methods have been used since 2006 to issue a periodic report entitled Health of Wisconsin Report Card. The report highlights Wisconsin's standing among other states and serves as an example for others seeking to measure and improve their population's health. For 2021, we revisited our approach with an increased emphasis on disparities and health equity, which required many choices about data, analysis, and reporting methods. In this article, we outline the decisions, rationale, and implications of several choices we made in assessing Wisconsin's health by answering several questions, among them: Who is the intended audience and which measures of length (eg, mortality rate, years of potential life lost) and quality of life (eg, self-reported health, quality-adjusted life years) are most relevant to them? Which subgroups should we report disparities about, and which metric is most easily understood? Should disparities be summarized with overall health or reported separately? Although these decisions are applicable to 1 state, the rationale for our choices could be applied to other states, communities, and nations. Consideration of the purpose, audience, and context for health and equity policy making is important in developing report cards and other tools that can improve the health of all people and places.

T1 Gastric Cancer Is Associated With a High Incidence of Regional Lymph Node Metastases.

INTRODUCTION: Early stage gastric cancer, particularly T1 disease, is associated with high recurrence-free and overall survival rates following resection with curative intent. However, rare cases of T1 gastric cancer have nodal metastasis and this is associated with poor outcomes. METHODS: Data from gastric cancer patients treated with surgical resection and D2 lymph node (LN) dissection at a single tertiary care institution from 2010 to 2020 were analyzed. Patients with early stage (T1) tumors were assessed in detail to identify variables associated with regional LN metastasis including histologic differentiation, signet ring cells, demographics, smoking history, neoadjuvant therapy, and clinical staging by endoscopic ultrasound (EUS). We used standard statistical techniques including Mann-Whitney U and Chi-squared tests. RESULTS: Of 426 patients undergoing surgery for gastric cancer, 34% (n = 146) were diagnosed with T1 disease on surgical pathology. Among 146 T1 (T1a, T1b) gastric cancers, 24 patients [(17%) T1a (n = 4), T1b (n = 20)] had histologically confirmed regional LN metastases. The age at diagnosis ranged between 19 and 91 y and 54.8% were male. Prior smoking status was not associated with nodal positivity (P = 0.650). Of the 24 patients with positive LN on final pathology, seven patients received neoadjuvant chemotherapy. EUS was performed on 98 (67%) of the 146 T1 patients. Of these patients, 12 (13.2%) had positive LN on final pathology; however, none (0/12) were detected on preoperative EUS. There was no association between node status on EUS and node status on final pathology (P = 0.113). The sensitivity of EUS for N status was 0%, specificity was 84.4%, negative predictive value was 82.2% and positive predictive value was 0%. Signet ring cells were identified in 42% of node negative T1 tumors and 64% of node positive T1 tumors (P = 0.063). For LN positive cases on surgical pathology, 37.5% had poor differentiation, 42% had lymphovascular invasion, and regional nodal metastases were associated with increasing T stage (P = 0.003). CONCLUSIONS: T1 gastric cancer is associated with a substantial risk (17%) of regional LN metastasis, when pathologically staged following surgical resection and D2 lymphadenectomy. Clinically staged N+ disease by EUS was not significantly associated with pathologically staged N+ disease in these patients.

Label-Free SERS for Rapid Differentiation of SARS-CoV-2-Induced Serum Metabolic Profiles in Non-Hospitalized Adults.

COVID-19 represents a multi-system infectious disease with broad-spectrum manifestations, including changes in host metabolic processes connected to the disease pathogenesis. Understanding biochemical dysregulation patterns as a consequence of COVID-19 illness promises to be crucial for tracking disease course and clinical outcomes. Surface-enhanced Raman scattering (SERS) has attracted considerable interest in biomedical diagnostics for the sensitive detection of intrinsic profiles of unique fingerprints of serum biomolecules indicative of SARS-CoV-2 infection in a label-free format. Here, we applied label-free SERS and chemometrics for rapid interrogation of temporal metabolic dynamics in longitudinal sera of mildly infected non-hospitalized patients (n = 22), at 4 and 16 weeks post PCR-positive diagnosis, and compared them with negative controls (n = 8). SERS spectral markers revealed distinct metabolic profiles in patient sera that significantly deviated from the healthy metabolic state at the two sampling time intervals. Multivariate and univariate analyses of the spectral data identified abundance dynamics in amino acids, lipids, and protein vibrations as the key spectral features underlying the metabolic differences detected in convalescent samples and perhaps associated with patient recovery progression. A validation study performed using spontaneous Raman spectroscopy yielded spectral data results that corroborated SERS spectral findings and confirmed the detected disease-specific molecular phenotypes in clinical samples. Label-free SERS promises to be a valuable analytical technique for rapid screening of the metabolic phenotype induced by SARS-CoV-2 infection to allow appropriate healthcare intervention.

Ecological Study of Urbanicity and Self-reported Poor Mental Health Days Across US Counties.

Geography may influence mental health by inducing changes to social and physical environmental and health-related factors. This understanding is largely based on older studies from Western Europe. We sought to quantify contemporary relationships between urbanicity and self-reported poor mental health days in US counties. We performed regression on US counties (n = 3142) using data from the County Health Rankings and Roadmaps. Controlling for state, age, income, education, and race/ethnicity, large central metro counties reported 0.24 fewer average poor mental health days than small metro counties (t = - 5.78, df = 423, p < .001). Noncore counties had 0.07 more average poor mental health days than small metro counties (t = 3.06, df = 1690, p = 0.002). Better mental health in large central metro counties was partly mediated by differences in the built environment, such as better food environments. Poorer mental health in noncore counties was not mediated by considered mediators.

Pharmacotypes across the genomic landscape of pediatric acute lymphoblastic leukemia and impact on treatment response.

Contemporary chemotherapy for childhood acute lymphoblastic leukemia (ALL) is risk-adapted based on clinical features, leukemia genomics and minimal residual disease (MRD); however, the pharmacological basis of these prognostic variables remains unclear. Analyzing samples from 805 children with newly diagnosed ALL from three consecutive clinical trials, we determined the ex vivo sensitivity of primary leukemia cells to 18 therapeutic agents across 23 molecular subtypes defined by leukemia genomics. There was wide variability in drug response, with favorable ALL subtypes exhibiting the greatest sensitivity to L-asparaginase and glucocorticoids. Leukemia sensitivity to these two agents was highly associated with MRD although with distinct patterns and only in B cell ALL. We identified six patient clusters based on ALL pharmacotypes, which were associated with event-free survival, even after adjusting for MRD. Pharmacotyping identified a T cell ALL subset with a poor prognosis that was sensitive to targeted agents, pointing to alternative therapeutic strategies. Our study comprehensively described the pharmacological heterogeneity of ALL, highlighting opportunities for further individualizing therapy for this most common childhood cancer.

Spatially Resolved Single-Cell Assessment of Pancreatic Cancer Expression Subtypes Reveals Co-expressor Phenotypes and Extensive Intratumoral Heterogeneity.

Pancreatic ductal adenocarcinoma (PDAC) has been classified into classical and basal-like transcriptional subtypes by bulk RNA measurements. However, recent work has uncovered greater complexity to transcriptional subtypes than was initially appreciated using bulk RNA expression profiling. To provide a deeper understanding of PDAC subtypes, we developed a multiplex immunofluorescence (mIF) pipeline that quantifies protein expression of six PDAC subtype markers (CLDN18.2, TFF1, GATA6, KRT17, KRT5, and S100A2) and permits spatially resolved, single-cell interrogation of pancreatic tumors from resection specimens and core needle biopsies. Both primary and metastatic tumors displayed striking intratumoral subtype heterogeneity that was associated with patient outcomes, existed at the scale of individual glands, and was significantly reduced in patient-derived organoid cultures. Tumor cells co-expressing classical and basal markers were present in > 90% of tumors, existed on a basal-classical polarization continuum, and were enriched in tumors containing a greater admixture of basal and classical cell populations. Cell-cell neighbor analyses within tumor glands further suggested that co-expressor cells may represent an intermediate state between expression subtype poles. The extensive intratumoral heterogeneity identified through this clinically applicable mIF pipeline may inform prognosis and treatment selection for patients with PDAC. SIGNIFICANCE: A high-throughput pipeline using multiplex immunofluorescence in pancreatic cancer reveals striking expression subtype intratumoral heterogeneity with implications for therapy selection and identifies co-expressor cells that may serve as intermediates during subtype switching.